Mylan Pharmaceuticals Inc.v.Novartis AG

Patent Trial and Appeal Board

Sep 28, 2015

09747519 (P.T.A.B. Sep. 28, 2015)

Trials@uspto.gov Paper 69
Tel: 571-272-7822 Entered: September 28, 2015

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

NOVEN PHARMACEUTICALS, INC.,
and MYLAN PHARMACEUTICALS INC.
Petitioner,

v.

NOVARTIS AG and LTS LOHMANN THERAPIE-SYSTEME AG,
Patent Owner.
____________

Case IPR2014-00549
1

Patent 6,316,023 B1
_____________

Before FRANCISCO C. PRATS, ERICA A. FRANKLIN, and
CHRISTOPHER G. PAULRAJ, Administrative Patent Judges.

FRANKLIN, Administrative Patent Judge.

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

1
Case IPR2015-00265 has been joined with this proceeding.
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I. INTRODUCTION
Noven Pharmaceuticals, Inc. (“Noven”) filed a petition to institute an
inter partes review of claims 1, 2, 4, 5, 7 and 8 of U.S. Patent No. 6,316,023
B1 (Ex. 1001, “the ’023 patent”). Paper 1 (“Petition” or “Pet.”).
2
Novartis
AG and LTS Lohmann Therapie-Systeme AG (collectively, “Patent
Owner”) filed a Preliminary Response to the Petition. Paper 7 (“Prelim.
Resp.”). In an Institution Decision (Paper 10), an inter partes review of
claims 1, 2, 4, 5, 7 and 8 was instituted.
After the Institution Decision, Mylan Pharmaceuticals Inc. (“Mylan”)
timely filed a separate petition to institute an inter partes review of claims 1,
2, 4, 5, 7 and 8 of the ’023 patent based on identical grounds as presented in
Noven’s Petition. Case IPR2015-00265, Paper 1. At the same time, Mylan
filed a Motion for Joinder with the instituted case. Id., Paper 3. Patent
Owner filed an Opposition to the Motion for Joinder and a Waiver of Patent
Owner’s Preliminary Response. Id., Papers 10, 13. In an Institution
Decision, an inter partes review of claims 1, 2, 4, 5, 7 and 8 was instituted in
IPR2015-00265, the Motion for Joinder was granted, and the proceeding in
IPR2015-00265 was terminated. Id., Paper 17. Therefore, in the instant
inter partes review, Noven and Mylan are, collectively, the “Petitioner.”
In the instant inter partes review, Patent Owner filed a Response to
the Petition. Paper 25 (“Patent Owner Response” or “PO Resp.”).
3

2
Pursuant to an order, Paper 27, granting an unopposed motion by
Petitioner, Paper 21, Petitioner filed a Corrected Petition, Paper 38, to
correct certain clerical and typographical errors in the list of exhibits
included in the Petition.
3
Pursuant to an order, Paper 28, granting an unopposed motion by Patent
Owner, Paper 26, Patent Owner filed a Corrected Patent Owner Response,
Paper 37, to correct clerical errors.
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Petitioner filed a Reply. Papers 31 and 32 (“Pet. Reply”).
4
Patent Owner
filed motions for observations on the cross-examinations of two deposed
declarant witnesses. Papers 43, 44, 45.
5
Petitioner filed oppositions to the
motions. Papers 52, 53 and 54.
6
Additionally, Petitioner filed a motion to
exclude a number of Patent Owner’s exhibits. Paper 48. Patent Owner filed
an opposition to the motion. Paper 49. Petitioner responded to the
opposition in a Reply in Support of the Motion to Exclude. Paper 57. On
June 2, 2015, the parties presented arguments at an oral hearing. Paper 67,
(“Tr.”).
7

The Board has jurisdiction under 35 U.S.C. § 6(c). In this Final
Written Decision, issued pursuant to 35 U.S. C. § 318(a) and 37 C.F.R.
§ 42.73, we determine Petitioner has shown by a preponderance of the
evidence that challenged claims 1, 2, 4, 5, 7 and 8 are unpatentable.
A. Related Proceedings
According to Petitioner and Patent Owner, the ’023 patent was
involved in various district court actions, including two actions involving the

4
Paper 31 was filed under seal and Paper 32 is a redacted public version.
5
Patent Owner filed a Confidential Motion for Observations on Cross-
Examination of Dr. Agis Kydonieus under seal, Paper 43, and a redacted,
“Non-Confidential” public version, Paper 44. Paper 45 is Patent Owner’s
Motion for Observation on Cross-Examination of Dr. Christian Schӧneich.
6
Petitioner filed a Response to Patent Owner’s Confidential Motion for
Observations on Cross-Examination of Dr. Kydonieus under seal, Paper 54,
and a redacted, “Non-Confidential” public version, Paper 53. Paper 52 is
Petitioner’s Response to Patent Owner’s Motion for Observation on Cross-
Examination of Dr. Schӧneich.
7
Patent Owner filed Objections to Petitioner’s Demonstrative Exhibits.
Paper 63. In this Final Written Decision, we have not considered any
arguments presented in the demonstrative exhibits that were not presented
previously and/or are not supported by the record.
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parties to this proceeding, titled: Novartis Pharm. Corp. v. Noven Pharm.
Inc., 1:13-cv-00527 (D. Del.); and Novartis Pharm. Corp. v. Noven Pharm.
Inc., 1:14-cv-00111 (D. Del.). Pet. 1–2; Paper 6 at 2. Those cases were
consolidated, and on August 31, 2015, the United States District Court for
the District of Delaware issued a decision finding that Noven failed to prove
by clear and convincing evidence that claims 7 and 16 of a related patent,
U.S. Patent No. 6,335,031 (“the ’031 patent”) are invalid as obvious or
invalid under the obviousness-type double patenting doctrine. Novartis
Pharm. Corp. v. Noven Pharm., Inc., –– F. Supp. 3d ––, Civ. Nos. 13-527-
RGA, 14-111-RGA, 2015 WL 5121157 (D. Del. Aug. 31, 2015). The
decision did not address the ’023 patent beyond stating that it was “no longer
at issue.” Id. at *1.
In another case involving Novartis, but not Noven or Mylan, the same
District Court held that claims 2 and 7 of the ’023 patent and claims 3, 7, 13,
16 and 18 of the ’031 patent are not invalid as obvious. Novartis Pharm.
Corp. v. Par Pharm., Inc., 48 F. Supp. 3d 733 (D. Del. 2014). The Court of
Appeals for the Federal Circuit affirmed that District Court decision
upholding the validity of the ’023 and ’031 patents. Novartis Pharms. Corp.
v. Watson Labs, Inc., –– F. App’x ––, Nos. 2014-1799 et al., 2015 WL
2403308 at *5–8 (Fed. Cir. May 21, 2015) (“Watson”). The Federal
Circuit’s Watson decision does not control here because Noven has
presented additional prior art and declaratory evidence that was not before
the Court in Watson.

Moreover, in an inter partes review, a petitioner’s
burden of proving unpatentability is by a preponderance of the evidence
rather than by clear and convincing evidence, as required in district court
litigation. Thus, while we have considered the Federal Circuit’s decision,
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we have independently analyzed patentability of the challenged claims based
on the evidence and standards that are applicable to this proceeding.
A final decision in an inter partes review of claims of the ’031 patent
has been entered concurrently with this decision. IPR2014-00550, Paper 69.
B. The ’023 Patent (Ex. 1001)
The ’023 patent is directed to a pharmaceutical composition
comprising (S)-N-ethyl-3-[(1-dimethylamino)ethyl]-N-methylphenyl
carbamate (“compound A”; “rivastigmine”; “S-enantiomer of RA7”) in the
form of a free base or acid addition salt, along with an antioxidant, and a
diluent or carrier. Ex. 1001, 1:7–47. “Compound A is useful in inhibiting
acetylcholinesterase in the central nervous system, e.g. for the treatment of
Alzheimer’s disease.” Id. at 1:15–17. A transdermal composition
comprising compound A in the form of a free base or acid addition salt, two
polymers, and a plasticizer is disclosed in the prior art. Id. at 1:18–22. The
inventors of the ’023 patent explained that the composition of the prior art
“is susceptible to degradation, particularly in the presence of oxygen.” Id. at
1:23–25. The ’023 patent states:
The present applicant has found that stable pharmaceu-
tical compositions comprising compound A can now be
obtained, which show insignificant degradation of
compound A over a prolonged time period, e.g. 2 years,
as indicated by standard tests, e.g. stress tests.

In one aspect, the invention provides a pharmaceutical
composition comprising Compound A in free base or
acid addition salt form and an anti-oxidant.

The pharmaceutical compositions of the present
invention show a reduction in degradation by-products in
stress stability tests.

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Id. at 1:30–39.
C. Illustrative Claims
Independent claims 1 and 7 of the ’023 patent are illustrative of the
claims at issue:
1. A pharmaceutical composition comprising 1 to 40
weight percent of (S)-N-ethyl-3-[(1-dimethylamino)ethyl]-N-
methylphenyl carbamate in the form of a free base or acid
addition salt, 0.01 to 0.5 weight percent of an antioxidant, and a
diluent or carrier, wherein the weight percents are based on the
total weight of the pharmaceutical composition.

Ex. 1001, 8:17–22.

7. A transdermal device comprising a pharmaceutical
composition comprising 1 to 40 weight percent of (S)-N-ethyl-
3-[(1-dimethylamino)ethyl]-N-methylphenyl carba[m]ate in the
form of a free base or acid addition salt, 0.01 to 0.5 weight
percent of an antioxidant, and a diluent or carrier, wherein the
weight percents are based on the total weight of the
pharmaceutical composition.

Id. at 8:44–50.
D. The Prior Art
Enz UK Patent Application GB 2,203,040 A,
published Oct. 12, 1988 (“Enz”)
Ex. 1002
Handbook HANDBOOK OF PHARMACEUTICAL EXCIPIENTS
(A. Wade & P.J. Weller eds., 2d ed. 1994)
(“the Handbook”)
Ex. 1003
Sasaki JP Patent Application 59-184121, published
Oct. 19, 1984 (“Sasaki”)
Ex. 1005

Ebert WO 95/24172, published Sept. 14, 1995
(“Ebert”)
Ex. 1006
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Kissel EP Patent Application 0155229A2, published
Sept. 18, 1985 (“Kissel”)
Ex. 1007
Rosin US 4,948,807, issued Aug. 14, 1990
(“Rosin”)
Ex. 1008
Elmalem Antagonism of Morphine-Induced
Respiratory Depression by Novel
Anticholinesterase Agents, 30
NEUROPHARMACOLOGY 1059–64 (1991)
(“Elmalem”)
Ex. 1009
Petitioner also relies on two declarations of Dr. Agis Kydonieus,
Ex. 1010; Ex. 1031, and two declarations of Dr. Christian Schöneich,
Ex. 1011; Ex. 1032. Patent Owner relies on the declaration of Dr. Alexander
M. Klibanov, Ex. 2012.
E. The Instituted Grounds of Unpatentability
Trial was instituted for claims 1, 2, 4, 5, 7 and 8 of the ’023 patent on
the following grounds:
References Basis ’023 Patent Claims
Enz, the Handbook, Rosin, Elmalem,
and Ebert
§ 103(a) 1, 7
Enz, the Handbook, Rosin, and Ebert § 103(a) 2
Enz and the Handbook, and Ebert § 103(a) 4, 5
Enz, the Handbook, and Ebert or Kissel § 103(a) 8
Enz and Sasaki § 103(a) 1, 2, 4, 5 and 7
Enz, Sasaki, and Ebert or Kissel § 103(a) 8

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III. ANALYSIS
A. Claim Construction
In an inter partes review, the Board interprets claim terms in an
unexpired patent according to the broadest reasonable construction in light
of the specification of the patent in which they appear. 37 C.F.R.
§ 42.100(b); In re Cuozzo Speed Techs., LLC, 793 F.3d 1268, 1278–79 (Fed.
Cir. 2015). Under that standard, and absent any special definitions, we give
claim terms their ordinary and customary meaning, as would be understood
by one of ordinary skill in the art at the time of the invention. In re
Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007). Any special
definitions for claim terms must be set forth with reasonable clarity,
deliberateness, and precision. In re Paulsen, 30 F.3d 1475, 1480 (Fed.
Cir. 1994).
The parties agree that the term “(S)-N-ethyl-3-[(1-dimethylamino)
ethyl]-N-methylphenyl carbamate” refers to rivastigmine, i.e., the S-
enantiomer of a racemic mixture known as RA7, i.e., N-ethyl-3-{(1-
dimethylamino)ethyl}-N-methyl-phenyl-carbamate HCl. Pet. 8; Prelim.
Resp. 9. Upon consideration of the record, we adopt that agreed-upon
construction as it is consistent with the plain and ordinary meaning in the
context of the Specification.
Based on our analysis, we determine that no express claim
construction is necessary for any remaining claim term.
B. Level of Skill in the Art
Petitioner asserts that the person of ordinary skill in the art at the time
of the invention would have: (a) been “a chemist, chemical engineer,
polymer chemist or pharmaceutical chemist working to develop
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pharmaceutical formulations, including transdermal drug deliver systems;”
(b) been familiar with testing that accompanies the development of any
pharmaceutical formulation, including testing efficacy and stability; (c) been
familiar with excipients typically employed in pharmaceutical formulations,
including transdermal devices; and (d) had knowledge of organic chemistry
and been able to predict the physical properties of a compound based on its
chemical structure. Pet. 5 (citing Decl. of Dr. Kydonieus, Ex. 1010 ¶ 9).
Patent Owner does not provide a statement in the Preliminary Response or
Patent Owner’s Response asserting a description of the level of ordinary
skill in the art.
The level of skill in the art is a factual determination that provides a
primary guarantee of objectivity in an obviousness analysis. Al-Site Corp. v.
VSI Int’l Inc., 174 F.3d 1308, 1324 (Fed. Cir. 1999)(citing Graham v. John
Deere Co., 383 U.S. 1, 17–18 (1966) and Ryko Mfg. Co. v. Nu-Star, Inc.,
950 F.2d 714, 718 (Fed. Cir. 1991)). Based on our consideration of the
record, we find that the evidence supports the Petitioner’s description of the
level of ordinary skill in the art, with the following modification to portion
(d) to read as follows: had knowledge of organic chemistry and been able to
analyze and recognize certain characteristics of a compound based on its
chemical structure. As explained by Petitioner’s declarants: the ability to
predict reactivity based on functional group properties is a foundation of
organic chemistry, Decl. of Dr. Schöneich, Ex. 1032 ¶¶ 22–25, and a person
of ordinary skill in the art would have understood that the presence of
particular functional groups in a molecule has consequences, Decl. of Dr.
Kydonieus, Ex. 1031 ¶¶ 28–29; Ex. 1032 ¶¶ 7–13, 24–25.
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C. Obviousness of Claims 1, 2, 4, 5 and 7 over
Enz (Ex. 1002) and Sasaki (Ex. 1005)
Petitioner contends that claims 1, 2, 4, 5 and 7 are rendered obvious
by the combination of Enz and Sasaki. Pet. 37–43. Patent Owner disagrees.
PO Resp. 10–23, 41–44.
1. Enz
Enz discloses compositions for systemic transdermal administration
containing (S)-N-ethyl-3-[(1-dimethylamino)ethyl]-N-methyl-phenyl
carbamate of formula I, reproduced below:

Ex. 1002, 2.
The compound of formula I may be in free base or acid addition salt
form. Id. Enz explains that the racemic mixture (±)-N-ethyl-3-[1-
dimethylamino)ethyl]-N-methyl-phenyl-carbamate in the form of its
hydrochloride is known as RA7. Id. at 3. Enz teaches that (S)-N-ethyl-3-
[(1-dimethylamino)ethyl]-N-methyl-phenyl-carbamate in free base may be
prepared from the racemate by separation of the enantiomers in accordance
with known methods. Id. The acid addition salts may be prepared from the
free base according to a known manner. Id. Enz teaches that Compound A,
the compound of formula I in the form of its hydrogen tartrate, is “slightly
superior than” the racemic mixture. Id. at 6.
Additionally, Enz discloses providing “a pharmaceutical composition
comprising a compound according to the invention in association with at
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least one pharmaceutical carrier or diluent.” Id. at 11. In Example 2, Enz
discloses a preparation of a transdermal composition comprising 20% of
compound A, 30% of a hydrophilic polymer, e.g., Eudragit
®
E 100, 44% of a
non-swellable acrylate polymer, e.g., Durotack
®
280-2416, and 6% of a
plasticizer, e.g., Brij
®
97. Id. at 20. The composition is spread on top of an
aluminized foil to produce a film that is allowed to dry. Id. Thereafter, the
aluminum foil is cut into patches. Id.
2. Sasaki
Sasaki discloses an acrylic adhesive plaster comprising tocopherol and
a drug. Ex. 1005, 1. Sasaki teaches that the therapeutic effect of a
preparation comprising a drug blended with a plaster comprising an acrylic
adhesive substance tends to be greatly reduced due to the breakdown and
dissipation of the drug when the adhesive substance is stored for a long time.
Id. Sasaki explains that breakdown of the drug in such a composition occurs
especially when the drug is a phenolic hydroxyl group-containing
compound, an amine compound, or the like. Id. Sasaki teaches that if a
tocopherol, an antioxidant, is blended in a plaster comprising a drug and an
acrylic adhesive substance, “the drug will be stably present without breaking
down.” Id. at 2.
Additionally, Sasaki discloses the amount of tocopherol blended is on
the order of 0.005 to 5 weight percent, and preferably on the order of 0.05 to
1 weight percent, relative to the acrylic adhesive. Id. Further, Sasaki
teaches that there are no particular limits on the drug which is blended in the
plaster of the present invention, so long as the drug can be formed into an
adhesive patch preparation and administered to a subject in such a dosage
form. Id. at 2–3.
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3. Analysis
Petitioner asserts that Enz teaches a composition that meets every
limitation of independent claims 1 and 7, except the addition of an
antioxidant. Pet. 37. Specifically, Petitioner asserts that Enz discloses in
Example 2 a pharmaceutical composition, e.g., a transdermal device,
comprising 20 weight percent of hydrogen tartrate salt of rivastigmine, i.e., 1
to 40 weight percent of (S)-N-ethyl-3-[(1-dimethylamino)ethyl]-N-methyl-
phenyl-carbamate, Eudragit
®
E 100 (a hydrophilic polymer) and Durotack
®

280-2416 (an acrylic adhesive), i.e., a diluent or carrier, and Brij
®
97 (a
plasticizer). Id. at 20–21. Patent Owner does not dispute that Enz discloses
these limitations of independent claims 1 and 7. PO Resp. 21–22.
Accordingly, our analysis turns to whether a preponderance of the
evidence establishes, based on the teachings of Enz and Sasaki, along with
the knowledge generally available to one of ordinary skill in the art, that it
would have been obvious to a person of ordinary skill in the art at the time
of the invention who endeavored to formulate rivastigmine into a
transdermal patch, as taught by Enz, to have added an antioxidant as taught
by Sasaki.
Petitioner, relying on the declaration testimony of Dr. Kydonieus,
asserts that Sasaki provides a person of ordinary skill in the art a reasonable
expectation that the rivastigmine transdermal patch formulation taught by
Enz would be unstable during long-term storage of two to three years. Pet.
40 (citing Ex. 1010 ¶ 78). Specifically, Petitioner asserts that Enz serves as
a starting point for formulating a rivastigmine transdermal patch, but does
not provide stability data or any discussion of susceptibility to oxidation, for
the product. Pet. 40; Ex. 1010 ¶ 76. Relying upon the declaration testimony
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of Dr. Kydonieus, Petitioner asserts that those having skill in the art would
have “strive[d] to develop stable pharmaceutical products with a
commercially viable shelf life.” Pet. 40–41 (quoting Ex. 1010 ¶ 79). In
furtherance of that goal, according to Petitioner and Dr. Kydonieus, “one of
the first steps a person of ordinary skill in the art would have taken when
formulating a drug product is to investigate the stability of the active
component.” Pet. 39; Ex. 1010 ¶ 77.
Petitioner asserts that Sasaki informs that investigation. Pet. 40. In
particular, Petitioner asserts that Sasaki teaches that compounds having an
amino group can undergo oxidative decomposition over the shelf life of the
product when the product comprises an acrylic adhesive. Id. (citing Ex.
1005, 1; Ex. 1010 ¶ 78). According to Petitioner and Dr. Kydonieus, based
on that teaching of Sasaki, a person of ordinary skill in the art would have
expected Enz’s transdermal patch to be unstable during long-term storage
because it comprised a drug having an amino group, i.e., rivastigmine, see
Ex. 1011 ¶ 12, and it was formulated with an acrylic polymer adhesive, i.e.,
Durotack
®
280-2416. Pet. 40 (citing Ex. 1010 ¶ 78).
Petitioner asserts further that the person of ordinary skill would have
been motivated to add an antioxidant, particularly tocopherol, as recited in
claim 2 of the ’023 patent, to Enz’s rivastigmine transdermal composition
with a reasonable expectation of maintaining the stability of the patch during
long-term storage, as this is the precise solution disclosed by Sasaki. Id. at
40–42. Moreover, at the time of the invention, antioxidants were commonly
included in pharmaceutical products, including transdermal devices, to
protect the drug and/or excipients from oxidative degradation. Id. (citing
Ex. 1010 ¶79; Ex. 1011 ¶50). Additionally, Petitioner asserts that the person
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of skill in the art would have been motivated to add the amount of
tocopherol disclosed by Sasaki, which amount encompasses the amounts
recited in claims 1, 4, 5 and 7 of the ’023 patent. Id. at 41–43.
Patent Owner contends that Sasaki does not teach or suggest any
oxidative degradation problem for rivastigmine, and, therefore, a person of
ordinary skill in the art would not have been motivated to include an
antioxidant in the rivastigmine transdermal formulation disclosed by Enz.
PO Resp. 44. In particular, Patent Owner challenges Sasaki by asserting that
it does not mention rivastigmine and discloses only two exemplary amine-
containing compounds in transdermal formulations. Id. at 41–42.
According to Patent Owner, and Patent Owner’s declarant, Dr.
Klibanov, Sasaki’s disclosure of only two amine-containing compounds
“would not have taught or suggested to a [person of ordinary skill in the art]
as of 1998 that all amine-containing compounds break down in any acrylic
adhesive.” Id. at 42 (citing Ex. 2012 ¶ 156). Specifically, Patent Owner
asserts that a person of skill in the art would not reasonably have predicted
from the presence of an amine group in rivastigmine’s structure that
rivastigmine would oxidatively degrade under pharmaceutically relevant
conditions.
8
Id. (citing Ex. 2012 ¶¶ 130–137, 150, 156.). Rather, Patent
Owner asserts, only “the structure of the molecule as a whole matters to its
chemical stability” and “whether a compound will degrade in a particular
formulation cannot be predicted in advance of testing.” Id. (citing Ex. 2012
¶¶ 132–137, 156). According to Patent Owner, both of Petitioner’s

8
At the oral hearing, Patent Owner explained that it uses the phrase
“pharmaceutically relevant conditions” as referring to “the types of
conditions that the drug would encounter during formulation and storage.”
Tr. 60:14–17.
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declarants, Dr. Kydonieus and Dr. Schöneich, agree that it cannot be
predicted whether a compound will degrade in a particular formulation in
advance of testing, and that Dr. Kydonieus “admitted that he could not be
certain whether rivastigmine would necessarily undergo oxidative
degradation in any acrylic adhesive.” Id. (citing Ex. 1026, 95:24–96:18,
232:6–13, 258:8–13, 283:12–284:19; Ex. 1030, 53:10–17).
Additionally, Patent Owner asserts that contrary to Sasaki’s teaching,
“there were numerous amine-containing drug compounds not reported to
contain antioxidants in their commercial formulations–including one in a
transdermal formulation using acrylic adhesives.” PO Resp. 42–43 (citing
Ex. 2012 ¶¶ 133–135, 157; Ex. 2022, 884). Patent Owner asserts also that
Enz contradicts Sasaki by not teaching or suggesting that rivastigmine will
break down in its transdermal formulation comprising an acrylic adhesive.
Id. at 43–44; Ex. 2012 ¶ 159).
After considering the record as a whole, we agree with Petitioner that
a person of ordinary skill in the art would have been motivated to add an
antioxidant to the transdermal rivastigmine formulation disclosed by Enz.
Sasaki teaches that if a drug is blended with a plaster comprising an acrylic
acid adhesive, there is a tendency for the therapeutic effect of the preparation
to be greatly reduced due to the breakdown and dissipation of the drug. Ex.
1005, 1. Sasaki explained that this breakdown occurs “especially” when the
drug is a phenolic hydroxyl group containing compound, an amine
compound, or the like. Id. Based on those teachings by Sasaki and the
knowledge in the art that rivastigmine is a compound comprising an amino
group, Ex. 1011 ¶ 12, it would have been reasonable for a person of
ordinary skill in the art to have expected Enz’s formulation comprising
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rivastigmine and an acrylic polymer adhesive, i.e., Durotack
®
280-2416, to
be unstable during long-term storage.
That rationale for applying Sasaki’s teaching to the rivastigmine
transdermal formulation disclosed by Enz is not diminished by Patent
Owner’s assertion that Sasaki did not mention expressly rivastigmine or
provide more than two exemplary amine compounds. The applicability of
Sasaki’s teaching regarding the stability of amine compounds formulated
with acrylic adhesives is not limited to its examples. See Merck & Co., Inc.
v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989). Moreover, a
motivation to combine teachings need not be expressly stated in any prior art
reference. In re Kahn, 441 F.3d 977, 987. (Fed. Cir. 2006). Rather, as here,
the reason to combine the teachings need only be an articulated with some
rational underpinning to support a conclusion of obviousness. KSR Int’l Co.
v. Teleflex Inc., 550 U.S. 398, 418 (2007) (citing Kahn, 441 F.3d at 988).
We determine also that Patent Owner’s argument does not overcome
Petitioner’s showing that, in view of Sasaki’s teaching, a person of ordinary
skill in the art would have been able to reasonably predict “in advance of
testing” that rivastigmine would degrade when formulated with an acrylic
adhesive. PO Resp. 42. In support of its contention to the contrary, Patent
Owner relies upon the declaration of Dr. Klibanov. On this point, Dr.
Klibanov discusses initially five exemplary pharmaceutical compounds
containing an amine, but not reported to contain an antioxidant in the
commercial formulation. Ex. 2012 ¶ 133 (referring to ampicillin,
hydroxyzine, meclizine, mirtazapine, and benzquiamide). However, as
acknowledged by Dr. Klibanov, id. ¶ 134, none of those five examples
referred to a transdermal formulation including an acrylic adhesive, so as to
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make them relevant to Sasaki’s disclosure.
Dr. Klibanov discusses next two compounds containing an amine and
formulated into commercial transdermal products that he asserts were not
reported to contain antioxidants prior to the claimed invention. Id. ¶ 135
(referring to Duragesic
®
comprising fentanyl and Trans-derm Scop
®

comprising scopolamine). Referring to the Physician’s Desk Reference
(“PDR”), Dr. Klibanov takes the position that the commercial formulations
for transdermal devices comprising those compounds are not reported to
undergo oxidative degradation. Id. ¶¶ 135–138 (citing, e.g., the 1997 PDR,
Ex. 2022, 890–91, 1336–40). However, Dr. Klibanov has not described
those formulations as including an acrylic adhesive, so as to make them
relevant to Sasaki’s disclosure.
Dr. Klibanov discusses also a nicotine patch, Habitrol
®
, that was
commercially available at the time of the invention, along with three other
amine containing compounds formulated as transdermal products that were
commercially available after 1998, each of which were formulated with an
acrylate adhesive and not reported to include an antioxidant. Ex. 2012 ¶ 157
(citing Ex. 2022, 884). However, neither Dr. Klibanov nor Patent Owner
has identified any statement in the PDR describing the stability or shelf-life
of any of those transdermal formulations. Nor has Dr. Klibanov discussed in
the declaration whether those commercial formulations address drug
stability by some means other than adding an antioxidant. Indeed, in his
deposition testimony, Dr. Klibanov acknowledged that conclusions
regarding a drug’s susceptibility to oxidation cannot be made based upon its
formulation being reported not to include an antioxidant, because other
means of preventing oxidation may have been employed. Ex. 1027, 551:9–
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553:6; Pet. Reply 9; Ex. 1032 ¶ 42. Thus, we find that Dr. Klibanov’s
declaration testimony challenging the legitimacy of Sasaki’s teaching is not
entitled to substantial persuasive weight as it is unsupported by evidence and
instead is based upon an assumption drawn from an incomplete analysis of
the asserted evidence. See Rohm & Haas Co. v. Brotech Corp., 127 F.3d
1089, 1092 (Fed. Cir. 1997)(no requirement to credit unsupported assertions
of an expert witness).
Similarly, we remain persuaded by Petitioner’s showing, despite
Patent Owner’s assertion that Enz contradicts Sasaki by not teaching or
suggesting that its formulation of rivastigmine and an acrylic adhesive
would undergo oxidative degradation. PO Resp. 42–43. Based upon an
observation that Enz does not discuss oxidative stability or degradation, Dr.
Klibanov concludes that “Enz teaches a transdermal device for an amine-
containing compound and an acrylic adhesive that does not undergo
oxidative degradation and does not require an antioxidant.” Ex. 2012 ¶ 158.
We find, once again, that Dr. Klibanov’s testimony is not entitled to
persuasive weight as it is not supported by the asserted evidence. Enz does
not address the stability of its formulation. Indeed, as acknowledged by
Patent Owner, “Enz moreover does not teach or suggest anything about the
oxidative degradation of rivastigmine.” PO Resp. 22. Dr. Klibanov has not
explained or provided evidence that one of ordinary skill in the art would
have reasonably drawn an inference about the stability or oxidative
degradation of a preparation from a disclosure that did not address
“anything” about the topic. See In re Preda, 401 F.2d 825, 826 (CCPA
1968) (inferences drawn from scope and content of prior art must be ones
that one of skill in the art would reasonably be expected to draw). As
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Petitioner explained, Enz provides a “starting point” for a rivastigmine
transdermal formulation. As the starting point, we agree with Petitioner that
a skilled artisan who endeavored to prepare Enz’s formulation as a
commercial product would have investigated its stability and taken steps to
ensure a viable shelf life. Id. at 39–41 (citing Ex. 1010 ¶¶ 77, 79).
Moreover, we disagree with Patent Owner’s assertion that Petitioner’s
declarants, Dr. Kydonieus and Dr. Schöneich, agree that it cannot be
reasonably predicted whether a compound will be susceptible to degradation
in a particular formulation in advance of testing. More precisely, we find
that the testimony of Dr. Kydonieus and Dr. Schöneich relied upon by Patent
Owner explains that susceptibility to oxidative degradation can be
reasonably predicted from a compound’s molecular structure, whereas,
whether and to what extent that expected degradation actually occurs needs
to be shown experimentally. See, e.g., Ex. 1026, 258:8–13 (testimony of Dr.
Kydonieus)
9
and 96:13–18 (testimony of Dr. Schöneich). Indeed, as Patent
Owner acknowledges, Dr. Kydonieus explained that without such testing “he
could not be certain whether rivastigmine would necessarily undergo
oxidative degradation in any acrylic adhesive.” PO Resp. 42 (citing Ex.
1026, 283:12–21).
In other words, Dr. Kydonieus and Dr. Schöneich agree that, although
a skilled artisan may not be able to predict absolutely whether a compound
will degrade oxidatively based on its structure alone, a reasonable prediction
can be made regarding its potential and susceptibility to do so. In an
obviousness analysis, absolute predictability is not the standard. In re

9
See also Ex. 1031 ¶ 54 (Dr. Kydonieus explaining that a person of ordinary
skill in the art “would not have understood the susceptibility of rivastigmine
to oxidative degradation to vary based on method of drug delivery”).
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O’Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988). Rather, the proper inquiry
focuses on reasonable expectations that a skilled artisan would gain from the
teachings or suggestions of the combined prior art. Id. at 903–04.
10
Patent
Owner and its declarant, Dr. Klibanov, have mistakenly disregarded the
significance of the suggestion provided by the combined prior art that a
compound having an amine group and formulated with an acrylic plaster is
susceptible to oxidative degradation. It is this susceptibility, i.e., a predicted
potential for oxidative degradation, that provides the skilled artisan with a
reasonable expectation that the formulation will oxidatively degrade and the
motivation to address that problem by employing a means known to avoid
that problem, such as adding an antioxidant, as taught by Sasaki.
Thus, contrary to Patent Owner’s contention, PO Resp. 5, this case
can be distinguished from the situation in Leo Pharmaceutical Products,
Ltd. v. Rea, 726 F.3d 1346, 1353 (Fed. Cir. 2013) because here, the problem
regarding oxidative degradation of certain compounds formulated in acrylic
adhesives was “recognized and solved” by the prior art. Patent Owner
asserts also that “as in Leo, the invention of the ’023 [p]atent did not appear
until a decade after the 1988 publication of Petitioner’s primary art
reference, Enz.” PO Resp. 8. However, unlike in Leo, here, a
preponderance of the evidence supports finding that a person of ordinary
skill in the art would have understood the addition of an antioxidant to Enz,
i.e., the invention of the ’023 patent, was suggested by the prior art.
Moreover, absent a long-felt need or the failure of others, the mere passage
of time without the claimed invention is not evidence of nonobviousness.

10
As Patent Owner’s counsel acknowledged at the hearing, “Absolute
predictability is not the standard. The standard is whether it was known or
reasonably suggested in the prior art.” Tr. 54:4–6.
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Iron Grip Barbell Co., Inc. v. USA Sports, Inc., 392 F.3d 1317, 1324-25
(Fed. Cir. 2004).
Similarly, contrary to Patent Owner’s contention, PO Resp. 5, this
case is also distinguishable from In re Omeprazole Patent Litigation, 536
F.3d 1361, 1380–81 (Fed. Cir. 2008) because here, the prior art suggested
the need to stabilize formulations such as that disclosed by Enz.
Based on the foregoing discussion and the record as a whole, we find
that a person of ordinary skill in the art would have predicted that the
transdermal formulation disclosed by Enz was susceptible to oxidative
degradation, based on an application of Sasaki’s teachings, and would have
been motivated to add an antioxidant to the formulation with a reasonable
expectation of successfully avoiding that predicted degradation.
Accordingly, we conclude that the preponderance of the evidence
demonstrates that the combined prior art renders obvious the inventions of
claims 1, 2, 4, 5 and 7 of the ’023 patent.
11

D. Obviousness of Claim 8 over Enz (Ex. 1002),
Sasaki (Ex. 1005) and Ebert (Ex. 1006) or Kissel (Ex. 1007)

Petitioner contends that claim 8 is rendered obvious by the
combination of Enz, Sasaki, and Ebert or Kissel. Pet. 44–45. Claim 8
depends from claim 7 and further comprises “a backing layer providing
support for the pharmaceutical composition; an adhesive for contacting and
fixing the pharmaceutical composition to the backing layer; and a release
liner releasably contacting said adhesive.”

11
Patent Owner does not raise separate arguments addressing dependent
claims 2, 4 and 5.
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1. Kissel
Kissel discloses pharmaceutical compositions for the transdermal
systemic administration of an active agent. Ex. 1007, Abstract. Kissel
teaches that pharmaceutical compositions for the sustained transdermal
administration of drugs may include a solid drug reservoir having a backing
member impermeable to the drug on one side and a protective peel strip on
the other side that is taken off before use. Id. at 2.
2. Analysis
Petitioner asserts that a person of ordinary skill in the art would have
been motivated to modify Enz’s transdermal patch by adding an antioxidant,
as taught by Sasaki, for the reasons discussed regarding the ground based
upon the combination of Enz and Sasaki. Pet. 44. Additionally, Petitioner
asserts that Enz discloses that its composition comprises an aluminum foil,
i.e., a backing layer providing support for the composition, and Durotack
®
,
an adhesive. Id.; Ex. 1002, 20 (Example 2). Petitioner asserts that Ebert and
Kissel each teach that a release liner was a common component of
transdermal patches, as it protects the composition prior to use and provides
convenient packaging. Id.; Ex. 1006, Abstract; Ex. 1007 at 2. Thus,
Petitioner asserts that a person of ordinary skill in the art at the time of the
invention would have been motivated to include a release liner on Enz’s
transdermal patch. Id.
Patent Owner does not raise separate arguments addressing claim 8.
Thus, for the same reasons discussed regarding obviousness over the
combination of Enz and Sasaki, we are persuaded that Petitioner has
established persuasively that the combined references would have provided a
reason to a person of ordinary skill in the art at the time of the invention to
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add an antioxidant to the composition disclosed by Enz.
Further, based on the record as a whole, we find that Petitioner has
established persuasively that it would have been obvious to a person of
ordinary skill in the art to add a release liner to the transdermal patch
disclosed by Enz. Based on the evidence, doing so would have amounted to
combining a familiar element according to a known method to yield no more
than a predictable result. See KSR Int’l Co., 550 U.S. at 416.
Accordingly, we conclude that Petitioner has established by a
preponderance of the evidence that claim 8 is rendered obvious by the
combination of Enz, Sasaki, and Ebert or Kissel.
E. Obviousness of Claims 1 and 7 over Enz (Ex. 1002),
the Handbook (Ex. 1003), Rosin (Ex. 1008),
Elmalem (Ex. 1009) and Ebert (Ex. 1006)

Petitioner contends that claims 1 and 7 are unpatentable over the
combination of Enz and the Handbook, optionally in view of Rosin and/or
Elmalem and/or Ebert. Pet. 21–32. Patent Owner disagrees. PO Resp. 10–
40. We incorporate here our earlier findings and discussion regarding the
disclosure of Enz.
1. The Handbook
The Handbook lists pharmaceutical excipients and provides a
description of each excipient, including nonproprietary and chemical names,
structural formula, functional category, applications in pharmaceutical
formulation or technology, and in some cases, the normal usage
concentration range. Ex. 1003, 5. The Handbook identifies several
excipients as antioxidants, including alpha tocopherol, normally used in the
concentration range of 0.001–0.05%. Id. at 5–7.

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2. Rosin
Rosin describes “a need to provide new carbamate derivatives which
show greater chemical stability than physostigmine.” Ex. 1008, 3:36–38.
Rosin discloses phenyl carbamates that inhibit acetylcholinesterase in the
mammalian brain after systemic administration. Id. at 4:16–20. Preferred
compounds of the invention include N-ethyl, N-methyl-3[(1-dimethyl-
amino)ethyl]phenyl carbamate, i.e., RA7. Id. at 5:40–45, 12:56–60, 14:17–
19. The compounds may be combined “with a physiologically acceptable
vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a
unit dosage form as called for by accepted pharmaceutical practice.” Id. at
7:19–24. Rosin discloses administering the compounds of the invention,
including RA7, by “any conventional route.” Id. at 13:8–10. Additionally,
Rosin states:
Sterile compositions for injection can be formulated
according to conventional pharmaceutical practice by
dissolving or suspending the active substance in a vehicle
such as water for injection. Buffers, preservatives,
antioxidants and the like can be incorporated as required.
Preferred antioxidants for use with the compounds of
the present invention include sodium metabisulphite
and ascorbic acid.

Id. at 7:45–53. Rosin discloses that compounds of the invention, including
RA7, showed greater in vivo potency than physostigmine, that “may be due”
to factors including “greater chemical stability.” Id. at 11:21–29.
3. Elmalem
Elmalem is a journal article discussing a study comparing the effects
of three synthesized anticholinesterase agents, including RA7, with those of
physostigmine on the respiratory depression induced by morphine in rabbits.
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Ex. 1009, 1059. Elmalem explains that physostigmine has “low chemical
stability,” whereas the three synthesized agents, including RA7, have a
greater chemical stability.” Id. Elmalem states that for the study all of these
four drugs were “made up freshly in sterile saline, which included an equal
weight of sodium metabisulphite, to prevent oxidation.” Id. at 1060.
4. Ebert
Ebert discloses a drug-containing adhesive composite transdermal
delivery device comprising a substantially drug impermeable proximal
release liner and a method for making the device. Ex. 1006, Abstract. Ebert
explains that although its disclosure specifically refers to nicotine as the
active drug, “any other liquid drug contained in an active gel which can be
transdermally or transmucosally delivered may be substituted in place of
nicotine.” Id. at 15:30–35. With respect to nicotine, Ebert explains that a
“trait of nicotine that can be problematic is its tendency to oxidize readily in
the presence of light and air.” Id. at 21:18–20. Ebert teaches that “[d]uring
fabrication of nicotine patches, oxidation is controlled by addition of an
antioxidant to the active gel,” wherein BHT is a preferred antioxidant. Id. at
21:23–26. Ebert teaches mixing BHT with nicotine preferably in the range
of about 0.01–1.0% w/w. Id. at 21:26–28.
5. Analysis
Petitioner asserts that Enz teaches a composition that meets every
limitation of claims 1 and 7, except for the addition of an antioxidant, as
previously discussed regarding the combination of Enz and Sasaki. Pet. 21.
Patent Owner does not dispute that Enz discloses these limitations of claims
1 and 7. See PO Resp. 21–22. Accordingly, our analysis turns to whether
the evidence establishes that, based on the combined teachings of Enz, the
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Handbook, Rosin, Elmalem, and Ebert, along with the knowledge generally
available to one of ordinary skill in the art, it would have been obvious to a
person of ordinary skill in the art at the time of the invention who
endeavored to formulate rivastigmine into a transdermal patch, as taught by
Enz, to have added an antioxidant.
As discussed previously, Petitioner asserts that at the time of the
invention, a person of ordinary skill in the art who desired to formulate
rivastigmine into a transdermal patch, as taught by Enz, would have
investigated the stability of the drug. Pet. 22–23; Ex. 1010 ¶¶ 23, 58.
According to Petitioner and Dr. Kydonieus, each of Elmalem and Rosin
informs such an investigation by teaching or suggesting the addition of an
antioxidant to compositions comprising RA7. Pet. 23 (citing Ex. 1009, 2;
Ex. 1008, 7:45–53); Ex. 1010 ¶ 58. Petitioner asserts that a person of
ordinary skill in the art would have understood from those references that
RA7 was susceptible to oxidation and “would have known that there would
be little or no difference between rivastigmine and RA7 with respect to
oxidation.” Id. (citing Ex. 1010 ¶ 29)(“[A] teaching that the racemic
compound RA7 is susceptible to oxidative degradation is equally applicable
to the single enantiomer rivastigmine.”).
Further, Petitioner asserts that when investigating the stability of
rivastigmine, a person of ordinary skill in the art “would have reasonably
expected, based on the molecular structure of the drug, that rivastigmine
would be susceptible to oxidative degradation.” Pet. 25 (citing Ex. 1010 ¶
58; Ex. 1011 ¶¶ 52–59). In particular, Petitioner submits the declaration of
Dr. Schӧneich as supporting the position that a person of ordinary skill in the
art would have recognized the similarities between the structure of
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rivastigmine and nicotine and “would have expected that rivastigmine would
be susceptible to oxidative degradation at the benzylic C-H bond and
adjacent tertiary amine via similar mechanisms as nicotine and to roughly
the same extent as nicotine.” Id. at 26–27; Ex. 1011 ¶¶ 57–59.
In this vein, Petitioner asserts that “Ebert taught that nicotine was
known to readily oxidize in the presence of light and air, and that adding an
antioxidant … could reduce that oxidation.” Pet. 27 (citing Ex. 1006, 21).
Therefore, according to Petitioner, a person of ordinary skill in the art would
have had reason to combine rivastigmine with an antioxidant to protect
against degradation with a reasonable expectation of successfully doing so
based upon the knowledge of an ordinarily skilled artisan regarding the
molecular structure of rivastigmine and the teachings of Rosin, Elmalem,
and Ebert. Id. (citing Ex. 1010 ¶ 58; Ex. 1011 ¶¶ 50, 61; Ex. 1006, 21; Ex.
1008, 5:44–45, 14:17–19, 7:45–53).
Patent Owner does not challenge as untrue Petitioner’s assertion that a
person of ordinary skill in the art who desired to formulate the transdermal
patch disclosed by Enz into a commercially available product would have
investigated the stability of drug and formulation. See, e.g., PO Resp. 9
(Patent Owner asserting only that Petitioner’s “contention is not proof of
obviousness”). Nor does Patent Owner challenge Petitioner’s assertion that
RA7 and rivastigmine have similar stability. PO Resp. 14 n.2 (citing Ex.
2012 ¶ 96 n.8) (explaining that a person of ordinary skill in the art would
have understood RA7 and rivastigmine to have the same oxidative stability).
Rather, Patent Owner asserts that, contrary to Petitioner’s argument, the
prior art does not teach or suggest that rivastigmine undergoes oxidative
degradation or requires an antioxidant. PO Resp. 2.
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In particular, Patent Owner asserts that Rosin does not teach or
suggest any oxidative degradation problem for RA7 or rivastigmine, and
therefore, a skilled artisan would not have known or had any motivation to
add an antioxidant to a rivastigmine formulation. Id. at 26–27. Relying
upon the declaration of Dr. Klibanov, Patent Owner asserts that what a
person of ordinary skill in the art would understand instead from Rosin is
that RA7 and rivastigmine are both oxidatively stable. Id. at 14–15, 26
(citing Ex. 2012 ¶¶ 48, 66; Ex. 1008, 3:37–39, 11:21–29). Patent Owner and
Dr. Klibanov draw this conclusion from Rosin’s teaching that compounds
such as RA7 show “greater chemical stability” than physostigmine. Id.
However, as Dr. Klibanov has acknowledged, “Rosin does not mention the
oxidative stability of RA7 and contains no test data concerning such
stability.” Ex. 2012 ¶ 47. Absent any discussion by Rosin regarding the
oxidative stability of the compound, Dr. Klibanov has not explained
adequately why a person of ordinary skill in the art would infer from Rosin’s
disclosure that RA7 and rivastigmine are both, in fact, oxidatively stable.
Rosin describes physostigmine as “chemically unstable” with a short half-
life of 20–40 minutes, and that it “must be prepared in solution with an
antioxidant.” Ex. 1008, 1:33–37. Thus, a comparative statement describing
RA7 as showing “‘greater chemical stability’ than physostigmine”
12
may
indicate only that RA7 is less “chemically unstable” than physostigmine. In
this respect, we are ultimately persuaded that the evidence supports the

12
We note that Rosin does not expressly teach that RA7 shows greater
stability than physostigmine. Rather, Rosin describes “a need to provide
new carbamate derivatives which show greater chemical stability than
physostigmine,” and suggests that the greater in vivo activity of RA7 “may
be due to” a number of factors, including, “greater chemical stability.” Ex.
1008, 3:37–39; 11:23–29.
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testimony of Dr. Kydonieus who explains that, to a person of ordinary skill
in the art, Rosin’s comparative statement “at best means that RA7 is more
stable than an unstable compound.” Reply Decl. of Dr. Kydonieus, Ex. 1031
¶ 48.
Further, Patent Owner asserts that Rosin does not teach or suggest any
oxidative degradation problem for RA7 or rivastigmine because Rosin’s
teaching to add an antioxidant “as required” is limited to injectable
formulations. PO Resp. 27. According to Patent Owner, Petitioner’s
declarants, Dr. Kydonieus and Dr. Schöneich, agree that whether a drug
oxidatively degrades is formulation specific. Id. (citing (Ex. 1026, 95:24–
96:18, 232:6–13, 258:8–13, 283:14–284:19; Ex. 1030, 53:10–17). Thus,
Patent Owner asserts that even if a skilled artisan understood Rosin to
suggest that an antioxidant may be required in an injectable formulation of
RA7, there would have been no reason to apply that teaching to the
transdermal formulation of rivastigmine taught by Enz. Id. at 27–28 (citing
Ex. 2012 ¶¶ 16, 50, 71).
Based on our analysis of the evidence, Dr. Kydonieus and Dr.
Schöneich agree that the susceptibility of a compound to oxidatively degrade
is not formulation specific. According to Dr. Kydonieus, a person of
ordinary skill in the art “would not have understood the susceptibility of
rivastigmine to oxidative degradation to vary based on method of drug
delivery–– the drug is inherently susceptible to oxidation, and this does not
change based on the particular formulation, or the particular drug delivery
method, in which the drug is employed.” Ex. 1031 ¶ 54. With respect to
Rosin, we note that apart from teaching the addition of an antioxidant “as
required,” Rosin discloses preferred antioxidants “for use with the
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compounds of the present invention,” without any indication that such use is
limited to any particular formulation. Ex. 1008, 7:51–53. Indeed, Rosin
discloses administering the compounds of the invention, including RA7, by
“any conventional route.” Id. at 13:8–10. As Dr. Kydonieus explained
persuasively, a person of skill in the art would have understood that
transdermal administration was such a conventional route of administration.
Ex. 1031 ¶ 53.
Although we do not agree with Patent Owner that Rosin teaches or
suggests that rivastigmine is oxidatively stable, we also do not find that
Rosin’s disclosure, by itself, would have suggested to a person of ordinary
skill in the art that rivastigmine required an antioxidant. So, we continue our
obviousness analysis by considering the additional prior art relied upon by
the Petitioner and the evidence of knowledge in the art at the time of the
invention.
Patent Owner asserts that Elmalem also does not teach or suggest that
rivastigmine requires an antioxidant in any pharmaceutical formulation. PO
Resp. 28 (citing Ex. 2012 ¶¶ 74, 108). As asserted with Rosin, Patent
Owner contends that a person of ordinary skill in the art would have
understood from Elmalem that RA7 and rivastigmine are both oxidatively
stable because Elmalem teaches that RA7 has a “greater chemical stability”
than physostigmine. Id. at 28–29 (citing Ex. 2012 ¶ 48). We remain
unpersuaded by this argument for the same reasons discussed with respect to
Rosin.
Additionally, Patent Owner asserts that Elmalem’s statement that
“[a]ll drugs were made up freshly in sterile saline, which included an equal
weight of sodium metabisulphite, to prevent oxidation,” did not mean that
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the sodium metabisulphite, an antioxidant, was included to prevent oxidation
of RA7. PO Resp. 30–34 (citing Ex. 1009, 1060). According to Patent
Owner, the antioxidant was added instead only to prevent oxidation of one
of the drugs, physostigmine, and was included in the preparation of the other
drugs only as a control. Id. (citing Ex. 2012 ¶¶ 77–110).
We have considered Patent Owner’s arguments in support of that
contention, see PO Resp. 31–34, as well as the cited testimony of Dr.
Klibanov, but do not find them to persuasively alter a plain reading of
Elmalem’s statement, for the reasons discussed by Petitioner and Dr.
Kydonieus. Pet. Reply 13; Ex. 1031 ¶¶ 56–63. In particular, we are not
persuaded by Patent Owner’s assertion that a person of ordinary skill in the
art would have understood that Elmalem added antioxidant also to the
saline-treated controls. PO Resp. 33. According to Patent Owner and Dr.
Klibanov, Elmalem refers to the saline control preparation expressly as a
“drug” in the “Summary” section, thus leading a skilled artisan to have
understood that Elmalem included an antioxidant in the saline control
preparation also. Id. (citing Ex. 2012 ¶ 104; Ex. 1009, 1059–60).
We disagree with Patent Owner. In the “Summary,” or abstract, of
Elmalem, it states, “Each drug, RA6, (1 mg i.v., 2 mg s.c.) RA7 (1 or 2 mg
i.v.); RA15 (0.25 or 0.5 mg i.v.), physostigmine (0.05 or 0.1 mg i.v.) or saline
(1 ml), was injected . . . .” Ex. 1009, 1059. We find that a person of
ordinary skill in the art would have understood the saline to be separated
from the “drug” listing, i.e., RA6, RA7, RA15, and physostigmine, by the use
of the term “or.” That reading recognizing only 4 drugs is further supported
by the statement in Elmalem’s “Discussion” section that “[a] highly
significant correlation was found for all 4 drugs . . . .” Id. at 1064.
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Moreover, we note that Elmalem described expressly the critical
aspects of its study, including the methods, materials, and controls, e.g., the
“saline-treated controls.” Ex. 1009, 1060. Rather than describing the
addition of an antioxidant as a control, Elmalem specifically explained that
the inclusion of the antioxidant in the preparation of each drug sample was
“to prevent oxidation.” Id.
Upon consideration of the evidence and arguments, we find no
persuasive reason why a person of ordinary skill in the art would not
understand Elmalem’s disclosure of including an antioxidant in each drug
sample, including the RA7 sample, “to prevent oxidation” to mean anything
other than just that.
Patent Owner asserts further that even if Elmalem is understood to
suggest adding an antioxidant to an RA7 or rivastigmine formulation, that
teaching is limited to aqueous injectable formulations, and a person of
ordinary skill in the art would not have been motivated to apply that
suggestion to the transdermal rivastigmine formulation taught by Enz. PO
Resp. 36 (citing Ex. 2012 ¶¶ 16, 50, 109). We remain unpersuaded by this
argument for the same reason discussed with respect to Rosin, i.e., we find
more persuasive the testimony of Dr. Kydonieus that a person of ordinary
skill in the art would not have understood a susceptibility of rivastigmine to
oxidative degradation to vary based on method of drug delivery, as the
evidence suggests that the susceptibility to oxidation is a property of a
compound that does not change based on the particular drug delivery
method. Ex. 1031 ¶ 54.
Patent Owner asserts that neither the Handbook nor Ebert teach or
suggest any oxidative problem for rivastigmine, or any other problem or
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solution relevant to the manufacture of a rivastigmine transdermal device.
PO Resp. 23–24, 37–40. However, Patent Owner does not address the
usefulness of the Handbook for determining the optimal antioxidant and its
concentration, or the relevance of Ebert’s disclosure of a peelable
impermeable backing material adapted for removal prior to administering
the transdermal device, i.e., the releasable liner, as relied upon and
established persuasively by the Petitioner. Id.
Turning to the knowledge in the art, Patent Owner asserts that
contrary to Petitioner’s argument, Pet. 25–28, a person of ordinary skill in
the art would not have predicted that rivastigmine would oxidatively degrade
based on its structure. PO Resp. 2, 16–20. In particular, Patent Owner
challenges Dr. Schöneich’s opinion that a person of ordinary skill in the art
would have recognized rivastigmine as being susceptible to oxidative
degradation based on the presence of two functional groups, i.e., a benzylic
C-H bond and an adjacent tertiary amine. PO Resp. 17.
13
According to Dr.
Schöneich, a person of skill in the art would have recognized also that
rivastigmine and nicotine, a drug known to be susceptible to oxidative
degradation at the time of the invention, as evidenced by Ebert, shared those
structural similarities. Ex. 1011 ¶ 56. Patent Owner asserts that Dr.
Schöneich’s opinion is unsupported by a comparison of rivastigmine to

13
Patent Owner challenges also Dr. Schöneich’s discussion of
dextromethorphan. PO Resp. 17. However, Petitioner has not relied on that
discussion in the Petition or Reply Brief. Dr. Schöneich’s discussion of
dextromethorphan was exemplified only as a compound comprising one of
the two functional groups forming the basis of his asserted susceptibility
analysis. See Ex. 1011 ¶ 47; Ex. 1032 ¶ 64 (describing dextromethorphan as
example of a drug having just one feature of the two features forming the
basis of the asserted oxidative degradation susceptibility analysis for
rivastigmine).
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nicotine because nicotine does not have a benzylic C-H bond, but instead an
N-substituted pyrrolidone. PO Resp. 16–17.
Although we agree with Patent Owner that nicotine does not have a
benzylic C-H bond, Petitioner and Dr. Schöneich used the term “benzylic” in
quotes, explaining specifically that with respect to the structure of nicotine,
the term “‘benzylic’ is in quotes because the aromatic ring adjacent to the
carbon identified with the arrow is a pyridine ring rather than a benzene
ring.” Ex. 1011 ¶ 49; see also Pet. 26, Fig. 1 (including quotes around the
term “benzylic” when referring to the structure of nicotine). As Dr.
Schöneich explained further, “the aromatic ring in nicotine contains a
nitrogen and is therefore a pyridine aromatic ring, while the aromatic ring in
rivastigmine has a carbon at that position and is called a benzene aromatic
ring.” Ex. 1032 ¶ 54. In other words, Dr. Schöneich’s opinion did not rely
upon or otherwise require nicotine to have a benzylic C-H bond. Rather, as
Dr. Schöneich explained persuasively, a person of ordinary skill in the art
would have understood that “the aromatic ring in both rivastigmine and
nicotine would have the same effect on the adjacent carbon-hydrogen bond.
Namely, both would cause that bond to be weaker by stabilizing a radical at
that position by electron delocalization (also called resonance) in the
aromatic ring.” Id. (citing Ex. 1011 ¶¶ 27–31, 48–49). Patent Owner has
not argued or established otherwise with persuasive evidence.
Patent Owner asserts also that Dr. Schöneich’s opinion is unsupported
by a comparison of rivastigmine to nicotine because no nicotine transdermal
devices commercially available at the time of the invention were reported to
include an antioxidant. PO Resp. 17–18 (citing Ex. 2012 ¶¶ 144–145, 150-
151). Patent Owner acknowledges that nicotine was known at the time of
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the invention to be susceptible to oxidative degradation; however, Patent
Owner contends that because that knowledge did not motivate a person of
ordinary skill in the art to add an antioxidant to nicotine, such knowledge of
susceptibility to rivastigmine would not either. PO Resp. 18 (citing Ex.
2012 ¶¶ 150–151). As we have discussed previously, we find more credible
the testimony of Dr. Kydonieus and Dr. Schöneich explaining that a person
of ordinary skill in the art would have understood that a manufacturer could
apply means to prevent oxidation in such commercial products other than by
adding an antioxidant. See, e.g., Ex. 1031 ¶ 90; Ex. 1032 ¶ 63.
After considering the record as a whole, and for the reasons discussed,
we find that a person of ordinary skill in the art would have predicted that
the transdermal formulation disclosed by Enz is susceptible to oxidative
degradation and would have been motivated to add an antioxidant to the
formulation with a reasonable expectation of successfully avoiding that
predicted degradation. Accordingly, we conclude that the preponderance of
the evidence demonstrates that the combined prior art renders obvious
claims 1 and 7 of the ’023 patent.
F. Obviousness of Claim 2 over Enz (Ex. 1002),
the Handbook (Ex. 1003) Rosin (Ex. 1008)
and Ebert (Ex. 1006)
Petitioner contends that claim 2 is rendered obvious by the
combination of Enz, the Handbook, Rosin, and Ebert. Pet. 32–34. Claim 2
depends from claim 1 and further recites “wherein the antioxidant is selected
from the group consisting of tocopherol, esters of tocopherol, ascorbic acid,
esters of ascorbic acid, butylhydroxytoluene, butylhydroxyanisole, propyl
gallate, and combinations thereof.” We incorporate here our earlier findings
and discussion regarding the disclosures and combination of the prior art.
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Regarding the additional limitations of dependent claim 2, Petitioner
asserts that many of the antioxidants recited in claim 2 are listed in the
Handbook. Pet. 32 (citing Ex. 1003, 3–23). According to Petitioner a
person of ordinary skill in the art at the time of the invention would have
been motivated to select one of these known antioxidants listed in the
Handbook because inclusion in the Handbook indicates approved use in
pharmaceuticals. Id. (citing Ex. 1010 ¶ 61).
Further, Petitioner asserts that Rosin provides motivation with a
reasonable expectation of success to select ascorbic acid as an antioxidant.
Pet. 32–33. Rosin teaches that preferred antioxidants for use with
compounds of its invention, e.g., RA7, include ascorbic acid. Ex. 1008,
7:51–53. Additionally, Petitioner asserts that Ebert provides motivation with
a reasonable expectation of success to select BHT, BHA, and tocopherol by
teaching the use of these antioxidants to prevent degradation of nicotine in
transdermal devices. Pet. 33 (citing Ex. 1006, 21).
Patent Owner does not raise any separate argument regarding claim 2
or otherwise address this ground.
For similar reasons previously discussed, we are persuaded that
Petitioner has established that the preponderance of the evidence shows that
the combination of Enz, the Handbook, Rosin, and Ebert would have
provided a reason to a person of ordinary skill in the art at the time of the
invention to add an antioxidant to the composition disclosed by Enz.
Further, Petitioner has established persuasively that a person of ordinary
skill in the art would have found it obvious to select one of the recited
antioxidants in claim 2 that is listed in the Handbook, and/or specifically
disclosed in Rosin or Ebert. Doing so would have amounted to combining a
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familiar element according to a known method to yield no more than a
predictable result. See KSR Int’l Co., 550 U.S. at 416.
Accordingly, we conclude that the preponderance of the evidence
establishes that claim 2 would have been obvious over the combination of
Enz, the Handbook, Rosin, and Ebert under 35 U.S.C. § 103(a).
G. Obviousness of Claims 4 and 5 over Enz (Ex. 1002),
the Handbook (Ex. 1003) and Ebert (Ex. 1006)
Petitioner contends that claims 4 and 5 are rendered obvious by the
combination of Enz, the Handbook, and Ebert. Pet. 34–36. Claim 4
depends from claim 1 and further recites “wherein the antioxidant is present
in an amount of from 0.05 to 0.2 weight percent.” Claim 5 recites, “wherein
the antioxidant is present in an amount of from 0.1 to 0.15 weight percent.”
We incorporate here our earlier findings and discussion regarding the
disclosures and combination of the prior art.
Regarding the additional limitations of dependent claims 4 and 5,
Petitioner asserts that the antioxidant concentration ranges recited in the
claims overlap with the ranges disclosed in the Handbook and in Ebert. Pet.
34; Ex. 1003 at 5–23; Ex. 1006 at 21.
Patent Owner does not raise any separate argument regarding the
claims 4 and 5 or otherwise address this ground.
For similar reasons previously discussed, we are persuaded that
Petitioner has established that the preponderance of the evidence shows that
the combination of Enz, the Handbook, Rosin, and Ebert would have
provided a reason to a person of ordinary skill in the art at the time of the
invention to add an antioxidant to the composition disclosed by Enz.
Further, Petitioner has established persuasively that a person of ordinary
skill in the art would have found the weight percent range of antioxidant
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recited in claims 4 and 5 obvious, considering the recited ranges overlap the
ranges disclosed in the Handbook. See In re Peterson, 315 F.3d 1325, 1329
(Fed. Cir. 2003).
Accordingly, we conclude that the preponderance of the evidence
establishes that claims 4 and 5 would have been obvious over the
combination of Enz, the Handbook, and Ebert under 35 U.S.C. § 103(a).
H. Obviousness of Claim 8 over Enz (Ex. 1002),
the Handbook (Ex. 1003) and Ebert (Ex. 1006) or Kissel (Ex. 1007)
Petitioner contends that claim 8 is rendered obvious by the
combination of Enz, the Handbook, and Ebert or Kissel. Pet. 36–37.
Claim 8 depends from claim 7 and further recites “a backing layer providing
support for the pharmaceutical composition; an adhesive for contacting and
fixing the pharmaceutical composition to the backing layer; and a release
liner releasably contacting said adhesive.” We incorporate here our earlier
findings and discussion regarding the disclosures and combination of the
prior art.
Regarding the additional limitations of dependent claim 8, Petitioner
asserts that Enz discloses that its composition comprises an aluminum foil,
i.e., a backing layer providing support for the composition, and Durotack
®
,
an adhesive. Pet. 36; Ex. 1002, 20 (Example 2). Petitioner asserts that Ebert
and Kissel each teach that a release liner was a common component of
transdermal patches, as it protects the composition prior to use and provides
convenient packaging. Id. at 36–37; Ex. 1006, Abstract; Ex. 1007, 2. Thus,
Petitioner asserts that a person of ordinary skill in the art at the time of the
invention would have been motivated to include a release liner on Enz’s
transdermal patch. Id.

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Patent Owner does not raise any separate argument regarding the
claim 8 or otherwise address this ground.
For similar reasons previously discussed, we are persuaded that
Petitioner has established that the preponderance of the evidence shows that
the combination of Enz, the Handbook, Ebert, and Kissel would have
provided a reason to a person of ordinary skill in the art at the time of the
invention to add an antioxidant to the composition disclosed by Enz.
Further, Petitioner has established persuasively that it would have been
obvious to a person of ordinary skill in the art to add a release liner, as
taught by each of Ebert and Kissel, to the transdermal patch disclosed by
Enz. On the current record, doing so would have amounted to combining a
familiar element according to a known method to yield no more than a
predictable result. See KSR Int’l Co., 550 U.S. at 416.
Accordingly, we conclude that the preponderance of the evidence
establishes that claim 8 would have been obvious over the combination of
Enz, the Handbook and Ebert or Kissel.
IV. MOTION TO EXCLUDE
Petitioner moves to exclude Exhibits 2015, 2032, 2053, 2059 and
2061, along with paragraphs 27, 159 and 162–166 of Exhibit 2012, and
sections 157:9–160:19, 171:16–179:10 and 185:24–189:6 of Exhibit 1049.
14

Paper 48, 1.
15
Additionally, Petitioner moves to exclude portions of the

14
Based on our review, Patent Owner has not referred to Exhibits 2059 and
2061, or sections 157:9–160:19, 171:16–179:10 and 185:24–189:6 of
Exhibit 1049 in the Patent Owner Response.
15
Petitioner asserts also that, to the extent that Patent Owner relies on Ex.
2059 or Dr. Schöneich’s testimony regarding that exhibit in their
Observations to Dr. Schöneich’s April 18, 2015 deposition, such
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Patent Owner’s Response, Dr. Klibanov’s declaration, Ex. 2012, and the
Deposition Transcript of Dr. Kydonieus, Ex. 1049, discussing the ’023
Specification statement that “[i]t has now been found after exhaustive testing
that compound A is susceptible to degradation, particularly in the presence
of oxygen,” Ex. 1001, 1:23–25. Paper 48, 1, 13–14. Patent Owner opposes
the motion. Paper 49. Petitioner responds to the opposition in a Reply in
Support of the Motion to Exclude. Paper 57.
Because our Decision does not rely on the challenged content of
Exhibits 2015, 2032, 2053, 2059, 2061, paragraphs 27, 159 and 162–166 of
Exhibit 2012, or sections 157:9–160:19, 171:16–179:10 and 185:24–189:6
of Exhibit 1049, we dismiss Petitioner’s Motion to Exclude those items as
moot.
Moreover, to the extent that Petitioner contends that portions of the
Patent Owner’s Response, Dr. Klibanov’s declaration, Ex. 2012, and the
Deposition Transcript of Dr. Kydonieus, Ex. 1049, improperly rely upon
unsupported statements and data from the ’023 patent Specification, Paper
48, 13–14, we are not persuaded. According to Petitioner, Patent Owner
should have provided a declaration from a person with first-hand knowledge
of the experiments discussed in the Specification, as required by 37 C.F.R.
§ 42.61(c). Paper 48, 14. However, contrary to Petitioner’s assertion, we do
not find that Patent Owner relied on the referenced statement in the
Specification, i.e., “[i]t has now been found after exhaustive testing that
compound A is susceptible to degradation, particularly in the presence of
oxygen,” Ex. 1001, 1:23–25, to prove a fact other than what the

Observations should be “entitled to no weight.” Paper 48, 1. We do not
further address this assertion as it goes beyond addressing admissibility.
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Specification describes. See 37 C.F.R. § 42.61(c) (specification of a patent
is admissible as evidence only to prove what the specification describes); see
also 77 Fed. Reg. 48,612, 48,624 (Aug. 14, 2012) (explaining that 7 C.F.R.
§ 42.61(c) addresses the “problem in which a party mistakenly relies on a
specification to prove a fact other than what the specification says”).
Accordingly, we deny Petitioner’s Motion to Exclude portions of
Patent Owner’s Response, Exhibit 2012, and Exhibit 1049 describing what
the Specification states.
V. CONCLUSION
We conclude that Petitioner has demonstrated by a preponderance of
the evidence that claims 1, 2, 4, 5, 7 and 8 instituted for inter partes review
are unpatentable under 35 U.S.C. § 103(a) as follows:

References Basis ’023 Patent Claims
Enz, the Handbook, Rosin, Elmalem,
and Ebert
§ 103(a) 1, 7
Enz, the Handbook, Rosin, and Ebert § 103(a) 2
Enz and the Handbook, and Ebert § 103(a) 4, 5
Enz, the Handbook, and Ebert or Kissel § 103(a) 8
Enz and Sasaki § 103(a) 1, 2, 4, 5 and 7
Enz, Sasaki, and Ebert or Kissel § 103(a) 8

ORDER
In consideration of the foregoing, it is hereby:
ORDERED that Petitioner’s Motion to Exclude is dismissed as moot
with respect to Exhibits 2015, 2032, 2053, 2059, 2061, paragraphs 27, 159
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and 162–166 of Exhibit 2012, and sections 157:9–160:19, 171:16–179:10
and 185:24–189:6 of Exhibit 1049;
Further ORDERED that Petitioner’s Motion to Exclude is denied with
respect to portions of the Patent Owner’s Response, Dr. Klibanov’s
declaration, Ex. 2012, and the Deposition Transcript of Dr. Kydonieus, Ex.
1049, asserted to rely improperly upon unsupported statements and data
from the ’023 patent Specification;
FURTHER ORDERED that claims 1, 2, 4, 5, 7 and 8 have been
shown by a preponderance of the evidence 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.

PETITIONER:

Steven J. Lee
Michael K. Levy
KENYON & KENYON LLP
slee@kenyon.com
mlevy@kenyon.com

PATENT OWNER:

Raymond R. Mandra
Nicholas N. Kallas
FITZPATRICK, CELLA, HARPER & SCINTO
rmandra@fchs.com
ExelonPatchIPR@fchs.com