`
`__________
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`__________
`
`
`REGENERON PHARMACEUTICALS, INC.,
`Petitioner
`
`v.
`
`NOVARTIS PHARMA AG,
`NOVARTIS TECHNOLOGY LLC,
`NOVARTIS PHARMACEUTICALS CORPORATION,
`Patent Owner
`
`__________
`
`
`Case IPR2020-01317 & IPR2020-1318
`Patent 9,220,631
`
`__________
`
`
`DECLARATION OF KARL R. LEINSING, PE, IN SUPPORT OF
`NOVARTIS’S
`PATENT OWNER PRELIMINARY RESPONSE
`
`
`
`
`
`
`
`
`
`
`Novartis Exhibit 2001.001
`Regeneron v. Novartis, IPR2020-01318
`
`
`
`
`
`TABLE OF CONTENTS
`
`
`
`Introduction ...................................................................................................... 1
`
`
`
`
`
`
`
`Background and Qualifications ....................................................................... 1
`
`Summary of Opinions ...................................................................................... 4
`
` Legal Principles ............................................................................................... 4
`
`
`
`
`
`
`
`
`
`Burden of Proof ..................................................................................... 4
`
`Prior Art ................................................................................................. 5
`
`Obviousness ........................................................................................... 5
`
`Reduction to Practice............................................................................. 8
`
`
`
`The ’631 Patent ................................................................................................ 9
`
` Person of Ordinary Skill in the Art ................................................................ 11
`
` Analysis of Prior Art Relied on by petitioner ................................................ 12
`
`
`
`
`
`
`
`
`
`Sigg ...................................................................................................... 12
`
`Boulange .............................................................................................. 18
`
`Lam ...................................................................................................... 25
`
`Reuter .................................................................................................. 27
`
` Analysis of 1317 Obviousness Arguments .................................................... 30
`
`ii
`
`Novartis Exhibit 2001.002
`Regeneron v. Novartis, IPR2020-01318
`
`
`
` A POSA Would Not Have Been Motivated to Combine Sigg
`
`and Boulange to Make a Prefilled Syringe Filled with a VEGF
`
`Antagonist for Intravitreal Injection. ................................................... 31
`
`
`
`A POSA Would Not Have Reasonably Expected a PFS
`
`Combining Sigg and Boulange to Succeed. ........................................ 39
`
` Analysis of 1318 Obviousness Arguments .................................................... 44
`
` A POSA would not have been Motivated to Combine Lam and
`
`Reuter to arrive at a PFS containing less than about 100 µg
`
`silicone oil ........................................................................................... 45
`
`
`
`A POSA would not have Reasonably Expected to Successfully
`
`Combine Lam and Reuter to Lower Silicone Oil Levels Below
`
`About 100 µg ....................................................................................... 49
`
`
`
`The Inventions Claimed in the ’631 Patent Were Constructively
`
`Reduced to Practice in EP ’649 and the ’352 Application ............................ 50
`
` Declaration ..................................................................................................... 70
`
`
`
`
`
`
`
`
`
`
`
`
`iii
`
`Novartis Exhibit 2001.003
`Regeneron v. Novartis, IPR2020-01318
`
`
`
`
`
`
`
`INTRODUCTION
`
`1.
`
`I, Karl R. Leinsing, MSME, PE, submit this declaration on behalf of
`
`Novartis Pharma AG, Novartis Technology LLC, and Novartis Pharmaceuticals
`
`Corp. (collectively, “Patent Owner” or “Novartis”), regarding IPR2020-1317 and
`
`IPR2020-1318. I understand that Regeneron Pharmaceuticals, Inc. (“Petitioner” or
`
`“Regeneron”) initiated these proceedings by filing Petitions seeking cancellation of
`
`all claims of U.S. Patent No. 9,220,631 (“the ’631 patent”).
`
`2.
`
`The subject of my declaration is the validity of the ’631 patent. This
`
`declaration is the result of my review and analysis of the petitions, declarations,
`
`and prior art submitted by the Petitioner in the above referenced IPR proceedings,
`
`as well as additional materials identified herein.
`
` BACKGROUND AND QUALIFICATIONS
`
`3.
`
`I received a Bachelor of Science (B.S.) degree in mechanical
`
`engineering from the University of New Hampshire in 1988 and a Master of
`
`Science (M.S.) degree in mechanical engineering from North Carolina A&T State
`
`University in 1995. I am also licensed as a Registered Professional Engineer in the
`
`state of New Hampshire.
`
`4.
`
`I have been a medical device engineer since 1992 and worked
`
`extensively with medical device disposables, including syringes of all types, since
`
`that date. I have extensive expertise in the mechanical design and manufacturing
`
`1
`
`Novartis Exhibit 2001.004
`Regeneron v. Novartis, IPR2020-01318
`
`
`
`
`
`of medical devices. My areas of expertise include full life-cycle product
`
`development of medical devices, including conception, patent applications,
`
`manufacturing, testing, verification, validation, packaging, bioburden testing,
`
`sterility assurance testing, biocompatibility, bacterial contamination testing,
`
`labeling, clinical trials, regulatory approval, marketing, and sales training.
`
`5.
`
`Since 2006, I have been President of ATech Designs, Inc., where I
`
`have worked in the development of various medical devices, including
`
`cardiovascular, surgical, intravenous, endoluminal, and percutaneous devices.
`
`More specifically, I have consulted in the development of various drug delivery
`
`devices, such as auto-injectors, pen injectors, syringes, safety syringes, and insulin
`
`pumps, among others.
`
`6.
`
`Previously, from 2005 to 2006, I worked as a Director of Biomedical
`
`Engineering at Mitralign, Inc., developing implants for heart valve repair. From
`
`2002 to 2005, I worked as a Manager of Design Engineering at ONUX Medical,
`
`Inc., developing fixation devices for abdominal aortic aneurysm repair.
`
`7.
`
`From 1992 to 2002, I worked as a Senior Principal Design Engineer at
`
`IVAC, which was a subsidiary of Eli Lilly & Company. There, I developed a
`
`number of medical drug infusion products, including disposable sets and
`
`components, IV and syringe pump systems, injection systems, vial adapters,
`
`syringes, and needle-free valves for the delivery of drugs. My work involved both
`
`2
`
`Novartis Exhibit 2001.005
`Regeneron v. Novartis, IPR2020-01318
`
`
`
`
`
`the conception and manufacturing of these devices. During this time, I was the
`
`sole inventor of the SmartSite® Needle-Free Valve for intravenous infusion pumps
`
`and disposables. This device utilized 3 types silicone lubricant (di-methyl, phenyl,
`
`and Fluoro-based) to minimize friction and prevent cross-linking of silicone
`
`rubber. And also relevant to the subject matter of this case, I was also involved in
`
`the development of a dual-acting pen injector, capable of dispensing both long- and
`
`short-term insulin, for Eli Lilly. This pen used glass syringe-type vials or
`
`cartridges. In addition to my extensive involvement with the design team for the
`
`entire device, my work focused on the specific development of the disposable
`
`needle, valve mechanism, and adapters that formed the device.
`
`8.
`
`I am a named inventor of over 35 patents, all of which relate to the
`
`medical device field. I have previously lectured on the product design and
`
`manufacturing process of medical devices. I was also named Chairman of the
`
`Medical Device and Manufacturing Conference in 2014 for the development
`
`process of medical devices.
`
`9.
`
`A copy of my curriculum vitae, attached as Exhibit A, contains further
`
`details concerning my education, experience, publications, patents, and other
`
`qualifications to render an expert opinion in this matter.
`
`3
`
`Novartis Exhibit 2001.006
`Regeneron v. Novartis, IPR2020-01318
`
`
`
`
`
` SUMMARY OF OPINIONS
`
`10. The ’631 patent is not obvious over the prior art cited by the Petitioner
`
`in IPR2020-1317 & 1318 at least because:
`
` A person of skill in the art would not have been motivated to combine the
`
`references relied upon by Petitioner to arrive at the claimed invention;
`
` A person of skill in the art would not have reasonably expected to
`
`successfully combine the references relied upon by Petitioner to arrive at the
`
`claimed invention.
`
`11. European application No. EP 12189649 and U.S. Application No.
`
`13/750,352 demonstrate a constructive reduction to practice of the claimed
`
`invention no later than October 23, 2012, and January 25, 2013, respectively.
`
` LEGAL PRINCIPLES
`
`12.
`
`I am not a lawyer. Therefore, in formulating my opinions and
`
`conclusions in this proceeding, I have been provided with an understanding of the
`
`prevailing principles of U.S. patent law that govern the issues of patent validity.
`
` Burden of Proof
`13.
`I have been informed by counsel that in this inter partes review,
`
`Regeneron bears the burden of establishing invalidity by a preponderance of the
`
`evidence. I understand this to mean that, for a claim to be found invalid as
`
`obvious, it must be found more probable than not to be obvious.
`
`4
`
`Novartis Exhibit 2001.007
`Regeneron v. Novartis, IPR2020-01318
`
`
`
`
`
`
`14.
`
`Prior Art
`I understand that, in this IPR proceeding, the prior art to the ʼ631
`
`patent includes patents and printed publications in the relevant field(s) that predate
`
`the ʼ631 patent’s priority date.
`
`15.
`
`I understand that the parties dispute the priority date of the ’631
`
`patent, and as a result, the prior art status of certain references. I have been asked
`
`to assume that any reference Petitioners rely upon is prior art for the purposes of
`
`my analysis and this declaration.
`
` Obviousness
`16.
`I understand that a claim of a patent may be obvious to a person of
`
`ordinary skill in the art if the differences between the subject matter set forth in the
`
`patent claim and the prior art are such that the claimed subject matter as a whole
`
`would have been obvious at the time of the invention.
`
`17.
`
`I understand that obviousness is a determination of law based on
`
`various underlying determinations of fact. In particular, these underlying factual
`
`determinations include (1) the scope and content of the prior art; (2) the level of
`
`ordinary skill in the art at the time the claimed invention was made; (3) the
`
`differences between the claimed invention and the prior art; and (4) the extent of
`
`any proffered objective “indicia” of non-obviousness. I understand that the
`
`objective indicia, also known as secondary considerations, which may be
`
`5
`
`Novartis Exhibit 2001.008
`Regeneron v. Novartis, IPR2020-01318
`
`
`
`
`
`considered in such an analysis include: commercial success of the patented
`
`invention (including evidence of industry recognition or awards), whether the
`
`invention satisfied a long-felt but unmet need in the field, the failure of others to
`
`arrive at the invention, industry acquiescence and recognition of the invention,
`
`initial skepticism of the invention by others in the field, whether the inventors
`
`proceeded in a direction contrary to the accepted wisdom of those of ordinary skill
`
`in the art, and the taking of licenses under the patent by others, among other
`
`factors.
`
`18. To ascertain the scope and content of the prior art, I understand it is
`
`necessary to first examine the field of the inventor’s endeavor and the particular
`
`problem for which the invention was made. The relevant prior art includes prior
`
`art in the field of the invention, and also prior art from other fields that a person of
`
`ordinary skill in the art would look to when attempting to solve the problem.
`
`19.
`
`I understand that a determination of obviousness cannot be based on
`
`the hindsight combination of components selectively culled from the prior art to fit
`
`the parameters of the patented invention. Instead, it is my understanding that in
`
`order to render a patent claim invalid as being obvious from a combination of
`
`references, there must be some evidence within the prior art as a whole to suggest
`
`the desirability, and thus the obviousness, of making the combination in a way that
`
`would produce the patented invention.
`
`6
`
`Novartis Exhibit 2001.009
`Regeneron v. Novartis, IPR2020-01318
`
`
`
`
`
`20.
`
`I further understand that in an obviousness analysis, neither the
`
`motivation nor the purpose of the patentee dictates whether an invention was
`
`obvious. What is important is whether there existed at the time of the invention a
`
`known problem for which there was an obvious solution encompassed by the
`
`patent’s claims.
`
`21.
`
`In addition, it is my understanding that in order to find a patent claim
`
`invalid as obvious, there must be a finding that each element in each limitation of
`
`the patent claim is disclosed, taught, or suggested by the asserted combination of
`
`prior art references or elsewhere in the relevant prior art. While multiple prior art
`
`references or elements may, in some circumstances, be combined to render a patent
`
`claim obvious, I understand that a patent claim composed of several elements is
`
`not proven obvious merely by demonstrating that each of its elements was,
`
`independently, known in the prior art. I understand that I should consider whether
`
`there is an “apparent reason” or motivation to combine the prior art references or
`
`elements in the way the patent claims. To determine whether such an “apparent
`
`reason” or motivation exists to combine the prior art references or elements in the
`
`way claimed by a patent, it will often be necessary to look to the interrelated
`
`teachings of multiple prior art references, to the effects or demands known to the
`
`design community or present in the marketplace, and to the background knowledge
`
`possessed by a person of ordinary skill in the art.
`
`7
`
`Novartis Exhibit 2001.010
`Regeneron v. Novartis, IPR2020-01318
`
`
`
`
`
`22.
`
`I also understand that when the prior art “teaches away” from
`
`combining prior art references or certain known elements, discovery of a
`
`successful means of combining them is more likely to be non-obvious. A prior art
`
`reference may be said to “teach away” from a patent when a person of ordinary
`
`skill in the art, upon reading the reference, would be discouraged from following
`
`the path set out in the patent or would be led in a direction divergent from the path
`
`that was taken by the patent. Additionally, a prior art reference may “teach away”
`
`from a claimed invention when substituting an element within that prior art
`
`reference for a claim element would render the claimed invention inoperable.
`
` Reduction to Practice
`23.
`I understand that a claimed invention is constructively reduced to
`
`practice by the filing of a patent application if the application provides written
`
`description for the invention and enables the invention.
`
`24.
`
`I understand that written description means that the patent
`
`specification reasonably conveys to a POSA that the inventor had possession of the
`
`subject matter of the claims as of the filing date.
`
`25.
`
`I understand that enablement means that a POSA, after reading the
`
`specification, could make and use the claimed invention without undue
`
`experimentation.
`
`8
`
`Novartis Exhibit 2001.011
`Regeneron v. Novartis, IPR2020-01318
`
`
`
`
`
` THE ’631 PATENT
`
`26. The ’631 patent is directed to the invention of a terminally-sterilized
`
`small-volume PFS for intravitreal injection of a VEGF antagonist, which includes
`
`low levels of silicone oil while maintaining low injection forces.
`
`27. The ’631 patent identifies several problems and challenges that are
`
`addressed by the invention. “It is important for patient safety and medicament
`
`integrity that the syringe and the contents of that syringe are sufficiently sterile to
`
`avoid infection, or other, risks for patients,” but there are “difficulties” associated
`
`with sterilization of syringes, particularly “small volume syringes” such as “those
`
`for injections into the eye.” Ex. 1001 at 1:14–25. For example, pressure changes
`
`during sterilization leading to movement of syringe parts and incorrect handling
`
`can compromise product sterility. Id. at 1:26–30. Furthermore, biologic molecules
`
`are “particularly sensitive to sterilization.” Id. at 1:31–33.
`
`28. Moreover, although glass syringes are typically lubricated with
`
`silicone oil, “silicone oil can cause proteins to aggregate,” and in syringes for
`
`ophthalmic use, “it is desirable to decrease the likelihood of silicone oil droplets
`
`being injected into the eye” because “silicone droplets can build up in the eye,
`
`causing potential adverse effects.” Id. at 4:50–56. The invention of the ’631
`
`achieves “a careful balancing act” of providing a PFS with “a suitable level of
`
`sterilisation” though “the syringe remains suitably sealed, such that the therapeutic
`
`9
`
`Novartis Exhibit 2001.012
`Regeneron v. Novartis, IPR2020-01318
`
`
`
`
`
`is not compromised.” Id. at 1:33–36. Meanwhile, the syringe “remain[s] easy to
`
`use” with “the force required to depress the plunger” not too high, including, e.g.,
`
`break loose and slide forces of “less than about 11N,” despite including levels of
`
`silicone oil as low as about 1 μg. Id. at 1:36–40, 4:48–5:50.
`
`29. The ʼ631 patent also enabled terminal sterilization of a PFS suitable
`
`for intravitreal injection through improvements to prior art syringe designs. These
`
`included a novel plunger rod configuration in order to “[r]estrict[] movement of the
`
`rod away from the outlet end” and thereby “maintain sterility during terminal
`
`sterilisation operations,” as well as an increased sterility zone on the stopper to
`
`“reduce the potential exposure of the medicament to the sterilizing agent.” Ex.
`
`1001 at 2:57–3:52.
`
`30. The ’631 patent includes 26 claims, of which only claim 1 is
`
`independent:
`
`1. A pre-filled, terminally sterilized syringe for intravitreal injection,
`
`the syringe comprising a glass body forming a barrel, a stopper and a
`
`plunger and containing an ophthalmic solution which comprises a VEGF-
`
`antagonist, wherein:
`
`(a) the syringe has a nominal maximum fill volume of between about
`
`0.5 ml and about 1 ml,
`
`10
`
`Novartis Exhibit 2001.013
`Regeneron v. Novartis, IPR2020-01318
`
`
`
`
`
`(b) the syringe barrel comprises from about 1 μg to 100 ug silicone
`
`oil,
`
`(c) the VEGF-antagonist solution comprises no more than 2 particles
`
`>50 μm in diameter per ml and wherein the syringe has a stopper
`
`break loose force of less than about 11N.
`
`The dependent claims are directed to limits on the properties and amount of
`
`silicone oil that can be present (claims 2–4, 10, 22, and 23), restrictions on the
`
`amount of particles that may be present (5, 6, and 10), particular VEGF antagonists
`
`(7–9 and 11–13), limitations on the break loose and glide force needed to move the
`
`stopper (14–16), details regarding sterilization (17–21), and methods of treating
`
`patients with the VEGF antagonist PFS for intravitreal injection (24–26).
`
` PERSON OF ORDINARY SKILL IN THE ART
`
`31.
`
`I understand that Petitioner has proposed that a POSA for the ’631
`
`patent as follows:
`
`A person having ordinary skill in the art (“POSITA”) relevant
`to the ’631 Patent as of July 3, 2012…would have had “at least
`an advanced degree (Dipl.Ing, M.S., or Ph.D.), with research
`experience in mechanical engineering, biomedical engineering,
`materials science, chemistry, or a related field, or at least 2–3
`years of professional experience in one or more of those fields”
`and that a POSA “would have had experience with (i) the
`design of pre-filled syringes; and (ii) sterilization of drug
`delivery devices, including those containing sterilization-
`sensitive therapeutics. Such sterilization experience would
`include experience with microbiology.”
`
`11
`
`Novartis Exhibit 2001.014
`Regeneron v. Novartis, IPR2020-01318
`
`
`
`
`
`32. For the purposes of my analysis and opinions, I have applied this
`
`definition of a POSA. I had qualifications consistent with that of a POSA during
`
`the 2012 time period.
`
` ANALYSIS OF PRIOR ART RELIED ON BY PETITIONER
`
`
`Sigg
`33. Sigg is a patent application concerning methods for terminally
`
`sterilizing the exterior of prefilled containers containing pharmaceutical products
`
`such as biologic drugs.
`
`34. Sigg discusses some of the challenges associated with terminal
`
`sterilization of prefilled containers filled with sensitive drugs such as biologics.
`
`For example, Sigg observes that some of the most common methods used to
`
`sterilize drugs and medical devices, such as steam sterilization (autoclaving) and
`
`radiation exposure, are incompatible with sterilization of biologic drugs: “high
`
`temperatures [applied during autoclaving] are known to denature proteins and
`
`gamma radiation has been shown to chemically modify biological solutions.
`
`Radiation techniques, such as sterilization using gamma or beta radiation causes
`
`discoloring of packaging material and affects the long term stability of therapeutic
`
`agents such as protein or peptide solutions.” Ex. 1007.003.
`
`35. Sigg states that with respect to autoclaving, “the high temperatures of
`
`the process (e.g. 120° C–132° C) preclude its use with heat sensitive materials,
`
`12
`
`Novartis Exhibit 2001.015
`Regeneron v. Novartis, IPR2020-01318
`
`
`
`
`
`such as biotech drug products, specifically protein or other biological solutions,”
`
`and with respect to sterilization by radiation, “[r]adiation exposure results in
`
`harmful damage to sensitive solutions, specifically causing destruction to sensitive
`
`biologicals such as proteins, as well as generation of massive amounts of peroxides
`
`in aqueous solutions that in a secondary reaction further may damage the active
`
`ingredient…Thus radiation is not an appropriate means for sterilizing prefilled
`
`containers, such as syringes, containing a biotech drug product.” Ex. 1007.002–
`
`.003.
`
`36.
`
`In light of these challenges, Sigg sought to develop methods for
`
`“terminal sterilization and surface decontamination treatment of prefilled
`
`containers, specifically for sterilization of prefilled containers containing sensitive
`
`solutions, such as a drug product or biological therapeutic, within secondary
`
`packaging.” Ex. 1007.004. To that end, Sigg discusses “cold sterilization” by
`
`treatment with sterilizing gasses “at temperatures substantially below those of the
`
`steam process,” i.e. temperatures well in excess of 100 °C. Ex. 1007.003.
`
`37. One method that Sigg discusses is vaporized hydrogen peroxide
`
`(“VHP”) treatment:
`
`[T]erminal sterilization is achieved by treating prefilled
`containers within secondary packaging with controllable
`vaporized-hydrogen peroxide (VHP). The principle is the
`formation a vapor of hydrogen peroxide in containment and a
`subsequent removal or inactivation of vapors in a controlled
`manner. Prior to removal or inactivation, VHP condenses on
`13
`
`Novartis Exhibit 2001.016
`Regeneron v. Novartis, IPR2020-01318
`
`
`
`
`
`all surfaces, creating a microbicidal film that decontaminates
`the container surface.
`Ex. 1007.004.
`
`38.
`
` Sigg, however, identifies several challenges associated with
`
`sterilization by sterilizing gasses, particularly VHP treatment, which a POSA
`
`would have been well aware of. For example, Sigg states that “[t]reatment with
`
`sterilizing gasses, however, bears the risk of insufficient removal of the oxidizing
`
`gas. Diffusion of gas into the product container affects the stability of the drug
`
`product through chemical modification by gas vapors, such as alkylation and
`
`oxidation.” Ex. 1007.003. Therefore, “oxidizing gases, while efficient for killing
`
`bacterial contamination, also harm biological molecules in sensitive therapeutic
`
`solutions.” Ex. 1007.003.
`
`39. With respect to VHP treatment in particular, Sigg states that “with
`
`sensitive solutions, such as protein solutions, leaching of vaporized-hydrogen
`
`peroxide into the prefilled container is detrimental to the molecular integrity of the
`
`solutions because hydrogen peroxide vapors that enter the container cause
`
`chemical modifications of the solution, such as oxidation.” Ex. 1007.014–015.
`
`Sigg discloses that, to address this challenge, “applying post-treatment, or post-
`
`application measures reduces or prevents the adverse effects of VHP on sensitive
`
`solutions and preserve the integrity, and thereby therapeutic efficacy, of otherwise
`
`sensitive solutions in prefilled containers.” Ex. 1007.015. In particular, Sigg
`14
`
`Novartis Exhibit 2001.017
`Regeneron v. Novartis, IPR2020-01318
`
`
`
`
`
`describes a method in which the hydrogen peroxide is deactivated following
`
`sterilization either by removing it or by inactivating or neutralizing it. Ex.
`
`1007.015.
`
`40. However, Sigg discloses that the VHP sterilization method cannot be
`
`used with many prefilled syringes containing sensitive biologic drugs because
`
`“among the commercially available primary packaging components, there are only
`
`very few packaging material combinations that provide the required tightness of
`
`the system such as to avoid ingress of sterilizing gases into the pharmaceutical
`
`liquid enclosed by the prefilled container.” Ex. 1007.004. “Primary packaging”
`
`refers to packaging components that make direct contact with the pharmaceutical
`
`dosage form, such as the syringe and stopper in the case of a prefilled syringe.
`
`Primary packaging is distinct from “secondary packaging,” which is additional
`
`packaging that does not make direct contact with the drug product and may enclose
`
`the prefilled container, such as plastic wrapping, foil wrapping, Tyvek pouches, or
`
`blister packs. See Ex. 1007.006–007; Ex. 1041.005.
`
`41. Although Sigg discloses that the described VHP sterilization method
`
`is limited to few packaging combinations, Sigg does not identify any suitable
`
`combinations of components (e.g. syringes and stoppers) that provide a tight
`
`enough seal to prevent VHP ingress and allow terminal sterilization of a sensitive
`
`biologic drug, or information about the design of such components. For example,
`
`15
`
`Novartis Exhibit 2001.018
`Regeneron v. Novartis, IPR2020-01318
`
`
`
`
`
`the only figure depicting a syringe in Sigg is a highly-simplified cartoon of a
`
`syringe intended to show the simple idea that filled syringes have an exterior
`
`surface that can be decontaminated, and that such syringes can be placed in
`
`secondary packaging. Ex. 1007.030.
`
`
`
`42.
`
` Sigg provides one example of the use of its VHP sterilization method
`
`to sterilize prefilled syringes. Ex. 1007.021–.022. Example 1 of Sigg describes
`
`sterilization of 0.5 mL syringes filled with “protein solutions,” i.e. “[a] formulation
`
`as described in U.S. Patent No. 7,060,269.”1 Ex. 1007.021. However, Sigg
`
`discloses no information about the material that the syringe barrel was made of.
`
`
`
`1 U.S. Patent No. 7,060,269 is a patent that describes many different antibodies and
`
`antibody fragments, and provides information about a variety of different
`
`formulations. Ex. 1023. Sigg does not make clear which of the many formulations
`
`disclosed in this patent was used in Sigg’s Example 1.
`
`16
`
`Novartis Exhibit 2001.019
`Regeneron v. Novartis, IPR2020-01318
`
`
`
`
`
`Syringe barrels can be made of a variety of materials, including glass and various
`
`plastic polymers, and a POSA would not have made any assumptions about the
`
`material of the syringe barrels used in Sigg. Sigg also discloses nothing about the
`
`stopper material or design, whether and how the stopper was lubricated, or what
`
`lubricant was used for the syringe barrel. Example 1 does not mention how much
`
`silicone oil was on the syringe barrels. Sigg therefore does not disclose any
`
`information about whether the syringe assembly used in Example 1 was one of the
`
`“very few packaging material combinations” compatible with the VHP sterilization
`
`method, and provides no insight into what those material combinations might be.
`
`43. As both a general matter and with respect to Example 1 in particular,
`
`Sigg does not mention silicone oil or syringe lubrication. There is no discussion
`
`about the amount of silicone oil on the syringes sterilized according to Sigg, and
`
`Sigg does not discuss whether the sterilization methods are compatible with
`
`syringes containing any particular levels of silicone oil, and particularly with
`
`syringes with silicone oil levels below those disclosed in the prior art. Sigg also
`
`has no mention about the interplay between syringe lubrication and the sterilization
`
`methods disclosed. Furthermore, contrary to petitioner’s assertion, a POSA would
`
`not assume that the VHP sterilization method discussed in Sigg would be broadly
`
`applicable to pre-filled glass syringes, (see IPR2020-01317, Pet. (“1317 Pet.”) at
`
`41), particularly in view of Sigg’s express statement to the contrary.
`
`17
`
`Novartis Exhibit 2001.020
`Regeneron v. Novartis, IPR2020-01318
`
`
`
`
`
`44. Sigg also has no discussion of the mechanical function, including the
`
`break loose and sliding forces, and there is no indication in Sigg that such
`
`properties were considered or tested. A POSA would have no way of knowing,
`
`and would not assume, that a syringe sterilized according to the disclosures of Sigg
`
`would have viable mechanical properties or whether the sterilization process would
`
`impact the injection forces.
`
`
`Boulange
`45. Boulange is an international patent application concerning the use of a
`
`purportedly novel chemical coating to coat the piston of a medical device.
`
`Boulange provides a summary of the purported invention:
`
`In order to improve the slip between said parts, it has been
`proposed for the entirety of the developed surface of one of the
`parts to be coated with a coating consisting of at least one
`polymer material, whether this is a true polymer or a
`copolymer, comprising polymer chains including repeats of one
`or more chemical units:
`
`
`in which X represents a halogen, for example F, or a hydrogen,
`and in which Y1, Y2, Y3, Y4 each independently represent a
`halogen, for example Cl, or a hydrogen.
`Ex. 1008.003-.004. Boulange focusses on the use of a “polymer material of the
`
`poly(p-xylylene) type,” and particularly a polymer called “Parylene C” as a novel
`
`18
`
`Novartis Exhibit 2001.021
`Regeneron v. Novartis, IPR2020-01318
`
`
`
`
`
`chemical piston coating. Boulange distinguishes between the polymer coating
`
`described in Boulange and “a conventional polymer material.” Ex. 1008.004.
`
`46. Boulange is mainly concerned with the mechanical properties of
`
`medical devices with Parylene C coated components, including syringes.
`
`Boulange states that “viscoelastic material of which the piston of a medical device
`
`such as a syringe may be made is generally an elastomeric material which alters, in
`
`particular degrades chemically over time,” and that such degradation can cause an
`
`increase in “the adhesion or friction with respect to one of the other parts of the
`
`medical device.” Ex. 1008.006.
`
`47.
`
` Boulange discloses that a “medical device of the invention,” i.e. a
`
`device with at least one poly(p-xylylene) type polymer (e.g. Parylene C)-coated
`
`component, can have “decreased activation, sustainable and final forces” for
`
`moving device components (such as the syringe stopper and barrel) relative to one
`
`another “thanks to a specific coating having a specific roughness range at the
`
`contact region between the piston and the container.” Boulange thus discloses that
`
`a Parylene C coating with particular physical properties can provide for relatively
`
`low break loose and sliding forces between components. In the case of syringes,
`
`Boulange discloses that the Parylene C coating allows the stopper “to be moved
`
`relative to the container or syringe body, through a gliding movement,” while also
`
`“ensuring the tightness with said container, so that all of the product to be
`
`19
`
`Novartis Exhibit 2001.022
`Regeneron v. Novartis, IPR2020-01318
`
`
`
`
`
`administered escapes only via the distal end of the container and does not leak out
`
`of said container via the piston at the proximal end of the container.” Ex.
`
`1008.008. In other words, according to B