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 PGR2020-00068
`Patent No. 10,583,155
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`PATENT OWNER’S
`PRELIMINARY RESPONSE
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`Attorney Docket: 48751-0007PS1
`Case No. PGR2020-00068
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`TABLE OF CONTENTS
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`B. 
`
`I. 
`II. 
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`III. 
`IV. 
`V. 
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`VI. 
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`Introduction ................................................................................................. 1 
`Background ................................................................................................ 11 
`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 ..................................... 11 
`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 ............................................ 16 
`Claim Construction ................................................................................... 20 
`Level of Ordinary Skill in the Art ............................................................ 20 
`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 .................................................................................. 22 
`Institution Should Be Denied Because Eton Cannot Prevail as to Any
`Challenged Claim ...................................................................................... 30 
`A.  Ground 1: Eton Fails to Demonstrate that Claims 1-16, 18, 23-24, and
`26-30 Would Have Been Obvious Over the Sandoz Label in View of
`the Hospira Label in view of the Knowledge of a POSITA ............... 31 
`1. 
`The Sandoz and Hospira Labels Do Not Disclose or Suggest the
`Claimed Limitations .................................................................... 31 
`Eton’s “Routine Optimization” Argument Is Based on Hindsight-
`Infected Assumptions and Ignores the Complex Interplay
`Between the Claimed Composition’s Features ........................... 38 
`Ground 2: Eton Fails to Demonstrate That Claims 17, 19-22, and 25
`Would Have Been Obvious Over the Sandoz Label in View of the
`Hospira Label in View of the Hospira 7.25% Cysteine HCl Package
`Insert (or 75 Fed. Reg. 31,790-791 (June 4, 2010)) in view of the
`Knowledge of a POSITA .................................................................... 59 
`i
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`2. 
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`B. 
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`VII.  Conclusion .................................................................................................. 60 
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`ii
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`EXHIBIT LIST
`Exhibit No.
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`Attorney Docket: 48751-0007PS1
`Case No. PGR2020-00068
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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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`INTRODUCTION
`Exela’s U.S. Patent No. 10,583,155 (“the ’155 patent;” Ex. 1001) relates to
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`I.
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`methods of using stable, highly pure L-cysteine compositions in parenteral
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`nutrition compositions to treat, primarily, preterm and underweight infants by
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`nourishing them during their fragile first days, weeks, or sometimes months of life.
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`While prior L-cysteine compositions contained up to 5,000 ppb1 of toxic
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`aluminum, the inventive L-cysteine compositions recited in the claims contain no
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`more than 250 ppb of aluminum, and in certain claims even less.2 Unlike prior L-
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`cysteine compositions which, as Eton acknowledges, had aluminum levels that
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`were known to increase over time,3 the aluminum and other impurity levels in the
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`1 “ppb” is also referred to as “mcg/L” or “µg/L” (“micrograms per Liter”).
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`2 See, e.g., Ex. 1001 (’155 Patent) at 58:45-56 (claims 1-3), 60:15-50 (claims
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`27 and 28); Ex. 1005 (Sandoz Label) at 10.
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`3 Paper 1 at 34, 42, 51; 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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`1
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`claimed compositions are stable over time so as to remain safe for administration
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`to infants throughout the product’s shelf life.4 Exela’s invention solved what was
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`by 2013 already a “decades old and still unresolved” 5 problem: aluminum toxicity
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`in parenteral nutrition solutions, including from the L-cysteine formulations
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`available at that time, whose aluminum levels increased over time to a maximum
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`of 5,000 ppb—twenty times higher than the maximum aluminum levels permitted
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`by the ’155 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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`4 See, e.g., Ex. 1001 (’155 Patent) at 16:44‒47; id. at 58:39,45; id. at
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`60:20,25; id. at 60:34.
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`5 See Ex. 1006 (Hernandez-Sanchez 2013) at 1; Paper 1 at 37.
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`6 Paper 1 at 34, 42, 51; 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 43.
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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 39; see also id. at 42‒45.
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`9 Ex. 1022 (Johnson Decl.) ¶¶ 8‒9.
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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®), the use of which is
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`embodied in the ’155 patented methods and parenteral compositions (this was
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`within just six weeks of FDA approval of ELCYS®).11 Sandoz’s motivation for
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`seeking a license could have only been because of the merits of Exela’s product; at
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`that time Exela’s patent applications were not public knowledge. After Exela
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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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`declined, Sandoz filed an ANDA seeking FDA approval of a generic (i.e., copy) of
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`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,” meaning Eton did not successfully employ the
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`“routine optimization” strategy it touts here.14 FDA identified numerous
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`deficiencies in the application, including that the drug product had “not been
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`shown to meet the required acceptance limit for aluminum content.”15 Rather than
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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.
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`13 Ex. 1022 (Johnson Decl.) ¶¶ 5‒6.
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`14 See id. ¶¶ 19‒20.
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`15 Id. ¶ 21; see also id. at 125.
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`fix these issues, Eton abandoned its NDA and chose to copy Exela’s ELCYS®
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`product instead, filing an ANDA in December 2019 seeking FDA approval for a
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`generic copy of ELCYS®.16 That ANDA filing triggered a Hatch-Waxman
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`litigation between Eton and Exela, now pending in the District of Delaware.17
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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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`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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`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 id.
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`belied by these failures and is textbook hindsight.18 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 30 claims as being obvious, on the grounds shown in the
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`table below:19
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`18 Paper 1 at 2‒3, 22, 26‒27, 44‒45, 48, 50‒51, 52‒62; 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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`19 Paper 1 at 7.
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`Eton admits that the asserted references fail to disclose numerous claim
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`limitations. See, e.g., Section VI(A)(1)(i). Eton argues that a POSITA would have
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`used “routine optimization” to achieve them. But missing from the Petition is any
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`explanation as to why or how a POSITA purportedly motivated to perform “routine
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`optimization” would have arrived at the claimed methods of treatment and
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`parenteral compositions that employ specific L-cysteine compositions having
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`particular components in particular amounts that the literature does not address.
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`See Section VI(A)(2).
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`Nor does the Petition explain how a POSITA applying “routine
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`optimization” would have achieved stable L-cysteine compositions that maintain
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`the recited amounts of those components over time. See Section VI(A)(2)(iii).
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`This is important. The “stable” L-cysteine composition used in the claimed
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`methods must, as Eton acknowledges, “contain the specified levels of all
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`components for sufficient period of time to enable the composition to be
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`commercially manufactured, stored, shipped, and administered in a clinical
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`setting.”20 In other words, it must remain stable for the entire time it is available
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`for administration to a patient as part of a parenteral nutrition composition, (i.e.,
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`throughout its shelf life). This is precisely where the prior L-cysteine
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`compositions—including that of the Sandoz Label—failed, and precisely the
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`problem neither Sandoz nor Eton was able to solve despite years of motivation and
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`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.21 See Section
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`VI(A)(2)(iv).
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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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`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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`20 Paper 1 at 30 (citing Ex. 1001 (’155 Patent) at 16:41-51).
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`21 See Ex. 1006 (Hernandez-Sanchez 2013) at 1 (emphasis added).
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`Eton’s asserted Grounds also lack 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.22 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.23
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`Institution should be denied for all of these reasons.
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`22 See Paper 1 at 34, 42, 50‒51; Ex. 1003 (Rabinow Decl.) ¶ 112; Ex. 1022
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`(Johnson Decl.) ¶¶ 5‒6, 13‒15.
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`23Ex. 1005 (Sandoz Label) at 5.
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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).24
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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”).25 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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`parenteral nutrition components.26 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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`24 Ex. 1007 (Poole 2011) at 2; Ex. 1006 (Hernandez-Sanchez 2013) at 2.
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`25 Ex. 2001 (Kuhn Decl.) ¶ 10.
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`26 Id. ¶¶ 11‒14.
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`ultimately administered by IV to the patient as part of a TPN regimen.27
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`Aluminum is a known contaminant in TPN formulations.28 As the Journal
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`of Parenteral and Enteral Nutrition reported in 2008, “there have been numerous
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`reports of aluminum toxicity from the contamination of [parenteral nutrition]
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`solutions over the past 3 decades.”29 Aluminum toxicity can cause “serious central
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`nervous system and bone toxicities,” as well as liver damage and anemia.30
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`27 Ex. 1003 (Rabinow Decl.) ¶¶ 107, 207 (stating that the Sandoz Label
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`composition’s expiration date was about 2 years post-manufacture); Ex. 2001
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`(Kuhn Decl.) ¶¶ 11‒14.
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`28 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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`29 Ex. 2012 (Poole 2008) at 3.
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`30 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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`Numerous components in a TPN solution can contribute to the total amount of
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`aluminum after admixing, with L-cysteine formulations historically being a
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`substantial contributor of aluminum.31 Before the ’155 patent’s inventions, the
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`amount of toxic aluminum in L-cysteine formulations was known to increase over
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`the product’s two-year shelf life, due at least in part to aluminum leaching into the
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`solution from its glass container.32
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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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`31 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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`32 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.) ¶ 96 (“[T]he
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`POSITA would have been motivated to optimize the product of the Sandoz Label
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`so that it was stable until at least the product’s expiration date (about 2 years post
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`manufacture).”).
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`aluminum toxicity.”33 These infants are particularly susceptible because they have
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`immature kidneys, which impairs elimination of aluminum from the body.34 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.35
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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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`100-point Bayley Mental Development Index (MDI).36 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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`33 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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`34 Ex. 1006 (Hernandez-Sanchez 2013) at 2; see also Ex. 2001 (Kuhn Decl.)
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`¶ 15.
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`35 Ex. 1006 (Hernandez-Sanchez 2013) at 2.
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`36 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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`educational problems) at 18 months, compared to infants treated with aluminum-
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`depleted solutions.37 Other studies have shown that the aluminum contamination
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`in TPN solutions impairs bone calcium uptake and contributes to osteopenia,38 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.39
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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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`vulnerable patients, like those with impaired kidney function.40 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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`
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`37 Id.
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`38 Ex. 2010 (Klein 1989) at 1.
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`39 Ex. 1064 (Fewtrell 2011) at 1; see also Ex. 1006 (Hernandez-Sanchez
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`2013) at 6.
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`40 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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`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.41
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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
`The inventors of the ’155 patent finally solved the aluminum problem with
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`parenteral L-cysteine compositions decades after its first recognition. Not only
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`were the inventors able to develop L-cysteine compositions with low aluminum
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`levels (no more than 120 ppb as embodied in the ELCYS® product and specifically
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`covered by the 150 ppb maximum recited in dependent claim 3 and independent
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`claim 27), but the inventors’ compositions are highly pure and remain stable over
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`time. The stable compositions “contain the specified levels of all components for
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`sufficient [sic] period of time to enable the composition to be commercially
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`manufactured, stored, shipped, and administered in a clinical setting.”42
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`In developing the stable L-cysteine compositions recited in the claims, the
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`
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`41 Ex. 2001 (Kuhn Decl.) ¶¶ 15, 35.
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`42 Ex. 1001 (’155 Patent) at 16:44‒47.
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`inventors had to overcome certain “unexpected technical hurdles,”43 all of which
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`Eton ignores. As discussed in more detail below, the kinetics and equilibrium
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`chemistry of the various L-cysteine and cystine species in any particular L-cysteine
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`solution are complex and influenced by multiple interacting variables of that
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`environment, including oxygen levels, pH, and the presence of trace metals.44
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`Moreover, multiple variables, including pH and cystine concentration, can further
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`affect the extent of aluminum leaching from the glass containers historically used
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`to store L-cysteine compositions.45
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`
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`43 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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`44 See, e.g., Ex. 1020 (Allen 2011) at 3 (stating that “[i]n neutral or slightly
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`alkaline aqueous solutions, [cysteine] is oxidized to cystine by air”); Ex. 1001
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`(’155 Patent) at 50:28‒55; Ex. 1003 (Rabinow Decl.) ¶ 46 (“[T]race amounts of
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`iron, copper, and peroxide play a key role in catalyzing the oxidation of L-
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`Cysteine.”); Ex. 1061 (Okabe 1927) at 3‒5 (demonstrating pH dependence of
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`cystine solubility).
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`45 See, e.g., Ex. 1012 (Bohrer 2003) at 7 (“[T]he action of chemicals on glass
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`and rubber depends on their nature; the three following properties of a solution can
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`The art did not predict—nor could it have predicted—how those variables
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`would interact, let alone how changing one variable would affect the other
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`variables. For example, Patent Owner “unexpected[ly]” encountered that
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`“removing Aluminum may have the unintended consequence of increased [L-
`
`cystine] precipitation and product failure in the presence of even small amounts of
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`oxygen in the container.”46 As explained during prosecution of the related ’453
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`patent, “the art did not know about the additional problems” of instability and L-
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`cystine precipitate formation upon significant reduction of the aluminum
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`concentration.47 The inventors uncovered that “the problems of safety, purity and
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`stability are results not simply or directly from the level of Aluminum, but are also
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`intertwined with dissolved oxygen levels in the composition and oxygen in the
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`headspace as well as certain heavy metals and certain ions that may leach or be
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`
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`lead to Al release: pH of the solution, similarity between Al and any cation in the
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`solution, and affinity to Al.”).
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`46 Ex. 1001 (’155 Patent) at 5:12‒15.
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`47 Ex. 1002 (’453 Patent File History) at 409.
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`extracted out of the container closure.”48
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`Nonetheless, and in spite of “the unpredictable nature of the art,” as the
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`Examiner acknowledged, the inventors addressed and overcame these multivariate
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`problems to arrive at the patented invention.49 In the Notice of Allowance for the
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`’453 patent, the Examiner explained that the inventors had “achieve[d] a
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`composition which is far below the FDA demand [for aluminum levels], filling an
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`unmet need which has been present for quite a number of years.”50 The Examiner
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`further recognized that this “unexpected result is due to the Applicants [sic]
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`unexpected findings resulting from testing combinations of theories with no
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`expectation of success.”51
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`The ’155 patent implements this “unexpected result” in parenteral
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`compositions comprising the inventors’ stable L-cysteine composition, and
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`
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`48 Ex. 1001 (’155 Patent) at 4:44‒49; Ex. 1002 (’453 Patent File History) at
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`408.
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`49 Ex. 1002 (’453 Patent File History) at 378‒79; see also Ex. 1083 (’155
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`Patent File History) at 175.
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`50 Ex. 1002 (’453 Patent File History) at 420.
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`51 Id.
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`methods of treatment using those compositions.52
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`Exela’s inventions, disclosed and claimed in the ’155 patent, are embodied
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`in ELCYS®, the first FDA-approved, low-aluminum L-cysteine hydrochloride
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`injection product, which is labeled as containing no more than 120 ppb of
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`aluminum for the duration of its two-year shelf life.53
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`III. CLAIM CONSTRUCTION
`Regarding the term “stable,” Eton admits that a “stable” composition must
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`“contain the specified levels of all components for [sic] sufficient period of time to
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`enable the composition to be commercially manufactured, stored, shipped, and
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`administered in a clinical setting.”54 The Board need not resolve the meaning of
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`this (or any other) claim term in order to deny the Petition because even under
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`Eton’s proposal, the Petition fails.
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`IV. LEVEL OF ORDINARY SKILL IN THE ART
`Eton’s proposal regarding the POSITA’s qualifications misses the mark at
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`least because it ignores the clinical nature of the ’155 patent’s claims. For
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`
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`52 Ex. 1001 (’155 Patent) at 58:34‒60:56.
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`53 Ex. 2004 (ELCYS® Label) § 11.
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`54 Paper 1 at 30.
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`example, claims 1-27 relate to methods of treating a patient by administering a
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`parenteral composition including a stable L-cysteine composition which
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`contributes no more than 250 mcg/L of aluminum to the solution.55 Claims 28-30
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`relate to the preparation of a TPN composition using Exela’s stable L-cysteine
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`composition.56 By limiting the POSITA to someone having a “Ph.D. in chemistry
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`or biochemistry with at least 2 years of work experience with pharmaceutical drug
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`product formulation analysis, development, optimization, and manufacture,”57
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`Eton’s description of the POSITA’s skill set does not extend to these claimed
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`clinical features, or otherwise suggest that the alleged POSITA would, for
`
`example, have had knowledge or experience in preparing pharmaceutical
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`admixtures in a clinical setting for administration to patients, in interpreting
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`pharmaceutical drug labels, or consulting with someone who routinely does these
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`things. Further, as demonstrated in the declaration of Dr. Robert Kuhn (Ex. 2001)
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`accompanying this preliminary response, clinical knowledge is pertinent to
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`interpreting the Sandoz Label.
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`
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`55 Ex. 1001 (’155 Patent) at 58:34‒60:31.
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`56 Id. at 60:32‒56.
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`57 Paper 1 at 29.
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`However, the Board need not resolve the level of ordinary skill in the art in
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`order to deny the Petition because, even under Eton’s definition, the Petition falls
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`short.
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`V. 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
`By statute, a Petition for Post-Grant Review must set out “in writing and
`
`with particularity, each claim challenged, the grounds on which the ch