Case 1:20-cv-00365-MN Document 14 Filed 07/28/20 Page 1 of 39 PageID #: 403
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`EXELA PHARMA SCIENCES, LLC,
`
`Plaintiff,
`
`v.
`
`Civil Action No.: 20-00365-MN
`
`ETON PHARMACEUTICALS, INC.,
`
`JURY TRIAL DEMANDED
`
`Defendant.
`
`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”), U.S. Patent No. 10,583,155 (“the ’155 patent”), and U.S. Patent No. 10,653,719 (“the
`
`’719 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, ’155, and ’719
`
`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.
`
`1
`
`EXELA 2006
`Eton Pharmaceuticals v. Exela Pharma Sciences
`PGR2020-00086
`
`

`

`Case 1:20-cv-00365-MN Document 14 Filed 07/28/20 Page 2 of 39 PageID #: 404
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`THE PARTIES
`
`2.
`
`Plaintiff Exela Pharma Sciences, LLC (“Exela”) is a company existing under the
`
`laws of the state of Delaware and having a principal place of business at 1245 Blowing Rock
`
`Blvd., Lenoir, NC 28645.
`
`3.
`
`On information and belief, Defendant Eton Pharmaceuticals, Inc. (“Eton”) is a
`
`corporation organized and existing under the law of the State of Delaware, having a principal
`
`place of business at 21925 West Field Parkway, Suite 235, Deer Park, IL 60010.
`
`JURISDICTION AND VENUE
`
`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 Eton Pharmaceuticals, Inc. because it is
`
`incorporated in Delaware and thus is present in and resides in this District, and because Eton is
`
`doing business in this District and thus has purposefully availed itself to the privileges of
`
`conducting business in Delaware. On information and belief, Cogency Global Inc., 850 New
`
`Burton Road, Suite 201, Dover, Delaware, is Eton’s registered agent in Delaware and is
`
`authorized to accept service on Eton’s behalf.
`
`6.
`
`Venue is proper in this District pursuant to 28 U.S.C. § 1400(b) and § 1391
`
`because Eton Pharmaceuticals, Inc. is incorporated in Delaware and thus resides in this District.
`
`FACTUAL BACKGROUND
`
`A.
`
`7.
`
`The Development and FDA Approval of Exela’s ELCYS® L-Cysteine
`Product
`
`Exela is a relatively small but fast-growing specialty pharmaceutical company
`
`focused on developing, manufacturing, and marketing injectable products.
`
`2
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`

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`8.
`
`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
`
`parenteral nutrition” (TPN).
`
`9.
`
`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. One significant drawback of such L-cysteine products
`
`is that they were known to contain high amounts of aluminum, labeled as containing up to 5,000
`
`mcg/L.
`
`10.
`
`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.
`
`11.
`
`In 2000, FDA issued regulations requiring manufacturers to reduce aluminum
`
`levels of parenteral products. Aluminum in Large and Small Volume Parenterals Used in Total
`
`Parenteral Nutrition, 65 Fed. Reg. 4103 (Jan. 26, 2000). That regulation became final in 2004.
`
`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). It requires
`
`3
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`manufacturers of TPN components to include the following warning on their product labeling:
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`“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.” Aluminum in
`
`Large and Small Volume Parenterals Used in Total Parenteral Nutrition, 65 Fed. Reg. 4103,
`
`4111 (Jan. 26, 2000). These regulations are codified at 21 C.F.R. § 201.323.
`
`12.
`
`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 product,
`
`[Ex. A (8/4/2017 FDA Letter)], 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.
`
`13.
`
`Exela is the holder of approved New Drug Application (“NDA”) No. 210660 for
`
`cysteine hydrochloride injection, sold under the brand name ELCYS®.
`
`14.
`
`Exela’s ELCYS® product is labeled to contain no more than 120 micrograms/liter
`
`(“mcg/L,” “μg/L” or, more commonly, parts per billion or ppb) of aluminum throughout the shelf
`
`life of the product, and is the only FDA approved L-cysteine product available on the market
`
`today. [Ex. B (ELCYS® Label), § 11.]
`
`15.
`
`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.” [Id. at § 11.] The chemical name of L-cysteine
`
`hydrochloride is L-cysteine hydrochloride monohydrate. [Id.]
`
`16.
`
`Exela’s ELCYS® product has a pH in the range of 1.0 to 2.5. [Id.]
`
`4
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`

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`17.
`
`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%.
`
`18.
`
`The FDA approved ELCYS® with a specification for visual particulate matter of
`
`“essentially free of visible particulate matter.” Exela’s ELCYS® product met that specification
`
`throughout 24 months of stability testing. Accordingly, Exela’s ELCYS® product remains free
`
`of visually detectable particulate matter for at least 24 months from the time of manufacture of
`
`the solution. Twenty-four months from the time of manufacture of the solution is the
`
`FDA-approved shelf-life of ELCYS®.
`
`19.
`
`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.]
`
`20.
`
`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 label and how to
`
`administer PN solutions containing ELCYS®. [Id. at §§ 2.2-2.5.]
`
`5
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`21.
`
`The FDA-approved labeling for ELCYS® further instructs healthcare providers to
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`“Remove ELCYS vial from the carton and inspect for particulate matter.” [Id. at § 2.3.]
`
`22.
`
`The FDA-approved labeling for ELCYS® further instructs healthcare providers to
`
`“Visually inspect the diluted PN solution containing ELCYS for particulate matter before
`
`admixing, after admixing, and prior to administration. The solution should be clear and there
`
`should be no precipitates.” [Id. at § 2.2.]
`
`23.
`
`The FDA-approved labeling for Exela’s ELCYS® product provides
`
`recommendage dosage and volume for pediatric patients from birth to less than 12 years of age,
`
`including for neonates and infants, e.g., preterm and term infants less than 1 month of age, and
`
`pediatric patients 1 month to less than 1 year of age. [Id. at § 2.5 & Tbl. 1.]
`
`24.
`
`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. § 2.4.]
`
`25.
`
`The FDA-approved labeling for ELCYS® includes the following warnings related
`
`to the level of aluminum patients receive: “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 bone toxicity.”
`
`[Id. at § 5.7.] It further instructs, “[e]xposure 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
`
`6
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`

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`Case 1:20-cv-00365-MN Document 14 Filed 07/28/20 Page 7 of 39 PageID #: 409
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`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.]
`
`B.
`
`The Asserted ’453 Patent
`
`26.
`
`On November 19, 2019, the United States Patent and Trademark Office
`
`(“USPTO”) issued the ’453 patent, entitled “Stable, Highly Pure L-Cysteine Compositions for
`
`Injection and Methods of Use,” and naming John Maloney, Aruna Koganti, and Phanesh Koneru
`
`as inventors. A copy of the ’453 patent is attached to this Complaint as Exhibit C.
`
`27.
`
`28.
`
`The ’453 patent is assigned to Plaintiff Exela.
`
`On November 19, 2019, Exela submitted the ’453 patent for listing in the
`
`“Approved Drug Products with Therapeutic Equivalence Evaluations,” commonly referred to as
`
`the “Orange Book,” which provides notice concerning patents covering FDA-approved drugs.
`
`29.
`
`On or about November 20, 2019, the FDA published the ’453 patent in the
`
`Orange Book.
`
`30.
`
`Claim 1 of the ’453 patent reads as follows:
`
`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;
`
`7
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`

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`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.
`
`Claim 4 of the ’453 patent reads as follows:
`
`
`31.
`
`The composition of claim 1, wherein said Aluminum is present in an amount from
`about 1.0 ppb to about 150 ppb.
`
`32.
`
`Claim 22 of the ’453 patent reads as follows:
`
`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 and/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 according to the directions and instructions
`
`
`33.
`
`on the FDA-approved label, is covered by at least claims 1, 4 and 22 of the ’453 patent.
`
`C.
`
`34.
`
`The Asserted ’155 Patent
`
`On March 10, 2020, the USPTO issued the ’155 patent, entitled “Stable, Highly
`
`Pure L-Cysteine Compositions for Injection and Methods of Use,” and naming John Maloney,
`
`Aruna Koganti, and Phanesh Koneru as inventors. A copy of the ’155 patent is attached to this
`
`Complaint as Exhibit D.
`
`8
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`

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`35.
`
`36.
`
`The ’155 patent is assigned to Plaintiff Exela.
`
`On March 10, 2020, Exela submitted the ’155 patent for listing in the Orange
`
`Book, which provides notice concerning patents covering FDA-approved drugs.
`
`37.
`
`On or about March 11, 2020, the FDA published the ’155 patent in the Orange
`
`Book.
`
`38.
`
`Claim 1 of the ’155 patent reads as follows:
`
`A method of treating a subject having an adverse health condition that is responsive to L-
`cysteine administration, said method comprising:
`parenterally administering to said subject a parenteral composition comprising a
`mixture of one or more amino acids, intravenous fluid, and a stable L-cysteine
`composition, wherein said stable L-cysteine composition contributes to said
`parenteral composition:
`a therapeutically effective amount of L-cysteine or a pharmaceutically acceptable
`salt thereof and/or hydrate thereof;
`per Liter of said stable L-cysteine composition, from about 1.0 mcg to about 250
`mcg of Aluminum;
`not more than about 2.0 wt% of cystine relative to L-cysteine; and
`not more than about 2.0 wt% of pyruvic acid relative to L-cysteine.
`
`
`39.
`
`Claim 3 of the ’155 patent reads as follows:
`
`The method of claim 1, wherein said stable L-cysteine composition contributes
`Aluminum in an amount less than 150 mcg/L.
`
`40.
`
`Claim 27 of the ’155 patent reads as follows:
`
`A method of treating a subject having an adverse health condition that is responsive to
`L-cysteine administration, said method comprising:
`parenterally administering to said subject a parenteral composition comprising a
`mixture comprising a stable L-cysteine composition, wherein said stable L-
`cysteine composition contributes to said parenteral composition:
`a therapeutically effective amount of L-cysteine or a pharmaceutically acceptable
`salt thereof and/or hydrate thereof;
`per Liter of said stable L-cysteine composition, not more than about 150 mcg of
`Aluminum;
`cystine relative to L-cysteine not more than about 2.0 wt%; and
`pyruvic acid relative to L-cysteine not more than about 2.0 wt%.
`
`Exela’s ELCYS® product, and its use according to the directions and instructions
`
`
`41.
`
`on the FDA-approved label, is covered by at least claims 1, 3 and 27 of the ’155 patent.
`
`9
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`D.
`
`42.
`
`The Asserted ’719 Patent
`
`On May 19, 2020, the USPTO issued the ’719 patent, entitled “Stable, Highly
`
`Pure L-Cysteine Compositions for Injection and Methods of Use,” and naming John Maloney,
`
`Aruna Koganti, and Phanesh Koneru as inventors. A copy of the ’719 patent is attached to this
`
`Complaint as Exhibit E.
`
`43.
`
`44.
`
`The ’719 patent is assigned to Plaintiff Exela.
`
`On or about July 1, 2020, Exela submitted the ’719 patent for listing in the
`
`Orange Book which provides notice concerning patents covering FDA-approved drugs.
`
`45.
`
`46.
`
`On or about July 8, 2020, the FDA published the ’719 patent in the Orange Book.
`
`Claim 12 of the ’719 patent reads as follows:
`
`A solution of L-cysteine comprising,
`a pharmaceutically acceptable carrier,
`about 50 mg/mL of L-cysteine hydrochloride monohydrate, or equivalent amount of
`a pharmaceutically acceptable L-cysteine or a salt or hydrate thereof,
`less than about 150 ppb of aluminum, and
`a pH from about 1.0 to about 2.5,
`wherein the solution is substantially free of visually detectable particulate matter for
`at least 6 months from the time of manufacture of the solution and is suitable for
`use as an additive in a parenteral nutrition composition for administration to a
`neonate or infant.
`
`
`47. Claim 13 of the ’719 patent reads as follows:
`
`
`The solution of claim 12, wherein the solution is substantially free of visually
`detectable particulate matter for at least 9 months from the time of manufacture of
`the solution.
`
`
`48. Claim 14 of the ’719 patent reads as follows:
`
`
`The solution of claim 12, wherein the solution is substantially free of visually
`detectable particulate matter for at least 12 months from the time of manufacture of
`the solution.
`
`
`49. Claim 15 of the ’719 patent reads as follows:
`
`
`10
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`

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`The solution of claim 12, wherein the solution is substantially free of visually
`detectable particulate matter for at least 24 months from the time of manufacture of
`the solution.
`
`Exela’s ELCYS® product, and its use according to the directions and instructions
`
`
`50.
`
`on the FDA-approved label, is covered by at least claims 12-15 of the ’719 patent.
`
`ACTS GIVING RISE TO THIS ACTION FOR DEFENDANT’S INFRINGEMENT
`OF THE PATENTS-IN-SUIT
`
`51.
`
`On or about February 3, 2020, Plaintiff received a letter, dated January 31, 2020,
`
`signed on behalf of Eton by Jeffrey Wolfson of the law firm Haynes Boone (“Eton’s Paragraph
`
`IV Letter”).
`
`52.
`
`Eton’s Paragraph IV Letter states that Eton had filed Abbreviated New Drug
`
`Application (“ANDA”) No. 214082 with the FDA seeking approval for Cysteine Hydrochloride
`
`Injection, USP, 500 mg/50 mL (50 mg/mL), 10 mL Fill (“Eton’s Proposed Generic Cysteine
`
`Hydrochloride Product”), which is a generic version of Exela’s ELCYS® product.
`
`53.
`
`This action is being commenced before the expiration of 45 days from the date
`
`Exela received Eton’s Paragraph IV Letter, which triggers a stay of FDA approval of Eton’s
`
`ANDA No. 214082 pursuant to 21 U.S.C § 355(j)(5)(B)(iii).
`
`54.
`
`Eton’s Paragraph IV Letter states that “[t]he basis of [its] proposed abbreviated
`
`new drug application (ANDA) for Cysteine Hydrochloride Injection, USP, 500 mg/10 mL (50
`
`mg/mL), 10 mL Fill, is the reference listed drug (RLD) and Reference Standard (RS), ELCYS®
`
`(Cysteine Hydrochloride) Injection, USP, 50 mg/mL, NDA 210660, approved on April 16, 2019,
`
`held by Exela Pharma Sciences, LLC, which is listed as the RLD and RS” in the Orange Book.
`
`55.
`
`Eton’s Paragraph IV Letter also states that ANDA No. 214082 contains any
`
`required bioavailability or bioequivalence data and a Paragraph IV certification for the ’453
`
`patent.
`
`11
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`
`56.
`
`On information and belief, Eton submitted to the FDA ANDA No. 214082 under
`
`Section 505(j) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. § 355(j)) seeking FDA’s
`
`approval to engage in the commercial manufacture, use, importation, offer for sale, and/or sale of
`
`Eton’s Proposed Generic Cysteine Hydrochloride Product before the expiration of the ’453
`
`patent.
`
`57.
`
`Attached to Eton’s Paragraph IV Letter is a statement of the factual and legal
`
`bases for Eton’s position that the ’453 patent is invalid and/or will not be infringed by the
`
`commercial manufacture, use, or sale of Eton’s Proposed Generic Cysteine Hydrochloride
`
`Product described in ANDA No. 214082.
`
`58.
`
`In particular, Eton’s Paragraph IV letter alleges that claims 1-21 of the ’453 patent
`
`are not infringed and claim 22 of the ’453 patent is invalid.
`
`59.
`
`Eton’s Paragraph IV Letter does not allege invalidity of claims 1-21 of the ’453
`
`patent or non-infringement of claim 22 of the ’453 patent.
`
`60.
`
`61.
`
`Eton’s Paragraph IV Letter is not marked confidential.
`
`Attached to Eton’s Paragraph IV Letter is an Offer of Confidential Access to
`
`ANDA No. 214082. The terms of the proposed Offer would not allow Plaintiff to conduct a
`
`complete and full investigation of the information contained in the ANDA and of the
`
`representations about Eton’s Proposed Generic Cysteine Hydrochloride Product that appear in
`
`Eton’s Paragraph IV Letter. For example, the Offer would not allow in-house counsel for
`
`Plaintiff to review the ANDA and only obligates Eton to produce the portions of the ANDA that
`
`Eton unilaterally deems “pertinent” to patent infringement rather the producing the entire
`
`ANDA. Thus, Plaintiff could not agree to the terms of the original Offer of Confidential Access.
`
`12
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`
`62.
`
`On February 13, 2020, counsel for Plaintiff sent a letter to counsel for Eton in an
`
`attempt to negotiate the terms of Plaintiff’s access to ANDA No. 214082. After counsel for Eton
`
`responded, counsel for Plaintiff followed up by providing a redlined version of the Offer of
`
`Confidential Access, setting forth terms for access that would be acceptable to Plaintiff. The
`
`parties were not able to reach an agreement regarding access to ANDA No. 214082 prior to the
`
`expiry of the time period set forth in 21 U.S.C. § 355(j)(5)(B)(iii). Plaintiff thus makes these
`
`allegations based on information and belief, the laws and regulations regarding generic drugs,
`
`and Eton’s Paragraph IV Letter.
`
`63.
`
`Because Eton’s Proposed Generic Cysteine Hydrochloride Product has not yet
`
`been approved by FDA and is not is yet commercially available, Plaintiff is not aware of any
`
`other means for obtaining information about Eton’s Proposed Generic Cysteine Hydrochloride
`
`Product other than pursuant to an Offer of Confidential Access from Eton. In the absence of
`
`additional information, Plaintiff resorts to the judicial process and the aid of discovery to obtain,
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`under appropriate judicial safeguards, such information as is required to confirm its allegations
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`of infringement and present to the Court evidence that Eton’s Proposed Generic Cysteine
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`Hydrochloride Product infringes one or more claims of the ’453, ’155, and ’719 patents.
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`64.
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`As of the date of this amended complaint, Eton has not produced ANDA No.
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`214082 to Exela.
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`65.
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`On or about May 7, 2020, Plaintiff received a second letter, dated May 6, 2020,
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`signed on behalf of Eton by Jeffrey Wolfson of the law firm Haynes Boone, reiterating Eton’s
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`prior filing of ANDA No. 214082 with FDA (“Eton’s Second Paragraph IV Letter”). Eton’s
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`Second Paragraph IV Letter alleges that claims 1-30 of U.S. Patent No. 10,586,155 are invalid.
`
`Eton’s Second Paragraph IV Letter does not allege that any of claims 1-30 of the ’155 patent is
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`Case 1:20-cv-00365-MN Document 14 Filed 07/28/20 Page 14 of 39 PageID #: 416
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`not infringed by Eton’s manufacture, sale, offer for sale, and/or importation of Eton’s Proposed
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`Generic Cysteine Hydrochloride Product.
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`66.
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`In filing and maintaining ANDA No. 214082, Eton has requested and continues to
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`request FDA’s approval to market a generic version of Exela’s ELCYS® product throughout the
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`United States, including in Delaware.
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`67.
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`On information and belief, following FDA approval of ANDA No. 214082, Eton
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`will offer for sale and sell the approved generic version of ELCYS® throughout the United
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`States, including in Delaware.
`
`68.
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`Eton’s effort to seek FDA approval to market a generic version of ELCYS® prior
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`to the expiration of the ’453, ’155, and ’719 patents constitutes an act of infringement pursuant to
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`35 U.S.C. § 271(e)(2). It also creates a justiciable controversy between the parties with respect
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`to the subject matter of ANDA No. 214082, the ’155 patent, the ’453 patent, and the ’719 patent,
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`as further evidenced by Eton’s Paragraph IV Letter.
`
`69.
`
`On information and belief, Eton’s Proposed Generic Cysteine Hydrochloride
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`Product will be sold and distributed with labeling that contains substantially the same
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`instructions for use as those in the label for Exela’s ELCYS® product, including instructions that
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`are substantially the same as those described above in paragraphs 14-25.
`
`70.
`
`For example, on information and belief, the labeling for Eton’s Proposed Generic
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`Cysteine Hydrochloride Product, like the labeling for ELCYS®, will instruct healthcare providers
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`that the product is indicated for use as an additive to amino acid solutions to meet nutritional
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`requirements of newborn infants requiring total parenteral nutrition and adult and pediatric
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`patients who may have impaired enzymatic processes and require TPN.
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`71.
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`On information and belief, based on that instruction, which will appear in the
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`indications and usage section of the label for Eton’s Proposed Generic Cysteine Hydrochloride
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`Product, the product will be used to treat patients who have adverse health conditions that are
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`responsive to L-cysteine administration.
`
`72.
`
`On information and belief, the labeling for Eton’s Proposed Generic Cysteine
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`Hydrochloride Product, like the labeling for ELCYS®, will contain recommendage dosage and
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`volume for pediatric patients from birth to less than 12 years of age, including for neonates and
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`infants, e.g., preterm and term infants less than 1 month of age, and pediatric patients 1 month to
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`less than 1 year of age.
`
`73.
`
`On information and belief, based on that information, which will appear in the
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`dosage and administration section of the label for Eton’s Proposed Generic Cysteine
`
`Hydrochloride Product, the product will be used to treat neonates and infants.
`
`74.
`
`Eton’s Proposed Generic Cysteine Hydrochloride Product contains L-cysteine
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`hydrochloride monohydrate in an amount from 10-100 mg/mL. Specifically, Eton’s Paragraph
`
`IV Letter states that its Proposed Generic Cysteine Hydrochloride Product is an injection
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`containing 500 mg/10mL (50 mg/mL) cysteine hydrochloride, USP in a 10 mL single-dose vial.
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`On information and belief, like ELCYS®, Eton’s Proposed Generic Cysteine Hydrochloride
`
`Product comprises water as the carrier for L-cysteine.
`
`75.
`
`On information and belief, Eton’s Proposed Generic Cysteine Hydrochloride
`
`Product will have a pH range from about 1.0 to about 2.5.
`
`76.
`
`On information and belief, Eton’s Proposed Generic Cysteine Hydrochloride
`
`Product is stable and will not be approved by FDA if it is not stable.
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`Case 1:20-cv-00365-MN Document 14 Filed 07/28/20 Page 16 of 39 PageID #: 418
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`77.
`
`On information and belief, and especially in view of the FDA-approved product
`
`specifications for ELCYS®, Eton’s Proposed Generic Cysteine Hydrochloride Product will not
`
`be approved unless it is substantially free of visually detetable particulate matter.
`
`78.
`
`On information and belief, and especially in view of the FDA-approved shelf life
`
`for ELCYS® and supporting 24-month stability data, Eton’s Proposed Generic Cysteine
`
`Hydrochloride Product will be approved for at least a 24-month shelf life, meaning that it will be
`
`substantially free of visually detetable particulate matter for at least 24 months from the time of
`
`manufacture of the solution.
`
`79.
`
`On information and belief, Eton’s Proposed Generic Cysteine Hydrochloride
`
`Product contains no more than 145 mcg/L of aluminum, per FDA’s requirements, and will state
`
`that on its labeling.
`
`80.
`
`On information and belief, and especially in view of the FDA-approved product
`
`specifications for ELCYS®, Eton’s Proposed Generic Cysteine Hydrochloride Product contains
`
`no more than 2.0% total impurities. On information and belief, because FDA had already
`
`approved ELCYS® with a specification limiting total impurities to no more than 2.0% before
`
`Eton filed ANDA No. 214082, FDA will not approve another cysteine hydrochloride product
`
`that permits impurities at a level greater than 2.0%.
`
`81.
`
`On information and belief, Eton’s Proposed Generic Cysteine Hydrochloride
`
`Product therefore contains less than 2.0% of the impurities cystine and pyruvic acid relative to L-
`
`cysteine, and thus, on information and belief, Eton’s Proposed Generic Cysteine Hydrochloride
`
`Product contains from about 0.001 wt % to about 2.0 wt% cystine (or L-cystine) relative to L-
`
`cysteine and from about 0.001 wt % to about 2.0 wt % pyruvic acid relative to L-cysteine.
`
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`82.
`
`On information and belief, Eton’s Proposed Generic Cysteine Hydrochloride
`
`Product contains dissolved oxygen present in the carrier in an amount from about 0.1 ppm to
`
`about 5 ppm from the time of manufacture to about 1 month from manufacture when stored at
`
`room temperature. Indeed, Eton’s Paragraph IV Letter makes no claim that its Proposed Generic
`
`Cysteine Hydrochloride Product does not have dissolved oxygen levels in this range.
`
`83.
`
`On information and belief, Eton’s Proposed Generic Cysteine Hydrochloride
`
`Product contains 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. As disclosed
`
`in the ’453 patent in Example 5, even when a robust process is followed to reduce headspace
`
`oxygen—for example, a high-speed filler capable of using vacuum and gas overlay in alternate
`
`pulses—the headspace oxygen in at least some vials so treated is present at about 0.5% v/v upon
`
`manufacture and from about 0.5% v/v to over 1.5% v/v (but less than 4.0% v/v) at about 1 month
`
`from the time of manufacture when stored at room temperature. [Ex. C at 48:15-49:67; 28:48-
`
`58.] In addition, as the ’453 patent discloses in Examples 4 and 5, when headspace oxygen is
`
`reduced by means of a lyophilization process, the headspace oxygen in vials containing a
`
`cysteine solution is present, o