UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`ETON PHARMACEUTICALS, INC.,
`Petitioner
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`v.
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`EXELA PHARMA SCIENCES, LLC,
`Patent Owner
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`Case PGR2020-00086
`Patent No. 10,653,719
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`PATENT OWNER’S
`PRELIMINARY RESPONSE
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`Attorney Docket: 48751-0009PS1
`Case No. PGR2020-00086
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`TABLE OF CONTENTS
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`I. 
`II. 
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`B. 
`
`Introduction ................................................................................................. 1 
`Background ................................................................................................ 13 
`A. 
`L-Cysteine Is an Essential Amino Acid, Primarily Administered to
`Infants, that Posed Devastating Health Risks Due to its High
`Aluminum Content Before Exela’s Invention ..................................... 13 
`The Patented Invention Solved the Long-Standing and Complex
`Problem to Fulfill an Unmet Need for a Stable, Highly Pure, Low-
`Aluminum L-Cysteine TPN Component Substantially Free of
`Visually Detectable Particulate Matter ............................................... 18 
`Claim Construction ................................................................................... 25 
`Level of Ordinary Skill in the Art ............................................................ 26 
`The Petition Fails to Meet the Particularity Requirement of 35 U.S.C.
`§ 322(A)(3) By Conflating the “Sandoz Label” With a “Sandoz
`Product” and Relying on Alleged Features of that Product that Lack
`Evidentiary Support .................................................................................. 27 
`Institution Should Be Denied Because Eton Cannot Prevail as to Any
`Challenged Claim ...................................................................................... 36 
`A. 
`Eton Fails to Demonstrate that Claims 1-27 Would Have Been
`Obvious Over the Sandoz Label in View of the Knowledge of a
`POSITA ............................................................................................... 36 
`i. 
`Eton Fails to Show that the Sandoz Label Discloses or Suggests
`the Claimed Amounts of Aluminum ........................................... 37 
`Eton’s “Routine Optimization” Argument Is Based on Hindsight-
`Infected Assumptions and Ignores the Complex Interplay
`Between the Claimed Composition’s Features ........................... 43 
`VII.  The Board Should Deny The Petition Under 35 U.S.C. § 324(a)
`Because the Parallel District Court Litigation Makes Institution
`Inefficient .................................................................................................... 64 
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`III. 
`IV. 
`V. 
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`VI. 
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`ii. 
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`VIII.  Conclusion .................................................................................................. 67 
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`EXHIBIT LIST
`Exhibit No.
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`Attorney Docket: 48751-0009PS1
`Case No. PGR2020-00086
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`Description
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`2001
`2002
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`2003
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`2004
`2005
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`2006
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`2007
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`2008
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`2009
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`2010
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`2011
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`2012
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`2013
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`Declaration of Dr. Robert J. Kuhn
`Aileen B. Sedman et al., Evidence of Aluminum Loading in Infants
`Receiving Intravenous Therapy, 312 NEW ENG. J. MED. 1337
`(1985)
`Nicholas J. Bishop et al., Aluminum Neurotoxicity in Preterm
`Infants Receiving Intravenous-Feeding Solutions, 336 NEW ENG. J.
`MED. 1557 (1997)
`ELCYS® Label, Exela Pharma Sciences, LLC
`Amended Complaint (Redacted), Exela Pharma Sciences, LLC v.
`Sandoz, Inc., No. 1:20-cv-00645-MN (D. Del. June 1, 2020), ECF
`No. 12
`Amended Complaint, Exela Pharma Sciences, LLC v. Eton
`Pharmaceuticals, Inc., No. 20-365-MN (D. Del. July 28, 2020),
`ECF No. 14
`Declaration of Mark Hartman (Redacted), Exela Pharma Sciences,
`LLC v. Sandoz Inc., No. 19-cv-00318-MR (W.D.N.C. Dec. 6,
`2019), ECF No. 26-1
`Megan Fortenberry et al., Evaluating Differences in Aluminum
`Exposure Through Parenteral Nutrition in Neonatal Morbidities, 9
`NUTRIENTS 1249 (2017)
`Kathleen M. Gura, Aluminum Contamination in Parenteral
`Products, 17 CURR. OPIN. CLIN. NUTR. & METAB. CARE 551
`(2014)
`Gordon L. Klein et al., Hypocalcemia Complicating Deferoxamine
`Therapy in an Infant with Parenteral Nutrition-Associated
`Aluminum Overload: Evidence for a Role of Aluminum in the Bone
`Disease of Infants, 9 J. PED. GASTR. & NUTR. 400 (1989)
`Jay M. Mirtallo, Aluminum Contamination of Parenteral Nutrition
`Fluids, 34 J. PARENTERAL & ENTERAL NUTR. 346 (2010)
`Robert L. Poole et al., Aluminum Exposure From Pediatric
`Parenteral Nutrition: Meeting the New FDA Regulation, 32 J.
`PARENTERAL & ENTERAL NUTR. 242 (2008)
`Eton Pharmaceuticals, Inc., Amendment No. 1 to Sales/Marketing
`Agreement (Form S-1/A, Exhibit 10.18) (Sept. 25, 2018)
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`2014
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`2015
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`2016
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`2017
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`2018
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`2019
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`2020
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`2021
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`Attorney Docket: 48751-0009PS1
`Case No. PGR2020-00086
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`Eton Pharmaceuticals, Inc. v. Exela Pharma Sciences, Inc.,
`PGR2020-00064, Paper 1 (P.T.A.B. May 19, 2020)
`Eton Pharmaceuticals, Inc. v. Exela Pharma Sciences, Inc.,
`PGR2020-00064, Paper 12 (P.T.A.B. Nov. 18, 2020)
`Eton Pharmaceuticals, Inc. v. Exela Pharma Sciences, Inc.,
`PGR2020-00068, Paper 1 (P.T.A.B. June 8, 2020)
`Eton Pharmaceuticals, Inc. v. Exela Pharma Sciences, Inc.,
`PGR2020-00068, Paper 11 (P.T.A.B. Dec. 15, 2020)
`Eton Letter to Judge Noreika, Exela Pharma Sciences, LLC v.
`Eton Pharmaceuticals, Inc., No. 20-00365-MN (D. Del. Nov. 18,
`2020), ECF No. 48
`Excerpt From the File History of U.S. Patent Application No.
`16/746,028 – Request for Continued Examination (May 28, 2020),
`Information Disclosure Statement (May 28, 2020), Information
`Disclosure Statement (June 11, 2020), and Notice of Allowance
`(Jan. 13, 2021)
`Excerpt From the File History of U.S. Patent Application No.
`16/773,641 – Request for Continued Examination (June 2, 2020),
`Information Disclosure Statement (June 11, 2020), Information
`Disclosure Statement (Nov. 9, 2020), and Notice of Allowance
`(Dec. 23, 2021)
`Opening Brief in Support of Defendant Eton Pharmaceuticals,
`Inc.’s Motion to Stay Pending Post-Grant Proceedings, Exela
`Pharma Sciences, LLC v. Eton Pharmaceuticals, Inc., No. 20-
`00365-MN (D. Del. Oct. 2, 2020), ECF No. 33
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`Attorney Docket: 48751-0009PS1
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`INTRODUCTION
`The arguments made in Eton’s Petition are nearly identical to arguments
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`I.
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`Eton made in two prior Petitions on related patents, and those arguments have
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`already been rejected twice by the Patent Trial and Appeal Board. See Sections
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`II.B and VII. Eton’s Petition here should be rejected for the same reasons. Just as
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`before, Eton fails to establish that a POSITA would have had a reasonable
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`expectation of success in making the low aluminum L-cysteine solutions claimed
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`in Exela’s U.S. Patent No. 10,653,719 (“the ’719 Patent;” Ex. 1106).
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`The ’719 Patent relates to highly pure L-cysteine solutions that are
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`substantially free of visually detectable particulate matter and suitable for use as an
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`additive in parenteral nutrition compositions. Parenteral nutrition compositions
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`containing L-cysteine are used to treat individuals with impaired kidney function,
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`including preterm and underweight infants, who need to be parenterally nourished
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`during their fragile first days, weeks, or sometimes months of life. While prior L-
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`cysteine solutions contained up to 5,000 ppb1 of toxic aluminum, the inventive L-
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`cysteine solutions recited in the claims contain less than about 150 ppb of
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`1 “ppb” is also referred to as “mcg/L” or “µg/L” (“micrograms per Liter”).
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`1
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`aluminum, and in certain claims even less.2 Unlike prior L-cysteine solutions
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`which, as Eton acknowledges, had aluminum levels that were known to increase
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`over time,3 the aluminum and other impurity levels in the claimed solutions are
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`stable over time, yielding a solution that will be suitable for use as an additive in a
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`parenteral nutrition composition and for administration in a clinical setting.4
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`2 See, e.g., Ex. 1106 (’719 Patent) at 58:34-67 (claims 1-11), 59:1-26 (claims
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`12-16), 59:27-60:33 (claims 17-27); Ex. 1005 (Sandoz Label) at 10.
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`3 Paper 1 at 29, 38, 43; see also Ex. 1008 (Bohrer 2001) at 1 (“[A]nalysis of
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`commercial formulations with and without cysteine” showed that “the
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`contamination is an ongoing process due to the presence of aluminium in glass
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`combined with the affinity of some amino acids for this element.”), 4, Table 2 and
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`Fig. 2.
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`4 See, e.g., Paper 1 at 17 (stating that “[t]he ’719 patent is generally directed
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`to ‘compositions for parenteral administration comprising L-cysteine that are stable
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`and have desirable safety attributes for extended periods of time.’”); id. at 39
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`(“FDA guidance makes clear that product quality must be guaranteed both at the
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`time of manufacture and throughout the product’s expected shelf-life.”); id. at 24
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`(stating that, in order to qualify as a POSITA, “[s]pecific experience with
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`2
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`Exela’s invention solved what was by 2013 already a “decades old and still
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`unresolved” 5 problem: aluminum toxicity in parenteral nutrition solutions,
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`including from the L-cysteine formulations available at that time, whose aluminum
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`levels increased over time to a maximum of 5,000 ppb—more than thirty-three
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`times higher than the 150 ppb recited by the ’719 independent claims.6
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`It is beyond dispute that strong motivation existed to solve this long-
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`standing problem. As Eton acknowledges, “[t]here were regulatory and market
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`forces pushing for the substantial reduction and elimination of aluminum from
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`parenteral drug products.”7 Even more specifically, in Eton’s words, “the POSITA
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`would have been motivated to substantially reduce and eliminate aluminum from
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`processes and techniques for minimizing impurities in and improving the stability
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`of pharmaceutical drug products during manufacture and storage would have been
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`a must”); id. at 44; Ex. 1106 (’719 Patent) at 1:1-3, 58:42-44, 59:10-12, 60:2-4.
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`5 See Ex. 1006 (Hernandez-Sanchez 2013) at 1; Paper 1 at 30.
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`6 Paper 1 at 29, 38, 43; Ex. 1005 (Sandoz Label) at 5; see also Ex. 1008
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`(Bohrer 2001) at 1, 4, Table 2 and Fig. 2.
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`7 Paper 1 at 38.
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`parenteral nutritional drug products such as the Sandoz product disclosed by the
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`Sandoz Label.”8
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`And yet, the problem went unsolved for years, including by Sandoz itself.
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`Sandoz’s alleged work on L-cysteine injection products dates to 2008.9
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`Despite the repeated pleas from the medical and academic communities for
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`manufacturers to substantially reduce the aluminum contamination of parenteral
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`products,10 Sandoz still had not solved the problem more than a decade later.
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`8 Id. at 32; see also id. at 39‒40.
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`9 Ex. 1022 (’453 Johnson Decl.) ¶¶ 8‒9; Ex. 1116 (’719 Johnson Decl.) ¶ 9.
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`10 Ex. 2012 (Poole 2008) at 1 (“Manufacturers must identify, develop, and
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`adopt new methods to reduce the aluminum contamination in their products.”): Ex.
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`2011 (Mirtallo 2010) at 2 (“We as clinicians should insist that small-volume
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`parenterals be packaged in polyethylene containers.”); Ex. 1006 (Hernandez-
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`Sanchez 2013) at 1 (“Unfortunately, manufacturers have not universally changed
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`their processes to obtain a lower Al content of parenteral drug products (PDP).”);
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`Ex. 2009 (Gura 2014) at 1 (“Unlike the rapid response to eliminating aluminum
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`toxicity in the dialysis patient population, similar successes have not been realized
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`in patients receiving parenteral nutrition solutions. Product formulation changes
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`Instead, in May 2019 Sandoz approached Exela for a license to sell Exela’s
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`low-aluminum, FDA-approved L-cysteine product (ELCYS®), which is embodied
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`in the ’719 patented solutions (this was within just six weeks of FDA approval of
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`ELCYS®).11 Sandoz’s motivation for seeking a license could have only been
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`because of the merits of Exela’s product; at that time Exela’s patent applications
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`have been slow to emerge from manufacturers.”); Ex. 1038 (Lima-Rogel 2016) at
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`1 (“Excessive aluminum intakes from intravenous solutions, drugs, and parenteral
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`nutrition still represent an unsolved problem. … Low-birth weight preterm infants,
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`long-term home parenteral nutrition adult patients, and patients with chronic
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`kidney disease are particularly exposed and considered high-risk populations. …
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`Efforts should be implemented to identify and subsequently reduce the amount of
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`aluminum in parenteral solutions.”).
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`11 Ex. 2007 (Declaration of Mark Hartman, Exela Pharma Sciences, LLC v.
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`Sandoz Inc., No. 19-cv-00318-MR (W.D.N.C. Dec. 6, 2019), ECF No. 26-1) ¶¶ 6,
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`11.
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`were not public knowledge. After Exela declined, Sandoz filed an ANDA seeking
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`FDA approval of a generic (i.e., copy) of Exela’s ELCYS® product.12
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`Sandoz is not alone in seeking to free-ride off of Exela’s inventive solution
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`to the long-standing aluminum problem for L-cysteine. Eton, in collaboration with
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`AL Pharma (formerly known as Allergy Labs, which had previously manufactured
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`an L-cysteine injection for Sandoz),13 also failed to solve the problem and
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`ultimately resorted to copying Exela’s inventions. As Eton’s Declarant explains, in
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`January 2018 AL Pharma submitted a New Drug Application (NDA) to FDA
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`seeking approval of an L-cysteine injection product with “an Aluminum Content of
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`not more than (NMT) 5,000 ppb.”14 FDA identified numerous deficiencies in the
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`application, including that the drug product had “not been shown to meet the
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`12 Ex. 2005 (Amended Complaint, Exela Pharma Sciences, LLC v. Sandoz,
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`Inc., No. 1:20-cv-00645-MN (D. Del. June 1, 2020), ECF No. 12) ¶ 12. This case
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`was closed on August 7, 2020.
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`13 Ex. 1022 (’453 Johnson Decl.) ¶¶ 5‒6; Ex. 1116 (’719 Johnson Decl.) ¶¶
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`6‒7.
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`14 See Ex. 1022 (’453 Johnson Decl.) ¶¶ 19‒20.
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`required acceptance limit for aluminum content.”15 Rather than fix these issues,
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`Eton abandoned its NDA and chose to copy Exela’s ELCYS® product instead,
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`filing an ANDA in December 2019 seeking FDA approval for a generic copy of
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`ELCYS®.16 In other words, Eton failed to employ the “routine optimization”
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`strategy it touts in its Petition for solving the purportedly “well-known and easily
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`rectified” problems of prior L-cysteine products.17 That ANDA filing triggered a
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`Hatch-Waxman litigation between Eton and Exela, now pending in the District of
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`Delaware.18
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`In short, even those who were motivated to solve the aluminum problem for
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`L-cysteine, experienced with L-cysteine products, and uniquely positioned with
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`manufacturing and analytical facilities to modify the Sandoz unstable, high-
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`aluminum L-cysteine product failed for years, and instead resorted to copying
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`15 Id. ¶ 21; see also id. at 125.
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`16 Ex. 2006 (Amended Complaint, Exela Pharma Sciences, LLC v. Eton
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`Pharmaceuticals, Inc., No. 20-365-MN (D. Del. July 28, 2020), ECF No. 14) ¶¶
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`51‒56.
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`17 See Paper 1 at Sections VIII.A.C.2 and VIII.A.C.3.
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`18 See id.
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`Exela’s inventive solution. Eton’s contention that the POSITA would have had a
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`“reasonable expectation of success” in arriving at the claimed invention through
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`“routine optimization” of the product that is the subject of the Sandoz label is
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`belied by these failures and is textbook hindsight.19 The Petition should be rejected
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`for this reason alone.
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`But there are numerous additional reasons to deny institution, as discussed
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`below.
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`Eton challenges all 27 claims as being obvious, on the ground shown in the
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`table below:20
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`19 See, e.g., Paper 1 at 2, 17, 21, 33, 39‒40, 44‒45; see In re
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`Cyclobenzaprine HCl Extended Release Capsule Patent Litig., 676 F.3d 1063,
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`1080‒82 (Fed. Cir. 2013) (reversing obviousness finding in part based on evidence
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`of failure of others); see also Leo Pharm. Prods., Ltd. v. Rea, 726 F.3d 1346,
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`1353‒56 (Fed. Cir. 2013) (reversing obviousness finding in part based on strong
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`objective indicia, including that the problem “was not solved for over a decade,”
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`and noting the Board “erred by collapsing the obviousness analysis into a
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`hindsight-guided combination of elements”).
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`20 Paper 1 at 6.
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`The Sandoz Label that serves as Eton’s primary reference fails to disclose
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`the claim limitations. See, e.g., Section VI(A)(i). Eton argues that a POSITA
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`would have used “routine optimization” to achieve them. But missing from the
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`Petition is any explanation as to why or how a POSITA purportedly motivated to
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`perform “routine optimization” would have arrived at the claimed L-cysteine
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`solutions that have low aluminum levels while also remaining substantially free of
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`visually detectable particulate matter. See Section VI(A)(ii).
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`Nor does the Petition explain how a POSITA applying “routine
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`optimization” would have achieved a stable L-cysteine solution that maintains less
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`than about 150 ppb of aluminum over time. See Section VI(A)(ii). This is
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`important. As Eton acknowledges, “product quality must be guaranteed both at the
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`time of manufacture and throughout the product’s expected shelf-life.”21 In other
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`21 Paper 1 at 39; see also id. at 17 (stating that “[t]he ’719 patent is generally
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`directed to ‘compositions for parenteral administration comprising L-cysteine that
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`are stable and have desirable safety attributes for extended periods of time.’”); id.
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`words, the claimed solutions must maintain the claimed low aluminum levels over
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`the solution’s shelf life such that it remains suitable for use in a parenteral nutrition
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`composition administered in a clinical setting.
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` This is precisely where the prior L-cysteine compositions—including that
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`of the Sandoz Label—failed, and precisely the problem neither Sandoz nor Eton
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`was able to solve despite years of motivation and effort.
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`Also missing from the Petition is any explanation as to why a POSITA
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`would have had a reasonable expectation of success in solving the “decades old”
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`aluminum problem through mere alleged “routine” optimization.22 See Section
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`VI(A)(ii).
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`The only filler offered for these gaps is hindsight, which of course is
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`impermissible. Indeed, instead of being based on reasoned analysis and
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`evidentiary support, Eton’s “routine optimization” argument impermissibly “use[s]
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`at 36 (“specifications (e.g., tests, procedures, and acceptance criteria) ‘play a major
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`role in assuring the quality of the new drug product at release and during shelf
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`life.’”) (emphasis in original); Ex. 1106 (’719 Patent) at 16:44‒48 (defining
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`“stable”).
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`22 See Ex. 1006 (Hernandez-Sanchez 2013) at 1 (emphasis added).
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`the challenged patent as a roadmap to reconstruct the claimed invention.” See TQ
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`Delta, LLC v. CISCO Sys., Inc., 942 F.3d 1352, 1361 (Fed. Cir. 2019).
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`Eton’s asserted Ground also lacks the particularity required by 35 U.S.C. §
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`322(a). Eton relies on a “Sandoz product” manufactured by Allergy Labs, and
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`refers to this product interchangeably with the Sandoz label and package insert at
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`Exhibit 1005 (“Sandoz Label”). Eton never establishes that any product, let alone
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`a product with characteristics beyond those described in the Sandoz Label,
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`qualifies as prior art. Yet Eton relies on characteristics of a product made by
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`Allergy Labs that were either unknowable to the POSITA (e.g., as-tested
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`aluminum levels of the product before release to the public), or for which there is
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`zero evidence in the record (e.g., as-tested aluminum levels of the product from 1-
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`24 months) beyond the say-so of an interested declarant with a huge financial
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`interest in Eton succeeding in this PGR proceeding.23 Eton must be limited to the
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`product characteristics described in the Sandoz Label, and that label makes clear
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`the product may contain up to 5,000 ppb of aluminum during its shelf life.24
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`23 See, e.g., Paper 1 at 29, 38, 43; Ex. 1003 (Rabinow Decl.) ¶ 33, 109; Ex.
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`1022 (’453 Johnson Decl.) ¶¶ 5‒6, 13‒15.
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`24Ex. 1005 (Sandoz Label) at 5.
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`Finally, institution should also be denied under 35 U.S.C. § 324(a) because it
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`would be inefficient and wasteful of resources for the Board to entertain Eton’s
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`arguments here, since those arguments will inevitably be addressed in a co-pending
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`district court litigation in the District of Delaware involving the same parties and
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`issues here. See Section VII. The district court litigation includes patent
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`infringement claims for the ’719 patent, as well as two other Exela patents in the
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`same family (U.S. Patent Nos. 10,478,453 and 10,583,155) that Eton has already
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`unsuccessfully petitioned for post-grant review. In those failed PGR petitions,
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`Eton presented arguments that are nearly identical to the arguments Eton presents
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`here. See Sections II.B and VII. Thus, the Board has already twice rejected the
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`arguments Eton repeats here. Eton has admitted that those same unsuccessful
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`invalidity arguments will be the “crux” of Eton’s invalidity case in district court.25
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`Because the arguments that form the basis of Eton’s Petition here will inevitably be
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`25 Ex. 2021 (Opening Brief in Support of Defendant Eton Pharmaceuticals,
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`Inc.’s Motion to Stay Pending Post-Grant Proceedings, Exela Pharma Sciences,
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`LLC v. Eton Pharmaceuticals, Inc., No. 20-00365-MN (D. Del. Oct. 2, 2020), ECF
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`No. 33) at 2‒3 (admitting that “[t]he grounds of [Eton’s] PGR petitions will form
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`the crux of [its] invalidity defenses in this litigation”).
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`addressed in the district court litigation, it would be inefficient and wasteful of
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`resources for the Board and parties to engage in a duplicative analysis here.
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`Institution should be denied for all of these reasons.
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`II. BACKGROUND
`A. L-Cysteine Is an Essential Amino Acid, Primarily Administered to
`Infants, that Posed Devastating Health Risks Due to its High
`Aluminum Content Before Exela’s Invention
`L-cysteine is an amino acid that performs a variety of metabolic functions
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`and is important for human life. While healthy adults can naturally synthesize
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`small amounts of L-cysteine, certain high-risk populations require supplementation
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`by parenteral administration (e.g., intravenous infusion or injection). These high-
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`risk populations include preterm and/or low birth weight infants and other
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`individuals with renal compromise (i.e., impaired kidney function).26
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`For these patients, L-cysteine is administered as a component of a nutritional
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`regimen, typically referred to as Total Parenteral Nutrition (“TPN”) or Parenteral
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`Nutrition (“PN”).27 A TPN regimen involves administering—typically
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`intravenously—a formulation that is a mixture (called an “admixture”) of various
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`26 Ex. 1007 (Poole 2011) at 2; Ex. 1006 (Hernandez-Sanchez 2013) at 2.
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`27 Ex. 2001 (Kuhn Decl.) ¶ 10.
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`parenteral nutrition components.28 Thus, L-cysteine is first manufactured as a
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`stand-alone component, then admixed with various other components, and
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`ultimately can be administered by IV to the patient as part of a TPN regimen.29
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`Aluminum is a known problematic contaminant in TPN formulations.30 As
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`the Journal of Parenteral and Enteral Nutrition reported in 2008, “there have been
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`numerous reports of aluminum toxicity from the contamination of [parenteral
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`nutrition] solutions over the past 3 decades.”31 Aluminum toxicity can cause
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`“serious central nervous system and bone toxicities,” as well as liver damage and
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`
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`28 Id. ¶¶ 11‒14.
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`29 See, e.g., Paper 1 at 29 (stating that the Sandoz product had a 2-year shelf-
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`life); Ex. 1003 (Rabinow Decl.) ¶¶ 55, 156 (stating that the Sandoz Label
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`solution’s shelf-life was 2 years post-manufacture); Ex. 2001 (Kuhn Decl.) ¶¶ 11‒
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`14.
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`30 Ex. 2002 (Sedman 1985) at 1; Ex. 2012 (Poole 2008) at 1 (“Aluminum is
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`a contaminant of parenteral nutrition (PN) solution components.”); Ex. 2001 (Kuhn
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`Decl.) ¶ 15; Ex. 1038 (Lima-Rogel 2016) at 4 (“Aluminum contamination in PN
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`admixtures remains an unsolved problem.”).
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`31 Ex. 2012 (Poole 2008) at 3.
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`anemia.32 Numerous components in a TPN solution can contribute to the total
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`amount of aluminum after admixing, with L-cysteine formulations historically
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`being a substantial contributor of aluminum.33 Before the ’719 patent’s inventions,
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`the amount of toxic aluminum in L-cysteine formulations was known to increase
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`over the product’s two-year shelf life, due at least in part to aluminum leaching
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`into the solution from its glass container.34
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`
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`32 Id.; see also Ex. 1007 (Poole 2011) at 1 (explaining that aluminum
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`toxicity can cause “fracturing osteomalacia and reduced bone mineralization,
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`neurological dysfunction and dialysis encephalopathy, microcytic hypochromic
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`anemia, and cholestasis”).
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`33 Ex. 1006 (Hernandez-Sanchez 2013) at 2; Ex. 2012 (Poole 2008) at Table
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`5; Ex. 2001 (Kuhn Decl.) ¶ 15.
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`34 Ex. 1008 (Bohrer 2001) at 1 (“[Aluminum] contamination is an ongoing
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`process due to the presence of aluminum in glass combined with the affinity of
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`some amino acids for this element.”); id. at 4, Table 2 and Fig. 2 (showing
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`significant increase in aluminum content of cysteine from days 0 to 400 “from
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`aluminum leached from glass containers”); Ex. 1003 (Rabinow Decl.) ¶ 33 (“The
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`POSITA would have understood that a likely source of the aluminum (as initially
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`The vulnerable infants who receive TPN (most generally while in the
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`Neonatal Intensive Care Unit (NICU)) are “predispose[d]” to a “high risk for
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`aluminum toxicity.”35 These infants are particularly susceptible because they have
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`immature kidneys, which impairs elimination of aluminum from the body.36 As
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`aluminum is prone to accumulate in bones, the central nervous system, and other
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`tissues in the body, their risk is exacerbated by the prolonged TPN treatment they
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`often require.37
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`The consequences are sobering. A 1997 study found that preterm infants
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`receiving the standard, high-aluminum TPN solutions lost one point per day on the
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`
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`observed and over time) was the glass vial in which the Sandoz L-Cysteine drug
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`product was packaged. Glass vials were known to leach aluminum.”); Paper 1 at
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`29, 33.
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`35 Ex. 2008 (Fortenberry 2017) at 1; see also Ex. 2001 (Kuhn Decl.) ¶ 15;
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`Ex. 1038 (Lima-Rogel 2016) at 1 (“Low birth-weight preterm infants (LBWPIs)
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`are one of the most exposed populations for aluminum toxicity.”).
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`36 Ex. 1006 (Hernandez-Sanchez 2013) at 2; see also Ex. 2001 (Kuhn Decl.)
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`¶ 15.
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`37 Ex. 1006 (Hernandez-Sanchez 2013) at 2.
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`100-point Bayley Mental Development Index (MDI).38 Infants receiving the
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`standard TPN solutions were also twice as likely to have MDI scores below 85 (the
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`MDI level that is predictive of delayed neurodevelopment and subsequent
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`educational problems) at 18 months, compared to infants treated with aluminum-
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`depleted solutions.39 Other studies have shown that the aluminum contamination
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`in TPN solutions impairs bone calcium uptake and contributes to osteopenia,40 and
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`can lead to significantly reduced hip bone mass, lumbar spine bone mineral
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`content, and total bone area by age 13-15 years.41
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`Due to the serious health risks associated with aluminum toxicity, the FDA
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`since 2004 has required the labels for parenteral nutrition components to contain a
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`“WARNING” that aluminum levels should not exceed 4 to 5 mcg/kg/day in
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`
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`38 Ex. 2003 (Bishop 1997) at 1; see also Ex. 2012 (Poole 2008) at 2
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`(summarizing Bishop study findings).
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`39 Id.
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`40 Ex. 2010 (Klein 1989) at 1.
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`41 Ex. 1064 (Fewtrell 2011) at 1; see also Ex. 1006 (Hernandez-Sanchez
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`2013) at 6.
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`vulnerable patients, like those with impaired kidney function.42 But it would take
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`nearly fifteen years before someone (Patent Owner, Exela) finally developed an
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`injectable L-cysteine composition with acceptably safe aluminum levels that
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`persist over time that would enable practitioners to comply with this warning for
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`the duration of the product’s shelf-life.43
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`B. The Patented Invention Solved the Long-Standing and Complex
`Problem to Fulfill an Unmet Need for a Stable, Highly Pure, Low-
`Aluminum L-Cysteine TPN Component Substantially Free of
`Visually Detectable Particulate Matter
`The inventors of the ’719 patent finally solved the aluminum problem with
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`parenteral L-cysteine solutions decades after its first recognition. Not only were
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`the inventors able to develop L-cysteine solutions with low aluminum levels (no
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`more than 120 ppb as embodied in the ELCYS® product and specifically covered
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`by the about 150 ppb maximum recited in independent claims 1, 12, and 17), but
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`the inventors’ solutions are highly pure, including being substantially free of
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`
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`42 21 C.F.R. § 201.323; Fed. Reg. 4103, 4111 (Jan. 26, 2000); 68 Fed. Reg.
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`32,979 (June 3, 2003); Ex. 1006 (Hernandez-Sanchez 2013) at 7; Ex. 1007 (Poole
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`2011) at 1‒2.
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`43 Ex. 2001 (Kuhn Decl.) ¶¶ 15, 35.
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`visually detectable particulate matter, and are stable over time, yielding a solution
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`that will be suitable for use as an additive in a parenteral nutrition composition and
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`for administration in a clinical setting.44
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`In developing the stable L-cysteine solutions recited in the claims, the
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`inventors had to overcome “unexpected technical hurdles,”45 all of which Eton
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`ignores. As discussed in more detail below, the kinetics and equilibrium chemistry
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`of the various L-cysteine and cystine species in any particular L-cysteine solution
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`
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`44 Ex. 1106 (’719 Patent) at 58:34‒60:33; Paper 1 at 17 (stating that “[t]he
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`’719 patent is generally directed to ‘compositions for parenteral administration
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`comprising L-cysteine that are stable and have desirable safety attributes for
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`extended periods of time.’”); id. at 36 (“specifications (e.g., tests, procedures, and
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`acceptance criteria) ‘play a major role in assuring the quality of the new drug
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`product at release and during shelf life.’”) (emphasis in original); Ex. 1106 (’719
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`Patent) at 16:44‒48 (defining “stable”); Paper 1 at 39 (“[P]roduct quality must be
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`guaranteed both at the time of manufacture and throughout the product’s expected
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`shelf-life.”).
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`45 Ex. 1002 (File History of earlier, related U.S. Patent No. 10,478,453 (“the
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`’453 Patent”)) at 407.
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`are complex and influenced by multiple interacting variables of that environment,
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`including oxygen levels, pH, and the presence of trace metals.46 Moreover,
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`multiple variables, including pH and cystine concentration, can further affect the
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`extent of aluminum leaching from the glass containers historically used to store L-
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`cysteine solutions.47
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`The art did not predict—n