P aperN o.__
`D ate Filed :September25,2017
`
`Filed O n B ehalf O f:
`N ovartis A G
`
`B y:
`N icholas N .Kallas
`N Kallas@ fchs.com
`ZortressA finitorIP R@ fchs.com
`(212)218 -2100
`
`UN ITE D S TA TE S P A TE N T A N D TRA D E M A RK O FFIC E
`
`B EFO RE TH E P A TEN T TRIA L A N D A P P EA L B O A RD
`
`P A R P H A RM A C EUTIC A L ,IN C .,
`
`P etitioner,
`
`v.
`
`N O V A RTIS A G,
`
`P atentO wner.
`
`C ase IP R2016-0147 9
`P atentN o.9,006,224
`
`N O V A RTIS ’S P A TE N T O W N E R O B S E RV A TIO N S O N
`C RO S S -E X A M IN A TIO N O FD R.M A RK J.RA TA IN
`
`
`D ate Filed :September25,2017
`
`Filed O n B ehalf O f:
`N ovartis A G
`
`B y:
`N icholas N .Kallas
`N Kallas@ fchs.com
`ZortressA finitorIP R@ fchs.com
`(212)218 -2100
`
`UN ITE D S TA TE S P A TE N T A N D TRA D E M A RK O FFIC E
`
`B EFO RE TH E P A TEN T TRIA L A N D A P P EA L B O A RD
`
`P A R P H A RM A C EUTIC A L ,IN C .,
`
`P etitioner,
`
`v.
`
`N O V A RTIS A G,
`
`P atentO wner.
`
`C ase IP R2016-0147 9
`P atentN o.9,006,224
`
`N O V A RTIS ’S P A TE N T O W N E R O B S E RV A TIO N S O N
`C RO S S -E X A M IN A TIO N O FD R.M A RK J.RA TA IN
`
`
`
`P aperN o.__
`D ate Filed :September25,2017
`TA B L E O FC O N TE N TS
`
`I. P N ETs A nd C arcinoid s W ere Evalu ated SeparatelyA nd Tested
`W ithD ifferentExperimentalTherapies..........................................................1
`
`II. There Is N o Evid ence ThatResistance To Second -L ine Therapy
`In A d vanced P N ETs W ou ld B e L imited To C ytotoxic
`C hemotherapies...............................................................................................1
`
`III. D u ran A nd Öberg2004 W ou ld N otH ave P rovid ed A
`Reasonable Expectation O f Su ccess................................................................5
`
`IV . RA D IA N T-3Resu lts W ou ld H ave B een Unexpected O verThe
`P riorA rt...........................................................................................................8
`
`V . Su nitinib D id N otM eetThe L ong-FeltN eed Exclu sive O f
`Everolimu s.......................................................................................................9
`
`V I. The Inventors A nd N ovartis H ad Expertise W ithP N ETs...............................9
`
`i
`
`
`
`P aperN o.__
`D ate Filed :September25,2017
`TA B L E O FA B B RE V IA TIO N S
`
`Ex.1011,D u ran,I.,et al.,“A P hase IITrialO f Temsirolimu s
`In M etastatic N eu roend ocrine C arcinomas (N EC s),”J. Clinical
`Oncology 23(16S):215S (2005)
`
`Transcriptofthe A u gu st28 ,2017 D eposition of M arkJ.Ratain
`
`neu roend ocrine tu mors
`
`Ex.1027 ,Öberg,K.,“TreatmentO f N eu roend ocrine Tu mou rs
`O f The GastrointestinalTract,”Oncología 27 (4):18 5-8 9 (2004)
`
`pancreatic neu roend ocrine tu mors
`
`N ovartis’s P atentO wnerResponse in Par Pharm., Inc. v.
`Novartis AG,IP R2016-0147 9,P aper17 (filed M ay11,2017 )
`
`P etitioner’s Replyin Par Pharm., Inc. v. Novartis AG,
`IP R2016-0147 9,P aper21 (filed A u g.3,2017 )
`
`D u ran
`
`Ex.2111
`
`N ETs
`
`Öberg2004
`
`P N ETs
`
`P O R __
`
`Reply__
`
`ii
`
`
`
`P aperN o.__
`D ate Filed :September25,2017
`I. P N E Ts A nd C arcinoids W ere E valu ated S eparately
`A nd Tested W ithD ifferentE xperimentalTherapies
`
`In Ex.2111 at25:9-11,28 :18 -25,and 30:8 -15,D r.Ratain ad mitted thatEx.
`
`2099 evalu ated P N ET and carcinoid resu lts separately,and Ex.2049 onlyenrolled
`
`carcinoid patients.This testimonyis relevantto P ar’s assertion thataP O SA wou ld
`
`reasonablyexpecteverolimu s to effectively treatP N ETs based on Öberg2004 and
`
`D u ran,whichrelate to N ETs,becau se priorartclinicaltrials enrolled bothP N ETs
`
`and carcinoid s.Reply4-6.Itis relevantbecau se itshows thattherapies were notall
`
`ad ministered to bothP N ETs and carcinoid s,and as P arad mitted ,“P N ETs and
`
`carcinoid s may have d ifferentspecific responses to atreatment,”and thu s clinical
`
`trials typicallyevalu ated them separately.Reply6;P O R 9-10.
`
`In Ex.2111 at254:16-255:10 and 256:19-257 :8 ,D r.Ratain ad mitted thata
`
`P O SA wou ld notrelyon Ex.1096’s statementabou tapossible common origin of
`
`d ifferenttu mors,su chas P N ETs and carcinoid s,and thatitwas nottru e in 2005
`
`thatthe tu mors listed in Ex.1096 had similartreatmentprograms.This testimony
`
`is relevantto P ar’s assertion based on Ex.1096 thatP N ETs and carcinoid s cou ld
`
`be treated similarly(Reply5)becau se the testimonycontrad icts thatassertion.
`
`II. There Is N o E vidence ThatResistance To S econd-L ine TherapyIn
`A dvanced P N E Ts W ou ld B e L imited To C ytotoxic C hemotherapies
`
`In Ex.2111 at49:7 -52:18 ,D r.Ratain ad mitted thatExs.2015and 2050
`
`d isclose clinicaltrials enrollingpatients (11 of33and 41 of 43,respectively)with
`
`1
`
`
`
`P aperN o.__
`D ate Filed :September25,2017
`priorcytotoxic chemotherapy.This testimonyis relevantto P ar’s assertion that
`
`molecu larlytargeted therapies were effective afterpriorcytotoxic chemotherapy.
`
`Reply11.Itis relevantbecau se,in Exs.2015and 2050,temsirolimu s failed to
`
`effectivelytreattu mors treated withpriorcytotoxic chemotherapy.P O R 15-16.
`
`In Ex.2111 at52:19-55:17 ,57 :7 -14,59:2-13,62:25-63:9,63:20-64:4,and
`
`66:24-67 :8 ,D r.Ratain ad mitted thatEx.1118 d iscloses atemsirolimu s P hase II
`
`trialin lymphoma,whichwas treated d ifferentlyfrom P N ETs;thatEx.107 8
`
`d iscloses an EGFR tyrosine kinase inhibitorP hase IItrialin squ amou s cell
`
`carcinomaof the head and neck,whichwas treated d ifferentlyfrom P N ETs;and
`
`thatEx.1116 d iscloses d u alEGFR and H ER2 inhibitorlapatinib stu d ies focu sed
`
`on breastcancer,notP N ETs.This testimonyis relevantto P ar’s assertion that
`
`molecu larlytargeted therapies exhibited antitu moractivityafterpriorcytotoxic
`
`chemotherapy.Reply11.Itis relevantbecau se there is no evid ence su pportinga
`
`reasonable expectation foreverolimu s in P N ETs and D r.Ratain fu rtherad mitted
`
`thathe d id notsu ggestthataP O SA cou ld make reasonable pred ictions for
`
`everolimu s based on anothercompou nd (su nitinib).Ex.2111 at33:17 -34:19.
`
`In Ex.2111 at101:13-104:7 ,D r.Ratain ad mitted thatExs.1092 and 1098
`
`d o notconcern the efficacyof molecu larly targeted therapies.This testimonyis
`
`relevantto P ar’s assertion thatthe mechanism of P N ET resistance to molecu larly
`
`targeted therapies wou ld notbe the same as forcytotoxic chemotherapies.Reply
`
`2
`
`
`
`P aperN o.__
`D ate Filed :September25,2017
`11;Ex.1119 ¶ 31.Itis relevantbecau se itshows thatneitherofD r.Ratain’s
`
`references concerningd ru gresistance ad d resses molecu larlytargeted agents.
`
`In Ex.2011 at24:5-14 and 25:9-26:7 ,D r.Ratain opined thatExs.1090 and
`
`2049 are “appropriatelysilent”on whetherresu lts were the same withand withou t
`
`priorcytotoxic chemotherapybecau se “it’s u nclearif there wou ld be enou gh
`
`patients… to d raw any comparisons”and “in an abstractone has alimited amou nt
`
`of space.”This testimonyis relevantto P ar’s assertion thatpriortreatmentwou ld
`
`notlikelyaffectthe resu lts becau se the priorartd id notcompare resu lts forP N ETs
`
`withand withou tpriorcytotoxic chemotherapy.Reply11-12.Itis relevantbecau se
`
`itcontrad icts P ar’s assertion that“[a] P O SA wou ld have expected anysu ch
`
`d ifference to be reported ”as there are otherreasons fornotreportingacomparison.
`
`In Ex.2111 at117 :17 -24 and 120:11-122:19,D r.Ratain ad mitted that
`
`streptozocin and chlorozotocin are alkylatingagents,5-flu orou racilis an
`
`antimetabolite,and d oxoru bicin is an anthracycline,and eachhas ad ifferent
`
`mechanism of action.This testimonyis relevantto P ar’s assertion thataP O SA
`
`wou ld be motivated to u se anticanceragents withd ifferentmechanisms of action
`
`and wou ld notexpectthe claimed P N ETs to be more resistantto ad ifferent
`
`therapy.Reply11.Itis relevantbecau se itconfirms thatP N ETs were stillhard erto
`
`treatwhen the above therapies withd ifferentmechanisms of action were u sed as
`
`second -line therapies.P O R 13-15.
`
`3
`
`
`
`P aperN o.__
`D ate Filed :September25,2017
`In Ex.2011 at111:13-113:5,D r.Ratain ad mitted thatthe same mechanism
`
`of resistance wou ld notapplyto allcytotoxic chemotherapies.This testimonyis
`
`relevantto P ar’s alleged “generalru le”thatP N ETs were less likelyto respond to a
`
`second -line cytotoxic chemotherapy.Reply 11.Itis relevantbecau se itshows
`
`mu ltiple mechanisms of resistance existed ;and becau se the stu d ies consistently
`
`showed thatP N ETs were resistantafterfailu re of cytotoxic chemotherapy,aP O SA
`
`wou ld notreasonably expecteverolimu s to overcome su chresistance.
`
`In Ex.2111 at106:13-107 :12 and 109:2-113:5,D r.Ratain ad mitted thatEx.
`
`1092 ind icates thatmu ltiple factors u nd erlie d ru gresistance,inclu d ing
`
`pharmacologic factors,e.g.,inad equ ate d ru gexposu re and inabilityto penetrate
`
`into poorlyvascu larized regions of alarge tu mor,and cellu larfactors,e.g.,
`
`d efective d ru gtransportacross the cellmembrane and altered levels of atarget
`
`enzyme,and thathe had notconsid ered whether,forexample,d evelopmentof
`
`poorlyvascu larized regions in tu mors wou ld red u ce efficacyof molecu larly
`
`targeted therapies,su chas mTO R inhibitors.This testimonyis relevantto P ar’s
`
`assertion thatD r.Ku lke’s priorartd emonstratingthatP N ETs were resistantto
`
`treatmentafterfailu re of cytotoxic chemotherapyare irrelevantto whethersu ch
`
`P N ETs wou ld be resistantto everolimu s.Reply11.Itis relevantbecau se it
`
`d emonstrates thatP ar’s assertion is u nsu pported .
`
`In Ex.2111 at114:3-25,D r.Ratain ad mitted thatEx.1092 states thatfailu re
`
`4
`
`
`
`P aperN o.__
`D ate Filed :September25,2017
`of cancercells to engage in apoptosis cou ld u nd erlie resistance.This testimonyis
`
`relevantto P ar’s assertion thataP O SA wou ld notreasonablyexpectad vanced
`
`P N ETs afterfailu re of cytotoxic chemotherapyto be resistantto everolimu s.Reply
`
`10-11.Itis relevantbecau se Ex.1092 states thatchanges in the expression of the
`
`B C L 2 and p53genes involved in apoptosis were potentiallylinked to d ru g
`
`resistance,and D r.Ku lke explained thatbcl-2 and mu tantp53were also associated
`
`withrapamycin resistance,and P N ETs overexpressed bcl-2.Ex.2041 ¶ ¶ 7 6,7 8 .
`
`III. D u ran A nd Öberg2004 W ou ld N otH ave
`P rovided A Reasonable E xpectation O f S u ccess
`
`In Ex.2011 at24:5-14,D r.Ratain opined thatforEx.1090,“it’s u nclearif
`
`there are enou ghpatients… to d raw anycomparisons”between patients withand
`
`withou tpriorcytotoxic chemotherapy.This testimonyis relevantto P ar’s assertion
`
`thatD u ran (Ex.1011)teaches the efficacy of temsirolimu s in N ETs afterfailu re of
`
`cytotoxic chemotherapy.Reply1,21.Itis relevantbecau se D u ran evalu ated only
`
`15patients,as compared to 37 in Ex.1090 (Ex.2111 at23:14-24 and 128 :11-
`
`129:15),and thu s,D u ran is likewise “appropriatelysilent”and aP O SA wou ld not
`
`d raw reasonable conclu sions regard ingefficacyaftercytotoxic chemotherapy.
`
`In Ex.2111 at129:20-130:12 and 131:7 -16,D r.Ratain ad mitted thatthe
`
`D u ran patientwithsome tu morshrinkage was stillclassified as havingstable
`
`d isease,notapartialresponse.This testimonyis relevantto P ar’s assertion that
`
`D u ran reports apartialresponse (Reply20)becau se itcontrad icts thatassertion
`
`5
`
`
`
`P aperN o.__
`D ate Filed :September25,2017
`and confirms thatD u ran onlyobserved stable d isease.Itis also relevantto P ar’s
`
`assertion thattemsirolimu s had antitu moractivitybased on D u ran (Reply20-21)
`
`becau se D r.Ratain ad mitted thatin 2005,aP O SA wou ld know thatN ETs are “an
`
`ind olentd isease forwhichone wou ld expectahighrate ofstable d isease in the
`
`absence oftreatment.”Ex.2111 at146:25-148 :6.
`
`In Ex.2111 at14:22-15:24,D r.Ratain agreed thatEx.1112 reported that11
`
`of 16 N ET patients had stable d isease atthe med ian evalu ation time of 12 weeks,
`
`bu tthe au thors conclu d ed thatthey “cannotattribu te stable d isease to the antitu mor
`
`effectofbortezomib in ou rsingle-arm stu d y”d u e to the slow-growingnatu re of
`
`N ETs.This testimony is relevantto P ar’s assertion thattemsirolimu s had antitu mor
`
`activitybased on D u ran.Reply20-21.Itis relevantbecau se D u ran reports 10 of 15
`
`patients had stable d isease similarto Ex.1112,bu tbortezomib (amolecu larly
`
`targeted therapy(Ex.1119 ¶ 37 ))was notconsid ered active.1 Ex.1112 at6117 .
`
`In Ex.2111 at17 8 :12-17 9:3,D r.Ratain agreed thatin the RA D IA N T-3trial,
`
`20.6% ofpatients on placebo had d ecrease in tu morsize and 5.3% had no change.
`
`1 To the extentP arargu es thatEx.1112 is d istingu ishable from D u ran becau se it
`
`d id notexpresslyrequ ire enrolled patients to have progressive d isease,D r.Ratain
`
`ad mitted thatpatients cou ld enrollin the D u ran stu d yif theyd emonstrated clinical
`
`d eterioration withou tan increase in tu morvolu me (Ex.2111 at133:22-134:20);
`
`thu s,D u ran also was notlimited to patients withgrowingtu mors.
`
`6
`
`
`
`P aperN o.__
`D ate Filed :September25,2017
`This testimonyis relevantto D r.Ratain’s assertion thatstable d isease in treated
`
`progressive tu mors su ggests thattemsirolimu s had antitu moractivity.Reply20-21.
`
`Itis relevantbecau se RA D IA N T-3requ ired patients to have progressive d isease
`
`priorto enrolling,bu t25.9% ofpatients had ad ecrease orno change in tu morsize
`
`d espite receivingno active treatment(Ex.2022 at515,520),whichis consistent
`
`withD r.Ratain’s ad mission thatin 2005aP O SA “wou ld expectahighrate of
`
`stable d isease [in N ETs] in the absence oftreatment.”Ex.2111 at147 :15-23.
`
`In Ex.2111 at132:14-133:21,D r.Ratain ad mitted thatD u ran d oes not
`
`reportthe progression free su rvival(P FS)and “itwou ld be d ifficu ltto d iscern from
`
`the limited d atain the abstract.”This testimonyis relevantto D r.Ratain’s assertion
`
`thatD u ran reports similarresu lts to Ex.2099.Ex.1119 ¶ 7 1;Reply21.Itis
`
`relevantbecau se Ex.2099 reports a40-weekmed ian P FS and 9 patients with
`
`partialresponses,whereas D u ran reports no med ian P FS and no partialresponses.
`
`In Ex.2111 at95:4-97 :8 ,D r.Ratain ad mitted thatEx.1064 d iscloses the
`
`firstP hase Itrialforrapamycin in cancerpatients and itwas notd irected to N ETs.
`
`This testimonyis relevantto P ar’s assertion thatthe “planned ”clinicaltrialof
`
`rapamycin mentioned in Öberg2004 (Ex.1027 )wou ld have provid ed areasonable
`
`expectation of efficacy in P N ETs.Reply19-20.Itis relevantbecau se Ex.1064 was
`
`pu blished in 2006 and there is no evid ence thatanyrapamycin clinicaltrialwas
`
`“planned ”in N ETs orP N ETs as of N ovember2005.
`
`7
`
`
`
`P aperN o.__
`D ate Filed :September25,2017
`In Ex.2111 at68 :15-7 2:11 and 266:21-267 :21,D r.Ratain ad mitted thatExs.
`
`107 1 and 107 3d isclose thatGleevec failed to treatcertain tu mors in P hase IItrials
`
`and rid aforolimu s (an mTO R inhibitor)entered clinicaltrials bu twas neverFD A
`
`approved .In Ex.2111 at197 :5-199:10,D r.Ratain also conced ed thatothers tried
`
`and failed to d evelopmethod s oftreatingthe claimed P N ETs.See also supra at6.
`
`This testimonyis relevantto P ar’s assertion thatthe “planned ”rapamycin clinical
`
`trialin Öberg2004 wou ld provid e areasonable expectation ofsu ccess.Reply19-
`
`20.Itis relevantbecau se mu ltiple “planned ”clinicaltrials failed and thu s,Öberg
`
`2004 wou ld nothave provid ed areasonable expectation of su ccess.
`
`IV . RA D IA N T-3Resu lts W ou ld H ave B een Unexpected O verThe P riorA rt
`
`In Ex.2111 at199:17 -200:20,D r.Ratain conced ed thatÖberg2004 (Ex.
`
`1027 )and D u ran (Ex.1011)are “the closestpriorart”and foru nexpected resu lts,
`
`“one wou ld tryto d o acomparison of whatwe know abou tthe u se of rapamycin…
`
`and … temsirolimu s forneu roend ocrine cancer… d epend ingon whatd atawere
`
`available.”This testimonyis relevantto P ar’s assertion thatD r.Ku lke d id not
`
`compare everolimu s withthe closestpriorart.Reply22-23.Itis relevantbecau se
`
`D r.Ku lke compared the RA D IA N T-3resu lts foreverolimu s withwhatwas known
`
`abou tthe u se of rapamycin and temsirolimu s forP N ETs.Ex.2041 ¶ ¶ 261-65.
`
`In Ex.2111 at17 6:5-12,D r.Ratain ad mitted thatmore was known abou t
`
`mTO R inhibitors and P N ETs in 2011 than 2005.This is relevantto P ar’s assertion
`
`8
`
`
`
`P aperN o.__
`D ate Filed :September25,2017
`thatEx.2022 d oes notd escribe everolimu s’s resu lts aftercytotoxic chemotherapy
`
`as u nexpected (Reply24)becau se Ex.2022 was based on 2011 knowled ge.
`
`V . S u nitinib D id N otM eetThe L ong-FeltN eed E xclu sive O f E verolimu s
`
`In Ex.2111 at194:3-195:2,D r.Ratain ad mitted thathis long-feltneed
`
`opinion is based on D r.Ku lke’s priortestimonyand the ongoingneed fornew
`
`N ET therapies.This testimonyis relevantto P ar’s assertion thateverolimu s d id not
`
`meetalong-feltneed .Reply25.Itis relevantbecau se in Ex.1095at7 99:3-16,D r.
`
`Ku lke testified thatalthou ghthere is stillaneed ,“thatshou ld notnecessarily
`
`overshad ow whathas reallybeen abigtransformation in the field withthe
`
`d evelopmentof these new therapies”of which“[e]verolimu s has also been part,”
`
`ind icatingthateverolimu s metalong-feltneed .
`
`V I. The Inventors A nd N ovartis H ad E xpertise W ithP N E Ts
`
`In Ex.2111 at222:16-23,226:10-227 :11,228 :16-21,and 267 :24-269:7 ,D r.
`
`Ratain ad mitted thatN ovartis had expertise withP N ETs,inclu d ingworkingwith
`
`EN ETS (Eu ropean N eu roend ocrine Tu morSociety)and d evelopingmu ltiple
`
`P N ET therapies.This is relevantto P ar’s d iscu ssion ofthe inventors’experience.
`
`Reply2-3.Itis relevantbecau se D r.Ratain fu rtherad mitted thatitwou ld be
`
`reasonable to assu me thatthe inventors learned information relevantto P N ETs
`
`from otherN ovartis employees.Ex.2111 at220:13-221:15.
`
`D ated :September25,2017
`
`/N icholas N .Kallas /
`N icholas N .Kallas (Reg.N o.31,530)
`
`9
`
`
`
`P aperN o.__
`D ate Filed :September25,2017
`C E RTIFIC A TE O FS E RV IC E
`
`Icertifythatacopyof the foregoingN ovartis’s P atentO wnerO bservations
`
`O n C ross-Examination O f D r.M arkJ.Ratain were served on September25,2017
`
`bycau singitto be sentbyemailto cou nselforP etitioneratthe followingemail
`
`ad d resses:
`
`D anielG.B rown (d aniel.brown@ lw.com)
`
`Jonathan M .Strang(jonathan.strang@ lw.com)
`
`B rend aL .D anek(brend a.d anek@ lw.com)
`
`D ated :September25,2017
`
`/N icholas N .Kallas /
`N icholas N .Kallas
`Registration N o.31,530
`L ead C ou nselforP atentO wner
`FITZP A TRIC K,C EL L A ,H A RP ER
`& SC IN TO
`1290 A venu e ofthe A mericas
`N ew Y ork,N Y 10104-38 00
`Tel.212-218 -2100
`
`10
`
`
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