Case 1:20-cv-00645-MN Document 12 Filed 06/01/20 Page 1 of 55 PageID #: 1101
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`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
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`EXELA PHARMA SCIENCES, LLC,
`
`Plaintiff,
`
`v.
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`SANDOZ, INC.,
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`Civil Action No.: 1:20-cv-645-MN
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`JURY TRIAL DEMANDED
`
`Defendant.
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`PUBLIC VERSION
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`AMENDED COMPLAINT
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`Plaintiff Exela Pharma Sciences, LLC (“Plaintiff” or “Exela”) by its attorneys, hereby
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`alleges as follows in this amended complaint:
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`NATURE OF ACTION
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`1.
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`This is an action for infringement of U.S. Patent No. 10,478,453 (“the ’453
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`patent”) and U.S. Patent No. 10,583,155 (“the ’155 patent”) under the Patent Laws of the United
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`States, 35 U.S.C. § 1 et seq., including §§ 271(e)(2), 271(a)-(c), and for a declaratory judgment
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`of infringement of the ’453 and ’155 patents under 28 U.S.C. §§ 2201 and 2202 and 35 U.S.C.
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`§§ 271(a)-(c). Plaintiff institutes this action to enforce its patent rights covering its
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`FDA-approved ELCYS® brand L-cysteine hydrochloride injection.
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`THE PARTIES
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`2.
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`Exela is a company existing under the laws of the State of Delaware and having a
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`principal place of business at 1245 Blowing Rock Blvd., Lenoir, NC 28645.
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`3.
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`On information and belief, Defendant Sandoz, Inc. (“Sandoz”) is a corporation
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`organized and existing under the laws of the State of Colorado and having a principal place of
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`business at 100 College Road West, Princeton, New Jersey 08540.
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`1
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`EXELA 2005
`Eton Pharmaceuticals v. Exela Pharma Sciences
`PGR2020-00086
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`

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`JURISDICTION AND VENUE
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`4.
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`This Court has subject matter jurisdiction over the action under 28 U.S.C. §§ 1331
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`and 1338(a) because the action concerns a federal question arising under the Patent Laws of the
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`United States, 35 U.S.C. § 1 et seq.
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`5.
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`This Court has personal jurisdiction over Sandoz because, on information and
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`belief, Sandoz has purposely availed itself of the benefits and protections of the State of
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`Delaware’s laws such that it should reasonably anticipate being haled into court in this judicial
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`district, and because this action arises from activities of Sandoz directed toward the State of
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`Delaware.
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`6.
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`On information and belief, Sandoz has engaged in systematic and continuous
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`business contacts within the State of Delaware, regularly conducts business in the State of
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`Delaware, and has purposefully availed itself of the privilege of doing business in the State of
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`Delaware.
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`7.
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`On information and belief, Sandoz develops, manufactures, imports, markets,
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`offers to sell, and/or sells pharmaceutical drug products, including generic drugs, throughout the
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`United States, including in the State of Delaware.
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`8.
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`On information and belief, Sandoz derives substantial revenue from
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`pharmaceutical drug products, including generic drugs, that are used and/or consumed within the
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`State of Delaware, and which are manufactured by or for Sandoz and for which Sandoz is the
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`named applicant on approved Abbreviated New Drug Applications (“ANDAs”).
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`9.
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`On information and belief, Sandoz contracts with drug wholesalers and
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`distributors to supply pharmaceutical drug products, including generic drugs, for which Sandoz
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`is the named applicant on approved ANDAs, throughout the United States, including in the State
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`of Delaware.
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`10.
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`On information and belief, the drug wholesalers and distributors Sandoz contracts
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`with to supply pharmaceutical drug products, including generic drugs, are licensed to sell those
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`products in the State of Delaware and are registered with the Delaware Board of Pharmacy as
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`licensed “Pharmacy-Wholesale” and “Distributor/Manufacturer CSR.”
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`11.
`
`On information and belief, various products for which Sandoz is the named
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`applicant on approved ANDAs are offered for sale to pharmacies and hospitals in the State of
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`Delaware, distributed to and available at pharmacies and hospitals in the State of Delaware,
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`prescribed by healthcare providers practicing in the State of Delaware, used by healthcare
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`providers, patients, and/or hospitals in the State of Delaware, and/or administered to patients in
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`the State of Delaware.
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`12.
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`Sandoz has filed ANDA No. 209994 (“Sandoz’s ANDA”) for Cysteine
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`Hydrochloride Injection, USP, 500 mg/10 mL (50 mg/mL) single-dose vials (“Sandoz’s ANDA
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`Product”), which is a generic version of Exela’s ELCYS® product, containing paragraph IV
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`certifications to Exela’s ’453 and ’155 patents.
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`13.
`
`Sandoz, through its counsel Abigail Langsam of the law firm Arnold & Porter
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`Kaye Scholer LLP, sent a letter dated April 2, 2020 to Exela, a Delaware corporation, notifying
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`Exela that Sandoz had filed with FDA, and FDA had received, Sandoz’s ANDA No. 209994
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`(“Sandoz’s Paragraph IV Letter”).
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`14.
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`Sandoz’s filing of ANDA No. 209994 constitutes a formal act that reliably
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`indicates Sandoz’s plans to engage in marketing of Sandoz’s ANDA Product throughout the
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`United States, including in the State of Delaware, so that Sandoz’s ANDA Product will be used
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`throughout the United States, including in the State of Delaware.
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`15.
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`On information and belief, upon approval of ANDA No. 209994, Sandoz will
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`engage in the marketing of the Sandoz ANDA Product and offer to sell and/or sell its ANDA
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`Product either directly or indirectly through its established channels of distribution via one or
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`more of its drug wholesalers and distributors throughout the United States, including in the State
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`of Delaware.
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`16.
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`On information and belief, Sandoz knows, expects, and intends that upon
`
`approval of ANDA No. 209994, Sandoz’s ANDA Product will be offered for sale to hospitals
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`and/or pharmacies in the State of Delaware, distributed to and available at hospitals and/or
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`pharmacies in the State of Delaware, prescribed by healthcare providers practicing in the State of
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`Delaware, used by healthcare providers, patients, and/or hospitals in the State of Delaware,
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`and/or administered to patients in the State of Delaware.
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`17.
`
`Sandoz’s marketing, offer to sell, and/or sales of its ANDA Product, and the use
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`of its ANDA Product, throughout the United States, including in the State of Delaware, before
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`expiry of Exela’s ’453 and ’155 patents will constitute infringement of the ’453 and ’155 patents,
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`resulting in harm and injury to Exela.
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`18.
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`Further, this Court has personal jurisdiction over Sandoz because Sandoz
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`regularly engages in patent litigation in this judicial district, has previously consented to personal
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`jurisdiction and venue in such litigation in this judicial district, has purposefully availed itself of
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`the rights and benefits of this Court numerous times by asserting claims and/or counterclaims in
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`this Court, and has in the past consented and continues to consent to personal jurisdiction and
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`venue in this judicial district. See, e.g., Otsuka Pharmaceutical Co., Ltd. et al. v. Sandoz Inc. et
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`al., 19-cv-02080, D.I. 11 (D. Del. March 16, 2020); Merck Sharp & Dohme Corp. v. Sandoz Inc.,
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`19-cv-00312, D.I. 10 (D. Del. April 10, 2019); Astellas US LLC et al. v. Sandoz Inc., 18-cv-
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`4
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`01676, D.I. 13 (D. Del. Nov. 30, 2018); Pharmacyclics LLC et al v. Sun Pharma Global FZE et
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`al., 18-cv-00192, D.I. 12 (D. Del. Feb. 26, 2018); H. Lundbeck A/S et al. v. Sandoz Inc. et al., 18-
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`cv-00177, D.I. 9 (D. Del. April 13, 2018); ViiV Healthcare Company et al. v. Sandoz Inc. et al.,
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`17-cv-01784, D.I. 12 (D. Del. Jan. 24, 2018); Biogen International GMBH et al. v. Sandoz Inc.,
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`17-00874, D.I. 9 (D. Del. Oct. 16, 2017); Bristol-Myers Squibb Company et al. v. Sandoz Inc.,
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`17-cv-00407, D.I. 9 (D. Del. June 12, 2017); Omeros Corporation v. Sandoz Inc., 17-cv-00799,
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`D.I. 11 (D. Del. Sept. 13, 2017).
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`19.
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`Venue is proper in this judicial district under at least 28 U.S.C. § 1391 and
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`including because Sandoz is subject to personal jurisdiction in this judicial district, has
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`previously consented to venue in this judicial district, and on information and belief will consent
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`to venue in this judicial district for the purpose of this case.
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`20.
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`Exela believes this case belongs in Delaware, but is also filing a case in the
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`United States District Court for the District of Colorado out of an abundance of caution.
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`FACTUAL BACKGROUND
`
`A.
`
`The Development and FDA Approval of Exela’s ELCYS® L-Cysteine
`Hydrochloride Injection Product
`
`21.
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`Exela is a relatively small but fast-growing specialty pharmaceutical company
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`focused on developing, manufacturing, and marketing injectable products.
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`22.
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`L-cysteine is an amino acid that is important for human life. While healthy adults
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`can naturally synthesize small amounts, high-risk patients such as preterm and/or low birth
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`weight infants and patients with severe liver disease require L-cysteine supplementation by
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`parenteral administration (i.e., injection or intravenous infusion). For these patients, L-cysteine
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`is administered as a component of a nutritional supplement regimen referred to as “total
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`parenteral nutrition” (TPN).
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`23.
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`At the time Exela began developing its L-cysteine product, there was no
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`FDA-approved intravenous L-cysteine hydrochloride product on the market in the United States.
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`However, multiple unapproved and compounded L-cysteine products were on the market during
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`that time that were used in TPN regimens, including an unapproved product sold by Sandoz
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`under FDA’s drug “shortage” program, which purports to permit importation of unapproved
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`drugs during a shortage (or in this case, absence) of an FDA-approved version of the drug in the
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`United States. One significant drawback of such L-cysteine products is that they were known to
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`contain high amounts of aluminum, labeled as containing up to as much as 5,000
`
`micrograms/liter (“mcg/L,” “μg/L” or, more commonly, “parts per billion” or “ppb”).
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`24.
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`TPN admixtures even without L-cysteine were also known to contain high
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`amounts of aluminum, and aluminum toxicity from their use had been reported. Aluminum
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`toxicity can cause serious health problems including dementia, impaired neurologic
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`development, Alzheimer’s disease, metabolic bone disease (including impaired bone growth,
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`growth failure, bone pain, muscle weakness, nonhealing fractures, and premature osteoporosis),
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`encephalopathy, and cholestasis (liver disease), among others.
`
`25.
`
`FDA has long been concerned about the presence of aluminum in parenteral drug
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`products.
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`26.
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`As early as 1986, FDA held meetings to discuss the risks posed by aluminum in
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`human drug products, including in parenteral drug products. Parenteral Drug Products
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`Containing Aluminum as an Ingredient or a Contaminant; Notice of Intent and Request for
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`Information, 55 Fed. Reg. 20799 (May 21, 1990).
`
`27.
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`In 1990, FDA gave public notice that it was considering proposing rules related to
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`the aluminum content in parenteral drug products. Id. In particular, FDA stated it “has become
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`increasingly concerned about aluminum content in parenteral drug products, including aluminum
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`present as a contaminant” because the literature contained reports “that neonates and other
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`patient populations may be at high risk of exposure to unsafe amounts of aluminum in drug
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`products.” Id. at 20800. FDA noted that “many drug products that are used routinely in
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`parenteral therapy have been reported to contain levels of aluminum sufficiently high to cause
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`clinical manifestations.” Id. FDA also expressed concern “that certain populations of patients
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`may be exposed to excess aluminum parenterally,” including “premature neonates and neonates
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`who have immature or impaired renal function [that] require total parenteral nutrition,” and
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`patients with renal failure or comprised renal function. Id. FDA’s notice cites several articles
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`reporting on the effects of aluminum in these susceptible patient populations. Id.
`
`28.
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`In 1998, and after a period of public comment, FDA proposed amending its
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`regulations “to add certain labeling requirements concerning aluminum in large volume
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`parenterals (LVP’s) and small volume parenterals (SVP’s) used in total parenteral nutrition
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`(TPN).” Aluminum in Large and Small Volume Parenterals Used in Total Parenteral Nutrition,
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`63 Fed. Reg. 176, 176 (Jan. 5, 1998). FDA proposed the regulations “because of evidence
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`linking the use of parenteral drug products containing aluminum to morbidity and mortality
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`among patients on TPN therapy, especially premature infants and patients with impaired kidney
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`function.” Id.
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`29.
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`L-cysteine hydrochloride injection is a Small Volume Parenteral (SVP) drug
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`product used in TPN.
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`30.
`
`The regulation proposed in 1998 contained five parts: “(1) Establish a maximum
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`permissible level of aluminum in LVP’s used in TPN therapy; (2) require that the maximum
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`level of aluminum permitted in LVP’s used in TPN therapy be stated on the package insert of all
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`LVP’s used in TPN therapy; (3) require that the maximum level of aluminum at expiry be stated
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`on the immediate container label of SVP’s and pharmacy bulk packages used in the preparation
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`of TPN solutions; (4) require that the package insert of all LVP’s and SVP’s, including pharmacy
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`bulk packages, contain a warning statement about aluminum toxicity in patients with impaired
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`kidneys and neonates receiving TPN therapy; and (5) require that applicants and manufacturers
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`develop validated assay methods for determining the aluminum content in parenteral drug
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`products and that applicants submit the validated assay methods to FDA for approval.” Id. at
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`177.
`
`31.
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`In 2000, FDA issued a regulation, 21 C.F.R. § 201.323, concerning aluminum in
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`large and small volume parenterals used in total parenteral nutrition that would become effective
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`January 26, 2001. Aluminum in Large and Small Volume Parenterals Used in Total Parenteral
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`Nutrition, 65 Fed. Reg. 4103 (Jan. 26, 2000). The regulation would, among other things, limit
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`the aluminum content in all LVP’s to 25 micrograms per liter (i.e., 25 parts per billion, or 25
`
`ppb), require the container label for SVP’s to state the maximum level of aluminum at expiry,
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`require LVP and SVP package inserts to include a particular warning statement about aluminum
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`toxicity, and require applicants for LVP and SVP products to use validated assay methods to
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`determine aluminum content in the products and submit to FDA release data concerning
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`aluminum content for several batches. Id. at 4104-4105.
`
`32.
`
`In January 2001, FDA delayed the effective date of the regulation until January
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`26, 2003 based on feedback from the industry that more time was need to comply with it.
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`Aluminum in Large and Small Volume Parenterals Used in Total Parenteral Nutrition; Delay of
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`Effective Date, 66 Fed. Reg. 7864 (Jan. 26, 2001).
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`33.
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`In August 2002, FDA proposed amending the regulation to require container
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`labeling for LVP’s and SVP’s containing 25 micrograms per liter (μg/L) or less of aluminum to
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`state “Contains no more than 25 μg/L of aluminum” instead of the exact amount of aluminum
`
`they contain. Amendment of Regulations on Aluminum in Large and Small Volume Parenterals
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`Used in Total Parenteral Nutrition, 67 Fed. Reg. 52429 (Aug. 12, 2002).
`
`34.
`
`In November 2002, FDA further delayed the effective date of the final regulation
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`until January 26, 2004 to allow FDA time to finalize the amendment proposed in August 2002.
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`Aluminum in Large and Small Volume Parenterals Used in Total Parenteral Nutrition;
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`Amendment; Delay of Effective Date, 67 Fed. Reg. 70691 (Nov. 26, 2002).
`
`35.
`
`In June 2003, FDA finalized the amendment to the regulation first proposed in
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`August 2002. Amendment of Regulations on Aluminum in Large and Small Volume Parenterals
`
`Used in Total Parenteral Nutrition; Delay of Effective Date, 68 Fed. Reg. 32,979 (June 3, 2003).
`
`36.
`
`The regulation became effective on July 26, 2004, and is codified at 21 C.F.R.
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`§ 201.323. 68 Fed. Reg. 32,979 (June 3, 2003).
`
`37.
`
`21 C.F.R. § 201.323 requires that “the maximum level of aluminum present at
`
`expiry must be stated on the immediate container label of all small volume parenteral (SVP) drug
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`products” unless the maximum level of aluminum is 25 mcg/L or less, in which case the
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`immediate container label may state “Contains no more than 25 [micro]g/L of aluminum.”
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`21 C.F.R. § 201.323(c)-(d).
`
`38.
`
`21 C.F.R. § 201.323(e) requires manufacturers of LVP’s and SVP’s to include the
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`following warning on their product labeling:
`
`WARNING: This product contains aluminum that may be toxic.
`Aluminum may reach toxic levels with prolonged parenteral administration
`if kidney function is impaired. Premature neonates are particularly at risk
`because their kidneys are immature, and they require large amounts of
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`calcium and phosphate solutions, which contain aluminum. Research
`indicates that patients with impaired kidney function, including premature
`neonates, who receive parenteral levels of aluminum at greater than 4 to 5
`[micro]g/kg/day accumulate aluminum at levels associated with central
`nervous system and bone toxicity. Tissue loading may occur at even lower
`rates of administration.
`
`21 C.F.R. § 201.323(e).
`
`39.
`
`On information and belief, the safety concerns with and risks posed by aluminum
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`exposure that drove FDA to enact 21 C.F.R. § 201.323 remain valid concerns today.
`
`40.
`
`In May 2017, Exela submitted to FDA a New Drug Application (“NDA”) under
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`Section 505(b) of the Federal Food, Drug, and Cosmetic Act seeking approval for an L-cysteine
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`hydrochloride injection product, which is an SVP subject to 21 C.F.R. § 201.323. After 6
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`months of storage at 25 °C and 60% relative humidity, Exela’s L-cysteine hydrochloride product
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`contained less than 570 mcg/L of aluminum. After 6 months of storage at 40 °C and 75%
`
`relative humidity, Exela’s L-cysteine hydrochloride product contained less than 1400 mcg/L of
`
`aluminum.
`
`41.
`
`On August 4, 2017, FDA sent Exela a General Advice letter concerning Exela’s
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`NDA signed on behalf of FDA by Dr. Donna Griebel, who at the time was the Director of the
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`Division of Gastroenterology and Inborn Errors Products at FDA’s Center for Drug Evaluation
`
`and Research. [Ex. A (FDA’s August 4, 2017 letter to Exela).]
`
`42.
`
`In the August 4, 2017 letter, FDA set forth a maximum aluminum content for
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`0.5g/10mL (50 mg/mL) L-cysteine hydrochloride injection products of no more than 145 mcg/L
`
`of aluminum during the product’s shelf life. [Ex. A at 1 (“a limit of ≤ 145 mcg/L aluminum is
`
`needed”).]
`
`43.
`
`On information and belief, FDA’s August 4, 2017 letter to Exela sets forth FDA’s
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`interpretation of 21 C.F.R. § 201.323, as applied specifically to L-cysteine hydrochloride
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`injection products (50 mg/mL), that the maximum amount of aluminum permitted in FDA
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`approvable L-cysteine hydrochloride injection products (50 mg/mL) is no more than 145 mcg/L.
`
`44.
`
`On information and belief, the scientific rationale underlying FDA’s setting an
`
`aluminum limit for L-cysteine hydrochloride injection products (50 mg/mL) to no more than
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`145 mcg/L during the product’s shelf life remains very much applicable today.
`
`45.
`
`In April of 2019, after extensive effort, research, and development, including
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`substantial work to achieve the ≤ 145 mcg/L aluminum level FDA mandated for the L-cysteine
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`hydrochloride injection product, Exela secured the first FDA approval for an injectable
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`L-cysteine hydrochloride product containing low aluminum levels, finally fulfilling a long-felt
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`need for such a low-aluminum injectable cysteine product that could be safely administered to
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`newborn patients, including premature babies weighing as little as 1 kilogram at birth.
`
`46.
`
`Exela is the holder of approved NDA No. 210660 for cysteine hydrochloride
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`injection, sold under the brand name ELCYS®.
`
`47.
`
`Exela’s ELCYS® product is labeled to contain no more than 120 mcg/L of
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`aluminum, and is the only FDA approved L-cysteine product available on the market today.
`
`[Ex. B (ELCYS® Label), § 11.]
`
`48.
`
`The labeling for Exela’s ELCYS® product states, “Exposure to aluminum from
`
`ELCYS is not more than 0.21 mcg/kg/day when preterm and term infants less than 1 month of
`
`age are administered the recommended maximum dosage of ELCYS (15 mg cysteine/g of amino
`
`acids and 4 g of amino acids/kg/day) [see Table 1, Dosage and Administration (2.5)].” [Id. at
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`§ 5.7.]
`
`49.
`
`The FDA’s Multi-Disciplinary Review and Evaluation for NDA No. 210660
`
`explains the basis for this Warning. [Ex. C (FDA Multi-Disciplinary Review NDA
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`11
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`No. 210660).] First, FDA calculated the maximum daily dose of cysteine in preterm and term
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`infants as 60 mg/kg/day, based on 4 g/kg/day amino acids and 15 mg cysteine/g amino acid
`
`(which corresponds to 22 mg ELCYS®/g amino acid), as stated in the labeling. Second, FDA
`
`identified the volume of ELCYS® needed to deliver the 60 mg/kg/day dose of cysteine as 1.76
`
`mL/kg of ELCYS®. Multiplying this volume of ELCYS® (1.76 mL/kg) by the maximum
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`amount of aluminum in ELCYS® (120 mcg/L) results in a maximum exposure of 0.21
`
`mcg/kg/day of aluminum. Thus, FDA concluded: “At the maximum dose in preterm and infants,
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`the aluminum limit of 120 mcg/L will allow a maximum dose of 0.21 mcg/kg/day.” [Id. at 65.]
`
`50.
`
`In other words, the maximum aluminum exposure amount reported in the
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`ELCYS® labeling (0.21 mcg/kg/day) is based specifically on a cysteine injection product that
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`contains no more than 120 mcg/L of aluminum.
`
`51.
`
`The FDA’s Multi-Disciplinary Review and Evaluation for NDA No. 210660
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`shows that FDA treats aluminum as a quality controlled impurity. [Id. at 44 (“Currently, without
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`any approved drug products available on the market, marketing approval of a product with
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`quality controlled impurities (i.e., leachables, extractables), especially aluminum exposure, offers
`
`a significant benefit.”).]
`
`52.
`
`The FDA’s Multi-Disciplinary Review and Evaluation for NDA No. 210660
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`states:
`
`
`[Id. at 24.]
`
`
`Since Elcys will be used as a component of TPN, the aluminum content of
`the drug product is controlled to 120 μg/L (equivalent to 0.0035 μg of
`aluminum per mg of cysteine) by the drug product specification per
`recommendation by the Pharm/Tox review team to ensure that infants and
`pediatric patient exposure to aluminum from the final TPN admixture
`remains at or below 5 mcg/kg/day per 21 CFR 201.323(e).
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`53.
`
`The FDA’s Multi-Disciplinary Review and Evaluation for NDA No. 210660
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`states the aluminum content of “other available marketed unapproved or compounded [L-
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`cysteine] products do not meet the regulatory requirements of 21 CFR 201.323 (e). The
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`proposed cysteine product [i.e., ELCYS®] significantly reduces the aluminum content (see
`
`Appendix 15.2) and ensures acceptable aluminum exposures in patients receiving this
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`formulation of cysteine hydrochloride.” [Id. at 42; see also id. at 51-52.]
`
`54.
`
`On information and belief, the only “marketed unapproved” cysteine injection
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`product available at the time of the FDA’s Multi-Disciplinary Review and Evaluation statement
`
`on April 16, 2019 was the unapproved, high-aluminum L-cysteine product that Sandoz had been
`
`marketing since at least 2016. On information and belief, the “other available marketed
`
`unapproved” cysteine product to which the FDA was referring was therefore the unapproved,
`
`high-aluminum L-cysteine product that Sandoz had been marketing since at least 2016.
`
`55. When FDA approved NDA No. 210660 on April 16, 2019, it applied the
`
`aluminum limit for L-cysteine hydrochloride injection products (50 mg/mL) set forth in FDA’s
`
`August 4, 2017 letter to Exela.
`
`56.
`
`FDA would not have approved NDA No. 210660 if ELCYS® contained more than
`
`145 mcg/L of aluminum at the expiry of its two-year shelf life.
`
`57.
`
`Exela’s ELCYS® product “is a sterile, nonpyrogenic solution for intravenous use.
`
`Each 10 mL of ELCYS contains 500 mg of cysteine hydrochloride, USP (equivalent of 345 mg
`
`of cysteine) in water for injection.” [Ex. B at § 11.]
`
`58.
`
`The FDA approved ELCYS® with a specification limiting the total impurities in
`
`the product, including pyruvic acid and cystine, both of which are observed as degradation
`
`products of L-cysteine, to no more than 2.0%.
`
`13
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`Case 1:20-cv-00645-MN Document 12 Filed 06/01/20 Page 14 of 55 PageID #: 1114
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`59.
`
`The FDA-approved labeling for Exela’s ELCYS® product instructs healthcare
`
`providers that “ELCYS is indicated for use as an additive to amino acid solutions to meet the
`
`nutritional requirements of newborn infants requiring total parenteral nutrition (TPN) and of
`
`adult and pediatric patients with severe liver disease who may have impaired enzymatic
`
`processes and require TPN. It can also be added to amino acid solutions to provide a more
`
`complete profile of amino acids for protein synthesis.” [Id. at § 1.]
`
`60.
`
`The FDA-approved labeling for ELCYS® further instructs healthcare providers
`
`that “ELCYS is for admixing use only. It is not for direct intravenous infusion. Prior to
`
`administration, ELCYS must be diluted and used as an admixture in parenteral nutrition (PN)
`
`solutions. The resulting solution is for intravenous infusion into a central or peripheral vein.”
`
`[Id. at § 2.1 (emphases in original).] It goes on to provide instructions for healthcare providers
`
`on how to prepare the admixture by following the steps laid out on the labeling and how to
`
`administer PN solutions containing ELCYS®. [Id. at §§ 2.2-2.5.]
`
`61.
`
`The FDA-approved labeling for ELCYS® instructs that “[t]he dosage of the final
`
`PN solution containing ELCYS must be based on the concentrations of all components in the
`
`solution and the recommended nutritional requirements [see Dosage and Administration (2.5)].”
`
`[Id. at § 2.4.]
`
`62.
`
`The FDA-approved labeling for ELCYS® includes the following Warning
`
`concerning aluminum toxicity:
`
`Aluminum may reach toxic levels with prolonged parenteral administration
`in patients with renal impairment. Preterm infants are particularly at risk
`for aluminum toxicity because their kidneys are immature, and they require
`large amounts of calcium and phosphate solutions, which also contain
`aluminum. Patients with renal impairment, including preterm infants, who
`receive greater than 4 to 5 mcg/kg/day of parenteral aluminum can
`accumulate aluminum to levels associated with central nervous system and
`
`14
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`Case 1:20-cv-00645-MN Document 12 Filed 06/01/20 Page 15 of 55 PageID #: 1115
`
`bone toxicity. Tissue loading may occur at even lower rates of
`administration.
`
`[Id. at § 5.7.] The Warning further instructs:
`
`Exposure to aluminum from ELCYS is not more than 0.21 mcg/kg/day
`when preterm and term infants less than 1 month of age are administered
`the recommended maximum dosage of ELCYS (15 mg cysteine/g of amino
`acids and 4 g of amino acids/kg/day) [see Table 1, Dosage and
`Administration (2.5)]. When prescribing ELCYS for use in PN containing
`other small volume parenteral products, the total daily patient exposure to
`aluminum from the admixture should be considered and maintained at no
`more than 5 mcg/kg/day [see Use in Specific Populations (8.4)].”
`
`[Id.]
`
`63.
`
`As explained above in paragraphs 49-50, the calculated exposure to aluminum
`
`from ELCYS® of not more than 0.21 mcg/kg/day referred to in the Warning is based on
`
`ELCYS® containing no more than 120 mcg/L of aluminum at expiry, as demonstrated by FDA’s
`
`calculations. [See Ex. C at 65.]
`
`B.
`
`FDA Approved NOURESS™, Another L-Cysteine Hydrochloride Injection
`Product, With a Limit of 145 mcg/L Aluminum
`
`64.
`
`On December 13, 2019, FDA approved NDA No. 212535 held by Avadel Legacy
`
`Pharmaceuticals LLC (“Avadel”) for NOURESSTM brand cysteine hydrochloride injection USP,
`
`50 mg/mL.
`
`65.
`
`The NOURESS™ Label states that “NOURESS contains no more than
`
`145 mcg/L of aluminum.” [Ex. D (NOURESSTM Label) at § 11.]
`
`66.
`
`The NOURESS™ Label states, “Exposure to aluminum from NOURESS is not
`
`more than 0.25 mcg/kg/day when preterm and neonates are administered the recommended
`
`maximum dosage of NOURESS (22 mg cysteine hydrochloride/g of amino acids and 4g of
`
`amino acids/kg/day) [see Dosage and Administration (2.5)].” [Ex. D at § 5.6.]
`
`15
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`Case 1:20-cv-00645-MN Document 12 Filed 06/01/20 Page 16 of 55 PageID #: 1116
`
`67.
`
`On information and belief, the calculated exposure to aluminum from
`
`NOURESS™ is not more than 0.2552 mcg/kg/day, and is based on NOURESS™ containing no
`
`more than 145 mcg/L of aluminum at expiry and, as with ELCYS®, a maximum daily dose of
`
`NOURESS™ of 1.76 mL/kg.
`
`68.
`
`The FDA’s Multi-Disciplinary Review and Evaluation for NDA No. 212535
`
`discloses that in a November 21, 2017 meeting between FDA and Avadel, FDA “[c]larified the
`
`requirement regarding aluminum content for L-cysteine product.” [Ex. E (FDA Multi-
`
`Disciplinary Review NDA No. 212535) at 21.]
`
`69.
`
`On information and belief, in the November 21, 2017 meeting between FDA and
`
`Avadel, FDA told Avadel that it will not approve L-cysteine hydrochloride injection products
`
`(50 mg/ml) that contain more than 145 mcg/L of aluminum during the product’s shelf life,
`
`consistent with and confirming the aluminum limit FDA set forth in its August 4, 2017 letter to
`
`Exela for L-cysteine hydrochloride injection products (50 mg/mL).
`
`70. When FDA approved NDA No. 212535 on December 13, 2019, it applied the no
`
`more than 145 mcg/L aluminum limit for L-cysteine hydrochloride injection products
`
`(50 mg/mL) set forth in FDA’s August 4, 2017 letter to Exela.
`
`71.
`
`FDA would not have approved NDA No. 212535 if NOURESS™ contained more
`
`than 145 mcg/L of aluminum at the expiry of its two-year shelf life.
`
`72.
`
`The FDA’s s Multi-Disciplinary Review and Evaluation for NDA No. 212535
`
`explains: “At the maximum cysteine dose in preterm and term infants, the aluminum limit of 145
`
`μg/L will allow a maximum dose of 0.26 μg/kg/day” of aluminum. [Ex. E at 56.]
`
`73.
`
`On information and belief, FDA used the same calculation to determine the
`
`maximum dose of aluminum of 0.26 μg/kg/day at the maximum dose of NOURESS™ as it did
`
`16
`
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`Case 1:20-cv-00645-MN Document 12 Filed 06/01/20 Page 17 of 55 PageID #: 1117
`
`to calculate the maximum dose of aluminum of 0.21 μg/kg/day at the maximum dose of
`
`ELCYS®, the only difference being the 145 mcg/L aluminum limit in NOURESS™ versus the
`
`120 mcg/L aluminum limit in ELCYS®.
`
`74.
`
`On information and belief, the calculated maximum dose of aluminum of
`
`0.26 μg/kg/day reflected in FDA’s Multi-Disciplinary Review and Evaluation for NDA No.
`
`212535 reflects a rounding of the 0.2552 mcg/kg/day value stated in paragraph 67.
`
`75.
`
`The FDA’s s Multi-Disciplinary Review and Evaluation for NDA No. 212535
`
`expresses FDA’s continuing concerns, as of December 2019, about the levels of aluminum in
`
`parenteral drug products. For example, FDA stated, “There have been numerous reports of
`
`aluminum toxicity resulting from this impurity found in PN [parenteral] solutions over the past
`
`three decades. . . . These findings suggest that the total aluminum exposure from prolonged TPN
`
`administration to premature infants is a contributing factor to adverse neurologic sequelae and
`
`altered bone development and mineralization.” [Ex. E at 37.]
`
`76.
`
`The FDA’s Multi-Disciplinary Review and Evaluation for NDA No. 212535
`
`states