`Trials@uspto.gov
`571-272-7822
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`
`
`
` Paper 113
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`Entered: October 25, 2022
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`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.
`____________
`
`IPR2021-00816
`Patent 9,220,631 B2
`____________
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`
`
`Before ERICA A. FRANKLIN, ROBERT L. KINDER, and
`JAMIE T. WISZ, Administrative Patent Judges.
`
`KINDER, Administrative Patent Judge.
`
`
`
`JUDGMENT
`Final Written Decision
`Determining All Challenged Claims Unpatentable
`35 U.S.C. § 318(a)
`
`
`
`
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`
`
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`IPR2021-00816
`Patent 9,220,631 B2
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`INTRODUCTION
`I.
`On April 16, 2021, Regeneron Pharmaceuticals, Inc. (“Petitioner” or
`“Regeneron”)1 filed a Petition to institute inter partes review of claims 1–26
`(all claims) of U.S. Patent No. 9,220,631 B2 (Ex. 1001, “the ’631 patent”).
`Paper 1 (“Petition” or “Pet.”). On October 26, 2021, we instituted the
`petitioned review (Paper 13, “Institution Decision” or “Inst. Dec.”).
`Novartis Pharma, AG, et al., (“Patent Owner” or “Novartis”)2 filed a
`Patent Owner Response (Papers 35, 403 “PO Resp.”) to oppose the Petition.
`Regeneron filed a Reply (Papers 72, 73 “Pet. Reply”) to the Patent Owner
`Response. Patent Owner filed a Sur-reply (Papers 92, 93 “Sur-reply”) to the
`Reply. We conducted an oral hearing on July 21, 2022. A transcript has
`been entered into the record (Paper 112, “Tr.”).
`We have jurisdiction under 35 U.S.C. § 6(b)(4) and § 318(a). This
`Decision is a final written decision under 35 U.S.C. § 318(a) and 37 C.F.R.
`§ 42.73 as to the patentability of claims 1–26 of the ’631 patent. We
`determine Petitioner has shown by a preponderance of the evidence that
`those claims are unpatentable.
`
`
`1 Petitioner identifies Regeneron Pharmaceuticals, Inc. as the real party in
`interest. Pet. 1.
`2 Patent Owner identifies the named parties (Novartis Pharma AG, Novartis
`Technology LLC, and Novartis Pharmaceuticals Corporation) as the real
`parties in interest. Paper 4, 2.
`3 Two papers listed include both the public, redacted, version and the sealed
`confidential version.
`
`
`2
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`BACKGROUND
`II.
` Related Cases and Proceedings
`The ’631 patent is involved in two district court cases. Pet. 1–2. On
`June 19, 2020, Patent Owner filed a complaint4 in the United States District
`Court for the Northern District of New York (NDNY) alleging that
`Petitioner infringes at least claim 1 of the ’631 patent. Pet. 2 (“parallel
`district court litigation”). On July 17, 2020, Regeneron filed a complaint5 in
`the Southern District of New York (SDNY) against Novartis and Vetter
`Pharma International GmbH seeking judgment that (i) Novartis’s and
`Vetter’s conduct violates Section 1 of the Sherman Act, (ii) Novartis’s
`conduct violates Section 2 of the Sherman Act, and (iii) the ’631 patent be
`declared unenforceable. Pet. 2–3 (“antitrust litigation”).
`On June 19, 2020, Novartis filed a complaint at the International
`Trade Commission (“ITC”) alleging that Regeneron infringes claims 1–6
`and 11–26 of the ’631 patent. Pet. 1–2 (“ITC Investigation”). On April 8,
`2021, Novartis filed a motion to terminate the ITC Investigation on the basis
`of withdrawal of the complaint. Pet. 2; Ex. 1006. On April 8, 2021, the
`Administrative Law Judge issued an initial determination terminating the
`ITC Investigation. Ex. 1010.
`On July 16, 2020, Petitioner filed petitions in IPR2020-01317
`(IPR’1317) and IPR2020-01318 (IPR’1318) challenging claims 1–26 of
`
`
`4 Novartis Pharma AG et al. v. Regeneron Pharms., Inc., No. 20-cv-690
`(N.D.N.Y.) (filed Jun. 19, 2020).
`5 Regeneron Pharms., Inc. v. Novartis Pharma AG et al., No. 20-cv-5502
`(S.D.N.Y.) (filed July 17, 2020).
`
`3
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`the ’631 patent. Pet. 2. On December 2, 2020, Petitioner filed a motion to
`terminate IPR’1318 and the Board issued an order terminating the
`proceeding on December 7, 2020. On January 15, 2021, the Board exercised
`its discretion under 35 U.S.C. § 314(a) and denied institution of IPR’1317
`based on the ITC Investigation that was co-pending at that time.
` The ’631 Patent
`The ’631 patent is titled “Syringe.” Ex. 1001, code (54). The ’631
`patent “relates to a syringe, particularly to a small volume syringe such as a
`syringe suitable for ophthalmic injections.” Id. at code (57). The U.S.
`application resulting in the ’631 patent was filed on January 25, 2013 (id.
`at code (22)), and identifies multiple purported foreign priority applications,
`the earliest of which was filed in July 20126 (id. at code (30)).
`The Specification notes that for small volume syringes intended for
`eye injections, sterilization can present issues that are not necessarily
`associated with larger syringes. Id. at 1:22–30. Further, certain therapeutics
`are particularly sensitive to sterilization techniques, thus it is important for
`the syringe to remain robustly sealed but also easy to use in that the force
`required to depress the plunger to administer the medicament must not be
`too high. Id. at 1:31–40.
`
`
`6 Patent Owner contends that the claims are entitled to a priority date of July
`3, 2012. PO Resp. 7. Whether the claims are entitled to the July 3, 2012
`priority date, or to the date of October 23, 2012 (Ex. 1003 ¶ 20) alleged by
`Petitioner, makes no difference in our ultimate patentability determination.
`4
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`Figure 2 of the ’631 patent, reproduced below, illustrates a cross
`section through the syringe. Id. at 10:60–67.
`
`
`Figure 2 (above) depicts a cross section of a top down view of a syringe. Id.
`at 10:48–49.
`As described, syringe 1 comprises body 2, stopper 10 and plunger 4. Id.
`at 10:61–67. Syringe 1 extends along first axis A, and body 2 comprises
`outlet 12 at outlet end 14. Id. Stopper 10 is arranged within body 2 such
`that front surface 16 of stopper 10 and body 2 define variable volume
`chamber 18. Id. Variable volume chamber 18 contains injectable
`medicament 20 comprising an ophthalmic solution comprising a VEGF
`antagonist. Id. at 10:67–11:2. Injectable fluid 20 can be expelled though
`outlet 12 by movement of stopper 10 towards outlet end 14 thereby reducing
`the volume of variable volume chamber 18. Id. at 11:3–5.
`
`
` Challenged Claims
`The ’631 patent includes twenty-six claims, and Petitioner challenges
`each claim. Claim 1 is illustrative and reads as follows:
`
`5
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`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 µg to 100 µg
`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.
`Ex. 1001, 19:2–13. Claim 24 is “[a] method of treating a patient . . . using a
`pre-filled syringe according to claim 1.” Id. at 20:29–38.
` Asserted Grounds of Unpatentability
`Petitioner asserts several grounds of unpatentability (Pet. 21–23),
`which are provided in the table below:
`
`6
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`1-3, 5-9, 14-22,24|103(a) Sigg.® Boulange,° “andif
`
`
`necessary USP789”!°
`
`1-3, 5-9, 14-22, 24|103(a) Lam"! and Boulange
`
`4, 10, 23
`
`4, 10, 23
`
`11-13
`
`103(a)
`
`103(a)
`
`103(a)
`
`Sigg, Boulange, Fries!”
`
`Lam, Boulange, Fries
`
`Sigg, Boulange, Furfine’?
`
`
`
`Lam, Boulange, Furfine
`103(a)
`11-13
`
`
`7 The Leahy-Smith America Invents Act, Pub. L. No. 112-29, 125 Stat. 284
`(2011) (*AIA”), amended 35 U.S.C. § 103. Because the challenged claims
`of the °631 patent have an effective filing date before the effective date of
`the applicable AIA amendments, werefer to the pre-AIA version of 35
`U.S.C. § 103 in this Decision.
`8 PCT Patent Publication No. WO 2011/006877 (Ex. 1007).
`° PCT Patent Publication No. WO 2009/030976 (Ex. 1008).
`10U_S. Pharmacopeia, USP 789, Particulate Matter in Ophthalmic
`Solutions, USP 34 NF 29 (2011) (“USP789”) (Ex. 1019). Petitioner
`contends that “USP789 demonstrates a POSITA would have knownthat
`Sigg and Lam were required to meetthe claimed particle amounts.. . .
`Petitioner’s obviousness arguments remain the same if USP789 should be
`explicitly listed in Grounds 1-10.” Pet. 21 n.7.
`| PCT Patent Publication No. WO 2008/077155 (Ex. 1029).
`” AmoFries, Drug Delivery of Sensitive Biopharmaceuticals With
`Prefilled Syringes, 9(5) DRUG DELIVERY TECH.22 (2009) (Ex. 1012).
`'3 PCT Patent Publication No. WO 2007/149334 (Ex. 1021).
`
`7
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`Regeneron Exhibit 1257.007
`Regeneron v. Novartis
`IPR2021-00816
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`35 U.S.C. §”
`Claim(s) Challenged|
`Sigg, Boulange, 2008 Macugen
`103(a)
`25
`
`Label!*
`Lam, Boulange, 2008 Macugen
`Label
`Sigg, Boulange, Dixon!»
`
`103(a)
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`103(a)
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`25
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`103(a)
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`Lam, Boulange, Dixon
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`The parties rely on numerousdeclarations and exhibits relevant to our
`
`determination as we examine below.
`
`Il. ANALYSIS
`
`A. Legal Standards ofObviousness
`
`Section 103(a) forbids issuance of a patent when “the differences
`
`between the subject matter sought to be patented andthe priorart are such
`
`that the subject matter as a whole would have been obviousat the time the
`
`invention was madeto a person havingordinary skill in the art to which said
`
`subject matter pertains.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406
`
`(2007).
`
`The question of obviousnessis resolved on the basis of underlying
`
`factual determinations, including: (1) the scope and contentofthe prior art;
`
`‘4 Internet Archive WayBack Machine, March 7, 2011 Record of
`Drugs.com, Macugen Prescribing Information, available at
`https://web.archive.org/web/20 11030706523 8/http://www.drugs.com:
`80/pro/macugen.html (Ex. 1009).
`15 James A. Dixon,et al. “VEGF Trap-Eyefor the treatment of
`neovascular age-related macular degeneration.” Expert opinion on
`investigational drugs 18.10 (2009): 1573-1580 (Ex. 1030).
`8
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`Regeneron Exhibit 1257.008
`Regeneron v. Novartis
`IPR2021-00816
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`(2) any differences between the claimed subject matter and the prior art;
`(3) the level of ordinary skill in the art; and (4) when available, evidence
`such as commercial success, long-felt but unsolved needs, and failure of
`others. Graham v. John Deere Co. of Kansas City, 383 U.S. 1, 17–18
`(1966); see KSR, 550 U.S. at 407 (“While the sequence of these questions
`might be reordered in any particular case, the [Graham] factors continue to
`define the inquiry that controls.”). The Court in Graham explained that
`these factual inquiries promote “uniformity and definiteness,” for “[w]hat is
`obvious is not a question upon which there is likely to be uniformity of
`thought in every given factual context.” Graham, 383 U.S. at 18.
`The Supreme Court made clear that we apply “an expansive and
`flexible approach” to the question of obviousness. KSR, 550 U.S. at 415.
`Whether a patent claiming the combination of prior art elements would have
`been obvious is determined by whether the improvement is more than the
`predictable use of prior art elements according to their established functions.
`Id. at 417. To reach this conclusion, however, it is not enough to show
`merely that the prior art includes separate references covering each separate
`limitation in a challenged claim. Unigene Labs., Inc. v. Apotex, Inc., 655
`F.3d 1352, 1360 (Fed. Cir. 2011). Rather, obviousness additionally requires
`that a person of ordinary skill at the time of the invention “would have
`selected and combined those prior art elements in the normal course of
`research and development to yield the claimed invention.” Id.
`A claimed invention may be obvious even when the prior art does not
`teach each claim limitation, so long as the record shows why one of skill in
`the art would have modified the prior art to obtain the claimed invention.
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`See Ormco Corp. v. Align Tech., Inc., 463 F.3d 1299, 1307 (Fed. Cir. 2006).
`As a factfinder, we also must be aware “of the distortion caused by hindsight
`bias and must be cautious of arguments reliant upon ex post reasoning.”
`KSR, 550 U.S. at 421. This does not deny us, however, “recourse to
`common sense” or to that which the prior art teaches. Id.
` Level of Ordinary Skill in the Art
`We are faced with the unusual situation where Petitioner advocates for
`two different standards for the person of ordinary skill in the art: one level
`of skill for the apparatus claims (1–23), and another unique level of skill for
`“the method of treating a patient” claims (24–26) of the ’631 patent.
`
`Petitioner first contends, with respect to claims 1–23, that
`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.
`Pet. 24 (citing Ex. 1003 ¶¶ 30–32). Petitioner also contends that “a POSITA
`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.” Id.
`With respect to “method claims 24–26, a POSITA would have an
`M.D. with a specialty in ophthalmology.” Id. (citing Ex. 1003 ¶¶ 30–32;
`Ex. 1031 ¶¶ 22–23). Petitioner’s declarant, Mr. Horst Koller, explains:
`Claims 24-26 relate to methods of treating a patient
`suffering from eye disease, by administering an ophthalmic
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`solution using the pre-filled syringe described in claim 1. Because
`such intravitreal administration must be performed by an
`ophthalmologist, it is my opinion that a POSITA with respect to
`claims 24-26 would be an ophthalmologist with experience
`administering VEGF-antagonist drugs
`to patients via
`the
`intravitreal route.
`Ex. 1003 ¶ 32. Petitioner also provides the declaration of Dr. Szilard Kiss,
`an ophthalmologist, in support of its contentions with respect to claims 24–
`26. Ex. 1031 ¶¶ 4–6.
`“Patent Owner disagrees with the split definition of POSA proposed
`by Petitioner, which presumes that a POSA would have had sufficient
`expertise to single-handedly develop a PFS,16 or a method of treatment using
`a PFS, as claimed in the ʼ631 patent.” PO Resp. 6. Patent Owner proposes
`that “a POSA designing a PFS or method of treatment using a PFS would
`have worked in collaboration with others having complementary skills and
`experience.” Id. (emphasis added). Similar to Petitioner, Patent Owner
`further proposes that the person of ordinary skill in the art would have had
`an advanced degree and at least 2–3 years of professional experience. Id.
`Patent Owner further advocates that “[s]uch a person would have been a
`member of a product development team and would have drawn upon not
`only his or her own skills, but also the specialized skills of team members in
`complementary fields including ophthalmology, microbiology and
`toxicology.” Id.
`
`
`16 PFS stands for pre-filled syringe and it “is a syringe that is packaged and
`sold with a drug formulation already loaded into the syringe.” Ex. 1003
`¶ 36.
`
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`In reply, Petitioner disagrees that a person of ordinary skill in the art
`would “consult someone with ‘specialized skills’ in toxicology.” Pet.
`Reply 1. Petitioner further notes that “Novartis previously acknowledged
`that toxicology was immaterial, as its definition in the ITC investigation
`included no such requirement.” Id. (citing Ex. 1253, 18–19).
`As both parties recognize, the disagreement in the level of ordinary
`skill in the art has no bearing on the ultimate determination of obviousness.
`See PO Resp. 7 (“Under either party’s proposed POSA definition, however,
`the challenged claims of the ʼ631 patent would not have been obvious.”);
`Pet. Reply 1 (“the claims would have been obvious under either definition”).
`Based on the final record, we adopt Petitioner’s unique approach for
`identifying the person of ordinary skill in the art. Specifically, for claims 1–
`23, the person of ordinary skill in the art would have had at least an
`advanced degree with research experience in mechanical engineering,
`biomedical engineering, materials science, chemistry, or a related field, or at
`least 2–3 years of professional experience. Further, the person of ordinary
`skill in the art would have had experience with the design of pre-filled
`syringes and sterilization of drug delivery devices. We recognize that claims
`24–26 require administering an ophthalmic solution using the pre-filled
`syringe described in claim 1, and agree with Petitioner that that a person of
`ordinary skill in the art for these claims would be an ophthalmologist with
`experience administering VEGF-antagonist drugs to patients via the
`intravitreal route.
`
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` Claim Construction
`Petitioner proposes claim interpretations for several claim terms or
`phrases. Pet. 24–26. Patent Owner does not object to Petitioner’s proposed
`constructions, or to our preliminary constructions set forth in the Institution
`Decision. See Inst. Dec. 31–34. We address those claim terms in the
`following discussion.
`
` “Stopper Break Loose Force”
`Claim 1 requires “the syringe has a stopper break loose force of less
`than about 11N.” In the Petition, Petitioner proposes construing the term
`“stopper break loose force” to mean “the force required to make the
`plunger/stopper move from its resting position in the syringe barrel.” Pet. 24
`(citing Ex. 1003 ¶¶ 47–52, 121). As for timing, Petitioner further argues that
`“[t]he ’631 Patent does not specify when the break loose force is measured
`(i.e., storage time prior to testing).” Id.
`Having reviewed the evidence of record, including the Specification
`of the ’631 patent, we find Petitioner’s proposed construction persuasive.
`See Ex. 1001, 5:15–21. Mr. Koller also persuasively shows that the term
`“stopper break loose force,” would have been known in the art. Ex. 1003
`¶¶ 47–52; Ex. 1001, 5:34–45. Thus, based on the final record, we are
`persuaded by Petitioner’s proposed construction. We do not find cause to
`limit the break loose force measurement to any specific time.
`“Stopper Slide Force”
`Claims 14–16 recite “a stopper slide force of less than” a specified
`amount. Petitioner also proposes construing the related term “stopper slide
`force” to mean “the force required to sustain movement of the stopper after
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`movement has already begun.” Pet. 25 (citing Ex. 1003 ¶¶ 47–52, 121). As
`for timing, Petitioner further argues that “the ’631 Patent does not specify
`when the stopper slide force is measured (i.e., storage time prior to testing).”
`Id.
`
`Mr. Koller has also persuasively shown that the term “stopper slide
`force,” would have been known in the art. Ex. 1003 ¶¶ 47–52; Ex. 1001,
`5:34–45. Based on the final record, we are persuaded by Petitioner’s
`proposed construction. We do not find cause to limit the stopper slide force
`measurement to any specific time.
`
`“Terminally Sterilized”
`
`Petitioner proposes construing “terminally sterilized.” Pet. 25. We
`agree with Petitioner that the term “terminally sterilized” should be
`construed because one issue in contention is whether or not the asserted
`prior art fully enables terminally sterilizing a VEGF antagonist-filled syringe
`for purposes of an obviousness analysis.
`Petitioner first notes that “‘[t]erminal sterilization’ can refer to
`sterilizing both the drug product in the container and the surface of the
`container in a single process.” Id. (citing Ex. 1003 ¶ 81). Petitioner
`contends that the ’631 patent discloses that in its specific “terminal
`sterilisation” methods, “[t]he package is exposed to the sterilising gas until
`the outside of the syringe is sterile,” but that “significant amounts of the
`sterilising gas should not enter the variable volume chamber of the syringe.”
`Id. (quoting Ex. 1001 at 9:49–56; 10:2–4) (alteration in original). Petitioner,
`and Mr. Koller, conclude that “in the ’631 Patent ‘terminally sterilized’
`refers to a process whereby the outside of a pre-filled syringe is sterilized,
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`while contact between the sterilizing agent and the drug product within the
`syringe is minimized.” Id. (citing Ex. 1003 ¶ 120).
`The Specification explains that traditional “[s]terilisation can be
`achieved by terminal sterilisation in which the assembled product, typically
`already in its associated packaging, is sterilised using heat or a sterilising
`gas.” Ex. 1001, 1:17–21. The Background section of the Specification also
`describes a goal “to ensure that while a suitable level of sterilisation is
`carried out, the syringe remains suitably sealed, such that the therapeutic is
`not compromised.” Id. at 1:33–36. In the section of the Specification
`labeled “Sterilisation,” it describes that “a terminal sterilisation process may
`be used to sterilise the syringe and such a process may use a known process
`such as an ethylene oxide (EtO) or a hydrogen peroxide (H2O2) sterilisation
`process,” and “[t]he package is exposed to the sterilising gas until the
`outside of the syringe is sterile.” Id. at 9:48–56. Further, the Specification
`notes that significant amounts of the sterilizing gas should not enter the
`chamber and then defines what significant amounts encompass. Id. at 10:2–
`7.
`
`Based on the final record, we are persuaded that a person of ordinary
`skill in the art would understand that the term “terminally sterilized,” as used
`in the ’631 patent, includes the sterilization of the outside of a pre-filled
`syringe (i.e., primary packaging component) while minimizing contact
`between the drug product within the pre-filled syringe and the sterilizing
`agent being applied. See Ex. 1003 ¶ 120. Notably, the ’631 patent
`recognizes that some amounts of the sterilizing gas may interact with the
`ophthalmic solution so long as the amount does not “cause unacceptable
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`modification of the ophthalmic solution within the variable volume
`chamber.” Ex. 1001, 10:5–7.
`“About”
`The claimed silicone oil ranges (claims 1, 3, 22), break loose force
`(claims 1, 14), stopper slide force (claims 14–16), and silicone oil thickness
`(claim 2) use the modifier “about.” Petitioner notes that the ’631 patent has
`provided its own definition for the term “about.” Pet. 25 (quoting Ex. 1001,
`10:24–29). Petitioner argues that for the term “about,” it is unnecessary to
`determine “the outer boundaries of the claimed ranges (e.g., whether ‘about
`1 μg to 100 μg’ encompasses 110 μg, 150 μg, etc.).” Pet. 25–26.
`We disagree with Petitioner that it is unnecessary to determine the
`boundaries of the term “about,” because the issue is before us for at least
`claim 14’s requirement of “a stopper slide force of less than about 5N.” We,
`however, agree with Petitioner’s remaining argument that the term “about”
`in relation to a numerical value x is defined by the ’631 patent to mean “for
`example, x±10%.” Ex. 1001, 10:24–29.
`
`
` Obviousness over Sigg, Boulange, and USP789
`Petitioner asserts that claims 1–3, 5–9, 14–22, and 24 would have
`been obvious over Sigg, Boulange, and USP789. Pet. 26–54, 71–74; Pet.
`Reply 1–17, 21–27. Patent Owner disagrees. PO Resp. 8–39, 46–60; Sur-
`reply 1–27.
`Based on our review of the parties’ arguments and the cited evidence
`of record, we determine that Petitioner has met its burden of showing by a
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`preponderance of the evidence that claims 1–3, 5–9, 14–22, and 24 are
`unpatentable.
`
`Sigg
`1.
`Sigg is titled, “Surface Decontamination of Prefilled Containers in
`Secondary Packaging.” Ex. 1007, code (54). Sigg is directed to “terminal-
`sterilization methods suitable for prefilled containers containing sensitive
`products, such as biotech (biological) drug solutions.” Id. at 7:29–8:2. Sigg
`explains that the “invention relates to a method and system for terminal
`sterilization of the outer surface and/or surface decontamination of prefilled
`containers in secondary packaging, wherein the prefilled container contains
`a pharmaceutical or biological drug product.” Id. at 1:5–7.
`Sigg notes that prior art sterilization techniques like high temperature
`steam and gamma irradiation risked denaturing or chemically modifying
`biologic drug solutions. Id. at 2:20–29. To solve this problem, Sigg
`proposes “treatment of prefilled containers in secondary packaging by an
`application of vaporized-hydrogen peroxide, in which vapors are
`controllable by certain post-treatment measures.” Id. at 8:8–13.
`Sigg discloses two post-application methods for removing or
`inactivating the hydrogen peroxide residue and thereby preventing the
`hydrogen peroxide from leaching into the pre-filled syringe: application of a
`vacuum to reverse the direction of vapor flow, and inactivation of the
`hydrogen peroxide vapors. Id. at 3:19–30, 14:9–23. Sigg provides
`Example 1, which discloses vaporized H2O2 (VHP) sterilization of 0.5 mL
`syringes filled with a protein solution such as the anti-VEGF antibody
`ranibizumab intended for intravitreal injection. Id. at 20:10–21:11, 9:11–14;
`17
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`Ex. 1003 ¶ 123. The results showed that with respect to byproducts and
`degradation products “there were no differences between the results of the
`untreated syringes and with hydrogen-peroxide treated syringes.” Ex. 1007,
`21:2–3.
`
`Boulange
`2.
`Boulange is titled “Medical Device and Smooth Coating Therefor.”
`Ex. 1008, code (54). Boulange discloses several syringes, including pre-
`filled syringes. Id. at code (71), 14:19–21. Boulange also discloses a series
`of examples in which the break loose and glide forces of syringes internally
`coated with silicone oil are compared to un-siliconized syringes. Id.
`at 18:15–19:10.
`Boulange relates “to a medical device, for example a syringe,
`comprising at least one smooth coated part, [] for example a container and/or
`a piston, said parts being able to move one relative to the other, for example
`translationally and/or rotationally, when the medical device is operated.” Id.
`at 1:3–7. Boulange discloses a pre-filled syringe with decreased silicone oil
`to limit the risk of interaction between the silicone oil and any drug stored in
`the syringe. Id. at 6:10–32 (“with the medical device of the invention, it is
`possible to decrease the total amount of lubricant, for example silicone oil,
`that is necessary in such a medical device”). Boulange further discloses that
`the pre-filled syringe has decreased break loose (activation) and slide
`(sustainable) forces while preserving a tight seal between the piston and
`barrel. Id.
`Boulange describes tests conducted to evaluate break loose and slide
`forces on 1 mL pre-filled glass syringes with different piston (stopper)
`18
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`configurations—labeled as A, B1, B2, and C, in Table 1 (“configurations of
`pistons”). Id. at 14 (“Table 1”), 13:11–12 (“[C]ontainer 2 is a glass syringe
`body accommodating a piston 3”), 14:19–21 (“tests were applied on
`containers filled with 1 mL of demineralised water”). “Regarding the coated
`pistons, several surface finishes or roughnesses of the outer surface of
`coating were tested, as summarized in Table 1 below.” Id. at 13:19–21.
`
`
`Table 1 from Boulange shows configurations of pistons A, B1, and C, with
`column headings of “Viscoelastic substrate,” “Coating,” “Coating
`thickness,” and “Surface finish.” Ex. 1008, 14.
`Boulange discloses measurements of “friction force B,” which corresponds
`to the claimed break loose force. Id. at 15:6–8 (“the force required, under
`static conditions, to break the contact . . . between the piston 3 and the
`container 2”). Boulange also discloses forces S and F, which are slide forces
`measured at different stopper positions. Id. at 15:9–11 (“S is the force . . .
`19
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`for moving the piston 3 . . . measured half way of the piston travel.”), 15:13–
`16 (“F is the force . . . to move the piston 3 when it reaches the end of its
`travel”).
`Boulange provides “Example 5,” wherein the forces with silicone oil
`either baked on (“Scenario 1”) or sprayed on (“Scenario 2”) to the syringe
`barrel are measured. Ex. 1008, 20:13–21. Boulange discloses baked-on
`silicone oil was applied to the barrel at “a rate of 40 μg for a surface area of
`10 cm2,” while spray-on silicone was applied “at a rate of 500 μg for a
`surface area of 10 cm2.” Id. at 20:15–21. Boulange’s Table 7 discloses that
`Pistons A and C had certain break loose and slide forces with the baked-on
`syringes when tested unaged (T=0), while Piston B1 had break loose and
`slide forces less than 5 N for both the unaged (T=0) and aged (T=1) syringe.
`Id. at 21.
`Boulange tested syringes with baked-on silicone oil, where the pistons
`(A, B1, and C) were also coated with silicone oil. For those syringes, Table
`5 discloses break loose and slide forces for Pistons B1 and C for both
`unaged (T=0) and aged (T=1) syringes.
`
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`Petitioner’s highlighted Table 5 of Boulange depicts activation and gliding
`forces for pistons A, B1, and C. Pet. 31; Ex. 1008, Table 5.
`USP789
`3.
`USP789 is a monograph in United States Pharmacopeia. Ex. 1019.
`USP789 is a well-known standard in the art for ophthalmic solutions.
`Pet. 36, 45, 59. Mr. Koller testifies that “[t]he applicable limits on
`particulate content are set forth in USP789.” Ex. 1003 ¶ 90 & n.10 (“USP is
`a nonprofit scientific organization founded in 1820 that develops and
`disseminates public compendial standards for drug products.”). According
`to Mr. Koller, although “the USP is not legally binding, it was well known
`in the art that USP specifications are de facto requirements for regulatory
`approval of a drug product.” Id. ¶ 92 (citing Ex. 1057, 1). Further,
`Mr. Koller opines that “a POSITA would have understood that it is
`effectively a requirement for all ophthalmic products to meet the USP789
`guidelines, including VEGF-antagonists for intravitreal administration.” Id.
`USP789 is also mentioned in the ’631 patent, “[i]n one embodiment, the
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`syringe has low levels of silicone oil sufficient to meet USP789.” Ex. 1001,
`2:1–4, 6:15–30.
`According to USP789, ophthalmic solutions are required to contain
`fewer than 50 particles per mL ≥ 10 μm, fewer than 5 particles per mL ≥
`25 μm, and fewer than 2 particles per mL ≥ 50 μm. Ex. 1019, 6 (citations to
`added pagination). “Every ophthalmic solution . . . is subject to the
`particulate matter limits set forth . . . unless otherwise specified.” Id. at 5.
`Petitioner relies on USP789 to demonstrate that a POSITA would
`have known that Sigg and Lam were required to meet the claimed particle
`amounts. Pet. 21 n.7. “Petitioner does not believe that USP789 needs to be
`listed in Grounds 1-10,” but nonetheless includes this reference in each
`ground, “if necessary.” Id. For example, Petitioner alleges that “[a]
`POSITA would understand that ranibizumab solution disclosed in Sigg is an
`ophthalmic solution,” and as such, “when making a pre-filled syringe as
`disclosed in Sigg, a POSITA would have been motivated to comply with the
`prior art particulate requirements for ophthalmic solutions set forth in
`USP789.” Pet. 36.
`Patent Owner notes that it “accepts Petitioner’s position that it did not
`need to list USP 789 in its Grounds because Sigg discloses an ‘ophthalmic
`solution’ and a POSA would have understood that USP 789 is a ‘de facto
`requirement for reg
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