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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 REQUEST FOR REHEARING
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`I.
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`II.
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`TABLE OF CONTENTS
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`Page
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`INTRODUCTION .......................................................................................... 1
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`BASIS FOR REHEARING ............................................................................ 1
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`A.
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`The Petition Demonstrates The POSITA Would Have Had A
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`Reasonable Expectation Of Success In Achieving The Claimed
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`Aluminum Levels ................................................................................. 1
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`B.
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`The Petition Meets The Particularity Requirement .............................. 8
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`III. CONCLUSION ............................................................................................. 14
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`i
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`Cases
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`TABLE OF AUTHORITIES
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` Page
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`Blue Coat Systems, Inc. v. Finjan, Inc.,
`IPR2016-01444, Paper 11 (P.T.A.B. July 18, 2017) ............................................ 1
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`Google Inc. v. Koninklijke Philips N.V.,
`Case IPR2017-00447, Paper 7 (P.T.A.B. June 8, 2017), aff’d, 948
`F.3d 1330 (Fed. Cir. 2020) ................................................................................. 10
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`Other Authorities
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`37 C.F.R. § 42.71(c) ................................................................................................... 1
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`37 C.F.R. § 42.71(d) .................................................................................................. 1
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`ii
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`I.
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`INTRODUCTION
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`Pursuant to 37 C.F.R. § 42.71(d), Petitioner requests rehearing of the Board’s
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`decision denying post grant review entered November 18, 2020 (Paper 12,
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`hereinafter “Decision”).
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`II. BASIS FOR REHEARING
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`A request for rehearing “must specifically identify all matters the party
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`believes the Board misapprehended or overlooked, and the place where each such
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`matter was previously addressed in a motion, opposition, or reply.” 37 C.F.R. §
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`42.71(d). The Board will review the decision for an abuse of discretion. 37 C.F.R.
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`§ 42.71(c). An abuse of discretion results from an erroneous interpretation of law,
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`a factual finding that is not supported by substantial evidence, or if the decision
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`represents an unreasonable judgment in weighing the relevant evidence. Blue Coat
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`Systems, Inc. v. Finjan, Inc., IPR2016-01444, Paper 11 at 2 (P.T.A.B. July 18, 2017).
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`A.
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`The Petition Demonstrates The POSITA Would Have Had A
`Reasonable Expectation Of Success In Achieving The Claimed
`Aluminum Levels
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`
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`The claimed aluminum levels were not new. As the Petition1 demonstrates,
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`numerous batches of the Sandoz product manufactured by Allergy Labs prior to the
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`1 The term “Petition” also includes the Rabinow Declaration, Johnson Declaration
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`and the prior art cited therein.
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`1
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`alleged invention contained aluminum within the claimed ranges shortly after
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`manufacture (i.e., at product release) without Allergy even taking affirmative steps
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`to control aluminum levels; namely, 17 ppb, 61 ppb, 37 ppb, 18 ppb, 50 ppb, 54 ppb,
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`46 ppb, 47 ppb, 48 ppb, and 43 ppb. (Pet., p. 41; Ex. 1022, Ex. B (pp. 103-112), and
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`Ex. C (pp. 113-123).)2 Post-release, aluminum was known to leach into the Sandoz
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`product from the glass vials in which the Sandoz product was stored, and could rise
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`to several hundred ppb by the product’s two-year expiration date (Ex. 1022, ¶ 15)3,
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`which was at the lower end of the “[c]ontains no more than 5,000 [ppb] of
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`aluminum” disclosed on the Sandoz Label. The POSITA motivated to reduce
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`aluminum would have reasonably expected that an optimized Sandoz Label product
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`would achieve and maintain low aluminum levels (as claimed) for long periods of
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`time by simply removing the known sources of aluminum contamination.
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`As the Petition explains, the POSITA would have known that the potential
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`sources of aluminum contamination in the Sandoz Label product included (1) the
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`drug product starting ingredients, (2) the manufacturing process, and/or (3)
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`2 The Sandoz product attributes are included within the knowledge of the POSITA.
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`(Paper 9, Pet. Reply, p. 2, n.4; Pet., p. 41.)
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`3 The Decision “accepts the disclosures for the matter asserted in the Johnson
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`declaration (Ex. 1022).” (Paper 12, p. 21, n.11.)
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`2
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`aluminum leaching from glass vials in which the Sandoz Label product was stored.
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`By eliminating these known sources of aluminum, the POSITA would have had a
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`reasonable expectation that the Sandoz Label product could be optimized to
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`substantially eliminate aluminum to the claimed levels over its projected shelf-life.
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`(Pet., pp. 37-38, 40-43.)4 The POSITA would have optimized the Sandoz Label
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`product in this manner by following these simple and straightforward steps: (1) using
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`starting ingredients substantially free of aluminum, (2) ensuring that the
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`manufacturing process did not contaminate the drug product with aluminum, and (3)
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`storing the optimized Sandoz Label product in a container that substantially prevents
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`aluminum from leaching into the drug product post-manufacture, such as the Schott
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`coated glass vials. (Id., pp. 38-39, 40-43, 46.)5 Respectfully, the Decision overlooks
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`4 The challenged claims require a “stable” composition. The specification explains
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`that a “stable” composition is one that has the claimed aluminum levels when
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`administered in a clinical setting, which can occur, three months post-manufacture
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`(Pet., p. 25), and likely sooner.
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`5 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, ¶¶ 56-60;
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`Ex. 1014 at 7-8 (explaining that the Schott coated glass vials include an inner surface
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`coated with “an ultrathin film of silicon dioxide [that] forms a highly efficient
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`3
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`the dispositive impact of this critical knowledge possessed by the POSITA, which is
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`unrebutted and demonstrate more than a reasonable expectation of success.6
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`diffusion barrier that practically eliminates glass leachables”); Ex. 1048 at 21, 12:20-
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`39 (the Schott coated glass vials substantially prevent aluminum leachables in an
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`Ibuprofen Lysine solution) see also Tables 16-18 (aluminum below 9 ppb in
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`solutions stored in the Schott coated glass vials after 9 months storage).)
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`6 Citing to Bohrer (Ex. 1012), which published in 2003, the Decision criticizes the
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`Petition for failing to explain why a POSITA would have optimized cystine levels
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`to “reduce aluminum concentrations.” (Paper 12, p. 16.) That criticism,
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`respectfully, is misplaced. The short answer is that, by the time of the alleged
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`invention, the POSITA would not have been concerned about cystine levels for
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`purposes of controlling aluminum levels. (Paper 9, Pet. Reply, pp. 4-5, n.8.) Bohrer
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`addresses the role of cystine and cysteine (and other amino acids) in causing
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`aluminum to leach from uncoated glass vials. By the time of the alleged invention
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`in January 2019, however, the POSITA would have packaged the Sandoz Label
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`product in Schott coated glass vials, which were known to substantially prevent
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`aluminum from leaching into the drug product (a teaching overlooked by the
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`Decision). (Pet., pp. 41-42, 45-46.)
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`4
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`The Decision’s conclusion that the Petitioner allegedly failed to demonstrate
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`a reasonable expectation of success is predicated on the Board’s finding that the
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`Sandoz Label’s disclosure of “[c]ontains no more than 5,000 ppb” aluminum
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`purportedly does not overlap with the 1-250 ppb range set forth in claim 1 of the
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`’453 patent. (See Paper 12, pp. 21-22 (“[b]ecause we do not find that the product
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`described in the Sandoz Label discloses a range for aluminum from 0 ppb to 5,000
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`ppb, we are not persuaded by Petitioner’s position that there is a reasonable
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`expectation that routine optimization would lead to aluminum concentrations as
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`recited in claim 1 of the ’453 patent based on optimizing overlapping ranges.”)
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`(emphasis added).) The Decision’s conclusion, however, (1) misapprehends the
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`Petitioner’s reasonable expectation of success assertions (which do not depend
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`exclusively on or require overlapping ranges but instead also assert that the claimed
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`ranges are the expected result of eliminating the art-recognized sources of aluminum
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`contamination) and (2) overlooks the unrebutted evidence that demonstrates that the
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`ranges do in fact overlap.
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`With respect to Petitioner’s first point, regardless of how the Sandoz Label is
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`interpreted, the Petition nevertheless demonstrates a reasonable expectation of
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`success. As the Decision acknowledges, the POSITA would have been motivated
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`to “lower aluminum contamination in total parenteral nutritional solutions . . . to
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`avoid aluminum toxicity.” (Paper 12, p. 18.) And, as the Petition explains, the
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`5
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`POSITA motivated to reduce aluminum contamination would have optimized the
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`Sandoz Label product by simply eliminating
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`the sources of aluminum
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`contamination. (Pet., pp. 37-38, 40-42, 45-46.) By eliminating the sources of
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`aluminum, the POSITA—quite logically, and as explained in the Petition—would
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`have had a reasonable expectation of substantially eliminating aluminum from the
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`product during its projected shelf-life, regardless of how the “no more than 5,000
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`[ppb]” on the Sandoz Label were interpreted.7
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`Turning to Petitioner’s second point, the Board, respectfully, abused its
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`discretion in finding that the Sandoz Label’s disclosure of “contains no more than
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`5,000 [ppb] of aluminum” does not overlap with (or encompass) the 1-250 ppb
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`aluminum range recited in claim 1 of the ’453 patent. In reaching this conclusion,
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`the Decision opted to accept the PO’s assertion that the POSITA would have
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`understood the not more than 5,000 ppb disclosure to be at the “upper end of the
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`7 Although the Petition also asserts prima facie obviousness based upon overlapping
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`ranges (Pet., pp. 44-45), neither the motivation for preventing aluminum nor the
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`reasonable expectation of success are predicated on overlapping ranges. As the
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`Decision implicitly recognizes, the Petition establishes that the POSITA would have
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`been motivated to reduce aluminum, regardless of how the Sandoz Label is
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`interpreted.
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`6
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`aluminum concentration that is expected in the [Sandoz Label] product” but leaves
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`unanswered what the POSITA would have understood the lower end to be, instead
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`noting that “zero” purportedly is not a reasonable starting point, because the “Sandoz
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`product even right after manufacture contains measurable aluminum.” (Paper 12, p.
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`21.) The Board’s analysis suffers from two fundamental misapprehensions of the
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`record. First, it conflates the Sandoz product with the Sandoz Label. As Petitioner’s
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`expert (Dr. Rabinow) testified, the POSITA would have interpreted the Sandoz
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`Label to disclose an aluminum concentration “falling somewhere within the range
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`of 0 ppb to 5,000 ppb” (i.e., 5,000 ppb aluminum or less) and that the claim 1 range
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`of from about 1-250 ppb aluminum is within the lower end of the not more than
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`5,000 ppb range disclosed by the Sandoz Label (Ex. 1003, ¶¶ 32, 98; Pet., p. 27, 44-
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`45.) That testimony is unrebutted.8 Second, not only do the aluminum levels in the
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`8 PO’s expert merely testified that a pharmacist “calculating the potential aluminum
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`exposure . . . would use the 5,000 [ppb] aluminum concentration to do so.” (Ex.
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`2001, ¶¶ 21-23.) But that does not address let alone rebut Dr. Rabinow’s testimony
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`that the POSITA (who has qualifications beyond those of a pharmacist) would have
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`understood from the Sandoz Label that the aluminum content was somewhere within
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`the range extending from 0 to 5,000 ppb, depending on the age of the product. (Paper
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`9, Pet. Reply, p. 2, n.3.)
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`7
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`Sandoz product manufactured by Allergy Labs overlap with the claimed aluminum
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`ranges, but also they corroborate the reasonableness of Dr. Rabinow’s interpretation
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`of the Sandoz Label. On the current record, the aluminum levels shortly after
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`manufacture (i.e., at product release) were as low as 17 ppb and ranged up to several
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`hundred ppb after two years of storage (Ex. 1022, ¶ 15), which certainly overlaps
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`with the 1-250 ppb range set forth in claim 1 of the ’453 patent, as well as with the
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`other, more narrowly claimed ranges. In short, the aluminum range disclosed by the
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`Sandoz Label and the actual aluminum levels in the Sandoz product manufactured
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`by Allergy Labs overlap with the ranges claimed in the ’453 patent.
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`B.
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`The Petition Meets The Particularity Requirement
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`Respectfully, the Board abused its discretion in finding a lack of particularity.
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`Focusing on asserted Ground 1, the Decision concludes that the Petition is allegedly
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`unclear about “what aspects” of the cited prior art Petitioner relies upon, which
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`allegedly leaves the PO (and the Board) “to guess how the references are applied to
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`each particular ground.” (Paper 12, p. 14.) The Decision, however, misapprehends
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`the asserted Grounds (which are based upon the Sandoz Label in combination with
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`the knowledge of the POSITA) and overlooks the particularity with which the
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`Petition identifies and explains how the POSITA would have applied that knowledge
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`to optimize the Sandoz Label product. The Petition provides a detailed roadmap;
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`8
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`there is no guess work required as demonstrated by the POPR, which unconvincingly
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`attacks several of the rationales set forth in the Petition.
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`More specifically, the asserted Grounds are based upon the combination of
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`the Sandoz Label product and the knowledge possessed by the POSITA. (Pet., p.
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`6.) The Petition identifies with particularity the knowledge possessed by POSITA
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`with citations to the prior art and explains in detail how the POSITA would have
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`applied that knowledge to optimize the Sandoz Label product as claimed. For
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`example, the Petition cites to Yaman, Waterman and Butler (among other prior art
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`references) to corroborate the knowledge possessed by the POSITA. (See Pet., pp.
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`27-40 (Sections VIII.B and VIII.C provide a detailed summary of the “Knowledge
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`of the POSITA”).) As the Petition explains, the POSITA would have readily
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`understood that removing head space and dissolved oxygen were well-known
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`techniques for preventing oxidative degradation of oxygen sensitive species such as
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`L-cysteine. (Id., pp. 29-30, 38-41, 46-49.) The Decision’s criticism that the Petition
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`fails to expressly identify Yaman, Waterman and Butler in the Grounds
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`misapprehends the asserted Grounds and conflates these references (which merely
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`corroborate the knowledge of the POSITA) with the “Knowledge of a POSITA” on
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`which the asserted Grounds are based. As controlling Federal Circuit precedent
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`demonstrates, the knowledge of a POSITA may be properly combined with the prior
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`art (in this case, the Sandoz Label product) to establish obviousness. See e.g.,
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`9
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`Google Inc. v. Koninklijke Philips N.V., Case IPR2017-00447, Paper 7 at 18
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`(P.T.A.B. June 8, 2017), aff’d, 948 F.3d 1330, 1337-38 (Fed. Cir. 2020) (Hua
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`reference, although not included in asserted ground, properly relied on as evidence
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`of the knowledge of the POSITA in finding claims obvious). The particularity
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`requirement does not require that the asserted Grounds expressly include the prior
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`art references that are relied upon to corroborate the POSITA’s knowledge. Id.
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`Stated differently, the knowledge of a POSITA must be substantiated with evidence,
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`which Petitioner has done by citing Yaman, Waterman and Butler (and other prior
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`art). The failure to substantiate the knowledge of a POSITA would result in a lack
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`of particularity, not the other way around, as the Decision erroneously suggests.
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`Respectfully, the Board thus abused its discretion in concluding that the Petition
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`lacks particularity.
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`The Decision also mistakenly asserts that the Petitioner’s citation to Yaman,
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`Waterman and Butler demonstrates reliance on “more than just the knowledge of the
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`ordinary artisan.” (Paper 12, pp.15-16.) Once again, the Decision misapprehends
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`the asserted Grounds. As noted above, the Petition relies on these references to
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`corroborate the knowledge of the POSITA set forth in the asserted Grounds. The
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`knowledge possessed by the POSITA is not independent of but is instead
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`corroborated by Yaman, Waterman, Butler, and the other prior art discussed in the
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`Petition.
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`10
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`The Decision also incorrectly concludes that the failure to expressly cite
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`Yaman, Waterman, and Butler in the asserted Grounds is an attempt to circumvent
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`the requirement of articulating a rationale for combining these references with the
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`Sandoz Label with a reasonable expectation of success. (Paper 12, p. 16.) But this
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`holding also misapprehends the asserted Grounds and overlooks the rationales for
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`optimizing the Sandoz Label product set forth in the Petition. The asserted Grounds
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`rely on the knowledge possessed by the POSITA, which is corroborated by Yaman,
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`Waterman and Butler (as well as other prior art) and the Petition articulates with
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`particularity how and why the POSITA would have applied that knowledge to
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`optimize the Sandoz Label product to arrive at the challenged claims. As the Petition
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`explains, the POSITA would have known that oxygen sensitive drugs such as L-
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`cysteine are stabilized by removing head space and dissolved oxygen from the drug
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`product, and that achieving the claimed head space and dissolved oxygen levels was
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`well within the capabilities of the POSITA. (Pet., pp. 29-30, 38-40, 42-43, 46-47.)
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`The Petition also articulates why the POSITA, armed with this knowledge, would
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`have applied these techniques to optimize the Sandoz Label product to prevent
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`oxidation of L-cysteine, a known oxygen sensitive drug, and why the POSITA would
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`have reasonably expected that these art-recognized techniques for removing oxygen
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`would substantially prevent oxidative degradation of L-cysteine to its known
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`impurities, L-cystine and pyruvic acid. (Id.)
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`11
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`Importantly, the Petition does not leave the PO (nor the Board) to guess about
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`how the POSITA would have applied their knowledge to optimize the Sandoz Label
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`product. As noted above, the Petition explains that the POSITA would have applied
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`the known techniques of removing headspace and dissolved oxygen to prevent
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`oxidation of L-cysteine in the Sandoz Product. (Id.) Similarly, the Petition explains
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`that the POSITA would have applied the knowledge that aluminum contamination
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`can be prevented by avoiding the known sources of contamination; namely, starting
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`materials contaminated with aluminum, a manufacturing process that contaminates
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`the drug product with aluminum, and a container that leaches aluminum into the drug
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`product. (Id., pp. 37-38, 40-42, 45-46.) The Petition also explains why the POSITA
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`would have had a reasonable expectation of success of achieving the claimed
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`aluminum levels during the projected shelf-life by simply using starting ingredients
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`substantially free of aluminum, a manufacturing process that does not contaminate
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`the drug product with aluminum, and packaging the optimized Sandoz Label product
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`in the Schott coated glass vials, which were known to prevent aluminum from
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`leaching into the drug product. (Id.)
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`In short, there is no ambiguity in the Petition, and the PO is on notice of how
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`the Petition applies the knowledge possessed by the POSITA to optimize the Sandoz
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`Label product to arrive at the claimed invention. The PO has a full and fair
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`opportunity to explain why the POSITA either lacks the knowledge alleged in the
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`12
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`Petition or would not have applied that knowledge in the manner set forth in the
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`Petition to optimize the Sandoz Label product as claimed with a reasonable
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`expectation of success.9
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` Finally, the Decision mistakenly concludes that the Petition “does not
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`sufficiently explain[] why one of ordinary skill in the art would want to look at
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`cystine levels” or maintain cystine “within the claimed range.” (Paper 12, p. 17.)
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`As explained in the Petition, cystine levels reflect the extent to which L-cysteine has
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`oxidatively degraded to L-cystine, which can form undesirable particulate matter.
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`(Pet., pp. 38, 42, 46-47.) Minimizing L-cystine is the reasonably expected result of
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`preventing oxidative degradation of L-cysteine. The Decision overlooks this
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`evidence. This is not a situation where Petitioner merely disagrees with the Board’s
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`9 The Decision cites Butler’s statement that a nitrogen purge is “a poor method to
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`preserve solutions containing redox-sensitive species.” (Paper 12, pp. 16-17.) The
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`PO is certainly free to argue that Butler, when considered in the relevant context,
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`would have allegedly discouraged the POSITA from applying a nitrogen purge to
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`the Sandoz Label product. However, Dr. Rabinow’s testimony that the POSITA
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`would have applied art recognized techniques such as a nitrogen or argon purge to
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`remove oxygen stands unrebutted. (Ex. 1003, ¶ 49; see also Paper 9, Pet. Reply at
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`p. 3, n.6.)
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`13
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`conclusion. Petitioner explained all of this, and more, in its Petition and is merely
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`pointing out what the Board overlooked and misapprehended.
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`III. CONCLUSION
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`
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`For these reasons, Petitioner respectfully requests rehearing and institution of
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`trial.
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`December 18, 2020
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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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`14
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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 December 18, 2020
`
`Person served Dorothy P. Whelan
`PGR48751-0005PSa@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
`
`
`
`
`
`