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 IPR2021-00816
`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, IPR2021-00816
`
`

`

`(cid:3)
`I.
`
`(cid:3)
`II.
`
`V.
`(cid:3)
`
`TABLE OF CONTENTS
`
`
`
`ii
`
`Introduction ...................................................................................................... 1(cid:3)
`Background and Qualifications ....................................................................... 1(cid:3)
`Summary of Opinions ...................................................................................... 4(cid:3)
`(cid:3)
`III.
`(cid:3) Legal Principles ............................................................................................... 5(cid:3)
`IV.
`Burden of Proof ..................................................................................... 5(cid:3)
`Prior Art ................................................................................................. 5(cid:3)
`Obviousness ........................................................................................... 5(cid:3)
`(cid:3)
`C.
`The ’631 Patent ................................................................................................ 9(cid:3)
`Prosecution History ............................................................................. 12(cid:3)
`(cid:3)
`A.
`(cid:3) Background on the Technology ..................................................................... 19(cid:3)
`VI.
`Pre-filled syringes ................................................................................ 19(cid:3)
`Components of a Pre-filled Syringe .................................................... 21(cid:3)
`Design Considerations of Pre-filled Syringes for Intravitreal
`Injection ............................................................................................... 22(cid:3)
`Syringe functioning ................................................................... 22(cid:3)
`(cid:3)
`1.
`Siliconization ............................................................................ 24(cid:3)
`(cid:3)
`2.
`Sterilization ............................................................................... 26(cid:3)
`(cid:3)
`3.
`Particulates ................................................................................ 29(cid:3)
`(cid:3)
`4.
`Elastomeric Closures and Coatings .......................................... 30(cid:3)
`(cid:3)
`5.
`(cid:3) Person of Ordinary Skill in the Art ................................................................ 35(cid:3)
`VII.
`(cid:3) Analysis of Prior Art Relied on by petitioner ................................................ 36(cid:3)
`VIII.
`Sigg ...................................................................................................... 36(cid:3)
`
`A.
`(cid:3)
`
`B.
`(cid:3)
`
`(cid:3)
`A.
`
`(cid:3)
`B.
`
`(cid:3)
`C.
`
`(cid:3)
`A.
`
`Novartis Exhibit 2001.002
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`B.
`(cid:3)
`
`C.
`(cid:3)
`
`(cid:3)
`1.
`
`2.
`(cid:3)
`
`(cid:3)
`3.
`
`(cid:3)
`4.
`
`D.
`(cid:3)
`
`Lam ...................................................................................................... 43(cid:3)
`Boulange .............................................................................................. 45(cid:3)
`2008 Macugen Label ........................................................................... 59(cid:3)
`(cid:3) Analysis of Petitioner’s Obviousness Arguments ......................................... 64(cid:3)
`IX.
`(cid:3) A POSA Would Not Have Been Motivated to Combine Sigg
`A.
`and Boulange to Make a Pre-filled Syringe Filled with a VEGF
`Antagonist for Intravitreal Injection. ................................................... 66(cid:3)
`Sigg’s sterilization method can only be used with “very
`few” syringes, but Sigg provides no guidance about
`which syringes ........................................................................... 66(cid:3)
`Boulange Teaches That Reducing Silicone Oil Requires
`the Use of Parylene C ............................................................... 68(cid:3)
`A POSA Would Have Avoided Parylene C in a
`Terminally Sterilized PFS Filled With a VEGF
`Antagonist for Intravitreal Injection ......................................... 70(cid:3)
`A POSA Would not Have Been Motivated to Use the
`Non-Parylene C Syringes that Boulange Used as Control
`Syringes to Compare with Parylene C ...................................... 93(cid:3)
`A POSA Would Not Have Reasonably Expected a PFS
`Combining Sigg and Boulange to Succeed. ......................................103(cid:3)
`A POSA would not have been Motivated to Combine Lam and
`Boulange to Make a Pre-filled Syringe Filled with a VEGF
`Antagonist for Intravitreal Injection. .................................................114(cid:3)
`(cid:3) A POSA would not have Reasonably Expected that a Boulange
`D.
`Syringe could be Successfully Combined with the Ethylene
`Oxide Sterilization Method of Lam to make a PFS for
`Intravitreal Injection of a VEGF Antagonist .....................................119(cid:3)
`Sigg and Lam Do Not Enable a POSA to Terminally Sterilize a
`PFS as Claimed in the ’631 Patent ....................................................121(cid:3)
`Secondary considerations ............................................................................129(cid:3)
`Long-felt Need ..................................................................................130(cid:3)
`iii
`
`B.
`(cid:3)
`
`C.
`(cid:3)
`
`(cid:3)
`E.
`
`A.
`(cid:3)
`
`X.
`(cid:3)
`
`Novartis Exhibit 2001.003
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`B.
`(cid:3)
`
`Failure of Others ................................................................................131(cid:3)
`Unexpected Results ...........................................................................132(cid:3)
`C.
`(cid:3)
`(cid:3) The Inventions Claimed in the ’631 Patent Were Constructively
`XI.
`Reduced to Practice in EP ’649 and the ’352 Application ..........................133(cid:3)
`(cid:3) Declaration ...................................................................................................153(cid:3)
`XTI.
`
` (cid:3)
`
`
`
`iv
`
`Novartis Exhibit 2001.004
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`
`I.
`
`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 IPR2021-00816. 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”). I previously submitted a
`
`declaration on behalf of Novartis regarding IPR2020-01317 (“1317 IPR”) and
`
`IPR2020-01318 (“1318 IPR”) concerning 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
`IT.
`
`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.
`
`1
`
`Novartis Exhibit 2001.005
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`4.
`
`I have been a medical device engineer since 1992 and have worked
`
`extensively with medical device disposables, including syringes of all types, since
`
`that date. I have extensive expertise in the mechanical design and manufacturing
`
`of medical devices. My areas of expertise include full-life cycle product
`
`development of medical devices, including conception, manufacturing, testing,
`
`verification, validation, packaging, bioburden testing, sterility assurance testing,
`
`residual 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, pre-filled
`
`saline and lubricating syringes used in urinary catheter kits, and insulin pumps,
`
`among others. In many of these applications, vaporized hydrogen peroxide was
`
`used during concept testing to sterilize surgical instruments and prototype devices
`
`used in testing.
`
`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,
`
`2
`
`Novartis Exhibit 2001.006
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`Inc., developing fixation devices for abdominal aortic aneurysm repair as well as
`
`laparoscopic devices for stapling and sutures. The reusable versions of these
`
`devices used syringes for flushing and autoclaving for sterilization. The
`
`disposable devices used Ethylene Oxide (EtO) or gamma irradiation for
`
`sterilization.
`
`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
`
`the conception and manufacturing of these devices, including both EtO and gamma
`
`irradiation sterilization of disposable medical devices such as syringes and male
`
`luer caps. During this time, I was the sole inventor of the SmartSite® Needle-Free
`
`Valve for intravenous infusion pumps and disposables. This device utilized three
`
`types of silicone lubricant (di-methyl, phenyl, and fluoro-based) to minimize
`
`friction and prevent cross-linking of silicone rubber. I was also involved in the
`
`development of a dual-acting pen injector, capable of dispensing both long-term
`
`and short-term insulin, for Eli Lilly (parent company of my employer IVAC). 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
`
`3
`
`Novartis Exhibit 2001.007
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`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.
`
` SUMMARY OF OPINIONS
`
`10. The ’631 patent is not obvious over the prior art cited by the Petitioner
`
`in IPR2021-00816 at least because:
`
`(cid:120) 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.
`
`(cid:120) 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.
`
`(cid:120) The prior art relied upon by the Petitioner would not have enabled a POSA
`
`to make or use the claimed invention.
`
`4
`
`Novartis Exhibit 2001.008
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`(cid:120) Secondary considerations support the non-obviousness of the ’631 patent.
`
`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
`IV.
`
`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
`A.
`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.
`
`
`B.
`14.
`
`Prior Art
`I understand that, in this IPR proceeding, the prior art to the (cid:1932)631
`
`patent includes patents and printed publications in the relevant field(s) that predate
`
`the (cid:1932)631 patent’s priority date.
`
` Obviousness
`C.
`15.
`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
`
`5
`
`Novartis Exhibit 2001.009
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`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.
`
`16.
`
`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
`
`considered in such an analysis include, among other factors: the commercial
`
`success of the patented invention (including evidence of industry recognition or
`
`awards), the existence of a long-felt but unmet need in the field satisfied by the
`
`invention, 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, the extent to which the inventors proceeded in a direction contrary to the
`
`accepted wisdom of those of ordinary skill in the art, and licensing of the patent.
`
`17. 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
`
`6
`
`Novartis Exhibit 2001.0010
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`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.
`
`18.
`
`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.
`
`19.
`
`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.
`
`20.
`
`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
`
`7
`
`Novartis Exhibit 2001.0011
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`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.
`
`21.
`
`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.
`
`22.
`
`I also understand that the prior art used to invalidate a claim must
`
`enable the invention. A claim cannot be obvious if the prior art as a whole does
`
`8
`
`Novartis Exhibit 2001.0012
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`not enable a POSA to make and use the claimed invention even if every separate
`
`element of the invention can be found somewhere in the prior art. I further
`
`understand that a reference used in an obviousness analysis must enable the
`
`portions of its disclosure being relied upon, particularly in the absence of
`
`supporting evidence to enable a POSA to make the claimed invention.
`
`Obviousness combinations that use such non-enabling prior art are not sufficient to
`
`invalidate a claim.
`
` THE ’631 PATENT
`
`23. The ’631 patent is directed to the invention of a terminally-sterilized
`
`small-volume pre-filled syringe (“PFS”) for intravitreal injection of a VEGF
`
`antagonist, which includes low levels of silicone oil while maintaining low
`
`injection forces.
`
`24. The ’631 patent identifies several problems and challenges that are
`
`addressed by the invention. For example, the patent explains that “[i]t 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
`
`also mentions that 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 one, biologic molecules are “particularly sensitive to
`
`sterilization.” Id. at 1:31–33. Moreover, pressure changes during sterilization can
`
`9
`
`Novartis Exhibit 2001.0013
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`lead to movement of syringe parts, potentially compromising product sterility. Id.
`
`at 1:26–30.
`
`25. 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” while “the syringe remains suitably sealed, such that the therapeutic
`
`is not compromised.” Id. at 1:33–36. Meanwhile, the syringe “remain[s] easy to
`
`use” with “the force required to depress the plunger” staying low (e.g., with break
`
`loose and slide forces of “less than about 11N”) notwithstanding the use of silicone
`
`oil levels as low as about 1 (cid:541)g. Id. at 1:36–40, 4:48–5:50.
`
`26. The (cid:1932)631 patent also describes terminal sterilization of a PFS suitable
`
`for intravitreal injection through improvements to prior art syringe designs. These
`
`included a novel plunger rod configuration designed 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.” Id. at
`
`2:57–3:52.
`
`10
`
`Novartis Exhibit 2001.0014
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`27. The ’631 patent includes 26 claims. Claim 1 is the only independent
`
`claim and recites:
`
`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,
`
`(b) the syringe barrel comprises from about 1 (cid:541)g to 100 ug silicone
`
`oil,
`
`(c) the VEGF-antagonist solution comprises no more than 2 particles
`
`>50 (cid:541)m 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
`
`number of particles that may be present (5, 6, and 10), particular VEGF antagonists
`
`(7–9 and 11–13), limitations on the break loose and slide 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).
`
`11
`
`Novartis Exhibit 2001.0015
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`
`A.
`28.
`
`Prosecution History
`I understand that the ’631 patent issued from an application that was
`
`filed on January 25, 2013 (Application No. 13/750,352). I understand that the ’631
`
`patent claims priority to a series of earlier applications filed between July 3, 2012
`
`and January 23, 2013, including EP 12174860 (filed July 3, 2012)1 and EP
`
`12189649 (filed October 23, 2012). I understand that in previous proceedings, the
`
`parties have disputed whether the claims of the ’631 patent are entitled to priority
`
`from certain earlier applications. I further understand that Petitioner has not raised
`
`that dispute in this IPR. Unless otherwise noted, for purposes of this IPR, I have
`
`assumed that any reference that Petitioner has asserted is prior art meets the
`
`qualifications of prior art for publication date and public accessibility.
`
`29. During prosecution, earlier versions of the claims were rejected a
`
`number of times including over prior art references Scypinski (Ex. 1017) and Hioki
`
`(Ex. 1020). Ex. 1002.1245–.1253, .1280–.1288, .1305–.1311, .1356–.1360. In
`
`addition to the references that were expressly discussed during prosecution, the
`
`Applicant disclosed numerous other references to the Examiner. Ex. 1002.0156,
`
`
`
`1 The ’631 patent indicates that EP 12174860 was filed on July 30, 2012. I
`
`understand that this is a typographical error, and the application was actually filed
`
`July 3, 2012.
`
`12
`
`Novartis Exhibit 2001.0016
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`.0463, .0706–07, .1115–.1117, .1228–.1230, .1313–.1315, .1361–.1366, .1504–
`
`.1507. I understand these references are listed at the beginning of the ’631 patent.
`
`Ex. 1001.001–.002.
`
`30.
`
`I understand that in the 1317 and 1318 IPR proceedings, Novartis
`
`argued that the art cited by Petitioner is cumulative with art and information that
`
`was considered by the Examiner during prosecution of the ’631 patent. Petitioner
`
`now responds to this argument by asserting that there was no art before the
`
`Examiner that disclosed terminal sterilization of a pre-filled syringe with a VEGF-
`
`antagonist. Pet. at 10. See also, Ex. 1003 ¶¶ 115–116. In particular, Mr. Koller
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`argues that WO 2007/084765 does not disclose “sterilizing a prefilled syringe after
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`it is filled and assembled.” Ex. 1003 ¶ 117 (discussing Ex. 1088 (“Deschatelets”)
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`at [00255]). I disagree with Mr. Koller’s interpretation of this reference. First, it
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`is clear that a focus of the reference is administration of VEGF antagonists by
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`intravitreal injection, including with pre-filled syringes filled with VEGF
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`antagonists. See, e.g., Ex. 1088 at [00010], [00014], [00017], [00243], [00252]–
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`[00254]. Second, Deschatelets discloses that the syringe for intravitreal injection
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`of a VEGF antagonist “may be preloaded with a composition comprising a
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`therapeutic agent,” and that “sterilization can be performed after manufacture”—
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`i.e., it can be terminally sterilized. Id. at [00254]–[00255].
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`13
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`Novartis Exhibit 2001.0017
`Regeneron v. Novartis, IPR2021-00816
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`31. Mr. Koller argues (incorrectly) that the passage from Deschatelets that
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`discusses sterilization “clearly” refers only to “sterilizing a drug composition,” not
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`to “sterilizing a prefilled syringe after it is filled and assembled.” Ex. 1003 ¶ 117.
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`The relevant passage states:
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`[00255] Preferably any composition to be administered to the
`eye is sterile. The composition can be made from sterile
`components, or sterilization can be performed after
`manufacture. Methods of sterilization include irradiation, heat,
`etc. Preferably, the sterilization method used does not
`substantially reduce the activity or biological or therapeutic
`activity of the therapeutic agents. Devices and instruments to be
`used for administration to the eye are also preferably sterile, at
`least to the extent they will enter the eye.
`Ex. 1088 at [00255]. This passage is from the section of Deschatelets entitled
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`“Articles of Manufacture.” Id. at [00251]–[00255]. The text of this section makes
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`clear that “articles of manufacture” in Deschatelets refers to containers (including
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`pre-filled syringes) already filled with drug compositions. See, e.g., id. at [00252]
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`(“[t]he article of manufacture can comprise a container and a label or package
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`insert on or associated with the container. Suitable containers include, for
`
`example… syringes.”); id. at [00014] (In some aspects “the invention provides
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`articles of manufacture… The article of manufacture may further comprise a
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`syringe. The syringe may contain a therapeutic agent.”). Thus, contrary to Mr.
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`Koller’s interpretation of paragraph [00255], the statement that “sterilization can
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`14
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`Novartis Exhibit 2001.0018
`Regeneron v. Novartis, IPR2021-00816
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`be performed after manufacture” refers to sterilization after filling and assembling
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`the syringe because “manufacture” includes the syringe.
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`32.
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`In addition to Deschatelets, the Applicant also disclosed WO
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`97/44068 (“Tack”). Ex. 1001.002. Tack is an international patent application
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`entitled “Method of Terminally Sterilizing Filled Syringes.” Ex. 1089.001. The
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`English-language abstract of Tack (WO 97/44068) discloses a method of
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`producing a “pre-filled sterile syringe” in which the syringe is filled with a fluid,
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`sealed, packaged, “and the package container is then sterilized once again.” Id.
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`This is also terminal sterilization.
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`33.
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`In addition to disclosing references that discuss terminal sterilization
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`of pre-filled syringes, Novartis also told the Examiner during prosecution that
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`gaseous terminal sterilization of glass syringes containing sensitive biologics, like
`
`VEGF antagonists, was known:
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`Consequently, terminal sterilization of [plastic] syringes is
`difficult. That is, because the seal is known to leak, it is
`possible for the sterilizing agent to leach into the syringe. For
`biologic products, this is critical as it is well known that they
`are particularly sensitive to terminal sterilizing agents such as
`hydrogen peroxide, which can oxidize the protein, and heat,
`which can denature the protein. As a result, syringes which are
`prefilled with biologics are comprised of glass barrels.
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`15
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`Novartis Exhibit 2001.0019
`Regeneron v. Novartis, IPR2021-00816
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`Ex. 1002.1275 (Aug. 13, 2014 Applicant Arguments).2 Neither Sigg nor Lam, the
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`two references on which Petitioner relies on for disclosure of terminal sterilization,
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`provides a material addition to the information about terminal sterilization of filled
`
`syringes that the Applicant disclosed to the Examiner during prosecution of the
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`’631 patent. As discussed in detail below, Sigg and Lam discuss in general terms
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`terminal sterilization of a PFS filled with a VEGF antagonist, but neither reference
`
`explains how this step could be accomplished nor does either reference enable a
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`POSA to apply the described method to a VEGF-filled PFS that would be
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`appropriate for intravitreal administration.
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`34. Similarly, Boulange, which Petitioner relies upon to teach that baked-
`
`on silicone oil could be used to reduce silicone oil levels into the claimed range,
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`adds nothing beyond the art and information that was considered by the Examiner.
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`For example, the Examiner extensively considered Hioki,3 which discloses
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`
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`2 Terminal sterilization of a PFS was also addressed at later points during
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`prosecution. See, e.g., Ex. 1002.1353–.1354 (Mar. 11, 2015 Applicant Argument);
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`Ex. 1002.1358–.1359 (Mar. 20, 2015 Final Rejection).
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`3 Ex. 1020.005 at [0021]; 1002.1245–.1253 (May 14, 2014 Non-Final Rejection)
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`(rejection over Hioki); Ex. 1002.1280–.1288 (Aug. 26, 2014 Final Rejection)
`
`(same); Ex. 1002.1305–.1311 (Dec. 12, 2014 Non-Final Rejection) (same); Ex.
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`16
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`Novartis Exhibit 2001.0020
`Regeneron v. Novartis, IPR2021-00816
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`siliconization of plastic (cyclic olefin copolymer, or “COP”) syringe barrels with
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`silicone oil “in an amount of 5 to 50 μg per 1 cm2”—an amount that is nearly
`
`identical to the silicone oil amounts used in Boulange (4 μg/cm2 to 50 μg/cm2).
`
`Compare Ex. 1020.005 at [0021] with Ex. 1008.023. Example 8 of Hioki discloses
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`COP syringes with 5 μg of silicone oil per cm2—the exact amount applied to the
`
`syringes in Boulange—and that the Example 8 syringes had “good” forces, with
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`“pressure when gasket starts moving being within the permitted range, and no
`
`variation in extrusion pressure after gasket starts moving.” Ex. 1020.013–.014 at
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`[0142]–[0144], [0158]–[0159], Table 6.4 In other words, Hioki discloses syringes
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`with 5 μg/cm2 silicone oil on the interior of the syringe barrel and acceptable
`
`syringe forces. Moreover, during prosecution of the ’631 patent, the Examiner
`
`interpreted Hioki’s teachings as applicable to glass syringes:
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`Hioki teaches applying silicone oil to the inner surface of a
`syringe barrel (paragraph 0021 ). It would have been obvious
`to one having ordinary skill in the art…to include silicone oil in
`the [glass] syringe barrel of Scypinkski [filled with a VEGF
`antagonist] as taught by Hioki…. It would have been within
`
`
`
`1002.1356–.1360 (Mar. 20, 2015 Final Rejection) (same). Baked-on siliconization
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`is also described in other references disclosed in prosecution. See, e.g., 2006.002.
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`4 Hioki refers to break loose force as “initial pressure” and sliding force as
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`“maxi