Filed on behalf of: Celltrion, Inc.
`By: Lora M. Green (lgreen@wsgr.com)
`
`Yahn-Lin Chu (ychu@wsgr.com)
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________________
`
`
`CELLTRION, INC.,
`Petitioner,
`
`v.
`
`REGENERON PHARMACEUTICALS, INC.,
`Patent Owner.
`
`_____________________________
`
`Case No. IPR2022-00258
`Patent No. 9,254,338
`
`_____________________________
`
`
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 9,254,338
`
`
`
`

`

`
`
`
`
`TABLE OF CONTENTS
`
`Page
`
`Introduction ...................................................................................................... 1 
`I. 
`II.  Mandatory Notices (37 C.F.R. § 42.8) ............................................................ 3 
`A. 
`Real-Parties-in-Interest (37 C.F.R. § 42.8(b)(1)) .................................. 3 
`B. 
`Related Matters (37 C.F.R. § 42.8(b)(2)) .............................................. 3 
`C. 
`Lead and Back-Up Counsel and Service Information (37 C.F.R.
`§ 42.8(b)(3), (4)) .................................................................................... 4 
`Payment of Fees Under 37 C.F.R. § 42.15(a) and § 42.103 ........................... 5 
`III. 
`IV.  Grounds for Standing (37 C.F.R. § 42.104(a)) ................................................ 5 
`V. 
`Threshold Requirement for Inter Partes Review ............................................ 5 
`VI.  Overview of Challenge and Precise Relief Requested .................................... 6 
`A. 
`Challenged Claims ................................................................................ 6 
`B. 
`Statutory Grounds of Challenge ............................................................ 6 
`VII.  Overview of the ’338 Patent ............................................................................ 7 
`A. 
`The ’338 Patent ..................................................................................... 7 
`B. 
`European Equivalent, EP-325 ............................................................. 10 
`VIII.  Claim Construction (37 C.F.R. § 42.204(b)(3)) ............................................ 11 
`A. 
`“Initial Dose,” “Secondary Dose,” and “Tertiary Dose” .................... 12 
`1. 
`Regeneron’s contradictory construction for “tertiary
`dose,” if presented here, must be rejected. ............................... 13 
`“4 Weeks” and “8 Weeks” After the Immediately Preceding
`Dose ..................................................................................................... 16 
`
`B. 
`
`-i-
`
`

`

`C. 
`
`
`
`D. 
`
`“VEGFR1 Component,” “VEGFR2 Component,” and the
`“Multimerization Component.” ........................................................... 17 
`“Treating” ............................................................................................ 17 
`1. 
`The “method for treating” element of the preamble is not
`a limitation on the Challenged Claims, and therefore,
`does not require construction .................................................... 17 
`Regeneron’s anticipated argument that the “method for
`treating” preamble is a positive limitation should be
`rejected ...................................................................................... 19 
`If construed to be a limitation, the preamble’s plain and
`ordinary meaning—which does not provide any specific
`efficacy requirement—must govern ......................................... 21 
`IX.  Person of Ordinary Skill in the Art ................................................................ 22 
`X. 
`The Scope and Content of the Prior Art ........................................................ 23 
`A.  VEGF Trap-Eye/aflibercept Background ........................................... 23 
`B. 
`Petitioner’s Prior Art References ........................................................ 26 
`1. 
`Dixon (EX1006) ........................................................................ 27 
`2. 
`Adis (EX1007) .......................................................................... 30 
`3. 
`Regeneron (8-May-2008) (EX1013) ........................................ 31 
`4. 
`NCT-795 (EX1014) .................................................................. 32 
`5. 
`NCT-377 (EX1015) .................................................................. 35 
`6. 
`The ’758 Patent (EX1010) ........................................................ 36 
`7. 
`Dix (EX1033) ............................................................................ 37 
`XI.  Grounds for Unpatentability – Detailed Analysis ......................................... 37 
`A.  Anticipation ......................................................................................... 37 
`1. 
`Legal Standards ......................................................................... 38 
`
`2. 
`
`3. 
`
`-ii-
`
`

`

`5. 
`
`B. 
`
`2. 
`3. 
`4. 
`
`
`Ground 1: Dixon Anticipates the Challenged Claims .............. 39 
`Ground 2: Adis Anticipates the Challenged Claims ................. 45 
`Ground 3: Regeneron (8-May-2008) anticipates the
`Challenged Claims .................................................................... 50 
`Grounds 4 and 5: NCT-795 and NCT-377 each anticipate
`the Challenged Claims .............................................................. 55 
`Obviousness ......................................................................................... 62 
`1. 
`Legal Standard .......................................................................... 62 
`2. 
`Ground 6: The Challenged Claims are obvious over
`Dixon (either alone or in combination with the ’758
`patent or Dix) ............................................................................ 63 
`No Secondary Considerations ................................................... 67 
`3. 
`XII.  Conclusion ..................................................................................................... 70 
`XIII.  Certificate of Compliance .............................................................................. 71 
`XIV.  Payment of Fees under 37 C.F.R. §§ 42.15(a) and 42.103 ........................... 72 
`XV.  Appendix – List of Exhibits ........................................................................... 73 
`
`
`
`
`
`-iii-
`
`

`

`
`
`Celltrion, Inc. (“Petitioner”) petitions for inter partes review (“IPR”) under
`
`35 U.S.C. §§ 311-319 and 37 C.F.R. §§ 42 et seq., seeking cancellation of claims
`
`1, 3-11, 13-14, 16-24, and 26 (the “Challenged Claims”) of U.S. Patent No.
`
`9,254,338 (“’338 patent”) (EX1001), currently assigned to Regeneron
`
`Pharmaceuticals, Inc. (“Regeneron” or “Patent Owner”).
`
`I.
`
`INTRODUCTION
`
`The Challenged Claims should have never issued. They are drawn to “VEGF
`
`Trap-Eye” dosing regimens known to persons of ordinary skill in the art (hereafter,
`
`“skilled artisans”) long before the patent’s alleged 2011 priority date. Regeneron’s
`
`age-related macular degeneration (“AMD”) clinical trials (VIEW1/VIEW2) with
`
`EYLEA® (a/k/a VEGF Trap-Eye or aflibercept) were designed to use the precise
`
`dosing regimens now covered by the Challenged Claims. The problem: Regeneron
`
`publicly disclosed these exact dosing regimens to skilled artisans as early as 2008,
`
`three years prior to filing its patent application. Regeneron then withheld those
`
`publications from the Examiner, allowing the ’338 patent to issue. For at least these
`
`reasons, the Challenged Claims are unpatentable.
`
`Petitioner thus files this Petition, supported by expert declarations from Dr.
`
`Thomas Albini—a renowned ophthalmologist (EX1002), and Dr. Mary Gerritsen—
`
`a pharmacologist with over thirty years’ experience (EX1003).
`
`-1-
`
`

`

`
`
`Anticipation. Each Challenged Claim is anticipated. VEGF Trap-Eye was a
`
`known blocker of vascular endothelial growth factor (“VEGF”) independently
`
`disclosed in the scientific literature, (see EX1004, Holash; EX1005, Nguyen-2009;
`
`EX1006, Dixon; EX1007, Adis) and patented (see EX1008, ’173 patent; EX1009,
`
`’664 patent; EX1010, ’758 patent) well before the alleged priority date.
`
`At least two VEGF Trap-Eye clinical trials—“VIEW1” and “VIEW2” and the
`
`dosing regimens used therein—were widely published in numerous, fully-enabled
`
`prior art references, by Regeneron and others, years before the alleged priority date.
`
`These publications disclosed all of the elements of the dosing regimen(s) claimed in
`
`the ’338 patent—including administering three monthly loading doses of VEGF
`
`Trap-Eye, followed by additional bi-monthly doses—and were published in
`
`numerous, fully-enabled prior art references.
`
`Obviousness. The claimed methods also would have been obvious. VEGF
`
`Trap-Eye nucleotide and amino acid sequences were patented and widely disclosed
`
`to skilled artisans. The prior art further demonstrates the frequency and financial
`
`burden of monthly intravitreal injections—recognized concerns with traditional
`
`dosing regimens for angiogenic eye disorders (EX1006, Dixon, 1574), motivating
`
`the skilled artisan to pursue less frequent dosing schedules compared to the monthly
`
`dosing often used for other anti-VEGF therapeutics. Regeneron itself (among
`
`others) placed into the public domain—as early as 2008—one such dosing regimen.
`
`-2-
`
`

`

`
`
`See, e.g., EX1006, Dixon, 5; EX1007, Adis, 268; EX1014, NCT-795; EX1015,
`
`NCT-377; EX1013, Regeneron (8-May-2008). Combined with the abundance of
`
`positive, prior art data from Regeneron’s clinical trials, a skilled artisan would have
`
`reasonably expected success at treating angiogenic eye disorders with the claimed
`
`dosing regimens.
`
`II. MANDATORY NOTICES (37 C.F.R. § 42.8)
`
`Pursuant to 37 C.F.R. §§ 42.8(a)(1) and 42.8(b), the following mandatory
`
`notices are provided as part of this Petition.
`
`A. Real-Parties-in-Interest (37 C.F.R. § 42.8(b)(1))
`
`Petitioner identifies the following real parties-in-interest: Celltrion, Inc.;
`
`Celltrion Healthcare Co. Ltd.; and Celltrion Healthcare U.S.A., Inc.
`
`B. Related Matters (37 C.F.R. § 42.8(b)(2))
`
`The ’338 patent is currently being challenged in Mylan Pharms. Inc. v.
`
`Regeneron Pharms., Inc., IPR2021-00881 (P.T.A.B.), instituted on November 10,
`
`2021. This petition is concurrently filed with Celltrion, Inc. v. Regeneron Pharms.,
`
`Inc., IPR2021-00257 (P.T.A.B.), challenging U.S. Patent No. 9,669,069 (“’069
`
`patent”). The ’069 patent is currently being challenged in Mylan Pharms. Inc. v.
`
`Regeneron Pharms., Inc., IPR2021-00880 (P.T.A.B.), instituted on November 10,
`
`2021. To the best of Petitioner’s knowledge, there are no other judicial or
`
`administrative matters that would affect, or be affected by, a decision in this
`
`-3-
`
`

`

`
`
`proceeding; nonetheless, out of an abundance of caution, Petitioner further
`
`identifies Chengdu Kanghong Biotechnology Co. v. Regeneron Pharms., Inc., Case
`
`No. PGR2021-00035 (P.T.A.B.).
`
`U.S. Patent Nos. 9,669,069 B2, 10,130,681 B2, 10,857,205 B2, 10,828,345
`
`B2, and 10,888,601 B2; and U.S. Patent Application Nos. 17/072,417, 17/112,063,
`
`and 17/112,404 claim the benefit of the ’338 patent filing date.
`
`C. Lead and Back-Up Counsel and Service Information (37 C.F.R. §
`42.8(b)(3), (4))
`
`Lead Counsel:
`
`Lora M. Green (Reg. No. 43,541)
`
`Back-Up Counsel: Yahn-Lin Chu (Reg. No. 75,946)
`
`
`
`
`
`
`
`
`
`
`
`
`
`Robert Cerwinski (to be admitted pro hac vice)
`
`Aviv Zalcenstein (to be admitted pro hac vice)
`
`Brigid Morris (to be admitted pro hac vice)
`
`
`
`Petitioner hereby consents to electronic service. Please direct all
`
`correspondence to lead and back-up counsel at the contact information below. A
`
`power of attorney accompanies this petition.
`
`Email: lgreen@wsgr.com; ychu@wsgr.com; rcerwinski@geminilaw.com;
`
`azalcenstein@geminilaw.com; bmorris@geminilaw.com
`
`Post: WILSON SONSINI GOODRICH & ROSATI, 1700 K Street NW
`
`5th Floor Washington, DC 20006
`
`Tel.: 202-791-8012
`
`-4-
`
`

`

`
`
`III. PAYMENT OF FEES UNDER 37 C.F.R. § 42.15(A) AND § 42.103
`
`The required fees are submitted herewith. If any additional fees are due at
`
`any time during this proceeding, the Office is authorized to charge such fees to
`
`Deposit Account No. 23-2415.
`
`IV. GROUNDS FOR STANDING (37 C.F.R. § 42.104(A))
`
`Petitioner certifies that the ’338 patent—which issued on February 9, 2016—
`
`is available for IPR and that Petitioner is not barred or estopped from requesting an
`
`IPR challenging any claim thereof on the grounds identified herein. Neither
`
`Petitioner nor any other real-party-in-interest has filed a civil action challenging
`
`the validity, or been served with a complaint alleging infringement, of the ’338
`
`patent, more than one year prior to the filing of this Petition. See Motorola Mobility
`
`LLC v. Arnouse, No. IPR2013-00010, 2013 WL 12349001, *3 (P.T.A.B. Jan. 30,
`
`2013).
`
`V. THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW
`
`This Petition meets and exceeds the threshold required under 35 U.S.C.
`
`§ 314(a). As explained below, for each ground, there is a reasonable likelihood that
`
`Petitioner will prevail with respect to at least one of the Challenged Claims.
`
`-5-
`
`

`

`
`
`VI. OVERVIEW OF CHALLENGE AND PRECISE RELIEF REQUESTED
`A. Challenged Claims
`
`Petitioner requests IPR of claims 1, 3-11, 13-14, 16-24, and 26 of the ’338
`
`patent, and cancellation of these claims as unpatentable.
`
`B.
`
`Statutory Grounds of Challenge
`
`Each of the following prior art references anticipate the Challenged Claims:
`
`Ground Proposed Rejections Under 35 U.S.C. § 102
`
`1
`
`2
`
`3
`
`4
`
`5
`
`Dixon
`
`Adis
`
`Regeneron (8-May-2008)
`
`NCT-795
`
`NCT-377
`
`
`In addition, at least the following render the Challenged Claims obvious:
`
`Ground Proposed Rejections Under 35 U.S.C. § 103
`
`6
`
`Dixon alone or in view of the ’758 patent and/or Dix
`
`
`
`-6-
`
`

`

`
`
`Petitioner’s full statement of reasons for the relief requested is set forth in
`
`greater detail below, and in the supporting declarations of Drs. Albini and
`
`Gerritsen.
`
`VII. OVERVIEW OF THE ’338 PATENT
`A. The ’338 Patent1
`
`The ’338 patent confirms that angiogenic eye disorders, such as AMD,
`
`diabetic macular edema (“DME”), and retinal vein occlusion (“RVO”) were known
`
`to be effectively treated through vascular endothelial growth factor (“VEGF”)2
`
`inhibition. EX1001, ’338 patent, 1:24-52. Indeed, prior to the ’338 patent priority
`
`
`1 Solely for purposes of this IPR, Petitioner assumes a January 13, 2011 priority
`
`date. However, Petitioner reserves all rights to challenge the extent to which
`
`Regeneron asserts application of pre-AIA standards of patentability. The ’338
`
`patent is subject to the AIA given the inclusion of new matter in the Continuation-
`
`In-Part Application No. 13/940,370, filed July 12, 2013.
`
`2 Vascular endothelial growth factor (VEGF) is a “naturally occurring
`
`glycoprotein in the body that acts as a growth factor for endothelial cells.”
`
`EX1011, Semeraro, 711. Early research linked activity of VEGF-A to the
`
`development of ocular diseases such as neovascular AMD. EX1043, Brown, 627-
`
`28.
`
`-7-
`
`

`

`
`
`date, ranibizumab (LUCENTIS®), an anti-VEGF antibody fragment marketed by
`
`Genentech, was FDA-approved for monthly administration via intravitreal injection
`
`to treat angiogenic eye disorders, including AMD. Id., 1:49-52; see also EX1048,
`
`Lucentis, 1. The ’338 patent asserts a need in the art for regimens that allow less
`
`frequent dosing. EX1001, ’338 patent, 1:53-59.
`
`The ’338 patent broadly claims dosing regimens for treating angiogenic eye
`
`disorders, including AMD, via: (1) administering a single initial dose of a VEGF
`
`antagonist (VEGF Trap-Eye), followed by (2) one or more “secondary doses”
`
`administered two to four weeks after the immediately preceding dose, followed (3)
`
`by one or more “tertiary doses” administered at least eight weeks apart. See, e.g.,
`
`id., 23:2-18 (Claim 1). The ’338 patent also specifically claims the prior art
`
`VIEW1/VIEW2 regimen, which eventually became the FDA-approved regimen for
`
`EYLEA® (i.e., VEGF Trap-Eye/aflibercept):
`
`[A] single initial dose of a VEGF antagonist is administered to a
`
`patient on the first day of the treatment regimen (i.e., at week 0),
`
`followed by two secondary doses, each administered four weeks after
`
`the immediately preceding dose (i.e., at week 4 and at week 8),
`
`followed by at least 5 tertiary doses, each administered eight weeks
`
`after the immediately preceding dose (i.e., at weeks 16, 24, 32, 40 and
`
`48).
`
`-8-
`
`

`

`
`
`Id., 3:57-64; id., 23:23-28, 24:20-25. This VIEW1/VIEW2 dosing regimen is
`
`described as “an exemplary dosing regimen of the present invention” and is depicted
`
`graphically by Figure 1 of the ’338 patent:
`
`
`
`Id., (Fig.1); see also id., 3:66-67; id., 2:54-60. Figure 1 illustrates and exemplifies
`
`a dosing regimen falling within the Challenged Claims.
`
`During prosecution, Regeneron argued, in response to double-patenting
`
`rejections, the (then-pending) Challenged Claims were patentably distinct from its
`
`Monthly-Dosing Patents3 on the ground that those prior patents did not disclose the
`
`exact regimen specified in the pending claims. EX1017, ’338 FH, 9/11/2015
`
`Response, 6. Regeneron further argued once-per-month dosing represented the
`
`
`3 Regeneron’s “Monthly-Dosing Patents” refers to U.S. Patent Nos. 7,303,746;
`
`7,303,747; 7,306,799; and 7,521,049; which generally disclose doses separated by
`
`at least two weeks. EX1016, Monthly-Dosing Patents; EX1017, ’338 FH, 6/23/15
`
`Office Action, 5-9.
`
`-9-
`
`

`

`
`
`standard of care and that the Challenged Claims were distinct because an infinite
`
`number of other treatment protocols could have been considered. Id., 6-9; EX1018,
`
`Heier-2012, 2537.
`
`Regeneron notably told the Examiner that Example 5 “illustrates an
`
`administration regimen encompassed by [issued claims 1 and 14] (i.e., 3 initial doses
`
`of VEGF Trap administered once every four weeks, followed by additional doses
`
`administered once every 8 weeks) for the effective treatment of diabetic macular
`
`edema (DME).” See EX1017, ’338 FH, 9/11/2015 Response, 8. One Example 5
`
`dosing regimen is identical to the VIEW1/VIEW2 regimen for AMD that was
`
`publicly disclosed years before the ’338 patent filing.
`
`B.
`
`European Equivalent, EP-325
`
`EP-325 (EX1062)—Regeneron’s then co-pending equivalent—included
`
`claims identical in scope to the Challenged Claims; however, EP-325 never issued
`
`and was abandoned. Compare EP-325, Claims 1 and 11 (EX1063, EP-325-FH,
`
`1/23/2012 Original Application, 19-22), with ’338 patent, Claim 1 (EX1001, ’338
`
`patent, 23:2-18); compare EP-325 Claim 31 (EX1062, 21 (identifying the “VEGF
`
`receptor-based chimeric molecule” by its amino acid sequence), with ’338 patent,
`
`Claim 14 (EX1001, ’338 patent, 24:3-15 (same)). The EPO Examiner rejected the
`
`EP-325 claims for, inter alia, lacking novelty/inventive step over several prior art
`
`references, including those disclosing aflibercept (i.e., VEGF Trap-Eye) as an anti-
`
`-10-
`
`

`

`
`
`angiogenesis agent (e.g., Wiegand (EX1084)); prior art ranibizumab
`
`(LUCENTIS®) dosing regimens (e.g., Shams (EX1085)); and prior art VEGF
`
`Trap-Eye dosing regimens (e.g., Regeneron Sept. 28, 2008 Press Release
`
`(EX1056)). See EX1063, EP-325-FH, 8/21/2014 Communication, 3-8.
`
`Regeneron tried narrowing the EP-325 claims to avoid the rejections (id.,
`
`12/17/2014 Amendment, 19); but the EPO Examiner—as well as third party
`
`observers—responded with additional prior art, including, inter alia Regeneron
`
`Press Releases, a 2008 conference slide presentation, a VIEW2 record from
`
`ClinicalTrials.gov, and Dixon (EX1006). Id., 9/5/2016 Observations, 2-8; id.,
`
`9/7/2016 Observations, 2-8; id., 1/3/2017 Communication, 1-8. Consequently,
`
`Regeneron abandoned EP-325. Id., 6/5/2017 Withdrawal.
`
`Regeneron never cited the EP-325 prior art references discussed above to the
`
`’338 patent Examiner.
`
`VIII. CLAIM CONSTRUCTION (37 C.F.R. § 42.204(B)(3))
`
`In accordance with 37 C.F.R. § 42.100(b), the Challenged Claims must be
`
`“construed using the same claim construction standard that would be used to
`
`construe the claim in a civil action under 35 U.S.C. § 282(b),” i.e., the Phillips
`
`standard. 83 Fed. Reg. 197, 51340-51359 (Oct. 11, 2018); Phillips v. AWH Corp.,
`
`415 F.3d 1303, 1312 (Fed. Cir. 2005). Petitioner and expert declarant, Dr. Albini,
`
`have applied this standard.
`
`-11-
`
`

`

`
`
`A.
`
`“Initial Dose,” “Secondary Dose,” and “Tertiary Dose”
`
`The Challenged Claims recite the phrases “initial dose,” “secondary dose,”
`
`and “tertiary dose.” A skilled artisan would understand each as expressly defined in
`
`the ’338 patent specification:
`
`
`EX1001, ’338 patent, 3:31-45 (emphasis added); EX1002, Albini ¶41. The
`
`
`
`specification further explains that “the immediately preceding dose” means “in a
`
`sequence of multiple administrations, the dose of VEGF antagonist which is
`
`administered to a patient prior to the administration of the very next dose in the
`
`sequence with no intervening doses.” EX1001, ’338 patent, 3:51-56; EX1002,
`
`Albini ¶41. Petitioner proposes that each claim term be construed consistent with
`
`these express definitions: “initial dose” means “the dose which is administered at the
`
`beginning of the treatment regimen”; “secondary dose(s)” means “the dose(s) which
`
`-12-
`
`

`

`
`
`are administered after the initial dose”; and “tertiary dose(s)” means “the dose(s)
`
`which are administered after the secondary dose(s).”
`
`1.
`
`Regeneron’s contradictory construction for “tertiary dose,”
`if presented here, must be rejected.
`To the extent Regeneron proposes a construction for “tertiary dose” that is
`
`consistent with its proposal in the ’345 Patent PGR—i.e., as “dose(s) that maintain(s)
`
`a therapeutic effect throughout the course of treatment,” (PO’s Preliminary
`
`Response, Chengdu Kanghong Biotechnology Co. v. Regeneron Pharms., Inc., No.
`
`PGR2021-00035, 9 (P.T.A.B. Apr. 15, 2021) (“’345 Patent PGR”)—it should be
`
`rejected for at least the following reasons.
`
`First and foremost, as described above, the ’338 patent specification recites
`
`an express definition that provides the patentees’ intended meaning to the claims:
`
`“the ‘tertiary doses’ are the doses which are administered after the secondary doses.”
`
`EX1001, ’338 patent, 3:36-38. The claim term is “set off by quotation marks,”
`
`which “[is] often a strong indication that what follows is a definition” and “the
`
`patentee must be bound by the express definition.” Sinorgchem Co., Shandong v.
`
`Int’l Trade Comm’n, 511 F.3d 1132, 1136 (Fed. Cir. 2007). In other words, the
`
`express definition of “tertiary dose” is “clearly, deliberately, and precisely defined,”
`
`id., in the ’338 patent—nothing more is needed to understand the term and there is
`
`no basis for straying from that express definition.
`
`-13-
`
`

`

`
`
`Second, Regeneron’s proposed construction is unsupported and the intrinsic
`
`record does not suggest reading-in limitations. Phillips, 415 F.3d at 1323 (affirming
`
`the general prohibition against reading limitations from the specification into the
`
`claims). For example, Regeneron relies exclusively on column 2 as purported
`
`support for its narrowed construction (’345 Patent PGR, 11), but that specification
`
`passage only describes a single embodiment, i.e., bi-monthly dosing.4 By
`
`comparison, the express definition recited in the specification (i.e., “doses which are
`
`
`4 Regeneron’s proposed construction for “tertiary doses” also is in conflict with
`
`the plain language of the ’338 patent claims, which require “tertiary doses”
`
`administered “at least 8 weeks after the immediately preceding dose” irrespective
`
`of whether the injection “maintain[s] a therapeutic effect.” See EX1001, ’338
`
`patent, claims 1, 17. Consequently, the ’338 patent—which derives from the same
`
`parent application as the Chengdu-challenged ’345 Patent—would improperly
`
`require a different construction of “tertiary dose” for those claims to have meaning,
`
`further illustrating the extent to which Regeneron’s proposed construction, if
`
`presented in this IPR, would inject indefiniteness into the claims. Samsung Elecs.
`
`Co. v. Elm 3DS Innovations, LLC, 925 F.3d 1373, 1378 (Fed. Cir. 2019) (“Where
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`multiple patents derive from the same parent application and share many common
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`terms, we must interpret the claims consistently across all asserted patents.”).
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`-14-
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`
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`administered after the secondary doses”) provides the exact temporal and sequential
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`distinction from the other doses in the regimen that the patent drafters envisioned for
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`all claimed dosing regimens. EX1001, ’338 patent, 3:31-38 (“The terms … refer to
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`the temporal sequence of administration.”); Merck & Co. v. Teva Pharms. USA,
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`Inc., 395 F.3d 1364, 1372 (Fed. Cir. 2005) (“A claim construction that gives
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`meaning to all the terms of the claim is preferred over one that does not do so.”). No
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`further construction is necessary. Multiform Desiccants, Inc. v. Medzam, Ltd., 133
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`F.3d 1473, 1478 (Fed. Cir. 1998) (“When the specification explains and defines a
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`term used in the claims, without ambiguity or incompleteness, there is no need to
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`search further for the meaning of the term.”).
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`Third, Regeneron’s proposal improperly injects ambiguity and indefiniteness
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`where there is none. Ruckus Wireless, Inc. v. Innovative Wireless Sols., LLC, 824
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`F.3d 999, 1004 (Fed. Cir. 2016) (rejecting a construction encompassing subject
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`matter that would render the claims invalid under § 112). Stated another way,
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`Regeneron’s proposed construction, itself, requires construction. Specifically, the
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`terms “maintain,” “therapeutic effect,” and “throughout the course of treatment” lack
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`both definition and plain and ordinary meaning. A skilled artisan is therefore left
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`wondering what Regeneron’s construction is supposed to mean, as well as what
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`metrics one is supposed to use to assess each imported limitation.
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`-15-
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`Finally, Regeneron notably ignores construing “initial” and “secondary.”
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`Consequently, a skilled artisan, under Regeneron’s proposal, is uncertain whether
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`those terms carry “therapeutic effect” limitations as well or whether the
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`specification’s express definitions apply—adding further uncertainty and ambiguity
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`to the Challenged Claims. Petitioner’s proposal to apply the express definitions for
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`all three terms, on the other hand, is clear to a skilled artisan and free of such
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`problems.
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`B.
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`“4 Weeks” and “8 Weeks” After the Immediately Preceding Dose
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`“4 weeks.” A skilled artisan would understand the phrase “4 weeks”—as it
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`appears in the Challenged Claims—to be synonymous with monthly
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`administration. EX1002, Albini ¶42; EX1001, ’338 patent, 7:54-56 (“‘[M]onthly’
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`dosing is equivalent to dosing once every four weeks.”); id., 14:41-52 (patients
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`received “monthly injections” which “means patients who received … injections
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`once every four weeks”).
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`“8 weeks.” A skilled artisan would similarly understand the phrase “8
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`weeks”—as it appears in the Challenged Claims—to be synonymous with bi-
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`monthly (or every-other-month administration). EX1001, ’338 patent, 7:54-56; id.,
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`14:41-52; EX1002, Albini ¶42.
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`-16-
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`C.
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`“VEGFR1 Component,” “VEGFR2 Component,” and the
`“Multimerization Component.”
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`Claim 1 of the ’338 patent recites that the “VEGF antagonist” comprises a
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`“VEGFR1 component,” a “VEGFR2 component,” and a “multimerization
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`component.” According to the ’338 patent, these terms all refer to separate amino
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`acid domains of “SEQ ID NO:2.” A skilled artisan would understand these terms to
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`collectively refer to aflibercept (a/k/a VEGF Trap or VEGF Trap-Eye or
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`VEGFR1R2-FcΔC1(a)). EX1001, ’338 patent, 2:32-37; EX1002, Albini ¶44.
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`D.
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`“Treating”
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`1.
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`The “method for treating” element of the preamble is not a
`limitation on the Challenged Claims, and therefore, does
`not require construction
`The “method for treating” preamble of independent claims 1 and 14 is “merely
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`a statement of purpose or intended use” for the claimed dosing regimen(s) and is
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`non-limiting. Bristol-Myers Squibb Co. v. Ben Venue Lab’ys, Inc., 246 F.3d 1368,
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`1375 (Fed. Cir. 2001); Vizio, Inc. v. Int’l Trade Comm’n, 605 F.3d 1330, 1340-41
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`(Fed. Cir. 2010); Arctic Cat Inc. v. GEP Power Prods., Inc., 919 F.3d 1320, 1327
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`(Fed. Cir. 2019) (“as a general rule preamble language is not treated as limiting”).
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`Indeed, “method for treating”—like the “method” preamble in Bio-Rad—neither
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`provides antecedent basis for any other claim element5 nor gives life, meaning or
`
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`5 “Treating” (or any form of “treat”) appears nowhere else in any of the claims.
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`-17-
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`vitality to the claimed dosing regimen, and thus, it is not a limitation. Bio-Rad
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`Lab’ys, Inc. v. 10X Genomics Inc., 967 F.3d 1353, 1371 (Fed. Cir. 2020) (citing
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`TomTom, Inc. v. Adolph, 790 F.3d 1315, 1322-25 (Fed. Cir. 2015)) (“In
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`TomTom … [t]he two-part preamble of the asserted claim recited: ‘[1] [a] method
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`for generating and updating data [2] for use in a destination tracking system of at
`
`least one mobile unit comprising … We held that the first part of the preamble,
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`‘method for generating and updating data,’ was not limiting and did not provide an
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`antecedent basis for any claim terms. We also found that the term did not recite
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`essential structure or steps, or give necessary life, meaning, and vitality to the claim;
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`rather, it stated ‘a purpose or intended use.’” (citations omitted)); In Re: Copaxone
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`Consol. Cases, 906 F.3d 1013, 1022-23 (Fed. Cir. 2018) (preamble was non-limiting
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`where it “does not change the express dosing amount or method already disclosed
`
`in the claims, or otherwise result in a manipulative difference in the steps of the
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`claims”). Nothing in the intrinsic record here suggests otherwise. For example,
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`there is no evidence that Regeneron asserted the “method for treating” preamble to
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`traverse any Examiner rejections. Instead, Regeneron relied on the dosing
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`frequencies required in the Challenged Claims to purportedly distinguish the prior
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`art, “standard of care.” See, e.g., EX1017, ’338 FH, 9/11/15 Remarks, 6-9.
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`Moreover, Regeneron is foreclosed by Federal Circuit precedent from arguing
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`that its reliance on alleged “unexpected results’ during prosecution demonstrates that
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`-18-
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`efficacy is a necessary feature of the claimed method. Purdue Pharma L.P. v. Endo
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`Pharms. Inc., 438 F.3d 1123, 1136-37 (Fed. Cir. 2006) (en banc) (holding that
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`patentee’s reliance on its “surprising discovery” of the four-fold dosage range to
`
`distinguish its oxycodone formulation from the prior art did not make the four-fold
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`range a necessary feature of the claimed formulations). The Board has also rejected
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`similar arguments. Mylan Lab’ys Ltd. v. Aventis Pharma S.A., No. IPR2016-00712,
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`2016 WL 5753968, *5 (P.T.A.B. Sept. 22, 2016) (holding that “method of treating
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`a patient” preamble was non-limiting despite patentee’s reliance on “surprising and
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`unexpected” clinical results of efficacy to distinguish the claimed invention from the
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`prior art).
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`For these reasons, Petitioner submits that the preamble is non-limiting and no
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`construction of “treating” is necessary to ascertain the scope of the Challenged
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`Claims.
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`2.
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`Regeneron’s anticipated argument that the “method for
`treating” preamble is a positive limitation should be
`rejected
`In the ’345 Patent PGR, Regeneron has asserted that an analogous “method
`
`for treating” preamble is a positive claim limitation requiring a therapeutically
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`effective method for treatment. ’345 Patent PGR, 7-9. To the extent Regeneron
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`raises the same argument here, it should be rejected. First, the “method for treating
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`an angiogenic eye disorder” phrase has no bearing on the dosing steps in the claim,
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`-19-
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`because “the steps … are performed in the same way regardless whether or not the
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`patient experiences” treatment of their angiogenic eye disorder. Bristol-Myers, 246
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`F.3d at 1375; EX1001, ’338 patent, 13:3-17 (Table 1) (showing that almost 5% of
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`the patients in the 2Q8 arm failed to maintain vision). In other words, the preamble
`
`is merely a statement of the intended purpose for the claimed regimen, and therefore,
`
`is not a limitation. Bristol-Myers, 246 F.3d at 1375; Copaxone, 906 F.3d at 1022-
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`23.
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`Second, as stated above, “method for treating” provides no antecedent basis
`
`for any other claim element, and any argument that the claim terms “the patient” and
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`“angiogenic eye disorders” find their respective meaning in the preamble is
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`meritless. Like in Copaxone, these terms do not “change the express dosing amount
`
`or method already disclosed in the claims, or otherwise re