`
`
`
`
`
`
`
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`ETON PHARMACEUTICALS, INC.,
`Petitioner
`
`v.
`
`EXELA PHARMA SCIENCES, LLC,
`Patent Owner
`
`
`
`
`
`
`
`
`
`
`
`
`Case PGR2020-00064
`Patent No. 10,478,453
`
`
`
`
`
`
`
`
`PATENT OWNER’S
`PRELIMINARY RESPONSE
`
`
`
`
`
`
`
`
`
`
`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
`
`
`TABLE OF CONTENTS
`
`I.
`II.
`
`III.
`IV.
`V.
`
`VI.
`
`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
`
`2.
`3.
`
`B.
`
`B.
`
`
`
`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
`
`
`2.
`
`VII.
`
`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
`
`B.
`
`C.
`
`ii
`
`
`
`EXHIBIT LIST
`Exhibit No.
`
`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
`
`
`Description
`
`2001
`2002
`
`2003
`
`2004
`2005
`
`2006
`
`2007
`
`2008
`
`2009
`
`2010
`
`2011
`
`2012
`
`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)
`
`i
`
`
`
`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
`
`
`INTRODUCTION
`Exela’s U.S. Patent No. 10,478,453 (“the ’453 patent;” Ex. 1001) relates to
`
`I.
`
`inventions for stable, highly pure L-cysteine compositions for parenteral
`
`administration to, primarily, preterm and underweight infants to nourish them
`
`during their fragile first days, weeks, or sometimes months of life. While prior L-
`
`cysteine formulations contained up to 5,000 ppb1 of toxic aluminum, the inventive
`
`compositions contain no more than 250 ppb of aluminum, and in certain claims
`
`even less.2 Unlike prior L-cysteine compositions which, as Eton acknowledges,
`
`had aluminum levels that were known to increase over time,3 the aluminum and
`
`other impurity levels in the claimed compositions are stable over time so as to
`
`remain safe for administration to infants throughout the product’s shelf life.4
`
`Exela’s invention solved what was by 2013 already a “decades old and still
`
`
`
`1 “ppb” is also referred to as “mcg/L” or “µg/L” (“micrograms per Liter”).
`
`2 See, e.g., Ex. 1001 (’453 Patent) at 59:8‒9; id. at 59:38‒39; Ex. 1005
`
`(Sandoz Label) at 10.
`
`3 Paper 1 at 34, 41, 45; see also Ex. 1008 (Bohrer 2001) at 1, 4, Table 2 and
`
`Fig. 2.
`
`4 See, e.g., Ex. 1001 (’453 Patent) at 16:44‒47, 59:2.
`
`1
`
`
`
`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
`
`unresolved” problem: aluminum toxicity in parenteral nutrition solutions, including
`
`from the high-aluminum L-cysteine formulations available at that time.5
`
`It is beyond dispute that strong motivation existed to solve this long-
`
`standing problem. As Eton acknowledges, “[t]here were regulatory and market
`
`forces pushing for the substantial reduction and elimination of aluminum from
`
`parenteral drug products.”6 Even more specifically, in Eton’s words, “the POSITA
`
`would have been motivated to substantially reduce and eliminate aluminum from
`
`parenteral nutritional drug products such as the Sandoz product that is the subject
`
`of the Sandoz Label.”7
`
`And yet, the problem went unsolved for years, including by Sandoz itself.
`
`Sandoz’s alleged work on L-cysteine injection products dates to 2008.8
`
`Despite the repeated pleas from the medical and academic communities for
`
`
`
`5 See Ex. 1006 (Hernandez-Sanchez 2013) at 1; Paper 1 at 35.
`
`6 Paper 1 at 41.
`
`7 Id. at 37; see also id. at 41‒42.
`
`8 Ex. 1022 (Johnson Decl.) ¶¶ 8‒9.
`
`2
`
`
`
`manufacturers to substantially reduce the aluminum contamination of parenteral
`
`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
`
`
`products,9 Sandoz still had not solved the problem more than a decade later.
`
`
`
`9 Ex. 2012 (Poole 2008) at 1 (“Manufacturers must identify, develop, and
`
`adopt new methods to reduce the aluminum contamination in their products.”): Ex.
`
`2011 (Mirtallo 2010) at 2 (“We as clinicians should insist that small-volume
`
`parenterals be packaged in polyethylene containers.”); Ex. 1006 (Hernandez-
`
`Sanchez 2013) at 1 (“Unfortunately, manufacturers have not universally changed
`
`their processes to obtain a lower Al content of parenteral drug products (PDP).”);
`
`Ex. 2009 (Gura 2014) at 1 (“Unlike the rapid response to eliminating aluminum
`
`toxicity in the dialysis patient population, similar successes have not been realized
`
`in patients receiving parenteral nutrition solutions. Product formulation changes
`
`have been slow to emerge from manufacturers.”); Ex. 1038 (Lima-Rogel 2016) at
`
`1 (“Excessive aluminum intakes from intravenous solutions, drugs, and parenteral
`
`nutrition still represent an unsolved problem. … Low-birth weight preterm infants,
`
`long-term home parenteral nutrition adult patients, and patients with chronic
`
`kidney disease are particularly exposed and considered high-risk populations. …
`
`Efforts should be implemented to identify and subsequently reduce the amount of
`
`aluminum in parenteral solutions.”).
`
`3
`
`
`
`Instead, in May 2019 Sandoz approached Exela for a license to sell Exela’s
`
`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
`
`
`low-aluminum, FDA-approved L-cysteine product (ELCYS®) that embodies the
`
`’453 patent (this was just two months after FDA approval of ELCYS®).10
`
`Sandoz’s motivation for seeking a license could have only been because of the
`
`merits of the product; at that time Exela’s patent applications were not public
`
`knowledge. After Exela declined, Sandoz filed an ANDA seeking FDA approval
`
`of a generic (i.e., copy) of Exela’s ELCYS® product.11
`
`Sandoz is not alone in seeking to free-ride off of Exela’s inventive solution
`
`to the long-standing aluminum problem for L-cysteine. Eton, in collaboration with
`
`AL Pharma (formerly known as Allergy Labs, which had previously manufactured
`
`an L-cysteine injection for Sandoz),12 also failed to solve the problem and
`
`ultimately resorted to copying Exela’s invention. As Eton’s Declarant explains, in
`
`
`
`10 Ex. 2007 (Declaration of Mark Hartman, Exela Pharma Sciences, LLC v.
`
`Sandoz Inc., No. 19-cv-00318-MR (W.D.N.C. Dec. 6, 2019), ECF No. 26-1) ¶¶ 6,
`
`11.
`
`11 Ex. 2005 (Amended Complaint, Exela Pharma Sciences, LLC v. Sandoz,
`
`Inc., No. 1:20-cv-00645-MN (D. Del. June 1, 2020), ECF No. 12) ¶ 12.
`
`12 Ex. 1022 (Johnson Decl.) ¶¶ 5‒6.
`
`4
`
`
`
`January 2018 AL Pharma submitted a New Drug Application (NDA) to FDA
`
`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
`
`
`seeking approval of an L-cysteine injection product with “an Aluminum Content of
`
`not more than (NMT) 5,000 ppb,” meaning Eton did not successfully employ the
`
`“routine optimization” strategy it touts here.13 FDA identified numerous
`
`deficiencies in the application, including that the drug product had “not been
`
`shown to meet the required acceptance limit for aluminum content.”14 Rather than
`
`fix these issues, Eton abandoned its NDA and chose to copy Exela’s ELCYS®
`
`product instead, filing an ANDA in December 2019 seeking FDA approval for a
`
`generic copy of ELCYS®.15 That ANDA filing triggered a Hatch-Waxman
`
`litigation between Eton and Exela, now pending in the District of Delaware.16
`
`In short, even those who were motivated to solve the aluminum problem for
`
`L-cysteine, experienced with L-cysteine products, and uniquely positioned with
`
`
`
`13 See id. ¶¶ 19‒20.
`
`14 Id. ¶ 21; see also id. at 125.
`
`15 Ex. 2006 (Amended Complaint, Exela Pharma Sciences, LLC v. Eton
`
`Pharmaceuticals, Inc., No. 20-365-MN (D. Del. July 28, 2020), ECF No. 14) ¶¶
`
`51‒56.
`
`16 See id.
`
`5
`
`
`
`manufacturing and analytical facilities to modify the Sandoz high-aluminum L-
`
`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
`
`
`cysteine product failed for years, and instead resorted to copying Exela’s inventive
`
`solution. Eton’s contention that the POSITA would have had a “reasonable
`
`expectation of success” in arriving at the claimed invention through “routine
`
`optimization” of the product that is the subject of the Sandoz label rings hollow. 17
`
`It is textbook hindsight. The Petition should be rejected for this reason alone.
`
`But there are numerous additional reasons to deny institution, as discussed
`
`below.
`
`Eton challenges all 21 claims as being obvious, on the grounds shown in the
`
`table below:18
`
`
`
`
`
`17 Paper 1 at 2, 44, 48‒53.
`
`18 Id. at 6.
`
`6
`
`
`
`Eton admits that the asserted references fail to disclose numerous claim
`
`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
`
`
`limitations. See, e.g., Section VII(A)(1)(i). Eton argues that a POSITA would
`
`have used “routine optimization” to achieve them. But missing from the Petition is
`
`any explanation as to why or how a POSITA purportedly motivated to perform
`
`“routine optimization” would have arrived at the specifically claimed
`
`compositions, which call out specific components and amounts that the literature
`
`does not address. See Section VII(A)(2). Also missing from the Petition is any
`
`explanation as to why a POSITA would have had a reasonable expectation of
`
`success in solving the “decades old” aluminum problem through mere alleged
`
`“routine” optimization.19 See Section VII(A)(2)(iv).
`
`The only filler offered for these gaps is hindsight, which of course is
`
`impermissible. Indeed, instead of being based on reasoned analysis and
`
`evidentiary support, Eton’s “routine optimization” argument impermissibly “use[s]
`
`the challenged patent as a roadmap to reconstruct the claimed invention.” See TQ
`
`Delta, LLC v. CISCO Sys., Inc., 942 F.3d 1352, 1361 (Fed. Cir. 2019).
`
`The Petition is deficient for yet another reason. Each ground relies directly
`
`or indirectly on the Allergy Process. However, Eton fails to establish that the
`
`
`
`19 See Ex. 1006 (Hernandez-Sanchez 2013) at 1 (emphasis added).
`
`7
`
`
`
`Allergy Process is prior art. This failure dooms Ground 3 and undermines
`
`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
`
`
`Grounds 1 and 2.
`
`Eton’s asserted Grounds also lack the particularity required by 35 U.S.C. §
`
`322(a). Eton points to various references not identified in the Grounds to establish
`
`claim limitations missing from the Sandoz Label. By doing so, Eton
`
`impermissibly side-steps the requirements for establishing obviousness, including
`
`motivation to combine the particular references to solve the problem and
`
`explaining why the POSITA would have had a reasonable expectation of success
`
`in doing so. Eton impermissibly attributes the content of these references to the
`
`“knowledge of the POSITA” instead of fairly including these references in its
`
`Grounds, and therefore its obviousness combinations. The result is an improper,
`
`indefinite catch-all approach that leaves Exela and the Board to guess what
`
`obviousness arguments Eton is actually making.
`
`Finally, the particularity deficiencies of Eton’s petition are exacerbated by
`
`Eton’s reliance on an undefined “Sandoz product,” and referring to this product
`
`interchangeably with the Sandoz label and insert at Exhibit 1005. Eton never
`
`establishes that any particular product, let alone a product with characteristics
`
`beyond those described in the Sandoz label, qualifies as prior art.
`
`Institution should be denied for all of these reasons.
`
`8
`
`
`
`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
`
`
`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
`
`and is important for human life. While healthy adults can naturally synthesize
`
`small amounts of L-cysteine, certain high-risk populations require supplementation
`
`by parenteral administration (e.g., intravenous infusion or injection). These high-
`
`risk populations include preterm and/or low birth weight infants and other
`
`individuals with renal compromise (i.e., impaired kidney function).20
`
`For these patients, L-cysteine is administered as a component of a nutritional
`
`regimen, typically referred to as Total Parenteral Nutrition (“TPN”) or Parenteral
`
`Nutrition (“PN”).21 A TPN regimen involves administering—typically
`
`intravenously—a formulation that is a mixture (called an “admixture”) of various
`
`parenteral nutrition components.22 Thus, L-cysteine is first manufactured as a
`
`stand-alone component, then admixed with various other components, and
`
`
`
`20 Ex. 1007 (Poole 2011) at 2; Ex. 1006 (Hernandez-Sanchez 2013) at 2.
`
`21 Ex. 2001 (Kuhn Decl.) ¶ 10.
`
`22 Id. ¶¶ 11‒14.
`
`9
`
`
`
`ultimately administered by IV to the patient as part of a TPN regimen.23
`
`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
`
`
`Aluminum is a known contaminant in TPN formulations.24 As the Journal
`
`of Parenteral and Enteral Nutrition reported in 2008, “there have been numerous
`
`reports of aluminum toxicity from the contamination of [parenteral nutrition]
`
`solutions over the past 3 decades.”25 Aluminum toxicity can cause “serious central
`
`nervous system and bone toxicities,” as well as liver damage and anemia.26
`
`
`
`23 Ex. 1003 (Rabinow Decl.) ¶ 96 (stating that the Sandoz Label
`
`composition’s expiration date was “about 2 years post-manufacture”); Ex. 2001
`
`(Kuhn Decl.) ¶¶ 11‒14.
`
`24 Ex. 2002 (Sedman 1985) at 1; Ex. 2012 (Poole 2008) at 1 (“Aluminum is
`
`a contaminant of parenteral nutrition (PN) solution components.”); Ex. 2001 (Kuhn
`
`Decl.) ¶ 15; Ex. 1038 (Lima-Rogel 2016) at 4 (“Aluminum contamination in PN
`
`admixtures remains an unsolved problem.”).
`
`25 Ex. 2012 (Poole 2008) at 3.
`
`26 Id.; see also Ex. 1007 (Poole 2011) at 1 (explaining that aluminum
`
`toxicity can cause “fracturing osteomalacia and reduced bone mineralization,
`
`neurological dysfunction and dialysis encephalopathy, microcytic hypochromic
`
`anemia, and cholestasis”).
`
`10
`
`
`
`Numerous components in a TPN solution can contribute to the total amount of
`
`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
`
`
`aluminum after admixing, with L-cysteine formulations historically being a
`
`substantial contributor of aluminum.27 Before the ’453 patent’s inventions, the
`
`amount of toxic aluminum in L-cysteine formulations was known to increase over
`
`the product’s two-year shelf life, due at least in part to aluminum leaching into the
`
`solution from its glass container.28
`
`The vulnerable infants who receive TPN (most generally while in the
`
`Neonatal Intensive Care Unit (NICU)) are “predispose[d]” to a “high risk for
`
`
`
`27 Ex. 1006 (Hernandez-Sanchez 2013) at 2; Ex. 2012 (Poole 2008) at Table
`
`5; Ex. 2001 (Kuhn Decl.) ¶ 15.
`
`28 Ex. 1008 (Bohrer 2001) at 1 (“[Aluminum] contamination is an ongoing
`
`process due to the presence of aluminum in glass combined with the affinity of
`
`some amino acids for this element.”); id. at 4, Table 2 and Fig. 2 (showing
`
`significant increase in aluminum content of cysteine from days 0 to 400 “from
`
`aluminum leached from glass containers”); Ex. 1003 (Rabinow Decl.) ¶ 96 (“[T]he
`
`POSITA would have been motivated to optimize the product of the Sandoz Label
`
`so that it was stable until at least the product’s expiration date (about 2 years post
`
`manufacture).”).
`
`11
`
`
`
`aluminum toxicity.”29 These infants are particularly susceptible because they have
`
`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
`
`
`immature kidneys, which impairs elimination of aluminum from the body.30 As
`
`aluminum is prone to accumulate in bones, the central nervous system, and other
`
`tissues in the body, their risk is exacerbated by the prolonged TPN treatment they
`
`often require.31
`
`The consequences are sobering. A 1997 study found that preterm infants
`
`receiving the standard, high-aluminum TPN solutions lost one point per day on the
`
`100-point Bayley Mental Development Index (MDI).32 Infants receiving the
`
`standard TPN solutions were also twice as likely to have MDI scores below 85 (the
`
`MDI level that is predictive of delayed neurodevelopment and subsequent
`
`
`
`29 Ex. 2008 (Fortenberry 2017) at 1; see also Ex. 2001 (Kuhn Decl.) ¶ 15;
`
`Ex. 1038 (Lima-Rogel 2016) at 1 (“Low birth-weight preterm infants (LBWPIs)
`
`are one of the most exposed populations for aluminum toxicity.”).
`
`30 Ex. 1006 (Hernandez-Sanchez 2013) at 2; see also Ex. 2001 (Kuhn Decl.)
`
`¶ 15.
`
`31 Ex. 1006 (Hernandez-Sanchez 2013) at 2.
`
`32 Ex. 2003 (Bishop 1997) at 1; see also Ex. 2012 (Poole 2008) at 2
`
`(summarizing Bishop study findings).
`
`12
`
`
`
`educational problems) at 18 months, compared to infants treated with aluminum-
`
`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
`
`
`depleted solutions.33 Other studies have shown that the aluminum contamination
`
`in TPN solutions impairs bone calcium uptake and contributes to osteopenia,34 and
`
`can lead to significantly reduced hip bone mass, lumbar spine bone mineral
`
`content, and total bone area by age 13-15 years.35
`
`Due to the serious health risks associated with aluminum toxicity, the FDA
`
`since 2004 has required the labels for parenteral nutrition components to contain a
`
`“WARNING” that aluminum levels should not exceed 4 to 5 mcg/kg/day in
`
`vulnerable patients, like those with impaired kidney function.36 But it would take
`
`nearly fifteen years before someone (Patent Owner, Exela) finally developed an
`
`injectable L-cysteine composition with acceptably safe aluminum levels that would
`
`
`
`33 Id.
`
`34 Ex. 2010 (Klein 1989) at 1.
`
`35 Ex. 1064 (Fewtrell 2011) at 1; see also Ex. 1006 (Hernandez-Sanchez
`
`2013) at 6.
`
`36 21 C.F.R. § 201.323; Fed. Reg. 4103, 4111 (Jan. 26, 2000); 68 Fed. Reg.
`
`32,979 (June 3, 2003); Ex. 1006 (Hernandez-Sanchez 2013) at 7; Ex. 1007 (Poole
`
`2011) at 1‒2.
`
`13
`
`
`
`enable practitioners to comply with this warning.37
`
`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
`
`
`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
`
`parenteral L-cysteine compositions decades after its first recognition. Not only
`
`were the inventors able to develop L-cysteine compositions with low aluminum
`
`levels (no more than 120 ppb as embodied in the ELCYS® product and specifically
`
`covered by dependent claim 4’s 150 ppb maximum), but the inventors’
`
`compositions are highly pure and remain stable over time. The stable
`
`compositions “contain the specified levels of all components for sufficient [sic]
`
`period of time to enable the composition to be commercially manufactured, stored,
`
`shipped, and administered in a clinical setting.”38
`
`In developing the patented inventions, the inventors had to overcome certain
`
`“unexpected technical hurdles,”39 all of which Petitioner ignores. As discussed in
`
`more detail below, the kinetics and equilibrium chemistry of the various L-cysteine
`
`
`
`37 Ex. 2001 (Kuhn Decl.) ¶¶ 15, 35.
`
`38 Ex. 1001 (’453 Patent) at 16:44‒47.
`
`39 Ex. 1002 (’453 Patent File History) at 407.
`
`14
`
`
`
`and L-cystine species in any particular L-cysteine solution are complex and
`
`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
`
`
`influenced by multiple interacting variables of that environment, including oxygen
`
`levels, pH, and the presence of trace metals.40 Moreover, multiple variables,
`
`including pH and L-cystine concentration, can further affect the extent of
`
`aluminum leaching from the glass containers historically used to store L-cysteine
`
`compositions.41
`
`The art did not predict—nor could it have predicted—how those variables
`
`would interact under the specific conditions of the claimed L-cysteine parenteral
`
`
`
`40 See, e.g., Ex. 1020 (Allen 2011) at 3 (stating that “[i]n neutral or slightly
`
`alkaline aqueous solutions, [cysteine] is oxidized to cystine by air”); Ex. 1001
`
`(’453 Patent) at 50:37‒66; Ex. 1003 (Rabinow Decl.) ¶ 44 (“[T]race amounts of
`
`iron, copper, and peroxide play a key role in catalyzing the oxidation of L-
`
`Cysteine.”); Ex. 1061 (Okabe 1927) at 3‒5 (demonstrating pH dependence of
`
`cystine solubility).
`
`41 See, e.g., Ex. 1012 (Bohrer 2003) at 7 (“[T]he action of chemicals on glass
`
`and rubber depends on their nature; the three following properties of a solution can
`
`lead to Al release: pH of the solution, similarity between Al and any cation in the
`
`solution, and affinity to Al.”).
`
`15
`
`
`
`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
`
`solution, let alone how changing one variable would affect the other variables. For
`
`example, Patent Owner “unexpected[ly]” encountered that “removing Aluminum
`
`may have the unintended consequence of increased [L-cystine] precipitation and
`
`product failure in the presence of even small amounts of oxygen in the
`
`container.”42 As explained during prosecution, “the art did not know about the
`
`additional problems” of instability and L-cystine precipitate formation upon
`
`significant reduction of the aluminum concentration.43 The inventors uncovered
`
`that “the problems of safety, purity and stability are results not simply or directly
`
`from the level of Aluminum, but are also intertwined with dissolved oxygen levels
`
`in the composition and oxygen in the headspace as well as certain heavy metals
`
`and certain ions that may leach or be extracted out of the container closure.”44
`
`
`
`42 Ex. 1001 (’453 Patent) at 5:4‒9.
`
`43 Ex. 1002 (’453 Patent File History) at 409.
`
`44 Ex. 1001 (’453 Patent) at 4:38‒43; see also Ex. 1002 (’453 Patent File
`
`History) at 408.
`
`16
`
`
`
`Nonetheless, and in spite of “the unpredictable nature of the art,” as the
`
`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
`
`
`Examiner acknowledged, the inventors addressed and overcame these multivariate
`
`problems to arrive at the patented invention.45 In the Notice of Allowance, the
`
`Examiner explained that the inventors had “achieve[d] a composition which is far
`
`below the FDA demand [for aluminum levels], filling an unmet need which has
`
`been present for quite a number of years.”46 The Examiner further recognized that
`
`this “unexpected result is due to the Applicants [sic] unexpected findings resulting
`
`from testing combinations of theories with no expectation of success.”47
`
`Exela’s invention, disclosed and claimed in the ’453 patent, is embodied in
`
`ELCYS®, the first FDA-approved, low-aluminum L-cysteine hydrochloride
`
`injection product, which is labeled as containing no more than 120 ppb of
`
`aluminum for the duration of its two-year shelf life.48
`
`
`
`45 Ex. 1002 (’453 Patent File History) at 378‒79.
`
`46 Id. at 420.
`
`47 Id.
`
`48 Ex. 2004 (ELCYS® Label) § 11.
`
`17
`
`
`
`III. CLAIM CONSTRUCTION
`The Board need not resolve the meaning of claim terms in order to deny the
`
`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
`
`
`Petition. Regarding the term “stable,” Exela notes that Eton admits the claimed
`
`compositions must be stable over a certain minimum time period.49
`
`IV. LEVEL OF ORDINARY SKILL IN THE ART
`Eton’s proposal regarding the POSITA’s qualifications misses the mark at
`
`least because it ignores the clinical features of, for example, claim 22, which
`
`relates to the preparation of a composition for a total parenteral nutrition regimen
`
`that cannot exceed 5 micrograms of aluminum per kilogram (weight of the patient)
`
`per day. By limiting the POSITA to someone having a “Ph.D. in chemistry or
`
`biochemistry with at least 2 years of work experience with pharmaceutical drug
`
`product formulation analysis, development, optimization, and manufacture,”50
`
`Eton’s description of the POSITA’s skill set does not extend to this claimed
`
`clinical feature, or otherwise suggest that the alleged POSITA would, for example,
`
`have had knowledge or experience in interpreting pharmaceutical drug labels or
`
`consulting with someone who did. But as demonstrated in the declaration of Dr.
`
`
`
`49 Paper 1 at 25‒26.
`
`50 Id. at 24.
`
`18
`
`
`
`Robert Kuhn (Ex. 2001) accompanying this preliminary response, clinical
`
`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
`
`
`knowledge is pertinent to interpreting the Sandoz Label.
`
`However, the Board need not resolve the level of ordinary skill in the art in
`
`order to deny the Petition because, even under Eton’s definition, the Petition falls
`
`short.
`
`V.
`
`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
`
`more likely than not that at least 1 of the claims challenged in the petition is
`
`unpatentable.” 35 U.S.C. § 324. This includes demonstrating that it is more likely
`
`than not that the prior art being relied upon actually qualifies as prior art. See, e.g.,
`
`AVX Corp. v. Samsung Electro-Mechanics Co., Ltd., PGR2017-00010, Paper 11,
`
`27, 30 (P.T.A.B. July 18, 2017).
`
`Here, Eton’s Ground 3 explicitly relies upon the Allergy Process, and Eton’s
`
`obviousness rationale supporting Grounds 1 and 2 refers to the Allergy Process for
`
`19
`
`
`
`support.51 Eton argues the Allergy Process is prior art because it qualifies as a
`
`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
`
`
`“public use,” and also because it was allegedly used to make, and is thus
`
`“embodied in,” the Sandoz product, but neither argument holds water.52
`
`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
`
`qualify as prior art. The Allergy Process was purportedly performed by a third
`
`party (Allergy Labs), making it a third-party process.53 Notably, “secret or
`
`confidential third-party uses do not invalidate later-filed patents.” Dey, L.P. v.
`
`Sunovion Pharm., Inc., 715 F.3d 1351, 1355 (Fed. Cir. 2013); BASF Corp. v. SNF
`
`Holding Co., 955 F.3d 958, 967 (Fed. Cir. 2020) (“In Gore, this court held that a
`
`third party’s sale of products made by a secret process, more than one year before
`
`the critical date, does not create a bar to another inventor patenting the process.”)
`
`
`
`51 Paper 1 at 6 (Ground 3), 41 (Grounds 1-2) (referring to Aluminum levels
`
`allegedly associated with the Allergy Process), 45 (Ground 1) (referring to
`
`Aluminum levels allegedly associated with the Allergy Process).
`
`52 Id. at 9.
`
`53 Ex. 1022 (Johnson Decl.) ¶¶ 16‒18.
`
`20
`
`
`
`(citing W.L. Gore & Assocs. v. Garlock, Inc., 721 F.2d 1540, 1550 (Fed. Cir.
`
`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
`
`
`1983)).54 This is because “patent law favors the later inventor who shares his
`
`knowledge with the public over the prior inventor who conceals his invention.”
`
`BASF Corp., 955 F.3d at 968 (citing Gore, 721 F.2d at 1550).
`
`Thus, for a third-party process—like the Allergy Process—to constitute prior
`
`art, that process must be “accessible to the public.” Dey, 715 F.3d at 1355. Eton
`
`has not made that showing here.
`
`1. The Johnson Declaration Does Not Support a Conclusion of
`Public Use
`The only evidence Eton