vy29
`
`Figure 8. intraviireaus
`receiving placebo
`and
`1
`gated an
`
`tr
`
`Vv
`
`Vv,
`
`S
`
`j
`
`ay
`
`rap
`
`ire
`
`ated
`
`in:
`k
`
`z
`
`a4
`
`{
`
`:
`
`15,
`
`and
`
`i
`
`?
`
`29
`
`i
`
`animats in ihe groups
`sentative
`he VEGF
`i
`3
`not VEGF Trap. Sy posilaser day
`
` & at postliser cays 15, 20
`
`Lesion Grade
`
`
`ang
`
`
`
`e,
`followbig treatmentin LG0%ofthe lesions (postlaser days
`
`20 and 29, respectively) (Table 3, Figure 6, aud Figate 7).
`effective ai preventing the developmentof grade 4 leak-
`
`
`iy
`ion of
`age on FA regardless of dose or whether it was admin-
`Akt
`
`placebo was not evaluated, grade 4
`tedfor
`istered intravenously on a weekly schedwe or intravit-
`
`the duration of
`study in all animals receiving mul-
`ushy every 2 weeks (Table 3, Figure 4, and Figure 3).
`
`
`
`:
`i
`stologicalassessment confirmedthat choroidal newves-
`tiple int
`
`
`ion revealed a
`(Yable 3).
`sel formation, fibrotic ch
`andretinal thickness also
`
`
`ward decreased CNYand Hobrosis relative to
`co
`were markedly less in the treated eyes (Table 5}.
`
`which was not statistically significant. VEGF is a pow-
`Moreover, when a single intraviireous injeclion of
`
`VEGF Trap was given aiter grade 4 CNYhad developed,
`erful mediator of vascular permeabilityin addition to new
`leakage was stopped within 5 days in approximately 95%
`vessel
`formation, so VEGF Trap mayhave blocked VEGF-
`of previously active grade 4 lesions and within 14days
`ind
`eeeeeeeeeeeen==:SORE.
`L729 (NO. @), AUG 2011
`
`
`1349
`
`©2031 American Medical Association. All rights reserved.
`Downloaded From: hitps://jamanetwork.com/ on 08/20/2021
`
`Celltrion Exhibit 1014
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`
`Day 2
`
`aEo2Oo
`
`2<
`
`P
`
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`

`

`
`
`Table S. Wistalogical Seates
`
`Score‘Mean
`Heereeeee|
`ENV Pravention#
`SHY Treatment?
`
`
`
`
`Feanoreminesqeutinnnirnonengarepesd :
`
`Histlogival Ringing
`Placebo
`VEGE hap
`Placebo
`VEGE Tap
`
`Hbrophigia
`ied
`EBS
`48S
`194
` Retisal:plawsticnt
`
`354
`CHES
`Be
`4s
`Nadvascdlanivation
`O59
`C128
`3.86
`6.58
`
`Rig qc7ge 430Tota) 3:92
`
`
`
`Abbreviation, ONY, choroidal neqvascularvation.
`"Mean scores forall lesions
`in all
`eves (n = 6 per group).
`
`Dean scores fo
`hat were grade 4 at posiiaser day 15 (priorto the single VEGF 7
`
`SP < 05, Mann-Whitney U test.
`
` D injection}.
`
`§i
`
`Figure 8. intravitreous prevenii
`29 and histoteg
`ons at postlaser
`
`
`
`
`methacrylate
`sections stained \
`’
`é
`0 yim) for 2 animais that received 3
`intravitreous doses of
`either placebo or VEGF Tr.
`
`ug/eye/dase}. The represeniative histaiogical sections
`correspond to the numbered lasertreatment areas in the fluorescein angiograms. The pla
`pomipared with
`
`the
`
`
`
`
`
`
`sections are thicker
`ane more vasct
`}
`VEGF Tre
`eated ayes. Note the presence
`af subsretinal Huid
`in fasion 3 on day 33
`
`tively, VEGF Trap may have reduced or stopped blood
`flow through the newvessels.
`Intravitreous administration of VEGF Trap was well
`tolerated, with only a mild inflammatory response noted
`in the eyes thal underwent inuravitreous VEGFTrap treat-
`mer. Except for 1+ or fewer anterior chamber and vit-
`reous cells in same eyes, no other ophthalmoscopie signs
`of inflammation were seen.
`
`riography,* although visual acuity was notsignificandy
`
`improved in this
`small safety study. However, 1 subject
`
`
`experienced grade 4 hypertension and i subject devel-
`oped grade 2 proteinuria. Ilypertension and proteinuria
`
`
`are nowwell-established class effects of systemic VEGF
`inhibition, and both panenis exhibiting these adverse events
`in the study by Nguyenet al? had received the highestin-
`travenous dose of VEGF Trap (3 mg/kg).
`Another phase 1 study (Clinical Evaluation of Anti-
`
`
`angiogenesis in the Retina, CLEAR-IT 1) used imtravit-
`reous administration of VEGETrap-Eve Gaflibercept oph-
`thalmic solution).the first part of this study was a
`VEGFTrap is nowin clinical trials (for a recent review,
`
`
`
`see the article by Dixon et al’). A phase | trial of25pa- sequential cohort dose escalation Grom 0.053 to 4.0 mg/
`lignls with exudative AMDevaluated the tolerability and
`eye} in 21 patients with exudative AMD. Noserious sys-
`
`eflicacyof intravenous administration o
`temic or ocular toxic elfects were observed. However, a
`
`
`ss and immprove-
`different dose Jevels. Subjects had a significant decrease
`marked decrease im retinal thicknes:
`ment in visual acuity? were noted, VEGF Trap-Eye also
`in retinal thickness as determined by optical coherence to-
`
`HUMAN TRIALS OF VEGF TRAP-EYE
`
` 13°30
`
`©2031 American Medical Association. All rights reserved.
`Downloaded From: hitps://jamanetwork.com/ on 08/20/2021
`
`Celltrion Exhibit 1014
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`
`

`

` Eve m wetAMDB, VIEW1 in the UnitedStates and Canada
`
`and VIEW2 in Europe, Japan, and Latin America?’ For
`
`both wials,VEGF Trap-Eye is being administered mntravit-
`reously. In the first year of treatment, VEGF Trap-Eye was
`aduninistered every 4 weeks at doses of either 0.5 or 2 meg,
`Another study arm used 3 initial monthly doses of 2 mg
`eae.
`& aC-
`
`followedby 2-mg doses giver at S-week intervals. Th
`uve control arm comprised subjects receiving ranibi-
`comes
`zumab (0.5 mg) at 4-week intervals. The 1-“year Ou
`fromthese studies are pendiag publication.
`
`
`
`
`ig an esiablished primate model of CNV, adminis-
`tration of VIGT Trap in a prevention protocol mark-
`edly reduced vasoproliferative respunses of the ma-
`
`
`caqueretina to laser injury, substantially preventing the
`development of all cormpunenis of CNVlesiuns as well
`as vascular leakage. When a single intravitreous VEGF
`Trap injection was given aftergrade4 lesions had devel-
`oped, there wasresolution of vascular leakage. Thisalso
`
`
`resulted in a trend toward lower histological scores tor
`Sh
`the weavascular components ofthe lesions,
`suggesting
`partial regression of newly formed vessels.
`
`
`nt stud
`g fate-ohase fluorescein
`Figure 18. Intraviireous treatment
`angiograms at postlaser cays 15 and 29 and hisi
`ological sections
`y 29
`
`
`eonanito the numberedlaser traaiment areas
`in the
`
`' obtained at a
`ser
`
`
`bar=250 ym} f
`
`af: animal that
`590-119 dase af VEGF
`
`ie marked reduction in
` grant
`Trap on day 15
`reas on the day 29 angi
`
`re
`t thicker and contain
`
`
`
`iological s
`ention
`oraidal new
`din the VEGE Trap prev
`
`@ Sand
`
`
`
`ceuticals, inc.
`Funding/Support: This study was funded by Regeneron
`Pharmaceuticals, Inc
`Additional Contributions: Hutihao Pan, MA, and Ajit
`
`Thakur, PhD, provided thestatistical analy:
`
`1. Friedman DS, 0°60:
`clmain Bu, Mufoz B, at aLeFyel
`
`# Diseases Prevalence Researc
`
`
`
`ment am
`sin the Ui
`
` Arok Op!
`
`
`far Photo
`
`Dohine
`HgB4¢
`vascular macuiopathy:
`Spina. 198,045894701.
`as
`san
`ater
`hfoueal
`4, Macular nateenSeyfou9. Laser photocoagulationofsubfoveal re-
`
`2.
`
`3.
`
`Submitted for Publication: February 17, 2010; final re-
`
`
`
`vision received February
`21, 201 Lb: accepted February24,
`has been used in a small open-
`y studyfor treat-
`ment of diabetic macular eder
`ingle dose of4 mg
`
`2011.
`was administered intravitreously7
`to 3 patients who had
`cot
`Correspondence: T. Michael Nork, MD, MS, Compara-
`tive Ophthalmic Research Laboratories (CORL), 600
`undergone maltiple prior treatments for diabetic macu-
`
`lar edema. There was a median decrease in central macu-
`HighlandAAve, 14/336, Madison, WI 33792-3220 Camnork
`
`
`
`
`ay thickness of nas wellassome improvernent in7
`
`
`Author Contributions: All of the authors hadfull ac-
`in diabetic macular edemais in
`progress.
`cess to all of the data in the study and take respansibil-
`Nowu
`}, VEGF
`ity for the integrity of the data and the accuracyof the
`ina double-masked phase 2 trial (CLEAR-IT|
`data analysis.
`Trap-Eye
`was evaluated in 157 patients with exudative
`AMD randomizedto either stonthly or quarterly intea-
`Financial Disclosure: Drs Cao, Zimmer, and Wiiegand
`vitreous injections for 12 weeks at doses of 0.5 or 2 mg
`own stock and/or siaock options in Regeneron Pharma-
`
`(monthly injec Hons) and 0.5, 2, oc 4 mg (quarterly).
`lowing the 12-week fixed dosing period, palents
`con-
`
`
`tinned to receive treatments on an as-needed basis at their
`originally assigned dusages. Reports of the L-year re-
`sults describeda statisticallysignificant irmprovementiin
`
`va, retimal thickness, and size of the CNY le-
`
`sions,***’ with fewre-treatments required duri
`> 40-
`week phase ofas-neededtreatment. Patients initially dosed
`on a schedule of 2.0 mg monthlyreceived, on average,
`only 1.6 additional injections during the 40-week pe-
`riod of as-needed treatment, and those inilially dused on
`Am
`wg
`ys
`a schedule of 0.5 mg monthly received, on average, 2.5
`
`lagjectious,While as-needed dosing followingafered quar-
`terly dosing regimen Gvith dosing at baseline and week
`
`a
`12) also yieeldedimgprovements u visual acuity at week
`52 as comparedwith baseline, theresults generally were
`
`iot
`as
`tobust
`as
`those obtained with
`initk if
`{monthly
`riotas robust as those obtained with initia
`d monthly
`
`
`dosing. VEGF Trap-Eve was generally well tolerated and
`
`
`there were no drug-related serious adverse events. The
`most common adverse eveuts were those typically asso-
`>
`ciated with intravitreousinjections.
`
`
`
`
`Two phase 3 wials o
`years’ duration are under wayte
`
`further investigate the
`acy and safety of VEGFTrap-
`
`
`
`5.
`
`8
`
`lariasions of ag
`
`al idlais. Arch Opty
`
`
`
`
`
`
`
` a (NO. 8), SUG 2313 ARCHOPHTHALMOL.COM
`AB's
`
`
`
`©2031 American Medical Association. All rights reserved.
`Downloaded From: hitps://jamanetwork.com/ on 08/20/2021
`
`Celltrion Exhibit 1014
`Page 890
`
`Celltrion Exhibit 1014
`Page 890
`
`

`

`
`
`
`zation. in-
`7, Macular Protocoagulation Study &
`a
`caguiaticn
`for
`juxtatoveal
`VEGFfam ly, contributas tothe Cavelopment ot charcidal neavass
`i
`i
`clini
`choroidal neovasculal
`ch
`
`arch Ophitiaimai. 19
`4):500-509.
`
`ult
`§. Macu
`
`yn Studypete Dee
`iuenGe 6
` ation. Arch . Murakami M, iwai
`
`
`ithag
`
`
`
`Ophthatnel. 138s
`9. Holash J, Bay
`‘er with ao-
`
` < 8(6}: 1849-1886
`
`
`
`3-41398
`ent antitumor offects, P
`chi K, aal, VEGE- RAP(RIR2} suppresses charai-
`
`
`
`
`mand VEGF-ind
`
`reakdown of the
`
`dlaod-retinal barrier,
`40. Krzystalik MG, AF
`
`
`roidal neovascy
`1-248
`1954
`ff Physiol.
`
`
`
`
`or antibody fragment. Arcii Ophthaimot 20 penne
`igfenC, Chen L, Borges LP, et ai. VEGF-A stimulates ymphangiogenesis an
`
`
`
`
`
`
`hemangagenesis in intlaramatory necvascularization via macrophage recruitment.
`V1. Ryan Su. Subretinal neovascitarization: natural history of ane
`
`
`
`A Ophihainar 198271
`J alia ievest OOS 1137} 7040- 1050.
`YL, ata. inh
`
`
`Ryan Sd. Experiment
`
`
`¥ ot new vessels. Arch Ophifaimon 1983101
`Tt
`giogenesis 4
`
`
`
`, Lee SY
`80 |, ettalPredilection of
`ihe macuiar
`regio!
`inci
`motes graft
`investOntthatraal¥
`
`
`
`
`of chor
`z
`34. Gao J, Zhao 1, LY, etal. A subretinal
`
`mkey. Arch Opathatmol. 2064;
`(CAV) modal a
`bition of CNVan
`
`
`
`
`aatment of Age-Rela
`ration With Photodynamic
`VEGF trap.
`Invest Qonibaimal
`Vis Soi 207
`
`
`
`
`dai neavas
`35. Dobi ET, Putiafita OA, Destro M.A new ma
`
`
`
`sults oftwo random
`vas
`on inthe rat. Arot seein198!
`nical trials with:
`: TAP report No. 8. Graefes Arch
`36. Tobe T, Okamoto N. Vinores MA, ef al. E
`
`
`
`
`
`with vere
`sion at vascular endothe
`o Oot imma
`
`ai model of chorea!
`£
`
`
`neovas:
`oor?704,
`38. Miller dW, W
`
`
`
`choroidal se
`
`
`Opthatine
`
`
`foporphyrin derivative
`verte-
`idal neovasculariza-
`
`
`, Fotie TE Grads
`
`a Archdphenaimo a
`
`-3.
`
`Intrave-
`
`i
`
`:
`;
`(
`neo
`2805-284 6.
`
`
`
`46. D'Amico DU, Masonson HN, Patel M, et al; VEGF inhibition Sludy in Ocular Neo-
`
`
`
`vascularization (ViS!GN}
`ClinicaTriat Group. Pegaptanib sodium
`for neavascti-
`
`jar age-related macular degeneration:
`two-year Safely rasults of the two pro-
`
`
`
`i
`center, comrolled clinical
`trials. Ogatnaivnciogy. 2000/1716:
`
`
`, at al MARINA Study Group. Ranibizumab
`4:
`macular degeneration. W Esai. Med. 2006:358for neavasc
`
`
`
`(4) 1499-1431
`ser PK, Mist
`
`cular aq
`18. an 0M,i
`
`yexten
` lanchuley
`
`1g. Brown OM,
`
`Hehetsi Kaiser PK, Heier JS, |
`therapyfor neovasoularage-
`(i2322-251
`Group. Ra
`jf photacyn:
`
`
`
`wDa
`related
`ults of the ANCHOR study.
`: two-year 7
` Olson JL, Mandava N. VEGF Trao-fye for the treatment of
`-65, 85.
`
`ated macular cegeneration. Spert Ooin investig Oras, 2009:
`
`peutic anti-VEGF in at
` mPa!
`
`YT
`Nowy
`etal: CLEAR-AMD ¢ Study Group. A phase| iria!
`
`92{8):.366-867.
`of an iv.
`endothelial growth factor trap for treatment in
`
`:
`i
`to age-related macular degeneration.
`
`
`
`
`Aamaan RO, Vascular
`at. amet AN, Vrensen GF. Van Noorden Gd. S
`patients with
`
`
`h1822.eo a522.14Aphase| study of
`. Prog Retin Eye Res. 2003;
`thelial growth jaciors
`and angiogenesis in eye ci
`Opbthaimelaay. 20k
`treal vascu-
`221} 1-28,
`Nou
`netial roth fa ctor tran-aye in pat ants with neovascular age-rela
`22, Magiione &, Guerriero V,
`Vigietto G, Delli-Bovi P, Persico MG. Isolation of a hu-
`
`lar end
`
`
`2144-2148, 83,
`
`manplacenta cDNA coding foraprotein related to the vascular permeability factor. macuiar degeneration. Gonthalmooagy. 2009:1 16014}
`
`
`Natt Acad Sci US A 1994 :88(20):9287. 0274
`45. Do BY, Nouyen OD, Shah SM, et al. Anexs
`
`
`
`
`JE, Chen HH. Winer J, Houck KA,
`cerita qrowtt
`1 growth
`
`
`i
`ar oedema. Br J Ophthalmol 2008;
`
`tiation ¢
`ilar endothelial growth factar
`bioa
`vite aa
`
`
`
`
`
`
`high affinity binding to AE-4 Sut not tu FIK-T/ADA. J dia! Chern. 199
`aT}:
`
`
`25646-25654.
`year results of a pha:
`. dose- ang
`
` yy of intravitreal VEGF T
`
`
`
`
`24, Clauss M, Weich H,eee 3, e {
`r endothelial grawih fact
`dlications for 2 fi
`lar degeneration. Paper presented at: 41s
`
`
`
`rocyle
`cherota
`of the Retina
`Society; September 28, 2608:
`Scottsdale, AZ
`activai
`
`
`
`ean read
`47, He AC. Optical coherence
`fluorescein angiography outcomes
`
`
`through one year for a phase
`25, Autiero M, Waitenberger J, Communi D,et al. Role of PIGF
`red, controiled dose and intervai rang-
`
`
`
`jacular cross talk between the VEGFreceptors FItT andF
`ing study of intravitreal VEGF Trag-Eve in patients with neovascular age-relates
`
`
`
`
`8-843,
`incur degeneration.aon presented at 41st Annual Meeting of the Retina
`ttsdate, AZ.
`Carmetiet P, Moons L, Luthin A. et al. Synergl
`
`
`
`
`
`
`growth factorarid bacetal growthfactor CO
`factor (VEGF) Trap-Eye: investigationof efficacy anc
`extrava
`tion (AMD) (VIEW1). attpy//clinicattrials
`
`
`
`27, Otani &
`3ed dune 8, anit.
`ation of efficacy and
`“Microvace Res.
`ceptor expression iin humansa choroidal neovascy
`ar snembraeres. /
`
`
`4Ct 162-4
`‘1.
`ittp:zclinicattrials
`
`
`28. Rak
`JM, Lambert V, Bevy £,
`nial growth tactor. a member of the
`
`govwcid/show/NCTIG837377.
`
`treatment Javes! Oshtharniol
`
`7 weeks after
`
`43.
`
`44,
`
`46
`
`26.
`
` ABZ
`
`©2031 American Medical Association. All rights reserved.
`Downloaded From: hitps://jamanetwork.com/ on 08/20/2021
`
`Celltrion Exhibit 1014
`Page 891
`
`Celltrion Exhibit 1014
`Page 891
`
`

`

`Patent No. 10,828,345
`Petition Por Post Grant Review
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`CHENGDU KANGHONG BIOTECHNOLOGYCO. LED.
`Petitioner
`
`Vv.
`
`REGENERON PHARMACEUTICALS, INC,
`Patent Owner
`
`Patent No. 10,828,345
`Issue Date: November 10, 2020
`Title: USE OF A VEGF ANTAGONIST TO TREAT ANGIOGENIC EYE
`DISORDERS
`
`Case: PGR2021-00035
`
`
`
`PETTPION FOR POST-GRANT REVIEW
`
`UNDER 35 U.S.C. §§ 321-329 AND 37 CLBLR. § 42.200 et seq.
`
`Mail Stop “Patent Board”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria,VA 22313-1450
`
`Celltrion Exhibit 1014
`Page 892
`
`Celltrion Exhibit 1014
`Page 892
`
`

`

`Post Grant Review of USP 10,828,345
`
`TABLE OF CONTENTS
`
`TABLE OF AUTHORITIES ooo cece tecseereeetseesssectecnsteenesteeentsesstecnss iV
`
`TABLE OF EXHIBITS ooo ccccccccceceeneeeueseneseeeesesteceeuesesnereueseseverseeseegaerentens Vi
`
`[
`
`H.
`
`TL
`
`TV.
`
`INTRODUCTION oo cccccccccccecccetecneecnecnecesecesersnsecnssuresseeuseneeneeseeenrenneess 1
`
`GROUNDS FOR STANDING0 ccc cercceeneeecseteecreetienieenaeeeaneessrens 4
`
`STATEMENT OF RELIEF REQUESTED oooooccccccccsceceeetseneestensenneens 5
`
`THE (°345 PATENT occ ccccccccecceeeceneeesceneeviesnsseeeenrseseteesieesreetsesarentereeieensd
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`Background: VEGF Trap and AMD ooo ccceenteetteeenee 7
`
`"34S Patent’s Speciication.occ ccc eens ce cee ceceteeenseeenteeeeseees 8
`
` Regeneron’s Clinical Trials and 2009 Press Release of VEGF
`Treatments for Angiogenic Eye Disorders... cc cceceeeereneee 12
`
`7345 Patent’s Prosecution History... ccc cceceeseseeneeeeneeeens 13
`
`Level of Ordinary Skill in the Arto cece ccecserteeseenerseeses 16
`
`VY.
`
`CLAIM CONSTRUCTION ooo cccccccceccecueseaseneecaeenscneenirsesereearenereeees 16
`
`Vi
`
`THE °345 PATENT IS ELIGIBLE FOR PGR ooo. cseeseeetnteenies 17
`
`A.
`
`B.
`
`“[T]he Angiogenic Eye Disorder Is... Branch Retinal Vein
`Occlusion” of Claim 8 Is not Supported by a Pre-ATA
`APPlCatiOn ooo ccc ccc cccseecetesecessceceescceasceasscesscccsseceesssseeusetueensiss 18
`
`The Dosing Regimen of Claim 1 Is not Supported by a Pre-AIA
`APICALocc cece cceccceceesseteusnsaeeneeeeseseusevessetaecesesaeeniaeneaes 23
`
`VI. GROUNDS 1 & 2: THE °345 PATENT’S CLAIMS ARE
`ANTICIPATED AND OBVIOUS ooo ceete ttt ct etree treet sntetneein 23
`
`A.
`
`Ground 1: The °345 Patent’s Claims Are Anticipated by Shams ......24
`
`f.
`
`SP AUNS oo cece es seeceeecesseesceceesasceeeeesesseeeeeasecseveesieenseeseeses 24
`
`2. NaDee ceec cence cece cess eeneeecaeeessecusecensenteeeneeeesreens 29
`
`a)
`
`Shams discloses a “method for treating an
`angiogenic eye disorder in a patient, said method
`comprising sequentially administering to the
`PATRI ccc cececccecesececseeseseeesueeccssesecsuessssevsasavenseees 29
`
`b)
`
`Shams discloses the claimed initial dose of VEGF.......30
`
`sf-4338006
`
`i
`
`Celltrion Exhibit 1014
`Page 893
`
`Celltrion Exhibit 1014
`Page 893
`
`

`

`Post Grant Review of USP 10,828,345
`
`c)
`
`d)
`
`Shams discloses the claimed “followed byone or
`more secondary doses of the VEGF antagonist...
`wherein each secondary dose is administered 4
`weeks after the immediately preceding dose”... 32
`
`Shams discloses the claimed “followed by one or
`more tertiary doses of the VEGF antagonist .. .
`gach tertiary dose is admunistered 12 weeksafter
`the wamediately preceding dose? ooo.l
`
`3,
`
`Dependent Claus occ ccccccseeceeeereesteetesettaatateesneese dD
`
`a)
`b)
`
`c)
`
`d)
`
`Claim 2: Shams discloses the claimed drug ...0....0........39
`Clans 3 and 4: Shams discloses the claimed
`modes of administration 000.00 ceteeeet eesti: 40
`
`Claims 5-7: Shams discloses the claimed dose
`AIOUNES 0c cceeccecceccececeeeeneenaeensevseeceeenssnsesueeesentenaeens 4}
`
`Claims 8-11: Shams discloses the disorders treated......41
`
`B.
`
`Ground 2: The °345 Patent’s Claims Are Rendered Obvious by
`the 2009 Press Release m viewof Shams 00.0000. 42
`
`1.
`
`2.
`
`The 2009 Press Release 2.00. eeseeeeeeeneteteens 42
`
`CV aT Doce cece ett c cece tect ee estes ttectecteetecuetieetteteetee 44
`
`a)
`
`b)
`
`ey)
`
`The 2009 Press Release teaches a “method for
`treating an angiogenic eye disorder in a patient,
`said method comprising sequentially administering
`fo the Pabenec cccec ccc ce cceeeceneeteneeteseteeaes 44
`
`The 2009 Press Release teaches the claimed initial
`dose Of VEGE ooo ccc ccseeec eens cee sectessetnasetieseties 45
`
`The 2009 Press Release teaches the claimed “one
`or more secondary doses? oo. cece tet eeeetees 47
`
`3.
`
`Dependent claims oo... cece cece tect tettteeree SO)
`
`a)
`
`Claim 2: The 2009 Press Release and Shams teach
`the claymeddrug oo...cece eee etetet eee IO
`
`b)=Clams 3 and 4: The 2009 Press Release and
`Shams teach the claimed modes of administration.......50
`
`c)
`
`Claims 5-7: The 2009 Press Release and Shams
`teach the claumed dose amounts 0000Ol
`
`sf-4338006
`
`i
`
`Celltrion Exhibit 1014
`Page 894
`
`Celltrion Exhibit 1014
`Page 894
`
`

`

`Post Grant Review of USP 10,828,345
`
`d)}
`
`Claims 8-11: The 2009 Press Release and Shams
`teach the disorders treated ooo.cette Od
`
`VIE. GROUND 3: CLAIMS 1-11 FAIL TO SATISFY THE WRITTEN
`DESCRIPTION REQUIREMENTooo cccceceteseettseetttetteeeseee
`
`A.
`
`The °345 Patent’s Disclosure of 12~-Week Dosing00 SA
`
`B.—Regeneron’s Discussion of 12-week Dosing During
`PEOSCCULIOT occ cece ceecceeeseceeereeececesecassaeesacertesiestascreesseneanseesersse toh
`
`C.
`
`D.
`
`The 345 Patent Lacks Written Description Support for the
`Same Reasons Regeneron Articulated in its Critique ofthe 2009
`Press Release o...cc cic ccccccceseceeeeeeeeeeceeteeeeseeaeenseeseseseeneeuesneeeeeenneneens 64
`
`The °345 Patent’s Undifferentiated Disclosure of Various
`Dosing Regimens Is Insufficient to Support a Claimto a
`Specific 4-Week Secondary and 12-Week Tertiary Dosing
`REQUTOT cece cccccccssecccssecensecesseceeseececeeeceeseeesececnieesceeeestrusscieesstenesnraes 65
`
`IX.
`
`THE BOARD SHOULD NOT EXERCISE DISCRETIONARY
`DENIAL UNDER 35 U.S.C. § 3250) oocccccccccccscscsssecesvseesesecesevevtnsestveessies 71
`
`A.
`
`B.
`
`C.
`
`Shams Was Not Considered on the Record, Is Not Cumulative
`of any Reference Consideredon the Record, and, Evenif It
`Was Considered, the Office Materially Erred by Allowing the
`"BAS Patent over SHAMS oo cect eee sees eeceteeceteesssanenentneces 7]
`
`The 2009 Press Release in View of Shams Was Not Considered
`on the Record nor Were any Similar Arguments Considered............ 74
`
`No Written Description Arguments Were Considered on the
`ReCOTE occ cece ec cceecee tee cae cee eee cceeseeeteeeesceeessscseceeetecnseseeeeeeees 76
`
`X. MANDATORY NOTICES ooo ccc cece ccc tee eters cece te tetttereneersteees 76
`
`A.
`
`Real Party-in-Interest 000000 ccc eee ctee cece cece te teen tneeetteenees 76
`
`B.—Related Matters Under 37 C.F.R. § 42. 8(0D)Q)on 76
`
`©.
`
`Lead and Back-Up Counsel and Service Information 0.000000... 76
`
`XL
`
`CONCLUSIONocc cece eects cette ca eteetntectetcctttssitnietieneces 77
`
`sf-4338006
`
`iit
`
`Celltrion Exhibit 1014
`Page 895
`
`Celltrion Exhibit 1014
`Page 895
`
`

`

`Post Grant Review of USP 10,828,345
`
`Cases
`
`TABLE OF AUTHORITIES
`
`Page
`
`Advanced Bionics, LLC v.MED-EL Elektromedizinische Gerdie
`GmbH,
`TPR2019-01469, Paper 6 (D.T.A.B. Feb. 13, 2020)... cccccccteteeteenes 71,72
`
`Agilent Techs., Inc. v. Affymetrix, [nc.,
`S67 F.3d 1366 (Ped. Cit, 2009) occ cecnrceeereeeteeneeseneeiteenssievaverenaneenrees 53
`
`Amazon Inc. v. M2MSols. LLC,
`IPR2019-01 204, Paper 14 (P.T.A.B. Jan. 23, 2020) occ ccceeeceteeeenteees 74
`
`Amgen Inc. v. Alexion Pharma., Inc.,
`IPR2019-00740, Paper 15 (PLT.A.B. Aug. 30, 2009) ccc cttettenees 74
`
`Ameen Inc. v. Hoechst Marion Roussel Inc.,
`344 F.3d 1313 ed. Cit, 2003)ccc cececetera
`
`Boston Sci. Corp. v. fohnson & Johnson,
`647 F.3d 1353 (Ped. Cir, OVD)ccc ccc ccc ceeeeensecseetsettseteenneesnes 65
`
`Pujikawa vy. Wattanasin,
`93 F.3d £559 (Fed. Cir, 1996) occ ccc ete seeeeenssetreetteeteees 54, 65, 69
`
`EWPIP ApS v. Biozen MA, Ine.,
`749 Fed. Appx. 969 (Fed. Cir. 2018) (unpublished)eet 69
`
`LEAHYSMITH AMERICA INVENTS ACT.
`PL 112-29, 125 Stat. 284 (Sept. 16, 2011)eee 3 fi 6
`
`Nevozymes A’S v. DuPont Nutrition Biosciences APS,
`723 F.3d 1336 (Fed. Cit. 20133ted, OS
`
`Phillips v.AWH Corp.,
`445 F.3d 1303 (Fed. Cir. 2005) Cen Bane) ooo ccc ccccecccce ccc c cece eeseetteeneneees 16
`
`Purdue Pharma LP. y. frautdinginc.,
`230 F.3d 1320 (Fed. Cir. 2000) oooetd, O4, 63, 66
`
`In re Ruschig,
`379 F.2d 990 (CC PLA. TQ6T) cece cee ceersteeseeeessceesscceesetsaseeenaeees 63, 69
`
`sf-4338006
`
`Celltrion Exhibit 1014
`Page 896
`
`Celltrion Exhibit 1014
`Page 896
`
`

`

`Post Grant Review of USP 10,828,345
`
`Univ. of W. Virginia Bd. of Trustees vy. VanVoorhies,
`278 F.3d 1288 (Ped. Cir. 2002) occ cece cece eceesceenscteesecetesenserniecteniees 19
`
`Vas-Cath Inc. v. Mahurkar,
`935 F.2d 1555 Wed. Cir, D99D)ccc eects sees tree eereteennectursereteeeeeseeeniees 34
`
`William Hill US Haldco, tne. v. CG Tech. Dev., LOC,
`IPR2019-00317, Paper 14 (PLT _A.B. May30, 2019) occ ccteeeeeencees 72
`
`Statutes
`
`
`
`38 ULS.C. 8 POOGTAD cece ccecnteeeteccsseesssttaesasenesneeesseeteetteeesesetseenss 18
`
`35 ULS.C, 8 PQOG)ODB) cece ett cteceteertecsenseeteeneceeesestieniettenteeseeeniees 17
`
`BS US. 8 DOD ce etctte es ceeeceteesaeteeeeersesecisecsssnesesesuaeseetestetsieeneseteees ,
`23,
`5,23, 24
`pond
`
`BSUS. 8 LOB cece ccc cec cece cece eeecesseeseceeceseesetassesessecnesessesssetseseenseseenses 5,24
`
`BS USC. BD2 cc cccccccccctesecssccsseeessseeesecsssseesesssaeesessssecestsssesscsssasesesaeeess PESSU
`
`SS USL § POCO cee cect en ect ec ee ne cnaseeerecenscotetsisttectenieeticrns 7
`
`B35 USC. 8 20 eee cece ce ees teneeaeeeeeeiecnescnseceeeusscaeseuecasenseeiesteesuaeneesneseeetieess 17
`
`BS USC. 8 B32 coccccccccccsseseesscsssesseecsssreessesestesessasisessssssvesseersstisessssssssassessssseeed
`
`38 US 8 B25) cc ccecceecceeeccetnesensueeeiueeesteceesteeesiueeessceesiseeesisessieeessaespassim
`
`37 CLPLR. § 42 BEDI) cece cece cenit teeta cteeceeetiecateceeesectesseetieensteeeeniees 76
`
`37 CPLR. § 42.200 2b SOQ. occ cc cecceccecceeec ene ceee ee cese cess sueeeaeeeecacessesieetaseaeesaseneesseesees 1
`
`37 CER. § 42 204) occ ccc eee cee ces seesecaecseteecesseeneaesaesesseeseeaseeseeseseeenseestenes 4
`
`83 Fed. Reg. S134ccc ee cee cee cence cesses cctesveeeniectesisesiectsteetentieeenees 16
`
`ATA § BOD) occ ec etett3, 9 £9. 6, 97
`
`ATA § GDA) occ cece estes ecceeeeseaeeeeeesneceieesesaeeneesuassigstessuivsiesereeneenegenrens 17
`
`sf-4338006
`
`Celltrion Exhibit 1014
`Page 897
`
`Celltrion Exhibit 1014
`Page 897
`
`

`

`Post Grant Review of USP 10,828. 345
`
`TABLE OF EXHIBITS
`
`
`
`
`
`100]
`
`1002
`
`1903
`
`1004
`
`1005
`
`L006
`
`1007
`
`1008
`
`LO09
`
`1010
`
`10H]
`
`1O12
`
` Number 12, December 2012, Page 2538
`
`U.S. Patent No. 10.828.345
`
`File History of U.S. Application No. 16/159,282 (US. Patent No.
`10,828,345}
`
`Declaration of Dr. David Wu
`
`International Publication No. WO 2006/047325 (May4, 2006)to
`Shams
`
`Regeneron “Press Release Dated September 14, 2009” (September
`14, 2009)
`
`Genentech “News Release dated June 30, 2006" (fine 30, 2006)
`
`Regeneron “Press Release dated November 18, 2011" (November
`18, 20113
`
`“Safety and Tolerahility Studyof Intravitreal VEGF-Trap
`Administration in Patents With Neovascular AMD”
`(NCT00320775)
`
`Neuven ef al, “Results of a Phase 1, Dose-Escalation, Safety,
`Tolerability, and Biocactivity Study ofintravitreous VEGF Trap im
`Patients with Neovascular Age-Related Macular Degeneration”
`ARVO Annual Meeting Abstract (May 1 2006)
`
`Benz et al, “CLEAR-IT-2: Interim Results Of The Phase IT,
`Randomized, Controlled Dose-and Interval-rangme Study Of
`Repeated Intravitreal VEGF Trap Administration In Patents With
`Neovascular Age-related Macular Degeneration (AMOVPARVO
`Annual Meeting Abstract (May 2007)
`
`US. Application No. 13/940,370
`
`Heieret al., “Intravitreal Aflibercept (VEGF Trap-Eve) in Wet
`Age-related Macular Degeneration,” Ophthalmology, Volume 119,
`
`sf$4338005
`
`Vi
`
`Celltrion Exhibit 1014
`Page 898
`
`Celltrion Exhibit 1014
`Page 898
`
`

`

`
`
`Curncuhuam Vitae of Dr. David Wu, M.D... Ph.D
`{OES
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`ix
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