Trials@uspto.gov Paper 9
`571-272-7822
`Date: October 20, 2023
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`________________________________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________________________________
`SAMSUNG BIOEPIS CO. LTD,
`Petitioner,
`v.
`REGENERON PHARMACEUTICALS, INC.,
`Patent Owner.
`________________________________________
`IPR2023-00739
`Patent 10,888,601 B2
`________________________________________
`
`
`
`Before JOHN G. NEW, ROBERT A. POLLOCK, and RYAN H. FLAX,
`Administrative Patent Judges.
`
`NEW, Administrative Patent Judge.
`
`
`
`DECISION
`Granting Institution of Inter Partes Review
`35 U.S.C. § 314
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`Samsung Bioepis Exhibit 1088
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`571-272-7822
`Date: October 20, 2023
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`________________________________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________________________________
`SAMSUNG BIOEPIS CO. LTD,
`Petitioner,
`v.
`REGENERON PHARMACEUTICALS, INC.,
`Patent Owner.
`________________________________________
`IPR2023-00739
`Patent 10,888,601 B2
`________________________________________
`
`
`
`Before JOHN G. NEW, ROBERT A. POLLOCK, and RYAN H. FLAX,
`Administrative Patent Judges.
`
`NEW, Administrative Patent Judge.
`
`
`
`DECISION
`Granting Institution of Inter Partes Review
`35 U.S.C. § 314
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`I. INTRODUCTION
`Petitioner Samsung Bioepis Co. Ltd. (“Petitioner”) has filed a Petition
`(Paper 1, “Pet. ”) seeking inter partes review of claims 10–12, 17–19, 21,
`25–28, and 331 of U.S. Patent 10,888,601 B2 (Ex. 1001, the “’601 patent”).
`Patent Owner Regeneron Pharmaceuticals, Inc. (“Patent Owner”) timely
`filed a Preliminary Response. Paper 6 (“Prelim. Resp.”). With our
`authorization (see Ex. 3001), Petitioner filed a Reply to the Preliminary
`Response (Paper 7 (“Reply”)), and Patent Owner filed a Sur-Reply. Paper 8
`(“Sur-Reply”).
`Under 35 U.S.C. § 314, the Board “may not authorize an inter partes
`review to be instituted unless … the information presented in the petition
`… and any response … shows that there is a reasonable likelihood that the
`petitioner would prevail with respect to at least 1 of the claims challenged in
`the petition.” Upon consideration of the Petition, Preliminary Response,
`Reply, Sur-Reply, and the evidence of record, we determine that the
`evidence presented demonstrates a reasonable likelihood that Petitioner
`would prevail in establishing the unpatentability of at least one challenged
`claim of the ’601 patent. We therefore institute inter partes review of the
`challenged claims.
`
`
`1 Petitioner originally challenged claims 10–33, 46, and 47 of the ’601
`patent. Pet. 1. Patent Owner states that claims 13–14, 22, and 29–30 were
`disclaimed on July 11, 2022, before the Petition was filed.
`Prelim. Resp. 1, n.1 (citing Ex. 2001). Patent Owner also states that,
`subsequent to the filing of the Petition, claims 15, 16, 20, 23, 24, 31, 32, 46
`and 47 were also disclaimed. Id. (citing Ex. 2002). Consequently, only
`claims 10–12, 17–19, 21, 25–28, and 33 of the ’601 patent remain
`challenged by Petitioner.
`
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`A.
`
`II. BACKGROUND
`Real Parties-in-Interest
`Petitioner identifies Samsung Bioepis Co. Ltd. as the real party-in-
`interest. Pet. 6. Patent Owner identifies Regeneron Pharmaceuticals, Inc. as
`the real party-in-interest. Paper 5 at 2.
`
`Related Matters
`B.
`Petitioner and Patent Owner identify Mylan Pharms. Inc. v.
`
`Regeneron Pharms., Inc., IPR2022-01226, as challenging different claims of
`the ’601 patent. Pet. 6–7, Paper 4, 1. Petitioner confirms that, in Samsung
`Bioepis Co., Ltd. v. Regeneron Pharms., Inc., IPR2023-00566, it filed a
`“copycat” petition, seeking joinder in IPR2022-01226, and proposing to join
`Mylan’s inter partes review as a “silent understudy.” Id. at 7 (citing
`IPR2023-00566, Papers 2, 3). Joinder of IPR2022-01226 and IPR2023-
`00566 was granted on March 22, 2023 in IPR2023-00566. Id. (citing
`IPR2023-00566, Paper 10).
`
`The parties also identify Mylan Pharms. Inc. v. Regeneron Pharms.,
`Inc., IPR2021-00880 and Mylan Pharms. Inc. v. Regeneron Pharms., Inc.,
`IPR2021-00881, challenging claims of US 9,254,338 and US 9,669,069,
`respectively, both of which are in the same family as the ’601 patent. Pet. 7,
`Paper 4, 2. Final Written Decisions were entered in both IPR2021-00880
`and -00881 on November 9, 2022, finding all challenged claims of both
`patents unpatentable. Id. Patent Owner has since appealed those decisions
`to the U.S. Court of Appeals for the Federal Circuit as Regeneron Pharms,
`Inc. v. Mylan Pharms. Inc., No. 2023-1395 (Fed. Cir.) and Regeneron
`
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`Pharms., Inc. v. Mylan Pharms. Inc., No. 2023-1396 (Fed. Cir.),
`respectively. Id.
`
`Furthermore, in Mylan Pharms. Inc. v. Regeneron Pharms., Inc.,
`IPR2022-01225, Mylan challenged the patentability of claims 1, 3–11, 13,
`14, 16–24, and 26 of US 10,130,681. Pet. 7. Petitioner has separately
`challenged the patentability of the same claims of that patent in in Samsung
`Bioepis Co., Ltd. v. Regeneron Pharms., Inc., IPR2023-00442, institution of
`which was granted on July 19, 2023. See IPR2023-00442, Paper 10.
`Celltrion, Inc. has similarly sought, and been granted, joinder with both
`IPR2022-001225 and -01226, and has also assumed a “silent understudy”
`posture in those cases. See IPR2023-00532, Papers 3, 7; IPR2023-00533,
`Papers 3, 7.
`
`The parties further identify Regeneron Pharms., Inc. v. Mylan
`Pharms. Inc., 1:22-cv-00061-TSK (N.D. W. Va.) as a related matter. See,
`e.g., Pet. 8. Petitioner also identifies as a related matter United States v.
`Regeneron Pharms., Inc., No. 1:20-cv-11217-FDS (D. Mass.). Id. Patent
`Owner also identifies Chengdu Kanghong Biotechnol. Co. v. Regeneron
`Pharms., Inc., PGR2021-00035 (PTAB) (proceeding terminated).
`Paper 4, 2.
`
`C.
`
`The Asserted Grounds of Unpatentability
`Petitioner contends that claims 10–12, 17–19, 21, 25–28, and 33 of
`the ’601 patent are unpatentable, based upon the following grounds:
`
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`Ground
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`22
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`3
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`6
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`Claim(s)
`Challenged
`10–12, 18, 19,
`21, 26–28
`10–12, 18, 19,
`21, 26–28
`17, 25, 33
`
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`
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`35 U.S.C. §
`
`Reference(s)/Basis
`
`1033
`
`103
`
`103
`
`2009 Press Release4,
`Shams5
`2009 Press Release,
`Elman6
`2009 Press Release,
`Elman, CATT7, PIER8
`
`
`2 Grounds 1, 4, and 5 of the Petition challenged claims that have been
`disclaimed by Patent Owner. See n.1, supra; Pet. 11. We therefore do not
`address those Grounds in this Decision.
`3 The Leahy-Smith America Invents Act (“AIA”), Pub. L. No. 112–29, 125
`Stat. 284 (2011), amended 35 U.S.C. §§ 102 and 103, effective March 16,
`2013. Because the application from which the ’601 patent issued has an
`effective filing date after that date, the AIA versions of §§ 102 and 103
`apply.
`4 Press Release, Regeneron, Enrollment Completed in Regeneron and Bayer
`HealthCare Phase 3 Studies of VEGF Trap-Eye in Neovascular Age-
`Related Macular Degeneration (Wet AMD) (September 14, 2009) (the
`“2009 Press Release”) Ex. 1009.
`5 Shams (WO 2006/047325 Al, May 4, 2006) (“Shams”) Ex. 1010.
`6 M.J. Elman et al., Randomized Trial Evaluating Ranibizumab Plus Prompt
`or Deferred Laser or Triamcinolone Plus Prompt Laser for Diabetic
`Macular Edema, 117(6) OPHTHALMOLOGy 1064–1077.e35 (2010)
`(“Elman”) Ex. 1006.
`7 CATT Patient Eligibility Criteria, retrieved from: https://web.archive.org/
`web/20100713035617/http:/www.med.upenn.edu/cpob/studies/documents/
`CATTEligibilityCriteria_000.pdf (“CATT”) Ex. 1018.
`8 C.D. Regillo et al., Randomized, Double-Masked, Sham-Controlled Trial of
`Ranibizumab for Neovascular Age-related Macular Degeneration: PIER
`Study Year 1, 145(2) AM. J. OPHTHALMOL. 239–48 (2008) (“PIER”)
`Ex. 1004.
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`Petitioner also relies upon the Declaration of Dr. Edward Chaum (the
`“Chaum Declaration,” Ex. 1002).
`
`The ’601 Patent
`D.
`The ’601 patent is directed to methods for treating angiogenic eye
`
`disorders by sequentially administering multiple doses of a vascular
`epithelial growth factor (“VEGF”) antagonist to a patient. Ex. 1001, Abstr.
`These methods include the administration of multiple doses of a VEGF
`antagonist to a patient at a frequency of once every 8 or more weeks, and are
`useful for the treatment of angiogenic eye disorders such as, inter alia, age
`related macular degeneration. Id.
`
`In an exemplary embodiment, a single “initial dose” of VEGF
`antagonist (“VEGFT”) is administered at the beginning of the treatment
`regimen (i.e., at “week 0”), two “secondary doses” are administered at
`weeks 4 and 8, respectively, and at least six “tertiary doses” are administered
`once every 8 weeks thereafter, i.e., at weeks 16, 24, 32, 40, 48, 56, etc.).
`Ex. 1001, cols. 2–3, ll. 63–2.
`
`E.
`
`Representative Claim
`Claim 10 is representative of the challenged claims, and recites:
`10. A method for treating diabetic macular edema in a patient
`in need thereof, comprising intravitreally administering, to said
`patient, an effective amount of aflibercept which is 2 mg
`approximately every 4 weeks for the first 5 injections followed
`by 2 mg approximately once every 8 weeks or once every 2
`months.
`Ex. 1001, col. 22, ll. 40–46.
`
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`Priority History of the ’601 Patent
`F.
`The ’601 patent issued from U.S. Application Ser. No. 16/397,267
`
`(the “’267 application”) filed on April 29, 2019, and claims the priority
`benefit of, inter alia, US Provisional Application Ser. No. 61/432,245,
`which was filed on January 13, 2011. Ex. 1001, code (60).
`The claims of the ’601 patent, including challenged claims 10–12, 17–
`19, 21, 25–28, and 33 were allowed on November 12, 2020, and the patent
`issued on January 12, 2021. Ex. 1017, 5591; Ex. 1001, code (45).
`
`
`III. ANALYSIS
`
`A.
`
`Claim Construction
`The Board applies the same claim construction standard that would be
`used to construe the claim in a civil action under 35 U.S.C. § 282(b). See
`37 C.F.R. § 100(b) (2020). Under that standard, claim terms “are generally
`given their ordinary and customary meaning” as understood by a person of
`ordinary skill in the art at the time of the invention. Phillips v. AWH Corp.,
`415 F.3d 1303, 1312–13 (Fed. Cir. 2005) (en banc). “In determining the
`meaning of the disputed claim limitation, we look principally to the intrinsic
`evidence of record, examining the claim language itself, the written
`description, and the prosecution history, if in evidence.” DePuy Spine, Inc.
`v. Medtronic Sofamor Danek, Inc., 469 F.3d 1005, 1014 (Fed. Cir. 2006)
`(citing Phillips, 415 F.3d at 1312–17). Extrinsic evidence is “less significant
`than the intrinsic record in determining ‘the legally operative meaning of
`claim language.’” Phillips, 415 F.3d at 1317 (quoting C.R. Bard, Inc. v. U.S.
`Surgical Corp., 388 F.3d 858, 862 (Fed. Cir. 2004)).
`
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`1.
`
`“A method for treating….”
`Petitioner initially accepts, for the purposes of this Decision, that the
`preamble of claim 1 is limiting, and agrees with the Board’s prior rejection,
`in the related IPR2021-00881 Final Written Decision, of Patent Owner’s
`position that the preamble requires a particular level of efficacy. Pet. 16
`(citing Ex. 1002 ¶¶ 82–91). Specifically, Petitioner notes that the Board
`found that administering a compound—the recited VEGF antagonist—“to
`[a] patient for the purpose of improving or providing a beneficial effect on
`their angiogenic eye disorder” satisfies the “treating” portion of the
`preamble. Id. at 17 (quoting Ex. 1025, 19; and citing id. at 23; Ex. 1053, 9–
`10; Ex. 1054).
`Patent Owner states that, for the purposes of this Decision only, it
`does not contest Petitioner’s proposed construction. Prelim. Resp. 11.
`Therefore, for the same reasons we explained in the Final Written
`Decision in related IPR2022-00881 concerning a related patent having
`claims with language similar to the presently challenged claims, and for the
`purposes of this Decision, we adopt Petitioner’s proposed construction of “a
`method for treating….”
`
`A Person of Ordinary Skill in the Art
`B.
`In determining the level of skill in the art, we consider the type of
`
`problems encountered in the art, the prior art solutions to those problems, the
`rapidity with which innovations are made, the sophistication of the
`technology, and the educational level of active workers in the field. See
`Custom Accessories, Inc. v. Jeffrey-Allan Industries, Inc., 807 F.2d 955, 962
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`(Fed. Cir. 1986); see also Orthopedic Equip. Co. v. United States, 702 F.2d
`1005, 1011 (Fed. Cir. 1983).
`
`Petitioner notes that, in the Final Written Decision in IPR2021-00881
`and in the Decision to Institute in IPR2022-01226, the Board adopted the
`following definition of a person of ordinary skill in the art:
`A person of ordinary skill in the art at the time of the invention
`would have had (1) knowledge regarding the diagnosis and
`treatment of angiogenic eye disorders,
`including
`the
`administration of therapies to treat said disorders; and (2) the
`ability to understand results and findings presented or published
`by others in the field, including the publications discussed herein.
`Typically, such a person would have an advanced degree, such
`as an M.D. or Ph.D. (or equivalent, or less education but
`considerable professional experience
`in
`the medical,
`biotechnological, or pharmaceutical field), with practical
`academic or medical experience in (i) developing treatments for
`angiogenic eye disorders (such as AMD), including through the
`use of VEGF antagonists, or (ii) treating of same, including
`through the use of VEGF antagonists.
`Pet. 14–15 (quoting Ex. Ex. 1025, 9–10). The Board found, in both
`proceedings, that this definition was consistent with the proper level of skill
`in the art. See, e.g., Ex. 1025, 10. Petitioner urges us to adopt this definition
`as being consistent with the ’681 patent, as well as the prior art cited by
`Petitioner. Id. at 18.
`Patent Owner does not disagree with Petitioner’s proposed definition
`for the purposes of the present decision Prelim. Resp. 11.
`We again determine, at this stage of the proceeding, that our previous
`definition of the requisite level of ordinary skill in the art is reasonable and
`consistent with the prior art of record. See Okajima v. Bourdeau, 261 F.3d
`1350, 1355 (Fed. Cir. 2001) (holding that “the prior art itself [may] reflect[]
`
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`an appropriate level” as evidence of the ordinary level of skill in the art)
`(quoting Litton Indus. Prods., Inc. v. Solid State Sys. Corp., 755 F.2d 158,
`163 (Fed. Cir. 1985)). For the purposes of this decision, and for the sake of
`consistency, we adopt our prior definition, quoted above, as the definition of
`a person of ordinary skill in the art.
`
`
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`IV. ANALYSIS
`
`A.
`1.
`
`Principles of Law
`Burden of Proof
`“In an [inter partes review], the petitioner has the burden from the
`onset to show with particularity why the patent it challenges is
`unpatentable.” Harmonic Inc. v. Avid Tech., Inc., 815 F.3d 1356, 1363 (Fed.
`Cir. 2016 (citing 35 U.S.C. § 312(a)(3) (requiring inter partes review
`petitions to identify “with particularity … the evidence that supports the
`grounds for the challenge to each claim”)). Therefore, in an inter partes
`review, the burden of proof is on the Petitioner to show that the challenged
`claims are unpatentable; that burden never shifts to the patentee. See
`35 U.S.C. § 316(e); In re Magnum Oil Tools Int’l, Ltd., 829 F.3d 1364, 1375
`(Fed. Cir. 2016) (citing Dynamic Drinkware, LLC v. Nat’l Graphics, Inc.,
`800 F.3d 1375, 1378 (Fed. Cir. 2015)).
`
`Obviousness
`To ultimately prevail in its challenge to Patent Owner’s claims,
`Petitioner must demonstrate by a preponderance of the evidence that the
`
`2.
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`claims are unpatentable.9 35 U.S.C. § 316(e); 37 C.F.R. § 42.1(d). A patent
`claim is unpatentable under 35 U.S.C. § 103 if the differences between the
`claimed subject matter and the prior art are such that the subject matter as a
`whole would have been obvious at the time the invention was made to a
`person having ordinary 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
`obviousness is resolved on the basis of underlying factual determinations
`including: (1) the scope and content of the prior art; (2) any differences
`between the claimed subject matter and the prior art; (3) the level of ordinary
`skill in the art; and (4) objective evidence of nonobviousness. Graham v.
`John Deere Co., 383 U.S. 1, 17–18 (1966).
`In determining obviousness when all elements of a claim are found in
`various pieces of prior art, “the factfinder must further consider the factual
`questions of whether a person of ordinary skill in the art would be motivated
`to combine those references, and whether in making that combination, a
`person of ordinary skill would have had a reasonable expectation of
`success.” Dome Patent L.P. v. Lee, 799 F.3d 1372, 1380 (Fed. Cir. 2015);
`see also WMS Gaming, Inc. v. Int’l Game Tech., 184 F.3d 1339, 1355 (Fed.
`Cir. 1999) (“When an obviousness determination relies on the combination
`of two or more references, there must be some suggestion or motivation to
`combine the references.”). “Both the suggestion and the expectation of
`
`
`9 The burden of showing something by a preponderance of the evidence
`requires the trier of fact to believe that the existence of a fact is more
`probable than its nonexistence before the trier of fact may find in favor of
`the party who carries the burden. Concrete Pipe & Prods. of Cal., Inc. v.
`Constr. Laborers Pension Tr. for S. Cal., 508 U.S. 602, 622 (1993).
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`success must be founded in the prior art, not in the applicant’s disclosure.”
`In re Dow Chemical Co., 837 F.2d 469, 473 (Fed. Cir. 1988); see also In re
`Magnum Oil Tools, 829 F.3d at 1381 (finding a party that petitions the
`Board for a determination of unpatentability based on obviousness must
`show that “a skilled artisan would have been motivated to combine the
`teachings of the prior art references to achieve the claimed invention, and
`that the skilled artisan would have had a reasonable expectation of success in
`doing so.”) (internal quotations and citations omitted).
`An obviousness analysis “need not seek out precise teachings directed
`to the specific subject matter of the challenged claim, for a court can take
`account of the inferences and creative steps that a person of ordinary skill in
`the art would employ.” KSR, 550 U.S. at 418; see In re Translogic Tech,
`Inc., 504 F.3d 1249, 1259 (Fed. Cir. 2007). In KSR, the Supreme Court also
`stated that an invention may be found obvious if trying a course of conduct
`would have been obvious to a person of ordinary skill in the art:
`When there is a design need or market pressure to solve a
`problem and there are a finite number of identified, predictable
`solutions, a person of ordinary skill has good reason to pursue
`the known options within his or her technical grasp. If this leads
`to the anticipated success, it is likely the product not of
`innovation but of ordinary skill and common sense. In that
`instance the fact that a combination was obvious to try might
`show that it was obvious under § 103.
`550 U.S. at 421. “KSR affirmed the logical inverse of this statement by
`stating that § 103 bars patentability unless ‘the improvement is more than
`the predictable use of prior art elements according to their established
`functions.’” In re Kubin, 561 F.3d 1351, 1359–60 (Fed. Cir. 2009) (citing
`KSR, 550 U.S. at 417).
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`1.
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`We analyze the asserted grounds of unpatentability in accordance with
`the principles stated above.
`
`B. Ground 2: Obviousness under 35 U.S.C. § 103 of claims 10–12, 18,
`19, 21, 26–28 over the 2009 Press Release (Ex. 1009) and Shams
`(Ex. 1010)
`Petitioner challenges claims 10–12, 18, 19, 21, 26–28 of the ’601
`patent as unpatentable under 35 U.S.C. § 103 as being obvious over the
`combination of the 2009 Press Release and Shams. Pet. 34–40.
`
`Overview of the prior art
`The 2009 Press Release
`a.
`The 2009 Press Release was released by Patent Owner on September
`
`14, 2009 and is prior art to the ’601 patent. The 2009 Press Release
`announces the completion of patient enrollment in two randomized, double-
`masked, Phase 3 clinical trials evaluating VEGF Trap-Eye (aflibercept), its
`VEGF inhibitor, in the treatment of the neovascular form of age-related
`macular degeneration (also known as “wet AMD”). Ex. 1009, 1. The 2009
`Press Release discloses that, in each study (respectively, VIEW-1 and
`VIEW-2), VEGF Trap-Eye was being evaluated for its effect on maintaining
`and improving vision when dosed as an intravitreal injection on a schedule
`of 0.5 mg every four weeks, 2.0 mg every four weeks, or 2.0 mg every eight
`weeks (following three monthly doses), as compared with intravitreal
`ranibizumab (Lucentis®) administered 0.5 mg every four weeks during the
`first year of the studies. Id. The 2009 Press Release further discloses that
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`as-needed (“PRN”) dosing with both agents would be evaluated during the
`second year of each study. Id.
`
`The 2009 Press Release further discloses that VEGF Trap-Eye was
`also in Phase 3 development for the treatment of Central Retinal Vein
`Occlusion (CRVO), another cause of blindness. Ex. 1009, 1. Patients in
`both studies would receive six monthly intravitreal injections of either
`VEGF Trap-Eye at a dose of 2 mg, or sham control injections. Id. At the
`end of the initial six months, patients would be dosed on a PRN basis for
`another six months. Id.
`Additionally, the 2009 Press Release states that VEGF Trap-Eye was
`also in Phase 2 development for the treatment of Diabetic Macular Edema
`(DME) a type of diabetic retinopathy. Ex. 1009, 1. Patients would be
`administered VEGF Trap-Eye at 0.5 mg or 2 mg monthly, 2 mg every eight
`weeks after three monthly loading doses, or 2 mg on a PRN basis after three
`monthly loading doses, and would be compared to focal laser treatment,
`which was the then-current standard of care in DME. Id. The 2009 Press
`Release relates that patient enrollment had been completed, with initial data
`expected in the first half of 2010. Id.
`
`Shams
`b.
`Shams is WIPO International Application WO 2006/047325 A1,
`published on May 4, 2006, and is prior art to the ’601 patent. Ex. 1010,
`codes (10), (43). Shams is directed to methods of administering to a
`mammal suffering from, or at risk for, an intraocular neovascular disorder,
`with regular dosing of a therapeutically effective amount of a VEGF
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`antagonist, followed by less frequent dosing of a therapeutically effective
`amount of VEGF antagonist. Id. at Abstr.
`Specifically, Shams teaches methods of administering to a mammal a
`number of first individual doses of a VEGF antagonist, followed by a
`number of second individual doses of the antagonist, with the second
`individual doses administered less frequently than the first individual doses.
`Ex. 1010, 4–5.
`Specifically, Shams teaches exemplary embodiments in which the
`first individual doses are administered at one-month intervals (e.g., about 3
`individual doses), and the second individual doses are administered at three-
`month intervals (e.g., about 6 individual doses), with the second individual
`doses administered beginning three months after the number of first
`individual doses. Ex. 1010, 5. In another exemplary embodiment, the first
`individual dose is administered at months 0, 1 and 2. In another aspect, the
`second individual dose is administered at months 5, 8, 11, 14, 17, 20 and 23.
`Id.
`Shams further teaches that “[t]he doses may be administered
`
`according to any time schedule which is appropriate for treatment of the
`disease or condition. For example, the dosages may be administered on a
`daily, weekly, biweekly or monthly basis in order to achieve the desired
`therapeutic effect and reduction in adverse effects.” Ex. 1010, 22. In this
`respect, Shams discloses that:
`The specific time schedule can be readily determined by a
`physician having ordinary skill in administering the therapeutic
`compound by routine adjustments of the dosing schedule within
`the method of the present invention. The time of administration
`of the number of first individual and second individual doses as
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`well as subsequent dosages is adjusted to minimize adverse
`effects while maintaining a maximum therapeutic effect. The
`occurrence of adverse effects can be monitored by routine patient
`interviews and adjusted to minimize the occurrence of side
`effects by adjusting the time of the dosing. Any dosing time is
`to be considered to be within the scope of the present invention
`so long as the number of first individual doses of the VEGF
`antagonist is administered followed by a number of second
`individual doses, which are less frequently administered. For
`example, doses may be administered on a monthly schedule
`followed by subsequent quarterly or more dose schedule.
`Maintenance doses are also contemplated by the invention.
`Id. at 22–23.
`
`2.
`
`Petitioner’s Argument
`Independent claims 10, 18, and 26
`a.
`Petitioner argues that independent claims 10, 18, and 26 recite treating
`diabetic retinopathy (“DR”) and diabetic macular edema (“DME”) by
`intravitreally injecting aflibercept using a dosing regimen of five initial
`injections of 2 mg (rather than two or more) that are spaced a month apart,
`followed by maintenance doses spaced eight weeks apart. Pet. 34 (citing
`Ex. 1001, 11).
`The 2009 Press Release teaches that Regeneron, the Patent Owner and
`manufacturer of aflibercept, was beginning clinical trials studying the
`efficacy of aflibercept to treat DME via three different dosing regimens for
`2 mg VEGF Trap-Eye (aflibercept), including the use of three initial
`injections of 2 mg that are spaced a month apart, followed by maintenance
`doses spaced eight weeks apart. Pet. 34–35 (citing Ex. 1009, 1; Ex. 1002
`¶ 147). Furthermore, argues Petitioner, the 2009 Press Release taught that a
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`regimen with more than three loading doses would be safe and tolerable and
`more likely to improve treatment for at least some patients. Id. at 35 (citing
`Ex. 1009, 1; Ex. 1002 ¶¶ 146–158).
`Petitioner notes that the 2009 Press Release also discloses two
`alternative regimens for the Phase II clinical trial: (1) a regimen of 12
`monthly doses of 2 mg aflibercept for the first year of treatment of DME—a
`standard and proven safe regimen for other anti-VEGF agents; and (2) a
`regimen of three initial loading doses followed by PRN dosing for treatment
`of DME. Pet. 35. According to Petitioner, the 2009 Press Release teaches
`that more than three initial doses would be safe and tolerable, and would
`suggest to a person of ordinary skill in the art that some patients might
`benefit from more than three loading doses, which could provide a
`reasonable expectation of success for such patients. Id.
`Petitioner notes that Shams teaches that it was known in the art at the
`time of the ’601 patent’s filing that “monthly dosing of a therapeutically
`effective amount of VEGF antagonist, followed by less frequent dosing of a
`therapeutically effective amount of VEGF antagonist.” Pet. 35, 2 (quoting
`Ex. 1010, 2; and citing Ex. 1002 ¶ 155). Petitioner also points to Shams’
`teaching “a treatment schedule comprising an initial interval of
`administration of a therapeutic compound [a VEGF antagonist], followed by
`a subsequent, less frequent interval of administration of the therapeutic
`compound” allows “one to decrease subsequent doses of the therapeutic
`compound, while at the same time maintaining the therapeutic efficacy.” Id.
`at 36 (quoting Ex. 1010, 22). Petitioner also notes that Shams further
`explains that “[t]he specific time schedule [for administering doses] can be
`readily determined by a physician having ordinary skill in administering the
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`therapeutic compound by routine adjustments of the dosing schedule within
`the method of the present invention [i.e., loading and maintenance dosing].”
`Id. (quoting Ex. 1010, 23–24; and citing Ex. 1002 ¶ 155).
`Petitioner contends that adjusting the 2009 Press Release protocol to
`administer 5 initial doses would be a product of a skilled artisan’s “routine
`adjustments” to the initial dosing schedule, i.e., a “routine application of a
`well-known problem-solving strategy.” Pet. 36 (citing, e.g., Pfizer, Inc. v.
`Apotex, Inc., 480 F.3d 1348, 1368 (Fed. Cir. 2007); Ex. 1002 ¶¶ 146–158).
`According to Petitioner, a person of ordinary skill in the art would follow
`such a routine strategy when evaluating the appropriate dosing regimen for
`an individual patient, based on their clinical judgment, precisely as described
`in the art as early as 2006. Id. (citing Ex. 1002 ¶¶ 58–61, 146–158).
`Petitioner also points to the Specification of the ’601 patent, which, it
`argues, discloses no data specific to the efficacy of five monthly loading
`doses versus three monthly loading doses, or to any efficacy data on five
`monthly loading doses at all. Pet. 37. Petitioner notes that the Specification
`explains that “[t]he methods of the invention may comprise administering to
`the patient any number of secondary and/or tertiary doses of a VEGF
`antagonist” including “e.g. 2, 3, 4, 5, 6, 7, 8, or more.” Id. (quoting
`Ex. 1001, col. 4, ll. 13–22). Furthermore, argues Petitioner, the use of five
`loading doses is disclosed by the Specification patent only as part of a list of
`twenty other variations on loading/maintenance dosing regimens that vary
`the number of initial doses, including from two to eight loading doses spaced
`four weeks apart. Id. (see Ex. 1001, cols. 15–17, ll. 40–8). Petitioner states
`that the Specification further discloses that “[a]ny of the foregoing
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`administration regimens may be used for the treatment of…” DME, among
`other angiogenic eye disorders. Id. (quoting Ex. 1001, col. 17, ll. 16–27).
`Petitioner asserts that person of ordinary skill in the art would have
`therefore considered it obvious to vary the number of initial loading doses
`disclosed in the art for the treatment of DR/DME before moving to
`maintenance dosing for individual patients, including the use of five loading
`doses. Pet. 38 (citing Ex. 1002 ¶¶ 58–61, 146–158). Petitioner’s Declarant,
`Dr. Chaum opines that such variation is a normal part of practice in treating
`DME and other angiogenic diseases. Id. According to Dr. Chaum, it was,
`and is, a routine clinical practice to continue monthly loading doses of anti-
`VEGF agents until the point at which the dosing interval can be reduced. Id.
`Petitioner argues that varying the amount of secondary doses would
`have been part of the basic problem solving strategy a skilled artisan would
`undertake in treating a patient with DR/DME. Pet. 38 (citing Ex. 1002
`¶¶ 146–158). Petitioner contends that the motivation for making such
`routine adjustments to a dosing regimen for treatment of a patient “flows
`from the ‘normal desire of scientists or artisans to improve upon what is
`already generally known.’” Id. at 38–39 (quoting Pfizer, 480 F.3d at 1368
`(quoting In re Peterson, 315 F.3d 1325, 1330 (Fed. Cir. 2003)); also citing
`Ex. 1002 ¶¶ 145–158).
`Petitioner contends that a person of ordinary skill in the art would also
`have had a reasonable expectation of success in using five initial loading
`doses instead of the three described in the 2009 Press Release. Pet. 39.
`Petitioner asserts that the 2009 Press Release’s disclosure of a Phase II trial
`using l
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