MARTA. W~ROSIN, JERUSALEM, ISRAEL; M~CHAEL CHOREV, J ERUSALEM~ ISRAEL;
`ZEE, T'ASHMA, JERUSALEM, ISRAEL.
`
`"*CONTINUING
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`IPR2014-00550
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`PATENl; APPLICATIO~ $ERIAL NO."
`
`83'5'· '468'
`
`"
`
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`u.s~ DEPAR'l'MENT' OP' COMKBaCE
`pAi'ENT AND, TRADEMAlUC~ OmCE
`FEE' RECORD SHEET
`
`/(
`
`0800:3/10/86 835<4-66
`
`,1 101
`
`'3<4-0.00 CK
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`NOVARTIS EXHIBIT 2058
`Noven & Mylan v. Novartis & LTS Lohmann
`IPR2014-00550
`Page 2 of 372
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`

`COMMISSIONER OF PATENTS & TRADEMARKS
`ashington,. D.C. 20231
`
`Car·'
`
`11 8:":6848
`
`I
`
`835~66
`
`herewith for filing is the pa.tent application of
`Marta Weinstock Rosin, Michael Chorev and
`Zeev Tashma
`·PHENYL CARBAMATES
`'Enclosed are:
`
`For:
`
`sheets of drawing
`
`Fee Calculation.:
`
`c=J
`o Associate power of attorney
`o Before calculating ~he fee, cancel claims
`
`Basic Fee
`
`Multiple Dependent Claims
`
`Yes 0 NOG
`
`Foreign
`
`Extra
`
`Claims
`
`Independent
`Claims
`
`13
`
`3
`
`20
`
`3
`
`0
`
`0
`
`Please charge Depc>sit Ac'count No. 13-2160 in the amount of
`A duplicate copy of this sheet is enclosed.
`$
`
`The Commissioner is hereby authorized.to charge any additional
`fees which may be required, or credit any overpayment to
`Account No. 13-1260.
`
`A chec·k in the amount of $ 340.00
`is enclosed., '
`
`to cover the filing fee
`
`o
`,0
`
`Dated:
`
`MATHEWS, WGODBRIDGE, GOEBEL,
`PUGH & COLLINS, P.A •.
`22 Park Plaee
`P.O. Box l12.-M
`Mor:ristown, New Jersey 07960
`Telephone: (201) 267-3444
`
`Express Mail mailing label number B2418697
`Date of Deposit: March 3, 1986:·
`I hereby certify that this ~ransmittal
`letter is being deposited with the
`united States Postal Service "Express
`Mail Post Office to Addressee" service.
`under 37,CFR 1.10 on the date indicated
`above and is addressed to the Hon.
`Commissioner of Patents and Trademarks,
`
`:'i&.J~
`
`- 3 -
`
`NOVARTIS EXHIBIT 2058
`Noven & Mylan v. Novartis & LTS Lohmann
`IPR2014-00550
`Page 3 of 372
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`'''''' -- .....
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`" ' .. :! .~
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`
`Case 118-68'48.:
`
`.
`
`Express Mail Mailing Label Number B2418697
`Date of Deposit: March 3, 19~6
`
`I hereby certify that this patent application
`is being deposited with the United States
`'Postal Service "Express Mail Post Office To
`Addre.ss.ee" service under 37 CFR 1.10 on the'
`date indicated above and isddressea to the
`Commissioner of patents, Wa
`ington, D.C. 20231.
`
`Robin J. Mo
`
`PHENYL
`
`Prof. Marta Weinstock Rosin
`Michael Chorev
`Zeev Tashmac
`
`Priority Claimed:
`
`P~iority Countiy:
`Application No.:
`Filing date:
`
`Israel
`74497
`March 5, 1985
`
`-4-
`
`NOVARTIS EXHIBIT 2058
`Noven & Mylan v. Novartis & LTS Lohmann
`IPR2014-00550
`Page 4 of 372
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`Case 118-6848 '
`
`SOl
`PHENYL CARBAMATES
`
`The present invention relates to novel phenyl carbamates which
`are useful as pharmaceutical compositions. The inve~tion further
`rel ates to pharmaceutical compositi ons havi ng anti~h.ol i nesterase.
`activity.
`
`5
`
`Acetylcholine is a major neurotransmitter which is found in all
`parts of the body. Any reduction in its activity, either as a
`result of neuronal damage, degeneration etc'. or as induced by
`. drugs. or toxins, causes marked changes in the function of the"
`organism. Acetylcholine itself has an extremely short half life,
`since it is rapidly hydrolysed at its ~it~ of action and in
`plasma by specific cholinesterase enzymes. Drugs that inhibit
`acetylcholinestera~e, markedly increase and prolong the action of
`.
`.
`acetylcholine, thereby.enhancing cholinergic transmission. Three
`such agents are used clinically, Le., physostigmine, a naturally
`occurring alkaloid,. and two synthetic ~nalogues, neo-stigmine and
`pyridostigmine., The latter two agents are strongly ionised at
`physiological pH' and therefore are only poorly absorbed from the
`,
`gastro .. intest ina 1 tract, and do· not penetrate the central nervous
`.system to any signifi~ant extent. Physostigmine is absorbed after
`
`~O
`
`15
`
`20
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`NOVARTIS EXHIBIT 2058
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`IPR2014-00550
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`118-6848
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`5
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`oral administration and readily enters the brain. As a thera(cid:173)
`peutic agent it has several disadvantages. It is, chemically
`unstable and must be prepared in solution with an antioxidant,
`and protected from light. It has a rel atiyely short half-l ife
`(20-40 mins) thereby necessitating frequent administration. The
`latter is of particular importance when, the drug is to be admi(cid:173)
`nistered chronically. It has a low therapeutic ratio, a value of
`3-5 being reported'in the majority of studies in laboratory ani(cid:173)
`ma,1s, and a small therapeutic window, i.e. small range of dose in
`10 which it can be gfven without the accompaniment of side effects.
`Although physostigmine is absorbed from the gastro-intestinal
`tract, this is reported to be irregular and unpredictable, and
`therefore it is usually preferred to 'administer the drug par(cid:173)
`enterally. This is a seriqus drawback, if it is to be used chroni-
`15 cally on an outpatient basis.
`
`20
`
`There are a numoer of clinical and pathological conditions which
`are associated with cholinergic under-activity which can be
`.improved by the administration of an anticholinesterase agent.
`These include'reduction in cholinergic transmission induced by a
`variety of exoge~ous sU.bstances acting. in the peripheral, or
`central nervous system. Peripherally acting agents ,are g.allamine,
`d-tubocurarine and pancuronium, which are used as muscle re(cid:173)
`laxants. Their ,action can' readily be overcome by an anticholin(cid:173)
`estera'se drug. Drugs which interfere with central cholinergic
`transmission are,numerous, anticholinergic, atropine-like drugs
`includ'ing antiparkinson drugs, tricyclic antidepressan~s, neuro(cid:173)
`leptics', opiate analgesics, benzodiazepines and some types of
`general anaesthetics. So far the only agent that has proved' to be
`of any value in reversi.ng the effects of the latter group of
`~O drugs, is physos t i gmi.ne·., In all reported cases of drug overdose or
`lack of recovery when the agent was ,used peri-operatively, physo-
`
`25
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`Noven & Mylan v. Novartis & LTS Lohmann
`IPR2014-00550
`Page 6 of 372
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`administration
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`'. '.:' Cti~brii~tre~tment w.ith neuro1ept:ic~': ~fteri'resu1ts"in' t'ardivedy~­
`·:',ki~~~i.as~rhe:~id~sprea:d .~seo·fag~nt~h~~i:ng~ritid~oliriester·ase·
`. : ~~: ia;;~i:yi tYfo~tiie treat~e~t ofsc·~.iiophteni ~mak'es: :.t:h·is·. S1 de .
`:'~ff~ct', an everiilc:r~a:s i~g PO~Si~i 1 it~. Physosti gm1:~e· '1 nje~ted
`f~~r;verio;uslY produc~~a 's i gn i fica~t 'bu:t' ·shor·t1 1 ved imp~o~eme~t :'
`'io"a' ~'rOPol"tiOi1 of pat ients.·
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`A,ntimber:)i p'atho1ogi c·a1. and .deg~ne~ative. di seases has a1 so beel'!
`.10shbwn fo be associated.with a re(fuctionor loss 01' 'cholinergic
`. . ·.transmission.This. includes myasthenia' grav1sand' EatQn Lambert
`.' :"~Y~dr(jme 'in whi ch' the~~" i s an' i ri.ter.TerenCe ;"'i~hne'uromus~u1 ar
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`A selective loss ofchorin'e acetyitrarisferase:('the enzyme that:
`15.: ~ynthesi's~s·a~~tY1Ch.ci i ine) ha~' be~n folind in specific 'brain'
`. . . . . .
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`. 'regioris of pati ~nts wi'th' pr~-s~ni1ecieme~ti a:of.. he~ 1 zheimer
`"
`··.oty~~~,. The~einclud~ theJt'~~t'al arid 't~mpor~l cortex.hipi;ocampus •.
`:·.···--.f··/:.:--~yg:d·ai~~~ .. ~a~:d·~t"~ nu~i.etis·~ ·~u'bs.tant\~ i.nno·~inat.a~ 'oegenera'tion of
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`. "in~rilorY\hat' dt¢u~sin "Alzh~im~ris 4i~ease. A.Si~·na~ type of' .
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`·,<dem.entiadsa1sdf9und 'rri' patleptS. wIth'Down'S syndrome that
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`NOVARTIS EXHIBIT 2058
`Noven & Mylan v. Novartis & LTS Lohmann
`IPR2014-00550
`Page 7 of 372
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`;·~hbt.in~·ste~a·se:.·Th~ fi~st grO:up was:"mode', l'~d;p~lma~i iy'onthe . - '.
`• ii~fJtar ~l ~~ici'id~PlJysosti gmin~( a"c~r~~~ate) . and . an ~i·~hibitor. ~f .
`· ¢hoH~~.~terase.'·a!1d· d-t~bcicur~rihe~"~na~t~g6nist' ·of.~~etyl~:
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`'. ···:co~p.o~nds, ·~udi. ~s d ii. so.p~op'y 1 f1 uQ~6~I)OSphoh~te, . par axiln i et·c •. The' :.
`.vast niajorityof .the conipounds. of,both the~ese~ies wer.ed.esigned
`.. : p\iniarily as insect i ci~es. tn the first "groUpof carbam~te dei"i- '.'
`~a~ives, alniost all of the potenti nsectici.des are morio~ethy1
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`15Jhy'siologic~1 pH; .This: g~e~tly'l;~it's"theiiil;~lOgicai action,in
`mainnials 'and makes thf:'!m lE~ss.·s·uita:ble :as 'pharni'aceu'tical or thera-
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`NOVARTIS EXHIBIT 2058
`Noven & Mylan v. Novartis & LTS Lohmann
`IPR2014-00550
`Page 8 of 372
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`fntestinal tract. Edrophonium.neostigm1ne and pyridosti'gmine and'
`...• ~ th~ ·biSq~a1:e~nary.anaiogu~s. a.;eused:in·anaestheti't;:practice for'
`'t~e reve~sal cif the act;'ori ofmuscie relaxants. They are also.
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`,;,y'~tion'of brain;'aCl~tylcho)iri~ activity is desired. These include.
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`NOVARTIS EXHIBIT 2058
`Noven & Mylan v. Novartis & LTS Lohmann
`IPR2014-00550
`Page 9 of 372
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`NOVARTIS EXHIBIT 2058
`Noven & Mylan v. Novartis & LTS Lohmann
`IPR2014-00550
`Page 10 of 372
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`is' commonly' eilcoun'tered with riarcotic.s, .without ·irilpai'r.ingtheir
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`NOVARTIS EXHIBIT 2058
`Noven & Mylan v. Novartis & LTS Lohmann
`IPR2014-00550
`Page 11 of 372
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`NOVARTIS EXHIBIT 2058
`Noven & Mylan v. Novartis & LTS Lohmann
`IPR2014-00550
`Page 12 of 372
`
`

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`". 'c~;~a~'n:c9mp~u:nds fal'~:1~9 'Wit~in thi/a~ri~.~ }Orm~:i.a 'flave pre~
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`.vtously.been described i.e. tht;! m disubstituted compciund in which
`..'·Rland Rj,iH. anci'it2 ;R4and RS ~: ~ethylwhith ~ts' kn~wn as
`.
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`' ..... :Mlotine(R) was claimed to.be an insec;ticide and a'myopH: agent
`5, :fo~ us'~ iileYoe' ~rops.· The .~ dPilib.st ifu~ed c~mpound. i.n '!'thich Ri
`,
`and R2' areinethyl, R3' ~ s H' and R4 an.d RS . are methyl lias been
`.... d~scr'lbed ~sa~in:sect 1cr;ie·. 'The pand q dis'ub~tituted deri-
`. vativesin which Ri' and R3 = H aridR2 .)4' a~cIRS> CH3 have been
`. shOwn to inhibit a prep'aration of liver chOliriesterase~ The m'
`disubstituted derivative 'in WhiCh'R1 =. H .alldR2,:R3, R~ and RS '"
`CHi has 'alsobeen shown fo irihibit'li~er cholinest·~r'ase.
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`:'1he remai n1ng c;mpounds' ~r.e bel,i eyed tobe' ~~vefanilt.~us the'
`....Pr.esent.in·vent i9n 'a 1 so prav; des novel phenYlcarbam~tederiva- .
`. ~ives o(the general formula .1 I
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`:·.RZ :i.S·hycirog~n·,··jl1EithYl~ettiY1o~prOPY1:,,or .
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`NOVARTIS EXHIBIT 2058
`Noven & Mylan v. Novartis & LTS Lohmann
`IPR2014-00550
`Page 13 of 372
`
`

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`....:.: R:,i"aild Rsf':a:re 'the same' or differehFandeachit~ 'lower alkyl; .: .
`.,>.":.·:·:·a~d ,the di alkyYami'no;i'lkyl gr'~up '1s'in the meta, ortho or para'
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`•. ~ '.:~ci.~Pou~d~\'Iherein R4 and R5 a~e:.botil m~thyl arid h~vingtheC .
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`i ~ hydrogen', . Rl i sriei ther hydrogen nor methyl, and when R2 and
`. Rj'ar~ methyl ~Rl is not hydrogen,'~ndfor compounds wherein R4
`and Rs a~.e both methyl andh;iving the dialkyHmi.no group in the
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`10
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`, ' . prefer~ed com~dlindS ~jf ~he ~bdv~f~rmula' are N~ethyl-3';(1-(dl- .
`m~thyl ami ~o)ethYljph~nYl'carb~mat~, N~propyl-3ci~fdi'methyl ami no) -' .
`ethyl ]pheriYl carb'&;'ate;, N-allyl-3-(1-(diinethyl ami~o)ethyl )phenyl
`'~arbainate: N-'e{h;d~ 'N'';methyl-3ci-" (dimeth'yl ami'~~)ethyl Jph~nyl
`·
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`carbam.ate'~ N ,N-dj ethyl';3(1~( dimethyl ami no )ethyl ]phenyl carbamate,
`.' 'N_b~tjl_3'_(i_(dimethy{~ino)ethyl jphenyl carbamate;N-meth'y1;
`-: "N~prcipyl-3[1';;( dimeth)tl ami no)ethyl ]phei1yl.carbaniate~ndN-ethyl,
`';,~~~methyl ~3(l- (d imethyrami rio) i sopropyl]phenyl carbamate ..
`. , .. : .. :
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`26A5 in~icated~ .. the i,;~~;'tioll ~J~o includes t'h~'ph'ar'macQlo9fcally
`,acc~ptable salts ~fthese compoun~s; such' as' the acetate, 5a'11cy(cid:173)
`'1 ate~ ·fu~~r,~te~.: ptiOSPh,~t'e;sulphate~::-~al e'ate, su~cinat~, citrate,
`~ar:trfli~~ p.riipf~nat'e~~dtiutyr~te 'sal tsther~of;' "
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`NOVARTIS EXHIBIT 2058
`Noven & Mylan v. Novartis & LTS Lohmann
`IPR2014-00550
`Page 14 of 372
`
`

`

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