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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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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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`U.S. PATENT NO. 10,583,155
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`PGR2020-00068
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`PETITIONER’S REPLY TO PATENT OWNER’S
`PRELIMINARY RESPONSE
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`PGR2020-00068: Reply to Patent Owner’s Preliminary Response
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`Petitioner files this reply to Patent Owner’s Preliminary Response (“POPR”).1
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`I. THE PETITION MEETS THE PARTICULARITY REQUIREMENT
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`The challenged claims are the result of optimizing the Sandoz Label product
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`using known techniques for substantially preventing (1) oxidative degradation of L-
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`Cysteine to L-cystine and pyruvic acid and (2) aluminum contamination.2
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`The Petition’s two grounds rely 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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`nutrition regimen. (Pet. at 31-34; Ex. 1003, ¶¶33-35.)3 The Sandoz Label product
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`1 The Board authorized a 6-page reply (Paper No. 7).
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`2 Shortly prior to the alleged invention, FDA demanded substantially reduced
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`aluminum levels in small volume parenteral (“SVP”) products. (Pet. at 36-39; Ex.
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`1003, ¶¶29-32, 36-43.) Even if not statutory prior art, these FDA communications
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`pre-date the alleged invention, are relevant to the skill of the POSITA and
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`demonstrate that companies promptly and concurrently reduced aluminum
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`contamination in response to FDA pressure. (E.g., Pet. at 38-39; Ex. 1003, ¶¶36-43.)
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`3 The attributes not expressly disclosed by the Sandoz Label are nevertheless
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`relevant to the state of the art and were readily ascertainable through routine testing
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`of the commercially available product.
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`1
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`PGR2020-00068: Reply to Patent Owner’s Preliminary Response
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`contains NMT 5,000 mcg/L (or ppb) aluminum,4 has a pH of 1.0-2.5, and air is
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`replaced with nitrogen.5 (Pet. at 31-32; Ex. 1003, ¶¶33-34.)
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`The Petition identifies with particularity the knowledge prompting the
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`POSITA to have optimized the Sandoz Label product as claimed.
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`o L-Cysteine oxidation occurs at alkaline, neutral and acidic pH. (Pet. at 40-
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`42; Ex. 1003, ¶¶44-46.)
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`o L-cystine (which forms 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 40, 43; Ex. 1003, ¶¶44, 47-49.)
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`4 Contrary to the PO’s assertions, the Sandoz Label product contained substantially
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`less than 5,000 ppb (less than 375 ppb aluminum) as demonstrated by the Geissler
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`Declaration submitted in the PO’s related applications discussed below. (Ex. 1116
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`at 2-8, 45, 49). Thus, even if the pharmacist would assume 5,000 ppb aluminum for
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`dosing purposes (as PO asserts), the POSITA would have understood (and could
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`have confirmed by routine testing) that the actual level was between 0-5,000 ppb.
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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. (Pet. at 31-32.)
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`2
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`PGR2020-00068: Reply to Patent Owner’s Preliminary Response
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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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`41-43; Ex. 1003, ¶¶50-52.)
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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 44-45; Ex. 1003, ¶¶61-62.)
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`o Aluminum leaching from glass vials was a significant source of aluminum
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`contamination (Pet. at 39-40, 42-43; Ex. 1003, ¶¶35, 58-59.)
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`o Coated Schott glass vials substantially prevent aluminum leaching. (Pet. at
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`41-43; Ex. 1003, ¶¶58-62.)
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`The Petition also demonstrates with particularity that the POSITA, armed with
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`this knowledge, would and could have optimized the Sandoz Label product to
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`minimize oxygen exposure (a result-effective variable) during manufacture and
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`storage to achieve the reasonably expected result of substantially preventing
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`oxidation of L-Cysteine to L-cystine and pyruvic acid. (Pet. at 44-45; Ex. 1003, ¶60-
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`62.)6 The POSITA would also have been motivated to manufacture the optimized
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`6 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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`PGR2020-00068: Reply to Patent Owner’s Preliminary Response
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`Sandoz Label product in a substantially aluminum-free environment and store the
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`product in a Schott coated glass container that is not only oxygen impermeable but
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`also substantially prevents aluminum from leaching into the product during its
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`projected shelf life. (Pet. at 44-45; Ex. 1003, ¶¶58-62.)7
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`7 PO’s assertion that solving the “high-aluminum problem” requires optimization of
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`cystine levels (and associated dissolved oxygen and head space oxygen levels)
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`(POPR at 39) not only lacks evidentiary support but also, even if true, does not make
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`the alleged invention patentable. The POSITA addressing the aluminum problem
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`would have also understood that L-Cysteine is oxygen-sensitive. As such, the
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`POSITA would have taken known steps to prevent oxidation while also eliminating
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`the sources for aluminum contamination. Thus, for example, the POSITA would
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`have selected a Schott coated glass container, which is both oxygen impermeable
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`and does not leach aluminum. (Pet. at 42-45; Ex. 1003, ¶¶58-62.) The ’155
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`patentee’s alleged discovery of the purported benefit of preventing oxidation to
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`minimizing aluminum contamination (even if true) is merely the discovery of an
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`additional benefit of optimizing the Sandoz Label product to prevent oxidation as
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`taught by the prior art. See In re Woodruff, 919 F.2d 1575, 1578 (Fed. Cir. 1990) (“It
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`is a general rule that merely discovering and claiming a new benefit of an old process
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`cannot render the process again patentable.”).
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`PGR2020-00068: 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 (“NOA”) in the parent ’453 patent
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`in arguing that the Examiner acknowledged that the alleged “unpredictable nature of
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`the art” and that the claimed subject matter allegedly achieved “unexpected
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`result[s].” (POPR at 19.) However, PO neglected to advise the Board that, on July
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`23, 2020 (before the POPR), the same Examiner—apparently no longer considering
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`the art “unpredictable” or the claimed aluminum levels and steps for preventing
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`oxidative degradation of L-Cysteine “unexpected”—rejected previously allowed
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`claims directed to this subject matter in two related applications after this Petition
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`and the Petition filed in related PGR No. 2020-00064 were made of record.8
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`Consistent with the Petition (Pet. at 37; Ex. 1003, ¶36), the Examiner noted
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`that Hernandez-Sanchez teaches that aluminum content should be limited in
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`8 Relevant file history excerpts included with this Reply are: claims as they existed
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`at the time of the NOAs (Ex. 1106 at 1-4; Ex. 1107 at 1-3), NOAs (Ex. 1108 at 1, 5-
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`7; Ex. 1109 at 1, 5-7), IDSs filed on April 17, 2020 (Ex. 1114 at 1, 4; Ex. 1115 at 1,
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`4) and associated Geissler declaration (Ex. 1116 at 2-8, 43, 45, 49); Requests for
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`Continued Examination and related IDSs (Ex. 1110 at 1-32; Ex. 1111 at 1-26), citing
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`Petitioner’s PGRs (Ex. 1110 at 7 (No. 241), 25 (No. 305); Ex. 1111 at 9 (No. 241),
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`19 (No. 305)), and the Examiner’s rejections (Ex. 1112 at 2-7; Ex. 1113 at 2-7).
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`5
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`PGR2020-00068: Reply to Patent Owner’s Preliminary Response
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`parenteral compositions, steps for reducing aluminum were known, but few
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`manufacturers put the procedures into use. (Ex. 1112 at 5; Ex. 1113 at 5). And,
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`notwithstanding PO’s spin otherwise, Hernandez-Sanchez does not recognize a
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`long-felt but unresolved need relevant to patentability. (POPR at 52.) Rather,
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`Hernandez-Sanchez recognized that the market had failed to demand manufacturers
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`meet this need, and as confirmed by the prior art and the contemporaneous FDA
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`communications cited in the Petition, manufacturers promptly and concurrently met
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`this need when pressed by the FDA. (Pet. at 36-39; Ex. 1003, ¶¶36-43.)
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`Finally, PO may quibble with the Examiner’s rejections such as their reliance
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`on Nakayama (Ex. 1117), which discloses a coating for preventing alkali earth metal
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`leaching that contains 0.1 ppm (100 ppb) aluminum. The POSITA interested in
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`preventing aluminum leaching would have opted for other coatings, such as the
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`Schott coated glass vials discussed in the Petition. (Pet. at 42-45; Ex. 1003, ¶¶58-
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`62.) Similarly, although the Examiner mistakenly cites Asquith for teaching
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`oxidative degradation of cysteine (it discusses cystine degradation), Petitioner’s
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`references address L-cysteine’s oxygen sensitivity. (Pet. at 40-42; Ex. 1003, ¶¶44-
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`53.) However, none of this diminishes the relevance of the Examiner’s rejections,
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`which confirm that the alleged invention is simply the reasonably expected result of
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`using known techniques for substantially preventing oxidative degradation of L-
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`Cysteine and aluminum contamination, as set forth in the Petition.
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`6
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`PGR2020-00068: Reply to Patent Owner’s Preliminary Response
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`October 19, 2020
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`Respectfully submitted,
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`/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
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`Counsel for Petitioner
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`7
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`PGR2020-00068: 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.
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`Date of service October 19, 2020
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`Person served Dorothy P. Whelan
`PGR48751-0005PSa@fr.com
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`Alana Mannige
`PTABInbound@fr.com
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`/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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`8
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