Case 1:16-cv-01221-LPS Document 69-1 Filed 07/17/18 Page 1 of 14 PageID #: 654
`Case 1:16-cv-01221-LPS Document 69-1 Filed 07/17/18 Page 1 of 14 PageID #: 654
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`EXHIBIT A
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`EXHIBIT A
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`

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`Under (in: We
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`
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`Ceniinued Examinatien {RCEE
`"E‘g‘afigmgfiag
`
`Case 1:16-cv-01221-LPS Document 69-1 Filed 07/17/18 Page 2 of 14 PageID #: 655
`Case 1:16-cv-01221-LPS Document 69-1 Filed 07/17/18 Page 2 of 14 Pa;%‘?nla%§§s§;§§m
`Apprcve-fi far; use through 027m“:i20i£?.<3'i»’i.53'085“.1993":
`
`*3" Minimal
`«weewewmy
`13523552; Cont". New; 3432
`Appiicetiun Number ~ June 15%
`
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`
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`‘
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`...................................................1 eeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeee
`Firs: Named inventor
`Scat: Wiiheim
`Ari Unit
`1629
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`Addreseto:
`' MaiEStep RCE
`
`Coar‘amissaicriei‘ fer Patents
`. Raymend J. Heniey
`Examiner Name
`pic}; 393(1450
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`""""'"""""'""""""""""""""""""""""""
`”””””””””””””””
`Aiexaridria. VA 22313-1456
`
`
`Nmy.“M...“‘v.w“\u\»wu\uwu\uwu\uwwu\“wv\mmuu».wu\u\»wu\uw“\umu\uwwu\m. v.\mmuu».mu\u\»mu\um“\uwu»wu\wmwWMw~wwm~www~Wafi
`
`wwvwwmmwW‘MMW‘W‘M‘
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`
`Niamey Becket Number
`E BAYER-3M3
`“.3
`
`' This is a Regime: fer fientinued Examinatian (Rea) uncles" 3?’ CFR 1.114%f the aboveuidemified appiicatien.
`Request for Ceniinued Examination (REE) practice under 33’ CFR 1.1% does not appiy to any uiiiity 0r piani appiication flied prim to
`
`
`w. W WV“ \
`June 8, 1995. or to any design appiicaiicm. See insiruciion Sheet for RCES (mi it: be submitted to ihe USPTO) em page 2.
`
`
`
`i, {MWMMWWWWWWMW
`
`.w- Nate: if the RCE is W098i. any previousiy fried unefltered
`..“5i3.2%”:Eiiifii‘iiiiflii‘iflgiifiZfiffifisjfi ‘3
`
`
`55' ESE: wiii be eniered in the erder in which they were iiieci uniese applicant
`emeriijn‘sents and emendmenie encieeesj w,
`j i
`ineia‘ueis otherwise. if eppiicarsi daes n01 wish in have any pa’evieusiy fiierfi uneniered arixendmentis) entered, zappiieani muet
`requeet neweniry of gush amendmenfis).
`
`a. C} Previousiy submitied. if a fine! fiffiee autism is eutetancfiing, any amenrjmeme filed afier the finai Cffice action may be
`CSiiSidei’i-l‘d as a submission even if this be): is. not checked.
`
`E: Congider the arguments in the Repiy previoueiy flied an ____________ .
`i.
`iii Other ____________
`ii.
`i). K Enciesed
`i.
`Amendmentl‘Repiy
`ii
`{:5 Affidavitisiffleciaraiionie)
`
`iii.
`iv.
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`[3 informaiien Dieeiosure Statement (iDS)
`{:1 {Ether
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`
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`Misceiianeeus
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`a. C: Sueeension oi eciien an the above-identified application is requested under 3? CFR 1.103(0) fer
`a periafi of wmmflmi‘rmPaths. (Pea‘ied of euseensiori ahaii not exceed 3 menihs. Fee under 3? CFR. 1.176) required)
`b. {:3 Other
`
`Feee - The ROE fee under :47 CFR. iifle‘; is required by 37' CFR. 1.1M when the RCE is flied.
`The Director is hereby auiiwerized to charge the required fees, er credit {my overpayments, t9 Depasii Account
`No.13u3402 .
`
`[3 RICE fee required under 37 GER. 1.17(e)
`{:5 Extensien 0f time fee (a? GER. 1.136 and 1.17)
`{:3 Ether ____________
`Check in the amount of $ mm enciosed
`Payment by credit car-:5 (Form PTGV‘zess enciesed)
`_; WARNENG: informatien era thie farm may heteme pubiic. Credit card:
`Previde credit card information and authorization cm PTQQQES.
` ‘\\m\\§v§~n~n~§
`ran““‘“‘“““““\““‘“‘““v“
`
`inforrrizaiiori shouifl net be inciurjeei en thie iorm.
`
`3
`
`
`Signature
`Name (Prim mes)
`
`
`Richard J. Traverse
`
`SiGNA HIRE 9F APPLKJANE A TTORNEY, OR AGENT REQUIKEE
`
`Nevember 5. 201.3
`
`.I’Richard J. Traverse."
`
`. 30.595
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`gate
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`Registraiien Ne.
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`I
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`CERTiFiCA TE OF MAKING GR TRANSMiSSiQN
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`i hereby cedify 2m.
`enveiepe addreeeei
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`
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` m
`
`I Name (Prim Hype}
`mafia" i3 wank-4" "
`rsiiaiixfe is governed ‘“ 35 USS i212 and :3? CFR 1.11 and 1 1-4. Thie coiieciien is estimated it: iake 12
`i0 20 precess; an 23;? Cams“:
`rm
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`minutes in compiete. inciuc‘ing gathering. preparing. and submitting the ec-meieted appi'
`‘c-n form to the USPTO.
`' 'me wiii van; depending upen {he
`
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`individual case. Any comments on the amouni 9? time you require it; campiete this form a
`In suggestiane for reducing this burden, shouid be sent is ihe
`Chief infermati-nn Officer. US. Patent and Traderriark Office, US. Deparimen: of Currimerce. 9.3-. Box. 14516. Aiexandria. VA 2231344543. DCI NOT SEND
`FEES OR COMPLETED FORMS TQ THES ADDRESS. SEND “f0: Maii Step REE, Cemmieeiener for Patents. P13. Bax iii-59, fliexandria, VA 22313-
`MSG.
`
`If yes: need assistance in mmpfetmg the) farm, can 7--800»P'§‘O-9 139 and seiect when 2
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`BAYER_ST|VARGA_00002182
`
`

`

`Case 1:16-cv-01221-LPS Document 69-1 Filed 07/17/18 Page 3 of 14 PageID #: 656
`Case 1:16-cv-01221-LPS Document 69-1 Filed 07/17/18 Page 3 of 14 PageID #: 656
`
`EN THE ENETED STATES PATENT ANB 'E‘RAEHCIWARK (HW‘ECE
`
`in "re Appiiaafion Of:
`
`Semi ‘WELHELM a? a1.
`
`Examiner: Henie‘y HIE, Raymenfi .3
`
`Seriai No.1 12/523,652
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`{Emu}; Ari Unit: 1629
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`Filed: June: 15, 2018
`
`Cenfirmmimu Ne; 3432
`
`Titifi:
`
`'I‘REfifl'k/EENT GE? CANCERS “WITH ACQUERED
`RQEESESTANCE TO KIT ENHEBITQRS
`
`1151-115111xu1-11‘xmi
`SEBREESSKEN 331$"?H RACE
`
`Mai} Smp: REE}:
`Commifisioner for Patents
`
`PEG” Box MSG
`
`Alexandria, VA 223 E 34 450
`
`Sir:
`
`Eh respwnse t0 the tastiest of Aiiewance dated August 9“ EMS, Applicants Submit the
`
`{Miewing amendments m acmmpany the Request for Ceniimued Examinatien flied
`
`cencuncnfiy in the abeve appiicafien:
`
`2‘2:
`5,
`a
`Amemfimeme m the Chime are reflected in the 133.3% m "5 efciaims which begins an age 2
`
`of this paper.
`
`RemarkfiiArgumentfi begin 311 page 1 1 {sf this paper»
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`~ 1 »
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`IKECKET NO: BA"§:’EZR~G§43
`
`BAYER_ST|VARGA_00002183
`
`

`

`Case 1:16-cv-01221-LPS Document 69-1 Filed 07/17/18 Page 4 of 14 PageID #: 657
`Case 1:16-cv-01221-LPS Document 69-1 Filed 07/17/18 Page 4 of 14 PageID #: 657
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`’BT'his listing efeiaims wiii replace 3&1 prier versiensg and listings? ofeleims ii} the application:
`
`Listing ef Chime:
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`1.
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`(Originai) A mefbecii 13f treating a cancer in a subject in need. thereef, wherein said
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`cancer was initiai if; sensitive to Ki"? tyresine kinase inhibiier and aeguimci resistance :9 said KIT
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`tymeine kii’lase inhibiier, Said methed wmprising:
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`aciministering te said 31.;bject, an effective ameunt 9f 4{4«{3~{4udflerem3w
`
`trifleommeihyiphenyi)~‘ureidoj “‘3 w'fluemphenoxy} upy‘ridi n_e~2-cerbexyfi ic acid met} yiemide Cafthe
`
`fermuia E heiew illeiuding 2111 pelymorpha‘sg hydrates, pharmaceutieaily aceepiabie salts,
`
`meta‘boiites, ymd‘rugsg seivates er mmbinefieng thereofo
`
`‘I‘an‘
`,
`CE “VI“;T‘TN‘ {13%;}
`i
`
`R Q»,-
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`Q
`ii
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`«5“
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`x
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`\T3‘%,r0‘3“???” N29?!“
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`V, C H e
`
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`(a)
`
`:3
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`1’
`‘
`Previeusb“ resented}
`
`A method as in claim} wherein fize cancer 11213 as: mixed
`
`resistance to one Ofthifi £6110“;ng KI? inhibiters:
`
`imaiimib mesyieie! 521113 01" imafinib meeyiefie; PP1{:4—Amine-—5{4=methyiphenyly74t~
`
`'butyimymzobfifiejpyrimidine); MENS 13 (5153518); PUZSGEWB; EU 1 124-81 $135416;
`
`$115414; $565977; 8156663 018116561.
`
`3.
`
`{Previeusiy presented) A methed an; in elaim 1 wherein said cancer is ene 01' were of a
`
`maiignam gestreiniestinai siremai tumor (GET), 2; Benign gesfiointesfiinai stremai tamer
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`(815?), a, £11ese11c2'1y13131 tumor 9f the intestinal tract chronic myeiegenous leukemia {{ZiMLL), a
`
`mast eel} turner, SCLC, a gem: cell Meyers, breast gamer; and/0r neurobiastonm
`
`4‘
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`{Previously presented) A method as in claim 1 wherein the cancer has acquired
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`resistance t0 imatizfib mesyiate,
`
`- 2 ~
`
`HOCKEY" NO: BAY EEK-@143
`
`BAYER_ST|VARGA_00002184
`
`

`

`Case 1:16-cv-01221-LPS Document 69-1 Filed 07/17/18 Page 5 of 14 PageID #: 658
`Case 1:16-cv-01221-LPS Document 69-1 Filed 07/17/18 Page 5 of 14 PageID #: 658
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`5.
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`(Previeusty mesemed)
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`A methad of claim t, wherein said acquired reeietamze
`
`et‘ saic‘t cancer is assecieted with a Seez‘pridmy nmtatien in a KIT gene mutated in the primary
`
`turner.
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`6.
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`(Previoueiy presented) A mefimd ef claim 53 wherein said seeenday mutatien is in the
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`kinase catalytic. demain.
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`7",
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`(Previeusty preeented)
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`A method as in claim 5 wherein the mutation is in Exens
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`E3” 14, and at E7,
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`85
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`{E’revieusly ptfesen‘iett}
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`A ttlfiithfxi as in claim 5 wherein the mutatien is at residues
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`6:34,, 679, 716,816, 3203 322, amt 32,3
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`9.
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`(Previeusiy presented)
`
`A methed as in eiaim S ‘4 'herein the mutation is at residues
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`55G~654.
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`m
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`(Previeusiy yresented)
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`A methed as in claim 5 wherein the metatien is at residues
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`67G~67£§x
`
`t i .
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`(Previously gt‘esen’ted)
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`A methed as in shim 5 wherein the mutation i3 at resitiues
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`816~824.
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`12.
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`(Previousiy presented}
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`A me‘thed as £23 etaim 5 wherein the secondary mutatien is
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`em: er more 0f‘E’Y654A {Exam 3 3), 167% (Exam 14'), T679133, {3?} 6N, S’HWF (Exam t4),1)316(t,
`
`{33163—3 (Exam E7), @3203 DSZGY, 1393205 N822K, YSEED (Exam 17), 91* deletiens and other
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`amino acid substitutiens at. such positiens or adjacent pesitiens,
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`13.
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`{Previeuety yresemed)
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`A methed as in stain: 5 wherein the sectandary mutation is
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`{me or mere of
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`i}
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`ii)
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`detetien efamine acid residues 5576582;
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`deietien 0f amine acid residues
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`U“:
`
`51655;
`
`2
`
`:
`
`1.9.)
`
`D GCKET N0; EEiAY‘EEEtuGE 43
`
`BAYER_ST|VARGA_00002185
`
`

`

`Case 1:16-cv-01221-LPS Document 69-1 Filed 07/17/18 Page 6 of 14 PageID #: 659
`Case 1:16-cv-01221-LPS Document 69-1 Filed 07/17/18 Page 6 of 14 PageID #: 659
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`deletion efamine acid residues 556—558;
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`deietien 0f amino acid residues 55.93560;
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`deietien efamine acid residues 557661;
`
`deietien efamine acid residues 546
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`delefien efamino acid residues; 5
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`x)
`“*5
`
`if!
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`mutefiene at residue 559, i11e1uding VSSQD, ViSQAS er V3598;
`
`mumfiens at residue 56$), including VSfifiD, Vfifififi, 01‘ V5606;
`
`W’Sfii’S; aiene, er in eembinmien with a deie’tien 05? 311113110 acids 552556;
`F:Il
`mutations at amine acid; residue :35 , ineiufiing W557R; anti
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`inmatiem at amine acid residue 576, including LS?€3P.
`
`xi)
`
`xii)
`
`E4:
`
`15.
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`{Efirevieusiy presea'lted)
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`A z'l‘iefhefl as in eiaim “2 wherein the seeemiary mutafijen is
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`deieflen 0f reeidues 5571558 and at 16:23.3? One ef the i’efiewing mutations: V654?“ T6701?
`
`ELESZZflYg N822}; {31” 3782313.
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`{Origin ai) A mefimfi 0f treating a. cancer in a subject in need thereef Said cancer
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`having. a primary andi’er seeendary KN? gene mutation in the primary miner, said Ineihfifj
`
`eempnsmg:
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`administering :0 said subjeetg an effective amount efthe eempeund 4~{4»{3-{4«eh§em~
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`3Kirifiuemmethylphenyi)mureidoj$«fiuerephemexy2» ~§§§rri<fiii‘xemliiwarbexyEie acid n'xethyiemide of
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`the fermela E beiew including aii pelymerphss hydrategfi phammceu‘tieafiy aeeeptabie 32:31:55,
`
`metabeiites, ester pl‘edmgs, selvetee er cem‘einatieng thereof.
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`{ii-*3
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`C§\1’”’i‘*\\~.
`it .55:
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`JN
`
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`
`16‘
`
`{Previeusiy presented) A method 0f eiaim 15, wherein said primaay and/’er seeendazy
`
`KET gene mutatien in the primary tumor i3 asseeiated with acquired resistance of said cancer
`
`to KIT ‘Eyreaine kimase inhibitors.
`
`BZBQCKET N0; BAYER-xi) ,E 43
`
`BAYER_ST|VARGA_00002186
`
`

`

`Case 1:16-cv-01221-LPS Document 69-1 Filed 07/17/18 Page 7 of 14 PageID #: 660
`Case 1:16-cv-01221-LPS Document 69-1 Filed 07/17/18 Page 7 of 14 PageID #: 660
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`1",".
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`(Previeusiy presented} A mauled oi’ciaim 15: wherein said secendary mutaiien is
`
`in the iiinase ca‘talyfie {iomain
`
`18,
`
`{Previeusiy presemed')
`
`A matched as in eiaim 15 wherein the il'xutation is in Eixons
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`13, i4, and 0117,
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`E9
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`(Previeusiy presented?)
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`A mail/10d as; in claim £5 wherein the mutatien is at residueg
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`654, 6W1 7E6, 816; 828, 822: and 81333.
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`‘20.
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`(Previeusiy presented)
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`A method as: in claim 15 wherein the mutation is 2v; residues
`
`6504354.
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`21 ,
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`(Previousiy pl‘fiSfii‘i'ii‘iifi)
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`A methed as in Main: E 5 whereii‘z the mu’tatimt is; at residues
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`678—6 74.
`
`22.
`
`(Previously mesented)
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`A methed as in cieim 15 wherein the mutatien is at. residues
`
`8‘: @824.
`
`23°
`
`{Frevieusiy presemefl}
`-Mfi
`
`A methed 2:5; in ciaim 15 wherein the: secondmy mutatixm i3
`
`{me or mere ef‘VfiMA (Exam '13), T6791 (Exam 14), T67CBE,'E:}?16N, $7=§Z=§EF {Eiixon 3,413,138166,
`
`1381613 (E2101: 1?), 3382031 DSZGY, DBZGS NSZZK, ‘(823D {EXOQ 37), Gr deie’iierm and other
`
`amine aeid substitutions at such pesitions or adjaeent pesiiions.
`
`24¢
`
`(Previamsiy presemed}
`
`A 1116‘:th as in claim 15 wherein {he seeomiary mumfien is
`
`en:- er more 0f
`
`1)
`
`ii")
`
`iii)
`
`iv)
`
`v}
`
`Vi)
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`deietien efzu‘nino acid resiiiues 5573558;
`
`deieticn {31’ amino acid resiaiues 55 E «555;
`1
`J? U; m
`
`deietian Qfamine acid reeidues SSE)
`
`deiefien 0f amine acid reeidues 559466;
`
`deieticn 0famine acid residues SS"‘~56§;
`
`5
`deieiien 0E amine acid residues 554: 58;
`
`vii)
`
`deletion Mamie-3 acid residues 1352»557;
`
`5 v
`
`DQCKET NOE: BAYERQMB
`
`BAYER_ST|VARGA_00002187
`
`

`

`Case 1:16-cv-01221-LPS Document 69-1 Filed 07/17/18 Page 8 of 14 PageID #: 661
`Case 1:16-cv-01221-LPS Document 69-1 Filed 07/17/18 Page 8 of 14 PageID #: 661
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`viii} maximums at. residue 559, inciuding X75591} VSS‘E‘A, er V5596;
`
`ix) muiafiens at residue 5695 ineluding V5689, V5693}; 0:“ ‘V’fléGG;
`
`x} WSWS, 310nm 01“ in combinafiien with a deiefion of amine acids 55?.«556;
`
`xii}
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`mutatim‘gs at amine amid residue 557,4 including 1NSS’XR; and
`
`xii) mutations at amine acid residue 576, including L576?
`
`25,
`
`{Previeusiy presenmai)
`
`A methed at: in cEaim 15 wherein the saeandaly mutatien is
`
`deiei‘ien efresidues 557~558 and at fleas: 011i? Ofthe fi'filewing Hawaiians: V654A, WWW,
`
`DEQEEY; NSZEKF or YS‘ZBD.
`
`265.
`
`(E’revieusly presented) A method eftreating a cancer in a swig; eat in need thereof
`
`said cancer having a primary and/0r semndmfi’ KB" gene: mutatien asseciated with resigtamce or:
`
`aequired resistance t0 imminib mesyiate or salts 0f imatinib mcsyiaie, saiefi method comprising:
`
`administering, 10 said subject, an effective ameum ofihe campeund 4{4~§3~{4~chi0m~
`
`3mfrifluemnmthyiphenyi)»ureid9]~3~fiu0mphenoxy§ ~pyridine~2mcarbaxylic. acid meihylamide 0f
`
`the farmula I belew inciufiing ail paiyma‘mms, hydrates, pharmaceuticaiiy flammable sake?
`
`membeliieej ester pmdmgsfi Sniwfieg er mnflsina‘tiom thereaf.
`
` £93
`
`§‘
`
`8
`
`F
`
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`1
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`f» ’2 \\g2»(v \:\§‘i.‘-' ktfii‘jé" SRXNH//
`er”
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`
`CH
`
`3
`
`i
`
`( 5
`
`27.
`
`{VPYSVEQU-ffiy presented);
`
`A methed fer {waiting cancer in, a human subject with
`
`imafiinib mesyiaie er Baits of imaiini‘o mesyia‘ieg which addiiienafiiy wmprisss;
`
`administering to Said hum an subjz set, an efl‘ecfive ameum 056,116: compound 4 {4% {4n
`
`ch10r0~3 mtrifl‘uoremeih yiph $13311)!» .11'61603-3 «fluemphenexfl "pyridinenLZ—aarbexyiic
`
`acid
`
`methyiamide 01E the formuia I 'behvw including a5} poiymmph?».~ hyciratesg pharmaceuticaiiy
`
`accegfiable wits, metabolites: ester pmdmgg, seivates m“ cambina’tiem thereof,
`
`, 6 -
`
`'EBOCKEH N0; BAYERufiiM-S
`
`BAYER_ST|VARGA_00002188
`
`

`

`Case 1:16-cv-01221-LPS Document 69-1 Filed 07/17/18 Page 9 of 14 PageID #: 662
`Case 1:16-cv-01221-LPS Document 69-1 Filed 07/17/18 Page 9 of 14 PageID #: 662
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`
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`28.
`
`is:
`
`(Egrevieusiy presented)
`
`A methea‘i as; in eiaim 1 wherein {he came-er which is; "treated
`
`Aeoeiex‘a‘ted Phage Chrenie Myeiegezmue Leukemia; Acute Erythreid Leukemia; Aeute
`
`Lymphebiamie Leukemia; Acute i..-},r‘111pii<)bizmiie Leukemia in Remission; Acute Lymphocytic
`
`Leukemia; Acute Menebiae‘tie and Acme; i‘vieneeyéiie Leukemia; Acute Myeiegenem leukemia;
`
`Aeuie Myeieifi Leukemia; Adeneeereinema {If t 1e Presmte; Adem‘aid {lyeiie Carcinoma. 0f the
`
`Head and Neck; Ad‘s-'eneed Gastreimestinai Stmmai 'i'umor; Agnegenie Myeieici; Metepiasie;
`
`Ane‘piastie Oiigedeedmgiiema; Asti‘eeymme; B~Ceii Aduit Acute Lymphebiastie Leukemia;
`
`Bieetie Phase Ciu'enie iv’iyeiegeneus Leukemia; Ben-e Metesi‘ases; Brain Tumer; Breaet Cancer;
`
`Cancer; Cen‘irai Nervous System Cancer; Chiidheed Acute Lymehobiastic Leukemia; Chiidhmad
`
`Acute Lymphebiesiie Leukemia in Remiseiem; Chiidheod Cemrai Neweus System Germ {Eel}
`
`Tumor; Chiidhood Chrenie Myeiegeneus Leukemia; Chiidheed Soft
`
`’E’isssue Sereeme;
`
`Chenieme; Chronic Easinephiiie Leukemia {CELL}; Chronic idiopamie Myeiei‘ibmeie; Chronic
`
`Myeiegeneus E,,eukemia; Chrenie Myeioid illeuicemia; Cinema: M'yeiei‘neneeytie Leukemia;
`
`Chmnie Phase Cinema Myeiegeneus Leukemia; Ceien Cane :1“; Ceiereetai Cancer;
`
`Dermetefibmsareema;
`
`iii}ermatefibreeercema
`
`Prem‘oemes
`
`{DESF}; Desmeifi Tumor;
`
`Eilesim‘aphiiia; Eiipidemie Kaposi“s Sarcoma; Essentiai Thrembeeythemia; Ewing‘s Family {3f
`
`‘i‘umers; Extensive Siege Email Ceii Lung Cancer; Faiiepien '1‘uhe (Imeer;
`
`F1 miiier
`
`Hypereesinephiiia; Fibresareema; Gastric. Adeiieearcinema; Gaeu‘einiestinai Neepiasm;
`
`Gesireintestinei Stromai Tumor; Giiobiastema; Giieme; fii-Eiesereeme; {Evade ii Merxingiema;
`
`Grade E Meningiema; Grade 111 h/ieningioma; i‘iematepeieiie and ii_,yir1§_1heid Cay-ricer; i-Eighfiimde
`
`Chiidheed Cereifirei Astraefiema; Hyeereesinephiiie Syndrome; {empathic Puie‘mnmy Fibresis;
`
`Li Admit Acute Lymphebiastie Leukemia; E92 Adult Acute Lymphehiasiie leukemia; Leukemia,
`
`Lymp heeytie, Acme L2; Leukemia Myeieid, Cimonie; Leukemia? Myeieid, Chronic: Phase; Liver
`
`Dysflmeiien and Neoeiasm; Lung Disease; Lympheid Eiaetie Phase 0f Chronic Myeis'aifi
`
`Leukemia; Male Breast Ceneer; Meiignent Fibreue i-iistieeyiema; E‘v'iaeieeytesieg Meningeal
`
`— 7 ~
`
`DQCKET Nil: BAYER-«0143
`
`BAYER_ST|VARGA_00002189
`
`

`

`Case 1:16-cv-01221-LPS Document 69-1 Filed 07/17/18 Page 10 of 14 PageID #: 663
`Case 1:16-cv-01221-LPS Document 69-1 Filed 07/17/18 Page 10 of 14 PageID #: 663
`
`33em2111g10per1cy€1m11 32313313113.031311121; Meningiama; Meningiema; Metastatic 3.3119111; 3223133213121336
`
`$1033.13 3111110175; Myebfibrosis;
`
`313511330313 Leukemia, Chronic;
`
`31/33’6303123
`
`.3..eu3<em321, Chrenic
`
`Aceekrai‘edanhase; Myeieid 3.131331112111321,
`
`(3311011311;
`
`C3‘3’3‘.’03‘33C~Ph23$6; Myek‘rid Meie‘phsie;
`
`Myeieprflfifiaregive Disorder
`
`{31/333333} with 33103311111331.33321;
`
`N111.111‘1'3231155111‘111121; N011~'3', Nem~3§
`
`(33133133101113 Acute Lymphobhsrie Leukemia; 0332;013e1113re 1233011121; Geteegw‘eema; 331121132111 Gem's
`
`C1333 firmer; (Mariam 3.11in fay/3233335113111 Patentizfi Tumor; Overim‘: Neephsms; Pancreatic (Sumter;
`
`3*13vieNe11pEasms;3‘61339116213CaviryCancm;3’131‘330116213’XC1121321211121 3’31333132311313213 311013101101111:
`
`3331333321: (131101131: 5323§ie311ge111ms3€113<e1‘11321;??’313321(3631‘13‘1121Pegitive Acute Lymphe‘alastie Leukemia;
`
`Ph33a13e3p31321 Pegifive (3312131132: Mye3eid Leukemia in 53v3‘yeieic3 B39153 Crisis; 3’03yeyt31emia Vera;
`
`331131111111313' 3331113333; Recurrent 23.131131333131311 ”53111117;11r Recurrent (31311335131333 33851113 Sareema;
`
`Recurreni Breast Canzeer Rev.urrerrt (303er C eneer; Reeurrerit2111;132:0021.
`
`(321.311.3131; Recurrent
`
`3321113333: Cancer; Recurrent (3331331335331113 Mu‘ififarme {3533333113}; Recurrent Kapesi’s Sermma;
`
`Recurrent Meia‘nemag Recurrent Merke3 Ce33 Carcinoma; Recurrent (Ex/2133,2111 33233331133333 Cancer;
`
`33131311116111 Pancreatic Cancer; Recurrent Preemie Cancer; Recurrent Ree-1213 Cane-er; Recurrent
`
`1732133121331 (33211113 (5‘arree3133e32111re1‘1’2 Smafl Ce33 311112; Cane-er; Recurrent, 33131101531311: Ewing s
`
`Farmfly; Ree1.11‘1‘e113 Uterine Saremr ag3ie3eg1sing7Chrenie 3‘1”“;3y13302113110115, 22131121113222.3121111121111123
`
`Aribritis; S3331;213}! (33211133 A13e11ei133”. 313131: 3:210311131112xfia1cein21 81112133 (”e33 Lung Cancer; Siege 33
`
`31363211191113; Stage 33 31323131233 C6133 (32110311031121.28321ge 3335 251331133 S033 ”353333.113 Sarcoma; Stage 333
`
`Eisephagefi Cancer; Stage 33331~I35er3<e3 Cefl Carcinoma; Stage 333 {31121332111333p3331e33213 Cancer; Stage
`
`3'33 Panereafie 351211113613‘5‘1111ge 333 S313'3vary {332113113 C arreer; 2333:1211: 333313 3331121113 C. 21116513.;Stage 333C
`
`3312521511125aneer; 1.321133: 3V 23.131133 Soft. 3353115: Sarcoma; Stage IV Breast Carlee}; Stage 3‘1! CW}
`
`Cancer; Stage 3V 311113312151321? (.2111cer; Stage 3V (3211:1131: Cancer; 3133:1112: 3V 322323111101112:; Stage. 3‘1?”
`
`01111132311 33033311333213 Cancer; Stage 35'33'3’10313313 Carreer;S12.ge 3V Rec:213 Cancer; Stage 3V 532133222113!
`
`(33211113
`
`(3211115111; Stage 3VA Pancreatic Cancer; Stage 3338 Panereaiie Cancer; Sysremie
`
`3133211301:32510335; T(31:33 3.3133133101113 Ac112: 53..ymp310313as€ie Leukemia; ”31333312113211 Cancer; ”3313110313
`
`Cancer; Unreseetebk:
`
`1.31"
`
`31631132333111333:
`
`31/3213igm111: Gasirmintesfinai
`
`313110111923
`
`"3511mm 3:83ST);
`
`Unspeeified Adah 803323 Turner; Untreated (71313313310013
`
`33131311 Siem (3331311113.;
`
`3331313112:
`
`(Liareii‘sesareeme, and 3.3‘3111'311e Sarcoma.
`
`29.
`
`{33121230313337 Preserfied)
`
`A mefimd 11311112113112; 8. cancer in 21 subject W310 has
`
`acquired resistance 11:} 3111213311331, earnprisirag:
`
`~ 8 ~
`
`DOCKET 3230.: BAYER~G3+3§3
`
`BAYER_ST|VARGA_00002190
`
`

`

`Case 1:16-cv-01221-LPS Document 69-1 Filed 07/17/18 Page 11 of 14 PageID #: 664
`Case 1:16-cv-01221-LPS Document 69-1 Filed 07/17/18 Page 11 of 14 PageID #: 664
`
`afiministering an effectivs ameum {332“ 4{4«{3~{4~chimra~3~1‘1’iflu0mmethyiphenyi)—umid0j~3u
`
`fluamphez‘mxy}«9indimIercafimxyiic acid methyiamidc 0f the fermuia E beigw including an
`
`poiymarphs, hydrates, phzsmmceufica} y flammable Salts, metzfmyfiites, pmdrugs,
`
`seivzfics Gr
`
`mmbinaiians flmreefi
`
`to said subieci.
`
`
`
`KWO \,
`-::‘x
`37
`1”
`"‘ {bin-"J!
`
`F
`
`x" CH"
`
`{:3
`;.. «21“: #J‘fiilm‘
`Ti
`
`“\.3 (SEN
`
`N“
`
`a
`i }
`
`31}.
`
`(vaicusly Frasented)
`
`A method fif treating a indignant gastmintestinai gamma?
`
`11.1mm (GIST) or a heérzign gfistminmstinai Simmaé tumor ((351817), in a subject who has b36111
`
`“awaited with imafinih,
`
`saits— Of
`
`imafinib masyiates PP.1{liIAminou5~(4~methyipi‘lenth‘i’~{t~
`
`bmyimymzoioif‘é,4~d}pyrimidine); MLNSlS {CTSBSES}; PD18Q§}?G; SUE 1248K $15416;
`
`SUE-414; SUz’jSW; SE16663 m”: $116562, said methed cempz‘ising administering an affective
`
`alumina: 9f 4 { 443 4441mm“ 3 «trifi1.10mmathyiphenyijmul'eido}“3 "fluflrophenaxy } ~pyridi 115:2»
`
`carhoxyiic acid mathyiamidfl of me fi‘:r:m.lia 1' to. said $13113th
`
` ‘G’HS
`
`(i)
`
`3 ”L
`
`(Previausiy EF’1'asented)
`
`A meflmd efireaiing a malignam
`
`gastmintsgtinai strmnai tumor (£3,581) 0? 21233::ng gasi‘mimesiinai Sta-03ml tumor {(EE'ES’E‘}, in a
`
`subjraut wha has bean twatsd wi’ah ia'nafinib, said mfihfid compriging administering an
`
`gffec‘iivs ammmt 0f 4{(1H3.{flinch}0m~3~irifiusmmethyiphm1y1)»urf:idsfl~3~fhsomphem'>xy}«
`
`pyridine~2uearboxyiis acid methyiamide 0f the .farrxmfia I to» said subject.
`gt;
`1.x SK ,CH3
`NH,
`
`
`
`1.
`a. {Pg
`
`(1)
`
`“ 9 '
`
`EGCKET N0: BAYERnQE 43
`
`BAYER_ST|VARGA_00002191
`
`

`

`Case 1:16-cv-01221-LPS Document 69-1 Filed 07/17/18 Page 12 of 14 PageID #: 665
`Case 1:16-cv-01221-LPS Document 69-1 Filed 07/17/18 Page 12 of 14 PageID #: 665
`
`32
`
`{vaiamsiy presented}
`
`A mefimfi 0f 313$ng a malignant gastrointastinal
`
`strmmafi tumor (GET) or a benign gafitmintegtinai gimme-d tamer {G131}, said method
`
`c0mpx‘i3i:‘:g afiminisim‘ing an efi’ectfiive anmum‘ {If 4{4*{3~(4~e;b}0m~3«trifiuammfimyiphen‘yi}
`
`ureide}—3—fiuumphenoxy} «pyric'iinen2~cafimxyiic acid methyiamide ofthe formula I :0 said.
`
`sub} em:
`
`
`
`33.
`
`{NEW} A. methad 9f elaim 3‘23 wherein said subject has 1101: been treatésd with imminib.
`
`34.
`
`(Haw) A method of ciaim 32 W’hsfit‘fiiifl said Subject has not acquired rcsistamc to cKit
`
`inhibitmc
`
`» ii? a
`
`DQCKET Nil); BA'Y'ER~GE43
`
`BAYER_ST|VARGA_00002192
`
`

`

`Case 1:16-cv-01221-LPS Document 69-1 Filed 07/17/18 Page 13 of 14 PageID #: 666
`Case 1:16-cv-01221-LPS Document 69-1 Filed 07/17/18 Page 13 of 14 PageID #: 666
`
`“en““.“““u1‘.:1.
`Remarks
`
`Amendment is file Chime
`
`Supper: fer new claims 33 we? 34 is famed in paragraph 21 0f the speeificafien which
`
`“The present invention provides methods eftreafing Gamers
`cemprisifig :3g cempyising administering to a subj eet in need; 1:11:33?er
`an effective ammum Df'DAST; wherein the cancer is treated”.
`
`GAE??? is. defined in paragraph 19 as,
`
`“The diphenyi urea referred m as 4v{4m{3n(4—ehimo~3~
`trifluemmethyiphenyi)sureido]93flamephmoxyi}~pyridine~2~
`earbexyiie acid methyl amiiie”.
`
`'E‘he metheds defined in paragraph 21 <10 m): require the patient be resistant to C-KET
`
`inhibiters, W'hiie the preferred. embodiments of the mesa“ inventien are dimmed t0 treating
`
`emieers with 311 aequired resistance :0 kit inhibitere, as etaied in paragraph 2%), the utiiity 0f
`
`the compound beyend the firea‘imem of resisLani cancers is recognized. by the diseiosure in
`
`paragraph 18.
`
`Faragraph 25 has indicates,
`
`“Any calmer 6.13:1 be Heated in aeeurdanee with the present
`invention, irreepeeiive 0f the type or cause of the Gaming and
`irrespective of the genetic; iesiong associated with it Eanpieg of
`cancer which can be tmated ineiudm but we met limiieii to, (£31371) acme
`myeieid Eeukemia, mast cell tumors»? SCLC, germ eeii miners, breasi
`cancer, neuroeiastomm Sinenasei 'Eyi‘nphema, etc.”
`
`Appliezmte neie that in the Notice Of Ailewabiliiy mailed Aprii, 3G, 2:313 the Examiner
`
`aiieged there is. a discrepancy in claim 32 and remarks made with the subi‘nissien. Appiicants
`
`maintain claim 32 eneempasses the treatment m“ pai‘iemts who have met. been treated with the
`
`imafinib and ($0 1101“. have resistanee t0 a. vial: inhibitm‘.
`
`‘Whfle eiaim 32 dees net expressly
`
` 1g}; acquired a
`
`resistance “m a ouki‘: inhibitor, such an expressed recitation. is unnecessary for the claim to
`
`enemnpass; this subj eet matter.
`
`in mating this dism‘epm‘aey, the fiffiee Amien suggegis a rejectien under 35 {NC
`
`Seetien 1 12, first paragraph {mitten deeeripfifm} wouid be appmjgriate if {he claims recited
`
`* 11 ~
`
`DOCKET N0; BAYERJBMB
`
`BAYER_ST|VARGA_00002193
`
`

`

`Case 1:16-cv-01221-LPS Document 69-1 Filed 07/17/18 Page 14 of 14 PageID #: 667
`Case 1:16-cv-01221-LPS Document 69-1 Filed 07/17/18 Page 14 of 14 PageID #: 667
`
`such failures, Naraw (:Eaims 33 arid 34 d0 expressiy recite {ham features and have been
`
`@3531“:th 1'0 addrms ihis issue. Appiiaamg submit them is written descriptien far thew claims
`
`fi’sund in the paragraphs 01" the Specificatian rapeaied above.
`
`Whiie prefm‘i‘ad embadimcmfis direcmd to flaming cancers which have an acquired
`
`resistance to imam??? or CKi‘i Inhibitors, there is clearly writtan description and ena'biemem
`
`far this matheds (16353336, in ciaimfi 332454.
`
`The Cgmmissioner is heyday miflmrized m charge any {has associated with this
`
`response 01‘ cradit any Ovemaymem: to Diapasit Acmum N0. 1384826
`
`Respectfufiy submitted,
`
`vavavavaiiiighwgifligiiméu___________
`Richard 3. "fraversau Raga Na; 303,395
`AfionwyiAgent for Appiicanm
`
`WELL-EN? WERE, ZELANO
`& BRANKSANS RC.
`
`Ariingmn {5011111191386 Plaza}
`2201") Cim‘ifi’ldfln Bivd, Sum": 3466
`
`Ariingmm Virgini a 2220 i
`Teiephana: {703) 243n§333
`Facsimiie:
`(793) 2436411)
`
`Attamay Hacks: N9; BAYER~G 1 43
`
`Date: Nevcmber 5, 20% 3
`
`~ 12 w
`
`DEWKET N0: BAYERQMB
`
`BAYER_ST|VARGA_00002194
`
`