`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`EXELA PHARMA SCIENCES, LLC,
`
`Plaintiff,
`
`v.
`
`SANDOZ, INC.,
`
`Civil Action No.: 1:20-cv-645-MN
`
`JURY TRIAL DEMANDED
`
`Defendant.
`
`PUBLIC VERSION
`
`AMENDED COMPLAINT
`
`Plaintiff Exela Pharma Sciences, LLC (“Plaintiff” or “Exela”) by its attorneys, hereby
`
`alleges as follows in this amended complaint:
`
`NATURE OF ACTION
`
`1.
`
`This is an action for infringement of U.S. Patent No. 10,478,453 (“the ’453
`
`patent”) and U.S. Patent No. 10,583,155 (“the ’155 patent”) under the Patent Laws of the United
`
`States, 35 U.S.C. § 1 et seq., including §§ 271(e)(2), 271(a)-(c), and for a declaratory judgment
`
`of infringement of the ’453 and ’155 patents under 28 U.S.C. §§ 2201 and 2202 and 35 U.S.C.
`
`§§ 271(a)-(c). Plaintiff institutes this action to enforce its patent rights covering its
`
`FDA-approved ELCYS® brand L-cysteine hydrochloride injection.
`
`THE PARTIES
`
`2.
`
`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.
`
`3.
`
`On information and belief, Defendant Sandoz, Inc. (“Sandoz”) is a corporation
`
`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.
`
`1
`
`EXELA 2005
`Eton Pharmaceuticals v. Exela Pharma Sciences
`PGR2020-00064
`
`
`
`Case 1:20-cv-00645-MN Document 12 Filed 06/01/20 Page 2 of 55 PageID #: 1102
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`JURISDICTION AND VENUE
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`4.
`
`This Court has subject matter jurisdiction over the action under 28 U.S.C. §§ 1331
`
`and 1338(a) because the action concerns a federal question arising under the Patent Laws of the
`
`United States, 35 U.S.C. § 1 et seq.
`
`5.
`
`This Court has personal jurisdiction over Sandoz because, on information and
`
`belief, Sandoz has purposely availed itself of the benefits and protections of the State of
`
`Delaware’s laws such that it should reasonably anticipate being haled into court in this judicial
`
`district, and because this action arises from activities of Sandoz directed toward the State of
`
`Delaware.
`
`6.
`
`On information and belief, Sandoz has engaged in systematic and continuous
`
`business contacts within the State of Delaware, regularly conducts business in the State of
`
`Delaware, and has purposefully availed itself of the privilege of doing business in the State of
`
`Delaware.
`
`7.
`
`On information and belief, Sandoz develops, manufactures, imports, markets,
`
`offers to sell, and/or sells pharmaceutical drug products, including generic drugs, throughout the
`
`United States, including in the State of Delaware.
`
`8.
`
`On information and belief, Sandoz derives substantial revenue from
`
`pharmaceutical drug products, including generic drugs, that are used and/or consumed within the
`
`State of Delaware, and which are manufactured by or for Sandoz and for which Sandoz is the
`
`named applicant on approved Abbreviated New Drug Applications (“ANDAs”).
`
`9.
`
`On information and belief, Sandoz contracts with drug wholesalers and
`
`distributors to supply pharmaceutical drug products, including generic drugs, for which Sandoz
`
`is the named applicant on approved ANDAs, throughout the United States, including in the State
`
`of Delaware.
`
`2
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`
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`Case 1:20-cv-00645-MN Document 12 Filed 06/01/20 Page 3 of 55 PageID #: 1103
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`10.
`
`On information and belief, the drug wholesalers and distributors Sandoz contracts
`
`with to supply pharmaceutical drug products, including generic drugs, are licensed to sell those
`
`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.”
`
`11.
`
`On information and belief, various products for which Sandoz is the named
`
`applicant on approved ANDAs are offered for sale to pharmacies and hospitals in the State of
`
`Delaware, distributed to and available at pharmacies and hospitals in the State of Delaware,
`
`prescribed by healthcare providers practicing in the State of Delaware, used by healthcare
`
`providers, patients, and/or hospitals in the State of Delaware, and/or administered to patients in
`
`the State of Delaware.
`
`12.
`
`Sandoz has filed ANDA No. 209994 (“Sandoz’s ANDA”) for Cysteine
`
`Hydrochloride Injection, USP, 500 mg/10 mL (50 mg/mL) single-dose vials (“Sandoz’s ANDA
`
`Product”), which is a generic version of Exela’s ELCYS® product, containing paragraph IV
`
`certifications to Exela’s ’453 and ’155 patents.
`
`13.
`
`Sandoz, through its counsel Abigail Langsam of the law firm Arnold & Porter
`
`Kaye Scholer LLP, sent a letter dated April 2, 2020 to Exela, a Delaware corporation, notifying
`
`Exela that Sandoz had filed with FDA, and FDA had received, Sandoz’s ANDA No. 209994
`
`(“Sandoz’s Paragraph IV Letter”).
`
`14.
`
`Sandoz’s filing of ANDA No. 209994 constitutes a formal act that reliably
`
`indicates Sandoz’s plans to engage in marketing of Sandoz’s ANDA Product throughout the
`
`United States, including in the State of Delaware, so that Sandoz’s ANDA Product will be used
`
`throughout the United States, including in the State of Delaware.
`
`3
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`15.
`
`On information and belief, upon approval of ANDA No. 209994, Sandoz will
`
`engage in the marketing of the Sandoz ANDA Product and offer to sell and/or sell its ANDA
`
`Product either directly or indirectly through its established channels of distribution via one or
`
`more of its drug wholesalers and distributors throughout the United States, including in the State
`
`of Delaware.
`
`16.
`
`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
`
`and/or pharmacies in the State of Delaware, distributed to and available at hospitals and/or
`
`pharmacies in the State of Delaware, prescribed by healthcare providers practicing in the State of
`
`Delaware, used by healthcare providers, patients, and/or hospitals in the State of Delaware,
`
`and/or administered to patients in the State of Delaware.
`
`17.
`
`Sandoz’s marketing, offer to sell, and/or sales of its ANDA Product, and the use
`
`of its ANDA Product, throughout the United States, including in the State of Delaware, before
`
`expiry of Exela’s ’453 and ’155 patents will constitute infringement of the ’453 and ’155 patents,
`
`resulting in harm and injury to Exela.
`
`18.
`
`Further, this Court has personal jurisdiction over Sandoz because Sandoz
`
`regularly engages in patent litigation in this judicial district, has previously consented to personal
`
`jurisdiction and venue in such litigation in this judicial district, has purposefully availed itself of
`
`the rights and benefits of this Court numerous times by asserting claims and/or counterclaims in
`
`this Court, and has in the past consented and continues to consent to personal jurisdiction and
`
`venue in this judicial district. See, e.g., Otsuka Pharmaceutical Co., Ltd. et al. v. Sandoz Inc. et
`
`al., 19-cv-02080, D.I. 11 (D. Del. March 16, 2020); Merck Sharp & Dohme Corp. v. Sandoz Inc.,
`
`19-cv-00312, D.I. 10 (D. Del. April 10, 2019); Astellas US LLC et al. v. Sandoz Inc., 18-cv-
`
`4
`
`
`
`Case 1:20-cv-00645-MN Document 12 Filed 06/01/20 Page 5 of 55 PageID #: 1105
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`01676, D.I. 13 (D. Del. Nov. 30, 2018); Pharmacyclics LLC et al v. Sun Pharma Global FZE et
`
`al., 18-cv-00192, D.I. 12 (D. Del. Feb. 26, 2018); H. Lundbeck A/S et al. v. Sandoz Inc. et al., 18-
`
`cv-00177, D.I. 9 (D. Del. April 13, 2018); ViiV Healthcare Company et al. v. Sandoz Inc. et al.,
`
`17-cv-01784, D.I. 12 (D. Del. Jan. 24, 2018); Biogen International GMBH et al. v. Sandoz Inc.,
`
`17-00874, D.I. 9 (D. Del. Oct. 16, 2017); Bristol-Myers Squibb Company et al. v. Sandoz Inc.,
`
`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).
`
`19.
`
`Venue is proper in this judicial district under at least 28 U.S.C. § 1391 and
`
`including because Sandoz is subject to personal jurisdiction in this judicial district, has
`
`previously consented to venue in this judicial district, and on information and belief will consent
`
`to venue in this judicial district for the purpose of this case.
`
`20.
`
`Exela believes this case belongs in Delaware, but is also filing a case in the
`
`United States District Court for the District of Colorado out of an abundance of caution.
`
`FACTUAL BACKGROUND
`
`A.
`
`The Development and FDA Approval of Exela’s ELCYS® L-Cysteine
`Hydrochloride Injection Product
`
`21.
`
`Exela is a relatively small but fast-growing specialty pharmaceutical company
`
`focused on developing, manufacturing, and marketing injectable products.
`
`22.
`
`L-cysteine is an amino acid that is important for human life. While healthy adults
`
`can naturally synthesize small amounts, high-risk patients such as preterm and/or low birth
`
`weight infants and patients with severe liver disease require L-cysteine supplementation by
`
`parenteral administration (i.e., injection or intravenous infusion). For these patients, L-cysteine
`
`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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`5
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`23.
`
`At the time Exela began developing its L-cysteine product, there was no
`
`FDA-approved intravenous L-cysteine hydrochloride product on the market in the United States.
`
`However, multiple unapproved and compounded L-cysteine products were on the market during
`
`that time that were used in TPN regimens, including an unapproved product sold by Sandoz
`
`under FDA’s drug “shortage” program, which purports to permit importation of unapproved
`
`drugs during a shortage (or in this case, absence) of an FDA-approved version of the drug in the
`
`United States. One significant drawback of such L-cysteine products is that they were known to
`
`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”).
`
`24.
`
`TPN admixtures even without L-cysteine were also known to contain high
`
`amounts of aluminum, and aluminum toxicity from their use had been reported. Aluminum
`
`toxicity can cause serious health problems including dementia, impaired neurologic
`
`development, Alzheimer’s disease, metabolic bone disease (including impaired bone growth,
`
`growth failure, bone pain, muscle weakness, nonhealing fractures, and premature osteoporosis),
`
`encephalopathy, and cholestasis (liver disease), among others.
`
`25.
`
`FDA has long been concerned about the presence of aluminum in parenteral drug
`
`products.
`
`26.
`
`As early as 1986, FDA held meetings to discuss the risks posed by aluminum in
`
`human drug products, including in parenteral drug products. Parenteral Drug Products
`
`Containing Aluminum as an Ingredient or a Contaminant; Notice of Intent and Request for
`
`Information, 55 Fed. Reg. 20799 (May 21, 1990).
`
`27.
`
`In 1990, FDA gave public notice that it was considering proposing rules related to
`
`the aluminum content in parenteral drug products. Id. In particular, FDA stated it “has become
`
`6
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`increasingly concerned about aluminum content in parenteral drug products, including aluminum
`
`present as a contaminant” because the literature contained reports “that neonates and other
`
`patient populations may be at high risk of exposure to unsafe amounts of aluminum in drug
`
`products.” Id. at 20800. FDA noted that “many drug products that are used routinely in
`
`parenteral therapy have been reported to contain levels of aluminum sufficiently high to cause
`
`clinical manifestations.” Id. FDA also expressed concern “that certain populations of patients
`
`may be exposed to excess aluminum parenterally,” including “premature neonates and neonates
`
`who have immature or impaired renal function [that] require total parenteral nutrition,” and
`
`patients with renal failure or comprised renal function. Id. FDA’s notice cites several articles
`
`reporting on the effects of aluminum in these susceptible patient populations. Id.
`
`28.
`
`In 1998, and after a period of public comment, FDA proposed amending its
`
`regulations “to add certain labeling requirements concerning aluminum in large volume
`
`parenterals (LVP’s) and small volume parenterals (SVP’s) used in total parenteral nutrition
`
`(TPN).” Aluminum in Large and Small Volume Parenterals Used in Total Parenteral Nutrition,
`
`63 Fed. Reg. 176, 176 (Jan. 5, 1998). FDA proposed the regulations “because of evidence
`
`linking the use of parenteral drug products containing aluminum to morbidity and mortality
`
`among patients on TPN therapy, especially premature infants and patients with impaired kidney
`
`function.” Id.
`
`29.
`
`L-cysteine hydrochloride injection is a Small Volume Parenteral (SVP) drug
`
`product used in TPN.
`
`30.
`
`The regulation proposed in 1998 contained five parts: “(1) Establish a maximum
`
`permissible level of aluminum in LVP’s used in TPN therapy; (2) require that the maximum
`
`level of aluminum permitted in LVP’s used in TPN therapy be stated on the package insert of all
`
`7
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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
`
`of TPN solutions; (4) require that the package insert of all LVP’s and SVP’s, including pharmacy
`
`bulk packages, contain a warning statement about aluminum toxicity in patients with impaired
`
`kidneys and neonates receiving TPN therapy; and (5) require that applicants and manufacturers
`
`develop validated assay methods for determining the aluminum content in parenteral drug
`
`products and that applicants submit the validated assay methods to FDA for approval.” Id. at
`
`177.
`
`31.
`
`In 2000, FDA issued a regulation, 21 C.F.R. § 201.323, concerning aluminum in
`
`large and small volume parenterals used in total parenteral nutrition that would become effective
`
`January 26, 2001. Aluminum in Large and Small Volume Parenterals Used in Total Parenteral
`
`Nutrition, 65 Fed. Reg. 4103 (Jan. 26, 2000). The regulation would, among other things, limit
`
`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,
`
`require LVP and SVP package inserts to include a particular warning statement about aluminum
`
`toxicity, and require applicants for LVP and SVP products to use validated assay methods to
`
`determine aluminum content in the products and submit to FDA release data concerning
`
`aluminum content for several batches. Id. at 4104-4105.
`
`32.
`
`In January 2001, FDA delayed the effective date of the regulation until January
`
`26, 2003 based on feedback from the industry that more time was need to comply with it.
`
`Aluminum in Large and Small Volume Parenterals Used in Total Parenteral Nutrition; Delay of
`
`Effective Date, 66 Fed. Reg. 7864 (Jan. 26, 2001).
`
`8
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`33.
`
`In August 2002, FDA proposed amending the regulation to require container
`
`labeling for LVP’s and SVP’s containing 25 micrograms per liter (μg/L) or less of aluminum to
`
`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
`
`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
`
`until January 26, 2004 to allow FDA time to finalize the amendment proposed in August 2002.
`
`Aluminum in Large and Small Volume Parenterals Used in Total Parenteral Nutrition;
`
`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
`
`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.
`
`§ 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
`
`products” unless the maximum level of aluminum is 25 mcg/L or less, in which case the
`
`immediate container label may state “Contains no more than 25 [micro]g/L of aluminum.”
`
`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
`
`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
`
`9
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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
`
`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
`
`Section 505(b) of the Federal Food, Drug, and Cosmetic Act seeking approval for an L-cysteine
`
`hydrochloride injection product, which is an SVP subject to 21 C.F.R. § 201.323. After 6
`
`months of storage at 25 °C and 60% relative humidity, Exela’s L-cysteine hydrochloride product
`
`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
`
`NDA signed on behalf of FDA by Dr. Donna Griebel, who at the time was the Director of the
`
`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
`
`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
`
`interpretation of 21 C.F.R. § 201.323, as applied specifically to L-cysteine hydrochloride
`
`10
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`injection products (50 mg/mL), that the maximum amount of aluminum permitted in FDA
`
`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
`
`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
`
`substantial work to achieve the ≤ 145 mcg/L aluminum level FDA mandated for the L-cysteine
`
`hydrochloride injection product, Exela secured the first FDA approval for an injectable
`
`L-cysteine hydrochloride product containing low aluminum levels, finally fulfilling a long-felt
`
`need for such a low-aluminum injectable cysteine product that could be safely administered to
`
`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
`
`injection, sold under the brand name ELCYS®.
`
`47.
`
`Exela’s ELCYS® product is labeled to contain no more than 120 mcg/L of
`
`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
`
`§ 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
`
`11
`
`
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`Case 1:20-cv-00645-MN Document 12 Filed 06/01/20 Page 12 of 55 PageID #: 1112
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`No. 210660).] First, FDA calculated the maximum daily dose of cysteine in preterm and term
`
`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
`
`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,
`
`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
`
`ELCYS® labeling (0.21 mcg/kg/day) is based specifically on a cysteine injection product that
`
`contains no more than 120 mcg/L of aluminum.
`
`51.
`
`The FDA’s Multi-Disciplinary Review and Evaluation for NDA No. 210660
`
`shows that FDA treats aluminum as a quality controlled impurity. [Id. at 44 (“Currently, without
`
`any approved drug products available on the market, marketing approval of a product with
`
`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
`
`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).
`
`12
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`53.
`
`The FDA’s Multi-Disciplinary Review and Evaluation for NDA No. 210660
`
`states the aluminum content of “other available marketed unapproved or compounded [L-
`
`cysteine] products do not meet the regulatory requirements of 21 CFR 201.323 (e). The
`
`proposed cysteine product [i.e., ELCYS®] significantly reduces the aluminum content (see
`
`Appendix 15.2) and ensures acceptable aluminum exposures in patients receiving this
`
`formulation of cysteine hydrochloride.” [Id. at 42; see also id. at 51-52.]
`
`54.
`
`On information and belief, the only “marketed unapproved” cysteine injection
`
`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
`
`
`
`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