`
`UNITED STATES PATENT AND TRADEMARK OFFICE
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`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`
`
`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 JOEL M. COHEN
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`Regeneron Exhibit 1108.001
`Regeneron v. Novartis
`IPR2021-00816
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`TABLE OF CONTENTS
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`Page
`I.
`INTRODUCTION ........................................................................................... 1
`QUALIFICATIONS AND COMPENSATION .............................................. 1
`II.
`PERSON OF ORDINARY SKILL IN THE ART .......................................... 5
`III.
`IV. BACKGROUND OF THE TECHNOLOGY .................................................. 6
`V.
`PRIOR ART ..................................................................................................... 7
`A.
`“Sigg” – WO 2011/006877 ................................................................... 7
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`B.
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`C.
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`“Lam” – International Pat. Appl. Pub. No. WO 2008/077155 ............. 7
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`“Boulange” – International Pat. Appl. Pub. No. WO
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`2009/030976 .......................................................................................... 7
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`VI. OVERVIEW OF PARYLENE C .................................................................... 8
`VII. A TOXICOLOGIST WOULD NOT HAVE BEEN DETERRED
`FROM USING PARYLENE C AS A STOPPER COATING IN A
`PRE-FILLED SYRINGE COMPRISING A VEGF ANTAGONIST .......... 11
`A.
`Protein Adsorption Would Not Deter One From Using
`
`Parylene C ................................................................................. 12
`
`B.
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`Purported Cytotoxic Characteristics Would Not
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`Discourage a Toxicologist from Supporting Use of
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`Parylene C in a PFS .................................................................. 16
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`VIII. DECLARATION ........................................................................................... 24
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`i
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`Regeneron Exhibit 1108.002
`Regeneron v. Novartis
`IPR2021-00816
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`I.
`
`INTRODUCTION
`1.
`I have been retained by Petitioner Regeneron Pharmaceuticals, Inc.
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`(“Petitioner” or “Regeneron”), as an independent expert witness in the above-
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`captioned inter partes review (“IPR”), in which Regeneron has requested that the
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`U.S. Patent and Trademark Office cancel as unpatentable all claims of U.S. Patent
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`No. 9,220,631 (“the ’631 patent”).
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`2.
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`This declaration sets forth my analyses and opinions in response to the
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`declaration of Dr. John E. Dillberger (Ex. 2202). As I explain below, it is my
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`opinion that a toxicologist, as a member of a product development team, would not
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`have considered Parylene C to be unsafe, toxic, or unacceptable to be used as a
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`stopper coating in a prefilled syringe for intravitreal injection of a VEGF
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`antagonist drug.
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`II. QUALIFICATIONS AND COMPENSATION
`3.
`I have a Sc.D. in Environmental Health from Harvard School of
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`Public Health, a B.A. in Anthropology, Environmental Science, and Public Health
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`from Tufts University, and am a certified Diplomate of the American Board of
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`Toxicology (DABT).
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`4.
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`In addition, I have worked in the field of toxicology since 2011,
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`including 8 years working as a toxicology consultant at Gradient which provides
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`Regeneron Exhibit 1108.003
`Regeneron v. Novartis
`IPR2021-00816
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`scientific consulting services specializing in toxicology, epidemiology, risk
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`assessment, and product safety, among others. In 2021 I was promoted to
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`Principal Scientist, and in 2022 I was promoted to Principal at the firm. My
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`professional experience in toxicology includes work in the pharmaceutical,
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`medical device, and product safety industries.
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`5.
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`As a Principal at Gradient, I provide scientific consulting services
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`related to medical device biocompatibility and toxicological risk assessment,
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`consumer product risk assessment, and evaluations of toxicology studies in
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`connection with human health risks. I have worked on pharmaceuticals, medical
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`devices, consumer product safety, and toxicological risk assessments.
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`6. With respect to the pharmaceutical industry, I have evaluated the
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`potential health risks from exposure to impurities in a drug product for juvenile
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`patients. To determine the health risks, I evaluated the repeated dose toxicity,
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`genotoxicity, and carcinogenicity of the components contained in the identified
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`impurities, including those that had little toxicological data. I have also conducted
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`human health hazard and risk assessments for potential impurities in cell-based
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`cancer treatments. The evaluation was used as manufacturing guidance, as well as
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`for regulatory applications. I have also evaluated the kinetics and biological effects
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`of a new chemical platform for drug development. Specifically, I worked on
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`understanding the potential off-target effects of the novel chemistry involved,
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`2
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`Regeneron Exhibit 1108.004
`Regeneron v. Novartis
`IPR2021-00816
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`including known pharmacokinetics and potential for adverse health effects. Most
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`recently I was hired to conduct a toxicological risk assessment on extractable and
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`leachables from a pre-filled syringe, which involved chemical risk assessment for
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`all compounds detected under aggressive extraction conditions (e.g. harsh polar
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`solvents and at elevated temperatures), as well as chemicals detected having
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`leached from the syringe into the drug formulation itself under more clinically
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`relevant test conditions.
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`7.
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`I have also worked on a number of medical device projects. I have
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`provided ISO-compliant toxicological risk assessments for chemicals identified in
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`extracts of implantable medical ports and catheter systems, a permanent implant
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`screw, dialysis equipment, and leached compounds from a dialysis machine. In
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`particular, I identified toxicological data for relevant endpoints and used the data to
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`derive chemical and device specific safety margins, in accordance with ISO10993-
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`17, ICH M7, and US FDA guidance. The risk assessments were used to support
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`safety evaluations of the medical devices, and specifically for addressing potential
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`risks related to systemic toxicity, genetic toxicity, carcinogenicity, and
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`reproductive and developmental toxicity.
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`8.
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`I have also established biocompatibility test plans involving
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`experimental testing on medical devices for cytotoxicity, sensitization, irritation,
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`genotoxicity, implantation, hemocompatibility, material mediated pyrogenicity,
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`3
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`Regeneron Exhibit 1108.005
`Regeneron v. Novartis
`IPR2021-00816
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`and systemic toxicity, all in accordance with the ISO 10993 series of international
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`standards and guidelines. I have then interpreted the results of experimental
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`biocompatibility testing, synthesizing the information into an overall conclusion
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`regarding biological safety of the final finished device.
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`9.
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`In addition to my professional experience at Gradient, I have also
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`published over 30 papers, including on risk assessments of extractables and
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`leachables in medical devices, predictive toxicology, and nanotoxicology.
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`10.
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`In addition to my professional experience, I have years of experience
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`participating in professional organizations and scientific panels relating to
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`toxicology. For example, I am the current President of the Northeast regional
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`chapter of the Society of Toxicology. I have also served as Secretary of the
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`Society of Toxicology Computational Toxicology Specialty Section, and Councilor
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`of the Nanoscience and Advanced Materials Toxicology Specialty Section. In
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`2019-2020, I served on United States Environmental Protection Agency (“US
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`EPA”) Scientific Advisory Board Peer Review Panel, applying my expertise in
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`physiologically based pharmacokinetic modelling to evaluate the US EPA All
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`Ages Lead Model. My findings and those of my fellow panel members were
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`summarized in a publicly available report submitted to the US EPA Administrator.
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`11.
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`In addition to the above, I have given numerous presentations at
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`symposiums, conferences, workshops, and other professional organizational
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`4
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`
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`Regeneron Exhibit 1108.006
`Regeneron v. Novartis
`IPR2021-00816
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`meetings, including many presentations on toxicology, toxicological risk
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`assessments, and biocompatibility for medical devices and pharmaceutical
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`components.
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`12. Through my professional experience, I have gained extensive
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`expertise in toxicological risk assessments in medical devices, including health
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`risk, biocompatibility, and analysis of substances with respect to leachables and
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`extractables.
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`13. Gradient is being compensated at my standard rate of $430/hour. My
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`compensation is in no way contingent upon my opinions or the outcome of the
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`proceeding.
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`14. My curriculum vitae is attached as Attachment A, and provides
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`further information about my experience, expertise, and presentations.
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`III. PERSON OF ORDINARY SKILL IN THE ART
`15.
`I have been informed that Novartis has offered the following
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`definition of a person of ordinary skill in the art (POSA):
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`A POSA would have 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
`5
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`
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`Regeneron Exhibit 1108.007
`Regeneron v. Novartis
`IPR2021-00816
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`not only his or her own skills, but also the specialized skills of team
`members in complementary fields including ophthalmology,
`microbiology and toxicology.
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`16. Under the definition of a POSA set forth by Novartis, I am qualified
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`to offer opinions from the perspective of a member of a product development team
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`with specialized skill of toxicology. In particular, I have provided toxicological
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`assessments of medical devices and drug products that were utilized by product
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`development teams to support safety evaluations and/or regulatory applications.
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`17.
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`I understand that the earliest claimed priority date for the ’631 patent
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`is July 3, 2012, and my opinions offered herein are from the perspective of a
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`member of a product development team with specialized skills in toxicology as of
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`that date. I note that my opinions would be the same if offered from the
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`perspective of a member of a product development team with specialized skills in
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`toxicology as of October 2011, which I understand is the date by which Novartis
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`has asserted that the named inventors conceived of the claims in the '631 patent.
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`IV. BACKGROUND OF THE TECHNOLOGY
`18.
`I have reviewed the ’631 patent and its claims. I am not an expert in
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`syringe design or sterilization techniques. I am, however, generally familiar with
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`syringes and am able to apply my specialized skill of toxicology and review of the
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`documents cited to syringes.
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`6
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`Regeneron Exhibit 1108.008
`Regeneron v. Novartis
`IPR2021-00816
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`19.
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`I am also currently conducting a toxicological risk assessment on
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`extractable and leachables from a pre-filled syringe, which involved chemical risk
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`assessment for all compounds detected under aggressive extraction conditions (e.g.
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`harsh polar solvents and at elevated temperatures), as well as chemicals detected
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`having leached from the syringe into the drug formulation itself under more
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`clinically relevant test conditions.
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`V.
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`PRIOR ART
`A.
`“Sigg” – WO 2011/006877
`20.
`I understand from the declaration of Horst Koller that Sigg discloses a
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`pre-filled syringe for intravitreal injection that contains the VEGF-antagonist
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`ranibizumab (Lucentis). Ex. 1003, ¶ 123.
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`B.
`21.
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`“Lam” – International Pat. Appl. Pub. No. WO 2008/077155
`I understand from the declaration of Horst Koller that Lam also
`
`discloses a pre-filled syringe for intravitreal injection containing the VEGF-
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`antagonist ranibizumab (Lucentis). Ex. 1003, ¶¶ 130-131.
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`C.
`22.
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`“Boulange” – International Pat. Appl. Pub. No. WO 2009/030976
`I understand from the declaration of Horst Koller that Boulange
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`discloses a pre-filled syringe. Ex. 1003, ¶ 140. I further understand from Mr.
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`Koller’s declaration that Boulange discloses an embodiment in which the stopper
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`of the pre-filled syringe includes a Parylene C coating. Id. at ¶ 172. Boulange
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`describes that Parylene materials “have various properties, for example
`7
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`Regeneron Exhibit 1108.009
`Regeneron v. Novartis
`IPR2021-00816
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`imperviousness to gases, for example oxygen, and to dry-lubricating liquids, for
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`example water, which make them particularly attractive for use in numerous
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`biomedical applications, particularly for certain medical devices.” Ex. 1008 at
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`2:21-24. Boulange further describes that Parylene materials are manufactured and
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`sold by companies such as Union Carbide Corporation and Specialty Coating
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`Systems. Id. at 2:10-13.
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`23. The ’631 Patent describes that the pre-filled syringe can include a
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`stopper that “may be made from rubber, silicone or other suitable resiliently
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`deformable material.” Ex. 1001 at 2:33-34. Based on my review of the ’631
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`Patent, it does not appear to describe what coatings are used on the stopper. I
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`understand from the declaration of Horst Koller, however, that it was common for
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`stoppers to be comprised of rubber and coated with silicone oil.
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`VI. OVERVIEW OF PARYLENE C
`24. Parylene C is a polymer material that is part of a class of materials
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`generally referred to as Parylene, which also includes Parylene N, Parylene D, and
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`Parylene HT. Ex. 1008 at 2:7-10; Ex. 1074.002. The chemical structure of
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`Parylene C is illustrated below:
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`8
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`Regeneron Exhibit 1108.010
`Regeneron v. Novartis
`IPR2021-00816
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`Ex. 1074.002
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`
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`Parylene polymers are usually applied to components by a direct dry vacuum
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`deposition process. Ex. 1008 at 2:27-28; see also Ex. 1074.003.
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`25. A 2007 publication from one of the manufacturers of Parylene
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`coatings, Specialty Coating Systems (SCS), describes that Parylene C has been
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`used in a number of different applications, including automotive, electronics,
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`military/aerospace, and medical. Ex. 1074.010. With respect to medical devices,
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`the publication further describes that Parylene coatings are “listed in the FDA’s
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`Biomaterials Compendium,” and “provide an ideal surface modification for
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`implantable and non-implantable devices such as catheters, seals, stents, cochlear
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`implants, surgical tools, pacemakers and components. The coatings protect devices
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`and components from moisture, biofluids and biogases and serves as a
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`biocompatible surface for tissue contact.” Id. Another prior art publication from
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`SCS dated August 2002 describes that Parylene coatings, including Parylene C,
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`have been used in a wide range of medical devices since the 1970s, including
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`9
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`Regeneron Exhibit 1108.011
`Regeneron v. Novartis
`IPR2021-00816
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`“catheters and mandrels, stents, needles, cannulae, cardiac assist devices, [and]
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`prosthetics….” Ex. 1075.002.
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`26. The prior art further describes that Parylene C has “been tested
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`according to the Biological Evaluations requirements of ISO 10993.” Ex.
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`1074.010. A toxicologist would have understood that ISO 10993 is a standard
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`established by the International Organization of Standardization (ISO) that sets
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`forth tests and evaluations for the Biological Evaluation of Medical Devices. See
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`e.g., Ex. 2042. Companies use the testing and evaluation protocols set forth in ISO
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`10993 as a means of demonstrating that a particular material is safe for use with
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`the human body. With respect to each medical device application that Parylene C
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`had been used in, a toxicologist would expect that Parylene C and all other
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`materials would have been evaluated via testing on the final finished device (e.g.,
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`in accordance with ISO 10993) given that thermal, mechanical, and chemical
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`processes used to manufacture, assemble, package and sterilize products can
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`influence the quantity and type of chemicals that could be released from the
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`product. Accordingly, a toxicologist would have expected that Parylene C had met
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`the ISO 10993 standard or was otherwise determined to be safe for human use with
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`respect to the medical device applications.
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`27. Additional prior art publications confirm that Parylene C had been
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`used in medical device applications. For example, a 2007 publication cited by Dr.
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`10
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`Regeneron Exhibit 1108.012
`Regeneron v. Novartis
`IPR2021-00816
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`Dillberger (Chang et al., 2007) states that Parylene C is “extensively used as a
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`coating for insulating implantable devices.” Ex. 2030.002. Chang et al. further
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`describes that Parylene C was known to be “chemically inert and
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`nonbiodegradable,” “highly resistant to most chemicals, as well as to fungal and
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`bacterial growth,” and that “new implementations of Parylene-C will likely lead to
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`new technologies and devices for biomedical applications.” Id.; see also id at .008.
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`Similarly, a 2009 publication cited by Dr. Dillberger (Kaminska et al., 2009)
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`describes Parylene C as “a promising candidate for metallic implant coatings
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`separating an implant body from the surrounding tissues,” and concludes that
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`“parylene C is a material worth considering for biomedical use.” Ex. 2031.001-
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`.002. And as explained above, Boulange describes using Parylene C as a coating
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`for a stopper in a pre-filled syringe, and explains that it is “particularly attractive
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`for use in numerous biomedical applications, particularly for certain medical
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`devices.” Ex. 1008.004.
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`VII. A TOXICOLOGIST WOULD NOT HAVE BEEN DETERRED FROM
`USING PARYLENE C AS A STOPPER COATING IN A PRE-
`FILLED SYRINGE COMPRISING A VEGF ANTAGONIST
`28. Dr. Dillberger identifies two purported issues that he contends would
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`have discouraged a toxicologist from using Parylene C as a coating in a PFS
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`comprising a protein-based drug. First, Dr. Dillberger contends that “high protein
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`adsorption” would have discouraged a toxicologist from using it. Ex. 2202.0038.
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`11
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`Regeneron Exhibit 1108.013
`Regeneron v. Novartis
`IPR2021-00816
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`Second, Dr. Dillberger contends that “Parylene C was known to potentially
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`generate harmful leachables.” Ex. 2202.0041. I address both of those issues
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`below.
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`A. Protein Adsorption Would Not Deter One From Using
`Parylene C
`I disagree that the evidence cited by Dr. Dillberger (Chang et al., 2007
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`29.
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`[Ex 2030] and Kaminska et al., 2009 [Ex 2031]) demonstrates that “high protein
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`adsorption” would have discouraged a toxicologist from using Parylene C. Chang
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`et al., for example, describe that the application of Parylene C can be “easily
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`modified” for different biomedical applications depending on the desired result.
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`Ex. 2030.008. In particular, Chang et al. disclose that different surface treatments
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`on Parylene C membranes (treatment with air plasma, and also coating with
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`fibronectin) lead to differences in the level of protein adsorption and cell adhesion.
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`Id. at .004, .006 (“The ability to modify the level of protein adsorption on the
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`parylene-C substrates is of potential value for various biomedical applications and
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`microfabrication techniques.”). Similarly, the findings in Kaminska et al. indicate
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`that the “parylene coating very well reproduces the surface texture of substrate
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`material and is an important factor improving the platelet adhesion.” Ex. 2031.006.
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`A toxicologist would understand from these references that Parylene C can be
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`combined with various substrates in a manner that enhances or diminishes the level
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`of protein adsorption. In other words, one would understand from these references
`12
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`Regeneron Exhibit 1108.014
`Regeneron v. Novartis
`IPR2021-00816
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`that Parylene C can be applied in a manner such that protein adsorption would be
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`minimized.
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`30.
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`In addition, although Dr. Dillberger contends that Chang et al. and
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`Kaminska et al. report that Parylene C’s protein adsorption is “high,” Dr.
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`Dillberger does not address the context of that finding. Ex. 2202 ¶ 66. In
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`particular, Chang et al. describes that Parylene C can adsorb the protein bovine
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`serum albumin (BSA), a serum albumin protein collected from cows often used in
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`laboratory experiments and that has similar function and physicochemical
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`properties to human serum albumin, at a rate three times higher than glass. Ex.
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`2030.005. Dr. Dillberger, however, has not explained why comparing Parylene
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`C’s protein adsorption to glass would be relevant in the context of evaluating the
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`performance and function of a stopper coating for a pre-filled syringe. Instead, a
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`toxicologist would evaluate Parylene C’s level of protein adsorption relative to
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`other lubricants that were typically and historically used in a prefilled syringe
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`system.
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`31.
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`I understand from Mr. Koller that a syringe designer would have
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`known that silicone oil was a known stopper coating for a PFS, and that poly-
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`(dimethylsiloxane) (“PDMS”) is composed of the same material as silicone oil.
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`Ex. 1003, ¶ 55. Chang et al., in turn, report a comparison between glass, Parylene
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`C and PDMS with respect to protein adsorption of BSA. As shown below, protein
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`13
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`Regeneron Exhibit 1108.015
`Regeneron v. Novartis
`IPR2021-00816
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`adsorption level of BSA on Parylene C is similar to adsorption on PDMS, both of
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`which exceed BSA adsorption levels observed for glass.
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`Ex. 2030 at Fig. 1A (annotated)
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`
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`32. Chang et al. also describe that protein adsorption is protein-
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`dependent. For example, Chang et al. also tested IgG with respect to protein
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`adsorption on glass, PDMS, and Parylene C. As shown below, Chang et al. show
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`that protein absorption for IgG is similar for Parylene C, glass, and PDMS. Id. at
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`.005. Thus, a toxicologist would discern from Chang that a VEGF-antagonist has
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`potential to adsorb to Parylene C at approximately the same rate as other stopper
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`coatings known in the art (e.g., silicone oil or PDMS).
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`14
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`Regeneron Exhibit 1108.016
`Regeneron v. Novartis
`IPR2021-00816
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`Ex. 2030 at Fig. 1B (annotated)
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`33. Dr. Dillberger also relies on Kaminska et al., a publication examining
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`the interactions of Parylene C on medical steel substrates, noting that Parylene C
`
`has potential for high protein adsorption. Ex. 2202.0038-39. However, the material
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`substrate that Parylene C is applied to has a significant effect on its protein
`
`adsorption. To this point, Kaminska et al. report differences in platelet adsorption
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`for Parylene C coated polished medical steel as compared to Parylene C coated
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`machined medical steel, following one-hour contact of test samples with citrated
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`whole blood. Ex. 2031.004. Specifically, Parylene C coated polished medical steel
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`exhibited significantly lower platelet absorption compared with Parylene C coated
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`15
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`
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`Regeneron Exhibit 1108.017
`Regeneron v. Novartis
`IPR2021-00816
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`machined medical steel. Furthermore, Kaminska assessed platelet adsorption using
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`uncoated medical steel (both polished and machined) as control samples. The
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`study authors reported a statistically significant decrease in platelet adsorption for
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`the Parylene C coated polished medical steel when compared to the uncoated
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`polished medical steel control sample. Altogether, none of these findings
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`demonstrate how Parylene C would adsorb to protein when coating a rubber
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`stopper in a pre-filled syringe.
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`34. Based on the results reported by Kaminska et al. and Chang et al.,
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`protein adsorption would not discourage a toxicologist from supporting use of
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`Parylene C in a PFS. As I explained above, these references describe that Parylene
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`C coatings exhibit protein adsorption potential that is comparable to silicone
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`oil/PDMS, which was a commonly used coating for stoppers in the art. Moreover,
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`neither Kaminska et al. nor Chang et al. suggest that Parylene C would have high
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`protein adsorption when coating a rubber stopper, which I understand would be the
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`intended application in Boulange.
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`B.
`
`Purported Cytotoxic Characteristics Would Not Discourage a
`Toxicologist from Supporting Use of Parylene C in a PFS
`35. A toxicologist would not expect Parylene C to have cytotoxic
`
`characteristics based on its prior use in implantable devices and interactions with
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`biological substances in the body. As described above in section VI, Parylene C
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`was a known biocompatible material that had been used in implantable devices for
`16
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`Regeneron Exhibit 1108.018
`Regeneron v. Novartis
`IPR2021-00816
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`decades. The literature as a whole describes Parylene C as biocompatible,
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`including meeting ISO guidelines such as ISO-10993. Dr. Dillberger cites to ISO-
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`10993, stating that a toxicologist would understand that syringe components would
`
`be evaluated for biocompatibility risks. Ex. 2202 ¶ 40. ISO-10993 provides a
`
`general framework for the biological evaluation of medical devices, including tests
`
`for in vitro cytotoxicity. Ex. 2181.004. ISO-10993-1 explains that it gives
`
`“preference to chemical constituent testing and in vitro models, in situations where
`
`these methods yield equally relevant information to that obtained from in vivo
`
`models.” Id. at .006. ISO-10993 Part 5 describes various testing methods to assess
`
`the in vitro cytotoxicity of medical devices. Thus, a toxicologist would have
`
`understood, upon reviewing the prior art as a whole (including its use in a variety
`
`of implantable medical devices), that Parylene C would not pose a toxicity risk
`
`given that it had been tested in accordance with ISO 10993.
`
`36. Dr. Dillberger incorrectly dismisses the fact that Parylene C has been
`
`tested according to the Biological Evaluation requirements of ISO-10993 simply
`
`because the statement is found in an article authored by a manufacturer of Parylene
`
`C—SCS. Id. at ¶ 71. Dr. Dillberger, however, does not consider the fact that
`
`Parylene C had been used in numerous medical applications, including implantable
`
`devices, since the 1970s. Accordingly, a toxicologist would have understood that
`
`Parylene C had not raised toxicity concerns for human implantables, and therefore
`
`17
`
`
`
`Regeneron Exhibit 1108.019
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`
`
`would not expect it to have toxicity concerns if used as a coating in a PFS storing a
`
`protein drug product.
`
`37. As noted above, a toxicologist would conduct ISO 10993 testing on
`
`the final finished syringe to confirm patient safety given that processes used during
`
`manufacturing, assembly, packaging and sterilization can impact chemical
`
`exposures from the final finished device with implications for patient safety. The
`
`need to conduct such testing to confirm patient safety would not deter a
`
`toxicologist from supporting use of Parylene C as a stopper coating in a pre-filled
`
`syringe, however, because a toxicologist would expect to conduct such testing
`
`regardless of what materials were used. As explained above, a toxicologist would
`
`have understood that Parylene C had passed ISO 10993 testing with respect to its
`
`prior uses in medical applications. And as explained below, the evidence cited by
`
`Dr. Dillberger would not give a toxicologist an expectation of a different result
`
`when using Parylene C as a stopper coating in a pre-filled syringe comprising a
`
`VEGF-antagonist.
`
`38. The two publications cited by Dr. Dillberger (Ex. 2030 and Ex. 2031)
`
`fail to support his opinion that Parylene C would have been of concern to a
`
`toxicologist for use as a coating in a pre-filled syringe that stores a protein drug
`
`product. Notably, neither publication provides evidence of in vivo cytotoxicity.
`
`Chang et al. tested Parylene C in cell culture systems, while Kaminska et al. tested
`
`18
`
`
`
`Regeneron Exhibit 1108.020
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`
`
`Parylene C for use in medical steel implants. Ex. 2030.002; Ex. 2031.002. As Dr.
`
`Dillberger states in his report, “[t]he safety, suitability, and compatibility of a
`
`material is dependent on the context in which that material is used.” Ex. 2202 ¶ 54.
`
`Here, however, neither publication identified by Dr. Dillberger relates to coating a
`
`stopper with Parylene C in a pre-filled syringe comprising a protein drug product.
`
`And to the extent that Chang et al and Kaminska et al. describe using Parylene C
`
`in contexts outside those tested in the references, both ultimately recommend its
`
`use for biological applications. Ex. 2030.008 (“Given that parylene-C has already
`
`been shown to be well suited for microfabrication, and that it can be made into
`
`flexible and robust devices, the data presented here would be useful for the
`
`implementations that tailor to the biocompatibility of parylene-C. The new
`
`implementations of parylene-C will likely lead to new technologies and devices for
`
`biomedical applications.”); Ex. 2031.006 (“The results presented strongly support
`
`the thesis that parylene C is worth considering for biomedical use.”).
`
`39. Dr. Dillberger also does not address the findings by Chang et al. (Ex.
`
`2030) indicating a lack of significant difference in cellular health (as indicated by
`
`adhesion and morphology) between PDMS and Parylene C, with PDMS being the
`
`closest appropriate comparator to Parylene C. Ex. 2030.008 (“The cell adhesion
`
`and morphology on as-deposited parylene-C and plain PDMS substrates were not
`
`significantly different (Figures 2 and 3), despite a clear difference in surface
`
`19
`
`
`
`Regeneron Exhibit 1108.021
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`
`
`roughness between the two materials (Table 2).”). This would teach a toxicologist
`
`that the characteristics of Parylene C are approximately the same as silicone oil
`
`with respect to potential cytotoxicity. And given that silicone oil was a known and
`
`accepted coating for rubber stoppers in syringes, a toxicologist would not be
`
`deterred from recommending Parylene C given that its characteristics were
`
`comparable to silicone oil.
`
`40. Moreover, Kaminska et al. (Ex. 2031) does not explicitly conclude
`
`that there is a cytotoxicity concern associated with Parylene C. Dr. Dillberger
`
`suggests that the lack of cell growth and changes in gene expression on Parylene C
`
`coated medical steel suggests generation of harmful leachable substances. Ex.
`
`2202, ¶ 68. However, the study authors make no such suggestion, and a
`
`toxicologist would not infer from the article that Parylene C would negatively
`
`impact a biologic drug product or a patient, as I explain in more detail below.
`
`41. Dr. Dillberger refers to two different assays that were reported by
`
`Kaminska et al. (Ex. 2031). The first assay measured cell proliferation and cell
`
`death, where an immortalized line of human umbilical vein endothelial cells (Ea.hy
`
`926) were cultured on a Parylene C coated medical steel surface. The control
`
`surface in this assay was a standard cell culture plate, which is optimized for cell
`
`growth and proliferation, and is thus an improper control in the context of a PFS.
`
`Instead, a toxicologist would have wanted to compare the Parylene C surface to an
`
`20
`
`
`
`Regeneron Exhibit 1108.022
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`
`
`uncoated medical steel surface to determine whether Parylene C, as opposed to
`
`some other variable, was responsible for the cell death. A toxicologist also would
`
`have needed a comparison between a Parylene C coated surface and a silicone oil
`
`coated surface to assess how Parylene C performed relative to other coatings used
`
`for stoppers (e.g., silicone oil). Because Kaminska et al. (Ex. 2031) did not
`
`provide either of these controls, a toxicologist would not conclude that Parylene C
`
`would pose a cytotoxicity concern when used as a stopper coating in a PFS
`
`comprising a protein drug product.
`
`42. Moreover, Dr. Dillberger did not consider that Kaminska et al. was
`
`ultimately inconclusive as to Parylene C’s potential cytotoxicity. In particular, the
`
`authors describe another study where cells were observed in proximity to a
`
`Parylene C coated device but not on the device surface, suggesting a lack of
`
`cytotoxicity associated with potential release or leaching of parylene C from the
`
`device surfa
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