UNITED STATES PATENT AND TRADEMARK OFFICE
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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 PGR2020-00068
`Patent No. 10,583,155
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`PATENT OWNER’S SUR-REPLY TO PETITIONER’S REPLY TO
`PATENT OWNER’S PRELIMINARY RESPONSE
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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 PGR2020-00068
`Patent No. 10,583,155
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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: 48751-0007PS1
`Case No. PGR2020-00068
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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)
`Eton Pharmaceuticals, Inc., Amendment No. 1 to Sales/Marketing
`Agreement (Form S-1/A, Exhibit 10.18) (Sept. 25, 2018)
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`i
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`Attorney Docket: 48751-0007PS1
`Case No. PGR2020-00068
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`Patent Owner files this sur-reply pursuant to the Board’s Order of October
`14, 2020 (Paper 7).
`I. THE PETITION LACKS PARTICULARITY
`The Petition continues to suffer from a lack of particularity. Eton says it is
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`relying on the “four-corners of the Sandoz label” as a printed publication and
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`admits that the label does not disclose every element of the claimed compositions.
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`Paper 8 (Petitioner’s Reply (“Reply”)) at 1‒2; Paper 1 (“Petition”) at 52. Eton
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`relies on the “knowledge of a POSITA” to fill in the gaps. Pet. at 42‒45. But what
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`is this alleged “knowledge?” This is where the lack of particularity comes in. In
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`its Petition, Eton relies on the properties of a product as measured shortly after
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`manufacture by Allergy Labs and before it is accessible to the public. See, e.g.,
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`Pet. at 50-51. Not only does this conflate two separate categories of prior art, but it
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`refers to information to which a person of ordinary skill would not have been
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`privy.
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`In its Reply, Eton now points to the Geissler Declaration, which includes
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`aluminum data of an L-cysteine product manufactured in June 2019 (i.e., after
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`Exela’s invention date) by a different entity (Avara) at a different facility
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`(Boucherville, Canada) than the “Sandoz Label” of Eton’s Grounds. Ex. 1116 at 6
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`¶ 12, 44‒45, 48‒49. Eton’s addition of this 2019 Avara product to what it
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`considers the “Sandoz Label” further compounds the lack of particularity and
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`1
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`undermines Eton’s own “four corners” argument.
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`Attorney Docket: 48751-0007PS1
`Case No. PGR2020-00068
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`Moreover, Eton’s reliance on the Geissler Declaration actually supports
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`Exela’s position. First, the Geissler Declaration shows only “release testing” data
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`for the Avara product, which means testing done before the Avara product was
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`released to the public—again, information to which a person of ordinary skill
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`would not have been privy. Ex. 1116 at 6, 44‒45, 48‒49. Moreover, the only
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`aluminum data in the Declaration is for an Avara product made in June 2019,
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`which is after Exela’s invention date and thus not prior art. Id. at 44‒45, 48‒49.
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`Finally, the Geissler Declaration shows that at release in August 2019—with
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`nearly 22 months of shelf-life (and aluminum leaching) to go—the Avara product
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`already contained up to 375 ppb of aluminum. Id. at 44‒45, 48‒49 (August 2019
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`release testing results for 2 batches of Avara product, both manufactured in June
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`2019 and expiring in June 2021).
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`In short, this different, later, non-prior art Avara L-cysteine product had
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`precisely the same problem as the Sandoz Label product of Eton’s grounds. See
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`Paper 6 (Patent Owner Preliminary Response (“POPR”)) at 1‒2, 12‒13; Ex. 2001
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`(Kuhn Decl.) ¶¶ 15, 21‒24. It was the inventors who solved this problem by
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`developing a stable, low aluminum L-cysteine composition that is safe for
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`administration to vulnerable infants over the shelf life of the product.
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`2
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`Eton continues to characterize this inventive work as mere “routine
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`Attorney Docket: 48751-0007PS1
`Case No. PGR2020-00068
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`optimization” in its Reply. Although the Board explicitly denied Eton’s request to
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`address its “routine optimization” argument in its Reply, Eton still did so under the
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`guise of addressing Exela’s particularity argument. Order at 2‒3; Reply at 2‒4.
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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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`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 53‒57. Balancing these interactions is integral to
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`Exela’s solution to the aluminum problem, which is not “merely the discovery of
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`an additional benefit of optimizing the Sandoz Label product to prevent oxidation
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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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`oxygen levels further, in the context of that pH range.
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`3
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`as taught by the prior art.” Reply at 4 n.7. Exela also highlighted that Eton
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`Case No. PGR2020-00068
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`provided no specifics as to why a skilled artisan would have arrived at the
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`particularly claimed amounts of impurities in the claims to achieve the claimed
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`stability requirement. Id. at 48‒52. 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.) ¶¶ 59,
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`67. 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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`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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`4
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`actions do not bolster Eton’s Petition or undermine the validity of the ’155 claims.
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`Attorney Docket: 48751-0007PS1
`Case No. PGR2020-00068
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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. 1112-1113. 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 on the combination of the Sandoz Label,
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`Hospira Label, and “routine optimization.” See id.
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` On the merits, the references the Examiner relies on do not support
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`obviousness of the ’155 claims. They support the opposite. For example, the
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`Hernandez-Sanchez reference recognizes the long-felt and unresolved need for a
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`low-aluminum product. Ex. 1006 (Hernandez-Sanchez 2013) at 1 (“Aluminum
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`(Al) toxicity in parenteral nutrition solutions (PNS) has been a problem for decades
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`and is still unresolved.”); POPR at 2‒3, 9 n.21. After embracing this reference in
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`its Petition to provide motivation to reduce aluminum, Eton now argues that
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`Hernandez-Sanchez merely “recognized that the market had failed to demand
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`manufacturers to meet this need,” and that manufacturers “promptly” met this need
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`only once FDA demanded it in 2017. Reply at 6. Not only does this contradict
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`Eton’s earlier reliance on Hernandez-Sanchez, it makes no sense. The FDA, in
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`2000, issued specific regulations requiring pharmaceutical manufacturers to reduce
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`5
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`aluminum levels of parenteral products. 65 F.R. 4103-4111 (made final July 26,
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`2004 at 68 FR 32979). Hernandez-Sanchez, in 2013, and many other publications
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`acknowledged the seriousness of the aluminum problem for vulnerable infants and
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`reiterated the need for manufacturers to take action. Yet Eton would have the
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`Board believe that manufacturers could have readily solved this problem to benefit
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`human health but chose not to do so until FDA in 2017 forced their hand.
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`The remaining references do nothing to remedy the deficiencies in Eton’s
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`Petition. The Nakayama patent teaches glass vials that are coated with a substance
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`containing aluminum. Ex. 1117 (Nakayama) at 5:20-6:49 (Example 1). Eton
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`admits that the POSITA would not have opted for this coating to solve the L-
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`cysteine aluminum problem. Reply at 6. Eton also admits the Examiner
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`misunderstood the Asquith reference. Id. Just like Eton, the Examiner offers no
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`reference or reasoned argument for zeroing in on an “oxygen head space problem”
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`(Ex. 1112 at 6) in trying to solve the decades-old problem of aluminum
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`contamination in L-cysteine solutions. But, unlike Eton, the Examiner correctly
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`reads the Sandoz Label as disclosing a “product [that] contains no more than 5,000
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`mcg/L (5,000 ppb) of aluminum,” not a range of 0-5,000 ppb. Ex. 1112 at 5.
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`Attorney Docket: 48751-0007PS1
`Case No. PGR2020-00068
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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 26, 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: 48751-0007PS1
`Case No. PGR2020-00068
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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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`26, 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 was provided via email
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`to the Petitioner by serving the correspondence email addresses of record as
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`follows:
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`
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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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`
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`
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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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