Paper No. _
`Filed: December 28, 2015
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`INNOPIIARMA LICENSING, INC., INNOPHARMA LICENSING LLC,
`INNOPHARMA INC., INNOPHARMA I.I.C, MYLAN PHARMACEUTICALS
`
`INC., and MYLAN INC.
`
`Pefifionen
`
`V.
`
`SENJU PHARMACEUTICAL CO., LTD, BAUSCH & LOMB, INC., and
`BAUSCH & LOMB PHARMA IIOLDINGS CORP.
`
`Patent Owner.
`
`Case IPR20l 5-00903
`
`Patent 8,129,431
`
`PATENT OWNER RESPONSE
`
`PURSUANT TO 37 C.F.R. § 42.120
`
`
`Filed: December 28, 2015
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`INNOPIIARMA LICENSING, INC., INNOPHARMA LICENSING LLC,
`INNOPHARMA INC., INNOPHARMA I.I.C, MYLAN PHARMACEUTICALS
`
`INC., and MYLAN INC.
`
`Pefifionen
`
`V.
`
`SENJU PHARMACEUTICAL CO., LTD, BAUSCH & LOMB, INC., and
`BAUSCH & LOMB PHARMA IIOLDINGS CORP.
`
`Patent Owner.
`
`Case IPR20l 5-00903
`
`Patent 8,129,431
`
`PATENT OWNER RESPONSE
`
`PURSUANT TO 37 C.F.R. § 42.120
`
`
`
`l]’R2Ul 5-O09t')3
`
`Patent Owner‘s P1‘e|i11linm‘y Response
`
`l’:.1tt:nt No. 8,129,431
`
`II.
`
`III.
`
`IV.
`
`VI.
`
`VII.
`
`Introduction
`
`Statement of relief requested
`
`Claim construction
`
`Level ofordinary skill in the 2111
`
`The ‘43l patent
`
`Background of ophthahllic fommlations
`
`The combination of"Ogawa and Sallmamn, in either direction. does not
`render any claim oftlie ’43l patent obvious
`
`A.
`
`B.
`
`No reason to focus on Ogawa and bromfenae preparations
`
`Design need and market demands would not have led a POSA
`in the direction that the inventors of the ’431 patent took
`
`C.
`
`A POSA would not have comlained Ogawa and Sallmzmn
`
`1.
`
`2.
`
`3.
`
`4.
`
`Ogawa and the problem it sought to solve
`
`Sallmamfs singular purpose does not align with
`Ogawafs
`
`It would not have been obvious to modify Ogawa
`Example 6 in View ofSallmann }:lxample 2
`
`lm1oPha1‘1na’s arguments of motivation and
`expectation of sue-.:ess ring hollow
`
`14
`
`14
`
`16
`
`18
`
`D.
`
`Sallmzinn in View ofOgaw:I: another hindsight-laden
`eoilihiilalion
`
`1.
`
`The proposed eolnbiiiation destroys the esselnial
`purpose ofSallmu1m and ignores the hli-l?.t: l]1ElI'kS
`in the art
`
`28
`
`
`
`lI‘R20lS-00903
`
`Patent Ownefs Pt'eliminz1t'y Response
`Patent No. 8,129,431
`
`2.
`
`Im1oPl1z-.tr1]1£.t"S :1t‘gt1t11e11ts to modify Sztllmemil in
`View ofOgawa are legally ixtsuffieiettt, intcmally
`inconsistent, and belied by the very art
`lI1noPl1a11na cites
`
`E.
`
`Fu does not remedy the deficiencies ofOgawa and Sallmann
`
`1.
`
`2.
`
`3.
`
`A POSA would not liave looked to FL1
`
`lrm0Pharma’s attempted connection between Fu
`and tyloxapol is untenable
`
`lnnoPhar1nz1 has failed to prove unpatentahility of
`claims 6, 15-17 and 20-22, requiring about 0.02
`w;"'\-' % tyloxapol
`
`VIII. Compelling objective evidence ofpzitcntahility
`
`A.
`
`Tyloxztpoh; unexpectedly superior chemical stabilizing effect
`
`I
`
`.
`
`2.
`
`3.
`
`4.
`
`Testing against the closest prior art
`
`A POSA’s expectation, if anything, ofpoly.<:orbatc
`80
`
`Tyloxapol‘s: unexpectedly superior stabilizing
`effect
`
`'l‘yloxap0l’s unexpectedly better maintenance of
`preservative efficacy
`
`B.
`
`Additional compelling objective evidence of patcntzibility
`
`IX.
`
`Conclusion
`
`3 I
`
`35
`
`35
`
`36
`
`40
`
`45
`
`46
`
`46
`
`4'7
`
`43
`
`54
`
`55
`
`60
`
`it
`
`
`
`EPRZU I 500903
`
`Puzcm Ow11er‘5; P1'eiiiniII;-n'_v Response
`Pa1cmNn, 3,l29,43|
`
`Table of Authorities
`
`Page(s)
`
`Cases
`
`Allergan 12. Samfoz,
`I 796 F.3d 1293 (Fed. Cir. 2015) ..................................................
`
`........ ..pu_s‘3im
`
`In re Antonie,
`
`559 F.2d 618 (C.C.P.A. 1977) .............................................................. ..41, 42, 45
`
`Atlas Powder C0. 1!. 13.1. dz: Pom‘ De Nemours & Ca,
`750 F.2d 1569 (Fed. Cir. 1984) ........................................................................ ..31
`
`Cadence Pharm. Inc.
`
`1-’. Etela PharmSc'z’h1c.,
`
`780 F.3d 1364 (l’cd. Cir. 2015) ................................................................. ..;)cz.'m'm
`
`Catalina Lsghrfng, Inc. v. Lamps Pz'ms, Inc,
`295 F.3d 12?? (Fed. Cir. 2002) ........................................................................ ..45
`
`Depuy Spfrze. Inc. 1-'. Medtmnic Sofamor I_)(meI(, Inc.-.,
`567 F.3d 1314 (Fed. Cir. 2009) ...................................................... ..10. 12, 27', 31
`
`Emu" Co. Ltd. 1»: Dr. Rea'dy’.s‘ Lr:Ib..s‘., I.rd.,
`533 F.3d 1353 (Fed. Cir. 2008)
`
`19, 23, 24
`
`In re Gordon,
`733 F.2d 900 (Fed. Cir. 1984) .......................................................................... ..28
`
`In re Gm'[<~:y,
`27 F.3d 551 (Fed. Cir. 1994) ...................................................................... ..13, 23
`
`In re Huai-Hung Km),
`639 F.3d 1057 (Fed. Cir. 20] 1) ..............
`
`....................................................... ..53
`
`Insile V:'.5'r'0n Inc” v, Sarzdoz, Inc,
`
`783 F.3d 853 (Fed. Cir. 2015) .............................................................. .. E 3, 30, 37
`
`fn31‘£n..*..* Pasterw v. I"ocrcm'mJ,
`
`738 F.3d 133? (Fed. Cir. 2013) ....................................................................... ..6{)
`
`iii
`
`
`
`lPR20l5-00903
`
`Patent Ownefs Preliminary Response
`Patent No. 8,129,431
`
`J(m.~;.s'en Finn-'r:'.t. NV V. MyI(t1'a Pharm., :’r1r_'.,
`456 F. Supp. 2d 644 (IJ.N.J. 200(3), r.3‘}"'c1per'curiarn, 223 Fed.
`Appx. 999 (Fed. Cir. 2007) ............................................................................... ..59
`
`I}9:’ej?e.\' M0,,
`KSR Ina"! Co. 1-:
`550 U.S. 398 (2007) ........................................................................................ ..32
`
`M.f.:'ros0_fi‘ Corp. 1». Pru.1‘ya;0nn, Inc.,
`789 F. 3d l292(I"ed.Ci1'.2{}15) ......................................................................... ..6
`
`Orfh(J-M'cNeif Phm"m. Inc. 12. fl/fyfcm L(zlJ.§'. Inc._,
`520 F.3d l358[Fed. Cir. 2008) ......................................................................... ..45
`
`In re Papesc/1,
`315 F.2d 381 (C.C.P.A.1963) .................................................................... ..42_. 53
`
`1'_’fEzer1nc. v. M}-*!(m Pharm. Ina,
`
`2014WL5388l00 (D. Dc1.20l4) .................................................. ..2l.30,36,37
`
`In re Siebenrrirz,
`
`372 F.2d 566 (C.C.P.A. 1967) .................................................................... ..18, 19
`
`Spe'c‘ia!.'_1-' C0 mp0.5‘."Ies v. Cabot Corp,
`845 F.2d 98E (Fed. Cir. 1988') .......................................................................... ..59
`
`Synte.1' LLC v. Apotm' Inc,
`2006 U.S. Dist. Lexis 36039 (ND. Cal. 2006), (zffd 221 Fed.
`Appx. l002(Ft:d.Ci1‘.2007) ................................................................. ..23, 25, 39
`
`Umgene Labs. 1*. /Ipotex. Inc,
`655 F.3d 1352 (Fed. Cir. 20} 1)
`
`....................................................................... .. 19
`
`In re Wesskru,
`
`353 F.2d 238 (C.C.P.A. 1965) ..............................
`
`.............................. .......22, 29
`
`Statutes
`
`35 U.S.C. § 316(9) ...............................
`
`................................................................. -1
`
`iv
`
`
`
`iPR2015—00903
`
`Patent Ownefs Prclin1inary Response
`Patent No. 8,129,431
`
`Other Authorities
`
`Apotex Inc, v. Wyeth LLC,
`IPR20l4-001 I5, slip op. (P.T.A.B. Apr. '20, 2015) .................................... ..I6, 35
`
`Exp-arte Whaler: er a{.,
`Appeal 207-4423 (B.P.A.I. July 23, 2008) ......................
`
`.................. ..-41, 44, 45
`
`
`
`IPRZOIS-00903
`
`Patent Owner}; Preliminary Response
`Patent No. 8,129,431
`
`Patci1tOwncr Senju Pharmaceutical Co., Ltd. et a1. (“Sen_iu"’) responds to the
`
`Petition filed by 1n1ioP11arma Licensing,
`
`Inc. et £11.
`
`(“1nnoP11ar1na'") coiuzerning
`
`claims 1-22 of US. Patent No. 8,129,431 (“the ’43] patent”). The Board instituted
`
`trial on 1nnoP}ianna‘s grounds that (21) claims 1-5, 7-14 and 18-19 are allegedly
`
`obvious over US. Patent No. 4,910,225 to Ogawa et al. (“Og21wa"} (EX1004) and
`
`US. Patent No. 5,891,913 to Sallmann et al.
`
`(“Sa11manri”) (EX1009), and (b)
`
`claims 6, 15-17' and 20-22 are allegedly obvious over Ogawa, Sallmzmn and AU—B—
`
`22042933 to Fu et 211. (“Pu”) (F.X1011}. As discussed below, 1nn0Pl1arma has failed
`
`to meet its “burden of proving a proposition of unpatentability by a preponderance
`
`ofthe evidence." 35 U.S.C. § 316(6).
`
`Indeed. as discussed further below, InnoPhanna has failed to prove that a
`
`POSA would have combined any of Ogawa, Sallmann and Iiu with any expectation
`
`of arriving at the claimed subject matter. lnno1’l1arma, moreover, has wholly failed
`
`to prove the existence of any prior art fonnulation containing 0.02 w/v% tyloxapol,
`
`which is an element of claims 6, 15-17 and 20-22. In addition, InnoPl1ar1na either
`
`ineffective];-‘ assails or simply ignores sigmilicant objectix-‘e indicia ofpateritability.
`
`which further support the I1-O11-Ol')V10lJSI1CS.‘§ of the ’431 patent claims. The Board
`
`accordingly Should uphold the patentability ofelaims 1-22 ofthe ‘#131 patent.
`
`
`
`ll’R20l5-00903
`
`Patent Owner‘s Preliminary Response
`Patent No. 8,l29,431
`
`I.
`
`Introduction
`
`The ’431 patent discloses and claims aqueous liquid preparations ofthe non-
`
`steroidal anti-inflammatory drug (“NS/\ID“) hromfenac, which are marketed as
`
`Prolensa® prescription eye drops for treatment of inflammation and pain in cataract
`
`surgery patients. ' These formulations are chemically stable,
`
`lack microbial
`
`contamination, and can be administered safely and effectively for ophthalmic use
`
`at a pH that does not cause eye irritation. (EXIOOI, 2:34-47; EX2082, ‘ll53.)
`
`The inventors successfully fonnulated these preparations using the non-ionic
`
`surfactant
`
`tyloxapol.
`
`(EX2082,
`
`‘fll5l.) Tyloxapol unexpectedly chemically
`
`stabilized bromfenac better than did the surfactant polysorbate 80, even at a low
`
`pH known to accelerate bromfenac’s degradation.
`
`(Id.,
`
`'.|1|
`
`l56. 166, 171.)
`
`Tyloxapol also unexpectedly maintained preservative efficacy
`
`i.c., prevented
`
`microbial contamination
`
`as compared to polysorbate 80, even when measured
`
`under the stringent European Pharmacopoeia standards. (Id., 1177.)
`
`'l‘yloxapol‘s unexpected stabilizing effect translated into significant medical
`
`benefits
`
`in l’I'0l€l’lSZiF‘. Tyloxapol‘/s
`
`stabilization effect pennitted fonnulating
`
`Prolensa® at pH 7.8, down from pl] 8.3 in non-prior art Xibrom® and Bromday®
`
`I Inn0Pl1anna’s expert admits that
`
`l’i‘olensa:r’ falls within the scope of the
`
`’431 patent claims. (FX2082, 11149.)
`
`
`
`|l’R2(}l 5-0090}
`
`Patent ()wncr’s E’rcli1nin;n'_v Response
`Patent No. 8,129,-43 "I
`
`formiilzitions (EXZUIB. 4; EX2026. 5;
`
`l;'K2027,
`
`-'1),
`
`21 stihstatitizil reduction on 2%
`
`logaritlltiiic scale and closer to the pl! of natural tears. [EXZI 16, '|[4t.}—
`
`mm the
`
`in pH_
`
`increased ocular eo1nl'ort and eliminated the bnriiing, and stinging associated with
`
`all other approved NSAID eye drops. Ud.) Lowering the pit also improved
`
`hroml'enac's intraocular penetration and permitted lowering its concentration to
`
`0.0 ‘Iii. down from 0.0‘)'":‘/u in Xibromlii and B1‘o111d;1yK, meaning that P1'olensaE
`
`advai1te'1g,eous1y puts less drug in Contact with surgically compromised ocular tissue
`
`without :1 reduction in efficacy. (Id. "' 42; EX2030. 1718.) More than :1 difference
`
`in Llcg,t'ee,
`
`tyloxapohs unexpectedly superior stabilizing effect constitutes a
`
`material and E‘-UbSl.2'il11'.l£ll difference, producing 2-1 more comfortable, non—irritating
`
`and more efficacious formulation crnhodied in P1‘OlCllS3iR:.
`
`As 2: result, Pi‘i'_ulci1safi has received significarrl medical imlustry alL}Cl£ii1'I1 by
`
`numerous leaders in the ‘field ofcatnrnct surgery extolling “the benelits o lithe new
`
`formulation." (E_X211t’1,"'5E>.) Since its Agni] 2013 launch, Pi‘ole1isai""'
`
`liars generated
`
`$240.9 million in revenue, despite critering, 8 market with at least six l1r';1iiileLltir'ugs
`
`5.»;
`
`
`
`ll’R?.U l 5-(}09{)3
`
`Patent (_"Jwnct"s l’relin1i11;iry Response
`Patent No. 8,129,431
`
`and three generic drugs approved by the FDA to treat similar
`
`indications.
`
`(EX2l30, 1ll33.) In fact, Pi‘olei1sai'ii} has achieved one of the highest shares of
`
`prescriptions and revenue among bramtletl drugs with similar l[1CllC‘c1Tl(JIlS. (.{d.)
`
`T\/loreovei‘, six. generic companies,
`
`including lnnoPharma, have submitted
`
`AND/Ks seeking to inarket exact copies ofPro1ensaim. (EX2082, 1[182.} One of
`
`these six, Lupin, which also has filed an IPR petition challenging the ‘43l patent,
`
`has projected PI'0l6IlSE1®'S sales to exceed $100 million annually, which will occur
`
`this year. (FX2022, 4; FI.X2l30, W5.) Three others, Apotex, Metrics and Paddock,
`
`initially challenged the ’431 patent in district court ('EX2l30, 1l1|'78—80;
`
`l:'X2()23;
`
`EX20l9; EX2Ul7; EX20l8) hut licensed the patent and took consent juclginents
`
`and injunctions, tying their acknowleclgeinent of the ’43l patent’s validity to their
`
`generic copies ot"Pro!ensa®. (EX2t3(), 111178-30; 12.30024; EX2l22; EX2l23.)
`
`Against these compelling objective indieia of non—obviousness_. lnnoPha1ma
`
`contends that tyloxapol in Sallmzinifs lixample 2 would have been “swapped” for
`
`polysorbate 80 in 0_g:1wa’s Example 6, or altematively, hromfenac in Ogawa‘s
`
`Exainple 6 would have been “swappe(l“ For dielolcnac in Sallmann’s Exan1ple 2.
`
`(Pet., 6-7.) As discussed below,
`
`lnnoPhaI'ma ot‘t'ers no reason, other
`
`than
`
`impermissible hindsight
`
`looking backward from the ‘-131 patent elniins, why a
`
`person of ordinary skill in the art (“l’OSA") would have chosen Ogawais lixainple
`
`
`
`ll’R20l5—OO903
`
`Patent Owner’.~: PI'Cli1}'lll1E1I"_V Response
`Patent No. 8,129,431
`
`6 or Sallinaiitfs lixample 2 and modified either with any reasonable expectation of
`
`arriving at any of the elaimed f‘o1mulatio:1s. Indeed, the evidence establishes that a
`
`POSA would not have been inotivated to purrsue bromfenae or tyloxapol at all, and
`
`would not have found hrornfenae and dielolenae, or tyloxapol and polysorbate 80,
`
`interchangeable given their vast chemical, physical and fimetional dil"t'erenees.
`
`Tellingly, lnnoPharma has failed to identify any prior art formulation containing
`
`0.02 W/v% tyloxapol, which is an element of elairns 6,
`
`l5—l 7, and 20-22, and thus
`
`lnnoPha1‘1na has wholly failed to meet its burden ofproving these claims obvious.
`
`lr1noPhanr1a eontends that
`
`its “swapping” theory allegedly Solves
`
`the
`
`problem of a “c:omplex” that bromfenae purportedly fonns with the preservative
`
`benzalkonium chloride ("'BAC"). Yet
`
`InnoPharma’s expert Dr. Paul Laskar
`
`candidly admits that no prior an Sl10WS that hromfenac actually t°orn1:s a “complex”
`
`with BAC, and that he in fact
`
`focused on BAC only because the claimed
`
`formulations ol" the V131 patent contain it, exposing lnnoPharma’s theory as
`
`impermissibly based on hindsight. Consistent with the teachings of the art, Dr.
`
`Laskar fuither admits that BAC is a
`
`‘'killer’’
`
`that should be eliminated fi'om
`
`formulations wherever possible. Proceeding contrary to accepted wisidoln, the 43]
`
`patent’s t'or1nL1Iation.~; utilize BAC, which alone constitutes strong evidence of non-
`
`oh v iousness.
`
`an
`
`
`
`I Pl{'_‘ll l 5410903
`
`Patent Owner's Preliininaty Response
`Patent No. 8,129,431
`
`The Board z-,1cc0rdir1g]y
`
`should reject
`
`the Petition
`
`and uphold the
`
`patentability cfall challenged claims.
`
`ll.
`
`Statement of relief requested
`
`Senju 1‘espectl11l|y requests that
`
`lnnoPha11na’s Petition be tlenietl at
`
`least
`
`because: (i) it fails tn prove that a person of ordinary Skill in the art would have
`
`combined Ogawa and Setllmann, or Ogawa, Sallmann and Fu, with any reasonable
`
`expectation of arriving at
`
`the claimed subject matter; (ii) it fails to prove the
`
`existence of any prior art formulation containing 0.02 w:’v°/o tyloxapol, which is an
`
`element of claims 6, 15-17, and 20-22; and (iii) it fails to rebut the compelling
`
`objective indicia of non-Obviousness ofthc claimed subject matter.
`
`III. Claim construction
`
`Senju believes that no claim term needs express constmctinn and that the
`
`plain and ordinary Ineaning consistent with the Specification and the prosecution
`
`ltistory should apply. M.r.'r;r0.s'qf't Corp.
`
`v. Pr-oxycortn, 1:10., 789 F.3d I292, 1298
`
`(Fed. Cir. 2015).
`
`IV’.
`
`Level of tlflllntif)-' skill in the art
`
`A person ol‘c1'dinary skill in the art 01‘ the "-431 patent would have at least a
`
`bachelor’s degree in 21 field such as chcinistry, phannaceutieal cliclliistry or a
`
`related discipline with
`
`--5 years 0t"wtn'l< experience. (E.X2082,1|1|41—42.)
`
`
`
`[l‘R2(}15-00903
`
`Patent Ownefs Preliminary Response
`Patent No. 8,129,431
`
`V.
`
`The ’431 patent
`
`The application for the ‘£131 patent was filed on January 16, 2004, and
`
`claims priority benefit of the January 2 I, 2003- filing date ofJP 2003-012427 under
`
`35 U.S.C. §l 19. (l:.'XlUUi; EX2002.) The ‘43l patent has two independent claims
`
`(claims 1 and 18) and 20 dependent claims, which are separately patcntable. The
`
`’43l patent is listed in the FDA’s Orange Book, and the parties agree that it covers
`
`Prolensa® ophthalmic brotnfenac (0.07%) solution. (EXIUO3, ‘l42; EX2082, ",ll52.)
`
`VI. Background of ophthalmic formulations
`
`As of the 2003 priority date of the "431 patent, drug forinulalion was a
`
`tlifticult and unpredictable endeavor, and it. remains so today. The lminulation of
`
`ophthalmic drugs is particularly complex. Formulating stable ophthalmic dosage
`
`forms
`
`such as
`
`the aqueous liquid preparations of the "£81 patent
`
`is more
`
`challenging and critical than with other dosage Forms such as tablets or capsules. in
`
`addition, the surf:-tee area of the eye is extremely small, and the residence time for
`
`an eye drop is quite short, which increases the eliallenge in designing an aqueous
`
`dosage form that can pass through the ll)/(ll'0pltObiC cornea membrarle of the eye to
`
`reach the intended site of action. Dr. Laskar himself has acknowledged these
`
`formulation challenges in sworn testimony in a patent infringement case involving
`
`the ophthalmic product eombigan"“‘. (i—;x2:35, 089, 1020, 1022.)
`
`
`
`IPR’-_‘(}15—009t}3
`
`Patent Owner’s Preliminary Response
`Patent No. 8,129,431
`
`VII. The combination of Ogawa and Sallnlaim, in either direction, does not
`render any claim ofthe ’431 patent obvious
`
`A.
`
`No reason to focus on Ogawa and bromfcnac preparations
`
`InnoPl1a11na‘s central theme of unpatc11tability is one of"‘swapping."' that is,
`
`swapping tyloxapol
`
`in Sallma.nn"s Exalnple 2 for polysorbate 80 in Ogau-'a’5
`
`Example 6, or alternatively, swapping hromfenae in Ogawa‘s fixainple 6 for
`
`diclofenae in Sa1ln1ann‘s Example 2, allegedly would have been obvious. (Pet, 6-
`
`T.) But this swappi11g theory is premised on a POSA having had :1 reason to focus
`
`on bromfenae FoL'i1'iL1latio11s. There was none, absent hindsight.
`
`By Janua1'_v 21, 2003,
`
`there were a number of FDA-approved aqueous
`
`ophthalmic Foimulations containing NSAIDS,
`
`including diclofenae (Voltaren®),
`
`ketorolac (Aetilaomj. Ilurbiprofcn (Oetlfenac) and suprofen (P1'ofenalm). (M, 27-28.)
`
`A POSA therefore would have had no reason or need to focus,
`
`for
`
`further
`
`development, on hromlienac to the exclusion of the other NSAIDS. (EX2082, T160-
`
`61.) Indeed,
`
`|nnoPhar1na admits there was no such reason, stating "[t]o the extent
`
`there was even any need for the claimed bromfenac ophthalmic Forilitllation, it was
`
`met by the disclosures of Ogawa and Ha1'a."' (l"et., 53 (emphasis added).) In fact,
`
`Ogawa states that
`
`its hromfenae f'onnuIations displayed 1*en1a:'l-(ably enhanced
`
`stability (EXIUU4, 8:46-9:3), and Dr.
`
`l.asl<ar acknowledged that ('_)gau.-'a satisfied
`
`bro1nfenae's stability problem. {_EX2l 14, ll5:2—l16»4.)
`
`
`
`ll’R20l5-00903
`
`Patent Ow-'ne:"s l’t'eli:ninary Response
`Patent No. 8,129,431
`
`Moreover, neither Mara nor Yanni supports a preference for hroinfenac over
`
`diclofenac, contrary to InnoPharma"s position. (EX2082, W59-I32.) Hara teaches
`
`that (1) both have “sL1perior” anti—inflam1nato:'y action (F.Xl002, 2, 3), (2) both
`
`treat postoperative inflammation of the eye (i‘d.)_. (3) diclofenac could treat anterior
`
`uveitis, while bromfenac was expressly not approved for this indication (aid), and
`
`(4) no toxicity issues were noted for commercialized dielotenac, while bromfeuac
`
`had serious liver disorders and even fatalities (r'd.), which prompted the FDA to
`
`pull bromfenatfs oral form, Duractfii, from the market. (EX2029,
`
`l.) ilara thus
`
`certainly does not endorse bromfenac over diclofenac. (EX2082, 1}60.)
`
`The same applies to Yanni, which actually disparages bromlenac, preferring
`
`esters and amides,
`
`like nepafenac. {l:'Xl{)33, 1:54-59, 4:84-52; EX2082, T62.)
`
`Focusing on a single in virm result from Table 1 of Yanni (EXIOO3, ‘ll 28), Dr.
`
`Laskar ignores important ex vivo and in w'1.'o data (EX2082, 1i‘1'_61—(12), which do not
`
`show superiority of b1'or1-tfenae over dielofenac and in fact Show superiority of
`
`other colnpouhds. (!c!., EX1033, Table 1.)
`
`B.
`
`Design need and market (temands would not have led a POSA in
`the direction that the inventors of the ’43l patent took
`
`I11i1oPl1a1‘ma's proffered motivation to substitute poiysorbatc 80 with
`
`tyloxapol
`
`is to prevr.-:11t the alleged l'ormation of a precipitate between an acidic
`
`NSAID and BAC. (EXIOO3, "|96.) Dr. Laskar admits, however.
`
`that he has no
`
`9
`
`
`
`ll’R2(_ll 5-ll09{’i3
`
`Patent Owt1e1"'s P1'eliminary Response
`Patent No. 8,l?,9.43l
`
`evidence that any such precipitate actually forms between broinfenae and BAC.
`
`(EXZI I4, 45:1 8—46:4.] But even if such a precipitate did fottn, which Dr. Laskar
`
`has not established,
`
`there would have been no motivation to use tyluxapol
`
`to
`
`address this issue.
`
`BAC was known to have significant toxicity to the eye. (EX2082, 1i65.)1n
`
`fact. in Allergen v. Saridoz, 796 F.3d I293, 1305 (Fed. Cir. 2015), the defendant’s
`
`expert 1‘el1:1‘red to BAC as a “natural born killer” that was “from Satan.” Dr. Laskar
`
`also cllaiaeterized BAC as a “killer,” known to cause adverse reactions in vitro and
`
`in t-1'1-w. (EX21 14, 7'8: I 3-25, 79: 13-23.)
`
`A POSA objectively viewing this alleged precipitation issue would have
`
`sought to eliminate BAG, thereby eliminating its harmful effects and avoiding the
`
`precipitation issue entirely, rather than only attempting to reduce it to some extent
`
`by adding a suifactattt. (EX2082, 1163.) By January 2003, the art
`
`taught using
`
`preservative-free formulations and well-tolerated preservatives in place oi" BAC
`
`(EXZOXZ, ‘E64; EXZI 16 '._i'l;45—47.) )D(3[)t{]y' .Spi'rie, Inc.
`
`1-‘. Metttlrroitic,‘ S0_fimior Danek.
`
`Inc., 567 F.3d 1314, I326 (Fed. Cir. 2009] (strong iitferenee ofnon—obviousness
`
`when the prior an undermines very reason offered for combining references). Dr.
`
`Laskar did not consider these solutions. He admitted to focusing on I3.-’\C.' because
`
`the "431 patent claims recite it. {F.X2‘1 14, 69:21-70:10.)
`
`ll}
`
`
`
`lPR20]5—OO903
`
`Patent Owners Prt'.‘lll‘.|]ll1'dI‘_V Response
`Patent No. 8,129,431
`
`Indeed by 2003, market demands sought to eliminate the highly toxic BAC
`
`from ophthalmic formulations. The 2111 urged that “[i It is
`
`ol'.s'rr:'!u'ng impormnce
`
`to become aware oj'preservar:'ve ro.r1'c:'ry in order 1'0 develop in the near furure
`
`many more rmpreserved drugs.” (EX2064, 1l5, emphasis added; EX2082, '|[‘|i'67-
`
`68.) The art taught that a preservative-fiee formulation of Fu’s ketorolac “may be
`
`better as a postoperative ocular analgesic" than preserved kerorolae. (EX2090,
`
`abstract; EX2ll6, ‘l44.) By November 1997, Acularfi PF —-a preservative—fi*ee
`
`ketorolae ophthalmic solution-—-1'eccived FDA approval. (EX2{}6l,
`
`l; EX2116,
`
`T29.)
`
`The art also taught using better-tolerated preservatives in place ot‘BAC. By
`
`2001, published clinical studies demonstrated that
`
`the preservative “stabilized
`
`oxyehloro complex“ ("SOC") could replace BAC in brimoiiidine ophthalmic
`
`formulations. By March 2001, briiiionidine-SOC was approved as Alphagarig P,
`
`with a superior comfort and reduced ocular allergy profile as compared to
`
`brimonidine-BAC. (EX2092; EXZI I6, 1 45.)
`
`Other replacement options for BAC included the preservative lauralkoniuin
`
`chloride (“LAC"), which D1". Laskar himselfadmittcdly used previously to avoid
`
`the interaction of‘ an acidic drug and BAC. (EXIOO3, T104; T.X2l 14, 33:4-34:1;
`
`EX2082, T52;
`
`l:ZXlt)2tl, 3:28—4:2, 6:11-7:10.) Desai also teaches the use of a
`
`1
`
`l
`
`
`
`IPREUI 5—{10‘:}03
`
`Patent On-=nci"s Prcliininary Response
`Patent No. 8.l29,43l
`
`different polymeric quaternary ammonium preservative compound, l‘Ol_,YQUAD®,
`
`which Dr.
`
`l..asl<ar admits would avoid the interaction problem.
`
`(l.L‘-(I005, 1:27-
`
`2:31; EXZI 14, 933-16; EX2082, '-'69.) Even ifa POSA still would have wanted to
`
`use BAC, the art provided a solution that would have addressed the NSAIDHBAC
`
`interaction that underlies Dr. Lasl<ar’s proffered motivation to use a soluhilizer.
`
`Yanni teaches hromfenac derivatives without free earboxyl groups, which would
`
`not interact with BAC and which have hetter ocuiar penetration and stability than
`
`bromfenae. (EXI033, 1:60-2:29; EX2082,1773); De.>p.'.ry Spine, 567 F.3d at 1326.
`
`Notwithstanding these clear teachings, Dr. Laskar selectively relies on
`
`Ogawa Example 6, which reported a residual amount of brom fcuac of 100.9%.
`
`(F.Xl003, W48.) But he ignores Ogawa Example 7', reporting an equally high
`
`residual amount of bromfenac (99.2%) and containing rncthylparaben and
`
`ethylparaben instead of BAC, which Dr.
`
`l.asl(ar testified do not
`
`interact and
`
`precipitate with b1'omlenac.
`
`(i£X2ll-4, 229:6~2l.) Thus, Ogawa implements a
`
`solution to Dr. I.asl<ar"s interactionfprccipitation problem in a chemically Stable
`
`formulation, yet Dr. Laskar ignores it because, as he testified, he focused on the
`
`fact that the claims ofthe ’43l patent recite BAC. (F.X2l 14, 6‘):2I—7tl:l0.)
`
`Based on a pas‘! hoc analysis that started with the claims, Dr. Laslcar
`
`postulated a motivation position premised on the interaction of an NSAID and
`
`
`
`]PR2Ul5—OO9U3
`
`Patent Owner‘s Preliminary Response
`Patent No. 3,129,431
`
`BAC. Defining a problem by its solution reveals itnproper hindsight, particularly in
`
`selecting the prior art “relevant” to the question of obviousness. t".*.'..\"lIt'?
`
`I/’t'.sz'on In-c..
`
`1:. Srmdoz. Inn, 783 |*'.3d 853, 859 (Fed. Cir. 2015). Selecting Ogawa. which does
`
`not teach that hro1nt'enai: had an interactiom'p1'eeipitatioi1 problem (i£X2l.l32, $100),
`
`and focusing on Example 6 rather than F,xan'1ple 7, which admittetliy solved l1is
`
`proffered problem, clearly exposes Dr. I.asl<ar’s improper post her: analysis. (Id)
`
`Contrary to Dr. I.askar‘s opinion. a POSA as of 2003 would have pursued
`
`non-BAC presewatives or unpresewed formulations to entirely elitninate a serious
`
`health risk. (EXZZI 16, 1|-47.) This also would have addressed any alleged interaction
`
`problem. (EX2082, fl[7 1 .) As such, the alt led in a direction divergent From the path
`
`chosen by the inventors of the ’43l patent, as Dr. Laskar admitted,
`
`thereby
`
`supporting the ne11—obviousness of the ’43l patent claims. (E3-(21 I-4, 32:22-34:1;
`
`EX2082, 111169-73); Sec /I/Iergan, 796 F.3d at 1305, ciririg In re G1U‘.i£’.y, 27 F.3d
`
`551, 553 (Fed. Cir. 1094) (“A reference may he said to teach away when a person
`
`of ordinary skill, upon reading the reference,
`
`.
`
`.
`
`. would be led in a direction
`
`divergent from the path that was taken by the [patentee].’’_)
`
`I3
`
`
`
`IPRZFH 5-00903
`
`Patent Owner’s Preliminary Response
`Patent No. 8,129,431
`
`C.
`
`A POSA would not have combined (lgawa and Sallmann
`
`1.
`
`Ogawa and the problem it sought to solve
`
`()gawa successfully formulated oplithaimic broinfi.-nae preparations that are
`
`stable For a long period of time without degradation of broznfeilae or the formation
`
`of red insoluble matters.
`
`(EXIOO4, 2:32-36; EX2082, 1|97.) Ogawals solution
`
`involved a water soluble polymer, e.g., polyvinyl pyrrolidone, and a suliite, i.e.,
`
`sodium sulfite. (EXIOO4, 3:7-15; EX2082, $97,} Sodium sulfite is a we1l—l<nown
`
`antioxidant. (EXZOI4, 3:51-S5; EX20-82, 1|97.) A POS/\ would have understood
`
`that Ogawa used sodium sulfite because broinfenae Chemically degrades by
`
`oxidation (EXZIOS, 1|37), and an antioxidant would prevent
`
`that degradation
`
`process.
`
`lnnoPhar'ma acknowledges that sodium snlfite is added “to prevent
`
`oxidation reactions.” (Pet, 49.)
`
`When bromfcnac oxidizes,
`
`its fonns an oxidation degradant referred to
`
`throughout Ogawa as red insoluble matters. (EXIOO4, 8:3-45; EXZOS2, 1198.) Dr.
`
`Laskar agrees that red insoluble mat1eI's indicate that broinfenae is chemically
`
`degrading. (EXZI 14, 228:l6—24.) These red insoluble particles do not constitute,
`
`tl1ereloi‘e. the result of‘ any physical interaction such as any precipitation between
`
`bromfenac and BAC. (EX2U82, W99.) [11 liael, none of the art of record ever states
`
`that bromfenae inlerai;ts with BAC to linni precipitate, and nowhere in Ogawa is
`
`[4
`
`
`
`ll’R20 15-00903
`
`Patent Ownefs Preliininuiy Response
`Patent No. 8,129,431
`
`such interaction ever mentioned. Ud.) Di‘. Laskar admitted that he cited no prior an
`
`and conducted no test to establish bromfenac interacts with BAC. (l£X2l 14, 45:18-
`
`46:4.) Given the complexities of ophilialinic fonnuiation systems. one cannot
`
`predict whether such an interaction does occur. (EX2082, "[99; EX2 l 05. “,:?T.)
`
`Polysorbate 80, moreover, plays no role in chemically stabilizing bromfenac
`
`from oxidizing. (EX2082, 17:97.) Ogawa is completely silent on the function of
`
`polysorbate 80. (1d.) It was not used to solubilizc bromfenac, for :1 POSA knew
`
`that bromfenac is freely soluble in water. (EXZO39, 6; EX2l4(},
`
`l56:20~15'7:6;
`
`EX2082, 1[l(}(J.) N01’ was it used as a stabilizer, for Ogawa’s examples establish
`
`that sodium sulfite produces “remarkably enhanced” stability. (LZXIOO4, 8:46-93;
`
`EX2082, 1Tl(]{}.) Citing to column 3, lines 49-53 of Ogawa, Dr. Laskar incorrectly
`
`states that polysorbate 80 contributes to stabilizing broinfenac. (EXIOO3,
`
`‘T50;
`
`EX2082,
`
`1110! .) This passage, however, nowhere refers to polysorbate 80,
`
`explicitly or implicitly. (EX2082, ‘1[l01.)
`
`The data from Ogawa Experimental Examples 4-6 actually confirin that
`
`polysorbate 80 does not stabilize bromfenac. (EX2095, 107; EXZOEZ, 1110! .) Upon
`
`storage at 60 °C for four weeks, the formulations in Experiinental Examples 4-6
`
`containing polysorbate 80 without sodium sulfite exhibited chemical instability, as
`
`evidenced by the fomiation ofrecl insoluble matter; i'.e., degi'adatio11 ol'bro11ifenac.
`
`
`
`lPR’l(JlS—009[}3
`
`Patent Owner’s Preliminary Response
`Patent No. 3,|29,-431
`
`(EXIGO4, 8:-4-925;
`
`I-iX2095_, 107; EX2082, 1|l(}2._) But adding sodium sulfite
`
`prevented the formation of red insoluble matter, prompting Ogawa to comment
`
`that bromfenac decomposition was not observed and bro1nfenae's stability was
`
`remarkably enhanced. (EXIOO4, 8:45—9:4; l3X2(l95, 107, Table I0; EX2082, '"«101.)
`
`Thus, polysorbate 80 has no effect on the stability ofbromfenae. (EX2082,1[101.)
`
`Dr. Laskar’s attempt to imbue polysorbatc 80 with an ability to stabilize
`
`bromfenae is fundamental
`
`to lnnoPhar1na’s position that a POSA would have
`
`simply “swapped” tyloxapol for polysorbate 80 with a reasonable expectation of
`
`success.
`
`(Pet, 5l~52; EX1003,
`
`'7'-'98—99_)
`
`~fhe data in Ogawa I-ixperirnental
`
`Examples 4-6. however,
`
`completely undermine
`
`InnoPhar1na‘s
`
`l’oundational
`
`premise for its obviousness arguments. (E.\’2(}82_. 11103.) .'5fee A;:rm.»_x- Inc.-._. v. Wyetiz
`
`LLC, IPR20l4-00115, slip op. at 22 (Paper 94) (P.T.A.B. Apr. 20, 2015) (it is
`
`improper hindsigltt to “imhuc one ol’nrdiriary skill in the an with knowledge of the
`
`claimed invention, when no prior art reference or references of record conveys or
`
`suggests that l<r1owIetlge_").
`
`2.
`
`Sallmanrfs singular purpose does not align with Ogawa’s
`
`Sallmann is uniquely directed to Fo1‘1nL1lations of the potassium salt of
`
`diclofenae. (EX2082, T126.) The essence oftlte Sallmann patent, indeed its entire
`
`purpose for existing,
`
`is
`
`the use of dielofcnac potassium in treating ocular
`
`It’)
`
`
`
`1l’1{2015+OO903
`
`Patent Owner’s Preliininar}-' Response
`Patent No. 8.129,431
`
`iifiiammation.
`
`(Id) The patent was presuinably awarded because diclofenae
`
`potassium had surprisingly better ocular penetration than ciielofenae sodium.
`
`(EX1009, 1:!-65: l£X2t}82, $105.)
`
`Sallmann formulates dieiofenae potassium with a number oi‘ additional
`
`inactive components,
`
`including separate categories of S0lLll')lll?'.t3I‘.‘~’, ehelating
`
`agents, and stabili7.ers. Tyloxapol is listed as one of a number ollsolubilizers, but
`
`Sallinann identifies the CrCIHOpl]0F® solttbilizers as “especially pre1L'rrecl,”" for they
`
`are “tolerated extremely well by the eye." (ISXIOO9, 4:52-62; EX2t)32, ‘.'106._)
`
`A POSA would not have selectively picked Sa1lmann’s tyloxapol for use in
`
`Ogawa. Ogawa teaches instead using antioxidants, like sodium sultite, to stabilize
`
`bromfenae. (EX2082, 1|1U4.) Sallmann lists tyloxapol as one ot'n1an}* solubilizers,
`
`but bromfenac, known to be _ti-eel}-' water soluble, does not need a solubilizer and
`
`tyloxapol would not be expected to address bromfenae’s oxidative degradation.
`
`(EX2082, 11104; HX2039, 6; EX2140, 156:20-157:6.) Indeed,
`
`there would have
`
`been no reason to look to Sallmann unless one knew from the ‘"431 patent that
`
`tyloxapol works to stabilize bromfenae.
`
`tIEX2082. T104.) Dr. Laskar candidly
`
`admitted as much, while also aekno\vletlging_ that there are 1nan3-* other surfactants
`
`used in ophthalmic tlornlulations (EX21 14, 94:15-20):
`
`1?
`
`
`
`lPl{2{ll 500903
`
`Patent (')wner"s Proliminaiy Response
`Patent No. 8,129,431
`
`Q: And you focu
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