Trials@uspto.gov Paper 21
`571-272-7822
`Date: November 10, 2021
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`________________________________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________________________________
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`v.
`REGENERON PHARMACEUTICALS, INC.,
`Patent Owner.
`________________________________________
`IPR2021-00880
`Patent 9,669,069 B2
`________________________________________
`
`
`
`Before ERICA A. FRANKLIN, JOHN G. NEW, and
`SUSAN L. C. MITCHELL, Administrative Patent Judges.
`
`NEW, Administrative Patent Judge.
`
`
`
`DECISION
`Granting Institution of Inter Partes Review
`35 U.S.C. § 314
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`571-272-7822
`Date: November 10, 2021
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`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`________________________________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________________________________
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`v.
`REGENERON PHARMACEUTICALS, INC.,
`Patent Owner.
`________________________________________
`IPR2021-00880
`Patent 9,669,069 B2
`________________________________________
`
`
`
`Before ERICA A. FRANKLIN, JOHN G. NEW, and
`SUSAN L. C. MITCHELL, Administrative Patent Judges.
`
`NEW, Administrative Patent Judge.
`
`
`
`DECISION
`Granting Institution of Inter Partes Review
`35 U.S.C. § 314
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`IPR2021-00880
`Patent 9,669,069 B2
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`I. INTRODUCTION
`Petitioner Mylan Pharmaceuticals Inc. (“Petitioner”) has filed a
`Petition (Paper 1, “Pet.”) seeking inter partes review of claim 1 and 8–12 of
`US Patent 9,669,069 B2 (Ex. 1001, the “’069 patent”). Patent Owner
`Regeneron Pharmaceuticals, Inc. (“Patent Owner”) timely filed a
`Preliminary Response. Paper 10 (“Prelim. Resp.”). With our authorization
`(see Paper 13), Petitioner filed a Reply to the Preliminary Response (Paper
`16 (“Reply”)), and Patent Owner filed a Sur-Reply. Paper 19 (“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 ’069 patent.
`
`
`A.
`
`II. BACKGROUND
`Real Parties-in-Interest
`Petitioner identifies Viatris Inc., Mylan Inc., Mylan Pharmaceuticals
`Inc., Momenta Pharmaceuticals, Inc., Janssen Research & Development
`LLC, and Johnson & Johnson as the real parties-in-interest. Paper 18.
`Patent Owner identifies Regeneron Pharmaceuticals, Inc. as the real party-
`in-interest. Paper 5, 2.
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`Related Matters
`B.
`Petitioner and Patent Owner identify Mylan Pharms. Inc. v.
`
`Regeneron Pharms., Inc., IPR2021-00881 (PTAB May 5, 2021) (the “-881
`petition”) as a related matter. Pet. 4; Paper 5, 2. The -881 petition
`challenges claims of U.S. Patent No. 9,254,338 B2 (“the ’338 patent”). The
`parties further identify Chengdu Kanghong Biotechnol. Co. v. Regeneron
`Pharms., Inc., PGR2021-00035 (PTAB Jan. 7, 2021) challenging the claims
`of U.S. Patent No. 10,828,345 B2 (“the ’345 patent”), which is related to the
`’069 patent and the ’338 patent. Pet. 5. This latter proceeding has been
`terminated. See Chengdu, PGR2021-00035, Paper 8.
`Petitioner also identifies additional patents and patent applications that
`claim priority to the ’069 patent, namely: U.S. Patent Nos. 10,130,681 B2,
`10,857,205 B2, 10,828,345 B2, and 10,888,601 B2, and U.S. Application
`Serial Nos. 17/072,417, 17/112,063, and 17/112,404. Pet. 5.
`
`C.
`
`The Asserted Grounds of Unpatentability
`Petitioner contends that claims 1 and 8–12 of the ’069 patent are
`unpatentable, based upon the following grounds:
`
`
`Ground
`
`I
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`Claim(s)
`Challenged
`1, 9–12
`
`35 U.S.C. §
`
`Reference(s)/Basis
`
`102
`
`Dixon1
`
`
`1J.A. Dixon et al., VEGF Trap-Eye for the Treatment of Neovascular Age-
`Related Macular Degeneration, 18(10) EXPERT OPIN. INVESTIG. DRUGS
`1573–80(2009) (“Dixon”) Ex. 1006.
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`Ground
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`Claim(s)
`Challenged
`1, 9–12
`1, 9–12
`1, 8–12
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`1, 8–12
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`II
`III
`IV
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`V
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`35 U.S.C. §
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`Reference(s)/Basis
`
`102
`102
`102 and/or
`103
`103
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`Heier 20092
`Regeneron I3
`Dixon
`
`Heier-2009 and Mitchell4
`or Dixon, and optionally,
`Papadopolous5 or Dix6
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`Petitioner also relies upon the Declarations of Dr. Thomas A. Albini
`(the “Albini Declaration,” Ex. 1002) and Dr. Mary Gerritsen (the “Gerritsen
`Declaration,” Ex. 1003).
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`2 J.S. Heier, Intravitreal VEGF Trap for AMD: An Update, October 2009
`RETINA TODAY 44–45 (2009) (“Heier 2009”) Ex. 1020.
`
` Press Release, Bayer and Regeneron Extend Development Program for
`VEGF Trap-Eye to Include Central Retinal Vein Occlusion, April 30, 2009
`(“Regeneron I”) Ex. 1028.
`
` P. Mitchell et al., Ranibizumab (Lucentis) in Neovascular Age-Related
`Macular Degeneration: Evidence from Clinical Trials, 94(2) Br. J.
`Ophthalmol. 2–13 (2010) Ex. 1030.
`
` Papadopoulos et al. (US 7,374,758 B2, May 20, 2008) (“Papadopolous”)
`Ex. 1010.
`
` Dix et al., (US 2006/0217311 A1, May 20, 2008) (“Dix”) Ex. 1033.
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`D.
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`The ’069 Patent
`The ’069 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 col. 2, ll. 56–62.
`
`E. Representative Claim
`Claim 1 is the sole independent claim of the ’069 patent, and recites:
`1. A method for treating an angiogenic eye disorder in a
`patient,
`said method
`comprising
`sequentially
`administering to the patient a single initial dose of a VEGF
`antagonist, followed by one or more secondary doses of
`the VEGF antagonist, followed by one or more tertiary
`doses of the VEGF antagonist;
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`wherein each secondary dose is administered 2 to 4 weeks
`after the immediately preceding dose; and wherein
`each tertiary dose is administered on an as needed/
`pro re nata (PRN) basis, based on visual and/or
`anatomical outcomes as assessed by a physician or
`other qualified medical professional;
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`wherein the VEGF antagonist is a receptor-based chimeric
`molecule comprising (1) a VEGFRl component
`comprising amino acids 27 to 129 of SEQ ID NO:2;
`(2) a VEGFR2 component comprising amino acids
`130–231 of SEQ
`ID NO:2; and
`(3) a
`multimerization component comprising amino
`acids 232–457 of SEQ ID NO:2.
`
`
`Ex. 1001, col. 21, ll. 42–60.
`
`Prosecution History of the ’069 Patent
`F.
`The ’069 patent issued from U.S. Application Ser. No. 14/972,560
`
`(the “’560 application”) filed on December 17, 2015, and claims the priority
`benefit of, inter alia, provisional Application Ser. No. Provisional
`application No. 61/432,245, which was filed on Jan. 13, 2011. Ex. 1001,
`code (60).
`The claims of the ’069 patent, including claims 1 and 8–12 were
`allowed on March 6, 2017, and the patent issued on June 6, 2017. Ex. 1017,
`162; 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
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`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)).
`Petitioner proposes constructions for the claim terms “initial dose,”
`“secondary dose,” “tertiary dose, ” “4 weeks,” “pro re nata (PRN),”
`“VEGFR1 Component,” “VEGFR2 Component,” and “Multimerization
`Component.” Pet. 13-19. Patent Owner responds that, although it does not
`agree with Petitioner’s proposed constructions for these terms, Patent Owner
`does not advance claim construction positions for these terms at this time
`because construction of these terms is not necessary to resolve the arguments
`presented in its Preliminary Response. Prelim. Resp. 19 (citing Nidec Motor
`Corp. v. Zhongshan Broad Ocean Motor Co., 868 F.3d 1013, 1017 (Fed.
`Cir. 2017)).
`
`Having reviewed the pleadings and evidence of record, we agree with
`Patent Owner that no construction of these claim terms is necessary for the
`purposes of this Decision to Institute a trial.
`
`
`B. A Person of Ordinary Skill in the Art
`
`Petitioner contends that a person of ordinary skill in the art would
`typically possess an advanced degree, such as an M.D. or Ph.D. (or
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`equivalent, or less education but considerable professional experience in the
`medical, biotechnological, or pharmaceutical field), with practical academic
`or medical experience in (1) developing treatments for angiogenic eye
`disorders (such as AMD), including through the use of VEGF antagonists, or
`(2) treating of angiogenic eye disorders (such as age-related macular
`degeneration (“AMD”)), including through the use of VEGF antagonists.
`Pet. 25 (citing Ex.1002 ¶¶ 26–28).
`Patent Owner does not expressly contest this definition of a person of
`ordinary skill in the art in its Preliminary Response, although Patent Owner
`contends that such a skilled artisan could not necessarily perform the
`limitation of claim 1 reciting “based on visual and/or anatomical outcomes
`as assessed by a physician or other qualified medical professional.” See,
`e.g., Prelim. Resp. 28. We address Patent Owner’s contentions with respect
`to this limitation in our analysis below. For the purposes of this decision,
`because we find Petitioner’s definition to be consistent with the level of skill
`in the art (see, e.g., Exs. 1006, 1020), and in the absence of a different
`proposed definition of the level of skill in the art by Patent Owner, we
`consequently adopt Petitioner’s definition.
`
`C. Discretionary Denial of Institution under 35 U.S.C. § 325(d)
`
`Patent Owner urges us to exercise our discretion to deny institution of
`trial under 35 U.S.C. §325(d). Prelim. Resp. 10. Under § 325(d), we have
`discretion to deny a petition that presents the same or substantially the same
`prior art or arguments as previously presented to the Office. See 35 U.S.C.
`§ 325(d). In evaluating whether the factual predicate under § 325(d) is met,
`we consider a number of non-exclusive factors, as set forth in our decision in
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`Becton, Dickinson and Co. v. B. Braun Melsungen AG, IPR2017-01586,
`Paper 8 at 17–18 (PTAB Dec. 15, 2017) (precedential) (“the Becton
`Dickinson factors”):
`(a)
`the similarities and material differences between the asserted art
`and the prior art involved during examination;
`
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`the cumulative nature of the asserted art and the prior art
`evaluated during examination;
`
`the extent to which the asserted art was evaluated during
`examination, including whether the prior art was the basis for
`rejection;
`
`the extent of the overlap between the arguments made during
`examination and the manner in which Petitioner relies on the
`prior art or Patent Owner distinguishes the prior art;
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`(e) whether Petitioner has pointed out sufficiently how the
`Examiner erred in its evaluation of the asserted prior art; and
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`(b)
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`(c)
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`(d)
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`(f)
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`the extent to which additional evidence and facts presented in
`the Petition warrant reconsideration of the prior art or
`arguments.
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`Becton, Dickinson, IPR2017-01586, Paper 8 at 17–18.
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`In performing an analysis under § 325(d), “the Board uses the
`following two-part framework: (1) whether the same or substantially the
`same art previously was presented to the Office or whether the same or
`substantially the same arguments previously were presented to the Office;
`and (2) if either condition of first part of the framework is satisfied, whether
`the petitioner has demonstrated that the Office erred in a manner material to
`the patentability of challenged claims. . . . If, after review of [Becton,
`Dickinson] factors (a), (b), and (d), it is determined that the same or
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`substantially the same art or arguments previously were presented to the
`Office, then factors (c), (e), and (f) relate to whether the petitioner has
`demonstrated a material error by the Office.” Advanced Bionics, LLC v.
`MED-EL Elektromedizinische Geräte GmbH, IPR2019-01469, Paper 6 at 8
`(PTAB Feb. 13, 2020) (precedential). Consequently, we first turn to an
`analysis of Becton-Dickinson factors (a), (b), and (d) to determine whether
`the same or substantially the same art previously was presented to the Office
`or whether the same or substantially the same arguments previously were
`presented to the Office.
`
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`Part One of the Advanced Bionics Analysis
`1.
`Becton Dickinson factors (a), (b), and (d) require us to determine,
`
`respectively: (a) “the similarities and material differences between the
`asserted art and the prior art involved during examination;” (b) “the
`cumulative nature of the asserted art and the prior art evaluated during
`examination,” and (d) “the extent of the overlap between the arguments
`made during examination and the manner in which Petitioner relies on the
`prior art or Patent Owner distinguishes the prior art.” Becton, Dickinson,
`IPR2017-01586, Paper 8 at 17.
`
`Patent Owner points out that Dixon is listed as a reference in the ’069
`patent (see Ex. 1001 code (56)), and was submitted to the Office in an IDS
`during prosecution and marked “considered” by the Examiner. Prelim.
`Resp. 10–11 (citing Ex. 1017, 121, 168). Patent Owner acknowledges that
`Heier 2009, Mitchell, Regeneron I, and Papadopolous, were not present
`before the Examiner during prosecution of the ’560 application, but argues
`that each of these references is cumulative of Dixon because each reference
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`is “substantially the same as” Dixon. Id. at 11–14 (citing NXP USA, Inc. v.
`Impinj, Inc., IPR2020-00519, 2020 WL 4805424, at *4-5 (Aug. 17, 2020)).
`
`Petitioner replies that Dixon was “neither applied against the claims
`nor discussed by the [E]xaminer.” Reply 3 (citing Amazon.com, Inc. v.
`M2M Solutions LLC, IPR2019-01205, Paper 14 at 16 (PTAB Jan. 27, 2020)
`(finding that “a reference that ‘was neither applied against the claims nor
`discussed by the Examiner’ does not weigh in favor of exercising the
`Board’s discretion under § 325(d) to deny a petition.”)). Petitioner asserts
`that the Examiner issued a single office action, issuing several rejections
`upon the grounds of obviousness-type double patenting over several prior
`patents, none of which disclosed CLEAR-IT-2. Id. (citing Ex.1017, 105–
`09).
`In fact, Petitioner argues, Dixon was not presented in full to the
`
`Examiner. Reply 4. According to Petitioner, the EFS Acknowledgment
`Receipt shows that the Examiner received only a single page. Id. (citing Ex.
`1017, 126). Petitioner also points to the certified file history as confirming
`that Patent Owner submitted only a one-page copy of Dixon. Id. (citing Ex.
`1087, 1). Petitioner asserts that, under 37 C.F.R. § 1.98(a)(2)7, Patent
`Owner thus informed the Examiner that its one-page copy represented the
`“portion which caused [Dixon] to be listed,” affirmatively excluding the rest
`of the reference. Id. Petitioner contends that the submitted page, however,
`
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`7 37 C.F.R. § 1.98(a)(2) states, in relevant part: “Any information disclosure
`statement filed under § 1.97 shall include the items listed in paragraphs
`(a)(1), (a)(2) and (a)(3) of this section…. A legible copy of… [e]ach
`publication or that portion which caused it to be listed, other than U.S.
`patents and U.S. patent application publications unless required by the
`Office. (Emphasis added).
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`does not disclose (or even mention) the prior art regimens described
`extensively in the complete Dixon reference. Id. See Ex. 1087, 1.
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`Patent Owner acknowledges that only one page of Dixon, instead of
`the whole paper, was filed, and asserts that it was unaware that Dixon was
`submitted as a single page prior to Petitioner’s Reply. Sur-Reply 8. Patent
`Owner contends that the full citation to the Dixon paper was presented in an
`IDS, that the reference was publicly available, and that it was marked
`considered by the Examiner. Id. (citing Ex. 1017 at 121, 168; MPEP
`§ 609.05(b)). Patent Owner notes that the record does not suggest that the
`Examiner found Patent Owner’s disclosure of Dixon to be defective or
`incomplete, because the Examiner did not draw a line through the citation on
`the IDS. Id. at 9.
`
`Patent Owner argues further that the Dixon disclosures relied upon by
`Mylan, viz., the CLEAR-IT-2 dosing regimen and results are also disclosed
`in the Thomson Reuters Integrity Press Release of September 28, 20088
`(“Thomson Reuters”), which was presented to, and considered by, the
`Examiner, and which was cited in the ’069 patent. Id. (citing Ex. 1017 at 68,
`114; Ex. 1001, code (56)). Patent Owner repeats that Petitioner’s secondary
`references are also cumulative of art that was considered by the Office. Id.
`
`We are not persuaded that Patent Owner has demonstrated that
`Becton-Dickinson factors (a), (b), and (d) have been satisfied. The evidence
`of record shows that the Dixon reference before the Examiner consisted of
`merely the first page of Dixon. See Ex. 1087. The single page of Dixon that
`
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`8 Thomas Reuters Integrity, VEGF Trap-Eye Final Phase II Results in
`Age-Related Macular Degeneration Presented at 2008 Retina Society
`Meeting, (Sep. 28, 2008). Ex. 2007.
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`was before the Examiner provides no disclosure of the claimed dosing
`regimen. It would consequently have been impossible for the Examiner to
`analyze the limitations of the challenged claims in view of the complete
`teachings of Dixon under these circumstances.
`
`We consequently find that the disclosure of Dixon that form the basis
`of Petitioner’s Grounds I and IV (of which Dixon is the sole reference) were
`not before the Examiner as prior art during examination (because the
`relevant disclosures were missing or omitted), and that there could therefore
`be no overlap between the arguments made during examination and the
`manner in which Petitioner relies on the prior art or Patent Owner
`distinguishes the prior art.
`
`Furthermore, we also reject Patent Owner’s argument that the Heier
`2009, Mitchell, Regeneron I, and Papadopolous references are cumulative of
`Dixon because, as we have explained, the single page of Dixon that was
`actually before the Examiner during prosecution does not teach all of the
`limitations of the challenged claims, nor does it disclose all of the relevant
`limitations that Petitioner relies upon those references as disclosing. The
`remaining references do not, consequentially, disclose the same, or
`substantially the same, subject matter as the one-page version of Dixon that
`was before the Examiner during prosecution.
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`Summary
`2.
`Because we find that the evidence of record demonstrates that Becton-
`Dickinson factors (a), (b), and (d) have not been satisfied, our analysis ends
`at this point, and we need not proceed to step two of the Advanced Bionics
`framework. See Advanced Bionics, IPR2019-01469, Paper 6 at 8. We
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`consequently decline to exercise our discretion to deny institution of
`Grounds I and IV. Furthermore, because, for the reasons we shall explain,
`we institute trial on at least one of the challenged claims, we similarly
`decline to exercise our discretion to deny institution on the remaining
`Grounds II, III, and V. See SAS Institute, Inc. v. Iancu, 138 S.Ct. 1348,
`1354–55 (2018) (holding that, when inter partes review is instituted, the
`Board shall issue a final written decision with respect to the patentability of
`any patent claim challenged by the petitioner).
`
`D. Grounds I and II: Alleged Anticipation of Claims 1 and 9-12 by Dixon
`or Heier 2009
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`1. Overview of Dixon
`
`Dixon was published in October, 2009, and is prior art to the ’069
`
`patent. Ex. 1006, 9. Dixon discloses that a new drug for the treatment of
`age-related macular degeneration (“AMD”) is aflibercept (“VEGF
`Trap-Eye”), a fusion protein that blocks all isoforms of VEGF-A and
`placental growth factors-1 and -2. Id. Abstr. Dixon discloses that VEGF
`Trap-Eye is a novel anti-VEGF therapy, with Phase I and II trial data
`indicating safety, tolerability and efficacy for the treatment of neovascular
`AMD. Id.
`
`Relevantly, Dixon discloses that, structurally, VEGF Trap-Eye is a
`fusion protein of key binding domains of human VEGFR-1 and -2 combined
`with a human IgG Fe fragment. Ex. 1006, 3, Fig. 1. Dixon also discloses
`the CLEAR-IT-1, CLEAR-IT-2, and VIEW1/VIEW2 clinical trials.
`(Ex. 1006, 3–4, Ex. 1002 ¶ 74). Dixon identifies “[d]esirable attributes for
`emerging therapies for neovascular AMD include higher visual
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`improvement rates and decreased dosing intervals” as a motivation for the
`“development of new drugs for neovascular AMD . . . focused on both
`improving efficacy and extending duration of action,” Ex.1006, 2, 5;
`Ex.1002 ¶ 78.
`
`Dixon further discloses results from the phase II clinical trial CLEAR-
`IT-2, which included four monthly doses (at weeks 0, 4, 8 and 12) followed
`by PRN administration. Id., 1576. Dixon reports that CLEAR-IT-2 subjects
`treated with that regimen exhibited mean improvement in visual acuity of
`nine letters and a mean decrease in retinal thickness of 143 μm. Id.; Ex.
`1002 ¶¶ 79–80. Dixon further reports that “patients dosed at 2.0 mg during
`the initial monthly dosing period required 1.6 injections on average during
`the p.r.n. dosing phase.” (Ex. 1006, 5). Dixon discloses that, in the CLEAR-
`IT-2 trial:
`Two groups received monthly doses of either 0.5 or 2.0 mg for
`12 weeks (at weeks 0, 4, 8 and 12) and three groups received
`quarterly doses of either 0.5, 2.0 or 4.0 mg for 12 weeks (at weeks
`0 and 12). Following this fixed dosing period, patients were
`treated with the same dose of VEGF Trap-Eye on a p.r.n. basis.
`Criteria for re-dosing included an increase in central retinal
`thickness of ≥ 100 μm by OCT, a loss of ≥ 5 ETDRS letters in
`conjunction with recurrent fluid by OCT, persistent fluid as
`indicated by OCT, new onset classic neovascularization, new or
`persistent leak on FA or new macular subretinal hemorrhage.
`
`Id. at 4. Dixon also discloses that “[p]atients initially treated with 2.0 or 0.5
`mg of VEGF TrapEye monthly achieved mean improvements of 9.0 (p <
`0.0001) and 5.4 (p < 0.085) ETDRS letters with 29 and 19% gaining,
`respectively, ≥ 15 ETDRS letters at 52 weeks.” Id.
`
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`Dixon also describes the then-ongoing VIEW 1 and VIEW 2 phase III
`
`clinical trials. Ex. 1006, 4. Dixon discloses that, with respect to the VIEW
`1 trial:
`This non-inferiority study will evaluate the safety and efficacy of
`intravitreal VEGF Trap-Eye at doses of 0.5 and 2.0 mg
`administered at 4-week dosing intervals and 2.0 mg at an 8 week
`dosing interval (following three monthly doses), compared with
`0.5 mg of ranibizumab administered every 4 weeks. After the
`first year of the study, patients will enter a second year of p.r.n.
`dosing evaluation. The VIEW 2 study has a similar study
`design….
`
`Id. (internal citations omitted).
`
`Overview of Heier 2009
`2.
`
`Heier 2009 was published in October, 2009, and is prior art to the
`
`’069 patent. Ex. 1020, 1. As in Dixon, Heier 2009 describes the CLEAR-IT
`2 trial, a phase 2 study of the safety and efficacy of VEGF Trap-Eye in
`patients with neovascular age-related macular degeneration (AMD). Id.
`
`Heier 2009 discloses that:
`VEGF Trap-Eye is a purified formulation of VEGF Trap, a
`vascular endothelial growth factor (VEGF) receptor fusion
`protein that binds all forms of VEGF-A. VEGF Trap-Eye,
`formulated for intraocular use, is being developed for the
`treatment of neovascular AMD, diabetic macular edema, and
`other ocular pathologies.
`
`Ex. 1020, 1–2 (internal reference omitted).
`With respect to the CLEAR-IT 2 trial, Heier 2009 relates that:
`CLEAR-IT 2 was a double-masked multicenter trial in which
`patients with neovascular AMD were randomly assigned to
`receive monthly intravitreal injections of VEGF Trap-Eye 0.5
`16
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`mg or 2.0 mg or quarterly injections of 0.5, 2.0 or 4.0 mg for an
`initial 3-month fixed-dose period, after which they received the
`same doses on an as needed basis at monthly visits out to 1 year.
`
`Ex. 1020, 2. Heier 2009 further discloses that:
`At 1 year, for all treated groups combined (n=157), there was a
`significant
`improvement in BCVA from baseline (mean
`improvement 5.3 letters; P<.0001). Patients who received three
`monthly doses of 2.0 mg followed by as-needed dosing achieved
`mean improvements in BCVA of 9.0 letters from baseline
`(P<.0001 vs baseline).
`….
`Patients receiving initial monthly doses of VEGF Trap-Eye
`achieved mean decreases in retinal thickness vs baseline at 1
`year. In addition, treatment with VEGF Trap-Eye was associated
`with a reduction in the size of the total active choroidal
`neovascular membrane (CNV).
`
`Id. at 2.
`
`
`3. Anticipation of claims 1 and 9–12 by Dixon (Ground I) and
`Heier 2009 (Ground II).
`
`
`
`
`
`a. Petitioner’s contentions
`
`i.
`Claim 1
`Petitioner argues that the disclosures of Dixon and Heier 2009 both
`anticipate each of the limitations of independent claim 1 and dependent
`claims 9–12. Pet. 26–33. Petitioner has provided a claim chart of the
`limitations of claim 1, and what it contends are the corresponding
`disclosures of each reference, which, for convenience, is reproduced below:
`
`
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`1. A method for treating|“The CLEAR-IT 2 trial|“VEGF Trap-Eye1s a novel
`all angiogenic eye
`was a phase 2 study of
`anti-VEGF therapy. with
`disorder in a patient
`the safety and efficacy
`Phase I and Phase II trial
`of VEGFTrap-
`data indicating safety,
`Eye... in patients with
`tolerability and efficacy for
`[AMD].” (Ex.1020,
`the treatment of [AMD].”
`Heier-2009, 44).
`(Ex.1006, Dixon, 1573: id..
`1575).
`
`year.” (Jd., 1577).
`
`Phase 2? patients “treated
`with 2.0 mg or 0.5 mg of
`VEGFTrap-Eye monthly
`achieved mean
`improvements of 9.0
`(p<0.0001) and 5.4
`(p<0.085) ETDRSletters.”
`(Id_. 1576).
`
`“Phase I data demonstrated
`acceptable safety and.
`tolerability of VEGF Trap-
`Eye in the treatment of
`neovascular AMD.” (Id..
`1577).
`
`“At l year... there
`was a significant
`improvement in BCVA
`from baseline...”
`(ld., 45).
`
`“Patients who received
`three monthly doses of
`2.0 mg followed by as-
`needed dosing achieved
`mean improvements in
`BCVAof9.0 letters
`from baseline.” (Jd_).
`
`(Ex.1002, Albini,
`©€ 116, 120).
`
`“(Patients .. . demonstrated
`stabilization of their vision
`that was similar to previous
`studies of ranibizumab at 1
`
`
`
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`18
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`Heier-2009:
`
`said method comprising
`sequentially
`administering to the
`patient a single initial
`dose of a VEGF
`antagonist, followed by
`one of more secondary
`doses of the VEGF
`antagonist, followed by
`one of more tertiary
`doses of the VEGF
`antagonist:
`
`(Ex.1002, Albini, 9 116,
`120).
`
`“Two groups received
`monthly doses of ether 0.5
`or 2.0 mg for 12 weeks (at
`weeks 0,4.8 and 12). ._..
`Following this fixed dosing
`period, patients were treated
`with the same dose of
`VEGF Trap-Eye on a pn
`basis.” (Ex.1006, Dixon,
`1576).*6
`
`(Ex.1002, Albini, 9 121-
`123).
`
`
`
`
`
`
`“Patients with
`neovascular AMD were
`tandomly assigned to
`receive monthly
`intravitreal injections
`of VEGF Trap-Eye 0.5
`mgor?.0 mg... for an
`initial 3-month fixed-
`dose period, after
`which they received the
`same doses on [a PRN]
`basis at monthly visits
`out to 1 year.”
`(Ex.1020, Heier-2009-_
`45).
`
`23).
`
`(Ex.1002. Albini.
`©© 121-23).
`
`wherein each secondary
`dose is administered 2
`to 4 weeks after the
`immediately preceding
`dose: and
`
`(Ex.1020, Heter-2009_
`45).
`
`(Ex.1002, Albini,
`121-23).
`
`(Ex.1006, Dixon, 1576).
`
`(Ex.1002, Albini, 99 121-
`
`
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`wherein each tertiary (Ex.1020, Heier-2009,|“Following this fixed
`
`
`dose is administered on|45). dosing period_ patients were
`an as-needed/pro re
`treated with the same dose
`
`nata (PRN) basis, based|(Ex.1002, Albina. of VEGF Trap-Eye on a
`on visual and/or
`7 121-23).
`pan. basis. Criteria for re-
`anatomical outcomes as
`dosing included an increase
`assessed by a physician
`in central retinal
`or other qualified
`thickness... aloss of = 5
`medical professional;
`ETDRSletters in
`conjunction with recurrent
`fluid by OCT, persistent
`fluid as indicated by OCT,
`new onset classic
`neovascularization, new or
`persistent leak on FA or
`new macular subretinal
`hemorrhage.” (Ex.1006,
`Dixon, 1576).
`
`product) have the same
`
`wherein the VEGF “VEGF Trap-Eyeisa|VEGF Trap-Eye 1s “a
`
`antagonist 1s a receptor-|purified formulation of|fusion protein of binding
`based chimeric VEGFTrap. a vascular|domains of VEGF
`
`molecule comprising
`endothelial growth
`receptors-1 and -? attached
`
`(1) a VEGFR1 factor (VEGF) receptor|to the Fc fragment of human
`
`component comprising|fusion protein that IgG.” (Jd., 1576 (Fig.1)).
`amino acids 27 to 129|binds all forms of
`of SEQ ID NO:2: (2)a_| VEGF-A.” (Ex.1020,|“VEGF Trap-Eye and
`VEGFR2 component
`Heier-2009, 44-45
`aflibercept (the oncology
`comprising amuno acids|(Fig.1)).!"
`
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`Pet. 46–49.
`
`
`
`
`Claims 9 and 10
`ii.
`
`Claim 9 is exemplary and recites:
`The method of claim 1, wherein the angiogenic eye
`9.
`disorder is selected from the group consisting of: age related
`macular degeneration, diabetic retinopathy, diabetic macular
`edema, central retinal vein occlusion, branch retinal vein
`occlusion, and corneal neovascularization.
`Ex. 1001 col. 22, ll. 53–57. Petitioner argues that Dixon discloses the
`employing the PRN regimen and results of CLEAR-IT 2 (Phase 2) in the
`treatment of AMD. Pet. 49 (citing Ex. 1006, 1, 4, 7). Similarly, Petitioner
`contends, Heier 2009 discloses CLEAR-IT-2 data confirming that the trial’s
`PRN regimen was successful at treating AMD. Id. (citing Ex. 1020, 2).
`Dixon similarly discloses the PRN regimen and results of CLEAR-IT-2
`(Phase 2) to treat AMD. (Ex. 1006, Dixon, 1573, 1576, 1579).
`
`
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`iii. Claim 11
`
`Dependent claim 11 recites:
`11. The method of claim 1, wherein all doses of the VEGF
`antagonist are administered
`to
`the patient by
`topical
`administration or by intraocular administration.
`
`Ex. 1001 col. 22, ll. 60–62.
`Petitioner contends that “intraocular administration” refers to
`administration to the eye generally, whereas intravitreal administration, a
`subset of intraocular administration, refers to administration directly into the
`vit
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