Trials@uspto.gov
`Tel: 571-272-7822
`
`
`
`Paper 69
` 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 IPR2014-005501
`Patent 6,335,031 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 IPR2015-00268 has been joined with this proceeding.
`
`
`
`

`

`IPR2014-00550
`Patent 6,335,031 B1
`
`
`I.
`
`INTRODUCTION
`
`Noven Pharmaceuticals, Inc. (“Noven”) filed a petition to institute an
`
`inter partes review of claims 1–3, 7, 15, 16 and 18 of U.S. Patent No.
`
`6,335,031 B1 (Ex. 1001, “the ’031 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 1–3, 7, 15, 16 and 18 was instituted.
`
`After the Institution Decision, Mylan Pharmaceuticals Inc. (“Mylan”)
`
`timely filed a separate petition to institute an inter partes review of claims
`
`1–3, 7, 15, 16 and 18 of the ’031 patent based on identical grounds as
`
`presented in Noven’s Petition. Case IPR2015-00268, 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 Patent
`
`Owner’s Preliminary Response. Papers 10, 13. In an Institution Decision,
`
`an inter partes review of claims 1–3, 7, 15, 16 and 18 was instituted in
`
`IPR2015-00268, the Motion for Joinder was granted, and the proceeding in
`
`IPR2015-00268 was terminated. 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.”). Petitioner
`
`filed a Reply. Papers 31 and 32 (“Pet. Reply”).3 Patent Owner filed motions
`
`for observations on the cross-examinations of two deposed declarant
`
`
`2 Pursuant to an order, Paper 27, granting an unopposed motion by
`Petitioner, Paper 21, Petitioner filed a Corrected Petition, Paper 37, to
`correct certain clerical and typographical errors in the list of exhibits.
`3 Paper 31 was filed under seal and Paper 32 is a redacted public version.
`2
`
`
`
`

`

`IPR2014-00550
`Patent 6,335,031 B1
`
`witnesses. Papers 42, 43, 44.4 Petitioner filed responses to the motions.
`
`Papers 52, 53 and 54.5 Additionally, Petitioner filed a motion to exclude a
`
`number of Patent Owner’s exhibits. Paper 47. Patent Owner filed an
`
`opposition to the motion. Paper 49. Petitioner responds 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.”).6
`
`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 1–3, 7, 15, 16 and 18 are unpatentable.
`
`A. Related Proceedings
`
`According to Petitioner and Patent Owner, the ’031 patent was
`
`involved in various district court actions, including two actions involving the
`
`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
`
`
`4 Patent Owner filed a Confidential Motion for Observations on Cross-
`Examination of Dr. Agis Kydonieus under seal, Paper 42, and a redacted,
`“Non-Confidential” public version, Paper 43. Paper 44 is Patent Owner’s
`Motion for Observation on Cross-Examination of Dr. Christian Schӧneich.
`5 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.
`6 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.
`
`
`
`3
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`

`IPR2014-00550
`Patent 6,335,031 B1
`
`the District of Delaware issued a decision finding that Noven failed to prove
`
`by clear and convincing evidence that claims 7 and 16 of 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) (“Noven”). Although in Noven, the District Court considered the
`
`same prior art presented in this inter partes review, the District Court’s
`
`opinion is not binding in this proceeding. We have independently analyzed
`
`the prior art in view of the record evidence as a whole, including the
`
`knowledge of a person of ordinary skill in the art. Our findings and
`
`conclusions differ from the District Court in that we have accorded
`
`persuasive weight to the testimony of Petitioner’s declarants. Moreover, the
`
`petitioner in an inter partes review proves unpatentability by a
`
`preponderance of the evidence (see 35 U.S.C. § 316(e)) rather than by clear
`
`and convincing evidence, as required in district court litigation.
`
`In another case involving Novartis, but not Noven or Mylan, the same
`
`District Court held that claims 3, 7, 13, 16 and 18 of the ’031 patent are not
`
`invalid as obvious. Novartis Pharms. 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 ’031
`
`patent. Novartis Pharm. 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, as discussed previously,
`
`in an inter partes review, a petitioner’s burden of proving unpatentability is
`
`
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`4
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`IPR2014-00550
`Patent 6,335,031 B1
`
`by a preponderance of the evidence rather than by clear and convincing
`
`evidence. Thus, while we have considered the Federal Circuit’s decision,
`
`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 a related patent,
`
`U.S. Patent No. 6,316,023 B1, has been entered concurrently with this
`
`decision. IPR2014-00549, Paper 69.
`
`B. The ’031 Patent (Ex. 1001)
`
`The ’031 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 1:14–16. 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 1:17–21. The
`
`inventors of the ’031 patent explained that the composition of the prior art
`
`“is susceptible to degradation, particularly in the presence of oxygen.” Id. at
`
`1:22–24. The ’031 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.
`
`
`
`5
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`IPR2014-00550
`Patent 6,335,031 B1
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`
`
`The pharmaceutical compositions of the present
`invention show a reduction in degradation by-products in
`stress stability tests.
`
`Id. at 1:29–39.
`
`The ’031 patent discloses that an effective stabilization effect is
`
`achieved “when the antioxidant is selected from tocopherol, esters thereof,
`
`e.g. tocopherol acetate, ascorbyl palmitate, ascorbic acid,
`
`butylhydroxytoluene, butylhydroxyanisone or propyl gallate, preferably α-
`
`tocopherol or ascorbyl palmitate.” Id. at 4:11–16. “The antioxidant may be
`
`conveniently present in an amount of from about 0.01 to about 0.5% . . . by
`
`weight based on the total weight of the pharmaceutical composition.” Id. at
`
`4:16–19.
`
`Additionally, the ’031 patent teaches that “[t]he pharmaceutical
`
`compositions of the invention may contain high amounts of compound A,
`
`e.g. from 1 to 40% by weight.” Id. at 1:40–42.
`
`C. Illustrative Claims
`
`Claims 1, 7 and 15 of the ’031 patent are illustrative of the claims at
`
`issue:
`
`1.
`(a)
`
`A pharmaceutical composition comprising:
`a therapeutically effective amount of (S)-N-ethyl-3-{(1-
`dimethylamino)ethyl}-N-methyl-phenyl-carbamate in
`free base or acid addition salt form (Compound A);
`about 0.01 to about 0.5 percent by weight of an
`antioxidant, based on the weight of the composition, and
`a diluent or carrier.
`
`Ex. 1001, 8:14–21.
`
`
`(b)
`
`(c)
`
`
`
`6
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`

`IPR2014-00550
`Patent 6,335,031 B1
`
`
`A transdermal device comprising a pharmaceutical
`7.
`composition as defined by claim 1, wherein the pharmaceutical
`composition is supported by a substrate.
`
`Id. at 8:49–51.
`
`
`(S)-N-ethyl-3-{(1-
`stabilizing
`of
`15. A method
`dimethylamino)ethyl}-N-methyl-phenyl-carbamate in free
`base or acid addition salt form (Compound A), wherein the
`method comprises forming a composition by combining
`Compound A with an amount of anti-oxidant effective to
`stabilize Compound A from degradation.
`
`Id. at 9:10–15.
`
`D. The Prior Art
`
`Enz
`
`UK Patent Application GB 2,203,040 A,
`published Oct. 12, 1988 (“Enz”)
`
`Handbook HANDBOOK OF PHARMACEUTICAL EXCIPIENTS
`(A. Wade & P.J. Weller eds., 2d ed. 1994)
`(“the Handbook”)
`
`Sasaki
`
`Ebert
`
`Rosin
`
`Elmalem
`
`JP Patent Application 59-184121, published
`Oct. 19, 1984 (“Sasaki”)
`
`WO 95/24172, published Sept. 14, 1995
`(“Ebert”)
`
`US 4,948,807, issued Aug. 14, 1990
`(“Rosin”)
`
`Antagonism of Morphine-Induced
`Respiratory Depression by Novel
`Anticholinesterase Agents, 30
`NEUROPHARMACOLOGY 1059–64 (1991)
`(“Elmalem”)
`
`Ex. 1002
`
`Ex. 1003
`
`Ex. 1005
`
`
`Ex. 1006
`
`Ex. 1008
`
`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
`
`
`
`7
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`

`IPR2014-00550
`Patent 6,335,031 B1
`
`M. Klibanov, Ex. 2012.
`
`E. The Instituted Grounds of Unpatentability
`
`Trial was instituted for claims 1–3, 7, 15, 16 and 18 of the ’031 patent
`
`on the following grounds:
`
`Reference(s)
`
`Basis
`
`Claims
`
`Enz, the Handbook, Rosin,
`Elmalem, and Ebert
`Enz, the Handbook, Rosin, and
`Ebert
`Enz and Sasaki
`
`§ 103(a)
`
`1, 2, 7, 15 and 18
`
`§ 103(a)
`
`3 and 16
`
`§ 103(a)
`
`1–3, 7, 15, 16 and 18
`
`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).
`
`Petitioner asserts that the claim term “stabilizing” means “reducing
`
`degradation.” Pet. 8 (citing Ex. 1001, 4:5–30). Patent Owner proposes that
`
`
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`8
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`IPR2014-00550
`Patent 6,335,031 B1
`
`this term means “significantly reducing degradation of Compound A over a
`
`prolonged period of time.” Prelim. Resp. 12.7
`
`The term “stabilizing” is recited in claim 15, i.e., “A method of
`
`stabilizing . . . Compound A.” The Specification does not define this term
`
`expressly. The Specification states, “stable pharmaceutical 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.” Ex. 1001, 1:29–33. The
`
`Specification discloses that the addition of tocopherol to a composition
`
`containing compound A resulted in a smaller percentage of degradation
`
`products as compared to compositions not containing tocopherol. Id. at
`
`4:20–30. The percentages of degradation products were determined using
`
`two or three month stress tests. Id. at 4:20–30.
`
`Based on the evidence and arguments, we determine that Petitioner’s
`
`interpretation is the broadest reasonable construction in light of the
`
`Specification. Although the Specification describes obtaining stable
`
`compositions which show insignificant degradation of compound A over a
`
`prolonged time period and using a two- or three-month stress test to
`
`determine a reduction in degradation, neither those disclosures nor the
`
`language of claim 15 limit “stabilizing” to refer only to a reduction in
`
`degradation that is significant, or over a “prolonged” period of time, as
`
`urged by Patent Owner. See Home Diagnostics, Inc., v. Lifescan, Inc., 381
`
`F.3d 1352, 1358 (Fed. Cir. 2004)(discussing a specification description that
`
`
`7 Patent Owner does not revisit the issue of claim construction for any term
`in the Patent Owner Response.
`
`
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`

`IPR2014-00550
`Patent 6,335,031 B1
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`does not amount to the kind of clear disavowal that supports importing an
`
`unclaimed limitation from the specification).
`
`
`
`Similarly, Petitioner asserts that the claim phrase “an amount of
`
`antioxidant effective to stabilize Compound A from degradation” means “an
`
`amount of antioxidant that reduces the oxidative degradation of Compound
`
`A.” Pet. 8 (citing Ex. 1001, 1:29–33). Patent Owner proposes that this term
`
`means “an amount of antioxidant that will significantly reduce degradation
`
`of Compound A over a prolonged period of time.” Prelim. Resp. 8–9. On
`
`the current record, we agree that Petitioner’s interpretation is the broadest
`
`reasonable construction in light of the Specification for the same reason
`
`discussed regarding the term “stabilizing.”
`
`
`
`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. 8–9; Prelim.
`
`Resp. 13. 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
`
`pharmaceutical formulations, including transdermal drug deliver systems;”
`
`(b) been familiar with testing that accompanies the development of any
`
`
`
`10
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`

`IPR2014-00550
`Patent 6,335,031 B1
`
`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. 5–6 (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.
`
`
`
`11
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`IPR2014-00550
`Patent 6,335,031 B1
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`
`C. Obviousness of Claims 1–3, 7, 15, 16 and 18 over
`Enz (Ex. 1002) and Sasaki (Ex. 1005)
`
`Petitioner contends that claims 1–3, 7, 15, 16 and 18 would have been
`
`obvious to a person of ordinary skill in the art at the time the invention was
`
`made over the combination of Enz and Sasaki. Pet. 43–51. Patent Owner
`
`disagrees. PO Resp. 9–22, 40–44.
`
`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
`
`
`
`12
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`IPR2014-00550
`Patent 6,335,031 B1
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`comprising a compound according to the invention in association with at
`
`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.
`
`Enz discloses a daily dosage in the range from about 0.1 to about 25
`
`mg, e.g., 0.1 to about 5 mg, of a compound according to the invention. Id. at
`
`10.
`
` 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. at 1. 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
`
`
`
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`Patent 6,335,031 B1
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`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.
`
`2.
`
`Analysis
`
`a.
`
`Claims 1 and 7
`
`Petitioner asserts that Enz teaches a composition that meets every
`
`limitation of claims 1 and 7, except the addition of an antioxidant. Pet. 43–
`
`44. Specifically, Petitioner asserts that Enz discloses in Example 2 a
`
`pharmaceutical composition, e.g., a transdermal device, comprising the
`
`hydrogen tartrate salt of rivastigmine, i.e., (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 30–31. Petitioner
`
`asserts also that Enz discloses a daily dosage of from about 0.1 to about 25
`
`mg of rivastigmine, i.e., a therapeutically effective amount of Compound A.
`
`Id. at 31 (citing Ex. 1002, 10). Patent Owner does not dispute that Enz
`
`discloses those limitations of 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, that along
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`with the knowledge generally available to one of ordinary skill in the art, it
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`would have been obvious to a person of ordinary skill in the art at the time
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`of the invention who endeavored to formulate rivastigmine into a
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`transdermal patch, as taught by Enz, to have added an antioxidant as taught
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`by Sasaki.
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`Petitioner, relying on the declaration testimony of Dr. Kydonieus,
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`asserts that Sasaki provides a person of ordinary skill in the art a reasonable
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`expectation that the rivastigmine transdermal patch formulation taught by
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`Enz would be unstable during long-term storage of two to three years. Pet.
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`46–47 (citing Ex. 1010 ¶ 85). Specifically, Petitioner asserts that Enz serves
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`as a starting point for formulating a rivastigmine transdermal patch, but does
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`not provide stability data or any discussion of susceptibility to oxidation, for
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`the product. Id. at 46. Relying upon the declaration testimony of Dr.
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`Kydonieus, Petitioner asserts that those having skill in the art would have
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`“strive[d] to develop stable pharmaceutical products with a commercially
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`viable shelf life.” Id. at 47 (quoting Ex. 1010 ¶ 86). In furtherance of that
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`goal, according to Petitioner and Dr. Kydonieus, “one of the first steps a
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`person of ordinary skill in the art would have taken when formulating a drug
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`is to investigate the stability of the active component.” Id. at 45–46 (citing
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`Ex. 1010 ¶ 83).
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`Petitioner asserts that Sasaki informs that investigation. Pet. 46–47.
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`In particular, Petitioner asserts that Sasaki teaches that compounds having an
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`amino group can undergo oxidative decomposition over the shelf life of the
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`product when the product comprises an acrylic adhesive. Id. at 46 (citing
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`Ex. 1005, 1; Ex. 1010 ¶ 85). According to Petitioner and Dr. Kydonieus,
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`based on that teaching of Sasaki, a person of ordinary skill in the art would
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`have expected Enz’s transdermal patch to be unstable during long-term
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`storage because it comprised a drug having an amino group, i.e.,
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`rivastigmine, see Ex. 1011 ¶ 12, and it was formulated with an acrylic
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`adhesive, i.e., Durotack® 280-2416. Pet. 46 (citing Ex. 1010 ¶ 85).
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`Petitioner asserts further that the person of ordinary skill would have
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`been motivated to add an antioxidant to Enz’s rivastigmine transdermal
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`composition with a reasonable expectation of maintaining the stability of the
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`patch during long-term storage, as this is the precise solution disclosed by
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`Sasaki. Id. at 48. Moreover, at the time of the invention, antioxidants were
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`commonly included in pharmaceutical products, including transdermal
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`devices, to protect the drug and/or excipients from oxidative degradation.
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`Id. at 47 (citing Ex. 1010 ¶ 86; Ex. 1011 ¶ 50). Additionally, Petitioner
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`asserts that the person of skill in the art would have been motivated to add
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`the amount of antioxidant disclosed by Sasaki, which amount meets the
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`requirements of claims 1 and 7 of the ’031 patent. Id. at 48.
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`Patent Owner contends that Sasaki does not teach or suggest any
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`oxidative degradation problem for rivastigmine, and, therefore, a person of
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`ordinary skill in the art would not have been motivated to include an
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`antioxidant in the rivastigmine transdermal formulation disclosed by Enz.
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`PO Resp. 43. In particular, Patent Owner challenges Sasaki by asserting that
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`it does not mention rivastigmine and discloses only two exemplary amine-
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`containing compounds in transdermal formulations. Id. at 40–41.
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`According to Patent Owner, and Patent Owner’s declarant, Dr.
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`Klibanov, Sasaki’s disclosure of only two amine-containing compounds
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`“would not have taught or suggested to a [person of ordinary skill in the art]
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`as of 1998 that all amine-containing compounds break down in any acrylic
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`adhesive.” Id. at 41 (citing Ex. 2012 ¶¶ 156–158). Specifically, Patent
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`Owner asserts that a person of skill in the art would not reasonably have
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`predicted from the presence of an amine group in rivastigmine’s structure
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`that rivastigmine would oxidatively degrade under pharmaceutically relevant
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`conditions.8 Id. at 41–42 (citing Ex. 2012 ¶¶ 130–137, 150, 156.). Rather,
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`Patent Owner asserts, only “the structure of the molecule as a whole matters
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`to its chemical stability” and “whether a compound will degrade in a
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`particular formulation cannot be predicted in advance of testing.” Id. at 42
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`(citing Ex. 2012 ¶¶ 130–137, 156). According to Patent Owner, both of
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`Petitioner’s declarants, Dr. Kydonieus and Dr. Schöneich, agree that it
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`cannot be predicted whether a compound will degrade in a particular
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`formulation in advance of testing, and that Dr. Kydonieus “admitted that he
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`could not be certain whether rivastigmine would necessarily undergo
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`oxidative degradation in any acrylic adhesive.” Id. (citing Ex. 1025, 95:24–
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`96:18, 232:6–13, 258:8–13, 283:12–284:19; Ex. 1029, 53:10–17).
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`Additionally, Patent Owner asserts that contrary to Sasaki’s teaching,
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`“there were numerous amine-containing drug compounds not reported to
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`contain antioxidants in their commercial formulations–including one in a
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`transdermal formulation using acrylic adhesives.” PO Resp. 42 (citing Ex.
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`2012 ¶¶ 133–135, 157; Ex. 2022, 884). Patent Owner asserts also that Enz
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`contradicts Sasaki by not teaching or suggesting that rivastigmine will break
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`down in its transdermal formulation comprising an acrylic adhesive. Id. at
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`43 (citing Ex. 2012 ¶ 158).
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`After considering the record as a whole, we agree with Petitioner that
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`a person of ordinary skill in the art would have been motivated to add an
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`antioxidant to the transdermal rivastigmine formulation disclosed by Enz.
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`Sasaki teaches that if a drug is blended with a plaster comprising an acrylic
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`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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`acid adhesive, there is a tendency for the therapeutic effect of the preparation
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`to be greatly reduced due to the breakdown and dissipation of the drug. Ex.
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`1005, 1. Sasaki explained that this breakdown occurs “especially” when the
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`drug is a phenolic hydroxyl group containing compound, an amine
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`compound, or the like. Id. Based on those teachings by Sasaki and the
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`knowledge in the art that rivastigmine is a compound comprising an amino
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`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
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`be unstable during long-term storage.
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`That rationale for applying Sasaki’s teaching to the rivastigmine
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`transdermal formulation disclosed by Enz is not diminished by Patent
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`Owner’s assertion that Sasaki did not mention expressly rivastigmine or
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`provide more than two exemplary amine compounds. The applicability of
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`Sasaki’s teaching regarding the stability of amine compounds formulated
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`with acrylic adhesives is not limited to its examples. Merck & Co., Inc. v.
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`Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989). Moreover, a
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`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,
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`the reason to combine the teachings need only be an articulated with some
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`rational underpinning to support a conclusion of obviousness. KSR Int’l Co.
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`v. Teleflex Inc., 550 U.S. 398, 418 (2007) (citing Kahn, 441 F.3d at 988).
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`We determine also that Patent Owner’s argument does not overcome
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`Petitioner’s showing that, in view of Sasaki’s teaching, a person of ordinary
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`skill in the art would have been able to reasonably predict “in advance of
`
`testing” that rivastigmine would degrade when formulated with an acrylic
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`adhesive. PO Resp. 42. In support of its contention to the contrary, Patent
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`Owner relies upon the declaration of Dr. Klibanov. On this point, Dr.
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`Klibanov discusses five exemplary pharmaceutical compounds containing an
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`amine, but not reported to contain an antioxidant in the commercial
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`formulation. Ex. 2012 ¶ 133 (referring to ampicillin, hydroxyzine,
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`meclizine, mirtazapine, and benzquiamide). However, as acknowledged by
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`Dr. Klibanov, id. ¶ 134, none of those five examples referred to a
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`transdermal formulation including an acrylic adhesive, so as to make them
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`relevant to Sasaki’s disclosure.
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`Dr. Klibanov discusses next two compounds containing an amine and
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`formulated into commercial transdermal products that he asserts were not
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`reported to contain antioxidants prior to the claimed invention. Id. ¶ 135
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`(referring to Duragesic® comprising fentanyl and Trans-derm Scop®
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`comprising scopolamine). Referring to the Physician’s Desk Reference
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`(“PDR”), Dr. Klibanov takes the position that the commercial formulations
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`for transdermal devices comprising those compounds are not reported to
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`undergo oxidative degradation. Id. ¶¶ 135–138 (citing, e.g., the 1997 PDR,
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`Ex. 2022, 890–91, 1336–40). However, Dr. Klibanov has not described
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`those formulations as including an ac