UNITED STATES PATENT AND TRADEMARK OFFICE
`
`———————
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`———————
`
`ETON PHARMACEUTICALS, INC.,
`
`Petitioner
`
`v.
`
`EXELA PHARMA SCIENCES, LLC,
`
`Patent Owner
`
`———————
`
`U.S. PATENT NO. 10,583,155
`
`PGR2020-00068
`
`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
`
`———————
`
`U.S. PATENT NO. 10,583,155
`
`PGR2020-00068
`
`PETITIONER’S REPLY TO PATENT OWNER’S
`PRELIMINARY RESPONSE
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`PGR2020-00068: Reply to Patent Owner’s Preliminary Response
`
`Petitioner files this reply to Patent Owner’s Preliminary Response (“POPR”).1
`
`I. THE PETITION MEETS THE PARTICULARITY REQUIREMENT
`
`The challenged claims are the result of optimizing the Sandoz Label product
`
`using known techniques for substantially preventing (1) oxidative degradation of L-
`
`Cysteine to L-cystine and pyruvic acid and (2) aluminum contamination.2
`
`The Petition’s two grounds rely on the four-corners of the Sandoz Label,
`
`which discloses an injectable L-Cysteine solution for use in a total parenteral
`
`nutrition regimen. (Pet. at 31-34; Ex. 1003, ¶¶33-35.)3 The Sandoz Label product
`
`
`1 The Board authorized a 6-page reply (Paper No. 7).
`
`2 Shortly prior to the alleged invention, FDA demanded substantially reduced
`
`aluminum levels in small volume parenteral (“SVP”) products. (Pet. at 36-39; Ex.
`
`1003, ¶¶29-32, 36-43.) Even if not statutory prior art, these FDA communications
`
`pre-date the alleged invention, are relevant to the skill of the POSITA and
`
`demonstrate that companies promptly and concurrently reduced aluminum
`
`contamination in response to FDA pressure. (E.g., Pet. at 38-39; Ex. 1003, ¶¶36-43.)
`
`3 The attributes not expressly disclosed by the Sandoz Label are nevertheless
`
`relevant to the state of the art and were readily ascertainable through routine testing
`
`of the commercially available product.
`
`
`
`
`
`1
`
`
`
`PGR2020-00068: Reply to Patent Owner’s Preliminary Response
`
`contains NMT 5,000 mcg/L (or ppb) aluminum,4 has a pH of 1.0-2.5, and air is
`
`replaced with nitrogen.5 (Pet. at 31-32; Ex. 1003, ¶¶33-34.)
`
`The Petition identifies with particularity the knowledge prompting the
`
`POSITA to have optimized the Sandoz Label product as claimed.
`
`o L-Cysteine oxidation occurs at alkaline, neutral and acidic pH. (Pet. at 40-
`
`42; Ex. 1003, ¶¶44-46.)
`
`o L-cystine (which forms unwanted precipitates) and pyruvic acid (which
`
`reduces efficacy) are oxidation degradation products of L-Cysteine. (Pet.
`
`at 40, 43; Ex. 1003, ¶¶44, 47-49.)
`
`
`4 Contrary to the PO’s assertions, the Sandoz Label product contained substantially
`
`less than 5,000 ppb (less than 375 ppb aluminum) as demonstrated by the Geissler
`
`Declaration submitted in the PO’s related applications discussed below. (Ex. 1116
`
`at 2-8, 45, 49). Thus, even if the pharmacist would assume 5,000 ppb aluminum for
`
`dosing purposes (as PO asserts), the POSITA would have understood (and could
`
`have confirmed by routine testing) that the actual level was between 0-5,000 ppb.
`
`5 PO’s assertion that the POSITA would not be concerned with oxidation at acidic
`
`pH is belied by the plain teaching of the Sandoz Label, which discloses replacing air
`
`with nitrogen in an L-Cysteine solution having a pH of 1.0-2.5. (Pet. at 31-32.)
`
`
`
`2
`
`
`
`PGR2020-00068: Reply to Patent Owner’s Preliminary Response
`
`o Removing head space and dissolved oxygen are result-effective variables
`
`for substantially preventing degradation of oxygen-sensitive drugs. (Pet. at
`
`41-43; Ex. 1003, ¶¶50-52.)
`
`o The reasonably expected result of minimizing head space and dissolved
`
`oxygen is the substantial prevention of oxidative degradation of L-
`
`Cysteine to L-cystine and pyruvic acid. (Pet. at 44-45; Ex. 1003, ¶¶61-62.)
`
`o Aluminum leaching from glass vials was a significant source of aluminum
`
`contamination (Pet. at 39-40, 42-43; Ex. 1003, ¶¶35, 58-59.)
`
`o Coated Schott glass vials substantially prevent aluminum leaching. (Pet. at
`
`41-43; Ex. 1003, ¶¶58-62.)
`
`The Petition also demonstrates with particularity that the POSITA, armed with
`
`this knowledge, would and could have optimized the Sandoz Label product to
`
`minimize oxygen exposure (a result-effective variable) during manufacture and
`
`storage to achieve the reasonably expected result of substantially preventing
`
`oxidation of L-Cysteine to L-cystine and pyruvic acid. (Pet. at 44-45; Ex. 1003, ¶60-
`
`62.)6 The POSITA would also have been motivated to manufacture the optimized
`
`
`6 E.g., Anacor Pharms., Inc. v. Flatwing Pharms., Inc., No. 2019-2264, 2020 WL
`
`5049229, at *4 (Fed. Cir. Aug. 27, 2020) (affirming Board’s obviousness finding
`
`where claims directed to routine optimization of result-effective variable).
`
`
`
`
`
`3
`
`
`
`PGR2020-00068: Reply to Patent Owner’s Preliminary Response
`
`Sandoz Label product in a substantially aluminum-free environment and store the
`
`product in a Schott coated glass container that is not only oxygen impermeable but
`
`also substantially prevents aluminum from leaching into the product during its
`
`projected shelf life. (Pet. at 44-45; Ex. 1003, ¶¶58-62.)7
`
`
`7 PO’s assertion that solving the “high-aluminum problem” requires optimization of
`
`cystine levels (and associated dissolved oxygen and head space oxygen levels)
`
`(POPR at 39) not only lacks evidentiary support but also, even if true, does not make
`
`the alleged invention patentable. The POSITA addressing the aluminum problem
`
`would have also understood that L-Cysteine is oxygen-sensitive. As such, the
`
`POSITA would have taken known steps to prevent oxidation while also eliminating
`
`the sources for aluminum contamination. Thus, for example, the POSITA would
`
`have selected a Schott coated glass container, which is both oxygen impermeable
`
`and does not leach aluminum. (Pet. at 42-45; Ex. 1003, ¶¶58-62.) The ’155
`
`patentee’s alleged discovery of the purported benefit of preventing oxidation to
`
`minimizing aluminum contamination (even if true) is merely the discovery of an
`
`additional benefit of optimizing the Sandoz Label product to prevent oxidation as
`
`taught by the prior art. See In re Woodruff, 919 F.2d 1575, 1578 (Fed. Cir. 1990) (“It
`
`is a general rule that merely discovering and claiming a new benefit of an old process
`
`cannot render the process again patentable.”).
`
`
`
`
`
`4
`
`
`
`PGR2020-00068: Reply to Patent Owner’s Preliminary Response
`
`II. REJECTIONS IN RELATED APPLICATIONS
`
`The POPR cites the Notice of Allowance (“NOA”) in the parent ’453 patent
`
`in arguing that the Examiner acknowledged that the alleged “unpredictable nature of
`
`the art” and that the claimed subject matter allegedly achieved “unexpected
`
`result[s].” (POPR at 19.) However, PO neglected to advise the Board that, on July
`
`23, 2020 (before the POPR), the same Examiner—apparently no longer considering
`
`the art “unpredictable” or the claimed aluminum levels and steps for preventing
`
`oxidative degradation of L-Cysteine “unexpected”—rejected previously allowed
`
`claims directed to this subject matter in two related applications after this Petition
`
`and the Petition filed in related PGR No. 2020-00064 were made of record.8
`
`Consistent with the Petition (Pet. at 37; Ex. 1003, ¶36), the Examiner noted
`
`that Hernandez-Sanchez teaches that aluminum content should be limited in
`
`
`8 Relevant file history excerpts included with this Reply are: claims as they existed
`
`at the time of the NOAs (Ex. 1106 at 1-4; Ex. 1107 at 1-3), NOAs (Ex. 1108 at 1, 5-
`
`7; Ex. 1109 at 1, 5-7), IDSs filed on April 17, 2020 (Ex. 1114 at 1, 4; Ex. 1115 at 1,
`
`4) and associated Geissler declaration (Ex. 1116 at 2-8, 43, 45, 49); Requests for
`
`Continued Examination and related IDSs (Ex. 1110 at 1-32; Ex. 1111 at 1-26), citing
`
`Petitioner’s PGRs (Ex. 1110 at 7 (No. 241), 25 (No. 305); Ex. 1111 at 9 (No. 241),
`
`19 (No. 305)), and the Examiner’s rejections (Ex. 1112 at 2-7; Ex. 1113 at 2-7).
`
`
`
`5
`
`
`
`PGR2020-00068: Reply to Patent Owner’s Preliminary Response
`
`parenteral compositions, steps for reducing aluminum were known, but few
`
`manufacturers put the procedures into use. (Ex. 1112 at 5; Ex. 1113 at 5). And,
`
`notwithstanding PO’s spin otherwise, Hernandez-Sanchez does not recognize a
`
`long-felt but unresolved need relevant to patentability. (POPR at 52.) Rather,
`
`Hernandez-Sanchez recognized that the market had failed to demand manufacturers
`
`meet this need, and as confirmed by the prior art and the contemporaneous FDA
`
`communications cited in the Petition, manufacturers promptly and concurrently met
`
`this need when pressed by the FDA. (Pet. at 36-39; Ex. 1003, ¶¶36-43.)
`
`Finally, PO may quibble with the Examiner’s rejections such as their reliance
`
`on Nakayama (Ex. 1117), which discloses a coating for preventing alkali earth metal
`
`leaching that contains 0.1 ppm (100 ppb) aluminum. The POSITA interested in
`
`preventing aluminum leaching would have opted for other coatings, such as the
`
`Schott coated glass vials discussed in the Petition. (Pet. at 42-45; Ex. 1003, ¶¶58-
`
`62.) Similarly, although the Examiner mistakenly cites Asquith for teaching
`
`oxidative degradation of cysteine (it discusses cystine degradation), Petitioner’s
`
`references address L-cysteine’s oxygen sensitivity. (Pet. at 40-42; Ex. 1003, ¶¶44-
`
`53.) However, none of this diminishes the relevance of the Examiner’s rejections,
`
`which confirm that the alleged invention is simply the reasonably expected result of
`
`using known techniques for substantially preventing oxidative degradation of L-
`
`Cysteine and aluminum contamination, as set forth in the Petition.
`
`
`
`6
`
`
`
`PGR2020-00068: Reply to Patent Owner’s Preliminary Response
`
`October 19, 2020
`
`
`
`
`
`Respectfully submitted,
`
`
`/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
`
`
`
`
`
`
`
`
`7
`
`
`
`PGR2020-00068: Reply to Patent Owner’s Preliminary Response
`
`CERTIFICATE OF SERVICE
`
`Pursuant to 37 C.F.R. §§ 42.105 and 42.6, I certify I caused a true and correct
`
`copy of the forgoing document on Patent Owner as detailed below.
`
`
`
`Date of service October 19, 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
`
`
`
`
`
`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
