`
`
`
`
`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 Owner.
`______________________
`
`Case No. IPR2021-00816
`U.S. Patent No. 9,220,631
`______________________
`
`DECLARATION OF W. GREG SAWYER, PH.D.
`
`
`
`
`
`Regeneron Exhibit 1101.001
`Regeneron v. Norvatis
`IPR2021-00816
`
`
`
`
`
`
`

`

`I.
`II.
`
`B.
`
`IX.
`
`
`TABLE OF CONTENTS
`
`INTRODUCTION ........................................................................................... 1
`SUMMARY OF OPINIONS ........................................................................... 1
`A. Written Description (112) ..................................................................... 1
`B.
`Inventorship (102f) ................................................................................ 2
`C.
`Enablement (112) .................................................................................. 3
`III. QUALIFICATIONS ........................................................................................ 4
`IV. BACKGROUND OF THE TECHNOLOGY .................................................. 8
`V.
`PERSON OF ORDINARY SKILL IN THE ART (POSITA) ...................... 11
`VI. UNDERSTANDING THE LAW .................................................................. 14
`A. New Matter / Written Description (35 U.S.C. § 112) ......................... 14
`B.
`Inventorship (35 U.S.C. § 102(f)) ....................................................... 15
`C.
`Enablement (35 U.S.C. § 112) ............................................................ 16
`VII. CLAIM CONSTRUCTION .......................................................................... 17
`VIII. WRITTEN DESCRIPTION .......................................................................... 20
`A.
`The Specification Does Not Demonstrate Possession of a Syringe
`Having 1 µg to 25 µg of Silicone Oil and a Break Loose Force Less
`Than 11N for up to 12 Months ............................................................ 20
`1.
`The ’352 Application (Ex. 2227) .............................................. 22
`2.
`EP ’649 (Ex. 2014).................................................................... 30
`The Specification Does Not Demonstrate Possession of a 1 ml Syringe
`Having 1 µg to 25 µg or 3 µg to 25 µg of Silicone Oil and a Break
`Loose Force of Less Than 11N ........................................................... 32
`INVENTORSHIP .......................................................................................... 36
`A.
`The Claimed Invention in the Substitute Claims ................................ 36
`B.
`Vetter Employees Made Significant Contributions to the Claimed
`Invention in the ’631 Patent ................................................................ 41
`1.
`The Novartis Inventors Did Not Have a Definite and Permanent
`Idea Before Working with Vetter ............................................. 41
`Vetter’s Work to Conceive of the Silicone Oil Ranges ............ 49
`
`
`
`2.
`
`i
`
`Regeneron Exhibit 1101.002
`Regeneron v. Norvatis
`IPR2021-00816
`
`

`

`
`
`X.
`
`3.
`
`
`
`Additional Documents Confirming Vetter’s Contribution to
`Conception ................................................................................ 70
`ENABLEMENT ............................................................................................ 73
`A.
`The ’352 Application Fails to Teach a POSITA How to Make a Pre-
`filled Syringe Where the Syringe Barrel Comprises “About 1 µg” or
`“About 3 µg” of Silicone Oil .............................................................. 74
`The Prior Art Does Not Disclose How to Make a Pre-filled Syringe
`Where the Syringe Barrel Comprises “About 1 µg” or “About 3 µg”
`of Silicone Oil ..................................................................................... 81
`1.
`Boulange (WO 2009/030976) (Ex. 1008) ................................. 81
`2.
`
`.............. 83
`Fries (Ex. 1012) ......................................................................... 84
`3.
`Hioki (US 2011/0276005) (Ex. 1020) ...................................... 85
`4.
`Chan (Ex. 2022) ........................................................................ 86
`5.
`Undue Experimentation Would be Necessary to Achieve the
`Minimum Claimed Amounts of Silicone Oil While Also Maintaining
`the Claimed Break Loose and Slide Force Amounts .......................... 87
`XI. DECLARATION ........................................................................................... 90
`
`
`
`
`
`B.
`
`C.
`
`
`
`ii
`
`Regeneron Exhibit 1101.003
`Regeneron v. Norvatis
`IPR2021-00816
`
`

`

`
`
`
`
`Ex. 1011
`
`Ex. 1015
`
`Ex. 1016
`
`Ex. 1008
`
`TABLE OF REFERENCED DOCUMENTS
`
`Ex. 1001 U.S. Patent No. 9,220,631 (“the ’631 Patent”)
`Ex. 1002
`Prosecution File History of U.S. Patent No. 9,220,631
`Ex. 1007
`PCT Patent Publication No. WO 2011/006877 to Sigg et al.
`(“Sigg”)
`PCT Patent Publication No. WO 2009/030976 to Boulange et al.
`(“Boulange”)
`Bhavnesh D. Shah & Bhupendra G. Prajapati, Pre-Filled
`Syringes: A New Concept, PHARMA BIO WORLD 51 (2009)
`(“Shah”)
`Ex. 1012 Arno Fries, Drug Delivery of Sensitive Biopharmaceuticals With
`Prefilled Syringes, 9(5) DRUG DELIVERY TECH. 22 (2009)
`(“Fries”)
`Sandeep Nema & John D. Ludwig, Pharmaceutical Dosage
`Forms: Parenteral Medications, Volume 1: Formulation and
`Packaging (3rd ed. 2010) (“Nema Vol. 1”)
`Sandeep Nema & John D. Ludwig, Pharmaceutical Dosage
`Forms: Parenteral Medications, Volume 2: Facility Design,
`Sterilization and Processing (3rd ed. 2010) (“Nema Vol. 2”)
`Ex. 1019 U.S. Pharmacopeia, USP 789, Particulate Matter in Ophthalmic
`Solutions, USP 34 NF 29 (2011)
`Ex. 1020 U.S. Patent Publication No. 2011/276005 to Hioki et al. (“Hioki”)
`Ex. 1021
`PCT Patent Publication No. WO 2007/149334 to Furfine et al.
`(“Furfine”)
`International Organization for Standardization, ISO 11040-4
`Prefilled Syringes – Part 4: Glass Barrels for Injectables (2nd ed.
`2007) (“ISO 11040-4”)
`PCT Patent Publication No. WO 2008/077155 to Lam et al.
`(“Lam”)
`International Standard ISO-9626, Stainless steel needle tubing for
`the manufacture of medical devices – Amendment 1, ISO
`9626:1991/Amd.1:2001(E) (“ISO-9626”)
`
`Ex. 1028
`
`Ex. 1029
`
`Ex. 1043
`
`iii
`
`Regeneron Exhibit 1101.004
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
`
`
`
`Ex. 1110
`
`Ex. 1044 Advait Badkar, et al. Development of Biotechnology Products in
`Pre-filled Syringes: Technical Considerations and Approaches,
`American Association of Pharmaceutical Sciences, June 2011,
`12(2): 564-572 (“Badkar”)
`Ex. 1082 U.S. Pharmacopeia, USP 789, Particulate Matter in Ophthalmic
`Solutions, USP 32 NF 27 (2009)
`Ex. 1109 Deposition of Kim Cameron, Ph.D., IPR2021-00816 (3/17/2022)
`– Filed Under Seal
`Persson, et. al., Elastic contact mechanics: Percolation of the
`contact area and fluid squeeze-out, Eur. Phys. J. E. (2012)
`Ex. 1112 NOVITC(CH)00137958 – Novartis Confidential Internal
`Memorandum Filed Under Seal
`Ex. 1113 NOVITC(CH)00143346 – Novartis Confidential Internal
`Memorandum Filed Under Seal
`Ex. 1114 NOVITC(CH)00258369 – Novartis Confidential Internal
`Memorandum Filed Under Seal
`“Highlights of Prescribing Information,” Lucentis, FDA, June
`2006, available at
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/1251
`56lbl.pdf
`Ex. 1116 NOVITC(CH)00195649 – Vetter Confidential Memorandum
`Filed Under Seal
`Ex. 1117 NOVITC(CH)00145642 – Novartis Confidential Meeting
`Minutes Filed Under Seal
`Ex. 1118 NOVITC(CH)00144912 – Novartis Confidential Meeting
`Minutes Filed Under Seal
`Ex. 1119 NOVITC(CH)00205699 – Vetter Confidential Presentation Filed
`Under Seal
`Ex. 1120 NOVITC(CH)00184035 – Vetter Confidential Memorandum
`Filed Under Seal
`Ex. 1121 NOVITC(CH)00198709 – Vetter Confidential Presentation Filed
`Under Seal
`
`Ex. 1115
`
`iv
`
`Regeneron Exhibit 1101.005
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
`
`
`Ex. 1122 NOVITC(CH)00867567 – Vetter Confidential Memorandum
`Ex. 1122|NOVITC(CH)00867567 — Vetter Confidential Memorandum
`Filed Under Seal
`Filed UnderSeal
`Ex. 1123 NOVITC(CH)00150140 – Vetter Confidential Emails Filed
`Ex. 1123.|NOVITC(CH)00150140 — Vetter Confidential Emails Filed
`Under Seal
`UnderSeal
`Ex. 1124 NOVITC(CH)00337493 – Vetter Confidential Presentation Filed
`Ex. 1124|NOVITC(CH)00337493 — Vetter Confidential Presentation Filed
`Under Seal
`UnderSeal
`
`Ex. 1125 NOVITC(CH)00352054 – Vetter Confidential Emails Filed
`Ex. 1125|NOVITC(CH)00352054 — Vetter Confidential Emails Filed
`Under Seal
`UnderSeal
`Ex. 1126 VETTER_00001432 – Vetter Confidential Presentation Filed
`Ex. 1126|VETTER_00001432 — Vetter Confidential Presentation Filed
`Under Seal
`UnderSeal
`Ex. 1127 NOVITC(CH)00170626 – Vetter Confidential Memorandum
`Ex.1127|NOVITC(CH)00170626 — Vetter Confidential Memorandum
`Filed Under Seal
`Filed UnderSeal
`Ex. 1128 NOVITC(CH)00170434 – Vetter Confidential Letter Filed Under
`Ex. 1128|NOVITC(CH)00170434 — Vetter Confidential Letter Filed Under
`Seal
`Seal
`
`REGITC01116474 – DE 20 2012 011 016.0
`Ex. 1129
`Ex. 1129|REGITCO1116474 — DE 20 2012 011 016.0
`Ex. 1131 NOVITC(CH)00217299 – Novartis Confidential Presentation
`Ex. 1131|NOVITC(CH)00217299 — Novartis Confidential Presentation
`Filed Under Seal
`Filed UnderSeal
`Ex. 1132 NOVITC(CH)00311660 – Novartis Confidential Report Filed
`Ex. 1132|NOVITC(CH)00311660 — Novartis Confidential Report Filed
`Under Seal
`UnderSeal
`Ex. 1133 NOVITC(CH)00133717 – Novartis Confidential Report Filed
`Ex. 1133.|NOVITC(CH)00133717 — Novartis Confidential Report Filed
`Under Seal
`UnderSeal
`Sigg ITC Deposition Transcript (12/17/2020) – Filed Under Seal
`Ex. 1158
`Ex. 1158|Sigg ITC Deposition Transcript (12/17/2020) — Filed Under Seal
`Ex. 1159
`Roettelle ITC Deposition Transcript (12/14/2020) – Filed Under
`Ex. 1159|Roettelle ITC Deposition Transcript (12/14/2020) — Filed Under
`Seal
`Seal
`Picci ITC Deposition Transcript (12/16/2020) – Filed Under Seal
`Ex. 1160
`Ex. 1160|Picci ITC Deposition Transcript (12/16/2020) — Filed UnderSeal
`Ex. 1162
`BD-ITC-000069 – Becton Dickinson Presentation Filed Under
`Ex. 1162|BD-ITC-000069 — Becton Dickinson Presentation Filed Under
`Seal
`Seal
`REGITC00138524 – Requirements on pre-fillable glass syringes
`Ex. 1163
`Ex. 1163|REGITC00138524 — Requirements on pre-fillable glass syringes
`Ex. 1164 Optical in Situ Micro Tribometer for Analysis of Real Contact
`Ex. 1164|Optical in Situ Micro Tribometerfor Analysis ofReal Contact
`Area for Contact Mechanics, Adhesion, and Sliding Experiments,
`Area for Contact Mechanics, Adhesion, and Sliding Experiments,
`B. A. Krick, J. R. Vail, B. N. J. Persson, and W. G. Sawyer,
`B. A.Krick, J. R. Vail, B. N. J. Persson, and W. G. Sawyer,
`Tribology Letters 45 (2012) 185-194
`Tribology Letters 45 (2012) 185-194
`
`
`
`
`
`v
`Vv
`
`Regeneron Exhibit 1101.006
`Regeneron v. Novartis
`IPR2021-00816
`
`Regeneron Exhibit 1101.006
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`Ex. 1165
`
`
`
`Ex. 1169
`
`Ex. 1166
`
`Plasmonic Diagnostics for Tribology: In Situ Observations using
`Surface Plasmon Resonance in Combination with Surface-
`Enhanced Raman Spectroscopy, B. A. Krick, D. H. Hahn, and W.
`G. Sawyer, Tribology Letters, 49 (2013) 95-102.
`Accessing Inaccessible Interfaces: In Situ Approaches to
`Materials Tribology, W. G. Sawyer & K. J. Wahl, Guest Editors
`MRS Bulletin 33 (2008) 1145-1189
`Lorenz, et al., Static or breakloose friction for lubricated
`contacts: the role of surface roughness and dewetting, J. Phys.
`Condens. Matter 25 (2013)
`Ex. 2002 Declaration of Marie Picci [Filed Under Seal]
`Ex. 2014
`European Patent Application No. EP 12189649 (EP '649)
`Ex. 2022
`Edwin Chan, et al., Syringe Siliconization Process Investigation
`and Optimization, PDA JOURNAL OF PHARMACEUTICAL
`SCIENCE AND TECHNOLOGY, 136-158 (2012) (“Chan”)
`Ex. 2049 Glen Petrie, The Need for Specificity in Accelerated Aging,
`Medical Device & Diagnostic Industry (2006) (“Petrie”)
`Ex. 2131 NOVITC(CH)00170304 [Filed Under Seal]
`Ex. 2143 NOVITC(CH)01495912 [Filed Under Seal]
`Ex. 2206 Declaration of Juergen Sigg, Ph.D. [Filed Under Seal]
`Ex. 2208 Declaration of Kimberly Cameron, Ph.D. In Support of Novartis’s
`Motion to Amend [Filed Under Seal]
`Ex. 2224 DSR5092D [Filed Under Seal]
`Ex. 2227 Application No. 13/750,352
`
`
`
`
`
`
`vi
`
`Regeneron Exhibit 1101.007
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
`
`
`
`INTRODUCTION
`1. My name is Dr. W. Gregory Sawyer. I have been retained as an
`
`
`I.
`
`independent expert on behalf of Petitioner Regeneron Pharmaceuticals, Inc.
`
`(“Regeneron”) in connection with the above-captioned inter partes review (“IPR”),
`
`in which Regeneron has petitioned the Patent Trial and Appeal Board (“PTAB”) to
`
`cancel as unpatentable all claims of U.S. Patent No. 9,220,631 (“the ’631 patent”),
`
`and in which Patent Owner Novartis has filed a contingent motion to amend the
`
`’631 patent in response to Regeneron’s petition.
`
`2.
`
`This declaration includes my analyses and opinions on the issues of
`
`written description, inventorship, and enablement with respect to the proposed
`
`substitute claims in Novartis’s contingent motion to amend. My opinions are
`
`based on my knowledge, experience, and the materials that I have reviewed and
`
`cited in this declaration.
`
`II.
`
`SUMMARY OF OPINIONS
`A. Written Description (112)
`The substitute claims were amended to require about 1 µg to 25 µg or
`3.
`
`3 µg to 25 µg of silicone oil on the syringe barrel and a shelf life of at least 12
`
`months after terminal sterilization. Novartis has also taken the position that the
`
`substitute claims require that the syringe has a break loose force of less than 11N
`
`twelve months after sterilization. See, e.g., MTA at 5 (“Nor do the Boulange
`
`1
`
`Regeneron Exhibit 1101.008
`Regeneron v. Norvatis
`IPR2021-00816
`
`

`

`
`
`
`syringes have a break loose force less than 11N twelve months after
`
`sterilization.”); MTA at 2 (“Nor do any of the references … provide the recited
`
`break loose force … let alone provide them over the course of a shelf-life of at
`
`least twelve months following terminal sterilization.”); Ex. 1109 (Cameron
`
`3/17/2022 Tr.) at 23:6-21. It is my opinion that the substitute claims are not
`
`supported by the original specification, and therefore the substitute claims
`
`introduce new matter. Neither the original application (Ex. 2227) nor the foreign
`
`priority application (Ex. 2014) conveys to a POSITA that the inventors possessed a
`
`syringe that has about 1 µg to 25 µg or 3 µg to 25 µg of silicone oil on the barrel
`
`and a break loose force of less than 11N twelve months after sterilization. The
`
`original application and foreign priority application also do not demonstrate
`
`possession of a 1 ml syringe having 1 µg to 25 µg or 3 µg to 25 µg of silicone oil
`
`and a break loose force of less than 11N.
`
`B.
`4.
`
`Inventorship (102f)
`The ’631 patent names as inventors the following five individuals:
`
`Juergen Sigg, Christophe Royer, Andrew Bryant, Heinrich Buettgen, and Marie
`
`Picci. It is my opinion that these Novartis inventors did not alone conceive of the
`
`subject matter claimed in the substitute claims of the ’631 patent. Instead, there is
`
`clear documentation demonstrating that
`
` and
`
`
`
`from Vetter made significant contributions to the claimed syringe of the ’631
`
`2
`
`Regeneron Exhibit 1101.009
`Regeneron v. Norvatis
`IPR2021-00816
`
`

`

`
`
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`patent, and specifically to the conception of the claimed silicone oil ranges and the
`
`force ranges in substitute claims 27, 29, 40, 42 and 48. As such,
`
` and
`
` are joint inventors of the claimed subject matter.
`
`C. Enablement (112)
`The substitute claims require a 0.5 ml to 1 ml pre-filled glass syringe
`5.
`
`comprising an amount of silicone oil on the glass syringe barrel as low as about 1
`
`µg (substitute claims 27, 48) or as low as about 3 μg (substitute claim 29) that
`
`results in break loose and slide forces of less than about 11N or 5N (substitute
`
`claims 27, 40, 42). The specification of the ’631 patent fails to teach those skilled
`
`in the art how to make a 0.5 ml to 1 ml pre-filled glass syringe where the syringe
`
`barrel comprises the minimum claimed amount of silicone oil (about 1 µg or about
`
`3 μg) while also achieving the claimed range of break loose and slide forces.
`
`Furthermore, while I understand that the ’631 patent does not need to disclose what
`
`is well known in the art, the prior art regarding siliconization of syringe barrels
`
`likewise does not disclose how to make a 0.5 ml to 1 ml syringe where the syringe
`
`comprises an amount of silicone oil as low as claimed in the ’631 patent. A
`
`POSITA would not be able to make a syringe where the syringe barrel comprises
`
`as low as about 1 µg or about 3 µg of silicone oil and where the syringe has the
`
`claimed ranges of break loose force and slide force without undue experimentation.
`
`3
`
`Regeneron Exhibit 1101.010
`Regeneron v. Norvatis
`IPR2021-00816
`
`

`

`
`
`
`It is therefore my opinion that the substitute claims of the ’631 patent are not
`
`enabled.
`
`III. QUALIFICATIONS
`I am currently a Professor of Mechanical and Aerospace Engineering
`6.
`
`at the University of Florida, a position I have held since 2008. Prior to being
`
`promoted to Professor, I was Associate Professor at the University of Florida from
`
`2005-2008, and I was an Assistant Professor at the University of Florida from
`
`1999-2005. I am a Distinguished Teaching Scholar at the University of Florida,
`
`which was awarded in 2010.
`
`7.
`
`I am a member of the Association for Research in Vision and
`
`Ophthalmology (ARVO), a member of the International Society for Contact Lens
`
`Researchers (ISCLR), a fellow of the Society of Tribologists and Lubrication
`
`Engineers (STLE), a member of the American Association for Cancer Research
`
`(AACR), a member of the Society of Neuro-Oncology (SNO), and a Fellow of the
`
`US National Academy of Inventors (NAI). I received my Ph.D. in Mechanical
`
`Engineering from Rensselaer Polytechnic Institute (“Rensselaer”) in 1999. Prior to
`
`my Ph.D., I earned a Master’s degree in Mechanical Engineering from Rensselaer
`
`in 1996, and a Bachelor’s degree in Mechanical Engineering from Rensselaer in
`
`1994. I have published over 200 peer-reviewed journal papers, have been on the
`
`editorial board of four journals, and have been granted over twenty U.S. patents.
`
`4
`
`Regeneron Exhibit 1101.011
`Regeneron v. Norvatis
`IPR2021-00816
`
`

`

`
`
`
`
`8.
`
`The majority of my research work has been in tribology and studying
`
`the dynamics of interfaces and interfacial surface films during direct contact shear.
`
`Tribology, as compactly defined in the Oxford English Dictionary, is the branch of
`
`science and technology concerned with interacting surfaces in relative motion and
`
`with associated matters such as friction, wear, lubrication, and the design of
`
`bearings. I have focused on developing instrumentation to study the evolution of
`
`these interacting surfaces using microscopy1, spectroscopy2, and interferometry3,
`
`modeling these processes to develop a fundamental understanding of the
`
`mechanisms leading to durability and low-friction, and using this knowledge to
`
`develop novel materials to provide lubrication for applications that are often
`
`characterized as novel or extreme: space, high temperature, cryogenic, electrical
`
`contacts, fluoropolymers, hydrogels, and biological systems. A major focus of my
`
`tribology research involves ocular health, particularly related to the cornea and dry
`
`eye, as well as the lubricity of contact lenses, friction induced inflammation, and
`
`contact lens discomfort.
`
`
`1 See Krick, et al., Optical in Situ Micro Tribometer for Analysis of Real Contact
`Area for Contact Mechanics, Adhesion, and Sliding Experiments, Tribology
`Letters 45 (2012) 185-194 (Ex. 1164).
`2 See Krick et. al., Plasmonic Diagnostics for Tribology: In Situ Observations
`using Surface Plasmon Resonance in Combination with Surface-Enhanced Raman
`Spectroscopy, Tribology Letters 49 (2013) 95-102 (Ex. 1165).
`3 See Sawyer et al., Accessing Inaccessible Interfaces: In Situ Approaches to
`Materials Tribology, MRS Bulletin 33 (2008) 1145-1189 (Ex. 1166).
`
`5
`
`Regeneron Exhibit 1101.012
`Regeneron v. Norvatis
`IPR2021-00816
`
`

`

`
`
`
`
`9.
`
`In 2013, I founded a Cancer Engineering Center at the University of
`
`Florida with the expressed purpose of enhancing collaborations between
`
`engineering and the physical sciences and cancer researchers. One aspect of my
`
`research is in developing the devices, tools, and infrastructures needed to create 3-
`
`dimensional models of patient-specific micro-tumoroids and tissue explants, and
`
`using these models for immuno-oncology, drug discovery, and understanding of
`
`disease progression, metastasis and immune cell interactions. My laboratory
`
`designs, builds, and sterilizes culture systems for maintaining the micro-tumoroids,
`
`interfaces with teams of surgeons, pathologists, and oncologists to collect and
`
`handle donor tissues, designs and fabricates novel 3-D perfusion systems for
`
`tumoroid maturation and handling, and we also design and build our own 3-D
`
`printers to fabricate micro-tumoroids and setup experiments. My laboratory
`
`maintains a microscopy and imaging facility with two resonant laser-scanning
`
`fluorescence confocal microscopes that we use for in situ studies of particle and
`
`cell tracking, immune cell killing of tumoroids, micro-rheology, and drug delivery.
`
`This work naturally involves the use of sensitive biologics, fine needle printing and
`
`handling, particle identification, and the use of antibodies, growth factors,
`
`chemotherapeutics, biologics, vaccines, nanoparticles, viruses, and the
`
`management of nutrient and waste metabolites.
`
`10. Additionally, and also important to this matter, I have extensive
`
`6
`
`Regeneron Exhibit 1101.013
`Regeneron v. Norvatis
`IPR2021-00816
`
`

`

`
`
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`experience in studying the interacting surfaces in pre-filled syringes, which
`
`includes studies of silicone oil lubrication, sealing, break loose forces, and sliding
`
`forces. In particular, I co-authored a set of papers with scientists at Becton
`
`Dickinson, a leading syringe manufacturer, studying the effects of time of
`
`stationary contact on the break loose force of siliconized pre-filled syringes.4 As
`
`part of this research project with Becton Dickinson, I also co-authored a paper
`
`using an in situ optical measurement system that my laboratory developed to
`
`analyze the real area of contact for elastomers against smooth glass surfaces.5
`
`11.
`
`I also have numerous publications on the ocular surface, spectroscopy,
`
`uncertainty in measurements, contact mechanics, elastomers, thin-films and
`
`interferometry, optical microscopy measurements of particles and cells, and fluid
`
`mechanics. I teach courses in fluid mechanics, tribology, materials science, rough
`
`surfaces, precision measurements, and mechanical design.
`
`12. With respect to syringes, my work has been focused on the
`
`stopper/glass barrel interface: sealing, break loose forces, sliding forces,
`
`
`4 Persson, et al., Elastic contact mechanics: Percolation of the contact area and
`fluid squeeze-out, Eur. Phys. J. E (2012) 35:5 (Ex. 1110); Lorenz, et al., Static or
`breakloose friction for lubricated contacts: the role of surface roughness and
`dewetting, J. Phys. Condens. Matter 25 (2013) (Ex. 1169).
`5 Krick, et al., Optical in Situ Micro Tribometer for Analysis of Real Contact Area
`for Contact Mechanics, Adhesion, and Sliding Experiments, Tribology Letters 45
`(2012) 185-194 (Ex. 1164).
`
`7
`
`Regeneron Exhibit 1101.014
`Regeneron v. Norvatis
`IPR2021-00816
`
`

`

`
`
`
`lubrication between the elastomer stopper and the glass barrel, surface roughness
`
`and surface topography, elastomer contact mechanics, elastomer materials,
`
`fluoropolymers and fluoropolymer coatings, adhesion and friction in elastomers,
`
`functionalization and siliconization of glass surfaces, and the mechanics associated
`
`with the force transmission between plunger rod and stopper sub-assembly.
`
`Regarding the components and subject matter of the ’631 patent, I have significant
`
`experience and knowledge regarding siliconization, stopper break loose forces,
`
`stopper sliding forces, and the measurements of particles using optical imaging and
`
`microscopy.
`
`13. Further details regarding my education, work experience, and
`
`publications are contained in my curriculum vitae, attached as Attachment A.
`
`14.
`
`I am being compensated at an hourly rate of $500, which is my
`
`standard rate for consulting engagements. My compensation is not dependent on
`
`the substance of my statements in this Declaration or the outcome of this case.
`
`IV. BACKGROUND OF THE TECHNOLOGY
`I have reviewed the ’631 patent from the perspective of a person of
`15.
`
`ordinary skill in the art (“POSITA”) as of the 2012-2013 timeframe. The ’631
`
`patent is directed to a pre-filled syringe containing a VEGF antagonist. The pre-
`
`filled syringe claimed in the ’631 patent includes a glass barrel, a stopper, and a
`
`8
`
`Regeneron Exhibit 1101.015
`Regeneron v. Norvatis
`IPR2021-00816
`
`

`

`
`plunger rod. These are typical components of a syringe, which are shown in
`
`Figure 1. Ex. 1011.
`
`
`
`
`
`Figure 1. Components of a pre-filled syringe, adapted from Shah and Prajapati
`“Prefilled Syringes: A New Concept”, Pharma Bio World (2009) (“Shah”). Ex.
`1011.
`
`
`16. The syringe barrels and needles have standard dimensions as
`
`established by the International Organization for Standardization (ISO), as
`
`indicated in Figures 2 and 3 from ISO 11040-4 (2007) and ISO 9626 (2001). Ex.
`
`1028; Ex. 1043. The ’631 patent claims are directed to 0.5 ml and 1 ml syringes
`
`and all calculations presented in this report use the standard dimensions and
`
`tolerances for syringe barrels defined by ISO 11040-4 and syringe needles defined
`
`by ISO 9626. Id.
`
`9
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`Regeneron Exhibit 1101.016
`Regeneron v. Norvatis
`IPR2021-00816
`
`

`

`
`
`
`
`Figure 2. Nominal dimensions of syringe barrels based on the ISO 11040-4 (Fig.
`1 and Table 1). Ex. 1028.007-.008.
`
`
`D, Nominal
`Internal
`Diameter (mm)
`Standard
`standa
`thin-
`Needles
`rd
`walled
`34 gauge 0.051
`
`33 gauge 0.089
`0.105
`32 gauge 0.089
`0.105
`31 gauge 0.114
`0.125
`30 gauge 0.133
`0.165
`29 gauge 0.133
`0.190
`28 gauge 0.133
`0.190
`27 gauge 0.184
`0.241
`
`r, nominal
`internal radius
`(mm)
`thin-
`standa
`walled
`rd
`
`0.0255
`0.0445 0.0525
`0.0445 0.0525
`0.0570 0.0625
`0.0665 0.0825
`0.0665 0.0950
`0.0665 0.0950
`0.0920 0.1205
`
`
`Figure 3. Dimensions of standard needles used for intravitreal injections: arranged
`from top to bottom by increasing nominal diameter (decreasing gauge) and
`nominal internal radius (r = ½D). Note that the internal diameters of 32-gauge and
`33-gauge needles are the same, and the internal diameter of 28-gauge and 29-gauge
`needles are the same. Dimensions of the 27-gauge - 33-gauge needles are taken
`from ISO 9626 (2001) Table 2. Ex.1043.006.
`
`
`
`
`
`
`10
`
`Regeneron Exhibit 1101.017
`Regeneron v. Norvatis
`IPR2021-00816
`
`

`

`
`
`
`
`17.
`
`It was well understood in the art before the ’631 patent that for a glass
`
`syringe, the syringe barrel and stopper need to be lubricated, most commonly with
`
`a silicone oil coating to make the syringe usable, i.e., to allow the stopper to be
`
`moved smoothly through the syringe barrel without the user having to apply an
`
`excess amount of force. This understanding is reflected in a January 2012 paper
`
`(Ex. 1110) from my lab in collaboration with scientists at Becton Dickinson:
`
`Syringes are the most common prefilled parenteral drug delivery
`systems, in which a rubber plunger stopper is actionated to expel the
`injectable liquid drug from a cylindrical glass or polymer barrel (see
`fig. 20). Low, uniform and stable gliding forces values of the plunger
`stopper are critical to patient comfort and healthcare professional
`convenience in manual use of prefillable syringes . . . . Traditionally
`the inner surface of the syringe is lubricated by a high viscosity
`silicone oil (viscosity η ≈ 0.35–10Pa s) to ensure good device’s
`gliding performance.
`
`Ex. 1110.012; See also Ex. 1015.065 (“Silicone oil coating is commonly used on
`
`stoppers and on the inside of syringes or cartridges as a lubricant to enable
`
`movement of the plunger. . . . Current processes for siliconization of prefilled
`
`syringes or cartridges apply well controlled amounts and involves baking of the
`
`silicone emulsion.”) (“Nema Vol. 1”).
`
`V.
`
`PERSON OF ORDINARY SKILL IN THE ART (POSITA)
`I have already opined in this case that a person of ordinary skill in the
`18.
`
`art with respect 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,
`
`11
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`Regeneron Exhibit 1101.018
`Regeneron v. Norvatis
`IPR2021-00816
`
`

`

`
`
`
`biomedical engineering, materials science, chemistry, or related field, or at least 2-
`
`3 years of professional experience in one or more of those fields. I have further
`
`previously explained that there are two areas of experience for a POSITA relevant
`
`to the ’631 patent (i) the design of pre-filled syringes; and (ii) sterilization of drug
`
`delivery devices, including those containing sterilization-sensitive therapeutics. On
`
`(ii), such sterilization experience would include experience with microbiology. It is
`
`my opinion that this is an appropriate definition. I have applied this definition of a
`
`POSITA when forming the opinions in this declaration; however, I provide some
`
`clarification below based on some additional evidence regarding the alleged
`
`invention in the ’631 patent.
`
`19. With respect to sterilization, I note that the named inventors on the
`
`’631 patent have testified during their depositions that the ’631 patent does not
`
`disclose a new process for sterilization or any details regarding optimization of a
`
`sterilization process; rather, the alleged invention instead relates to the design of
`
`the pre-filled syringe components, such as the siliconization, the stopper design
`
`and the plunger rod design. See, Ex. 1160 (Picci 12/16/2020 Tr.) at 90:6-94:20; Ex.
`
`1158 (Sigg 12/17/2020 Tr.) at 72:1-12, 75:11-76:1, 81:22-85:16, 90:6-91:2.6 As
`
`
`6 Ms. Picci testified that the features of the syringe disclosed in the ’631 patent that
`allowed it to be sterilized using EtO was a “special plunger rod with a disk that
`enters an interface with a backstop to prevent and limit movement of the stopper
`when vacuum is applied” and the distance between the ribs on the stopper. Ex.
`
`12
`
`Regeneron Exhibit 1101.019
`Regeneron v. Norvatis
`IPR2021-00816
`
`

`

`
`
`
`noted above, I have significant experience with those aspects of a pre-filled
`
`syringe. The ’631 patent states that the sterilization process may use a “known
`
`process such as ethylene oxide (EtO) or a hydrogen peroxide (H2O2) sterilisation
`
`process.” ’631 patent, 9:49-52. Through my laboratory research activities in
`
`biomedicine, cancer research, tissue engineering, and drug discovery, I have
`
`practical experience using sterilization, although not with respect to a pre-filled
`
`syringe specifically, and I have not been involved in developing sterilization
`
`processes for syringes. Given this context, the sparse detail in the ’631 patent
`
`regarding sterilization, and the nature of the alleged invention, I am able to offer
`
`opinions on the ’631 patent from the perspective of a POSITA.
`
`20.
`
`I understand that Patent Owner has proposed the following definition
`
`of a POSITA:
`
`A POSA would have had an advanced degree (i.e., an M.S., a Ph.D., or
`equivalent)
`in mechanical engineering, biomedical engineering,
`materials science, chemistry, chemical engineering, or a related field,
`and at least 2–3 years of professional experience, including in 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.
`
`
`1160 (Picci 12/16/2020 Tr.) at 90:6-98:9. The disk on the plunger rod and the
`distance between the ribs on the stopper that Ms. Picci referred to in her deposition
`are not clai