Trials@uspto.gov Paper No. 12
`571-272-7822
`
` Entered: November 18, 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.
`____________
`
`PGR2020-00064
`Patent US 10,478,453 B1
`____________
`
`
`
`Before ULRIKE W. JENKS, SUSAN L.C. MITCHELL, and
`CHRISTOPHER G. PAULRAJ, Administrative Patent Judges.
`
`JENKS, Administrative Patent Judge.
`
`
`
`
`DECISION
`Denying Institution of Post-Grant Review
`35 U.S.C. § 324
`
`
`
`
`
`
`571-272-7822
`
` Entered: November 18, 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.
`____________
`
`PGR2020-00064
`Patent US 10,478,453 B1
`____________
`
`
`
`Before ULRIKE W. JENKS, SUSAN L.C. MITCHELL, and
`CHRISTOPHER G. PAULRAJ, Administrative Patent Judges.
`
`JENKS, Administrative Patent Judge.
`
`
`
`
`DECISION
`Denying Institution of Post-Grant Review
`35 U.S.C. § 324
`
`
`
`
`
`
`
`PGR2020-00064
`Patent US 10,478,453 B1
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`Eton Pharmaceuticals Inc. (“Petitioner”) filed a Petition requesting a
`post-grant review of claims 1–22 (“the challenged claim”) of Patent US
`10,478,453 B1(Ex. 1001, “the ’453 patent”). Paper 1 (“Pet.”). Exela Pharma
`Sciences, LLC (“Patent Owner”) filed a Preliminary Response to the
`Petition. Paper 6 (“Prelim. Resp.”). With our authorization (Paper 7),
`Petitioner filed a reply to Patent Owner’s Preliminary Response (Paper 9
`(“Pet. Reply”)), and Patent Owner filed a Sur-reply (Paper 11 (“Sur-reply”)).
`We granted additional briefing to allow Petitioner to clarify the record with
`respect to assertions made in Patent Owner’s preliminary response, and to
`allow Patent Owner the opportunity to address alleged conflicting arguments
`made in a related proceeding.
`We have authority to determine whether to institute a post-grant
`review. 35 U.S.C. § 324. After considering all the papers submitted, for the
`reasons discussed below, we deny the Petition and do not institute a post-
`grant review.
`
`A.
`
`BACKGROUND
`
`I.
`Real Parties in Interest
`Petitioner identifies itself as the real party in interest. Pet. 2. Patent
`Owner identifies itself as the real party in interest. Paper 3, 2.
`B.
`Related Proceedings
`Petitioner identifies as related matter Exela Pharma Sciences, LLC v.
`Eton Pharms., Inc., Case No. 1:20-cv-00365-MN (D. Del., filed March 16,
`2020) (“District Court Action”); Exela Pharma Sciences LLC v. Avadel
`Legacy Pharms., LLC, No. 1:20-cv-00024-MN (D. Del., filed January 7,
`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.
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`Sandoz Inc., Case No. 1:20-cv-01393 (D. Colo., filed May 15, 2020). Pet. 3;
`Paper 3, 1.
`Petitioner also identifies U.S. Patent No. 10,583,155, U.S. Patent
`Appl. No. 16/746,028, U.S. Patent Appl. No.16/773,563 (now U.S. Patent
`No. 10,653,719), U.S. Patent Appl. No.16/773,641, U.S. Patent Appl.
`No.16/850,726, U.S. Patent Appl. No.16/850,962, and U.S. Patent Appl.
`No.16/850,973 as claiming benefit of priority to U.S. Application No.
`16/248,460 which issued as the ’453 patent. Pet. 3–4; Paper 3, 2.
`C.
`The ’453 Patent (Ex. 1001)
`The ’453 patent is titled “STABLE, HIGHLY PURE L-CYSTEINE
`COMPOSITIONS FOR INJECTION AND METHODS OF USE.”
`Ex. 1001, (54). The ’453 patent issued from Application No. 16/248,460
`(“the ’460 application”), filed January 15, 2019. Id. at (21), (22).
`The ’453 patent describes stable L-cysteine compositions for
`injection, comprising: L-cysteine or a pharmaceutically acceptable salt
`thereof and/or hydrate thereof in an amount from about 10 mg/mL to about
`100 mg/mL, and aluminum in an amount from about 1.0 parts per billion
`(ppb) to about 250 ppb. Id. at (57).
`“L-cysteine is a sulfur-containing amino acid that can be synthesized
`de novo from methionine and serine in adult humans.” Id. at 1:14–16.
`Because L-cysteine can be synthesized by the body, it is considered a non-
`essential amino acid. Id. at 1:20. “L-cysteine can be conditionally essential
`in preterm infants due to biochemical immaturity of the enzyme
`cystathionase that is involved in L-cysteine synthesis. Thus, there are a
`number of circumstances in which L-cysteine supplementation can be
`desirable.” Id. at 1:26–31.
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`According to the specification, “[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, pyruvic acid, certain heavy metals and certain ions.” Id. at 4:25–
`30. Moreover, the specification discloses that:
`[T]he 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 4:37–43.
`The specification discloses that “known L-cysteine compositions
`contain up to 5000 ppb Aluminum.” Id. at 7:8–9. In contrast, the
`specification describes “compositions that provide a therapeutically effective
`amount of L-cysteine, while containing less than 250 ppb Aluminum.” Id. at
`7:10–13. The specification discloses that reduced aluminum compositions
`“permit[ ] 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 7:21–25.
`The specification 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
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`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 25:6–9.
`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 26:5–8.
`D.
`Illustrative Claim
`Claim 1 of the ’453 patent is illustrative and reproduced below (with
`added bracketing for reference):
`A stable L-cysteine composition for parenteral administration,
`comprising:
`[(A)] L-cysteine or a pharmaceutically acceptable salt
`thereof and/or hydrate thereof in an amount from about 10
`mg/mL to about 100 mg/mL;
`[(B)] Aluminum (Al) in an amount from about 1.0 parts
`per billion (ppb) to about 250 ppb;
`[(C)] L-cystine in an amount from about 0.001 wt% to
`about 2.0 wt % relative to L-cysteine;
`[(D)] pyruvic acid in an amount from about 0.001 wt% to
`about 2.0 wt % relative to L-cysteine;
`[(E)] a pharmaceutically acceptable carrier, comprising
`water;
`[(F)] headspace oxygen that is from about 0.5% v/v to
`4.0% v/v from the time of manufacture to about 1 month from
`manufacture when stored at room temperature;
`[(G)] dissolved oxygen present in the carrier in an
`amount from about 0.1 parts per million (ppm) to about 5 ppm
`from the time of manufacture to about 1 month from
`manufacture when stored at room temperature,
`[(H)] wherein the composition is enclosed in a single-use
`container having a volume of from about 10 mL to about 100
`mL.
`Ex. 1001, 59:2–25.
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`E.
`
`Hospira Label
`
`Ex. 1009
`
`Ex. 1022
`
`Prior art
`Petitioner relies upon the following prior art references1 (Pet. 6):
`References
`Patent / Publication
`Exhibits
`Sandoz Label
`L-CYSTEINE HYDROCHLORIDE –
`Ex. 1005
`cysteine hydrochloride injection, solution
`Sandoz Inc.
`AMINOSYN® A Crystalline Amino Acid
`Solution
`Allergy Process Exhibit A (Declaration of Harry “Warren”
`Johnson)
`Petitioner relies on affidavits of Christopher Butler of the Internet
`Archive (Ex. 1004; Ex. 1010) and the attached exhibits to establish the
`availability of certain references.
`F.
`Asserted Grounds of Unpatentability
`Petitioner challenges the patentability of claims 1–22 of the ’453
`patent on the following grounds (Pet. 6):
`Ground Claim(s)
`Basis Reference(s)
`Challenged
`1–14
`
`1
`
`§ 103 The Sandoz Label in view of the
`knowledge of a person of ordinary skill
`in the art
`§ 103 The Sandoz Label and the Hospira
`Label, in view of the knowledge of a
`person of ordinary skill in the art
`§ 103 The Sandoz Label and the Allergy
`Process, in view of the knowledge of a
`person of ordinary skill in the art
`Petitioner also relies on the Declarations of Barrett Rabinow, Ph.D.
`(Ex. 1003) and Harry “Warren” Johnson (Ex. 1022) to support its assertions.
`
`2
`
`3
`
`15–20, 22
`
`21
`
`
`1 Petitioner additionally cites references in support of “the knowledge of
`POSITA [(person of ordinary skill in the art)].” See Pet. 27–34.
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`A.
`
`Patent Owner relies on the Declaration of Robert J. Kuhn, PharmD (Ex.
`2001) in support of its Patent Owner Preliminary Response.2
`II. DISCUSSION
`Overview of Petitioner’s References
`1.) “Sandoz Label” (Ex. 1005)
`The Sandoz Label3 describes a solution containing 50 mg of L-
`cysteine hydrochloride monohydrate, water, with the air replaced with
`nitrogen, and the solution having a pH 1.0–2.5. Ex. 1005, 5. The product
`comes in either 10 ml or 50 ml containers. Id. at 9. “L-Cysteine is a sulfur-
`containing amino acid. In premixed solutions of crystalline amino acids,
`cysteine is relatively unstable over time, eventually converting to insoluble
`cystine.” Id. at 1. The indicated use of L-cysteine hydrochloride injection as
`described in the Sandoz Label is for dilution as an additive to crystalline
`amino acid injections to meet the intravenous amino acid nutritional
`requirements of infants receiving total parenteral nutrition. Id. at 2. The label
`describes that “[a]ny unused portion of the vial must be discarded within 4
`hours after initial entry.” Id. at 9.
`
`
`2 To the extent a genuine issue of material fact arises from the testimony of
`Dr. Kuhn, we view that issue in the light most favorable to Petitioner solely
`for purposes of this Decision. See 37 C.F.R. § 42.108(c).
`3 Petitioner identifies “the Sandoz Label” as including the product, package
`insert, and package label. Pet. 1. Patent Owner contends that the “label”
`reaches three distinct sources of alleged prior art: the product itself, the
`package label, and the package insert (i.e. printed matter). Prelim. Resp. 29.
`Patent Owner contends that each source should be treated as a separate prior
`art. Id. at 31.
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`The label indicates that the product contains no more than 5000
`mcg/L [(5000 ppb)4] of aluminum. The Sandoz Label provides a warning
`that the product contains aluminum that may be toxic. Id. at 2. “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.
`2.) “Hospira Label” (Ex. 1009)
`Hospira Label describes Aminosyn® as sterile crystalline amino acid
`solution for intravenous infusion. Ex. 1009, 1. Aminosyn provides
`crystalline amino acids to promote protein synthesis and wound healing and
`to reduce the rate of endogenous protein catabolism. Id. at. 2.
`3.) “Allergy Process” from the Johnson Declaration (Ex. 1022)
`Allergy Laboratories, Inc. (“Allergy”), manufactured the Sandoz
`product that is the subject of the Sandoz Label. Pet. 33 (citing Ex. 1022
`¶¶ 8–9). The Allergy Process5 included the following steps:
`a. Stirring water for injection, USP (WFI) in a vessel at temperature
`not more than (NMT) about 60ºC;
`b. Allowing the vessel to cool to a temperature of NMT 30ºC;
`c. Contacting the WFI with L-Cysteine Hydrochloride, Monohydrate,
`USP (L-Cysteine) for not longer than (NLT) 15 minutes;
`
`
`4 5000 mcg/L corresponds to 5,000 ppb. See Ex. 1003 ¶ 98; Ex. 2001 ¶ 20.
`5 Patent Owner contends that the Allergy Process does not qualify as prior
`art. See Prelim Resp. 19–28. Because we deny the Petition on the merits we
`do not address the prior art status of the Allergy Process.
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`d. Adjusting the pH, if needed, with concentrated Hydrochloric Acid,
`NF and/or 5.0N Sodium Hydroxide, NF;
`e. Mixing for a minimum of about 10 minutes;
`f. Capping the vessel and allowing to stand;
`g. Filling said mixture into container of use;
`h. Reducing the head space oxygen in said containers of use; and
`i. Sealing said containers of use.
`Pet. 33 (citing Ex. 1022 ¶¶ 16–18). The product made by the Allergy Process
`contained Aluminum at the very low end (e.g., typically < 100 ppb) of the
`no more than 5,000 mcg/L (i.e., ppb) range disclosed by the Sandoz Label.
`Id. (citing Ex. 1022 ¶ 15).
`B.
`The Parties’ Contentions
`Petitioner contends that the challenged claims are obvious based
`primarily on the Sandoz Label. Pet. 43–72.
`Petitioner’s first obviousness ground, challenging claims 1–14, relies
`on the Sandoz Label in conjunction with the knowledge of a person of
`ordinary skill in the art.6 Pet. 43. Petitioner contends that claim elements
`1(A), 1(B), 1(E), and 1(H) are disclosed in the Sandoz Label. Pet. 44–47, 50.
`
`
`6 Petitioner identifies that the ordinary skilled artisan “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. 24. Patent Owner contends that
`Petitioner’s definition misses the mark because it ignores the need for the
`artisan to also have “knowledge or experience in interpreting pharmaceutical
`drug labels or consulting with someone who did.” Prelim. Resp.18. We note
`the parties’ differences with respect to level of skill in the art, but because
`we deny institution for other reasons, we do not need to resolve this conflict
`here.
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`Petitioner concedes that elements 1(C), 1(D), 1(F), and 1(G) are not recited
`in the Sandoz Label, but contends that these elements would be obvious in
`light of the knowledge of a person of ordinary skill in the art. See Pet. 47
`(“[T]he claimed ranges are the reasonably expected result of taking art-
`recognized steps to prevent oxidative degradation of L-Cysteine to L-
`Cystine during manufacture and storage.” (citing Ex. 1003 ¶¶ 100–105)); 48
`(“[T]he claimed range encompasses what was known in the art . . . .” (citing
`Ex. 1003 ¶¶ 107, 109–110; Ex. 1027, Ex. 1029), 49 (“[T]he claimed range
`encompasses dissolved oxygen levels known in the prior art . . . .” (citing
`Ex. 1003 ¶ 112; Ex. 1082)). With respect to independent claim 1, Petitioner
`contends that the skilled artisan would have relied on routine optimization
`using well-known techniques to achieve the reasonably expected result of
`preventing oxidative degradation of L-Cysteine. Pet. 49 (citing Ex. 1003
`¶ 113). Petitioner contends that dependent claims 2–14 would have similarly
`been obvious based on the Sandoz Label in conjunction with the knowledge
`of one of ordinary skill in the art and/or based on routine optimization. See
`Pet. 50–56 (citing Ex. 1003 ¶¶ 50, 54–58, 117–134, 136, 138, 139, 141–147,
`150–156, 158; Ex. 1006; Ex. 1007; Ex. 1008; Ex. 1011; Ex. 1012; Ex. 1013;
`Ex. 1014; Ex. 1027; Ex. 1036; Ex. 1038; Ex. 1039; Ex. 1048; Ex. 1064; Ex.
`1070; Ex. 1071).
`Petitioner’s second obviousness ground, challenging claims 15–20
`and 22, relies on the Sandoz Label and the Hospira Label in conjunction
`with the knowledge of a person of ordinary skill in the art. Pet. 56–67.
`Petitioner contends that claim elements of claim 15 corresponding to claim
`elements 1(A), 1(B), 1(E), and 1(H) are disclosed in the Sandoz Label. Pet.
`56–57. Petitioner contends that claim elements corresponding to additional
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`amino acid compositions as recited in claim 15 are taught by the Hospira
`Label. Petitioner concedes that the claim elements in claim 15 that
`correspond to claim elements 1(C), 1(D), 1(F), and 1(G) are not recited in
`the Sandoz Label, but contends that these elements would be obvious in light
`of the knowledge of a person of ordinary skill in the art. See Pet. 58–59.
`Petitioner’s third obviousness ground, challenging claim 21, relies on
`the Sandoz Label and the Allergy Process in conjunction with the knowledge
`of a person of ordinary skill in the art. Pet. 67–72 (citing Ex. 1003 ¶¶ 48–49,
`195, 198–207; Ex. 1022 ¶ 16; Ex. 1027; Ex. 1028; Ex. 1031; Ex. 1032; Ex.
`1033; Ex. 1036; Ex. 1041; Ex. 1069; Ex. 1082).
`In response, Patent Owner argues that Petitioner is using additional
`references, specifically Waterman,7 Yaman,8 and Butler,9 as more than just
`evidence of the knowledge of the person having ordinary skill in the art, but
`instead Petitioner is using these references to try and establish that specific
`claim elements were taught in the art. Prelim. Resp. 33 (citing Adaptics
`Limited v. Perfect Company, IPR2018-01596, Paper 20 at 20‒23 (PTAB
`Mar. 6, 2019) (Informative Decision); see also EnergySource Materials,
`LLC v. Terralithium LLC, IPR2019-01605, Paper 7 at 30 (PTAB Apr. 6,
`2020)). Waterman, Yaman, and Butler describe techniques for removing
`
`
`7 Kenneth C. Waterman et al., Stabilization of Pharmaceuticals to Oxidative
`Degradation, 7 Pharm. Develop. & Tech, 1–32 (2002) (Ex. 1027).
`8 Alpaslan Yaman, Chapter 7: Engineering Considerations in Sterile
`Powder Process, in Sterile Pharmaceutical Products: Process Engineering
`Application (Kenneth. E. Avid ed., 1995) (Ex. 1029).
`9 Ian B. Butler et al., Removal of Dissolved Oxygen from Water a
`Comparison of Four Common Techniques, 41 Talenta 211–215 (1994)
`(Ex. 1082).
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`oxygen from either the headspace or from a liquid carrier as recited in claim
`elements 1(F) and 1(G). Patent Owner argues that, by taking a “catch-all”
`approach without identifying what specific combinations are intended and
`instead placing everything under the umbrella of either “routine
`optimization” or “knowledge of the ordinary artisan,” the Petition lacks the
`required particularity that would allow Patent Owner a fair opportunity to
`formulate a response to the intended combinations. Prelim. Resp. 33 (“These
`‘back door’ combinations should be rejected . . . .”).
`C.
`Claim Construction
`Petitioner proposes constructions for two claim terms: “about” and
`“stable.” See Pet. 25–26 (citing Ex. 1001, 16:40–51; 58:28–39). Patent
`Owner contends that there is no need to resolve any claim construction
`terms, but notes that the term “stable” requires that the composition must be
`stable over certain minimum time period. Prelim Resp. 18.
`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’”) (quoting Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200
`F.3d 795, 803 (Fed. Cir. 1999)).
`D.
`Analysis
`1.) Particularity Requirement
`The relevant statute provides that a determination whether to institute
`a post-grant review shall be made based on “the information presented in the
`petition.” 35 U.S.C. § 324(a). Under 35 U.S.C. § 324(a), a post-grant review
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`can be instituted only if it is more likely than not that the petitioner would
`prevail with respect to at least one of the claims challenged in the petition.
`35 U.S.C. § 324(a). In addition, 35 U.S.C. § 322(a)(3) provides that the
`petition identify “in writing and with particularity, each claim challenged,
`the grounds on which the challenge to each claim is based, and the evidence
`that supports the grounds for the challenge to each claim.” Section
`§ 42.22(a)(2) of Title 37 of the US Code of Federal Regulations provides
`that each petition includes, “[a] full statement of the reasons for the relief
`requested, including a detailed explanation of the significance of the
`evidence including material facts, and the governing law, rules, and
`precedent.” See also 37 C.F.R. § 42.204.
`In a post-grant review, as in an inter partes review, “the petitioner has
`the burden from the onset to show with particularity why the patent it
`challenges is unpatentable.” Harmonic Inc. v. Avid Tech., Inc., 815 F.3d
`1356, 1363 (Fed. Cir. 2016) (emphasis added) (citing 35 U.S.C. §312(a)(3)
`as applied to inter partes review, which is equivalent to the 35 U.S.C.
`§322(a)(3) as applied to post-grant review). This burden of persuasion never
`shifts to Patent Owner. See Dynamic Drinkware, LLC v. Nat’l Graphics,
`Inc., 800 F.3d 1375, 1378 (Fed. Cir. 2015); see also In re Magnum Oil Tools
`Int’l, Ltd., 829 F.3d 1364, 1375–78 (Fed. Cir. 2016) (discussing the burden
`of proof in AIA trials).
`Consistent with the statute and case law, our Consolidated Trial
`Practice Guide10 advises that petitioners should “avoid submitting a
`
`
`10 Consolidated Trial Practice Guide Update, 59 (Nov. 2019), available at
`www.uspto.gov/trialpracticeguideconsolidated, (“TPG”).
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`repository of all the information that a judge could possibly consider, and
`instead focus on concise, well-organized, easy-to-follow arguments
`supported by readily identifiable evidence of record.” TPG 39.
`In this case, we agree with Patent Owner that the Petition suffers from
`a lack of particularity because it is not clear what aspects of the numerous
`references cited in the body of the Petition, but not listed in the grounds of
`unpatentability, Petitioner relies on to establish a basis for “routine
`optimization” as the reason for arriving at claim elements 1(C), 1(D), 1(F),
`and 1(G). By not including references in the formulation of the ground
`unpatentability Petitioner is not providing an articulated reason that allows
`Patent Owner the ability to respond and leaves Patent Owner, and the Board
`for that matter, to guess how the references are applied to each particular
`ground. Prelim. Resp. 33 (“[Petitioner] is relying on its ‘additional
`references’ to create back-up obviousness combinations without identifying
`those combinations to Exela and the Board.” (emphasis omitted)); cf. In re
`Hoch, 428 F.2d 1341, 1342 n.3 (CCPA 1970) (“Where a reference is relied
`on to support a rejection, whether or not in a ‘minor capacity,’ there would
`appear to be no excuse for not positively including the reference in the
`statement of rejection.”).
`Petitioner relies on the Sandoz Label in conjunction with the
`knowledge of a person of ordinary skill in the art to arrive at the L-cysteine
`composition as recited in independent claim 1. See Pet. 43–50. Patent Owner
`argues that Petitioner relies on more than the general knowledge of the
`ordinary artisan because Petitioner uses Waterman and Yaman to establish a
`headspace oxygen range that meets the claim requirements, yet does not
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`recite these references in the stated ground of unpatentability. Prelim Resp.
`32 (citing Ex. 1027 and Ex. 1029).
`For example, Petitioner contends that the oxygen sensitivity of L-
`cysteine is well-known in the art and easily addressed. See Pet. 38–40.
`Petitioner notes that in “the Sandoz Label, headspace air is replaced with
`nitrogen to address L-Cysteine’s oxygen sensitivity.” Pet. 39 (citing Ex.
`1003 ¶ 31; Ex. 1005, 1), 48 (citing Ex. 1003 ¶ 109; Ex. 1029, 41; Ex. 1027,
`27). Petitioner then notes that given the disclosure of the Sandoz Label in
`conjunction with teachings in Yaman and Waterman, “the percent oxygen in
`the vial headspace” of the Sandoz Label encompasses the claimed range
`based on what was known in the art. Pet. 48. Here, the Petition cites Yaman
`and Waterman to establish the oxygen level in the headspace of the product
`described in the Sandoz Label. Id. (citing Ex. 1003 ¶¶ 107–108). The
`Petition, however, does not cite these references in the ground of
`unpatentability, and instead, Petitioner appears to be relying on routine
`optimization based on the knowledge of one of ordinary skill in the art to
`arrive at the conclusion that the Sandoz Label meets the claimed elements.
`Another example of Petitioner’s reliance on more than just the
`knowledge of the ordinary artisan is with respect to the dissolved oxygen
`range in water as disclosed in Butler. See Pet. 49 (citing Ex. 1082), Prelim
`Resp. 32 (citing Ex. 1082). Butler describes several techniques to remove
`dissolved oxygen from a liquid. These are: purging with nitrogen, argon, or a
`similar inert gas; boiling at 1 atm; sonication under “vacuum”; and boiling
`under “vacuum.” Ex. 1082, 1. Butler concludes that a nitrogen purge is an
`efficient method for removing dissolved oxygen from deionized water but
`concludes “it is a poor method to preserve solutions containing redox-
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`sensitive species.” Id. at 5. Here, Petitioner acknowledges that the Sandoz
`Label does not disclose dissolved oxygen content in the carrier, but finds
`that purging with nitrogen is a known way to reduce oxygen levels. Pet. 49
`(citing Ex. 1003 ¶ 112; Ex. 1082, 1; Ex. 1069, 1; Ex. 1032 at 17–18; Ex.
`1033, 13; Ex. 1027, 27). There is nothing in the Sandoz Label that suggests
`that the carrier was purged with nitrogen. Thus, Petitioner is relying on
`teachings in Waterman, Butler, and others to establish an oxygen range for
`water and a reason to reduce the oxygen content in the liquid carrier of the
`product described in the Sandoz Label. Id. (citing Ex. 1003 ¶¶ 111–113).
`Again, rather than citing these references in the ground of unpatentability,
`which necessitates articulating a rationale to combine the teachings of the
`references with a reasonable expectation of success, Petitioner instead is
`relying on routine optimization based on the insufficiently articulated
`knowledge of one of ordinary skill in the art to arrive at the conclusion that
`the Sandoz Label meets the claimed elements.
`Petitioner contends that “L-Cysteine was known to oxidatively
`degrade to L-Cystine, which can form undesired particulate matter.” Pet. 46
`(citing Ex. 1003 ¶ 42; Ex. 1020 at 3; Ex. 1031 at 2; Ex. 1061 at 1–2). Patent
`Owner argues that Petitioner has not demonstrated that the oxidative
`behavior of L-cysteine in the pH range of 1.0–2.5 as listed on the Sandoz
`Label converts the L-cysteine to the unwanted cystine. Prelim. Resp. 47
`(citing Ex. 1020, 3 (“In neutral or slightly alkaline aqueous solutions,
`[cysteine hydrochloride] is oxidized to cystine by air. It is more stable in
`acidic solutions.”). Patent Owner contends that the Petition has not
`articulated a reason why a person having ordinary skill in the art would have
`sought to reduce aluminum concentrations by optimizing the cystine levels
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`in a composition that has the recited low pH. Id. 49. In other words, Patent
`Owner’s contention is that Petitioner has not explained why one of ordinary
`skill in the art would have thought that cystine levels would have had any
`bearing on the aluminum content of the composition. We agree with Patent
`Owner that the Petition does not sufficiently explained why one of ordinary
`skill in the art would want to look at cystine levels in the product disclosed
`in the Sandoz Label in the first place and what reason there is to maintain it
`within the recited range.
`Based on the above examples, we agree with Patent Owner and find
`that the Petition fails to meet the particularity requirement of 35 U.S.C.
`§ 322(a)(3) with regard to Petitioner’s assertion that the subject matter of
`claims 1–14 would have been obvious over the Sandoz Label in conjunction
`with the knowledge of a person of ordinary skill in the art, and we decline to
`institute a post-grant review on that ground. We also decline to identify and
`analyze all possible permutations of prior art combinations that Petitioner
`may have sought to include in this ground but did not expressly articulate.
`2.) Routine Optimization
`According to Petitioner, the Sandoz Label already warns that
`aluminum may be toxic to certain patient populations. Pet. 44. Petitioner
`contends that in response to FDA regulatory demand, articulated market
`pressures, and recognized toxicity, there was a motivation to lower the
`aluminum content in total parenteral nutrition (TPN) solutions. Pet. 35. As
`recognized in the prior art:
`[T]o limit the risk of aluminum toxicity, the U.S. Food and
`Drug Administration (FDA) modified its ‘‘Regulations on
`Aluminum in Large and Small Volume Parenterals Used in
`Total Parental Nutrition’’ with the January 2000 Final Rule,
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`enacted in July 2004. The Final Rule limits the aluminum
`concentration of large-volume parenteral products to 25
`mcg/L . . . and a recommended maximum daily aluminum dose
`of 4 to 5 mcg/kg/ day to prevent accumulation and toxicity
`Ex. 1007, 2 (citations omitted). The FDA in communication with Patent
`Owner indicated that the aluminum dose associated with the L-cysteine drug
`product in their new drug application “should be limited to ≤ 0.6
`mcg/kg/day. To comply with this dose level, a limit of ≤ 145 mcg/L
`aluminum is needed.” Ex. 1019, 1. This aluminum level in the FDA demand
`is even lower than the previously recited aluminum dose for parenteral
`nutrition enacted in July 2004. Compare Ex. 1019, 1 (aluminum limited to
`limited to ≤ 0.6 mcg/kg/day) with Ex. 1007, 2 (aluminum dose of 4 to 5
`mcg/kg/ day). The letter to Patent Owner also noted that due to the
`extremely low pH of their drug product, pH 1–2.5, it is also necessary to
`assess the leachables/extractables from any new container Exela Pharma
`Sciences may wish to use. Ex. 1009, 2. Based on these disclosures, we agree
`with Petitioner that the evidence supports the position that there is
`motivation to lower aluminum contamination in total parenteral nutritional
`solutions, specifically, to avoid aluminum toxicity.
`Motivation alone, however, is not sufficient for reaching a conclusion
`of obviousness. Obviousness also requires a reasonable expectation of
`success. Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d
`1359, 1367 (Fed. Cir. 2016). As Patent Owner argues, Petitioner’s reliance
`on the FDA regulation regarding aluminum threshold goal does not say
`anything about how to achieve the goal. Prelim. Resp. 61. In other words,
`knowing the FDA’s goal may provide a motivation to try and lower
`aluminum levels in total parenteral nutritional supplements but that does not
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`provide a path of how to achieve the stated goal. Prelim Resp. 61–62 (citing
`Endo Pharm. Inc. v. ActavisLLC, 922 F.3d 1365, 1376 (Fed. Cir. 2019)
`(finding that FDA communications did not show a reasonable expectation of
`success where they merely “recite[d] a goal without teaching how the goal is
`attained”); In re Cyclobenzaprine HCl Extended Release Capsule Patent
`Litig., 676 F.3d 1063, 1074 (Fed. Cir. 2013) (reversing obviousness
`determination and rejecting district court’s reliance on FDA guidance
`document about approval requirements for extended-release formulations
`because “‘knowledge of the goal does not render its achievement obvious’”
`(quoting Abbott Labs, Inc. v. Sandoz, Inc., 544 F.3d 1341, 1352 (Fed. Cir.
`2009))). To be sure, “[o]bviousness does not require absolute predictability
`of success.” In re O’Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988). But it is
`also not permissible to reach an obviousness conclusion by allowing each of
`numerous possible choices to be tried until one possibly arrived at a
`successful result. See id.
`Petitioner attempts to further bolster its routine o
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