Case 1:20-cv-01630-RGA-JLH Document 17 Filed 01/25/21 Page 1 of 54 PageID #: 367
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`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`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.
`
`C.A. No. 20-1630-RGA
`
`JURY TRIAL DEMANDED
`
`FIRST AMENDED COMPLAINT FOR PATENT INFRINGEMENT AND DEMAND
`FOR JURY TRIAL
`
`Plaintiffs Amarin Pharma, Inc. and Amarin Pharmaceuticals Ireland Limited (“Amarin”)
`
`and Mochida Pharmaceutical Co., Ltd. (“Mochida”) (collectively, “Plaintiffs”), by their
`
`attorneys, hereby allege as follows:
`
`THE NATURE OF THE ACTION
`
`1.
`
`This is an action for infringement of U.S. Patent Nos. 9,700,537 (“the ’537 patent”),
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`8,642,077 (the “’077 patent”), and 10,568,861 (the “’861 patent”) (collectively, the “Asserted
`
`Patents”) under the Patent Laws of the United States, 35 U.S.C. § 100 et seq., including § 271(b).
`
`In violation of these laws, the Hikma Defendants are marketing their generic version of Amarin’s
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`ground-breaking VASCEPA® product to reduce the risk of cardiovascular events such as heart
`
`attack and stroke (“cardiovascular risk reduction”), and Health Net is inducing pharmacies to
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`dispense, and patients to use it, for that purpose. VASCEPA® is the first and only innovative
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1022, p. 1 of 54
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`

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`Case 1:20-cv-01630-RGA-JLH Document 17 Filed 01/25/21 Page 2 of 54 PageID #: 368
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`omega-3 acid-based product approved for cardiovascular risk reduction by the United States Food
`
`and Drug Administration.
`
`THE PARTIES
`
`2.
`
`Amarin Pharma, Inc. is a company organized under the laws of Delaware with its
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`principal place of business at 440 Route 22, Suite 330, Bridgewater, NJ 08870.
`
`3.
`
`Amarin Pharmaceuticals Ireland Limited is a company incorporated under the laws
`
`of Ireland with registered offices at 88 Harcourt Street, Dublin 2, Dublin, Ireland.
`
`4. Mochida Pharmaceutical Co., Ltd. is a company incorporated under the laws of Japan
`
`with its principal place of business at 1-1, Ichigayahonmuracho, Shinjuku-ku, Tokyo 162-0845,
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`Japan.
`
`5.
`
`On information and belief, Defendant Hikma Pharmaceuticals USA Inc. is a
`
`corporation organized and existing under the laws of Delaware with its principal place of business
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`at 246 Industrial Way West, Eatontown, NJ 07724.
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`6.
`
`On information and belief, Defendant Hikma Pharmaceuticals PLC is a corporation
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`organized and existing under the laws of the United Kingdom with its principal place of business
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`at 1 New Burlington Place, London W1S 2HR.
`
`7.
`
`Upon information and belief, Hikma Pharmaceuticals USA Inc. is a wholly-owned
`
`subsidiary of Hikma Pharmaceuticals PLC.
`
`8.
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`Upon information and belief, Hikma Pharmaceuticals USA Inc. acts at the direction,
`
`and for the benefit, of Hikma Pharmaceuticals PLC, and is controlled and/or dominated by Hikma
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`Pharmaceuticals PLC. Hikma Pharmaceuticals USA Inc. and Hikma Pharmaceuticals PLC are
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`hereinafter referred to together as “the Hikma Defendants” or “Hikma.”
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`2
`
`Hikma Pharmaceuticals
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`IPR2022-00215
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`Ex. 1022, p. 2 of 54
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`

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`9.
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`Upon information and belief, the Hikma Defendants collaborate with respect to the
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`development, regulatory approval, marketing, sale, and/or distribution of pharmaceutical products.
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`On further information and belief, the Hikma Defendants are agents of each other and/or operate
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`in concert as integrated parts of the same business group, and enter into agreements with each other
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`that are nearer than arm’s length.
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`10. Upon information and belief, Hikma Pharmaceuticals USA Inc. is the current owner
`
`of ANDA No. 209457 for 1g and 0.5 g icosapent ethyl capsules purportedly bioequivalent to
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`VASCEPA®.
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`11. Upon information and belief, on May 21, 2020, FDA granted final approval for the
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`Hikma Defendants’ 1g icosapent ethyl capsules under ANDA No. 209457.
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`12. Attached hereto as Exhibit A is a press release issued by Hikma Pharmaceuticals PLC
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`on or about May 22, 2020 announcing that “Hikma Pharmaceuticals USA Inc. has received
`
`approval from the US Food and Drug Administration (FDA) for its Icosapent Ethyl Capsules, 1
`
`gm, the generic equivalent to Vascepa®.”
`
`13. Attached hereto as Exhibit N is a press release issued by Hikma Pharmaceuticals PLC
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`on or about November 5, 2020 announcing the launch of Hikma’s icosapent ethyl capsules. On
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`information and belief, on November 5, 2020, Hikma launched and began offering for sale and/or
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`selling its generic icosapent ethyl capsules in the United States, including this jurisdiction.
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`14. Upon information and belief, the Hikma Defendants act collaboratively to
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`commercially manufacture, market, distribute, offer for sale, and/or sell Hikma’s icosapent ethyl
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`capsules in the United States, including this jurisdiction.
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`15. On information and belief, Health Net, LLC is a limited liability company organized
`
`and existing under the laws of the State of Delaware with a principal place of business at 21281
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`3
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`Hikma Pharmaceuticals
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`IPR2022-00215
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`Ex. 1022, p. 3 of 54
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`

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`Case 1:20-cv-01630-RGA-JLH Document 17 Filed 01/25/21 Page 4 of 54 PageID #: 370
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`Burbank Boulevard in Woodland Hills, California 91367. Health Net, LLC is referred to herein
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`as “Health Net” and collectively with the Hikma Defendants as “Defendants.”
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`16. On information and belief, Health Net, on its own and through its various
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`subsidiaries, provides insurance coverage for patients in the United States.
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`JURISDICTION AND VENUE
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`17. This Court has subject matter jurisdiction over the action under 28 U.S.C. §§ 1331
`
`and 1338(a).
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`18. This Court has personal jurisdiction over Hikma Pharmaceuticals USA Inc. because
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`it is incorporated in Delaware and thus is present in and resides in this District, and because Hikma
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`Pharmaceuticals USA Inc. is doing business in this District and has thus purposefully availed itself
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`to the privileges of conducting business in Delaware.
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`19. Venue is proper in this District over Hikma Pharmaceuticals USA, Inc. under 28
`
`U.S.C. § 1400(b).
`
`20. This Court has personal jurisdiction over Hikma Pharmaceuticals PLC because, on
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`information and belief, it manufactures, imports, offers for sale, and sells pharmaceutical drugs
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`that are sold in the United States, including in Delaware, and derives substantial income therefrom.
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`21.
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`In the alternative, this Court may exercise personal jurisdiction over Hikma
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`Pharmaceuticals PLC pursuant to Fed. R. Civ. P. 4(k)(2) because (a) Plaintiffs’ claims arise under
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`federal law; (b) Hikma Pharmaceuticals PLC is a foreign company not subject to personal
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`jurisdiction in the courts in any state, and (c) Hikma Pharmaceuticals PLC has sufficient contacts
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`with the United States as a whole, including but not limited to marketing and/or selling generic
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`pharmaceutical products that are distributed and sold throughout the United States, such that this
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`Court’s exercise of jurisdiction over Hikma Pharmaceuticals PLC satisfies due process.
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`
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`4
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`Hikma Pharmaceuticals
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`IPR2022-00215
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`Ex. 1022, p. 4 of 54
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`

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`22. Venue is proper in this District with respect to Hikma Pharmaceuticals PLC pursuant
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`to 28 U.S.C. § 1391(c)(3) because it is not resident in the United States.
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`23. This Court has personal jurisdiction over Health Net because it is organized under
`
`the law of Delaware and thus is present in and resides in this District.
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`24. Venue is proper in this District over Health Net under 28 U.S.C. § 1400(b).
`
`FACTUAL BACKGROUND
`
`A.
`
`VASCEPA®, REDUCE-IT, JELIS and EPA’s Reduction of Cardiovascular
`Risk
`
`25. The three types of omega−3 fatty acids involved in human physiology are α-linolenic
`
`acid (ALA), found in plant oils, and eicosapentaenoic acid (EPA) and docosahexaenoic
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`acid (DHA), both commonly found in marine (fish) oils.
`
`26. Amarin and Mochida are recognized worldwide as the leading innovation-driven
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`companies committed to the research and development of EPA-based drug products to treat the
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`needs of millions of patients who are at risk of cardiovascular disease.
`
`27. Mochida developed and markets a prescription pure EPA drug product, Epadel, in
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`Japan.
`
`28. Amarin developed and markets VASCEPA®, a prescription drug that contains pure
`
`EPA, in the United States.
`
`29. Amarin conducted a series of clinical trials to support FDA approval of VASCEPA®.
`
`30.
`
`In the MARINE trial that led to VASCEPA®’s first approval, VASCEPA® was
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`found to lower triglycerides in patients with severe hypertriglyceridemia (≥500 mg/dL) without
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`raising bad cholesterol, or LDL-C, levels. Upon FDA approval in 2012, VASCEPA® became the
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`first (and still only) approved medication for treating severe hypertriglyceridemia that does not
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`raise LDL-C.
`
`
`
`5
`
`Hikma Pharmaceuticals
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`IPR2022-00215
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`Ex. 1022, p. 5 of 54
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`

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`Case 1:20-cv-01630-RGA-JLH Document 17 Filed 01/25/21 Page 6 of 54 PageID #: 372
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`31. After that approval to treat severe hypertriglyceridemia, Amarin continued its clinical
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`work towards its primary goal, approval of VASCEPA® for use in cardiovascular risk reduction.
`
`Based on an agreed protocol with the FDA, Amarin had conducted a clinical trial known as
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`ANCHOR, in which Amarin examined VASCEPA® as an add-on to statin therapy in patients with
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`persistent high (≥200 mg/dL and <500 mg/dL) triglycerides. As agreed with FDA, Amarin
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`evaluated VASCEPA®’s effect on cardiovascular risk reduction based on triglyceride level
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`lowering as a surrogate, or substitute, for cardiovascular risk reduction while awaiting the results
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`of Amarin’s REDUCE-IT trial.
`
`32. While ANCHOR met its clinical endpoints, including the exploratory endpoint of
`
`median placebo-adjusted percent change in high-sensitivity C reactive protein (hs-CRP), see Ex.
`
`U (Ballantyne), FDA’s view on the use of triglyceride levels as a surrogate for cardiovascular risk
`
`changed. Ex. BB. FDA identified several clinical trials where other therapies, including other
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`omega-3 based therapies, lowered triglyceride levels in this patient population but did not show an
`
`actual reduction in cardiovascular risk. The trials failing to show a cardiovascular risk reduction
`
`included ACCORD-Lipid, AIM-HIGH, and HPS2-THRIVE.
`
`33.
`
` Accordingly, Amarin proceeded to complete REDUCE-IT, a trial in which the
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`effects of VASCEPA® on cardiovascular risk reduction were evaluated directly. The REDUCE-
`
`IT study was completed by Amarin at great cost. In REDUCE-IT, Amarin followed more than
`
`8000 patients over a median of five years and evaluated the effectiveness of VASCEPA® as an
`
`add-on to statin therapy in reducing major cardiovascular events in patients with persistent elevated
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`triglycerides. See Ex. V (Bhatt).
`
`34. The results of REDUCE-IT, first announced in 2018, see Ex. H, were hailed as one
`
`of the most important developments in the prevention and treatment of cardiovascular disease since
`
`
`
`6
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`Hikma Pharmaceuticals
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`IPR2022-00215
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`Ex. 1022, p. 6 of 54
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`

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`Case 1:20-cv-01630-RGA-JLH Document 17 Filed 01/25/21 Page 7 of 54 PageID #: 373
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`statins. Compared to statins alone on top of other contemporaneous medical therapy, VASCEPA®
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`showed a 25% reduction in major cardiovascular events such as cardiovascular death, myocardial
`
`infarction, and stroke. Based on those results, in December 2019, FDA approved VASCEPA®
`
`for a second indication as an adjunct to maximally tolerated statin therapy to reduce the risk of
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`myocardial infarction, stroke, coronary revascularization, and unstable angina requiring
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`hospitalization in adult patients with elevated triglyceride (TG) levels (≥ 150 mg/dL) and
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`established cardiovascular disease or diabetes mellitus and 2 or more additional risk factors for
`
`cardiovascular disease. Ex. I. Similar to the ANCHOR results, a reduction in hs-CRP was
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`observed in REDUCE-IT which may in part explain the cardiovascular risk benefit. See Ex. V
`
`(Bhatt) at 20. This is consistent with the investigators in the ANCHOR trial, who stated that one
`
`of the potential explanations for increased cardiovascular risk might be inflammation and
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`VASCEPA® showed a 22% reduction of hs-CRP in the mixed dyslipidemia population studied in
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`ANCHOR. See Ex. U (Ballantyne); see also Exhibit O at col. 18, 1. 11-12.
`
`35.
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`In a press release about this additional approval, FDA recognized that “VASCEPA
`
`is the first FDA-approved drug to reduce cardiovascular risk among patients with elevated
`
`triglyceride levels as an add-on to maximally tolerated statin therapy.” Ex. J. The results of
`
`REDUCE-IT were met with widespread enthusiasm and surprise in the field and have been hailed
`
`as a “game changer” in medicine. Ex. Y; Ex. Z.
`
`36. Amarin’s work in the MARINE, ANCHOR, and REDUCE-IT clinical trials was
`
`preceded by other work done by Mochida, in Japan. In the late 1990s and early 2000s, Mochida
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`sponsored a cardiovascular outcomes trial with Epadel in Japan, called JELIS (Japanese EPA Lipid
`
`Intervention Study). JELIS was the world’s first large-scale randomized controlled cardiovascular
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`outcomes trial of a prescription pure EPA drug product. The JELIS results reported that pure EPA
`
`
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`7
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`Hikma Pharmaceuticals
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`IPR2022-00215
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`Ex. 1022, p. 7 of 54
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`Case 1:20-cv-01630-RGA-JLH Document 17 Filed 01/25/21 Page 8 of 54 PageID #: 374
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`suppressed coronary artery disease in Japanese hypercholesterolemic patients who routinely
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`consume a large amount of EPA and DHA (another poly unsaturated fatty acid) from fish oil in
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`their diet.
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`37. A further statistical analysis of JELIS was undertaken to assess the effect of EPA on
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`patients with a particular profile of risk factors for coronary artery disease, and reported beneficial
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`effects of the drug in further reducing cardiovascular events in statin-treated, hypercholesterolemic
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`Japanese patients.
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`38. Those effects are published in Saito et al., titled, “Effects of EPA on coronary artery
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`disease in hypercholesterolemic patients with multiple risk factors: Sub-analysis of primary
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`prevention cases from the Japan EPA Lipid Intervention Study (JELIS), 200 Atherosclerosis 135-
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`400 (2008) [hereinafter, the “Saito Article”]. The Saito Article is attached hereto as Exhibit B.
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`39. The Saito Article reports on a statistical analysis of patients studied in the JELIS trial
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`who had no history of coronary artery disease (i.e., the patients had not previously had a
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`cardiovascular event). Ex. B (Saito) at § 2.1. The primary endpoint was major coronary events
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`(MCE): sudden cardiac death, fatal myocardial infarction, nonfatal myocardial infarction, unstable
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`angina pectoris
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`including hospitalization
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`for documented
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`ischemic episodes, and
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`angioplasty/stenting or coronary artery bypass grafting. Ex. B (Saito) at § 2.3.
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`40. The Saito Article reports that the “EPA treatment lowered the risk for MCE for the
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`[studied population] by 53% (HR: 0.47; 95% CI: 0.23-0.98; P = 0.43; Fig. 3).” Ex. B (Saito) at
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`138. By comparison, MCE risk was reduced by 18% in all primary prevention subjects treated in
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`the JELIS clinical study. Ex. B (Saito) at 139.
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`B.
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`The Asserted Patents
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`41. On July 11, 2017, the United States Patent and Trademark Office (“USPTO”) duly
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`and legally issued the ’537 patent, titled “Composition for Preventing the Occurrence of
`
`
`
`8
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`Hikma Pharmaceuticals
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`IPR2022-00215
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`Ex. 1022, p. 8 of 54
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`

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`Case 1:20-cv-01630-RGA-JLH Document 17 Filed 01/25/21 Page 9 of 54 PageID #: 375
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`Cardiovascular Event in Multiple Risk Patient,” and naming Mitsuhiro Yokoyama, Hideki
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`Origasa, Masunori Matsuzaki, Yuji Matsuzawa and Yasushi Saito as inventors. A true and correct
`
`copy of the ’537 patent is attached to this complaint as Exhibit C.
`
`42. The ’537 patent is assigned to Mochida Pharmaceutical Co., Ltd.
`
`43. Amarin Pharma, Inc. holds an exclusive license to the ’537 patent.
`
`44. The ’537 patent reflects and claims the analysis and outcome published in the Saito
`
`Article. See, e.g., Ex. C at Example 1 (col. 13, ll. 1 to col. 15, ll. 61 (including the referenced
`
`tables and figures)).
`
`45. Claim 1 of the ’537 patent recites as follows:
`
`1. A method of reducing occurrence of a cardiovascular event
`hypercholesterolemia patient consisting of:
`
`in a
`
`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, and administering ethyl icosapentate in combination with a
`3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor,
`
`wherein said 3-hydroxyl-3-methylglutaryl coenzyme A reductase inhibitor is
`administered to the patient at least one of before, during and after administering
`the ethyl icosapentate; and
`
`wherein the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor is
`selected from the group consisting of pravastatin, lovastatin, simvastatin,
`fluvastatin, atorvastatin, pitavastatin, rosuvastatin, and salts thereof, and
`
`wherein daily dose of the 3-hydroxy-3-methylglutaryl coenzyme A reductase
`inhibitor are 5 to 60 mg for pravastatin, 2.5 to 60 mg for simvastatin, 10 to 180
`mg for fluvastatin sodium, 5 to 120 mg for atorvastatin calcium hydrate, 0.5 to
`12 mg for pitavastatin calcium, 1.25 to 60 mg for rosuvastatin calcium, 5 to 160
`mg for lovastatin, and 0.075 to 0.9 mg for cerivastatin sodium.
`
`
`46. On February 4, 2014, the USPTO duly and legally issued the ’077, titled “Stable
`
`Pharmaceutical Composition and Methods of Using Same,” and naming Mehar Manku, Ian
`
`Osterloh, Pierre Wicker, Rene Braeckman, and Paresh Soni as inventors. A true and correct copy
`
`of the ’077 patent is attached to this complaint as Exhibit O.
`
`
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`9
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`Hikma Pharmaceuticals
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`IPR2022-00215
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`Ex. 1022, p. 9 of 54
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`

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`Case 1:20-cv-01630-RGA-JLH Document 17 Filed 01/25/21 Page 10 of 54 PageID #: 376
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`47. The ’077 patent is assigned to Amarin Pharmaceuticals Ireland Limited.
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`48. Amarin Pharma, Inc. holds an exclusive license to the ’077 patent.
`
`49. Claims 1 and 8 of the ’077 patent recites as follows:
`
`1. A method of reducing triglycerides in a subject with mixed dyslipidemia on statin
`therapy comprising, administering to the subject a pharmaceutical composition
`comprising about 2500 mg to 5000 mg per day of ethyl eicosapentaenoate and not
`more than about 5%, by weight of all fatty acids, docosahexaenoic acid or its esters
`to effect a reduction in fasting triglyceride levels in the subject.
`
`
`
`8. The method of claim 1 wherein the subject exhibits a reduction in hs-CRP
`compared to placebo control.
`
`
`50. On February 25, 2020, the USPTO duly and legally issued the ’861 patent, titled
`
`“Methods of reducing the risk of a cardiovascular event in a subject at risk for cardiovascular
`
`disease,” and naming Paresh Soni as the inventor. A true and correct copy of the ’861 patent is
`
`attached to this complaint as Exhibit P.
`
`51. The ’861 patent is assigned to Amarin Pharmaceuticals Ireland Limited.
`
`52. Amarin Pharma, Inc. holds an exclusive license to the ’861 patent.
`
`53. Claims 1 and 2 of the ’861 patent recite as follows:
`
`1. A method of reducing risk of cardiovascular death in a subject with established
`cardiovascular disease, the method comprising administering to said subject about
`4 g of ethyl icosapentate per day for a period effective to reduce risk of
`cardiovascular death in the subject.
`
`
`
`2. The method of claim 1, wherein the subject has a fasting baseline triglyceride
`level of about 135 mg/dL to about 500 mg/dL and a fasting baseline LDL-C level
`of about 40 mg/dL to about 100 mg/dL.
`
`
`
`C.
`
`Amarin’s VASCEPA® Receives FDA Approval for Reducing the Risk of
`Certain Cardiovascular Events in Patients with High Triglycerides and Low
`HDL-C Levels Concurrently on Statin Therapy
`
`54. Amarin Pharmaceuticals Ireland Limited is the current holder of NDA No. 202057
`
`for 1 g and 0.5 g icosapent ethyl capsules. Amarin Pharma, Inc. is Amarin Pharmaceuticals Ireland
`
`
`
`10
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`Hikma Pharmaceuticals
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`IPR2022-00215
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`Ex. 1022, p. 10 of 54
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`Case 1:20-cv-01630-RGA-JLH Document 17 Filed 01/25/21 Page 11 of 54 PageID #: 377
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`Limited’s agent in the United States for purposes of communicating with the FDA regarding NDA
`
`No. 202057. Amarin Pharmaceuticals Ireland Limited and Amarin Pharma, Inc. market both
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`strengths of the approved drug product under the tradename VASCEPA®.
`
`55. A true, correct, and complete copy of the current FDA-approved Prescribing
`
`Information for VASCEPA®, covering both the 1 g and 0.5 g strengths, is attached as Exhibit D.
`
`56. VASCEPA® is indicated as (1) an adjunct to diet to reduce triglyceride levels in adult
`
`patients with severe (≥ 500 mg/dL) hypertriglyceridemia (the “Severe Hypertriglyceridemia
`
`Indication”), and (2) as an adjunct to maximally tolerated statin therapy to reduce the risk of
`
`myocardial infarction, stroke, coronary revascularization, and unstable angina requiring
`
`hospitalization in adult patients with elevated triglyceride (TG) levels (≥ 150 mg/dL) and
`
`established cardiovascular disease or diabetes mellitus and 2 or more additional risk factors for
`
`cardiovascular disease (the “CV Indication”). Ex. D, § 1.
`
`57. FDA first approved 1 g strength icosapent ethyl capsules, sold under the trade name
`
`VASCEPA®, pursuant to NDA No. 202057 on July 26, 2012.
`
`58. A supplement to NDA No. 202057 for the 0.5 g strength of icosapent ethyl capsules
`
`was approved on February 16, 2017.
`
`59. From July 26, 2012 through December 12, 2019, the sole indication for which
`
`VASCEPA® had received FDA approval was the Severe Hypertriglyceridemia Indication. FDA
`
`approval was based, in part, on the MARINE clinical trial and information from that trial is
`
`included on the VASCEPA® label. See Ex. E (VASCEPA® July 2012 label); Ex. F (VASCEPA®
`
`Feb. 2017 label).
`
`60. From 2012 through December 12, 2019, the label for VASCEPA® contained the
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`following limitation of use: “The effect of VASCEPA on cardiovascular mortality and morbidity
`
`
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`11
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`Hikma Pharmaceuticals
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`IPR2022-00215
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`Ex. 1022, p. 11 of 54
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`Case 1:20-cv-01630-RGA-JLH Document 17 Filed 01/25/21 Page 12 of 54 PageID #: 378
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`in patients with severe hypertriglyceridemia has not been determined” (the “CV Limitation of
`
`Use”). See Ex. E (VASCEPA® July 2012 label); Ex. F (VASCEPA® Feb. 2017 label). The CV
`
`Limitation of Use appeared in three places on the VASCEPA® label during that time period. See
`
`Ex. E at Highlights of Prescribing Information and Sections 1 and 14; Ex. F (same). The CV
`
`Limitation of Use as it appears in the VASCEPA® Label approved by FDA in February 2017 is
`
`reproduced below with annotations in red:
`
`Ex. F at Highlights of Prescribing Information.
`
`12
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`Hikma Pharmaceuticals
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`IPR2022-00215
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`Ex. 1022, p. 12 of 54
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`Case 1:20-cv-01630-RGA-JLH Document 17 Filed 01/25/21 Page 13 of 54 PageID #: 379
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`Id. § 1.
`
`Id. § 14.
`
`
`
`
`
`61. The CV Limitation of use appearing on the VASCEPA® label from 2012 through
`
`December 12, 2019 was consistent with other products in the therapeutic category, such as
`
`LOVAZA®, a combination of ethyl esters of omega 3 fatty acids including EPA. To illustrate,
`
`the version of the LOVAZA® label approved by FDA on April 3, 2019 also contained the CV
`
`Limitation of Use, as shown below with an annotation in red:
`
`
`
`13
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`Hikma Pharmaceuticals
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`IPR2022-00215
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`Ex. 1022, p. 13 of 54
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`

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`Case 1:20-cv-01630-RGA-JLH Document 17 Filed 01/25/21 Page 14 of 54 PageID #: 380
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`
`
`Ex. S at Highlights of Prescribing Information.
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`62. On December 13, 2019, FDA approved VASCEPA® for the CV Indication, based
`
`on the results of the REDUCE-IT clinical trial. See Ex. G.
`
`63.
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`In conjunction with VASCEPA®’s approval for the CV Indication, the VASCEPA®
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`label was modified to remove the CV Limitation of Use and add the CV Indication, among other
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`changes. Compare Ex. D, with Exs. E and F.
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`64. To illustrate, the Highlights of Prescribing Information of the VASCEPA® label as
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`approved by FDA in December 2019 lacks the CV Limitation of Use:
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`
`
`14
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`Hikma Pharmaceuticals
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`IPR2022-00215
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`Ex. 1022, p. 14 of 54
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`

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`Case 1:20-cv-01630-RGA-JLH Document 17 Filed 01/25/21 Page 15 of 54 PageID #: 381
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`See Ex. D. This is in contrast with the 2019 LOVAZA® label which still contains the CV
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`Limitation of Use. See Ex. S.
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`65. The current VASCEPA® label instructs, recommends, and encourages administering
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`icosapent ethyl in combination with a statin to patients with baseline triglycerides ≥ 150 mg/dL to
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`reduce the risk of a cardiovascular event in a daily dose of 4 grams per day. See Ex. D. Notably,
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`FDA did not include an upper limit on the triglyceride range for the CV Indication.
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`66. FDA’s December 13, 2019 approval of VASCEPA® for the CV Indication was
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`hailed as “a major milestone in cardiovascular prevention.” Ex. I. As the lead investigator for the
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`REDUCE-IT study explained, “Nothing this significant has happened in the world of
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`cardiovascular prevention since the introduction of statins nearly three decades ago. Many patients
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`stand to benefit from this historic advance in care.” Id.
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`15
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`Hikma Pharmaceuticals
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`IPR2022-00215
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`Ex. 1022, p. 15 of 54
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`

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`Case 1:20-cv-01630-RGA-JLH Document 17 Filed 01/25/21 Page 16 of 54 PageID #: 382
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`67. On information and belief, following VASCEPA®’s approval for the CV Indication
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`and the concurrent removal of the CV Limitation of Use from the VASCEPA® label, healthcare
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`providers rapidly associated administration of icosapent ethyl together with a statin as a method
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`for reducing risk of cardiovascular events in patients with baseline triglycerides ≥ 150 mg/dL.
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`68. On information and belief, the Hikma Defendants learned that FDA approved
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`VASCEPA® for the CV Indication on or around December 13, 2019 because, on information and
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`belief, the Hikma Defendants regularly monitor the approval status of brand-name drugs serving
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`as the RLD for its generic drug candidates, and thus learned of VASCEPA® additional approval
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`either from the FDA’s press release announcing the same (Ex. J), Amarin’s press release
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`announcing the same (Ex. I), or in some other form.
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`69. On information and belief, Health Net, which is a health insurance provider, learned
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`that FDA approved VASCEPA® for the CV Indication on or around December 13, 2019 because,
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`on information and belief, Health Net regularly monitors the approved indications for drugs that it
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`covers for its health insurance plans and on its formulary lists and for which it directs or provides
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`payment.
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`D.
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`Amarin Listed the Asserted Patents Patent in the FDA’s Orange Book as
`Covering VASCEPA®
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`70.
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`In conjunction with NDA No. 202057, Amarin submitted patent information relating
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`to VASCEPA® to FDA for listing in the “Approved Drug Products with Therapeutic Equivalence
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`Evaluations,” commonly referred to the “Orange Book,” which provides notice concerning patents
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`covering FDA-approved drugs.
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`71. On January 9, 2020, Amarin timely submitted patent information regarding the ’537
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`patent to FDA for listing in the Orange Book as covering methods of using VASCEPA® pursuant
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`to 21 U.S.C. § 355(c)(2) and 21 C.F.R. § 314.53(d)(3).
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`16
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`Hikma Pharmaceuticals
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`IPR2022-00215
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`Ex. 1022, p. 16 of 54
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`

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`Case 1:20-cv-01630-RGA-JLH Document 17 Filed 01/25/21 Page 17 of 54 PageID #: 383
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`72. The ’537 patent was listed in the Orange Book on or about January 10, 2020 with
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`patent use code U-2707, “Use of VASCEPA as an adjunct to statin therapy to reduce the
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`occurrence of a cardiovascular event in an adult patient with hypercholesterolemia.”
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`73. Methods of using VASCEPA® (icosapent ethyl) capsules, 1 g and 0.5 g, for treating
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`patients as provided in the VASCEPA® label are covered by at least one claim of the ’537 patent.
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`74. On January 6, 2020, Amarin timely submitted patent information regarding the ’077
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`patent to FDA for listing in the Orange Book as covering methods of using VASCEPA® pursuant
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`to 21 U.S.C. § 355(c)(2) and 21 C.F.R. § 314.53(d)(3).
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`75. The ’077 patent was listed in the Orange Book on or about January 6, 2020 with
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`patent use code U-2693, “Use of VASCEPA to reduce triglycerides in a mixed dyslipidemia adult
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`patient with elevated triglyceride (TG) levels (>= 150 mg/dL) and on statin therapy.”
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`76. Methods of using VASCEPA® (icosapent ethyl) capsules, 1 g and 0.5 g, for treating
`
`patients as provided in the VASCEPA® label are covered by at least one claim of the ’077 patent.
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`77. On March 20, 2020, Amarin timely submitted patent information regarding the ’861
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`patent to FDA for listing in the Orange Book as covering methods of using VASCEPA® pursuant
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`to 21 U.S.C. § 355(c)(2) and 21 C.F.R. § 314.53(d)(3).
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`78. The ’861 patent was listed in the Orange Book on or about March 20, 2020 with
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`patent use code U-2756, “Use of VASCEPA as an adjunct to statin therapy to reduce the risk of
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`cardiovascular death in an adult patient with established cardiovascular disease.”
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`79. Methods of using VASCEPA® (icosapent ethyl) capsules, 1 g and 0.5 g, for treating
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`patients as provided in the VASCEPA® label are covered by at least one claim of the ’861 patent.
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`80. On information and belief, the Hikma Defendants learned that Amarin listed the ’537,
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`’077, and ’861 patents in the Orange Book as covering VASCEPA® at or around their time of
`
`
`
`17
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`Hikma Pharmaceuticals
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`IPR2022-00215
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`Ex. 1022, p. 17 of 54
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`

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`Case 1:20-cv-01630-RGA-JLH Document 17 Filed 01/25/21 Page 18 of 54 PageID #: 384
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`listing in the Orange Book because, on information and belief, the Hikma Defendants regularly
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`monitor the Orange Book for updated patent listings made for brand-name drugs serving as the
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`RLD for their generic drug candidates.
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`81. On information and belief, Health Net monitors FDA approval of generic versions of
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`drugs that are listed on its formularies, on which VASCEPA® was and still is listed. Exs. CC,
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`DD, and EE. As such, Health Net would have been aware of the FDA-approved indication for the
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`Hikma Defendants’ generic version of VASCEPA®.
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`82. The Hikma Defendants’ generic version of VASCEPA® was FDA approved for only
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`the Severe Hypertriglyceridemia Indication, and not for the CV Indication.
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`83.
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`It is known in the field, and Health Net would have been aware, that when a generic
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`product is approved for fewer than all the indications than its corresponding branded drug, it is
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`often because there are patents that cover the indications for which the generic is not approved.
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`84.
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`It is known in the field, and Health Net would have been aware, that any patents
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`covering a branded drug, such as VASCEPA®, are listed in the Orange Book. Thus, on
`
`information and belief, once the Hikma Defendants’ generic version of VASCEPA® was approved
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`with only the Severe Hypertriglyceridemia Indication, Health Net knew, or should have known,
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`that the CV Indication was covered by patents, including the patents-in-suit, listed in the Orange
`
`Book.
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`85. Alternatively, on information and belief, Health Net was aware that the ’537, ’077,
`
`and ’861 patents are listed in the Orange Book as covering VASCEPA® on or around the date that
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`Plaintiffs filed the original Complaint in this matter asserting that the Hikma Defendants’ generic
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`version of VASCEPA® infringed those patents.
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`
`
`18
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`Hikma Pharmaceuticals
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`IPR2022-00215
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`Ex. 1022, p. 18 of 54
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`

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`Case 1:20-cv-01630-RGA-JLH Document 17 Filed 01/25/21 Page 19 of 54 PageID #: 385
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`86. On November 30, 2020, Amarin issued a press release about the filing of the original
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`Complaint. Ex. FF. The press release states that “Hikma has induced the infringement of U.S.
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`Patent Nos. 9,700,537 (Composition for preventing the occurrence of cardiovascular event in
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`multiple risk patient), 8,642,077 (Stable pharmaceutical composition and methods of using same),
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`and 10,568,861 (Methods of reducing the risk of a cardiovascular event in a subject at risk for
`
`cardiovascular disease) by making, selling, offering to sell and importing generic icosapent ethyl
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`capsules in or into the United States.” It further states