UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`REGENERON PHARMACEUTICALS, INC.
`Petitioner,
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`V.
`
`NOV ARTIS PHARMA AG,
`NOV ARTIS TECHNOLOGY LLC,
`NOV ARTIS PHARMACEUTICALS CORPORATION,
`Patent Owners.
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`Patent Number: 9,220,631
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`DECLARATION OF HORST KOLLER
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`Regeneron Exhibit 1003.001
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`TABLE OF CONTENTS
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`Page
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`I. Introduction ...................................................................................................... l
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`II.Summary of Opinions ...................................................................................... 1
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`III.Qualifications and Compensation .................................................................... 3
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`IV.Relevant Legal Standards ................................................................................ 7
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`A. Claim Construction ............................................................................... 8
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`B. Invalidity ............................................................................................... 9
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`C. Person
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`of Ordinary Skill in the Art ..................................................... 12
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`V. Background
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`of the Technology ..................................................................... 14
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`A. Intravitreal Administration of VEGF Antagonists .............................. 14
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`B. Pre-filled syringes ................................................................................ 15
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`C. Syringe Stopper Forces ....................................................................... 20
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`D. Siliconization of Pre-filled Syringe Components ............................... 24
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`26
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`11comza 10n ........................................ .
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`1 y or pray-on
`1 "0·1 " "S
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`"s·1· 1·
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`2. "Baked-On" Siliconization ....................................................... 30
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`3. Coated, Uncoated, and Siliconized Stoppers ............................ 36
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`E. Sterilization of Pre-filled Syringes ...................................................... 39
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`F. Particulate Content .............................................................................. 46
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`VI.The '631 Patent .............................................................................................. 48
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`A. The Claims .......................................................................................... 48
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`B. Overview of Specification ................................................................... 52
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`1. The '631 patent fails to disclose a process for applying
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`low levels of silicone oil ........................................................... 52
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`2. The '631 patent fails to disclose the process for terminal
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`sterilization ................................................................................ 53
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`C. Meaning of the Claim Terms .............................................................. 53
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`i
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`Regeneron Exhibit 1003.002
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`VII.The Prior Art to the '631 Patent .................................................................... 55
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`A. "Sigg" - WO 2011/006877 ................................................................. 55
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`B. "Lam" -International Pat. Appl. Pub. No. WO 2008/077155 ........... 60
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`Pat. Appl. Pub. No. WOC. "Boulange" -International
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`2009/030976 ........................................................................................ 65
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`D. "Reuter" -Bruno Reuter & Claudia Petersen, Syringe
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`Siliconization, 4 TechnoPharm 2,238 (2012) ..................................... 71
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`E. "Fries" -A. Fries, Drug Delivery of Sensitive
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`Biopharmaceuticals with Prejilled Syringes, Drug Delivery
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`Technology, Vol. 9, No. 5 ................................................................... 77
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`F. "Furfine" - WO 2007 /149334 ............................................................. 78
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`G. "Macugen Label" - Macugen
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`:w Prescribing Information .................... 78
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`Renders ObviousVIII.Petition 1, Ground I: Sigg in View of Boulange
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`Claims 1-3, 5-9, and 14-22 ............................................................................ 79
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`A. Motivation to Combine Sigg and Boulange ........................................ 79
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`1. Silicone Oil and Break Loose / Slide Forces ............................ 79
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`2. Particulate Content .................................................................... 87
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`B. Claim I ................................................................................................ 89
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`barrel, a stopper and a plunger .................................................. 90
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`intravitreal injection .................................................................. 89
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`1. [I .a] A pre-filled, terminally sterilized syringe for
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`2. [l .b] the syringe comprising a glass body forming a
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`3. [l .c] and containing an ophthalmic solution which
`comprises a VEGF-antagonist, wherein: .................................. 92
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`4. [l .d] the syringe has a nominal maximum fill volume of
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`between about 0.5 mL and about I mL .................................... 93
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`5. [ l.e] the syringe barrel comprises from about I µg to I 00
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`µg silicone oil ............................................................................ 95
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`6. [l .f] the VEGF-antagonist solution comprises no more
`than 2 particles> 50 µmin diameter per mL ............................ 96
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`7. [l .g] and wherein the syringe has a stopper break loose
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`force of less than about I IN ..................................................... 99
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`ii
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`Regeneron Exhibit 1003.003
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`100 C. Claims 2, 3, 5-9, 14, 16-22 and 24 ....................................................
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`1. Claim 2 .................................................................................... 100
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`2. Claims 3 and 22 ....................................................................... 102
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`3. Claims 5 and 6 ......................................................................... 103
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`4. Claims7,8,and 9 .................................................................... 103
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`5. Claims 14 and 16 ..................................................................... 104
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`6. Claim 15 .................................................................................. 106
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`7. Claim 17 .................................................................................. 109
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`8. Claims 18 and 19 ..................................................................... l 10
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`9. Claim 20 .................................................................................. 112
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`10.Claim 21 .................................................................................. l 14
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`IX.Petition 1, Ground 2: Sigg in View of Boulange and Fries Renders
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`Obvious Claims 4, 10 and 23 ....................................................................... l 16
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`X. Petition 1, Ground 3: Sigg in view of Boulange and Furfine Renders
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`Obvious Claims 11-13 ................................................................................. 118
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`A. Claims 11 and 12 ............................................................................... 119
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`B. Claim 13 ............................................................................................ 120
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`XI.Petition 2, Ground I: Lam in View of Reuter Renders Obvious Claims
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`1-10 and 14-23 ............................................................................................. 121
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`A. Motivation to Combine Lam and Reuter .......................................... 121
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`1. Silicone Oil and Break Loose/ Slide Forces .......................... 121
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`2. Particulate Content .................................................................. 128
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`B. Claim I .............................................................................................. 130
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`barrel, a stopper and a plunger ................................................ 132
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`1. [I .a] A pre-filled, terminally sterilized syringe for
`
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`
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`intravitreal injection ................................................................ 130
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`2. [l .b] the syringe comprising a glass body forming a
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`3. [l .c] and containing an ophthalmic solution which
`comprises a VEGF-antagonist, wherein: ................................ 133
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`4. [l .d] the syringe has a nominal maximum fill volume of
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`between about 0.5 mL and about I mL .................................. 134
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`5. [ l.e] the syringe barrel comprises from about I µg to I 00
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`µg silicone oil .......................................................................... 134
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`iii
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`Regeneron Exhibit 1003.004
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`6. [l .f] the VEGF-antagonist solution comprises no more
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`than 2 particles >50 µmin diameter per mL ........................... 137
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`7. [l .g] and wherein the syringe has a stopper break loose
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`force of less than about l lN ................................................... 140
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`142 C. Claims 2-10 and 14-24 ......................................................................
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`1. Claim 2 .................................................................................... 142
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`2. Claims 3 and 22 ....................................................................... 142
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`3. Claims 4, 10, and 23 ............................................................... 143
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`4. Claims 5 and 6 ......................................................................... 144
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`5. Claims7,8, and9 .................................................................... 145
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`6. Claims 14 and 16 ..................................................................... 146
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`7. Claim 15 .................................................................................. 147
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`8. Claim 17 .................................................................................. 150
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`9. Claims 18 and 19 ..................................................................... 151
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`10.Claim 20 .................................................................................. 152
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`11.Claim 21 .................................................................................. 153
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`XII.Petition 2, Ground 2: Lam in view of Reuter and F urfine Renders
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`Obvious Claims 11-13 ................................................................................. 155
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`A. Claims 11 and 12 ............................................................................... 156
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`B. Claim 13 ............................................................................................ 157
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`XIII.Declaration ................................................................................................... 159
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`iv
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`Regeneron Exhibit 1003.005
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`I.
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`Introduction
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`1.
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`I have been retained by Petitioner Regeneron Pharmaceuticals, Inc.
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`("Petitioner" or "Regeneron"), as an independent expert witness in the above(cid:173)
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`captioned inter partes review ("IPR"), in which Regeneron has requested that the
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`U.S. Patent and Trademark Office cancel as unpatentable all claims of U.S. Patent
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`No. 9,220,631 ("the '631 patent").
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`2.
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`This declaration sets forth my analyses and opinions based on my
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`knowledge, experience, and the materials I have considered. As I explain below, it
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`is my opinion that all claims of the '631 patent are directed to subject matter that
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`was routine, conventional, and well known in the art before the '631 patent priority
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`date. As would be readily appreciated by one of skill in the art, the '631 patent is
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`rendered obvious by the combination of prior art references discussed herein.
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`3.
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`I have reviewed the documents referenced in this declaration.
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`I
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`understand they have been submitted as exhibits in conjunction with Regeneron's
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`Petitions for IPR.
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`II.
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`Summary of Opinions
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`4.
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`Based on my knowledge, experience, and the materials that I have
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`reviewed, it is my opinion that claims 1-23 of the '631 patent are obvious.
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`Specifically:
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`Regeneron Exhibit 1003.006
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`(i)Claims 1-3, 5-9, and 14-22 are obvious based on International
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`Patent Application Publication No. WO 2011/006877 to Sigg et al. ("Sigg")
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`(Ex. 1007) in view of International Patent Application Publication No. WO
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`2009/030976 to Boulange et al. ("Boulange") (Ex. 1008), and if necessary,
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`USP Chapter <789>, titled "Particulate Matter in Ophthalmic Solutions."
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`("USP789") (Ex. 1019);
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`(ii)Claims 4, 10 and 23 are obvious based on Sigg in view of
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`Boulange, further in view of A. Fries, Drug Delivery of Sensitive
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`Biopharmaceuticals with Prefilled Syringes, Drug Delivery Technology, Vol.
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`9, No. 5 (May 2009) ("Fries") (Ex. 1012), and if necessary, USP789;
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`(iii)Claims 11-13 are obvious based on Sigg in view of Boulange,
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`further in view of International Patent Application Publication No.
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`WO 2007/149334 ("Furfine") (Ex. 1021), and if necessary, USP789;
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`(iv)Claims 1-10, and 14-23 are obvious based on Lam in view of
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`Bruno Reuter & Claudia Petersen, Syringe Siliconization, 4
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`TECHNOPHARM 2, 238 (2012) ("Reuter") (Ex. 1010) , and if necessary,
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`USP789;
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`(v)Claims 11-13 are obvious based on the combination of Lam in
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`view of Reuter, further in view ofFurfine, and if necessary, USP789.
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`2
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`Regeneron Exhibit 1003.007
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`III. Qualifications and Compensation
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`5.
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`I have a Diplom-Ingenieur ("Dipl.Ing.") degree in biotechnology from
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`Hochschule Mannheim, which I earned in 1993. A Di pl.Ing is considered equivalent
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`to a master's engineering degree that would be awarded by a U.S. university. Prior
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`to that I had several years of apprenticeship and work experience as a medical
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`technician in Germany.
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`6.
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`I am currently the CEO of HK Packaging Consulting, and have held
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`this position since 2015. In this role, I consult worldwide on parenteral packaging,
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`which includes consulting on syringe selection and related primary packaging issues,
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`and consulting on the role of primary and secondary packaging in dosage form and
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`drug product development.
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`7.
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`At HK Packaging Consulting, I provide technical and regulatory
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`support to both primary packaging manufacturers and pharmaceutical companies.
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`For primary packaging manufacturers, I work on choosing pharmaceutical container
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`materials and components ( vials and syringes), setting container specifications,
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`ensuring compliance and testing in accordance with compendia such as the U.S.,
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`European Pharmacopeias, and the International Organization for Standardization
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`("ISO"), and providing support for regulatory filings with the U.S. Food and Drug
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`Administration ("FDA") and the European Medicines Agency ("EMA" or
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`"EMEA"). For pharmaceutical companies, I work as a consultant to provide
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`3
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`Regeneron Exhibit 1003.008
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`

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`troubleshooting services, including technical support and testing methods relating to
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`primary packaging, design and test manufacturing processes relating to filling and
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`finishing of pharmaceutical containers
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`including syringes,
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`selection and
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`optimization of syringe materials and evaluation of components, and assistance with
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`compendia! compliance and testing and regulatory filings.
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`8.
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`Prior to my current role, I worked at Schott Pharmaceutical Packaging
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`m Germany and Switzerland from 2000 to 2015.
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`Schott is a well-known
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`manufacturer of both glass and polymer pre-filled syringes. At Schott I held the
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`following roles in the Syringe Department: Head of Product Technology for New
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`Products from 2000-01; Manager for Research & Development and Quality
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`Management from 2001-03; Head of Scientific and Regulatory Advisory from 2004-
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`07; Manager of Scientific Advisory from 2007-09; Global Quality Manager for
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`Regulatory Affairs from 2009-11; and finally, Head of Technical and Quality
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`Support for the Syringe Business from 2011-15.
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`9.
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`At Schott, my responsibilities included support of the global syringe
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`business unit regarding questions of technical product requirements and
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`specifications, and support of the global packaging development group for primary
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`and secondary packaging systems with regard to technical, quality and regulatory
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`requirements. My role also included designing and conducting testing programs for
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`packaging systems, especially for glass and polymer syringe systems, including
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`4
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`Regeneron Exhibit 1003.009
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`

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`machine packaging and validation.
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`I coordinated test programs with external
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`partners for extractables and leachables analyses and material testing.
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`10. After earning my degree and prior to working at Schott, I was the
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`Engineering Supervisor at Abbott GmbH in Germany from 1994 to 1999. At Abbott,
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`I was a Research Technician from 1994-95, and then a Supervisor in Engineering
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`Processes from 1995-99. At Abbott, my responsibilities included maintenance and
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`calibration of equipment for manufacturing and research & development, and
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`optimizing packaging lines for pharmaceutical primary and secondary packaging,
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`including container filling and blister packaging.
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`I also lead the cleaning and
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`sterilization center for glass equipment at Abbott.
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`11.
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`In addition to my work experience, I have many years of experience
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`participating in professional organizations, standards setting organizations, and
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`pharmacopeias relating to pharmaceutical packaging including syringes. For
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`example, I am an active member of the ISO technical committee, TC 84 on "Devices
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`for administration of medicinal products and catheters," wherein I am a member of
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`several working groups including WG 3 (needle-based injection systems - injector,
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`container and pen needle) and WG 11 (syringes). I am also an active member of the
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`ISO technical committee, TC 76 on "Transfusion, infusion and injection, and blood
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`processing equipment for medical and pharmaceutical use," wherein I am a member
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`of several working groups including: WG 2 (rigid container system and related
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`5
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`Regeneron Exhibit 1003.010
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`accessories for parenterals and injectables) of which I am the Convenor, WG 4
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`( elastomeric parts and components and related secondary packaging), and WG 6
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`(primary packaging systems for medicinal products). I was ad hoc group leader for
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`the WG 2 ISO committee that developed standard 11040-4 for glass syringes and
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`11040-6 for polymer syringes. I am also the Swiss Medic Delegate for the European
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`Directorate for the Quality of Medicines (EDQM) working group WG 16 on the
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`European Pharmacopoeia Chapter 3 relating to plastics.
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`12.
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`In addition to the above, I have given numerous presentations at
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`symposiums, conferences, and other professional organizational meetings, including
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`many presentations over the years that relate to parenteral manufacturing, pre-filled
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`syringes, extractables, leachables, the packaging of syringe systems, and regulatory
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`(FDA/EMEA) requirements for the packaging of parenterals.
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`13. My curriculum vitae is attached as Exhibit 1004, and provides further
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`information about my experience, expertise, and presentations.
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`14. Through my professional experience, I have gained extensive expertise
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`m synnge manufacturing, testing, siliconization, characterization, regulatory
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`compliance, sales, and have a deep understanding of the worldwide syringe market.
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`Through this experience, I have gained knowledge and experience relating to pre(cid:173)
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`filled syringes, the characterization of syringe stopper movement forces within a
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`syringe, issues relating to syringe component leachables and extractables, issues
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`6
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`Regeneron Exhibit 1003.011
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`

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`relating to siliconization, regulatory requirements on particulate matter for
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`parenterals, and sterilization of container closure systems.
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`15.
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`I am being compensated at my standard rate of $450/hour. My
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`compensation is in no way contingent upon my opinions or the outcome of the
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`proceeding.
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`IV. Relevant Legal Standards
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`16.
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`I am not an attorney, and therefore my understanding of patent law and
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`the legal standards set forth in this report is based on explanations provided to me
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`by counsel.
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`17.
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`I understand that for any claim of a patent to claim priority to an earlier
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`application (i.e., to benefit from the earlier application's filing date), the claims of
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`the later patent must be fully supported by the disclosure of the earlier patent
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`application to which priority is claimed. I understand that in order for the claims to
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`be supported, the earlier application's disclosure must be sufficient to allow a person
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`of ordinary skill in the art to reasonably conclude that the inventors were in
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`possession of the claimed invention.
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`18.
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`I understand that the '631 patent claims priority to a number of patent
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`applications,
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`the earliest of which are European Patent Application No.
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`EP12174860, filed on July 3, 2012, and European Patent Application No.
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`EP12189649, filed on October 23, 2012. However, as I explain in Section VI.A
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`7
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`Regeneron Exhibit 1003.012
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`below, the July 3, 2012 Application No. EP12174860 filing does not support the
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`issued claims of the '631 patent, and therefore the patent claims are not entitled to
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`that priority date, and instead should have a priority date of no earlier than October
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`23, 2012. Nevertheless, for the purposes of my opinions, I have considered the state
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`of the art as of and shortly before July 3, 2012, and the level of knowledge that a
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`POSITA would have possessed at that time. Unless I state otherwise, whenever I
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`refer to any principle or technical subject matter as having been known or
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`understood, this is meant to denote the knowledge and understanding of a POSIT A
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`at or prior to July 3, 2012. 1
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`A.
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`Claim Construction
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`19.
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`It is my further understanding that the numbered paragraphs at the end
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`of the disclosure of a U.S. Patent are the patent "claims" that define the metes and
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`bounds of the alleged invention. I understand that these claims of the '631 patent
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`are what is being challenged in the present IPR proceeding.
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`20.
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`I have been informed that, in this proceeding, the Board must determine
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`the scope of the claims by giving the claims their ordinary and customary meaning
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`1 It is my opinion that there is no appreciable difference between the state of the art
`as of July 3, 2012 and as of October 23, 2012, as it relates to the subject matter
`claimed in the '631 patent. To the extent I have cited any references herein whose
`publication date is after July 3, 2012 (e.g., the Reuter reference), it is my opinion
`that the subject matter disclosed in such references was well-known in the art prior
`to July 3, 2012 as well.
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`8
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`Regeneron Exhibit 1003.013
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`

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`in light of the specification, as the claims would be interpreted by one of ordinary
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`skill in the art.
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`21.
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`I understand that patent claims generally include a "transitional" term
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`or phrase, such as "consisting" or "comprising," which may connect the preamble
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`of the claim to the body of the claim. I have been informed that if a claim uses the
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`term "consisting" as a transition term, that means that the claim is a "closed" claim,
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`which means that the claim is limited to the claim features that follow the transition
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`term and nothing else. On the other hand, I understand that the transition term
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`"comprising" denotes an "open" claim, which means that the claim is not limited to
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`only the features recited in the claim, and could encompass the listed elements as
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`well as other unrecited elements.
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`B.
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`Invalidity
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`22.
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`I understand that Regeneron bears the burden of proving that the
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`challenged claims of the '631 patent are invalid, and must prove this by a
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`preponderance of the evidence, which means that invalidity must be shown to be
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`more likely than not.
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`23.
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`I have been asked to consider the question of whether the claims of the
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`'631 patent would have been obvious.
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`I understand that this analysis must be
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`conducted from the perspective of the person of ordinary skill in the art, and whether
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`the skilled artisan would consider any differences between the prior art and what is
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`9
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`Regeneron Exhibit 1003.014
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`

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`claimed to have been obvious. To make this assessment, I have been informed that
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`the concept of patent obviousness involves four factual inquiries: (1) the scope and
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`content of the prior art; (2) the differences between the claimed invention and the
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`prior art; (3) the level of ordinary skill in the art; and ( 4) secondary considerations
`
`of non-obviousness. I have been instructed that one must not engage in hindsight.
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`Rather, I understand that one should instead consider what the person of ordinary
`
`skill in the art would have reason to pursue further, and steps that were routinely
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`done, such as in response to known problems, steps or obstacles.
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`24.
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`It is my understanding that the following is a non-exhaustive list of
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`rationales that may support the obviousness of an invention: combining prior art
`
`elements according to known methods to yield predictable results; simple
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`substitution of one known element for another to obtain predictable results; use of a
`
`known technique to improve a similar device (method, or product) in the same way;
`
`applying a known technique to a known device (method, or product) ready for
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`improvement to yield predictable results; choosing from a finite number of
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`identified, predictable solutions, with a reasonable expectation of success; and some
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`teaching, suggestion, or motivation in the prior art that would have led a POSIT A to
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`modify the prior art reference or to combine prior art reference teachings to arrive at
`
`the claimed invention.
`
`10
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`Regeneron Exhibit 1003.015
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`

`

`25.
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`It is my understanding that the motivation to combine pnor art
`
`references may be implicit and may be found in the knowledge of one of ordinary
`
`skill in the art, or in the nature of the problem to be solved. Specifically, it is my
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`understanding that an implicit motivation to combine exists not only when a
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`suggestion may be gleaned from the prior art as a whole, but when the
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`"improvement" is technology-independent and the combination of references results
`
`in a product or process that is more desirable, for example because it is stronger,
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`cheaper, cleaner, faster, lighter, smaller, more durable or more efficient. It is my
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`further understanding that the motivation to combine references may be found in the
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`nature of the problem to be solved where prior art references are directed to precisely
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`the same problem.
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`26.
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`I also understand that pnor art may be relied on for its express
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`disclosure and teachings. I also understand that the prior art may be relied upon for
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`a teaching of features that are necessarily present in the prior art reference even if
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`that specific feature is not expressly or explicitly disclosed.
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`27.
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`I understand that before reaching any final conclusion on obviousness,
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`the obviousness analysis requires consideration of objective indicia of non(cid:173)
`
`obviousness, if any such indicia are offered. These must be considered to ensure that,
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`for example, there were not some unanticipated problems, obstacles or hurdles that
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`may seem easy to overcome in hindsight, but which were not readily overcome prior
`
`11
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`Regeneron Exhibit 1003.016
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`

`

`to the relevant invention date of the patents/claims at issue here. I understand that
`
`these objective indicia are also known as "secondary considerations of non(cid:173)
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`obviousness," and may include long-felt but unmet need and unexpected results,
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`among others. I also understand, however, that any offered evidence of secondary
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`considerations of non-obviousness must be comparable with the scope of the
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`challenged claims. This means that for any offered evidence of secondary
`
`considerations of non-obviousness to be given substantial weight, I understand the
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`proponent of that evidence must establish a "nexus" or a sufficient connection or tie
`
`between that evidence and the merits of the claimed invention, which I understand
`
`specifically incorporates any novel element( s) of the claimed invention.
`
`If the
`
`secondary consideration evidence offered actually results from something other than
`
`the merits of the claim, then I understand that there is no nexus or tie to the claimed
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`invention. I also understand it is the Patent Owner who has the burden of proving
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`that a nexus exists, and I understand that secondary considerations will not overcome
`
`a strong showing of obviousness.
`
`C.
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`Person of Ordinary Skill in the Art
`
`28.
`
`I have been asked to review U.S. Patent No. 9,220,631 ("the '631
`
`patent") from the perspective of a person of ordinary skill in the art ("POSIT A") as
`
`of the earliest claimed priority date for the patent-July 3, 2012. I have been asked
`
`to evaluate the disclosure and claims of the '631 patent. I have been further asked
`
`12
`
`Regeneron Exhibit 1003.017
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`to consider whether the prior art renders obvious the pre-filled syringe covered by
`
`claims 1-23 of the '631 patent.
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`29.
`
`It is my opinion that a POSITA relevant to the '631 patent would have
`
`had at least an advanced degree (Dipl.Ing, M.S., or Ph.D.), with research experience
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`in mechanical engineering, biomedical engineering, materials science, chemistry, or
`
`a related field, or at least 2-3 years of professional experience in one or more of those
`
`fields. Furthermore, it is my opinion that a POSITA would have had experience
`
`with (i) the design of pre-filled syringes; and (ii) sterilization of drug delivery
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`devices, including those containing sterilization sensitive therapeutics. Such
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`sterilization experience would include experience with microbiology. Based on my
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`education, training and experience, it is my opinion that I can accurately represent
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`the views of a POSIT A as of the earliest claimed priority date of July 3, 2012, as to
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`at least claims 1-23 of the '631 patent. The opinions I provide in this declaration are
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`provided using the viewpoint of the POSITA as of July 3, 2012.
`
`30. Claims 24-26 relate to methods of treating a patient suffering from eye
`
`disease, by administering an ophthalmic solution using the pre-filled syringe
`
`described in claim 1. Because such intravitreal administration must be performed
`
`by an ophthalmologist, it is my opinion that a POSITA with respect to claims 24-26
`
`would be an ophthalmologist with experience administering VEGF-antagonist drugs
`
`to patients via the intravitreal route. See Ex. 1015.036 ("Since an excellent
`
`13
`
`Regeneron Exhibit 1003.018
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`

`

`knowledge of the anatomy and function of the eye 1s required, only an
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`ophthalmologist should attempt these procedures.").
`
`V.
`
`Background of the Technology
`
`31.
`
`I understand that the claims of the '631 patent are generally directed to
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`pre-filled, terminally-sterilized, low volume glass syringes containing a VEGF(cid:173)
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`antagonist solution, and having low amounts of silicone oil and possessing low break
`
`loose and glide forces for the syringe stopper. In this section, I explain the technical
`
`concepts underlying the claims of the '631 patent, and also how each of these
`
`concepts were well known in the art prior to the effective filing date of the '631
`
`patent.
`
`A.
`
`Intravitreal Administration of VEGF Antagonists
`
`32.
`
`"Intravitreal administration" refers to "injection directly into the
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`vitreous cavity of the eye." Ex. 1015.035. For such injections, "[e]xtreme care and
`
`precise technique are required to minimize or prevent damage to the eye, especially
`
`to the corneal endothelium." Id. at .036. Numerous medical complications could
`
`occur from incorrect intravitreal administration, and only small volumes of around
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`0.1 mL or less should be injected. Id. As such, intravitreal injections are typically
`
`administered only by ophthalmologists. Id.
`
`33.
`
`Several VEGF-antagonists were known and commercially available,
`
`and utilized to various degrees for different reasons beyond the scope of my opinion,
`
`14
`
`Regeneron Exhibit 1003.019
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`

`

`before the earliest priority date of the
`
`'631 patent, including ranibizumab
`
`(Lucentis®), aflibercept (Eylea®), and pegaptanib (Macugen®). See Ex. 1027, Ex.
`
`1040, Ex. 1009. All three of these VEGF-antagonist drug formulations are intended
`
`for
`
`intravitr