UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`APOTEX INC.,
`
`Petitioner
`
`v.
`
`REGENERON PHARMACEUTICALS, INC.,
`Patent Owner
`
`
`Inter Partes Review No.: IPR2022-00301
`
`
`U.S. Patent No. 9,669,069 B2
`Filed: December 17, 2015
`Issued: June 6, 2017
`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. 9,669,069 B2
`
`1
`
`

`

`
`
`TABLE OF CONTENTS
`
`EXHIBIT LIST ...................................................................................................... viii
`I.
`INTRODUCTION. .......................................................................................... 1
`II. OVERVIEW. ................................................................................................... 1
`III. MANDATORY NOTICES (37 C.F.R. § 42.8). .............................................. 4
`A.
`REAL PARTIES-IN-INTEREST (37 C.F.R. § 42.8(b)(1)). ................. 4
`B.
`RELATED MATTERS (37 C.F.R. § 42.8(b)(2)). ................................ 5
`C.
`LEAD AND BACK-UP COUNSEL AND SERVICE
`INFORMATION (37 C.F.R. § 42.8(b)(3), (4)). ..................................... 5
`IV. PAYMENT OF FEES UNDER 37 C.F.R. § 42.15(a) AND § 42.103 ............ 6
`V. GROUNDS FOR STANDING (37 C.F.R. § 42.104(a)). ................................ 7
`VI. THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW. ............. 7
`VII. OVERVIEW OF CHALLENGE AND PRECISE RELIEF REQUESTED. .. 7
`A.
`CHALLENGED CLAIMS. ................................................................... 7
`B.
`STATUTORY GROUNDS OF CHALLENGE. .................................. 7
`VIII. OVERVIEW OF THE ’069 PATENT AND PROSECUTION HISTORY ....... 8
`A.
`THE ’069 PATENT. ............................................................................. 8
`B.
`PROSECUTION HISTORY. .............................................................. 11
`IX. CLAIM CONSTRUCTION (37 C.F.R. § 42.104(b)(3)). .............................. 13
`A.
`“INITIAL DOSE,” “SECONDARY DOSE,” AND “TERTIARY
`DOSE.” ................................................................................................ 13
`1.
`Regeneron’s contradictory construction for “tertiary dose,” if
`presented here, must be rejected. .............................................. 15
`
`i
`
`

`

`3.
`
`2.
`
`“4 WEEKS” AND “PRO RE NATA (PRN).” .................................... 18
`B.
`“VEGFR1 COMPONENT,” “VEGFR2 COMPONENT,” AND THE
`C.
`“MULTIMERIZATION COMPONENT.” ............................................................. 19
`D.
`“TREATING.” .................................................................................... 19
`1.
`The “method for treating” element of the preamble is not a
`limitation on the Challenged Claims, and therefore, does not
`require construction................................................................... 19
`Regeneron’s anticipated argument that the “method for
`treating” preamble is a positive limitation should be rejected. .. 22
`If construed to be a limitation, the preamble’s plain and
`ordinary meaning—which does not provide any specific
`efficacy requirement—must govern. ........................................ 23
`PERSON OF ORDINARY SKILL IN THE ART. ....................................... 24
`X.
`XI. THE SCOPE AND CONTENT OF THE PRIOR ART. ............................... 25
`A. VEGF TRAP-EYE/AFLIBERCEPT BACKGROUND. .................... 25
`B.
`PETITIONER’S PRIOR ART REFERENCES. ................................. 28
`1.
`Dixon (Ex.1006)........................................................................ 31
`2.
`Regeneron (28-April-2008) (Ex.1012). .................................... 33
`3.
`Heier-2009 (Ex.1020). .............................................................. 34
`4.
`Regeneron (30-April-2009) (Ex.1028). .................................... 35
`5.
`The ’758 patent (Ex.1010). ....................................................... 37
`6.
`Dix (Ex.1033). ........................................................................... 37
`7. Mitchell (Ex.1030). ................................................................... 38
`8.
`Lalwani (Ex.1035). ................................................................... 40
`XII. GROUNDS FOR UNPATENTABILITY—DETAILED ANALYSIS. ....... 40
`A. ANTICIPATION AND OBVIOUSNESS. ......................................... 40
`
`ii
`
`

`

`3.
`
`4.
`
`5.
`
`1.
`2.
`
`Legal standards. ........................................................................ 40
`Grounds 1&2: Claims 1 and 9-12 are anticipated by both Heier-
`2009 and Dixon, respectively. .................................................. 44
`Ground 3: Regeneron (30-April-2009) anticipates claims 1 and
`9-12. .......................................................................................... 49
`Ground 4: VIEW1/VIEW2 disclosures in Dixon anticipate
`and/or render obvious claims 1 and 8-12. ................................. 52
`a.
`Anticipation. ................................................................ 53
`b.
`Obviousness. ................................................................ 57
`Ground 5: The Challenged Claims are obvious over Heier-
`2009 in combination with either Mitchell or Dixon—and,
`optionally, either the ’758 patent or Dix. .................................. 59
`a.
`A skilled artisan would have been motivated to combine
`Heier-2009 with either Mitchell or Dixon. ............................... 61
`b.
`Independent Claim 1. ...................................................... 61
`c.
`Claim 8. ........................................................................... 65
`d.
`Claims 9 and 10. ............................................................. 65
`e.
`Claim 11. ......................................................................... 65
`f.
`Claim 12. ......................................................................... 66
`g.
`A skilled artisan would have reasonably expected
`success. ........................................................................... 66
`No Secondary Considerations. ............................................... 68
`6.
`XIII.  CONCLUSION. ............................................................................................. 71 
`
`
`
`
`
`
`
`
`iii
`
`

`

`TABLE OF AUTHORITIES
`Cases
`Advanced Display Sys., Inc. v. Kent State Univ.,
`212 F.3d 1272 (Fed. Cir. 2000) .......................................................................... 39
`Arctic Cat Inc. v. GEP Power Prods., Inc.,
`919 F.3d 1320 (Fed. Cir. 2019) .......................................................................... 20
`Ariosa Diagnostics v. Verinata Health, Inc.,
`805 F.3d 1359 (Fed. Cir. 2015) .......................................................................... 25
`Bio-Rad Lab’ys, Inc. v. 10X Genomics Inc.,
`967 F.3d 1353 (Fed. Cir. 2020) .......................................................................... 20
`Bristol-Myers Squibb Co. v. Ben Venue Lab’ys, Inc.,
`246 F.3d 1368 (Fed. Cir. 2001) ........................................................ 19, 22, 41, 42
`Chengdu Kanghong Biotechnology Co. v. Regeneron Pharms., Inc.,
`No. PGR2021-00035, Paper 6, 9 (P.T.A.B. Apr. 15, 2021) ............................... 15
`Cubist Pharms., Inc. v. Hospira, Inc.,
`75 F. Supp. 3d 641 (D. Del. 2014) ...................................................................... 42
`GlaxoSmithKline LLC v. Glenmark Pharms., Inc.,
`No. 14-877-LPS- CJB, 2016 WL 3186657 (D. Del. June 3, 2016).................... 23
`Grünenthal GmbH v. Antecip Bioventures II LLC, No. PGR2019-
`00026, 2020 WL 4341822, at *8 (P.T.A.B. July 28, 2020) ............................... 38
`In re Antor Media Corp.,
`689 F.3d 1282 (Fed. Cir. 2012) .......................................................................... 42
`In re Baxter Travenol Labs,
`952 F.2d 388 (Fed. Cir. 1991) ............................................................................ 55
`In Re: Copaxone Consol. Cases,
`906 F.3d 1013, 1022-23 (Fed. Cir. 2018) ..................................................... 20, 22
`In re Cruciferous Sprout Litig.,
`301 F.3d 1343 (Fed. Cir. 2002) .......................................................................... 40
`
`iv
`
`

`

`In re Huai-Hung Kao,
`639 F.3d 1057 (Fed. Cir. 2011) .................................................................... 44, 68
`In re Omeprazole Patent Litig.,
`483 F.3d 1364 (Fed. Cir. 2007) .......................................................................... 41
`King Pharms., Inc. v. Eon Lab’ys, Inc.,
`616 F.3d 1267 (Fed. Cir. 2010) .............................................................. 24, 41, 64
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) .......................................................................... 25, 43, 44, 61
`Merck & Co. v. Teva Pharms. USA, Inc.,
`395 F.3d 1364, 1372 (Fed. Cir. 2005) ................................................................ 17
`Motorola Mobility LLC v. Arnouse,
`No. IPR2013-00010, 2013 WL 12349001 (P.T.A.B. Jan. 30, 2013) ................... 7
`Multiform Desiccants, Inc. v. Medzam, Ltd.,
`133 F.3d 1473, 1478 (Fed. Cir. 1998) ................................................................ 17
`Mylan Lab’ys Ltd. v. Aventis Pharma S.A.,
`No. IPR2016-00712, 2016 WL 5753968, *5 (P.T.A.B. Sept. 22,
`2016) ................................................................................................................... 21
`Mylan Pharms. Inc. v. Regeneron Pharms., Inc.,
`Case No. IPR2021-00881 (P.T.A.B.), May 5, 2021. ............................................ 5
`Mylan Pharms. Inc. v. Regeneron Pharms., Inc.,
`No. IPR2021-00880 (P.T.A.B.), May 5, 2021. ............................................... 5, 73
`Ormco Corp. v. Align Tech., Inc.,
`463 F.3d 1299 (Fed. Cir. 2006) .................................................................... 44, 68
`Perricone v. Medicis Pharm. Corp.,
`432 F.3d 1368 (Fed. Cir. 2005) .................................................................... 24, 41
`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005) .............................................................. 13, 15, 23
`Power Mosfet Techs., L.L.C. v. Siemens AG,
`378 F.3d 1396 (Fed. Cir. 2004) .......................................................................... 18
`
`v
`
`

`

`Purdue Pharma L.P. v. Endo Pharms. Inc.,
`438 F.3d 1123 (Fed. Cir. 2006) (en banc) .......................................................... 21
`Rasmusson v. SmithKline Beecham Corp.,
`413 F.3d 1318 (Fed. Cir. 2005) .......................................................................... 41
`Rosco, Inc. v. Mirror Lite Co.,
`304 F.3d 1373 (Fed. Cir. 2002) .......................................................................... 27
`Ruckus Wireless, Inc. v. Innovative Wireless Sols., LLC,
`824 F.3d 999 (Fed. Cir. 2016) ............................................................................ 17
`Samsung Elecs. Co. v. Elm 3DS Innovations, LLC,
`925 F.3d 1373, 1378 (Fed. Cir. 2019) ................................................................ 16
`Sinorgchem Co., Shandong Int’l Trade Comm’n, 511 F.3d 1132, 1136
`(Fed. Cir. 2007) ................................................................................................... 15
`TomTom, Inc. v. Adolph,
`790 F.3d 1315 (Fed. Cir. 2015) .......................................................................... 20
`VidStream LLC v. Twitter, Inc.,
`981 F.3d 1060, 1065 (Fed. Cir. 2020) ................................................................ 38
`Vizio, Inc. v. Int’l Trade Comm’n,
`605 F.3d 1330 (Fed. Cir. 2010) .......................................................................... 20
`Wyers v. Master Lock Co.,
`616 F.3d 1231 (Fed. Cir. 2010) .......................................................................... 68
`Statutes
`35 U.S.C. § 102 .................................................................................................passim
`35 U.S.C. § 103(a) ................................................................................................... 43
`35 U.S.C. §§ 311-319 ................................................................................................ 1
`35 U.S.C. § 314(a) ..................................................................................................... 7
`Other Authorities
`83 Fed. Reg. 197, 51340-51359 (Oct. 11, 2018) ..................................................... 13
`
`vi
`
`

`

`Trial Practice Guide, 77 Fed. Reg. 48759-60 (Aug. 14, 2021).................................. 4
`Regulations
`37 C.F.R. §§ 42 et seq. ............................................................................................... 1
`37 C.F.R. §§ 42.8(a)(1) .............................................................................................. 4
`(37 C.F.R. § 42.8(b)(2)) ............................................................................................. 5
`37 C.F.R. § 42.10(b). ................................................................................................. 5
`37 C.F.R. § 42.100(b) .............................................................................................. 13
`37 C.F.R. § 42.103 ..................................................................................................... 6
`(37 C.F.R. § 42.8(b) ................................................................................................... 4
`
`vii
`
`

`

`EXHIBIT LIST
`
`Exhibit
`
`Description
`
`1001
`
`U.S. Patent No. 9,669,069 B2 (“’069 patent”)
`
`
`1002
`
`
`1003
`
`
`1004
`
`
`1005
`
`
`1006
`
`
`1007
`
`1008
`
`1009
`
`1010
`
`
`1011
`
`Expert Declaration of Dr. Thomas A. Albini in Support of Petition
`for Inter Partes Review of Patent No. 9,669,069 B2, dated May 4,
`2021 (“Albini”)
`
`Expert Declaration of Mary Gerritsen, Ph.D. in Support of Petition
`for Inter Partes Review of U.S. Patent No. 9,669,069 B2, dated Apr.
`26, 2021(“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”)
`
`viii
`
`

`

`
`
`1012
`
`
`1013
`
`
`
`1014
`
`
`1015
`
`1016
`
`Press Release, Regeneron, Regeneron and Bayer Health Care
`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)”)
`
`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=3940
`65 (“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”)
`
`U.S. Patent Nos. 7,303,746 B2; 7,303,747 B2; 7,306,799 B2; and
`7,521,049 B2 (“Monthly-Dosing-Patents”)
`
`1017
`
`File History of U.S. Patent No. 9,669,069 B2 (“’069 FH”)
`
`
`1018
`
`Jeffrey S. Heier et al., Intravitreal Aflibercept (VEGF Trap-Eye) in
`Wet Age-Related Macular Degeneration, 119 OPHTHALMOLOGY
`2537 (2012) (“Heier-2012”)
`
`1019
`
`U.S. Patent No. 9,254,338 B2 (“’338 patent”)
`
`1020
`
`1021
`
`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”)
`
`1022
`
`U.S. Patent No. 7,374,757 B2 (“’757 patent”)
`
`ix
`
`

`

`1023
`
`U.S. Patent No. 7,070,959 B1 (“’959 patent”)
`
`1024
`
`File History of U.S. Patent No. 7,374,758 B2, 12/22/2011 Patent
`Term Extension Application (“’758 FH, 12/22/2011 PTE”)
`
`1025
`
`1026
`
`1027
`
`1028
`
`1029
`
`1030
`
`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, J.
`RETINAL & VITREOUS DISEASES 1368 (2010) (“Engelbert-2010”)
`
`Michael Engelbert et al., “Treat and Extend” Dosing of Intravitreal
`Antivascular Endothelial Growth Factor Therapy For Type 3
`Neovascularization/Retinal Angiomatous Proliferation, 29 J.
`RETINAL & VITREOUS DISEASES 1424 (2009) (“Engelbert-2009”)
`
`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”)
`
`Press Release, Regeneron, Bayer and Regeneron Extend
`Development Program for VEGF Trap-Eye to Include Central
`Retinal Vein Occlusion (Apr. 30, 2009),
`https://investor.regeneron.com/news-releases/news-release-
`details/bayer-and-regeneron-extend-development-program-vegf-trap-
`eye (“Regeneron (30-April-2009)”)
`
`Vascular Endothelial Growth Factor (VEGF) Trap-Eye:
`Investigation of Efficacy and Safety in Central Retinal Vein
`Occlusion (CRVO), NCT01012973, ClinicalTrials.gov (Nov. 12,
`2009), https://clinicaltrials.gov/ct2/show/NCT01012973 (“NCT-
`973”)
`
`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”)
`
`1031
`
`Pascale G. Massin, Anti-VEGF Therapy for Diabetic Macular
`Edema: An Update, RETINA TODAY, SEPT./Oct. 2008, 54 (“Massin”)
`
`x
`
`

`

`1032
`
`Press Release, Bayer AG, Bayer and Regeneron Start Additional
`Phase 3 Study for VEGF Trap-Eye in Wet Age-Related
`MacularDegeneration (May 8, 2008) (“Bayer (8-May-2008)”)
`
`1033
`
`U.S. Patent Application Publication No. 2006/0217311 A1 (“Dix”)
`
`1034
`
`1035
`
`1036
`
`1037
`
`1038
`
`1039
`
`1040
`
`1041
`
`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”)
`
`Peter A Campochiaro et al., Ranibizumab for Macular Edema Due
`to Retinal Vein Occlusions: Implication of VEGF as a Critical
`Stimulator, 16 MOLECULAR THERAPY 791 (2008) (“Campochiaro”)
`
`Robert Steinbrook, The Price of Sight — Ranibizumab,
`Bevacizumab, and the Treatment of Macular Degeneration, 355 N.
`ENG. J. MED. 1409 (2006) (“Steinbrook”)
`
`Curriculum Vitae of Dr. Thomas Albini (“Albini CV”)
`
`U.S. Patent No. 7,378,095 B2 (“’095 patent”)
`
`International Nonproprietary Names for Pharmaceutical
`Substances (INN), 20 WHO DRUG INFORMATION 115 (2006)
`(“WHO Drug Info”)
`
`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)”)
`
`xi
`
`

`

`1042
`
`1043
`
`1044
`
`1045
`
`1046
`
`1047
`
`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-
`Retinopathy-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”)
`
`1048
`
`LUCENTIS® Prescribing Information (2006) (“Lucentis”)
`
`1049
`
`1050
`
`1051
`
`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”)
`
`Ursula Schmidt-Erfurth, Current Concepts in the Management of
`Diabetic Macular Edema, 7 PROCEEDINGS 52 (2010) (“Schmidt-
`Erfurth”)
`
`Pearse A. Keane et al., Effect of Ranibizumab Retreatment
`Frequency on Neurosensory Retinal Volume in Neovascular AMD,
`
`xii
`
`

`

`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)”)
`
`Press Release, Regeneron, VEGF Trap-Eye Shows Positive Results
`in a Phase 2 Study in Patients with Diabetic Macular Edema (Feb.
`18, 2010), https://investor.regeneron.com/news-releases/news-
`release-details/vegf-trap-eye-shows-positive-results-phase-2-study-
`patients?releaseid=445521 (“Regeneron (18-February-2010)”)
`
`1052
`
`1053
`
`1054
`
`1055
`
`1056
`
`1057
`
`xiii
`
`

`

`1058
`
`1059
`
`1060
`
`1061
`
`1062
`
`1063
`
`1064
`
`1065
`
`1066
`
`1067
`
`1068
`
`ASS’N FOR RES. VISION & OPHTHALMOLOGY, ARVO® News
`(Winter/Spring 2008) (“ARVONews Winter/Spring 2008”)
`
`ASS’N FOR RES. VISION & OPHTHALMOLOGY, ARVO® News
`(Summer 2007) (“ARVONews Summer 2007”)
`
`Jean-François Korobelnik et al., Intravitreal Aflibercept Injection for
`Macular Edema Resulting from Central Retinal Vein Occlusion, 121
`OPHTHALMOLOGY 202 (2014) (“Korobelnik”)
`
`Curriculum Vitae of Dr. Mary Gerritsen (“Gerritsen CV”)
`
`EP 2 663 325 (published as WO 2012/097019 (A1)) (“EP-325”)
`
`File History of EP 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”)
`
`Press Release, Bayer, VEGF Trap-Eye Shows Positive Results in
`Phase II Study in Patients with Diabetic Macular Edema (Feb. 18,
`2010) (“Bayer (18-February-2010)”)
`
`Press Release, Bayer, Bayer HealthCare and Regeneron Announce
`Encouraging 32-Week Follow Up Results From A Phase 2 Study of
`VEGF Trap-Eye in Age-Related Macular Degeneration (Apr. 28,
`2008) (“Bayer (28-April-2008)”)
`
`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://newsroom.regeneron.com/news-releases/news-release-
`details/enrollment-completed-regeneron-and-bayer- healthcare-phase-3
`
`xiv
`
`

`

`(“Regeneron (14-September-2009)”)
`
`
`1069
`
`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)
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`Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW 2),
`NCT00637377, ClinicalTrials.gov (Aug. 13, 2009), dated January
`20, 2021 (“Wayback-Affidavit-069”)
`
`Frank G Holz et al., VEGF Trap-Eye for Macular Oedema
`Secondary to Central Retinal Vein Occlusion: 6-Month Results of
`the Phase III GALILEO Study, 97 BRITISH J.
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`
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`Owen A. Anderson et al., Delivery of Anti-Angiogenic Molecular
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`Growth Factor Therapy For Neovascular Age-Related Macular
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`(2009) (“Ciulla”)
`
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`Age-Related Macular Degeneration, 223 OPHTHALMOLOGICA
`401 (2009) (“Ni”)
`
`1070
`
`1071
`
`1072
`
`1073
`
`1074
`
`1075
`
`xv
`
`

`

`1076
`
`1077
`
`Marco A. Zarbin & Philip J. Rosenfeld, Pathway-Based Therapies
`for Age-Related Macular Degeneration: An Integrated Survey of
`Emerging Treatment Alternatives, 30 RETINA 1350 (2010)
`(“Zarbin”)
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`Public Companies,
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`filings/sec-filings/ (last visited May 5, 2021) (“Corporate Finance
`Institute”)
`
`1078
`
`Carl W. Schneider, Nits, Grits, and Soft Information in SEC Filings,
`121 U. PA. L. REV. 254 (1972) (“Schneider”)
`
`1079
`
`1080
`
`1081
`
`1082
`
`1083
`
`Justin Kuepper, The Best Investment Information Sources: Using
`SEC Filings, Analyst Reports, and Company Websites, BALANCE
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`investor-information-1979207 (“Kuepper”)
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`stop-shop-170000800.html (“Zucchi”)
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`forms.asp (“Hayes”)
`
`Amino acid sequence alignment of SEQ ID NO:2 of the ’069 patent
`with SEQ ID NO:16 of the ’758 patent and SEQ ID NO:4 of Dix
`(“’069 Amino Acid Sequences”)
`
`Nucleotide sequence alignment of SEQ ID NO:1 of the ’069 patent
`with SEQ ID NO:15 of the ’758 patent and SEQ ID NO:3 of Dix
`(“’069 Nucleotide Sequences”)
`
`xvi
`
`

`

`
`
`INTRODUCTION.
`Apotex Inc. (“Petitioner”) petitions for inter partes review (“IPR”) under 35
`
`U.S.C. §§ 311-319 and 37 C.F.R. §§ 42 et seq., seeking cancellation of claims 1 and
`
`8-12 (the “Challenged Claims”) of U.S. Patent No. 9,669,069 (“’069 patent”)
`
`(Ex.1001), assigned to Regeneron Pharmaceuticals, Inc. (“Regeneron” or “Patent
`
`Owner”).
`
` OVERVIEW.
`The Challenged Claims are drawn to nothing more than a known, mental step
`
`dosing regimen (i.e., “as-needed” or “pro re nata” (“PRN”) administration) using a
`
`drug known to persons of ordinary skill in the art (referred to herein as a “skilled
`
`artisan(s)”) to treat angiogenic eye disorders. These claims should have never issued.
`
`Each is anticipated and obvious over the prior art, which expressly disclosed skilled
`
`artisans actively practicing these exact methods on patients—with success. Indeed,
`
`Regeneron’s own clinical trials for EYLEA® (aka “VEGF Trap-Eye” or
`
`“aflibercept”)—widely published—utilized the claimed PRN dosing regimen to
`
`treat age-related macular degeneration (“AMD”) years before Regeneron filed the
`
`’069 patent application in 2011. Regeneron withheld those publications from the
`
`Examiner, allowing the ’069 patent to issue.
`
`By 2010, ophthalmologists were moving away from monthly dosing regimens
`
`for vitreoretinal disease therapies due to problems with patient compliance and
`
`1
`
`

`

`discomfort associated with
`
`intravitreal
`
`injections. For example,
`
`in 2007,
`
`LUCENTIS® (ranibizumab), an anti-VEGF therapy approved for monthly dosing,1
`
`was undergoing a series of clinical trials to assess less frequent dosing regimens.
`
`These clinical assessments included, inter alia, PRN dosing (including, PRN after
`
`three monthly loading doses). Motivated to keep pace with the LUCENTIS® trials,
`
`Regeneron initiated a clinical program for EYLEA® that implemented those same
`
`regimens—e.g., Regeneron’s Phase 2 clinical trials for age-related macular
`
`degeneration (“CLEAR-IT-2”) assessing PRN dosing after four monthly doses. The
`
`problem: this trial regimen was widely launched, published and thus known to
`
`skilled artisans long before 2011. The prior art includes numerous Regeneron press
`
`releases, which were directed to skilled artisans to attract their interest in EYLEA®,
`
`along with publications directed to practicing ophthalmologists. Many disclosed the
`
`CLEAR-IT-2 trial details, including, most notably, the later-claimed PRN dosing
`
`regimen. Those public disclosures render the Challenged Claims unpatentable.
`
`Petitioner files this Petition and supporting expert declarations from: (i)
`
`renowned ophthalmologist, Dr. Thomas Albini (Ex.1002), to apprise the Board of
`
`invalidating prior art—much of which was not before the Examiner when
`
`prosecuting the ’069 patent; and (ii) Dr. Mary Gerritsen, a pharmacologist with over
`
`
`1 LUCENTIS® is the primary competitor to EYLEA®.
`
`2
`
`

`

`thirty years’ experience, (Ex.1003) to confirm the public availability of certain prior
`
`art disclosures relied upon herein.
`
`Anticipation. Challenged Claims 1 and 9-12 are anticipated by three separate
`
`prior art references: Dixon, Heier-2009, and Regeneron (30-April-2009). Dixon and
`
`Heier-2009 disclose Regeneron’s Phase 2 CLEAR-IT-2 trial. Regeneron (30- April-
`
`2009) discloses Regeneron’s Phase 3 RVO trial regimen.
`
`Further, claims 1 and 8-12 are anticipated by Dixon in light of arguments that
`
`Regeneron itself made during prosecution of the ’069 patent. Dixon discloses
`
`Regeneron’s Phase 3 AMD (VIEW1/VIEW2) trial, which evaluated every-eight-
`
`week dosing (following a fixed monthly loading dose period)—a regimen
`
`Regeneron told the Examiner fell within the scope of the C