`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`MYLAN PHARMACEUTICALS INC., CELLTRION, INC., and
`APOTEX, INC
`Petitioners.
`
`v.
`REGENERON PHARMACEUTICALS, INC.,
`Patent Owner.
`
`
`Inter Partes Review No.: IPR2021-00880
`
`
`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
`
`
`PETITIONER’S REPLY
`
`

`

`TABLE OF CONTENTS
`
`I. 
`
`II. 
`
`INTRODUCTION. .......................................................................................... 1 
`
`PERSON OF ORDINARY SKILL IN THE ART (“POSA”). ........................ 2 
`
`III.  CLAIM CONSTRUCTION. ........................................................................... 4 
`
`IV.  PETITIONER’S REFERENCES ANTICIPATE CLAIMS 1 AND 9-
`12. .................................................................................................................... 7 
`
`  VEGF TRAP-EYE/AFLIBERCEPT PRN ADMINISTRATION WAS
`EXPRESSLY DISCLOSED IN PETITIONER’S ASSERTED REFERENCES. ........ 7 
`
` 
`
` 
`
`THE VEGF TRAP-EYE/AFLIBERCEPT SEQUENCE WAS
`INHERENTLY DISCLOSED IN EACH OF PETITIONER’S ASSERTED
`REFERENCES. .......................................................................................... 7 
`
`1. 
`
`The VEGF Trap-Eye/Aflibercept sequence is in the prior
`art. ................................................................................................ 7 
`
`THERE WAS NO CONFUSION IN THE PRIOR ART ABOUT THE
`IDENTITY OF VEGF TRAP-EYE/AFLIBERCEPT. ..................................... 10 
`
`1. 
`
`2. 
`
`3. 
`
`4. 
`
`5. 
`
`“VEGF Trap-Eye” and “aflibercept” were known to have
`the same molecular structure. ................................................... 10 
`
`“VEGF Trap-Eye” and “aflibercept” molecular weight
`reports were, in fact, consistent................................................. 11 
`
`VEGF Trap-Eye is not a genus of proteins. .............................. 13 
`
`Flt1D2.Fll1D3.FcΔC1(a) was not, and would not be,
`confused with VEGF Trap-Eye. ............................................... 16 
`
`PO’s confidentiality claims are irrelevant. ............................... 16 
`
`V.  GROUND 4: DIXON ANTICIPATES AND/OR RENDERS
`OBVIOUS CLAIMS 1 AND 8-12. ............................................................... 18 
`
` 
`
`PO SECURED ALLOWANCE BY EQUATING THE CLAIMS TO ITS
`2Q8 VIEW REGIMEN. .......................................................................... 18 
`
`i
`
`

`

` 
`
`CLAIMS 1 AND 8-12 ARE ANTICIPATED AND/OR OBVIOUS OVER
`THE PRIOR ART VIEW 2Q8 DOSING ARM. .......................................... 20 
`
`VI.  GROUND 5: THE CLAIMS ARE RENDERED OBVIOUS BY THE
`VEGF TRAP-EYE/AFLIBERCEPT CLINICAL TRIALS AND
`PRIOR ART PRN REGIMENS. ................................................................... 24 
`
`  VEGF TRAP-EYE WAS IDENTIFIED IN THE PRIOR ART. ....................... 24 
`
`  MOTIVATION TO REDUCE TOTAL NUMBER OF INJECTIONS. ................. 25 
`
` 
`
`PO’S REBUTTAL ARGUMENTS LACK MERIT AND IGNORE THE
`PREVAILING PRACTICE IN ANTI-VEGF THERAPY. ............................... 31 
`
`VII.  CONCLUSION. ............................................................................................. 37 
`
`
`
`
`
`
`
`ii
`
`

`

`TABLE OF AUTHORITIES
`
`Cases 
`
`Abbott Lab’ys v. Geneva Pharms., Inc.,
`182 F.3d 1315 (Fed. Cir. 1999) .............................................................................. 9
`
`Al-Site Corp. v. VSI Int’l Inc.,
`174 F.3d 1308 (Fed. Cir. 1999) .............................................................................. 2
`
`Amgen, Inc. v. Alexion Pharms., Inc.,
`IPR2019-00740, Paper 15 (P.T.A.B. Aug. 30, 2019) .......................................... 17
`
`Cisco Sys., Inc. v. C-Cation Techs., LLC,
`IPR2014-00454, Paper 12 (P.T.A.B. Aug. 29, 2014) ............................................ 5
`
`DeSilva v. DiLeonardi,
`181 F.3d 865 (7th Cir. 1999) .................................................................................. 5
`
`Ex Parte Urban Weber,
`Appeal 2020-005142, 2021 WL 4319420 (P.T.A.B Sept. 21, 2021) ..................... 9
`
`Honeywell Int'l Inc. v. Universal Avionics Sys. Corp.,
`488 F.3d 982 (Fed. Cir. 2007) .............................................................................. 20
`
`Hospira, Inc. v. Fresenius Kabi USA, LLC,
`946 F.3d 1322 (Fed. Cir. 2020) .............................................................................. 8
`
`HVLPO2, LLC v. Oxygen Frog, LLC,
`949 F.3d 685 (Fed. Cir. 2020) ............................................................................2, 3
`
`In re Baxter Travenol Labs.,
`952 F.2d 388 (Fed. Cir. 1991) ................................................................................ 9
`
`In re Fulton,
`391 F.3d 1195 (Fed. Cir. 2004) ............................................................................ 36
`
`In re Omeprazole Patent Litig.,
`483 F.3d 1364 (Fed. Cir. 2007) .............................................................................. 9
`
`iii
`
`

`

`King Pharms., Inc. v. Eon Labs, Inc.,
`616 F.3d 1267 (Fed. Cir. 2010) .............................................................................. 6
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ............................................................................................... 2
`
`Microsoft Corp. v. Multi-Tech Sys., Inc.,
`357 F.3d 1340 (Fed. Cir. 2004) ............................................................................ 19
`
`Minn. Mining Mfg. Co. v. Fellowes Mfg. Co.,
`76 F. Supp. 2d 972 (D. Minn. 1999) .................................................................... 18
`
`Monsanto Tech. LLC v. E.I. DuPont de Nemours & Co.,
`878 F.3d 1336 (Fed. Cir. 2018) .............................................................................. 8
`
`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005) .............................................................................. 4
`
`Ryko Mfg. Co. v. Nu-Star, Inc.,
`950 F.2d 714 (Fed. Cir. 1991) ................................................................................ 2
`
`Samsung Elecs. Co. v. Elm 3DS Innovations, LLC,
`925 F.3d 1373 (Fed. Cir. 2019) .............................................................................. 5
`
`Schering Corp. v. Geneva Pharms.,
`339 F.3d 1373 (Fed. Cir. 2003) .............................................................................. 8
`
`Senmed, Inc. v. Richard-Allan Med. Indus.,
`888 F.2d 815 (Fed. Cir. 1989) .............................................................................. 18
`
`Toro Co. v. Deere & Co.,
`355 F.3d 1313 (Fed. Cir. 2004) .............................................................................. 8
`
`Trane U.S. Inc. v. Semco, LLC,
`IPR2018-00514, Paper 36 (P.T.A.B. April 17, 2019) ............................................ 5
`
`Typhoon Touch Techs. v. Dell, Inc.,
`659 F.3d 1376 (Fed. Cir. 2011) ............................................................................ 18
`
`iv
`
`

`

`Rules 
`Rules
`
`37 C.F.R. § 42.6(a)(3) ................................................................................................ 5
`37 CLF.R. § 42.6(a)(3) cceccccsessccssecsccssssscssusscsssssccersucsesssseecsssssesssutecssneesessseceessuesessseeeeen 5
`
`37 C.F.R. §1.56 ........................................................................................................ 20
`37 CLLR. § 1.56 eee cceeesseesseeeseeeseeeseeesseeeaeeeseeesaecsaeesaeseseeeseeeeeesaeecaeeesaessaeceeeseaeneae20
`
`
`
`
`
`
`
`v
`
`

`

`Exhibit
`1001
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`1009
`1010
`
`1011
`
`1012
`
`1013
`
`EXHIBIT LIST
`
`Description
`U.S. Patent No. 9,669,069 B2 (“’069 patent”)
`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”)
`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),
`
`vi
`
`

`

`Exhibit
`
`1014
`
`1015
`
`1016
`1017
`
`1018
`
`1019
`1020
`
`1021
`1022
`1023
`1024
`
`1025
`
`1026
`
`1027
`
`Description
`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”)
`U.S. Patent Nos. 7,303,746 B2; 7,303,747 B2; 7,306,799 B2; and
`7,521,049 B2 (“Monthly-Dosing-Patents”)
`File History of U.S. Patent No. 9,669,069 B2 (“’069 FH”)
`Jeffrey S. Heier et al., Intravitreal Aflibercept (VEGF Trap-Eye) in
`Wet Age-Related Macular Degeneration, 119 OPHTHALMOLOGY
`2537 (2012) (“Heier-2012”)
`U.S. Patent No. 9,254,338 B2 (“’338 patent”)
`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”)
`U.S. Patent No. 7,374,757 B2 (“’757 patent”)
`U.S. Patent No. 7,070,959 B1 (“’959 patent”)
`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, 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”)
`
`vii
`
`

`

`Exhibit
`
`1028
`
`1029
`
`1030
`
`1031
`
`1032
`
`1033
`
`1034
`
`1035
`
`1036
`
`1037
`
`1038
`1039
`
`Description
`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”)
`Pascale G. Massin, Anti-VEGF Therapy for Diabetic Macular
`Edema: An Update, RETINA TODAY, SEPT./Oct. 2008, 54 (“Massin”)
`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”)
`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”)
`
`viii
`
`

`

`Exhibit
`
`1040
`
`1041
`
`1042
`
`1043
`
`1044
`
`1045
`
`1046
`
`1047
`
`1048
`
`1049
`
`1050
`
`Description
`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)”)
`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”)
`LUCENTIS® Prescribing Information (2006) (“Lucentis”)
`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”)
`
`ix
`
`

`

`Exhibit
`
`1051
`
`1052
`
`1053
`
`1054
`
`1055
`
`1056
`
`1057
`
`1058
`
`Description
`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)”)
`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)”)
`ASS’N FOR RES. VISION & OPHTHALMOLOGY, ARVO® News
`(Winter/Spring 2008) (“ARVONews Winter/Spring 2008”)
`
`x
`
`

`

`Exhibit
`1059
`
`1060
`
`1061
`1062
`1063
`
`1064
`
`1065
`
`1066
`
`1067
`
`1068
`
`1069
`
`1070
`
`Description
`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/on
`linefirst.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 (“Regeneron (14-September-2009)”)
`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
`
`xi
`
`

`

`Exhibit
`
`1071
`
`1072
`
`1073
`
`1074
`
`1075
`
`1076
`
`1077
`
`1078
`
`1079
`
`1080
`
`Description
`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-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. OPHTHALMOLOGY 278
`(2013) (“Holz”)
`Janice M. Reichert, Antibody-Based Therapeutics To Watch In 2011,
`3 MABS 76 (2011) (“Reichert”)
`Owen A. Anderson et al., Delivery of Anti-Angiogenic Molecular
`Therapies for Retinal Disease, 15 DRUG DISCOVERY TODAY 272
`(2010) (“Anderson”)
`Thomas A. Ciulla & Philip J. Rosenfeld, Antivascular Endothelial
`Growth Factor Therapy For Neovascular Age-Related Macular
`Degeneration, 20 CURRENT OPINION OPHTHALMOLOGY 158 (2009)
`(“Ciulla”)
`Zhang Ni & Peng Hui, Emerging Pharmacologic Therapies for Wet
`Age-Related Macular Degeneration, 223 OPHTHALMOLOGICA 401
`(2009) (“Ni”)
`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”)
`Corporate Finance Institute, SEC Filings: Public Disclosures About
`Public Companies,
`https://corporatefinanceinstitute.com/resources/data/public-
`filings/sec-filings/ (last visited May 5, 2021) (“Corporate Finance
`Institute”)
`Carl W. Schneider, Nits, Grits, and Soft Information in SEC Filings,
`121 U. PA. L. REV. 254 (1972) (“Schneider”)
`Justin Kuepper, The Best Investment Information Sources: Using
`SEC Filings, Analyst Reports, and Company Websites, BALANCE
`(Jan. 13, 2021), https://www.thebalance.com/top-best-sources-of-
`investor-information-1979207 (“Kuepper”)
`Kristina Zucchi, EDGAR: Investors’ One-Stop-Shop For Company
`Filings, YAHOO!LIFE (Jan. 31, 2014),
`
`xii
`
`

`

`Exhibit
`
`1081
`
`1082
`
`1083
`
`1084
`
`1085
`
`1086
`
`1087
`
`1088
`
`1089
`
`
`1090
`
`1091
`1092
`1093
`
`Description
`https://www.yahoo.com/lifestyle/tagged/health/edgar-investors-one-
`stop-shop-170000800.html (“Zucchi”)
`Adam Hayes, SEC Filings: Forms You Need To Know,
`INVESTOPEDIA (Jan. 18, 2021),
`https://www.investopedia.com/articles/fundamental-analysis/08/sec-
`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”)
`Declaration of William A. Rakoczy in support of Mylan
`Pharmaceuticals Inc.’s Unopposed Motion for Pro Hac Vice
`Admission (dated June 18, 2021) (“Rakoczy Decl.”)
`Declaration of Heinz J. Salmen in support of Mylan Pharmaceuticals
`Inc.’s Unopposed Motion for Pro Hac Vice Admission (dated June
`18, 2021) (“Salmen Decl.”)
`Transcript of the Teleconference before the United States Patent
`Trial and Appeal Board on September 8, 2021 (“Transcript (8-
`September-2021)”)
`Certified File History of U.S. Patent No. 9,669,069, Jan. 27, 2017
`Information Disclosure Statement, Reference “OBS5,” James A
`Dixon et al., VEGF Trap-Eye for the Treatment of Neovascular Age-
`Related Macular Degeneration, 18 EXPERT OPINION ON
`INVESTIGATIONAL DRUGS 1 (2009) (“One Page Dixon IDS
`Disclosure”)
`Excerpted File History of U.S. Patent No. 8,115,597 (NXP) (“’597
`FH Excerpts (NXP)”)
`Transcript of the Teleconference before the United States Patent
`Trial and Appeal Board on February 23, 2022 (“Transcript (23-
`February-2022)”)
`Declaration of Eric R. Hunt in support of Mylan Pharmaceuticals
`Inc.’s Unopposed Motion for Pro Hac Vice Admission (dated April
`20, 2022) (“Hunt Decl.”)
`Exhibit Number Unused
`Exhibit Number Unused
`Brown Dep. Ex. 12, W. Lloyd Clark, Treatment Paradigms in AMD
`
`xiii
`
`

`

`Exhibit
`
`1094
`
`1095
`
`1096
`1097
`1098
`1099
`1100
`1101
`1102
`
`1103
`
`1104
`
`1105
`
`1106
`
`1107
`
`Description
`Management: Assessing Consistent Long-Term Dosing, RETINA
`TODAY SUPP., Sept. 2017 (“Brown Dep. Ex. 12, Clark”)
`Hajir Dadgostar et al., Evaluation of Injection Frequency and
`Visual Acuity Outcomes for Ranibizumab Monotherapy in Exudative
`Age-related Macular Degeneration, 116 OPHTHALMOLOGY 1740
`(2009) (“Dadgostar”)
`Omesh P. Gupta et al., A Treat and Extend Regimen Using
`Ranibizumab for Neovascular Age-Related Macular Degeneration,
`117 OPHTHALMOLOGY 2134 (2010) (“Gupta”)
`Exhibit Number Unused
`Exhibit Number Unused
`Exhibit Number Unused
`Exhibit Number Unused
`Exhibit Number Unused
`Exhibit Number Unused
`File History for U.S. Patent No. 7,070,959, 12/22/2011 Patent Term
`Extension Application (“’959 FH, 12/22/2011 PTE”)
`Klibanov Dep. Ex. 3, Amgen v. F. Hoffman-La Roche, Ltd., Case No.
`05-cv-12237 (D. Mass.), ECF 610-3, Declaration of Alexander M.
`Klibanov, Ph.D. in Support of Defendants’ Opposition to Amgen’s
`Motion for Summary Judgment of Infringement of ‘422 Claim
`1,’933 Claim 3, and ‘698 Claim 6 (June 28, 2007) (“Klibanov Dep.
`Ex. 3, Klibanov Amgen Decl.”)
`Klibanov Dep. Ex. 18, J. Hanhart & I. Chowers, Correspondence
`regarding Fellow Eye Effect of Unilateral Intravitreal Anti-VEGF
`Injections in Eyes with Diabetic Macular Edema, 29 EYE 292 (2015)
`(“Klibanov Dep. Ex. 18, Hanhart”)
`Klibanov Dep. Ex. 19, Marianne O. Stefanini et al., Increase of
`Plasma VEGF after Intravenous Administration of Bevacizumab Is
`Predicted by a Pharmacokinetic Model, 70 CANCER RESEARCH 9886
`(2010) (“Klibanov Dep. Ex. 19, Stefanini”)
`Klibanov Dep. Ex. 20, Jihong Yang, Comparison of Binding
`Characteristics and In Vitro Activities of Three Inhibitors of
`Vascular Endothelial Growth Factor A, 11 Molecular Pharmaceutics
`3421 (2014) (“Klibanov Dep. Ex. 20, Yang”)
`Klibanov Dep. Ex. 22, International Nonproprietary Names for
`Pharmaceutical Substances (INN), 20 WHO DRUG INFORMATION
`118 (2006) (“Klibanov Dep. Ex. 22, WHO Drug Info”)
`
`xiv
`
`

`

`Exhibit
`1108
`
`1109
`
`1110
`
`1111
`
`1112
`
`1113
`
`1114
`
`1115
`
`1116
`
`1117
`
`1118
`
`1119
`
`1120
`
`Description
`Alexander Klibanov Deposition Transcript (March 24, 2022)
`CONFIDENTIAL MATERIAL - SUBJECT TO PROTECTIVE
`ORDER (“Klibanov Dep. Tr.”)
`Diana V. Do Deposition Transcript (April 21, 2022) (“Do Dep. Tr.”)
`
`David M. Brown Deposition Transcript (April 26, 2022) (“Brown
`Dep. Tr.”)
`Lucian V. Del Priore Deposition Transcript (April 29, 2022)
`CONFIDENTIAL MATERIAL - SUBJECT TO PROTECTIVE
`ORDER (“Del Priore Dep. Tr.”)
`Klibanov Dep. Ex. 14, W. Colin Duncan et al., Inhibition of Vascular
`Endothelial Growth Factor in the Primate Ovary Up-Regulates
`Hypoxia-Inducible Factor-1α in the Follicle and Corpus Luteum,
`149 ENDOCRINOLOGY 3313 (2008) (“Klibanov Dep. Ex. 14,
`Duncan”)
`Del Priore Dep. Ex. 10, John S. Rudge et al., CLINCAL
`DEVELOPMENT OF VEGF TRAP, in ANGIOGENESIS (William D. Figg
`& Judah Folkman eds. 2008) (“Del Priore Dep. Ex. 10, Rudge
`2008”)
`Expert Declaration of Dr. Thomas A. Albini in Support of
`Petitioner’s Reply, dated May 27, 2022 (“Albini Reply Decl.”)
`Expert Declaration of Mary Gerritsen, Ph.D. in Support of
`Petitioner’s Reply, dated May 26, 2022 (“Gerritsen Reply Decl.”)
`Transcript of the Teleconference before the United States Patent
`Trial and Appeal Board on May 19, 2022 (“Transcript (19-May-
`2022)”)
`Klibanov Dep. Ex. 6, amino acid sequence alignment of SEQ ID
`NO:2 of the ’338 patent, aflibercept amino acid sequence from WHO
`2006, and SEQ ID NO:2 of the ’173 patent (“Klibanov Dep. Ex. 6,
`’173 patent SEQ. ID No:2”)
`Klibanov Dep. Ex. 9, CAS registry for No. 862111-32-8 (“Klibanov
`Dep. Ex. 9, CAS”)
`Klibanov Dep. Ex. 12, 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) (“Klibanov Dep. Ex. 12, Rudge 2007”)
`Klibanov Dep. Ex. 13, Candelaria Gomez-Manzano et al., VEGF
`Trap Induces Antiglioma Effect at Different Stages of Disease, 10
`
`xv
`
`

`

`Exhibit
`
`1121
`
`1122
`
`1123
`
`1124
`
`1125
`
`1126
`
`1127
`
`1128
`
`1129
`
`1130
`
`1131
`
`Description
`NEURO-ONCOLOGY 940 (2008) (“Klibanov Dep. Ex. 13, Gomez-
`Manzano”)
`Klibanov Dep. Ex. 21, Lily Liu et al., A Novel Engineered VEGF
`Blocker with an Excellent Pharmacokinetic Profile and Robust Anti-
`Tumor Activity, 15 BMC CANCER 1 (2015) (“Klibanov Dep. Ex. 21,
`Liu”)
`Amino acid sequence alignment of SEQ ID NO:2 of the ’338 and
`’069 patents with aflibercept amino acid sequence from WHO 2006,
`SEQ ID NO:16 of the ’758 patent, and SEQ ID NO:16 of the ’959
`patent (“AA Alignment”)
`Polly A. Quiram & Yahui Song, Exudative Age-Related Macular
`Degeneration: Current Therapies and Potential Treatments, 1
`CLINICAL MEDICINE: THERAPEUTICS 1003 (2009) (“Quiram”)
`Nucleic acid sequence alignment of SEQ ID NO:1 of the ’338 and
`’069 patents with SEQ ID NO:15 of the ’758 patent and SEQ ID
`NO:15 of the ’959 patent (“NA Alignment”)
`HANDBOOK OF PHARMACEUTICAL EXCIPIENTS (5th ed. 2006) (“HPE
`2006”)
`D.B. Volkin & A.M. Klibanov, Alterations in the Structure of
`Proteins that Cause Their Irreversible Inactivation, 74
`DEVELOPMENTS BIOLOGICAL STANDARDIZATION 73 (1992) (“Volkin
`& Klibanov 1992”)
`File History for U.S. Patent No. 7,070,959, 4/5/2016 Election for
`Patent Term Extension (“959 FH, Election re PTE”)
`File History for U.S. Patent No. 7,070,959, 5/25/2016 Patent Term
`Extension Certificate (“959 FH, PTE Certificate”)
`Christine Wulff et al., Prevention of Thecal Angiogenesis, Antral
`Follicular Growth, and Ovulation in the Primate by Treatment
`with Vascular Endothelial Growth Factor Trap R1R2, 143
`ENDOCRINOLOGY 2797 (2002) (“Wulff”)
`Do Dep. Ex. 2, Regeneron’s Yancopoulos Receives Columbia
`College’s Alexander Hamilton Award (Nov. 22, 2019)
`(https://www.prnewswire.com/news-releases/regenerons-
`yancopoulos-receives-columbia-colleges-alexander-hamilton-award-
`300963506.html) (“Do Dep. Ex. 2, (“Regeneron (22-Nov-2019)”)
`Do Dep. Ex. 3, Laura Vanderkam, George Yancopoulos: Doing Well
`by Trying to Do Good, SCIENTIFIC AMERICAN (Oct. 6, 2008)
`
`xvi
`
`

`

`Exhibit
`
`Description
`(https://www.scientificamerican.com/article/george-yancopoulos-
`westinghouse/) (“Do Dep. Ex. 3, Vanderkam”)
`
`xvii
`
`

`

`I.
`
`INTRODUCTION.
`
`Patent Owner (“PO”) does not dispute that the prior art disclosed the dosing
`
`regimen set forth in claims 1 and 8-12 (“the Claims”) of U.S. Patent No. 9,669,069
`
`(“’069 patent”). PO cannot distinguish the Claims from Petitioner’s art, or the prior
`
`practice of physicians, many of whom, including PO’s expert, Dr. Brown, had
`
`adopted PRN dosing as their default anti-VEGF regimen. Instead, PO improperly
`
`attempts to sow confusion—where none exists—about the identity of VEGF Trap-
`
`Eye. In fact, there was no confusion—VEGF Trap-Eye and its sequence were set
`
`forth in the prior art, used in Regeneron’s prior art clinical trials, and—only later—
`
`included in the Claims. The efforts by PO and its experts to obfuscate the identity
`
`of PO’s own molecule should be disregarded as legally irrelevant. Independently,
`
`the Claims would have been obvious for adopting known, prior art, dosing regimens
`
`involving three monthly loading doses, followed by as-needed dosing—an
`
`administration scheme
`
`that had been a mainstay
`
`treatment strategy for
`
`ophthalmologists administering anti-VEGF agents, and incorporated into numerous
`
`Regeneron VEGF Trap-Eye/aflibercept clinical trials, well before the ’069 patent
`
`filing date. Accordingly, the Claims should be held unpatentable on all instituted
`
`grounds.
`
`1
`
`

`

`II.
`
`PERSON OF ORDINARY SKILL IN THE ART (“POSA”).
`
`“The level of skill in the art is a factual determination that provides a primary
`
`guarantee of objectivity in an obviousness analysis.” IPR2021-00881, Paper 21, 15
`
`(citing Al-Site Corp. v. VSI Int’l Inc., 174 F.3d 1308, 1324 (Fed. Cir. 1999)); see also
`
`Ryko Mfg. Co. v. Nu-Star, Inc., 950 F.2d 714, 718 (Fed. Cir. 1991)). PO’s position
`
`flouts that legal foundation and trivializes the POSA’s role in an invalidity analysis.
`
`Rather than stand behind and justify its proposed POSA, PO offers a “heads-I-win,
`
`tails-you-lose” catchall,