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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`ETON PHARMACEUTICALS, INC.,
`Petitioner
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`v.
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`EXELA PHARMA SCIENCES, LLC,
`Patent Owner
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`Case PGR2020-00064
`Patent No. 10,478,453
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`PATENT OWNER’S SUR-REPLY TO PETITIONER’S REPLY TO
`PATENT OWNER’S PRELIMINARY RESPONSE
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`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
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`EXHIBIT LIST
`Description
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`Exhibit No.
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`2001
`2002
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`2003
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`2004
`2005
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`2006
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`2007
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`2008
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`2009
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`2010
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`2011
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`2012
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`2013
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`Declaration of Dr. Robert J. Kuhn
`Aileen B. Sedman et al., Evidence of Aluminum Loading in Infants
`Receiving Intravenous Therapy, 312 NEW ENG. J. MED. 1337
`(1985)
`Nicholas J. Bishop et al., Aluminum Neurotoxicity in Preterm
`Infants Receiving Intravenous-Feeding Solutions, 336 NEW ENG. J.
`MED. 1557 (1997)
`ELCYS® Label, Exela Pharma Sciences, LLC
`Amended Complaint (Redacted), Exela Pharma Sciences, LLC v.
`Sandoz, Inc., No. 1:20-cv-00645-MN (D. Del. June 1, 2020), ECF
`No. 12
`Amended Complaint, Exela Pharma Sciences, LLC v. Eton
`Pharmaceuticals, Inc., No. 20-365-MN (D. Del. July 28, 2020),
`ECF No. 14
`Declaration of Mark Hartman (Redacted), Exela Pharma Sciences,
`LLC v. Sandoz Inc., No. 19-cv-00318-MR (W.D.N.C. Dec. 6,
`2019), ECF No. 26-1
`Megan Fortenberry et al., Evaluating Differences in Aluminum
`Exposure Through Parenteral Nutrition in Neonatal Morbidities, 9
`NUTRIENTS 1249 (2017)
`Kathleen M. Gura, Aluminum Contamination in Parenteral
`Products, 17 CURR. OPIN. CLIN. NUTR. & METAB. CARE 551
`(2014)
`Gordon L. Klein et al., Hypocalcemia Complicating Deferoxamine
`Therapy in an Infant with Parenteral Nutrition-Associated
`Aluminum Overload: Evidence for a Role of Aluminum in the Bone
`Disease of Infants, 9 J. PED. GASTR. & NUTR. 400 (1989)
`Jay M. Mirtallo, Aluminum Contamination of Parenteral Nutrition
`Fluids, 34 J. PARENTERAL & ENTERAL NUTR. 346 (2010)
`Robert L. Poole et al., Aluminum Exposure From Pediatric
`Parenteral Nutrition: Meeting the New FDA Regulation, 32 J.
`PARENTERAL & ENTERAL NUTR. 242 (2008)
`U.S. Patent No. 4,385,086
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`i
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`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
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`Patent Owner files this sur-reply pursuant to the Board’s Order of September
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`24, 2020 (Paper 7).
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`I. THE PETITION LACKS PARTICULARITY
`The ’453 claimed invention relates to L-cysteine parenteral compositions for
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`treating vulnerable infants in which the compositions have very low levels of toxic
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`aluminum that are stable over time. As a result, the claimed compositions remain
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`safe for administration over the shelf life of the product.
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`Eton argues that a POSITA would know that actual aluminum levels in the
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`Sandoz product ranged from 0-5,000 ppb because it was known that aluminum
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`content increased over a product’s shelf life. Paper 9 (Petitioner’s Reply
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`(“Reply”)) at 2 n.3. This is precisely the problem with earlier L-cysteine
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`formulations. See Paper 6 (Patent Owner Preliminary Response (“POPR”)) at 1,
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`11; Ex. 2001 (Kuhn Decl.) ¶¶ 15, 21-24. It was the inventors who solved this
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`problem. Eton’s statements are an admission that the Sandoz Label describes a
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`product no different from earlier, unsuccessful products.
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`The Petition suffers from a lack of particularity. Eton says it is relying on
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`the “four-corners of the Sandoz label” as a printed publication and admits that the
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`label does not disclose every element of the claimed compositions. Reply at 1‒2;
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`Paper 1 (“Petition”) at 47‒49. Eton relies on the “knowledge of a POSITA” to fill
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`in the gaps. Pet. at 43. But what is this alleged “knowledge?” This is where the
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`1
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`lack of particularity comes in. In some instances, Eton relies on the properties of a
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`product as measured shortly after manufacture by Allergy Labs and before it is
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`accessible to the public. Pet. at 45‒46. Not only does this conflate two separate
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`categories of prior art, but it refers to information to which a person of ordinary
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`skill would not have been privy. Eton never explains how a person of ordinary
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`skill would have been able to access Allergy Labs’ data or make its own
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`measurements within the same time frame.
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`In other instances, Eton relies on no fewer than 77 “additional references” to
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`supply specific claim limitations that the Sandoz Label lacks. This is an improper
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`“catch-all” approach that Eton does not (and cannot) defend. See POPR at 31‒36.
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`Eton’s “routine optimization” arguments mischaracterize the problem the
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`inventors discovered and solved by treating the solution as if it involved two
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`independent variables: (1) removing head space and dissolved oxygen to prevent
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`oxidation of L-cysteine1 and (2) storing the product in a coated glass vial to prevent
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`1 Eton points out that the Sandoz Label recites a pH of 1.0 to 2.5 and that air
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`was replaced with nitrogen. Reply at 2 n.5. Yet Eton fails to explain in the
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`Petition or Reply why a skilled artisan would have been concerned with addressing
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`2
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`aluminum from leaching into the composition. See Reply at 2‒4. In its POPR,
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`Exela showed—based on Eton’s own references—how and why L-cysteine
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`parenteral solutions are sensitive to an array of multivariate and interrelated
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`interactions. See POPR at 57‒60. Eton considered none of this. Exela also
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`highlighted that Eton provided no specifics as to why a skilled artisan would have
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`arrived at the particularly claimed amounts of impurities in the claims. Id. at 54‒
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`57. Eton still has no answer.
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`Regarding the vial, multiple references taught using a plastic vial to reduce
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`aluminum levels. Ex. 2011 (Mirtallo 2010) at 2; Ex. 1008 (Bohrer 2001) at 5.
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`However, plastic vials are permeable to oxygen. Ex. 1003 (Rabinow Decl.) ¶¶ 57,
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`65. This is proof that the art failed to appreciate the severity of L-cysteine’s
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`oxygen sensitivity or the relationship between oxygen levels and aluminum levels.
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`It also shows that Eton’s focus on optimizing oxygen levels to solve the aluminum
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`problem is improperly based on the inventors’ own path.
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`Eton’s “routine optimization” arguments beg the question: given the
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`seriousness of the aluminum problem with vulnerable infants, why had the
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`oxygen levels further, in the context of that pH range, let alone to the particular
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`amounts claimed.
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`3
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`problem persisted for more than a decade? Neither Sandoz nor Eton was able to
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`solve it despite the incentive. Only in hindsight can Exela’s invention be seen as
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`“routine optimization” of the Sandoz labeled product.
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`II. THE OFFICE ACTIONS IN RELATED CASES DO NOT SUPPORT
`OBVIOUSNESS
`Eton’s submission of office actions in Exela’s pending patent applications is
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`an attempt to distract the Board from the failings of Eton’s Petition. The office
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`actions do not bolster Eton’s Petition or undermine the validity of the ’453 claims.
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`These are non-final rejections, issued after Exela submitted IDS’s containing
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`the Petition and all accompanying exhibits to the PTO in Exela’s pending
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`applications, on claims not at issue in this Petition, and to which Exela intends to
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`respond and overcome. Exs. 1088‒1091. Moreover, the rejections assert
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`obviousness based on a combination of six references, in contrast to Eton’s
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`Ground 1 allegation of obviousness based solely on the Sandoz Label and “routine
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`optimization.” Exs. 1090‒1091.
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` On the merits, which Eton ignores, the references the Examiner relies on do
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`not support obviousness of the ’453 claims. They support the opposite. For
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`example, the Hernandez-Sanchez reference recognizes the long-felt and unresolved
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`need for a low-aluminum product. Ex. 1006 (Hernandez-Sanchez 2013) at 1;
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`POPR at 2‒3, 7 n.19. The Nakayama patent teaches glass vials that are coated
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`4
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`with a substance containing aluminum. Ex. 2013 (Nakayama) at 5:20-6:49
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`(Example 1). Given L-cysteine’s known affinity for aluminum (see Ex. 1008
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`(Bohrer 2001) at 4), the use of Nakayama’s container would be counter to solving
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`the L-cysteine aluminum problem. The Asquith reference, which the Examiner
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`misquotes as teaching degradation of cysteine in air, actually concerns
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`photochemical degradation of cystine. Compare Ex. 1090 at 5 with Ex. 1024
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`(Asquith 1969) at 1. Just like Eton, the Examiner offers no reference or reasoned
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`argument for zeroing in on an “oxygen head space problem” (Ex. 1090 at 6) in
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`trying to solve the decades-old problem of aluminum contamination in L-cysteine
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`solutions. But, unlike Eton, the Examiner correctly reads the Sandoz Label as
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`disclosing a “product [that] contains no more than 5,000 mcg/L (5,000 ppb) of
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`aluminum,” not a range of 0-5,000 ppb. Ex. 1090 at 5.
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`III. ETON HAS NOT SHOWN A LIKELIHOOD THAT THE ALLERGY
`PROCESS IS PRIOR ART
`Eton’s Petition and Reply both flout the legal standard for qualifying the
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`Allergy Process as a prior public use: public accessibility. See POPR at 20‒21
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`and cases cited therein. The test for public accessibility requires consideration of
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`what activity actually occurred in public, actual public access to the use, and any
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`confidentiality obligations imposed on members of the public who observed the
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`use. See Dey, L.P. v. Sunovion Pharms., 715 F.3d 1351, 1355 (Fed. Cir. 2013); see
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`5
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`also BASF Corp. v. SNF Holding Co., 955 F.3d 958, 967 (Fed. Cir. 2020). The
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`policy behind the public use bar is to discourage removing from the public domain
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`an invention the public reasonably believes is freely available. Dey, 715 F.3d at
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`1360. The Petition, including Mr. Johnson’s declaration, comes nowhere close to
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`putting the Allergy Process in the public domain.
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`Nothing in the record shows that anyone from the public ever had access to
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`or observed the Allergy Process. See Reply at 6. Mr. Johnson’s statement that the
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`Allergy Labs process “was generally known by Allergy Labs personnel” (Ex. 1022
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`(Johnson Decl.) ¶ 18) is uncorroborated and, in any event, does not speak to the
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`number of personnel—let alone the public—with that knowledge, or their
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`confidentiality obligations. Mr. Johnson’s statement that “Allergy Labs did not
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`take any overt efforts to conceal the manufacturing process for the Sandoz L-
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`Cysteine Product” (Ex. 1022 (Johnson Decl.) ¶ 18) is likewise uncorroborated. It
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`also lacks specificity.
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`What Mr. Johnson does not say in his declaration is conspicuous. He does
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`not say anyone from the public actually observed the process (let alone without any
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`implied obligation of secrecy), or that the Allergy Labs personnel with access to it
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`were not under any kind of confidentiality obligation. Eton’s claim of public use
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`should be rejected outright.
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`6
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`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
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`Respectfully submitted,
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`/Dorothy P. Whelan/
`Dorothy P. Whelan, Reg. No. 33,814
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`Counsel for Patent Owner
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`Date: October 5, 2020
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`Customer Number 26191
`Fish & Richardson P.C.
`Telephone: (612) 337-2509
`Facsimile: (877) 769-7945
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`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
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`CERTIFICATE OF SERVICE
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`Pursuant to 37 CFR §§ 42.6(e)(4), the undersigned certifies that on October
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`5, 2020, a complete and entire copy of this Patent Owner’s Sur-Reply to
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`Petitioner’s Reply to Patent Owner’s Preliminary Response and accompanying
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`exhibit were provided via email to the Petitioner by serving the correspondence
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`email addresses of record as follows:
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`Ralph J. Gabric
`Eugene Goryunov
`Judy K. He
`Jeff Wolfson
`Haynes and Boone LLP
`2323 Victory Ave., Suite 700
`Dallas, TX 75219
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`Email: ralph.gabric.ipr@haynesboone.com
`Email: eugene.goryunov.ipr@haynesboone.com
`Email: judy.he.ipr@haynesboone.com
`Email: jeff.wolfson.ipr@haynesboone.com
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`/Edward G. Faeth/
`Edward G. Faeth
`Fish & Richardson P.C.
`60 South Sixth Street, Suite 3200
`Minneapolis, MN 55402
`(202) 626-6420
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