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.
`
`Patent Number: 9,220,631
`
`DECLARATION OF HORST KOLLER
`
`Novartis Exhibit 2004.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`TABLE OF CONTENTS
`
`I.
`
`II.
`
`III.
`
`IV.
`
`Introduction
`
`Summary of Opinions
`
`Qualifications and Compensation
`
`Relevant Legal Standards
`
`A.
`
`B.
`
`C.
`
`Claim Construction
`
`Invalidity
`
`Person of Ordinary Skill in the Art
`
`V.
`
`Background of the Technology
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`F.
`
`Intravitreal Administration of VEGF Antagonists
`
`Pre-filled Syringes
`
`Syringe Stopper Forces
`
`Siliconization of Pre-filled Syringe Components
`
`1.
`
`2.
`
`3.
`
`“Oily” or “Spray-on” Siliconization
`
`“Baked-On” Siliconization
`
`Coated, Uncoated, and Siliconized Stoppers
`
`Sterilization of Pre-filled Syringes
`
`Particulate Content
`
`VI.
`
`The ‘631 Patent
`
`Page
`
`l1
`
`1
`
`3
`
`79
`
`810
`
`911
`
`1214
`
`1416
`
`1416
`
`1517
`
`2023
`
`2428
`
`2630
`
`3033
`
`3640
`
`3944
`
`4653
`
`4855
`
`4855
`
`The Claims
`
`A.
`
`B.
`
`5259
`Overview of Specification
`1.
`The ‘631 patent fails to disclose a process for applying lowthe claimed
`5259
`levels of silicone oil
`
`Novartis Exhibit 2004.002
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`2.
`
`The ‘631 patent fails to disclose the process details for terminal
`sterilization
`
`C.
`
`Prosecution History
`
`CD. Meaning of the Claim TermsConstruction
`
`VII.
`
`The Prior Art to the ‘631 Patent
`
`A.
`B.
`
`C.
`
`D.
`
`E.
`
`F.
`
`G.
`
`“Sigg” -WO 2011/006877
`“Lam” -International Pat. Appl. Pub. No. WO 2008/077155
`
`“Boulange” -International Pat. Appl. Pub. No. WO 2009/030976
`
`“Reuter” -Bruno Reuter & Claudia Petersen, Syringe Siliconization, 4
`TechnoPharm 2, 238 (2012)2008 Macugen Label
`
`“Fries” -A. Fries, Drug Delivery of Sensitive Biopharmaceuticals with
`prefilledPrefilled Syringes, Drug Delivery Technology, Vol. 9, No. 5
`
`“Furfine” -WO 2007/149334
`
`“Macugen Label” -Macugen® Prescribing Information
`
`5361
`
`64
`
`5368
`
`5570
`
`5570
`6076
`
`6581
`
`7189
`
`7792
`
`7893
`
`78
`
`VIII. Petition 1, Ground 1: Sigg in View of Boulange Renders Obvious Claims 1-3,5-9, and1-3,
`5-9, 14-22
`7994
`
`A.
`
`Motivation to Combine Sigg and Boulange
`
`1.
`2.
`
`3.
`
`Silicone Oil and Break Loose / Slide Forces
`Particulate Content
`
`Stopper Configurations
`
`Reasonable Expectation of Success
`
`7994
`
`7994
`87101
`
`103
`
`111
`
`B.
`
`BC.
`
`Claim I
`1.
`
`891
`[1.a] A pre-filled, terminally sterilized syringe for intravitreal injection89116
`
`116
`
`2.
`
`3.
`
`[1.b] the syringe comprising a glass body forming a barrel, a stopper and
`90118
`a plunger
`
`[1.c] and containing an ophthalmic solution which comprises a
`VEGF-antagonist, wherein:
`
`92120
`
`Novartis Exhibit 2004.003
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`4.
`
`5.
`
`6.
`
`7.
`
`[1.d] the syringe has a nominal maximum fill volume of between about
`93122
`0.5 mL and about 1 mL
`
`[1.e] the syringe barrel comprises from about 1 μgµg to 100 μgµg
`silicone oil
`
`95124
`
`[1.f] the VEGF-antagonist solution comprises no more than 2 particles >
`96127
`50 μm in diameter per mL
`
`[1.g] and wherein the syringe has a stopper break loose force of less than
`99129
`about 11N
`
`CD.
`
`Claims 2, 3, 5-9, 14, 16-22 and 2414-22
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`Claim 2
`
`Claims 3 and 22
`
`Claims 5 and 6
`
`Claims 7, 8, and 9
`
`Claims 14 and 16
`
`Claim 15
`
`Claim 17
`
`Claims 18 and 19
`
`Claim 20
`
`10.
`
`Claim 21
`
`100132
`
`100132
`
`102133
`
`103134
`
`103135
`
`104136
`
`106139
`
`109141
`
`110142
`
`112144
`
`114146
`
`IX.
`
`X.
`
`Petition 1, Ground 23: Sigg in View of Boulange and Fries Renders Obvious Claims 4,
`l16148
`10, and 23
`
`Petition 1, Ground 35: Sigg in view of Boulange and Furfine Renders Obvious Claims
`118151
`11-13
`
`A.
`
`B.
`
`Claims 11 and 12
`
`Claim 13
`
`119
`
`120
`
`XI.
`
`PetitionGround 2, Ground I: Lam in View of ReuterBoulange Renders Obvious Claims
`1-101-3, 59, and 14-2314-22
`121154
`
`A.
`
`Motivation to Combine Lam and Reuter121Boulange With a Reasonable Expectation of Success
`
`Novartis Exhibit 2004.004
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Silicone Oil and Break Loose / Slide Forces
`
`Particulate Content
`
`1.
`
`2.
`
`B.
`
`Claim I
`
`121155
`
`128157
`
`1301
`
`159
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`[1.a] A pre-filled, terminally sterilized syringe for intravitreal injection130159
`
`[1.b] the syringe comprising a glass body forming a barrel, a stopper and
`132160
`a plunger
`
`[1.c] and containing an ophthalmic solution which comprises a
`VEGF-antagonist, wherein:
`
`133161
`
`[1.d] the syringe has a nominal maximum fill volume of between about
`134162
`0.5 mL and about 1 mL
`
`[1.e] the syringe barrel comprises from about 1 μgµg to 100 μgµg
`silicone oil
`
`134163
`
`[1.f] the VEGF-antagonist solution comprises no more than 2 particles
`137163
`>50 μm in diameter per mL
`
`[1.g] and wherein the syringe has a stopper break loose force of less than
`140166
`about 11N
`
`C.
`
`Claims 2-102, 3, 5-9, and 14-2414-22
`
`1.
`
`2.
`
`3.
`
`43.
`
`54.
`
`65.
`
`76.
`
`87.
`
`98.
`
`Claim 2
`
`Claims 3 and 22
`
`Claims 4, 10, and 23
`
`Claims 5 and 6
`
`Claims 7, 8, and 9
`
`Claims 14 and 16
`
`Claim 15
`
`Claim 17
`
`Claims 18 and 19
`
`109.
`
`Claim 20
`
`142166
`
`142166
`
`142166
`
`143
`
`144167
`
`145167
`
`146168
`
`147168
`
`150169
`
`151170
`
`152172
`
`Novartis Exhibit 2004.005
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`1110. Claim 21
`
`153173
`
`XII. Ground 4: Lam in View of Boulange and Fries Renders Obvious Claims 4, 10, and
`23
`176
`
`XII.
`
`Petition 2, XIII.Ground 26: Lam in view of ReuterBoulange and Furfine Renders Obvious Claims 11-13155
`
`XIV. SECONDARY CONSIDERATIONS
`
`177
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`Claims 11 and 12
`
`Claim 13
`
`Industry Praise
`
`Commercial Success
`
`Failure of Others
`
`156Long-Felt Need
`
`157Unexpected Results
`
`177
`
`184
`
`189
`
`191
`
`192
`
`XIIIXV.
`
`Declaration
`
`159193
`
`Novartis Exhibit 2004.006
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`I.
`
`Introduction
`
`1.
`
`I have been retained by Petitioner Regeneron Pharmaceuticals, Inc. (“Petitioner”
`
`or “Regeneron”), as an independent expert witness in the above-captioned inter partes review
`
`(“IPR”), in which Regeneron has requested that the U.S. Patent and Trademark Office cancel as
`
`unpatentable all claims of U.S. Patent No. 9,220,631 (“the ‘631 patent”).
`
`2.
`
`This declaration sets forth my analyses and opinions based on my knowledge,
`
`experience, and the materials I have considered. As I explain below, it is my opinion that all
`
`claims of the ‘631 patent are directed to subject matter that was routine, conventional, and well
`
`known in the art before the ‘631 patent priority date. As would be readily appreciated by one of
`
`skill in the art, the ‘631 patent is rendered obvious by the combination of prior art references
`
`discussed herein.
`
`3.
`
`I have reviewed the documents referenced in this declaration. I understand they
`
`have been submitted as exhibits in conjunction with Regeneron’s Petitions for IPR.
`
`II.
`
`Summary of Opinions
`
`-
`
`4.
`
`Based on my knowledge, experience, and the materials that I have reviewed, it is
`
`my opinion that claims 1-23 of the ‘631 patent are obvious. Specifically:
`
`(i)
`
`Claims 1-3, 5-9, and 14-22 are obvious based on International Patent
`
`Application Publication No. WO 2011/006877 to Sigg et al. (“Sigg”) (Ex. 1007) in view
`
`of International Patent Application Publication No. WO 2009/030976 to Boulange et al.
`
`(“Boulange”) (Ex. 1008), and if necessary, USP Chapter <789>, titled “Particulate
`
`Matter in Ophthalmic Solutions.” (“USP789”) (Ex. 1019);
`
`Novartis Exhibit 2004.007
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`(ii)
`
`Claims 1-3, 5-9, and 14-22 are obvious based on International Patent
`
`Application Publication No. WO 2008/077155 to Lam et al. (“Lam”) (Ex. 1029) in
`
`view of Boulange, and if necessary, USP789;
`
`(iiiii) Claims 4, 10 and 23 are obvious based on Sigg in view of Boulange,
`
`further in view of A. Fries, Drug Delivery of Sensitive Biopharmaceuticals with Prefilled
`
`Syringes, Drug Delivery Technology, Vol. 9, No. 5 (May 2009) (“Fries”) (Ex. 1012), and
`
`if necessary, USP789;
`
`(iv) Claims 4, 10 and 23 are obvious based on Lam in view of Boulange,
`
`further in view of Fries, and if necessary, USP789;
`
`(iiiv) Claims 11-13 are obvious based on Sigg in view of Boulange, further in
`
`view of International Patent Application Publication No. WO 2007/149334 (“Furfine”)
`
`(Ex. 1021), and if necessary, USP789;
`
`(iv) Claims 1-10, and 14-23 are obvious based on Lam in view of Bruno
`
`Reuter & Claudia Petersen, Syringe Siliconization, 4 TECHNOPHARM 2, 238 (2012)
`
`(“Reuter”) (Ex. 1010) , and if necessary, USP789;
`
`(vvi) Claims 11-13 are obvious based on the combination of Lam in view of
`
`ReuterBoulange, further in view of Furfine, and if necessary, USP789.
`
`III.
`
`Qualifications and Compensation
`
`5.
`
`I have a Diplom-Ingenieur (“Dipl.Ing.”) degree in biotechnology from Hochschule
`
`Mannheim, which I earned in 1993. A Dipl.Ing is considered equivalent to a master’s engineering
`
`degree that would be awarded by a U.S. university. Prior to that I had several years of
`
`apprenticeship and work experience as a medical technician in Germany.
`
`Novartis Exhibit 2004.008
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`6.
`
`I am currently the CEO of HK Packaging Consulting, and have held this position
`
`sincewhich is a consulting company that I formed in 2015. In this role, I consult worldwide
`
`on parenteral packaging, which includes consulting on syringe selection and related primary
`
`packaging issues, and consulting on the role of primary and secondary packaging in dosage form
`
`and drug product development.
`
`7.
`
`At HK Packaging Consulting, I provide technical and regulatory support to both
`
`primary packaging manufacturers and pharmaceutical companies. For primary packaging
`
`manufacturers, I work on choosing pharmaceutical container materials and components (vials,
`
`cartridges, and syringes), setting container specifications, ensuring compliance and testing in
`
`accordance with compendia such as the U.S., European Pharmacopeias, and the International
`
`Organization for Standardization (“ISO”), and providing support for regulatory filings with the
`
`U.S. Food and Drug Administration (“FDA”) and the European Medicines Agency (“EMA” or
`
`“EMEA”). For pharmaceutical companies, I work as a consultant to provide troubleshooting
`
`services, including technical support and testingtest methods relating to primary packaging,
`
`design and test manufacturing processes relating to filling and finishing of pharmaceutical
`
`containers including syringes, selection and optimization of syringe materials and evaluation of
`
`components, and assistance with compendial compliance and testing and regulatory filings.
`
`8.
`
`Prior to my current role, I worked at Schott Pharmaceutical Packaging
`
`(“Schott”) in Germany and Switzerland from 2000 to 2015. Schott is a well-known
`
`manufacturer of both glass and polymer pre-filled syringes. At Schott, I held the following roles
`
`in the Syringe Department: Head of Product Technology for New Products from 2000-01;
`
`Manager for Research & Development and Quality Management from 2001-03; Head of
`
`Scientific and Regulatory Advisory from 2004-07; Manager of Scientific Advisory from 2007-09;
`
`Novartis Exhibit 2004.009
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Global Quality Manager for Regulatory Affairs from 2009-11; and finally, Head of Technical and
`
`Quality Support for the Syringe Business from 2011-15.
`
`9.
`
`At Schott, my responsibilities included support of the global syringe business unit
`
`regarding questions of technical product requirements and specifications, and support of the
`
`global packaging development group for primary and secondary packaging systems with regard
`
`to technical, quality and regulatory requirements. My role also included designing and conducting
`
`testing programs for packaging systems, especially for glass and polymer syringe systems,
`
`including machine packaging and validation. I coordinated test programs with external partners
`
`for extractables and leachables analyses and material testing.
`
`10. After earning my degree and prior to working at Schott, I was the Engineering
`
`Supervisor at Abbott GmbH (“Abbott”) in Germany from 1994 to 1999. At Abbott, I was a
`
`Research Technician from 1994-95, and then a Supervisor in Engineering Processes from
`
`1995-99. At Abbott, my responsibilities included maintenance and calibration of equipment for
`
`manufacturing and research & development, and optimizing packaging lines for pharmaceutical
`
`primary and secondary packaging, including container filling and blister packaging. I also leadled
`
`the cleaning and sterilization center for glass equipment at Abbott.
`
`11. During my time at Abbott and Schott I was actively involved in different
`
`types of sterilization validation according to ISO requirements for, e.g., steam sterilization,
`
`VHP sterilization and decontamination, radiation sterilization (gamma, ebeam and x-ray),
`
`and ETO sterilization. My experience includes cycle development, PCD-development, and
`
`BI positioning studies as well as cycle confirmation runs. I have performed studies on both
`
`empty Container Closure Systems (“CCS”) at the pre-sterilization step prior to filling and
`
`on pre-filled CCS products for terminal sterilization. My experience includes such studies
`
`Novartis Exhibit 2004.0010
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`for pre-filled syringe systems, for which I monitored the sterile field application (blister),
`
`viscosity adjustments, and sterilization after non-aseptic processes.
`
`12. During my time at Schott and Abbott, I designed and analyzed sterilization
`
`techniques and processes for both empty CCS, i.e., pre-sterilization prior to filling (i.e.,
`
`empty syringes), in addition to terminal sterilization with filled CCS (i.e., sterilization that
`
`occurs after the syringe has been filled) depending on the intended use for the pre-filled
`
`syringe system. I gained experience with respect to pre-filling sterilization because syringe
`
`suppliers typically sterilize syringes before providing them to customers. I also gained
`
`extensive experience with respect to the sterilization of pre-filled syringes because syringe
`
`suppliers often perform testing on such syringes to ensure that a syringe design will satisfy
`
`the downstream needs of customers, including syringes for use with any drug products that
`
`were to be terminally sterilized (i.e., sterilized after filling).
`
`1113. In addition to my work experience, I have many13 years of experience
`
`participating in professional organizations, standards setting organizations, and pharmacopeias
`
`relating to pharmaceutical packaging including syringes. For example, I am an active member of
`
`the ISO technical committee, TC 84 on “Devices for administration of medicinal products and
`
`catheters,” wherein I am a member of several working groups including WG 3 (needle-based
`
`injection systems -injector, container and pen needle) and WG 11 (syringes). I am also an active
`
`member of the ISO technical committee, TC 76 on “Transfusion, infusion and injection, and
`
`blood processing equipment for medical and pharmaceutical use,” wherein I am a member of
`
`several working groups including: WG 2 (rigid container system and related accessories for
`
`parenterals and injectables) of which I am the Convenor1, WG 4 (elastomeric parts and
`=
`
`1 As convenor, I lead the WG experts participating from 22 member countries (TC76)
`which have been delegated from national standardization bodies, e.g. ANSI (USA),
`
`Novartis Exhibit 2004.0011
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`components and related secondary packaging), and WG 6 (primary packaging systems for
`
`medicinal products). I was ad hoc group leader for the WG 2 ISO committee that developed
`
`standard 11040-4 for glass syringes and 11040-6 for polymer syringes. I am also the Swiss Medic
`
`Delegate for the European Directorate for the Quality of Medicines (EDQM) working group
`
`WG 16 on the European Pharmacopoeia Chapter 3 relating to plastics. In addition, I am the
`
`faculty head for the area: Transfusion, Infusion and Injection within the German
`
`Standardization Body (DIN) for NA 063 Medicine. This faculty leads 6 subgroups related
`
`to Injection systems, Transfusion and Infusion container including single use container for
`
`IVD, Packaging Systems for filling and application of medicinal products, Fridges and
`
`Freezers for medicinal products, Quality Management for Primary Packaging and
`
`Elastomers for Primary Packaging.
`
`1214. In addition to the above, I have given numerous presentations at symposiums,
`
`conferences, and other professional organizational meetings, including many presentations over
`
`the years that relate to parenteral manufacturing, pre-filled syringes, extractables, leachables, the
`
`packaging of syringe systems, and regulatory (FDA/EMEA) requirements for the packaging of
`
`parenterals.
`
`1315. My curriculum vitae is attached as Exhibit 1004Appendix 1 to my report, and
`
`provides further information about my experience, expertise, and presentations.
`
`1416. Through my professional experience, I have gained extensive expertise in syringe
`
`and syringe materials and components, including their manufacturing, testing, siliconization,
`
`which have been delegated from national standardization bodies, e.g. ANSI (USA),
`AFNOR (France), DIN (Germany), for that group.
`
`Novartis Exhibit 2004.0012
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`characterization, regulatory compliance, sales, and have a deep understanding of the worldwide
`
`syringe market. Through this experience, I also have gained knowledge and experience relating
`
`to pre-filled syringes, the characterization of syringe stopper movement forces within a syringe,
`
`issues relating to syringe component leachables and extractables, issues relating to siliconization,
`
`regulatory requirements on particulate matter for parenterals, and sterilization of container
`
`closure systems.
`
`1517. I am being compensated at my standard rate of $450/hour. My compensation is in
`
`no way contingent upon my opinions or the outcome of the proceeding.
`
`IV.
`
`Relevant Legal Standards
`
`1618. I am not an attorney, and therefore my understanding of patent law and the legal
`
`standards set forth in this report is based on explanations provided to me by counsel.
`
`1719. I understand that for any claim of a patent to claim priority to an earlier
`
`application (i.e., to benefit from the earlier application’s filing date), the claims of the later patent
`
`must be fully supported by the disclosure of the earlier patent application to which priority is
`
`claimed. I understand that in order for the claims to be supported, the earlier application’s
`
`disclosure must be sufficient to allow a person of ordinary skill in the art to reasonably conclude
`
`that the inventors were in possession of the claimed invention.
`
`1820.
`
`I understand that the ‘631 patent claims priority to a number of patent applications, the
`
`earliest of which are European Patent Application No. EP12174860, filed on July 3, 2012, and
`
`European Patent Application No. EP12189649, filed on October 23, 2012. However, as I explain
`
`in Section VI.A below, the July 3, 2012 Application No. EP12174860 filing does not support the
`
`issued claims of the ‘631 patent, and therefore the patent claims are not entitled to that priority
`
`date, and instead should have a priority date of no earlier than October 23, 2012. Nevertheless,
`
`Novartis Exhibit 2004.0013
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`for the purposes of my opinions, I have considered the state of the art as of and shortly before
`
`July 3, 2012, and the level of knowledge that a POSITA would have possessed at that time.
`
`Unless I state otherwise, whenever I refer to any principle or technical subject matter as having
`
`been known or understood, this is meant to denote the knowledge and understanding of a
`
`POSITA at or prior to July 3, 2012.12
`
`A. Claim Construction
`
`1921. It is my further understanding that the numbered paragraphs at the end of the
`
`disclosure of a U.S. Patent are the patent “claims” that define the metes and bounds of the
`
`alleged invention. I understand that thesethe claims of the ‘631 patent are what is being
`
`challenged in the present IPR proceeding.
`
`2022. I have been informed that, in this proceeding, the Board must determine the scope
`
`of the claims by giving the claims their ordinary and customary meaning in light of the
`
`specification, as the claims would be interpreted by one of ordinary skill in the art.
`
`2123. I understand that patent claims generally include a “transitional” term or phrase,
`
`such as “consisting” or “comprising,” which may connect the preamble of the claim to the body
`
`of the claim. I have been informed that if a claim uses the term “consisting” as a transition term,
`
`that means that the claim is a “closed” claim, which means that the claim is limited to the claim
`
`features that follow the transition term and nothing else. On the other hand, I understand that the
`
`transition term “comprising” denotes an “open” claim, which means that the claim is not limited
`
`12 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.
`
`Novartis Exhibit 2004.0014
`Regeneron v. Novartis, IPR2021-00816
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`

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`to only the features recited in the claim, and could encompass the listed elements as well as other
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`unrecited elements.
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`B. Invalidity
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`2224. I understand that Regeneron bears the burden of proving that the challenged
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`claims of the ‘631 patent are invalid, and must prove this by a preponderance of the evidence,
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`which means that invalidity must be shown to be more likely than not.
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`2325. I have been asked to consider the question of whether the claims of the ‘631
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`patent would have been obvious. I understand that this analysis must be conducted from the
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`perspective of the person of ordinary skill in the art, and whether the skilled artisan would
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`consider any differences between the prior art and what is claimed to have been obvious. To
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`make this assessment, I have been informed that the concept of patent obviousness involves four
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`factual inquiries: (1) the scope and content of the prior art; (2) the differences between the
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`claimed invention and the prior art; (3) the level of ordinary skill in the art; and (4) secondary
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`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
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`would have reason to pursue further, and steps that were routinely done, such as in response to
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`known problems, steps or obstacles.
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`2426. It is my understanding that the following is a non-exhaustive list of rationales that
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`may support the obviousness of an invention: combining prior art elements according to known
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`methods to yield predictable results; simple substitution of one known element for another to
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`obtain predictable results; use of a known technique to improve a similar device (method, or
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`product) in the same way; applying a known technique to a known device (method, or product)
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`ready for improvement to yield predictable results; choosing from a finite number of identified,
`
`Novartis Exhibit 2004.0015
`Regeneron v. Novartis, IPR2021-00816
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`

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`predictable solutions, with a reasonable expectation of success; and some teaching, suggestion,
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`or motivation in the prior art that would have led a POSITA to modify the prior art reference or
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`to combine prior art reference teachings to arrive at the claimed invention.
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`2527. It is my understanding that the motivation to combine prior art references may be
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`implicit and may be found in the knowledge of one of ordinary skill in the art, or in the nature of
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`the problem to be solved. Specifically, it is my understanding that an implicit motivation to
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`combine exists not only when a suggestion may be gleaned from the prior art as a whole, but
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`when the “improvement” is technology-independent and the combination of references results in
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`a product or process that is more desirable, for example because it is stronger, cheaper, cleaner,
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`faster, lighter, smaller, more durable or more efficient. It is my further understanding that the
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`motivation to combine references may be found in the nature of the problem to be solved where
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`prior art references are directed to precisely the same problem.
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`2628. I also understand that prior art may be relied on for its express disclosure and
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`teachings. I also understand that the prior art may be relied upon for a teaching of features that
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`are necessarily present in the prior art reference even if that specific feature is not expressly or
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`explicitly disclosed.
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`2729. I understand that before reaching any final conclusion on obviousness, the
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`obviousness analysis requires consideration of objective indicia of non-obviousness, if any such
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`indicia are offered. These must be considered to ensure that, for example, there were not some
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`unanticipated problems, obstacles or hurdles that may seem easy to overcome in hindsight, but
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`which were not readily overcome prior to the relevant invention date of the patents/claims at
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`issue here. I understand that these objective indicia are also known as “secondary considerations
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`of non-obviousness,” and may include long-felt but unmet need and unexpected results, among
`
`Novartis Exhibit 2004.0016
`Regeneron v. Novartis, IPR2021-00816
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`

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`others. I also understand, however, that any offered evidence of secondary considerations of
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`non-obviousness must be comparablecommensurate with the scope of the challenged claims.
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`This means that for any offered evidence of secondary considerations of non-obviousness to be
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`given substantial weight, I understand the proponent of that evidence must establish a “nexus” or
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`a sufficient connection or tie between that evidence and the merits of the claimed invention,
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`which I understand specifically incorporates any novel element(s) of the claimed invention. If the
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`secondary consideration evidence offered actually results from something other than the merits of
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`the claim, then I understand that there is no nexus or tie to the claimed invention. I also
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`understand it is the Patent Owner who has the burden of proving that a nexus exists, and I
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`understand that secondary considerations will not overcome a strong showing of obviousness.
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`C. Person of Ordinary Skill in the Art
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`2830. I have been asked to review U.S. Patent No. 9,220,631 (“the ‘631 patent”) from
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`the perspective of a person of ordinary skill in the art (“POSITA”) as of the earliest claimed
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`priority date for the patent—July 3, 2012. I have been asked to evaluate the disclosure and claims
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`of the ‘631 patent. I have been further asked to consider whether the prior art renders obvious
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`the pre-filled syringe covered by claims 1-23 of the ‘631 patent.
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`2931. It is my opinion that a POSITA relevant to the ‘631 patent would have had at
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`least an advanced degree (Dipl.Ing, M.S., or Ph.D.), with research experience in mechanical
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`engineering, biomedical engineering, materials science, chemistry, or a related field, or at least
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`2-3 years of professional experience in one or more of those fields. Furthermore, it is my opinion
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`that a POSITA would have had experience with (i) the design of pre-filled syringes; and (ii)
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`sterilization of drug delivery devices, including those containing sterilization sensitive
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`therapeutics. Such sterilization experience would include experience with microbiology. Based
`
`Novartis Exhibit 2004.0017
`Regeneron v. Novartis, IPR2021-00816
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`

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`on my education, training and experience, it is my opinion that I can accurately represent the
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`views of a POSITA as of the earliest claimed priority date of July 3, 2012, as to at least claims
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`1-23 of the ‘631 patent. The opinions I provide in this declaration are provided using the
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`viewpoint of the POSITA as of July 3, 2012.
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`3032. Claims 24-26 relate to methods of treating a patient suffering from eye disease, by
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`administering an ophthalmic solution using the pre-filled syringe described in claim 1. Because
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`such intravitreal administration must be performed by an ophthalmologist, it is my opinion that a
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`POSITA with respect to claims 24-26 would be an ophthalmologist with experience
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`administering VEGF-antagonist drugs to patients via the intravitreal route. See Nema Vol. 1 at
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`21 (Ex. 1015.036)
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`(“Since an excellent knowledge of the anatomy and function of the eye is required, only an
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`ophthalmologist should attempt these procedures.”).
`
`V.
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`Background of the Technology
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`3133. I understand that theThe asserted claims of the ‘631 patent are generally directed
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`to a pre-filled, terminally-sterilized, low volume0.5-1 ml glass syringessyringe containing a
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`VEGF-antagonist solution, and having low amounts ofbetween about 1-100 µg, about 3-100 µg
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`or about 1-50 µg silicone oil on the barrel, and possessing low break loose and glide forces for
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`the syringe stopper that are less than about 11N or 5N. In this section, I explain the technical
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`concepts underlying the claims of the ‘631 patent, and also explain how each of these concepts
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`were well known in the art prior to the effective filing date of the ‘631 patent.
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`A. Intravitreal Administration of VEGF Antagonists
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`3234. “Intravitreal administration” refers to “injection directly into the vitreous cavity of
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`the eye.” Nema Vol. 1 at 20 (Ex. 1015.035). For such injections, “[e]xtreme care and precise
`
`Novartis Exhibit 2004.0018
`Regeneron v. Novartis, IPR2021-00816
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`

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`technique are required to minimize or prevent damage to the eye, especially to the corneal
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`endothelium.” Id. at .03621 (Ex. 1015.036). Numerous medical complications could occur from
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`incorrect intravitreal administration, and only small volumes of around 0.1 mL or less should be
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`injected. Id. As such, intravitreal injections are typically administered only by ophthalmologists.
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`Id.
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`3335. Several VEGF-antagonists were known and commercially available, and utilized
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`to various degrees for different reasons beyond the scope of my opinion, before the earliest
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`priority date of the ‘631 patent, including ranibizumab (Lucentis®), aflibercept (Eylea®), and
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`pegaptanib (Macugen®). See Lucentis Label (Ex. 1027), Eylea Label (Ex. 1040), 2008
`-==
`Macugen Label (Ex. 1009). All three of these VEGF-antagonist drug formulations are intended
`
`for intravitreal administration. Because VEGF-antagonist formulations are administered by
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`injection into the eye, they are typically dispensed either in vials to be used with empty disposable
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`syringes (see Eylea Label at 14 (Ex. 1040.014),) or in what is known as a pre-filled syringe (see
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`2008 Macugen Label (Ex. 1009.0011009)).
`
`B. Pre-filled Syringes
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`3436. As the name suggests, a pre-filled syringe (“PFS”) is a syringe that is packaged
`
`and sold with a drug formulation already loaded into the syringe. See Sigg (Ex. 1007) at 1:10-12,
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`15-17 (“Prefilled containers are a type of medical device that are filled by the manufacturer at the
`
`time of assembly and provided to the end user, generally a health-care provider or a patient
`
`requiring treatment, in a sterile condition. ... Of the various types of prefilled containers, prefilled
`
`syringes are the most common and best suited for parenteral administration of therapeutic
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`products.”). The drug in a pre-filled syringe is typically in a form that is ready to be administered
`
`Novartis Exhibit 2004.0019
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`to a patient. Thus, “[p]refilled syringes are containers and drug delivery systems at the same
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`time.” Fries at 26 (Ex. 1012.006).
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`3537. Pre-filled syringes are considered to be a type of “primary packaging,” which
`
`generally refers to the components of a drug delivery system that are in direct contact with the
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`drug formulation. Primary packaging also includes components such as vials, bottles, closures,
`
`etc. Primary packaging can be distinguished from “secondary packaging,” where the latter refers
`
`to packaging components such as aluminum caps, cardboard boxes and blister packs that are not
`
`intended to come into direct contact with the drug formulation. The following description, taken
`
`from FDA’s drug packaging documentation, reflects generally accepted definitions of packaging
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`components:
`
`A primary packaging component means a packaging component that is or may be in
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`direct contact with the dosage form. A secondary packaging component means a packaging
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`component that is not and will not be in direct contact with the dosage form.
`
`A container c