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`53455
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE NORTHERN DISTRICT OF WEST VIRGINIA
`
`REGENERON PHARMACEUTICALS, INC.,
`Plaintiff,
`
`v.
`MYLAN PHARMACEUTICALS INC., and
`BIOCON BIOLOGICS, INC.,
`Defendants.
`
`CIVIL NO. 1:22-CV-61
`(KLEEH)
`
`**SEALED**
`MEMORANDUM OPINION AND ORDER FOLLOWING BENCH TRIAL
`I.
`INTRODUCTION
`In this patent infringement action, the plaintiff, Regeneron
`Pharmaceuticals, Inc., (“Regeneron”), and the Defendants, Mylan
`Pharmaceuticals Inc. and Biocon Biologics, Inc. (collectively,
`“the Defendants”),1 dispute whether the Defendants have infringed
`claims 6 and 25 of Regeneron’s U.S. Patent No. 11,253,572 (“the
`’572 Patent”); Claims 11 and 19 of Regeneron’s U.S. Patent No.
`10,888,601 (“the ’601 Patent”); and claims 4, 7, 9, 11, 14, 15,
`16, and 17 of Regeneron’s U.S. Patent No. 11,084,865 (“the ’865
`Patent”). They also dispute whether each of these asserted claims
`is valid and enforceable.
`
`1 Regeneron initially brought this lawsuit against only Defendant
`Mylan Pharmaceuticals Inc. (“Mylan”). (ECF No. 1). Defendant
`Biocon Biologics, Inc. was added later by stipulation (ECF No.
`523).
`
`
`53455
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE NORTHERN DISTRICT OF WEST VIRGINIA
`
`REGENERON PHARMACEUTICALS, INC.,
`Plaintiff,
`
`v.
`MYLAN PHARMACEUTICALS INC., and
`BIOCON BIOLOGICS, INC.,
`Defendants.
`
`CIVIL NO. 1:22-CV-61
`(KLEEH)
`
`**SEALED**
`MEMORANDUM OPINION AND ORDER FOLLOWING BENCH TRIAL
`I.
`INTRODUCTION
`In this patent infringement action, the plaintiff, Regeneron
`Pharmaceuticals, Inc., (“Regeneron”), and the Defendants, Mylan
`Pharmaceuticals Inc. and Biocon Biologics, Inc. (collectively,
`“the Defendants”),1 dispute whether the Defendants have infringed
`claims 6 and 25 of Regeneron’s U.S. Patent No. 11,253,572 (“the
`’572 Patent”); Claims 11 and 19 of Regeneron’s U.S. Patent No.
`10,888,601 (“the ’601 Patent”); and claims 4, 7, 9, 11, 14, 15,
`16, and 17 of Regeneron’s U.S. Patent No. 11,084,865 (“the ’865
`Patent”). They also dispute whether each of these asserted claims
`is valid and enforceable.
`
`1 Regeneron initially brought this lawsuit against only Defendant
`Mylan Pharmaceuticals Inc. (“Mylan”). (ECF No. 1). Defendant
`Biocon Biologics, Inc. was added later by stipulation (ECF No.
`523).
`
`
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`Regeneron has sued the Defendants under the Biologics Price
`Competition and Innovation Act (“BPCIA”), which “governs a type of
`drug called a biosimilar, which is a biologic product that is
`highly similar to a biologic product that has already been approved
`by the Food and Drug Administration (FDA).” Sandoz Inc. v. Amgen
`Inc., 582 U.S. 1, 5 (2017). The BPCIA provides an abbreviated
`route for FDA approval of biosimilars.
`The patents-in-suit are associated with Regeneron’s FDA
`approved Eylea® product, which contains a biological product known
`as aflibercept. The Defendants filed a Biologics License
`Application (“BLA”) seeking FDA approval to market a biosimilar
`aflibercept product under the trade name YesafiliTM prior to the
`expiration of the patents in suit.2 The Court is tasked with
`deciding the following:
`(1)
`whether the Defendants’ BLA products infringe claims 4,
`7, 9, 11, 14, 15, 16, and 17 of the ’865 Patent;
`whether the Defendants’ proposed label induces
`infringement of claims 6 and 25 of the ’572 Patent and
`claims 11 and 19 of the ’601 Patent;
`
`(2)
`
`2 Mylan filed BLA No. 761274 with the FDA on October 29, 2021. It
`transferred ownership of that BLA to Biocon effective March 31,
`2023. (ECF No. 523).
`
`2
`
`
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`(4)
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`(3)
`whether claims 4, 7, 9, 11, 14, 15, 16, and 17 of the
`’865 Patent are invalid as anticipated or obvious or
`invalid under 35 U.S.C. § 112 for lack of written
`description, lack of enablement, or indefiniteness;
`whether claims 6 and 25 of the ’572 Patent are invalid
`as anticipated or obvious or invalid under 35 U.S.C. §
`112 for lack of written description, lack of enablement,
`or indefiniteness; and
`whether claims 11 and 19 of the ’601 Patent are invalid
`as anticipated or obvious or invalid under 35 U.S.C. §
`112 for lack of written description, lack of enablement,
`or indefiniteness.
`Following a nine-day bench trial, the parties submitted their
`memoranda of law of these issues, and the case is ripe for the
`Court’s decision.
`
`(5)
`
`A.
`
`FINDINGS OF FACT
`II.
`Parties, Jurisdiction, and Venue
`Regeneron is a corporation organized under the laws of the
`State of New York, with its principal place of business at 777 Old
`Saw Mill River Road, Tarrytown, NY 10591. Mylan is a company
`organized under the laws of the State of West Virginia with its
`principal place of business at 3711 Collins Ferry Road, Morgantown,
`West Virginia 26505. Mylan is an indirect wholly-owned subsidiary
`3
`
`
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`of Viatris Inc. Biocon is a company based in India. The Court
`has subject matter and personal jurisdiction, and venue in this
`District is proper.
`
`B.
`
`The BPCIA
`Under the Public Health Service Act (“PHSA”), a sponsor
`seeking to market a biologic drug must file a BLA with the Food
`and Drug Administration (“FDA”) that details the biologic’s
`chemistry, pharmacology, manufacturing process, and medical
`effects. Sandoz, 582 U.S. at 6. Through the BPCIA, Congress
`amended the Public Health Service Act and the Patent Act in an
`effort to balance the goals of competition and innovation. BPCIA
`§ 7001(b), Pub. L. No. 111-148. To expedite getting competing
`“biosimilars” to market, Congress created an abbreviated
`regulatory approval pathway so that the biosimilar applicant does
`not have to regenerate early preclinical and clinical studies;
`rather, the applicant can instead rely, in part, on the data
`supporting the previous approval of a reference biologic product.
`42 U.S.C. § 262(i)(2), (k); Sandoz, 582 U.S. at 7. A biosimilar
`“is a biologic product that is highly similar to a biologic product
`that has already been approved.” Sandoz, 582 U.S. at 5.
`The Defendants’ BLA for its biosimilar product, Yesafili,
`relies on the Eylea BLA data as the reference biologic product
`
`4
`
`
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`under the statute. (ECF No. 1, ¶ 3; ECF No. 435, Answer to ¶ 3).
`To compensate the reference product sponsor (“RPS”), here
`Regeneron, for the use of these data, Congress grants the RPS a
`valuable twelve (12) years of marketing exclusivity, independent
`of any patent protection to which it is entitled. Sandoz, 582
`U.S. at 7 (“the manufacturer of a new biologic enjoys a 12-year
`period when its biologic may be marketed without competition from
`biosimilars”). Regeneron’s marketing exclusivity period (which
`includes an additional extension for performing a pediatric study)
`is set to expire on May 18, 2024. ECF Nos. 5, 7.
`
`C.
`
`Procedural Background
`By letter dated January 5, 2022, Mylan notified Regeneron
`that “FDA has received a BLA from Mylan for M710, a proposed
`biosimilar to aflibercept, which was submitted under 42 U.S.C.
`§ 62(k).” By letter dated February 22, 2022, Regeneron served on
`Mylan a list of patents pursuant to 42 U.S.C. § 262(l)(3)(A), that
`Regeneron believed “could reasonably be asserted against a person
`‘engaged in the making, using, offering to sell, selling or
`importing into the United States of the biological product that is
`the subject of’ Mylan’s BLA No. 761274.” Regeneron’s list of
`patents pursuant to 42 U.S.C. § 262(l)(3)(A) included each patent-
`in-suit as well as additional patents. Mylan subsequently served
`
`5
`
`
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`detailed statements related to the identified patents, on April
`14, 2022, pursuant to 42 U.S.C. § 262(l)(3)(B). Regeneron provided
`its responsive detailed statements on June 10, 2022, pursuant to
`42 U.S.C. § 262(l)(3)(C). The parties conducted negotiations
`pursuant to 42 U.S.C. § 262(l)(4)(A) and exchanged lists of patents
`to litigate pursuant to 42 U.S.C. § 262(l)(5)(B).
`Pursuant to 42 U.S.C. § 262(l)(6)(B), Regeneron brought suit
`against Mylan on the patent-in-suit, among other patents, on August
`2, 2022.3 In accordance with the Court’s Scheduling Order,
`following claim construction, Regeneron reduced its asserted
`patents and claims to claims 11, 19, and 27 of the ‘601 Patent,
`claims 4, 7, 9, 11, and 14-18 of the ‘865 Patent and claims 6, 7,
`12, 13, 18, 19, 22, 23, and 25 of the ‘572 Patent. (ECF No. 433).
`Regeneron also stipulated to the invalidity of claims 5-6 and 9 of
`the ‘601 Patent and claims 1-5, 8-11, 14, 26-28 of the ‘865 Patent
`under the Court’s claim construction. Id.
`Thereafter, the parties filed cross motions for summary
`judgment, which the Court denied. (ECF Nos. 428, 429, 525). The
`Court held a final pretrial conference on May 30, 2023. (ECF No.
`
`3 Regeneron sued on 24 patents, U.S. Patent Nos. 7,070,959;
`9,222,106;
`9,254,338;
`9,669,069;
`9,816,110;
`10,130,681;
`10,406,226; 10,415,055; 10,464,992; 10,669,594; 10,857,205;
`10,888,601; 10,927,342; 10,973,879; 11,053,280; 11,066,458;
`11,084,865; 11,104,715; 11,174,283; 11,186,625; 11,253,572;
`11,299,532; 11,306,135; and 11,332,771. (ECF No. 1, ¶ 6).
`6
`
`
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`512). The Court denied the Defendants’ request to challenge
`inventorship, and to challenge the enforceability of the claims
`based on inequitable conduct. (ECF No. 524, 1-2).
`D.
`Technical Background
`The general background to this art involves biologic
`molecules, and their use as anti-VEGF compounds.
`
`1.
`
`The aflibercept molecule and anti-VEGF clinical targets
`a.
`Vascular endothelial growth factor (“VEGF”)
`In the early 1990s, targeted gene inactivation studies in
`mice showed that a particular signaling compound in the body called
`Vascular Endothelial Growth Factor (VEGF) “is necessary for the
`early stages of vascular development.” (DTX 3619.8; DTX 4041.2).
`In layman’s terms, this growth factor stimulates the body to
`assemble cells to grow new blood vessels. Angiogenesis is the
`beginning part of that process to signal new blood vessel growth.
`VEGF-mediated angiogenesis is a normal part of human
`functioning. (DTX 4041.2) But too much of the VEGF protein can
`lead to undesirable effects, such as blood vessel growth for
`cancerous tumors, or abnormal growth of blood vessels under the
`retina in the eye, which can lead to fluid leakage or undesirable
`blood vessel growth in and around the retina. Id.; Tr. 111:5-15
`
`7
`
`
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`(Yancopoulos); Tr. 280:8-25, 282:18-24, 287:8-17 (Csaky); Tr.
`921:18-922:3 (Albini).
`By 1993, “Ferrara and colleagues” showed that anti-VEGF
`antibodies “could inhibit the growth of several human tumor types”
`in mice; but varying results based on targeting pathways
`“highlighted the need to optimize blockade of this [VEGF] pathway.”
`(DTX 3592.3). Regeneron’s early patents, including one that
`published in 2000, noted that “[p]ersistent angiogenesis may cause
`or exacerbate certain diseases such as . . . diabetic retinopathy
`and neovascular glaucoma. An inhibitor of VEGF activity would be
`useful as a treatment for such diseases and other VEGF-induced
`pathological angiogenesis and vascular permeability conditions,
`such as tumor vascularization.” DTX 3619.6, ll. 8-13; see also
`DTX 3619.36-37 (anti-VEGF compounds are useful for treating “eye
`disorders such as age-related macular degeneration and diabetic
`retinopathy”)).
`VEGF binds to receptors in the body. (Tr. 111:5-9
`(Yancopoulos); DTX 3619.5-6). A “portion of the receptor that is
`displayed on the surface of the cell” is “generally the most
`distinctive portion of the molecule.” (DTX 3619.2). One of these
`receptors was designated as Receptor 1 (“R1”), another as Receptor
`2 (“R2”). PTX 3333.25). “VEGF-R1 binds to VEGF with [the] highest
`affinity.” (Id.) Anti-VEGF compounds were designed to mimic these
`8
`
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`receptor binding sites, to capture circulating VEGF before it
`reaches a receptor in the body. (DTX 4041.3, 5; Tr. 111:18-112:1
`(Yancopoulos)).
`
`b.
`
`The therapeutic goal and structural rationale for
`aflibercept
`Regeneron identified the therapeutic goal that it sought to
`solve with its aflibercept molecule: “produce a receptor based
`VEGF antagonist that has a pharmacokinetic profile that is
`appropriate for consideration of the antagonist as a therapeutic
`candidate,” and which has “improved pharmacokinetic properties as
`compared to other known receptor-based VEGF antagonists.” (DTX
`3619.29-30). Pharmacokinetic properties of the drug are commonly
`assessed to see how the drug is absorbed, distributed, moves and
`works, and then eventually metabolizes, through the body. (Tr.
`461:2-8 (Furfine)); see, e.g., Persion Pharms. LLC v. Alvogen Malta
`Operations Ltd., 945 F.3d 1184, 1187 (Fed. Cir. 2019) (noting
`pharmacokinetic effects included clinical effects such as blood
`concentration levels of the drug, and side effects associated with
`administering the drug).
`Aflibercept is a man-made protein. (Tr. 448:1-8 (Furfine)).
`Regeneron disclosed in the prior art that it had prepared anti-
`VEGF compounds, which had one segment designed to mimic the VEGF
`binding segments of the R1 and R2 receptors, fused together; and
`
`9
`
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`then an antibody segment, allowing the whole molecule to more
`strongly bind to VEGF. (DTX 3619.11-14, 16; Tr. 114:1-17
`(Yancopoulos); Tr. 448:1-8 (Furfine) (“Aflibercept is a man-
`made . . . protein where you take two receptors that are normally
`on the surface of the cell and you genetically engineer them to be
`on an antibody part” called “the Fc domain,” and “that creates a
`drug”)).
`The full protein sequence of the R1 receptor “has poor
`pharmacokinetics that make it difficult to use as a therapeutic
`agent,” so modifying it in the way that Regeneron did (including
`replacing some parts with parts of the VEGF R2 receptor region)
`produced a molecule with better pharmacokinetics, including, e.g.,
`VEGFR1R2-Fc(cid:507)C1(a). (DTX 3619.59-60).
`One of the preferred embodiments that Regeneron disclosed was
`the fusion polypeptide that had “the amino acid sequence set forth
`in Figure 24A-24C,” which was VEGFR1R2Fc(cid:507)Cl(a). (DTX 3619.16, 60,
`23 (“Figure 24A-24C. Nucleotide and deduced amino acid sequence of
`the modified FIt1 receptor termed VEGFR1R2Fc(cid:507)Cl(a)”)).
`Regeneron secured a patent to the aflibercept molecule, the
`‘959 patent, which issued in 2006. (DTX 7.1; Tr. 1432:23-1433:23
`(MacMichael)). Example 20 of the ‘959 patent explains how to
`prepare VEGFR1R2Fc(cid:507)Cl(a), and provides the complete sequence
`
`10
`
`
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`across Figures 24A-24C. (DTX 7.73, 29:13:29; DTX 7.63, 9:65-67;
`DTX 7.42-44).
`Regeneron has assigned various descriptors to the molecule
`known as aflibercept, including VEGF Trap, VEGF Trap-Eye
`(formulated for use in the eye); and VEGFR1R2Fc(cid:507)Cl(a). (DTX
`4008.1, DTX 7.63, 9:65-67, DTX 3592.3 (describing structural
`features of protein “that we term VEGF Trap”); DTX 4957.5 (“[VEGF
`Trap-Eye] has been purified and formulated in concentrations
`suitable for direct injection into the eye.”); Tr. 1227:9-12 (Chu
`30(b)(6)); Tr. 208:25-209:10 (Yancopoulos); Tr. 1432:8-1438:24
`(MacMichael)).
`2.
`Early anti-VEGF performance: non-human data
`Before a drug goes into human use, it is required to be tested in
`preclinical animal models pertaining to the mechanism of action
`and/or for the disease, and to get a sense of what range of doses
`will likely work to accomplish the drug’s effect. (Tr. 459:2-
`21, 462:15-465:14 (Furfine)).
`
`a.
`
`Establishing aflibercept’s anti-angiogenic effect,
`dose amounts
`By 2002, Regeneron published papers in the scientific
`literature touting aflibercept’s potency. In Holash, Regeneron
`explained its “hope” that “anti-VEGF approaches can be generalized
`to many different types of cancer, as well as to other diseases in
`
`11
`
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`which pathologic angiogenesis contributes, such as diabetic
`retinopathy.” (DTX 3549.1). Regeneron stated that it had
`“engineer[ed] a very potent high-affinity VEGF blocker” with
`“prolonged in vivo” activity, which “lacks nonspecific toxicities,
`and can effectively suppress the growth and vascularization of a
`number of different types of tumors in vivo.” (Id.) Regeneron
`reported that its studies using cell lines and rats “indicated
`that VEGF-TrapR1R2 has the potential to be a long-term and potent
`pharmacologic blocker of VEGF-mediated activities in vivo, far
`superior to that of parental VEGF-Trap.” (DTX 3549.4). Regeneron
`reiterated that this “combination of high-affinity and improved
`pharmacokinetics apparently contributes toward making VEGF-TrapR1R2
`one of the most, if not the most, potent and efficacious VEGF
`blocker available.” (DTX 3549.5; Tr. 114:14-17 (Yancopoulos)).
`Much of Regeneron’s early work with aflibercept focused on
`the anti-angiogenic effects of the drug in connection with cancer
`applications. (Tr. 449:14-16 (Furfine); PTX 3333.27). But
`Regeneron also assessed the anti-angiogenic effects of aflibercept
`in animal eyes specific to treating eye disease. In 2003, Saishin
`et al. reported their results with both subcutaneous and
`intravitreal injection of aflibercept into mice eyes. (DTX 2751.1;
`Tr. 1050:24-1051:11, 1080:10-18 (Rabinow)). The authors confirmed
`that VEGF-TRAPR1R2 given as a single intravitreous injection
`12
`
`
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`“markedly
`suppressed
`the
`development
`of
`choroidal
`neovascularization over the course of two weeks.” (DTX 2751.7).
`While the subcutaneous dosing method also produced good results,
`it required five injections to produce the reported results. (DTX
`2751.4; Tr. 1090:5-22 (Rabinow)).
`After seeing aflibercept’s performance in vivo in mice and
`rats, the next step was to assess how it performed in primates,
`and better identify the dose ranges to target. Regeneron
`specifically assessed which primate doses produced the desired
`anti-angiogenic effects. (Tr. 1067:9-22 (Rabinow)). Fraser et
`al. published these results in 2005, reporting among other things
`“the minimal dose of VEGF TrapRlR2 that would be required to
`interrupt follicular development,” which is the time period when
`angiogenesis occurs, and whether the dose amount impacted the
`“duration” of the anti-VEGF effect. (DTX 729.2). Fraser reported
`that the “VEGF TrapR1R2 was well tolerated at all doses tested.”
`(Id., 3). The 4 mg/kg and the 1 mg/kg doses “resulted in a
`significantly longer” period of activity compared to the lower
`doses. (Id., 5).
`In 2005, Regeneron’s published patent application reported
`the results of aflibercept injections into mouse eyes, including
`intravitreally. (DTX 4229.24 [0031]).
`
`13
`
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`In U.S. Patent No. 7,303,747 (“the ‘747 patent”), which
`published February 9, 2006, and which issued on December 4, 2007,
`Regeneron characterized the disclosed invention as involving a
`“therapeutic method for treating or ameliorating an eye disorder,”
`including “age related macular degeneration” and “diabetic
`retinopathy.” (DTX 2730.13, 1:49-54). The compounds preferred to
`use for this purpose included VEGFR1R2Fc(cid:507)Cl(a). (Id., 1:64-2:2).
`Regeneron disclosed that the initial dose should be “at least
`approximately 25-4000 micrograms [4 mg] VEGF inhibitor protein to
`an affected eye.” (Id., 2:14-15; DTX 2730.16, 7:52-55). The
`‘747
`patent
`included
`preclinical
`data
`that
`tested
`VEGFR1R2Fc(cid:507)Cl(a), aflibercept, in various retinal models in
`animals, reporting good results with intravitreal injections.
`(DTX 2730.13-14 (referencing data in Figures 4-9)). The ‘747
`patent confirms that “[p]referably” the drugs would be
`administered “directly to the eye,” including through
`“intravitreal injections.” (DTX 2730.16, 7:5-10). The aqueous
`solutions would have “ophthalmically compatible pH and
`osmolality.” (Id., 7:26-28).
`The intravitreal injections in the Examples were dosed at 50,
`250, or 500 mcg/eye [0.05, 0.25, or 0.5 mg doses/eye]. (DTX
`2730.20, 15:2-4). The specification reports that “a single
`intravitreal injection (500 mcg) [0.5 mg] of VEGFR1R2-Fc(cid:507)Cl(a)
`14
`
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`made following the laser injury [to the eye] reduced the incidence
`of grade 4 lesions from 44% to 0% within 10 days of treatment.”
`(Id., 15:19-23). Example 16 tested VEGFR1R2Fc(cid:507)Cl(a) to assess the
`“ability of an intravitreally administered protein to reach the
`desired site of action, i.e. the macula in the case of macular
`degeneration,” and concluded that it would in fact reach “both
`ocular tissue (vitreous humor, retina and choroid) and that “if a
`compound is delivered into the vitreous humor, it can be cleared
`from that region and be distributed into the surrounding tissue,
`i.e. retina and choroid.” (DTX 2730.21-22). The larger VEGF trap
`protein stayed in the eye tissue longer in comparison to its
`smaller mini-VEGF trap version. (DTX 2730.22). The specification
`then proposed treatment in human patient eyes, including that the
`“eye to be treated is injected with 25-4000 micrograms [4 mg] of
`VEGF trap protein in an ophthalmic solution.” (Id. (Example 17)).
`
`Other anti-VEGF compounds: dosing methods
`b.
`Regeneron closely monitored Genentech, as well as how
`Genentech planned to dose its anti-VEGF compounds. (See, e.g.,
`Tr. 448:16-449:6 (Furfine); DTX 710.1 (noting Genentech had dosed
`ranibizumab in rabbits subconjunctivally, intracamerally, and
`intravitreally)). By March 1, 2004, Genentech reported the
`
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`“highest levels [of ranibizumab were] observed for ITV,”
`intravitreal doses. (DTX 710.2).
`Genentech compared how ranibizumab performed intravitreally
`and intravenously in monkeys, confirming by January 2005 that based
`on the systemic clearance rates, ranibizumab would be “favorable
`for its clinical use in treating neovascular AMD by monthly ITV
`injection.” (DTX 2265.1; DTX 714.1 (Regeneron calling the
`Gaudreault paper a “nice find”). Gaudreault likewise evaluated
`different dosing ranges in primates. (DTX 2265.2 (February 2005
`publication by Gaudreault, comparing the performance of
`intravitreal and intravenous formulations, including 10 mg/mL and
`40 mg/mL in 50 microliters dosed intravitreally)).
`
`c.
`
`The human clinical activity with anti-VEGF
`compounds
`By 2005, clinicians pursued anti-VEGF strategies, including
`with intravitreal injections, to treat their patients.
`i.
`The first FDA-approved anti-VEGF agent:
`Macugen
`The anti-VEGF agent, Macugen (pegaptanib), was in Phase I
`clinical studies as early as April 1999, and had proceeded to Phase
`II/III studies by 2001. (DTX 209.2-3). In the Phase III studies,
`“1186 patients were enrolled to test the efficacy of intravitreal
`injections of pegaptanib every six weeks.” (DTX 209.3). By August
`
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`31, 2004, Regeneron knew that the FDA’s advisory committee had
`considered the Phase III clinical and safety data, and that “70%
`of patients met the primary endpoint” of “patients losing less
`than 15 letters, or three lines, of visual acuity on the eye chart
`from baseline after 54 weeks.” (DTX 209.1, 5). FDA approved
`Macugen in December 2004. (DTX 4041.1).
`ii.
`Avastin—approved as an anti-VEGF cancer drug,
`but used by physicians intravitreally to
`target wet AMD and DME
`FDA approved the anti-VEGF Avastin (bevacizumab) as an
`intravenous anti-cancer therapy in February 2004. (DTX 210.2).
`By March 3, 2005, the Bascom Palmer Eye Institute issued a press
`release (which Regeneron received) confirming that it had used
`Avastin to treat wet AMD. (DTX 210.1; Tr. 1240:22-1242:19 (Chu
`30(b)(6))). The study’s lead, Dr. Phil Rosenfeld, explained that
`“[w]e’ve been injecting anti-VEGF drugs into the eye for the past
`3 years with very encouraging results.” (DTX 210.1). Dr.
`Rosenfeld also studied systemic patient dosing because even though
`“[s]ome people would rather have an injection in the eye than worry
`about the risks from a systemic drug” systemic dosing would offer
`“a new potential option for patients with wet AMD.” (DTX 210.2).
`He acknowledged that “the potential disadvantage” of Avastin given
`systemically was “the risk of systemic side-effects,” but
`
`17
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`indicated that thus far, patients’ blood pressure increases were
`readily controlled with medication. (Id.)
`Shortly thereafter, in July/August 2005, Dr. Rosenfeld and
`others published further details about their intravitreal Avastin
`injection process, confirming that Avastin produced efficacious
`results in a human patient, when injected intravitreally at a
`concentration of 25 mg/mL. (DTX 3058.2; Tr. 528:2-12 (Furfine);
`DTX 3510; DTX 2264.1-2; DTX 9036.5-6 (Avery publication from March
`3, 2006 dosing 1.25 mg of Avastin in 0.05 mL); DTX 9036.3 (library
`receipt page showing Avery publication received by March 3, 2006)).
`The injections were described as “well tolerated in all patients,”
`with no ocular toxicity, “or thromboembolic events,” or
`“significant elevation” in blood pressure “observed over the
`course of the study.” (DTX 2264.3; DTX 9036.7). The “vast
`majority of patients demonstrated stability or improvement” of
`their visual acuity,” and four weeks after the injections, many
`“demonstrated complete resolution of retinal edema”; even some
`non-responders “also showed resolution” after they “received
`reinjections at week 12.” (DTX 2264.3-4; DTX 9036.7-8).
`Avery also addressed the theory in the literature that had
`warned that there might be a “lack of retinal penetration beyond
`the [internal limiting membrane] after intravitreal administration
`of full-length antibodies,” which was plainly contradicted by “the
`18
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`apparent rapid biologic effect demonstrated in this current study
`with bevacizumab.” (DTX 2264.8; DTX 9036.12). Avery proposed
`that the use of a larger dose, human anatomy versus primate
`anatomy, and the methodology used in the primate studies could
`account for why the theory did not lead to failure for bevacizumab.
`(Id.)
`Avastin was then tested in clinical trials on extended dosing
`intervals, with Bashur et al. reporting in 2008 that after three
`monthly injections, visual acuity gains could be maintained for
`several months by giving just 3.4 injections on average for the
`remainder of the year. (DTX 4013.1; Tr. 768:2-10 (Albini)).
`iii.
`Lucentis (ranibizumab)
`At the July 2005 American Society of Retinal Specialists
`meeting,” the results from a “large phase Ill clinical trial”
`demonstrated that ranibizumab was “effective in the treatment of
`neovascular AMD.” (DTX 2264.1-2; DTX 9036.5-6). The active
`ingredient in Lucentis, ranibizumab, is an antibody fragment. Tr.
`2014:5-7 (Trout); Tr 1832:11-1833:1 (Csaky); Tr. 113:7-18
`(Yancopoulos); Tr. 452:7-14 (Furfine).
`Dr. Rosenfeld presented his one-year PrONTO outcomes at the
`May 2006 Association for Research in Vision and Ophthalmology
`(“ARVO”) meeting. (DTX 218.2; DTX 3131.3 (dosing patients on a
`PRN basis after 3 monthly doses)). On May 9, 2006, Regeneron
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`internally circulated a copy of Dr. Rosenfeld’s press release about
`the study, including that he had dosed ranibizumab using
`intraocular injections for wet AMD, and that most patients had
`only needed 5 or 6 injections in the year. (DTX 218.1-2). He
`reported that “82% of patients had the same or better vision after
`one year and 35% of patients experienced a two-fold improvement in
`vision as defined by gaining three lines of vision on a
`standardized visual acuity chart.” (Id., 1). Dr. Rosenfeld did
`this work even though Lucentis had not yet been officially approved
`by FDA, and was still being tested in Phase III studies. (Id.,
`2).
`
`By May 4, 2006, Genentech’s patent to Dr. Shams published.
`Example 1 included a study protocol for the “efficacy and safety
`of intravitreal injections of VEGF antagonist (e.g., ranibizumab)
`administered monthly for 3 doses followed by doses every 3 months.”
`(DTX 726.32).
`FDA approved Lucentis for wet AMD in June 2006. (See DTX
`3040.1). By October 5, 2006, Dr. Rosenfeld and others published
`the successful Phase III clinical trial results with monthly dosing
`of ranibizumab for wet AMD in the New England Journal of Medicine.
`(DTX 2034). Mitchell summarized data for the ANCHOR monthly dosing
`(2006), PRONTO PRN dosing (2007), and EXCITE quarterly dosing
`(2008), showing visual acuity gains over many months of time. (DTX
`20
`
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`4061.4; see also DTX 3115.1 (Fung, Rosenfeld et al. reported on
`using OCT to guide extended-interval dosing after three monthly
`loading doses)).
`Once the efficacy of ranibizumab for AMD was established,
`doctors quickly began using it for other indications, namely DME,
`DR, and RVO, and also on extended dosing intervals. One review
`article summarizing DME clinical work included Lalwani 2009, where
`patients received three monthly doses of ranibizumab (baseline,
`month 1, month 2), followed by dosing at an extended two month
`interval, at months 4 and 6, for a mean gain of 8 letters by month
`12. (DTX 2733.1; Tr. 768:24-769:14 (Albini)).
`iv.
`Aflibercept
`Regeneron initially began its aflibercept work for cancer
`indications, as part of a partnership with Sanofi. (Tr. 112:19-
`20 (Yancopoulos); DTX 4956.3-4). Regeneron disclosed that the
`“results in animal models have supported the exploration of the
`VEGF Trap in human studies of vascular eye diseases. Initial
`clinical studies in human patients suffering from both AMD and
`diabetic edema and retinopathy appear quite promising, with
`evidence in early trials that the VEGF Trap can rapidly and
`impressively decrease retinal swelling.” (DTX 3592.4)
`
`21
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`a)
`Regeneron tries, and rejects, systemic
`aflibercept
`and
`instead
`pursues
`intravitreal aflibercept for human use
`Regeneron initiated its first Phase I study with aflibercept
`through intravenous delivery, by January 2004. (DTX 207.1-2; Tr.
`1238:13-19 (Chu)). Like Dr. Rosenfeld, Regeneron initiall
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