UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`CELLTRION, INC.,
`Petitioner
`v.
`REGENERON PHARMACEUTICALS, INC.,
`Patent Owner
`
`Inter Partes Review No.: IPR2023-00533
`
`U.S. Patent No. 10,888,601 B2
`Filed: April 29, 2019
`Issued: January 12, 2021
`Inventor: George D. Yancopoulos
`
`Title: USE OF A VEGF ANTAGONIST TO TREAT
`ANGIOGENIC EYE DISORDERS
`
`PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT NO. 10,888,601 B2
`
`

`

`TABLE OF CONTENTS
`
`Page
`
`TABLE OF AUTHORITIES .................................................................................... v
`EXHIBIT LIST ........................................................................................................ xi
`I.
`INTRODUCTION. ......................................................................................... 1
`II. MANDATORY NOTICES (37 C.F.R. § 42.8). ............................................. 3
`A.
`REAL PARTIES-IN-INTEREST (37 C.F.R. § 42.8(B)(1)). .......................... 3
`B.
`RELATED MATTERS (37 C.F.R. § 42.8(B)(2)). ....................................... 3
`C.
`LEAD AND BACK-UP COUNSEL AND SERVICE INFORMATION (37
`C.F.R. § 42.8(B)(3)-(4)). ....................................................................... 5
`PAYMENT UNDER 37 C.F.R. § 42.15(a) AND § 42.103. .......................... 6
`III.
`IV. GROUNDS FOR STANDING (37 C.F.R. § 42.104(a)). ............................... 6
`V.
`THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW. ............. 6
`VI.
`35 U.S.C. §325(d) DISCRETIONARY DENIAL IS
`UNWARRANTED. ........................................................................................ 6
`VII. OVERVIEW OF PETITIONER’S CHALLENGES AND
`REQUESTED RELIEF. ............................................................................... 11
`A.
`STATUTORY GROUNDS OF CHALLENGE. .............................................. 11
`VIII. OVERVIEW OF THE ’601 PATENT. ........................................................ 12
`IX. CLAIM CONSTRUCTION (37 C.F.R. § 42.104(b)(3)). ............................. 14
`A.
`“A METHOD FOR TREATING AN ANGIOGENIC EYE DISORDER IN A
`PATIENT IN NEED THEREOF” AND “A METHOD FOR TREATING
`AGE RELATED MACULAR DEGENERATION.” ....................................... 15
`1.
`The “method for treating” preamble is non-limiting, and
`does not require construction. .................................................. 15
`
`ii
`
`

`

`2.
`
`3.
`
`X.
`XI.
`
`Regeneron’s argument that the “method for treating”
`preamble is a positive limitation should be rejected. ............... 16
`If a limitation, the preamble’s plain and ordinary
`meaning—which does not provide any specific efficacy
`requirement— must govern. .................................................... 18
`“INITIAL DOSE,” “SECONDARY DOSE,” AND “TERTIARY DOSE.” ........ 21
`“WHEREIN EXCLUSION CRITERIA FOR THE PATIENT INCLUDE.” .......... 22
`1.
`The Claimed Exclusion Criteria Are Entitled No
`Patentable Weight Under the Printed Matter Doctrine. ........... 22
`PERSON OF ORDINARY SKILL IN THE ART. ...................................... 25
`TECHNOLOGICAL BACKGROUND AND SCOPE AND
`CONTENT OF THE PRIOR ART. .............................................................. 25
`A.
`VEGF TRAP-EYE/AFLIBERCEPT BACKGROUND. ................................. 26
`B.
`ANTI-VEGF THERAPY. ....................................................................... 28
`C.
`EXCLUSION CRITERIA. ......................................................................... 29
`D.
`PETITIONER’S PRIOR ART REFERENCES. .............................................. 30
`1.
`Dixon (Ex.1006)....................................................................... 30
`2.
`Adis (Ex.1007). ........................................................................ 33
`3.
`Regeneron (8-May-2008) (Ex.1013). ...................................... 35
`4.
`NCT-795 (Ex.1014). ................................................................ 35
`5.
`’758 patent (Ex.1010). ............................................................. 37
`6.
`’173 patent (Ex.1008). ............................................................. 38
`7.
`Rosenfeld-2006 (Ex.1058). ...................................................... 39
`8.
`Heimann-2007 (Ex.1040). ....................................................... 40
`XII. GROUNDS FOR UNPATENTABILITY—DETAILED ANALYSIS. ...... 42
`
`B.
`C.
`
`iii
`
`

`

`A.
`
`ANTICIPATION. .................................................................................... 42
`1.
`Legal standards. ....................................................................... 42
`2.
`Ground 1: Dixon anticipates the Challenged Claims. ............ 43
`3.
`Grounds 2, 3, and 4: Adis, Regeneron (8-May-2008),
`and NCT-795 anticipate the Challenged Claims. .................... 50
`OBVIOUSNESS. ..................................................................................... 58
`1.
`Legal standard. ......................................................................... 58
`2.
`Ground 5: The Challenged Claims are obvious over
`Dixon (either alone or in combination with the ’758
`patent or the ’173 patent). ........................................................ 59
`Grounds 6 and 7: Claims 9 and 36 are obvious over
`Dixon in combination with Rosenfeld-2006 (Ground 6),
`or in combination with Heimann-2007 (Ground 7) (and if
`necessary, in combination with the ’758 and ’173
`patents). .................................................................................... 63
`No secondary considerations. .................................................. 67
`4.
`XIII. CONCLUSION. ............................................................................................ 69
`
`B.
`
`3.
`
`iv
`
`

`

`TABLE OF AUTHORITIES
`
`Page(s)
`
`CASES
`Advanced Bionics, LLC v. Med-EL Elektromedizinische Geräte GmbH,
`IPR2019-01469, 2020 WL 740292 (P.T.A.B. Feb. 13, 2020) .................. 7, 10
`Amazon.com, Inc. v. M2M Sols. LLC,
`IPR2019-01205, 2020 WL 448385 (P.T.A.B. Jan. 27, 2020) ......................... 8
`Amgen Inc. v. Alexion Pharms., Inc.,
`IPR2019-00739, Paper 15 (P.T.A.B. Aug. 30, 2019) ...................................... 8
`Amneal Pharms. LLC v. Alkermes Pharma Ireland Ltd.,
`IPR2018-00943, Paper 8 (P.T.A.B. Nov. 7, 2018) .......................................... 8
`Arctic Cat Inc. v. GEP Power Prods., Inc.,
`919 F.3d 1320 (Fed. Cir. 2019) ..................................................................... 16
`Ariosa Diagnostics v. Verinata Health, Inc.,
`805 F.3d 1359 (Fed. Cir. 2015) ..................................................................... 27
`Bayer Healthcare Pharms., Inc. v. Watson Pharms., Inc.,
`713 F.3d 1369 (Fed. Cir. 2013) ..................................................................... 61
`Bayer Schering Pharma AG v. Barr Lab’ys, Inc.,
`575 F.3d 1341 (Fed. Cir. 2009) ..................................................................... 64
`Becton, Dickinson & Co. v. B. Braun Melsungen AG,
`IPR2017-01586, Paper 8 (P.T.A.B. Dec. 15, 2017) .............................. 7, 9, 10
`Bio-Rad Lab’ys, Inc. v. 10X Genomics Inc.,
`967 F.3d 1353 (Fed. Cir. 2020) ..................................................................... 16
`Bristol-Myers Squibb Co. v. Ben Venue Lab’ys, Inc.,
`246 F.3d 1368 (Fed. Cir. 2001) ................................................... 16, 18, 44, 58
`Chengdu Kanghong Biotechnology Co. v. Regeneron Pharms., Inc.,
`No. PGR2021-00035 (P.T.A.B.) ..................................................................... 4
`Cubist Pharms., Inc. v. Hospira, Inc.,
`75 F. Supp. 3d 641 (D. Del. 2014) ................................................................ 57
`
`v
`
`

`

`Geneva Pharms., Inc. v. Glaxosmithkline PLC.,
`213 F. Supp. 2d 597 (E.D. Va. 2002), aff’d, 349 F.3d 1373 (Fed. Cir.
`2003) .............................................................................................................. 58
`Geneva Pharms., Inc. v. GlaxoSmithKline PLC,
`349 F.3d 1373 (Fed. Cir. 2003) ..................................................................... 21
`GlaxoSmithKline LLC v. Glenmark Pharms., Inc.,
`No. 14-877-LPS-CJB, 2016 WL 3186657 (D. Del. June 3, 2016) ............... 18
`Grünenthal GMBH v. Antecip Bioventures II LLC,
`No. PGR2019-00026, 2020 WL 4341822 (P.T.A.B. May 5, 2020) ............. 37
`Guardian Indus. Corp. v. Pilkington Deutschland AG,
`IPR2016-01635, Paper 9 (P.T.A.B. Feb. 15, 2017) ...................................... 11
`Horizon Healthcare Servs., Inc. v. Regeneron Pharms., Inc.,
`No. 1:22-cv-10493-FDS (D. Mass.) ................................................................ 4
`Hulu, LLC v. Sound View Innovations,
`No. IPR2018-01039, 2019 WL 7000067 (P.T.A.B. Dec. 20, 2019) ............. 37
`In re Ackenbach,
`45 F.2d 437 (C.C.P.A. 1930) ............................................................. 48, 49, 55
`In re Antor Media Corp.,
`689 F.3d 1282 (Fed. Cir. 2012) ..................................................................... 57
`In re Copaxone Consol. Cases,
`906 F.3d 1013 (Fed. Cir. 2018) ......................................................... 16, 18, 20
`In re Cruciferous Sprout Litig.,
`301 F.3d 1343 (Fed. Cir. 2002) ..................................................................... 43
`In re Distefano,
`808 F.3d 845 (Fed. Cir. 2015) ................................................................. 23, 24
`In re Gulack,
`703 F.2d 1381 (Fed. Cir. 1983) ..................................................................... 25
`In re Huai-Hung Kao,
`639 F.3d 1057 (Fed. Cir. 2011) ..................................................................... 59
`
`vi
`
`

`

`In re O’Farrell,
`853 F.2d 894 (Fed. Cir. 1988) ....................................................................... 64
`In re Omeprazole Patent Litig.,
`483 F.3d 1364 (Fed. Cir. 2007) ..................................................................... 43
`King Pharms., Inc. v. Eon Labs, Inc.,
`616 F.3d 1267 (Fed. Cir. 2010) ................................................... 43, 48, 49, 55
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007)........................................................................... 27, 59, 61
`Motorola Mobility LLC v. Arnouse,
`No. IPR2013-00010, 2013 WL 12349001 (P.T.A.B. Jan. 30, 2013) .............. 7
`Mylan Lab’ys Ltd. v. Aventis Pharma S.A.,
`No. IPR2016-00712, 2016 WL 5753968 (P.T.A.B. Sept. 22, 2016) ............ 17
`Nitto Denko Corp. v. Hutchinson Tech. Inc.,
`IPR2018-00955, Paper 7, 15-17 (P.T.A.B. Dec. 4, 2018) ............................... 9
`Oakley, Inc. v. Sunglass Hut Int’l,
`316 F.3d 1331 (Fed. Cir. 2003) ..................................................................... 21
`Ormco Corp. v. Align Tech., Inc.,
`463 F.3d 1299 (Fed. Cir. 2006) ..................................................................... 59
`Perricone v. Medicis Pharm. Corp.,
`432 F.3d 1368 (Fed. Cir. 2005) .............................................43, 48, 49, 55, 63
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) ..................................................................... 64
`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005) ..................................................................... 15
`Praxair Distrib., Inc. v. Mallinckrodt Hosp. Prod. IP Ltd.,
`890 F.3d 1024 (Fed. Cir. 2018) ............................................................... 24, 25
`Purdue Pharma L.P. v. Endo Pharms. Inc.,
`438 F.3d 1123 (Fed. Cir. 2006) ..................................................................... 17
`
`vii
`
`

`

`Rasmusson v. SmithKline Beecham Corp.,
`413 F.3d 1318 (Fed. Cir. 2005) ..................................................................... 44
`Regeneron Pharms., Inc. v. Novartis Pharma AG,
`IPR2021-00816, Paper No. 1 (Apr. 16, 2021) ............................................... 31
`Rhine v. Casio, Inc.,
`183 F.3d 1342 (Fed. Cir. 1999) ..................................................................... 22
`Samsung Elecs. Co. v. Elm 3DS Innovations, LLC,
`925 F.3d 1373 (Fed. Cir. 2019) ............................................................... 19, 23
`Sandoz Inc. v. Abbvie Biotechnology Ltd.,
`No. IPR2018-00156, 2018 WL 2735468 (P.T.A.B. June 5, 2018) ............... 37
`SciMed Life Sys., Inc. v. Advanced Cardiovascular Sys., Inc.,
`242 F.3d 1337 (Fed. Cir. 2001) ..................................................................... 20
`Shenzhen Zhiyi Tech. Co. v. iRobot Corp.,
`IPR2017-02137, Paper 9 (P.T.A.B. Apr. 2, 2018) .......................................... 8
`Takeda Pharm. Co. v. Zydus Pharms. USA, Inc.,
`743 F.3d 1359 (Fed. Cir. 2014) ..................................................................... 21
`Tandus Flooring, Inc. v. Interface, Inc.,
`IPR2013-00333, 2013 WL 8595289 (P.T.A.B. Dec. 9, 2013) ...................... 11
`Taro Pharms. U.S.A., Inc. v. Apotex Techs., Inc.,
`IPR2017-01446, 2017 WL 6206129 (P.T.A.B. Nov. 28, 2017) ................... 11
`TomTom, Inc. v. Adolph,
`790 F.3d 1315 (Fed. Cir. 2015) ..................................................................... 16
`United States v. Regeneron Pharms., Inc.,
`No. 1:20-cv-11217-FDS (D. Mass.) .................................................... 4, 53, 55
`Vizio, Inc. v. Int’l Trade Comm’n,
`605 F.3d 1330 (Fed. Cir. 2010) ..................................................................... 16
`Wyers v. Master Lock Co.,
`616 F.3d 1231 (Fed. Cir. 2010) ..................................................................... 68
`
`viii
`
`

`

`STATUTES
`STATUTES
`35 U.S.C. § 101 ........................................................................................................ 25
`35 U.S.C. § LOD cecccssssssssssccsssssssssessscsssssssssessccssssssssserseceesssssssetsecsssssssnsetsecsesssssusenseese25
`35 U.S.C. § 102 ....................................................................................... 8, 11, 25, 31,
`35 U.S.C. § 102 cccsssssssssscsssssssssesssssssssssssesssssesssssssesseseesssssnsessessesssssnsesees 8, 11, 25, 31,
`34, 36, 37, 38,
`34, 36, 37, 38,
`39, 40, 41
`39, 40, 41
`35 U.S.C. § 103 ........................................................................................ 8, 12, 25, 64
`35 U.S.C. § 103 cecccsssssssevssscsssssssssvessccsssssssssessscsssssssssetsecsssssssssessessesssssneesss 8, 12, 25, 64
`35 U.S.C. § 103(a) ................................................................................................... 59
`35 U.S.C. § 103(a) sesssecsssccsssssssssessscsssssssssessecsssssssssersesesstsssssetsecsssssssusetsecsssssssnsenseeee 59
`35 U.S.C. § 112 .................................................................................................. 10, 22
`35 U.S.C. § V2 cccssssssssessccsssssssesessccsssssssssessscsssssssesessecesssssseessecsssssnseusessesssssseeses 10, 22
`35 U.S.C. § 282(b) ................................................................................................... 15
`35 U.S.C. § 282(b) verceessssccsssssssssesssccssssssssetsccsssssssssersecessssssssensecsesssssuseisecsssssssnvensecee 15
`35 U.S.C. § 311 .......................................................................................................... 1
`35 U.S.C. § 31D ccccsssssssessssccsssssssesssscssssssssseesecessssssesetsecessssssuvesseceestsssnsessecessssssesetseeess 1
`35 U.S.C. § 312 .......................................................................................................... 1
`35 U.S.C. § B12 cecccsssssssessssccsssssssessssccssssssssessecessssssesetsecessssssuvessecsestsssnsessecesssssunsetseees 1
`35 U.S.C. § 313 .......................................................................................................... 1
`35 U.S.C. § 313 cccccsssssssessssscsssssssessssscssssssseseesscsssssssestsecessssssusesseceestsssnsessecessnsssevetseees 1
`35 U.S.C. § 314 .......................................................................................................... 1
`35 U.S.C. § 314 ceccsssssssessssccsssssssessssccsssssssesesecsssssssesetsecessssssssesseceestsssssessecessnssunsetseees 1
`35 U.S.C. § 314(a) ..................................................................................................... 7
`35 U.S.C. § 314(a) cecsesessssccsssssssevsssccssssssssseesscssssssseseesecessssssssesseceestsssssessecessrsssesenseeees 7
`35 U.S.C. § 315 .......................................................................................................... 1
`35 U.S.C. § 315 cccccsssssssesssscssssssssesssscsssssssseseesscsssssssesetsecessssssevetsecesstsssnsessecessrassesetseeess 1
`35 U.S.C. § 316 .......................................................................................................... 1
`35 U.S.C. § 316 vecccsssssssessssccsssssssevssscsssssssseseesscsssssssestsecessssssesensecsestsssnsessecessssssesenseeees 1
`35 U.S.C. § 317 .......................................................................................................... 1
`35 U.S.C. § 317 ccccsssssssessssccsssssssesessccessssssssessecessssssevessecessssssuvessecssstsssnsessecessnsssuverseees 1
`35 U.S.C. § 318 .......................................................................................................... 1
`35 U.S.C. § 318 vecccsssssssessssccsssssssesssecsssssssssessssssssssevetsecessssssusessecsestsssnsessecesssassusetseees 1
`35 U.S.C. § 319 .......................................................................................................... 1
`35 U.S.C. § 319 vcccccssssssessssccsssssssessssssssssssseeesecsssssssevetsecessssssesetsecsestsssnsessecesssssunsetseees 1
`35 U.S.C. § 325(d) ................................................................................. 7, 8, 9, 10, 11
`35 U.S.C. § 325(d) sessssesscscssssssssessessssssssssesssssesssssssessesesessssnsvsseseesssssnsesss 7, 8, 9, 10, 11
`RULES
`RULES
`37 C.F.R. § 42 ............................................................................................................ 1
`37 CFR. § 42 ccccccsssssssssssscssssssssessssccsssssssssesscssssssseseseceesssssuvesseceesssssnsessecessssssnsetseees 1
`37 C.F.R. § 42.8 ......................................................................................................... 3
`37 CAFR. § 42.8 vecccsssssssssssccsssssssessssccssssssseseesecessssssesessecessssssssessecssstsssnsessecessssssuvetseees 3
`37 C.F.R. § 42.8(b)(1) ................................................................................................ 3
`37 CAFR. § 42.8(b)(L)cccccscccsssssssessssccssssssssessccssssssseveesecessssssssesseceestssssvessecessnsssnvenseeess 3
`
`ix
`1X
`
`

`

`37 C.F.R. § 42.8(b)(2) ................................................................................................ 4
`37 C.F.R. § 42.8(b)(3) ................................................................................................ 5
`37 C.F.R. § 42.8(b)(4) ................................................................................................ 5
`37 C.F.R. § 42.10(b) .................................................................................................. 5
`37 C.F.R. § 42.15(a) ................................................................................................... 6
`37 C.F.R. § 42.24(a) ................................................................................................... 2
`37 C.F.R. § 42.24(d) .................................................................................................. 2
`37 C.F.R. § 42.100(b) .............................................................................................. 15
`37 C.F.R. § 42.103 ..................................................................................................... 6
`37 C.F.R. § 42.104(a) ................................................................................................. 6
`37 C.F.R. § 42.104(b)(3) .......................................................................................... 15
`MISCELLANEOUS
`83 Fed. Reg. 197, 51340-51359 (Oct. 11, 2018) ..................................................... 15
`Trial Practice Guide, 77 Fed. Reg. 48759-60 (Aug. 14, 2021).................................. 3
`
`x
`
`

`

`EXHIBIT LIST
`
`Exhibit
`1001
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`1009
`1010
`
`1011
`
`1012
`
`Description
`U.S. Patent No. 10,888,601 B2 (“’601 patent”)
`Expert Declaration of Dr. Thomas A. Albini in Support of Petition
`for Inter Partes Review of Patent No. 10,888,601 B2, dated June 30,
`2022 (“Albini”)
`Expert Declaration of Mary Gerritsen, Ph.D. in Support of Petition
`for Inter Partes Review of U.S. Patent No. 10,888,601 B2, dated
`June 30, 2022 (“Gerritsen”)
`Jocelyn Holash et al., VEGF-Trap: A VEGF Blocker with Potent
`Antitumor Effects, 99 PROC. NAT’L ACAD. SCI. 11393 (2002)
`(“Holash”)
`Quan Dong Nguyen et al., A Phase I Study of Intravitreal Vascular
`Endothelial Growth Factor Trap-Eye in Patients with Neovascular
`Age-Related Macular Degeneration, 116 OPHTHALMOLOGY 2141
`(2009) (“Nguyen-2009”)
`James A Dixon et al., VEGF Trap-Eye for the Treatment of
`Neovascular Age-Related Macular Degeneration, 18 EXPERT
`OPINION ON INVESTIGATIONAL DRUGS 1573 (2009) (“Dixon”)
`Adis R&D Profile, Aflibercept: AVE 0005, AVE 005, AVE0005,
`VEGF Trap – Regeneron, VEGF Trap (R1R2), VEGF Trap-Eye, 9
`DRUGS R&D 261 (2008) (“Adis”)
`U.S. Patent No. 7,531,173 B2 (“’173 patent”)
`U.S. Patent No. 7,396,664 B2 (“’664 patent”)
`U.S. Patent No. 7,374,758 B2 (“’758 patent”)
`F Semeraro et al., Aflibercept in Wet AMD: Specific Role and
`Optimal Use, 7 DRUG DESIGN, DEV. & THERAPY 711 (2013)
`(“Semeraro”)
`Press Release, Regeneron, Regeneron and Bayer HealthCare
`Announce Encouraging 32-Week Follow-Up Results from a Phase 2
`Study of VEGF Trap-Eye in Age-Related Macular Degeneration
`(Apr. 28, 2008),
`http://investor.regeneron.com/releasedetail.cfm?releaseid=394066
`(“Regeneron (28-April-2008)”)
`
`xi
`
`

`

`Exhibit
`
`1013
`
`1014
`
`1015
`
`1016
`1017
`
`1018
`
`1019
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`Description
`Press Release, Regeneron, Bayer and Regeneron Dose First Patient
`in Second Phase 3 Study for VEGF Trap-Eye in Wet Age-Related
`Macular Degeneration (May 8, 2008),
`http://investor.regeneron.com/releasedetail.cfm?ReleaseID=394065
`(“Regeneron (8-May-2008)”)
`Vascular Endothelial Growth Factor (VEGF) Trap-Eye:
`Investigation of Efficacy and Safety in Wet Age-Related Macular
`Degeneration (AMD) (VIEW1), NCT00509795, ClinicalTrials.gov
`(Apr. 28, 2009), https://clinicaltrials.gov/ct2/show/NCT00509795
`(“NCT-795”)
`VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD
`(VIEW 2), NCT00637377, ClinicalTrials.gov (Mar. 17, 2008),
`https://clinicaltrials.gov/ct2/show/NCT00637377 (“NCT-377”)
`IPR2021-00881 Ex.1109, Diana V. Do Deposition Transcript (April
`21, 2022) (“IPR2021-00881 Ex.1109”)
`File History of U.S. Patent No. 10,888,601 B2 (“’601 FH”)
`Jeffrey S. Heier et al., Intravitreal Aflibercept (VEGF Trap-Eye) in
`Wet Age-Related Macular Degeneration, 119 OPHTHALMOLOGY
`2537 (2012) (“Heier-2012”)
`IPR2021-00881 Ex.2051, Expert Declaration of Dr. Diana V. Do,
`M.D. (“IPR2021-00881 Ex.2051”)
`Jeffrey S. Heier, Intravitreal VEGF Trap for AMD: An Update,
`RETINA TODAY, Oct. 2009, 44 (“Heier-2009”)
`Regeneron Pharm., Inc., Quarterly Report (Form 10-Q) (Sept. 30,
`2009) (“2009 10-Q”)
`IPR2021-00881 Ex.1110, David M. Brown Deposition Transcript
`(April 26, 2022) (“IPR2021-00881 Ex.1110”)
`File History for U.S. Patent No. 7,070,959, 12/22/2011 Patent Term
`Extension Application (“’959 FH, 12/22/2011 PTE”)
`File History of U.S. Patent No. 7,374,758 B2, 12/22/2011 Patent
`Term Extension Application (“’758 FH, 12/22/2011 PTE”)
`Michael Engelbert et al., Long-Term Follow-Up for Type 1
`(Subretinal Pigment Epithelium) Neovascularization Using a
`Modified “Treat And Extend” Dosing Regimen Of Intravitreal
`Antivascular Endothelial Growth Factor Therapy, 30 RETINA 1368
`(2010) (“Engelbert-2010”)
`
`xii
`
`

`

`Exhibit
`
`1026
`
`1027
`
`1028
`
`1029
`
`1030
`
`1031
`
`1032
`
`1033
`
`1034
`
`1035
`
`1036
`
`Description
`John S. Rudge et al., VEGF Trap Complex Formation Measures
`Production Rates of VEGF, Providing a Biomarker for Predicting
`Efficacious Angiogenic Blockade, 104 PNAS 18363 (2007)
`(“Rudge-2007”)
`Richard F. Spaide et al., Prospective Study of Intravitreal
`Ranibizumab as a Treatment for Decreased Visual Acuity Secondary
`to Central Retinal Vein Occlusion, 147 AM. J. OPHTHALMOLOGY
`298 (2009) (“Spaide”)
`IPR2021-00881 Ex.2080, Jeffery S. Heier, VEGF Trap-Eye for
`Exudative AMD, RETINAL PHYSICIAN, Apr. 2009 (“IPR2021-00881
`Ex.2080”)
`Candelaria Gomez-Manzano et al., VEGF Trap Induces Antiglioma
`Effect at Different Stages of Disease, 10 NEURO-ONCOLOGY 940
`(2008) (“Gomez-Manzano”)
`P Mitchell et al., Ranibizumab (Lucentis) in Neovascular
`Age-Related Macular Degeneration: Evidence from Clinical Trials,
`94 BRIT. J. OPHTHALMOLOGY 2 (2009) (date of online publication)
`(“Mitchell”)
`Polly A. Quiram & Yahui Song, Exudative Age-Related Macular
`Degeneration: Current Therapies and Potential Treatments, 1
`CLINICAL MEDICINE: THERAPEUTICS 1003 (2009) (“Quiram”)
`Press Release, Bayer AG, Bayer and Regeneron Start Additional
`Phase 3 Study for VEGF Trap-Eye in Wet Age-Related Macular
`Degeneration (May 8, 2008) (“Bayer (8-May-2008)”)
`U.S. Patent Application Publication No. 2006/0217311 A1 (“Dix”)
`Anne E. Fung et al., An Optical Coherence Tomography-Guided,
`Variable Dosing Regimen with Intravitreal Ranibizumab (Lucentis)
`for Neovascular Age-related Macular Degeneration, 143 AM. J.
`OPHTHALMOLOGY 566 (2007) (“Fung”)
`Geeta A. Lalwani et al., A Variable-dosing Regimen with
`Intravitreal Ranibizumab for Neovascular Age-Related Macular
`Degeneration: Year 2 of the PrONTO Study, 148 AM. J.
`OPHTHALMOLOGY 43 (2009) (“Lalwani”)
`Hamish M. Fraser et al., The Role of Vascular Endothelial Growth
`Factor and Estradiol in the Regulation of Endometrial Angiogenesis
`and Cell Proliferation in the Marmoset, 149 ENDOCRINOLOGY 4413
`(2008) (“Fraser”)
`
`xiii
`
`

`

`Exhibit
`1037
`1038
`1039
`
`1040
`
`1041
`
`1042
`
`1043
`
`1044
`
`1045
`
`1046
`
`1047
`
`1048
`
`Description
`CENTER FOR DRUG EVALUATION & RESEARCH, BLA No. 125156,
`Lucentis Medical Review (“Lucentis MR”)
`Curriculum Vitae of Dr. Thomas Albini (“Albini CV”)
`U.S. Patent No. 7,378,095 B2 (“’095 patent”)
`Heinrich Heimann, Intravitreal Injections:
`Techniques and Sequelae, in MEDICAL RETINA 67 (Frank G. Holtz &
`Richard F. Spaide eds. 2007) (“Heimann-2007”)
`Press Release, Regeneron, Regeneron Reports Full Year and Fourth
`Quarter 2008 Financial and Operating Results (Feb. 26, 2009),
`https://investor.regeneron.com/news-releases/news-release-
`details/regeneron-reports-full-year-and-fourth-quarter-2008-financial
`(“Regeneron (26-February-2009)”)
`U.S. DEP’T HEALTH & HUMAN SERVS., NAT’L INST. HEALTH, NAT’L
`EYE INST., Age-Related Macular Degeneration: What You Should
`Know (Sept. 2015),
`https://www.nei.nih.gov/sites/default/files/health-pdfs/WYSK_AMD
`_English_Sept2015_PRINT.pdf (“NIH AMD”)
`David M. Brown & Carl D. Regillo, Anti-VEGF Agents in the
`Treatment of Neovascular Age-Related Macular Degeneration:
`Applying Clinical Trial Results to the Treatment of Everyday
`Patients, 144 AM. J. OPHTHALMOLOGY 627 (2007) (“Brown”)
`U.S. DEP’T HEALTH & HUMAN SERVS., NAT’L INST. HEALTH, NAT’L
`EYE INST., Diabetic Retinopathy: What You Should Know (Sept.
`2015),
`https://www.nei.nih.gov/sites/default/files/2019-06/Diabetic-Retinop
`athy-What-You-Should-Know-508.pdf (“NIH DR”)
`Napoleone Ferrara & Kari Alitalo, Clinical Applications of
`Angiogenic Growth Factors and Their Inhibitors, 5 NATURE MED.
`1359 (1999) (“Ferrara-1999”)
`Napoleone Ferrara & Robert S. Kerbel, Angiogenesis as a
`Therapeutic Target, 438 NATURE 967 (2005) (“Ferrara-2005”)
`Ziad F. Bashshur et al., Intravitreal Bevacizumab for the
`Management of Choroidal Neovascularization in Age-Related
`Macular Degeneration, 142 AM. J. OPHTHALMOLOGY 1 (2006)
`(“Bashshur”)
`LUCENTIS® Prescribing Information (2006) (“Lucentis”)
`
`xiv
`
`

`

`Exhibit
`
`1049
`
`1050
`
`1051
`
`1052
`
`1053
`
`1054
`
`1055
`
`1056
`
`Description
`L. Spielberg & A. Leys, Intravitreal Bevacizumab for Myopic
`Choroidal Neovascularization: Short-Term and 1-Year Results, 312
`BULLETIN SOCIETE BELGE D’OPHTALMOLOGIE 17 (2009)
`(“Spielberg”)
`CENTER FOR DRUG EVALUATION & RESEARCH, BLA No. 125-387,
`Eylea Medical Review (“Eylea MR”)
`Pearse A. Keane et al., Effect of Ranibizumab Retreatment
`Frequency on Neurosensory Retinal Volume in Neovascular AMD,
`29 RETINA 592 (2009) (“Keane”)
`J.S. Rudge et al., VEGF Trap as a Novel Antiangiogenic Treatment
`Currently in Clinical Trials for Cancer and Eye Diseases, and
`VelociGene®-Based Discovery of the Next Generation of
`Angiogenesis Targets, 70 COLD SPRING HARBOR SYMPOSIA
`QUANTITATIVE BIOLOGY 411 (2005) (“Rudge”)
`
`Press Release, Regeneron, Positive Interim Phase 2 Data Reported
`for VEGF Trap-Eye in Age-Related Macular Degeneration (Mar. 27,
`2007), https://newsroom.regeneron.com/news-releases/news-release-
`details/positive-interim-phase-2-data-reported-vegf-trap-eye-age-
`related?releaseid=394105 (“Regeneron (27-March-2007)”)
`Press Release, Regeneron, Regeneron and Bayer HealthCare Initiate
`Phase 3 Global Development Program for VEGF Trap-Eye in Wet
`Age-Related Macular Degeneration (AMD) (Aug. 2, 2007),
`https://investor.regeneron.com/news-releases/news-release-
`details/regeneron-and-bayer-healthcare-initiate-phase-3-global
`(“Regeneron (2-August-2007)”)
`Retina Society, VEGF Trap-Eye in Wet AMD CLEAR-IT 2:
`Summary of One-Year Key Results, A Phase 2, Randomized,
`Controlled Dose-and Interval-Ranging Study of Intravitreal VEGF
`Trap-Eye in Patients With Neovascular, Age-Related Macular
`Degeneration (Sept. 28, 2008) (“Retina Society Meeting
`Presentation”)
`Press Release, Regeneron, VEGF Trap-Eye Final Phase 2 Results in
`Age-related Macular Degeneration Presented at 2008 Retina Society
`Meeting (Sept. 28, 2008), https://investor.regeneron.com/news-
`releases/news-release-details/vegf-trap-eye-final-phase-2-results-
`age-related-macular?ReleaseID=393906 (“Regeneron (28-
`September-2008)”)
`
`xv
`
`-
`

`

`Exhibit
`
`1057
`
`1058
`
`1059
`
`1060
`
`1061
`1062
`1063
`
`1064
`
`1065
`
`1066
`1067
`
`1068
`
`Description
`Rama D. Jager, Risks of Intravitreous Injection:
`A Comprehensive Review, 24 J. RETINAL & VITREOUS DISEASE 676
`(2004) (“Jager-2004”)
`Philip J. Rosenfeld et al., Ranibizumab for Neovascular Age-Related
`Macular Degeneration, 355 N. ENG. J MED. 1419 (2006)
`(“Rosenfeld-2006”)
`Erik Christensen, Methodology of Superiority vs. Equivalence Trials
`and Non-Inferiority Trials, 46 J. HEPATOLOGY 947 (2007)
`(“Christensen”)
`Jorma B. Mueller & Christopher M. McStay, Ocular Infection and
`Inflammation, 26 EMERGENCY MED. CLINICS N. AM. 57 (2008)
`(“Mueller”)
`Curriculum Vitae of Dr. Mary Gerritsen (“Gerritsen CV”)
`European Patent No. 2 663 325 (published as WO 2012/097019 A1)
`(“EP-325”)
`File History of European Patent No. 2 663 325 (“EP-325-FH”)
`BMJ Publishing Group Ltd., Online First, BJO ONLINE, (Feb. 11,
`2009), https://bjo.bmj.com/onlinefirst.dtl
`[http://web.archive.org/web/20090212162702/https://bjo.bmj.com/o
`nlinefirst.dtl] (“Wayback-BJO-Online First”)
`BMJ Publishing Group Ltd., Review: Ranibizumab (Lucentis) In
`Neovascular Age-Related Macular Degeneration: Evidence From
`Clinical Trials, BRITISH J. OPHTHALMOLOGY (Dec. 2020),
`https://bjo.bmj.com/content/94/1/2.altmetrics (“BJO-Article
`Metrics”)
`European Patent No. 3 222 285 (“EP-285”)
`File History of European Patent No. 3 222 285 (“EP-285-FH”)
`Press Release, Regeneron, Enrollment Completed in Regeneron and
`Bayer HealthCare Phase 3 Studies of VEGF Trap-Eye in
`Neovascular Age-Related Macular Degeneration (Wet AMD) (Sept.
`14, 2009), https://investor.regeneron.com/news-releases/news-
`release-details/enrollment-completed-regeneron-and-bayer-
`healthcare-phase-3?ReleaseID=408872 (“Regeneron (14-September-
`2009)”)
`
`xvi
`
`-
`

`

`Exhibit
`
`1069
`
`1070
`
`1071
`1072
`
`1073
`
`1074
`
`1075
`
`1076
`
`1077
`
`1078
`
`Description
`ClinicalTrials.gov, What Is ClinicalTrials.gov?, U.S. NAT’L
`LIBRARY MED. (Jan. 2018), https://www.clinicaltrials.gov/ct2/about-
`site/background (“Background-ClinicalTrials.gov“)
`Affidavit of Duncan Hall (Internet Archive Records Request
`Processor) Regarding Vascular Endothelial Growth Factor (VEGF)
`Trap-Eye: Investigation of Efficacy and Safety in Central Retinal
`Vein Occlusion (CRVO) (GALILEO), NCT01012973,
`ClinicalTrials.gov (Apr. 8, 2011); Vascular Endothelial Growth
`Factor (VEGF) Trap-Eye: Investigation of Efficacy and Safety in
`Wet Age-Related Macular Degeneration (AMD) (VIEW1),
`NCT00509795, ClinicalTrials.gov (Apr. 8, 2011); and VEGF Trap-
`Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW 2),
`NCT00637377, ClinicalTrials.gov (Aug. 13, 2009), dated January
`20, 2021 (“Wayback-Affidavit”)
`U.S. Patent No. 9,254,338 (“’338 patent”)
`Janice M. Reichert, Antibody-Based T