Case 1:22-cv-00061-TSK-JPM Document 593 Filed 07/28/23 Page 1 of 19 PageID #: 46473
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE NORTHERN DISTRICT OF WEST VIRGINIA
`
`
`Plaintiff,
`
`
`v.
`
`
`REGENERON PHARMACEUTICALS, INC.,
`
`
`
`
`MYLAN PHARMACEUTICALS INC.
`and BIOCON BIOLOGICS INC.,
`
`
`
`
`
`
`Case No. 1:22-cv-00061-TSK
`
`
`
`
`
`
`
`
`
`
`Defendants.
`
`DEFENDANTS’ REPLY POST TRIAL BRIEF – ISSUES
`WHERE DEFENDANTS BEAR THE BURDEN OF PROOF
`
`
`
`

`

`Case 1:22-cv-00061-TSK-JPM Document 593 Filed 07/28/23 Page 2 of 19 PageID #: 46474
`
`TABLE OF CONTENTS
`
`I.
`
`THE DOSING PATENTS. ................................................................................................. 1
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`F.
`
`Claim 6 – the isotonic solution is anticipated by Dixon (DTX 204). ..................... 1
`
`Claim 6 – using an isotonic solution would have been obvious. ............................ 2
`
`The DME/DR claims are anticipated. ..................................................................... 3
`
`The DME/DR claims would have been obvious..................................................... 5
`
`Regeneron continues to blur lines on secondary considerations. ........................... 5
`
`The claims are invalid under 35 U.S.C. § 112. ....................................................... 6
`
`II.
`
`THE ‘865 FORMULATION PATENT. ............................................................................. 8
`
`A.
`
`B.
`
`C.
`
`D.
`
`Dix ‘226 anticipates and renders the claims obvious. ............................................. 8
`
`The combinations: Fraser + Lucentis or Fraser + Liu. .......................................... 9
`
`Other secondary considerations. ........................................................................... 10
`
`The claims fail to comply with § 112. .................................................................. 10
`
`III.
`
`CONCLUSION. ................................................................................................................ 10
`
`
`
`
`
`
`
` i
`
`

`

`Case 1:22-cv-00061-TSK-JPM Document 593 Filed 07/28/23 Page 3 of 19 PageID #: 46475
`
`TABLE OF AUTHORITIES
`
`Cases
`
`Abbott Lab’ys v. Baxter Pharm. Prods., Inc.,
`471 F.3d 1363 (Fed. Cir. 2006) .................................................................................................. 1
`
`Allergan, Inc. v. Sandoz Inc.,
`796 F.3d 1293 (Fed. Cir. 2015) .................................................................................................. 7
`
`Amazon.com, Inc. v. Barnesandnoble.com, Inc.,
`239 F.3d 1343 (Fed. Cir. 2001) .................................................................................................. 5
`
`Andrew Corp. v. Gabriel Elecs., Inc.,
`847 F.2d 819 (Fed. Cir. 1988) .................................................................................................... 7
`
`Bayer Healthcare Pharms., Inc. v. Watson Pharms., Inc.,
`713 F.3d 1369 (Fed. Cir. 2013) .................................................................................................. 6
`
`Crown Ops. Int’l, Ltd. v. Solutia Inc.,
`289 F.3d 1367 (Fed. Cir. 2002) .................................................................................................. 6
`
`Estee Lauder Inc. v. L’Oreal, S.A.,
`129 F.3d 588 (Fed. Cir. 1997) .................................................................................................... 8
`
`Graham v. John Deere Co. of Kan. City,
`383 U.S. 1 (1966) ........................................................................................................................ 2
`
`Hoffmann-La Roche Inc. v. Apotex Inc.,
`748 F.3d 1326 (Fed. Cir. 2014) .................................................................................................. 2
`
`Immersion Corp. v. Motorola Mobility LLC,
`2018 WL 5294508 (D. Del. Oct. 25, 2018) ................................................................................ 8
`
`In re Copaxone Consol. Cases,
`906 F.3d 1013 (Fed. Cir. 2018) .................................................................................................. 2
`
`In re Kubin,
`2007 WL 2070495 (P.T.A.B. May 31, 2007) ............................................................................. 5
`
`In re Kubin,
`561 F.3d 1351 (Fed. Cir. 2009) .................................................................................................. 5
`
`In re Petering,
`301 F.2d 676 (C.C.P.A. 1962) .................................................................................................... 9
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ................................................................................................................ 2, 3
`
` ii
`
`

`

`Case 1:22-cv-00061-TSK-JPM Document 593 Filed 07/28/23 Page 4 of 19 PageID #: 46476
`
`Net MoneyIN, Inc. v. VeriSign, Inc.,
`545 F.3d 1359 (Fed. Cir. 2008) .................................................................................................. 4
`
`Oka v. Youssefyeh,
`849 F.2d 581 (Fed. Cir. 1988) .................................................................................................... 8
`
`PAR Pharm., Inc. v. TWI Pharms., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) .................................................................................................. 3
`
`Parker Compound Bows, Inc. v. Hunter’s Mfg. Co., Inc.,
`2016 WL 617464 (W.D. Va. Feb. 12, 2016) .............................................................................. 8
`
`Rasmusson v. SmithKline Beecham Corp.,
`413 F.3d 1318 (Fed. Cir. 2005) .................................................................................................. 7
`
`UCB, Inc. v. Actavis Lab’ys UT, Inc.,
`65 F.4th 679 (Fed. Cir. 2023) ..................................................................................................... 5
`
`Warner Chilcott Co., LLC v. Teva Pharms. U.S.A, Inc.,
`642 Fed. App’x 996 (Fed. Cir. 2016) ......................................................................................... 2
`
`Statutes
`
`35 U.S.C. § 102(a) .......................................................................................................................... 8
`
`35 U.S.C. § 103(c) .......................................................................................................................... 8
`
`35 U.S.C. § 112 ......................................................................................................................... 1, 10
`
`
`
`
`
`
` iii
`
`

`

`Case 1:22-cv-00061-TSK-JPM Document 593 Filed 07/28/23 Page 5 of 19 PageID #: 46477
`
`Abbreviation
`‘572 patent
`‘601 patent
`‘747 patent
`‘865 patent
`‘959 patent
`
`7-20-23 PTAB
`
`AMD
`
`Asserted Patents
`
`Asserted Claims
`
`BCVA
`
`DA VINCI
`
`Defs.’ FOF, Defendants’
`Proposed Findings
`Defendants
`Dix ‘226
`
`Dixon
`
`DME
`Dosing Patents
`DR
`FDA
`
`TABLE OF ABREVIATIONS
`
`Description
`U.S. Patent No. 11,253,572 B2 (PTX 3)
`U.S. Patent No. 10,888,601 B2 (PTX 1)
`U.S. Patent No. 7,303,474 B2 (DTX 2730)
`U.S. Patent No. 11,084,865 B2 (PTX 2)
`U.S. Patent No. 7,070,959 B1 (DTX 7)
`Celltrion, Inc. v. Regeneron Pharms., Inc., IPR2023-00462, Paper
`11 (P.T.A.B. July 20, 2023)
`Age-related macular degeneration
`The ‘601 patent (PTX 1), ‘865 patent (PTX 2), and ‘572 patent
`(PTX 3)
`Claims 11 and 19 of the ‘601 patent, claims 6 and 25 of the ‘572
`patent, and claims 4, 7, 9, 11, and 14-17 of the ‘865 patent
`Best corrected visual acuity
`Phase II Regeneron clinical trial for the use of aflibercept to treat
`DME
`Defendants’ Proposed Findings of Fact and Conclusions of Law
`(Dkt. 587)
`Biocon Biologics Inc. and Mylan Pharmaceuticals Inc.
`U.S. Patent No. 10,406,226 B2 (DTX 13)
`James A. Dixon et al., VEGF Trap-Eye for the Treatment
`of Neovascular Age-Related Macular Degeneration, 18 EXPERT
`OPINION INVESTIGATIONAL DRUGS 1573 (2009) (DTX 204)
`Diabetic macular edema
`The ‘572 patent and the ‘601 patent
`Diabetic retinopathy
`United States Food and Drug Administration
`
` iv
`
`

`

`Case 1:22-cv-00061-TSK-JPM Document 593 Filed 07/28/23 Page 6 of 19 PageID #: 46478
`
`Abbreviation
`
`Fraser
`
`Gaudreault
`
`Hecht
`
`Liu
`
`mg
`mL
`POSA
`PRN
`PTAB
`PVR
`Regeneron
`
`Press Release
`
`Saishin
`
`Tr.
`VEGF
`VEGF Trap
`
`VIEW 1/VIEW 2
`
`Description
`Hamish M. Fraser et al., Single Injections of Vascular Endothelial
`Growth Factor Trap Block Ovulation in the Macaque and
`Produce a Prolonged, Dose-Related Suppression of
`Ovarian Function, 90 CLINICAL ENDOCRINOLOGY & METABOLISM
`1114 (2005) (DTX 729)
`Jacques Gaudreault et al., Preclinical Pharmacokinetics of
`Ranibizumab (rhuFabV2) after a Single Intravitreal
`Administration, 46 INVESTIGATIVE OPHTHALMOLOGY & VISUAL
`SCIENCE 726 (2005) (DTX 2265/PTX 1839)
`Gerald Hecht, Ophthalmic Preparations, in 2 REMINGTON: THE
`SCIENCE AND PRACTICE OF PHARMACY, 1563 (Alfonso R. Gennaro
`et al. eds.,19th ed. 1995) (DTX 3588)
`US. Patent Application Publication No. 2004/0197324 A1 (DTX
`730)
`Milligram
`Milliliter
`Person of ordinary skill in the art
`Pro re nata or as-needed dosing
`Patent Trial and Appeal Board
`Proliferative vitreoretinopathy
`Regeneron Pharmaceuticals, Inc.
`Regeneron Press Release, Enrollment Completed in Regeneron and
`Bayer HealthCare Phase 3 Studies of VEGF Trap-Eye in
`Neovascular Age-Related Macular Degeneration (Wet AMD)
`(September 14, 2009) (DTX 3198)
`Yoshitsugu Saishin et al., VEGF-TRAPR1R2 Suppresses Choroidal
`Neovascularization and VEGF-Induced Breakdown of the Blood-
`Retinal Barrier, 195 J. CELLULAR PHYSIOLOGY 241 (2003) (DTX
`2751)
`Trial Transcript
`Vascular endothelial growth factor
`Regeneron development name for aflibercept
`Phase III Regeneron clinical trials for the use of aflibercept to treat
`AMD
`
` v
`
`

`

`Case 1:22-cv-00061-TSK-JPM Document 593 Filed 07/28/23 Page 7 of 19 PageID #: 46479
`
`Abbreviation
`Dkt. 427
`
`Dkt. 432-17
`
`Dkt. 432-18
`
`Dkt. 433
`
`Dkt. 445-17
`Dkt. 584
`
`Dkt. 587
`
`TABLE OF RECORD CITATIONS
`
`Description
`Order on Claim Construction (April 19, 2023)
`Opening Expert Report of Bernhardt L. Trout, Ph.D., with Appendices A
`and B, dated February 2, 2023
`Reply Expert Report of Bernhardt L. Trout, Ph.D., Appendices A and B,
`dated March 30, 2023
`Regeneron’s Stipulation Regarding Summary Judgment and Case
`Narrowing (April 27, 2023)
`Response Expert Report of Dr. Bernhardt L. Trout, dated March 2, 2023
`Regeneron’s Responsive Post-Trial Brief (July 24, 2023)
`Defendants’ Proposed Findings of Fact and Conclusions of Law (July 24,
`2023)
`
` vi
`
`

`

`Case 1:22-cv-00061-TSK-JPM Document 593 Filed 07/28/23 Page 8 of 19 PageID #: 46480
`
`Regeneron’s asserted claims are invalid, as Defendants’ Proposed Findings (Dkt. 587) and
`
`prior briefing detail. What the Dosing Patent claims cover was inherent (in Dixon’s clinical trial
`
`2 mg dose, in a comfortable and non-irritating formulation, in a press release’s PRN dosing
`
`regimen) and obvious (an isotonic formulation, 5 loading doses). The specification fails under §
`
`112 for angiogenic eye disorders, isotonicity, and 5 loading doses, while using uncertain claim
`
`terms (“approximately”). The ‘865 patent claims are anticipated by Dix ‘226 (which is prior art;
`
`and its teachings, examples, and embodiments disclosed what is claimed), obvious over Dix ‘226
`
`or combinations (Fraser + Lucentis, Fraser + Liu); and invalid for claiming a broad genus from
`
`limited examples, and using the indefinite phrase “suitable for intravitreal administration.”
`
`I.
`
`THE DOSING PATENTS.
`
`A.
`
`Claim 6 – the isotonic solution is anticipated by Dixon (DTX 204).
`
`Dixon describes clinical trials with the claimed dosing regimen at 2 mg of aflibercept.
`
`(Dkt. 584, 24-25). That 2 mg dose was Regeneron’s Eylea®, and had the property of being isotonic.
`
`Regeneron wrongly insists a POSA must know this inherent property “before the priority date.”
`
`(Id., 24). But a reference anticipates “even when the relevant properties of the thing disclosed
`
`were not appreciated at the time.” Abbott Lab’ys v. Baxter Pharm. Prods., Inc., 471 F.3d 1363,
`
`1367 (Fed. Cir. 2006). At the time, a POSA knew that Phase 3 trials test the product for
`
`commercial marketing. (Tr. 827:17-25 (Albini)). Over 220 retinal practices across 43 U.S. states
`
`had access to the Eylea® formulation via the Phase 3 trials.1 Dixon also listed three criteria for the
`
`aflibercept formulation: (1) “comfortable;” (2) “non-irritating;” and (3) for “direct injection into
`
`the eye.” (DTX 204.3). The “non-isotonic” formulations Regeneron relies on at most meet the
`
`last; only an isotonic formulation meets all three. (Tr. 1096:15-1098:8 (Rabinow); DTX 3588.11,
`
`
`1 (DTX 231.3-7 (listing the states with participating sites); see also PTX 188.1 (noting “we cannot
`significantly increase the number of sites beyond the 220 or so already assumed” in the U.S and Canada)).
`
`1
`
`

`

`Case 1:22-cv-00061-TSK-JPM Document 593 Filed 07/28/23 Page 9 of 19 PageID #: 46481
`
`13). A non-isotonic formulation can injure eyes—the antithesis of comfortable and non-irritating.
`
`(Tr. 1098:9-1099:10, 1173:6-13 (Rabinow); DTX 9038.2 (non-isotonic ziv-aflibercept may cause
`
`retinal toxicity and detachment)). A POSA knows a harmful formulation is not put to Phase 3
`
`clinical trials. The isotonic solution thus was inherent2 and known. Dixon anticipates claim 6.
`
`B.
`
`Claim 6 – using an isotonic solution would have been obvious.
`
`Defendants focused on “isotonic” because the obviousness test requires considering “the
`
`differences between the prior art and the claims at issue.” KSR Int’l Co. v. Teleflex Inc., 550 U.S.
`
`398, 399 (2007) (quoting Graham v. John Deere Co., 383 U.S. 1, 17-18 (1966)). Regeneron admits
`
`Dixon taught the claim 6 regimen (Dkt. 433), arguing “the only claim limitation it [expressly] lacks
`
`is” isotonic; thus, that limitation received “the prominence that it must” in Defendants’ analysis.
`
`Warner Chilcott Co., LLC v. Teva Pharms. U.S.A, Inc., 642 Fed. App’x 996, 1002 (Fed. Cir. 2016).
`
`Dixon gave a POSA a reason to pursue the claimed regimen and dose (it was in clinical
`
`trial human use), and the injected dose’s properties—comfortable and non-irritating. (DTX 204.3-
`
`4). An isotonic formulation is obvious and “obvious to try” because only it meets Dixon’s criteria.
`
`Even if the options include hypertonic and hypotonic formulations, it remains a preferred 1 of a
`
`limited 3 options. (Tr. 212:14-24 (Yancopoulos)). Hecht confirms why an isotonic formulation
`
`also meets the criteria. (DTX 3588.11, 13). Regeneron does not contest this. (Dkt. 584, 25-27).
`
`Regeneron argues this is not viewing the claims “as a whole.” (Dkt. 584, 26). Finding a
`
`regimen a POSA is motivated to consider, then how to dose the regimen, is a proper path to show
`
`obviousness. See In re Copaxone Consol. Cases, 906 F.3d 1013, 1025-29 (Fed. Cir. 2018);
`
`Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1332 (Fed. Cir. 2014). Dixon described
`
`an actual regimen in human clinical use. (DTX 204.4). It is a “design step well within the grasp
`
`
`2 Dr. Trout did not opine on inherency in his expert reports. (See generally Dkt. 432-17, 432-18, 445-17).
`Regeneron is prohibited from using him for that purpose here.
`
` 2
`
`

`

`Case 1:22-cv-00061-TSK-JPM Document 593 Filed 07/28/23 Page 10 of 19 PageID #:
`46482
`
`of a person of ordinary skill in the relevant art.” KSR, 550 U.S. at 427. The claims have no efficacy
`
`requirements. (Dkt. 427, 26-28). Defendants need only prove a “suitable” regimen and dose, PAR
`
`Pharm., Inc. v. TWI Pharms., Inc., 773 F.3d 1186, 1197-98 (Fed. Cir. 2014), not those superior to
`
`Lucentis or the “most effective.” (Dkt. 584, 26).
`
`Even so, POSAs expected the Phase 3 trials would hit the primary endpoint and have a
`
`better interval compared to Lucentis. VIEW 1 clinician Dr. Nguyen, (DTX 2053.13), in 2010
`
`explained the 4- and 8-week arms were designed “to get the maximum result;” the dose would
`
`“most likely have a longer duration of action,” and it was expected that “every eight weeks let’s
`
`just say to be conservative work as well as every four weeks of Lucentis,” which would make it
`
`“a winner.” (DTX 2053.17). Dr. Rosenfeld also opined it would be the “duration of effect that
`
`really shows the benefit.” (DTX 2053.18; see also DTX 917.1). Nor were the clinical results
`
`unexpected given the robust Phase II results seen in Dixon, showing patients gaining an average
`
`of 9 BCVA letters and 29% gaining ≥ 15 letters, on a regimen that involved even fewer doses than
`
`the claimed regimen. (Tr. 840:15-844:23 (Albini); DTX 204.4; DTX 3173.6, 9, 12, 16 19).
`
`Dr. Csaky’s so-called “praise” was a routine press release announcing the FDA approved
`
`the drug, (DTX 3112.1), for the expected outcome. Dr. Albini viewed the claim as a whole to
`
`show that Dixon’s disclosed claim 6 regimen and formulation guidance taught isotonicity. (Tr.
`
`811:13-813:12; 826:7-23 (Albini); DTX 204.4). Industry never praised the isotonic solution in the
`
`regimen. (Tr. 845:1-18; 846:12-15 (Albini)). Claim 6 was obvious.
`
`C.
`
`The DME/DR claims are anticipated.
`
`Regeneron’s DME/DR claims lack any limitations that Regeneron raises against the prior
`
`art.3 (Dkt. 584, 18; PTX 3.25, claim 25; PTX 1.21, claim 11; PTX 1.22, claim 19).
`
`
`3 Dr. Csaky argued the art did not reduce office visits; fully fix the regimen; was not “reliable,” etc. (See,
`e.g., Tr. 293:25-295:2, 1816:4-24, 1824:1-19, 1849:22-25, 1914:18-1915:6, 1915:21-1916:4 (Csaky)).
`
` 3
`
`

`

`Case 1:22-cv-00061-TSK-JPM Document 593 Filed 07/28/23 Page 11 of 19 PageID #:
`46483
`
`
`
`Regeneron cites Net MoneyIN, Inc. v. VeriSign, Inc., 545 F.3d 1359, 1369 (Fed. Cir. 2008);
`
`it is distinguishable. (Dkt. 584, 18). Those claims had a 5-step secured transaction process in a
`
`precise order; the prior art had two distinct protocols. Id. at 1363, 1368-69. The two protocols the
`
`prior art deliberately kept distinct could only be combined for obviousness, not anticipation. Id.
`
`at 1371. Here, the Press Release has one regimen, the PRN regimen, which includes the 5 loading
`
`dose option plus 8-week interval within its existing range:
`
`
`
`
`
` Y Y Y Y/N Y/N Y/N Y/N
`
`
` 20 24
` 12 16
` Week: 0 4 8
`
`(PDX 1.124; Tr. 1958:19-1961:24 (Csaky) (conceding the regimen that meets the claims in the
`
`
`
`above)). The order of the protocol thus is as arranged as in the claim. Defendants’ experts did not
`
`accept Regeneron’s contrary arguments.4 Regeneron argues that a POSA could not know PRN
`
`visits would occur monthly. (Dkt. 584, 20). A POSA understands that PRN dosing uses monthly
`
`visits. (Tr. 782:8-10 (Albini); see also DTX 915.8 (subjects in Regeneron trials being evaluated
`
`monthly); Tr. 227:3-228:8 (Yancopoulos) (clinical trials require monthly visits no matter the
`
`regimen)). A POSA also knows clinical trial arms are on the same schedule to mask who gets
`
`which dose. (Tr. 1233:8-1234:7 (Chu(30(b)(6)) (discussing maintaining the mask); Tr. 1591:8-
`
`1592:6 (Chu) (sham injections as another part of the mask)). Here it was every 4 weeks. (DTX
`
`3198.2). Dr. Do also published that patients were seen every 4 weeks/monthly in the trial. (DTX
`
`3105.2-3). Further, Dr. Csaky’s invalidity position (PRN regimens do not invalidate) and
`
`infringement opinions (a PRN regimen might infringe) conflict. (Tr. 416:13-17 (Csaky)). The
`
`claims cannot “be twisted one way to avoid anticipation and another to find infringement.”
`
`
`4 Dr. Stewart did not admit the press release PRN regimen lacked 5 loading doses; he confirmed the
`disclosed PRN regimen permits a 5-dose/8-week method for patients. (Tr. 1358:20-1359:5 (Stewart)).
`
` 4
`
`

`

`Case 1:22-cv-00061-TSK-JPM Document 593 Filed 07/28/23 Page 12 of 19 PageID #:
`46484
`
`Amazon.com, Inc. v. Barnesandnoble.com, Inc., 239 F.3d 1343, 1351 (Fed. Cir. 2001).
`
`
`
`Regeneron argues that DR is not a genus to the DME species; that contradicts its
`
`representations to FDA. (PTX 3332.3-4). FDA gave Regeneron “breakthrough designation” for
`
`DR in DME patients, because they are a subset of DR patients. (PTX 3332.35-36). FDA did not
`
`accept the reverse—that the same data supports treating DR patients without DME. (PTX
`
`3332.35).5 Dr. Albini confirmed that “DME is technically a type of diabetic retinopathy,” namely
`
`“a complication of diabetic retinopathy or a subtype of diabetic retinopathy,” (Tr. 779:6-22
`
`(Albini)), thus treating DME treats a type, complication, or species of DR.
`
`D.
`
`The DME/DR claims would have been obvious.
`
`Defendants did not simply “assume without basis” that it was obvious to treat all DR
`
`patients with every method to treat DME. (Dkt. 584, 24). Defendants proved that DME patients
`
`are a “species” of DR patients; since claim 19 covers a method of treating the DR “genus,” that is
`
`anticipated by, and obvious over, the same method for treating DME. In re Kubin, 2007 WL
`
`2070495, at *4 (P.T.A.B. May 31, 2007), aff’d, 561 F.3d 1351, 1361 (Fed. Cir. 2009) (“A single,
`
`obvious species within a claimed genus renders the claimed genus unpatentable under § 103.”).
`
`E.
`
`Regeneron continues to blur lines on secondary considerations.
`
`The Phase 3 VIEW 1/VIEW 2 results were not unexpected; Regeneron publicized those
`
`“successful[]” results before the patents were filed. (See generally DTX 917; DTX 915; DTX
`
`2053). Success was also expected for the 8-week DME regimen. Dr. Rosenfeld stated that after
`
`seeing the 6-month DA VINCI data for DME (the data from the Press Release’s regimen), “I said
`
`wow, dosing every two months with VEGF-Trap and diabetic macular edema is as good as
`
`
`5 This is why the full scope of DR uses is not enabled (because the full scope of the DR disease includes
`types of patients not experiencing DME, (see Tr. 1287:2-7 (Stewart)), but is anticipated by the DR in DME
`patient species; once the prior art “discloses a point within the claimed range, the prior art anticipates the
`claim.” UCB, Inc. v. Actavis Lab’ys UT, Inc., 65 F.4th 679, 687 (Fed. Cir. 2023).
`
` 5
`
`

`

`Case 1:22-cv-00061-TSK-JPM Document 593 Filed 07/28/23 Page 13 of 19 PageID #:
`46485
`
`monthly dosing … I thought wow that’s a winner.” (DTX 2053.18-19). The results were not
`
`unexpected, did not satisfy a long-felt need, or solve others’ failures. (Dkt. 587, 160-68). Copying
`
`further is not “probative of nonobviousness,” since “a showing of bioequivalence is required for
`
`FDA approval.” Bayer Healthcare Pharms., Inc. v. Watson Pharms., Inc., 713 F.3d 1369, 1377
`
`(Fed. Cir. 2013). (Tr. 790:22-793:10 (Albini); DTX 3102.1, .5; DTX 2733.1-2).
`
`F.
`
`The claims are invalid under 35 U.S.C. § 112.
`
`Regeneron argues Dr. Stewart wrongly required proof of specification examples. (Dkt.
`
`584, 29). He did not assume the wrong standard for his testimony. (Tr. 1358:5-8 (Stewart)).
`
`Isotonic. A POSA did not have common structural features or properties for “isotonic”
`
`from the specification. Dr. Yancopoulos disagreed a physiological saline formulation with the
`
`structural features Dr. Trout relies on is isotonic. (Tr. 181:19-25 (Yancopoulos)). He argued only
`
`a formulation identical to the eye’s was isotonic; which differs from Dr. Graham’s standard (300-
`
`320 mOsm); both differ from Dr. Trout’s. (Compare Tr. 139:14-140:13 (Yancopoulos), and Tr.
`
`1721:23-24 (Graham), with Tr. 640:20-642:4 (Trout)). Under the “isotonic” standards of
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`Yancopoulos/Graham, YESAFILITM does not infringe. Nor did Dr. Trout find “blaze marks” to
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`combine the isotonic solution from the myriad of formulations disclosed (emulsion, oily medium;
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`non-isotonic solutions, etc.) with the specific regimen claimed.
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`Angiogenic eye disorder. When a 2022 reference explains that “a pharmacologic method
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`of inhibiting PVR remains elusive,” (DTX 5430.7); or physicians must dose the drug four times
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`daily, (DTX 9031.1-2); or move injection sites to better target the disease, (DTX 5429.1); that
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`shows the claim 6 dosing regimen, at the time of filing, did not work across the full claim scope
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`absent an undue experimental burden. Regeneron could have shown that a POSA could as a matter
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`of routine exclude the inoperative embodiments, but did not, and thus the claims are invalid.
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`Crown Ops. Int’l, Ltd. v. Solutia Inc., 289 F.3d 1367, 1380-81 (Fed. Cir. 2002).
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`DME/DR: no written description. The specifications lack the 5-dose regimen species
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`“arranged as in the claim.” (See Dkt. 584, 18). The lists of “preferred” methods and materials
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`starting at column 3 never lead to the claimed DME or DR regimen; it’s buried in a million
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`possibilities to combine.6 Example 7 does not tie any of its laundry list of regimens to a specific
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`disease state, let alone DR. (See Tr. 1292:25-1294:9, 1296:14-18, 1297:2-19 (Stewart)). The
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`working Example for DME lists the same Press Release regimens that Regeneron insists teach
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`away from 5 loading doses. (Tr. 1846:11-1847:3, 1848:8-1849:2, 1958:19-1961:24 (Csaky)).
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`From this, a POSA sees the forest; not the tree.
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`DME/DR: no enablement. Whether a POSA “could” make injections into the eye is not
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`dispositive of whether he believes he should. Regeneron’s obviousness defense insists there is “no
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`indication” in which a POSA would “accept without question” the use of 5 loading doses. The
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`specifications here lack the data and reasoning Dr. Csaky insists a POSA would need to pursue 5
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`loading doses; and contains the same data Dr. Csaky argues discourages using 5 loading doses.
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`(Tr. 1846:11-1847:3, 1848:8-1849:2 (Csaky)). This precludes enablement. Rasmusson v.
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`SmithKline Beecham Corp., 413 F.3d 1318, 1323 (Fed. Cir. 2005). This also distinguishes
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`Allergan, Inc. v. Sandoz Inc., 796 F.3d 1293, 1310 (Fed. Cir. 2015); there the prior art taught that
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`BAK would not increase permeability; the specification’s test data resolved this to show it did.
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`Approximately is indefinite. Andrew Corp. v. Gabriel Elecs., Inc., 847 F.2d 819, 821-22
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`(Fed. Cir. 1988) allowed “closely approximate” because the technology “could not reasonably be
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`expressed more precisely.” Regeneron touts its regimens as “fixed,” thus should not need
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`approximation. Immersion Corp. v. Motorola Mobility LLC, 2018 WL 5294508, at *7 (D. Del.
`
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`6 (See PTX 1.13, 5:21-39 (listing angiogenic eye disorders); PTX 3.16, 5:30-48 (same); PTX 1.13-14, 6:25-
`7:44 (describing dosing routes, ranges, and injection numbers); PTX 3.16-17, 6:35-7:52 (same); see also
`Tr. 1271:23-1272:7, 1280:24-1281:3, 1283:2-16 (Stewart))
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`Oct. 25, 2018) just pushed the indefiniteness issue to summary judgment; in Parker Compound
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`Bows, Inc. v. Hunter’s Mfg. Co., Inc., 2016 WL 617464, at *23 (W.D. Va. Feb. 12, 2016), the
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`specification “describe[d] how” the term approximated “is measured.” The Dosing Patents defined
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`“about” to mean “no more than 1%” variation. (PTX 1.12, 3:14-23; PTX 3.15, 3:24-32). It lacks
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`a comparably-defined standard for “approximately.”7 Thus, the claims are indefinite.
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`II.
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`THE ‘865 FORMULATION PATENT.
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`The asserted ‘865 claims blazed no new trail—they follow Dix ‘226; Fraser + Lucentis;
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`and Fraser + Liu. Regeneron complains these references lack one example combining 40 mg/ml,
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`glycosylated aflibercept, buffer, stabilizing agent and polysorbate to achieve 98% native
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`conformation. (Dkt. 584, 4). But applying Regeneron’s logic, so does the ‘865 patent, which
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`never states the Example VEGFs are glycosylated, never injects the formulation, never shows lack
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`of inflammation, and is silent on efficacy. These claims are not new, and are also obvious.
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`A.
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`Dix ‘226 anticipates and renders the claims obvious.
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`Regeneron lacks evidence of a pre-filing date conception of, or testing across, the full claim
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`scope. Oka v. Youssefyeh, 849 F.2d 581, 584 (Fed. Cir. 1988) (conception of a species inadequate
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`to support the generic count); Estee Lauder Inc. v. L’Oreal, S.A., 129 F.3d 588, 594-95 (Fed. Cir.
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`1997) (when tests are in the claims, there must be “appreciation that the tests were successful”).
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`It also cannot support its claims with its provisional application given the new matter added. (Dkt.
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`587, 326-28). Thus, Dix ‘226 (or its publication, DTX 4121) is prior art, at least under § 102(a);
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`hence avoiding § 103(c) prohibitions. (See Dkt. 587, 325-29, 422-52).
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`Regeneron argues there is no overlap with its 40 mg/mL element; or disclosure of 98%
`
`
`7 The art Regeneron cites applies different ranges even when applied to days. (See Tr. 1343:23-1349:22,
`1353:23-1354:11 (approximately used consistently in cited art, not in multiple ways like in the Dosing
`Patents)). Regeneron at trial also defined the term differently to mean schedule ranges or efficacy outcomes.
`(Tr. 1312:24-1313:22, 1315:2-22, 1316:19-1317:14 (Stewart)).
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`native conformation. (Dkt. 584, 3-4, 12-13). Dix ‘226 used “specific embodiment” and
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`“preferred” guidance to narrow the scope to a limited set, including 40 mg/mL. In re Petering,
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`301 F.2d 676, 681 (C.C.P.A. 1962). Dix disclosed “a specific embodiment” of “SEQ ID NO:4”
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`that “is glycosylated” at the same asparagine residues (DTX 13.6, 5:37-42), and preserved the
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`native conformation of 98% at both higher and lower concentrations, rendering it “a natural result
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`of the formulation ingredients,” as the PTAB recently observed. (Ex. 1, Celltrion, Inc. v.
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`Regeneron Pharms., Inc., IPR2023-00462, Paper 11, 20-21, 31-32 (P.T.A.B. July 20, 2023) (“7-
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`20-23 PTAB”); see also Tr. 2148:17-2150:5 (Trout) (Dix’s 50 mg/mL formulation was stable and
`
`not aggregating; the 40 mg/mL would be as well)). Dix ‘226 also overlaps with the claims viewed
`
`as a whole, with buffers, stabilizers, co-solvents, and the like. Dix ‘226 anticipates.
`
`B.
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`The combinations: Fraser + Lucentis or Fraser + Liu.
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`The PTAB also recently rejected the arguments Dr. Trout made about Fraser. The PTAB
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`stated Fraser was “one clear starting point” for formulations; disclosed the VEGF TrapR1R2
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`sequence; taught preparing aflibercept in CHO cells; and was the Dix ‘226 Example 5 formulation,
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`and hence inherently stable with the proper native conformation. (7-20-23 PTAB at 28-33, 38-39;
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`DTX 13.9 (Dix Table 9 shows native confirmation)). The ‘865 patent admits CHO cell synthesis
`
`produces glycosylated structures. (PTX 2.6, 6:32-37).
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`Saishin (DTX 2751) showed one more-potent aflibercept “markedly suppressed” VEGF
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`(Tr. 1080:6-18 (Rabinow); DTX 2751.7). Dr. Trout insists a POSA would want lower, non-
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`intravitreal doses with ranibizumab. (Tr. 2033:14-20, 2072:21-2073:6 (Trout)). That is not
`
`credible. At the time clinicians thought aflibercept had “a better probability” to show a more
`
`durable treatment effect,” and encouraged Regeneron to increase doses to “2 mg and 4 mg.” (DTX
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`222.1). In the intravitreal injection volume, those doses are 40 mg/mL and 80 mg/mL; Gaudreault
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`used 40 mg/mL. (Tr. 1645:3-15; 1650:3-25 (Chu); Tr. 1033:10-19, 1035:4-24, 1072:23-1073:4
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` 9
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`Case 1:22-cv-00061-TSK-JPM Document 593 Filed 07/28/23 Page 17 of 19 PageID #:
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`(Rabinow); DTX 2264.2; DTX 9036.6; DTX 726.32; DTX 2265.2). Dr. Trout’s teaching away
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`theories for Gaudreault also are not credible. The field intravitreally dosed the much-larger
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`bevacizumab, at higher doses (1.0/1.25 mg), to good results. (DTX 3058.1; DTX 2264.1; 9036.5).
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`Regeneron moved aflibercept, not mini-Trap, to human trials. (Tr. 548:13-22 (Furfine); DTX
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`4957.5). The Eylea® formulation was not unexpectedly safer—Regeneron told FDA it also had
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`“transient ocular inflammation.” (PTX 3255.4, 19; Tr. 546:25-548:12 (Furfine)).
`
`C.
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`Other secondary consid