EXHIBIT 2
`
`T he New E 11!~l.111J /ouriul uf Medicine
`
`lNHALE D lLOPROST F OR SEVERE P ULMONARY HYPERTENSION
`
`HORST 0LSCHEWSKI, M.0., GERALO SIMONNEAU, M .0., NAZZARENO GAUE, M.0 ., TIMOTHY HIGENBOTTAM, M.0.,
`ROBERT NllEIJE, M.0 .. LEWIS J. RUBIN, M .D .. SYLVIA NIKKHO, M.D .. RuOOLF SPEICH, M.D., M/IRIUS M. HOEPER, M.D.,
`JURGEN BEHR. M.D .. JoRG W INKLER, M.0., OLIVIER S1TOON, M.D .. WLADIMIR POPOV, M.D.,
`H. ARDESCHIR GHOFRANI, M .D •• A LESSANDRA MANES, M .D .. DAVID G. KIELY, M.0., RALPH EWERT, M .D.,
`ANDREAS MEYER, M.D .. PAUL A. CORRIS, F.R.C.P., MARION DELCROIX, M.D., MIGUEL GOMEZ-SANCHEZ, M. D ..
`HARALO SIEDENTOP, DIPL.STAT .. ANO WERNER SEEGER, M.0 ..
`FOR THE AEROSOLIZED ILOPROST R/INOOMIZED STUDY GROUP*
`
`ABSTRACT
`Bnckgr111md Uncon trolled studies suggested that
`aerosolized iloprost, a st able analogue of prostacyclin,
`causes selective pulmonary vasodilatation and im(cid:173)
`proves hemodynamics and exercise capacity in pa(cid:173)
`tients w ith pulmonary hypertension.
`Method.r We ·compared repeated daily inhalations
`o f 2.5 or 5.0 µg of iloprost (six or nine times per d ay;
`median inhaled dose, 30 µg per day) with inhalation
`of placebo. A total of 203 patients with selected forms
`o f severe pulmonary arterial hypertension and chronic
`thromboembolic pulmonary hypertension (New York
`Heart Association [N YHAJ functional class Ill or IV)
`were included. The primary end point was met if, af(cid:173)
`ter w eek 12, the NYHA class and distance walked in
`six minutes were improved by at least one class and
`at least 10 percent, respectively, in the absence of clin(cid:173)
`ical deterioration according t o predefin ed criteria and
`death.
`R ernltI The com bined clin ical end point was met
`by 16.8 percent of the patients receiving iloprost, as
`compared w ith 4.9 percent o f the patients receiving
`placebo (P= 0.007). T here were increases in the dis(cid:173)
`tance w alked in six m inutes of 36.4 m in the iloprost
`group as a w hol e (P= 0.004) and of 58.8 m in the sub(cid:173)
`group of patients w ith primary pulmonary hyperten(cid:173)
`sion. Overall, 4_0 percent of patients in the iloprost
`g roup (including one who died) an d 13.7 percent of
`those in the placebo group (including four who died)
`did not complete the study (P=0.024); t he most com(cid:173)
`mon reason for withdrawal was clinical deterioration.
`As compared with base-line values, hemodynamic
`values were significantly improved at 12 weeks when
`measured after iloprost inhalation (P< 0.001), were
`largely unchanged w hen measured before iloprost
`inhalation, and were significantly worse in the placebo
`group. Further s.ignificant beneficial effects of iloprost
`treatm ent included an improvement in the NYHA class
`(P=0.03). dyspnea (P=0.015), and quality of life IP=
`0.026). Syncope occurred with similar frequency in the
`two groups but was more frequently rated as serious
`in the iloprost group, although this adverse effect was
`not associated w ith clinical deterioration.
`Conclusions
`Inhaled iloprost is an effective thera(cid:173)
`py for patients with severe pulmon ary hypertension.
`(N Engl J M ed 2002;347:322-9.)
`Copyright ~ 2002 Mlassachusetts Medical Society.
`
`A CONTINU OUS infilsion of prosrncyclin
`
`was the first therapy sh own t o reduce m or(cid:173)
`tality in a conrrollcd study of paricms with
`severe p11l111011ary hypcrti:nsion. 1 Hnwevt r,
`its use is asso<.:iatcd with a numb er of serious draw(cid:173)
`backs. The lack of pulmo n ary selectivity results in
`svslcmic siJc dkcts, tulcrJncc leads to prof!,rcssivc
`in.:ccases in t he dose , and there m ay b e recurrent in(cid:173)
`fections of the inm1veno11s .:arherer.l As an aln..:rnative,
`inhaled n itric oxide pu&~csscs p ulmo n ary selectivity,
`h ut it is less p u tent rl1;u1 prusta~ydi11 i11 the pulmo(cid:173)
`nary vascubt urc.·'-·1 Moreover, <111 interruptio n in the
`inhalation of continuo us ni tric oxide may C<\USC re(cid:173)
`bound pulmonary hypertcnsio n.>-6 D esig ned to com (cid:173)
`bine che bcm:fa:ial effects of pros1acydin with Lhose
`nf an i nhalarional applical io n, aeroso lized prost~qr­
`din wa s found ro be ~ potent pulmonary vasodibror
`in patients with acu te respiratory failure, cxening
`prctcrcntial vasodilatation in well-ventilated lung rc(cid:173)
`gions.7·1U Sim.ibr re.snit s wrre o btaincri in spontant'.(cid:173)
`ously breathing patients who had lung fibrosis ,md
`seven: pulmonary hypertensio n.' '
`Iloprost is a st;1hle analu)!.lle of prostaq1cJin 1 hat is
`;issuci;ltt:d with a lunger duratio n of vasodilatatiun. 12
`\Nben administered during a short acrosolization ma-
`
`(!rom t11c D'-'.p.1rtmcnt of lntcm;.tl Medid nc- JI , University Clinic, Gies-(cid:173)
`Sell, Gcnl 1.111y (l l .0 ., 11.A.G., \\r.S.); Scn·ic.:c \h: l;nc:-unu'.>lo~ic, l l (>pitJl An (cid:173)
`winc U.CclC1't'. Cl.u11:irt. Fr.ti\t."\" (G.S .. 0.S.); l$1iluto d1 Cu-tlit>lo~i.t, Univcr·
`sir.\ di Bolo~n.t, llolo~uJ.1 luJ~· ( N.c;., A.M.}; ttoy.11 H.d!Jm.sh1rc.: t-lo!pit:il.
`ShdTicld. United Kin~dom (T.H , D .. G. K.}~ o~:pamucm ofC.;mliololls· .fa(cid:173)
`.tsme U11ivcrsi1y Ho!ipir.11 1 Hrus...:c."ho, Bd~ium (R.N.i; L'nivt'r~i1y of C.1lifm·-
`11iJ ,u S.111 Diq;o McJi~a.I Center, L.t Joll.1 {L.J.R.): Scl11:riug, Rcrliu, Ger·
`111J11~· cS.:-..l., I I.S.)~ f>cpJrl111c111 of I 111cm..1I Mt'dicinc, Uuivcn;ity l Tu~pi1.1I.
`Zurich. Swi1zi.:rlJ11d !R . .S., W.P); D....:r'·'n111cn1 of Pn::omolog}'. llJ11110\'c;r
`McJic.11 SdK.Kli, llJmttwr.::r. Gcnn:;nv (M.M.l L)~ lhc Di\'i$ion (lf ft11hnon.1r\>'
`Diseases. University or Munil:h-G~•!)h.1dcm. Munkh, <.>t•rm:my {J.B.): D~~
`p.1rtmcn1 of Prn.:umol(l~~'· Univcrsi1y Clink . Ldpzi~. Germany (l.W.): Dc(cid:173)
`p.utmcm flf Pn..:11molo~y .md lnfo.:tious Di..,r.::.uc.s... Erns1 t\lO'rilz Amdt
`lJnin:csirr. Greissw.1M. Genn.ut)' (R.E.): Rcreil'h 1'1)(.urno!o,;ic, Mcdizi.nisdlc
`1'.t:.1·nkli11ik un1i PolikUrnk, t;ni\'Cl'SLt:il~klinik11m H.11nb1rrt:.· Eppcndnr1: H.mt·
`burg. Geun.my (1\ .M.); Frccm:tfl Ho.'11\pit.ll, Hi~h Ht·;1rnn. >Je\\~cainlc·11pn11·
`Tynt·. t Jnircti Kin~tfom (l~A.C.); Ocp.:1runc11r o t' l'th.:111nolo~'. G.tithuisbe~
`lirn\l\'rsirr• Clinic. Lcuve1l, Kdgium ( M .P.); .md Pulmo11;\ty J l~1pcrrcn~ion
`U111t, llvspit.d 12 de O..:tubrc:, .\ .{.idrid (M G.·S.). Addf"<:'ss rc:prim rc:qucs1s
`to l )r. Scc~er ,tt rlH.: lk pJrtmc11t of l11tcrn.d Medicine II , U1\iwrsity Cli11i..:,
`K.liuilstr. 36. 1).35392 Gicssc11, Gernuny, or .u wc:rner.srt"gcr@innc:re.111cd.
`11Hi·;1it5Kl1.1..k.
`en1e. oiht:r mc:mhcr~ of rhc A1·rnsolizc<l llo11rost Ra1i.lomi7l~d (r\IR.I
`'rn(jy grmiJ' .ire fom:ct iu the Ap11..:11<l:ix.
`
`322 · N F,ngl J M!cd, Vnl. 3'.7, Nn. 5 • Aug ust l , 2002 · W\\w.ncjm.org
`
`The- New f i g:l!lrc JOi.ltMI of M&GCtM
`00\lon!obdlitC lrotTI ie,11ft.Of9 l)n Ni:weml:OJ' l. 201S. ror pet!onal usl!l ott!y. N3oth$! uses11o1lnot:t p&rmiUfOtl..
`Copyngnt C 1002 l.44$$.&;hU:S'Jllts ~-dlul Soc:~ly All ngho1~ roM rved.
`
`UNITED THERAPEUTICS, EX. 2005
`WATSON LABORATORIES V UNITED THERAPEUTICS, IPR2017-01622
`Page 1of92
`
`

`

`INHALED ILOPROST FOR SEVERE PULMONARY HYPERTENSION
`
`11cuvcr to paricms with pulrnrm.1ry hi•pcrtcnsion, its
`p ulmonar y v:i>odih 1 ivc p mcncy was $imil:tr to that of
`prosta(yclin, bllt its cflccts lasted for 30 to 90 min(cid:173)
`utes, as comp.ut'd with l5 min11tcs.•.ll.JJ.1s Scvcr3)
`npc11-lalicl, 11ncunt rulk d studies lJf pat icnts wit h sc(cid:173)
`\'Crc pulm o n ar y hypcrrcnsio n sug.gcsrcd that long (cid:173)
`term use: of aerosolized iloprosr rcsulrs in s11bsranri<ll
`di11ical improvcmcntu.1;.1o.20 Our objective in this
`rrial W<tS to cv:iluatc t he etlccrs of inh<tled iloprost
`using a rigorous end point of clinical dTlca..:y.
`
`MET HODS
`
`Selection of Patictnts
`
`l,Jri~nrs " 1th pr111l,try pulmo 11,1r y l1~rpcrtcnsi1 HI Jue.\ M.:k i.:-ced ti inns
`~if 11on p ri111.1ry pul1mnu J.ry hypertension \Vere CJ.11Jid,1tt:s for the
`sf\Jd)1 • T l1c fon11s of 11011pri1nary p u lim mary hypl.'.rtt:usion indud(cid:173)
`l:d .\ppctitc>supprc ssanr-associ:m:d 1nd s.:k1u <lc:rm.1-assodatcd
`pulmonary hypcrrcnsio n .,~ wdl as i11<1pcrahlc cbr1it1k thrombocm(cid:173)
`bo lic pult11onJ1-y hypcrtcn.sio n. The indusion Cl'itx:ria were a mc:an
`pulmonary .1rtery 1>rcssurc p;rcater rh:m ~O m m Hg. the .1bility to
`cover belw1:cn 50 3nd 500 m w ilhout c11l.'.ou1~aHc111i.:111 rn1 a six· min·
`urc walk t e:ior)l1 and ._1 Nt:w Yo l'k Ht••ut Associ.trio n ( NYHA) func(cid:173)
`tional class of 111 or I\112 d espite rhe use o f sr.mdard ..:on"cmional
`thcrnpy ( . .uHiclM!~ulants~ d iuretics, di~ir,1lis~ c,1kium-chan nd l>kn:k(cid:173)
`crs) ,md s11pplc1m:1nal uxygt'.n). Patients who '"'i;::rc taking: i11vcsri(cid:173)
`g.11ional drn~s. p rost1n uids) o r bc:t.1-blockc rs wc:n.; cxduclcd . The
`do.~.~ ofc,,h.:i11m-rh;~nnd hlo..:kcrs h<td ro he co nstant for more rh<ln
`~i:t w t.:l'k.s hd~m.; Mu.dy l'.1ll1y. E.xdusiv11 uitcri;,i wi.:1l'. , l pt1l1110 11.Lrr
`.irh_·r~· wedge pn:.s..•n-m· .ir n·."it of m()n- than 15 mm H g ) a 1.:.1rdia(
`illdcx Jl n.·st uf le~ th.u1 l .5 o r 111ort' tfun 4 litt.:rs per 111im1t~ per
`~quar~ m eter nf))c)d)r·:iurf.tcc ;w ;:,1., bkcding J isor'dcrs, .1 bilir'u bin
`lc:v\.'.I of nmrc th.Lil 3 mg per dC"ciliter ( 5 1 µ 11101 per licer). crcJtiuinc(cid:173)
`dc .. r;lncc below 30 ml pc:r minurc:, a fcm:cd vit.iJ cJpJcity below
`50 pcrtent . a forcc:d ~xpirarory vo lume in o n e SC.."i.'.Olld rhat was less
`th~m the 111eJn nonn .ll vJlut: minus twice tbc St';Jndard dt:viat ion l
`.md clini~al insrabiliry.
`
`Study Design
`A tm:il of 203 paricnrs parricip-.ucd after giving wrirrcn informed
`conscm .rnd afrcr the snidy had been ••pprovcd by rhc local crhics
`'' 1mmirrc.c:S .1t 37 F.11n 1pc.a11 spcci:tlisr <:t:nrers. Patic:nrs \\'cn.; ran(cid:173)
`domJy ,\s-si_g.ncd rv recd''' 1lvp n1St ( llum cd1n , Schi:ring) or pl:.u.:.d.>o
`.ilicr str.ttifi<•ation .iccordin~ to :-IYHA fun ctional dass (!II o r IV)
`.u1d t ype of pulmonary h)'pcnension (primory or nonprimary) hy
`an indcp-c11Jc.11t l'Ol'nmirti.:-c whose mcmhl"rs wc1'<..· u11.1wdrL'. of pJ.(cid:173)
`ricncs· idcntitit.:s. A torJI of IOI patients Wt'rl.!" r.rndomly .1ssigncJ ro
`the iloprost ~roup, Jnd l 02 were .1>signcd to t he pl.1'ebo g roup.
`Fq r inh;,1latio 11 , ilClprc1st o r pbn::bo \\~1s d iluted with saline to :1
`conccutr:.it1011of10 µg per nuUilitcr • • md 2 1nl w;.i~ added to a nclJ(cid:173)
`u lizer ( H.1l0Litc, M cdicAid). This tk ,.icc d,-livcrcd short p ulse.> o f
`Jcrosoli1.ed particles' 11;comctric meuian [ ::SD j acrodynamic diam·
`acr ofp:irt icks, 4.3~ 0.05 µm) l..t during the tirst pJrt vf c:id1 in(cid:173)
`spimion until a predefined m tal inhakd dose nf 2.5 µg h ad been
`d ispcnsc:<l. The inhl.htion w.;i.s then sropped or rcpc:ucd once~ to
`.Khicw: ·' m tal dose of 5.0 µ g, c.tepend ing on ho w well t he pari~nr
`tokratcd the m:aun.cm. After cadi mlrJIJtiuu , the rtsidual rnlume
`in rhc ncbulizcr W:ls di~c;-irclcct. This m:1n\"t1~··cr w:ts rcpt;:ltcd !iix o r
`nin;: rimi.:s d~1ily. with an ov1::rmght break. The th;t111c111.:y of inha(cid:173)
`Luivn ~rnrl the d ose \\'ere individually dctcrminc:ci w ithin the first
`eight <bys ot" therapy .lcl'o rding to a prcddiucd ciosing .tlgorithm.
`Riµht-hc.art 1,,~athctcriz.nion was pt.:rfom1cd in all pJticnts at h.L~c
`line Jnd .l.frc r l 2 weeks. T he ,)(Ute ctfo..:ts o f i11hakd iloprosr were
`'""1lua1etl .ilkr 12 wcrks 111 .ill paLirnLS, bul 110 1 Jl !JUSC lint', lu d\'l:ll
`u n blinding. 1\t h~asc line .md ,1ftcr 4, 8, Jnd l 2 \\i.'cks, p.1ticnts com (cid:173)
`rktcd 3 si:'l:-mimitc \\"•J l k Lest, the Mo1hlcr Dyspnc.i Index qucs-
`
`tio11n~1in.:1l • t he EurnQnl qucst kioniuirc:,g .md the 12-in:rn Mcdic.1!
`Uultwm:s S1miv Slmrt-h,.·u1 Ut111.:r.1I HcJlth Survcv.21>
`P.1tii.:nt.s were rc:mov...:d fr<)m the: study if they inct .rwc> 1>r mtln:
`of1hc: t4.tllowiny. prnldincd t.:ritc r-i.1 fcff .1 dcterior<'lrirm in thcir ron(cid:173)
`dirion : r.cfrJctory .sysrolk: JrtcriJI hypot~nsion ( blood pressure, less
`dun 85 rnm Hg); worsening: right w mricular fuilurc (e.g .. :is in(cid:173)
`d1c.u..:d by chc dc.vclopmcm of rcl"r.11..'.tory c.l.klll.l or .iscitcs); rapid1~·
`progrcssin~ C.ltdio~cnic, hepatic, or n.:nJ.I failure; J dccrc-::tsc.: ot' at
`lca)I 30 pcn.:cnr i111lu: di~cm..:e walked in six mi.mires~ :u1d ·' d!!din~
`in mc.unrcs oflh.·mody1u.mic fi111ction, su.:h .-lS C!.'.lllT.ll \'crnous p1~s­
`sure :rnd mixc-d \\;:llUl!S. c ~xygcn .s:u11ration.
`
`Outcome Measures
`
`T he prim.1ry \'IH.i point () f l hc :1itudy l.'.crnsistcd of ,lll ii.11.:rc . .isc of
`.tl' k·.•st I 0 pcn..:cnt in the d istJni.:c walked in six minutes Jnd .m
`
`CHARACTtRISTIC
`
`k~
`
`110_ l%i
`
`110. ('~}
`
`)'<
`Ag< -
`Wd~hl -
`Sc-x -%
`.\.1.1le
`Pcm:.ile
`no. (~)
`Undcrl)•ing <h.\~:tsc -
`rrim:1ry pulmon:u y hy1'JCncm.io o
`'.\Jtmpr11nary p11lfm)1i.'1ry 11rpt..·rn·n:;;:ion
`,\ppctirc suppre..~s.t11rs
`Coll,1)'.:.en ,-,uc.·ul1r tli.sc.\SC
`Chmnic thrombocmbolic p11h11on.try
`l1rpcr1cnslon
`Or.1.l 1.1.L.:;odil.ator 1ha.1py -
`N'\"l IA l\111c:1io11.li d.L~~ -
`ff!
`IV
`M •• hlcr Dyspnt:..i lndcl: t
`6-i\liuu1c wJlk. &s1:m..::c - m
`I knH1(h'l'r.unil.'. v,,ri.1bkst
`P11lm;1111Ary-ancty pressure - mm H~
`C.m1i.1c ourpur -
`liters/min
`I'ulmon:1ry v.•:si.::ular r~isr.rncc -
`1lvn·scc · ~·m -~
`Sy~t.cmic \~\St:ul:t.r n'SiM·~ncc -
`dvn·~c·cm·"
`c~,;l'l"';d, '.'CllO llS pn.·s.surc - mm Hg
`Pulrnonj_ry·,trtcry W~(t~c prc.ssur'C
`- m m Hg
`:\rtcri,11 oxy~cn ,s,1tur.11ion -
`'J4
`Mixr.:d ' YllOU5- oxv.~<n 5Jln1.i1ion - %
`hi:.its/min
`l=ti::m r JlC: -
`
`ILOPROST
`GAoU~
`IN• 1011
`
`PUC HO
`GAOtJP
`!N• 1D21
`
`51.1 + 13.2
`71.3:!: 14.6
`
`52.8 • t 2.0
`72.6 :!: 13.9
`
`_; 1 7
`68.3
`
`:U:I
`66.7
`
`5 1 (::.0.5)
`50 (-t9.5)
`4 1~.0)
`13 ( 12.9)
`33 (32.7)
`
`5 1 ('iO.O)
`5 1 {50.0)
`5 (4.9)
`22 (2 1.6)
`24 123.5)
`
`5 2 (:" l .fi)
`
`$8 (;i(. _9)
`
`60 (:\9.4)
`41 (40.6)
`4.14+ 1.8
`332: 93
`
`59 (i\7.R\
`·B (42.2 >
`4.27.!: t.8
`315.!_96
`
`52.S:t ! l.:1
`3.8 :!:1.l
`l029 '!"39()
`
`53.8:!:14.l
`3.8:!0.9
`t041:!:493
`
`1872= 673
`
`1827:!:503
`
`9.2: 5.3
`7.5:!:3.3
`
`8.2:!:5.0
`7.6:!:3.9
`
`92.6 ::!:4.4
`60.4 :!:7.5
`S3.9 j; 12.2
`
`V2.2:t 5.0
`60.5±8 .2
`R l.8 ..t l.:;.4
`
`• r1us-mi11us v.tlucs • .re nu:au~ =.Sn. NYl-IA dc.·nori.·~ Nr.:w Y'ork I k .u·r
`r\s~nd~1iu11. llKn.: \\'t:r..: 110 s1gnilic.mt ditlCn:.ncc.:s bcl\Hr.:n 1hc ilupn1.~1 .111d
`tl1..: pfa<:ch<> 5;,r<mps. lhta t)ll .111 ~·.tri.iblc.s ''"(!re ,1v.11f.,blc for ,Iii p.111c;111s cxc:epr
`in the fr,llowin~ t·.ucgori-cs: p11lmun.1n·-:.nc:ry pressure. I p.llknt in c.tc.h
`~roup~ t:'J1"\liJ..: outjlul. I p.H1c1H m 1h e tlo pro51 _£.roup .md 6 in 1hr.: pl.1et.:lm
`g ro up, pulmonar~· vJSL'ulAr ro1st.uh'c , JO .mil 6, n:spcn i11dv; :iy:.1emi~ vJs(cid:173)
`ntl·1' 1esi:i.t:.i111.:c. l l .111\I 14; •.:emrnl vcnou~ prt..Ssurc. 5 .rntl 7~ puhnon.1ry~·
`.u-h::ry wedJ!..: pr(s.surt, 8 .u1d 3; .mcri;ll v.w~c:n $.Ullr.11ion, .35 Ju.I 3 1; mixed
`\'c11ous ox\'gcn s.m1r.uio11, 16 .mtl 18~ .u1d hean race. 2 ;ul\t 3.
`T0rl thiSc l .2-point :S,f,1k, hi~hcr KOl"C:i 111du;;1llC k-SS dWipn~.l.
`tP.trii.:nrs who \\"c:n:: f\"i.'.civin~· lung-rc:nn oxr!?cn rher,t('IY r'"·cei"t:rl nasal
`oxn .• .-cn during 1lte llleJSUl't.."lll(nt of basc-li11c hcmod)'IMmir variotblcs.
`
`N En1;I J /\!eel, Vol. 347, No. 5 · August I, 2002 · '''ww.ncjm.org · 323
`
`Tre lieNt f ng18f'IC' Journ~ ot Mk.:il'lit
`Oo'l\'rtoadea from rie;M.OIQ ()fl November 3, 201S. For C&")Oflftl UJb o"ll)", No OthGr u~ W.ll'OJI perm~ior.,
`Copyru;i"rt C> 2002 M~~h\4$tb ll«t.:61 Sool!fr. All tigtit:s re!O'Vtd.
`
`UNITED THERAPEUTICS, EX. 2005
`WATSON LABORATORIES V UNITED THERAPEUTICS, IPR2017-01622
`Page 2 of 92
`
`

`

`The 1'cw Engl.ind / ou rn ,11 <>l Medicine
`
`imprrwcmrut i11 rh:.: NYHA fi.1m:rion;_1I l.'.Lt:ss in the ,1b~c11cc of .1
`Jdi:.rior.nio11 u1 tlu:. 1:li11ic.1I i.:011d1tion or ck.11h durin"!; the: 12 wt:.eks
`of rlw srud)'· Sl'COIH'fary t•fri.1.:.Ky \':ll'i:ihic ... \wrc ( h<.l 11b;S in rhc v:1lw.·s
`tor the si:'\~ 1111nut~ '"Jlk. l:.:,s-1, 1hc :-.:YHA da$S, MJhlt:c lJy$p11cJ In(cid:173)
`dex stores, lwn1odrn~unic variabks, .md th..: qualiry of lifr; clinical
`.. lL"rcrior:uion: de~1th: .md the 111.:c:J for 1ransplant;•ticm.
`
`Stat istical Ana lysi5
`Tiu.:: pri1n~try tvalual iu11 of c:fli1.:Jcy illdudcd all nmdomizcd p.t(cid:173)
`rii:ms. OM;i :lrc pn:.:o;cntcd .u me.ms -::SD, u 11!.:ss uthc.;rwi~c sf:ltcti.
`\Ve included ~Lua 0 11 p.1:iicnl"s who prematurely dis~o11tim11:d rhc
`~tudy using :.l b.st-ohscrv~tti<>n-c.uricd-forw,ud .u1:t\~rsi.fi for rh1.· s.h:(cid:173)
`milllHC walk test. Paticnu; who died wcri.= ,1$siµncd a v.1luc of 0 m.
`t\11 .st.iLi.<tkJI te sts for \:"f)ic,tey v.lriJhlcs \~CR'. l\, n-t,1ih.·J, with .111
`.1lph:i h:vd of 0 .05 .
`·re, .111.ilyzc tfo.; 1-"··im~u y cftic.1i.:y end puint .1m.J the.: imviovi.::nn.::nl
`critl·ri,l, w..: used rhe 1\'Lintd - HJcnsiel te!'St,27 strJtitied .iccon::tint: to
`i-hc type o f µulmo11.iry hy~c:rtt:nsion (prinury or 11012pri111ary' ~m.l
`N\1 IA chss ( I !I or IV). 1'.tticnts with missing dJt'1 on tlw prirmry
`end point at week L 2 we.re c.:onsidcri.:c..f nor ro ha\'c had a response.
`Clung« in the results \)f the six-min ute w:ll~ were cvoluotcd
`\\'ith '1o;;c. clf 11<l llp :tr:"l11w tril'" .1n:tlysis nf ( 1w::triancc ~tr:ltitied :tc~:j)rd ·
`i11);. to the type of pulmo nary hypertension ( primn y or nonpri(cid:173)
`nury I and the NYHA cbss ( Il l or IV), wirh use of the basc· linc
`\•.1luc as chc. cov.ui.ul.'. (a1ulysis of cuvari:m\.'.e, .. ind the \Vilcuxon
`sign..:d·r·:m k tl.'.St.
`Ch:ingi.:s from base lini.: in hcmodynamk yaJucs were ~111:.li>·itd
`v • .-ith t·st.uistics. Th~ invi:sti::tatvrs hild full .u.:ccss to thl" d.u.t .md
`pe rformed the analyses indt:pcndcmly of 1hc .~punsor.
`
`K.tSULT S
`Base-Jim: dcn.10graphic and hcmodynami..: data arc
`?.ivrn in "fable 1. The mean frcqw.:ncy of inhalation
`w,1s 7.5 times per day. ~i nery-onc pcn:em ofparicnts
`received 5.0 µ,p, per inhahuion, and 9 percent n.:ceivcd
`2.5 µ,g, corresponding tO a medi:111 inhaled dose of
`30 µ,g per day.
`
`Prim ary Efficacy End Point
`
`For the primary end point, we found a sig niJicmr
`dfocr nf treatment in favor or iloprusr ( P = 0.007)
`(Fi)!;. 1). The estimated odds uLm dli.:ct in the ilo (cid:173)
`pro.1t g roup, as cumpan:d wirh the plaeeho g.roup,
`were 3.97 (95 percent contid cm:e intcrv,11, 1.47 to
`l0.75, by rhc Mamcl- Hacnszcl resr). with no signif(cid:173)
`icrnt heterogeneity among the four subg roups care·
`gorized according to type of pulmonary hypcrrcn·
`sion aml NYHA class at base line (P = 0.79 liy the
`Breslow-Day test). T he secondary arn1Jysis of the pri-
`1miry end po inr was a logistic-regression model that
`indmlcd treatment assignment, demographic Jar-.i,
`and b,1sc-linc char'1cterisrics. Only treatment assign -
`111cnt ( P ~ 0.01) contributed signiJicandy to the prob·
`ability o f a response.
`
`Secondary End Points
`
`Six·lfAinut~ Walk Tes t
`
`The percentage of paticm s who had an increase o f
`<lt lc<ISt l 0 percent in the d istance walked in six min·
`utes ar week 12 was slightly, bur nor signi ficantly,
`higher in the iloprost gro u p than in the pl:Kebo
`group (l' = U.06) (Table 2 ). The type of pulmonary
`hypertension had no significant effect on the ourcome
`in either group (P= 0.90). A higher pcrcem age of
`po:iticnts in the plJccbo group th;m in the iloprost
`g roup .had a decrease in the distance walked of at least
`IO perccnr or did not complete the srudy (Table 2 ).
`The absolute ch ange in the distance walked in six
`minutes was signific;uirly larger (by 36.4 m) in rhc
`
`E
`"C "'
`..><
`<ii
`$
`"' 0
`~
`"'
`a
`.S
`"' °' c
`"' .r::. u
`"' "' ::!;
`
`c
`
`40
`
`20
`
`0
`
`-20
`
`- 40
`
`lloprost
`
`Base Line
`
`4Wk
`
`8Wk
`
`12 Wk
`
`Figur e 1. Effect of lnh"led lloprost and Placebo on the Mean (~SE) Change from Base Line in the OisA
`tance Walked in Six Minutes. According to a n Intention-to-Treat Analysis.
`Th e P value was obtained w ith Wilcoxon"s test for two independent sample>.
`
`3 24 · N Eni;I J 1\;1cd, Vol. 347, No.
`
`· Aui;ust l. 2002 · www.ncjm.01t1
`
`D~ l!QfTI nDJl'PI o"gef'I NovC~t3. 201&. ForpefSonol Jseort)'. Nootner US03WiWtoot1:1«ms1on.
`Cci:i)11ghl IP 2002 Ma-ssecrws~ Mt;t(hCal SOCll)to,'. A.II righl.$ f(l3orved.
`
`ff'la flll)N EnQlilOO JOU'MI °' Me1Jic1r f!I
`
`UNITED THERAPEUTICS, EX. 2005
`WATSON LABORATORIES V UNITED THERAPEUTICS, IPR2017-01622
`Page 3 of 92
`
`

`

`I NHA LED I LO PROST FOR SEVERE PULMONARY HYPERTENSION
`
`iloprosr group rhan in rhc pbn:bo group (P = 0 .004)
`( h g,. 1): 58.8 111 among_ those with primary pulmo(cid:173)
`narv hypertension and 12 m among those wirh non(cid:173)
`pri111ary p11!11mn.1rv hypcn e 11sirn1. A par.1111ctri<: analv(cid:173)
`sis o f covarianc.:, which included the absolute.: value
`o n rhc six-minure walk rcsr at week 12 as a dcpendenr
`'~1ri;1bk and the treatment assignme nt ( P = 0 .02), t)'pc
`o f pu lm onary hypencnsion (P o:0. 06), and distam:e
`w<1lkcd at hasc line ( P< 0 .0 0 I} did 1101 show a staris(cid:173)
`tically signifiom interaction between trc;\tlncm and
`rypc of pulmonary hypertension ( I'= 0.09).
`
`NYHA Class
`More p;1ticnts in rhc iloprost g roup than in the pla(cid:173)
`~cbo g roup h,1<l an im provement in rhe severity of
`lu::irt failure, as :isscsscd by d1c NYHA dass ( P ~ 0 .03)
`('fable 2 ). The typ e of pulmonary hypertensio n had
`no eftt:cr on rhe o u tcome in c.:irher group (1'= 0.39).
`The perccnt;igc of patients with ;1 <lcterion1tion in
`NYHA class did nor differ sign.ilkamly between che
`p,rou ps, bur the analvsis d id nor include patients who
`left the study c:trly owing to death o r other reasons.
`A hirgcr p ro port ion of pat icnts in rhe pbcebo !l.roup
`th<rn in the iloprost group did not complete the study
`("fable 2 and l:'ig . 2 ). R.c:1sons inclu<lcd dcJth, discon (cid:173)
`tiirnation of study mcdic,1tion, ;md withdrawal of con-
`
`sent, 111ostly owing ro dinica.J detlTior;ltion, insuHicicnt
`clinic~ ! benclit, o r both.
`
`Hemodynamics and Gas Exch•nge
`In the placebo group, cardiac outp ut, systemic ar(cid:173)
`teri<ll oxygen saturation, and mixed venous ox1·gen
`saturation decreased significantly ;1fter 12 weeks and
`pulmonary '"1scular resistance and rig ht atrial pressure
`increased significantly (1:11>lc 3 ). In 1 ht: iloprosr group,
`v;1lues assessed at 12 wee ks, before the first morning
`dose of inhaled iloprost, were largely 1111changed from
`base line, w h.:rcas val ues assessed attcr inhalation
`\\·crc significantly dcacascd (in the case of pulmonary(cid:173)
`.1rtc.ry pressure, pulmonary v.1s.:ida.r rcsisl~1.nc.:e, sysrc1n(cid:173)
`ic arterial pressure, and S)'Stcmic ;1rtcrial oxygen saru(cid:173)
`rntion) o r increased (in the cas.: of carbon monoxide
`and pulmonary-artery wedge pressure). At the.: com(cid:173)
`pletion of rhe 12 -wcck srndy, :icure hemodynamic n:(cid:173)
`sponsivc;n~'SS to inhaled iluprost was cquivaknt in the
`placebo group and the iloprost group, though the lat·
`tcr gro up hJd been exposed to d.1ily iloprost in hab(cid:173)
`tion for three months (d<tta not shown).
`
`Mahler Dyspnea Index
`The: mean Mahler Dyspnca Index transition score
`wM; significantly better at week 12 in the ilo prost
`
`TABLE 2 . "Er-rncrs 01' 12 WI'EK< or- TMERNY \<.~TM l >iHALf.D [!.() PROST O R ['I.ACEBO
`o .'3 TllE NEw Y<HlK H L'\N.T A~.soc1ATION ( NYHA) C1.A S.'li AND T l IE .S1x-MrNUTE \ VALK Tr ... ,T.
`
`VARIA8l.f
`
`lt.Of'ROST GROUP
`
`)1.-\"J'l!-::..~T' \\'l'rJI
`rllJAL\R.Y
`
`P.\Tff_., -no WITH
`XO~l'JUM.\RY
`M1f_\ 10:-.0.MW
`?r 11 .\lU~AA~
`1 1\'PL:.~fLS.~ION [(YrhkT L:J"ltUN
`
`.\l.L 1'.\T!I:.-..:~
`
`PLACEBO G'ROUP
`
`r.n1£'."'n> WITH
`tt~J.\.L-\1'.Y
`:'l lU.to;..'.Ait.\'
`~·~ "L ~ tON.AR.Y
`! IYrt:Rn:~:.;:10~ 11rri:a11:.-.:!'IOS
`
`:'.\Tlf ... "fl). w .Ul
`~O~l'KJM.\t4.!'
`
`,\Lt f',\'rlf:-.~1~
`
`percentage of patienlS
`
`Ch.111~.c: in NY.HA d.1:.s
`l111p1ovt'tl by l i.:Lis:)CS:
`lmµwvctl IJy 1 d.is:.
`Lr11ch.u1gnt
`\\'c>rscm:d
`D.tra 111is:si11~
`>-l'o11complcrion of study
`\)caih
`Other
`Ch.tHf l"' in 6 ·minu1e "~,dk disrnncc.
`~ 1 0% inrrl.";.l_'>t:.
`< 10% im·rf';.i~ ro < 10% ,ii:~n:.1sc
`;:;. 10% dt:cr~-..1..sc
`11,11.1 mi,~in!~
`Combined cud poi1H
`
`t.u·
`238 "
`64.4
`5.9
`1.0
`4.0
`l.O
`3.0t
`
`.i7.f>§
`t2.6
`l.~.9
`5.9
`lf>.R1
`
`1.9
`22 6
`66.0
`.l.S
`1.9
`3.8
`1.9
`1.9
`
`-19. 1
`.l7.7
`~.7
`7.5
`20 R
`
`0.0
`25.0
`62.5
`8.3
`0.0
`4.2
`0.0
`4.2
`
`2S.O
`47.9
`22.9
`·1.2
`12.5
`
`0.0
`12.7
`65.7
`7 .8
`0.0
`l3.7
`3.9
`9.St
`
`25 .• ::t
`.12.4
`25 ;
`16.7
`·1.9
`
`u.o
`7.3
`69.l
`l0.9
`0.0
`l2.7
`36
`9.1
`
`.l0.9
`lO.O
`U.7
`164
`
`:). :l
`
`o.o
`19.1
`6 l.7
`4.3
`0.0
`l4.?
`4.3
`10.6
`
`19 .1
`4(; 8
`17.0
`17 0
`·U
`
`~ r 0.03 f(>I' 1hc i:cimpMison oi' r.llCS of impro''l':mcm (by o ne or 1wo ..:JJsscs:) with the pl:Kcbo µtoup.
`tTn;.umc111 w .. ~ dist"ontimu:d io .111 t lnct: p.u1cnu.
`fTn•;umcnr "'"'s di:s~·,mtinnc:cl in 1(1.wcn p aticnt.s, .met thrc:e patient.i.: withd rC\'/ rhi:~r ..:(m~ellf.
`§P'='"' 0.06 for the i:ump.irison wi1h 1hc pbi;:clu..1 ~roup.
`1r""0.007 tCw •he ' omp;u ison wirh the pl.tcclx> w-oup.
`
`N En~d J Med, Vol. 347, :-."o. 5 · August l , 2002 · www.ncjm.org
`
`· 325
`
`Th11 Naw Engl:wld Jou'l\1.11 d llecicin11
`Ckiw~d!!d from n@lm org en Novemtier 3. 201.S c-0! ~I He o.,fy Noolher UlliH W4i"ioo4 iierrrt!Mion.
`
`CopyrigM C ?00, \'3?1Sdciil.JSflil!S MllObl Sl)d8)'. A l! ng"ll~ ra.~•Nl!Jd.
`
`UNITED THERAPEUTICS, EX. 2005
`WATSON LABORATORIES V UNITED THERAPEUTICS, IPR2017-01622
`Page 4 of 92
`
`

`

`Th ~ Ne"' Engl.ind Jou rn.tl <Jf 1\lcdi.:i n c
`
`Placebo
`
`Cl
`.S
`c
`"' E
`er:>
`~ -0
`c
`:J
`·~ u;
`"' ., 0.8
`0.. .t: o.s
`c ·¥
`0
`c.
`0
`~ 0. 6 -t-~--,~~-,-~~.--~-..~~..-~--.~~...,-~~.--~-,
`80
`40
`90
`0
`20
`30
`50
`70
`10
`60
`Days
`
`11)
`
`0.9
`
`0.7
`
`Figure 2. Kaplan- Meier Estimates of the Likelihood of Completing the 12·Week Study.
`Reasons for not com p leting tho study included death, d iscontinuation of study medication, and
`w ithdrawal of consent lsee Table 2).
`
`TABLE 3. MIJAN ( :!:$0) CllA:<(;E FROM llAS!i LINE <:-.: H !i,'10nY'1MllC VALUES
`()VRJ:-./( ; 12 \Vi;i:~.$ «W Tr urn.Ar\' WITH l~tlAI l~ll ILOPRO"T OR. PJ •. \ CF.BO . •
`
`VARIA8lf
`
`PLACEBO GROil.if>
`
`Pulmon.uy .urn y pn::ssuri.:: (mm H~)
`Cmfo1r omput (liters/ min)
`1~11lmon.uy \.';ls.cubr n:sist;uwc (d~·n· ~cr ·on .,)
`Sys1~mic <ll1cril1 prc~urc: ~mm H~)
`Rii:hr itrfl·ri.1l 1ucssure (mm HtJ
`l'ulmo n.wy·.Hrt·ry \\'t.·d~~e pn:ss.url'" (mm Hf,)
`Art:.:ri,1.1 c1xy~c11 .t,u nr.lli01l ~ 't)
`l\lix('d WllOUS UXV~t·n S..tll!r.lt lrnl (%)
`I lc.n 1 r.&h: 1 hc..·.1ts/nun >
`
`- 0.2= 6.9
`-0.19:!:0.SLt
`• 96 :!:.122:
`-0.2Z l 2.~
`> 1.-1:!:-l.Rf
`l 0.7T .l 1>
`- 1 .r~·-t.4!
`- .t2 t-- 6.7t
`-1.2 !:9 .5
`
`ILOPROST G ROUP
`r.r:ruRl:
`\•n.::-l
`::-.•!t.\l.:\l ll) N
`INl lAl,..\ f lON
`
`m 1t11n !.SO
`
`--0. 1 = 7 .. ~
`+ 0.05 ::0 .86
`90:275§
`- l.7 +12.S
`• 0.5 ! 4.6
`f l.l +4.7+
`- 0.4:!: 3.7
`- J. 1•7.6
`- 1.8 ± 12.4
`
`- -1.6 ± 9 . .lt
`+ 0.55 ::1.lt
`·- 239 :?:279t
`-·1 .. l :! l3.61
`- 0 .R:!:4.6
`• l.8 +5.31
`- 1 A • ~t7;
`; l.M I X.J
`-2.25.!: 12.6
`
`· r··or tht: ilopws1 ~nn1p. bo1h prdnhalJtion and po..,1inhal.11io11 v,tlues .l licr 12 weeks ~uc ..:omp.m~d
`with 1hc h"sc-line ""h u:~ .11 swd~· 1,:nlr)'·
`f P< 0.001J(1r1hc JiOCn.:1Kc from IM$c-linc vJlucs.
`jl'< 0.05 for the di:tl'c:rcni.:e frorn b.1sc:·lillc:. v.1l11c.s.
`§l'<..0.0 1 tbr th~ .. :omp:irison with the pl.Ki:bo group.
`1JY< O.Ol for the diOCreucc from b.uc· line '"l.lues.
`
`group than in rhc placebo group ( change, I 1.4 2 :!:
`2.59 vs. -r0.30± 2.45; 1'= 0.015). The 1ypc of pulmo(cid:173)
`nary hypcrtrnsio n had no dfcct on this out..:omc.
`
`Quality of life
`l'vkan scores o n the EuroQol visual-,maloguc scale
`improved significanrly (from 46.9 ± L5.9 to 52.8 :: !9.1)
`in the iloprost group but. were virtually unchanged
`
`in the placebo group (dropping from 48.6± 16.9 to
`47.4:!: 2 1.l, l'= 0.026 by analysis of..:ov"ria.t1Ce). The
`EuroQol health-state score improved from 0.49± 0.28
`to 0.58:!:0.27 in the iloprost group and was un(cid:173)
`changed in the placebo g roup (0.56:!:0.29 w 0.56:!:
`0.3 1, P=O.l! by analysis o fcovaria.ri.:c). None of the
`other measures ofrhe quality oflife were signLficantly
`different between the groups.
`
`326 N F.ngl I lvfoi , Vol. 347. No. 5 · Aug u<r 1. 2002 · www.nejm .org
`
`The NBW' E.n;mnd Joomal of MIMl11:1r:e
`0 oo¥niolllded lrom tHt.i'Tl.Of9U\ NovetnDl!r 3, 2015. Forpel"JOl'\91 JH °'"'Y· .'-'ootlier uSP.SW\~(JUI Detmi!.9t01.
`Cc»; n.gt'lt@ 2COO M°'$.s1K,usttlh M~i,I SXMJ!y. All ni:Jhl:s ~.S()!'\iod,
`
`UNITED THERAPEUTICS, EX. 2005
`WATSON LABORATORIES V UNITED THERAPEUTICS, IPR2017-01622
`Page 5 of 92
`
`

`

`I N HALED I LO PROST FOR S EVERE PULM ON A RY HYPERTENSI O N
`
`Clinical Deterioration a n d Deatn
`One patien t <lied in the iloprosr group during the
`12-wcck srudy, ;1s co mpared wirh t<.iur patients in the
`plao:bu g,ruup ( P = 0.:'17) ('fable 2 ). Critcri,1 for clin·
`ic1l deterioration were met in 4.9 percent of pJticnts
`in the iloprost g ru11p and 8.8 percent of rhose in rhe
`placebo p;roup (P = 0.41). This in<liotcd th,1t fewer
`patients either died o r deterio rated in rhe iloprosc
`group than in tE1c placebo group (4 .9 percent vs. 11.8
`percent, P= (l.09). T he type o f pulmonary h}•pcm:n·
`sion had no cffen on the outcome. During the st udy
`period , n o ne of the patients rcceiveJ a lung transplant.
`
`Safety
`T he tOtJl number of potients who lud serious ad(cid:173)
`verse events diJ n m diller si~ni lic;int l v between the
`g.roups (1c1bk 4 ). Right ven~riculru- failure and ede(cid:173)
`ma were m un: than rwice as frequenr in the plaedw
`~roup as in the ilo prost gro up. Thc total number of
`synco pal events in ca(h of the two g ro ups was sim(cid:173)
`ib1· (eight in 1hc iloprost g ro up and fh·e in the pla(cid:173)
`..:ebo group), but these events were m o re ofren con(cid:173)
`sidered serio us in rhe ilo prost g roup. Sy1Kope was
`not associated w ith clinical d eterioration o r prema(cid:173)
`ture withdrawa.1 from rhe srndy. S~·m:opal cvenrs oc(cid:173)
`curred m o re th.111 two hours afrtr the last i11hahitio11
`( ofren afrer an overnight break ), were exercise-induced
`in two patie nts, were indtKe<l by br;i<lwardia in two
`patients ( associmed with gastroenteritis. in one patient
`.md wi th verapamil therapy in the other), and rcs1ilted
`in head trau ma in o ne pati<:nt. Flus hing and jaw pain
`were more common in rite ilo prost g;ruup, bur these
`.1dverse efli.:cts were mostlv transient ;md mild and
`were nor considered to be "serio us in anv patiem.
`
`DISCUSSION
`The results of this dini..:<11 rrial demonstrate that
`long-term inhaled administration of aerosolized ilo (cid:173)
`p rost , a stable .analogue of prostacyclin, improves a
`..:Linically important combined end point consisting
`ol' exercise capacity, NYH.'\ class, a nd cli11ic1l deteri(cid:173)
`o ratio n in patients with selected forms of pulmo nary
`.1rtcrial hyperrcnsio11 and chronii; thrrn11bncn1bolic
`pulmo nary hypertension. t.forcovcr, iloprost improved
`several sccunda ry me! points.
`Since intr.wcnous cpoprosteno l was shown to im(cid:173)
`prove survival among the most severely ill patients
`with primarv pulmo nary hyperte11sio11, it has been
`lll1ethical to perform rando mized clinical trials among
`patients with pulmonary hypertensio n in whic h sur(cid:173)
`vival is useJ as an end point. We c hose a combined
`rather than a single end po int ( e.g., rhe d istance
`walked in six m inutes) in order to make a more rig(cid:173)
`o ro us determination of whether in h~led iloprost w~~
`e tlkacious. Nearly 40 percent of all p<1tic11ts who wen:
`trea.tcd with iloprost increased their six-minute w,1lk-
`
`ing: distance by at least J 0 percent. I lowcvc:r, only half
`.. 1s many patients also had improvement in the NYHA
`da .... ,; conve rsely, 1101 all pa1i.-n1s w ith an irnprnvc1m;nt
`in ::-JYHA class had <ll1 iJicreasc; o f ,It le.1st l 0 pcr<:em in
`the distance wal ked in six minntes. Thus, althu11gh
`o n ly 17 percent of patie nts in the iloprost group
`reached the combined end po int, a s\lbst;1nti.al num·
`ber o f the re maining patie nts met less strict criteria
`lo r clinical improvement rhat would warrant contin111;d
`thcn1py. Furthermore, siguilic.mtly fewer patiems in
`the iloprost g ro up than in the placebo grou p prcina·
`turclv discontinued the s tudy as a result of lack o f
`effi..;,;cy or other reasons, suggesting that even when
`iloprost therapy docs not pro duce substanti<tl improve·
`rnent, it 111ay stabilize rhc. clinical condition .
`The mean inhaled dose of ilo prost correspo nded
`ro 0.37 ng per kilogram u r budy weight per minllle,
`which is eonsiderabl)' lower than an effective iJ1travc(cid:173)
`no us o r subcutaneous d ose.z.ix 1lms, targeted deLivcry
`of prostanoids to the pulmonary vasculaturc by means
`of inhalation may substantially reduce the d rug re·
`q uirements.
`
`T ABLE 4 . 1:-<CID!l N CIC OF SERJOU'S "-"fl O TllER A D\ '(i!<.)E E\'EN'l'S.'
`
`VAKIAIU:
`
`ILOPROS