UNITED STATES PATENT AND TRADEMARK OFFICE
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`———————
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`———————
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`ETON PHARMACEUTICALS, INC.,
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`Petitioner
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`v.
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`EXELA PHARMA SCIENCES, LLC,
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`Patent Owner
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`———————
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`U.S. PATENT NO. 10,478,453
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`PGR2020-00064
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`PETITIONER’S REPLY TO PATENT OWNER’S
`PRELIMINARY RESPONSE
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`———————
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`———————
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`ETON PHARMACEUTICALS, INC.,
`
`Petitioner
`
`v.
`
`EXELA PHARMA SCIENCES, LLC,
`
`Patent Owner
`
`———————
`
`U.S. PATENT NO. 10,478,453
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`PGR2020-00064
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`PETITIONER’S REPLY TO PATENT OWNER’S
`PRELIMINARY RESPONSE
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`
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`PGR2020-00064: Reply to Patent Owner’s Preliminary Response
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`Pursuant to the Order (Paper No. 7) entered September 24, 2020, Petitioner
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`files this reply to the Patent Owner’s Preliminary Response (“POPR”).1
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`I. THE PETITION MEETS THE PARTICULARITY REQUIREMENT
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`The claimed invention is the result of optimizing the product of the Sandoz
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`Label using art-proven techniques for substantially preventing (1) oxidative
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`degradation of L-Cysteine to L-cystine and pyruvic acid and (2) aluminum
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`contamination.2
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`Patent Owner’s (“PO”) assertion that the Petition (Paper 1, “Pet.”) lacks
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`particularity is incorrect. The Petition relies on the four-corners of the Sandoz Label,
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`which discloses an injectable L-Cysteine solution for use in a total parenteral
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`1 The Order authorizes a 6-page reply.
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`2 Shortly prior to the alleged invention, FDA began requiring substantially reduced
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`aluminum levels as a condition for approving small volume parenteral (“SVP”)
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`products. (Pet. at 35-37; Ex. 1003, ¶¶29-30, 34-41.) Although PO asserts that those
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`FDA communications do not qualify as prior art, they nevertheless pre-date the
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`alleged invention, are relevant to the skill of the POSITA and demonstrate that
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`several companies promptly and successfully reduced aluminum contamination in
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`their respective SVPs in response to FDA pressure. (E.g., Pet. at 36; Ex. 1003, ¶¶34-
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`41.)
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`1
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`PGR2020-00064: Reply to Patent Owner’s Preliminary Response
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`nutrition regimen. (Pet. at 6, 27-29; Ex. 1003, ¶¶31-32.) According to its four
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`corners, the Sandoz Label product contains NMT 5,000 mcg/L (or ppb) aluminum3,
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`has a pH of 1.0-2.5, and air is replaced with nitrogen. (Pet. at 27; Ex. 1003, ¶¶31-
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`32.)4
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`The Petition also identifies with particularity the knowledge prompting the
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`POSITA to optimize the Sandoz Label product as claimed.
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`o L-Cysteine oxidation occurs at alkaline, neutral and acidic pH. (Pet. at 38-
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`40, 42; Ex. 1003, ¶¶42-47.)5
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`3 Even if, as PO asserts, the clinician would assume 5,000 ppb aluminum in the
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`Sandoz Label product for dosing purposes the POSITA would nevertheless have
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`understood that that the actual aluminum levels in the Sandoz Label product ranged
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`from 0-5,000 ppb depending on the age of the product, which PO acknowledges
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`increases in aluminum content over the product’s shelf life. (POPR (Paper 6) at 11.)
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`4 The product attributes not expressly disclosed within the four corners of the Sandoz
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`Label are nevertheless relevant to the level of skill of the POSITA.
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`5 PO’s assertion that the POSITA would not be concerned with oxidation at acidic
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`pH is belied by the plain teaching of the Sandoz Label, which discloses replacing air
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`with nitrogen in an L-Cysteine solution having a pH of 1.0-2.5. (Ex. 1003, ¶31)
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`
`
`
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`2
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`
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`PGR2020-00064: Reply to Patent Owner’s Preliminary Response
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`o L-cystine (which form unwanted precipitates) and pyruvic acid (which
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`reduces efficacy) are oxidation degradation products of L-Cysteine. (Pet.
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`at 38; Ex. 1003, ¶¶42-47.)
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`o Removing head space and dissolved oxygen are result-effective variables
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`for substantially preventing degradation of oxygen sensitive drugs. (Pet. at
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`29-30, 39, 42, 46, 48-49; Ex. 1003, ¶¶48-51, 107-110, 112-113.)6
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`o The reasonably expected result of minimizing head space and dissolved
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`oxygen is the substantial prevention of oxidative degradation of L-
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`Cysteine to L-cystine and pyruvic acid. (Pet. at 38-40, 46-47; Ex. 1003,
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`¶¶42, 45-51, 59-60, 100-105.)
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`o Aluminum leaching from glass vials was a significant source of aluminum
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`contamination (Pet. at 37-38; Ex. 1003, ¶¶33, 54-58.)
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`o Coated glass vials substantially prevent aluminum leaching. (Pet. at 41, 46;
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`Ex. 1003, ¶¶56-57.)
`
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`6 Butler, which is relied upon to show that the claimed dissolved oxygen levels were
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`known and achievable, does not “teach away.” (POPR at 35). Butler’s concerns
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`about trace oxygen when mimicking the sulfide chemistry of the ancient Earth’s
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`oxygen-free environment would not have discouraged the POSITA from using
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`nitrogen (as taught by the Sandoz Label) to prevent oxidation of L-Cysteine.
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`
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`3
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`
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`PGR2020-00064: Reply to Patent Owner’s Preliminary Response
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`o Heavy metals are toxic and can influence efficacy and thus should be
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`minimized within acceptable limits. (Pet. at 40, 42, 56; Ex. 1003, ¶¶52,
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`158.)
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`The Petition demonstrates that the POSITA, armed with this knowledge,
`
`would and could have optimized the Sandoz Label product to substantially prevent
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`oxidation of L-Cysteine to L-cystine and pyruvic acid by limiting oxygen exposure
`
`at the claimed dissolved and headspace oxygen concentrations, which are merely
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`result-effective variables to achieve the reasonably expected result of preventing
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`oxidation of L-Cysteine to L-cystine and pyruvic acid. (Pet. at 29-30, 40-43, 46-49;
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`Ex. 1003, ¶¶53-70, 96, 100-113.)7 The POSITA would also have been motivated to
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`store the optimized Sandoz Label product in a container that substantially prevents
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`aluminum from leaching during the product’s projected shelf life. (Pet. at 38, 42, 45-
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`46; Ex. 1003, ¶¶56-58).8
`
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`7 E.g., Anacor Pharms., Inc. v. Flatwing Pharms., Inc., No. 2019-2264, 2020 WL
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`5049229, at *4 (Fed. Cir. Aug. 27, 2020) (affirming Board’s obviousness finding
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`where claims directed to routine optimization of result-effective variable).
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`8 PO’s assertion that the “POSITA would have had to know before attempting any
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`optimization that L-cystine and oxygen levels were relevant to solving the aluminum
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`problem” is incorrect. (POPR at 46.) Setting aside that PO has not demonstrated that
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`
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`4
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`PGR2020-00064: Reply to Patent Owner’s Preliminary Response
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`II. REJECTIONS IN RELATED APPLICATIONS
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`The POPR cites the Notice of Allowance in the ’453 patent in arguing that the
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`art is “unpredictable” and the claimed invention achieved unexpected results. (POPR
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`at 17.) However, PO neglected to advise the Board that, on July 23, 2020 (more than
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`a month prior to filing the POPR), the same Examiner recently rejected previously
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`allowed claims in two related applications after the PO’s citation of this Petition.9
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`L-cystine and oxygen levels unpredictably impact the “aluminum problem,” the
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`POSITA would have reasonably expected that the aluminum problem would be
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`addressed by storing the Sandoz Label product (optimized to prevent oxidation of
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`L-Cysteine) in coated glass vials treated to prevent aluminum leaching. (Pet. at 41;
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`Ex. 1003, ¶¶56-70.)
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`9 Relevant file history excerpts include: claims as they existed at the time of the
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`Notice of Allowances (“NOA”) (Ex. 1084 at 1-4; Ex. 1085 at 1-3), NOAs (Ex. 1086
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`at 1, 5-7; Ex. 1087 at 1, 5-7), Information Disclosure Statements (“IDS”) filed on
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`April 17, 2020 (Ex. 1092 at 1, 4; Ex. 1093 at 1, 4) and associated Geissler declaration
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`(Ex. 1094 at 2-8, 43, 45, 49); Requests for Continued Examination and related IDSs
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`(Ex. 1088 at 1-32; Ex. 1089 at 1-26), citing to Petitioner’s PGRs (Ex. 1088 at 7 (No.
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`241), 25 (No. 305); Ex. 1089 at 9 (No. 241), 19 (No. 305)), and the Examiner’s
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`rejections (Ex. 1090 at 2-7; Ex. 1091 at 2-7).
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`5
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`PGR2020-00064: Reply to Patent Owner’s Preliminary Response
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`III. THE ALLERGY PROCESS IS A PUBLIC USE
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`Contrary to PO’s assertion, the Johnson declaration includes corroborating
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`evidence. These documents are not marked confidential and corroborate Mr.
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`Johnson’s testimony that the Allergy Process was used in the ordinary course of
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`business, was known to Allergy Labs personnel and no steps were taken to keep the
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`process confidential. (Ex. 1022 at ¶18 and pp.13-67, 69-101, 113-124.) There is
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`simply no evidentiary support for PO’s speculation that the Allergy Process was
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`subject to an implied expectation of secrecy. At most, the third-party COAs from
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`KABS demonstrate that KABs owed Allergy Labs an obligation of confidentiality
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`with respect to these preliminary test results. However, the final test results are
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`recorded on Allergy Labs COAs that are not marked confidential. Moreover,
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`regardless of the confidentiality of the preliminary test results from KABS, Mr.
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`Johnson’s testimony and the corroborating evidence demonstrate a reasonable
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`likelihood that the Allergy Process itself qualifies as a public use.10
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`Respectfully submitted,
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`
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`10 Even if not a public use (and it is), the Allergy Process is nevertheless relevant to
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`the skill of the POSITA. See Newell Co., Inc. v. Kenney Mfg. Co., 864 F.2d 757, 766
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`n.12 (Fed. Cir. 1988) (information not prior art may nevertheless be relevant to level
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`of skill in the art at the time of alleged invention).
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`6
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`PGR2020-00064: Reply to Patent Owner’s Preliminary Response
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`September 28, 2020
`
`
`
`
`
`
`/s/ Ralph J. Gabric
`
`Ralph J. Gabric (Reg. No 34,167)
`HAYNES and BOONE LLP
`2323 Victory Ave. Suite 700
`Dallas, TX 75219
`Tel.: (312) 216-1620
`ralph.gabric.ipr@haynesboone.com
`
`Counsel for Petitioner
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`
`
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`
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`7
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`PGR2020-00064: Reply to Patent Owner’s Preliminary Response
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`CERTIFICATE OF SERVICE
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`Pursuant to 37 C.F.R. §§ 42.105 and 42.6, I certify I caused a true and correct
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`copy of the forgoing document on Patent Owner as detailed below.
`
`
`
`Date of service September 28, 2020
`
`Person served Dorothy P. Whelan
`PGR48751-0005PS1@fr.com
`
`Alana Mannige
`PTABInbound@fr.com
`
`
`
`
`
`/s/ Ralph J. Gabric
`Ralph J. Gabric (Reg. No 34,167)
`HAYNES AND BOONE LLP
`2323 Victory Ave. Suite 700
`Dallas, TX 75219
`Tel.: (312) 216-1620
`ralph.gabric.ipr@haynesboone.com
`Counsel for Petitioner
`
`
`
`
`
`8
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`
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