Case 1:20-cv-00024-UNA Document 1 Filed 01/07/20 Page 1 of 23 PageID #: 1
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`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
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`EXELA PHARMA SCIENCES, LLC,
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`Civil Action No.: _________
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`JURY TRIAL DEMANDED
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`Plaintiff,
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`AVADEL LEGACY
`PHARMACEUTICALS, LLC; and
`AVADEL US HOLDINGS, INC.,
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`v.
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`Defendants.
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`
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`COMPLAINT
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`Plaintiff Exela Pharma Sciences, LLC (“Plaintiff” or “Exela”) by its attorneys, hereby
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`alleges as follows:
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`NATURE OF ACTION
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`1.
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`This is an action for a declaratory judgment of infringement of U.S. Patent No.
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`10,478,453 (“the ’453 patent”) under 28 U.S.C. §§ 2201 and 2202 and the Patent Laws of the
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`United States, 35 U.S.C. § 1 et seq., including §§ 271(a)-(c). Exela brings this action to enforce
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`its patent rights covering ELCYS® brand L-cysteine hydrochloride injection, which is approved
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`by the United States Food and Drug Administration (“FDA”) for use as an additive to amino acid
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`solutions to meet the nutritional requirements of newborn infants requiring total parenteral
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`nutrition (TPN) and of adult and pediatric patients with severe liver disease who may have
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`impaired enzymatic processes and require TPN.
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`

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`Case 1:20-cv-00024-UNA Document 1 Filed 01/07/20 Page 2 of 23 PageID #: 2
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`THE PARTIES
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`2.
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`Plaintiff Exela Pharma Sciences, LLC (“Exela”) is a company existing under the
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`laws of the state of Delaware and having a principal place of business at 1245 Blowing Rock
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`Blvd., Lenoir, NC 28645.
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`3.
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`On information and belief, Defendant Avadel Legacy Pharmaceuticals, LLC is a
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`company existing under the laws of the State of Delaware and having a principal place of
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`business at 16640 Chesterfield Grove Road, Suite 200, Chesterfield, MO 63005.
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`4.
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`On information and belief, Defendant Avadel US Holdings Inc. is a company
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`existing under the laws of the State of Delaware and having a principal place of business at
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`16640 Chesterfield Grove Road, Suite 200, Chesterfield, MO 63005.
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`5.
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`On information and belief, Avadel Legacy Pharmaceuticals, LLC is a wholly-
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`owned subsidiary of Avadel US Holdings, Inc.
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`6.
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`On information and belief, Defendants Avadel Legacy Pharmaceuticals, LLC and
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`Avadel US Holdings, Inc. (collectively, “Avadel”) are in the business of formulating,
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`developing, manufacturing, importing, marketing, offering for sale, and/or selling
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`pharmaceutical products that are distributed in and sold throughout the United States, including
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`in this District.
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`JURISDICTION AND VENUE
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`7.
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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), 2201 and 2202, because the action concerns a federal question arising under the
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`Patent Laws of the United States, 35 U.S.C. § 1 et seq.
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`8.
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`This Court has personal jurisdiction over Avadel US Holdings, Inc., and Avadel
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`Legacy Pharmaceuticals, LLC, because each is incorporated in this District and is doing business
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`in this District.
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`2
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`9.
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`Venue is proper in this District with respect to Avadel US Holdings, Inc., and
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`Avadel Legacy Pharmaceuticals, LLC, pursuant to 28 U.S.C. § 1391 and § 1400(b) because each
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`resides in this District.
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`10.
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`Joinder of both Defendants in this action is proper under 35 U.S.C. § 299(a)
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`because Plaintiff’s right to relief is asserted against the parties jointly and arising out of the same
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`transaction, occurrence, or series of transactions or occurrences relating to the making, using,
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`importing into the United Sates, offering for sale, and/or selling of the same accused product or
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`process; and questions of fact common to all Defendants will arise in the action.
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`FACTUAL BACKGROUND
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`A.
`
`The Development and FDA Approval of Exela’s ELCYS® L-Cysteine
`Product
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`11.
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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, including L-cysteine.
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`12.
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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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`13.
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`Before Exela began work on 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. One significant drawback of such L-cysteine products
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`is that they were known to contain high amounts of aluminum, for example, 5,000 mcg/L.
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`3
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`14.
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`TPN solutions were also known to contain high amounts of aluminum, and
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`aluminum toxicity from their use had been reported. Aluminum toxicity can cause serious health
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`problems including dementia, impaired neurologic development, Alzheimer’s disease, metabolic
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`bone disease (including impaired bone growth, growth failure, bone pain, muscle weakness,
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`nonhealing fractures, and premature osteoporosis), encephalopathy, and cholestasis (liver
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`disease), among others.
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`15.
`
`In 2000, FDA issued regulations requiring manufacturers to reduce aluminum
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`levels of parenteral products. 65 Fed. Reg. 4103 (Jan. 26, 2000). That regulation became final
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`in 2004. 68 Fed. Reg. 32,979 (June 3, 2003). It requires manufacturers of TPN components to
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`include the following warning on their product labeling: “Research indicates that patients with
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`impaired kidney function, including premature neonates, who receive parenteral levels of
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`aluminum at greater than 4 to 5 [micro]g/kg/day accumulate aluminum at levels associated with
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`central nervous system and bone toxicity.” 65 Fed. Reg. 4103, 4111 (Jan. 26, 2000). These
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`regulations are codified at 21 C.F.R. § 201.323.
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`16.
`
`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 product,
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`[Ex. A (8/4/2017 FDA Letter)], Exela secured FDA approval for an injectable L-cysteine
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`hydrochloride product containing low aluminum levels, finally fulfilling a long-felt need for a
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`low-aluminum injectable cysteine product.
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`17.
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`Exela’s FDA approved L-cysteine hydrochloride product, sold under the brand
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`name ELCYS®, is labeled to contain no more than 120 micrograms/liter (“mcg/L,” “μg/L” or,
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`more commonly, parts per billion or ppb) of aluminum, and is the only FDA approved L-
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`cysteine product available on the market today. [Ex. B (ELCYS® Label), §11.]
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`4
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`Case 1:20-cv-00024-UNA Document 1 Filed 01/07/20 Page 5 of 23 PageID #: 5
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`18.
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`Exela’s ELCYS® product is a sterile, nonpyrogenic solution for intravenous use.
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`Each 10 mL of ELCYS® contains 500 mg of cysteine hydrochloride, USP (equivalent of 345 mg
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`of cysteine) in water for injection. [Id. at §11.]
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`19.
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`The FDA-approved labeling for Exela’s ELCYS® product instructs healthcare
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`providers that “ELCYS is indicated for use as an additive to amino acid solutions to meet the
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`nutritional requirements of newborn infants requiring total parenteral nutrition (TPN) and of
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`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
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`complete profile of amino acids for protein synthesis.” [Id. at §1.]
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`20.
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`The FDA-approved labeling for Exela’s ELCYS® product instructs healthcare
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`providers that “Prior to administration, ELCYS must be diluted and used as an admixture in
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`parenteral nutrition (PN) solutions.” [Id. at §2.1.] It further instructs, “ELCYS is for addition to
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`amino acid solutions prior to further admixing with dextrose injection using a PN container.”
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`[Id. at §2.2.]
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`21.
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`The FDA-approved labeling for Exela’s ELCYS® product instructs healthcare
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`providers:
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` “Transfer the required amount of ELCYS to an amino acid solution . . . .”
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` “The amino acid solution containing ELCYS can then be used to prepare
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`admixtures in the PN container . . . .”
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` “Amino acid solutions containing ELCYS may be mixed with dextrose injection.
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`The following proper mixing sequence must be followed to minimize pH related
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`problems:
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`1. Transfer dextrose injection to the parenteral nutrition pooling container
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`5
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`Case 1:20-cv-00024-UNA Document 1 Filed 01/07/20 Page 6 of 23 PageID #: 6
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`2. Transfer phosphate salt
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`3. Transfer ELCYS-containing amino acid solution
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`4. Transfer electrolytes
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`5. Transfer trace elements”
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`[Id. at §2.3.]
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`22.
`
`The FDA-approved labeling for Exela’s ELCYS® product includes the following
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`Warnings: “Aluminum may reach toxic levels with prolonged parenteral administration in
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`patients with renal impairment. Preterm infants are particularly at risk for aluminum toxicity
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`because their kidneys are immature, and they require large amounts of calcium and phosphate
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`solutions, which also contain aluminum. Patients with renal impairment, including preterm
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`infants, who receive greater than 4 to 5 mcg/kg/day of parenteral aluminum can accumulate
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`aluminum to levels associated with central nervous system and bone toxicity.” [Id. at §5.7.] It
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`further instructs, “[e]xposure to aluminum from ELCYS is not more than 0.21 mcg/kg/day when
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`preterm and term infants less than 1 month of age are administered the recommended maximum
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`dosage of ELCYS (15 mg cysteine/g of amino acids and 4 g of amino acids/kg/day) [see Table 1,
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`Dosage and Administration (2.5)]. When prescribing ELCYS for use in PN containing other
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`small volume parenteral products, the total daily patient exposure to aluminum from the
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`admixture should be considered and maintained at no more than 5 mcg/kg/day [see Use in
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`Specific Populations (8.4)].” [Id.]
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`B.
`
`The Asserted ’453 Patent
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`23.
`
`On November 19, 2019, the United States Patent and Trademark Office
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`(“USPTO”) duly and legally issued the ’453 patent, entitled “Stable, Highly Pure L-Cysteine
`
`Compositions for Injection and Methods of Use,” and naming John Maloney, Aruna Koganti,
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`6
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`Case 1:20-cv-00024-UNA Document 1 Filed 01/07/20 Page 7 of 23 PageID #: 7
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`and Phanesh Koneru as inventors. A true and correct copy of the ’453 patent is attached to this
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`Complaint as Exhibit C.
`
`24.
`
`25.
`
`The ’453 patent is assigned to Plaintiff Exela.
`
`On November 19, 2019, Exela submitted the ’453 patent for listing in the
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`“Approved Drug Products with Therapeutic Equivalence Evaluations,” commonly referred to as
`
`the “Orange Book,” which provides notice concerning patents covering FDA-approved drugs.
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`26.
`
`On or about November 20, 2019, the FDA published the ’453 patent in the
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`Orange Book.
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`27.
`
`Claim 1 of the ’453 patent reads as follows:
`
`1. A stable L-cysteine composition for parenteral administration, comprising:
`L-cysteine or a pharmaceutically acceptable salt thereof and/or hydrate thereof in an
`amount from about 10 mg/mL to about 100 mg/mL;
`Aluminum (Al) in an amount from about 1.0 parts per billion (ppb) to about 250 ppb;
`L-cystine in an amount from about 0.001 wt % to about 2.0 wt % relative to L-cysteine;
`pyruvic acid in an amount from about 0.001 wt % to about 2.0 wt % relative to L-
`cysteine;
`a pharmaceutically acceptable carrier, comprising water;
`headspace oxygen that is from about 0.5% v/v to 4.0% v/v from the time of
`manufacture to about 1 month from manufacture when stored at room temperature;
`dissolved oxygen present in the carrier in an amount from about 0.1 parts per million
`(ppm) to about 5 ppm from the time of manufacture to about 1 month from
`manufacture when stored at room temperature,
`wherein the composition is enclosed in a single-use container having a volume of from
`about 10 mL to about 100 mL.
`
`28.
`
`Claim 4 of the ’453 patent reads as follows:
`
`
`
`4. The composition of claim 1, wherein said Aluminum is present in an amount from
`about 1.0 ppb to about 150 ppb.
`
`
`29.
`
`Claim 5 of the ’453 patent reads as follows:
`
`5. The composition of claim 1, wherein said Aluminum is present in an amount from
`about 1.0 ppb to about 100 ppb.
`
`
`30.
`
`Claim 6 of the ’453 patent reads as follows:
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`7
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`6. The composition of claim 1, wherein said Aluminum is present in an amount from
`about 1.0 ppb to about 50 ppb.
`
`
`31.
`
`Claim 7 of the ’453 patent reads as follows:
`
`7. The composition of claim 1, wherein said Aluminum is present in an amount from
`about 1.0 ppb to about 20 ppb.
`
`32.
`
`Claim 22 of the ’453 patent reads as follows:
`
`
`
`22. A method of preparing a reduced Aluminum composition for a total parenteral
`nutrition regimen comprising L-cysteine, the method comprising:
`mixing a composition comprising L-cysteine or a pharmaceutically acceptable salt
`thereof and/or hydrate thereof comprising:
`Aluminum in an amount from about 1.0 parts per billion (ppb) to about 250 ppb;
`L-cystine in an amount from about 0.001 wt % to about 2.0 wt % relative to L-
`cysteine; and
`pyruvic acid in an amount from about 0.001 wt % to about 2.0 wt % relative to L-
`cysteine;
`with a composition comprising one or more amino acids selected from the group
`consisting of: leucine, isoleucine, lysine, valine, phenylalanine, histidine, threonine,
`methionine, tryptophan, alanine, arginine, glycine, proline, serine, and tyrosine; and a
`pharmaceutically acceptable carrier, comprising water, to form a composition for
`infusion having a volume of about 100 mL to about 1000 mL,
`wherein the Aluminum provided in said parenteral nutrition regimen is from about 1-2
`to about 4-5 micrograms/kg/day.
`
`Exela’s ELCYS® product, and its use, is covered by at least claims 1, 4-7, and 22
`
`
`33.
`
`of the ’453 patent.
`
`ACTS GIVING RISE TO THIS ACTION FOR DEFENDANTS’ INFRINGEMENT OF
`THE PATENT-IN-SUIT
`
`34.
`
`On December 13, 2019, FDA approved NDA No. 212-535 for NOURESSTM
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`brand cysteine hydrochloride injection USP, 50 mg/mL (the “Accused Product”).
`
`35.
`
`The FDA-approved labeling for the Accused Product (the “NOURESS Label”)
`
`states that it is “Manufactured for: Avadel Legacy Pharmaceuticals, LLC.” [Ex. D (NOURESS
`
`Label) at §17.]
`
`36.
`
`On information and belief, Avadel Legacy Pharmaceuticals, LLC currently
`
`markets and sells three FDA-approved, sterile injectable drug products—Bloxiverz®,
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`8
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`Vazculep®, and Akovaz®—throughout the United States in active concert with and/or for the
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`benefit of Avadel US Holdings, Inc.
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`37.
`
`Each of the current FDA approved labels for Bloxiverz®, Vazculep®, and
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`Akovaz® states, as the NOURESS Label states, that the product is “Manufactured for: Avadel
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`Legacy Pharmaceuticals, LLC.”
`
`38.
`
`On information and belief, Avadel Legacy Pharmaceuticals, LLC will import,
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`manufacture, market, offer for sell, and/or sell the Accused Product throughout the United States,
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`including in this District, in active concert with and/or for the benefit of Avadel US Holdings,
`
`Inc.
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`39.
`
`On December 16, 2019, a press release was issued announcing the approval of
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`NOURESS™. [Ex. E (12/16/2019 Press Release).]
`
`40.
`
`In that December 16, 2019 press release, the Accused Product was identified by
`
`the code name AV001.
`
`41.
`
`In its Form 10-Q Quarterly Report dated November 12, 2019, Avadel US Holding
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`Inc.’s parent company, Avadel Pharmaceuticals plc, represented: “AV001, if approved, could
`
`contribute revenues to Avadel starting in 2020.”
`
`42.
`
`In an earnings call dated August 9, 2019, the Chief Executive Officer of Avadel
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`Pharmaceuticals plc represented: “It is our expectation that if approved AV001 will begin to
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`contribute to revenues in the first quarter of 2020.”
`
`43.
`
`The December 16, 2019 press release stated that, “With FDA approvals of
`
`Nouress and another U.S. company’s cysteine hydrochloride injection earlier this year, Avadel
`
`expects domestic supply of cysteine hydrochloride injection earlier this year, Avadel expects
`
`domestic supply of cysteine hydrochloride injection will be sufficient to support the entire U.S.
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`9
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`market, which, under FDA regulations, should preclude further import or U.S. marketing of
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`unapproved cysteine hydrochloride injection products. Under these potential market conditions,
`
`the U.S. annual market for cysteine hydrochloride could be greater than $50 million.” [Ex. E
`
`(12/16/2019 Press Release).]
`
`44.
`
`On information and belief, the manufacture and/or launch of the Accused Product
`
`in the United States by Avadel Legacy Pharmaceuticals, LLC, in active concert with and/or for
`
`the benefit of Avadel US Holdings, Inc. is imminent.
`
`45.
`
`The December 16, 2019 press release states that the Accused Product is covered
`
`by U.S. Patent No. 10,493,051 (“the ’051 patent”), entitled “Cysteine Composition and
`
`Injection.” [Ex. E (12/16/2019 Press Release).] The ’051 patent is attached hereto as Exhibit F.
`
`46.
`
`The December 16, 2019 press release states that the ’051 patent is listed in the
`
`Orange Book for the Accused Product.
`
`47.
`
`The NOURESS Label states that “NOURESS (cysteine hydrochloride injection)
`
`is a sterile, nonpyrogenic solution for intravenous use supplied as 500 mg/10mL cysteine
`
`hydrochloride, USP in a single-dose vial. Each mL of NOURESS contains 50 mg of cysteine
`
`hydrochloride, (equivalent to 34.5 mg of cysteine), and 0.006 mL of hydrochloric acid (6M) in
`
`water for injection.” [Ex. D (NOURESS Label) at §11.]
`
`48.
`
`The NOURESS Label states that “NOURESS contains no more than 145 mcg/L
`
`of aluminum.” [Ex. D (NOURESS Label) at §11.]
`
`49.
`
`The ’051 patent, which has been represented to cover the Accused Product,
`
`discloses solutions of cysteine having less than 3 ppb Aluminum when stored at room
`
`temperature for up to 9 months. [Ex. F, ’051 patent at 13:17-41 (Tbl. 5).]
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`10
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`50.
`
`Accordingly, on information and belief, the actual amount of aluminum in the
`
`Accused Product is from about 1.0 ppb to about 20 ppb.
`
`51.
`
`52.
`
`L-cystine is a degradation product of L-cysteine.
`
`The ’051 patent, which has been represented to cover the Accused Product,
`
`discloses solutions of cysteine “having a cysteine monomer content of at least 99% by weight
`
`and a cystine dimer content of less than 1% by weight.” [See, e.g., Ex. F., ’051 patent at 2:29-
`
`32; see also id. at 4:48-56, 5:53-57.]
`
`53.
`
`Accordingly, on information and belief, the Accused Product contains L-cystine
`
`in an amount between about 0.001 wt % and about 2.0 wt % relative to L-cysteine.
`
`54.
`
`55.
`
`Pyruvic acid is a degradation product of L-cysteine.
`
`On information and belief, pyruvic acid is present in low amounts in cysteine
`
`hydrochloride solutions and will not exceed about 2.0 wt % relative to L-cysteine over the FDA-
`
`approved shelf life for a cysteine hydrochloride injection product.
`
`56.
`
`Accordingly, on information and belief, the Accused Product contains pyruvic
`
`acid in an amount between about 0.001 wt % and about 2.0 wt % relative to L-cysteine.
`
`57.
`
`The ’051 patent, which has been represented to cover the Accused Product, states
`
`that its cysteine solutions “include low levels of dissolved oxygen content” and that “some
`
`solutions may have a dissolved oxygen content of less than 2 mg/L.” [Ex. F, ’051 patent at 1:57-
`
`63; see also id. at 2:29-33, 3:1-4, 5:8-19.]
`
`58.
`
`The ’051 patent further states that “exemplary embodiments” include those
`
`comprising a “50 mg/mL solution of cysteine hydrochloride monohydrate.” The ’051 patent
`
`further states that this exemplary “50 mg/mL solution of cysteine hydrochloride monohydrate
`
`may have a dissolved oxygen content of less than 2 mg/L.” [Ex. F, ’051 patent at 6:33-45.]
`
`11
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`59.
`
`60.
`
`2 mg/L is equivalent to 2 ppm.
`
`The ’051 patent, which has been represented to cover the Accused Product, states,
`
`“In some embodiments of the above-described processes for preparing cysteine, the filtered
`
`solution in the container may be overlaid with a layer of nitrogen, and the container may be
`
`sealed.” [Ex. F, ’051 patent at 3:5-8; see also id. at 2:13-16.]
`
`61.
`
`The ’051 patent further discloses that, “[o]nce filled with the appropriate volume,
`
`the cysteine solution generally is overlaid with nitrogen, and then the vial is sealed using
`
`conventional means.” [Ex. F, ’051 patent at 7:57-59.]
`
`62.
`
`On information and belief, the purpose of overlaying nitrogen above the cysteine
`
`solution in the container is to reduce or remove oxygen from the container’s headspace.
`
`63.
`
`The ’051 patent discloses that reduction of oxygen in the cysteine composition,
`
`including by use of nitrogen overlay before sealing the container, reduces the formation of
`
`cystine. [Ex. F, ’051 patent at 10:62-13:16 (Exs. 4-6).]
`
`64.
`
`On information and belief, especially in view of the ’051 patent and the
`
`NOURESS Label, the container for the Accused Product is a 10 mL Type I plus® vial coated
`
`with silica. [See, e.g., Ex. D (Nouress Label) §3; Ex. F, ’051 patent at 7:66-8:1; id. at 9:45-66.]
`
`65.
`
`On information and belief, in the absence of overlaying nitrogen or an inert gas,
`
`the headspace oxygen in a 10 mL coated glass container comprising a cysteine solution is
`
`approximately 8% v/v.
`
`66.
`
`On information and belief, reduction of headspace oxygen in a 10 mL coated
`
`glass container comprising a cysteine solution to about 4% v/v or less increases stability and
`
`decreases likelihood cysteine oxidizes to cystine.
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`12
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`67.
`
`On information and belief, during manufacture of the Accused Product, the
`
`cysteine solution in the container is overlaid with nitrogen prior to sealing.
`
`68.
`
`On information and belief, the amount of headspace oxygen in the Accused
`
`Product is about 4.0% v/v or less.
`
`69.
`
`On information and belief, including because it has received FDA approval, the
`
`Accused Product is stable for at least one month from manufacture when stored at room
`
`temperature.
`
`70.
`
`In addition, the ’051 patent, which has been represented to cover the Accused
`
`Product, discloses solutions of cysteine that are stable when stored at room temperature for up to
`
`18 months. [Ex. F, ’051 patent at 13:17-41 (Ex. 7 & Tbl. 5).]
`
`71.
`
`The ’051 patent further states that its “cysteine compositions or solutions, when
`
`dispensed into vials as described above, are substantially stable for at least one month . . . when
`
`stored at 25° C and 60% relative humidity or 40° C and 75% relative humidity.” [Ex. F, ’051
`
`patent at 6:10-15.]
`
`72.
`
` Accordingly, on information and belief, the Accused Product contains dissolved
`
`oxygen present in the carrier in an amount from about 0.1 ppm to about 5 ppm, and headspace
`
`oxygen that is from about 0.5% v/v to 4.0% v/v, from the time of manufacture to about 1 month
`
`from manufacture when stored at room temperature.
`
`73.
`
`Accordingly, on information and belief, the Accused Product infringes claims 1
`
`and 4-7 of the ’453 patent, either literally or under the doctrine of equivalents.
`
`74.
`
`The NOURESS Label instructs healthcare providers that “NOURESS is indicated
`
`for use as an additive to amino acid solutions to meet nutritional requirements of neonates
`
`13
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`Case 1:20-cv-00024-UNA Document 1 Filed 01/07/20 Page 14 of 23 PageID #: 14
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`(preterm and term infants less than one month of age) requiring total parenteral nutrition.” [Ex.
`
`D (NOURESS Label) at §1.]
`
`75.
`
`The NOURESS Label instructs healthcare providers that “Prior to administration,
`
`NOURESS must be diluted and used as an admixture in parenteral nutrition solutions.” [Id. at
`
`§2.2.] It further instructs, “NOURESS is for addition to amino acid solutions prior to further
`
`admixing with dextrose injection using a parenteral nutrition container.” [Id.]
`
`76.
`
`The NOURESS Label instructs healthcare providers:
`
` “Transfer the required amount of NOURESS to an amino acid solution . . . .”
`
` “The amino acid solution containing NOURESS can then be used to prepare
`
`admixtures in the parenteral nutrition container . . . .”
`
` “Amino acid solutions containing NOURESS may be mixed with dextrose
`
`injection. The following proper mixing sequence must be followed to minimize
`
`pH related problems:
`
`1. Transfer dextrose injection to the parenteral nutrition pooling container
`
`2. Transfer phosphate salt
`
`3. Transfer NOURESS-containing amino acid solution
`
`4. Transfer electrolytes
`
`5. Transfer trace elements”
`
`[Id. at §2.3.]
`
`77.
`
`The NOURESS Label contains the Warning: “Aluminum may reach toxic levels
`
`with prolonged parenteral administration in patients with renal impairment. Neonates and
`
`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
`
`14
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`

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`Case 1:20-cv-00024-UNA Document 1 Filed 01/07/20 Page 15 of 23 PageID #: 15
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`aluminum. Patients with renal impairment including neonates and 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 bone toxicity.” [Id. at §5.6.] It further instructs,
`
`“[e]xposure to aluminum from NOURESS is not more than 0.25 mcg/kg/day when preterm and
`
`term neonates are administered the recommended maximum dosage of NOURESS (22 mg
`
`cysteine/g of amino acids and 4 g of amino acids/kg/day) [see Dosage and Administration (2.5)].
`
`When prescribing NOURESS for use in parenteral nutrition 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.]
`
`78.
`
`The volume of TPN solution prepared for a given patient depends upon the
`
`patient’s weight and nutritional needs and, on information and belief, neonates and preterm
`
`infants typically receive around 100 mL of TPN while larger patients receive around 1000 mL of
`
`TPN solution. Thus, on information and belief, when healthcare providers admix the Accused
`
`Product with amino acid compositions and other components to prepare a TPN regimen for such
`
`patients, they will prepare compositions having a volume of about 100 mL to about 1000 mL.
`
`79.
`
`In the “Preparation and Administration Information” section, the NOURESS
`
`Label instructs that “NOURESS is for addition to amino acid solutions prior to further admixing
`
`with dextrose injection using a parenteral nutrition container,” and that “[c]alcium and phosphate
`
`ratios must be considered.” [Ex. D (NOURESS Label) at §2.2.]
`
`80.
`
`In the “Preparation Instructions for Admixing Using a Parenteral Nutrition
`
`Container” section, the NOURESS Label instructs the admixing of “dextrose injection,”
`
`15
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`Case 1:20-cv-00024-UNA Document 1 Filed 01/07/20 Page 16 of 23 PageID #: 16
`
`“phosphate salt,” “NOURESS-containing amino acid solution,” “electrolytes,” and “trace
`
`elements.” [Id. at §2.3.]
`
`81.
`
`In the “Aluminum Toxicity” section, the NOURESS Label teaches that
`
`“[n]eonates and preterm infants…require large amounts of calcium and phosphate solutions,
`
`which also contain aluminum,” and instructs that “[w]hen prescribing NOURESS for use in
`
`parenteral nutrition 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.” [Id. at § 5.6.]
`
`82.
`
`On information and belief, when healthcare providers admix the Accused Product,
`
`NOURESS™, with other components as instructed by the NOURESS Label to prepare
`
`compositions for a TPN regimen, they will prepare compositions that provide aluminum from
`
`about 1-2 to about 4-5 mcg/kg/day. For example, a healthcare provider making an admixture of
`
`the Accused Product, an amino acid composition such as Travasol®, dextrose injection, calcium
`
`and/or phosphate solutions, electrolytes, and trace elements for use with a 1 kg infant according
`
`to the instructions on the respective product labels, will prepare the composition in a volume of
`
`about 100 mL to about 1000 mL, and the admixture will provide, when dosed, from about 1-2
`
`mcg/kg/day to about 4-5 mcg/kg/day of aluminum, in compliance with FDA regulations.
`
`83.
`
`Accordingly, on information and belief, healthcare providers that follow the
`
`instructions on the NOURESS Label will directly infringe claim 22 of the ’453 patent, either
`
`literally or under the doctrine of equivalents.
`
`84.
`
`The commercial manufacture, importation, use, sale, or offer for sale of the
`
`Accused Product will result in infringement of the ’453 patent.
`
`
`
`
`
`16
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`Case 1:20-cv-00024-UNA Document 1 Filed 01/07/20 Page 17 of 23 PageID #: 17
`
`COUNT I
`
`(Declaratory Judgment of Infringement of the ’453 Patent Under
`35 U.S.C. § 271(a), (b), and/or (c))
`
`Plaintiff incorporates each of the preceding paragraphs as if fully set forth herein.
`
`This claim arises under the Declaratory Judgment Act, 28 U.S.C. §§ 2201 and
`
`85.
`
`86.
`
`2202.
`
`87.
`
`There is an actual case or controversy such that the Court may entertain Plaintiff’s
`
`request for declaratory relief consistent with Article III of the United States Constitution, and
`
`that actual case or controversy requires a declaration of rights by this Court.
`
`88.
`
`On information and belief, Avadel will engage in the commercial manufacture,
`
`use, offer for sale, sale, and/or importation of the Accused Product immediately and imminently.
`
`89.
`
`The actions alleged herein, including but not limited to, the development of the
`
`Accused Product, the filing of NDA No. 212-535, the content of the NOURESS Label, and
`
`representations in SEC filings and on earnings calls and in a press release, as detailed herein,
`
`reliably predict that Avadel has made and will continue to make substantial preparations to
`
`manufacture, sell, offer to sell, and/or import the Accused Product.
`
`90.
`
`On information and belief, Avadel became aware of the ’453 patent no later than
`
`when it was listed in the Orange Book as covering ELCYS®.
`
`91.
`
`Alternatively, Avadel knew of the ’453 patent at least by December 16, 2019,
`
`when a press release was issued acknowledging the ’453 patent. [Ex. E (12/16/2019 Press
`
`Release).]
`
`92.
`
`On information and belief, and as detailed herein, the Accused Product practices
`
`all limitations of claims 1 and 4-7 of the ’453 patent, and thus the manufacture, importation, use,
`
`17
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`

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`Case 1:20-cv-00024-UNA Document 1 Filed 01/07/20 Page 18 of 23 PageID #: 18
`
`sale, and/or offer for sale of the Accused Product in the United States will constitute an act of
`
`infringement of the ’453 patent.
`
`93.
`
`On information and belief, Avadel will include within the packaging of the
`
`Accused Product, or will otherwise make available, a label and/or instructions for use that
`
`instruct healthcare providers to perform the method of at least claim 22 of the ’453 patent.
`
`94.
`
`On information and belief, healthcare providers preparing a total parenteral
`
`nutrition regimen using the Accused Product within the United States and according to the
`
`instructions in the NOURESS Label will directly infringe at least claim 22 of the ’453 patent.
`
`95.
`
`On information and belief, Avadel possesses specific intent to encourage direct
`
`infringement of at least claim 22 of the ’453 patent, including because the NOURESS Label
`
`instructs users to perform the patented method of claim 22, providing evidence of an affirmative
`
`intent to induce infringement.
`
`96.
`
`In addition, the ’051 patent, which has been rep