NOVITC(US)00394737
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`February 2019
`
`Retina Cl Review
`
`Novartis Exhibit 2167.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`NOVITC(US)00394 738
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`2
`Novartis Pharmaceuticals I Ophthalmology
`
`Business Use Only
`
`6. Retina Biosimilar Landscape
`5. Conbercept (Kanghong)
`4. Abicipar (Allergan)
`3. Ranibizumab (Roche/Genentech)
`2. Aflibercept (Regeneron)
`1 . Retina Landscape
`
`Agenda
`
`Novartis Exhibit 2167.002
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`NOVITC(US)00394739
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`Retina Landscape
`
`Novartis Exhibit 2167.003
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`NOVITC(US)00394 7 40
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`4
`Novartis Pharmaceuticals I Ophthalmology
`
`Business Use Only
`
`without reformulation
`Inflammation rates unsustainable
`
`inflammation
`possible but poor efficacy and >15%
`CEDAR/ SEQUOIA Ph3: 012 fixed dosing
`
`(DARPin)
`Abicipar Pegol
`
`Allergan
`
`BCVA superiority
`Non-contender without significant
`
`endpoint with extended durability
`AVENUE/ STAIRWAY Ph2: HIH RBZ 36w
`
`(RG7716)
`Faricimab
`
`Roche
`
`limited R&D spend to date
`before entry of biosimilars due to
`Ability to offer low branded price
`
`results expected 2H 2019
`PANDA Ph3: Q12 and 08 fixed dosing
`
`Conbercept
`
`Kanghong
`Chengdu
`
`innovation
`the market, game-changing
`Addressing largest unmet need fro
`
`4. Brolucizumab parity expected
`
`2019
`Ph3 initiated, first readouts throughout
`refills;
`LADDER Ph2: median 15 months between
`4. More concentrated dose
`
`Lucentis
`
`Approval Supplement
`after 1H19 resubmission of Prior(cid:173)
`
`3. Now just as convenient as
`
`3. Pre-filled syringe launch later in 2019
`
`population
`
`2. Access to broader patient
`
`2. DR Indication PDUFA May 13, 2019
`
`1. Facilitates T&E adopters
`
`1. VIEW extension: 012 Y2 PDUFA
`
`fixed Q12 arm, readout 1 H 2019
`ARIES Ph4: Early vs late T&E with
`Aug '18
`
`System
`Port Delivery
`
`Genentech
`
`Eylea
`
`Regeneron
`
`NVS Perspective
`
`Market Reception
`
`Key Data and Timing
`
`Product
`
`Company
`
`Competition generating interest outside "ability to dry"
`
`Novartis Exhibit 2167.004
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`NOVITC(US)00394 7 41
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`5
`Novartis Pharmaceuticals I Ophthalmology
`
`Business Use Only
`
`Last Update: Feb19
`
`2025
`
`i~-Exploratory MOAs
`
`2023
`
`2022
`
`2019
`2024
`D Key Competitors A Anti-VEGFs ✓.t~. PDGFs (single/ combination) ~ Steroids
`
`2021
`
`2020
`
`2018
`
`Estimated Approval Timeline
`Retina Landscape
`
`Novartis Exhibit 2167.005
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`NOVITC(US)00394 7 42
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`6
`Novartis Pharmaceuticals I Ophthalmology
`
`Business Use Only
`
`2022
`
`2021
`
`2020
`
`2019
`
`Retina Landscape -Near Term Highlights
`
`Novartis Exhibit 2167.006
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`NOVITC(US)00394743
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`Aflibercept (Regeneron)
`
`Novartis Exhibit 2167.007
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`NOVITC(US)00394 7 44
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`8
`Novartis Pharmaceuticals I Ophthalmology
`Source: Regeneron's Q4 2018 Earnings Report/Call; JP Morgan Healthcare Conference (Jan19)
`
`Business Use Only
`
`whether it can safely provide improved efficacy and longer-lasting benefit
`■ High-Dose aflibercept clinical study to be initiated in 2019 to determine
`
`■ PFS -REGN anticipates PFS launch later in 2019 after 1 H 19 resubmission of
`
`Prior-Approval Supplement
`
`-52 week PANORAMA study data presented at Angiogenesis conference (2/9/19)
`-REGN sees indication as major growth opportunity for Eylea
`
`■ DR indication -PDUFA date of May 13, 2019 remains unchanged
`
`■ Eylea 2018 US Net Sales grew +10% vs. prior year to $4.1 Billion
`
`Eylea/Regeneron -Recent News
`
`Novartis Exhibit 2167.008
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`NOVITC(US)00394 7 45
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`9
`Novartis Pharmaceuticals I Ophthalmology
`Source: Regeneron's Q4 2018 Earnings Report/Ca II; JP Morgan Healthcare Conference (Jan19)
`
`Business Use Only
`
`~ This likely is an attempt to develop the market for the DR indication by expanding their reach into
`
`General Ophthalmology where many DR patients are being diagnosed
`
`reimbursement team by 25 new field sales staff and +5 reimbursement field staff.
`To supporl their pending DR indication, intel indicates that they are expanding their field sales and
`
`*
`NOTE:
`
`df.scrNJnt that 'il','.,:!S p1-ovided across the board fn 2018. ·'·'
`trends. .... But our price has b-een marked veq,·· .modestiy impacted to thf~ rregaf./.:.,'e side JJased up-on a slight
`but frorn .a gen-erai paint of 1-"ieH!', t think it's going to take· some time to develop that mark,et Pricing
`lrs going to take a tot of patient education because it's a _paradigm shift So we donJ gii/e guidance,
`2019 and pricing trends. for Eylea in 20"1:9· ..... "J .thin·k it ,.vm be in the eariy stages ofthe launch that indication.
`
`• CE.Os co-mments, 1Nhen asked about NPDR indication could be significant growth driver for Eylea in
`
`new growth opportunity in NPDR and increased patient support programs
`Increase in 2019 SG&A spent for Eylea will be focused on capitalizing on potential
`early treatment in NPDR
`Comprehensive plans are in place to support disease education focused on benefits of
`Company sees a major growth opportunity for Eylea in NPDR
`
`■ About Eylea's DR indication
`
`Eylea/Regeneron -What are they saying?
`
`Novartis Exhibit 2167.009
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`NOVITC(US)00394 7 46
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`10 Business Use Only
`Novartis Pharmaceuticals I Ophthalmology
`Source: Regeneron's Q4 2018 Earnings Report/Ca II; JP Morgan Healthcare Conference (Jan19)
`
`• During Q&A session,. CEO made= following comments. on Broluciz:umab, ''vVe saw some .s}ide loday from N&%\iti(?., that they Jij\~ji®ik
`
`comp-eMon .....
`that sL1g9es:ts that there's a whet.le new approa,ch to tn3af,n9 .this disease. So, the on{y -so vvhat ,we W do is 1,ve 'H adfust to the
`:mijf\%\1@:tb:ii&fa#bi#fef.;{f!foivi/il/¢{1t, But the botto,m :line fr;, it doesn't seem to be a=nything padk;uiady disruptive about any of the ,data
`iifrtiit¥MMilibttlfiiiM?tiM~kmfliJWJWijbi#:Wlto)ii?rd#iti:Mtiit::@ltl:c~i':M\H#wii:Jiii@f:i#:tttiitfoU@iJ#\#MiftiMt.1:iitii&Jmtr:M&\ii@'
`ijf:ijgifit}q\-jg)if~~f1gg(t(mij:fMi:lgp(~pffigJtil4(ti-)!fulli@tt6.~fl}diiit?Jki}Qiii:if4)m!iiMf~f}di'!!AiH:iiin}fijyiffg:ij}if:t~Mfii)fiii@
`
`tni@ij~irM~Mi:iijf \Hi~t J1i1ij::ryij;m#pip1ii!f~irni~ijJi~1:1.
`shows ... i%.o.ij:@J::1r~E~nfng/1itlbij}ij!:ijfMihiiNfv.4iJh:~ijWJhijf@lidnli~dnif11:ilimi:@pi@rfilWf!ii:J\t:~miliri#.%~1#:'@:e:t::t.ePMhMMM:U¢.it~Iij/iji
`:1)@!$.b¥ii¢$. The reason 'i:Ve haven't up until no\<V, entered something is because it's be-en so hard to top EYLEA, as history
`iiIWiriij}ijijt~f1#iijijJ(@~i!ijiii)if'9ilWW---•fhif~j:1j/Jy~friihiflijfijpjlij~f:~m1:#Mii~fj:i#!ili~:ififfjM{fugtff~Iidfiijl~#:lijijiijfiij9Ji:iNi
`iittir.iill.ijfid:t##n@exw.11@)iil%iiffi/6¥te;1m1.tJ:if}tttli+l*'$iji,ijimW:tfmiMm:jij@iij:!ii@im¥~friltMft#itliiM%[bij:ijiiiM!virijq@~j#1MtMWi:iji
`wh•o:(e field, there could! still be substantial gro•.vth.,., .And even novv tfuijtijw:m~mJMtfiiJW$W{Q6Pf$ij]ij!Jijj(:Jgijij$d!B.ij:~tJW@iffifiij!!irjg!f
`threate:ning ctJ=mpfrcations. Thafs a whole ne\N oppmtunity. So. ·with -the whole field grow's. Even 1f we get a smaller s=hare-0fthe
`the opport1..mit~es= \Ne Just have recently revealed the data in diabetic retinopathy tNhern v,•e're having this drnrnatic reduction in vision(cid:173)
`iiiiBlilBitlliillililiiitlllR01itffi61itlllllid11liliMffillllillllfilHlldM!ffll■l01ffiill-ButoveraD,thec~ass and
`• Addrr[lon a! comments fro1n Ch lef. $.Wlijijt~i@@ffiiitrnf fiji,iM/@jl!t:ijjfiijir$\mij~fa!iiij\i~iijjij#9:ffi:pijt!t~i:lijJ!Jlri¥itfiMiI~f!iil)igJij;rn1)fij
`
`vlsu.al gains than are aliready achievab~e with Ey!ea
`Co1::r:1pany mentioned that there are no near term potential agents that can provide s.ubstanUalty different dosing He-xibilit~·. duration or
`
`"
`
`Eylea/Regeneron -What are they saying?
`
`■ About the competition ...
`
`Novartis Exhibit 2167.0010
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`NOVITC(US)00394 7 4 7
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`11
`Novartis Pharmaceuticals I Ophthalmology
`Source: HYO Cl Team Coverage: Macula Society 2019
`
`Business Use Only
`
`Response -Post-Hoc Analysis of VIEW trials (Michael Singer, M.D.)
`
`■ Macula Society 2019: Association of Vision-related QOL and Anatomic Dryness
`
`Eylea/Regeneron -Data Presentations (1/2)
`
`Novartis Exhibit 2167.0011
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`NOVITC(US)00394 7 48
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`12 Business Use Only
`Novartis Pharmaceuticals I Ophthalmology
`Source: HYO Cl Team Coverage: Macula Society 2019
`
`Response -Post-Hoc Analysis of VIEW trials (Michael Singer, M.D.)
`
`■ Macula Society 2019: Association of Vision-related QOL and Anatomic Dryness
`
`Eylea/Regeneron -Data Presentations (2/2)
`
`Novartis Exhibit 2167.0012
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`NOVITC(US)00394749
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`Ranibizumab-Port Delivery System (R-PDS)
`Lucentis
`
`Ranibizumab (Roche/Genentech)
`
`Novartis Exhibit 2167.0013
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`NOVITC(US)00394 750
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`14 Business Use Only
`Novartis Pharmaceuticals I Ophthalmology
`Source: Roche's Q4 2018 Earnings Report/Call
`
`Butln terms.of continuedlncren-utntai gaJnsi rm not-sure_ we·reproJecting -,1 lot ntore/
`there were_son1e. one .. ti(negain,,,.Andso iMe tfuhkLUCENTIS vr-Hlpequ#ea$tror19$how.In thisyear_
`1-thinJ,, lue!ecd the. gro'!Nth. in .2Q1B., ln 2019~ there¥s• a potenlfal. launc!J of another. competitor. _ ! thihk
`addtliott-we launched• a prefilled _ syrlng-et which has· been-very popular'.._ And so tht.d. combination.
`of the.competitors had .a bit of a challenge last year r1nt:1 Jed to some switching.~.,.And In
`$enfor ~x~cutive ccnnrn~nts on the growthsustarna.bllity of· LucenUs '-Nith. lntr,:>duction of PF Si ;, . ,; . one
`
`.
`
`'.
`
`. "' .
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`■ What are they saying?
`
`First in class launch in mCNV and DR w/o DME on-going
`indications
`Accelerated growth attributed to PFS launch, with market share gains in all approved
`
`■ Lucentis 2018 sales in US were CHF 1.7 Billion, +18% increase compared to
`
`2017 (2017 sales: CHF 1.4 Billion)
`
`Lucentis/Roche -Recent News
`
`Novartis Exhibit 2167.0014
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`NOVITC(US)00394 751
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`15 Business Use Only
`Novartis Pharmaceuticals I Ophthalmology
`Source: HYO Cl Team Coverage: Macula Society 2019
`
`Degeneration? -Post-Hoc Analysis of HARBOR trial (Nancy M Holekamp, M.D.)
`
`■ Macula Society 2019: Is Drier Always Better in Neovascular Age-Related Macular
`
`Lucentis/Roche -Data Presentations (1/1)
`
`Novartis Exhibit 2167.0015
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`NOVITC(US)00394 752
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`16 Business Use Only
`Novartis Pharmaceuticals I Ophthalmology
`Source: HYO Cl Team Coverage: Macula Society 2019
`
`(Dennis M. Marcus, M.D.)
`AMD: How LADDER Phase 2 Results Informed ARCHWAY Phase 3 Study Design
`
`■ Macula Society 2019: Port Deliver System with Ranibizumab (PDS) in Neovascular
`
`RPDS/Roche -Data Presentations (1/3)
`
`Novartis Exhibit 2167.0016
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`NOVITC(US)00394 753
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`17 Business Use Only
`Novartis Pharmaceuticals I Ophthalmology
`Source: HYO Cl Team Coverage: Macula Society 2019
`
`(Dennis M. Marcus, M.D.)
`AMD: How LADDER Phase 2 Results Informed ARCHWAY Phase 3 Study Design
`
`■ Macula Society 2019: Port Deliver System with Ranibizumab (PDS) in Neovascular
`
`RPDS/Roche -Data Presentations (2/3)
`
`Novartis Exhibit 2167.0017
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`NOVITC(US)00394 754
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`18 Business Use Only
`Novartis Pharmaceuticals I Ophthalmology
`Source: HYO Cl Team Coverage: Macula Society 2019
`
`(Dennis M. Marcus, M.D.)
`AMD: How LADDER Phase 2 Results Informed ARCHWAY Phase 3 Study Design
`
`■ Macula Society 2019: Port Deliver System with Ranibizumab (PDS) in Neovascular
`
`RPDS/Roche -Data Presentations (3/3)
`
`Novartis Exhibit 2167.0018
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`NOVITC(US)00394 755
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`!I Genentech.
`II si miJar ec(inornics depending on the priCing and contracting strategy irnp!ernented by
`I device is refillable using :a c:ustmnized ne-ed!e. physicians might be alAe to :achieve
`I reduce payrnent'3 to physicians, potentially H'npacting: uptake_ Ho;..•rever, glven t!·1at the
`•I An implantable device 'N(Juld reduce the number of i rueG-tion visits by patients, but
`!: Economics to physicians may b& Mgatively impacted by implant use
`
`19 Business Use Only
`Novartis Pharmaceuticals I Ophthalmology
`Source: Investor Reports
`
`Cannacord C3enuity 7/25/18
`
`REG,N Coverage
`
`ls ,;J_slrnple, rnlnlni;:llfY•hiv.t~h,,1' pn::lcedtfre ahd.H: c:;:irr_t:i•f,as.ity-t•:~p-Lmttid if n~tO::f:::i~MJf.
`tH}i!l•-cHKh~,d:ertd _--~ tt:2Jte9y k} innu:~f lnt:::JV<.lh:, Pt'r · QU{ t'.Xpt~rt, _ in~t>ftkm of.· tht: . dt~vke
`a~~ i;:<:':·!:-H U,,:~>..i~.U,'i:-Al.L i.m ~
`;.,,s.te.nd~ ff::'>J,,l,°l<.,~-;~ v1n~1 f~.ql!J,~
`.;:;'··•,·-
`i,•--·f--
`n~i<J~ pts·lnifr~Hy, SpF.dfiG~l.ly., (it.r di:R thrnJJht the !)10$t ippr::tprb~t{' ptt >,'<,•H~ nlI?f.'Ht
`Thf·-~Ktl f;:o:pftted JQ first '"~dc,pt tucerru~ PDS.•in >f:k~:tte<I ti~t&s,. ,a.v01din9 t.reilttntrrt~
`Our E~p~:rt R-evfo,w~d R~al,W~,rM <<:snddtrathu1s f<►r Usa9tl'-i):f Luumth PD.S;
`
`.... , .... ,,---i+i·•·-
`
`--·
`
`,tih~
`
`·I"···;. ___ ,,_~1 h··-t-
`
`.;:,,,~. iA,j/"/19
`,•l:
`
`t~:"'''0
`-~l--l!:;•
`
`·--,,,,,·I-~ •.. ,··.,
`
`REGN Coverage
`Jeffe,ri1e,s 712'611 8:
`
`............. ·····.·.-'······ ........ -·".-.-.·.·
`
`..... ,t ...................... ·····.·.· .·,
`
`........ ···.·.·:\.•I•.·.•.•:-~.-.·.•:',!;:.:".-~.--·.·
`
`•·· Ro4".h:e'~ D~pot.thHbe:ry UkiHy-lo a~·co111p'etl'Uve hiwAMD: R~ctdlth~_PH.LADDtR
`••• ~nd bceyontt
`••• are lfk~ly bt f'JJt tntr\t~~ing pre~u,re oui the ly!:e~ fr~tnd1i'¢e in WAMD in 2020
`••·• with• POS, Th.el-¢ data. •afong wtth othe:f c.!'.lmp-etittif' readouh · on thee · horaou,,
`••• a:tb ltw~•d • by rrw!!<t pt~· c~mpellh,g • ~ltbougb +'i!J:So . hlgbHghted ~om-e • t:baUet19-ei
`•••· th~· btt:.-iid-et thetapeutk · 1at1<btap~, • (hn ~Hped· 1'6und dt<e 6+ rtH► · r~tu I-dm~
`{ data _for th~.lu(:~ntb_ Port D~lh.H~t)".System.(PDS) -pr~l-ent~t:t·,rt .A:SRS ·118 :and
`w:e h~it~d a ,t.¥H with ~ re:Un~t :$p=ed.¥!jit t~ r~v-~w 1ht} Plll.ADllER topUn~
`••• m~y 1tlhNh¥~~:f
`
`RPDS/Roche -What does ''the Street'' say?
`
`Novartis Exhibit 2167.0019
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`NOVITC(US)00394756
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`Abicipar (Allergan)
`
`Novartis Exhibit 2167.0020
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`NOVITC(US)00394 757
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`21
`Novartis Pharmaceuticals I Ophthalmology
`Source: JP Morgan Healthcare Conference (Jan19)
`
`Business Use Only
`
`" MAPLE study results to determine abicipar safety perception and regulatory filing timelines in H1
`NVS lmRlications:
`
`2019
`
`■ Biologics license application submission for Abicipar in nAMD expected in H1
`
`pegol in nAMD patients -final results expected in H 1 2019
`open-label Phase 2 MAPLE study evaluating purer formulation of Abicipar
`
`■ Allergan stated that they are moving in right direction based on early data from
`
`■ Allergan provided update on MAPLE study at Annual JP Morgan Healthcare
`
`conference (Jan 07, 2019)
`
`2019
`
`Abicipar/Allergan -Recent News
`
`Novartis Exhibit 2167.0021
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`NOVITC(US)00394 758
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`22
`Novartis Pharmaceuticals I Ophthalmology
`Source: JP Morgan Healthcare Conference (Jan19)
`
`Business Use Only
`
`==· ·r1)rr---to1
`
`Abicipar/Allergan -What are they saying?
`
`Novartis Exhibit 2167.0022
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`NOVITC(US)00394 759
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`23 Business Use Only
`Novartis Pharmaceuticals I Ophthalmology
`Source: JP Morgan Healthcare Conference (Jan19)
`
`(EY'E) Targeting Unmet Needs in. Retinal Diseases
`
`\~':•~:..: ...... ;--:-:·~'5l
`
`Abicipar/Allergan -What are they saying?
`
`Novartis Exhibit 2167.0023
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`NOVITC(US)00394 760
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`24 Business Use Only
`Novartis Pharmaceuticals I Ophthalmology
`Source: Credit Suisse Healthcare Conference (Nov18)
`
`Liff'€ .. ,,,,f.:'fe rf.:*ty@rnrnirnrwtrmmmntwwrn::nrn:1:11@t:MWJ@Irn#@%Mt Ant ~,o it" -'<'f? <...,m tJA'€ ,JJ the
`'M#MWW••M>••mt~••nt•rnw·•&m•••lt••Inm••t••WWR••M=wrn••m=:t;@ifflt:lf••nwtwt•• A,nd 11·'1; ·•,::;';)fth tht\ 1IT01•t· bf.:i:•::'l\:1i$ th~l· opp:>11=,inl•ty
`•1tm••rnmtM••rnMttM•••••ttm••nmn••:m•mt••rn'@@rrnt••w@•••r•ru&•••••+@:•••W•tmww:•••=+rmi4••*MW=lt••lt•••••Hm•lhrn••rnm••M¥••w••ttmm1@1i*·
`./l<f.•·~·~· Jtc~·i• fi~'':i(ilt1:-f,·cnt tl·H~••MBWkff••rtM@•lrt••rmnrl••:tW•@•@••••}}b=•t••Wtn••:t@M@it••:~m•••MPA••W@i•
`,:.,;.;,t
`•mmm••tt•••Jtt••m••tIM••rntt:••M#.lm••l.rt••WM@••mt*t••WMfi•
`t,,;\ ,i <:orit,rt,,,i:.,,c-11, n·=::i:t,1,tq, ;:,rot,r::rn
`MhWW%M¥Mfa@mtMm&zvnMmtt@@@;fff~'f@Mdtt@t@Hf%fitlift@mM@t@tl@MY%'@W tNWMAHtfi!i@#A
`=C:>n fr...:i ~ditty 5':<it. t::-,:A the @1W@@Mi Wt\ti@l.MM. d o:,tlfM,. = hiinkfaWMtl@fM@W.#M.f.:M'JfotMttkMQ.@W H':WM
`
`,t \::,•:fa'.:
`
`t=> ,:1,:>.
`
`ntttt~ •;;;o::,-:e
`
`\;::::?.t: tan -chect n-~-e t~>\ tt;::· ::'.t~::lcip:~t. ~ tb}nt tl~:~t ·:;::t?::=:s )y:: p:~):J::~nt i1r~:. t~:::k~irt t<;:r :gn~~r~t?.t=d
`t:;~>k £-st -~1 tt~:ed ·~ 2:-:,\:~•:e?.:::l: :J~')fa~{\j r~:g:lr:ntff:: .· :;::{:\e:tt::~:-f /<::t~ (:(:-'.:::~< -~1 n:::~.h=:t~1=ltdf!{3 V~$k>n'
`
`•t@Mt@@tw••mrn••rn••~t••,@mt¥MJ11••:tw£Mtt•tt••mf••m~Mwt•mt@
`#N#@ltMtl@W snwmm WWi%W¥?Mi@¥Mt MM%UW:;f#®tttNt@tM%%Mtt¥tt@Mtf '4tMtitiMt-#
`tt=mrn@@Wt&ffWtMWW?M mwm JM@tlHt }.:,::_: think.. tA· )ndbCf.'.:Jl:bb] 100•·16.: )HJMfWKMWWt@lJMNM'Jf:¥ WW#
`l tbt+:: "-\'i,;;,;~ tt?:J:Bd k=J, t:et;l':(i' biJ jnst nr==8 thm ""B\'B S:f.fH, ,1~ ilitb bH irnx:f. nf ihe:\ prnMB,f@MiJ%%NM#W~@nrwt
`
`Abicipar/Allergan -What are they saying?
`
`Novartis Exhibit 2167.0024
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`NOVITC(US)00394 761
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------·
`
`Sources: Strat Plan 2016 estimates based on Clearview qual/quant PMR (20113); Phase II (REACH study) data release, Phase Ill results from CEDAR and SEQUOIA
`
`I Novartis Confidential I abicipar pegol update I Oct 20181 Business Use Only
`
`Novartis Pharmaceuticals I Ophthalmology
`
`CEDAR Abicipar +6.7 letters (QB\/\/) +5.6 (Q12\/\1); Lucent is +8.5 (04\/\1)
`
`··•SEQUQIA: Abicipar +8.31etters(QBV'J), +73(Cl12VV);Lucentis+8.3 (Q4W)
`
`VA gains at week 52: · ·
`
`. CEDAR. Abicipa[ 91.7% (QBW), 91 •. 2% (2Q12); • L.Ucentis 95.5% (Q4W)
`•• SEQUQIA Abicipar 94.8%(Q8\N),913%,.(q12W); Lucentis96% (Q4VVJ••
`
`• % of patients vvith stable vision at week 52 •
`
`ibizuriiab with 6, a and 13 irijectioris required;• respectively
`on-inferiority was demonstrated for abicipar with fewer injections required for Cl1
`.• rimary endpoint.% of Patients1A1ith BCVA change frortibaseline ,;;t5Lettersiht
`• • 2mg dose of abicipar pegol at 2q8 of 2q1 2 or monthly ranibizumab mono therapy .
`_ • ies: nAMD: Two phase Ill clinical trial (SEQUOIA, CEDAR) initiated in Jun, 201
`
`. ,
`
`. .
`
`.
`
`. . . .
`
`~~~~rii
`letter higher mean baseline BOVA in ra
`ibizumab 0.5 mg evi:iry A weeks3A
`· · · ·
`erical difference observed iri
`CH study} data2: •
`
`potential for quarterly dosing
`Factor A (VEGF-A) that inhibits all relevant subtypes of VEGF-A with high potency. It has
`It's a DARPin-based anti-angiogenic drug. It is an antagonist of Vascular Endothelial Growth
`
`What is it?
`
`Allergan
`
`Company
`
`Abidpar pegol (anti-VEGF Darpin) Allergan
`
`Novartis Exhibit 2167.0025
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`NOVITC(US)00394 762
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`I Novartis Confidential I abicipar pegol update I July 20181 Business Use Only
`
`Novartis Pharmaceuticals I Ophthalmology
`
`5 Simeon R & Chen Z Protein Celi 2017 doi 10 1007/s13238-017-0386-6 [Epub ahead of print]; 6 Vazquez-Lombardi R Drug Discove1y Today 2015; 20:1271-83
`Partners/reports-and-presentations/2015/mp-corporate-presentation-02-sep-2015. pdf. 4. Souied EH, et al. Am J Ophtha/mol. 2014; 158:724-732; 102:407-416;
`2008;13:695-701; 3. Molecular Partners. Corporate presentation. September 2015. Available at: http://investors.mclecularpartners.com/~/media/Files/M/Molecular(cid:173)
`1. Molecular Partners. About DARPin® Technology. Available at: https://www.molecularpartners.com/aboutdarpinsl: 2. Stumpp MT, et al, Drug Discov Today.
`
`interface (red)
`
`• Randomized interaction
`
`Constant framework (blue)
`
`DARPin target complex
`
`DARPin
`
`DARPin scaffold
`
`the number of ankyrin repeats2,5,6
`Small molecular size (14-21 kDa) depending on
`
`interface for specific target binding1,2,5
`repeat modules with a randomized interaction
`Typically composed of a framework of 4-6
`
`diverse protein-protein interactions5
`on ankyrin repeat proteins, which mediate
`
`■ Composed of artificial protein scaffolds based
`
`classical antibody elements1-4
`affinity to antibody therapeutics without using
`designed for high selectivity and binding
`■ DARPins are antibody mimetic proteins,
`
`DARPins: Designed Ankyrin Repeat Pruteins
`
`Novartis Exhibit 2167.0026
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`NOVITC(US)00394 763
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`i
`
`presentation. AAO 2016.
`next-am:J-drug; 3 Stumpp MT, et al Drug Discov Today 2008;13:695-701 4 Sv,,erczff;;,ska M, et al Expet1 Op1n Emerg Drugs 2015;20:531-536; 5 Hassan T, et al Oral
`phase-i i-study-exud?page=ful I; 2. Review of ophthalmology. August 2015. Meet your next AMO drug Available at: https://\Swvvreviewofophthalmology.com/article/meet-your(cid:173)
`1 Ophthalmology Ti mes 2014. Ava, I able at: httpi/ophthalmologytimes. modern medicine .com/ophthal mologyti mes/RC/tags/ab1c1 par -pegol/darpin-delivers-promisi ng-resu lts(cid:173)
`
`I Novartis Confidential I abicipar pegol update I July 20181 Business Use Only
`
`Novartis Pharmaceuticals I Ophthalmology
`
`Anti-VEGF DARPin5
`Abicipar pegol:
`
`PEG, polyethylene glycol; PK, pharmacokinetic
`
`shape
`Translate into a lower diffusion coefficient compared to smaller spherical
`binding events to the intended target4
`Reduce drug potency by impeding a drug's active site and reducing
`
`Larger hydrodynamic radius can potentially:
`Increasing the systemic half-life of a drug4
`
`■ However, PEGylation can have drawbacks, including:
`
`vivo4
`generally limited by poor physiochemical and PK properties in
`PEGylation is a commonly used technique for molecules that are
`hours in vivo3
`Unmodified DARPins have predicted half-lives in the range of
`
`■ Abicipar was PEGylated to increase its ocular half-life2
`
`:
`
`i
`
`:
`
`J.lbie.ipar pegol I$ a REG.ylate.a DAFIR~n antagonist of NIEGF-J.l (3.i kDa)1~
`
`............ ·! .................... !· .................... ·! ........... .
`
`1he treatment of nAMD and DME
`Al-lar Partners are developing abiciparpegol for
`
`Novartis Exhibit 2167.0027
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`NOVITC(US)00394 764
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`Cell. 2017. doi 10.1007/s13238-017-0386-6. [Epub ahead of print]
`12. Souied EH. et al. Am J Ophthalmol. 2014;158:724-732; 102:407-416; 13. Campochiaro, PA et al. Am J Ophthalmol. 2013;155: 697-704; 14. Simeon R & Chen Z. Protein
`[poster 4996 -B0202]; 9. Krohne TU, et al. Am J Op/Jt/Jalmol. 2012;154:682-686; 10. Lucentis SmPC. December 2016; 11. Regeneron. Data on file (Maculart symposium 2017)
`Sci 2016 572612-2617; 6. RTH258 Investigator Brochure v1 0 Nov 2015; 7 Gaudreau It J, et al. Invest Ophlhalmol Vis Sci. 200546 726-733; 8. Nimz EL, et al. ARVO 2016
`next-amd-drug; 3. Gaudreau It J, et al. Retina. 2007; 27:1260-1266; 4. Australian Public Assessment Report for Aflibercept; July 2012; 5. Park SJ, et al. Invest Ophthalomo Vis
`phase-i i-study-exud?page=fu 11; 2. Review of Ophthalmology. August 2015. Meet your next AMO drug. Available at: https://www.reviewofophthalmology.com/article/meet-your(cid:173)
`1 . Ophthalmology Ti mes 2014. Avai I able at: http://ophthalmologyti mes. modern medicine. com/ophthal mologyti mes/RC/tags/abici par -pegol/darpi n-delivers-promisi ng-resu lts(cid:173)
`
`l
`~
`
`I Novartis Confidential I abicipar pegol update I July 20181 Business Use Only
`
`Novartis Pharmaceuticals I Ophthalmology
`
`13-14 days12-14
`
`Data pending
`
`9.1 days11
`
`7.2-9 days9•10
`
`Humans
`
`N/A
`
`(2.1-2.6 days)8
`
`(1.6-2.6 days)4
`
`50.5-62.4 h
`
`40-64 h
`
`3 days7
`
`Monkeys
`
`6 days1•2
`
`(~2.9 days)6
`
`(~3.9-4.8 days)4•5
`
`70.6 h
`
`94.1-115 h
`
`2.9 days3
`
`Rabbits
`
`. . ·e·~~p~~j~~~~ ~f PK 'aat~ f~~~ ~c~~~ th~· iit~~~tu~~ ~ay l~ad t~ ~~ i~t~~p~~t~tio~ ..
`action vs cunent anti-VEGFs 1,2
`half.life of abicipar pegol may lead to a longer duration of
`Al-lar partners suggest tllat a longer intraocular
`
`that compounds with a s.11otte.r halftlife rnay also nave less dtnrability
`
`Novartis Exhibit 2167.0028
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`NOVITC(US)00394 765
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`I Novartis Confidential I abicipar pegol update I Oct 20181 Business Use Only
`
`Novartis Pharmaceuticals I Ophthalmology
`
`Secondary endpoints: .Ghange in BC\/A,.C:RJ. and.proportion.pf patients\lVith.>15. letter gain .at wee.k 52 ••.
`primaryendpojnt proportion.pf patientswith•stahlevislon (loss of <15.ETDRS letters comparedwith•BL)atvveek 52
`Both studies were. randomized, double .rnasked,parallel group studiesCIEDAR•(N;;;1498), SE9U()IA(N;;;1435l•••
`
`CEDAR and SEQUOIA
`Abicipar pegol Phase 3 studies in nAMD:
`
`... , .......... ~~ .201.a .... , .... , ....
`
`Novartis Exhibit 2167.0029
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`NOVITC(US)00394 766
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`I Novartis Confidential I abicipar pegol update I Oct 20181 Business Use Only
`
`Novartis Pharmaceuticals I Ophthalmology
`
`-CEDAR: Abicipar 91. 7% (Q8W), 91.2% (2Q12); Lucentis 95.5% (Q4W)
`-SEQUOIA: Abicipar 94.8% (Q8W), 91.3% (Q12W); Lucentis 96% (Q4W)
`
`■ % of patients with stable vision at week 52
`
`■ Non-inferiority was demonstrated for abicipar with fewer injections required for Q 12 and Q8 abicipar vs. Q4
`
`ranibizumab with 6, 8 and 13 injections required, respectively
`
`regimens
`stable vision at week 52 and demonstrated statistical non-inferiority to Q4 ranibizumab for both the Q12 and Q8 dosing
`In both the SEQUOIA and CEDAR, abicipar met the pre-specified primary endpoint of the proportion of patients with
`
`■
`
`forboth
`
`■ Abicipar (q8w, q12w) vs. ranibizumab (q4w) (N=1885), Primary endpoint of study being proportion of patients with
`abicipar arms, along with need for fewer injections
`Non inferiority compared to Q4 ranibizumab was d
`
`stable vision at week 52
`
`... , .......... ~~ .201.a .... , .... , ....
`
`Novartis Exhibit 2167.0030
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`NOVITC(US)00394 767
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`I Novartis Confidential I abicipar pegol update I Oct 20181 Business Use Only
`
`Novartis Pharmaceuticals I Ophthalmology
`
`0.3% for ranibizumab. The most commonly reported adverse event were uveitis followed by vitritis and iridocyclitis
`Incidence of intraocular inflammation events was 15.3% and 15.4% for abicipar Q12 and abicipar Q8, compared to
`
`■
`
`-CEDAR: Abicipar -142µm (Q8W); -150µm (Q12W); Lucentis -141 µm (Q4W)
`-SEQUOIA: Abicipar-147µm (Q8W), -142µm (Q12W); Lucentis -142µm (Q4W)
`
`■ Change in CRT was similar for both treatment groups and Lucentis
`
`-CEDAR: Abicipar +6.7 letters (Q8W); +5.6 (Q12W); Lucentis +8.5 (Q4W)
`-SEQUOIA: Abicipar +8.3 letters (Q8W), +7.3 (Q12W); Lucentis +8.3 (Q4W)
`
`■ VA gains at week 52:
`with over 11% moderate to sewre IOI cases
`52 week results showed potential for q12 dosing with abicipar, along
`
`.... : ............ GfiG) .. 201.1 ................. .
`
`Novartis Exhibit 2167.0031
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`NOVITC(US)00394 768
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`I Novartis Confidential I abicipar pegol update I July 20181 Business Use Only
`
`::
`
`alleviate that.
`today's topline data did nothing to
`concern on the inflammation rates and
`Feedback from clinicians reflected
`
`model
`commercial potential for abicipar in our
`approach before assigning significant
`We're going to take a wait and see
`
`Novartis Pharmaceuticals I Ophthalmology
`
`injections
`
`regarding the product's commercial potential
`inflammation rates should give pause
`are encouraging in some, though the
`
`. We recognize the value-add of fewer
`
`. The efficacy and duration data for abicipar
`
`(on Allergan)
`19th July 2018
`Barclays,
`
`informative.
`The primary efficacy endpoint is not as
`trials.
`actually numerically worse than past
`The inflammation rate is not better,
`
`viability of the compound
`questions regarding the commercial
`data for the meantime, and raise
`unexpected, overshadow the efficacy
`The high inflammation rates, while not
`
`commercially meaningful drug.
`to be before abicipar becomes a
`resolved in this trial, but does need
`
`Allergan did not provide.
`BCVA and measure of CRT, which
`
`. Inflammation was not going to be
`. The drugs should be compared on
`
`this is reversible).
`for commercial viability (assuming
`serious inflammation as acceptable
`
`. A threshold of 2% incidence of
`
`market.
`treatment options already on the
`given other safe and effective
`determine commercial success,
`inflammation and market access
`Based on KOL opinion,
`
`.
`
`indicate negative data.
`We want more, but lack of release does not
`
`1 gh July 2018
`Bernstein,
`
`(on Allergan) . The data presented show they have a
`
`competitive drug.
`
`. Only the primary endpoint was presented.
`
`Lucent is.
`inferiority on the primary efficacy endpoint to
`care, with both studies demonstrating non-
`durability of the agent vs. current standard of
`Encouraging efficacy data regarding the
`
`(on Allergan)
`1 gh July 2018
`CITI,
`
`()\/ti rJ. CI::\
`:::::::::::::::::::::::::::::;:::::::]]
`;,;:;=!~~~~~~:;;;;;::::;:;:;:;;;;:::::;:;::;;,:::::,:::,:
`~;~~~~~~;
`
`').._
`
`~=
`
`l
`
`:::,::: ::::;:, :::::::::::: ::::;: :::,:::
`:::::
`::::: ::::: :::::: ::::::: ::::: :::::: ::::::: :;:::::::::: ::::: ::::::
`::::: /: :/ :::::: /:/ :/ :// /
`:/:
`::::: :::::: :::::: ::::::: ::::: :::::: ::::::: :;::;:;::::: ::::: ,::::::
`:::::: :::: ::::::: :/ :// /
`:::::::
`::::: ;;::: ::C::;:
`::::::: :,:,:, ,::::: ;;;:: :::::: :::::::: :::: ::::::
`:::,: ;;;:::
`::::::
`;:;:;:; ::: :::::: :::::: :;::::;::: :;::
`:::, ::::: :::;::
`:::::::
`::::: /: :/ :::::: /:/ :/ :// /
`:::: :::: :;:::: :::::: :::: :::::: :::::: :::::::: :::: ::::::
`::::::
`::::: ::;: :::::: :::::: ::: ::::: :::::: :;::::;::: :;::
`:-:•:•
`:::::
`:;:;:;.
`
`:-:-:-:-:-:::
`
`:;:;:;. :-:-:::
`
`:-:•:•
`
`.;:;::
`
`:;:;,:.
`
`:-:•:•
`
`::::::: ::::: ::::;:
`
`::::;:
`
`:::: :::: :;:::: :::::: :::: :::::: :::::: :::::::: :::: ::::::
`::::: ::;: :::::: :::::: ::: ::::: :::::: :;::::;::: :;::
`::::::
`:::::::
`::::: /: :/ :::::: /:/ :/ :// /
`:::: :::: :;:::: :::::: :::: :::::: :::::: :::::::: :::: ::::::
`::::: ::::: :