IPR2022-01524
`Patent 11,253,572 B2
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`i
`
`103
`
`NCT-377, Hecht
`
`6,
`6,
`
`12, 13
`7,
`7,12, 13
`
`Regeneron 2008, Hecht
`NCT-795, Hecht
`
`See Pet. 12.
`
`In support of these grounds for unpatentability Petitioner submits,
`
`inter alia, the Declaration of Angelo P. Tanna, MD (Ex. 1002). Inthe
`
`absence of evidence to the contrary, we find Dr. Tanna competentto testify
`
`on the subject matter of his declaration. See infra Section II.A; see Ex. 1002
`
`qf 3-11, 15-18; Ex. 1003. We understandthat Patent Ownerhas not
`
`submitted a similar witness declaration specifically directed to this
`
`proceeding, nor wasit required to do so. Patent Ownerhas, however,
`
`submitted witness declarations from related proceedings before the Board,
`
`including the Declaration of Lucian V. Del Priore, MD, PhD, which was
`
`submitted in related matters IPR2021-00880 and IPR2021-00881 (and notes
`
`that IPR2022-00257, IPR2022-00258, IPR2022-00298, and IPR2022-00301
`
`were joined therewith). See Ex. 2021; see also Prelim. Resp.viti, 37, 40; see
`
`Investigation ofEfficacy andSafety in Wet AMD (VIEW2) (Nov.28, 2014),
`accessed Dec. 29, 2020, at https://clinicaltrials. gov/ct2/history/
`NCT006373777A =1&B=1&C=nerged#StudyPageTop (Ex. 1011,
`“NCT-377’).
`7 Grounds S5a—5dlisted here are presented by Petitioner as a single
`“Ground 5”; however, because that ground actually asserts four separate
`challenges for unpatentability premised on separate combinationsofthe
`references ofGrounds 1—4 in combination with Hecht, we separate these
`into separate grounds.
`® Gerald Hecht, PhD, Ophthalmic Preparations, in I] REMINGTON: THE
`SCIENCE AND PRACTICE OF PHARMACY, 19" ed., Ch. 89, 1563-76 (Alfonso
`R. Gennaro ed., 1995) (Ex. 1025, “Hecht”).
`
`9
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`IPR2022-01524
`Patent 11,253,572 B2
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`supra Section I.B (Related Matters). Inthe absence of evidence to the
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`contrary, we also find Dr. Del Priore to be competentto testify on the
`
`subject matter of his declaration, whichis related to the subject matterof this
`
`proceeding. See Ex. 2021 §§ 3-10, 16-18; see also infra Section IL.A
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`(identifying the parties’ proposed definition of the ordinarily skilled artisan,
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`whichis the same as that addressed by Dr. Del Priore).
`
`Il. DISCUSSION
`
`A.
`
`LEVEL OF ORDINARYSKILL IN THE ART
`
`In determining the level of ordinary skill in the art, we consider the
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`types of problems encounteredin theart, the prior art solutions to those
`
`problems,the rapidity with which innovations are made, the sophistication
`
`of the technology, and the educationallevel of active workers in the field.
`
`Custom Accessories, Inc. v. Jeffrey-Allan Indus., Inc., 807 F.2d 955, 962
`
`(Fed. Cir. 1986).
`
`Petitionerstates,
`
`A POSAhere would have: (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 understandresults 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 pharmaceuticalfield), with
`practical academic or medical experience tn (1) developing
`treatments for angiogenic eye disorders (such as AMD),
`
`10
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`IPR2022-01524
`Patent 11,253,572 B2
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`including through the use of VEGF antagonists, or(11) treating
`of same, including through the use of VEGF antagonists.
`Pet. 23 (citing Ex. 1002 ¥ 16).° Patent Ownerneither contests this proposed
`
`definition ofthe ordinarily skilled artisan noroffers its own. See generally
`
`Prelim. Resp.
`
`For the purposesofthis decision, we accept Petitioner’s proposed
`
`definition of the person of ordinary skill in the art (or ordinarily skilled
`
`artisan), which appears to be consistent with the level of skill in the art
`
`reflected in the prior art ofrecord andthe disclosure of the °572 patent. See
`
`Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001) (“the priorart
`
`itself [may] reflect[]” evidence of the ordinary level of skill in the art)
`
`(quoting Litton Indus. Prods., Inc. v. SolidState Sys. Corp., 755 F.2d 158,
`
`163 (Fed. Cir. 1985)).
`
`B.
`
`CLAIM CONSTRUCTION
`
`same claim construction standardthat 1s used to construe claimsinacivil
`
`The Boardinterprets claim termsin an inferpartes review using the
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`action in federal district court. 37 C.F.R. § 42.100(b). In construing claims,
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`district courts and the Board here, by default, give claim termstheir ordinary
`
`and customary meaning, whichis “the meaningthat the term would haveto
`
`a person of ordinary skill in the art in question at the time ofthe invention.”
`
`Phillipsv. AWH Corp., 415 F.3d 1303, 1312-13 (Fed. Cir. 2005) (en banc).
`
`Should claim terms require express construction, sources for claim
`
`interpretation include “the wordsofthe claims themselves, the remainder of
`
`the specification, the prosecution history [1.¢., the intrinsic evidence], and
`
`extrinsic evidence concerning relevantscientific principles, the meaning of
`
`’ Petitioner uses “POSA”to refer to the person of ordinary skill in the art.
`
`11
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`technical terms, and the state ofthe art.” /d. at 1314 (quoting nnova/Pure
`
`Water, Inc. v. Safari Water Filtration Sys., Inc.,381 F.3d 1111, 1116 (Fed.
`
`Cir. 2004)). “[T]he claims themselves [may] provide substantial guidance as
`
`to the meaningofparticular claim terms.” /d. However, the claims “do not
`
`stand alone,” but are part of ““‘a fully integrated written instrument’... .
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`consisting principally ofa specification that concludes with the claims,” and,
`
`therefore, the claims are “read in viewofthe specification.” /d. at 1315
`
`(quoting Markman v. Westview Instruments, Inc. , 52 F.3d 967, 978-79 (Fed.
`
`Cir. 1995) (en banc)). Any special definition for a claim term must beset
`
`forth in the specification “with reasonable clarity, deliberateness, and
`
`precision.” /nre Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994). Without
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`sucha special definition, however, limitations may not be read from the
`
`specification into the claims. /n re Van Geuns, 988 F.2d 1181, 1184 (Fed.
`
`Cir. 1993),
`
`“[WJe need only construe terms “that are in controversy, and only to
`
`the extent necessary to resolve the controversy.’” Nidec Motor Corp. v.
`
`Zhongshan Broad Ocean MotorCo. , 868 F.3d 1013, 1017 (Fed. Cir. 2017)
`
`(quoting Vivid Techs., Inc. v. Am. Sci. & :ng’g, Inc. ,200 F.3d 795, 803
`
`(Fed. Cir. 1999)).
`
`Wenow turn to the parties’ positions on claim construction.
`
`1.
`
`“initial dose,” “secondary doses,” and “tertiary doses”
`29 66
`
`Oneorall of the terms “initial dose,”
`
`“secondary doses,”and “tertiary
`
`doses,” appear in clams 1, 4,9, 15, 16, 20, 24—27, and 29 (as noted, not all
`
`of these claims are challenged). See Ex. 1001, 23:1—25:5 (claims).
`
`12
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`Petitionerasserts that the °572 patent expressly defines the claim
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`terms“initial dose,” “secondary doses,” and “tertiary doses,”in its
`
`Specification, as follows:
`
`92360
`
`“secondary doses,” and “tertiary
`The terms“initial dose,”
`doses,” refer to the temporal sequence of administration ofthe
`VEGFantagonist. Thus, the “initial dose”is the dose whichis
`administered at the beginning of the treatment regimen(also
`referred to as the “baseline dose’); the “secondary doses”are
`the doses which are administered after the initial dose: and the
`“tertiary doses” are the doses which are administered after the
`secondary doses. Theinitial, secondary, and tertiary doses may
`all contain the same amount of VEGFantagonist, but will
`generally differ from one anotherin termsof frequency of
`administration.
`In certamm embodiments, however, the amount
`of VEGF antagonist contained in the initial, secondary and/or
`tertiary doses will vary from one another(e.g., adjusted up or
`downas appropriate) during the course of treatment.
`
`Pet. 16 (quoting Ex. 1001, 3:51-65; citing Ex. 1002 4 62).
`
`Patent Owner “does not propose a constructionof“initial dose,’
`
`“secondary dose[s],’ or “tertiary dose[s]’ that is different than that proposed
`
`by Petitioner,” although it also does not concede Petitioner’s proposalis
`
`correct. Prelim. Resp. 18.
`
`“Whenthe specification explains and defines a term used in the
`
`claims, without ambiguity or incompleteness, there is no need to search
`
`further for the meaning of the term.” Mu/tiform Dessicants Inc. v. Medzam
`
`Ltd., 133 F.3d 1473, 1478 (Fed. Cir. 1998). We agree with Petitioner’s
`
`unopposedposition that the Specification of the °572 patent expressly and
`99 66
`
`unequivocally defines the claim terms “initial dose,”
`
`“secondary doses,” and
`
`“tertiary doses,” as set forth in the quote above, as meaning, respectively,
`
`(1) the dose which is administeredat the beginning ofthe treatment
`
`regimen, (2) the doses administeredafter the initial dose; and (3) the doses
`
`13
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`Patent 11,253,572 B2
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`administeredafter the secondary doses. We interpret these terms consistent
`
`with the Specification’s definitions.
`
`2.
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`“4 weeks” and “8 weeks”after the immediatelypreceding dose
`
`Petitioner contendsthat “[a] skilled artisan would understand the
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`phrase “‘4 weeks’—asit appears in the Challenged Claims—to be
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`synonymous with monthly administration” and “*8 weeks’ .. . to be
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`synonymouswith bi- monthly (or every-other-month admmnistration).”
`
`Pet. 17 (citing Ex. 1001, 8:9-11, 15:19—30; Ex. 1002 4] 65-66). Patent
`
`Ownerdoes not challenge this construction. Prelim. Resp. 18.
`
`Wedetermine that express construction of these claim termsis
`
`unnecessary for purposes ofrendering this Decision. See Nidec Motor
`
`Corp., 868 F.3d at 1017.
`
`3.
`
`“wherein the patient achieves/gains”
`
`Claim | recites as its concluding clause, “whereinthepatient achieves
`
`a gain in visual acuity within 52 weeksfollowing the initial dose.” Ex. 1001,
`
`23:13—14 (italics added). Claims 2—4 and 8-10 further define this “gain in
`
`visual acuity.” /d. at 23:15—25, 23:32—38. Independentclaim 15 andits
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`dependent claims 16—26 are not challenged in this proceeding, and, although
`
`claim 15 has no gain in visual acuity requirement, claims 16—23 do.
`
`/d. at
`
`23:53-24:21. Independent claim 26 recites as its concluding clause,
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`“wherein the methodis as effective in achieving a gain in visual acuity as
`
`monthly administration of0.5 mg ofranibizumab by intravitreal injectionin
`
`human subjects with age-related macular degenerationat 52 weeks
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`followingthe initial dose,” and dependentclaim 28 further defines this “gain
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`m visual acuity.” /d. at 24:40—44, 24:47—49(italics added). Finally,
`
`independentclaim 29recites as its concluding clause, “wherein the method
`
`14
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`is as effective in maintaining visualacuity as monthly administration of0.5
`
`me ofranibizumab by intravitreal injection in human subjects with age-
`
`related macular degeneration at 52 weeksfollowing the initial dose, ” and
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`dependent claim 30further defines this “gain in visual acuity.” Id. at 24:63—
`
`25:5 (italics added). Collectively we refer to these clauses, particularly of
`
`independentclaims 1, 26, and 29, as the “results limitations.”
`
`Petitionerasserts that the results limitations merely state the intended
`
`results of the otherwise claimed methods of administering aflibercept and,as
`
`such, have no patentable weight because they do notalter the steps of the
`
`methods. Pet. 17. Petitioner’s position is that the resu/ts limitations should
`
`not be treated as limitations.
`
`/d. 17-20 (citing Ex. 1002 § 67; Syntex
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`(U.S.A.) LLCy. Apotex, Inc., 407 F.3d 1371, 1378 (Fed. Cir. 2005); Bristol-
`
`Myers Squibb Co. v. Ben Venue Labs., Inc. , 246 F.3d 1368, 1376 (Fed. Cir.
`
`2001); In re Copaxone, 2016 WL 873062, at *2 n.1—2 (D. Del. Mar. 7,
`
`2016); Endo Pharm. Inc. v. Watson Labs., Inc., 2014 WL 2859349,at *6, *8
`
`(E.D. Tex. Jun. 23, 2014)). Petitioner, however, accountsfor the possibility
`
`that wefind its position incorrect and alternatively argues under Grounds 1—
`
`4 that, if the results limitations are given patentable weight, then the asserted
`
`prior art inherently anticipated theselimitations. See, e.g., id. at 38-39, 44—
`
`45 (citingEx. 1002 9 148; /n re Montgomery, 677 F.3d 1375, 1382 (Fed.
`
`Cir. 2012)).
`
`Patent Ownerarguesthat the results limitations require that the
`
`claimed patients and methodsachieveparticular “endpoints as assessed by
`
`the physician,” and that the results limifationsare “*condition[s| material to
`
`patentability,’ and therefore ‘cannot be ignored.’” Prelim. Resp. 18-19
`
`(citing Hoffer v. Microsoft Corp., 405 F.3d 1326, 1329 (Fed. Cir. 2005)).
`
`15
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`Patent 11,253,572 B2
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`Patent Ownerarguesthat “[t]he Visual Acuity [1.¢., resz/ts] /imitations in the
`
`Challenged Claims add additional requirements that may be—butare not
`
`necessarily—metupon performanceofthe dosing steps recited earlier in the
`
`claim,” and addsthat the resw/ts limitations requirements are “not met unless
`
`the patient receiving the doses does,in fact, experience the required gain.”
`
`Id. at 20, 25 (italics added).
`
`The facts here are similar to those ofLos Angeles Biomedical
`
`ResearchInstitute at Harbor-UCLA Medical Centerv. Eli Lilly & Co., 849
`
`F.3d 1049 (Fed. Cir. 2017) (“Los Angeles Biomed.”), where claims covered
`
`administering a pharmaceutical according to a certain regimen, to a person
`
`in need of treatment, and includeda limitation in the body of the
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`independentclaim to a treatmentresult of “arresting or regressing” a tissue
`
`fibrosis by the administration of the recited dosage.
`
`/d. at 1053-54.
`
`Similarly here, as can be seen from claim 1 reproduced aboveat Section I.C
`
`(and each challenged independent claim), the claims are similarly directed to
`
`administering a pharmaceutical (aflibercept) to patients in need thereof, ata
`
`specified regimen and dosage, wherea result ofthat treatment is expressly
`
`recited in the body of the independent claims. See Ex. 1001, 23:2—14 (claim
`
`1), 24:26—43 (claim 26), 24:50-67 (claim 29).
`
`In Los Angeles Biomed, in an interpartes review the Board construed
`
`the “arresting or regressing” clause to have no limiting role and to merely
`
`State an intendedresult, ultimately finding the claims unpatentable as
`
`obvious.
`
`/d. at 1054-57. TheFederal Circuit disagreed and the Board’s
`
`decision wasvacated and the case was remanded on,in/er alia, that issue.
`
`Id. at 1067-68.
`
`16
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`Relating to the claim construction, the Federal Circuit found that
`
`patent at issue was “clear” that the tissue fibrosis, recited by the claim as
`
`arrested or regressed by the otherwise recited treatment, was not the same as
`
`and did not necessarily accompany the symptomoferectile disfunction
`
`(taught in and the focus of the relied-upon priorart), although the former
`
`(fibrosis) may frequently result in the latter (disfunction). 7d. at 1059. The
`
`Federal Circuit held that the “arresting or regressing’ clause was more than a
`
`mere statementofintended result, but was a limitation carrying patentable
`
`weight because the phrase wasdrafted as a part of a separate step of the
`
`method rather than of the preamble, the “arresting or regressing” language
`
`demandedefficacy, and the efficacy waslinked to specific treatment
`
`minimum duration and dosage.
`
`/d. at 1060-61. The patients exhibiting
`
`these two issues were not necessarily the same.
`
`In part because the Board did not considerthe arresting/regressing
`
`result limitation tn its unpatentability analysis, the Federal Circuit agreed
`
`with the patent ownerthat the Board’s findings were insufficient.
`
`/d. at
`
`1064, 1067. The Federal Circuit foundthat that prior art reference relied
`
`upon in the Board’s decision for teaching the claimed treatment, and also
`
`relied uponto link the condition of fibrosis with the symptom oferectile
`
`dysfunction, did not teach treating a population of patients suffering from
`
`erectile dysfunction on/y becauseofa fibrosis condition and, even though
`
`such patients may have hadfibrosis, if was not certain; and further found
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`that othercited prior art did not make certain a link betweenfibrosis and
`
`such dysfunction.
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`/d. at 1065—66. This, the Federal Circuit found, was
`
`error.
`
`17
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`Wefind in agreement with Patent Ownerthat the results limitations of
`
`the challenged claimsare limitations and must be given patentable weight
`
`for the samereasonsarresting or regressing a tissuefibrosis was a
`
`limitation in Los Angeles Biomed.
`
`Similarly, here the claims are directed to expressly required results of
`
`the administration of aflibercept to patients at 2 mg at an initial dose,in at
`
`least one secondary dose 4 weekslater, and in at least one tertiary dose 8
`
`weekslater. Therefore, we find that in claim 1, “wherein thepatient
`
`achieves a gain in visual acuity within 52 weeksfollowingtheinitial dose,”
`
`is a limitation. Further, in claim 26, “wherein the methodis as effective in
`
`achieving a gain in visual acuity as monthly administrationof0.5 mg of
`
`ranibizumabby intravitreal injection in human subjects withage-related
`
`macular degeneration at 52 weeksfollowingthe initialdose,”1s a Imitation.
`
`And, in claim 29, “wherein the methodis as effective in maintaining visual
`
`acuity as monthly administration of0.5 mg ofranibizumab by intravitreal
`
`injection in human subjects with age-related macular degeneration at 52
`
`weeksfollowingthe initial dose,”is a limitation.
`
`4,
`
`“wherein exclusion criteriafor thepatient include both of...”
`
`Claim 14, which depends from claim 1, recites “exclusion criteria for
`
`the patient include both of: (1) active ocular inflammation; and (2) active
`
`ocular or periocular infection.” Ex. 1001, 23:49-53.
`
`Petitionerasserts that this recited subject matter should be entitled to
`
`no patentable weight under the printed matter doctrine becauseit is directed
`
`only to a mentalstep on the basis of information,i.e., deciding whether to
`
`treat a patient based on an instruction, with no functionalrelationship to the
`
`rest of the claamed method. Pet. 20—23.
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`18
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`Patent Ownerarguesthat the printed matter doctrine does not apply
`
`and the exclusion criteria should be given patentable weight because it
`
`defines the scope ofpatients to be treated and requires an assessmentby the
`
`clinician. Prelim. Resp. 28-30.
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`Wedetermine that express construction of this claim term is
`
`unnecessary for purposes ofrendering this Decision. See Nidec Motor
`
`Corp., 868 F.3d at 1017.
`
`C.
`
`APPLICABLE LEGAL STANDARDS
`
`“In an IPR,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 interpartes review petitionsto identify “with
`
`particularity . .. the evidence that supports the groundsfor the challenge to
`
`each claim’’)). This burden of persuasion nevershifts to Patent Owner. See
`
`Dynamic Drinkware, LLC v. Nat’] Graphics, Inc. , 800 F.3d 1375, 1378
`
`(Fed. Cir. 2015) (discussing the burden of proof in interpartes review).
`
`An interpartes review may beinstituted if the information presented
`
`by Petitioner in the Petition, in view of Patent Owner’s Preliminary
`
`Response and the preliminary record, showsthatthere is a reasonable
`
`likelihood that Petitioner would prevail with respect to at least one of the
`
`claims challenged in the Petition. 35 U.S.C. §314.
`
`“Anticipation requiresthatall of the claim elements and their
`
`limitations are shown in a single prior art reference.” /n re Skvorecz, 580
`
`F.3d 1262, 1266 (Fed. Cir. 2009). To anticipate “it is not enough that the
`
`prior art reference discloses part of the claimed invention, which an ordinary
`
`artisan might supplement to make the whole,or that it includes multiple,
`
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`distinct teachings that the artisan might somehow combineto achieve the
`
`claimed invention.” Net MoneyIN, Inc. v. VeriSign, Inc., 545 F.3d 1359,
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`1371 (Fed. Cir. 2008). “However, a reference can anticipate a claim even if
`
`it “d[oes] not expressly spell out’ all the limitations arranged or combined as
`
`in the claim,if a person of skill in the art, reading the reference, would ‘at
`
`once envisage’ the claimed arrangement or combination.” Kennametal, Inc.
`
`v. Ingersoll Cutting Tool Co., 780 F.3d 1376, 1381 (Fed. Cir. 2015) (quoting
`
`Inre Petering, 301 F.2d 676, 681 (CCPA 1962)).
`
`A prior art reference without express referenceto a claim limitation
`
`may anticipate by inherency. See /n re Cruciferous Sprout Litig., 301 F.3d
`
`1343, 1349 (Fed. Cir. 2002). “Underthe principles of inherency,if the prior
`
`art necessarily functions in accordance with, or includes, the claimed
`
`limitations, it anticipates.” /d. (quoting MEHL/Biophile Int’! Corp.v.
`
`Milgraum, 192 F.3d 1362, 1365 (Fed. Cir. 1999)).
`
`Regarding obviousness, the Supreme Court in KSR /nternational Co.
`
`v. Teleflex Inc. , 550 U.S. 398 (2007), reaffirmed the framework for
`
`determining obviousnessset forth in Graham v. John Deere Co., 383 U.S. 1
`
`(1966). The KSR Court summarized the four factual inquiries set forth in
`
`Graham(383 U.S. at 17-18) that are applied in determining whethera claim
`
`is unpatentable as obvious under 35 U.S.C. § 103 as follows: (1) determining
`
`the scope and content ofthe prior art; (2) ascertaming the differences
`
`betweenthe prior art and the claimsat issue; (3) resolving the level of
`
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`ordinary skill in the art;!° and (4) considering objective evidence indicating
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`obviousness or non-obviousness. !! KSR, 550 U.S. at 406.
`
`“The combination of familiar elements according to known methods
`
`is likely to be obvious whenit does no more than yield predictable results.”
`
`Id. at 416. “[W]hen the question is whether a patent claiming the
`
`combination of elements ofprior art is obvious,” the answer depends on
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`“whether the improvement is more than the predictable use ofprior art
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`elements accordingto their established functions.” /d. at 417.
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`With these standards in mind, and in view of the definition of the
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`ordinarily skilled artisan, we address Petitioner’s challenges below.
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`D._PETITIONER’S ASSERTED PRIOR ART
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`1,
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`Dixon
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`Dixon1s an article that indicates on its face its publication in 2009.
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`Ex. 1006, 1573. There is currently no dispute that Dixon is prior art. See
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`generally Prelim. Resp.; see also Pet. 26 n.4 (“the asserted priorart
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`referenceall qualify as publications that were available to—and indeedcited
`
`by—uinterested, skilled artisans before the ’572 patent’s earliest, purported
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`priority date.”’).
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`Dixon is a reviewofclinical trials regarding administering VEGF
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`Trap-Eyeto treat neovascular AMD. Ex. 1006, 1573. Dixondiscloses that
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`“VEGFTrap-Eyeis a novel anti-VEGF therapy, with Phase I and IJ trial
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`data indicating safety, tolerability and efficacy for the treatment of
`
`neovascular AMD.” /d. Dixon describes VEGF Trap-Eyeas“a fusion
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`10 See supra Section II.A.
`1! There is no evidence pertaining to objective indicia of non-obviousness.
`See Prelim. Resp.
`
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`protein of key binding domains of human VEGFR-1 and -2 combined with a
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`human IgG Fc fragment.” /d. at 1575. Dixon discloses that “VEGF Trap-
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`Eye and aflibercept (the oncology product) have the same molecular
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`structure, but there are substantial differences between the preparation ofthe
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`purified drug product and their formulations.” /d.
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`Dixondiscloses that current therapy requires “frequent intraocular
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`injections, as often, as monthly, without a defined stopping point,” and that
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`“|t|he time and financial burden of monthly injections hasled to the
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`initiation of studies to examinethe efficacy of alternative dosing schedules.”
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`Id. at 1574, 1577. Dixon discloses that:
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`[d]ue to its high binding affinity and the ability to safely inject
`high doses into the eye, VEGF Trap-Eye may havelonger
`duration of effect in the eye. Two PhaseIII studies in wet
`AMD, VIEW 1 and VIEW 2,are currently under way and seek
`to compare monthly ranibizumab to monthly or bimonthly
`VEGF Trap-Eye.
`
`Id. at 1577. Specifically, Dixon discloses that the PhaseIII trial initiated in
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`August of 2007 “will evaluate the safety and efficacy of intravitreal VEGF
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`Trap-Eyeat doses of 0.5 and 2.0 mg administered at 4-week dosingintervals
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`and 2.0 mg at an 8 week dosing interval (following three monthly doses),
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`compared with 0.5 mg of ranibizumab administered every 4 weeks.” /d. at
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`1576. Dixon discloses that in a previous PhaseII trial, patients treated with
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`monthly doses of 2.0 or 0.5 mg VEGF Trap-Eye achieved improvements
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`according to the Early Treatment ofDiabetic Retinopathy Study ““ETDRS”)
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`scale.
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`/d.
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`2.
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`Regeneron 2008
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`Regeneron 2008 1s a press release by Bayer HealthCare and
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`Regeneron dated May 8, 2008. Ex. 1009, 1. There is currently no dispute
`
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`that Regeneron 2008 1s prior art. See generally Prelim. Resp.; see also Pet.
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`26 n.4.
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`Regeneron 2008 states that a “first Phase 3 trial, VIEW 1, began
`
`enrolling patients in August 2007 in the United States and Canada,” and
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`announces“that thefirst patient has been dosed in the VIEW2trial, a
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`second Phase3 clinical study in a development program evaluating VEGF
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`Trap-Eyefor the treatment ofthe neovascular form of Age-related Macular
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`Degeneration (wet AMD).” Ex. 1009, 1. Regeneron 2008 discloses that
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`“TbJoth VIEW 1 and VIEW 2 are designedto evaluate the efficacy and
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`safety of VEGF Trap-Eye administered by intravitreal injection, at dosing
`
`intervals of 4 and 8 weeks” and “will include visual acuity endpoints and
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`anatomical endpoints, including retinal thickness, a measure ofdisease
`
`activity. Thetrial is intended to establish non-inferiority of VEGF Trap-Eye
`
`with Lucentis®* (ranibizumab), an antiangiogenic agent approvedforuse in
`
`wet AMD in major markets globally.” /d. Regeneron 2008 more
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`specifically states that the VIEW2study “will evaluate the safety and
`
`efficacy of VEGF Trap-Eye at doses of0.5 milligrams (mg) and 2.0 mg
`
`administered at 4-weekintervals and 2.0 mg at an 8-week dosing interval,
`
`including one additional 2.0 mg dose at week four.” /d.
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`Regeneron 2008 discloses that in a Phase 2 trial announced in October
`
`2007, “VEGF Trap-Eye met both primary and secondary key endpoints: a
`
`Statistically significant reduction in retinal thickness (a measure of disease
`
`activity) after 12 weeks of treatment compared with baseline and a
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`statistically significant improvementfrom baseline in visual acuity (ability to
`
`read letters onan eye chart).” /d. at 1-2.
`
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`3.
`
`NCT-795
`
`NCT-795 disclosesclinical trial information for the VIEW1 study and
`
`indicates it is the “[I]atest version (submitted December 20, 2012),” but also
`
`indicates it discloses “Changes (Merged) for Study: NCT00509795, March 3
`
`2009 (v8) -- April 28, 2009 (v9).” Ex. 1010, 1,3. Petitioner asserts this
`
`document “waspublicly available on the ClinicalTrials. gov website prior to
`
`January 13,2011.” Pet. 30-31 (citing Ex. 1002 7 108-116, 123; Ex. 1006,
`
`1579; Ex. 1010, 8; Ex. 1022, 1-2, 8-11). There is currently no dispute that
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`NCT-795 is prior art. See Generally Prelim. Resp.; see also Pet. 26 n.4.
`
`NCT-795 describes the VIEW 1 study as “a phase III, double-masked,
`
`randomized, study of the efficacy and safety of VEGF Trap-Evein patients
`
`with neovascular age-related macular degeneration.” Ex. 1011,5. NCT-795
`
`discloses “Experimental: 3” arm, which includes “2.0 mg VEGF Trap-Eye
`
`administered every 8 weeks (including one additional 2.0 mg dose at week
`
`4) during the first year. Thereaftera dose may be administered as frequently
`
`as every 4 weeks, but no less frequently than every 12 weeks.” /d. at6. For
`
`such an experimental arm, NCT-795 discloses “Key Inclusion Criteria” and
`
`“Key Exclusion Criteria.” /d. at9—11.
`
`4.
`
` NCT-377
`
`NCT-377 disclosesclinical trial information for the VIEW2 study and
`
`indicates it is the “[I]atest version (submitted November28, 2014),” but also
`
`indicates a “Submitted Date [of] March 17, 2008 (v1),” and Petitioner
`
`asserts it “was publicly available and accessible to interested, skilled artisans
`
`prior to January 13, 2011.” Ex. 1011, 1, 3; Pet. 32 (citing Ex. 1002 4] 108—
`
`123; Ex. 1006, 1579; Ex. 1011, 1-3; Ex. 1020, 95-96; Ex. 1022, 1-2, 4-7).
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`Thereis currently no dispute that NCT-377 1s prior art. See generally
`
`Prelim. Resp.; see also Pet. 26 n.4.
`
`NCT-377 describes the VIEW2study as “phase II, double-masked,
`
`randomized, study ofthe efficacy and safety of VEGF Trap-Eyein patients
`
`with neovascular age-related macular degeneration.” Ex. 1011,5. NCT-377
`
`discloses “Experimental: Arm 3,” which includes “2.0 mg VEGF Trap-Eye
`
`administered every 8 weeks (including one additional 2.0 mg dose at Week
`
`4) during the first year. Thereaftera dose may be administered as frequently
`
`as every 4 weeks, but no less frequently than every 12 weeks.” /d. at6. For
`
`such an experimental arm, NCT-377 discloses “Inclusion Criteria” and
`
`“Exclusion Criteria.” /d. at 7-8.
`
`E.—PETITIONER’S PATENTABILITY CHALLENGES
`
`As summarized above,Petitioner asserts eight grounds (with ground 5
`
`separated into its four alternatives) for unpatentability of the claims of the
`
`*572 patent. See supra Section I.D; see also Pet. 12. We review Petitioner’s
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`challenges and Patent Owner’s arguments below.
`
`1,
`
`Anticipation by Dixon, Regeneron 2008, NCT-795, or NCT-377
`(Grounds 1-4)
`
`Petitioner’s Grounds 1-4assert the challenged claimsare anticipated
`
`by each of Dixon, Regeneron 2008, NCT-795, and NCT-377. See Pet. 35—
`
`68. Petitioner asserts each ofthese prior art references in substantially
`
`similar ways against the challenged claims, Patent Ownerargues against
`
`them together as a group, and the samefacts and law are determinative for
`
`each of Grounds 1-4. Therefore, we address Grounds 1—4 together.
`
`Petitionerasserts that independent claims 1, 26, and 29, as well as
`
`dependentclaims 2-5, 8-11, 14,27, 28, and 30, are anticipated by each of
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`(individually) Dixon Regeneron 2008, NCT-795, and NCT-377. Pet. 35-68
`
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`(citing, concerning the independentclaims, Ex. 1001, 2:51—56, 5:23—26,
`
`5:30-48, 9:29-14:30 (Example 4), 23:2—14 (claim 1); Ex. 1002 § 137-138,
`
`140-141, 143-145, 157-168, 170-171, 174-179, 181, 183-185, 187-192,
`
`194, 197-201; Ex. 1005, Table 1; Ex. 1006, 1573, 1575-77; Ex. 1009, 1-2:
`
`Ex. 1010, 3, 4, 8-9; Ex. 1011, 3-4, 6; Ex. 1014, 2537; Ex. 1019, 2;
`
`Ex. 1023, 3; Ex. 1026; Ex. 1030 (App’x 2); Ex. 1031, 15-16; Ex. 1032, 67,
`
`69, 76, 81, 85). Foundationally,it is Petitioner’s position that each of these
`
`referencesdiscloses the sameclinicaltrials identified in the *572 patent at
`
`Example 4—the VIEW1and VIEW?trials—including the samedrug
`
`(aflibercept/VEGF Trap-Eye), dose (2 mg), administration (intravitreal
`
`injection), and dosing regimen(initial, 4-week secondary, and 8-week
`
`tertiary doses) of that Example 4 and as recited by the independentclaims.
`
`Id. This point is not currently disputed by Patent Owner. See generally
`
`Prelim. Resp.
`
`Petitioner does not assert that any of Dixon, Regeneron 2008,
`
`NCT-795, and NCT-377 expressly discloses “[t]he last clause of claim 1”
`
`(and ofclaims 26 and 29), 1.e., the results limitations addressed abovein the
`
`Claim Construction Section of this Decision (s