Trials@uspto.gov
`571-272-7822
`
`Paper 11
`Entered: December 15, 2020
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`ETON PHARMACEUTICALS, INC.,
`Petitioner,
`
`v.
`
`EXELA PHARMA SCIENCES, LLC,
`Patent Owner.
`
`PGR2020-00068
`Patent 10,583,155 B1
`
`
`
`
`
`
`
`
`
`Before ULRIKE W. JENKS, SUSAN L. C. MITCHELL, and
`CHRISTOPHER G. PAULRAJ, Administrative Patent Judges.
`
`PAULRAJ, Administrative Patent Judge.
`
`DECISION
`Denying Institution of Post-Grant Review
`35 U.S.C. § 324
`
`
`
`
`
`
`
`

`

`PGR2020-00068
`Patent 10,583,155 B1
`
`I.
`
`INTRODUCTION
`
`Eton Pharmaceuticals, Inc. (collectively, “Petitioner”) filed a Petition
`
`requesting post-grant review of claims 1–30 (the “challenged claims”) of
`
`U.S. Patent No. 10,583,155 (Ex. 1001, “the ’155 patent”). Paper 1 (“Pet.”).
`
`Exela Pharma Sciences, LLC (“Patent Owner”) filed a Preliminary Response
`
`to the Petition. Paper 6 (“Prelim. Resp.”). We have jurisdiction under
`
`35 U.S.C. § 324.
`
`To institute a post-grant review, we must determine whether the
`
`information presented in the petition “would demonstrate 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(a). After considering the Petition and the
`
`Preliminary Response, we determine, for the reasons set forth below, that
`
`Petitioner has failed to demonstrate that it is “more likely than not” that any
`
`of the challenged claims are unpatentable based on the grounds presented.
`
`Therefore, we do not institute a post-grant review of those claims.
`
`A. Real Parties in Interest
`
`Petitioner identifies itself as the real party in interest. Pet. 3–4. Patent
`
`Owner identifies itself as the real party in interest. Paper 4, 2.
`
`B. Related Matters
`
`The ’155 patent is the subject of the following litigation matters:
`
`Exela Pharma Sciences, LLC v. Eton Pharms., Inc., Case No. 1:20-cv-
`
`00365-MN (D. Del., filed March 16, 2020); Exela Pharma Sciences LLC v.
`
`Sandoz Inc., Case No. 1:20-cv-00645-MN (D. Del., filed May 14, 2020);
`
`and Exela Pharma Sciences LLC v. Sandoz Inc., Case No. 1:20-cv-01393
`
`(D. Colo., filed May 15, 2020). Pet. 3–4; Paper 4, 2.
`
`2
`
`

`

`PGR2020-00068
`Patent 10,583,155 B1
`
`Petitioner filed a petition for post-grant review against a related
`
`patent, U.S. Patent No. 10,478,453 B1 (“the ’453 patent”), for which we
`
`previously denied institution. Pet. 4; PGR2020-00064, Paper 12.
`
`Petitioner lists the following related patents and published
`
`applications: Appl. No. 16/248,460 (“the ’460 application,” which issued as
`
`the ’453 patent); Appl. No. 16/746,028; U.S. Appl. No. 16/773,563 (issued
`
`as U.S. Patent No. 10,653,719 B1); U.S. Appl. No. 16/850,726; U.S. Appl.
`
`No. 16/850,962; and U.S. Application No. 16/850,973. Pet. 4–5.
`
`C. The ’155 Patent
`
`The ’155 patent, titled “Stable, Highly Pure L-Cysteine Compositions
`
`for Injection and Methods of Use,” discloses stable L-cysteine compositions
`
`for injection. Ex. 1001, (54), (57). The ’155 patent issued from Application
`
`No. 16/665,702, which is a continuation of the ’460 application filed on
`
`January 15, 2019. Id., (63).
`
`L-cysteine is a “conditionally essential” sulfur-containing amino acid
`
`involved in growth and protein synthesis. Id. at 1:21–29. L-cysteine
`
`supplements may be administered to preterm infants who lack the natural
`
`ability to synthesize L-cysteine due to biochemical immaturity of the
`
`enzyme cystathionase. Id. at 1:29–37. Although L-cysteine compositions
`
`were known in the prior art, the ’155 patent states that these prior art
`
`compositions for infusion failed to address issues related to aluminum and
`
`cystine impurities, and thus were considered less safe for preterm infants,
`
`pediatric patients, and critically ill adults. Id. at 4:25–31.
`
`According to the ’155 patent, “[i]t has now been found that L-cysteine
`
`compositions for injection can be prepared using the methods described
`
`herein whereby the compositions unexpectedly comprise exceedingly low
`
`levels of Aluminum and other undesirable impurities, such as cystine,
`
`3
`
`

`

`PGR2020-00068
`Patent 10,583,155 B1
`
`pyruvic acid, certain heavy metals and certain ions.” Id. at 4:31–36.
`
`Moreover, the patent discloses 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.
`
`Id. at 4:43–49.
`
`The ’155 patent discloses that “known L-cysteine compositions
`
`contain up to 5000 ppb Aluminum.” Id. at 7:16–17. In contrast, the patent
`
`describes “compositions that provide a therapeutically effective amount of
`
`L-cysteine, while containing less than 250 ppb Aluminum.” Id. at 7:18–22.
`
`The patent further discloses that reduced aluminum compositions “permits
`
`exposure to less than or equal to 4–5 micrograms per kilogram per day
`
`(μg/kg/d) to avoid or minimize Aluminum toxicity while still providing
`
`therapeutically effective L-cysteine in a stable composition.” Id. at 7:29–35.
`
`The ’155 patent expressly defines the term “stable” as a composition
`
`that will contain the specified levels of all components, e.g., Aluminum,
`
`cystine, and pyruvic acid, “for [a] sufficient period of time to enable the
`
`composition to be commercially manufactured, stored, shipped, and
`
`administered in a clinical setting.” Id. at 16:41–52. For example, the
`
`Specification discloses compositions wherein “cystine is present in the
`
`composition in an amount not more than 2.0 wt % relative to L-cysteine
`
`after storage at ambient temperature for a period of 6 months.” Id. at 25:4–
`
`9. The Specification also discloses compositions wherein “pyruvic acid is
`
`present in the composition in an amount not more than 2.0 wt % relative to
`
`L-cysteine after storage at ambient temperature for a period of 6 months.”
`
`Id. at 25:51–59.
`
`4
`
`

`

`PGR2020-00068
`Patent 10,583,155 B1
`
`Example 1 of the ’155 patent describes a method of compounding an
`
`L-cysteine composition as follows:
`
`40±1.0 kg of Water for Injection, USP (WFI) was added . . . A
`target 65 water temperature of NMT 60° C. was maintained
`throughout WFI addition using a heat exchanger. With
`continuous mixing at a speed of 126 rpm, Argon overlaying of
`the WFI began in the mixing bag and continued until the
`dissolved oxygen was NMT 1 ppm; then the mixing bag was
`allowed to cool to a temperature of NMT 30° C.
`
`. . . L-Cysteine Hydrochloride, Monohydrate, USP (L-Cysteine)
`was added . . . The mixing continued for NLT 15 minutes or until
`complete dissolution was observed. . . . Argon overlaying
`continues until the dissolved 15 oxygen was NMT 1 ppm.
`
`. . . [T]he solution’s pH was adjusted to a target of 1.8 with
`concentrated Hydrochloric Acid, NF and/or 5.0 N Sodium
`Hydroxide, NF.
`
`. . . [T]he solution was q.s.’d with the WFI to a final weight of
`50.6 kg and allowed to mix for approximately 10 minutes. The
`final solution weight, solution temperature, solution pH, and
`dissolved oxygen was then measured and recorded. Following
`these steps, the mixing bag was fully inflated with Argon and
`capped, and the solution was transferred from the mixing bag to
`the solution holding bag.
`
`Id. at 41:60–42:32.
`
`
`
`Example 2 describes a test for aluminum levels in L-Cysteine
`
`injections compounded as per Example 1. Id. at 42:34–60. The bulk
`
`solution was filled into uncoated Schott Type 1 USP glass vials. Id.
`
`Although “[t]he product was quite stable for all the time points tested up to
`
`12 months[,] . . . the product resulted in an unacceptably high aluminum
`
`content.” Id. at 43–49. The aluminum levels are shown in Table 6,
`
`reproduced below. Id.
`
`
`
`5
`
`

`

`PGR2020-00068
`Patent 10,583,155 B1
`
`TABLE 6
`
`Aluminum Levels
`
`
`
`6 Months
`
`Lot #
`
`Release
`
`25° C./60% RH
`
`40° C./75% RH
`
`XMHH1609
`XMHH1610
`XMHH1611
`
`212 ppb
`199 ppb
`230 ppb
`
`569 ppb
`748 ppb
`726 ppb
`
`1,306 ppb
`1,374 ppb
`1,044 ppb
`
`
`
`
`
`Example 6 also describes the stability of L-Cysteine injections
`
`compounded as per Example 1. Id. at 49:54–50:22. The bulk solution was
`
`filled into Scott Type 1 USP Plus glass, which is internally coated with
`
`silicon dioxide. Id. Unlike Example 2, the L-Cysteine compositions stored
`
`in coated glass vials did not show increases aluminum content when stored
`
`upright at room temperature for 9 months at 25° C./60% RH. Id. The
`
`stability data is shown in Table 18, reproduced-in-part below. Id.
`
`TABLE 18
`
`Characterization of L-Cysteine Composition for Injection
`
`Test
`
`XMHJ1705
`
`XMHJ1706
`
`XMHJ1707
`
`L-Cysteine HCl
`
`Related Compounds
`
`L-Cystine
`Pyruvic Acid
`Aluminum Content
`
`
`Up
`100.4%
`
`0.3%
`0.1%
`3.2 ppb
`
`D. Illustrative Claims
`
`Up
`101.3%
`
`0.3%
`0.2%
`2.9 ppb
`
`Up
`101.2%
`
`0.3%
`0.1%
`5.6 ppb
`
`Petitioner challenges claims 1–30 of the ’155 patent, of which claims
`
`1, 27, and 28 are independent. Claim 1 is representative of the independent
`
`claims and recites:
`
`6
`
`

`

`PGR2020-00068
`Patent 10,583,155 B1
`
`1. A method of treating a subject having an adverse health
`condition that is responsive to L-cysteine administration, said
`method comprising:
`
`parenterally administering to said subject a parenteral
`composition comprising a mixture of one or more amino acids,
`intravenous fluid, and a stable L-cysteine composition, wherein
`said stable L-cysteine composition contributes to said parenteral
`composition:
`
`a therapeutically effective amount of L-cysteine or a
`pharmaceutically acceptable salt thereof and/or hydrate
`thereof;
`
`per Liter of said stable L-cysteine composition, from about
`1.0 mcg to about 250 mcg of Aluminum;
`
`not more than about 2.0 wt % of cystine relative to L-
`cysteine; and,
`
`not more than about 2.0 wt % of pyruvic acid relative to
`L-cysteine.
`
`Ex. 1001, 56:34–50.
`
`E. Prior Art and Asserted Grounds
`
`Petitioner asserts that claims 1–30 would have been unpatentable
`
`based on the following grounds. Pet. 7. Petitioner also offers the
`
`Declarations of Barrett Rabinow, Ph.D (Ex. 1003) and Harry “Warren”
`
`Johnson (Ex. 1022) in support of the Petition.
`
`35 U.S.C. §
`103
`
`Reference(s)/Basis
`Sandoz Label,1 Hospira Label,2
`knowledge of POSITA
`
`Claim(s) Challenged
`1–16, 18, 23, 24, 26–
`30
`
`1 Sandoz, Inc., L-CYSTEINE HYDROCHLORIDE, DrugsDB.eu. (Revised
`June 2010) (Ex. 1005) (“Sandoz Label”) (characterized as archived on
`August 24, 2016 by Internet Archive organization’s “Wayback Machine,”
`see Ex. 1004).
`2 Hospira, Inc., AMINOSYN, DrugsDB.eu. (Revised October 2004) (Ex.
`1009) (“Hospira Label”) (characterized as archived on August 31, 2018 by
`Internet Archive organization’s “Wayback Machine,” see Ex. 1010).
`
`7
`
`

`

`PGR2020-00068
`Patent 10,583,155 B1
`
`Claim(s) Challenged
`17, 19–22, 25
`
`35 U.S.C. §
`103
`
`Reference(s)/Basis
`Sandoz Label, Hospira Label,
`Hospira Package Insert,3
`Federal Register Notice,4
`knowledge of POSITA
`
`
`
`II. ANALYSIS5
`
`A. Level of Ordinary Skill in the Art
`
`Petitioner proposes that a person of ordinary skill in the art
`
`(“POSITA”) “would have had a Ph.D. in chemistry or biochemistry and at
`
`least 2 years of work experience with pharmaceutical drug product
`
`formulation analysis, development, optimization, and manufacture.” Pet. 29
`
`(citing Ex. 1003 ¶ 26). Petitioner adds that “[s]pecific experience with
`
`processes and techniques for minimizing impurities in and improving the
`
`stability of pharmaceutical drug products during manufacture and storage
`
`would have been a must.” Id. (citing Ex. 1003 ¶ 26).
`
`Patent Owner contends Petitioner’s definition “misses the mark at
`
`least because it ignores the clinical nature of the ’155 patent’s claims.”
`
`Prelim. Resp. 21. Patent Owner contends Petitioner’s definition of the
`
`POSITA does not extend to the claimed clinical features, “or otherwise
`
`suggest that the alleged POSITA would, for example, have had knowledge
`
`or experience in preparing pharmaceutical admixtures in a clinical setting for
`
`
`3 Hospira, Inc., 7.25% Cysteine Hydrochloride Injection, USP (0.5 g
`Cysteine), Package Insert (1986) (Ex. 1092) (“Hospira Package Insert”).
`4 Determination that Cysteine Hydrochloride Injection, USP, 7.25%, Was
`Not Withdrawn From Sale for Reasons of Safety or Effectiveness, 75 Fed.
`Reg. 31,790 (June 4, 2010) (Ex. 1091) (“Federal Register Notice”)
`5 Patent Owner does not challenge the eligibility of the ’155 patent for post
`grant review. We assume arguendo that the ’155 patent is eligible for post-
`grant review for purposes of our analysis herein.
`
`8
`
`

`

`PGR2020-00068
`Patent 10,583,155 B1
`
`administration to patients, in interpreting pharmaceutical drug labels, or
`
`consulting with someone who routinely does these things.” Id. Patent
`
`Owner, however, does not propose its own alternative definition of a
`
`POSITA. See id. at 21–22.
`
`For purposes of our analysis in this Decision, we hereby adopt
`
`Petitioner’s definition of a POSITA. Although we recognize that the
`
`claimed method is directed to treating a subject having an adverse health
`
`condition that is responsive to L-cysteine administration, the focus of the
`
`invention described in the ’155 patent is on the stable L-cysteine
`
`composition and the method of formulating such a composition rather than
`
`any particular clinical techniques associated with the administration of the
`
`composition. We also note that Petitioner’s proposed definition appears to
`
`be consistent with the cited prior art. See Okajima v. Bourdeau, 261 F.3d
`
`1350, 1355 (Fed. Cir. 2001) (explaining that specific findings regarding
`
`ordinary skill level are not required “where the prior art itself reflects an
`
`appropriate level and a need for testimony is not shown” (quoting Litton
`
`Indus. Prods., Inc. v. Solid State Sys. Corp., 755 F.2d 158, 163 (Fed. Cir.
`
`1985))).
`
`B. Claim Construction
`
`Petitioner proposes constructions for two claim terms: “about” and
`
`“stable.” See Pet. 29–30. Patent Owner contends that there is no need to
`
`resolve any claim construction terms. Prelim Resp. 20. Because this
`
`decision declining to institute trial does not turn on the adoption of any
`
`particular claim construction, we need not construe any terms. See Nidec
`
`Motor Corp. v. Zhongshan Broad Ocean Motor Co., 868 F.3d 1013, 1017
`
`(Fed. Cir. 2017) (noting that “we need only construe terms ‘that are in
`
`controversy, and only to the extent necessary to resolve the controversy’”)
`
`9
`
`

`

`PGR2020-00068
`Patent 10,583,155 B1
`
`(quoting Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803
`
`(Fed. Cir. 1999)).
`
`C. Grounds 1 and 2: Obviousness under 35 U.S.C. § 103
`
`Petitioner contends that claims 1–16, 18, 23, 24, and 26–30 are
`
`obvious over the combination of the Sandoz Label, the Hospira Label, and
`
`the knowledge of a POSITA. Pet. 45–69. Petitioner further contends that
`
`claims 17, 19–22, and 25 are obvious over the combination of the Sandoz
`
`Label, the Hospira Label, the Hospira Package Insert, the Federal Register,
`
`and the knowledge of a POSITA. For these grounds, we provide an
`
`overview of the prior art, followed by our analysis of the merits.
`
`1. Overview of the Prior Art
`
`a) Sandoz Label (Ex. 1005)
`
`The “Sandoz Label” includes product information for L-CYSTEINE
`
`HYDROCHLORIDE (cysteine hydrochloride injection, solution)
`
`manufactured by Sandoz, Inc. Ex. 1005. The reference bears a revision date
`
`of “06/2010.” Id. at 11. Petitioner contends “[t]he Sandoz Label was
`
`available by no later than 2016.” Pet. 31. Patent Owner does not challenge
`
`the reference’s status as a printed publication. See generally Prelim. Resp.
`
`The Sandoz Label discloses that “L-Cysteine Hydrochloride Injection,
`
`USP, 50 mg/ml, is a sterile, nonpyrogenic solution. Each ml contains: 50
`
`mg of L-Cysteine Hydrochloride Monohydrate USP; Water for Injection,
`
`USP q.s.; Air replaced With Nitrogen. pH 1.0-2.5.” Ex. 1005, 1. The
`
`Sandoz Label discloses that:
`
`Each 0.5 gram of L-Cysteine Hydrochloride Monohydrate
`should be combined aseptically with 12.5 grams Crystalline
`Amino Acid Injection, such as that present in 250 mL of 5%
`Crystalline Amino Acid Injection. The admixture is then diluted
`with 250 mL of dextrose 50% or such lesser volume as indicated.
`
`10
`
`

`

`PGR2020-00068
`Patent 10,583,155 B1
`
`Equal volumes of 5% Crystalline Amino Acid Injection and
`dextrose 50% produce a final solution which contains Crystalline
`Amino Acid 2.5% Injection in dextrose 25%, which is suitable
`for administration by central venous infusion. Administration of
`the final admixture should begin within one hour of mixing.
`Otherwise, the admixture should be refrigerated immediately and
`used within 24 hours of the time of mixing.
`
`Id. at 3.
`
`
`
`The Sandoz Label further describes product packaging disclosing that
`
`the product “contains no more than 5,000 mcg/L of aluminum.” Id. at 5.
`
`The Sandoz Label includes the following warning:
`
`This product contains aluminum that may be toxic.
`Aluminum may reach toxic levels with prolonged parenteral
`administration if kidney function is impaired. Premature
`neonates are particularly at risk because their kidneys are
`immature, and they require large amounts of calcium and
`phosphate solutions, which contain aluminum.
`
`Research indicates that patients with impaired kidney
`function, including premature neonates, who receive parenteral
`levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate
`aluminum at levels associated with central nervous system and
`bone toxicity. Tissue loading may occur at even lower rates of
`administration.
`
`Id. at 2.
`
`b) Hospira Label (Ex. 1009)
`
`The “Hospira Label” includes product information for AMINOSYN
`
`(isoleucine, leucine, lysine acetate, methionine, phenylalanine, threonine,
`
`tryptophan, valine, alanine, arginine, histidine, proline, serine, tyrosine and
`
`glycine injection, solution) manufactured by Hospira, Inc. Ex. 1009. The
`
`reference bears a revision date of “October 2004.” Id. at 9. Petitioner
`
`contends the Hospira Label “was available no later than 2013.” Pet. 34.
`
`11
`
`

`

`PGR2020-00068
`Patent 10,583,155 B1
`
`Patent Owner does not challenge the reference’s status as a printed
`
`publication. See generally Prelim. Resp.
`
`The Hospira Label discloses a crystalline amino acid solution
`
`containing the following amino acids:
`
`Essential Amino Acid
`
`(mg/100 mL)
`
`Isoleucine
`
`Leucine
`
`Lysine (excluding acetate)
`
`Methionine
`
`Phenylalanine
`
`Threonine
`
`Tryptophan
`
`Valine
`
`
`Ex. 1009, 1–2.
`
`
`360
`
`470
`
`360
`
`200
`
`220
`
`260
`
`80
`
`400
`
`c) Hospira 7.25% Cysteine HCl Package Insert (Ex. 1092)6
`
`The “Hospira Package Insert” includes product information for 7.25%
`
`Cysteine Hydrochloride Injection, USP (0.5 g Cysteine) distributed by
`
`KabiVitrum, Inc. Ex. 1092. The reference bears a date of “March 1986.”
`
`Id. at 9. Petitioner contends the Hospira 7.25% Package Insert “was
`
`available no later than July 2017.” Pet. 35. Patent Owner does not
`
`challenge the reference’s status as a printed publication. See generally
`
`Prelim. Resp.
`
`
`6 Petitioner submits an alternative version of the Hospira 7.25% Package
`Insert as Ex. 1093.
`
`12
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`

`

`PGR2020-00068
`Patent 10,583,155 B1
`
`The Hospira Package Insert discloses that “7.25% Cysteine
`
`Hydrochloride Injection, USP (0.725 as the monohydrate), is a sterile,
`
`nonpyrogenic solution. Each 10 ml provides 0.5 g cysteine and 4.13 mEq of
`
`chloride in Water for Injection, USP. The pH range is 1.0 to 2.5.” Ex. 1092,
`
`9. The Hospira Package Insert discloses that the product “is indicated for
`
`use as an additive to amino acids solutions to meet nutritional requirements
`
`of newborn infants requiring total parenteral nutrition (TPN) and of adult
`
`and pediatric patients with severe liver disease who may have impaired
`
`enzymatic processes and require TPN.” Id. at 10.
`
`d) The Federal Register Notice - 75 Fed. Reg. 31,790 (Exhibit
`1091)
`
`The Federal Register Notice was published June 4, 2010 and discloses
`
`the Food and Drug Administration’s (FDA) determination that “that
`
`Cysteine Hydrochloride Injection, USP, 7.25% (Cysteine HCl), was not
`
`withdrawn from sale for reasons of safety or effectiveness.” Ex. 1091, 1.
`
`The Federal Register Notice further discloses that:
`
`Cysteine HCl is the subject of NDA 19–523, most recently
`held by Hospira, Inc. (Hospira), and initially approved on
`October 22, 1986. Cysteine HCl is indicated for use as an
`additive to amino acid solutions to meet the nutritional
`requirements of newborn infants requiring total parenteral
`nutrition (TPN) and of adult and pediatric patients with severe
`liver disease who may have impaired enzymatic processes and
`require TPN. It can also be added to amino acid solutions to
`provide a more complete profile of amino acids for protein
`synthesis.
`
`Id. at 2.
`
`13
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`

`

`PGR2020-00068
`Patent 10,583,155 B1
`
`2. Analysis of Ground 1 (Obviousness based on the Sandoz Label
`and the Hospira Label)
`
`Petitioner contends that claims 1–16, 18, 23, 24, and 26–30 are
`
`obvious over the combination of the Sandoz Label, the Hospira Label, and
`
`the knowledge of a POSITA. Pet. 45–69. Petitioner provides a detailed
`
`analysis of how each claim element is allegedly described by the prior art.
`
`Id. Petitioner also relies on the declaration of Dr. Rabinow to support this
`
`challenge. See id. We focus our analysis on representative claim 1 as it is
`
`dispositive to our conclusion.
`
`Petitioner contends that the preamble of claim 1, reciting “a method of
`
`treating a subject having an adverse health condition that is responsive to L-
`
`cysteine administration” is disclosed by the Sandoz Label. Id. at 46–47
`
`(citing Ex. 1003 ¶ 105; Ex. 1005, 2, 7).
`
`With respect to the step of “parenterally administering . . . a parenteral
`
`composition,” Petitioner relies on the Sandoz Label’s dosing instructions to
`
`combine the L-Cysteine composition with crystalline amino acids injection
`
`and dilute the admixture with dextrose solution, i.e., an intravenous fluid.
`
`Id. at 47–48 (citing Ex. 1003 ¶ 106, Ex. 1005, 3, 9).
`
`With respect to the limitation of a “stable L-cysteine composition,”
`
`Petitioner contends that a POSITA would have been motivated to “optimize
`
`the product disclosed by the Sandoz Label to be ‘stable’ as that term is
`
`defined in the ’155 patent.” Id. at 48 (citing Ex. 1003 ¶ 107). Specifically,
`
`Petitioner contends that the “POSITA would have been motivated to remove
`
`oxygen during manufacture and storage of the L-Cysteine composition to
`
`prevent [] oxidative degradation.” Id.
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`Petitioner further contends the components of the “stable L-cysteine
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`composition” would have been obvious to a POSITA applying the Sandoz
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`Label and the Hospira Label. Id. at 49–52. With respect to “a
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`therapeutically effective amount of L-cysteine,” Petitioner contends “the
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`combination of the Sandoz and Hospira Labels teaches that the Sandoz
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`Label product contributes 142 mg/kg/day of L-Cysteine.” Id. at 49 (citing
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`Ex. 1003 ¶¶ 109–110).
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`With respect to the recited range of “from about 1.0 mcg to about 250
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`mcg of Aluminum” per Liter of said stable L-cysteine composition,
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`Petitioner contends that the Sandoz Label teaches a range of 0 to 5,000
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`mcg/L of aluminum by disclosing that the Sandoz L-Cysteine Product
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`“[c]ontains no more than 5,000 mcg/L of aluminum,” thereby encompassing
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`the claimed range.7 Id. at 49–50 (citing Ex. 1003 ¶¶ 34, 111; Ex. 1005, 5,
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`10; Ex. 1004, 8, 13). Petitioner further contends that a POSITA would have
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`optimized the Sandoz product to meet the regulatory and market pressures to
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`substantially reduce aluminum. Id. at 50 (citing Ex. 1003 ¶¶ 112–113).
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`Petitioner further contends that the aluminum levels in the Sandoz product
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`disclosed by the Sandoz Label “were typically less than 100 ppb shortly
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`after manufacture and increased to several hundred ppb[] during storage.”
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`Id. at 50–51 (citing Ex. 1003 ¶ 112; Ex. 1022 ¶ 15). Petitioner contends that
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`“by optimizing the product disclosed by the Sandoz Label, its method of
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`manufacture, and its container to substantially reduce and eliminate
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`aluminum, the POSITA would have reasonably expected to achieve
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`aluminum levels within the claimed range during manufacture and storage,
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`including for 3–24 months post-manufacture.” Id. at 51 (citing Ex. 1003
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`¶ 113).
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`7 Petitioner contends mcg/L is interchangeable with ppb. Pet. 50.
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`Additionally, with respect to the claimed aluminum range, Petitioner
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`contends that in 2004 the FDA issued a rule governing aluminum content in
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`compositions used to prepare parenteral nutrition solutions (“PNS”). Pet. 36
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`(citing Ex. 1003 ¶¶ 31-32; Ex. 1006, 1; Ex. 1007, 1–2). The 2004 Rule
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`required PNS compositions to include a standardized warning describing the
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`presence of aluminum in the products, aluminum’s risk to infants, and a
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`recommended maximum daily aluminum dose of 4 to 5 mcg/kg/day. Id. at
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`37 (citing Ex. 1003 ¶ 32; Ex. 1006, 7; Ex. 1007, 1–2). Petitioner contends
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`that, given the ongoing concerns about aluminum toxicity, the FDA imposed
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`stricter aluminum limits on parenteral drug products in August 2017. Id. at
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`28 (citing Ex. 1053). For example, Petitioner contends that FDA instructed
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`Patent Owner that “the aluminum dose delivered by your drug product, L-
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`Cysteine Hydrochloride Injection, 0.5g/10mL should be limited to ≤ 0.6
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`mcg/kg/day. To comply with this dose level, a limit of ≤ 145 mcg/L [i.e., ≤
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`145 ppb] aluminum is needed.” Id. at 38 (citing Ex. 1003 ¶ 36; Ex. 1019, 1).
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`Petitioner contends that a POSITA would have addressed “well-
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`known” sources of potential aluminum contamination, including: (1)
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`component ingredients; (2) other amino acid compositions combined with
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`the parenteral drug product; and (3) “glass containers, which were known to
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`leach aluminum into the drug product.” Id. at 39 (citing Ex. 1003 ¶¶ 56–60).
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`Petitioner further contends that a POSITA would have also been motivated
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`to prevent the “known oxidative degradation of oxygen sensitive drugs such
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`as L-Cysteine.” Id. at 41 (citing Ex. 1003 ¶¶ 50–53). Petitioner contends
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`that “oxidative degradation can be prevented by adding antioxidants or by
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`removing dissolved oxygen and/or replacing headspace air with an inert gas,
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`such as nitrogen or argon, during manufacture and storage.” Id. (citing Ex.
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`1003 ¶ 51). For example, Petitioner contends that the Sandoz Label
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`describes replacing headspace air with nitrogen. Id. (citing 1003 ¶ 33; Ex.
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`1005, 1, 6; Ex. 1004, 5, 11). Petitioner contends that a POSITA would have
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`also used an oxygen impermeable container, such as silicon dioxide coated
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`glass containers which did not leach aluminum. Id. at 41–42 (citing Ex.
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`1003 ¶ 59; Ex. 1014, 8).
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`With respect to the recited ranges of “not more than about 2.0 wt % of
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`cystine,” and “not more than about 2.0 wt % of pyruvic acid,” both relative
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`to L-cysteine, Petitioner acknowledges that the Sandoz Label does not
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`expressly disclose the amount of cystine or pyruvic acid in the composition.
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`Id. at 51–52. Petitioner, however, contends that a POSITA would have
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`taken art-recognized steps to prevent the oxidative degradation of L-
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`Cysteine, such as replacing the headspace air with nitrogen. Id. (Ex. 1003
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`¶ 116; Ex. 1005, 1, 6). Petitioner contends that a POSITA would have
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`known that preventing oxidative degradation of L-Cysteine would avoid its
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`oxidative degradation products, i.e., cystine, which further degrades into
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`pyruvic acid. Id. (citing Ex. 1003 ¶ 114–119).
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`In its Preliminary Response, Patent Owner contends that the Sandoz
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`Label and the Hospira Labels do not disclose the limitations of claim 1.
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`Prelim. Resp. 31. In particular, Patent Owner contends that Petitioner
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`“expressly admits that the Sandoz Label does not disclose the cystine and
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`pyruvic acid limitations” of claim 1. Id. Patent Owner further contends that
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`Petitioner “implicitly admits that the Sandoz Label does not disclose the
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`‘stable’ limitation of each claim by asserting that the Sandoz Label
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`composition would need to be ‘optimize[d]’ to be stable.” Id. at 31–32.
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`Additionally, with respect to the recited amount of aluminum, Patent
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`Owner contends that the Sandoz Label discloses a maximum amount of
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`aluminum and not a range of 0–5,000 mcg/L. Id. at 34–35. Patent Owner
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`contends that the amount of 5,000 mcg/L was derived from FDA regulations
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`requiring a disclosure of the maximum amount of aluminum at product
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`expiry. Id. (citing Ex. 1007, 1). Patent Owner contends that “any prudent
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`pharmacist would interpret the Sandoz Label as disclosing up to 5,000
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`mcg/L of aluminum, and would use that maximum aluminum level in
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`calculating a patient’s aluminum exposure.” Id. at 35 (citing Ex. 2001
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`¶¶ 20–24).
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`Patent Owner further contends that Petitioner’s “routine optimization”
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`analysis is based on hindsight reasoning for several reasons. See id. at 38–
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`59. First, Patent Owner contends that Petitioner does not establish that
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`optimizing “cystine levels [was] relevant to solving the aluminum problem.”
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`Id. at 42. Second, Patent Owner contends that Petitioner’s routine
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`optimization “does not explain why a POSITA purportedly optimizing the
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`Sandoz Label composition to reduce aluminum would have arrived at the
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`specific claimed amounts of cystine,” and thus lacks evidentiary support. Id.
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`at 48–49. Patent Owner contends that Petitioner improperly relies “on the
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`patent’s specification to buttress the assumption that the claimed amounts
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`are the result of routine optimization.” Id. at 49. Third, Patent Owner
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`contends that the “stable” limitation requires that the claimed amounts of
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`each component remain stable from the time of manufacturing to the time
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`when “the L-cysteine composition is admixed and administered in a clinical
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`setting, which could be up to two years after manufacture.” Id. at 51.
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`Fourth, Patent Owner contends that Petitioner’s “‘routine optimization’
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`argument . . . fails to account for the complexity of the claimed
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`composition,” which solved an unmet need despite the unpredictable nature
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`of the art. Id. at 52–53 (citing Ex. 1002, 378–379, 420; Ex. 1006, 1).
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`Having considered the arguments and evidence of record, we
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`determine that Petitioner has not demonstrated that it is more likely than not
`
`that claim 1 is obvious over the combination of the Sandoz Label, the
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`Hospira Label, and the knowledge of a POSITA In particular, the evidence
`
`of record does not show that Petitioner will likely be able to meet its burden
`
`of establishing that a POSITA would have had a reasonable expectation of
`
`success with respect to lowering the amount of aluminum content within the
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`Sandoz L-Cysteine Product to within the claimed range of 1.0 mcg to about
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`250 mcg of Aluminum per Liter of said stable L-cysteine composition.
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`Additionally, we do not find that the indication in the Sandoz Label that the
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`product “[c]ontains no more than 5,000 mcg/L of aluminum” reasonably
`
`suggests a range of 0–5,000 mcg/L of the aluminum amount that would be
`
`subject to routine optimization. We agree with Patent Owner that the
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`recitation of “contains no more than 5000 mcg/ml (i.e. 5000 ppm)
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`aluminum” is more reasonably interpreted to be the upper end of the
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`aluminum concentration that is expected in the product rather than a
`
`teaching of any lower limit for the aluminum content that overlaps with the
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`claimed range. Prelim. Resp. 34–38.
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`As noted above, Petitioner also relies on the FDA regulations and
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`other communications directing a lower amount of aluminum for L-cysteine
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`compositions. Although we agree with Petitioner that this evidence supports
`
`the position that there would have been a motivation to avoid aluminum
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`toxicity, the presence of such motivation alone is insufficient for reaching a
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`conclusion of obviousness. Obviousness also re