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 IPR2014-005491
`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.
`
`
`
`

`

`IPR2014-00549
`Patent 6,316,023 B1
`
`
`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.
`
`
`
`2
`
`

`

`IPR2014-00549
`Patent 6,316,023 B1
`
`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.
`
`
`
`3
`
`

`

`IPR2014-00549
`Patent 6,316,023 B1
`
`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,
`
`
`
`4
`
`

`

`IPR2014-00549
`Patent 6,316,023 B1
`
`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.
`
`
`
`
`5
`
`

`

`IPR2014-00549
`Patent 6,316,023 B1
`
`Id. at 1:30–39.
`
`C. Illustrative Claims
`
`Independent claims 1 and 7 of the ’023 patent are illustrative of the
`
`claims at issue:
`
`A pharmaceutical composition comprising 1 to 40
`1.
`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.
`
`
`A transdermal device comprising a pharmaceutical
`7.
`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”)
`
`Handbook HANDBOOK OF PHARMACEUTICAL EXCIPIENTS
`(A. Wade & P.J. Weller eds., 2d ed. 1994)
`(“the Handbook”)
`
`Sasaki
`
`Ebert
`
`JP Patent Application 59-184121, published
`Oct. 19, 1984 (“Sasaki”)
`
`WO 95/24172, published Sept. 14, 1995
`(“Ebert”)
`
`Ex. 1002
`
`Ex. 1003
`
`Ex. 1005
`
`
`Ex. 1006
`
`
`
`6
`
`

`

`IPR2014-00549
`Patent 6,316,023 B1
`
`Kissel
`
`EP Patent Application 0155229A2, published
`Sept. 18, 1985 (“Kissel”)
`
`Rosin
`
`Elmalem
`
`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. 1007
`
`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
`
`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
`Enz, the Handbook, Rosin, and Ebert
`
`§ 103(a)
`
`1, 7
`
`§ 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
`
`
`
`7
`
`
`
`

`

`IPR2014-00549
`Patent 6,316,023 B1
`
`
`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
`
`
`
`8
`
`

`

`IPR2014-00549
`Patent 6,316,023 B1
`
`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.
`
`
`
`9
`
`

`

`IPR2014-00549
`Patent 6,316,023 B1
`
`
`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
`
`
`
`10
`
`

`

`IPR2014-00549
`Patent 6,316,023 B1
`
`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.
`
`
`
`11
`
`

`

`IPR2014-00549
`Patent 6,316,023 B1
`
`
`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
`
`
`
`12
`
`

`

`IPR2014-00549
`Patent 6,316,023 B1
`
`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
`
`
`
`13
`
`

`

`IPR2014-00549
`Patent 6,316,023 B1
`
`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.
`
`
`
`14
`
`

`

`IPR2014-00549
`Patent 6,316,023 B1
`
`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
`
`
`
`15
`
`

`

`IPR2014-00549
`Patent 6,316,023 B1
`
`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
`
`
`
`16
`
`

`

`IPR2014-00549
`Patent 6,316,023 B1
`
`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–
`
`
`
`17
`
`

`

`IPR2014-00549
`Patent 6,316,023 B1
`
`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
`
`
`
`18
`
`

`

`IPR2014-00549
`Patent 6,316,023 B1
`
`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 need