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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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`———————
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`U.S. PATENT NO. 10,653,719
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`PGR2020-00086
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`PETITIONER’S REPLY TO PATENT OWNER’S
`PRELIMINARY RESPONSE
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`TABLE OF CONTENTS
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`I. The Petition Establishes A Reasonable Expectation of Success ......................... 1
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`II. The Petition Meets The Particularity Requirement ............................................. 8
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`III. Discretionary Denial Under 35 U.S.C. § 324(A) Is Not Appropriate ................. 9
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`i
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`Petitioner files this Reply to Patent Owner’s Preliminary Response
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`(“POPR”).1
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`I.
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`The Petition Establishes A Reasonable Expectation of Success
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`Patent Owner (“PO”) argues that the Petition fails to establish a reasonable
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`expectation of success in achieving the claimed aluminum levels, urging the Board
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`to adopt the reasoning from the decisions denying institution in related PGR2020-
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`00064 and PGR2020-00068. Paper 6 at 1, 24-25, n.61, 54-55, n.120. However, PO
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`neglects to address Petitioner’s pending Requests for Rehearing in those PGRs,
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`copies of which are submitted herewith.2 As explained in those Requests, regardless
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`of how the Sandoz Label’s “no more than 5,000 [ppb]” of aluminum is interpreted,
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`the POSITA would have had a reasonable expectation of success of achieving the
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`claimed aluminum levels by simply preventing the known sources of aluminum
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`contamination. Ex. 1125 at 5-9; Ex. 1126 at 5-9.3
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`1 The Board authorized a 10-page reply. Ex. 1124 at 16.
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` Exhibit 1125 (PGR2020-00064 Paper 13) and Exhibit 1126 (PGR2020-00068
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` 2
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`Paper 12).
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`3 The Requests for Rehearing also explain that the POSITA would have interpreted
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`“no more than 5,000 [ppb]” to disclose aluminum levels ranging between 0 up to
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`1
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`Similarly, the current Petition demonstrated that a reasonable expectation of
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`success existed regardless of how the Sandoz Label’s “no more than 5,000 [ppb]” of
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`aluminum is interpreted. The POSITA motivated to reduce aluminum would have
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`reasonably expected that the Sandoz Label product could have been optimized to
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`achieve the claimed aluminum levels by simply removing the known sources of
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`aluminum contamination; namely, (1) using starting ingredients substantially free of
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`aluminum, (2) ensuring that the manufacturing process did not contaminate the drug
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`product with aluminum, and (3) storing the Sandoz Label product in a container that
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`substantially prevents aluminum from leaching into the drug product, such as the
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`Schott coated glass vials. Paper 1 at 32-33, 38 (last bullet point), 40, 44.4 By
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`5,000 ppb, depending on the age of product. Ex. 1125 at 9-11; Ex. 1126 at 9-11.
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`The current Petition explained this, as well. Paper 1 at 27.
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`4 The Schott coated glass vials (aka Schott Type I Plus® vials) were known to
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`substantially eliminate glass leachables including aluminum. Ex. 1003, ¶61 (and
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`n.86), 70, 94; Ex. 1014 at 7-8 (explaining that the Schott coated glass vials include
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`an inner surface coated “with an ultrathin film of silicon dioxide [that] forms a highly
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`efficient diffusion barrier that practically eliminates glass leachables”); Ex. 1048 at
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`12, 12:20-39 (the Schott coated glass vials substantially prevent aluminum
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`leachables in an Ibuprofen Lysine solution) see also Ex. 1048 at 14, Tables 16-18
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`2
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`eliminating the known sources of aluminum, the POSITA—quite logically—would
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`have had a reasonable expectation of achieving the claimed aluminum levels,
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`regardless of how the POSITA interpreted the Sandoz Label’s “no more than 5,000
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`[ppb].” Paper 1 at 44.5
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`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.
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`However, PO does not cite to any failed attempts. To the contrary, years before the
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`alleged invention, the Sandoz Label product manufactured by Allergy Labs had the
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`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-
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`(aluminum below 9 ppb in solutions stored in the Schott coated glass vials after 9
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`months storage). The POSITA would have reasonably expected that the Schott
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`coated glass vials would be similarly effective in preventing aluminum from
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`leaching into the Sandoz Label product. Paper 1 at 43-44; Ex. 1003, ¶61.
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`5 Although the Petition also asserted prima facie obviousness based upon
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`overlapping ranges (Paper 1 at 42), the reasonable expectation of success did not
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`require overlapping ranges. Id. at 43-44.
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`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-
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`cysteine contain specified aluminum levels during the product’s shelf-life below
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`those previously mandated, the industry promptly complied, reducing aluminum
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`levels as reflected by the product labels. Paper 1 at 31-32; Ex. 1003, ¶¶ 34-38. Thus,
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`in response to FDA regulatory pressure the industry promptly “solved” the PO’s
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`alleged aluminum “problem” – a problem that was to a large extent already solved
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`by the Sandoz Label product and, as the POSITA would have reasonably expected,
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`readily solvable by eliminating the known sources of aluminum contamination.
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`PO attempts to inject phantom complexity into what, by the time of the alleged
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`invention, was a straight forward and simple solution to minimizing or preventing
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`aluminum contamination. For example, PO irrelevantly argues that multiple
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`variables (i.e., oxygen levels, pH, trace metals, cystine concentration) can “affect the
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`6 PO’s assertion that the Sandoz Label product manufactured by Allergy does not
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`qualify as prior art is without merit. Prior to the ’719 patent’s effective filing date,
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`Allergy sold the Sandoz Label product to Sandoz (Ex. 1022, ¶¶8-11 (Ex. A (pp. 49.
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`53-55)) and post-release the product was publicly available. For at least these two
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`separate reasons, the Sandoz Label product manufactured by Allergy qualifies as
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`prior art under 35 U.S.C. §102(a).
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`4
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`extent of aluminum leaching from glass containers historically used to store L-
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`cysteine solutions.” Paper 6 at 20 (emphasis added). However, by the time of the
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`alleged invention in or around 2019, the POSITA motivated to reduce aluminum
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`contamination would not have opted for the “historically”-used glass vials, because
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`they were not coated or otherwise treated to prevent leachables such as aluminum.
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`Paper 1 at 33. Instead, the POSITA would have packaged the Sandoz Label product
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`in the Schott coated glass vials, which were known to substantially prevent
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`aluminum from leaching into the drug product (Id. at 33, 40, 43), thereby removing
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`the alleged “variables” that influenced aluminum leaching from glass vials that were
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`“historically” used.
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`PO also argues (citing to 5:19-23 of the patent specification) that the inventors
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`unexpectedly discovered that “removing Aluminum may have the unintended
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`consequence of increased [cystine] precipitation. . . in the presence of even small
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`amounts of oxygen in the container.” Paper 6 at 21 (emphasis added). Not only is
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`this assertion unsupported by reliable data, but also even if accepted as true (and it
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`should not be at this stage of the proceedings), it is nevertheless immaterial. As the
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`Petition explains, the POSITA would have taken steps to substantially eliminate
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`oxygen to prevent oxidative degradation of L-cysteine into cystine. Paper 1 at 33-
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`35; Ex. 1003, ¶ 42 (noting that cystine forms particulate matter). As the POSITA
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`would have reasonably expected, by substantially eliminating oxygen and
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`5
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`controlling pH (and thus the known oxidation of L-cysteine to cystine) the formation
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`of cystine precipitates would be substantially prevented regardless of the alleged
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`stabilizing influence of aluminum on cystine. Paper 1 at 33-35, 47.
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`Relatedly, the PO incorrectly argues that Petitioner must show that
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`“particulate matter (and by association, cystine, dissolved oxygen, and headspace
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`oxygen) represent result-effective variables” in solving the aluminum problem.
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`Paper 6 at 45-47. Not so. As the Petition explains, the known result-effective
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`variables for preventing aluminum contamination were (1) using drug product
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`starting materials substantially free of aluminum, (2) preventing aluminum
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`contamination during the manufacturing process, and (3) packaging the finished
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`product in Schott coated glass vials, which were known to substantially prevent
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`aluminum contamination. Paper 1 at 32-33, 43-44. By controlling these variables,
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`the POSITA would have reasonably expected to optimize the Sandoz Label product
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`to have the claimed aluminum levels.
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`The POSITA would have been motivated to keep the Sandoz Label product
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`free of visually detectable particulate matter, including cystine precipitates, for a
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`different reason. Particulate matter was known to be dangerous in injectable drug
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`products such as the Sandoz Label product. Paper 1 at 35-37. Indeed, the Sandoz
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`6
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`Label cautions that the product should be checked for visually detectable particulate
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`matter before use. Id. at 28; Ex. 1005 at 3, 9; Ex. 1004 at 7, 12.7
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`Finally, minimizing dissolved oxygen and headspace oxygen were known
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`result-effective variables for preventing the oxidative degradation of L-cysteine and
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`the formation of cystine precipitates. Paper 1 at 33-35.8
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`In summary, PO’s argument that the Petitioner was required to show that the
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`POSITA would have understood the alleged interrelatedness of aluminum
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`contamination and particulate matter formation is without merit. Not only does the
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`PO fail to provide reliable data establishing that these problems are interrelated, but
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`even if interrelated, the POSITA would have reasonably expected to simultaneously
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`7 The Sandoz Label product manufactured by Allergy Labs was free of visually
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`detectable particulate matter over its projected 24-month shelf-life. Paper 1 at 29;
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`Ex. 1116, ¶¶10-12, 14 (and Ex. A).
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`8 The Sandoz Label belies PO’s argument that the POSITA would have been
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`unconcerned with the potential for oxidative degradation of L-cysteine at the acidic
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`pH levels (i.e., 1.0-2.5) of the Sandoz Label product. As the POSITA would have
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`understood, air was replaced with nitrogen in the Sandoz Label product to address
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`L-cysteine’s oxygen sensitivity. Paper 1 at 34. If oxidation were not a concern, then
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`there would have been no need to replace air with nitrogen.
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`7
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`– and successfully – address both known problems. The POSITA would have
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`reasonably expected to substantially eliminate aluminum by addressing the known
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`sources of aluminum contamination. The POSITA would have reasonably expected
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`to keep the Sandoz Label product free of visually detectable particulate matter by
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`preventing oxidative degradation of L-cysteine.
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`II. The Petition Meets The Particularity Requirement
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`The Petition’s sole Ground relies on the four corners of the Sandoz Label in
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`view of the Knowledge of a POSITA. Paper 1 at 6. The Petition identifies the
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`POSITA’s Knowledge with citations to corroborating prior art and explains by
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`chapter and verse how the POSITA would have applied their knowledge to optimize
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`the Sandoz Label product to arrive at the claimed invention.
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`Relying on the institution decision in related PGR2020-00064, PO argues that
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`the Petition lacks particularity for failing to expressly list the corroborating prior art
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`in the asserted Ground. Paper 6 at 28, n.65. However, PO ignores the Request for
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`Rehearing in that PGR, which explains (with citation to controlling Federal Circuit
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`precedent) that the asserted Ground need not expressly list the corroborating prior
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`art. Ex. 1125, PGR2020-00064, Paper 13 at 12-13. The PO also ignores that in
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`related PGR2020-00068, the Board did not accept PO’s similar particularity
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`challenge. Ex. 2017, PGR2020-00068, Paper 11 at 2.
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`8
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`Equally without merit is PO’s charge that the Petition improperly “backfills”
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`the Sandoz Label with the aluminum levels found in the Sandoz product
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`manufactured by Allergy Labs. Paper 6 at 28-29. However, no backfilling is
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`required to establish obviousness. Regardless of the actual aluminum levels in the
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`Sandoz product, the POSITA would have had a reasonable expectation of achieving
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`the claimed aluminum levels by simply eliminating the known sources of aluminum
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`contamination. Paper 1 at 32-33, 43-44. Moreover, as noted above, the pre-release
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`aluminum levels in the Sandoz Label product manufactured by Allergy Labs expose
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`the fallacy of PO’s assertion that Allergy tried but failed to achieve the claimed
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`aluminum levels.
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`III. Discretionary Denial Under 35 U.S.C. § 324(A) Is Not Appropriate
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`PO incorrectly assumes that a trial on the two related ’453 and ’155 patents is
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`a foregone conclusion; it is not. Eton withdrew its motion to stay the district court
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`action without prejudice after the Board denied institution in PGR2020-00064. Ex.
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`2018. If the Board grants the pending Requests for Rehearing in related PGRs 2020-
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`00064 and 2020-00068 and institutes a trial in this PGR, then Petitioner will renew
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`its motion to stay the district court action. The district court can then decide, in its
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`discretion, whether to proceed in view of these PGRs. If the PO is truly interested
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`in avoiding parallel proceedings and purportedly unnecessary litigation, it can join
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`Petitioner’s motion and urge the district court to stay that action.
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`9
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`February 17, 2021
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`/s/ Ralph J. Gabric
`Ralph J. Gabric (Reg. No 34,167)
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`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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`10
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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 February 17, 2021
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`Person served Dorothy P. Whelan
`PGR48751-0005PS1@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)
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`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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`11
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