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 PGR2020-00064
`Patent No. 10,478,453
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`PATENT OWNER’S
`PRELIMINARY RESPONSE
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`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
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`TABLE OF CONTENTS
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`I. 
`II. 
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`III. 
`IV. 
`V. 
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`VI. 
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`Introduction ................................................................................................. 1 
`Background .................................................................................................. 9 
`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 ....................................... 9 
`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 ............................................ 14 
`Claim Construction ................................................................................... 18 
`Level of Ordinary Skill in the Art ............................................................ 18 
`Institution Should Be Denied Because Eton Has Not Demonstrated
`That the Allergy Process Qualifies as Prior Art ..................................... 19 
`A. 
`Eton Does Not Demonstrate That the Allergy Process Qualifies as a
`“Public Use” ........................................................................................ 20 
`1. 
`The Johnson Declaration Does Not Support a Conclusion of
`Public Use .................................................................................... 21 
`The Johnson Declaration Lacks the Required Corroboration ..... 23 
`Eton’s Case Law Does Not Support a Finding of Public
`Accessibility ................................................................................ 25 
`Eton’s “Embodiment” Theory Lacks Merit ........................................ 27 
`B. 
`Institution Should Be Denied Because The Petition Fails to Meet the
`Particularity Requirement of 35 U.S.C. § 322(A)(3) .............................. 28 
`A.  Grounds 1-3 Lack Particularity Because Eton Is Improperly Blending
`Different Types of Prior Art Within the Definition of the “Sandoz
`Label” .................................................................................................. 29 
`Grounds 1-3 Lack Particularity Because of Eton’s “Catch-all”
`Approach ............................................................................................. 31 
`i
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`2. 
`3. 
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`B. 
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`B. 
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`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
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`2. 
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`VII. 
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`Institution Should Be Denied Because Eton Cannot Prevail as to Any
`Challenged Claim ...................................................................................... 36 
`A.  Ground 1: Eton Fails to Demonstrate That Claims 1-14 Would Have
`Been Obvious Over the Sandoz Label in View of the Knowledge of a
`POSITA ............................................................................................... 37 
`1. 
`The Sandoz Label Does Not Disclose or Suggest the Claimed
`Limitations ................................................................................... 37 
`Eton’s “Routine Optimization” Argument Is Based on Hindsight-
`Infected Assumptions and Ignores the Complex Interplay
`Between the Claimed Composition’s Features ........................... 43 
`Ground 2: Eton Fails to Demonstrate That Claims 15-20 and 22
`Would Have Been Obvious Over the Sandoz Label in View of the
`Hospira Label in View of the Knowledge of a POSITA .................... 62 
`Ground 3: Eton Fails to Demonstrate That Claim 21 Would Have
`Been Obvious Over the Sandoz Label in View of the Allergy Process
`in View of the Knowledge of a POSITA ............................................ 64 
`VIII.  Conclusion .................................................................................................. 68 
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`B. 
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`C. 
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`ii
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`EXHIBIT LIST
`Exhibit No.
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`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
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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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`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)
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`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
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`INTRODUCTION
`Exela’s U.S. Patent No. 10,478,453 (“the ’453 patent;” Ex. 1001) relates to
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`I.
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`inventions for stable, highly pure L-cysteine compositions for parenteral
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`administration to, primarily, preterm and underweight infants to nourish them
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`during their fragile first days, weeks, or sometimes months of life. While prior L-
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`cysteine formulations contained up to 5,000 ppb1 of toxic aluminum, the inventive
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`compositions contain no more than 250 ppb of aluminum, and in certain claims
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`even less.2 Unlike prior L-cysteine compositions which, as Eton acknowledges,
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`had aluminum levels that were known to increase over time,3 the aluminum and
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`other impurity levels in the claimed compositions are stable over time so as to
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`remain safe for administration to infants throughout the product’s shelf life.4
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`Exela’s invention solved what was by 2013 already a “decades old and still
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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 (’453 Patent) at 59:8‒9; id. at 59:38‒39; Ex. 1005
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`(Sandoz Label) at 10.
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`3 Paper 1 at 34, 41, 45; see also Ex. 1008 (Bohrer 2001) at 1, 4, Table 2 and
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`Fig. 2.
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`4 See, e.g., Ex. 1001 (’453 Patent) at 16:44‒47, 59:2.
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`1
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`Attorney Docket: 48751-0005PS1
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`unresolved” problem: aluminum toxicity in parenteral nutrition solutions, including
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`from the high-aluminum L-cysteine formulations available at that time.5
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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.”6 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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`parenteral nutritional drug products such as the Sandoz product that is the subject
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`of the Sandoz Label.”7
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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 2008.8
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`Despite the repeated pleas from the medical and academic communities for
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`5 See Ex. 1006 (Hernandez-Sanchez 2013) at 1; Paper 1 at 35.
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`6 Paper 1 at 41.
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`7 Id. at 37; see also id. at 41‒42.
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`8 Ex. 1022 (Johnson Decl.) ¶¶ 8‒9.
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`2
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`manufacturers to substantially reduce the aluminum contamination of parenteral
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`products,9 Sandoz still had not solved the problem more than a decade later.
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`9 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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`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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`3
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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®) that embodies the
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`’453 patent (this was just two months after FDA approval of ELCYS®).10
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`Sandoz’s motivation for seeking a license could have only been because of the
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`merits of the product; at that time Exela’s patent applications were not public
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`knowledge. After Exela declined, Sandoz filed an ANDA seeking FDA approval
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`of a generic (i.e., copy) of Exela’s ELCYS® product.11
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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),12 also failed to solve the problem and
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`ultimately resorted to copying Exela’s invention. As Eton’s Declarant explains, in
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`10 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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`11 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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`12 Ex. 1022 (Johnson Decl.) ¶¶ 5‒6.
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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.13 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.”14 Rather than
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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®.15 That ANDA filing triggered a Hatch-Waxman
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`litigation between Eton and Exela, now pending in the District of Delaware.16
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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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`13 See id. ¶¶ 19‒20.
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`14 Id. ¶ 21; see also id. at 125.
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`15 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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`16 See id.
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`manufacturing and analytical facilities to modify the Sandoz high-aluminum L-
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`cysteine product failed for years, and instead resorted to copying Exela’s inventive
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`solution. Eton’s contention that the POSITA would have had a “reasonable
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`expectation of success” in arriving at the claimed invention through “routine
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`optimization” of the product that is the subject of the Sandoz label rings hollow. 17
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`It is textbook hindsight. The Petition should be rejected 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 21 claims as being obvious, on the grounds shown in the
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`table below:18
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`17 Paper 1 at 2, 44, 48‒53.
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`18 Id. at 6.
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`Eton admits that the asserted references fail to disclose numerous claim
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`limitations. See, e.g., Section VII(A)(1)(i). Eton argues that a POSITA would
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`have used “routine optimization” to achieve them. But missing from the Petition is
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`any explanation as to why or how a POSITA purportedly motivated to perform
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`“routine optimization” would have arrived at the specifically claimed
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`compositions, which call out specific components and amounts that the literature
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`does not address. See Section VII(A)(2). Also missing from the Petition is any
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`explanation as to why a POSITA would have had a reasonable expectation of
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`success in solving the “decades old” aluminum problem through mere alleged
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`“routine” optimization.19 See Section VII(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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`The Petition is deficient for yet another reason. Each ground relies directly
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`or indirectly on the Allergy Process. However, Eton fails to establish that the
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`19 See Ex. 1006 (Hernandez-Sanchez 2013) at 1 (emphasis added).
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`Allergy Process is prior art. This failure dooms Ground 3 and undermines
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`Grounds 1 and 2.
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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 points to various references not identified in the Grounds to establish
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`claim limitations missing from the Sandoz Label. By doing so, Eton
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`impermissibly side-steps the requirements for establishing obviousness, including
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`motivation to combine the particular references to solve the problem and
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`explaining why the POSITA would have had a reasonable expectation of success
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`in doing so. Eton impermissibly attributes the content of these references to the
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`“knowledge of the POSITA” instead of fairly including these references in its
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`Grounds, and therefore its obviousness combinations. The result is an improper,
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`indefinite catch-all approach that leaves Exela and the Board to guess what
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`obviousness arguments Eton is actually making.
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`Finally, the particularity deficiencies of Eton’s petition are exacerbated by
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`Eton’s reliance on an undefined “Sandoz product,” and referring to this product
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`interchangeably with the Sandoz label and insert at Exhibit 1005. Eton never
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`establishes that any particular product, let alone a product with characteristics
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`beyond those described in the Sandoz label, qualifies as prior art.
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`Institution should be denied for all of these reasons.
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`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
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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).20
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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”).21 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.22 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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`20 Ex. 1007 (Poole 2011) at 2; Ex. 1006 (Hernandez-Sanchez 2013) at 2.
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`21 Ex. 2001 (Kuhn Decl.) ¶ 10.
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`22 Id. ¶¶ 11‒14.
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`ultimately administered by IV to the patient as part of a TPN regimen.23
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`Aluminum is a known contaminant in TPN formulations.24 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.”25 Aluminum toxicity can cause “serious central
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`nervous system and bone toxicities,” as well as liver damage and anemia.26
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`23 Ex. 1003 (Rabinow Decl.) ¶ 96 (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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`24 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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`25 Ex. 2012 (Poole 2008) at 3.
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`26 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.27 Before the ’453 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.28
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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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`27 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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`28 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.”29 These infants are particularly susceptible because they have
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`immature kidneys, which impairs elimination of aluminum from the body.30 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.31
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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).32 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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`29 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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`30 Ex. 1006 (Hernandez-Sanchez 2013) at 2; see also Ex. 2001 (Kuhn Decl.)
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`¶ 15.
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`31 Ex. 1006 (Hernandez-Sanchez 2013) at 2.
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`32 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.33 Other studies have shown that the aluminum contamination
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`in TPN solutions impairs bone calcium uptake and contributes to osteopenia,34 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.35
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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.36 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 would
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`33 Id.
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`34 Ex. 2010 (Klein 1989) at 1.
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`35 Ex. 1064 (Fewtrell 2011) at 1; see also Ex. 1006 (Hernandez-Sanchez
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`2013) at 6.
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`36 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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`enable practitioners to comply with this warning.37
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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 ’453 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 dependent claim 4’s 150 ppb maximum), but the inventors’
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`compositions are highly pure and remain stable over time. The stable
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`compositions “contain the specified levels of all components for sufficient [sic]
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`period of time to enable the composition to be commercially manufactured, stored,
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`shipped, and administered in a clinical setting.”38
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`In developing the patented inventions, the inventors had to overcome certain
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`“unexpected technical hurdles,”39 all of which Petitioner ignores. As discussed in
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`more detail below, the kinetics and equilibrium chemistry of the various L-cysteine
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`37 Ex. 2001 (Kuhn Decl.) ¶¶ 15, 35.
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`38 Ex. 1001 (’453 Patent) at 16:44‒47.
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`39 Ex. 1002 (’453 Patent File History) at 407.
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`and L-cystine species in any particular L-cysteine solution are complex and
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`influenced by multiple interacting variables of that environment, including oxygen
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`levels, pH, and the presence of trace metals.40 Moreover, multiple variables,
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`including pH and L-cystine concentration, can further affect the extent of
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`aluminum leaching from the glass containers historically used to store L-cysteine
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`compositions.41
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`The art did not predict—nor could it have predicted—how those variables
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`would interact under the specific conditions of the claimed L-cysteine parenteral
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`40 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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`(’453 Patent) at 50:37‒66; Ex. 1003 (Rabinow Decl.) ¶ 44 (“[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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`41 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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`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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`solution, let alone how changing one variable would affect the other variables. For
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`example, Patent Owner “unexpected[ly]” encountered that “removing Aluminum
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`may have the unintended consequence of increased [L-cystine] precipitation and
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`product failure in the presence of even small amounts of oxygen in the
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`container.”42 As explained during prosecution, “the art did not know about the
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`additional problems” of instability and L-cystine precipitate formation upon
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`significant reduction of the aluminum concentration.43 The inventors uncovered
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`that “the problems of safety, purity and stability are results not simply or directly
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`from the level of Aluminum, but are also intertwined with dissolved oxygen levels
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`in the composition and oxygen in the headspace as well as certain heavy metals
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`and certain ions that may leach or be extracted out of the container closure.”44
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`42 Ex. 1001 (’453 Patent) at 5:4‒9.
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`43 Ex. 1002 (’453 Patent File History) at 409.
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`44 Ex. 1001 (’453 Patent) at 4:38‒43; see also Ex. 1002 (’453 Patent File
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`History) at 408.
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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.45 In the Notice of Allowance, the
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`Examiner explained that the inventors had “achieve[d] a composition which is far
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`below the FDA demand [for aluminum levels], filling an unmet need which has
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`been present for quite a number of years.”46 The Examiner further recognized that
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`this “unexpected result is due to the Applicants [sic] unexpected findings resulting
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`from testing combinations of theories with no expectation of success.”47
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`Exela’s invention, disclosed and claimed in the ’453 patent, is embodied in
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`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.48
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`45 Ex. 1002 (’453 Patent File History) at 378‒79.
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`46 Id. at 420.
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`47 Id.
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`48 Ex. 2004 (ELCYS® Label) § 11.
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`III. CLAIM CONSTRUCTION
`The Board need not resolve the meaning of claim terms in order to deny the
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`Petition. Regarding the term “stable,” Exela notes that Eton admits the claimed
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`compositions must be stable over a certain minimum time period.49
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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 features of, for example, claim 22, which
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`relates to the preparation of a composition for a total parenteral nutrition regimen
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`that cannot exceed 5 micrograms of aluminum per kilogram (weight of the patient)
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`per day. By limiting the POSITA to someone having a “Ph.D. in chemistry or
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`biochemistry with at least 2 years of work experience with pharmaceutical drug
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`product formulation analysis, development, optimization, and manufacture,”50
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`Eton’s description of the POSITA’s skill set does not extend to this claimed
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`clinical feature, or otherwise suggest that the alleged POSITA would, for example,
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`have had knowledge or experience in interpreting pharmaceutical drug labels or
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`consulting with someone who did. But as demonstrated in the declaration of Dr.
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`49 Paper 1 at 25‒26.
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`50 Id. at 24.
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`Robert Kuhn (Ex. 2001) accompanying this preliminary response, clinical
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`knowledge is pertinent to interpreting the Sandoz Label.
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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.
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`INSTITUTION SHOULD BE DENIED BECAUSE ETON HAS NOT
`DEMONSTRATED THAT THE ALLERGY PROCESS QUALIFIES
`AS PRIOR ART
`Post-Grant Review can only be instituted if Eton “demonstrate[s] that it is
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`more likely than not that at least 1 of the claims challenged in the petition is
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`unpatentable.” 35 U.S.C. § 324. This includes demonstrating that it is more likely
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`than not that the prior art being relied upon actually qualifies as prior art. See, e.g.,
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`AVX Corp. v. Samsung Electro-Mechanics Co., Ltd., PGR2017-00010, Paper 11,
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`27, 30 (P.T.A.B. July 18, 2017).
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`Here, Eton’s Ground 3 explicitly relies upon the Allergy Process, and Eton’s
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`obviousness rationale supporting Grounds 1 and 2 refers to the Allergy Process for
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`support.51 Eton argues the Allergy Process is prior art because it qualifies as a
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`“public use,” and also because it was allegedly used to make, and is thus
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`“embodied in,” the Sandoz product, but neither argument holds water.52
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`A. Eton Does Not Demonstrate That the Allergy Process Qualifies as a
`“Public Use”
`Eton has failed to show that the Allergy Process was in “public use” so as to
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`qualify as prior art. The Allergy Process was purportedly performed by a third
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`party (Allergy Labs), making it a third-party process.53 Notably, “secret or
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`confidential third-party uses do not invalidate later-filed patents.” Dey, L.P. v.
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`Sunovion Pharm., Inc., 715 F.3d 1351, 1355 (Fed. Cir. 2013); BASF Corp. v. SNF
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`Holding Co., 955 F.3d 958, 967 (Fed. Cir. 2020) (“In Gore, this court held that a
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`third party’s sale of products made by a secret process, more than one year before
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`the critical date, does not create a bar to another inventor patenting the process.”)
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`51 Paper 1 at 6 (Ground 3), 41 (Grounds 1-2) (referring to Aluminum levels
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`allegedly associated with the Allergy Process), 45 (Ground 1) (referring to
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`Aluminum levels allegedly associated with the Allergy Process).
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`52 Id. at 9.
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`53 Ex. 1022 (Johnson Decl.) ¶¶ 16‒18.
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`(citing W.L. Gore & Assocs. v. Garlock, Inc., 721 F.2d 1540, 1550 (Fed. Cir.
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`1983)).54 This is because “patent law favors the later inventor who shares his
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`knowledge with the public over the prior inventor who conceals his invention.”
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`BASF Corp., 955 F.3d at 968 (citing Gore, 721 F.2d at 1550).
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`Thus, for a third-party process—like the Allergy Process—to constitute prior
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`art, that process must be “accessible to the public.” Dey, 715 F.3d at 1355. Eton
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`has not made that showing here.
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`1. The Johnson Declaration Does Not Support a Conclusion of
`Public Use
`The only evidence Eton