CONTAINS HIKMA CONFIDENTIAL INFORMATION
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`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
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`AMARIN PHARMA, INC., AMARIN
`PHARMACEUTICALS IRELAND
`LIMITED, MOCHIDA
`PHARMACEUTICAL CO., LTD.,
`
`Plaintiffs,
`
`v.
`
`HIKMA PHARMACEUTICALS USA INC.,
`HIKMA PHARMACEUTICALS PLC, AND
`HEALTH NET, LLC,
`
`Defendants.
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`C.A. No. 20-1630-RGA-JLH
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`PLAINTIFFS’ INITIAL INFRINGEMENT CONTENTIONS AND CLAIM CHARTS
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`Pursuant to Paragraph 7(c) of the Court’s Scheduling Order (D.I. 50), Plaintiffs Amarin
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`Pharma, Inc., Amarin Pharmaceuticals Ireland Limited (“Amarin”), and Mochida Pharmaceutical
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`Co., Ltd. (“Mochida”) (collectively “Plaintiffs”) provide their Initial Infringement Contentions and
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`Claim Charts to Defendants Hikma Pharmaceuticals USA Inc. and Hikma Pharmaceuticals PLC
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`(“Hikma”) and Health Net, LLC (“Health Net”) (collectively “Defendants”), including Exhibits A
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`through F.
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`In support of their Initial Infringement Contentions and Claim Charts, Plaintiffs have cited
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`representative documents from Hikma’s generic icosapent ethyl product’s ANDA No. 2094571, as
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`well as the related labelling and marketing materials, and documents related to Health Net’s
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`relevant formularies and prior authorization for VASCEPA® (icosapent ethyl). Plaintiffs
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`expressly reserve the right to modify, amend, and/or supplement their Initial Infringement
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`1 “Hikma’s generic product” as used herein refers to Hikma’s icosapent ethyl capsule product
`described in ANDA No. 209457.
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`1
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`Hikma Pharmaceuticals
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`IPR2022-00215
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`Ex. 1020, p. 1 of 32
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`CONTAINS HIKMA CONFIDENTIAL INFORMATION
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`Contentions and Claim Charts based on their continued investigation, study and analysis,
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`Defendants’ document productions, discovery taken in the case, the claim construction positions
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`taken by the parties, any orders from the Court, or any information learned subsequent to the date
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`of these Initial Infringement Contentions and Claim Charts, consistent with the Federal Rules of
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`Civil Procedure, Local Rules of this District, and this Court’s procedures and Orders.
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`In particular, Plaintiffs expressly reserve the right to modify, amend, and/or supplement
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`their Initial Infringement Contentions and Claim Charts upon learning further information about
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`Hikma’s generic product and/or the Defendants’ inducing acts during discovery. As of the date of
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`this submission, Defendants have not produced information regarding their knowledge of the
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`FDA’s approval of the CV Indication for VASCEPA® or documents regarding non-infringing
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`uses of Hikma’s generic product. Further, Hikma has not produced requested documentation
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`regarding the planning, decision, and/or strategy to market Hikma’s generic product, the total
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`volume of Hikma’s generic product prescribed or dispensed versus VASCEPA®, the percentage
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`or volume of Hikma’s generic product being prescribed to treat the CV Indication, or
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`correspondence with insurers and pharmacies regarding this litigation. Additionally, thus far,
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`Health Net has produced zero documents in this litigation. Plaintiffs reserve the right to
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`supplement these disclosures after Defendants provide the requested discovery. Plaintiffs thus
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`expressly reserve the right to identify and advance alternative theories of literal infringement
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`and/or infringement under the doctrine of equivalents as well as additional indirect infringement
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`theories.
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`I.
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`ACCUSED PRODUCT
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`Plaintiffs accuse Hikma and Health Net of indirectly infringing the below Asserted Claims
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`by inducing the infringing use of Hikma’s generic product for reasons including but not limited to
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`2
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`those set forth in Plaintiffs’ Amended Complaint and Plaintiffs’ Oppositions to Defendants’
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`Motions to Dismiss, and as further discussed in the Report and Recommendation to deny the
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`Motions to Dismiss. (D.I. 17 (¶¶ 80, 92-135 as to the Hikma Defendants and ¶¶ 81-92, 136-162
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`as to Health Net); D.I. 22 (as to the Hikma Defendants), D.I. 42 (as to Health Net); D.I. 64).
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`Plaintiffs’ inducement theories are further discussed in Plaintiffs’ forthcoming responses to both
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`Hikma’s and Health Net’s objections to the Report and Recommendations to deny the Motions to
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`Dismiss.
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`II.
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`ASSERTED CLAIMS
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`Plaintiffs contend that Defendants infringe the following claims (the “Asserted Claims”):
`
`Patent Number
`8,642,077
`9,700,537
`10,568,861
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`Asserted Claims
`1, 8, 14, 15, 16, 17, 18, and 19
`1, 4, 5, 7, 8, 9, 12, 13, 15 and 16
`1-7
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`
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`Hikma infringes each Asserted Claim under 35 U.S.C. § 271(b) by making, using, offering
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`to sell, selling, importing, promoting, distributing, and/or acting in concert with other entities to
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`sell Hikma’s generic product and inducing healthcare providers and/or patients (either by acting
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`alone, or directing and/or controlling the infringing actions of others) to use Hikma’s generic
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`product within the United States for patented uses covered by these claims and according to the
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`instructions set forth in Hikma’s Label2, including the affirmative removal of the CV Limitation
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`of Use, and any other instructions, recommendations or communications made by Hikma and/or
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`its agents to healthcare providers, such as through promotional and marketing materials, to use
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`
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`2 “Hikma’s Label” refers to what Plaintiffs understand to be the FDA-approved label for
`Hikma’s generic product, 1 gram, produced with at the following bates number range:
`HIK(ICO)-DE-00009675-9685.
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`3
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`IPR2022-00215
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`Ex. 1020, p. 3 of 32
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`Hikma’s generic product according to the methods of these claims or as a substitute for
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`VASCEPA® to reduce CV risk and lower TGs in specific patient populations.
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`Health Net indirectly infringes each Asserted Claim under 35 U.S.C. § 271(b) by inducing
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`healthcare providers, including physicians and/or pharmacies (either by acting alone, or directing
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`and/or controlling the infringing actions of others), to use Hikma’s generic product within the
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`United States for patented uses covered by these claims through its instructions, recommendations
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`or communications made by Health Net and/or its agents, including those related to the relevant
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`formularies and prior authorizations, to healthcare providers to use Hikma’s generic product
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`according to the methods of these claims or as a substitute for VASCEPA® to reduce CV risk and
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`lower TGs in specific patient populations.
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`III.
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`INFRINGEMENT
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`As described below and in the accompanying claim charts, Exhibits A-C, Hikma’s generic
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`product, when offered for sale, sold, prescribed, or used for the patented used, including for the
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`CV Indication or to lower TGs in specific patient populations, meets each element of the Asserted
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`Claims.
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`IV. HIKMA HAS INDUCED INFRINGEMENT OF THE ASSERTED CLAIMS
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`As described below and in the accompanying claim charts, Exhibits A-C, Hikma’s Label
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`demonstrates that Hikma’s generic version of VASCEPA® product is marketed and sold with
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`instructions to healthcare providers to administer it to patients according to the methods of the
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`relevant Asserted Claims.
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`In 2016, Hikma submitted its ANDA to the FDA with proposed labeling that included the
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`same Severe Hypertriglyceridemia Indication (“SH Indication”) and CV Limitation of Use that
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`appeared on the VASCEPA® label at that time. See HIK(ICO)-DE-00000035; see also
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`4
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`HIK(ICO)-DE-00002474. From 2016 to 2018, Hikma revised its label three times, with each
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`revision maintaining the SH Indication and CV Limitation of Use. See, e.g., HIK(ICO)-DE-
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`00000111; HIK(ICO)-DE-00000135; HIK(ICO)-DE-00003028; HIK(ICO)-DE-00003052;
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`HIK(ICO)-DE-00004435; HIK(ICO)-DE-00004573. One of these revisions, occurring in October
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`2018, was in response to a Complete Response Letter from the FDA requesting the labelling be
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`revised “in accordance with the most recently approved labeling for the reference listed drug
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`(RLD), VASCEPA, NDA 202057.” HIK(ICO)-DE-00004429; see also HIK(ICO)-DE-00004427;
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`HIK(ICO)-DE-00004435; HIK(ICO)-DE-00004573.
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`In 2019, VASCEPA® was approved for the Cardiovascular Risk Indication (“CV
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`Indication”) allowing Amarin to remove the CV Limitation of Use from the VASCEPA® label.
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`See HIK(ICO)-DE-00006942; see also HIK(ICO)-DE-00005969 at -5986.This set VASCEPA®
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`apart from the other FDA-approved drugs in its therapeutic category. For example, the FDA
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`required the labelling for LOVAZA®, an omega-3 acid ethyl ester, approved by the FDA for the
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`reduction of triglyceride levels in patients with triglyceride (TG) levels ≥ 500 mg/dL, to include
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`the CV Limitation of Use. D.I. 17-20 (Pls.’ Am. Compl. Ex. S (LOVAZA® Label)) (example of
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`how CV Limitation of Use was required by the FDA for other products in the therapeutic category).
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`Along with the changes in labelling, various patents covering the use of VASCEPA® for
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`the CV Indication were listed in the Orange Book, including those asserted here. HIK(ICO)-DE-
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`00008864. Hikma thus had to choose between including the CV Indication on its own label and
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`challenging the Asserted Patents or avoid the Asserted Patents by “carving out” the CV Indication
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`through Section viii statements. Hikma chose to carve-out the CV Indication from its label and
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`submitted its Section viii statements to the FDA. HIK(ICO)-DE-00005895; see HIK(ICO)-DE-
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`00006090; HIK(ICO)-DE-00010526.
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` By including these self-proclaimed “section viii
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`statements”, Hikma represented to the FDA and to Plaintiffs that it would not market its generic
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`product for uses covered by those patents, namely, to reduce CV risk and lower TGs in specific
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`patient populations. See 21 U.S.C. § 355(j)(2)(A)(viii). However, Hikma’s actions demonstrate
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`it never intended to keep that promise.
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`Hikma’s intention for healthcare providers to use its generic product for the CV Indication
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`is evidenced by Hikma’s voluntary revision of its label in December 2019. After VASCEPA®
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`was approved for the CV Indication, the FDA never requested that Hikma revise its label to reflect
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`VASCEPA®’s new indication or alter any other sections of its label. Instead Hikma affirmatively
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`submitted an unsolicited label revision to the FDA and claimed that “[Hikma]’s labelling omits
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`any reference to the newly approved indication . . . .” HIK(ICO)-DE-00005694. But Hikma never
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`called to the FDA’s attention that it also removed the CV Limitation of Use from its Label. See
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`id.; HIK(ICO)-DE-00005717. Such an affirmative removal by Hikma has resulted in a Label that
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`instructs, encourages, and promoted the claimed uses.
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`Hikma’s intent for its generic product to be used just like VASCEPA®, including for the
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`claimed uses, is further evidenced by Hikma’s public statements in its press releases and website.
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`For example, on March 31, 2020, Hikma issued a press release promoting its product as a “generic
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`version of Amarin Corporation’s Vascepa® 1 gm (icosapent ethyl) capsules.” D.I. 17-13 (Pls.’
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`Am. Compl. at Ex. L). Hikma’s March 2020 Press Release cited the sales figures for VASCEPA®
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`without differentiating the sales for Hikma’s labelled SH indication and the “carved out” CV
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`Indication, even though Hikma was aware that the CV Indication made up a “vast majority” of
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`prescriptions for VASCEPA®. Id.; D.I. 17-24 ¶¶ 115, 116, 440 (Pls.’ Am. Compl. at Ex. W
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`(Nevada Case, D.I. 377)); D.I. 17-28 at 1252-1253 (Pls.’ Am. Compl. at Ex. AA (Nevada Case
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`Trial Tr.)) (Hoffman); see also D.I. 17-18 (Pls.’ Am. Compl. at Ex. Q (Nevada Case DDX_1.36));
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`D.I. 17-19 (Pls.’ Am. Compl. at Ex. R (Nevada Case DDX_8.13)). Hikma continued representing
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`its generic product as being equivalent to VASCEPA® in a press release dated September 2020.
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`D.I. 17-14 (Pls.’ Am. Compl. at Ex. M). In its March and September 2020 press releases, Hikma
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`failed to state that Hikma’s “generic version” of VASCEPA® was not approved for the CV
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`Indication, should not be used for the CV Indication, or that its effect of its generic version on
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`cardiovascular mortality and morbidity had not yet been determined.
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`Furthermore, having familiarity with the VASCEPA® label, Hikma is aware that the CV
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`Indication specifies the relevant patient population includes adult patients with TG levels ≥ 150
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`mg/dL. HIK(ICO)-DE-00006942, § 1. Because the CV Indication has no upper limit on the TG
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`range for this use, see id., the patient populations for the CV Indication and the SH Indication
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`necessarily overlap. Even Hikma has acknowledged that there is an overlap between Hikma’s
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`approved use for SH and the unapproved use for the CV Indication. See D.I. 17-18 (Pls.’ Am.
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`Compl. at Ex. Q). In fact, Hikma represented this to the District of Nevada Court with the figure
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`reproduced below:
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`Id. Although the drawing is not to scale, Hikma’s illustration contains two overlapping
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`circles: a yellow circle that refer to the SH Indication, and a blue circle that refers to the CV
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`Indication. Id. With regard to the CV Indication, Hikma admitted use for the CV Indication is
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`“separately patented.” Id. (emphasis added). Thus, Hikma had knowledge of Plaintiffs’ patents
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`covering the CV Indication as well as that the patient populations for SH and CV overlap when a
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`patients TG levels are ≥ 500 mg/dL. Because the patient populations overlap as described,
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`Hikma’s Label thus instructs infringement of the Asserted Claims. To date, Hikma’s public
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`product catalog continues to promote and instruct that its generic version of VASCEPA® is “AB”
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`rated
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`for
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`“Hypertriglyceridemia.”
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`See
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`Products:
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`Icosapent Ethyl Capsules,
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`https://www.hikma.com/products/us-products (last accessed Aug. 26, 2021); see also D.I. 17-21
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`(Pls.’ Am. Compl. at Ex. T); HIK(ICO)-DE-00009694. This therapeutic category does not align
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`with the “Severe Hypertriglyceridemia” indication that appears on Hikma’s Label and requires
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`TGs ≥ 500 mg/dL. See Hikma’s Label, § 1. Hypertriglyceridemia encompasses lower TG levels
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`such as those found in the claimed uses and recited in the CV Indication. See Pejic, R. & Lee, T.,
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`Hypertriglyceridemia, 19 J. Am. Bd. Family Med. 310, 310 (May 2006), available at
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`https://www.jabfm.org/content/jabfp/19/3/310.full.pdf
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`(defining hypertriglyceridemia as a
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`triglyceride level ≥ 150 mg/dL); see also HIK(ICO)-DE-00006942, § 1 (CV Indication specifies
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`adult patients with triglyceride (TG) levels ≥ 150 mg/dL).
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`Hikma is an experienced and savvy generic drug manufacturer that has been in business
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`for more than 40 years. About: History, https://www.hikma.com/about/history (last accessed Aug.
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`26, 2021). Hikma is aware that listing its generic product as “AB-rated” for an indication broader
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`than that approved by the FDA, and one that includes patients in the claimed patient populations,
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`would result in its generic product being substituted for VASCEPA® even for uses not indicated
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`on Hikma’s Label, such as the CV Indication.
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`In sum, Hikma’s voluntary label amendment (removing the CV Limitation of Use from its
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`Label), marketing, and promotional materials demonstrate that Hikma always intended that its
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`generic product be used to reduce CV risk according to the claimed methods. See, e.g., D.I. 17-24
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`¶¶ 115, 116, 440 (Pls.’ Am. Compl. at Ex. W (Nevada Case, D.I. 377)); D.I. 17-28 at 1252-1253
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`(Pls.’ Am. Compl. at Ex. AA (Nevada Case Trial Tr.)) (Hoffman); see also D.I. 17-18 (Pls.’ Am.
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`Compl. at Ex. Q (Nevada Case DDX_1.36)); D.I. 17-19 (Pls.’ Am. Compl. at Ex. R (Nevada Case
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`DDX_8.13)); see Exhibits A-C; see also HIK(ICO)-DE-00005916; HIK(ICO)-DE-00005694;
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`HIK(ICO)-DE-00005696.
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`Further, Hikma has not put forward an affirmative argument that the administration of its
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`generic version of VASCEPA®, according to the Hikma Label, does not meet any of the method
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`steps recited in the relevant Asserted Claims, either literally or under the doctrine of equivalents.
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`A. U.S. Patent No. 8,642,077
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`Healthcare providers who administer Hikma’s generic product according to the Hikma
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`Label, and patients following their healthcare providers instructions, directly infringe the asserted
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`claims of the ’077 patent, as described below. Hikma, through its Label, as well as its marketing
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`and promotional materials, instructs, recommends, and encourages healthcare providers to use
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`Hikma’s generic product for the uses claimed in the ’077 patent.
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`1) Hikma’s Label Promotes and Encourages Using Hikma’s Generic
`Product to Reduce Triglycerides in a Subject with Mixed
`Dyslipidemia on Statin Therapy
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`Independent claims 1 and 8 of the ’077 patent require treating mixed dyslipidemia patients
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`who are on statins with about 4g daily of a highly pure EPA to reduce fasting TG levels and
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`hs-CRP. AM_ 00000054 at -82. Section 14.2 of Hikma’s Label promotes and encourages treating
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`patients with abnormal lipid levels, who thus have mixed dyslipidemia, and who are “on
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`concomitant statin therapy.” Hikma’s Label, § 14.2 (enrolling patients with TG levels between
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`500 and 2,000 mg/dL with a baseline median LDL-C of 86 mg/dL and HDL-C of 27 mg/dL, with
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`25% of studied patients receiving “concomitant statin therapy,” and teaching administration of
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`EPA with atorvastatin (citing id. §§ 12.3, 14.2)); id. § 14.2, tbl. 2 (reporting those in the study
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`treated with icosapent ethyl 4 g/day had LDL-C baseline of 91 mg/dL and HDL-C baseline of 27
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`mg/dL); see id. § 14.2 (“Twenty-five percent of patients were on concomitant statin therapy”).
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`2) Hikma’s Label Instructs Health Providers to Administer its
`Generic Product that Comprises about 2500 mg to 5000 mg Per Day
`Ethyl Eicosapentaenoate and Not More Than About 5%, By Weight
`of All Fatty Acids, Docosahexaenoic Acid or its Esters
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`Hikma’s Label instructs the “daily dose of icosapent ethyl is 4 grams per day.” Hikma’s
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`Label, § 2.2; see also HIK(ICO)-DE-00000430. A gram is equivalent to 1,000 mg. Thus, 4 grams
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`of ethyl eicosapentaenoate (also referred to as “icosapent ethyl”) is 4,000 mg. Further, Hikma’s
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`ANDA recognizes that icosapent ethyl is also referred to as ethyl eicosapentaenoate. HIK(ICO)-
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`DE-00001869. Further, Hikma stipulated to, and the District of Nevada Court found, that Hikma’s
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`generic product, once approved, would “comprise ‘at least about 96%, by weight of all fatty acids,
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`of ethyl eicosapentaenoate[,] and substantially no docosahexaenoic acid or its esters.” HIK(ICO)-
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`DE-00006146, ¶ 178; HIK(ICO)-DE-00010059; see also HIK(ICO)-DE-00000179; HIK(ICO)-
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`DE-00000239; HIK(ICO)-DE-00000456 at -497; HIK(ICO)-DE-000002586 at -2627. Thus the
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`Hikma’s Label instructs a physician to administer Hikma’s generic product wherein the
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`pharmaceutical composition comprises 4,000 mg per day of ethyl eicosapentaenoate and not more
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`than about 5%, by weight of all fatty acids, docosahexaenoic acid or its esters, falling squarely
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`within the claimed range.
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`3) Hikma’s Label Instructs, Encourages, and Recommends Effecting
`a Reduction in Fasting Triglyceride Levels in the Subject
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`Hikma’s Label instructs that its generic product “is indicated as an adjunct to diet to reduce
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`triglyceride (TG) levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia.”
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`Hikma’s Label, § 1. Hikma’s Patient Information Leaflet instructs both healthcare providers and
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`patients that Hikma’s generic product is “a prescription medicine used . . . to lower high levels of
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`triglycerides (fats) in adults.” Id. at Patient Information Leaflet; see also id. § 17 (“Advise the
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`patient to read the FDA-approved patient labeling before starting icosapent ethyl (Patient
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`Information).”). Hikma’s Label also instructs and promotes the reduction in triglyceride levels of
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`treated patients in Section 14.2 where Hikma reports a 27% TG level reduction in subjects treated
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`with 4 grams per day of icosapent ethyl (or ethyl eicosapentaenoate). Hikma’s Label, § 14.2; id.
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`§ 14.2, tbl. 2. Those of skill in the art know and understand that such triglyceride levels would be
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`monitored and assessed when the patient is in a fasted state. Thus, Hikma through its Label is
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`encouraging and recommending that physicians administer its generic product according to the
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`label to reduce triglyceride levels, i.e. effect a reduction in triglyceride levels, in the patient as
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`claimed.
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`4) Hikma’s Label Instructs and Encourages Healthcare Providers to
`Administer Its Generic Product so that the Subject Exhibits a
`Reduction in hs-CRP Compared to Placebo Control
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`Section 14.2 of the Hikma Label promotes and encourages treating patients with abnormal
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`lipid levels, who thus have mixed dyslipidemia, and who are “on concomitant statin therapy.”
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`Hikma’s Label, § 14.2, tbl. 2 (enrolling patients with TG levels between 500 and 2,000 mg/dL
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`with a baseline median LDL-C of 91 mg/dL and HDL-C of 27 mg/dL, with 25% of studied patients
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`receiving “concomitant statin therapy,” and teaching administration of EPA with atorvastatin
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`(citing id. §§ 12.3, 14.2)); id. § 14.2; see id. § 14.2 (“Twenty-five percent of patients were on
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`concomitant statin therapy”). Generally mixed dyslipidemia patients when administered
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`VASCEPA®, according to its label, experience a reduction in CV risk demonstrated by a reduction
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`in hs-CRP. See HIK(ICO)-DE-00006942, §14.1 & § 14.1 tbl.1, fig.1 (VASCEPA® Label); see
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`also D.I. 17-22 at Abstract, Fig. 3, 5 (Pls.’ Am. Compl. at Ex. U (Ballantyne)). Hikma is aware
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`and intends that its product will be used for the same purposes, for patients to experience a
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`reduction in CV risk demonstrated by a reduction in hs-CRP, see, e.g., D.I. 17-24 ¶¶ 115, 116, 440
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`(Pls.’ Am. Compl. at Ex. W (Nevada Case, D.I. 377)); D.I. 17-28 at 1252-1253 (Pls.’ Am. Compl.
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`at Ex. AA (Nevada Case Trial Tr.)) (Hoffman); see also D.I. 17-18 (Pls.’ Am. Compl. at Ex. Q
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`(Nevada Case DDX_1.36)); D.I. 17-19 (Pls.’ Am. Compl. at Ex. R (Nevada Case DDX_8.13)),
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`and demonstrated that awareness and intention by removing the CV Limitation of Use from its
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`Label, as well as by marketing and promoting its generic product for uses broader than the FDA-
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`approved indication. HIK(ICO)-DE-00005694; HIK(ICO)-DE-00005696; D.I. 17-13 (Pls.’ Am.
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`Compl. at Ex. L); D.I. 17-14 (Pls.’ Am. Compl. at Ex. M); Products: Icosapent Ethyl Capsules,
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`https://www.hikma.com/products/us-products (last accessed Aug. 26, 2021); D.I. 17-21 (Pls.’ Am.
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`Compl. at Ex. T); HIK(ICO)-DE-00009694. Thus, Hikma’s generic product, when administered
`
`according to Hikma’s Label, results in a reduction in CV risk for mixed dyslipidemia patients.
`
`Hikma’s voluntary choice to amend its Label and remove the CV Limitation of Use, as
`
`well as its affirmative marketing and promotion of using its generic for uses broader than those
`
`approved by the FDA, further evidence inducement as these actions communicate to healthcare
`
`providers, and the market at large, that Hikma’s generic product has been shown to reduce
`
`cardiovascular risk, demonstrated by the reduction in hs-CRP. HIK(ICO)-DE-00005694-5695;
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`HIK(ICO)-DE-00005696-5705; D.I. 17-13 (Pls.’ Am. Compl. at Ex. L); D.I. 17-14 (Pls.’ Am.
`
`Compl. at Ex. M); Products: Icosapent Ethyl Capsules, https://www.hikma.com/products/us-
`
`products (last accessed Aug. 26, 2021); D.I. 17-21 (Pls.’ Am. Compl. at Ex. T); HIK(ICO)-DE-
`
`00009694.
`
`
`
`
`
`12
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`Hikma Pharmaceuticals
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`IPR2022-00215
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`Ex. 1020, p. 12 of 32
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`CONTAINS HIKMA CONFIDENTIAL INFORMATION
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`5) Hikma’s Label Instructs Administering Ethyl Eicosapentaenoate in
`Dosage Units Each Comprising About 500 mg to About 1.5 g, About
`900 mg to About 1 g, and About 1 g of Ethyl Eicosapentaenoate and
`that the Dosage Units are Capsules
`
`Hikma’s Label instructs healthcare providers to administer Hikma’s generic product in
`
`dosage units of 1 gram capsules. Hikma’s Label, Dosage and Administration (“The daily dose of
`
`icospent ethyl is 4 grams per day taken as two 1-gram capsules twice daily with food.”), Dosage
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`Forms and Strengths (“Capsules: 1 gram”), §§ 2.2, 3 (“Icosapent Ethyl Capsules are supplied as a
`
`1 gram, clear, oblong capsule . . . .”); see also HIK(ICO)-DE-00000430; HIK(ICO)-DE-00010059.
`
`Thus, Hikma’s Label instructs healthcare providers to administer Hikma’s generic product in
`
`dosage units each comprising about 500 mg to about 1.5 g, about 900 mg to about 1 g, and about
`
`1 g of ethyl eicosapentaenoate and that the dosage units are capsules.
`
`6) Hikma’s Label Instructs that Ethyl Eicosapentaenoate Comprises
`At Least About 90%, by Weight, of All Fatty Acids.
`
`Hikma’s Label instructs administering a pharmaceutical composition of icosapent ethyl.
`
`Hikma’s Label, Dosage and Administration, § 2.2. Hikma’s ANDA recognizes that icosapent
`
`ethyl is also referred to as ethyl eicosapentaenoate. HIK(ICO)-DE-00001869. Further, Hikma
`
`stipulated to, and the District of Nevada Court found, that Hikma’s generic product, once
`
`approved, would “comprise ‘at least about 96%, by weight of all fatty acids, of ethyl
`
`eicosapentaenoate[,] and substantially no docosahexaenoic acid or its esters.” HIK(ICO)-DE-
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`00006146, ¶ 178; HIK(ICO)-DE-00010059; see also HIK(ICO)-DE-00000179; HIK(ICO)-DE-
`
`00000239; HIK(ICO)-DE-00000456 at -497; HIK(ICO)-DE-000002586 at -2627. Thus, the
`
`Hikma’s label instructs healthcare providers to administer Hikma’s generic product wherein the
`
`pharmaceutical composition wherein the ethyl eicosapentaenoate comprises at least about 90%, by
`
`weight, of all fatty acids.
`
`13
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`Hikma Pharmaceuticals
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`IPR2022-00215
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`Ex. 1020, p. 13 of 32
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`CONTAINS HIKMA CONFIDENTIAL INFORMATION
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`B. U.S. Patent No. 9,700,537
`
`Healthcare providers who administer Hikma’s generic product according to the Hikma
`
`Label, and patients following their healthcare providers instructions, directly infringe the asserted
`
`claims of the ’537 patent, as described below. Hikma, through its Label, as well as marketing and
`
`promotional materials, instructs, recommends, and encourages healthcare providers to use
`
`Hikma’s generic product for the uses claimed in the ’537 patent.
`
`1) Hikma’s Label Instructs Healthcare Providers to Administer
`Hikma’s Generic Product to Hypercholesterolemia Patients to
`Reduce Occurrence of a Cardiovascular Event
`
`Claims 1 and 9 of the ’537 patent requires treating hypercholesterolemia patients with the
`
`goal of reducing the occurrence of a CV event. The ’537 patent defines hypercholesterolemia as
`
`“the condition with an increased serum triglyceride (TG) concentration, and strictly, with the
`
`serum TG concentration of at least 150 mg/dL.” AM_00000090 at 10:59-61. Section 14.2 of
`
`Hikma’s Label describes and encourages treating patients with hypercholesterolemia (patients
`
`with median triglyceride levels of 680 mg/dL, which is ≥ 150 mg/dL). Hikma’s Label, § 14.2, tbl.
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`2; id. § 12.3.
`
`Hikma’s Label also reflects that patients with cardiovascular disease or risk factors for
`
`cardiovascular disease are within the population that is intended to take the product, and
`
`encourages healthcare providers as well as patients to monitor and assess cardiovascular events
`
`and risk factors prior to and during treatment. Hikma’s Label, Patient Information Leaflet (“Heart
`
`rhythm problems which can be serious and cause hospitalization have happened in people who
`
`take icosapent ethyl, especially in people who have heart (cardiovascular) disease or diabetes with
`
`a risk factor for heart (cardiovascular) disease, or who have had heart rhythm problems in the
`
`
`
`
`
`14
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`Hikma Pharmaceuticals
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`IPR2022-00215
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`Ex. 1020, p. 14 of 32
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`CONTAINS HIKMA CONFIDENTIAL INFORMATION
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`past.”); id. § 17 (“Advise the patient to read the FDA-approved patient labeling before starting
`
`icosapent ethyl (Patient Information).”)).
`
`Further, healthcare providers administer Hikma’s generic product to reduce occurrences of
`
`cardiovascular events because VASCEPA®, the brand name comparator drug, has been shown to
`
`reduce occurrences of cardiovascular events. See HIK(ICO)-DE-00006942, §14.1 & § 14.1 tbl.1
`
`(VASCEPA® Label). Hikma is aware its product will be used for the same purposes, for patients
`
`to experience a reduction in cardiovascular events, see, e.g., D.I. 17-24 ¶¶ 115, 116, 440 (Pls.’
`
`Am. Compl. at Ex. W (Nevada Case, D.I. 377)); D.I. 17-28 at 1252-1253 (Pls.’ Am. Compl. at Ex.
`
`AA (Nevada Case Trial Tr.)) (Hoffman); see also D.I. 17-18 (Pls.’ Am. Compl. at Ex. Q (Nevada
`
`Case DDX_1.36)); D.I. 17-19 (Pls.’ Am. Compl. at Ex. R (Nevada Case DDX_8.13)), and
`
`demonstrated that awareness and intention by removing the CV Limitation of Use from its Label
`
`as well as by marketing and promoting its generic product for uses broader than the FDA-approved
`
`indication. HIK(ICO)-DE-00005694; HIK(ICO)-DE-00005696; D.I. 17-13 (Pls.’ Am. Compl. at
`
`Ex. L); D.I. 17-14 (Pls.’ Am. Compl. at Ex. M); Products: Icosapent Ethyl Capsules,
`
`https://www.hikma.com/products/us-products (last accessed Aug. 26, 2021); D.I. 17-21 (Pls.’ Am.
`
`Compl. at Ex. T); HIK(ICO)-DE-00009694.
`
`Hikma’s voluntary choice to amend its Label and remove the CV Limitation of Use, as
`
`well as its affirmative marketing and promotion of using its generic for uses broader than those
`
`approved by the FDA, further evidence inducement as these actions communicate to healthcare
`
`providers, and the market at large, that Hikma’s generic product has been shown to reduce the
`
`occurrence of cardiovascular events. HIK(ICO)-DE-00005694-5695; HIK(ICO)-DE-00005696-
`
`5705; D.I. 17-13 (Pls.’ Am. Compl. at Ex. L); D.I. 17-14 (Pls.’ Am. Compl. at Ex. M); Products:
`
`
`
`
`
`15
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`Hikma Pharmaceuticals
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`IPR2022-00215
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`Ex. 1020, p. 15 of 32
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`CONTAINS HIKMA CONFIDENTIAL INFORMATION
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`Icosapent Ethyl Capsules, https://www.hikma.com/products/us-products (last accessed Aug. 26,
`
`2021); D.I. 17-21 (Pls.’ Am. Compl. at Ex. T); HIK(ICO)-DE-00009694.
`
`2) Hikma’s Label
`Instructs, Recommends, and Encourages
`Identifying a Patient Having Triglycerides (TG) of At Least 150
`mg/dL and HDL-C of Less Than 40 mg/dL in a Blood Sample Taken
`from the Patient as a Risk Factor of a Cardiovascular Event
`Wherein the Patient has not Previously had a Cardiovascular Event
`
`Claim 1 of the ’537 patent requires “identifying a patient having triglycerides (TG) of at
`
`least 150 mg/dL and HDL-C of less than 40 mg/dL in a blood sample taken from the patient as a
`
`risk factor of a cardiovascular event.” AM_00000083 at -93. Claim 9 of the ’537 patent requires
`
`“identifying a patient having (i) total cholesterol (TC) of at least 220 mg/dL or LDL-cholesterol
`
`(LDL-C) of at least 140 mg/dL, and (ii) triglycerides (TG) of at least 150 mg/dL and HDL-C of
`
`less than 40 mg/dL in a blood sample taken from the patient as a risk factors of a cardiovascular
`
`event.” AM_00000083 at -93-94 (emphasis added). Thus. both asserted independent claims of
`
`the ’537 patent require identifying patients having triglycerides (TG) of at least 150 mg/dL and
`
`HDL-C of less than 40 mg/dL via blood sample, and claim 9 additionally requires a patient have
`
`either total cholesterol (TC) of at least 220 mg/dL or LDL-cholesterol (LDL-C) of at least 140
`
`mg/dL. Id.
`
`Hikma’s Label encourages, promotes, and instructs healthcare providers to determine a
`
`patient’s lipid levels, which a person of skill in the art would recognize as requiring a blood sample
`
`to determine at least the patient’s TC, TG, and HDL-C levels. Hikma’s Label, § 2 (“Assess lipid
`
`levels before initiating t