`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`___________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________________
`
`
`NOVEN PHARMACEUTICALS, INC.
`AND MYLAN PHARMACEUTICALS INC.,
`Petitioners
`
`v.
`
`NOVARTIS AG AND LTS LOHMANN THERAPIE-SYSTEME AG,
`Patent Owners
`
`___________________
`
`
`No. IPR2014-005491 (U.S. Patent No. 6,316,023)
` No. IPR2014-005502 (U.S. Patent No. 6,335,031)3
`
`PETITIONERS’ DEMONSTRATIVES
`
`
`1 Case IPR2015-00265 has been joined with this proceeding.
`2 Case IPR2015-00268 has been joined with this proceeding.
`3 Petitioner Noven attests that the word-for-word identical paper is filed in each
`proceeding identified in the heading.
`
`
`
`
`
`
`
`Pursuant to 37 C.F.R. § 42.70(b), Petitioner Noven Pharmaceuticals, Inc.
`
`files the attached demonstrative exhibits for oral hearing scheduled for June 2,
`
`2015.
`
`
`
`Dated: May 26, 2015
`
`
`
`Respectfully submitted,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`/Michael K. Levy/
`Steven J. Lee (Reg. No. 31,272)
`Michael K. Levy (Reg. No. 40,699)
`KENYON & KENYON LLP
`One Broadway
`New York, NY 10004-1007
`Tel: 212-425-7200
`Fax: 212-425-5288
`
`Counsel for Petitioner Noven Pharmaceuticals,
`Inc.
`
`
`
`
`
`Noven Pharmaceuticals, Inc. and Mylan
`Pharmaceuticals Inc., Petitioners
`
`1/.
`
`Novartis AG and LTS Lohmann Therapie-
`Systeme AG, Patent Owner
`
`1Joined with IPR2015—00265 and IPR2015—00268
`
`No. IPR2014—00549 and IPR2014—005501 (citations to 550 IPR unless noted)
`
`Patent Nos. 6,316,023 and 6,335,031
`
`June 2, 2015
`
`
`
`There is No Dispute That .
`
`.
`
`.
`
`All the elements of the challenged claims of the ’023 and
`
`’031 patents are found in the prior art;
`
`Enz is a proper starting point for the obviousness analysis;
`
`Paper 25 pp. 20-21; Paper 31 pp. 1, 3; Ex. 1031 1] 25 n.2.
`
`The particular features of any dependent claim do not
`
`independently support patentability;
`
`It would have been routine work for a POSA to select an
`
`effective amount of an appropriate antioxidant;
`
`Evidence of secondary considerations has not been
`
`presented.
`
`
`
`Grounds for Institution ’023 Patent
`
`Ebert
`
`Referee @—
`Enz and the Handbook, optionally in
`§ 103(a)
`1, 7
`view of Rosin and/or Elmalem and/or
`
`IPR2014-00549 Institution Decision, Paper 10 p. 25.
`
`Enz and the Handbook, and/or Rosin,
`and/or Ebert
`
`§ 103(a)
`
`Enz and the Handbook and/or EbeIt
`
`§ 103(a)
`
`Enz, the Handbook, and Ebert or
`Kissel
`
`§ 103(a)
`
`Enz and Sasaki
`
`§ 103(a)
`
`1, 2, 4, 5, and 7
`
`Enz, Sasaki, and Ebert or Kissel
`
`§ 103(a)_
`
`
`
`Grounds for Institution ’031 Patent
`
`eeeeeeeo
`
`Enz, the Handbook, Rosin,
`Elmalem, and Ebert
`
`Enz and Sasaki
`
`§ 103(a)
`
`1—3, 7, 15, 16, and 18
`
`IPR2014-00550 Institution Decision, Paper 10 p. 28.
`
`Enz, the Handbook, Rosin, and
`Ebert
`
`§ 103(a)
`
`1, 2, 7, 15, and 18
`
`§ 103(a)
`
`3 and 16
`
`
`
`’023 and ’031 Patent Claim 1
`
`Claim 1 ’031 Patent
`
`Claim 1 ’023 Patent
`
`A pharmaceutical composition
`
`A pharmaceutical composition
`
`comprising:
`
`comprising:
`
`(a) a therapeutically effective
`amount of (S)-N-ethyl-3-{(1—
`dimethylamino)ethyI}-N-methyl-
`
`1 to 40 weight percent of (S)
`-N—ethyl-3-[(1—dimethylamino)
`ethyl]-N-methylphenyl carbamate
`
`phenyl-carba mate in free base
`
`in the form of a free base or acid
`
`lPR2014-00549, EX. 1001; lPR2014-00549, EX. 1001.
`
`or acid addition salt form
`( ompoun
`)'
`(b) about 0.01 to about 0.5 percent
`by weight of an antioxidant,
`
`C
`
`d A -
`
`based on the weight of the
`
`composition, and
`
`(c) a diluent or carrier.
`
`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.
`
`
`
`Other Claims of the ’023 and ’031 Patents
`
`Method Claim
`
`with an amount of antioxidant effective to stabilize. (Claim 15,
`
`’031 patent.)
`
`A method of stabilizing rivastigmine by combining rivastigmine
`
`IPR2014-00550, EX. 1001; lPR2014-00549, EX. 1001.
`
`Elements of Remaining Claims
`
`° Specific antioxidants: tocopherol, ascorbic acid, BHT, BHA,
`
`propyl gallate;
`
`Narrowed antioxidant ranges;
`
`Elements of a transdermal system, including release liners,
`
`backing layer, adhesive.
`
`
`
`Person of Ordinary Skill
`
`Collaborative team of individuals;
`
`Included team members from a variety of disciplines
`
`involved in formulating pharmaceutical compounds;
`
`Familiar with pharmaceutical formulation development,
`
`Paper 1 pp. 5-6; Ex. 1010 1] 31; Ex. 1011 1] 11; EX. 1031 171/ 13-14; EX. 1032 1”] 4-5.
`
`including transdermals, and the conventional excipients
`
`employed therewith;
`
`Included organic chemist with sufficient knowledge to
`
`make predictions based on the chemical structure of a
`
`compound.
`
`
`
`A POSA Would Have Expected That Rivastigmine is
`Susceptible to Oxidative Degradation
`
`- Based on the chemical structure of rivastigmine;
`
`- Based on the similarity of rivastigmine’s structure
`
`Paper 1 pp. 4, 32-36, 42-43, 46-47; Paper 31 pp. 4-9; Ex. 1010 171] 31, 63; EX. 1011 111] 12, 53-59; Ex. 1031 111] 24-32; Ex. 1032 171] 22-67.
`
`to nicotine, which was known to be susceptible to
`
`oxidation;
`
`- Based on prior art, including Elmalem, Rosin,
`
`Sasaki, Ebert, and Enz.
`
`
`
`° A POSA was instructed by the prior art to examine
`
`the structure of a molecule during preformulation
`
`and make predictive assessments;
`
`° Applying functional group chemistry to anticipate
`
`potential modes of degradation;
`
`A POSA Would Have Reasonably Expected Rivastigmine
`to Oxidatively Degrade Based on Its Chemical Structure
`
`EX. 2014 p. 181; EX. 2020 p. 110.
`
`° The mechanistic pathways of a reaction are different
`
`from the threshold question of susceptibility to
`
`oxidative degradation.
`
`
`
`Pharmaceutical Dosage Forms and Drug Delivery Systems (Ex. 2020)
`
`Pharmaceutical
`
`.
`
`‘ I
`udhydraymmommwbdyikyflr
`and an] In- mum: am: and:
`u
`o
`
`n
`
`”H“
`“'k ”Wm
`undo”mp-nu ”In labial-rim
`«Jawuumu "Wm“.
`I
`
`Paper 31 p. 7; Ex. 1031 111] 28, 30,‘ EX. 1032 1] 23; EX. 2020 p. 110.
`
`Initial investigation begins through knowl-
`': edge of the drug'5 chemical structure which a1—
`,{ lows the preformulation scientist to anticipate
`"
`the possible degradation reactions.
`
`$|)§Ili|£]
`
`1
`
`_
`
`III-1M?!wruMIruw-puumuf
`
`“" «mummwgnmmmm
`nImmqu-Ilppuunnuywmmnam
`WWIil-Wwfihmw‘yhml
`l-h. Jim-t- I. m a: manly «and lo
`mpmm Iiw'v rm.- 0' dng Wm inaus— n. 5..“ 0| I» 1mm Mm u,
`Mmm-mImdumml Mme-duo(”Md-“404
`mumemmMmthul-vawp mm uanrmotn‘l‘r
`.9 W macs luau-eel and Lam-IA
`(«awn-u umIMMWM-
`nudism:“Wad lmlIIImp-In» nwngwnpmwwlnm-w mu
`muuwmn‘Mlflifl! lam an; mMMW-xbmluuqyw
`NImMMm¢wynunK\ncfhflcll. 1k
`:dnwuum Mar-MWIII-u». ml.
`
`
`wet-Anna Jamar;HhMplI-v-Ik mixlhmhm IWImb-Wannix-Ida; trim-mu!Manuals. flhvlmalu dvrnw- IIquIn-Idwbure
`Gut-mu], mldIumuwdv-ncmd-hx- WfirhlI-‘H‘uudbul'lH—IM
`min-nunIumnrumlewk Mhm mauphmfirfiummhgmm
`mm mam 7w
`DI’II - was III-Ln Lon-I-
`Ivar-Am
`n9- su-I
`
`
`
`Modern Pharmaceutics (Ex. 2014)
`
`"MINI I’llill'lllflllflllllfl
`“Wm“
`J M
`
`ambush—Ilk-mmnuuaqum-‘um
`“Hum—Inh-til-h In.An ImmkmdmhflmFfl-‘I
`III“I
`wwwmnnt nmnum WWI-21mm!1mm
`rum-uwilyM.“—Hum»Mummy-u-mm- «a.ma
`“rum.
`.Mfihu) "In-din
`.
`11‘s.“: nm ForI-ah
`muum
`.m n.- nun-ml «a an
`.m mm mm myl mm; s.
`own- .4 mun: «gunk awn-3
`m rain-(u Hanna: '9de
`
`m
`mw-byflnuh-lfinllllla-l
`mum-s [1mm :ou
`Mm v MW usw
`wemwmao
`up a u! a:
`
`Paper 31 p. 8,‘ EX. 1031 1”] 29-30; EX. 1032 1] 25; Ex. 2014 p. 181.
`
`thc follownng discussmn therefore, degradative routes are demonstrated by calling attention to
`the reactive functional groups present in drug molecules. 'li -"'." k a i z.
`x
`~.
`v
`.
`z
`.1 x ..
`
`A cognizance of reactions of particular functional groups is important if one is to gain a
`
`broad view of drug degradation. It
`
`is a difficult task to recall degradative pathways of all
`
`
`
`
`
`Leffler, A Short Course of Organic Chemistry (Ex. 1047)
`
`~————
`
`I
`
`r"-
`
`EX. 1032 1724; EX. 1047 p. 46.
`
`A study of functional groups is especially profitable because the reactions
`of a functional group tend to be about the same, regardless of the nature of
`the rest of the 11101801116.
`_.
`__
`1
`.'
`.1.‘;.1.... 1::4...‘
`
`...,
`
`.
`.
`..
`.4
`d-luuflklflmphndwhab-Mflumo.
`the run a! flu: molecule. Par cnmolo [M rompou“d2 IIIII'mpnpum-um I»
`a
`.
`.
`.
`.
`-u
`»
`1
`.
`Tho!ud'wnhumfiullyamm‘Ioolih hlnrfinmlgmuplmlnulhinum
`imponnntlunwwthemtoltho melanin.
`
`|
`(HI—CH; + 211,0
`-(2H. + :5". ->-"-0 CH.
`CHI—$1]
`NH;
`NO:
`Sailwno
`I.Mump—
`
`Similarly.
`
`and
`
`cnxzumo. + an. —" ~ autumn. + 2M)
`no.
`Nn.
`If 1H“)+ an, -L~OJS 4 sun
`\/‘ v.
`v
`I~,\imln|hhnm
`l-Au'notnyllhdfly:
`Nov-"Elam IW
`WV. my: usmmmmums:
`50'”
`fl
`
`
`
`Morrison & Boyd, Organic Chemistry (Ex. 1038)
`
`Paper 31 p. 8; EX. 1031 17 14; EX. 1038 p. 6.
`
`A molecule is often represented by a picture or a model—sometimes by several
`pictures or several models. The atomic nuclei are represented by letters or plastic
`balls, and the electrons that join them by lines or dots or plastic pegs. These crude
`Pictures and models are useful to us only if we understand what they are intended
`to mean. Interpreted in terms of the structural theory, they tell us a good deal about
`the compound whose molecules they represent: how to go about making it; what
`PhYSical properties to expect of it—melting point, boiling point, specific gravity,
`the kind of solvents the compound will dissolve in, even whether it will be colored
`or not; what kind of chemical behavior to expect—the kind of reagents the
`comPound will react with and the kind of products that will be formed, whether it
`will react rapidly or slowly. We would know all this about a compound that we
`had never encountered before, simply on the basis of its structural formula and
`What we understand its structural formula to mean.
`'
`
`
`
`Rivastigmine
`
`Paper 1 p. 9; Ex. 1011 1] 53; Ex. 1032 1] 14; Ex. 1002 p. 2.
`
`H3CVNI_\|”/O\©/\C\CH3/CH3
`
`H CH3
`
`N
`
`
`
`Rivastigmine
`
`C
`
`N
`
`Paper 1 p. 9; Ex. 1011 1] 53; Ex. 1032 1] 14; Ex. 1002 p. 2.
`
`H3\/CH\H/O©/\N/3 3
`
`H CH3
`\C
`
`CH
`
`
`
`Rivastigmine is Susceptible to Oxidative Degradation
`
`Additional
`
`carbon bond
`
`H CH3
`
`Paper 1 p. 9; Ex. 1011 1] 53; Ex. 1032 1] 14; Ex. 1002 p. 2.
`
`H3\/CH\H/O©/\\N/3 3
`
`C
`
`N
`
`CH
`
`Aromatic ring
`
`Tertiary amine
`
`
`
`Chemical Principals
`
`Oxidation often involves breaking a covalent chemical
`
`bond, resulting in the formation of a radical;
`
`Radicals are molecules with an unpaired electron that
`
`are formed by breaking a chemical bond;
`
`Paper 1 pp. 34-36; Paper 31 pp. 4-5; Ex. 1011 111] 15-35, 47-49; 54-59; EX. 1032 flfl 7-15, 22-30.
`
`depending on the structural context in the molecule
`(the ”electronic neighborhood”), and thus are more
`
`Some chemical bonds are weaker than others
`
`prone to oxidation;
`
`A drug molecule containing a chemical bond prone to
`
`oxidation can lead to degradation of the drug.
`
`
`
`Relative Stability of Carbon Radicals
`
`primary
`
`radical
`
`secondary
`
`radical
`
`Ex. 1011 1] 20.
`
`R is an alkyl group (e.g., —CH3)
`
`radical
`
`(least stable)
`
`tertiary
`
`radical
`
`(most stable)
`
`
`
`Carey & Sund berg, Advanced Organic Chemistry (Ex. 1007)
`
`Table 12.4. Bond Dissociation Energies (kcallmol)'
`
`Bond
`
`D.E.
`
`Bond
`
`FR.-‘\\‘('I.\ »\. CARI‘Y
`and RILHARD J. SL'\DBER(:
`
`has In I— fill—1.. ”mum—tr
`
`.. .
`
`5‘
`
`H—Br
`H—l
`
`HOCHz—H
`
`cmcnzocucrq3
`{i
`
`CH2=CH—H
`CH2
`
`CH3CCHz—H
`(.H,—LH~H
`— NECCHrH
`LHZ=(,HLH,—H
`8S
`PhS_H
`
`©<
`
`H
`
`H
`
`E‘C—H
`C13C—H
`Czfls—F
`C,H,—Cl
`22:: i”
`2
`5
`H—F
`H—Cl
`
`b
`
`73
`
`96
`106
`81
`‘5’:
`
`136
`103
`
`Paper 31 pp. 7-8; Ex. 1032 1] 21; Ex. 1007 p. 683.
`
`1...“..M MW
`... .n m.
`M mu .m- ll row luv-o. u: umnm mm... “on m
`..
`,
`_
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`¢
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`ma".- ..1 sm- a nun... .4! mumm. Almaty-mu n. "4...: 4a....»-
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`.. .w-.. . M- .m. . w.-. .m .. n... WW... r m
`....
`
`(CHJ)JSi——H
`
`(CH,)3Gc—H
`
`(CaHthn—H
`
`(II)
`fl)
`.
`(AHJCO OCCH3
`(CH,),c0—0H
`F— F
`C1—C1
`Br—Br
`I—I
`
`44
`38
`58
`46
`36
`
`a. Except where noted otherwise, dutu are from J. A. Kerr, Chain. Rev. 66, 465 (1966); S. W.
`Benson, J, Chem. Edam ‘2' 501 (1965).
`b. T. J. Burkey, M. Majcwski, and D. Grillcr. I. Am. Chem, Soc. 108, 2218 (1986).
`c. S, W. Benson, Chem. Rev. 18, 23 (I978).
`d. R. A. Jackson, J. Organamcl. Chem. [66, 17 (1979).
`
`
`
`Aromatic Rings Contribute to Radical Stability
`
`EX. 1011 1] 27.
`
`a benzylic carbon
`
`(carbon atom adjacent
`
`to aromatic ring)
`
`
`
`H
`
`H
`
`H
`
`H
`
`Aromatic Rings Contribute to Radical Stability by
`Electron Delocalization
`
`EX. 1011 1129.
`
`
`
`Carey & Sund berg, Advanced Organic Chemistry (Ex. 1007)
`
`I’RANFIK -\. (“\RI'Y
`and RICH»\RI) J. Sl :\I)BI:RU
`
`1
`PhCWCHfl:
`PhC-HzC‘H—fi-CHz
`(If’hhcflz; ‘
`‘
`
`1.0
`91$ ,
`9.35
`
`Paper 31 p. 8; Ex. 1032 1]” 11, 13; Ex. 1007 p. 693.
`
`Table 127;. mum 'R‘eactivmgs of Some Aromatic
`Hydmcarbnm tam" Qxygen'
`
`:Phcfigcz—g
`PhCHS
`'
`
`_
`
`70.7%
`0.015
`
`a. Data {ham 6 A. Wit-LAM Giana. Sat. 38. 1047 (1956}.
`
`
`
`Rivastigmine is Susceptible to Oxidative Degradation
`
`Additional
`
`carbon bond
`
`H CH3
`
`Paper 1 p. 9; Ex. 1011 1] 53; Ex. 1032 1] 14; Ex. 1002 p. 2.
`
`H3\/CH\H/O©/\\N/3 3
`
`C
`
`N
`
`CH
`
`Aromatic ring
`
`Tertiary amine
`
`
`
`Carey & Sundberg, Advanced Organic Chemistry (Ex. 1007)
`
`l’R:\.\J('IK \. ('\l\’l'\
`1m3l\‘|(H\l\‘lll
`\1\lllll‘\'(.
`
`.The ease of autoxidationis therefore largely governed
`,
`.
`by the case of hydrogen abstraction1n the second step ofthe propagation sequence.
`The alkylperoxy radicals that act as the chain camer are fairly selective. Substrates
`.that are relatively electromrich or that proVide particularly stable radicals are the
`most easily oxidized. Benzylic, allylic, and tertiary positions are especially suscept-
`ible to- oxidation. This selectivity make radical chain oxidation a preparatively useful
`reaction in some cases.
`'
`
`Paper 31 pp. 4-5; EX. 1007 p. 693.
`
`m mm: n...— r... mus-nun m mm“: at. only an
`Illa-«y mm mm... . “Id-bl: far “a... n- auumn aw
`beau-1mm) .tmmw-uwaamwmmn
`. (»...qr--.n-l~r_n.-aur.xmn
`hunt—inun-Ix‘m? wt
`
`
`
`Nicotine
`
`Paper 1 p. 14; Paper 31 pp. 5—6; Ex. 1032 171] 52-59; Ex. 1011 1m 48-49, 56-59; Ex. 1021 pp. 2—3.
`
`
`
`Nicotine Reinforced the POSA’s Expectation of
`Oxidative Susceptibility
`
`Paper 1 p. 14; Paper 31 pp. 5-6; Ex. 1032 111] 52-59; Ex. 1011 111] 48-49, 56-59; Ex. 1021 pp. 2-3.
`
`
`
`H 9H3
`
`N
`
`Nicotine
`
`Rivastigmine is Structurally Similar to Nicotine
`
`Rivastigmine
`
`H3CVN:]/O@C\CH3/CH3
`
`Paper 31 pp. 5-6; EX. 1032 111] 52-59; EX. 1011 111/ 48-49, 56-59; EX. 1021 pp. 2-3.
`
`
`
`The Prior Art Confirms That a POSA Would Have Maintained
`
`The prior art instructed a POSA to make assessments
`
`about a molecule’s chemical and physical properties
`
`during preformulation;
`
`a Reasonable Expectation of Oxidative Instability
`
`Paper 31 pp. 4—5.
`
`The prior art taught that structural features affect bond
`
`strength, and in turn susceptibility to oxidation;
`
`The reasonable expectation is confirmed by structurally
`
`similar compounds and the prior art;
`
`Dr. Schoneich concluded that a POSA would have
`
`predicted rivastigmine’s susceptibility to oxidative
`
`degradation based on the molecule’s chemical structure.
`
`
`
`Exhibit 1002
`
`Enz
`
`
`
`Enz (Ex. 1002) Discloses .
`
`.
`
`.
`
`The structure of rivastigmine;
`
`A therapeutically effective amount of rivastigmine;
`
`How to separate rivastigmine from RA7;
`
`Paper 1 pp. 13-14; Paper 31 p. 12; Ex. 1010 111] 32-35; EX. 1002 pp. 14-15; Ex. 1031 171] 98-99.
`
`Superiority of transdermal delivery over oral or injectable;
`
`Use of rivastigmine in oral, injectable, and transdermal
`
`formulations;
`
`An unfinished transdermal formulation containing
`
`rivastigmine, but no express inclusion of an antioxidant
`
`(Example 2).
`
`
`
`The Handbook
`
`of
`
`Exhibit 1003
`
`Pharmaceutical
`
`Excipients
`
`
`
`The Handbook (Ex. 1003) Discloses .
`
`.
`
`.
`
`A compendium of conventional and well-characterized
`
`pharmaceutical excipients, including antioxidants;
`
`Many antioxidants generally regarded as safe (GRAS)
`and/or listed in FDA’s Inactive Ingredients Guide;
`
`180:13-183:6,' Ex. 1026 513:1-516:14.
`
`Typical antioxidant amounts used in pharmaceutical
`
`compositions, overlapping claimed amounts;
`
`Known incompatibilities for antioxidants;
`
`Respective entries for each of the antioxidants recited in
`
`dependent claims of the ’023 and ’031 patents.
`
`
`
`
`
`
`
`Rosin (Ex. 1008) Discloses .
`
`.
`
`.
`
`Discloses a series of compounds having greater in vivo
`activity than prior art compounds, including
`
`physostigmine;
`
`Experimental data for eleven RA—series compounds; most
`
`preferred compounds of the RA series: RA4, RA5, RAG, RA7,
`RA8, RA14, and RA15;
`
`Paper 1 p. 11; Paper 31 p. 13; EX. 1008 7:51-53, 10:9-11:16, 12:56-57, 14:11-30; Ex. 1010 111] 28-29, 59; EX. 1031 171] 39-43.
`
`Three of these RA-series compounds, including RA7, are
`individually claimed;
`
`”Preferred antioxidants for use with the compounds of the
`
`present invention include sodium metabisulphite and
`
`ascorbic acid.”
`
`
`
`Physostigmine vs. Rivastigmine
`
`° The alleged teaching that rivastigmine is more stable than
`
`physostigmine only implies that rivastigmine is more stable
`
`than a very unstable compound;
`
`Physostigmine is ”chemically unstable”;
`
`Ex. 2012 1] 82.
`
`unstable in solution and hydrolyse readily at
`physiological pH”;
`
`Physostigmine has a very short, 20-40 minute, half-life;
`
`Monomethyl derivatives, like physostigmine, ”tend to be
`
`°
`
`Improved in vivo activity is not synonymous with oxidative
`
`stability in a formulation.
`
`
`
`Rosin (Ex. 1008)
`
`' Disclosure of preferred antioxidants for ”compounds of the
`
`present invention” not limited to injectable formulations.
`
`Rosin discloses other modes of drug administration, e.g.,
`
`oral, tablet, capsule;
`
`' Rosin discloses administration by any conventional
`
`route, which a POSA would understand to include
`
`transdermal;
`
`Paper 1 p. 33; Paper 31 p. 12; EX. 1010 fl 61; EX. 1008 7:15-19, 7:51-53, 8:56-59, 13:8-10,‘ Ex. 1031 171/ 38-42, 50-54.
`
`° A POSA would understand that RA7 was one of the
`”compounds of the present invention” and the designation
`
`of ”preferred antioxidants” for compounds of the present
`invention connotes that work was done to arrive at that
`
`conclusion.
`
`
`
`Exhibit 1009
`
`Elmalem
`
`
`
`Elmalem (Ex. 1009)
`
`ANTAWNISM 0F MOI-’HlvalNDUCIJJ 1!!!“le
`DEPRM.‘ UV NOVEL ANHCNOLINESVKIASE
`
`° A comparative
`
`mamggawm
`
`Hun. ...‘
`
`.
`
`Drugs
`The agents tested were RA6 (N ethyl-SU-(dimethyl-
`amino)ethyl]phenyl carbamate) HCl. RA, (N-ethyl,
`N -methyl-3[1 -(dimethylamino)ethyl] phenyl carba-
`mateHCI. RA1,(N-propyl-3(I -dimethylamino)-ethyl]-
`phenyl carbamate HCl. Physostigmine salicylate
`(Sigma Ltd ; Mo -hine HCl Teva Pharmaceuticals,
`
`doses are
`:11 ' r
`"
`,,
`expressed as mg per kg of body weight of the
`pp 9
`
`to riate salt.
`
`a
`
`'
`
`Paper 1 pp. 12, 19; Paper 31 p. 13; EX. 1009 pp. 1-2,‘ EX. 1010 111] 30, 59; EX. 1031 TH] 55, 77, 123, 134-138.
`
`investigation of several
`drugs: Physostigmine vs.
`.
`RAG! RA7I a n d RA15:
`_
`_
`_
`° SO d | U m m eta b IS U l p h lte
`anthdea nt added t0
`
`_
`_
`° The amount of anthdeant
`added to RA7 solutions IS
`0.3% and 0.6%.
`
`.
`
`.
`
`
`
`Elmalem (Ex. 1009) and Weinstock 1981 (Ex. 2046)
`
`Elmalem (Ex. 1009)
`
`The agents tested were RA6 (N ethyl-fl 1 -(dimethyl-
`amino)cthyl]phenyl carbamate) HCl. RA7 (N-ethyl,
`N -methyl-3[1-(dimethylamino)ethyl] phenyl carba-
`mateHCl.RA.,(N-propyl-3(l-dimethylamino)-ethyl]-
`phenyl carbamate HCI. Physostigmine salicylate
`(Sigma Ltd ; Mo hine HCI Teva Pharmaceuticals,
`
`
`
`EX. 1031 flfl 59—60; Ex. 1009 p. 2; EX. 2046 p. 2.
`
`(1961). Drugs used were: ATMN, hyoscine hydrobromide, neostigmine
`hydrobromide and physostigmine salicylate (Sigma Chemical Com-
`pany, St. Louis, MO); morphine hydrochloride (U.S. Vitamins Labo-
`ratories Division, 'Ihckahoe. NY); and naloxone hydrochloride (Endo
`Laboratories, Inc" Garden City, NY).
`v
`~
`.
`v . m?
`.
`.,
`
`expressed as mg per kg of body weight of the
`appropriate salt.
`
`All doses are
`
`Weinstock 1981 (Ex. 2046)
`
`doses are expressed in milligrams per kilogram of body weight of the
`appropriate salt.
`
`
`
`Elmalem Did Not Use Antioxidants Indiscriminately
`
`Reference
`
`Antioxidant
`
`Morphine:
`
`YES (sodium metabisulphite)
`
`EX. 1031 171757-59; EX. 1009 p. 1,‘ Ex. 2046 p. 2.
`
`NO
`Hyoscine:
`
`
`Physostigmine:
`
`RAG:
`
`RA7:
`
`RA15:
`
`YES
`
`YES
`
`YES
`
`YES
`
`Ex. 2046:
`
`Weinstock
`
`1981
`
`Morphine:
`
`YES (ascorbic acid)
`
`Physostigmine:
`
`YES
`
`Neostigmine:
`
`Naloxone:
`
`ATMN:
`
`NO
`
`NO
`
`NO
`
`
`
`Elmalem (Ex. 1009)
`
`° Elmalem unambiguously discloses that an
`antioxidant is added ”to prevent oxidation”;
`
`Paper 1 pp. 19, 42; Paper 31 p. 13; Ex. 1031 111] 57, 61-63, 77, 104-105; Ex. 2012 fl 96 n.8.
`
`It is undisputed that RA7 and rivastigmine behave
`the same with respect to oxidation.
`
`- The amount of antioxidant used is within the
`
`Handbook range;
`
`-
`
`
`
`Exhibit 1006
`
`Ebert
`
`
`
`Ebert (Ex. 1006) Discloses .
`
`.
`
`.
`
`Transdermal system with nicotine and antioxidants;
`
`Nicotine oxidizes when exposed to air;
`
`transdermal patch;
`
`Antioxidant use is a solution to oxidative degradation in a
`
`Paper 1 pp. 14-16; Paper 31 p. 12; EX. 1010 171] 36-39; EX. 1031 171/ 108-109; Ex. 1006 13:33-36.
`
`Antioxidants include BHT, BHA, and OL-tocopherol;
`
`Most preferred weight percentage of BHT is 0.05 to 0.2
`
`weight percentage of nicotine;
`
`Applicable to ”any other liquid drug” that can be
`
`transdermally administered.
`
`
`
`Ebert (Ex. 1006)
`
`during the short duration of the manufacture of a
`
`transdermal formulation, which a POSA would find
`
`relevant to stabilizing a rivastigmine formulation
`
`during a multi-year shelf life;
`
`° Ebert discloses controlling oxidation of nicotine even
`
`Paper 1 p. 16; Paper 31 p. 12; Ex. 1010 1] 39; EX. 1031 171] 106-110; Ex. 1006 pp. 3, 5, 13.
`
`° A POSA would understand that Ebert is not limited
`
`to a particular manufacturing method; other liquid
`
`drugs, regardless of volatility, can be substituted.
`
`
`
`
`
`
`
`Sasaki (Ex. 1005) Discloses .
`
`.
`
`.
`
`Broad range of amine-containing compounds
`(like rivastigmine) will often degrade when
`
`combined with an acrylic adhesive;
`
`198:14-199:18.
`
`Oxidative degradation prevented by antioxidant,
`(tocopherol; 0.022 to 0.44% weight percent);
`
`Oxidative degradation not prevented by
`
`oxygen-impervious packaging;
`
`Three-month stability study of amine-containing
`
`compounds combined with an acrylic adhesive,
`with and without antioxidant.
`
`
`
`Enz (Ex. 1002) 8: Sasaki (Ex. 1005)
`
`° Enz discloses a transdermal device and formulation
`
`of the amine-containing compound rivastigmine
`combined with an acrylic adhesive;
`
`Paper 1 pp. 46-47; EX. 1010 flfl 85-86; EX. 1031 fl 89; EX. 1025 199:19-200:10.
`
`Sasaki discloses that amine-containing compounds
`will degrade when combined with an acrylic adhesive
`in a transdermal device, and teaches that an
`
`antioxidant prevents this degradation.
`
`
`
`Addressing Patent Owners’ Arguments
`
`The expectation that rivastigmine would be
`
`susceptible to oxidative degradation is not
`
`unreasonable;
`
`The prior art did not teach that rivastigmine was
`stable;
`
`Paper 31 pp. 4—15.
`
`A POSA would have been motivated to combine the
`
`teachings of the prior art to arrive at the claimed
`
`invention;
`
`The prior art did not discourage the use of an
`
`antioxidant.
`
`
`
`The Expectation of Susceptibility to Oxidative Degradation
`is Not Unreasonable
`
`° A POSA assessed the stability of a drug molecule under
`
`pharmaceutica||y-re|evant conditions applying functional—group
`
`chemistry;
`
`° No dispute that the particular structural features of rivastigmine
`
`result in a weakened C-H bond;
`
`Paper 31 pp. 4-5, 7-8, 13; EX. 1032 TH] 14, 18-19, 30-36; EX. 1008, 7:48-53; EX. 1009 p. 1060; EX. 1006, 19:17-33.
`
`° Rosin discloses the use of antioxidant with RA7, among others,
`as required;
`
`° The prior art is consistent with the POSA’s expectation that the
`
`rivastigmine molecule is susceptible to oxidative degradation:
`
`° Elmalem discloses the use of antioxidant with RA7 to prevent
`
`oxidation;
`
`° Ebert discloses the use of antioxidant with transdermally-
`
`delivered nicotine.
`
`
`
`° A POSA would have been aware that rivastigmine is
`
`particularly susceptible to oxidative degradation;
`
`The Expectation of Susceptibility to Oxidative Degradation
`is Not Unreasonable
`
`Paper 31 pp. 6-8; EX. 1032 111] 15, 22-26, 30-36; Ex. 1031 111] 10, 25, 28-37, 92; EX. 1048 91:15-92:15.
`
`° The POSA would not have been surprised to observe
`
`oxidative degradation;
`
`° A POSA would conduct testing to confirm the extent
`
`of oxidative degradation in a particular formulation.
`
`
`
`The Prior Art Does Not Teach That Rivastigmine is
`Oxidatively Stable
`
`- The prior art discloses use of antioxidant with RA7;
`
`° The prior art comparison of rivastigmine with
`
`physostigmine does not teach that rivastigmine is
`
`oxidatively stable;
`
`Paper 31 pp. 9-10; Ex. 1032 111] 37-40, 41-51, 57.
`
`° Commercial formulations containing a drug otherwise
`
`having the same structural features as rivastigmine
`
`giving rise to susceptibility to oxidation, but not
`
`reporting an antioxidant, do not demonstrate that a
`
`molecule’s structure has no predictive value.
`
`
`
`Alleged “Real World” Examples are Irrelevant
`
`Q. Will you agree with me that a commercial
`
`Novartis v. Noven, Cross-Examination of Dr. Klibanov:
`
`EX. 1026 553:1-6,’ Ex. 1031 1] 90.
`
`product that does not list an antioxidant among
`
`its ingredients does not necessarily tell you that
`
`the API, the active drug is not subject to oxidative
`
`degradation?
`
`A. Yes, I agree with that.
`
`
`
`Motivation to Add an Antioxidant
`
`Chemical structure of rivastigmine indicated susceptibility to
`
`oxidative degradation;
`
`Analogous structure to nicotine, which was known to be
`
`susceptible to oxidation;
`
`84-86, 88-89, 92, 109, 116-23.
`
`with an expectation of compatibility and successful
`formulation.
`
`Prior art, including Elmalem, Rosin, Sasaki, Ebert, and Enz, was
`
`consistent with POSA’s expectations;
`
`No dispute that antioxidants were conventionally employed to
`
`address oxidative degradation issues in pharmaceutical
`
`compositions;
`
`Prior art use of antioxidants and Handbook provide the POSA
`
`
`
`The Prior Art Did Not Discourage the Use of an Antioxidant
`
`Numerous antioxidants were classified by the FDA as
`Generally Recognized as Safe (GRAS);
`
`Several antioxidants (sodium metabisulfite, ascorbic acid)
`
`were known to be compatible with rivastigmine;
`
`Paper 31 pp. 14-15; EX. 1031 1m 12, 76, 84, 90, 93, 116—123; Ex. 1003 pp. 5-22; EX. 1008 7:51-53; EX. 1009 p. 1060; EX. 2019 p. 2/4.
`
`Other means of preventing oxidation were understood to be
`sometimes difficult to employ;
`
`It would have been routine work for a POSA to select an
`
`effective amount of an appropriate antioxidant;
`
`Prior art may counsel judicious use, but not discourage use.
`
`
`
`Duration of Action in vivo is Not Oxidative Stability
`
`° ”Greater” stability than the very unstable physostigmine is not
`
`significant, and also...
`
`° Rosin, Weinstock 1986, Enz 1991, Weinstock 1994 refer to in vivo
`
`activity of rivastigmine, not stability in pharmaceutical
`
`Paper 31 p. 10; EX. 1031 TH] 46, 68-70; EX. 1008 11:22-25, 11:29-35; EX. 2036 p. 546; EX. 2026 p. 272; EX. 2027 p. 219.
`
`four possible reasons (e.g., metabolism,
`lipid solubility) for greater activity in the body;
`
`compositions:
`
`° Rosin (Ex. 1008):
`
`° Weinstock 1986 (Ex. 2036):
`
`greater in vivo activity, same four
`
`possible reasons as stated in Rosin;
`
`° Enz 1991 (Ex. 2026):
`
`longer duration of action;
`
`° Weinstock 1994 (Ex. 2027):
`
`duration of action in animals and humans.
`
`
`
`Petitioner’s Motion to Exclude: Exhibits
`
`: Compilation of two Patent Owner internal documents;
`
`: Compilation of three Patent Owner internal documents;
`
`: Selected portions of Dr. Tiemessen’ testimony from the
`
`Novartis v. Watson trial;
`
`Paper 4 7, 5 7.
`
`: Ex. 2053 with additional pages of testimony added, first
`
`introduced at Dr. Kydonieus’ April 20, 2015 deposition;
`
`: One-page excerpt of internal Novartis document, first
`
`introduced at Dr. Schoneich’s April 18, 2015 deposition;
`
`: Ex. 2059 with the additional 29 pages of the underlying
`
`document that were originally omitted, filed
`
`May 12, 2015.
`
`
`
`CERTIFICATE OF SERVICE
`
` I
`
` certify that, on May 26, 2015, the foregoing PETITIONERS’
`
`DEMONSTRATIVES was served electronically on Patent Owners and Mylan
`
`using the following email addresses:
`
`ExelonPatchIPR@fchs.com
`
`Joseph M. Reisman (BoxMylan2@knobbe.com)
`
`Jay R. Deshmukh (BoxMylan2@knobbe.com)
`
`William R. Zimmerman (BoxMylan@knobbe.com)
`
`
`
`Dated: May 26, 2015
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`/Christopher J. Coulson/
`Christopher J. Coulson (Reg. No. 61,771)
`KENYON & KENYON LLP
`One Broadway
`New York, NY 10004-1007
`Tel: 212-425-7200
`Fax: 212-425-5288
`Counsel for Petitioner Noven Pharmaceuticals,
`Inc.
`
`
`
`
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