`
`
`
`Lucentis — Pre-filled syringes
`Pharmaceutical development aspects
`
`a
` éh, NOVARTIS
`
`PFS “fumata bianca* Workshop
`
`December 17, 2007
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`NOVITC(CH)00217650
`Novartis Exhibit 2138.001
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`ontents
`
`
`be
`
`
`necenaner 7 207
`
`| Baines
`
`Use Oey
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`
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`Oe
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`
`* Current knowledge on GNE PFS
`
`« Guidelines / pharmacopoeial references to
`» Silicon leaching
`» Particle counts
`
`* Hurdles and risks
`
`
`
`ies
`
`PES Yeeakehed
`
`PSonrea a. boson . ds NOVARTIS
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`NOVITC(CH)00217650
`Novartis Exhibit 2138.002
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`
`
`Data about GNE Lucentis PFS
`
`
`
`
`NOVARTIS
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`Technical R&D
`Uae Orly
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`Sp hingenaes PIS o Yeerkehe
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`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)0021 7650
`Novartis Exhibit 2138.003
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Lucentis syringe in development by Genentech
`
`Barrel
`
`Tip Cap
`
`
`
`
`
`
`
`
`
`
`Plunger Stopper
`
`
`
`Plunger Rod
`I
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00217650
`
`Novartis Exhibit 2138.004
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`
`Lucentis syringe in development by Genentech
`
`>t
`fis MOVARTH
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00217650
`
`Novartis Exhibit 2138.005
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Lucentis syringe in development by Genentech
`
`
`
`
`
`Or,
`
`3 NOVARTIS
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00217650
`
`Novartis Exhibit 2138.006
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Lucentis syringe in development by Genentech
`
`ee» ¢
`‘
`2f
`gis NOVA i>
`
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00217650
`
`Novartis Exhibit 2138.007
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Lucentis syringe in development by Genentech
`
`|
`
`|
`
`
`
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00217650
`
`Novartis Exhibit 2138.008
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`
`
`
`
`Silicon leaching
`
`
`
`
`
`raperas
`2
`3 NOVARTIS
`we ogee ve
`.
`:
`Uae Ona
`‘ i”! Secagaten 87,
`2007
`| Bauinets
`Technical R&D
`tb
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`NOVITC(CH)00217650
`Novartis Exhibit 2138.009
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Silicon leaching into PFS
`
`
`Guidelines / regulations
`
`* To the best of our knowledge, there are no guidelines / regulations
`about silicon content in PFS
`
`
`
`
`
`ds NOVARTIS
`.
`oo
`.
`.
`bt
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`NOVITC(CH)00217650
`Novartis Exhibit 2138.0010
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Silicon leaching into Lucentis placebo
`
`|
`
`According to siliconization method
`
`>t
`fis MOVARTH
`
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00217650
`
`Novartis Exhibit 2138.0011
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Silicon in Xolair syringes
`12-month data
`
` 2f
`
`
`‘
`fis NWOVAE
`
`ee» ¢
`i>
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00217650
`
`Novartis Exhibit 2138.0012
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`
`
`Particle counts
`
`ds NOVARTIS
`—
`
`eh hl! ersper WY. 200?#Boe ernee LegeOnay Technical R&D
`
`
`
`
`
`
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`NOVITC(CH)00217650
`Novartis Exhibit 2138.0013
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`
`
`» USP 31 <789> Particulate Matter in Ophthalmic
`Solutions
`
`* EP 2.9.19 Particulate contamination: subvisible particles
`
`» EP has no specifications for Ophthalmic solutions
`
`Particles in pharmaceutical containers
`Regulatory requirements
`
`
`* USP 31* <788 > Particulate Matter in Injections
`This general chapter is harmonized with the corresponding texts of the European
`Pharmacopoeia and/or the Japanese Pharmacopoeia.
`
`be
`
`
`* USP 31 will be official as of May 1, 2008
`
`. a
`.
`oy II ner. 200 amet ve
`
`ds sovaRTiS
`ovans
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`NOVITC(CH)0021 7650
`Novartis Exhibit 2138.0014
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`|
`
`Particulate matter determination at Novartis
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00217650
`
`Novartis Exhibit 2138.0015
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`USP <789> Particulate matter in ophthalmic solutions
`
`|
`|
`
`Taken from USP37, valid from May 2008 on
`
`
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00217650
`
`Novartis Exhibit 2138.0016
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Particulate matter: USP criteria
`
`|
`
`
`
`
`* Container <100 mL
`
`pera
`‘
`2f
`fs MOVARTES
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00217650
`
`Novartis Exhibit 2138.0017
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Particle counts in batches producedat Stein
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00217650
`
`Novartis Exhibit 2138.0018
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`
`
`
`
`be
`
`
`Hurdles and risks
`
`ds NOVARTIS
`—
`
`eheea ersper WY. 200?#Boe ernee LegeOnay Technical R&D
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`NOVITC(CH)00217650
`Novartis Exhibit 2138.0019
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Hurdles and risks (1)
`
`
`>t
`fs NWOVARTE
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00217650
`
`Novartis Exhibit 2138.0020
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Hurdles and risks (2)
`
`>t
`fis MOVARTH
`
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00217650
`
`Novartis Exhibit 2138.0021
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Hurdles and risks (3)
`
`>t
`fis MOVARTH
`
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00217650
`
`Novartis Exhibit 2138.0022
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Hurdles and risks (4)
`
`
`>t
`fis MOVARTH
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00217650
`
`Novartis Exhibit 2138.0023
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Hurdles and risks (5)
`
`
`
`fis MOVARTES
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00217650
`
`Novartis Exhibit 2138.0024
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`
`
`
`
`
`.
`pis breng Loe Ory
`
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`Technical R&D
`
`Backup slides
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`200?
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`NOVITC(CH)00217650
`Novartis Exhibit 2138.0025
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`
`
`Molecule description
`
`* RhuFab V2 is an antibody fragment derived from expression of the
`Fab portion of a full-length recombinant IgG antibody
`
`RhuFab V2 (Ranibizumab)
`
`
`et
`
`
`* The fragment blocks binding of VEGFto its receptors
`
`* RhuFab V2 is not glycosylated
`
`« RhuFab V2 has a molecular mass of ~48’000 daltons
`
`é; MCOVARTES
`.
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`.
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`fn
`
`
`Storms 2 « Wht MM fSesernes 17, 2002|Biers aeOry Technical R&D
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`NOVITC(CH)00217650
`Novartis Exhibit 2138.0026
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`RhuFab V2 (Ranibizumab)
`
`
`
`ee» ¢
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`
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00217650
`
`Novartis Exhibit 2138.0027
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Se
`
`cc
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`Characteristics of GNE Lucentis PFS
`
`t
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`fy uoeres AS oWether V7. DOU?|De nrg Lae Oty sNOVART!
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`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`NOVITC(CH)00217650
`Novartis Exhibit 2138.0028
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`|
`
`Lucentis syringe as developed by Genentech
`Components of Lucentis Drug Product
`
`
`
`sera
`‘
`2t
`{s NOVARTIS
`“ oes “ees Technical R&D
`
`
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00217650
`
`Novartis Exhibit 2138.0029
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`|
`
`Extractables Characterization of
`
`BEE32° Stoppers 2t
`
`
`sera
`‘
`fs MOVARTES
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00217650
`
`Novartis Exhibit 2138.0030
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Methods for Control Leachables
`|
`(Target Compounds)in Lucentis Drug Product PFS
`|
`
`
`|
`|
`
`
`
`>t
`fis MOVARTH
`
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00217650
`
`Novartis Exhibit 2138.0031
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`|
`|
`
`|
`
`Leachable Compounds (HPLC-UV) in Drug
`Product Lot PT1977H03a
`
`|
`
`
`
`BL=Belowlimit
`ds SOVARTI
`
`
` prea Uae Ory° ND=Not detéoted | wen VT, DOD?PBie Technical R&D
`
`
`
`
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00217650
`
`Novartis Exhibit 2138.0032
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Leachable Compounds (GC-MS)in Drug Product
`
`Lot PT1977H03a
`
`|
`|
`
`
`
`BL=Belowlimit
`dhs SOVARTIES
`
` ND=Net detéctod «oe 9 Technical R&D 220 oemsctecns
`
`
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00217650
`
`Novartis Exhibit 2138.0033
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`MetalAnalysis ofIIScpperby cP
`MS & ICP-AES
`
`
`
`fis MOVAR TES
`>t oo
`|
`oe _— Technical R&D
`
`
`
`
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00217650
`
`Novartis Exhibit 2138.0034
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`|
`|
`
`
`Metal Analysis of 0.5 ccsyringe
`
`Barrel by ICP-MS & ICP-AES
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00217650
`
`Novartis Exhibit 2138.0035
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`|}
`
`|
`|
`|
`
`
`
`|
`
`
`
`Stability Data for rnuFab V2 Roche Lot PT1977H03a (10 mg/mL)
`Product Code: G188EH
`Parent Bulk Drug S
`»
`Lot M30582 (Run 14}
`0.18 mL fill in 0.5cc
`re-filled Syringes
`Date of Manufacture: 21 March 2005
`
`|
`Storage Q12003
`| Temperature
`(Months)
`}
`4
`| Acceptance Criteria
`
`012005
`
`L
`
`12495
`SEC
`(% Mi
`
`012496
`IEC
`(% Main
`Peak)
`Report
`
`Q12495
`CE-SOS
`(2%Main
`
`012502
`RUVEC
`{x10 U/mg)
`
`Q12152
`Comainer/
`Closure
`Pass
`
`Q12121
`Particulate
`Pass
`
`* Color, Appearance and Clarity.
`colorless topale yellow sottion; clear to slightly opalescent sdiution
`
`
`clear, SOPL
`(CO=celorless
`lightly opalescent, PY=pate yellow,
`
`) (rhuFab V2 conc, by HUVEC)thuFab V2 conc. by UV Spec Scan)
`* %Specific Activity—(1
`“ Pass for Container/Closure, No leakage detected
`|
`* Basefor Particulate Analysis using Membrane Filtration method: Meet current USP fer aphthalmic scution
`
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00217650
`
`Novartis Exhibit 2138.0036
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Stability Data for rhuFab V2 Roche Lot PT1977H03a (10 mg/mL)
`Product Code: G188EH
`Parent Bulk Drug
`+
`Lot M@80352 (Run 14}
`0.18 mL fill in 0.5c¢
`Pre-filled Syringes
`Date of Manufacture:
`arch 2005
`
`
`~ Dateof EtO treatmentat Salt Lake, Utah (Cycle #75); June 29,2005.
`|}}
`
`12152
`@1zs02
`012498
`|
`EC
`Q12421
`Q12044
`Storage Q12003 Q12005
`Container/
`HUVEC
`SEC
`| Temperature
`(% Main
`(% Main
`
`
`
`
`
`
`
`
`
` (°C) (Months) pH CAC Peak) Peak)| UV Spec Scan=(% Monomer} (x10° Using}=Closure
`tance Criteria: Report §.520.5 Selution” 10.0+1.0 mgimte 95% Report
`
`
`
`
`
`
`
`
`ance and Clarity ccloriess to pale yellow solution, clear to slightly opalescent solution
`(CO=cdlorless, CL=clear, SOPL=sightly coalescent, PY=pale yellow)
`Specific Activty= (100%) (rhuFab V2 core. by HUVEC)mhuFab V2 conc. by UV Spee Scan)
`
`* Pass for Container/Closure; Noleakage detect ed
`
`tone hod Meet current USP for ophthalmic solution
`i Pass for Particulate Analyst
`sy:
`|
`
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)0021 7650
`
`Novartis Exhibit 2138.0037
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`
`
`_lnjection
`
`Testing |
`
`
`
`
`
`
`
`* Breaking Force
`The minimum force that is required to
`initiate movement of the plunger stopper.
`
`* Glide Force
`A steady force that is required to extrude
`the solution through a needle
`
`egIcer 2007
`
`eases toes
`
`és MCFVARTES
`LNovany
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`NOVITC(CH)0021 7650
`Novartis Exhibit 2138.0038
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`-LucentisPFSa)Injection|
`
`fis NOVA TES
`
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00217650
`
`Novartis Exhibit 2138.0039
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`-LucentisPFS—)Injection
`
`| UNBRITNetelENFereRENesenna SinneNRND
`
`
`
`
`
`
`
`eroniRaNRNaNRipeN NiSNpaarSmBNRwiNNatsForces’APNENNEScereNNNeara RTeenaetinNeNRCEThinaEREelonarabiNinnparnyaleigi
`
`sora
`.
`3
`fs NOVARTIS
`AAS ENS? oe Oy* hm” ERE Bes Technical R&D
`
`
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00217650
`
`Novartis Exhibit 2138.0040
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`-LucentisPFS—)Injection
`
`| UNBRITNetelENFereRENesenna SinneNRND
`
`eroniRaNRNaNRipeN NiSNpaarSmBNRwiNNatsForces’APNENNEScereNNNeara RTeenaetinNeNRCEThinaEREelonarabiNinnparnyaleigi
`
`ats maIVARTES
`
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00217650
`
`Novartis Exhibit 2138.0041
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`
`
`Forces
`
`
`
`
`
`
`
`is
`Ss LV AR
`soe 2? 2k be OptyShia Technical R&D
`
`
`
`
`
`
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00217650
`
`Novartis Exhibit 2138.0042
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Injection Force Results for Lucentis PFS
`
`is MOVAR TES
`
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00217650
`
`Novartis Exhibit 2138.0043
`Regeneron v. Novartis, IPR2021-00816
`
`
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