DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This application claims the benefit of priority under 35 U.S.C §119 to U.S. Provisional
Application No. 63/411,588, filed on September 29, 2022.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 10/18/2024 and 01/15/2025 were filed in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Status of the Application
Claims 1-20 are pending and currently under examination. Claims 1, and 6-13 been amended. Claims 14-20 are new.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (page 13, line23, page 34, lines 10-11). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claim 4 is objected to because of the following informalities: there appears to be an omission of the words –selected from—in claim 4, line 2 between “is cimetidine” and/or the word --or—between “, vandetanib” in claim 4, line 3. Appropriate correction is required.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Cohen (U.S. 2021/0186990Al) in view of Nath (WO2017/059122A1) and further in view of Yoo (U.S. 2006/0142241A1).
The instant claims are directed to a method of treating at least one symptom of Amyotrophic Lateral Sclerosis (ALS) in a subject, the method comprising:
(a) orally administering to a subject who has received an inhibitor of a OATP1B3, MATE2-K, or OAT3 transporter, a first dosage of a composition comprising Taurursodiol (TURSO) and sodium phenylbutyrate;
(b) determining or having determined a first level of TURSO, sodium phenyl butyrate, or a metabolite thereof, in a first biological sample from the subject; and
(c) administering to the subject a second dosage of the composition, wherein 1 gram of TURSO and about 3 grams of sodium phenylbutyrate are administered once or twice a day.
(d), determining or having determined a second level of TURSO, sodium phenyl butyrate, or the metabolite thereof in a second biological sample from the subject.
Cohen et al. teach methods and compositions for treating at least one symptom of ALS, slowing ALS disease progression, or reducing the deterioration of one or more bodily functions affected by ALS in a subject which include administering a bile acid or a pharmaceutically acceptable salt thereof and a phenylbutyrate compound (Abstract). Cohen teaches in some embodiments, a subject in the methods described herein has been previously treated with one or more additional therapeutic agents (e.g., any of the additional therapeutic agents described herein, such as riluzole, edavarone, and mexiletine) [0170]. Cohen discloses evaluating a level of a biomarker in a biological sample obtained from the subject wherein the biological sample is blood [0016]. Cohen teaches in some embodiments of any of the methods described, the bile acid is taurursodiol (TURSO) [0017]. Cohen also teaches “methods of treating at least one symptom of ALS or preventing the onset of ALS in a human subject, the methods include administering TURSO and sodium phenylbutyrate to the human subject according to a first regimen followed by a second regimen, where the first regimen includes administering for at least 14 days about 1 gram of TURSO once a day and about 3 grams of sodium phenylbutyrate once a day, and the second regimen includes administering for at least 30 days about 1 gram of TURSO twice a day and about 3 grams of sodium phenylbutyrate twice a day” [0021]. Cohen also discloses that the terms of "tauroursodeoxycholic acid" (TUDCA) and "taurursodiol" (TURSO) are used interchangeably [0047]. Cohen discloses “1 gram of TURSO once a day and about 3 grams of sodium phenylbutyrate once a day “ [0082]. Cohen also discloses AMX0035 is a combination therapy comprised of two active pharmaceutical ingredients, sodium phenylbutyrate (PB) and tauroursodeoxycholic acid (TUDCA) [0288]. Cohen also discloses embodiments wherein the bile acid and phenylbutyrate compounds are administered orally or through a feeding tube [0018]. Cohen discloses each twice daily sachet of AMX0035 contains 3 g PB and 1 g TUDCA [0285]. Cohen also discloses table 2 which discloses a biological sample taken as a blood draw on days -42, 0 and weeks 3-6, 12, 18 and 24 (Table 2, pages 39-40). Cohen teaches that Agents which might impair bile acid processing or renal function are contraindicated with AMX0035. Prohibited medications include probenecid for potential kidney interaction [0348-0358].
However, Cohen et al. fail to disclose the transporter of OATP1B3, MATE2-K, or the inhibitors thereof.
Nath et al. teach a method of treating or preventing amyotrophic lateral sclerosis (ALS) in a subject by administering to a subject diagnosed with ALS, or a subject at risk for developing ALS the inhibitors of Lopinavir, Atazanavir or Ritonavir page 4, lines 5-19. Nath discloses dolutegravir as an FDA approved integrase inhibitor (page 53, lines 17-18). Nath also discloses dolutegravir used in comparative inhibitor complex modeling (page 45, lines 13-17).
However, Nath et al. does not explicitly teach the administration of a MATE2-k inhibitor prior to administering treatment of ALS.
Yoo et al. teach a solution of the disclosure may be used, in some embodiments, to treat or ameliorate ALS disease and/or advanced ALS disease wherein an example solution of the disclosure may include a pharmaceutical compound that decreases motor neuron death such as probenecid [0035]. Yoo teaches additional examples of pharmaceutical compounds that may be included in the formulation are any compounds which remain soluble when added to the formulation. With an additional pharmaceutical compound in the formulation, a bile acid in solution may act as an adjuvant, carrier, or enhancer for the solubility of certain therapeutically active agents, wherein Cimetidine is a therapeutically active agent [0066].
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, prior to the effective filing date of the instant application, to treat at least one symptom of ALS in a subject by combining Cohens teachings of administering AMX00335, comprised of sodium phenylbutyrate (PB) and tauroursodeoxycholic acid (TUDCA), after a transporter inhibitor of probenecid has been given and Nath’s teachings of treating ALS with the inhibitors of dolutegravir, atazanavir, ritonavir, and lopinavir, and further with Yoo’s contribution of ALS treatment improved by use of a bile acid used to promote solubility of the active agent of cimetidine because Cohen teaches a potential kidney interaction between a transporter inhibitor and AXM0035 and therefore a transporter inhibitor would preferably be administered before AMX0035. A skilled artisan would have also monitored the bioavailability of AMX0035 in a human subject through routine blood samples, before administering another dose of transporter inhibitors for the purpose of avoiding the known harmful drug interactions disclosed by Cohen and repeating the regimen based on the progression of ALS and patient response to treatment. Furthermore, a person of ordinary skill would have also found it prima facie obvious to try orally administering 1 gram of TURSO and about 3 grams of sodium phenylbutyrate once or twice a day to a human subject with ALS symptoms in need thereof following the teachings of Cohen. See MPEP 2144.07, MPEP 2144.05 and MPEP2131.03.
A person of ordinary skill in the art would have been motivated to combine the administration of an ALS treatment regimen of TURSO and sodium phenylbutyrate (AMX0035) after administration of a transporter inhibitor as disclosed by Cohen with the disclosures of Nath and Yoo concerning solubility and inhibitor compounds of dolutegravir, atazanavir, ritonavir, and lopinavir, and cimetidine because of the beneficial results of treating ALS in a human subject from the combined cumulative effects of administering AMX0035 as disclosed by Cohen with the teachings of transporter inhibitor compounds taught by Nath and Yoo. A person of ordinary skill would have therefor had a reasonable expectation of success in treating a symptom of ALS in a human subject by combining the disclosed treatments of Cohen, Nath and Yoo through routine experimentation. See MPEP 2143.02 and MPEP 2144.05.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 6-7 and 8-17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4 and 5-11 of U.S. Patent No. 12,138,272 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims meet the limitations of instant claims 1, 6-7 and 8-17 wherein the method of administering Taurursodiol (TURSO) and sodium phenylbutyrate to a human subject having at least one symptom of Amyotrophic Lateral Sclerosis (ALS) who has received a first dosage of cyclosporine (inhibitor of transporter OATP1B3). Followed by determining or having determined a first level of serum transaminases and/or bilirubin in a first biological sample from the human subject and then administering to the human subject a second dosage of cyclosporine and administering to the human subject a composition comprising about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate.
A person of ordinary skill would have found it prima facie obvious to administer a method of treating at least one symptom of Amyotrophic Lateral Sclerosis (ALS) in a subject, comprising: (a) administering to a subject who has received an inhibitor of a transporter a first dosage of a composition comprising Taurursodiol (TURSO) and sodium phenyl butyrate; (b) determining or having determined a first level of TURSO, sodium phenyl butyrate, or a metabolite thereof, in a first biological sample from the subject; and (c) administering to the subject a second dosage of the composition with the expectation of successfully treating a symptom of ALS by following the teachings of U.S. Patent No. 12,138,272 B2 claims 1, 2, 4 and 5-11.
Conclusion
All claims are rejected, no claims are allowed.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERNESTO VALLE JR whose telephone number is (703)756-5356. The examiner can normally be reached 0730-1700 M-F EST, 1st Friday off.
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/E.V./Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
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