UNITED STATES PATENT AND TRADEMARK OFFICE
`
`———————
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`———————
`
`ETON PHARMACEUTICALS, INC.,
`
`Petitioner
`
`v.
`
`EXELA PHARMA SCIENCES, LLC,
`
`Patent Owner
`
`———————
`
`U.S. PATENT NO. 10,653,719
`
`PGR2020-00086
`
`PETITIONER’S REPLY TO PATENT OWNER’S
`PRELIMINARY RESPONSE
`
`
`
`
`
`
`
`———————
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`———————
`
`ETON PHARMACEUTICALS, INC.,
`
`Petitioner
`
`v.
`
`EXELA PHARMA SCIENCES, LLC,
`
`Patent Owner
`
`———————
`
`U.S. PATENT NO. 10,653,719
`
`PGR2020-00086
`
`PETITIONER’S REPLY TO PATENT OWNER’S
`PRELIMINARY RESPONSE
`
`
`
`
`
`
`
`
`
`TABLE OF CONTENTS
`
`I. The Petition Establishes A Reasonable Expectation of Success ......................... 1
`
`II. The Petition Meets The Particularity Requirement ............................................. 8
`
`III. Discretionary Denial Under 35 U.S.C. § 324(A) Is Not Appropriate ................. 9
`
`
`
`i
`
`
`
`
`
`Petitioner files this Reply to Patent Owner’s Preliminary Response
`
`(“POPR”).1
`
`I.
`
`The Petition Establishes A Reasonable Expectation of Success
`
`Patent Owner (“PO”) argues that the Petition fails to establish a reasonable
`
`expectation of success in achieving the claimed aluminum levels, urging the Board
`
`to adopt the reasoning from the decisions denying institution in related PGR2020-
`
`00064 and PGR2020-00068. Paper 6 at 1, 24-25, n.61, 54-55, n.120. However, PO
`
`neglects to address Petitioner’s pending Requests for Rehearing in those PGRs,
`
`copies of which are submitted herewith.2 As explained in those Requests, regardless
`
`of how the Sandoz Label’s “no more than 5,000 [ppb]” of aluminum is interpreted,
`
`the POSITA would have had a reasonable expectation of success of achieving the
`
`claimed aluminum levels by simply preventing the known sources of aluminum
`
`contamination. Ex. 1125 at 5-9; Ex. 1126 at 5-9.3
`
`
`1 The Board authorized a 10-page reply. Ex. 1124 at 16.
`
` Exhibit 1125 (PGR2020-00064 Paper 13) and Exhibit 1126 (PGR2020-00068
`
` 2
`
`Paper 12).
`
`3 The Requests for Rehearing also explain that the POSITA would have interpreted
`
`“no more than 5,000 [ppb]” to disclose aluminum levels ranging between 0 up to
`
`1
`
`
`
`
`
`Similarly, the current Petition demonstrated that a reasonable expectation of
`
`success existed regardless of how the Sandoz Label’s “no more than 5,000 [ppb]” of
`
`aluminum is interpreted. The POSITA motivated to reduce aluminum would have
`
`reasonably expected that the Sandoz Label product could have been optimized to
`
`achieve the claimed aluminum levels by simply removing the known sources of
`
`aluminum contamination; namely, (1) using starting ingredients substantially free of
`
`aluminum, (2) ensuring that the manufacturing process did not contaminate the drug
`
`product with aluminum, and (3) storing the Sandoz Label product in a container that
`
`substantially prevents aluminum from leaching into the drug product, such as the
`
`Schott coated glass vials. Paper 1 at 32-33, 38 (last bullet point), 40, 44.4 By
`
`
`5,000 ppb, depending on the age of product. Ex. 1125 at 9-11; Ex. 1126 at 9-11.
`
`The current Petition explained this, as well. Paper 1 at 27.
`
`4 The Schott coated glass vials (aka Schott Type I Plus® vials) were known to
`
`substantially eliminate glass leachables including aluminum. Ex. 1003, ¶61 (and
`
`n.86), 70, 94; Ex. 1014 at 7-8 (explaining that the Schott coated glass vials include
`
`an inner surface coated “with an ultrathin film of silicon dioxide [that] forms a highly
`
`efficient diffusion barrier that practically eliminates glass leachables”); Ex. 1048 at
`
`12, 12:20-39 (the Schott coated glass vials substantially prevent aluminum
`
`leachables in an Ibuprofen Lysine solution) see also Ex. 1048 at 14, Tables 16-18
`
`2
`
`
`
`
`
`eliminating the known sources of aluminum, the POSITA—quite logically—would
`
`have had a reasonable expectation of achieving the claimed aluminum levels,
`
`regardless of how the POSITA interpreted the Sandoz Label’s “no more than 5,000
`
`[ppb].” Paper 1 at 44.5
`
`Attempting to bolster its alleged no expectation of success argument, PO
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`incorrectly argues that others tried but failed to solve the aluminum problem.
`
`However, PO does not cite to any failed attempts. To the contrary, years before the
`
`alleged invention, the Sandoz Label product manufactured by Allergy Labs had the
`
`claimed aluminum levels shortly prior to product release; namely, 17 ppb, 61 ppb,
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`37 ppb, 18 ppb, 50 ppb, 54 ppb, 46 ppb, 47 ppb, 48 ppb, and 43 ppb. Paper 1 at 28-
`
`
`(aluminum below 9 ppb in solutions stored in the Schott coated glass vials after 9
`
`months storage). The POSITA would have reasonably expected that the Schott
`
`coated glass vials would be similarly effective in preventing aluminum from
`
`leaching into the Sandoz Label product. Paper 1 at 43-44; Ex. 1003, ¶61.
`
`5 Although the Petition also asserted prima facie obviousness based upon
`
`overlapping ranges (Paper 1 at 42), the reasonable expectation of success did not
`
`require overlapping ranges. Id. at 43-44.
`
`3
`
`
`
`
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`29; Ex. 1022, ¶15 (Ex. B (pp. 103-112) and Ex. C (pp. 114-123)).6 And, once the
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`FDA required that small volume parenteral (“SVP”) drug products such as L-
`
`cysteine contain specified aluminum levels during the product’s shelf-life below
`
`those previously mandated, the industry promptly complied, reducing aluminum
`
`levels as reflected by the product labels. Paper 1 at 31-32; Ex. 1003, ¶¶ 34-38. Thus,
`
`in response to FDA regulatory pressure the industry promptly “solved” the PO’s
`
`alleged aluminum “problem” – a problem that was to a large extent already solved
`
`by the Sandoz Label product and, as the POSITA would have reasonably expected,
`
`readily solvable by eliminating the known sources of aluminum contamination.
`
`PO attempts to inject phantom complexity into what, by the time of the alleged
`
`invention, was a straight forward and simple solution to minimizing or preventing
`
`aluminum contamination. For example, PO irrelevantly argues that multiple
`
`variables (i.e., oxygen levels, pH, trace metals, cystine concentration) can “affect the
`
`
`6 PO’s assertion that the Sandoz Label product manufactured by Allergy does not
`
`qualify as prior art is without merit. Prior to the ’719 patent’s effective filing date,
`
`Allergy sold the Sandoz Label product to Sandoz (Ex. 1022, ¶¶8-11 (Ex. A (pp. 49.
`
`53-55)) and post-release the product was publicly available. For at least these two
`
`separate reasons, the Sandoz Label product manufactured by Allergy qualifies as
`
`prior art under 35 U.S.C. §102(a).
`
`4
`
`
`
`
`
`extent of aluminum leaching from glass containers historically used to store L-
`
`cysteine solutions.” Paper 6 at 20 (emphasis added). However, by the time of the
`
`alleged invention in or around 2019, the POSITA motivated to reduce aluminum
`
`contamination would not have opted for the “historically”-used glass vials, because
`
`they were not coated or otherwise treated to prevent leachables such as aluminum.
`
`Paper 1 at 33. Instead, the POSITA would have packaged the Sandoz Label product
`
`in the Schott coated glass vials, which were known to substantially prevent
`
`aluminum from leaching into the drug product (Id. at 33, 40, 43), thereby removing
`
`the alleged “variables” that influenced aluminum leaching from glass vials that were
`
`“historically” used.
`
`PO also argues (citing to 5:19-23 of the patent specification) that the inventors
`
`unexpectedly discovered that “removing Aluminum may have the unintended
`
`consequence of increased [cystine] precipitation. . . in the presence of even small
`
`amounts of oxygen in the container.” Paper 6 at 21 (emphasis added). Not only is
`
`this assertion unsupported by reliable data, but also even if accepted as true (and it
`
`should not be at this stage of the proceedings), it is nevertheless immaterial. As the
`
`Petition explains, the POSITA would have taken steps to substantially eliminate
`
`oxygen to prevent oxidative degradation of L-cysteine into cystine. Paper 1 at 33-
`
`35; Ex. 1003, ¶ 42 (noting that cystine forms particulate matter). As the POSITA
`
`would have reasonably expected, by substantially eliminating oxygen and
`
`5
`
`
`
`
`
`controlling pH (and thus the known oxidation of L-cysteine to cystine) the formation
`
`of cystine precipitates would be substantially prevented regardless of the alleged
`
`stabilizing influence of aluminum on cystine. Paper 1 at 33-35, 47.
`
`Relatedly, the PO incorrectly argues that Petitioner must show that
`
`“particulate matter (and by association, cystine, dissolved oxygen, and headspace
`
`oxygen) represent result-effective variables” in solving the aluminum problem.
`
`Paper 6 at 45-47. Not so. As the Petition explains, the known result-effective
`
`variables for preventing aluminum contamination were (1) using drug product
`
`starting materials substantially free of aluminum, (2) preventing aluminum
`
`contamination during the manufacturing process, and (3) packaging the finished
`
`product in Schott coated glass vials, which were known to substantially prevent
`
`aluminum contamination. Paper 1 at 32-33, 43-44. By controlling these variables,
`
`the POSITA would have reasonably expected to optimize the Sandoz Label product
`
`to have the claimed aluminum levels.
`
`The POSITA would have been motivated to keep the Sandoz Label product
`
`free of visually detectable particulate matter, including cystine precipitates, for a
`
`different reason. Particulate matter was known to be dangerous in injectable drug
`
`products such as the Sandoz Label product. Paper 1 at 35-37. Indeed, the Sandoz
`
`6
`
`
`
`
`
`Label cautions that the product should be checked for visually detectable particulate
`
`matter before use. Id. at 28; Ex. 1005 at 3, 9; Ex. 1004 at 7, 12.7
`
`Finally, minimizing dissolved oxygen and headspace oxygen were known
`
`result-effective variables for preventing the oxidative degradation of L-cysteine and
`
`the formation of cystine precipitates. Paper 1 at 33-35.8
`
`In summary, PO’s argument that the Petitioner was required to show that the
`
`POSITA would have understood the alleged interrelatedness of aluminum
`
`contamination and particulate matter formation is without merit. Not only does the
`
`PO fail to provide reliable data establishing that these problems are interrelated, but
`
`even if interrelated, the POSITA would have reasonably expected to simultaneously
`
`
`7 The Sandoz Label product manufactured by Allergy Labs was free of visually
`
`detectable particulate matter over its projected 24-month shelf-life. Paper 1 at 29;
`
`Ex. 1116, ¶¶10-12, 14 (and Ex. A).
`
`8 The Sandoz Label belies PO’s argument that the POSITA would have been
`
`unconcerned with the potential for oxidative degradation of L-cysteine at the acidic
`
`pH levels (i.e., 1.0-2.5) of the Sandoz Label product. As the POSITA would have
`
`understood, air was replaced with nitrogen in the Sandoz Label product to address
`
`L-cysteine’s oxygen sensitivity. Paper 1 at 34. If oxidation were not a concern, then
`
`there would have been no need to replace air with nitrogen.
`
`7
`
`
`
`
`
`– and successfully – address both known problems. The POSITA would have
`
`reasonably expected to substantially eliminate aluminum by addressing the known
`
`sources of aluminum contamination. The POSITA would have reasonably expected
`
`to keep the Sandoz Label product free of visually detectable particulate matter by
`
`preventing oxidative degradation of L-cysteine.
`
`
`
`II. The Petition Meets The Particularity Requirement
`
`The Petition’s sole Ground relies on the four corners of the Sandoz Label in
`
`view of the Knowledge of a POSITA. Paper 1 at 6. The Petition identifies the
`
`POSITA’s Knowledge with citations to corroborating prior art and explains by
`
`chapter and verse how the POSITA would have applied their knowledge to optimize
`
`the Sandoz Label product to arrive at the claimed invention.
`
`Relying on the institution decision in related PGR2020-00064, PO argues that
`
`the Petition lacks particularity for failing to expressly list the corroborating prior art
`
`in the asserted Ground. Paper 6 at 28, n.65. However, PO ignores the Request for
`
`Rehearing in that PGR, which explains (with citation to controlling Federal Circuit
`
`precedent) that the asserted Ground need not expressly list the corroborating prior
`
`art. Ex. 1125, PGR2020-00064, Paper 13 at 12-13. The PO also ignores that in
`
`related PGR2020-00068, the Board did not accept PO’s similar particularity
`
`challenge. Ex. 2017, PGR2020-00068, Paper 11 at 2.
`
`8
`
`
`
`
`
`Equally without merit is PO’s charge that the Petition improperly “backfills”
`
`the Sandoz Label with the aluminum levels found in the Sandoz product
`
`manufactured by Allergy Labs. Paper 6 at 28-29. However, no backfilling is
`
`required to establish obviousness. Regardless of the actual aluminum levels in the
`
`Sandoz product, the POSITA would have had a reasonable expectation of achieving
`
`the claimed aluminum levels by simply eliminating the known sources of aluminum
`
`contamination. Paper 1 at 32-33, 43-44. Moreover, as noted above, the pre-release
`
`aluminum levels in the Sandoz Label product manufactured by Allergy Labs expose
`
`the fallacy of PO’s assertion that Allergy tried but failed to achieve the claimed
`
`aluminum levels.
`
`III. Discretionary Denial Under 35 U.S.C. § 324(A) Is Not Appropriate
`
`PO incorrectly assumes that a trial on the two related ’453 and ’155 patents is
`
`a foregone conclusion; it is not. Eton withdrew its motion to stay the district court
`
`action without prejudice after the Board denied institution in PGR2020-00064. Ex.
`
`2018. If the Board grants the pending Requests for Rehearing in related PGRs 2020-
`
`00064 and 2020-00068 and institutes a trial in this PGR, then Petitioner will renew
`
`its motion to stay the district court action. The district court can then decide, in its
`
`discretion, whether to proceed in view of these PGRs. If the PO is truly interested
`
`in avoiding parallel proceedings and purportedly unnecessary litigation, it can join
`
`Petitioner’s motion and urge the district court to stay that action.
`
`9
`
`
`
`
`
`
`February 17, 2021
`
`
`
`
`
`/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
`
`
`
`10
`
`
`
`
`
`
`
`
`
`CERTIFICATE OF SERVICE
`
`Pursuant to 37 C.F.R. §§ 42.105 and 42.6, I certify I caused a true and correct
`
`copy of the forgoing document on Patent Owner as detailed below.
`
`
`
`Date of service February 17, 2021
`
`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
`
`
`
`11
`
`
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