UNITED STATES PATENT AND TRADEMARK OFFICE
`
`———————————
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`———————————
`
`REGENERON PHARMACEUTICALS, INC.,
`Petitioner,
`
` v.
`
`NOVARTIS PHARMA AG,
`NOVARTIS TECHNOLOGY LLC,
`NOVARTIS PHARMACEUTICALS CORPORATION,
`Patent Owners.
`
`———————————
`Case IPR2021-00816
`Patent Number: 9,220,631
`
`
`
`REPLY DECLARATION OF HORST KOLLER
`
`
`
`
`
`Regeneron Exhibit 1105.001
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
`
`
`
`
`
`
`
`TABLE OF CONTENTS
`
`
`
`
`
`
`
`
`
`
`
`
`
`Page
`
`
`INTRODUCTION ........................................................................................... 1
`I.
`II. ADDITIONAL LEGAL STANDARDS ......................................................... 1
`A. Motion to Amend .................................................................................. 1
`B.
`Enablement ............................................................................................ 1
`C.
`Indefiniteness ......................................................................................... 2
`III. DEFINITION OF POSITA ............................................................................. 2
`IV. RESPONSES TO ASSERTIONS BY NOVARTIS’S EXPERTS
`CONCERNING THE ORIGINAL CLAIMS OF THE ’631 PATENT .......... 5
`A.
`FREE V. TOTAL SILICONE OIL ....................................................... 5
`B. A POSITA Would Have Had A Reasonable Expectation Of
`Success In Combining Boulange With Sigg Or Lam To Arrive
`At The Claimed Invention ..................................................................... 6
`A POSITA Would Have Been Motivated To Use
`1.
`Boulange’s Stopper B1 ............................................................... 6
`A POSITA Would Not Be Deterred from Using
`a.
`Parylene C ......................................................................... 6
`Parylene C Would Not Come in Contact with the
`VEGF-Antagonist ...........................................................10
`A POSITA Would Have Been Motivated to Use
`Boulange’s Stopper C ...............................................................12
`A POSA Would Have Been Motivated to Make a VEGF-
`Antagonist Solution Having No More Than 2 Particles
`(cid:42)(cid:85)(cid:72)(cid:68)(cid:87)(cid:72)(cid:85)(cid:3)(cid:55)(cid:75)(cid:68)(cid:81)(cid:3)(cid:24)(cid:19)(cid:3)(cid:541)(cid:80)(cid:3)(cid:76)(cid:81)(cid:3)(cid:39)(cid:76)(cid:68)(cid:80)(cid:72)(cid:87)(cid:72)(cid:85)(cid:3)(cid:83)(cid:72)(cid:85)(cid:3)(cid:48)(cid:76)(cid:79)(cid:79)(cid:76)(cid:79)(cid:76)(cid:87)(cid:72)(cid:85) ........................18
`C. A POSITA Would Have Had A Reasonable Expectation Of
`Success In Combining Boulange With Sigg Or Lam To Arrive
`At The Claimed Invention ...................................................................19
`Boulange Discloses Components that Ensure A
`1.
`Sufficiently Tight Seal ..............................................................20
`The Prior Art Taught How to Prevent Stopper Movement
`During Sterilization ...................................................................23
`
`b.
`
`2.
`
`3.
`
`2.
`
`
`
`
`i
`
`Regeneron Exhibit 1105.002
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`3.
`
`5.
`
`D.
`
`E.
`
`F.
`
`G.
`
`H.
`
`Sigg Discloses Terminal Sterilization with Minimal
`Pressure Change, Eliminating Any Problems Created by
`Pressure Changes during Terminal Sterilization ......................26
`4. Macugen PFS Demonstrates that a POSITA Would Have
`Expected to Succeed in Terminally Sterilizing a PFS ..............28
`Eylea PFS Demonstrates a POSITA Would Have
`Reasonably Expected to Succeed with Terminal
`Sterilization ...............................................................................28
`Sigg And Lam Enable a Terminally Sterilized PFS In View of
`the Prior Art .........................................................................................29
`1.
`Sigg Is Enabled .........................................................................29
`2.
`Lam Is Enabled .........................................................................32
`The Potency Data in Lam Would Not Have Deterred a POSITA
`from Using Its Method ........................................................................33
`The Additional Limitations In Claims 17 and 21 Are Obvious
`Over Sigg In View Of Boulange .........................................................34
`1.
`Claim 17 ....................................................................................34
`2.
`Claim 21 ....................................................................................35
`The Additional Limitations In Claims 17 and 21 Are Obvious
`Over Lam In View Of Boulange .........................................................36
`The Additional Limitations In Claims 24-26 Are Obvious Over
`Sigg Or Lam In View Of Boulange ....................................................38
`1.
`Claim 24 ....................................................................................39
`2.
`Claim 25 ....................................................................................39
`3.
`Claim 26 ....................................................................................40
`SECONDARY CONSIDERATIONS ...........................................................41
`A.
`Commercial Success............................................................................41
`Ophthalmologists Do Not Use Lucentis PFS Because Of
`1.
`The Features Claimed In The ’631 Patent ................................41
`There Is No Nexus Between Lucentis PFS And The ’631
`Patent .........................................................................................42
`Long Felt, Unmet Need .......................................................................46
`
`V.
`
`
`
`
`2.
`
`B.
`
`ii
`
`Regeneron Exhibit 1105.003
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`Skepticism ...........................................................................................50
`C.
`Failure Of Others .................................................................................52
`D.
`Licensing .............................................................................................53
`E.
`VI. EACH SUBSTITUTE CLAIMS PROPOSED BY NOVARTIS IS
`UNPATENTABLE ........................................................................................59
`A. Novartis’s Proposed Substitute Claims ...............................................59
`B. Overview of Additional Prior Art References to Proposed
`Substitute Claims .................................................................................61
`BD – The Hypak 1 mL LLA EZGTC syringe offered for
`1.
`sale by Becton Dickinson (“BD 1 mL Hypak”) .......................61
`2. Macugen Pre-Filled Syringe .....................................................66
`“Nema” – Sandeep Nema & John D. Ludwig,
`3.
`Pharmaceutical Dosage Forms: Parenteral Medication,
`Volume 1-2 (3rd ed. 2010). .......................................................76
`Sigg in View of Boulange or BD 1 mL Hypak and Nema
`Renders Obvious the Substitute Claims 27-29, 31-35, 40-48,
`and 50 ..................................................................................................77
`1. Motivation to Combine Sigg, Boulange or BD 1 mL
`Hypak, and Nema ....................................................................78
`a.
`Silicone Oil and Break Loose / Slide Forces ..................78
`b.
`Particulate Content .........................................................78
`c.
`Terminal Sterilization .....................................................79
`d.
`Twelve-Month Shelf-life ................................................79
`Reasonable Expectation of Success .......................................80
`a.
`(cid:54)(cid:76)(cid:79)(cid:76)(cid:70)(cid:82)(cid:81)(cid:72)(cid:3)(cid:50)(cid:76)(cid:79)(cid:3)(cid:47)(cid:72)(cid:89)(cid:72)(cid:79)(cid:3)(cid:37)(cid:72)(cid:79)(cid:82)(cid:90)(cid:3)(cid:68)(cid:69)(cid:82)(cid:88)(cid:87)(cid:3)(cid:21)(cid:24)(cid:3)(cid:541)(cid:74) ...........................81
`b.
`Twelve-Month Shelf Life ...............................................85
`Sigg in View of Boulange or BD 1 mL Hypak and Nema
`Discloses Each Limitation of Substitute Claim 27 ...................97
`[27.a] A pre-filled, terminally sterilized syringe for
`a.
`intravitreal injection ........................................................97
`[27.b] the syringe comprising a glass body forming
`a barrel, a stopper and a plunger .....................................97
`
`b.
`
`
`
`
`iii
`
`Regeneron Exhibit 1105.004
`Regeneron v. Novartis
`IPR2021-00816
`
`C.
`
`2.
`
`3.
`
`

`

`e.
`
`f.
`
`g.
`
`h.
`
`[27.c] and containing an ophthalmic solution
`which comprises a VEGF-antagonist, wherein: .............99
`[27.d] the syringe has a nominal maximum fill
`volume of between about 0.5 ml and about 1 ml .........100
`[27.e] the syringe barrel comprises from about 1
`(cid:541)(cid:74)(cid:3)(cid:87)(cid:82)(cid:3)(cid:68)(cid:69)(cid:82)(cid:88)(cid:87)(cid:3)(cid:21)(cid:24)(cid:3)(cid:541)(cid:74)(cid:3)(cid:86)(cid:76)(cid:79)(cid:76)(cid:70)(cid:82)(cid:81)(cid:72)(cid:3)(cid:82)(cid:76)(cid:79) .......................................100
`[27.f] the VEGF antagonist solution comprises no
`(cid:80)(cid:82)(cid:85)(cid:72)(cid:3)(cid:87)(cid:75)(cid:68)(cid:81)(cid:3)(cid:21)(cid:3)(cid:83)(cid:68)(cid:85)(cid:87)(cid:76)(cid:70)(cid:79)(cid:72)(cid:86)(cid:3)(cid:33)(cid:24)(cid:19)(cid:3)(cid:541)(cid:80)(cid:3)(cid:76)(cid:81)(cid:3)(cid:71)(cid:76)(cid:68)(cid:80)(cid:72)(cid:87)(cid:72)(cid:85)(cid:3)(cid:83)(cid:72)(cid:85)(cid:3)(cid:80)(cid:79) ........102
`[27.g] and wherein the syringe has a stopper break
`loose force of less than about 11N ...............................102
`[27.h] and has a shelf life of at least twelve months
`after terminal sterilization .............................................106
`Substitute Claim 28 .................................................................106
`4.
`Substitute Claims 29 and 48 ...................................................107
`5.
`Substitute Claims 31-35 ..........................................................108
`6.
`Substitute Claim 40 .................................................................108
`7.
`Substitute Claim 41 .................................................................111
`8.
`Substitute Claim 42 .................................................................112
`9.
`10. Substitute Claims 43-47 ..........................................................115
`11. Substitute Claim 50 .................................................................115
`Sigg in View of Boulange or BD 1 mL Hypak, Nema, and
`Further in View of Fries, Renders Obvious Substitute Claims
`30, 36, and 49 ....................................................................................116
`Sigg in View of Boulange or BD 1 mL Hypak, Nema, and
`Further in View of Furfine, Renders Obvious Substitute Claims
`37-39 ..................................................................................................117
`Sigg in View of Boulange or BD 1 mL Hypak, Nema, and
`Further in View of Macugen PFS 2008 Label, Renders Obvious
`Substitute Claim 51 ...........................................................................118
`Sigg in View of Boulange or BD 1 mL Hypak, Nema, and
`Further in View of Dixon, Renders Obvious Substitute Claim
`52 .......................................................................................................119
`
`c.
`
`d.
`
`D.
`
`E.
`
`F.
`
`G.
`
`
`
`
`iv
`
`Regeneron Exhibit 1105.005
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`b.
`
`H. Macugen PFS in View of Boulange or BD 1 mL Hypak
`Renders Obvious Substitute Claims 27-29, 31-32, 37, 40-48,
`and 50-51 ...........................................................................................119
`1. Motivation to Combine Macugen and Boulange and/or
`BD 1 mL Hypak with a Reasonable Expectation of
`Success ....................................................................................120
`2. Macugen PFS in View of Boulange or BD 1 mL Hypak
`Renders Obvious Each Limitation of Substitute Claim 27 .....123
`[27.a] A pre-filled, terminally sterilized syringe for
`a.
`intravitreal injection ......................................................123
`[27.b] the syringe comprising a glass body forming
`a barrel, a stopper and a plunger ...................................127
`[27.c] and containing an ophthalmic solution
`which comprises a VEGF-antagonist, wherein: ...........131
`[27.d] the syringe has a nominal maximum fill
`volume of between about 0.5 ml and about 1 ml .........131
`[27.e] the syringe barrel comprises from about 1
`(cid:541)(cid:74)(cid:3)(cid:87)(cid:82)(cid:3)(cid:68)(cid:69)(cid:82)(cid:88)(cid:87)(cid:3)(cid:21)(cid:24)(cid:3)(cid:541)(cid:74)(cid:3)(cid:86)(cid:76)(cid:79)(cid:76)(cid:70)(cid:82)(cid:81)(cid:72)(cid:3)(cid:82)(cid:76)(cid:79) .......................................133
`[27.f] the VEGF antagonist solution comprises no
`(cid:80)(cid:82)(cid:85)(cid:72)(cid:3)(cid:87)(cid:75)(cid:68)(cid:81)(cid:3)(cid:21)(cid:3)(cid:83)(cid:68)(cid:85)(cid:87)(cid:76)(cid:70)(cid:79)(cid:72)(cid:86)(cid:3)(cid:33)(cid:24)(cid:19)(cid:3)(cid:541)(cid:80)(cid:3)(cid:76)(cid:81)(cid:3)(cid:71)(cid:76)(cid:68)(cid:80)(cid:72)(cid:87)(cid:72)(cid:85)(cid:3)(cid:83)(cid:72)(cid:85)(cid:3)(cid:80)(cid:79) ........134
`[27.g] and wherein the syringe has a stopper break
`loose force of less than about 11N ...............................136
`[27.h] and has a shelf life of at least twelve months
`after terminal sterilization .............................................138
`Substitute Claim 28 .................................................................138
`3.
`Substitute Claims 29 and 48 ...................................................139
`4.
`Substitute Claims 31 and 32 ...................................................140
`5.
`Substitute Claim 37 .................................................................141
`6.
`Substitute Claims 40 and 41 ...................................................142
`7.
`Substitute Claim 42 .................................................................143
`8.
`Substitute Claim 43 .................................................................144
`9.
`10. Substitute Claims 44 and 45 ...................................................148
`11. Substitute Claim 46 .................................................................152
`v
`
`e.
`
`f.
`
`g.
`
`h.
`
`c.
`
`d.
`
`
`
`
`Regeneron Exhibit 1105.006
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`12. Substitute Claim 47 .................................................................155
`13. Substitute Claim 50 .................................................................157
`14. Substitute Claim 51 .................................................................158
`I. Macugen PFS in View of Boulange or BD 1 ml Hypak, and
`Further in View of Fries, Renders Obvious Substitute Claims
`30, 36, and 49 ....................................................................................159
`J. Macugen PFS in View of Boulange or BD 1 ml Hypak, and
`Further in View of Sigg, Renders Obvious Substitute Claims
`33-35 ..................................................................................................159
`K. Macugen PFS in View of Boulange or BD 1 mL Hypak, and
`Further in View of Furfine, Renders Obvious Substitute Claims
`37-39 ..................................................................................................161
`L. Macugen PFS in View of Boulange and/or BD 1 mL Hypak,
`and Further in View of Dixon, Renders Obvious Substitute
`Claim 52 ............................................................................................162
`M. Lam In View of Boulange or BD 1 ml Hypak and Nema
`Renders Obvious Substitute Claims 27-29, 31-35, 40-48, and 50 ....163
`1. Motivation to Combine Lam, Boulange and/BD 1 mL
`Hypak, and Nema with a Reasonable Expectation of
`Success ....................................................................................163
`Lam in View of Boulange and/or BD 1 mL Hypak and
`Nema Discloses Each Limitation of Substitute Claim 27 ......163
`[27.a] A pre-filled, terminally sterilized syringe for
`a.
`intravitreal injection ......................................................163
`[27.b] the syringe comprising a glass body forming
`a barrel, a stopper and a plunger ...................................164
`[27.c] and containing an ophthalmic solution
`which comprises a VEGF-antagonist, wherein: ...........164
`[27.d] the syringe has a nominal maximum fill
`volume of between about 0.5 ml and about 1 ml .........164
`[27.e] the syringe barrel comprises from about 1
`(cid:541)(cid:74)(cid:3)(cid:87)(cid:82)(cid:3)(cid:68)(cid:69)(cid:82)(cid:88)(cid:87)(cid:3)(cid:21)(cid:24)(cid:3)(cid:541)(cid:74)(cid:3)(cid:86)(cid:76)(cid:79)(cid:76)(cid:70)(cid:82)(cid:81)(cid:72)(cid:3)(cid:82)(cid:76)(cid:79) .......................................165
`[27.f] the VEGF antagonist solution comprises no
`(cid:80)(cid:82)(cid:85)(cid:72)(cid:3)(cid:87)(cid:75)(cid:68)(cid:81)(cid:3)(cid:21)(cid:3)(cid:83)(cid:68)(cid:85)(cid:87)(cid:76)(cid:70)(cid:79)(cid:72)(cid:86)(cid:3)(cid:33)(cid:24)(cid:19)(cid:3)(cid:541)(cid:80)(cid:3)(cid:76)(cid:81)(cid:3)(cid:71)(cid:76)(cid:68)(cid:80)(cid:72)(cid:87)(cid:72)(cid:85)(cid:3)(cid:83)(cid:72)(cid:85)(cid:3)(cid:80)(cid:79) ........165
`
`2.
`
`b.
`
`c.
`
`d.
`
`e.
`
`f.
`
`
`
`
`vi
`
`Regeneron Exhibit 1105.007
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`g.
`
`h.
`
`N.
`
`O.
`
`[27.g] and wherein the syringe has a stopper break
`loose force of less than about 11N ...............................165
`[27.h] and has a shelf life of at least twelve months
`after terminal sterilization .............................................165
`Substitute Claim 28 .................................................................166
`3.
`Substitute Claims 29 and 48 ...................................................166
`4.
`Substitute Claims 31 and 32 ...................................................167
`5.
`Substitute Claim 33-35 ...........................................................167
`6.
`Substitute Claims 40 and 41 ...................................................168
`7.
`Substitute Claim 42 .................................................................168
`8.
`Substitute Claim 43 .................................................................169
`9.
`10. Substitute Claim 44 and 45 .....................................................169
`11. Substitute Claim 46 .................................................................170
`12. Substitute Claim 47 .................................................................170
`13. Substitute Claim 50 .................................................................170
`Lam in View of Boulange or BD 1 mL Hypak, Nema, and
`Further in View of Fries, Renders Obvious Substitute Claims
`30, 36, and 49 ....................................................................................171
`Lam in View of Boulange and/or BD 1 mL Hypak, Nema, and
`Further in View of Furfine, Renders Obvious Substitute Claims
`37-39 ..................................................................................................172
`Lam in View of Boulange or BD 1 ml Hypak, Nema, and
`Further in View of Macugen PFS 2008 Label, Renders Obvious
`Substitute Claim 51 ...........................................................................173
`Lam in View of Boulange and/or BD 1 mL Hypak, Nema, and
`Further in View of Dixon, Renders Obvious Substitute Claim
`52 .......................................................................................................174
`The ’631 Patent Does Not Enable Each of the Substitute Claims ....174
`R.
`Each Substitute Claim is Indefinite ...................................................178
`S.
`VII. DECLARATION .........................................................................................180
`
`
`P.
`
`Q.
`
`
`
`
`vii
`
`Regeneron Exhibit 1105.008
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`I.
`
`INTRODUCTION
`1.
`I have been retained as an expert by Weil, Gotshal & Manges LLP
`
`(“Counsel”) for Petitioner Regeneron Pharmaceuticals, Inc. (“Petitioner” or
`
`“Regeneron”) in connection with a petition for inter partes review of U.S. Patent
`
`No. 9,220,631 (the “’631 Patent”). My qualifications and compensation are set
`
`forth in my Original Declaration that I signed on April 16, 2021 (“Original
`
`Declaration”). See Ex. 1003 at ¶¶ 5-17.
`
`II. ADDITIONAL LEGAL STANDARDS
`2.
`I describe below the legal standards I considered when forming this
`
`supplemental declaration, in addition to the legal standards I considered in forming
`
`my Original Declaration. See Ex. 1003 at ¶¶ 18-32.
`
`A. Motion to Amend
`3.
`I understand that the Patent Owner may move to amend the
`
`challenged patent in an IPR proceeding. I further understand that such motion is
`
`contingent upon the Board finding the original claims invalid.
`
`B.
`4.
`
`Enablement
`I understand that a patent satisfies the enablement requirement if the
`
`disclosure in the patent, coupled with information in the art, allows a POSITA to
`
`make or use the full scope of the claimed invention without undue
`
`experimentation. I understand that the question of undue experimentation may
`
`depend on several factors including the time and cost of any necessary
`
`
`
`1
`
`Regeneron Exhibit 1105.009
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`experimentation, how routine any such experimentation is in the field, whether the
`
`patent discloses specific working examples of the claimed invention, the amount of
`
`guidance presented in the patent, the nature and predictability of the field, the level
`
`of ordinary skill in the field, and the nature and scope of the claimed invention. I
`
`further understand that the enablement requirement is assessed from the viewpoint
`
`of a person of ordinary skill in the art as of the effective filing date.
`
`C.
`5.
`
`Indefiniteness
`I understand that a claim is indefinite if the claim, read in light of the
`
`specification and prosecution history, fails to inform with reasonable certainty
`
`those skilled in the art about the scope of the invention.
`
`III. DEFINITION OF POSITA
`6.
`I understand that Mr. Leinsing has proposed a definition of a
`
`POSITA. See Ex. 2201 at ¶ 16. I reproduce Mr. Leinsing’s and my definitions of a
`
`POSITA below:
`
`Regeneron
`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 in mechanical
`engineering, biomedical engineering,
`materials science, chemistry, or a
`related field, or at least 2-3 years of
`
`Novartis
`a POSA for all claims of the ’631
`patent would have had an advanced
`degree (i.e., an M.S., a Ph.D., or
`equivalent), and at least 2-3 years of
`professional experience, in mechanical
`engineering, biomedical engineering,
`materials science, chemistry, chemical
`
`
`
`
`2
`
`Regeneron Exhibit 1105.010
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`Regeneron
`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 devices, including those
`containing sterilization sensitive
`therapeutics. Such sterilization
`experience would include experience
`with microbiology.
`
`Novartis
`engineering, or a related field,
`including experience with the design of
`a PFS and/or the development of
`ophthalmologic drug products or drug
`delivery devices. Such a person would
`have been a member of a product
`development team and would have
`drawn upon not only his or her own
`skills, but also the specialized skills of
`team members in complementary fields
`including ophthalmology,
`microbiology and toxicology.
`
`
`
`7.
`
`Under Mr. Leinsing’s definition, “[a POSITA] would have been a
`
`member of a product development team and would have drawn upon not only his
`
`or her own skills, but also the specialized skills of team members in
`
`complementary fields including ophthalmology, microbiology and toxicology.”
`
`This additional requirement does not materially impact my definition of POSITA
`
`because it would have been common for a POSITA to have been part of a product
`
`development team and have drawn upon specialized skills of other team members,
`
`to the extent necessary, during the development of the product.
`
`8. My opinions do not change and are equally valid under either
`
`definition of POSITA. Furthermore, based on my education, training and
`
`
`
`
`3
`
`Regeneron Exhibit 1105.011
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`experience, it is my opinion that I can accurately represent the views of a POSITA
`
`as of the earliest claimed priority date of July 3, 2012 under either definition of
`
`POSITA.
`
`9. Mr. Leinsing asserts that the subject matter described in the ’631
`
`Patent would require reference to someone with “specialized skills” in toxicology
`
`and microbiology. I disagree.
`
`10. The ’631 Patent, for example, is silent as to toxicology concerns
`
`associated with designing a PFS for intravitreal injection. Aside from describing a
`
`glass syringe barrel coated with silicone oil, the ’631 Patent does not describe what
`
`stopper materials and coatings would be suitable for a PFS for intravitreal injection
`
`from a toxicology standpoint. In my experience, syringe designers have sufficient
`
`knowledge concerning toxicology issues as it relates to assessing and selecting
`
`suitable materials for a PFS. In contrast, toxicologists are generally involved in the
`
`design process only with respect to conducting and analyzing testing required for
`
`FDA approval.
`
`11. Mr. Leinsing further asserts that specialized skills concerning
`
`“microbiology” are required based on the disclosure in the ’631 Patent. I disagree.
`
`12. The ’631 Patent does not identify any specific microbiology issues
`
`associated with designing a PFS. Microbiology is only pertinent to the ’631 Patent
`
`to the extent that the purpose of terminal sterilization is to kill any bacteria and
`
`
`
`
`4
`
`Regeneron Exhibit 1105.012
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`other microorganisms that may be present on the outer surface of the syringe.
`
`Thus, in my opinion a POSITA having knowledge of syringe design and terminal
`
`sterilization would have sufficient knowledge of microbiology as it relates to the
`
`’631 Patent.
`
`IV. RESPONSES TO ASSERTIONS BY NOVARTIS’S EXPERTS
`CONCERNING THE ORIGINAL CLAIMS OF THE ’631 PATENT
`13.
`In the sections below, I respond to certain issues raised by Novartis’s
`
`experts concerning the original claims of the ’631 Patent.
`
`A.
`FREE V. TOTAL SILICONE OIL
`14. Mr. Leinsing asserts that the prior art does not teach that baked-on
`
`siliconization “uses less total silicone oil …, only less free silicone oil, i.e., silicone
`
`oil that is not tightly bonded to the glass surface.” Ex. 2201 at ¶¶ 19-20. I disagree.
`
`15. Further to my explanation in my Original Declaration (Ex. 1003 at ¶¶
`
`64-66), Boulange clearly discloses that baked-on siliconization decreases the
`
`amount of total silicone oil, and specifically describes applying 4 (cid:541)(cid:74) per cm2 ± 1
`
`using baked-on versus 50 (cid:541)(cid:74) per cm2 with a sprayed on process. See Ex. 1008 at
`
`Table 7. Although the prior art also describes baked-on siliconization providing a
`
`benefit of less free silicone oil (i.e., less silicone oil that can migrate into the drug
`
`product), Boulange reflects a POSITA’s understanding that the baked-on process
`
`was also known to apply less total silicone oil.
`
`
`
`
`5
`
`Regeneron Exhibit 1105.013
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`B. A POSITA Would Have Had A Reasonable Expectation Of
`Success In Combining Boulange With Sigg Or Lam To Arrive At
`The Claimed Invention
`1.
`A POSITA Would Have Been Motivated To Use Boulange’s
`Stopper B1
`16. Mr. Leinsing has opined that a POSITA would not have been
`
`motivated to use Parylene C in a PFS filled with a VEGF antagonist. Ex. 2201,
`
`§V.B.1. I disagree.
`
`17. For several reasons, I disagree that any concerns about purported
`
`compatibility issues between Parylene C and the VEGF antagonist contained in the
`
`PFS would have deterred a POSITA from using Boulange’s stopper B1.
`
`a.
`
`A POSITA Would Not Be Deterred from Using
`Parylene C
`18. Mr. Leinsing and Dr. Dillberger identify two articles (Exs. 2030 and
`
`2031) that they contend would have deterred a POSITA from using Parylene C due
`
`to purported cytotoxicity concerns and high protein adsorption. I disagree that the
`
`teachings of these references would have deterred a POSITA from using Parylene
`
`C as a stopper coating in a PFS.
`
`19. Both Exs. 2030 and 2031 describe the use of Parylene C to coat
`
`biomedical devices which are implanted in the body. Ex. 2030.001-.002
`
`(“parylene-C, is one such potential candidate for fabricating biomedical devices.”);
`
`Ex. 2031.002 (“Parylene C, is a promising candidate for metallic implant coatings
`
`separating an implant body from the surrounding tissues.”). First, because these
`6
`
`
`
`
`Regeneron Exhibit 1105.014
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`references related to a different application of Parylene C, they would not have
`
`dissuaded a POSITA designing a PFS from using Parylene C as a stopper coating.
`
`20. Second, to the extent a POSITA would find these references relevant
`
`to the use of Parylene C on a stopper, because both describe that Parylene C had
`
`been used in implantable devices, they would indicate to a POSITA that Parylene
`
`C had been tested for and met requirements for toxicity, such as ISO 10993. See
`
`Ex. 1074.010 (describing Parylene C passing ISO 10993 testing).
`
`21. Third, even though they are directed to a different use for Parylene C,
`
`both Exs. 2030 and 2031 encourage the use of Parylene C in medical devices. Ex.
`
`2030.002 (“Parylene-C is a thermoplastic, crystalline, and transparent polymer that
`
`is extensively used as a coating for insulating implantable biomedical devices.”);
`
`Ex. 2031.006 (“The results presented strongly support the thesis that parylene C is
`
`worth considering for biomedical use.”); Ex. 1209 (Dillberger Dep. Tr.) at 63:16-
`
`64:5, 69:2-22. Thus, if anything, these references would indicate to a POSITA that
`
`Parylene C did not create toxicity concerns when implanted into the human body
`
`and/or when it interacts with proteins, and would thus be a promising material
`
`candidate for use as a coating in a PFS comprising a VEGF-antagonist.
`
`22. Mr. Leinsing also asserts that a POSITA would not have been
`
`motivated to use a Parylene C coated stopper because “multiple prior art references
`
`
`
`
`7
`
`Regeneron Exhibit 1105.015
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`indicate that Parylene C has high adsorption of proteins.” Ex. 2001 at ¶ 162. I
`
`disagree.
`
`23. Mr. Leinsing relies on Ex. 2030, which shows that for the proteins
`
`tested, the protein adsorption of silicone oil was roughly comparable to that of
`
`Parylene C. Ex. 2030.004 (Figure 1 showing protein adsorption of PDMS (silicone
`
`oil) and parylene-C). Comparing each to glass, Ex. 2030 explains that for one
`
`protein “adsorption level on plain PDMS and as-deposited parylene-C were 3 times
`
`higher relative to glass,” but for the other proteins “adsorption levels on plain
`
`PDMS and as-deposited parylene-C were similar to adsorption on glass.” Ex.
`
`2030.005. The conclusion that is drawn is that the “discrepancy is caused by the
`
`intrinsic difference in the structure of two proteins.” Ex. 2030.006. A POSITA
`
`would understand from this data that silicone oil and Parylene C adsorption are
`
`approximately the same, and can also depend on the precise structure of a given
`
`protein. See also Ex. 1209 (Dillberger Dep. Tr.) at 23:19-24:6, 61:19-62:21.
`
`Further, Ex. 2030 found that the level of adsorption can be modified, and “plasma
`
`treatment of parylene-C and PDMS increased the hydrophilicity of the surfaces and
`
`reduced the adhesion of both.” Ex. 2030.006.
`
`24. The other article cited by Mr. Leinsing states that the adsorption
`
`properties depend on the underlying materials, which in this case was steel and not
`
`
`
`
`8
`
`Regeneron Exhibit 1105.016
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`glass or rubber. Thus, Ex. 2031 would not inform a POSITA how Parylene C
`
`would adsorb to proteins if applied to a rubber stopper.
`
`25. Mr. Leinsing also asserts that testing requirements would have
`
`dissuaded a POSITA from using Parylene C in a PFS. I disagree.
`
`26. A POSIT