UNITED STATES PATENT AND TRADEMARK OFFICE
`_________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_________________________________
`
`
`NOVEN PHARMACEUTICALS, INC.,
`Petitioner
`
`v.
`
`NOVARTIS AG AND LTS LOHMANN THERAPIE-SYSTEME AG,
`Patent Owners
`
`_________________________________
`
`
`Inter Partes Review No.: 2014-00550
`
`
`PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT 6,335,031 UNDER
`35 U.S.C. §§ 311-319 AND 37 C.F.R. § 42
`
`
`
`

`

`TABLE OF CONTENTS
`
`
`TABLE OF CONTENTS ........................................................................................... i
`
`LIST OF EXHIBITS ................................................................................................ iii
`
`I.
`
`MANDATORY NOTICES ............................................................................. 1
`
`A.
`
`B.
`
`C.
`
`D.
`
`Real Party-In-Interest ............................................................................ 1
`
`Related Matters ...................................................................................... 1
`
`Lead and Back-Up Counsel ................................................................... 2
`
`Service Information ............................................................................... 2
`
`II.
`
`III.
`
`GROUNDS FOR STANDING ........................................................................ 3
`
`IDENTIFICATION OF CHALLENGE AND STATEMENT OF THE
`PRECISE RELIEF REQUESTED .................................................................. 3
`
`IV. THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW ............. 3
`
`V.
`
`STATEMENT OF REASONS FOR THE RELIEF REQUESTED ............... 4
`
`A.
`
`B.
`
`C.
`
`Level of Ordinary Skill in the Art ......................................................... 5
`
`Claim Construction................................................................................ 6
`
`Scope and Content of the Prior Art .....................................................10
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`Rivastigmine Was Being Developed for the Treatment of
`Alzheimer’s Disease .................................................................10
`
`Rosin Taught the Use of Antioxidants in Compositions
`Comprising RA7 (Racemic Rivastigmine) ...............................11
`Elmalem Taught Adding Antioxidants to a Compositions
`Comprising RA7 to Prevent Oxidation .....................................12
`Enz Taught Transdermal Rivastigmine Compositions ............13
`
`Ebert Taught a Transdermal Drug Delivery System For
`Liquid, Oxidizable Drugs .........................................................14
`
`i
`
`

`

`6.
`
`7.
`
`Sasaki Taught Using the Antioxidant Tocopherol to
`Promote Storage Stability of the Active Ingredient in
`Transdermal Compositions .......................................................16
`
`The Handbook of Pharmaceutical Excipients Detailed
`Common Antioxidants Used in Approved
`Pharmaceutical Compositions ..................................................17
`
`D. Ground 1: Claim 15 is Unpatentable as Anticipated by
`Elmalem ...............................................................................................19
`
`E.
`
`The Challenged Claims are Unpatentable as Obvious Over the
`Prior Art ...............................................................................................22
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`There was motivation to select rivastigmine and modify
`existing rivastigmine treatments ...............................................22
`
`Ground 2: Claims 16 and 18 are Unpatentable as
`Obvious Over Elmalem and the Handbook ..............................24
`
`Ground 3: Claims 1, 2, 7, 15, and 18 are Obvious Over
`Enz and the Handbook, Optionally in View of Rosin
`and/or Elmalem and/or Ebert ....................................................30
`
`Ground 4: Dependent Claims 3 and 16 are Unpatentable
`as Obvious Over Enz and the Handbook and/or Rosin
`and/or Ebert ...............................................................................41
`
`Ground 5: The Challenged Claims Are Unpatentable As
`Obvious over Enz and Sasaki ...................................................43
`
`VI. CONCLUSION ..............................................................................................52
`
`
`
`
`
`
`ii
`
`

`

`
`
`LIST OF EXHIBITS
`
`Noven
`Exhibit
`No.
`Ex. 1001 U.S. Patent No. 6,335,031, issued January 1, 2002
`
`Description
`
`Ex. 1002 UK Patent Application GB 2,203,040 A, to Enz, published October
`
`12, 1988 (“Enz”)
`
`Ex. 1003 Handbook of Pharmaceutical Excipients, A. Wade and P. J. Weller
`
`(eds.) 1994, 2nd Edition, The Pharmaceutical Press London (the
`
`“Handbook”)
`
`Ex. 1004 Japanese Patent Application Publication No. JP 59-184121 to
`
`Sasaki et al., published October 19, 1984
`
`Ex. 1005 Certified English Translation of Japanese Patent Application
`
`Publication No. JP 59-184121 to Sasaki et al. (“Sasaki”)
`
`Ex. 1006 PCT Publication No. WO 95/024172 to Ebert et al, published
`
`September 14, 1995 (“Ebert”)
`
`Ex. 1007 Carey & Sundberg, ADVANCED ORGANIC CHEMISTRY, 2nd
`
`ed. Part A: Structure and Mechanism, Plenum Press, New York,
`
`1984, pp. 652
`
`iii
`
`

`

`Ex. 1008 U.S. Patent 4,948,807 (“Rosin”)
`
`Ex. 1009 Elmalem et al. 1991, Neuropharmacology 30: 1059-1064
`
`(“Elmalem”)
`
`Ex. 1010 Declaration of Agis Kydonieus, Ph.D.
`
`Ex. 1011 Declaration of Christian Schöneich, Ph.D.
`
`Ex. 1012 “Safety/Tolerability Trial of SDZ ENA 713 in Patients with
`
`Probable Alzheimer’s Disease,” John J. Sramek et al., Life
`
`Sciences, Vol. 58, No. 15, pp. 1201-1207 (1996) (“Sramek”)
`
`Ex. 1013 “New acetylcholinesterase inhibitor shows promise in largest
`
`Alzheimer’s trial to date,” Formulary, Vol. 32, Dec. 1997
`
`(“Formulary Article”)
`
`Ex. 1014 ICH Topic Q 1 A, Stability Testing Guidelines: Stability Testing
`
`of New Drug Substances and Products (CPMP/ICH/380/95)
`
`Ex. 1015 Connors, Amidon, & Stella, Oxidation and Photolysis in Chemical
`
`Stability of Pharmaceuticals – A Handbook for Pharmacists (2nd
`
`Edition), John Wiley & Sons, NY (1986), pp. 82-114
`
`Ex. 1016 Howard C. Ansel, Introduction to Pharmaceutical Dosage Forms,
`
`iv
`
`

`

`4th Edition, Lea & Febiger, Philadelphia (1985), pp. 83-116
`
`Ex. 1017 Ho-Leung Fung, Chapter 7 – Chemical Kinetics and Drug Stability
`
`in MODERN PHARMACEUTICS (G.S. Banker and C.T. Rhodes,
`
`eds.), Marcel Dekker, NY (1978), pp. 227-62
`
`Ex. 1018 Miguel-Hidalgo, J., 2000, Current Opinion in CPNS Investigations
`
`Drugs, 2000 2(4):438-453
`
`Ex. 1019 Boccardi G. et al. Photochemical Iron(III)-Mediated Autoxidation
`
`of Dextromethorphan. Chemical & Pharmaceutical Bulletin. Vol.
`
`37, 308–310 (1989)
`
`Ex. 1020 Bateman, L., Olefin Oxidation, Quarterly Review (1954) Vol. 8,
`
`pp. 147–167
`
`Ex. 1021 Linnell, R.H., The Oxidation of Nicotine. I. Kinetics of the Liquid
`
`Phase Reaction Near Room Temperature. Tobacco Science, Vol.
`
`4, pp. 89–90 (1960)
`
`Ex. 1022 Resume/Curriculum Vitae of Agis Kydonieus, Ph.D.
`
`Ex. 1023 Resume/Curriculum Vitae of Christian Schöneich, Ph.D.
`
`Ex. 1024 U.S. Patent No. 5,602,176, issued Feb. 11, 1997
`
`v
`
`

`

`Pursuant to 35 U.S.C. §§ 311–319 and 37 C.F.R. § 42, Noven
`
`Pharmaceuticals, Inc. (“Petitioner”) petitions for Inter Partes Review (“IPR”) of
`
`claims 1-3, 7, 15, 16, and 18 of U.S. Patent No. 6,335,031 to Asmussen et al.,
`
`titled “TTS containing an antioxidant” (“the ’031 patent,” Ex. 1001). Concurrently
`
`filed herewith is a Power of Attorney pursuant to 37 C.F.R. § 42.10(b). The Office is
`
`authorized to charge Deposit Account 11-0600 for the fee set forth in 37 C.F.R. §
`
`42.15(a), and is authorized to charge any additional fees to the same account.
`
`I. MANDATORY NOTICES
`
`A. Real Party-In-Interest
`
`Noven Pharmaceuticals, Inc., Noven Therapeutics, LLC, and Hisamitsu
`
`Pharmaceutical Co., Inc. are the real parties-in-interest for Petitioner.
`
`B. Related Matters
`
`The ’031 patent is being asserted in the following patent infringement
`
`lawsuits: (1) Novartis Pharm. Corp. et al. v. Par Pharm. Inc. et al., 1:11-cv-01077
`
`(D. Del.); (2) Novartis Pharm. Corp. et al. v. Watson Labs. Inc. et al., No. 1:11-cv-
`
`01112 (D. Del.); (3) Novartis Pharm. Corp. et al. v. Alvogen Pine Brook Inc. et
`
`al., 1:13-cv-00052 (D. Del.); (4) Novartis Pharm. Corp. et al. v. Alvogen Pine
`
`Brook Inc. et al., 1:13-cv-00370 (D. Del.); (5) Novartis Pharm. Corp. et al. v.
`
`Actavis, Inc. et al., No. 1:13-cv-00371 (D. Del.); (6) Novartis Pharm. Corp. et al.
`
`v. Noven Pharm. Inc., 1:13-cv-00527 (D. Del.); (7) Novartis Pharm. Corp. et al. v.
`
`1
`
`

`

`Par Pharm. Inc. et al., No. 1:13-cv-01467 (D. Del.); and (8) Novartis Pharm. Corp.
`
`et al. v. Noven Pharm. Inc., 1:14-cv-00111 (D. Del.).
`
`The ’031 patent is the parent to U.S. Application 09/747,519, now U.S. Patent
`
`6,316,023 (“the ’023 patent”). The ’023 patent is also asserted in each of the above-
`
`listed lawsuits. The ’023 patent is also the subject of a petition for Inter Partes
`
`Review, IPR2014-00549, filed on April 2, 2014.
`
`C. Lead and Back-Up Counsel
`
`Lead Counsel
`Steven J. Lee
`(Reg. No. 31,272)
`KENYON & KENYON LLP
`One Broadway
`New York, NY 10004-1007
`slee@kenyon.com
`Tel: 212-908-6305
`Fax: 212-425-5288
`
`Back-up Counsel
`Cynthia Lambert Hardman
`(Reg. No. 53,179)
`KENYON & KENYON LLP
`One Broadway
`New York, NY 10004-1007
`chardman@kenyon.com
`Tel: 212-908-6370
`Fax: 212-425-5288
`
`D.
`
`Service Information
`
`Please direct all correspondence to lead counsel at the contact information
`
`above. Petitioner consents to service by electronic mail at slee@kenyon.com and
`
`chardman@kenyon.com.
`
`2
`
`

`

`II. GROUNDS FOR STANDING
`
`As required by 37 C.F.R. § 42.104(a), Petitioner certifies that the ’031
`
`patent is available for IPR and that the Petitioner is not barred or estopped from
`
`requesting IPR on the grounds identified herein.
`
`III.
`
`IDENTIFICATION OF CHALLENGE AND STATEMENT OF THE
`PRECISE RELIEF REQUESTED
`
`Petitioner requests inter partes review and cancellation of claims 1-3, 7, 15,
`
`16, and 18 of the ’031 patent on one or more of the grounds under 35 U.S.C. §§
`
`102 and 103 set forth herein. Petitioner’s detailed statement of the reasons for the
`
`relief requested is set forth below in the section titled “Statement of Reasons for
`
`Relief Requested.” In accordance with 37 C.F.R. § 42.6(c), copies of the exhibits
`
`are filed herewith. In addition, this Petition is accompanied by the declarations of
`
`Agis Kydonieus, Ph.D. (Ex. 1010) and Christian Schöneich, Ph.D. (Ex. 1011).
`
`IV. THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW
`
`A petition for inter partes review must demonstrate “a reasonable
`
`likelihood that the petitioner would prevail with respect to at least 1 of the claims
`
`challenged in the petition.” 35 U.S.C. § 314(a). This Petition meets this
`
`threshold. As explained below, for each of the grounds of unpatentability
`
`proposed below, there is a reasonable likelihood that Petitioner will prevail with
`
`respect to at least one of the challenged claims.
`
`3
`
`

`

`V.
`
`STATEMENT OF REASONS FOR THE RELIEF REQUESTED
`
`The challenged claims of the ’031 patent are generally directed to
`
`pharmaceutical compositions, including transdermal devices, comprising rivastigmine
`
`and a specified amount of antioxidant.
`
`Prior to the ’031 patent, the compound rivastigmine was patented. The use of
`
`rivastigmine to treat Alzheimer’s disease was patented. Compositions containing
`
`rivastigmine, including transdermal devices, were also patented. The sole alleged
`
`advance claimed in the ’031 patent is adding an antioxidant to compositions containing
`
`rivastigmine. The ’031 patent asserts that the inventors were the first to recognize that
`
`rivastigmine was subject to oxidative degradation and that compositions containing
`
`rivastigmine required an antioxidant. (Ex. 1001 at 1:22-24; 4:8-10.) But as will be
`
`discussed, that was not so.
`
`Compositions containing an antioxidant and a racemic mixture that includes
`
`rivastigmine were described in the prior art, as were methods of combining
`
`rivastigmine with antioxidant per some of the challenged claims, demonstrating that it
`
`was known that rivastigmine was susceptible to oxidative degradation. Further, one of
`
`ordinary skill in the art would have recognized, based on the chemical structure of
`
`rivastigmine, that it was susceptible to oxidative degradation. The person of ordinary
`
`skill would have reasonably expected that this oxidative degradation could be addressed
`
`with antioxidants, and would have been motived to use conventional amounts of
`
`4
`
`

`

`antioxidants taught in the prior art, which overlap with the claimed range. Accordingly,
`
`the person of ordinary skill would have been motivated to combine rivastigmine with
`
`the claimed amount of antioxidant in a pharmaceutical composition, and thus the
`
`claimed subject matter as a whole would have been obvious to a person of ordinary
`
`skill in the art at the time of the alleged invention.
`
`A. Level of Ordinary Skill in the Art
`
`The subject matter of the ʼ031 patent draws from several disciplines, and as
`
`such, the patent is directed to a collaborative team of individuals in which each
`
`person would have been able to draw upon the experiences and knowledge of the
`
`others. In particular, the person of ordinary skill in the art at the time of the
`
`alleged invention would have been a chemist, chemical engineer, polymer chemist
`
`or pharmaceutical chemist working to develop pharmaceutical formulations,
`
`including transdermal drug delivery systems. The person of ordinary skill would
`
`have been familiar with testing that accompanies the development of any
`
`pharmaceutical formulation, including testing for efficacy and stability. The
`
`person of ordinary skill would have been familiar with excipients typically
`
`employed in pharmaceutical formulations, including transdermal devices. The
`
`person of ordinary skill would have had knowledge of organic chemistry, or
`
`would have collaborated with a person having knowledge of organic chemistry,
`
`5
`
`

`

`and would have been able to predict the physical properties of a compound based
`
`on its chemical structure. (Ex. 1010 ¶ 9.)
`
`B. Claim Construction
`
`Claim 1 of the ’031 patent reads:
`
`1. A pharmaceutical composition comprising
`
`(a) 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),
`
`(b) about 0.01 to about 0.5 percent by weight of an
`antioxidant, based on the weight of the composition, and
`
` (c) a diluent or carrier.
`
`Claim 2 depends from claim 1 and adds that the amount of Compound A in
`
`the pharmaceutical composition is between 1 and 40% by weight. Claim 3
`
`depends from claim 1 and identifies specific antioxidants. Claim 7 depends from
`
`claim 1 and is directed to a transdermal device, wherein the pharmaceutical
`
`composition is supported by a substrate.
`
`Independent claim 15 is directed to a method of stabilizing Compound A
`
`comprising forming a composition by combining Compound A with an amount of
`
`antioxidant effective to stabilize Compound A from degradation. Claim 16
`
`depends on claim 15 and identifies specific antioxidants. Claim 18 depends on
`
`6
`
`

`

`claim 15 and specifies that the antioxidant is present in an amount of from about
`
`0.01–0.5% by weight based on the weight of the composition.
`
`The terms in the challenged claims are presumed to take on their ordinary
`
`and customary meaning based on the broadest reasonable interpretation of the
`
`claim language in view of the specification. Under this standard, the Patentee has
`
`not acted as its own lexicographer for any of the claim terms, nor has it attributed
`
`any special meaning to the any of the claim terms.
`
`For example, when the broadest reasonable interpretation is applied, the
`
`term “pharmaceutical composition” means a composition suitable for
`
`pharmaceutical use, e.g., for administration to a patient. (See, e.g., Ex. 1001 at
`
`col. 3, line 60–col. 4, line 4; col. 4, lines 35–54.) The composition may be
`
`designed for administration to a subject in any acceptable way, e.g., orally,
`
`parenterally (e.g. by injection), or topically (including via transdermal
`
`administration). It would be inappropriate to limit claim 1 to transdermally-
`
`administered compositions because nothing in the claim language or specification
`
`requires such a construction, and further, such a construction would render claims
`
`1 and 7 identical in scope.
`
`The term “antioxidant” means a compound that reduces or prevents the
`
`oxidative decomposition of other compounds. (See, e.g., Ex. 1001 at col. 4, lines
`
`20–30; Ex. 1010 ¶ 15.) In the context of the challenged claims, which are directed
`
`7
`
`

`

`to compositions comprising rivastigmine, the antioxidant reduces the amount of
`
`oxidative decomposition of rivastigmine relative to a composition which does not
`
`contain said compound. (See, e.g., Ex. 1001 at col. 1, lines 29–33.)
`
`The term “diluent or carrier” means inactive ingredient(s) of the
`
`pharmaceutical composition that aid(s) in the administration of the drug. (See,
`
`e.g., id. at col. 1, line 44 – col. 2, line 9.)
`
`The term “transdermal device” means medical device for systemic drug
`
`administration through skin. (See, e.g., id. at col. 5, lines 31–37 and col. 6, lines
`
`59–62.)
`
`The term “substrate” means a backing layer providing structural support
`
`for the pharmaceutical composition. (See, e.g., id. at col. 5, lines 55–59.)
`
`The term “adhesive layer” means layer of adhesive.
`
`The term “stabilizing” means reducing degradation. (See, e.g., id. at col. 4,
`
`lines 5–30.)
`
`The term “amount of antioxidant effective to stabilize Compound A
`
`from degradation” means an amount of antioxidant that reduces the oxidative
`
`degradation of Compound A. (See, e.g., id. at col. 1, lines 29-33.)
`
`For clarity, the term “(S)-N-ethyl-3-{(1-dimethylamino) ethyl}-N-
`
`methylphenyl carbamate” refers to rivastigmine, which has the following
`
`chemical structure:
`
`8
`
`

`

`CH3
`
`O
`
`N
`CH3
`
`CH3
`N
`
`CH3
`
`(S)
`
`O
`
`CH3
`rivastigmine
`
`H
`
`
`
`Rivastigmine is the S-enantiomer of a racemic compound known as RA7. (Ex.
`
`1010 ¶ 15; Ex. 1002 at 3.) As a racemate, RA7 is comprised of an equal mixture of
`
`rivastigmine and its enantiomer ent-rivastigmine, or (R)-rivastigmine:
`
`O
`
`N
`CH3
`
`O
`
`RA7
`
`CH3
`N
`
`CH3
`
`=
`
`CH3
`
`H
`
`CH3
`
`(Id.)
`
`CH3
`
`CH3
`
`O
`
`N
`CH3
`
`O
`
`N
`CH3
`
`O
`
`+
`
`O
`
`CH3
`N
`
`CH3
`
`(S)
`
`CH3
`
`H
`
`CH3
`N
`
`CH3
`
`(R)
`
`CH3
`
`H
`
`rivastigmine
`
`ent-rivastigmine
`
`
`
`In addition, each of the challenged claims contains the transition
`
`“comprising.” Accordingly, while the claims require the presence of
`
`rivastigmine, they do not exclude other components from the claimed
`
`composition, including ent-rivastigmine. The challenged claims do not recite a
`
`degree of optical purity, nor does the specification suggest that the claims be
`
`limited to a single isomer. As such, the claims embrace compositions containing
`
`both rivastigmine and its enantiomer, including compositions containing racemic
`
`RA7.
`
`9
`
`

`

`Petitioner’s positions regarding the scope of the claims should not be
`
`construed as an assertion regarding the appropriate claim scope in other
`
`adjudicative forums, where a different claim interpretation standard may apply.
`
`C.
`
`Scope and Content of the Prior Art
`
`1.
`
`Rivastigmine Was Being Developed for the Treatment of
`Alzheimer’s Disease
`
`At the time of the alleged invention, the person of ordinary skill in the art
`
`would have been aware of the compound rivastigmine (also known as ENA 713),
`
`and that it was being developed as a treatment for Alzheimer’s disease. (See, e.g.,
`
`“Safety/Tolerability Trial of SDZ ENA 713 in Patients with Probable Alzheimer’s
`
`Disease,” John J. Sramek et al., Life Sciences, Vol. 58, No. 15, pp. 1201-1207,
`
`1996 (“Sramek,” Ex. 1012 at 1); “New acetylcholinesterase inhibitor shows
`
`promise in largest Alzheimer’s trial to date,” Formulary, Vol. 32, Dec. 1997 (the
`
`“Formulary Article,” Ex. 1013 at 3); see also Ex. 1010 ¶26.) Both Sramek and the
`
`Formulary Article are prior art under 35 U.S.C. § 102(b), and were not of record
`
`during the ’031 patent prosecution.
`
`Rivastigmine was reportedly well-tolerated, with the majority of patients
`
`experiencing only mild-to-moderate adverse events. (Ex. 1012 at 6; Ex. 1013 at
`
`3.) Rivastigmine was characterized as an improvement over tacrine, a first-
`
`generation acetylcholinesterase inhibitor used to treat Alzheimer’s disease. (Ex.
`
`1012 at 1-2.)
`
`10
`
`

`

`2.
`
`Rosin Taught the Use of Antioxidants in Compositions
`Comprising RA7 (Racemic Rivastigmine)
`
`
`
`U.S. Patent 4,948,807 (“Rosin,” Ex. 1008), titled “Phenyl Carbamates,”
`
`issued on August 14, 1990 and is prior art under 35 U.S.C. § 102(b).
`
`
`
`Rosin discloses a genus of acetylcholinesterase inhibitors, with one of the
`
`seven preferred species being RA7.1 (Ex. 1008 at, e.g., 5:44-45, 14:17-19, 10:9-27;
`
`see also Ex. 1010 ¶¶ 28-29.) Rosin teaches that these compounds are superior to
`
`physostigmine, a known acetylcholinesterase inhibitor, because they have, e.g.,
`
`greater in vivo activity, slower metabolic degradation, higher lipid solubility, and
`
`more efficient absorption. (Id. at 11:28-35.)
`
`Rosin teaches that the compounds may be administered by conventional
`
`methods, and that when they are administered orally or parenterally (e.g., by
`
`injection), they may be combined with conventional excipients such as carriers,
`
`binders, preservatives, and stabilizers. (Id. at 7:15-26.) Rosin also teaches that
`
`“[b]uffers, preservatives, antioxidants and the like can be incorporated as
`
`required,” and identifies sodium metabisulphite and ascorbic acid as “preferred
`
`antioxidants.” (Id. at 7:45-53.)
`
`
`1
`
`As noted above, RA7 is a racemic mixture that includes rivastigmine. (Ex.
`
`1010 ¶ 15.)
`
`11
`
`

`

`3.
`
`Elmalem Taught Adding Antioxidants to a Compositions
`Comprising RA7 to Prevent Oxidation
`
`Elmalem is an article titled “Antagonism of Morphine-Induced Respiratory
`
`Depression by Novel Anticholinesterase Agents,” by Ester Elmalem and others,
`
`published in 1991 in Neuropharmacology 30:1059-1064 (“Elmalem,” Ex. 1009).
`
`Elmalem is prior art under 35 U.S.C. § 102(b), and was not of record during the
`
`’031 patent prosecution.
`
`Elmalem describes experiments designed to compare three drugs, RA6, RA7,
`
`and RA15, to physostigmine with respect to the drugs’ ability to counteract
`
`morphine-induced respiratory depression in rabbits. (Ex. 1009 at 1; see also Ex.
`
`1010 ¶¶ 30-31.) The authors prepared aqueous solutions of physostigmine, RA6,
`
`RA7, and RA15 with sodium metabisulphite. (Ex. 1009 at 2.) Elmalem explicitly
`
`states that the sodium metabisulphite was added to prevent oxidation of the drug:
`
`“All drugs were made up freshly in sterile saline, which included an equal weight
`
`of sodium metabisulphite, to prevent oxidation.” (Id.) (emphasis added).2
`
`
`2
`
`To avoid the clear teaching in Elmalem that the function of the antioxidants
`
`in the drug solutions was to “prevent oxidation,” the Patentees may argue that a
`
`person of ordinary skill in the art would have understood that physostigmine (one
`
`of the other tested drugs) required an antioxidant, and therefore an antioxidant had
`
`
`
`12
`
`

`

`4.
`
`Enz Taught Transdermal Rivastigmine Compositions
`
`Enz is U.K. Patent 2,203,040 to Albert Enz, titled “Phenyl carbamate,”
`
`published on October 12, 1988 (“Enz,” Ex. 1002). Enz is prior art under 35 U.S.C.
`
`§ 102(b).
`
`Enz teaches that the (-) enantiomer of the racemic compound RA7 is useful
`
`to treat cognitive diseases including Alzheimer’s disease. (Ex. 1002 at 10; see also
`
`Ex. 1010 ¶ 32.) Enz also teaches that the (-) enantiomer is superior to both the
`
`racemic mixture and the (+) enantiomer. (Ex. 1002 at 6.) Enz teaches that the (-)
`
`enantiomer can be obtained by converting the racemic RA7 into the diastereomeric
`
`tartrate salts, followed by selective crystallization of the (-) enantiomer. (Id. at 3,
`
`11.)
`
`Enz teaches that rivastigmine, either as the free base or acid addition salt,
`
`may be advantageously administered transdermally. (Id. at 4-9.) Enz teaches that
`
`the pharmacokinetic profile from transdermal administration is superior to that of
`
`either oral or subcutaneous administration. (Id. at 15-16.)
`
`
`
`to be added to all other test compositions, including the saline placebo, as a
`
`control. This argument is contrary to Elmalem’s clear statement that the
`
`antioxidant was added to the drugs to prevent oxidation. (Ex. 1009 at 2.)
`
`13
`
`

`

`Enz discloses an exemplary composition of rivastigmine suitable for
`
`transdermal administration. (Id. at 20, Example 2.) Rivastigmine tartrate
`
`(“Compound A”) is combined with Eudragit E 100 (a hydrophilic polymer),
`
`Durotack 280-2416 (an acrylic adhesive), and Brij 97 (a plasticizer) in a volatile
`
`organic solvent. (Id.) The viscous composition is spread on a polyester foil and
`
`the solvent is allowed to evaporate at room temperature. (Id.)
`
`5.
`
`Ebert Taught a Transdermal Drug Delivery System For
`Liquid, Oxidizable Drugs
`
`PCT Publication WO 95/24172, entitled “Drug-containing adhesive
`
`composite transdermal delivery device,” lists Charles D. Ebert and others as
`
`inventors, and published on September 14, 1995 (“Ebert,” Ex. 1006). It is prior art
`
`under 35 U.S.C. § 102(b), and was not of record during the ’031 patent
`
`prosecution.
`
`Ebert is directed to a transdermal drug delivery device for nicotine and other
`
`drugs. (Ex. 1006 at 3; see also Ex. 1010 ¶ 36.)3 Ebert teaches that conventional
`
`methods of preparing transdermal devices containing drugs such as nicotine are
`
`
`3
`
`As discussed below (pages 35 to 37), nicotine, which is susceptible to
`
`oxidation, is a good model for the susceptibility of rivastigmine to oxidation. See
`
`also Dr. Schöneich’s declaration, Ex. 1011, at paragraphs 56 to 57.
`
`14
`
`

`

`problematic for a variety of reasons. For example, Ebert teaches that because
`
`nicotine is volatile, it can evaporate if a drying step is employed, leading to
`
`reduced and uneven concentrations of the drug throughout the composition. (Id. at
`
`5.)
`
`To solve this problem, Ebert describes the preparation of a transdermal
`
`device that avoids the use of drying. (Id. at 7.) The drug, in gel form, is extruded
`
`onto one or two adhesive layers, one of which has an impermeable backing layer
`
`and the other of which has a peelable layer. The layers are then laminated together
`
`to produce the transdermal drug delivery system. (Id. at 7-8.) A schematic of the
`
`device is reproduced below:
`
`14 = drug impermeable backing layer
`
`18 = drug containing composite
`
`19 = distal adhesive layer
`
`20 = proximal adhesive layer
`
`21 = gelled drug layer
`
`
`
`22 = drug impermeable release layer
`
`(Id. at 1.)
`
`Ebert teaches that nicotine was known to oxidize readily in the presence of
`
`light and air, and that to minimize oxidation, the transdermal device should be keep
`
`in the dark and under an inert atmosphere. (Id. at 21.) Ebert also teaches that
`
`15
`
`

`

`oxidation during manufacturing may be further reduced by adding an antioxidant
`
`to the active gel, and that the most preferred antioxidant is butylated
`
`hydroxytoluene (BHT) in a range of 0.05-0.2% by weight. (Id.) Ebert teaches that
`
`other antioxidants such as butylated hydroxyanisole (BHA), sodium metabisulfite,
`
`EDTA, and α-tocopherol are also useful. (Id.)
`
`Although the exemplified device is described with respect to nicotine (id. at
`
`3), Ebert explicitly teaches that the device is suitable for any chemical or biological
`
`material that may be delivered transdermally. (Id. at 10-11 and 15.)
`
`6.
`
`Sasaki Taught Using the Antioxidant Tocopherol to
`Promote Storage Stability of the Active Ingredient in
`Transdermal Compositions
`
`Japanese Patent Application Publication No. JP 59-184121 to Sasaki et al.,
`
`titled “Acrylic Plaster,” published on October 19, 1984 (“Sasaki”). The original
`
`Japanese language document is Exhibit 1004, and a certified translation is Exhibit
`
`1005. Sasaki is prior art under 35 U.S.C. § 102(b). Sasaki was not of record
`
`during the ’031 patent prosecution.
`
`Sasaki is directed to methods of stabilizing pharmaceutical compounds in
`
`transdermal compositions. Sasaki teaches that when an active ingredient is
`
`combined with an acrylic adhesive, the drug will often oxidatively degrade upon
`
`long term (2-3 years) storage. (Ex. 1005 at 1; see also Ex. 1010 ¶ 40.) Sasaki
`
`notes that this degradation often cannot be prevented by protecting the composition
`
`16
`
`

`

`from light by using aluminum packaging, and that certain drugs, especially those
`
`drugs “having a phenolic hydroxyl group or an amino group,” are especially
`
`susceptible to oxidative degradation over this time frame. (Id. at 1.)
`
`Sasaki teaches that blending a tocopherol antioxidant into the composition
`
`prevents the drug from degrading. (Id. at 2.) Sasaki discloses using an amount of
`
`tocopherol of 0.005–5% by weight relative to the acrylic adhesive of the patch, and
`
`a preferred amount of 0.05–1 wt%. (Id.)
`
`7.
`
`The Handbook of Pharmaceutical Excipients Detailed
`Common Antioxidants Used in Approved Pharmaceutical
`Compositions
`
`
`
`The Handbook of Pharmaceutical Excipients (2nd Ed. 1994, Wade, A. and
`
`Weller, P.J., Eds., the “Handbook”) published in 1994. Excerpts of the Handbook
`
`are marked as Ex. 1003. The Handbook is prior art under 35 U.S.C. § 102(b), and
`
`was not of record during the ’031 patent prosecution.
`
`
`
`The Handbook is a reference textbook that lists inactive ingredients and their
`
`physical and chemical properties. (Ex. 1010 ¶ 42.) Persons of ordinary skill in the
`
`art routinely consult the Handbook to determine what excipients had been
`
`previously approved for use in pharmaceuticals and food products, and in what
`
`amounts. (Id.)
`
`The Handbook provides an overview of antioxidants (including ascorbic
`
`acid, butylated hydroxytoluene (BHT), α-tocopherol, and ascorbyl palmitate)
`
`17
`
`

`

`suitable for use in products intended for human use, and the concentrations at
`
`which they are commonly employed, as shown in Table 1:
`
`Antioxidant
`
`Concentration Typically Used in
`
`Citation in the
`
`Pharmaceutical Products
`
`Handbook (Ex. 1003)
`
`Ascorbic acid
`
`In aqueous formulations, 0.01–0.1 %
`
`p. 8
`
`w/v
`
`BHT
`
`In IV injections, 0.0009–0.002 % w/v
`
`pp. 19-20
`
`In topical formulations, 0.0075–0.1 %
`
`w/w
`
`α-tocopherol
`
`0.001 to 0.05 wt%
`
`Ascorbyl
`
`Not provided
`
`palmitate
`
`pp. 5-6
`
`pp. 12-13
`
`BHA
`
`In IV injections, 0.0002-0.0005 % w/v
`
`pp. 17-18
`
`In topical formulations, 0.005-0.02 %
`
`w/w
`
`Propyl gallate ≤0.1% % w/v
`
`pp. 21-23
`
`Table 1: Excerpt of Antioxidant Information from the Handbook of
`
`Pharmaceutical Excipients
`
`18
`
`

`

`D. Ground 1: Claim 15 is Unpatentable as Anticipated by Elmalem
`
`In the Elmalem reference, the authors report making two different
`
`compositions of RA7: one comprising 1 mg/kg RA7 and 1 mg/kg sodium
`
`metabisulphite in sterile saline, and the other comprising 2 mg/kg RA7 and 2
`
`mg/kg sodium metabisulphite in sterile saline. (Ex. 1009 at 2.) Elmalem
`
`explicitly states that the sodium metabisulphite was added to prevent oxidation of
`
`the drug: “All drugs were made up freshly in sterile saline, which included an
`
`equal weight of sodium metabisulphite, to prevent oxidation.” (Id.)
`
`Independent claim 15 is directed to a method of stabilizing Compound A
`
`comprising forming a composition by combining Compound A with an amount of
`
`antioxidant effective to stabilize Compound A from degradation. Elmalem meets
`
`every limitation of this claim. In Elmalem, two solutions of RA7 with an equal
`
`weight of antioxidant were reported. RA7 is comprised of an equal mixture of
`
`rivastigmine and its enantiomer ent-rivastigmine, or (R)-rivastigmine. (Ex. 1010 ¶
`
`15.) Accordingly, the ratio of rivastigmine to antioxidant on a wt/wt basis was
`
`0.5:1, or 67% antioxidant. Elmalem taught that this amount of rivastigmine was
`
`added to prevent oxidation (Ex. 1009 at 2), and indeed the Patentee discloses that
`
`a much smaller amount of antioxidant (0.01 to 0.5%) in a pharmaceutical
`
`composition comprising rivastigmine is sufficient to prevent oxidation. (Ex. 1001
`
`at 4:15–19.) Accordingl