UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`
`
`
`
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`ETON PHARMACEUTICALS, INC.,
`Petitioner
`
`v.
`
`EXELA PHARMA SCIENCES, LLC,
`Patent Owner
`
`
`
`
`
`
`
`
`
`
`
`
`Case PGR2020-00064
`Patent No. 10,478,453
`
`
`
`
`PATENT OWNER’S SUR-REPLY TO PETITIONER’S REPLY TO
`PATENT OWNER’S PRELIMINARY RESPONSE
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`ETON PHARMACEUTICALS, INC.,
`Petitioner
`
`v.
`
`EXELA PHARMA SCIENCES, LLC,
`Patent Owner
`
`
`
`
`
`
`
`
`
`
`
`
`Case PGR2020-00064
`Patent No. 10,478,453
`
`
`
`
`PATENT OWNER’S SUR-REPLY TO PETITIONER’S REPLY TO
`PATENT OWNER’S PRELIMINARY RESPONSE
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
`
`
`EXHIBIT LIST
`Description
`
`Exhibit No.
`
`2001
`2002
`
`2003
`
`2004
`2005
`
`2006
`
`2007
`
`2008
`
`2009
`
`2010
`
`2011
`
`2012
`
`2013
`
`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
`
`i
`
`
`
`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
`
`Patent Owner files this sur-reply pursuant to the Board’s Order of September
`
`24, 2020 (Paper 7).
`
`I. THE PETITION LACKS PARTICULARITY
`The ’453 claimed invention relates to L-cysteine parenteral compositions for
`
`treating vulnerable infants in which the compositions have very low levels of toxic
`
`aluminum that are stable over time. As a result, the claimed compositions remain
`
`safe for administration over the shelf life of the product.
`
`Eton argues that a POSITA would know that actual aluminum levels in the
`
`Sandoz product ranged from 0-5,000 ppb because it was known that aluminum
`
`content increased over a product’s shelf life. Paper 9 (Petitioner’s Reply
`
`(“Reply”)) at 2 n.3. This is precisely the problem with earlier L-cysteine
`
`formulations. See Paper 6 (Patent Owner Preliminary Response (“POPR”)) at 1,
`
`11; Ex. 2001 (Kuhn Decl.) ¶¶ 15, 21-24. It was the inventors who solved this
`
`problem. Eton’s statements are an admission that the Sandoz Label describes a
`
`product no different from earlier, unsuccessful products.
`
`The Petition suffers from a lack of particularity. Eton says it is relying on
`
`the “four-corners of the Sandoz label” as a printed publication and admits that the
`
`label does not disclose every element of the claimed compositions. Reply at 1‒2;
`
`Paper 1 (“Petition”) at 47‒49. Eton relies on the “knowledge of a POSITA” to fill
`
`in the gaps. Pet. at 43. But what is this alleged “knowledge?” This is where the
`
`1
`
`
`
`lack of particularity comes in. In some instances, Eton relies on the properties of a
`
`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
`
`
`product as measured shortly after manufacture by Allergy Labs and before it is
`
`accessible to the public. Pet. at 45‒46. Not only does this conflate two separate
`
`categories of prior art, but it refers to information to which a person of ordinary
`
`skill would not have been privy. Eton never explains how a person of ordinary
`
`skill would have been able to access Allergy Labs’ data or make its own
`
`measurements within the same time frame.
`
`In other instances, Eton relies on no fewer than 77 “additional references” to
`
`supply specific claim limitations that the Sandoz Label lacks. This is an improper
`
`“catch-all” approach that Eton does not (and cannot) defend. See POPR at 31‒36.
`
`Eton’s “routine optimization” arguments mischaracterize the problem the
`
`inventors discovered and solved by treating the solution as if it involved two
`
`independent variables: (1) removing head space and dissolved oxygen to prevent
`
`oxidation of L-cysteine1 and (2) storing the product in a coated glass vial to prevent
`
`
`
`1 Eton points out that the Sandoz Label recites a pH of 1.0 to 2.5 and that air
`
`was replaced with nitrogen. Reply at 2 n.5. Yet Eton fails to explain in the
`
`Petition or Reply why a skilled artisan would have been concerned with addressing
`
`2
`
`
`
`aluminum from leaching into the composition. See Reply at 2‒4. In its POPR,
`
`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
`
`
`Exela showed—based on Eton’s own references—how and why L-cysteine
`
`parenteral solutions are sensitive to an array of multivariate and interrelated
`
`interactions. See POPR at 57‒60. Eton considered none of this. Exela also
`
`highlighted that Eton provided no specifics as to why a skilled artisan would have
`
`arrived at the particularly claimed amounts of impurities in the claims. Id. at 54‒
`
`57. Eton still has no answer.
`
`Regarding the vial, multiple references taught using a plastic vial to reduce
`
`aluminum levels. Ex. 2011 (Mirtallo 2010) at 2; Ex. 1008 (Bohrer 2001) at 5.
`
`However, plastic vials are permeable to oxygen. Ex. 1003 (Rabinow Decl.) ¶¶ 57,
`
`65. This is proof that the art failed to appreciate the severity of L-cysteine’s
`
`oxygen sensitivity or the relationship between oxygen levels and aluminum levels.
`
`It also shows that Eton’s focus on optimizing oxygen levels to solve the aluminum
`
`problem is improperly based on the inventors’ own path.
`
`Eton’s “routine optimization” arguments beg the question: given the
`
`seriousness of the aluminum problem with vulnerable infants, why had the
`
`
`
`oxygen levels further, in the context of that pH range, let alone to the particular
`
`amounts claimed.
`
`3
`
`
`
`problem persisted for more than a decade? Neither Sandoz nor Eton was able to
`
`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
`
`
`solve it despite the incentive. Only in hindsight can Exela’s invention be seen as
`
`“routine optimization” of the Sandoz labeled product.
`
`II. THE OFFICE ACTIONS IN RELATED CASES DO NOT SUPPORT
`OBVIOUSNESS
`Eton’s submission of office actions in Exela’s pending patent applications is
`
`an attempt to distract the Board from the failings of Eton’s Petition. The office
`
`actions do not bolster Eton’s Petition or undermine the validity of the ’453 claims.
`
`These are non-final rejections, issued after Exela submitted IDS’s containing
`
`the Petition and all accompanying exhibits to the PTO in Exela’s pending
`
`applications, on claims not at issue in this Petition, and to which Exela intends to
`
`respond and overcome. Exs. 1088‒1091. Moreover, the rejections assert
`
`obviousness based on a combination of six references, in contrast to Eton’s
`
`Ground 1 allegation of obviousness based solely on the Sandoz Label and “routine
`
`optimization.” Exs. 1090‒1091.
`
` On the merits, which Eton ignores, the references the Examiner relies on do
`
`not support obviousness of the ’453 claims. They support the opposite. For
`
`example, the Hernandez-Sanchez reference recognizes the long-felt and unresolved
`
`need for a low-aluminum product. Ex. 1006 (Hernandez-Sanchez 2013) at 1;
`
`POPR at 2‒3, 7 n.19. The Nakayama patent teaches glass vials that are coated
`
`4
`
`
`
`with a substance containing aluminum. Ex. 2013 (Nakayama) at 5:20-6:49
`
`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
`
`
`(Example 1). Given L-cysteine’s known affinity for aluminum (see Ex. 1008
`
`(Bohrer 2001) at 4), the use of Nakayama’s container would be counter to solving
`
`the L-cysteine aluminum problem. The Asquith reference, which the Examiner
`
`misquotes as teaching degradation of cysteine in air, actually concerns
`
`photochemical degradation of cystine. Compare Ex. 1090 at 5 with Ex. 1024
`
`(Asquith 1969) at 1. Just like Eton, the Examiner offers no reference or reasoned
`
`argument for zeroing in on an “oxygen head space problem” (Ex. 1090 at 6) in
`
`trying to solve the decades-old problem of aluminum contamination in L-cysteine
`
`solutions. But, unlike Eton, the Examiner correctly reads the Sandoz Label as
`
`disclosing a “product [that] contains no more than 5,000 mcg/L (5,000 ppb) of
`
`aluminum,” not a range of 0-5,000 ppb. Ex. 1090 at 5.
`
`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
`
`Allergy Process as a prior public use: public accessibility. See POPR at 20‒21
`
`and cases cited therein. The test for public accessibility requires consideration of
`
`what activity actually occurred in public, actual public access to the use, and any
`
`confidentiality obligations imposed on members of the public who observed the
`
`use. See Dey, L.P. v. Sunovion Pharms., 715 F.3d 1351, 1355 (Fed. Cir. 2013); see
`
`5
`
`
`
`also BASF Corp. v. SNF Holding Co., 955 F.3d 958, 967 (Fed. Cir. 2020). The
`
`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
`
`
`policy behind the public use bar is to discourage removing from the public domain
`
`an invention the public reasonably believes is freely available. Dey, 715 F.3d at
`
`1360. The Petition, including Mr. Johnson’s declaration, comes nowhere close to
`
`putting the Allergy Process in the public domain.
`
`Nothing in the record shows that anyone from the public ever had access to
`
`or observed the Allergy Process. See Reply at 6. Mr. Johnson’s statement that the
`
`Allergy Labs process “was generally known by Allergy Labs personnel” (Ex. 1022
`
`(Johnson Decl.) ¶ 18) is uncorroborated and, in any event, does not speak to the
`
`number of personnel—let alone the public—with that knowledge, or their
`
`confidentiality obligations. Mr. Johnson’s statement that “Allergy Labs did not
`
`take any overt efforts to conceal the manufacturing process for the Sandoz L-
`
`Cysteine Product” (Ex. 1022 (Johnson Decl.) ¶ 18) is likewise uncorroborated. It
`
`also lacks specificity.
`
`What Mr. Johnson does not say in his declaration is conspicuous. He does
`
`not say anyone from the public actually observed the process (let alone without any
`
`implied obligation of secrecy), or that the Allergy Labs personnel with access to it
`
`were not under any kind of confidentiality obligation. Eton’s claim of public use
`
`should be rejected outright.
`
`
`
`6
`
`
`
`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
`
`
`Respectfully submitted,
`
`/Dorothy P. Whelan/
`Dorothy P. Whelan, Reg. No. 33,814
`
`Counsel for Patent Owner
`
`
`
`
`
`
`
`
`Date: October 5, 2020
`
`
`
`
`Customer Number 26191
`Fish & Richardson P.C.
`Telephone: (612) 337-2509
`Facsimile: (877) 769-7945
`
`
`
`
`
`
`
`
`7
`
`
`
`Attorney Docket: 48751-0005PS1
`Case No. PGR2020-00064
`
`
`CERTIFICATE OF SERVICE
`
`Pursuant to 37 CFR §§ 42.6(e)(4), the undersigned certifies that on October
`
`5, 2020, a complete and entire copy of this Patent Owner’s Sur-Reply to
`
`Petitioner’s Reply to Patent Owner’s Preliminary Response and accompanying
`
`exhibit were provided via email to the Petitioner by serving the correspondence
`
`email addresses of record as follows:
`
`
`
`Ralph J. Gabric
`Eugene Goryunov
`Judy K. He
`Jeff Wolfson
`Haynes and Boone LLP
`2323 Victory Ave., Suite 700
`Dallas, TX 75219
`
`Email: ralph.gabric.ipr@haynesboone.com
`Email: eugene.goryunov.ipr@haynesboone.com
`Email: judy.he.ipr@haynesboone.com
`Email: jeff.wolfson.ipr@haynesboone.com
`
`
`
`
`
`/Edward G. Faeth/
`Edward G. Faeth
`Fish & Richardson P.C.
`60 South Sixth Street, Suite 3200
`Minneapolis, MN 55402
`(202) 626-6420
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`8
`
`
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
