UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`
`SAMSUNG BIOEPIS CO., LTD.,
`Petitioner,
`v.
`
`REGENERON PHARMACEUTICALS, INC.,
`Patent Owner.
`
`Patent No. 10,888,601
`_______________
`
`Inter Partes Review No. IPR2023-00739
`____________________________________________________________
`
`PATENT OWNER’S PRELIMINARY RESPONSE
`
`Biocon Exhibit 1064 - Page 1
`
`

`

`IPR2023-00739
`
`TABLE OF CONTENTS
`
`Page
`
`I.
`
`II.
`
`INTRODUCTION .......................................................................................... 1
`
`BACKGROUND ............................................................................................ 4
`
`A.
`
`B.
`
`C.
`
`EYLEA® .............................................................................................. 4
`
`The ’601 Patent .................................................................................... 8
`
`District Court Litigation ....................................................................... 9
`
`III.
`
`LEVEL OF ORDINARY SKILL IN THE ART .......................................... 11
`
`IV. CLAIM CONSTRUCTION ......................................................................... 11
`
`V.
`
`PETITIONER HAS NO REASONABLE LIKELIHOOD OF
`SUCCESS BECAUSE THE RECITED DOSING REGIMEN IS NOT
`DISCLOSED OR SUGGESTED BY THE PRIOR ART ............................ 11
`
`A.
`
`Petitioner Fails to Show That the 2009 Press Release or Shams
`Would Lead a POSA to the Recited Dosing Regimen (Ground
`2) ......................................................................................................... 11
`
`1.
`
`2.
`
`3.
`
`The References Neither Disclose the Recited Dosing
`Regimen nor Provide Any Reason for a POSA to Adopt
`That Regimen ........................................................................... 12
`
`The Relied-Upon Prior Art Teaches Away from the
`Recited Dosing Regimen ......................................................... 17
`
`The “Routine Adjustments” Methodology Petitioner
`Advocates Does Not Render the Challenged Claims
`Obvious .................................................................................... 22
`
`B.
`
`Petitioner Fails to Show That Elman 2010 in Combination with
`the 2009 Press Release Would Lead a POSA to the Recited
`Dosing Regimen (Grounds 3 and 6) ................................................... 25
`
`1.
`
`2.
`
`Petitioner’s References Do Not Disclose, and Instead
`Teach Away from, the Recited Dosing Regimen .................... 25
`
`Petitioner Fails to Show a Motivation to Combine ................. 34
`
`VI.
`
`THE FINTIV FACTORS WEIGH AGAINST INSTITUTION ................... 37
`
`A.
`
`Legal Standard for Fintiv Discretionary Denial ................................. 39
`
`i
`
`Biocon Exhibit 1064 - Page 2
`
`

`

`IPR2023-00739
`
`TABLE OF CONTENTS
`(continued)
`
`Page
`
`
`
`1.
`
`Fintiv Factors One, Two, Three, Four, and Six Favor
`Denial ....................................................................................... 40
`
`2.
`
`Fintiv Factor Five Is Neutral .................................................... 44
`
`VII. CONCLUSION ............................................................................................. 45
`
`
`
`
`
`ii
`
`
`
`Biocon Exhibit 1064 - Page 3
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`

`

`IPR2023-00739
`
`Cases
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Apotex Inc. v. Novartis AG,
`IPR2017-00854, 2018 WL 3414289 (P.T.A.B. July 11, 2018) .......................... 21
`
`Apple Inc. v. Fintiv, Inc.,
`IPR2020-00019, 2020 WL 2126495 (P.T.A.B. Mar. 20, 2020) ..................passim
`
`In re Bell,
`991 F.2d 781 (Fed. Cir. 1993) ............................................................................ 15
`
`Biomarin Pharm. Inc. v. Genzyme Theraputic Prods. Ltd. P’ship,
`IPR2013-00534, Paper 81 (P.T.A.B. Feb. 23, 2015) .......................................... 23
`
`Commscope Techs. LLC v. Dali Wireless, Inc.,
`No. IPR2022-01293, 2023 WL 2604001 (P.T.A.B. Mar. 9, 2023) .................... 41
`
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Pat.
`Litig.,
`676 F.3d 1063 (Fed. Cir. 2012) .................................................................... 16, 21
`
`Fitbit, Inc. v. Philips N. Am. LLC,
`IPR2020-00828, 2020 WL 6470312 (P.T.A.B. Nov. 3, 2020)........................... 45
`
`Google LLC v. Personalized Media Commc’ns, LLC,
`IPR2020-00724, 2020 WL 6530785 (P.T.A.B. Nov. 5, 2020)........................... 45
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ...................................................................................... 15, 16
`
`In re Kubin,
`561 F.3d 1351 (Fed. Cir. 2009) .......................................................................... 16
`
`Leo Pharm. Prods., Ltd. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) .................................................................... 16, 36
`
`Life Spine, Inc. v. Globus Medical, Inc.,
`IPR2022-01603, Paper 8 (P.T.A.B. June 12, 2023) ........................................... 14
`
`
`
`iii
`
`
`
`Biocon Exhibit 1064 - Page 4
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`

`

`IPR2023-00739
`
`
`
`
`
`NHK Spring Co. v. Intri-Plex Techs., Inc.,
`IPR2018-00752, Paper 8 (P.T.A.B. Sept. 12, 2018)..................................... 38, 41
`
`In re NTP, Inc.,
`654 F.3d 1279 (Fed. Cir. 2011) .......................................................................... 15
`
`Ortho-McNeil Pharm., Inc. v. Mylan Lab'ys, Inc.,
`520 F.3d 1358 (Fed. Cir. 2008) .......................................................................... 36
`
`Portney v. CIBA Vision Corp.,
`401 F. App’x 526 (Fed. Cir. 2010) ..................................................................... 10
`
`Regeneron Pharms., Inc. v. Mylan Pharms. Inc.,
`1:22-cv-00061-TSK-JPM (N.D. W. Va.) ........................................................... 37
`
`Samsung Elecs. Co. v. Clear Imaging Rsch., LLC,
`IPR2020-01399, Paper 13 (P.T.A.B. Feb. 3, 2021) ............................................ 42
`
`Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd.,
`492 F.3d 1350 (Fed. Cir. 2007) .......................................................................... 16
`
`TWI Pharms, Inc. v. Merck Serono SA,
`IPR2023-00050, Paper 8 (P.T.A.B. Mar. 28, 2023) ........................................... 17
`
`Unigene Lab’ys, Inc. v. Apotex, Inc.,
`655 F.3d 1352 (Fed. Cir. 2011) .......................................................................... 36
`
`Volvo Penta of the Ams., LLC v. Brunswick Corp.,
`IPR2022-01366, Paper 15 (P.T.A.B. May 2, 2023) ........................................... 41
`
`Statutes
`
`35 U.S.C. § 314(a) ............................................................................................. 37, 38
`
`42 U.S.C. § 262 .......................................................................................................... 9
`
`
`
`iv
`
`
`
`Biocon Exhibit 1064 - Page 5
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`

`

`IPR2023-00739
`
`Exhibit List
`
`Exhibit Description|Exhibit#|
`U.S. 10,888,601 Patent Disclaimer (July 11, 2022)
`2001
`
`U.S. 10,888,601 Patent Disclaimer (July 25, 2023)
`
`2002
`
`Jean-Francois Korobelniket al., /ntravitreal Afliberceptfor Diabetic|2003
`Macular Edema, 121 OPHTHALMOLOGY 2247 (2014)
`
`
`
`
`
`LUCENTIS® Label (rev. Aug. 2012)
`
`Declaration of David M. Brown, M.D., Mylan Pharms.Inc. v.
`Regeneron Pharms., Inc., 1PR2021-00880, Ex.2050 (Feb. 10, 2022)
`
`Prema Abrahamet al., Randomized, Double-Masked, Sham-
`Controlled Trial ofRanibizumabfor Neovascular Age-Related
`Macular Degeneration: PIER Study Year 2, 150 AM.J.
`OPHTHALMOLOGY315 (2010)
`
`Retinal Physician Symposium Covers Broad Rangeof Topics,
`Retinal Physician (Sept. 1, 2006),
`https://www.retinalphysician.com/issues/2006/september-
`2006/retinal-physician-symposium-covers-broad-range-of.
`
`DMEand VEGFTrap-Eye [Intravitreal Aflibercept Injection
`(IAI;EYLEA®;BAY86-5321)] Investigation of Clinical Impact (DA
`VINCD,
`https://classic.clinicaltrials.gov/ct2/show/study/NCT00789477
`
`Trial Transcript (unsealed portions), Regeneron Pharms., Inc. v.
`Mylan Pharms. Inc., No. 1:22-cv-00061-TSK-JPM (N.D.W.Va.)
`
`Press Release, Regeneron Announces FDA Acceptance of
`EYLEA®(aflibercept) Injection Supplemental Biologics License
`Application for Review for Diabetic Macular EdemaIndication
`(Dec. 18, 2013)
`
`2004
`
`2005
`
`2006
`
`2007
`
`2008
`
`2009
`
`2010
`
`Provisional Application No. 61/432,245 (Jan. 13, 2011)
`
`2011
`
`Mylan Pharmaceuticals Inc.’s Answer, Defenses, and Counterclaims|2012
`to Plaintiff's Complaint, Regeneron Pharms., Inc. v. Mylan Pharms.
`Inc., No. 1:22-cv-00061-TSK-JPM (N.D.W. Va.), ECF No. 47 (filed
`Aug. 25, 2022)
`
`Biocon Exhibit 1064 - Page 6
`
`

`

`IPR2023-00739
`
`
`
`
`
`Complaint for Patent Infringement, Regeneron Pharms., Inc. v.
`Mylan Pharms. Inc., No. 1:22-cv-00061-TSK-JPM (N.D.W. Va.),
`ECF No. 1 (filed Aug. 2, 2022)
`
`Order on Claim Construction, Regeneron Pharms., Inc. v. Mylan
`Pharms. Inc., No. 1:22-cv-00061-TSK-JPM (N.D.W. Va.), ECF
`No. 427 (filed Apr. 19, 2023)
`
`Scheduling Order, Regeneron Pharms., Inc. v. Mylan Pharms. Inc.,
`No. 1:22-cv-00061-TSK-JPM (N.D.W. Va.), ECF No. 87 (filed
`Oct. 25, 2022)
`
`Regeneron’s Stipulation Regarding Summary Judgment and Case
`Narrowing, Regeneron Pharms., Inc. v. Mylan Pharms. Inc.,
`No. 1:22-cv-00061-TSK-JPM (N.D.W. Va.), ECF No. 433 (filed
`Apr. 27, 2023)
`
`Stipulation and Order Joining Biocon Biologics Inc. as Defendant,
`Regeneron Pharms., Inc. v. Mylan Pharms. Inc., No. 1:22-cv-
`00061-TSK-JPM (N.D.W. Va.), ECF No. 523 (filed June 5, 2023)
`
`Defendant’s Opening Post Trial Brief - Issues Where Defendants
`Bear the Burden of Proof, Regeneron Pharms., Inc. v. Mylan
`Pharms. Inc., No. 1:22-cv-00061-TSK-JPM (N.D.W. Va.), ECF
`No. 576 (filed July 7, 2023)
`
`Order Setting Briefing Schedule, Regeneron Pharms., Inc. v. Mylan
`Pharms. Inc., No. 1:22-cv-00061-TSK-JPM (N.D.W. Va.), ECF
`No. 514 (filed May 30, 2023)
`
`Transcript of the Status Conference held on Sept. 28, 2022,
`Regeneron Pharms., Inc. v. Mylan Pharms. Inc., No. 1:22-cv-
`00061-TSK-JPM (N.D.W. Va.), ECF No. 90 (filed Nov. 2, 2022)
`
`Irene Barbazetto et al., Dosing Regimen and The Frequency of
`Macular Hemorrhages in Neovascular Age-Related Macular
`Degeneration Treated with Ranibizumab, 30 RETINA 1376 (2010)
`
`Michael Engelbert et al., The “Treat and Extend” Dosing Regimen
`of Intravitreal Anti-Vascular Endothelial Growth Factor Therapy
`for Neovascular Age-Related Macular Degeneration (June 2010)
`www.visioncareprofessional.com/emails/amdupdate/index42.htm
`
`
`2013
`
`2014
`
`2015
`
`2016
`
`2017
`
`2018
`
`2019
`
`2020
`
`2021
`
`2022
`
`
`
`vi
`
`Biocon Exhibit 1064 - Page 7
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`

`

`IPR2023-00739
`
`
`
`
`
`David S. Boyer et al., A Phase IIIb Study to Evaluate the Safety of
`Ranibizumab in Subjects with Neovascular Age-related Macular
`Degeneration, 116 OPHTHALMOLOGY 1731 (2009)
`
`2023
`
`
`
`
`
`vii
`
`Biocon Exhibit 1064 - Page 8
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`

`

`IPR2023-00739
`
`I.
`
`INTRODUCTION
`
`Samsung’s petition does not demonstrate a reasonable likelihood that any of
`
`claims 10–12, 17–19, 21, 25–28, or 33 are invalid.1 Each of these claims requires
`
`treating diabetic macular edema or diabetic retinopathy with a specific dosing
`
`regimen of aflibercept: “2 mg approximately every 4 weeks for the first
`
`5 injections followed by 2 mg approximately once every 8 weeks or once every
`
`2 months” (“the recited regimen”). The prior art does not teach five loading doses,
`
`and Petitioner fails to articulate why a POSA would have modified the prior art
`
`regimens to arrive at the recited regimen.
`
`Petitioner relies for its primary reference of Grounds 2–3 and 6 on the
`
`2009 Press Release, a prospective disclosure of Regeneron’s DA VINCI clinical
`
`
`1 Claims 10–12, 17–19, 21, 25–28, and 33 are the only remaining challenged
`
`claims in this proceeding. Although Samsung listed claims 13–14, 22, and 29–30
`
`among the challenged claims in its petition, Patent Owner disclaimed these claims
`
`on July 11, 2022, before the petition was filed. Ex.2001. Additionally, to narrow
`
`the issues in this proceeding, Patent Owner has disclaimed claims 15–16, 20, 23–
`
`24, 31–32, and 46–47. Ex.2002. Because Grounds 1, 4, and 5 related solely to
`
`claims that have been disclaimed, Patent Owner does not address those grounds
`
`here.
`
`
`
`1
`
`Biocon Exhibit 1064 - Page 9
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`

`

`IPR2023-00739
`
`
`
`
`
`trial. The trial involved four dosing regimens, none of which was the recited
`
`regimen. Petitioner argues that a POSA would select a certain regimen from the
`
`2009 Press Release but would then promptly modify it to match the recited dosing
`
`regimen, allegedly because the Press Release teaches a POSA that more loading
`
`doses will benefit patients. But the 2009 Press Release contains no such teaching,
`
`nor does it disclose any results of the DA VINCI trial it describes. Petitioner’s
`
`arguments are therefore based on hindsight, not the prior art and knowledge of a
`
`POSA at the time of the invention.
`
`Petitioner next argues that if the recited dosing regimen is not obvious based
`
`on the 2009 Press Release alone, a POSA would combine one of the dosing
`
`regimens from the 2009 Press Release with the teachings of either Shams
`
`(Ground 2) or Elman 2010 (Grounds 3 and 6). But Petitioner fails to articulate a
`
`sufficient reason to combine Shams or Elman 2010 with the 2009 Press Release.
`
`Both Shams and Elman 2010 involved ranibizumab, a different drug, and Elman
`
`2010 disclosed fixed dosing followed by individualized, assessment-based dosing,
`
`rather than the claimed regimen, which involves fixed dosing throughout.
`
`Moreover, Shams does not disclose five fixed loading doses and neither does
`
`Elman 2010. Elman 2010 describes a clinical trial protocol that provided for four
`
`fixed monthly loading doses for all patients. Thereafter, patients could receive
`
`monthly loading doses based on an assessment, rather than on a fixed regimen.
`
`2
`
`Biocon Exhibit 1064 - Page 10
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`

`

`IPR2023-00739
`
`
`
`
`
`Nothing about the protocol suggested the desirability of even more initial monthly
`
`doses: The protocol involved a transition from fixed to assessment-based dosing
`
`after four doses, and then after six doses provided for a second transition to another
`
`assessment-based regimen. By contrast, the claims recite fixed dosing throughout,
`
`with a transition from monthly to eight-week dosing after five fixed monthly
`
`loading doses. Shams similarly does not help Petitioner. Shams discusses the
`
`general concept of more-frequent followed by less-frequent dosing, which would
`
`not be enough to motivate a POSA to use exactly five monthly doses followed by
`
`additional doses every eight weeks, as claimed. This is particularly true in view of
`
`the complete disclosure of Shams, which describes a clinical trial that was widely
`
`regarded as a failure. Shams discloses as its sole example the dosing regimen of
`
`Genentech’s PIER trial for ranibizumab (which used three loading doses followed
`
`by quarterly dosing, administered to subjects with choroidal neovascularization
`
`secondary to age-related macular degeneration). The PIER trial results revealed
`
`that this less-frequent dosing regimen was ineffective, and the trial was widely
`
`regarded by the priority date of the ’601 patent as a failure. The ranibizumab art
`
`would not have led a POSA to the claimed dosing regimen.
`
`Finally, discretionary denial is appropriate under Fintiv. Two of the
`
`challenged claims of the ’601 patent were recently tried in the Northern District of
`
`West Virginia, and post-trial proceedings are underway. Court proceedings
`
`3
`
`Biocon Exhibit 1064 - Page 11
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`

`

`IPR2023-00739
`
`
`
`
`
`involve many of the issues Petitioner raises: The trial involves two ’601 claims—
`
`11 and 19—that are challenged here and that are also representative of other
`
`challenged claims in this proceeding. The district court is adjudicating a validity
`
`challenge based on Petitioner’s primary reference, the 2009 Press Release. The
`
`district court’s final ruling on these claims, as well as the district court’s
`
`construction of the exclusion criteria claim limitations that were not tried, will be
`
`subject to appeal to the Federal Circuit. A parallel IPR proceeding on the same
`
`issues would be a duplicative, wasteful effort.
`
`II. BACKGROUND
`
`A. EYLEA®
`
`Diabetic macular edema (DME) is a common complication of diabetes that
`
`leads to vision loss. Chronic high blood sugar in diabetes patients causes damage
`
`to small blood vessels throughout the body. Ex.2003, 1. Some of these small
`
`blood vessels are found in the back of the eye, surrounding the macula, which is
`
`the light-sensitive part of the retina responsible for sharp, direct vision. Ex.2003,
`
`1; Ex.1001, 1:42–44. Damage to the blood vessels in the back of the eye can cause
`
`fluid to leak into the macula, resulting in edema, or swelling. Ex.1001, 1:41–42.
`
`Macular edema can cause severe vision loss or blindness. Ex.1001, 1:44–45.
`
`4
`
`Biocon Exhibit 1064 - Page 12
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`

`

`IPR2023-00739
`
`
`
`
`
`Historically, laser photocoagulation was used to manage DME. It could
`
`slow or stop vision loss, but few patients saw large gains in their visual acuity with
`
`this therapy. Ex.2003, 1.
`
`Researchers discovered that a protein called vascular endothelial growth
`
`factor (VEGF) is present at elevated levels in DME patients and contributes to the
`
`pathophysiology of DME. Ex.1045, 1. By the late 2000s and early 2010s, several
`
`clinical trials were underway to evaluate the efficacy of anti-VEGF agents to treat
`
`DME. Ex.1045, 1; Ex.2003, 1. The different trials tested a wide range of dosing
`
`regimens and combination therapies, and results varied.
`
`The first such anti-VEGF agent approved to treat DME was Lucentis
`
`(ranibizumab), marketed by Genentech. Lucentis is an antibody fragment that
`
`binds to VEGF. Ex.1015, 5. Lucentis was approved in 2006 as an intravitreal
`
`injection for the treatment of a different condition, age-related macular
`
`degeneration (AMD). Ex.1015, 2. FDA approved DME as an additional
`
`indication in 2012. Ex.2004, 1.
`
`For AMD and DME, the Lucentis label recommends monthly dosing.
`
`Ex.2004, 1. This is because, despite the discomfort, inconvenience, and risks
`
`associated with monthly injections into the eye, dosing ranibizumab less frequently
`
`produces dramatically lower efficacy. As just one example, in Genentech’s PIER
`
`study, AMD patients in the treatment arms received ranibizumab every month for
`
`5
`
`Biocon Exhibit 1064 - Page 13
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`IPR2023-00739
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`three doses, followed by quarterly doses. Ex.1004, 2. Patients in the treatment
`
`arm gained visual acuity during the first three monthly injections but then lost all
`
`visual acuity gains after moving to fixed quarterly dosing. Ex.1004, 5 fig. 1. By
`
`2011, the PIER trial was regarded as “highly disappointing,” and a “failure,”
`
`Ex.2005 ¶¶ 46–59, and Genentech amended the protocol to allow all patients in the
`
`quarterly arms to roll over from quarterly dosing to receiving monthly dosing for
`
`the remainder of the two-year study. Ex.2006, 2; Ex.2007, 2. The Lucentis label
`
`itself notes that quarterly dosing is “less effective” and “[c]ompared to continued
`
`monthly dosing, dosing every 3 months will lead to an approximate 5-letter (1-line)
`
`loss of visual acuity benefit, on average, over the following 9 months.” Ex.2004,
`
`1.
`
`Regeneron developed a different anti-VEGF agent, EYLEA® (aflibercept).
`
`Aflibercept is not an antibody or antibody fragment but rather a fusion protein
`
`made from domains of human VEGF receptors grafted onto an FC portion of an
`
`antibody. Ex.1050, 12. FDA first approved EYLEA® in November 2011, for
`
`AMD. Ex.1001, 2:51–57.
`
`In 2008, Regeneron began enrolling DME patients in a phase II trial, DA
`
`VINCI, “to determine whether different doses and dosing regimens of intravitreal
`
`VEGF Trap-Eye are superior to standard macular laser treatment . . . in eyes with
`
`DME.” Ex.1045, 2. Subjects were assigned to one of five treatments: “0.5 mg
`
`6
`
`Biocon Exhibit 1064 - Page 14
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`

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`IPR2023-00739
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`VEGF Trap-Eye every 4 weeks (0.5q4); 2 mg VEGF Trap-Eye every 4 weeks
`
`(2q4); 2 mg VEGF Trap-Eye for 3 initial monthly doses and then every 8 weeks,
`
`(2q8); 2 mg VEGF Trap-Eye for 3 initial monthly doses and then on an as-needed
`
`(PRN) basis (2 PRN); or macular laser treatment.” Ex.1045, 2. DA VINCI’s
`
`primary endpoint was change in best corrected visual acuity (BCVA) from baseline
`
`to 24 weeks; a secondary endpoint was change from baseline to 52 weeks.
`
`Ex.2008, 4; Ex.2009, 1408 (1615:15–20).
`
`Regeneron obtained the primary, 24-week DA VINCI results by mid-2010,
`
`Ex.2009, 1408 (1615:15–24), and Do et al. published these results in May 2011.
`
`Ex.1045, 8. At 24 weeks, “[i]n the 2Q8 and 2 PRN arms, the treatment interval for
`
`VEGF Trap-Eye administration was prolonged after the loading phase without a
`
`trade-off in efficacy, because all VEGF Trap-Eye–treated groups manifested
`
`comparable gains in visual acuity versus baseline.” Ex.1045, 6. With these results
`
`in hand, Regeneron began planning its phase III trials. As of October 2010,
`
`Regeneron planned to test the 2q4 and 2q8 regimens it had used in the DA VINCI
`
`trial, Ex.2009, 153 (162:7–9), 1409 (1616:19–25), but it awaited the DA VINCI
`
`52-week data to “provide additional guidance on the number of loading doses,” id.
`
`153-154 (162:10–163:3).
`
`Then, in late 2010, Regeneron received the complete 52-week data from the
`
`DA VINCI trial. Senior management reviewed the unpublished aggregate and
`
`7
`
`Biocon Exhibit 1064 - Page 15
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`

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`IPR2023-00739
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`
`
`
`
`patient-level data. Ex.2009, 154-55 (163:5–165:13), 1413-14 (1620:6–1621:23).
`
`Dr. George Yancopoulos, co-founder and chief scientific officer, and sole inventor
`
`of the ’601 patent, made the decision to test in the phase III trial a dosing regimen
`
`of five loading doses followed by additional doses every eight weeks. Id. 1415–16
`
`(1622:15–1623:14), 1096–97 (1234:8–1235:4), 194 (203:5–13), 158–59 (167:25–
`
`168:22); Ex.2003, 2.
`
`Regeneron completed its phase III trial, see generally Ex.2003 and FDA
`
`approved an additional EYLEA® indication for DME in December 2013.
`
`Ex.2010. For DME, the EYLEA® label recommends the dosing regimen recited
`
`in the ’601 patent: five monthly loading doses followed by additional doses every
`
`eight weeks. Ex.1050, 1.
`
`B.
`
`The ’601 Patent
`
`On January 13, 2011, after the DA VINCI trial ended but before Do 2011
`
`reported the results, Regeneron filed provisional application No. 61/432,245, to
`
`which the ’601 patent claims priority. Ex.1001, 1:7–20. Example 5 in the
`
`provisional application, and in the ’601 patent, reports the DA VINCI trial protocol
`
`and results. See Ex.2011, ¶¶ 61–62; Ex.1001, 14:6–54. The provisional
`
`application and ’601 patent further disclose administering four secondary doses
`
`after the initial dose (i.e., five loading doses) to the patient. Ex.2011, ¶ 18;
`
`Ex.1001, 4:17–19.
`
`8
`
`Biocon Exhibit 1064 - Page 16
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`IPR2023-00739
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`The ’601 patent, which issued on January 12, 2021, claims methods of
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`treating angiogenic eye disorders by administering aflibercept in specific, fixed
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`dosing regimens. The remaining challenged claims are drawn to methods of
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`treating diabetic macular edema and the related condition diabetic retinopathy
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`using specific dosing regimens: five monthly loading doses followed by less-
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`frequent dosing, i.e., every eight weeks. The dosing regimen does not vary based
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`on individualized patient assessments.
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`C. District Court Litigation
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`Regeneron is litigating the validity of the ’601 patent in the Northern District
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`of West Virginia against Defendants Mylan Pharmaceuticals Inc. and Biocon
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`Biologics Inc., under the provisions of the Biologics Price Competition and
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`Innovation Act (BPCIA) (42 U.S.C. §262). See Ex.2012, 105 ¶ 122. Regeneron
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`filed its BPCIA complaint on August 2, 2022, but Regeneron and Mylan had been
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`engaged in the BPCIA’s “Patent Dance” exchanges since at least January 2022.
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`Ex.2013; Ex.2012, 11–12 ¶ 18.2
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`On April 19, 2023, the court construed multiple claim limitations in the
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`’601 patent, including the visual acuity and exclusion criteria limitations. Ex.
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`2014. As required by the scheduling order in the district court litigation, Ex.2015,
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`2 Biocon was added to the litigation in June 2023. Ex.2017.
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`9
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`Biocon Exhibit 1064 - Page 17
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`IPR2023-00739
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`Regeneron narrowed the number of claims for the June 2023 trial a week after the
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`district court’s claim construction order, selecting three claims of the ’601 patent at
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`that time. Ex.2016, 2.
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`Simultaneously, Regeneron stipulated to summary judgement of invalidity
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`with respect to certain claims of the ’601 patent (not including the claims selected
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`for trial or challenged in this proceeding) as a procedural vehicle to obtain an
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`appealable decision on the construction of those claims. See Portney v. CIBA
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`Vision Corp., 401 F. App’x 526, 529 (Fed. Cir. 2010) (“This court has generally
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`refrained from granting [petitions for interlocutory review] to resolve claim
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`construction disputes, instead, leaving such matters to be determined after entry of
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`final judgment.”); Ex.2016, 1 (Regeneron declining to oppose summary judgment
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`“[s]ubject to all appellate rights, including but not limited to rights of appeal
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`concerning claim construction.”).
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`A trial was held June 12–23. Ultimately, Regeneron selected claims 11 and
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`19 of the ’601 patent to assert in the trial, and the defendants challenged the
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`validity of these claims on several bases including obviousness, with the
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`2009 Press Release as the primary reference. Ex.2018, 27-28. Patent Owner and
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`Defendants are expected to present closing arguments on August 3, 2023, and
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`thereafter await the district court’s judgment. Ex.2019. An expedited appeal is
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`10
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`Biocon Exhibit 1064 - Page 18
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`likely to follow. See Ex.2020, 20:11–19 (counsel for Regeneron explaining
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`process by which it will seek to expedite any appeal); Ex.2016].
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`III. LEVEL OF ORDINARY SKILL IN THE ART
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`For purposes of this Preliminary Response, Patent Owner has used
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`Petitioner’s definition of the POSA. Patent Owner reserves the right to propose
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`another definition if review is instituted.
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`IV. CLAIM CONSTRUCTION
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`For purposes of this Preliminary Response only, Patent Owner does not
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`challenge Petitioner’s proposed constructions, because Petitioner has failed to
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`show a reasonable likelihood of prevailing on any ground, even under its own
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`constructions. Patent Owner reserves the right to propose alternative or additional
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`constructions if review is instituted.
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`V.
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`PETITIONER HAS NO REASONABLE LIKELIHOOD OF SUCCESS
`BECAUSE THE RECITED DOSING REGIMEN IS NOT
`DISCLOSED OR SUGGESTED BY THE PRIOR ART
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`A.
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`Petitioner Fails to Show That the 2009 Press Release or Shams
`Would Lead a POSA to the Recited Dosing Regimen (Ground 2)
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`Each of the claims challenged in this ground requires treating DR or DME
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`using a fixed dosing regimen that consists of (a) five monthly initial injections of
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`2 mg each, followed by (b) additional doses spread eight weeks apart. None of
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`Petitioner’s references discloses such a regimen, and Petitioner’s hindsight-riddled
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`mixing and matching of different disclosures from the 2009 Press Release and
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`11
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`Biocon Exhibit 1064 - Page 19
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`IPR2023-00739
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`Shams fails to cure this deficiency. Petitioner also ignores express teachings of the
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`references on which it relies. Neither reference discloses the recited dosing
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`regimen. Neither reference discloses that such a regimen would be desirable. And
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`the Shams reference was known by the priority date to describe a failed regimen
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`when extending dosing intervals beyond one month; Petitioner does not explain
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`why a POSA would have adopted Shams’ proposed regimen rather than rejecting
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`it—as POSAs, in fact, did.
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`1.
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`The References Neither Disclose the Recited Dosing
`Regimen nor Provide Any Reason for a POSA to Adopt
`That Regimen
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`The 2009 Press Release prospectively discloses aspects of the design of a
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`Phase 2 DME trial (DA VINCI) conducted by Regeneron, which contained four
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`arms: (1) VEGF Trap-Eye dosed at 0.5 mg monthly; (2) VEGF Trap-Eye dosed at
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`2 mg monthly; (3) VEGF Trap-Eye dosed at 2 mg every eight weeks after three
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`monthly loading doses; and (4) VEGF Trap-Eye dosed at 2 mg on a pro re nata
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`(as-needed) basis after three monthly loading doses. Ex.1009, 1.
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`Petitioner’s reliance on the 2009 Press Release suffers from two major
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`flaws. First, none of the four dosing regimens disclosed by the 2009 Press Release
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`is the five-loading-dose regimen required by all the claims challenged in this
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`ground. Second, the 2009 Press Release was issued before the DA VINCI clinical
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`trial began, and therefore, the 2009 Press Release does not disclose the results of
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`12
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`Biocon Exhibit 1064 - Page 20
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`any of the four regimens—much less results that would motivate a POSA to modify
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`one of the proposed regimens to add loading doses despite the obvious treatment
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`burden, as would be required to arrive at the recited dosing regimen.
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`In classic hindsight, the Petition also mixes and matches the dosing regimens
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`without articulating a rationale for doing so. Petitioner begins by emphasizing the
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`2q8 dosing arm of DA VINCI—which administered three monthly doses followed
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`by doses every eight weeks, see Pet. at 34–35—but then suggests that the monthly
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`(2q4) and as-needed dosing arms (2 PRN) would “suggest to a POSA that some
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`patients might benefit from more than three loading doses and would provide a
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`reasonable expectation of success for such patients.” Pet. 35. Petitioner does not
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`explain how these prospective arms could provide any such motivation, given that
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`the 2009 Press Release does not report the results for these arms—because no
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`results were available to be reported.
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`Even if results had been reported, Petitioner does not explain why the 2 PRN
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`regimen (as-needed dosing after three loading doses) would suggest that some
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`patients would benefit from more than three loading doses, much less five loading
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`doses. The 2q8 regimen involves three loading doses, and so does 2 PRN;
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`combining them does not disclose, let alone motivate, five loading doses. Nor does
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`the Petition explain why the 2 PRN regimen, which involves a switch from fixed
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`dosing to individualized patient assessment after three doses, would provide a
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`13
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`Biocon Exhibit 1064 - Page 21
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`motivation to achieve the claimed dosing regimen, which involves fixed dosing
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`throughout the course of treatment.
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`The addition of the Shams reference into the mix renders Petitioner’s ground
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`even more illogical. Shams concerns a different drug, Lucentis (ranibizumab) and
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`does not disclose the recited dosing regimen, let alone any results that a POSA
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`could reasonably expect from implementing such a regimen. Neither Shams nor
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`the 2009 Press Releases discloses five loading doses, and Petitioner has not
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`articulated any reason to modify the dosing regimens of the prior art beyond a
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`hindsight desire to arrive at the invention of the claims. This dooms Petitioner’s
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`obviousness argument. See Life Spine, Inc. v. Globus Medical, Inc., IPR2022-
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`01603, Paper 8 at 41 (P.T.A.B. June 12, 2023) (denying institution where record
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`“d[i]d not reveal a reason for making the multiple modifications Petitioner
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`proposes in its combination other than a desire to arrive at device [sic] with all the
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`elements recited in claim”).
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`Petitioner instead relies on Shams for the general concept of “a treatment
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`schedule comprising an initial interval of administration of a therapeutic compound
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`[an VEGF antagonist], followed by a subsequent, less frequent interval of
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`administration of the therapeutic compound.” Pet. 36 (quoting Ex.1010, 22)
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`(alteration in original). But Petitioner identifies nothing in Shams that would point
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`the way specifically towards the recited dosing regimen. Petitioner admits as
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`14
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`Biocon Exhibit 1064 - Page 22
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`much—it concedes that, by its own logic, “other dosing regimens with a different
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`number of monthly doses—such as three, four, six, etc.” were also obvious.
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`Pet. 38 (emphasis added).
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`Petitioner’s argument that any number of monthly loading doses were
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`obvious is a misapplication of core obviousness law. The Supreme Court has
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`noted that it is not “obvious to try” multiple possibilities unless “there are a finite
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`number of identified, predictable solutions.” KSR Int’l Co. v. Teleflex Inc.,
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`550 U.S. 398, 421 (2007). And the Federal Circuit has