~~, .. ~.
`
`~[~~~ib ~r~
`it
`a~r~►ir~~stir~.l T~~t~~i~~
`c~~~~~i~l ,r~t~~~fl.rr~~.c~r r~s
`~~r°~~~id /~r~hritis
`~~~,r~thri~i~ ~.n
`~t~r
`The CLASS Study: A Randomized Controlled Trial
`
`•~~1P ~- ~''~~'~'~`'"~- 1~C~
`~~, `~iir~~ ui ~fl1
`L~
`
`I'h~~~~~l~~re f ~nc~~ : !I I)
`
`-- - —
`
`~IIIII, \1 ~~~'IE ~I1111 ~I ~~
`
`Rnl~rri Alal,urli, I'hl)
`-
`_
`__
`_.
`Glenn l~,i~E~n ~Ai I)
`
`--
`~ -
`
`;A nii uir YI ~~~,i i~~~,~L :A1U
`
`.---- .
`
`\\ illi yin I'. tii~~u~~~ci, X111
`---
``~If1I[~` ~~. ~jUil ~"~~
`-._-
`__~. _ ...
`_.
`\V'rlli~wi AV~ /,li~in. I'I~O
`~ r,~~~~,~ ~~. ~~~ ~~~ ~~~~ ~
`—
`.~rIl11 C`~ ~~. ~,i`~~~Ut61~~1 ~~~~
`_.__..
`___
`I~enn~~ili .~1. V~~rhnr~:, I'liU
`
`(;. `~~mcn (.~~i-. I'I~[) .l1U
`
`context Conventional nonsterolddl anti-in(larnmatory chugs (~lS~IDs) are associ-
`P~~~1 I . 5ih~ i~t~•in, III)
`^__.
`_
`__
`Gr ~ rill (~'~iirli. A) I) atecl with a spectrum of t~~r,lc effects, notabiR ~ ttsh-ointestinal (~q effects, t7Fcause~ of
`~~~—~ inhibition of cyclooxygenase (COX)-1. AMhether CC>X~2-spedfic inhibitoi_S are asso-
`ciatecl ta~ith fervor clinical GI toxic effFrcts is unknov~m.
`a~7)ECtIVC ZO C~f'~('. ffD ~f1P_ WriE:tf1P( CE (E:COXIk), d ~.~X~2-5~72CIfIC It1f11 E)ICUt, IS t7550C1-
`ateci with a IoUrar incidence of si nificant upper GI tc~xu, effects an~i other adverse rf-
`l~c~~rn ~ional NSAIC~s.
`~~ .
`Desi n The Celecox b Lc~n ;-4t+rm F1rCIiriCiS S~1feCy Study (CLASS), a doubie~falird, r~n-
`~
`ucfec! from SeF~ternl~er'I998 to Mart:h 200U.
`-- dcm~ig~lncont oile< ire
`Setting Three hunci:ed eighty-six clini[:ai sites in khe Unileu Stzikres and Canada.
`-~ ~_ ParCicipants R Cotal of 8059 F>aticnis (- 1Fi years old) avltri ~steo~rthritis (QA} or
`rf~ieumatoid arthritis (P,R) v~~Fre enrolled in thu turfy, ~nc1 74)6~i received <zt east 1 c ose
`of study cJru~. N, tc~talc7f ~I~/3 pat~ionts (57~~,) r€ceived treatment ibr 6 montl~is.
`--- II7~p YVQt1~Id Y15 f G1filQilt$ V~JP.I"@ Yd t1 C~011'l~y ~ `.iSl mil ('. (~ CO IN(.t(VE Ct%~F,COXIE?, a~~ fYIP }~MIC~
`~~ar day (2 and ~1 tunes tY~e maximum h~ rind OA dosages, respectively; n=3987);
`~ IP~uprofen, 8U0 r~7~, 3 times Fier day (n=1980; or didofenac, 75 m~ twice ~~er day
`(Il =1~~~~. ~4~It 1[l 1158 fOr C1f'C~IpV2l SGll~tll' pI O~J ~ly~2XIS (` 3Z~J ITI~~C~) Wr7S ~]FIl7lItrP. C~.
`_~~_ amain Outcome Measures Incidence of prospectively dEfined syrnp[omatic upper
`GI ulcers and ulcer cornpiicakions (bleeding, perforation, lricl obstruction) and ~lher
`ldversc effects elurin;; the 6-month trcatn7ent perigd,
`Results For <tN patients, the annuaiizecf incidence rates oP up~~er GI idcer comp6caPioru
`alone end corribined with syr7ipt9matie ulcers F~~r celEcoxih vs N$AIDs Nrere 0J6°a vs
`t~ti P ~ rit°~t~~ ~~ CfII ~it,s~ t;~Li>~
`skcic•ial ~lisordcrs, con~~en- 1,«SS% (P=.09) and 2.08`%~ vs 3.51% (P,.02), res~ectivefy. Far pa(ir~nts not taking as~
`Clonal nu~~~teroid<i( ttn[i-. plan,tl~+E.',~nnualizedincidencerZtesoFupperGlulcerca,nplicatlons~Ioneandcombined
`iri(lamrnru~~i~- ~{~u.;s (\ti;UDs) with symplomali~ u~cers frn celecoxih v; NSAI[]s we°re U 'I~}4~ vs 9.~7 % (P-.04) and
`L40 ~n vs 2,9"1 i<> (P-.02). For patients tzkin~ a~piiin, tl~~. anni.ial~zed incictenee rates of
`,~u~ a i~izun~ta~' of clinicatl cau~r.' ' \~b~ell-
`cs t ai b I i5hecl I i rni to t io n s o C \ 5,~A l D uPP~' GI ulcer coiY~iplic<itit~rts alone zmd combine cl with symptomatic ulcers fvr celecoxib
`vsNS~lf~swere~-09 ~6vs212`! (P :.92} ~nd47~ 6vs6.00)`:~ (F=.49?.Fe~~vercelecoxib-
`tlicrn~n~, l~c~~+~cve~r, inrludr i(~~e rlsl: izf
`trr-~stk<d Fa~itients GPru~ ~~1SAID-treatEd patients Pxpc~rlcncaz,i chronic GI b(opd loss, GI in-
`cl~~~~elupin;,5i~;nific~~~nt injury ~n the up ~
`~~~ler~.ncc, heF~atokoxicity, car rer7al toxicity. t~Jo rlif(erence was noted in tine incidence of
`p~~r z;asirointcstitr.tl c C";1) tract, "" 11~c ~,.irdiovascular'evF;«ls l>etwren celecoxib ttncl NSAILs, irrespectivia off' aspirin use.
`x~inunlized mc~denec ~~.~te of syu~p~c~rt~-
`Conclusions In this study, celecvxi6, at dosages greater than those indicated dini-
`atic G I ulcci:s a~itl ~~I~~cr con;plica~it~ns Gaily, ~~v3s a~s~ciated vrith :-~. In4ver incidenee of syir~ptamatic uice~•s atnci ulcer c~mpiV-
`in ~S~U'U u5ics i ~aric;cs froiai >`.'~, ru ~E`;£,
`c<atior~s con~rbined, as well as other clinically irriportant toxic effects, compai~e<l v~iikh
`NSAIC)s ~t standard d~>>age;s. The clecrcase in upper CSI toxicity was stirongest ~rnong
`(I ~~-2~;f~ [or ulcer t~c,~n >lic€tti~~~iis
`1
`alone•)."' ~fS;UC7-rcltttecl iil~u co[n-~ patients not takm~; aspirin roncc~mikar7tiy.
`,~<,-, r;z~;r,
`plic~~Uii,n4 .u~e cstim2ti~d io ltR~cl to ~,,,•,
`
`Yo,~~mccr~r~
`
`Author A~~liations and Finarei2l Disde~sures i < I ~~ed
`i. ;trig
`I ~ € t~is aitnle.
`~6Y @Ci l~bl'Id) CtltTtITl2ftt 9C'C' Q l ~~7
`-- Caltesponding Author acid Reprlat5: larn~•s [;.
`_.
`.--
`
`Lc iaoeviti~, h L~ F harinncr;a Cfirtical Ri~~,eaida ~ncl De~
`< nl, ~Oi 5 ~~rle Pk~r~ hlo ; i 3F S Coale, IL
`i
`,l~ -ra..~~ J1n ~~li.l~F.r„~itl ~i,n ~,~,~h~.mml.
`
`~~
`
`~ lit,il
`
`i11 i is1-._si ~*.. .,.
`
`{R~: rnl~cl}1F,~ vA
`
`,i";;~_i i
`
`~..
`
`l
`
`.. ,.. lit 1247
`
`DO~rnloadrd P"coin: IiUp://jama.jnmancE~vnrl<.com( lir t~ Reprints Dcs~: User on U(113R(116
`Page 1 of 9
`
`Patent Owner Ex. 2019
`CFAD v. Pozen
`PR2015-01718
`
`

`
`Gi i ~~~Cct~r~~ bG~i'r~i t.~ i ~~cc)~Ii; e ~ ~.~~.v~~~ t ~7a ni~i~t~~,rri5
`
`1t1~ (7C~ll lio5}~~tt~iliz~~ti~>~i~; <E~t~l i t, ~0O
`dc<<dis ~=c<~rl~° in the t~nitc<I ~i~itcs."'
`1S.~If)s inhibit cycic~o~yncnasc
`(C,C)\},ihecn~yme: i~-,~aon~siblc farc~7n-
`~~crsi~~n of ~u~aicludonic acid ~o ~>ros~a..
`ti,I~tnJi~is.'" C:U\ cxisl5 fn 2 i~,nln~~ins.~~
`Cl)\-1 i4 ti ~il~iquitou> ccrostituti~~c isi~
`z~~~iie producing f-'rost~igl~uidiiis r~~spt~rr
`Bible Ir~r hrnueostauc Cunctirin5 such as
`maintcnaircc ~~f GI mttcosal iriti~h~~it~-.',
`C:t ~\-2 Lv I~u< cfy i c~~ol:uie-indu~e<l i50-
`~-~t~e producing pro~tas;lancifns thzitrnc.
`ch;ttc~~~tinindin(lammttiion,'" \S!lll~a
`inhibit hc~th CC11-1 ~irzcl (;O'~-'? to~~aiy-
`in~,el t;rocs"'~~[him,thethertipeuucef-
`I~r:~ts c~l~C'onventi~~n~il ~;`;~llDS an~e <le-
`ii~°cd fio~n inhihi(ton ~~I C_OX-2, ~vhllc the
`ad~~crsc~ clTccts ~,f thc5c a~;e~~~ts. p.u~iiit~-
`I<t~ h~ in tl~c: upper (.;f ti~u~[,.~rise from in
`€i~iivity.
`hihiuon of ~:OX- I
`C,ciccosib, ,i CC?X-~ 4Ezc~cilic inhibi-
`tn~, tec~ntl4~ ~~~t+s appro~~ccl by the l ti
`P~unil <ind flrii}, :~lclnri4~i.slratior~ (f~[7~U
`fui >~~n~,tonralic t~'c~if~~u~ru nl c'Iactirnzi-
`tol~t tu~tlu~ius (Rrli rind osteoar~lu~l~is
`(Cl~\) T~~clf~ten~~inrtt~l7ci~~~ rihcCO\-"?
`s~i~ cificilti~ ~~i crlccoxil> ~~.~~-.~,ci.0 rct with
`lo~~~c~ l O\ I,relate~l tui~~_ ~ ,~ ~ fl. ~~ts~~vc
`cc,mpare~l ~~~ Ieco~ib r~diulnistercd ~ai
`rind ~~ tiiucs ~.k,iE~ iva~itnucn F~f)A-
`cipprove~l cfleriiF~r d~~sti~;cs Cur It<1 ru~cl
`(~,A, i~~~:pe~ uvcly~,v. itl~ c~7ninu~nl~ used
`tlacr~~~cutic d~ ~agcsof i6u~?ro(enancldi-
`r,lc~~cnac_ (h~ clu~agc of celecc~xl~i ~~-
`r~~€elect the rna~imnnt ~luca~~i:~ apJ~rovccl
`b~~ thr FDr\ for 0:1 ~md RA tc~ pa rinit <<
`~,~lety~ as~ewsnicui oC the hi~;I1~~r c(os-
`ng~.s. 1 (onr~~~~er, l~ascd on pre~~ious5[ucl-
`its,'0~`' Cxceeelio~a, 11~c dos:~.;cs <<~>
`~~r~>vcc1 by tl~c f D~\ ~;~uul~ln<~t int~7a~vc
`pal~ruts's~~u~~xo~za relicl~. ~[~he ~lc~5a~;c~s cif
`ihupr<~fcn <ind iliclvlcnEicti~~crc bsisccl o~~~
`pi cscri~iiion clzua, `1~"i~~ ttu~1('al~"ii r~l~ C)~A
`smd R_A patii'nts, r~spectivcl~-. ~vhu rc-
`cciv~~t! ibtq~r~i~un ~vcrc ~>> cscrihed tt dos.
`a~~c «f <i~ lc;ist 2-fC?i? nix,,/t.l, anal S(~`;4, and
``;~a oC Q.~1 Euirl 1~,'~ ~aueiii,; t~csE2ec-
`ti~ el~~. ~vh~~+~xci~=cd dictafen<~c ~ti rt~~ pre-
`si eibcd r~ elus.ihz; of ~u lea~~~ 1>p iu~/i(.''
`
`METHOAS
`5Eudy Population
`l7iupscticrrt.;t~ed l~3)~~Fu:4ors~l~ler~ceie
`eli~ihle ~o ~,:~rticipeu~~ u~ thestudv if, on
`su~cc ninE. ~hcv ti~er~~ ~li~i~nu~ecta~ lir~v-
`
`ink t2r\ nr Orl cvicicnt (~~r ~~i Ic,iti~ 3
`nu~n~h~ and ~~c~~~ cxE~ec~ccl ~c~ recjuirc
`conlinnu~~s ueau~i<nt ~vilh ari A5.AlD
`for the c!uratic~n of (Jic trial. i'atients
`~~~ere e~t•ludccl l~rt~m slucl~~ ~rtrtici~~~t-
`tion N at se~reen~n~, tnc~ lead ttcth~~ CSI,
`rentil, hrpt~tic, ~~r c~~agul.ition clisr>r-
`d~i~s; in~tlign<<nc~~ Cuulc~ti~emo~cdstu'
`z;icailly ~a~i~h no recur~enC~c ~vi~hiri ~~
`~~cars~; esu~~ha~,~ul or ~.;<~st'rc~cl~~od~n~rl
`~ticcr~t~i~~n tvithii i the ~~~c~ u~us 3V d~z}:7;
`hiior~~ nl gxsu-ic orcluoclenal si~r~cr}'
`oilier than an <,~~i~~.-~~; ~r I.i7o~~rn~itYr-
`n~tedi~i~c~-type I~~~~ie~ wcnsi~ a il.~ to CO\-2
`inhib~tnr~,sulCon<in~idcs, ibiy~rofen,or
`dicloicn,tc. 4Vo~ncn were cxcluc_1e41 if
`lftCy' ~~Clt' )iregn~ini, might have be
`co~iie E~rem~mt, or ~~cs~e laclatirig.
`
`Study Protocol
`Thin ~~rotipi~cti~~c, r<nitlui~iizecl double-
`I~lind u~i~il ~~~~~ti conductc~cf .0 3i?h ctn
`tcrs h~ t17~° Unitccl Si~i(c~ and Canada
`G~c~~~a ~c}~teinbrr lS)yS tea \,l~~r~lt 'COQ
`in eGccorclancc ~~~ith tl~e~ princi~~lcs ul
`~r~acl c'linic'al Inactive 4tiul the Drclrna-
`tion u(k Itlsir:l~i. l~k~e }>>~~tcicol ~~as ap-
`~~~ot~ed b~=the iii ut~Uional rt:vit~e~~ f>o~ir~~l
`at each suul~~r;itc_, sancl'all patierus pro-
`viticd «~rittei7 iArC~,rnied ruu.weni. Prier
`i~ enrollment, patients contplcted ~i
`pl~iysi~al cxamin<uiou acid clinical I~ibo-
`rtiton iesiir>>~ ,11ter ~t ba~elzne ~~i:;u,1Ul-
`Ip~~~-it{7 cGrtir_~~~,~it9 Gaol: ~~I~aolt«s~i'cl~s
`-E, 13. ~rnd Z~ ~iltt°r Elie initial dose ~I
`med~c~atic>n, send i~~rer4 13 ~rcel<s tlicrc-
`a[tcr .AIl paticuty were pr~>videcl gut op-
`portunity t~~ co~n~~lr,t° a rriiuimi.un of fi
`ixi~~i~i~h, of trc.,une~n~.
`Ptr[icrats ~~~itE~d iawinri fro~r~ study par-
`tic ipo-llioti Cn [r7r to 6 months ~verc clrt5-
`siliccl .~5 (i,IIt,~F,: precxistingviolaUon
`oCcntr~' ni~e~ii~~, air~,~t~xol nonct~mpli-
`nn~~c (in4~entiga~or-delin~cl f<<ilure u~
`conr~7ly with tlu: rcgturein<>nt~; ol~. the
`pro(oc<~I, c~;, (ailtire w t t' c at (c~s5t i(l~"~,
`o[ tha• stud~~ iticdfc~ition fri ariy~ 1-3-
`~i~eck 'tntcrval), tr:e~iuuca'~t f:ulure (ir~-
`Fes~i~a~ur-de(incd failu~c ~ikstu<ly «~ecli-
`C:tLIOt'i LO COtl 1.1~U~ ;U to Cl ttS ti1~ti f15 .l t7 C~
`5~~itt~>ioniti}, Ui ,~~I~ ~;`SC cf~eck (in~~~Sti-
`z~~tCc~r-delitied signs or 5}'mpton'~s tta-
`rclatrd to <zrtitriti~; srr~ `C:Ifi~~cal A-
`Ses9ntintS" I,tercin;. T6~'se })alicnis
`noiuthelcss ~ti•c're fullo~v~ed ttp (cn' cnd-
`
`pc>ii~t c~ralu~uic~n [or ? o~c~a~ths or uuiil
`study terrninati<,n.
`
`Treatment
`I';iticnt~ ~+°cre rancloinll~ a~signcd to
`r~cei~~e h~ctitments fcc•Icco~it~, 4Q0 rri~;
`twice Fier d€i~~; il~upruf~~n. 5t10 iug 3 tin'~es
`~~crday: oc dicic~fen<ic, [`> run uvict~ per
`da}~) ou a "L:l ~, l ba5i~ b~~~ <tn tntcrtc~i~~e
`~ ~>xc r~s~unSeSyst~zit'~ (Clinl'V~~>~tc, Not-
`tir~~;hacn, [:nglantl) acc~~~ciin~co ~i corz~r
`,later-~cr74rated ranclnn7i~atioirsched-
`rtle•. :111 treannen~ rc~;iincns s~~rrc
`blirdcd acrd double du~i~i~~~, "f"rcak-
`rnent assignment I~ar 3 }?;uf~•n[s w3~5
`unl,iEindcd by suul)'sittt (>ersonncl rlur..
`htg trill conduct (J at [Ile invt:s~iga-
`tir~ii site, 2 efa rile h~teracti~e voice
`iespoi~ac~~~;tcm}.~c>i~co[`h ,~ ~~<i~ ~-nts
`ccperit~n~ c<I tt5luc(y b~4< <~tn- c ccnl. Cane
`c~~Iccuxib ~~alient c~pi•iic.nced c(i~~tr.r-
`licul~u- bli'~xlic~~,; Z p.ttfent~ (I cele-
`~~»ib zincl I Gii<loicnaC~~ c~~7criencecl
`ttoo—Gi-related ~id~ crse e<<enls; c-tncl io
`nip inslan~c c~~as the u~sitn~~rtl,issiyn-
`ment matil~~ lU~oev3~i ~o per t~nnCl of the
`drugcan~~~,tuv(I'h.~rivac.irl, Sl~ol.itt, llil
`or fb itu~ribers e~i the our rsi~ht ct~~~~~i..
`mit[ec~; prior to Final rc~ie~v ref all end
`p~~iuls 1?~~ ,~ UI cvcii~y c«i~t~iiiucc.
`
`Concomitant Medica#ions
`SU Ds (e.xce~pi [or stable dn5a~cs b[ ~~s-
`~~~irii~ u~~ t~~ 3 ~~ n~~~.~,/c17; .~ntit~lccr clru~,y
`(~~,ticcpt (gin occasion~il ~ntr~ci~l use); an-
`tibiolic~!~ u~ccl atlone nr iu romhinatio~i
`~~ ith om~ ~ro-iznit~. (cinso~~rz..ole, G~nclxa-
`nilidine for treauncril oI ilirHeoE~~uler~~~
`1or~i infct:tion, and .,uatit~ecr~~ltiytics (ex~-
`~~c~~t ui~~lhoh~cx<ttt or <iz~tthi<~~7rine [or
`[.~#) were ~~rohibiteciclttrin~ tlteslitdy.
`Ltsc of ~~xsil, i~~tr~musculiu~, and [riu~a-
`~trlicular glttcoc~>iU~oids .iitd dise~isa-
`mu~li[ying.intinc~iunati~ clru~se~~•~is per_
`rniti~°d.
`
`Clinical Assessments
`
`l tt~'CSIL~;tU OCS ~4'C'YC Ill Sti'UCIC(~ LO IC1t711-
`uli~aa<I rcpoc7 ~~Il ~ixcntial upper G1 al-
`~~cr coinE-}licsiuz~ns. E.ralu,iuun of such
`cvent5 wa~t~utlSnecl ina prc~,pccifict) itl-
`~:;i~rithm SU~ucu:u'(`d to re(ar~>cltice clini-
`~~al pt~actt~i: nurni5 kv~~aluati<,n ~cas
`eequired fur a;~y of the E'alh~~vin~ pre-
`sc~ltau~i~s: licEnruurrc~is; ~ticli~na;ric~ite
`
`7248 1AtJ~A , :cini;r. i
`
`~t'~`C~...
`
`~ .,. ~. kt,. ICS {Repri~if~:~~l)
`
`~,~iii7tl au,~ric a ~e~.iii'~il,~~.>~ir~i~l~n.;~.IIxi~,ill ~.^,creed.
`
`Dor~~nlouticd Prom: 6tl~a:/ljuma.,jtunanct~sork.cnmt b~' n ReF>t'ints Dcxk I.!scr un 0612,1/1011
`Page 2 of 9
`
`Patent Owner Ex. 2019
`CFAD v. Pozen
`IPR2015-01718
`
`

`
`c~~~ ~r~~aic~~r~~ ~~~~rzr c.i i
`
`i c~~~ii, ~ ~ ~s~v[~~ r~c~a =~a 1 <<ait[.~
`
`l~i}~~~vvolc~tii<4/h }pott~ris[ui~; dc~~ela;~p-
`rncnt ~~(~p~~suu;il c1i~.~iness, li,~llthe~id_
`cclncs~, or 5yncu~~c; history o[ ds~rl:
`stoat, kicmntochc~i~i. c>r;~inc~l ~~r rect~il
`hle<~tln~~;; dc~~cic~~~mctit of itr~~~~ aric•ini~i
`tdcfined ~i5 a licmaioc~~il le~~el outside:
`of the rel~~rt~iiet~ ~ur~;,c~7 ar a cl~crr~s~• ire
`l~~~si.u~.~crit ~>f =u 1ca5t :i peiccnla~~c
`~;c~int5; dc~~elopmcnl of d1~5~~x pia, ab-
`dominal p7in, or nantiea or aorniting;
`or G1cvclG~pmcnt ~,~( occult blovd-
`~~e~4itivester~,k I:aidixcopy~~`asencotu'
`a~;ecl to tloc~m~cnt blecc(i n~ li•siuns bait
`coulci:ilso he ~~~erlonncd iI incl;cateel 1~~~
`the in~~cstigator's clinical jud~;mcnt.
`:111 ~l~~c~niu~n<<itlon rcl~uin~ i~> pi~tcn-
`liul iilc:rr e~cnn}~lirtiiiuns t+~.ts lonv.u'dcd
`to ~i f.~l eveiu5 cornEn~U~~e (J.[ C;., C~. .,
`N.I.;\.. ~in~(~~ . ~~.Sl. I h~° co~iamittfee cc,l-
`l~ciiai~l>> re~~ii~~.~~c<I Cash raise in .~ Ir~ea!-
`mcnt-l7linciccl l~asluon.uui<i5si~,nccl it h~~
`iinai~im~~us et~nsenstis as ci[hir n~eet-
`iru, car r~cn rncctin,y, the dcFi~~ition oC~tri
`tipperC~! til<i~c coiuplic:itic,rz (~I~,ti(;t I~ 11.
`S}~inptoni~itic ulcer-~ ccrosisial ni cttscti
`tlrit Clid riot mtcc'~ tltc ~lei~initi~n of~m ul-
`ccr compli~atioa but diGl h~x~e cnelo-
`sco~~ie i~r x r.iG~ evi<lencc oCa ~,F~=,uic of
`duodenal ulcer ~i~ judhecl by llte cvm-
`❑iiu~ e_.11l~~~iucnts ~,~uh ~~~iu~~xom~ilic ul-
`cei ; ~~~r ulcer c~omplic.uions evert: ~~~ith-
`clra4i nfrom the slttciv ,inel inclucicd In
`the rural}"pis tts hati~ing htid a stu<Iv end
`point.
`,dd~ ~~rse clli~ct data ~~~cre c~~ll~c[e~3 at
`each visit (and as rcportccl sC~~>rUanc
`ot~sl~°1 usuir; [he l~allc>~vint yu~stion:
`"Since prnir last vi~~,it, have you e:~~>e-
`ricn~sil or clo ti~c~u t nu'entl~~ hay-e: un~
`s~~ir~ptuin~ Ilra~ru~e n~7t <«r~c•iatecl ~vitl~
`~=o~i~ artluilis?„ r\II al(ir~zi,u.i~~tt rr
`~,~~unses kvi~i c rccciril~ d ic~~au rile 5~ oCs~e-
`~~crilp ur i~•lationshy~ [o studs- cErt~~;.
`Labe-<iton' d~ua were ail v colleeied at
`c~iC li ~~i it ~tnd ~i5 Tncli~at: ~.0 xiccui ~Hrig t~~
`the in~~cstigaturs' ~lise~rc~i~i~r_ C'.lini-
`cxlly si~ni[icaG~t ch ~ne~', in hcmatu-
`crit <~iacl hcin~_~};1abn~ ~~ere ~~~cilcCincd
`au dec_reast~< o(~i~ Icsist 10 ~~e~rceEita;r~
`~~i>ints:u~c( 2U;;/L, rc,pectivel~~ Cliaii-
`f all~~signii ic~tnt cl~ang~~~s in ~criim un.~i
`nin~t,,;cn ae~d crc~icininc ~ccrc prc-
`tl~~f;ueil ~t. ~~ilu~~s at (~-uaonth fol
`lo~v-~tp o~ xi lczist `f(? ~l~s;ldl_ C 14.1
`~nuiol/I..) <tnd l .t3 tn~.;l~it (I >~) ~nrtol/L),
`
`Table 1. Pro>>cok Spec:l(ied Ui.~finition5 and Adj~~db . ' _~n Cri>.~ ~ for Ulcer C omplictrtions
`CritHria nor Cr~nfirmr.d Event
`Event
`~
`
`_
`
`~
`
`r
`
`-- _
`
`~
`
`_.
`
`_
`
`i
`
`t~~~:~,., tr~
`
`~~iai
`
`f
`
`~.
`
`~.r
`
`~,.
`
`...:..
`
`~~
`___.
`
`resk~ecti~~cly. C:Iinicrally -i~n'ifi~,tui
`cJtan~~~t ir~i <tlnninc.nnur~~~rsntsic~r~sc
`(A[_'f) and ~~spartate arn~notric~sl~~~,~,~-~
`(:~S'C) ~~~s~rc prrcl~~line~i ~~4 ~ncr: ~,~~. to
`:u IE^utit 3 tin~Gcti the up~~er 11mii of nur-
`maL 'I i oil 4aCei~ (;~.>crG~iiis such-ei~,r rC..
`Cec~s) ~~as mU~ut~~r<~cl in ri u~c<«mc~i~-
`blin~lecl frisiiion during; th~~stac(y h~~ ~hc
`d~itt~ tiEi[zty monlu>riaig board (C;.F..
`T.P., r1.~~"_,and R.~L).
`
`Statistical Analysis
`5am~~l~ size cal ~t1rU inm ~~~cre ba5~~d on
`~hr ~~ssumptlnn that th~~ ~n~lkiali; e<,I in-
`cicict~ce cif up~~er (..I ulcer co~Tap~icta-
`uotts would lac U ; ?~, I~oi «~Iccc~xila and
`I r`',lor`~5;11C1,. Lc~dc~ccttlz[sdi(~cr-
`c~cc .~ nh,~ 2-sic(ccl .~~'i s~~tinific<tncc le~~et
`with .~taii:Uc~~t1 poti~°err of ~3`~u incl as-
`suiuin<;a i~"rE,~uithcl<<«v~il iaie,a5ample
`;i_e of ttppri~xiivat~~l} 40UU p~~(ien~s vas
`regtutccl for the ccleco~ih ;;roue and
`~0007 ~~au~ Diu ~vi~rc needed (ur each oC
`
`plvin~~~,enci€~ ofth, ueauncut~;rcaups
`<tt bis~huc ti~~tts ui,tlyzcd ~i,ing tl~c ~~ test
`I~r aut~oric~al clat<i ~md ? ~vsiy analysis
`of~ariance~~iith trc~~tmciit atidccnte~r ef-
`Irct. f ~zr run! is ~t,iuu5-t~alu~cl data, Stsrtis-
`tic~il aual~,Us wrre conduc~ccl on the in-
`teni-i~7-tre~~i ~7~.~~~ulati-_m, dc(incd a ~~riori
`
`in the pr<>tocc>I a_; ~on~;istini; oC ~tll ~7.i-
`tit nt~ ~~~h~~ i ccei~~cd xt least 1 <li »e of i~s-
`s~~ned sttul~~ 'medication. x1n aticli-
`tio~nsil ~~res~~eciTicd ~nHIySiS 4c~at
`perfc~rmccl can ttic pc~~aul~u'ic~n of pa-
`tic~it~ not t~i.Eu; ~i~~nrio Ctiiur~~ aspirin
`~i5c +~a~ ~i predcEii~cd risk (i~u~r (oG~GI
`events}. ~Ciu~e-to-r~cnt ~ural.,~5 oi. up-
`perC~ C ~ileer coxnplic.itions~lone c~a~ cc~n1-
`bincd Frith ~~~rnExcrmatie ulcers were per
`fe~rmrd bawccl <m run~ulativc event rites
`(s}°~nptc~m<ilie ulc~r>anclror ulccrcanr
`~>li~-e~drros7 I'c~r tl~te (~-month s~.uclp pe-
`i iod a~~d ~ir~ expresMt d as annualised in-
`c ida•nri~ r~ut~s (i~urnbcr c~Ccvcnls ~~~~~ 1 ~0
`~~~uient-yexr,o[ex~,o~urc or ~~ecccrnEigel.
`1 he Ir~~-i ~~nk tcsi ~~<<fs used to comFaare
`umc-tr,~-e~~enL cni~~~s xn7on~ h•ertUncru
`:;rt~u~~,. [t;i.ec1 orz the recon~mei~dntion
`n(thc Ca t c~~erits cornmiuee ~incl ~~S speci-
`fiecl b}~~ the protocol ~i ~~riUri, ~ip~ce GI
`i~lrcr cou~pfic~a~iosis ~~~crc cic[ined as a
`~,tud~~ end ~~nint Cie. ari uucensured
`c~cri~t) i( they t~zcttrred evithin thr
`(~-it~n~~h treatG~i~rit peG~iod a~~cl oc-
`currecl ~~f5l~toius ~illcr the [~ir~t dose t[ay
`ar belor~~ 14 da~~s ttftcr~ the I,~ct I;~to~vn
`cl~~5c o(stiid}= cin.~n (ta av~7icl c«nfound-
`iii7 due to prestud<<<~~ ~,~is~~~utly~ NS~~LD
`~i;e). T'aUcnts u~ho hoc! uj7l~tr Crl tilccr
`c~rn~~~~lici~tions o~uside oC the specilled
`
`'.;?t~Ut~ %:n;rii~,~n :1ic~ ~
`
`~~ :~n ;'~1i n,~t~: tc:~~crFc~!
`
`(Reprinted} IAr R~1
`
`..
`
`i
`
`I
`
`~ '_t~Vc
`
`d >ti i. Po, lid 1249
`
`Dn~enloaicled 1~'rom: b~ip:ll,jam;~.jarnanct«nrk.conU be a 2epriutx i)cck Il.cr on U(i123/:016
`Page 3 of 9
`
`Patent Owner Ex. 2019
`CFAD v. Pozen
`IPR2015-01718
`
`

`
`Cat It~U(-(~Iti'11"II~flli I
`
`C~.~Vl.. ,),`~ti.UDS(t11tr11:[IIf~l~l~t
`
`Figure 1. Flowdi<:ri of I ,bent Di g c =.Ginn Zt
`6 Nlonth;
`
`~~
`
`ea u
`
`Table 2. Baseline I''aiientCnarar~tc~uk~r,"
`
`tlrne G~rnni ~~~erc censored fur purpi~,es
`cif tune-~o-cvciit anal~~si5. this r~cunt-
`mcnd.t~ic>n ~~t~~ based on the pharitri-
`culc~gic ~~~~~sliout pet`od for i~ri>st z.o~ir
`iron ~A`;,rll[)> ~~u<.I c~~idener In ~hc
`lite~raturcof cart}vc+c cfCcctso(~'S,AIf?s
`fn tcru» of Gi [o~ic e(Ict~tS -'',~1nnl}s4s
`t> ere contlucteci evithz~ncl wit6otu ik~rse
`cens«red pauen[s. "fhc cll~~css o(~ ~iotE~n-
`~ial ri,l: I~ictors (~or the de~~cel<~~~mei:u ~>f
`an ulccrc~>triplication (InclucluGgLut not.
`limfterl to roncwrcnt ~ispii in use) ti4cec
`tu~aE}~z~cl b?~ C:<<s prod>ix~tional htl~<trds
`~rGuclel5. I~Ilc in~•ida•~zces of u~~atnii~~ni.
`e~nei~~;en~ad4~er5~~ effcc(s or clinical I~il~o~
`i;uor}' <h~ngcs ui rhr cliif~~rent ucat-
`nicnf groups during;hc (~ mon[Iis yvere.
`<xn~ ~arcd 1~sin~~ tlic Fisher c~~ict resl_ r111
`~ ~'uc~ <intl ~) ~'io a~r~iCidciice it~tervitls
`Cls) Otte 2- icled. ~o s~~nilicunt cli(fer-
`_r~cc+~ in adv<:e4c c~rnls we;rc no[e~l E~y
`~c..,sci re,ultsziic~~tcscritcd ~~3ith ~vorn~_n
`and rnen con~ibi~i~~il. ~\chc~~e everus Cor
`dicic~fcitac .i~~cl tl~upreCen «~cre ~[~nilru
`
`i
`
`r
`
`~, u
`
`c.~cc~x [or (i~>cr en~yrne etc~a~ti«cis, Cor
`~t~hich resul~s are ~~resentcd 5eparatcl~-.
`
`RESULTS
`r1 tolrtl uk~80:~9 p~itients ~acic~ rartdi~rtt-
`i~ed U'iG~ a[~: 11. ~~inety-one patients
`slid nog rcc ci~~c study drug (3? were razt-
`tlt,n'~ized and found u~ be incligil~lc prier
`to adil7ir~isu~alic~u of stud~~ cli~i,;; `i~)
`~vith~fr~tivconscr~[~riorto lakit7~;sCucly
`d~uy?,C~~tlicwc~31 Ca.iti~=nts,4~H~vcrerar~-
`dou~ii~~t~d to c ~~leco:~ib and 47 ~l~ere ran-
`~lun~ized t~ti \~:\117ti.
`,1 total «I~ 7968 ~>aticnts received at
`least 1 dcrsc nC medication. 11{ these,
`39{i7 patir~i~t~ ~~=ere 1~'cati:d with ccle•-
`cu~il~, ~{(?D nig t~virc ~~cr dad, <i~ul39~1
`~~aUcritsi~t•r~ lretueil~~~itli N5111)ti(L9~;'3
`iccE~iti-ed lbupt'ol~~,~i. SUO nz~; i tttne~s per
`clay, and l9~)t~ rec:~i~ ed tlirl~~[<~nHe, r 5~ng
`i~~aeperdEi~~). Checelec'oxibsin~l~1SU(7
`s;ro4ipslt~ld I'F41 and F.,3S'f total patieri[-
`~c<irs olcxpostu~e, ic~5pcct~i~~cl~~. T3<ise-
`1 ii~e, cht~r<icte~~zstic~: clicl not. t(iffi r signi0~
`e~izuly bete=ec-n groups (`C~131.e ?). AMore
`than 2t)~i~ ol~ thr ptuients ~~~rre taking
`l~n~-dostt~;e asa~iri❑ {•-3'75 in~fel). =\p-
`~>ro~i'ni<itrly 77`x, of tlic ~7titie~~7ts
`(it -1~7`i? ~orn~ileiecl b tr~on~h•, ~~I ~reat-
`tricGit (Fi,~;urF~ I). ~(orc p~uie~~tts iu Ll~tt
`NtiAIU u~t:wl~cnt group Fvilhdre~v Croir~
`the s~ud~~ (or either acl~~•ersc eC[~cxis
`f.n=82? [~?O.ti'«,~l <>r Iacl: of thcrapei_i-
`ur cl(icatc'}' 1~~= ~8~) ~ L-H.~`;*,J) thsui did
`cciccotib-trcat~d ~iatientw to=732
`(1~3 +`ion urtG( n-5113 C~12.U`o~, res~~co-
`tn~cly; P-,~1 ;i«d P .t1~`~; Pi~;~~re 1). ~o
`paiicn~5 eti<~re lost to follo~~~-t~p 'tic, ~i
`r~iuse°oC~~ith~tra~vs~l vasdetcrmtne~dIcyr
`u1l ~~atient~ ~~~lio ~4~ifiitlrex•).
`
`i
`
`-- ,,,
`
`_. __
`
`I
`
`._. ..~
`
`Y)._~-._.._.
`
`--
`
`__
`_
`
`~~ G1 Toxicity
`_ ~l~~,ittilc>C>6t~c<<scs~~~~reselectedbythe
`__ CSI events cotnntiuee (or ~~djttdic~~iun.
`1 heconuniucc~ icl~~nu~ict~ 35 u~~~7rrC;I ul-
`3 _._.
`c~ r coinplic<uions ~uul rtnothrr 4S cases
`--'--- ~ttai re~rrc~cntcd s}'mptc~inatic b~u ~~n-
`",
`ioni~il~talczl ~.~strvtluocicr~~il ulcers
`„3,.
`(`I'.~ut t. 3). Four ii~zper CST ulccrcamlali-
`r _ _
`.;, i caucus (2 tii ecl~coxib-treat~xl ~~ati~nts
`- — -- an<l 2 iri ;CIS:-UD-tr~~i(efl p<iticnt5} ~~~~rEt
`c.cnsorcd ac~nrcfi~7g (~> predctri nuncd cri-
`~cr<<i ~s~~e ti~Ic~h~7d~~~ ~rcdnCl) Clac rc-
`- maining I i7 vises riot i7ieetin~ thc de(i-
`ni~ior~ c>C,~;~utrnduodcri~il utcc~r c.>r ~ilc~er
`
`7250 JAA~tA,
`
`~.~i ~~
`
`i
`
`,:~ is: (I,e~~ri;:frzd7
`
`~.>!?f)4~ ~i~ncr4 c.0 ~:.:l ical ,l~"-c'i:i~i~ n -All ri i~I~~~ re:cnctl.
`
`Do~cnlpadcll Il-om: IHlp:il,jnnu~.,jnmanchrnrk.cond b~~ ti 12cprinta Dell: Uycr uu I)(i121/?016
`Page 4 of 9
`
`Patent Owner Ex. 2019
`CFAD v. Pozen
`IPR2015-01718
`
`

`
`GI Ct~\I(:.1~[1" t-~,'ITLI (1.t f CO\il; SS 1~~5.AII)~ Ft)R AR"f~llltll l.5
`
`L=}~1L puuc~'i[ }~rAes~' Fluc! 3.68°0 ~5l
`c~~ent,,/l ~~ p~l~iert~-~'c,n_Sl Cor c~1e-
`co~ib rind \,\IDs, ~e5ptctivel~
`(1'=.t1;~LC:uriicn>~croid rise k~°as not. sir;-
`niCi~„ui~ly~ ~issoct.~trd ~i ith ~hc incidc ncr
`oC u~~per F~l ttl~°~~r ccrnplications in ci-
`~her trrarinen~ group (12 f:, 0.~. ~uul ~).6 (or
`pttticnt-> trcaeecl ~~~itl~, cc~lcci~xcb art~l
`~'Sr11 f 7s. ~ ~ sperU~~~ ~}~; E'=.l a ~tnd [ - .27).
`
`~,roup). t'hc annu~lizccl ittcldcrtce o(up-
`per GC tticcr coinplicattoi~s in no~~—
`sisE~irin ~~~~.~~~ ~r'~~~ ,i~;nific~~nil4 Ioever
`with •;; l~ ~~~~.ib v=, '~,~tiritDs s11.~}4`Y> ('i
`c~en~4~l 1 ; Z Er~tien!-yc;tr~~ ~ti l2r`•6 ~1={
`G~1e~1ts/I l01 Eiatient-Vesusl,F .l)4;F~'tg_
`urC 213). 1"hc CLR Ixir celecu~ib com-
`parccl «~llt tvS~°~tOti was 0.3 ~ Cc}7`;u C_;l,
`O.l~-C).~)8}. Che<inuu~tlized irtciClcncc
`
`coiztplicauon ~vcre awi~;ncc(a cliarnosii
`Cann the c~u~gt7rics lisped in Liblc~.
`The unnunlized incidc~ic~of r~~~~crGl
`ulc~cr complications ii7 cc~lcc~oxib-
`U et~te<~ E~~~ttiCnl3 sc<i~: O.Ifi~p~ (I i c~eatt~,l
`1 ~{~}t ~~ati~ ut-t°ears? ~t,;in incidence oC
`l ~}if;~;, (?(~ i~~ents!1 i~i~ paut~n~ ~c~ir_,}
`[or ~>aticnts tal<ira,~ \S,°11(_~s (t'=.C}9;
`Fic,t~~ic'2~i). Thy rel~in~~e risk tltlZl (~i
`c~•Ic~p~il> c ~>nlparcd ~~[lh N`+.111)s ~~~7s
`t? 73 (z)~`% CI, O.L(a-~L 11). 1 Inc zuu~a-
`ali_ccl inridciicc of u~~~~cr C;1 ~~ilcer c~~m-
`~~HceUions E~lua ti~~u7ptcmn(ic tilccrs with
`celccc~~ib ~v~is ?.O8'}'6 X30 c~cntsll#-E1
`P ~uen~-gears) vs > `i~4 n`~ (.~F9 e~~cnt~/
`13~`~} C>~tlicnt ~~rrn,5} for paui~i~is t~tl<-
`iu~„ tiS,AIl>~ tl' <.O2 ! i~,uri~ ?A). The ftR
`Gn ~~elccorih com~~arcd with V'St11D9
`
`Inclusion v(thc ' ce~~~sorc~l cv~~ntsrn
`each ~,rciup did not s~l~er the inier~~rctt~r
`th7n ~(resul~s. (=e>r upper G[ ulcer t'c~ai-
`C71iz~atior~s, the mica n~9ihout censuring;
`~i~cie 0.00`0 (1 e~~~nt,IL~~FI ~7s~tient-
`y c ~t ~s) ~tncl 1 `~~)`ib i 2 ~ evciit~l l 3~3~F ~~si-
`~i~:n~-~'t~~u:~l I~or celr~ a~ib nxl \tiFt1C>s,
`rr~~iecuvel~~ {P=.1 l). Poe u~z~~er Gl tt1-
`ccr rortiJ~lic~ilions'plu~ s}~nrpton~alic ttI-
`cers, the r=uc~; «~crc ~.21`~~ { 3? ci~c:r~lsl
`
`GI Toxitity itVith Aspirin Use
`t3as~~d inn tiiur-to-eti~cr7r mal~~scs using;
`~i Cox prn~~i~rtir:,n~il hnza~r~l niodcl. li~1v..
`cic>s~atie ~~spiri~i u~;e teas Eou~cl to have a
`sl~ni(icant effcc[on ifir incidcnt~co(t~p-
`per (.l ulcrr com~~lic~ttions in celcc~~~ih.
`trr~it~d ~;,iucnts. 4tiii~hin the eelcioxib
`lrc~~~tmer~t ;;rnu~~, the RR ~7(ari upper C.1
`ulcE~r compliratiar~ ~~~a, ~1. with l«~~ ,,
`dos~i;c~ <ipiriii ct;e~: (~ cvc7~ts iti 5i3 ~a~i_
`tieuts Ial.in~ Ic~~~`-c1~>tiarc tisE~irin cs 7
`event~ in ~1~~~ ncri—aspirin users
`C,F'=.O l). Lo~~=-dt,~a~(ei~w~~irin uscctici nol
`h<«~e.isi<;riificant ef(cct oix the i'a~co(~up-
`per Gl cilc~~r coinpiir_ations iu patifr~ts
`rccen in.; \!~:ltDs (It R, 1 I; P-.:.2~?).
`bl~lie~~ t,Jre nc~Ct—aspirin-u,5in,:; co-
`hort ~~as cx~irriin~d, 2 u~~~~er Gl ulc~cr
`complicttion~, e~~erc ccn~gred (I in c~ich
`
`Pigure 2. Annualized incidence of Upper
`Gastro(rr[eskir,a(Tracf Ulcer ~C~mE>Iicailoas
`Alone ~n~:l With Symptomatic
`Gasiroduadenal Ulcers
`
`B, h>edlents NnY l2ktnq IYSpltin
`
`~in~
`
`t'-
`
`~
`
`~
`
`i
`
`~('~ PtiNents Taking Aspirin
`
`,—~
`
`Table 3. A~l~udi~:ated Lases A/tee fng and Nc~t PAerF[in { ta5pedafizezl UeFinitiony of
`C astrr,duodtn.il Ulcers ar,cl Ulr,:~i l o;~nplic~<':h~ins''
`
`NSAIO Group
`(n = 3~J81)
`...I, t; i.
`
`_..
`
`~i
`
`I
`
`i
`
`_~~,.
`
`~~..
`
`(•
`
`~
`
`.
`
`~
`
`Cciccnxi~ Group
`(n ; 3~J87)
`iii
`
`--
`
`7 ;'
`1`~
`
`--~~
`
`_.
`
`_. __.
`
`_
`
`...._....~
`
`Toltd
`
`p
`
`__
`(..
`
`Tr,f~l
`
`_..
`
`iE
`
`1
`
`79
`
`'(
`
`1 £;
`
`_._
`
`1
`
`$2
`
`_. ,_t i. .tu. ,.~. ..~. li~., ... ,. s, ,,,gin. ,. ~i ..;[5 :, _...—
`
`__.
`
`l)
`
`(?
`~._......_
`J I
`
`ll .~
`
`. ~.
`
`i
`
`..
`
`i
`
`t
`li .0
`
`,
`
`(Jura
`
`i
`
`~.buw >ars i~iU < .le, ~ vent. (~ ~i ~>ai l.iei~Y-
`, ~ir^_.N5.411rvndifal:~:r rnist~ro~~.l,.ldnh~
`~.. ; dr« „s,
`
`r.,.cl3!~.r.'..~
`
`,!~i;
`
`~,l~t;'r ;~.,~. li) 1251
`
`Dou- nloadMl From: h11~y:Ujuma.iamanct~cork.contJ liv si Reprints Ucsk t}5cr nn Q6l23f201(i
`Page 5 of 9
`
`Patent Owner Ex. 2019
`CFAD v. Pozen
`IPR2015-01718
`
`

`
`t"~l I (~XIC.t t Y lVlTil t.i.LC~~(?\1(4 \ ~ i~~ \!i>> I~~R ~~11tt1IRCClS
`
`of upC~cr Gl tticcr complieauons p[us
`syinp~omriiir ~alce~~s i~~ pa[icn~ not t;il~-
`in~„ si~.~~i rill ~ti ~~v also ~i:;nil ic:ti~tly lo«~~~~
`~ti iih ~clecoxib tl~atr ~vitl~ ASAtC'3s
`(l E0`j;, ~ lPi c~~erilslll=F"~ patic~iil-
`s~etu5~ v5 ~ UI`ib ~~? e~~entsllJC)l pa-
`ticn~-aeac5~, F'=.P?;P~i~;~~r~e~ ~13~ the C'Zl:
`e
`(or ccicrosab t~caipac'cd ~vitli \SAIDs
`
`Inclusion of the: ! , i~ ~ :. ~ 1 ~ ~ c7it in
`ea~klgrotip diet n~~,~Iier the in~~~~~reta-
`
`tic~r~ ~~f results. (~or ttp~~e~ GI ulcer coin.--
`plic'~iu~m, tli~ i~ltcstiv'tih~~ut ccns~~iin;ry
`~~er~ L~.~2ge (fi cYcnL/I 193 l~~ttien~-
`}'er~rs) ~uict 1.364, (1~ ~wc~nUsllli)1 psi..
`iictit~}~ars? I~ot ~~•lecoxib <uid N5r\IL?s,
`rc~spe~tive:l} (l,- U~l. I~or upper Cpl ul-
`cer coira~~lic<i~iims F~ilus se~ni~~inimtlic it1-
`ccis, the i~a~es ~~crc 1.-F~)'?o f I7 r~~enisl
`L1-~3 p~tie~nt ~~ri~s~ acid 3.QQ`;~ X33
`er~~~i7tslllDt ~~.tticnt-~'e~u~t,) for cele..
`c«~Ib:incl +~5:i 11?.,, rc.~~cctivcly CP—~.(}~}.
`
`Table 4. i,<~ rr
`
`F ! , -r puriris tine 6-1:<lonk~~ T~reti[ment P;rric>r1
`AU Patients
`
`t'a6ents Not Taking 1~spirin
`
`Adverse Effects
`
`Celecoxib GrouF~ NSAIb Group Celec~xib Graup NSAID Gro~~}~
`(n = 3169)
`(n = 3JF~i) (n = 37:4)
`(n =. 3987)
`
`~
`
`,, ,
`
`Tot;:l
`
`_
`
`_17">~i
`
`~
`
`~
`
`14h5 ~
`
`° 4. ,
`
`t1^7
`
`i
`
`,.
`~
`
`7~~t..i
`
`__
`
`~a
`
`,.
`~~
`s3 ~
`~j i
`
`_..
`
`_
`
`i
`
`t,;.
`
`T',r,i
`
`1?R.. ~~
`
`?3A ~.
`
`~ ~
`
`~
`
`111
`
`i
`
`__..
`
`'i.
`
`,~
`
`<<i:>n~
`
`i}
`
`__
`
`~i
`
`Tol:il
`
`~.,, i
`
`:37
`
`39.
`
`1Ei.~
`
`I,1
`
`i
`
`r~
`
`r
`~
`
`i
`
`Tol,~l
`
`----- 1~~;:
`
`tU:S
`
`241 ;.-
`
`73C
`
`i,
`
`1 c,r ~~~tucnts tsi:in~, ic~>irii7 ([~i~~ure
`~C), the .innu~i'litrcl in~idenu~5 ~,(s~=rnp-
`~urn~~~ie ulcersiincUc~r uppc~ C.1 conr~li-
`cEitions n~u•re ix~l ~igitii~ic~ntly diFferent
`to patit'nl~ 1~t1:in~; cciccc~xib v 5 ;\SrU Ds.
`1-or i~~~~)ci (rl G~oit~pliiations, Cht-ol~-
`srt~++c<i r~lte~; ti~~erc Z.(~ t% for ~r~iients tal~.-
`mt; celeco.zil> r,s ?. I?4, [or ~~~uients tttl:-
`ui~ NSr~~IDs (6 c~~:nts%2~)~`~ patient-
`~~ca~s ~s 6 cv~:nts12~3 ~~aUen~-ye€irs,
`rc~pccLi~~cl}; N=.9.?). Cor upper C;I ul-
`ccrcf?niplic:ttians~>Etttisvm{~tcnnaiict.tl.
`re~_ti, tl~c obscn~ccl rates ~~~erc -F.%l)`ib Fo1
`p~ilicnts t.tf.i~~~ ccla:o~ib ~5 (i i~0°;, fcir
`pal icnt~s l.il~i~it; ~s5r1! C)s (I •~ eventsl298
`~~~~tiGtit-}a~ars cs I ~ c~~c~~ts1283 ~~aticn~..
`~rir,, resper~iti~~ly; f'~.=191. IncluQinglhe
`~en~;or~~d e~~ents t t in each ~~r<~up), the
`~<ut~5 ~cete~ 1.3~`;'~, and ?.~'k~;(, ~t~s~~ec-
`tn~ely. f~~r u~~~pt'r C;l ulcer cc~inplica
`iion~; and 5.O:3`%; and fi.iE~ o, resE~ec-
`~i~cl~~, C<~~ Gtp~7crGi ulcereomplicatici~~;
`ploy 5~~mptc~mtuic ulcers.
`
`Other Adverse Effects
`\tivertic- tiie~~ts ~~~ith atl ine~tis'n~:e c~i tiC
`I~~r~St i~viocititc~rue~ntrn~~.nt,,rou~~cliir-
`tn~; tlr~• C7-~~tontl~ Ire~t~mcru p4rio~l wine
`CSI r;yrnp[um~;, upper rF:s(~irziLory U~act
`sirC~>ctinn i~r relalctl y}'~i~p~onis, lie<~tl-
`a<~Irc, ar~d r<isl~, Aclvcrse e[fe~cts catis-
`uig~~-i~hclr~ttivril~Guh mincidri7cccif~~t
`Iasi t`Y,incitherueattm~[xtgt~aup~i~cr~~
`CG7 sy~eiF~~u~n~is, rash, rtnci ele~.ttccl u~ans_
`aminasc I~ v cis. 1 ~or thesis esucgories, ce-
`(ccr~.cit~ Fvas a~soci~ui~d with equiva-
`lecri or I~r~~ve~r irxtulc~tCe>s ~~I .~~dverse
`cf~ccts anct ~,vithdra~,val~; cc~itiparcd with
`VSAll7 tl~ierap4`, ~~iih the c:.cepuoris of
`r~t~h anal pruritus ~`"~~~~DCr. 4)~
`Scei~~u5 ads erne cC(ccts (rc~~rc~saiting
`i~ospital~~.itit?ns ur nirili~tiatncics dc-
`tc•itedc[uriii~,tl~e6 iuonllitmaln~ent~ac-
`riod) were. rc~~~orted for ~+.,~~, ~~f celc-
`coxib pal.ient,ti (1 [L t~cnt5l3~$7
`E~atient5) arc( 4.2`.., c,l h5,lll) ~>a[ie~iks
`(16S e~~<~nt5/39S1 ~~atients). ~i"hc ttit~st
`coiY~iiaon t;e~zoti5 a~h~crse cffccis In p,i-
`tientst~ikiu~celeeoxih~incl~~.w,1[I~s~vere
`;accidental fracuires 17 <~nd ~i e~rcnt~, rc-
`5~~~•~ti~~clvj, back pa9n CS ~ind ~ c~~ents,
`~i~;~~Ccti~ely_?, pneumonia {9 and ~)
`c~ enls, r~~pc~.ti~~rl}'), czirdinc failu~~~ ~9
`and lD e~~~~ents, res~~rc~ively7, myoctrr..
`cNal inCzu~~uan (I0 sini( I0 r~~cnts, rc_
`
`1252 1r1~,'i
`
`I °
`
`- ~
`
`~ . r i, `, ~
`
`l~'~ (Rt=pr~nted)
`
`t `?p9ir -i iue~ri~ n'~ ~.d i;_~.
`
`~
`
`~
`
`~i. ;Ali rl~, a-, ir;cct c>i.
`
`I]o~~nloaeicd from: hUp:!(jfmuyjumanet~vi~rk.cuml b~- a Rcprinis Dc~i: User nn Ofii23/201(i
`Page 6 of 9
`
`Patent Owner Ex. 2019
`CFAD v. Pozen
`IPR2015-01718
`
`

`
`Cl ((f\ICt~C1' WCCEI C.f t I~C.t7;~11315 i~i,5:AI[>S (t7R tlI2TE[RCCLS
`
`spectiGely~). and coronary artery dis-
`e.isc t9 aiid 7 c~~cnts, i~s[>ccticd~~). t~;i~
`sc•rtott; r'.~~;IiGs or unc~~~cctecl scr~i~~us s~~l
`t=rr,c c~°ctit5 ~verc ab,crcc<1 in paticnls
`t<~l<iirg <:elcc<~zib.
`I~Iic overall inG~idcnce r~T CSI s}-mJ>-
`tnni; esprriinccd b~' pruieii(s talting cc-
`lca~~ib c~:i4~igni~icantl~r I~>~Ycr tY~nn b~;
`thi~se t~ikin~, A~,',TC)s, pis w~~s t h~~ r~uc of
`~~Fithdr.r~e~.il d~~c ro GI intolcruhilit~
`(~I':iblc ~Fl, C~[~ this mast commonly re..
`7~Urtcrl <~l x~lvcr~rcll~•c~s, cl}~s~~i~~~51t~, ~b-
`clomin,il 'p,iin, nittuca, and ~unstip~i-
`tic~n ~~~crc s~ nilic~util~ loss coiYiiuon
`tirith c'c~lccosii~ then ~~ith \tti;~lf7s. ~t(.
`ihott;,~h there ~~~as n~~ dil~icrence in tltc
`inciclent~c a[ diarrh~~.i C~Cablc ~F).
`I~hc o~cr<~Il inticicnce of~ hlcerlin~;-
`related acl~~r~,~~ t~vc~inti~und specifically°,
`ancniiti [tntl I~i~tntttochczia, cx~i~t ienccd
`by p.uien~~ taking ccicc~~~ih i~~~ts sirc,~nili-
`cantlt' In~~~-r than shat <in~ong ~~aueryts
`tcd in~~ ~S~\IDs (car alI patl_ient~ ariil fc~r
`ilw5e out lal.m,L tis~au i n (Cable 4). S nu
`I~~r res~dts ~~'ere iaote<l Ccn~ ~~etients tal:-
`ins,aspirin; the inciticnce6 ul .ilk bleed ire<.,-
`rcl,ited .id~eisE~ c~en~s 1~~cre: S.Q`'„ zicul
`8 >~,4, li7r 7~al.ients t~ii~ing ce(cc<~:vih and
`~ASAlI?s. ~cspcc~i~-ely, and Ic~r auie~t'nia
`~sEie Z.~s°o and (7, 4 u, re9~~u:cti~~~l)'
`f p ~ ,001. for l7uih c~,mp<u~isutts). Ccic-
`c~n~ib ~vt:is a15Ci as5oci~ucd with ~l lo~vci
`Incidr_G~ce CP' ~.c~iJ l) caC ~:IinicnU}` ~L'ie~~n-.
`u~~~lul redu~-li~~ns iii hcrnrtlaet'it ancll~r
`hcmz~globin (~«r iftr entire ~~aticnt c~-
`hnri ihan \S;AID• (I~ic;t:iii: 3J. ,~1 Io~Grcr
`inc'icicr~cir.~~a~ noted 6~nh iG~ p,itict~t not
`l~~l~in;; ~ttipii in i l _ ~~f~ ~~s '> =~`n in paCierita
`tal~in~= i:eleaf~ib ,uxl \5AE1.)5. ~espec-
`li~cl~~. P~=.l)i1l j <inel patients lakira~; as
`piz'u~ (2.6~~', ~~, E ~)',o ire tl~c~ ~,~ ~~roups, re
`s7icctivclt; P=.0?). "f hi4 cliflcrcnc'c
`~~ereis~e~l ~vhG~n all c.~s~~, µele~~~ie~cl hy~ the
`GI c~~ents coiiimi