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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`
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`SAMSUNG BIOEPIS CO., LTD. and BIOCON BIOLOGICS INC.,
`Petitioners,
`
`v.
`
`REGENERON PHARMACEUTICALS, INC.,
`Patent Owner.
`
`
`U.S. Patent No. 10,888,601
`
`_______________
`
`Inter Parts Review No. IPR2023-007391
`____________________________________________________________
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`PATENT OWNER’S RESPONSE
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`
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`1 IPR2024-00201 has been joined with IPR2023-00739.
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`IPR2023-00739
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`TABLE OF CONTENTS
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`I.
`
`II.
`
`INTRODUCTION ........................................................................................... 1
`
`BACKGROUND ............................................................................................. 4
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`A. Diabetic retinopathy and diabetic macular edema ................................ 4
`
`B.
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`C.
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`D.
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`Prior art therapies for angiogenic eye disorders .................................... 5
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`Eylea® ................................................................................................... 7
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`The Challenged Claims of the ’601 Patent ......................................... 10
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`III.
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`PRIOR ART ................................................................................................... 12
`
`A.
`
`B.
`
`C.
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`2009 Press Release (Ex.1009) ............................................................. 12
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`Shams (Ex.1010) ................................................................................. 12
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`Elman 2010 (Ex.1006) ........................................................................ 13
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`IV. PRIORITY DATE ......................................................................................... 14
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`V.
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`CLAIM CONSTRUCTION .......................................................................... 16
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`A.
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`“[E]very 4 weeks for the first 5 injections followed by … every
`8 weeks” .............................................................................................. 16
`
`B.
`
`“[M]ethod for treating”/“effective amount” ........................................ 21
`
`1.
`
`2.
`
`The challenged claims require effective treatment ................... 21
`
`The claims require intent to treat a specific
`angiogenic eye disorder ............................................................ 22
`
`VI. THE CLAIMED FIVE LOADING-DOSE REGIMEN IS
`NON-OBVIOUS ............................................................................................ 23
`
`A.
`
`Petitioner has not demonstrated obviousness over the 2009
`Press Release alone or in view of Shams (all claims; Grounds 2
`and 6) ................................................................................................... 24
`
`1.
`
`The 2009 Press Release and Shams do not teach
`toward the claimed five loading-dose regimen ......................... 24
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`2.
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`Petitioner does not show that the POSA would
`arrive at the claimed regimen with “routine
`optimization” and “routine adjustments” .................................. 31
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`B.
`
`The recited dosing regimen is not obvious over the 2009 Press
`Release in view of Elman 2010 (all claims; Grounds 3 and 6) ........... 39
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`1.
`
`2.
`
`Elman 2010 does not teach toward five loading
`doses .......................................................................................... 40
`
`There is no motivation to combine Elman 2010
`with the 2009 Press Release ...................................................... 44
`
`VII. THE PRIOR ART DOES NOT DISCLOSE THE REQUIRED
`EFFICACY (ALL CLAIMS AND GROUNDS) .......................................... 51
`
`VIII. PETITIONER FAILS TO SHOW INTENT TO TREAT DIABETIC
`RETINOPATHY (CLAIMS 18-19, 21, 25-28, 33; ALL GROUNDS) ........ 54
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`A.
`
`B.
`
`C.
`
`The record evidence distinguishes between DR and DME................. 54
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`The 2009 Press Release does not disclose intent to treat DR ............. 56
`
`Petitioner’s assertion that intent to treat DR is shown by intent
`to treat DME is unsupported and inconsistent with product
`labeling ................................................................................................ 58
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`IX. EYLEA’S COMMERCIAL SUCCESS IS AN OBJECTIVE
`INDICATOR OF NON-OBVIOUSNESS .................................................... 60
`
`A.
`
`B.
`
`Eylea® Has a Nexus to the Challenged Claims .................................. 60
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`Eylea® Is a Commercial Success ........................................................ 61
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`X.
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`CONCLUSION .............................................................................................. 62
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`TABLE OF AUTHORITIES
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` Page(s)
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`Cases
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`Arendi S.A.R.L. v. Apple Inc.,
`832 F.3d 1355 (Fed. Cir. 2016) .................................................................... 38, 39
`
`Chemours Co. FC, LLC v. Daikin Indus., Ltd.,
`4 F.4th 1370 (Fed. Cir. 2021) ............................................................................. 61
`
`Cont’l Can Co. USA v. Monsanto Co.,
`948 F.2d 1264 (Fed. Cir. 1991) .......................................................................... 60
`
`Eli Lilly & Co. v. Teva Pharms. Int’l GmbH,
`IPR2018-01710, 2020 WL 1540364 (P.T.A.B. Mar. 31, 2020),
`aff’d 8 F.4th 1331 ................................................................................................ 23
`
`In re Fowler,
`APPEAL 2018-003968, 2020 WL 289565 (P.T.A.B. Jan. 15, 2020) ................ 25
`
`Genetics Inst., LLC v. Novartis Vaccines & Diagnostics, Inc.,
`655 F.3d 1291 (Fed. Cir. 2011) .................................................................... 32, 33
`
`Merck & Co., Inc. v. Teva Pharms. USA, Inc.,
`395 F.3d 1364 (Fed. Cir. 2005) .......................................................................... 22
`
`Nidec Motor Corp. v. Zhongshan Broad Ocean Motor Co,
`868 F.3d 1013 (Fed. Cir. 2017) .......................................................................... 16
`
`Ortho-McNeil Pharm., Inc. v. Mylan Lab'ys, Inc.,
`520 F.3d 1358 (Fed. Cir. 2008) .......................................................................... 51
`
`Pacing Techs., LLC v. Garmin Int’l, Inc.,
`778 F.3d 1021 (Fed. Cir. 2015) .......................................................................... 20
`
`Red Diamond, Inc. v. S. Visions, LLP,
`No. PGR2019-00045, 2020 WL 2046054 (P.T.A.B. Apr. 28, 2020) ................. 33
`
`Roxane Lab’ys, Inc. v. Vanda Pharms. Inc.,
`No. IPR2016-00690, 2016 WL 5226531 (P.T.A.B. Aug. 30, 2016) ............ 30, 50
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`Sanofi-Aventis U.S. LLC v. Sandoz, Inc.,
`No. 20-804-RGA, 2023 WL 4175334 (D. Del. Jun. 26, 2023) .......................... 52
`
`In re Sebek,
`465 F.2d 904 (CCPA 1972) ................................................................................ 33
`
`In re Stepan Co.,
`868 F.3d 1342 (Fed. Cir. 2017) .......................................................................... 34
`
`Unigene Lab’ys, Inc. v. Aptoex, Inc.,
`655 F.3d 1352 (Fed. Cir. 2011) .......................................................................... 51
`
`Volvo Penta of the Ams., LLC v. Brunswick Corp.,
`81 F.4th 1202 (Fed. Cir. 2023) ........................................................................... 60
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`Other Authorities
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`21 CFR § 201.57(c)(2) (2010) ................................................................................. 58
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`I.
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`INTRODUCTION
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`In 2006, the FDA approved Genentech’s anti-VEGF agent Lucentis® for
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`wet age-related macular degeneration (AMD). Lucentis® set the new standard for
`
`efficacious treatment of angiogenic eye disorders, and with that, an expectation
`
`about how frequently patients should be given anti-VEGF agents. The
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`recommended dosing regimen for Lucentis® was (and still is) monthly injections
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`into the eye—a burdensome regimen carrying risks with each injection that
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`patients will endure for life. And yet, despite the best efforts of Genentech and
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`other research groups, that was the standard for years, because that was the
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`regimen that worked. No fixed-interval regimen with a more extended schedule
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`was as good as monthly Lucentis®.
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`Against this backdrop, Regeneron developed a different anti-VEGF agent,
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`Eylea® (known prior to approval as VEGF Trap-Eye). In its clinical trials,
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`Regeneron discovered that a VEGF Trap-Eye dosing regimen of several monthly
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`loading doses followed by doses every eight weeks—not monthly—was as
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`effective as monthly Lucentis®. At the outset of the trials, prevailing wisdom and
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`the prior art taught that Regeneron would fail, but Regeneron nevertheless began
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`testing the regimen in its Phase III trial in AMD, and in 2009 it initiated a Phase II
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`trial for diabetic macular edema (DME). Regeneron tested a number of regimens
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`in its Phase II DME clinical trial, DA VINCI, including a regimen of three loading
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`doses followed by doses every eight weeks. Then, based on confidential results of
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`its DA VINCI trials obtained in late 2010, Regeneron proceeded with the fixed
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`eight-week interval in its Phase III VIVID and VISTA trials but increased the
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`number of loading doses from three to five. VIVID and VISTA measured the
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`effect of Eylea® on subjects’ DME, i.e., fluid buildup in the center of the retina,
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`and on the diabetic retinopathy (DR), i.e., hemorrhages and other microvascular
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`abnormalities across the retina. The VIVID and VISTA trials confirmed that a
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`regimen of five monthly loading doses followed by doses every eight weeks was
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`highly effective. These results supported the addition of DME and DR indications
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`to the Eylea® label, which recommends the five-loading-dose regimen.
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`Regeneron’s innovative work led to the challenged claims of the
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`’601 Patent, which cover the five loading-dose regimen for DME and DR. The
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`’601 Patent claims priority to January 2011, when Regeneron had obtained the
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`Phase II DA VINCI results and was finalizing the protocol for its VIVID/VISTA
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`clinical trials, but notably before either the full DA VINCI results or the
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`VIVID/VISTA dosing regimen had published. Petitioner does not contend that the
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`claimed five-loading dose regimen of VEGF Trap-Eye was disclosed in the prior
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`art. Instead, Petitioner challenges these claims as obvious over the Regeneron’s
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`own 2009 Press Release, which does not disclose five loading doses at all, let
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`alone five loading doses administered every four weeks, followed by maintenance
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`doses administered every eight weeks. Moreover, Regeneron’s 2009 Press Release
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`does not disclose any results. Recognizing the deficiencies in the 2009 Press
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`Release alone, Petitioner therefore proposes combining the three-loading dose arm
`
`from the 2009 Press Release with two references, Shams and Elman 2010, that
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`describe clinical trials for an entirely different anti-VEGF agent, Genentech’s
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`Lucentis®.
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`Petitioner’s hindsight-driven arguments fail and cannot establish
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`obviousness by a preponderance of the evidence for the following reasons:
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`First, the proper construction of the claim language “every 4 weeks for the
`
`first 5 injections followed by … every 8 weeks” requires a predetermined dosing
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`schedule. But Petitioner’s obviousness theories focus on individualized dosing
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`regimens, which are not determined ex ante. Dosing is instead determined on an
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`“as needed” basis, which is not covered by the claims.
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`Second, a POSA would not consider Shams or Elman 2010 in combination
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`with the 2009 Press Release, because both Shams and Elman 2010 pertain to
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`Lucentis®, and the POSA would not rely on Lucentis® dosing regimens to guide
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`dosing of a different anti-VEGF agent. Moreover, Shams teaches using three or
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`fewer monthly doses of Lucentis®. Elman 2010 does not disclose any subject
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`receiving exactly five monthly doses of Lucentis® either, let alone a subject that
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`received exactly five monthly doses, followed by doses every eight weeks.
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`Third, even if the POSA had some reason to consider modifying the dosing
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`regimens set forth in the prior art as Petitioner contends, the POSA could do so in
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`innumerable ways besides adding exactly two more loading doses to the three-
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`loading dose, every eight weeks arm described in the 2009 Press Release.
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`“Routine optimization” case law does not apply here because the ways to add
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`doses is not limited to a range encompassing exactly five loading doses; that is a
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`relevant number only in hindsight. Further, the optimization would be challenging,
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`and the POSA would have no reasonable expectation of success, because using an
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`“as needed” dosing strategy on individual patients, would not demonstrate whether
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`a given dosing regimen was actually optimal.
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`For at least these reasons, and those discussed in further detail below, the
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`patentability of the challenged claims should be upheld.
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`II. BACKGROUND
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`A. Diabetic retinopathy and diabetic macular edema
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`DR and DME are angiogenic eye disorders that are common complications
`
`of diabetes. Ex.2027 ¶¶20-23; Ex.2003, 1. Chronic high blood sugar in
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`individuals with diabetes causes damage to small blood vessels throughout the
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`body. Ex.2027 ¶20; Ex.2089, 2-3; Ex.2090, 2; Ex.2003, 1. DR and DME result
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`from damage to the small blood vessels in the retina, which is the light-sensitive
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`layer of tissue at the back of the eye. Ex.2027 ¶20-23.
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`DR is characterized by a range of abnormalities in the retinal
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`microvasculature, including microaneurysms, hemorrhages, and venous beading.
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`Ex.2027 ¶21; Ex.2089, 6 Table 2; Ex.2091, 2. In clinical trials, DR can be
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`assessed using the Diabetic Retinopathy Severity Scale (DRSS), a composite
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`measure of microvascular abnormalities. Ex.2027 ¶22; Ex.2091, 8; e.g., Ex.2092,
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`2.
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`Some DR patients also experience DME. DME is swelling of the macula,
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`which is the part of the retina responsible for sharp, direct vision. Ex.2027 ¶23;
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`Ex.2003, 1; Ex.1001, 1:42-44; Ex.2029, 30:24-31:15. DME occurs when the
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`microvasculature becomes leaky, which can occur at any stage of DR. Ex.2027
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`¶23; Ex.2090, 1; Ex.2029,19:19-20:2. Macular edema can be assessed with optical
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`coherence tomography, which allows a physician to measure the thickness of the
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`retina. Ex.2027 ¶24; Ex.2093, 2; Ex.2029, 32:7-17.
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`B.
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`Prior art therapies for angiogenic eye disorders
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`A protein called vascular endothelial growth factor (VEGF) is present at
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`elevated levels in angiogenic eye disorders such as DR and DME and contributes
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`to the pathophysiology of these disorders. Ex.2027 ¶27; Ex.1045, 1; see Ex.2089,
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`3; Ex.2029, 18:13-20:2. From 2004 to 2006, FDA approved the first anti-VEGF
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`agents that were used to treat angiogenic eye disorders, including the antibody
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`fragment Lucentis® (ranibizumab) and the full-length antibody Avastin®
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`(bevacizumab), which is approved for cancer but used off-label for angiogenic eye
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`disorders. Ex.2027 ¶28; Ex.1015, 2, 5; Ex.2030, 2, 7; Ex.2031.
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`Lucentis® was initially approved for only one angiogenic eye disorder: wet
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`age-related macular degeneration. Ex.2027 ¶28; Ex.1015, 2. But by 2010, a
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`number of trials were completed or underway to confirm that anti-VEGF agents
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`were effective to treat other angiogenic eye disorders, including DME and DR.
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`Ex.2027 ¶32; e.g., Ex.2032; Ex.1006. The FDA approved DME as an indication
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`for Lucentis® in 2012 and approved DR as an indication in 2015. Ex.2027 ¶32;
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`Ex.2004, 1; Ex.2033.
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`For AMD, DME, and DR, the Lucentis® label recommends monthly dosing.
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`Ex.2027 ¶34; Ex.2034, 2. Despite the discomfort, inconvenience, and risks
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`associated with injections into the eye, the label recommends monthly dosing
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`because a less-frequent dosing interval was shown to be far less effective. Ex.2027
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`¶¶34-35. In Genentech’s PIER study, AMD patients in the treatment arms
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`received ranibizumab every month for three doses, followed by quarterly doses.
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`Ex.2027 ¶35; Ex.2035 ¶20; Ex.1004, 2. Subjects gained visual acuity from the
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`first three monthly injections but then lost all visual acuity gains after moving to
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`fixed quarterly dosing. Ex.2027 ¶35; Ex.2035 ¶22; Ex.1004, 5 Fig.1. By 2011, the
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`PIER trial was regarded as “highly disappointing,” and a “failure,” Ex.2035 ¶¶22-
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`23; Ex.2027 ¶35, and Genentech allowed all patients in the quarterly arms to
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`switch from quarterly dosing to monthly dosing for the remainder of the study.
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`Ex.2035 ¶25; Ex.2027 ¶35; Ex.2006, 2; Ex.2007, 2.2 The Lucentis® label itself
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`notes that quarterly dosing is “less effective.” Ex.2027 ¶35; Ex.2035 ¶31;
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`Ex.2004, 1.
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`C. Eylea®
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`Regeneron developed a different anti-VEGF agent, sometimes referred to as
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`VEGF Trap-Eye, and now known as Eylea® (aflibercept). Aflibercept is not an
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`antibody or antibody fragment but rather a fusion protein made from domains of
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`human VEGF receptors grafted onto an Fc portion of an antibody. Ex.1050, 12.
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`FDA first approved Eylea® in November 2011 for AMD. Ex.1001, 2:51-57.
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`In 2008, Regeneron began enrolling DME patients in a Phase II trial,
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`DA VINCI. Ex.1045, 2; Ex.2027 ¶38. Subjects were assigned to five treatment
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`arms: “0.5 mg VEGF Trap-Eye every 4 weeks (0.5q4); 2 mg VEGF Trap-Eye
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`every 4 weeks (2q4); 2 mg VEGF Trap-Eye for 3 initial monthly doses and then
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`every 8 weeks, (2q8); 2 mg VEGF Trap-Eye for 3 initial monthly doses and then
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`on an as-needed (PRN) basis (2 PRN); or macular laser treatment.” Ex.1045, 2;
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`2 The sole example of Petitioner’s Shams reference is a prospective disclosure of
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`the PIER trial protocol, without any of these results showing failure of the trial.
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`Ex.1010.
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`Ex.2027 ¶38. DA VINCI’s primary endpoint was change in best corrected visual
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`acuity (BCVA) from baseline to 24 weeks; a secondary endpoint was change from
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`baseline to 52 weeks. Ex.2008, 4; Ex.2009, 1615:15-20.3
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`Regeneron obtained the 24-week DA VINCI results by mid-2010, Ex.2009,
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`1615:15-24, and published the full 24-week results in May 2011, Ex.1045, 8. At
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`24 weeks, “[i]n the 2Q8 and 2 PRN arms, the treatment interval for VEGF Trap-
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`Eye administration was prolonged after the loading phase without a trade-off in
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`efficacy, because all VEGF Trap-Eye–treated groups manifested comparable gains
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`in visual acuity versus baseline.” Ex.1045, 6; Ex.2027 ¶38. With these results in
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`hand, Regeneron began planning its Phase III trials. As of October 2010,
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`Regeneron planned to test the 2q8 regimen that it had used in the DA VINCI trial,
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`Ex.2009, 162:7-9, 1616:19-25, but it awaited the DA VINCI 52-week data to
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`“provide additional guidance on the number of loading doses,” id. 162:10-163:3.
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`Then, in late 2010, Dr. George Yancopoulos, Regeneron’s co-founder, and
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`sole inventor of the ’601 Patent, reviewed the 52-week data, including unpublished
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`patient-level data. Ex.2009, 163:5-165:13, 1620:6-1621:23. He made the decision
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`3 Citations in the page:line format use the original page numbering of the
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`document.
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`to test five loading doses followed by additional doses every eight weeks in the
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`Phase III trial. Id. 1622:15-1623:14, 1234:8-1235:4, 167:25-168:22; Ex.2003, 2.
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`Regeneron completed its Phase III VIVID and VISTA trials, and FDA
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`approved an additional Eylea® indication for DME in December 2013. See
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`Ex.2003; Ex.2010. For DME, the Eylea® label recommends the dosing regimen
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`recited in the challenged claims of the ’601 Patent: five monthly loading doses
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`followed by additional doses every eight weeks. Ex.1050, 1.
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`In VIVID and VISTA, Regeneron measured the effect of Eylea® on the
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`subjects’ DR. All subjects in the trial had both DR and DME, and one endpoint
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`was change in central retinal thickness, a measure of DME. Ex.2003, 2; Ex.2027
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`¶40. But in addition, the trials included an endpoint specific to DR: “proportion of
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`eyes with a ≥2 step improvement in the ETDRS Diabetic Retinopathy Severity
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`Scale (DRSS) score.” Ex.2003, 2; Ex.2027 ¶41. Significantly more subjects in the
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`VEGF Trap-Eye 2q8 arm (five initial doses followed by doses every eight weeks)
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`achieved a ≥2 step improvement in DRSS compared to the laser arm. Ex.2027
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`¶41; Ex.2003, 6. With the DRSS data from VIVID and VISTA, Regeneron
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`obtained FDA approval for the indication “treatment of Diabetic Retinopathy (DR)
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`in patients with Diabetic Macular Edema (DME).” Ex.2037; Ex.1050, 2, 24;
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`Ex.2027 ¶41.
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`After VIVID and VISTA, Regeneron undertook a trial called PANORAMA,
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`which enrolled patients with severe non-proliferative diabetic retinopathy without
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`center-involved DME. Ex.2027 ¶42; Ex.2092, 2. The primary endpoint was “the
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`proportion of eyes with a 2-step or greater improvement in DRSS level from
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`baseline to week 24 … and week 52.” Ex.2027 ¶43; Ex.2092, 3. Significantly
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`more subjects in the VEGF Trap-Eye 2q8 arm (five initial doses followed by doses
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`every eight weeks) achieved a ≥2 step improvement in DRSS compared to sham
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`treatment. Ex.2027 ¶43; Ex.2092, 5 Fig.2. With the DRSS results of VIVID,
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`VISTA, and PANORAMA, Eylea® was approved for DR in May 2019. Ex.2027
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`¶44; Ex.2038; Ex.1016.
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`D. The Challenged Claims of the ’601 Patent
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`The challenged claims of the ’601 Patent are directed to therapeutic
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`treatments for DME and DR. Independent claim 10 is specifically directed to a
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`“method for treating diabetic macular edema.” Independent claim 18 is
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`specifically directed to a “method for treating diabetic retinopathy,” and
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`independent claim 26 is specifically directed to a “method for treating diabetic
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`retinopathy in a patient with diabetic macular edema.”4
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`4 On December 27, 2023, the U.S. District Court for the Northern District of West
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`Virginia held claims 11 and 19 of the ’601 Patent invalid. Ex.2039.
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`The specification explains the state of the art and notes a “need in the art for
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`new administration regimens for angiogenic eye disorders, especially those which
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`allow for less frequent dosing while maintaining a high level of efficacy.”
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`Ex.1001, 1:64-67. The inventor “surprisingly discovered that beneficial
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`therapeutic effects can be achieved in patients suffering from angiogenic eye
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`disorders by administering a VEGF antagonist to a patient at a frequency of once
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`every 8 or more weeks.” Ex.1001, 2:11-18.
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`All of the challenged claims require five monthly loading doses followed by
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`doses every eight weeks. As explained below, this is a predetermined dosing
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`regimen with fixed dosing intervals, in contrast to other regimens disclosed in the
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`specification, which may vary during the course of treatment based on patient
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`outcomes. For example, at column 16, lines 23-26, the ’601 Patent describes the
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`dosing regimen set forth in the challenged claims, which Petitioner’s expert
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`acknowledges is a predetermined dosing schedule, (Ex.2029, 220:4-221:7),
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`decided upon before treatment has begun. The ’601 separately describes a PRN
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`dosing schedule at column 16, lines 33-38 (Ex.2029, 216:17-217:4), in which the
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`dosing schedule after five loading does is not predetermined, but is instead
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`determined at each office visit and on an “as needed” basis, based on physician
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`assessment after treatment has begun. Ex.1001, 16:33-38.
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`III. PRIOR ART
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`A.
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`2009 Press Release (Ex.1009)
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`The 2009 Press Release is a Regeneron press release that discloses certain
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`aspects of the design of Regeneron’s Phase II DA VINCI clinical trial for DME.
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`Ex.1009; Ex.2027 ¶50. The press release discloses that the trial included four
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`different VEGF Trap-Eye dosing regimens, “0.5 mg or 2 mg monthly, 2 mg every
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`eight weeks after three monthly loading doses, 2 mg on an as-needed (PRN) basis
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`after three monthly loading doses….” Ex.1009.
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`B.
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`Shams (Ex.1010)
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`Shams is the publication of a Genentech patent application filed in 2004.
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`Ex.1010, 1; Ex.2027 ¶¶51-52. Shams discusses the general concept of more-
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`frequent followed by less-frequent dosing, but without any evidence that such
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`regimens could work. It broadly discloses that the invention encompasses “[a]ny
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`compound which binds to VEGF or a VEGF receptor and reduces the severity of
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`symptoms … may be used in this embodiment of the invention,” Ex.1010, 26:6-8,
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`6:27-7:16, and “[t]he doses may be administered according to any time schedule
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`which is appropriate,” Ex.1010, 22:30-31, 23:7-9. Shams asserts that “the specific
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`time schedule can be readily determined by a physician having ordinary skill in
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`administering the therapeutic compound by routine adjustments of the dosing
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`schedule” by monitoring patients. Ex.1010, 22:30-23:7.
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`Through the rest of the specification and claims, Shams focuses on a
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`regimen of three or fewer monthly loading doses followed by quarterly dosing.
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`Ex.1010, 5:20-6:2; 23:13-16, 36:30-37:25. Not only did Shams not show that
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`quarterly dosing would work, but the opposite is true: Shams’ sole example is a
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`prospective disclosure of the dosing regimen used by Genentech in the PIER trial,
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`which would ultimately fail. Ex.1010, 31:8-19; Ex.2027 ¶52 Ex.2035 ¶¶22-31;
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`Ex.1004.
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`C. Elman 2010 (Ex.1006)
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`Elman 2010 is an article that describes a study comparing various
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`ranibizumab (Lucentis®), laser, and steroid regimens for DME. Ex.1006; Ex.2027
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`¶¶53-54. In one arm of the trial, referred to as the “ranibizumab + deferred laser
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`group,” subjects followed a three-part dosing protocol. Ex.1006, 3. First,
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`ranibizumab was administered every four weeks through the 12-week visit (i.e.,
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`four monthly doses). Ex.1006, 3. Second, at the 16- and 20-week visits (i.e., fifth
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`and sixth monthly visits), subjects were evaluated to determine if they met the
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`“success criteria” of a visual acuity letter score of 84 (corresponding to 20/20
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`vision) or central retinal thickness <250μm. Ex.1006, 3, 15-16. Subjects who did
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`not meet the success criteria received a dose of ranibizumab, and those who met
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`the success criteria also received a dose at the investigator’s discretion. Ex.1006,
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`3, 15-16. Third, at the 24-week and later visits, drug was administered at the
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`investigator’s discretion if the study eye was deemed “no improvement,” and laser
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`photocoagulation could be applied as well. Ex.1006, 3, 15-16.
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`Elman 2010 does not disclose individual results data, but, but it does report
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`average outcomes. Ex.2027 ¶54. In the deferred laser group, the average visual
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`acuity improved quickly over the first two to three months, and then climbed
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`slowly through week 52. Ex.1006, 6 Fig.3; Ex.1006, 35 Fig.8.
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`IV. PRIORITY DATE
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`The challenged claims of the ’601 Patent have a priority date of January 13,
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`2011, at the latest. The disclosure of provisional application No. 61/432,245, filed
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`on January 13, 2011, provides adequate written description support for the
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`elements of the challenged claims.
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`Petitioner contends that the date should instead be no earlier than July 12,
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`2013. Petitioner points to the recited dosage, the recited interval between
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`secondary (loading) doses and tertiary (maintenance) doses, the recited indications,
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`and the “effective” combination of those variables as aspects that allegedly lack
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`written description prior to July 12, 2013. Each of these elements, however, is
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`supported by the original provisional application.
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`The Board addressed a virtually identical argument in Samsung’s challenge
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`to the related ’572 Patent, IPR2023-00884. One claim of that patent covers a
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`method for treating DME involving five monthly loading doses followed by
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`bimonthly dosing. The Board found this claim to be entitled to a priority date of
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`January 2011.5 IPR2023-00884, Paper 13, 33-34. The Board noted the provisional
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`application expressly identifies four secondary doses (i.e., five loading doses total)
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`as an embodiment of the invention, reasoning that “[a] specific example perfectly
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`and verbatim embodying [the claim with 5 loading doses] is not required.” Id., 33
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`(citing Ex.2011, [0018-19]). The same analysis applies here.
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`Example 5 of the ’245 application discloses all but one limitation of
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`claim 10. It discloses a clinical trial testing DME treatment, where one of the
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`tested groups received “three initial doses of 2 mg VEGFT once every four weeks
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`… followed through week 52 by [] once every 8 weeks dosing….” Ex.2011,
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`[0061]. The trial includes efficacy results for the group. Ex.2011, Table 2. This
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`Example discloses the dosage, interval between doses, the DME indication, and a
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`level of efficacy. The only other limitation of claim 10, five loading doses (i.e.,
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`one initial dose plus four secondary doses), is expressly disclosed in paragraph 18,
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`which states that “In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or
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`more) secondary doses are administered to the patient.” Ex.2011, [0018]. The
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`5 The Petitioner and Board in IPR2023-00884 relied on Regeneron’s January 21,
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`2011 provisional application, 61/434,836, but the January 13, 2011 provisional
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`application includes the same relevant disclosures.
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`’245 application also discloses both DR and DME as potential targeted diseases.
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`Ex.2011, [0024].
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`Dr. Chaum’s opinion regarding priority date should be given no weight. In
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`his deposition, Dr. Chaum demonstrated a lack of understanding of the written
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`description requirement. Ex.2029,40:13-22. Dr. Chaum also did not review any
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`provisional applications in reaching his opinion regarding priority date. Ex.2029,
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`154:4-22. When presented with disclosure present in the provisional application,
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`he agreed that it disclosed five monthly doses. Ex.2029, 230:6-19.
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`V. CLAIM CONSTRUCTION6
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`A.
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`“[E]very 4 weeks for the first 5 injections followed by … every 8
`weeks”
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`The plain and ordinary meaning of the challenged independent claims makes
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`clear that the administered dosing regimen follows a predetermined, fixed dosing
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`schedule, “every 4 weeks for the first 5 injections followed by … every 8 weeks,”
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`6 Patent Owner disagrees with Petitioner’s argument that the exclusion criteria
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`limitations of claims 17, 25, and 33 are entitled to no patentable weight. Pet. 21-
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`22. Petitioner does not advance any non-obviousness arguments involving these
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`limitations, so the Board need not resolve the dispute in this proceeding. Nidec
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`Motor Corp. v. Zhongshan Broad Ocean Motor Co, 868 F.3d 1013, 1017 (Fed. Cir.
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`2017).
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`that is determined before treatment begins. Ex.2027 ¶61. Petitioner argues that the
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`claims should not be limited to predetermined, fixed dosing schedules, and should
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`instead be broadly construed to encompass individualized, variable dosing
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`schedules, which are decided during (not before) treatment. Paper 7, 6-9.
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`According to Petitioner, provided that the dosing intervals of such individualized
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`schedules coincidentally line up with the intervals specified in the claims, the
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`claimed dosing regimen is met. Paper 7, 7.
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`Not so. The specification explicitly distinguishes between the individualized
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`dosing strategies contemplated by Petitioner and the predetermined, fixed dosing
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`schedules actually claimed. Ex.2027 ¶¶62-67. Indeed, as discussed above, at
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`column