UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`CHENGDU KANGHONG BIOTECHNOLOGY CO., LTD.
`Petitioner
`
`v.
`
`REGENERON PHARMACEUTICALS, INC.
`Patent Owner
`
`____________
`
`Case PGR2021-00035
`Patent 10,828,345
`____________
`
`PRELIMINARY RESPONSE OF PATENT OWNER
`REGENERON PHARMACEUTICALS, INC.
`
`Mylan Exhibit 1141
`Mylan v. Regeneron, IPR2021-00881
`Page 1
`
`

`

`Contents
`INTRODUCTION ........................................................................................... 1
`BACKGROUND ............................................................................................. 4
`A.
`The ’345 Patent Claims ......................................................................... 4
`THE LEVEL OF ORDINARY SKILL IN THE ART .................................... 5
`III.
`IV. CLAIM CONSTRUCTION ............................................................................ 6
`A.
`Claim 1’s Preamble Is a Positive Limitation That Requires A
`Therapeutically Effective Method of Treatment ................................... 7
`The “Tertiary Dose” Must Maintain the Therapeutic Effect
`During Treatment .................................................................................. 9
`THE ’345 PATENT IS NOT ELIGIBLE FOR POST-GRANT
`REVIEW ........................................................................................................ 11
`A.
`The Examiner Already Determined That the ’345 Patent Should
`Be Reviewed Under Pre-AIA Standards ............................................. 12
`The 2011 Provisional Applications Describe Treatment of Branch
`Retinal Vein Occlusion (BRVO) ........................................................ 14
`1.
`Because the 2011 Provisional Applications Support the
`Challenged Claims, the ’345 Patent Is Not PGR Eligible ........ 14
`Treatment of Branch Retinal Vein Occlusion (BRVO) Was
`Described by the 2011 Provisional Applications ...................... 16
`The Claimed Twelve-Week Dosing Regimen Is Fully Supported
`by the 2011 Provisional Applications ................................................. 21
`THE BOARD SHOULD DENY INSTITUTION UNDER 35 U.S.C.
`§ 325(d) .......................................................................................................... 21
`A.
`The Examiner Considered the Same or Substantially the Same
`Art and Arguments During Prosecution (Becton, Dickinson
`factors (a), (b), and (d)) ....................................................................... 23
`
`B.
`
`B.
`
`C.
`
`2.
`
`I.
`II.
`
`V.
`
`VI.
`
`TABLE OF CONTENTS
`
`Page No.
`
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`B.
`
`Shams (Ex. 1004) ...................................................................... 23
`1.
`2009 Press Release (Ex. 1005).................................................. 25
`2.
`3. Written Description ................................................................... 26
`Petitioner Fails to Show That the Examiner Erred in a Manner
`Material to Patentability (Becton, Dickinson factors (c), (e), and
`(f)) ........................................................................................................ 31
`1.
`Petitioner Fails to Show That the Examiner Erred in a
`Manner Material to Patentability in His Analysis of Shams
`(Ground 1) ................................................................................. 31
`Petitioner Does Not Argue That the Examiner Erred in a
`Manner Material to Patentability as to the 2009 Press
`Release or Written Description (Grounds 2 and 3) .................. 34
`VII. THE BOARD SHOULD DENY INSTITUTION BECAUSE
`PETITIONER FAILS TO MAKE ITS THRESHOLD SHOWING
`THAT AT LEAST ONE CHALLENGED CLAIM IS
`UNPATENTABLE ........................................................................................ 37
`A.
`Ground 1: Petitioner Fails to Demonstrate That It Is More Likely
`Than Not That At Least One of the Challenged Claims Is
`Anticipated .......................................................................................... 38
`1.
`Petitioner Fails to Demonstrate That Shams’ Treatment
`Schema Discloses the Recited Fusion Protein .......................... 39
`Petitioner Fails to Demonstrate That Shams’ Reference to
`“VEGF-Trap (Regeneron)” Discloses the Recited Fusion
`Protein ....................................................................................... 41
`Shams Does Not Disclose the ’345 Patented Invention As
`Arranged in the Claims ............................................................. 45
`Petitioner Fails to Show That Shams Discloses or Enables
`A Therapeutically Effective Method of Treating an
`Angiogenic Eye Disorder .......................................................... 50
`Shams Fails to Disclose A Tertiary Dose That Maintains the
`Therapeutic Effect Throughout the Course of Treatment
`When Administered 12 Weeks After the Immediately
`Preceding Dose ......................................................................... 57
`
`2.
`
`2.
`
`3.
`
`4.
`
`5.
`
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`2.
`
`C.
`
`B.
`
`Ground 2: Petitioner Fails to Demonstrate That It Is More Likely
`Than Not That At Least One of the Challenged Claims Is
`Obvious................................................................................................ 58
`1.
`The Board Should Deny Institution Under 35 U.S.C. §
`324(a) Because Petitioner Has Failed to Address, Let Alone
`Overcome, the Examiner’s Finding of Unexpected Results ..... 59
`A POSA Would Not Reasonably Expect to Treat an
`Angiogenic Eye Disorder Using the Claimed Regimen by
`Combining the 2009 Press Release and Shams ........................ 61
`Ground 3: Petitioner Fails to Demonstrate That It Is More Likely
`Than Not That At Least One of the Challenged Claims Lacks
`Written Description ............................................................................. 69
`1.
`Petitioner Fails to Demonstrate That the Claims More
`Likely Than Not Lack Written Description Because
`the ’345 Patent Specification Discloses as a Specific
`Example the Exact Dosing Regimen Claimed .......................... 70
`None of Petitioner’s Cases Involve a Specification That
`Actually Discloses the Claimed Species ................................... 72
`Petitioner’s Argument Based on the Prosecution History Is
`Legally Irrelevant to Written Description and Factually
`Unsupported .............................................................................. 76
`VIII. CONCLUSION .............................................................................................. 79
`
`2.
`
`3.
`
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`

`TABLE OF AUTHORITIES
`
`Cases
`
`Advanced Bionics, LLC v. MED-EL Elektromedizinische Geräte GmbH,
`IPR2019-01469, 2020 WL 740292 (Feb. 13, 2020) .................................... passim
`
`Align Tech., Inc. v. 3Shape A/S,
`PGR2018-00103, 2019 WL 2112182 (May 13, 2019) ........................................43
`
`Am. Hoist & Derrick Co. v. Sowa & Sons, Inc.,
`725 F.2d 1350 (Fed. Cir. 1984) ............................................................................59
`
`Amgen Inc. v. Hoechst Marion Roussel, Inc.,
`314 F.3d 1313 (Fed. Cir. 2003) ............................................................................57
`
`Apotex Inc. v. Celgene Corp.,
`IPR2018-00685, 2020 WL 2095846 (Apr. 30. 2020) ..........................................42
`
`Ariad Pharms., Inc. v. Eli Lilly & Co.,
`598 F.3d 1336 (Fed. Cir. 2010) ..................................................................... 79, 86
`
`Balt USA, LLC v. Microvention, Inc.,
`IPR2020-01259, 2021 WL 219251 (Jan. 21, 2021) ...................................... 29, 39
`
`Becton, Dickinson & Co. v. B. Braun Melsungen AG,
`IPR2017-01586, Paper 8 (Dec. 15, 2017) ............................................... 25, 26, 35
`
`Biocon Pharma Ltd. v. Novartis Pharms. Corp.,
`IPR2020-01263, 2021 WL 608300 (Feb. 16, 2021) ..................................... 28, 42
`
`Boehringer Ingelheim Vetmedica, Inc. v. Schering-Plough Corp.,
`320 F.3d 1339 (Fed. Cir. 2003) .............................................................................. 8
`
`Boragen, Inc. v. Syngenta Participations AG,
`IPR2020-00124, 2020 WL 2206972 (May 5, 2020) ............................................30
`
`Boston Sci. Corp. v. Johnson & Johnson,
`647 F.3d 1353 (Fed. Cir. 2011) ............................................................................84
`
`Coalition for Affordable Drugs V LLC v. Hoffmann-La Roche Inc.,
`IPR2015-01792, Paper 14 (Mar. 11, 2016) ................................................... 67, 69
`
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`Coherus Biosciences, Inc. v. AbbVie Biotechnology Ltd.,
`IPR2017-00822, 2017 WL 3974063 (Sept. 7, 2017) .................................... 56, 57
`
`Commonwealth Sci. & Indus. Research v. BASF Plant Sci. GMBH,
`PGR2020-0003, Paper 11 (Sept. 10, 2020) ..........................................................15
`
`Cubist Pharms., Inc. v. Hospira, Inc.,
`75 F. Supp. 3d 641 (D. Del. 2014) .......................................................................58
`
`E.I. Du Pont de Nemours & Co. v. Monsanto Tech. LLC,
`IPR2014-00333, 2014 WL 3507803 (July 11, 2014) ............................................. 9
`
`Endo Pharms. Inc. v. Depomed, Inc.,
`IPR2014-00655, 2014 WL 4925714 (Sept. 29, 2014) .........................................56
`
`Endo Pharms. Sols., Inc. v. Custopharm Inc.,
`894 F.3d 1374 (Fed. Cir. 2018) ............................................................................51
`
`Erfindergemeinschaft UroPep v. Eli Lilly & Co.,
`276 F. Supp. 3d 629 (E.D. Tex. 2017), aff’d, 739 F. App’x 643 ...... 79, 81, 84, 85
`
`Eton Pharms., Inc. v. Exela Pharma Scis., LLC,
`PGR2020-00064, Paper 12 (Nov. 18, 2020) ........................................................43
`
`Flex Logix Techs., Inc. v. Konda,
`IPR2020-00262, 2020 WL 4462127 (Aug. 3, 2020) ...........................................29
`
`Free Stream Media Corp. v. Alphonso Inc.,
`IPR2019-00762, 2019 WL 4200650 (Sept. 4, 2019) ...........................................33
`
`Fujikawa v. Wattanasin,
`93 F.3d 1559 (Fed. Cir. 1996) ..............................................................................84
`
`FWP IP ApS v. Biogen MA, Inc.,
`749 F. App’x 969 (Fed. Cir. 2018) .......................................................................84
`
`Gilead Scis., Inc. v. United States,
`IPR2019-01453, Paper 14 (Feb. 20, 2020) .................................................... 68, 69
`
`GlaxoSmithKline Consumer Healthcare Holdings (US) LLC v. Cipla Ltd.,
`IPR2020-00369, 2020 WL 4390663 (July 31, 2020) ...........................................40
`
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`GlaxoSmithKline Consumer Healthcare Holdings (US) LLC v. Cipla Ltd.,
`IPR2020-00371, 2020 WL 4390665 (July 31, 2020) ...........................................30
`
`GlaxoSmithKline LLC v. Glenmark Pharms. Inc. USA,
`No. 14-877-LPS-CJB, Dkt. 133 (D. Del. June 3, 2016) adopted, 2017 WL
`658468 ..................................................................................................................10
`
`Gofire, Inc. v. Canopy Growth Corp.,
`IPR2020-00044, 2020 WL 5991725 (Oct. 9, 2020) .............................................29
`
`Griffin v. Bertina,
`285 F.3d 1029 (Fed. Cir. 2002) ..........................................................................7, 8
`
`Hulu, LLC v. Sound View Innovations, LLC,
`IPR2018-01039, Paper 29 (Dec. 20, 2019) ................................................... 23, 60
`
`Husky Injection Molding Sys., Ltd. v. Plastipak Packaging, Inc.,
`IPR2020-00438, 2020 WL 4353621 (July 29, 2020) ...........................................36
`
`Hybridgenics v. Forma Therapeutics,
`PGR2018-00098, Paper 10 (Mar. 20, 2019) ........................................................32
`
`Illumina, Inc. v. Complete Genomics, Inc.,
`IPR2020-00079, Paper 7 (Apr. 22, 2020) ............................................................71
`
`Impax Lab’ys, Inc. v. Aventis Pharms., Inc.,
`468 F.3d 1366 (Fed. Cir. 2006) ..................................................................... 51, 54
`
`In re Antor Media Corp.,
`689 F.3d 1282 (Fed. Cir. 2012) ............................................................................60
`
`In re Arkley,
`455 F.2d 586 (CCPA 1972) ..................................................................................55
`
`In re Robertson,
`169 F.3d 743 (Fed. Cir. 1999) ..............................................................................50
`
`In re Ruschig,
`379 F.2d 990 (CCPA 1967) ..................................................................................82
`
`vi
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`

`

`Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd.,
`821 F.3d 1359 (Fed. Cir. 2016) ............................................................................70
`
`Irdeto Access, Inc. v. Echostar Satellite Corp.,
`383 F.3d 1295 (Fed. Cir. 2004) ..................................................................... 11, 12
`
`Jansen v. Rexall Sundown, Inc.,
`342 F.3d 1329 (Fed. Cir. 2003) .............................................................................. 8
`
`Kennecott Corp. v. Kyocera Int’l Inc.,
`835 F.2d 1419 (Fed. Cir. 1987) ............................................................................18
`
`Kolmes v. World Fibers Corp.,
`107 F.3d 1534 (Fed. Cir. 1997) ............................................................................34
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ...................................................................................... 69, 71
`
`KVK-Tech, Inc. v. Shire PLC,
`IPR2018-00290, 2019 WL 2884463 (July 3, 2019) .............................................70
`
`Merck Sharp & Dohme Corp. v. Wyeth LLC,
`PGR2017-00016 & PGR2017-00017, Paper 9 (Oct. 20, 2017) .................... 15, 17
`
`Monolithic Power Sys., Inc. v. Volterra Semiconductor LLC,
`IPR2020-01348, 2021 WL 838428 (Mar. 4, 2021) ..............................................33
`
`Mylan Pharms. Inc. v. Merck Sharp & Dohme Corp.,
`IPR2020-00040, 2020 WL 2478503 (May 12, 2020) ..........................................28
`
`Mylan Pharms. Inc. v. Yeda Research & Dev. Co. Ltd.,
`PGR2016-00010, Paper 9 (Aug. 15, 2016) ..........................................................14
`
`MyMail, Ltd. v. Am. Online, Inc.,
`476 F.3d 1372 (Fed. Cir. 2007) ..................................................................... 11, 12
`
`Net MoneyIN, Inc. v. VeriSign, Inc.,
`545 F.3d 1359 (Fed. Cir. 2008) ..................................................................... 52, 55
`
`NOF Corp. v. Nektar Therapeutics,
`IPR2019-01392, Paper 23 (Feb. 4, 2020) .............................................................71
`
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`

`Novartis Pharms. Corp. v. Accord Healthcare Inc.,
`387 F. Supp. 3d 429 (D. Del. 2019) ....................................................................... 8
`
`Novozymes A/S v. DuPont Nutrition Bioscis. APS,
`723 F.3d 1336 (Fed. Cir. 2013) ............................................................................85
`
`NXP USA, Inc. v. Impinj, Inc.,
`IPR2020-00519, 2020 WL 4805424 (Aug. 17, 2020) .........................................40
`
`Omron Oilfield & Marine, Inc. v. MD/Totco, a division of Varco, L.P.,
`IPR2013-00265, Paper 11 (Oct. 31, 2013) .................................................... 67, 69
`
`One World Techs., Inc. v. Chervon (HK) Ltd.,
`PGR2020-00059, 2020 WL 7222691 (Dec. 7, 2020) ..........................................43
`
`Pharmacosmos A/S v. Am. Regent, Inc.,
` PGR2020-00009, Paper 17 (Aug. 14, 2020) ......................................................... 4
`
`Philip Morris Prods., S.A. v. Rai Strategic Holdings, Inc.,
`IPR2020-00921, 2020 WL 6750120 (Nov. 16, 2020) .........................................28
`
`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Circ. 2005) ......................................................................6, 11
`
`Purdue Pharma L.P. v. Faulding Inc.,
`230 F.3d 1320 (Fed. Cir. 2000) ............................................................................85
`
`Rapoport v. Dement,
`254 F.3d 1053 (Fed Cir. 2001) .............................................................................10
`
`Reckitt Benckiser LLC v. GEMAK Tr.,
`IPR2020-00184, 2020 WL 2511249 (May 15, 2020) ..........................................56
`
`Regeneron Pharms., Inc. v. Kymab Ltd.,
`IPR2020-00389, 2020 WL 2738613 (May 26, 2020) ..........................................38
`
`Robert Bosch Tool Corp. v. SD3, LLC,
`IPR2016-01751, Paper 15 (Mar. 22, 2017) ................................................... 68, 69
`
`Samsung Elec. Co., Ltd. v. Neodron Ltd.,
`IPR2020-00334, 2020 WL 3892132 (Jul. 10, 2020) ............................................30
`
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`

`Sanofi Mature IP v. Mylan Labs. Ltd.,
`757 F. App’x 988 (Fed. Cir. 2019) ......................................................................... 9
`
`SAS Inst., Inc. v. Iancu,
`138 S. Ct. 1348 (2018) .........................................................................................59
`
`Schering Corp. v. Geneva Pharms.,
`339 F.3d 1373 (Fed. Cir. 2003) ............................................................................50
`
`See Amgen, Inc. v. Alexion Pharms., Inc.,
`IPR2019-00739, Paper 15 (Aug. 30, 2019) ..........................................................51
`
`Sony Interactive Entm’t LLC v. Terminal Realty, Inc.,
`IPR2020-00711, 2020 WL 6065188 (Oct. 13, 2020) ...........................................39
`
`Stryker Corp. v. KFX Med., LLC,
`IPR2019-00817, Paper 10 (Sept. 16, 2019) .................................................. 68, 69
`
`Takeda Pharm. Co., Ltd v. Handa Pharms., LLC,
`No. C-11-00840 JCS, 2013 WL 9853725 (N.D. Cal. Oct. 17, 2013) ..................60
`
`Telemac Cellular Corp. v. Topp Telecom, Inc.,
`247 F.3d 1316 (Fed. Cir. 2001) ............................................................................33
`
`Therma-Tru Corp. v. Peachtree Doors Inc.,
`44 F.3d 988 (Fed. Cir. 1995) ................................................................................18
`
`Thermo Fisher Sci. Inc. v. Regents of the Univ. of Calif.,
`IPR2018-01156, 2018 WL 6318146 (Dec. 3, 2018) ............................................70
`
`United States v. Adams,
`383 U.S. 39 (1966) ...............................................................................................57
`
`Universal Imaging Indus., LLC v. Lexmark Int’l Inc.,
`IPR2019-01387, 2020 WL 2201770 (May 4, 2020) ............................................30
`
`Universal Imaging Indus., LLC v. Lexmark Int’l, Inc.,
`IPR2019-01387, 2020 WL 959375 (Feb. 27, 2020) ..................................... 31, 36
`
`Vitronics Corp. v. Conceptronic, Inc.,
`90 F.3d 1576 (Fed. Cir. 1996) ..............................................................................11
`
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`

`

`Statutes
`
`35 U.S.C. § 100 ........................................................................................................15
`
`35 U.S.C. § 112 ........................................................................................................16
`
`35 U.S.C. § 322 ....................................................................................... 4, 37, 58, 69
`
`35 U.S.C. § 324 ................................................................................................ passim
`
`35 U.S.C. § 325 ................................................................................................ passim
`
`Regulations
`
`21 C.F.R. § 312.7 .....................................................................................................65
`
`Other Authorities
`
`AIA § 3(n)(1) .................................................................................................... 13, 15
`
`Changes to the Claim Construction Standard for Interpreting Claims in
`Trial Proceedings Before the Patent Trial and Appeal Board,
`83 Fed. Reg. 51,340 (Oct. 11, 2018) ...................................................................... 6
`
`MPEP § 210 .............................................................................................................15
`
`MPEP § 2103 ...........................................................................................................29
`
`MPEP § 211.05 I.B ..................................................................................................16
`
`MPEP § 2163 ...........................................................................................................28
`
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`

`TABLE OF EXHIBITS
`
`Exhibit
`2001
`2002
`2003
`
`Description
`Declaration of Diana V. Do, M.D.
`Declaration of David M. Brown, M.D.
`T.A. Ciulla & P.J. Rosenfeld, Anti-vascular endothelial growth factor
`for neovascular ocular diseases other than age-related macular
`degeneration, 20 CURR. OPIN. OPTHAMOL. 166 (2009)
`2004 A.P. Adamis, Ocular angiogenesis: vascular endothelial growth factor
`and other factors, pp. 23-36, RETINAL PHARMACOTHERAPY (Q.D.
`Nguyen et al., (eds.) 2010)
`2005 Approval Letter and Labeling Excerpts from CDER Approval Package
`for 125156/S053 (Lucentis®), dated June 22, 2010
`2006 D.L. Shechtman & P.M. Karpecki, A Look at CRUISE and BRAVO,
`147 REV. OPTOMETRY 133 (2010) (available at
`https://www.reviewofoptometry.com/article/a-look-at-cruise-and-
`bravo)
`File History for U.S.S.N. 15/471,506, G.D. Yancopoulos, filed March
`28, 2017
`File History for U.S.S.N. 14/972,560, G.D. Yancopoulos, filed
`December 17, 2015
`File History for U.S.S.N. 13/940,370, G.D. Yancopoulos, filed July 12,
`2013
`Clinicaltrials.gov study NCT00090623, A Study of rhuFab V2
`(Ranibizumab) in Subjects With Subfoveal Choroidal
`Neovascularization Secondary to Age-Related Macular Degeneration,
`last updated June 21, 2013
`J. Holash et al., VEGF-Trap: A VEGF blocker with potent antitumor
`effects, 99 PROC. NATL. ACAD. SCI. 11393 (2002)
`2012 WO 2005/000895 A2 (PCT/US2004/021059), T.J. Daly et al.,
`published January 6, 2005
`Excerpts from File History for U.S.S.N. 11/738,284, N. Shams, Filed
`April 20, 2007
`Excerpts from File History for U.S.S.N. 13/780,239, N. Shams, Filed
`February 28, 2013
`Retinal Physician Symposium Covers Broad Range of Topics, RETINAL
`PHYSICIAN, September 1, 2006 (available at
`https://www.retinalphysician.com/issues/2006/september-2006/retinal-
`physician-symposium-covers-broad-range-of)
`
`2013
`
`2007
`
`2008
`
`2009
`
`2010
`
`2011
`
`2014
`
`2015
`
`xi
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`

`2016
`
`2017
`
`2018
`
`2019
`
`2020
`
`2021
`
`P. Abraham et al., Randomized, Double-Masked, Sham-Controlled
`Trial of Ranibizumab for Neovascular Age-Related Macular
`Degeneration: PIER Study Year 2, 150 AM. J. OPTHAMOLOGY 315
`(2010)
`Press Release, PIER data suggest a need for tailored injection
`schedule, dated September 1, 2006 (available at
`https://www.healio.com/news/ophthalmology/20120331/pier-data-
`suggest-a-need-for-tailored-injection-schedule)
`J.P. Levine et al., Macular Hemorrhage in Neovascular Age-Related
`Macular Degeneration After Stabilization With Antiangiogenic
`Therapy, 29 RETINA 1074 (2009)
`R. Margolis & K.B. Freund, Hemorrhagic Recurrence of Neovascular
`Age-Related Macular Degeneration not Predicted by Spectral Domain
`Optical Coherence Tomography, 4 RETINAL, CASES & BR. REPS. 1
`(2010)
`I. Barbazetto et al., Dosing Regimen and the Frequency of Macular
`Hemorrhages in Neovascular Age-Related Macular Degeneration
`Treated With Ranibizumab, 30 RETINA 1376 (2010)
`J.S. Heier et al., lntravitreal Aflibercept (VEGF Trap--Eye) in Wet
`Age-related Macular Degeneration, 119 OPTHAMOLOGY 2537 (2012)
`CV for Diana V. Do, M.D.
`CV for David M. Brown M.D.
`S. Michels et al., Systemic Bevacizumab (Avastin) Therapy for
`Neovascular Age-Related Macular Degeneration, 112 OPTHAMOLOGY
`1035 (2005)
`P.J. Rosenfeld et al., Ranibizumab for Neovascular Age-Related
`Macular Degeneration, 355 N. ENG. J. MED. 1419 (2006)
`2026 D.M. Brown et al., Ranibizumab versus Verteporfin for Neovascular
`Age-Related Macular Degeneration, 355 N. ENG. J. MED. 1432 (2006)
`2027 D.M. Brown et al., Ranibizumab versus Verteporfin Photodymanic
`Therapy for Neovascular Age-Related Macular Degeneration, 116
`OPTHALMOLOGY 57 (2009)
`CDER Approved Labeling for BLA Application 125156 (LucentisTM),
`dated 2006
`F. Prager et al., Intravitreal bevacizumab (Avastin®) for macular
`oedema secondary to retinal vein occlusion, 93 BR. J. OPTHALMOL.
`452 (2009)
`2030 D.M. Brown, Clinical Implications of the BRAVO and CRUISE
`Trials, RETINA TODAY 38-40 (April 2010)
`
`2022
`2023
`2024
`
`2025
`
`2028
`
`2029
`
`xii
`
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`

`

`2031
`
`2032
`
`2033
`
`2034
`
`Press Release, Genentech, Inc. Submits Biologics License Application
`For FDA Review Of Lucentis(TM) In Wet Age-Related Macular
`Degeneration (Dec. 30, 2005), available at
`https://www.biospace.com/article/releases/genentech-inc-submits-
`biologics-license-application-for-fda-review-of-lucentis-tm-in-wet-
`age-related-macular-degeneration-/.
`T. Shihua, China’s Kanghong Pharma Hits Limit Down as France
`Stops Trials of Ophthalmic Drug, YiCai Global (April 12, 2021),
`available at https://www.yicaiglobal.com/news/china-kanghong-
`pharma-hits-limit-down-as-france-stops-trials-of-ophthalmic-drug.
`Securities Daily, Announcement of Chengdu Kanghong
`Pharmaceutical Group Co., Ltd. on stopping the global multi-center
`clinical trial of Conbercept ophthalmic injection (April 13, 2021)
`(PDF of original article in Chinese), available at
`http://epaper.zqrb.cn/html/2021-04/10/content_716426.htm?div=-1.
`Securities Daily, Announcement of Chengdu Kanghong
`Pharmaceutical Group Co., Ltd. on stopping the global multi-center
`clinical trial of Conbercept ophthalmic injection (April 13, 2021)
`(PDF of machine translation in English), available at
`http://epaper.zqrb.cn/html/2021-04/10/content_716426.htm?div=-1.
`
`xiii
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`Mylan Exhibit 1141
`Mylan v. Regeneron, IPR2021-00881
`Page 14
`
`

`

`I.
`
`INTRODUCTION
`Patent Owner Regeneron Pharmaceuticals, Inc. (“Regeneron”) is an
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`innovative U.S. biotechnology company that invents life-changing medicines for
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`people with serious diseases. Regeneron was founded and has been led for more
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`than 30 years by physician-scientists and has developed nine FDA-approved
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`medicines, including EYLEA®. The active agent in EYLEA®, aflibercept, is a
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`novel fusion protein developed by Regeneron that binds to and neutralizes
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`Vascular Endothelial Growth Factor (VEGF), a key contributor to angiogenesis.
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`By binding and neutralizing VEGF, aflibercept is able to prevent blood vessel
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`leakage and block the growth of abnormal blood vessels in the back of the eye and
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`effectively treat angiogenic eye disorders. Since its approval by FDA in 2011,
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`EYLEA® has revolutionized the treatment of angiogenic eye disorders including
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`age-related macular degeneration (AMD), macular edema, and diabetic
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`retinopathy.
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`Before the development of EYLEA®, the standard of care for treatment of
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`angiogenic eye disorders was monthly intravitreal injections of ranibizumab (an
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`anti-VEGF antibody fragment) or off-label use of bevacizumab (an anti-VEGF
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`antibody). The great treatment burden of monthly eye injections led to extensive
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`efforts in the art to decrease injection frequency and physician monitoring. Ex.
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`1012 at 1, 9. However, before EYLEA, fixed quarterly or “as needed” (pro re
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`nata) dosing regimens with existing VEGF inhibitors, without monthly
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`monitoring visits, were not effective at maintaining vision. Ex. 1012 at 1.
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`1
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`Mylan Exhibit 1141
`Mylan v. Regeneron, IPR2021-00881
`Page 15
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`

`

`Regeneron’s Phase III clinical trial results surprisingly demonstrated
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`“remarkably similar improvement in vision and anatomic measures can be
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`achieved” with less frequent dosing of aflibercept as compared to monthly
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`injections of ranibizumab. Ex. 1012 at 10-11. Indeed, the Examiner relied on this
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`evidence of unexpected results during prosecution of U.S. Patent No. 10,828,345
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`(the “’345 Patent”). Not surprisingly, given the long-felt need and repeated
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`failures in the art to reduce treatment burden and injection frequency, EYLEA has
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`enjoyed great commercial success.
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`Petitioner Chengdu Kanghong Biotechnology Co., Ltd.’s (“Kanghong” or
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`“Petitioner”) seeks to capitalize on Regeneron’s hard-earned success by
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`commercializing conbercept, a “me too” fusion protein, in the United States.1
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`Petitioner seeks to invalidate Regeneron’s ’345 Patent claims to extended (12-
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`week) dosing regimens for treating angiogenic eye disorders using the claimed
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`VEGF antagonist fusion proteins, by arguing that Regeneron’s claims are
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`1 Petitioner seeks to invalidate the ’345 Patent even before the safety and efficacy of
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`its infringing conbercept product has been demonstrated. Indeed, Petitioner recently
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`suspended one of its two Phase III pivotal clinical trials for conbercept in the United
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`States based on a mid-term review of data generated in the study. In addition, the
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`National Agency for the Safety of Medicines and Health Products of France recently
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`halted a Phase III trial of conbercept in Europe. See Ex. 2032; Ex. 2033; Ex. 2034.
`
`2
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`Mylan Exhibit 1141
`Mylan v. Regeneron, IPR2021-00881
`Page 16
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`

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`anticipated or obvious based on a prior art dosing regimen, and are not adequately
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`described. However, the Shams prior art dosing regimen on which Petitioner
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`relies was an acknowledged failure and Petitioner assiduously avoids any
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`discussion of Regeneron’s demonstration of unexpected results in prosecution, on
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`which the Examiner relied in allowing the ’345 Patent. Moreover, Petitioner
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`overlooks the fact that the dosing regimen claimed is described as a specific
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`example in the specification.
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`Patent Owner submits this preliminary response pursuant to 35 U.S.C. §
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`323 and 37 C.F.R. § 42.207 to Petitioner’s request for post-grant review (“PGR”)
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`of Claims 1-11 of the ʼ345 Patent, Ex. 1001. This preliminary response is timely
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`filed within three months of the Patent Trial & Appeal Board’s (“Board”) notice
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`(Paper No. 3), mailed January 15, 2021, indicating that the Petition was accorded
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`a filing date. As set forth herein and in the accompanying exhibits, the Petition
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`should be denied for at least the following reasons:
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`First, the ’345 Patent is not eligible for PGR because its effective filing date
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`is before March 16, 2013.
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`Second, the prior art asserted by Petitioner in Grounds 1 and 2, and the §112
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`disclosure challenged in Ground 3, were previously before the Examiner, and
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`Petitioner has not sufficiently alleged that the Examiner erred in a manner material
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`to the patentability of the challenged claims in considering the art and arguments,
`
`3
`
`Mylan Exhibit 1141
`Mylan v. Regeneron, IPR2021-00881
`Page 17
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`

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`warranting discretionary denial under 35 U.S.C. § 325(d). See Pharmacosmos A/S
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`v. Am. Regent, Inc., PGR2020-00009, Paper 17 at 27-28 (Aug. 14, 2020).
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`Third, Petitioner has failed to meet its threshold burden under 35 U.S.C. §§
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`324(a) and 322(a)(3) to show that it is more likely than not that at least one of the
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`claims of the ’345 Patent is unpatentable because (1) Shams does not anticipate
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`the ’345 Patent claims, (2) Shams and the 2009 Press Release do not render the ’345
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`Patent claims obvious, and (3) the ’345 Patent claims are adequately supported by
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`the pre-March 16, 2013 priority applications.
`
`II.
`
`BACKGROUND
`A.
`The ’345 Patent Claims
`The ’345 Patent’s single independent claim, Claim 1, recites a method for
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`treating an angiogenic eye disorder in a patient by administering a single dose of a
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`VEGF antagonist followed by one or more secondary doses that are administered
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`four weeks after the preceding dose, followed by tertiary or maintenance doses that
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`are administered twelve weeks apart. Ex. 1001 at 21:55-22:56. Claim 1 also recites
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`that the claimed VEGF antagonist is a receptor-based chimeric molecule comprising
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`an immunoglobulin-like (Ig) domain 2 of VEGF receptor Flt1, Ig domain 3 of the
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`VEGF receptor Flk1, and a multimerizing component. Id. In other words, Claim 1
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`recites a method of treating an angiogenic eye disorder by administering a recited
`
`4
`
`Mylan Exhibit 1141
`Mylan v. Regeneron, IPR2021-00