,. ... ( ............. .;.
`2~0lli PO 005
`
`Cont.(lo(;t Jnformm.lon:
`r'" M11~--· P!\11"'1\D
`Cll~a1Aff.11rS
`~·LOmb.ftll.
`SOT-=~ DIN~!
`ll'llr ... CA92618
`~ (~9) 788-Sl88
`f'OTI1'1 tm ~Nnatt~ttr4Gbbotteh tl)l'l•
`:zr~~~~~y~~~.a~~rw.a:;maaz :~;mm:a:sa ~=-~~«~w:m~r!Zi'!~31Zl~<:::=m~~mw~~~.t'~~~~
`J.A Gow, 1 D.F. Goldberg, 2 J.H. Peace, 3 T.R. Wa lters, 4 J.P. Gira, 5 S.M. Klier, 1 T.R. McNa mara 1
`for the Low Concentra tion Bromfenac Ophtha lmic Solution Once Daily Study Group
`1Bausch & Lomb Inc., Irvine, CA; ' Wolstan Eye Associates, Torrance, CA; ' United Me::lical Research Institute, Inglewood, CA; • Texan Eye, Auston, TX; ' Ophthalmology Consultants, Ltd, St. Louis, MO
`
`Integrated Phase III Clinical Trials of Low-Concentration, Modified
`Bromfenac Ophthalmic Solution Dosed Once Daily for Cataract Surgery
`
`f)'.)~:){).~~: To evaluate the effiCacy and safety of tow~concentntson,
`modihd brom(enac solution dosed QO for catar.tet surverv.
`t-1--:\C:'y6;.. S4.1bjtcts rece•ved tither b~mftMC (n• 222) or pl.-ctbo
`(n•218) QD. Oosi"Q began 1 day before cataract surver'V Md
`contin~d dalty through post-surgery Day 14. Pnmary efficacy
`ondpomt was no oculo\r lnfltmmation by Oay lS; secof'ldary efficacy
`endpoint was no ocul.-r pain at Day 1
`
`*~)::~:.. Ekomfenac was superior to placebo for primary and
`secondary efficacy endpoints (P<0.0001). Compared to pl.acebo,
`bromfenlK. had a
`lower lncide:nce of ocu4ar adverse events
`(P•0.0001).
`f. : t c•.::eo..::.e.·~~ LOw·concentntton, modified bromfenac sotvdon dosed
`QO k nfe and effective to treat the inntrntNtlon .-nd paln auodated
`wfth cataract surgery.
`
`,) &romten"c Is:~ non-neroldal cantl tnftamm~to.rv drvg (NSAJO) w•th
`~n extensi v-e his.oory of cltnic~t effic~ey; It Kts by bkxklno
`prostaglandin synthesis by inhibiting cydooxygenase 1 and 2 1n
`the arachidonk acid pathway a
`
`~ The bf'Omlne MOitety In bromtenac enhances Jlpophillclty and
`facititatt:s t>tnftf.)tion throughout OC.\Ilal' tissues N
`
`"' Bronuclo;® (bromfe.nac sodlum ophtha1rnK wlution) 0.1% was
`initiallY approved m Japan in July 2000 nd was $ubSequenuv
`approved for the treatment of l>lephanbs, conjunctivitis, scleritis
`(lnc:tudlno epis<:lentk) and post·optrauve lnRammation4
`
`Xibmm•• (bromfe.nac ophthalmic solution) 0.~. administered
`cwke da1l)', was approved by the Food and Drug .odmlnistration
`(FDA) on •larc.h 24, 2005 for the treatment of patients with post·
`C.ltar.ct OCuflr infllmmotion, :tnd In JanlH!ry 2006 for tN
`ttea:trne:nt of oeular ~In following taCII!ract Sur'Q~
`
`" Bromday' .. (bromfe.nac ophthalmic solution) 0 .09o/o administered
`one• <tatty, was ap-proved by the R>A on October 10. 2010 tor tht
`tteatmenc: of postoperative lnlhu·nn'labon and reduction ot ocufar
`pain in patl~nts who nave und~rgone: cataract extractiont
`eo Ba.std on extensive posNr~rketing experience 1nd data from
`clinical trials, bromfenac ophthalmic solubon has demonstrated •
`r ..... o,.,b~ wf-c:ty ~o~rurlh!
`o The modified forrnv1~r10n of bromfen1c fJCitltitet tnttiocuflr
`penetration,
`thereby allowing a
`lower medkatlon load whUe
`maintaining cllnic.al efflc.acy with once dalty dosing
`
`o To evaluate the effic.acy and safety of low-<oncentratlon, modified
`bromttnac. sodium ophthalmic .solution dosed once daily for the
`treatment ot ocular inflammation and ocular pain assodated with
`utar.cL survtry In subject'$ who nJ~• uneltrgont C4t:J~n
`extraction with postt®r chamber int:ra-oc:ut.r lens Implantation
`
`::~::::y t;s:.:=t(~{: {~((« $.«~;«ct~
`
`• Phase .3, placebo-controlled, randomized, double·masked, m1ld·
`center study
`
`• 440 subject; randomiz.~ (222 In the bromfenac group, 2181n the
`placebo 9r'Oup)at 39 clii'M¢a:l SiteS
`o Biglble subjects were scheduled F« a unilateral cataract surgery
`(pt'lacoe!mulsitkatlon Ol' txtracapsul.lr) with POOL Implantation
`
`Sc,....ling Ph<~'s..: O~y$ ..-.$to .,.1
`. • s ubje(b W.;r. aJ~igM(f to re~lve elt,tt.er bi-o111fe,..e sodium
`ophthalmk•olutf.o:n or plaG•bo doftd QO
`:
`• Subjects must h»ve met inc.lus1on and eXdu:SAon criteria to b•
`eltgfble fo.r (Un"iea,l trial
`• Pri•••rv ett.C.-.cy ~tt4pol~">~ w.u <;.I~:HaftOJI of o~~r
`lntlamn:taUon {Summed OcuJar Jnfllmma:tkm Sco re (SOl S) a
`OJ by day 1S
`• S~ond.ary efficacy endpoint was propofti~hl of subjeCts paio·
`,
`:·····.+··~~··~·-···--··-··~·~··-..··~··~·~···-~-.. ·--· .. -·-··~·-········~··~··,-·· · ;,'
`0 , , . .... t da~'-!,W.0,'Y4'M'MOMW,>W,'«'W,:.••,•~~
`
`·
`
`.0.
`
`Treatment Phase: Day •lto o~v 1.5
`• S ubjects !Mgan dosing on Da y .. 1 (- 24 hours bef ore s uroery)
`·SUbj.c.'tt returned to the oUic. on Day 1 for evatuaUon of ufety
`alld efr.acv
`•Subjects returned to the offke on Day 3*1 tor ev aluation of
`safety and e fflacy
`•SUbjects returned to the of fice on Oay a~u for evaluation of
`aaJety and effiacy
`•OitlC:ontinued test •o-nt on day 14 ilnd subject• returtl-.d to t he
`, offke.on oav 15.:tl for evaluaUon of Sil.fety :and efficacy
`
`"''
`
`F..L
`""'7
`follow--up Phase: Day 22+3 or 7 +3 Days Afte r Final Dose
`
`• subjects returned to th• omce on Day 22.+3 or 7+3 days afur
`dlscontJnua tlon o f t•st agent tot termination evatuatlon
`
`"'-·-· ··- ··-""'""' '"'""- . - ----- --- ·-· --- '--- --
`a~~~m.m~~-11
`
`1111 Sromfenac
`
`l:ll< Placebo
`
`' :
`l
`
`eye Pain
`Anterior chamber inflammation
`ConJur.etJval hype.remt~,
`Photqihobilo
`Corneal edema
`Lacrltn<ltion lncrused
`Fot«ign bOdY ..sensation
`
`6(2.8'10)
`5(2.4%)
`2 (0-9•~>
`1(0.5%)
`1(0.5%)
`l(C>-5%)
`
`16(7.8%)
`11 (5.4%)
`8(3.9'-'>)
`8 (3.9'-'>)
`5(2.~)
`5(2-5%)
`S (2 SOH)
`4
`
`""'The incidence of CME/ME was O.S% (1/212) in the bromfenac
`Qr'Oup compartd with 2.0% (4/204)., the placebo oroup.
`
`Low-oonce ntr<1tion, n•odified broM t enac s-oluUon do.se:d QD
`Is ote a nd e ltective to tl"eat the ln lt.anu r.at lon and pain
`••aod•tccl w hh c•t•~r•c:t •uf'lcty .
`~--------------------------------
`
`Orof\'ltWf"'(~I~IJ II'IVl<f.CA 15'1JI.P~et1NQIT..Ib.;./ll'-lrc;2010
`etQito'oll\~ T~P Ill HM4ot'WI~UmbirOL1.,McfoncifR;t,ettl.-tt..OoodlftM'Ianoll
`~~l t1o$ ~oo:te.ell &Mts ttl lhel'ao.wea. WI e<1 ~.., r~ MeG,..·
`ttll,t906a••~
`3 Ul..t~GA.~...,_ ~0: et• JO<ul ... "'-"'tc>oi'Th-er~
`;oos..~<~n»
`"-":19'to'I~C0..tU~A..~SP•tflf Ql~tfOO?'f inll; H82a.;:o.•
`O<;w-N"ltol~to.O'"""~A.fnt4t'~fi"''CJQWI ~.AE-~ 1 -40
`
`l'tlw.o.,twcoert.~&lOfT'Ib loclr-~CA,I.ISA
`Ft~-dota~ lAOOw~J~t>c~~Mr.Nt"*•"~""~ucf6t~Aa'I81'-0t!'O. I"t.9'
`Hleru•!b:"'"'"4~0f'Md~au.wil, IIV CI~'OJ, )1~~. •od!tltO.O• •4
`~·.,....r#IIIIC,~$t.~l.nc
`
`Pre.se.nted ilt the 2012 An n .at Me eting of the Ame ricu Acaden•r of Oph t:b~ lruology, Nove mber 10•13, 2012, Ch icago,. Jl
`
`SENJU EXHIBIT 2227
`INNOPHARMA v SENJU
`IPR2015-00903
`
`PAGE 1 OF 1
`2~0lli PO 005
`
`Cont.(lo(;t Jnformm.lon:
`r'" M11~--· P!\11"'1\D
`Cll~a1Aff.11rS
`~·LOmb.ftll.
`SOT-=~ DIN~!
`ll'llr ... CA92618
`~ (~9) 788-Sl88
`f'OTI1'1 tm ~Nnatt~ttr4Gbbotteh tl)l'l•
`:zr~~~~~y~~~.a~~rw.a:;maaz :~;mm:a:sa ~=-~~«~w:m~r!Zi'!~31Zl~<:::=m~~mw~~~.t'~~~~
`J.A Gow, 1 D.F. Goldberg, 2 J.H. Peace, 3 T.R. Wa lters, 4 J.P. Gira, 5 S.M. Klier, 1 T.R. McNa mara 1
`for the Low Concentra tion Bromfenac Ophtha lmic Solution Once Daily Study Group
`1Bausch & Lomb Inc., Irvine, CA; ' Wolstan Eye Associates, Torrance, CA; ' United Me::lical Research Institute, Inglewood, CA; • Texan Eye, Auston, TX; ' Ophthalmology Consultants, Ltd, St. Louis, MO
`
`Integrated Phase III Clinical Trials of Low-Concentration, Modified
`Bromfenac Ophthalmic Solution Dosed Once Daily for Cataract Surgery
`
`f)'.)~:){).~~: To evaluate the effiCacy and safety of tow~concentntson,
`modihd brom(enac solution dosed QO for catar.tet surverv.
`t-1--:\C:'y6;.. S4.1bjtcts rece•ved tither b~mftMC (n• 222) or pl.-ctbo
`(n•218) QD. Oosi"Q began 1 day before cataract surver'V Md
`contin~d dalty through post-surgery Day 14. Pnmary efficacy
`ondpomt was no oculo\r lnfltmmation by Oay lS; secof'ldary efficacy
`endpoint was no ocul.-r pain at Day 1
`
`*~)::~:.. Ekomfenac was superior to placebo for primary and
`secondary efficacy endpoints (P<0.0001). Compared to pl.acebo,
`bromfenlK. had a
`lower lncide:nce of ocu4ar adverse events
`(P•0.0001).
`f. : t c•.::eo..::.e.·~~ LOw·concentntton, modified bromfenac sotvdon dosed
`QO k nfe and effective to treat the inntrntNtlon .-nd paln auodated
`wfth cataract surgery.
`
`,) &romten"c Is:~ non-neroldal cantl tnftamm~to.rv drvg (NSAJO) w•th
`~n extensi v-e his.oory of cltnic~t effic~ey; It Kts by bkxklno
`prostaglandin synthesis by inhibiting cydooxygenase 1 and 2 1n
`the arachidonk acid pathway a
`
`~ The bf'Omlne MOitety In bromtenac enhances Jlpophillclty and
`facititatt:s t>tnftf.)tion throughout OC.\Ilal' tissues N
`
`"' Bronuclo;® (bromfe.nac sodlum ophtha1rnK wlution) 0.1% was
`initiallY approved m Japan in July 2000 nd was $ubSequenuv
`approved for the treatment of l>lephanbs, conjunctivitis, scleritis
`(lnc:tudlno epis<:lentk) and post·optrauve lnRammation4
`
`Xibmm•• (bromfe.nac ophthalmic solution) 0.~. administered
`cwke da1l)', was approved by the Food and Drug .odmlnistration
`(FDA) on •larc.h 24, 2005 for the treatment of patients with post·
`C.ltar.ct OCuflr infllmmotion, :tnd In JanlH!ry 2006 for tN
`ttea:trne:nt of oeular ~In following taCII!ract Sur'Q~
`
`" Bromday' .. (bromfe.nac ophthalmic solution) 0 .09o/o administered
`one• <tatty, was ap-proved by the R>A on October 10. 2010 tor tht
`tteatmenc: of postoperative lnlhu·nn'labon and reduction ot ocufar
`pain in patl~nts who nave und~rgone: cataract extractiont
`eo Ba.std on extensive posNr~rketing experience 1nd data from
`clinical trials, bromfenac ophthalmic solubon has demonstrated •
`r ..... o,.,b~ wf-c:ty ~o~rurlh!
`o The modified forrnv1~r10n of bromfen1c fJCitltitet tnttiocuflr
`penetration,
`thereby allowing a
`lower medkatlon load whUe
`maintaining cllnic.al efflc.acy with once dalty dosing
`
`o To evaluate the effic.acy and safety of low-<oncentratlon, modified
`bromttnac. sodium ophthalmic .solution dosed once daily for the
`treatment ot ocular inflammation and ocular pain assodated with
`utar.cL survtry In subject'$ who nJ~• uneltrgont C4t:J~n
`extraction with postt®r chamber int:ra-oc:ut.r lens Implantation
`
`::~::::y t;s:.:=t(~{: {~((« $.«~;«ct~
`
`• Phase .3, placebo-controlled, randomized, double·masked, m1ld·
`center study
`
`• 440 subject; randomiz.~ (222 In the bromfenac group, 2181n the
`placebo 9r'Oup)at 39 clii'M¢a:l SiteS
`o Biglble subjects were scheduled F« a unilateral cataract surgery
`(pt'lacoe!mulsitkatlon Ol' txtracapsul.lr) with POOL Implantation
`
`Sc,....ling Ph<~'s..: O~y$ ..-.$to .,.1
`. • s ubje(b W.;r. aJ~igM(f to re~lve elt,tt.er bi-o111fe,..e sodium
`ophthalmk•olutf.o:n or plaG•bo doftd QO
`:
`• Subjects must h»ve met inc.lus1on and eXdu:SAon criteria to b•
`eltgfble fo.r (Un"iea,l trial
`• Pri•••rv ett.C.-.cy ~tt4pol~">~ w.u <;.I~:HaftOJI of o~~r
`lntlamn:taUon {Summed OcuJar Jnfllmma:tkm Sco re (SOl S) a
`OJ by day 1S
`• S~ond.ary efficacy endpoint was propofti~hl of subjeCts paio·
`,
`:·····.+··~~··~·-···--··-··~·~··-..··~··~·~···-~-.. ·--· .. -·-··~·-········~··~··,-·· · ;,'
`0 , , . .... t da~'-!,W.0,'Y4'M'MOMW,>W,'«'W,:.••,•~~
`
`·
`
`.0.
`
`Treatment Phase: Day •lto o~v 1.5
`• S ubjects !Mgan dosing on Da y .. 1 (- 24 hours bef ore s uroery)
`·SUbj.c.'tt returned to the oUic. on Day 1 for evatuaUon of ufety
`alld efr.acv
`•Subjects returned to the offke on Day 3*1 tor ev aluation of
`safety and e fflacy
`•SUbjects returned to the of fice on Oay a~u for evaluation of
`aaJety and effiacy
`•OitlC:ontinued test •o-nt on day 14 ilnd subject• returtl-.d to t he
`, offke.on oav 15.:tl for evaluaUon of Sil.fety :and efficacy
`
`"''
`
`F..L
`""'7
`follow--up Phase: Day 22+3 or 7 +3 Days Afte r Final Dose
`
`• subjects returned to th• omce on Day 22.+3 or 7+3 days afur
`dlscontJnua tlon o f t•st agent tot termination evatuatlon
`
`"'-·-· ··- ··-""'""' '"'""- . - ----- --- ·-· --- '--- --
`a~~~m.m~~-11
`
`1111 Sromfenac
`
`l:ll< Placebo
`
`' :
`l
`
`eye Pain
`Anterior chamber inflammation
`ConJur.etJval hype.remt~,
`Photqihobilo
`Corneal edema
`Lacrltn<ltion lncrused
`Fot«ign bOdY ..sensation
`
`6(2.8'10)
`5(2.4%)
`2 (0-9•~>
`1(0.5%)
`1(0.5%)
`l(C>-5%)
`
`16(7.8%)
`11 (5.4%)
`8(3.9'-'>)
`8 (3.9'-'>)
`5(2.~)
`5(2-5%)
`S (2 SOH)
`4
`
`""'The incidence of CME/ME was O.S% (1/212) in the bromfenac
`Qr'Oup compartd with 2.0% (4/204)., the placebo oroup.
`
`Low-oonce ntr<1tion, n•odified broM t enac s-oluUon do.se:d QD
`Is ote a nd e ltective to tl"eat the ln lt.anu r.at lon and pain
`••aod•tccl w hh c•t•~r•c:t •uf'lcty .
`~--------------------------------
`
`Orof\'ltWf"'(~I~IJ II'IVl<f.CA 15'1JI.P~et1NQIT..Ib.;./ll'-lrc;2010
`etQito'oll\~ T~P Ill HM4ot'WI~UmbirOL1.,McfoncifR;t,ettl.-tt..OoodlftM'Ianoll
`~~l t1o$ ~oo:te.ell &Mts ttl lhel'ao.wea. WI e<1 ~.., r~ MeG,..·
`ttll,t906a••~
`3 Ul..t~GA.~...,_ ~0: et• JO<ul ... "'-"'tc>oi'Th-er~
`;oos..~<~n»
`"-":19'to'I~C0..tU~A..~SP•tflf Ql~tfOO?'f inll; H82a.;:o.•
`O<;w-N"ltol~to.O'"""~A.fnt4t'~fi"''CJQWI ~.AE-~ 1 -40
`
`l'tlw.o.,twcoert.~&lOfT'Ib loclr-~CA,I.ISA
`Ft~-dota~ lAOOw~J~t>c~~Mr.Nt"*•"~""~ucf6t~Aa'I81'-0t!'O. I"t.9'
`Hleru•!b:"'"'"4~0f'Md~au.wil, IIV CI~'OJ, )1~~. •od!tltO.O• •4
`~·.,....r#IIIIC,~$t.~l.nc
`
`Pre.se.nted ilt the 2012 An n .at Me eting of the Ame ricu Acaden•r of Oph t:b~ lruology, Nove mber 10•13, 2012, Ch icago,. Jl
`
`SENJU EXHIBIT 2227
`INNOPHARMA v SENJU
`IPR2015-00903
`
`PAGE 1 OF 1
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