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 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
`
`
`
`__________
`
`
`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
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
