Filed: November 13, 2014
`
`
`Filed on behalf of:
`Mylan Pharmaceuticals Inc.
`Joseph M. Reisman
`Jay R. Deshmukh
`
`KNOBBE, MARTENS, OLSON & BEAR, LLP
`2040 Main Street, 14th Floor
`Irvine, CA 92614
`Fax: (949) 760-9502
`Ph.: (949) 760-0404
`E-mail: BoxMylan@knobbe.com
`
`
`
`By:
`
`
`
`
`
`
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________________________
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner
`
`v.
`
`NOVARTIS AG AND LTS LOHMANN THERAPIE-SYSTEME AG,
`Patent Owners
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Case No. TBD
`Patent 6,316,023
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT 6,316,023
`
`
`
`

`

`TABLE OF CONTENTS
`
`Page No.
`
`Exhibit list .................................................................................................................. v 
`
`I. 
`
`MANDATORY NOTICES ............................................................................. 1 
`
`A. 
`
`B. 
`
`C. 
`
`D. 
`
`Real Party-In-Interest ............................................................................ 1 
`
`Related Matters ...................................................................................... 1 
`
`Lead and Back-Up Counsel ................................................................... 3 
`
`Service Information ............................................................................... 3 
`
`II. 
`
`GROUNDS FOR STANDING ........................................................................ 4 
`
`IDENTIFICATION OF CHALLENGE AND STATEMENT OF THE
`III. 
`PRECISE RELIEF REQUESTED ............................................................................. 4 
`
`IV.  THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW .............. 4 
`
`V. 
`
`STATEMENT OF REASONS FOR THE RELIEF REQUESTED ............... 5 
`
`A. 
`
`B. 
`
`C. 
`
`Level of Ordinary Skill in the Art ......................................................... 6 
`
`Claim Construction ................................................................................ 7 
`
`Scope and Content of the Prior Art ..................................................... 11 
`
`1. 
`
`2. 
`
`3. 
`
`4. 
`
`5. 
`
`Rivastigmine Was Being Developed for the Treatment of
`Alzheimer’s Disease ................................................................ 11 
`
`Rosin Taught the Use of Antioxidants in Compositions
`Comprising RA7 (Racemic Rivastigmine) .............................. 12 
`Elmalem Taught Adding Antioxidants to a Composition
`Comprising RA7 to Prevent Oxidation .................................... 13 
`Enz Taught Transdermal Rivastigmine Compositions ........... 14 
`
`Ebert Taught a Transdermal Drug Delivery System For
`Liquid, Oxidizable Drugs ........................................................ 15 
`
`i
`
`

`

`TABLE OF CONTENTS
`(cont’d)
`
`Page No.
`
`6. 
`
`7. 
`
`Sasaki Taught Using the Antioxidant Tocopherol to Promote
`Storage Stability of the Active Ingredient in Transdermal
`Compositions ........................................................................... 17 
`
`The Handbook of Pharmaceutical Excipients Detailed
`Common Antioxidants Used in Approved Pharmaceutical
`Compositions ........................................................................... 18 
`
`8. 
`
`Kissel Disclosed a Transdermal Drug Delivery System With a
`Release Liner ........................................................................... 20 
`The Challenged Claims are Unpatentable as Obvious Over the Prior
`Art ........................................................................................................ 20 
`
`D. 
`
`1. 
`
`2. 
`
`3. 
`
`4. 
`
`5. 
`
`6. 
`
`There was Motivation to Select Rivastigmine and Modify
`Existing Rivastigmine Treatments .......................................... 21 
`
`Ground 1: Independent Claims 1 and 7 are Obvious Over Enz
`and the Handbook, Optionally in View of Rosin and/or
`Elmalem and/or Ebert .............................................................. 22 
`(1)  No Secondary Considerations Support Non-
`Obviousness .................................................................. 31 
`
`Ground 2: Dependent Claim 2 is Unpatentable as Obvious
`Over Enz and the Handbook and/or Rosin and/or Ebert ......... 34 
`
`Ground 3: Dependent Claims 4 and 5 are Unpatentable As
`Obvious Over Enz and the Handbook and/or Ebert ................ 36 
`
`Ground 4: Dependent Claim 8 is Unpatentable As Obvious
`Over Enz, the Handbook, and Ebert or Kissel ........................ 38 
`
`Ground 5: Claims 1, 2, 4, 5, and 7 Are Unpatentable As
`Obvious over Enz and Sasaki .................................................. 39 
`
`7. 
`
`Ground 6: Dependent Claim 8 is Unpatentable As Obvious
`Over Enz, Sasaki, and Ebert or Kissel .................................... 46 
`VI.  CONCLUSION .............................................................................................. 48
`
`ii
`
`

`

`TABLE OF AUTHORITIES
`
`Page No(s).
`
`Asyst Techs., Inc. v. Emtrak, Inc.,
`544 F.3d 1310 (Fed. Cir. 2008) .......................................................................... 33
`
`In re Boecsh,
`617 F.2d 272 (CCPA 1980) ................................................................................ 38
`
`In re Geisler,
`116 F.3d 1465 (Fed. Cir. 1997) .......................................................................... 30
`
`In re Kao,
`639 F.3d 1057 (Fed. Cir. 2011) .......................................................................... 33
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ...................................................................................... 33, 34
`
`MeadWestVaco Corp. v. Rexam Beauty & Closures, Inc.,
`731 F.3d 1258 (Fed. Cir. 2013) .......................................................................... 31
`
`Merck & Co. v. Teva Pharms. USA, Inc.,
`395 F.3d 1364 (Fed. Cir. 2005) .................................................................... 32, 33
`
`In re Peterson,
`315 F.3d 1325 (Fed. Cir. 2003) ...................................................................passim
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .......................................................................... 31
`
`OTHER AUTHORITIES
`35 U.S.C. § 102 .................................................................................................passim
`
`35 U.S.C. § 103 .......................................................................................................... 4
`
`35 U.S.C. § 311 .......................................................................................................... 1
`
`35 U.S.C. § 312 .......................................................................................................... 1
`
`35 U.S.C. § 313 .......................................................................................................... 1
`
`35 U.S.C. § 314 ...................................................................................................... 1, 4
`
`iii
`
`

`

`TABLE OF AUTHORITIES
`(cont’d)
`
`Page No(s).
`
`
`35 U.S.C. § 315 .......................................................................................................... 1
`
`35 U.S.C. § 316 .......................................................................................................... 1
`
`35 U.S.C. § 317 .......................................................................................................... 1
`
`35 U.S.C. § 318 .......................................................................................................... 1
`
`35 U.S.C. § 319 .......................................................................................................... 1
`
`37 C.F.R. § 42 ........................................................................................................ 1, 3
`
`37 C.F.R. § 42.10 ....................................................................................................... 1
`
`37 C.F.R. § 42.15 ....................................................................................................... 1
`
`37 C.F.R. § 42.100 et seq. .......................................................................................... 1
`
`37 C.F.R. § 42.104 ..................................................................................................... 4
`
`
`
`iv
`
`

`

`Mylan v. Novartis
`IPR Petition - U.S. Pat. 6,316,023
`
`
`EXHIBIT LIST
`
`Exhibit No.
`
`Description
`
`Ex. 1001
`
`U.S. Patent No. 6,316,023, issued November 13, 2001
`
`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
`
`European Patent Application No. 0155 229 A2 to Kissel et al.,
`published September 18, 1985 (“Kissel”)
`
`Ex. 1008
`
`U.S. Patent No. 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.
`
`Exhibit List, Page v
`
`

`

`Mylan v. Novartis
`IPR Petition - U.S. Pat. 6,316,023
`
`
`Exhibit No.
`
`Ex. 1012
`
`Ex. 1013
`
`Ex. 1014
`
`Ex. 1015
`
`Ex. 1016
`
`Ex. 1017
`
`Ex. 1018
`
`Description
`
`“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”)
`
`“New acetylcholinesterase inhibitor shows promise in largest
`Alzheimer’s trial to date,” Formulary, Vol. 32, Dec. 1997
`(“Formulary Article”)
`
`ICH Topic Q 1 A, Stability Testing Guidelines: Stability
`Testing of New Drug Substances and Products
`(CPMP/ICH/380/95)
`
`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
`
`Howard C. Ansel, Introduction to Pharmaceutical Dosage
`Forms, 4th Edition, Lea & Febiger, Philadelphia (1985), pp.
`83-116
`
`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
`
`Carey & Sundberg, ADVANCED ORGANIC CHEMISTRY, 2nd
`ed. Part A: Structure and Mechanism, Plenum Press, New York,
`1984, pp. 652
`
`Ex. 1019 Miguel-Hidalgo, J., 2000, Current Opinion in CPNS
`Investigations Drugs, 2000 2(4):438-453
`
`Ex. 1020
`
`Boccardi G. et al. Photochemical Iron(III)-Mediated
`Autoxidation of Dextromethorphan. Chemical &
`Pharmaceutical Bulletin. Vol. 37, 308–310 (1989)
`
`Exhibit List, Page vi
`
`

`

`Mylan v. Novartis
`IPR Petition - U.S. Pat. 6,316,023
`
`
`Exhibit No.
`
`Ex. 1021
`
`Ex. 1022
`
`Description
`
`Bateman, L., Olefin Oxidation, Quarterly Review (1954) Vol. 8,
`pp. 147–167
`
`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. 1023
`
`Resume/ Curriculum Vitae of Agis Kydonieus, Ph.D.
`
`Ex. 1024
`
`Resume/ Curriculum Vitae of Christian Schöneich, Ph.D.
`
`Ex. 1025
`
`U.S. Patent No. 5,602,176, issued Feb. 11, 1997
`
`Exhibit List, Page vii
`
`

`

`Mylan v. Novartis
`IPR Petition - U.S. Pat. 6,316,023
`
`
`
`
`Pursuant
`
`to 35 U.S.C. §§ 311–319 and 37 C.F.R. § 42, Mylan
`
`Pharmaceuticals Inc. (“Petitioner” or “Mylan”) petitions for Inter Partes Review
`
`(“IPR”) of claims 1, 2, 4, 5, 7, and 8 of U.S. Patent No. 6,316,023 to Asmussen et
`
`al., titled “TTS Containing an Antioxidant” (“the ’023 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 11-1410 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
`
`Mylan Inc., Mylan Technologies Inc., and Mylan Pharmaceuticals Inc. are
`
`the real parties-in-interest for Petitioner.
`
`B. Related Matters
`
`The ’023 patent is being asserted in the following patent infringement
`
`lawsuits: Novartis Pharm. Corp. et al. v. Mylan Inc. et al., 1:14-cv-00777 (D.
`
`Del.); Novartis Pharm. Corp. et al. v. Mylan Inc. et al., 1:14-cv-00106 (N.D.
`
`W.Va.); Novartis Pharm. Corp. et al. v. Noven Pharm. Inc., 1:13-cv-00527 (D.
`
`Del.); Novartis Pharm. Corp. et al. v. Noven Pharm. Inc., 1:14-cv-00111 (D.
`
`Del.); Novartis Pharm. Corp. et al. v. Par Pharm. Inc. et al., 1:11-cv-01077 (D.
`
`Del.); Novartis Pharm. Corp. et al. v. Watson Labs. Inc. et al., 1:11-cv-01112 (D.
`
`1
`
`

`

`Mylan v. Novartis
`IPR Petition - U.S. Pat. 6,316,023
`
`
`
`Del.); Novartis Pharm. Corp. et al. v. Alvogen Pine Brook Inc. et al., 1:13-cv-
`
`00052 (D. Del.); Novartis Pharm. Corp. et al. v. Alvogen Pine Brook Inc. et al.,
`
`1:13-cv-00370 (D. Del.); Novartis Pharm. Corp. et al. v. Actavis, Inc. et al., No.
`
`1:13-cv-00371 (D. Del.); Novartis Pharm. Corp. et al. v. Par Pharm. Inc. et al.,
`
`No. 1:13-cv-01467 (D. Del.); Novartis Pharm. Corp. et al. v. Zydus Noveltech
`
`Inc. et al., No. 1:14-cv-05405 (D. N.J.); Novartis Pharm. Corp. et al. v. Zydus
`
`Noveltech Inc. et al., No. 1:14-cv-01104 (D. Del.); Par Pharm. Inc. et al. v.
`
`Novartis Pharm. Corp. et al., 1:14-cv-00843 (D. Del.); Watson Labs Inc. v.
`
`Novartis Pharm. Corp et al., 14-1799 (C.A.F.C.); Novartis Pharm. Corp et al. v.
`
`Par Pharm. Inc. et al, 15-1061 (C.A.F.C.); Novartis Pharm. Corp et al. v. Par
`
`Pharm. Inc. et al, 15-1062 (C.A.F.C.); Par Pharm. Inc. v. Novartis Pharm Corp. et
`
`al., 15-1120 (C.A.F.C.); and Par Pharm. Inc. v. Novartis Pharm Corp. et al., 15-
`
`1121 (C.A.F.C.).
`
`The ’023 patent is also the subject of Inter Partes Review IPR2014-00549,
`
`filed by Noven Pharmaceuticals, Inc. on April 2, 2014 (“the Noven IPR”) and
`
`instituted on all proposed grounds of invalidity on October 14, 2014. Mylan has
`
`submitted herewith a Motion for Joinder, requesting that upon institution of this
`
`Petition, the present IPR be joined with the Noven IPR pursuant to 35 U.S.C. §
`
`315(c).
`
`2
`
`

`

`Mylan v. Novartis
`IPR Petition - U.S. Pat. 6,316,023
`
`
`
`The ’023 patent is a continuation of U.S. Application 09/291,498, now U.S.
`
`Patent 6,335,031 (“the ’031 patent”). The ’031 patent is also asserted in each of the
`
`above-listed lawsuits. The ’031 patent is also the subject of a petition for Inter
`
`Partes Review, IPR2014-00550, filed on April 2, 2014 by Noven Pharmaceuticals,
`
`Inc. Concurrent with this petition, Mylan is also filing a petition for Inter Partes
`
`Review of the ’031 patent.
`
`C. Lead and Back-Up Counsel
`
`Lead Counsel
`Joseph M. Reisman
`(Reg. No. 43,878)
`KNOBBE, MARTENS, OLSON &
`BEAR, LLP
` 2040 Main Street, 14th Floor
` Irvine, CA 92614
` Ph.: (949) 760-0404
` Fax: (949) 760-9502
` E-mail: BoxMylan@knobbe.com
`
`Back-up Counsel
`Jay R. Deshmukh
`(Reg. No. 34,507)
`KNOBBE, MARTENS, OLSON &
`BEAR, LLP
` 2040 Main Street, 14th Floor
` Irvine, CA 92614
` Ph.: (949) 760-0404
` Fax: (949) 760-9502
`E-mail: BoxMylan@knobbe.com
`
`
`
`D.
`
`Service Information
`
`Please direct all correspondence to lead counsel at the contact information
`
`above.
`
`Petitioner
`
`consents
`
`to
`
`service
`
`by
`
`electronic mail
`
`at
`
`BoxMylan@knobbe.com.
`
`
`
`
`
`3
`
`

`

`Mylan v. Novartis
`IPR Petition - U.S. Pat. 6,316,023
`
`
`II. GROUNDS FOR STANDING
`
`As required by 37 C.F.R. § 42.104(a), Petitioner certifies that the ’023
`
`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, 2, 4, 5,
`
`7, and 8 of the ’023 patent on one or more of the grounds under 35 U.S.C. § 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.
`
`4
`
`

`

`Mylan v. Novartis
`IPR Petition - U.S. Pat. 6,316,023
`
`
`V.
`
`STATEMENT OF REASONS FOR THE RELIEF REQUESTED
`
`The challenged claims of the ’023 patent are generally directed to pharmaceutical
`
`compositions, including transdermal devices, comprising rivastigmine and a specified
`
`amount of antioxidant.
`
`Prior to the ’023 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 ’023 patent is adding an antioxidant to compositions containing
`
`rivastigmine. The ’023 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 1:23-25; 4:11-13.) 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, 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 antioxidants
`
`5
`
`

`

`Mylan v. Novartis
`IPR Petition - U.S. Pat. 6,316,023
`
`
`taught in the prior art, which overlap with the claimed ranges. 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 ʼ023 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, and would have
`
`6
`
`

`

`Mylan v. Novartis
`IPR Petition - U.S. Pat. 6,316,023
`
`
`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 ’023 patent reads (spacing added for ease of reading):
`
`1.
`
`A pharmaceutical composition comprising
`
`1 to 40 weight percent of (S)-N-ethyl-3-[(1-dimethylamino)
`
`ethyl]-N-methylphenyl carbamate in the form of a free base or acid
`
`addition salt,
`
`0.01 to 0.5 weight percent of an antioxidant, and
`
`a diluent or carrier,
`
`wherein the weight percents are based on the total weight of the
`
`pharmaceutical composition.
`
`Claim 2 depends from claim 1 and identifies specific antioxidants. Claims 4
`
`and 5 depend from claim 1 and more narrowly claim the numeric range of
`
`antioxidant.
`
`Independent claim 7 is identical to claim 1, except the preamble adds
`
`reference to a transdermal device, i.e., “A transdermal device comprising a
`
`pharmaceutical composition comprising. . . .” Claim 8 depends from claim 7 and
`
`specifies additional features of the transdermal device, including a backing layer
`
`7
`
`

`

`Mylan v. Novartis
`IPR Petition - U.S. Pat. 6,316,023
`
`
`and release liner.
`
`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 Patentees have not
`
`acted as their own lexicographer for any of the claim terms, nor have they
`
`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 63–col. 4, line 7; 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
`
`24–34; Ex. 1010 ¶ 15.) In the context of the challenged claims, which are directed
`
`to compositions comprising rivastigmine, the antioxidant reduces the amount of
`
`8
`
`

`

`Mylan v. Novartis
`IPR Petition - U.S. Pat. 6,316,023
`
`
`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.,
`
`Ex. 1001 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., Ex. 1001 at col. 5, lines 34–40 and col. 6,
`
`lines 60–63.)
`
`For clarity,
`
`the
`
`term “(S)-N-ethyl-3-[(1-dimethylamino) ethyl]-N-
`
`methylphenyl carbamate” refers to rivastigmine, which has the following
`
`chemical structure:
`
`
`
`9
`
`

`

`Mylan v. Novartis
`IPR Petition - U.S. Pat. 6,316,023
`
`
`
`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:
`
`
`
`(Id.)
`
`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.
`
`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.
`
`10
`
`

`

`Mylan v. Novartis
`IPR Petition - U.S. Pat. 6,316,023
`
`
`
`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 ¶¶ 26-27.) Both Sramek
`
`and the Formulary Article are prior art under 35 U.S.C. § 102(b), and were not of
`
`record during the ’023 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.)
`
`11
`
`

`

`Mylan v. Novartis
`IPR Petition - U.S. Pat. 6,316,023
`
`
`
`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 ¶ 32.)
`
`12
`
`

`

`Mylan v. Novartis
`IPR Petition - U.S. Pat. 6,316,023
`
`
`
`3.
`
`Elmalem Taught Adding Antioxidants to a Composition
`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
`
`’023 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
`
`to be added to all other test compositions, including the saline placebo, as a
`
`13
`
`

`

`Mylan v. Novartis
`IPR Petition - U.S. Pat. 6,316,023
`
`
`
`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 ¶¶ 32-35.) 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 14-19.) Enz teaches
`
`that the pharmacokinetic profile from transdermal administration is superior to that
`
`of either oral or subcutaneous administration. (Id. at 15-16.)
`
`Enz discloses an exemplary composition of rivastigmine suitable for
`
`transdermal administration. (Id. at pg. 20, Example 2.) Rivastigmine tartrate
`
`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.)
`
`14
`
`

`

`Mylan v. Novartis
`IPR Petition - U.S. Pat. 6,316,023
`
`
`(“Compound A,” see id. at 4) 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 ’023 patent prosecution.
`
`Ebert is directed to a transdermal drug delivery device for nicotine and other
`
`drugs. (Ex. 1006 at 3; see also Ex. 1010 ¶¶ 36-39.)3
`
` Ebert teaches that
`
`conventional methods of preparing transdermal devices containing drugs such as
`
`nicotine are 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
`
`
`3
`As discussed below (pages 27 to 28), 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 ¶¶ 56–57.
`
`
`
`15
`
`

`

`Mylan v. Novartis
`IPR Petition - U.S. Pat. 6,316,023
`
`
`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 l