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 .
DETAILED ACTION
Status
Claims 9, 13, 17-19, 21, 22, 27-29, 32-35, 37 and 38 are pending. Claim 9 was amended to incorporate routes of administration and corresponding dose amounts for methylnaltrexone (MNTX), for example, 50 mg to 600 mg oral methylnaltrexone (moved from dependent Claim 19). Claims 22, 27-29, 32-35 and 37 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention Therefore, Claims 9, 13, 17-19, 21, and 38 are presented for examination.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 3/12/2026 has been entered.
Election/Restrictions
Applicant elected without traverse Group I (drawn to a method of treating increased gut permeability, a disease/condition associated with increased gut permeability, and/or reducing gut permeability) in the reply filed on 10/30/2024.
Priority
This application is a continuation of International Application No. PCT/EP2020/065374, filed on June 3, 2020, which claims the benefit of U.S. Provisional Application Nos. 62/856,497, filed on June 3, 2019, and 62/937,606, filed on November 19, 2019.
Information Disclosure Statement
No Information Disclosure Statement was filed with Applicant’s most recent response.
Response to Arguments
Applicant’s arguments regarding the dose amount for oral MNTX in the remarks filed 3/12/2026 with respect to the rejection of the claims under 35 USC 102 and 35 USC 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of the amended claims being rendered obvious by Wu et al. (US 2017/0304294 A1) in view of Abdel-Razik et al., Zacny et al., and RELISTOR® package insert (2016) as outlined below.
Claim Rejections - 35 USC § 103
Rejection maintained
The factual inquiries 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 9, 13, 17-19, 21, and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Wu et al. (US PG-PUB 2017/0304294 A1) in view of Abdel-Razik et al. (“Rifaximin in nonalcoholic fatty liver disease: hit multiple targets with a single shot. European Journal of Gastroenterology & Hepatology 30(10):p 1237-1246, October 2018. | DOI: 10.1097/MEG.0000000000001232), taken in further view of Zacny et al. (Psychopharmacology (Berl). 2014 May 29; 232(1):63–73. doi: 10.1007/s00213-014-3637-8) and
Claimed invention
Independent Claim 9 is drawn to a method of treating nonalcoholic steatohepatitis (NASH) or nonalcoholic fatty liver disease (NAFLD) in a subject in need thereof, the method comprising administering to the subject methylnaltrexone or a salt thereof at a dose of either 50-600 mg orally or 5-12 mg subcutaneously and rifaximin.
Prior art
Wu teaches the treatment of NASH (non-alcoholic steatohepatitis), NAFLD (non-alcoholic fatty liver disease) and/or ASH (alcoholic steatohepatitis) with a morphinan such as naltrexone or an analog thereof and pharmaceutical formulations thereof. See Wu, abstract, 0002. Wu discloses that naltrexone has demonstrated its efficacy in preventing and treating NAFLD, NASH, and ASH. See Wu, 0005. See also Wu, Claims 1, 5-7.
While Wu teaches treatment of NAFLD or NASH by administering naltrexone or analog thereof, Wu does not expressly teach 1) rifaximin or 2) methylnaltrexone.
Regarding 1) rifaximin:
It was already known that NAFLD and NASH can be treated with rifaximin. For example, Abdel-Razik teaches the treatment of NASH and NAFLD with administration of 1100 mg/day of rifaximin. See abstract.
A person of ordinary skill in the art (POSA) would have found it obvious to combine rifaximin with naltrexone to treat NAFLD or NASH because both were already described in the prior art as useful agents for treating NASH and NAFLD. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). See MPEP .Section 2144.06. The POSA would have had a reasonable expectation of success that the combination therapy with naltrexone and rifaximin would provide efficacy for treating NASH or NAFLD given that the agents are known to be effective for treating NASH or NAFLD.
Regarding 2) methylnaltrexone:
Wu further teaches, the compound or composition of the invention is suitable for administration to a subject to achieve the treatments described, without unduly deleterious side effects in light of the severity of the disease and necessity of the treatment. See Wu, 0091. Additionally, methylnaltrexone is a known analog of naltrexone that, like naltrexone, is an opioid receptor antagonist. While naltrexone is centrally-acting, i.e., acting in the CNS, the design of methylnaltrexone (MNTX) – the addition of a methyl group to naltrexone – hinders its ability to cross the blood-brain barrier (BBB), minimizing its effects in the CNS and, therefore, focusing its effects on the periphery. See Zacny, Abstract; see also ‘Introduction’ at pp. 2-3.
A person of ordinary skill in the art (POSA) would have found it obvious to incorporate methylnaltrexone (MNTX) in the place of naltrexone in the suggested method of treating NASH or NAFLD with naltrexone and rifaximin because Wu and Abdel-Razik suggest treating NASH or NAFLD with naltrexone and rifaximin while Zacny teaches MNTX is a known analog of naltrexone with opioid receptor-inhibiting activity like naltrexone but acts more on the periphery instead of centrally within the CNS. Zacny refers to the RELISTOR® Salix Pharmaceuticals, Inc in Raleigh, NC as the source of MNTX further references their RELISTOR® label. See Zacny, section ‘Experimental design and drugs’ bridging pages 4 and 5. Similar to Zacny, the RELISTOR® label also recognized the difficulty methylnaltrexone has with crossing the BBB. See RELISTOR® section ’12.1 Mechanism of Action.; at p. 8. This can allow methylnaltrexone to function as a peripherally-acting mu-opioid receptor antagonist in tissues such as the gastrointestinal tract, thereby decreasing the constipating effects of opioids without impacting effects on the central nervous system. See Id.
The POSA would have substituted naltrexone for a structurally similar analog such as MNTX in order to focus its activity on the peripheral tissue to treat the liver conditions of NAFLD or NASH without also inducing unnecessary CNS effects as would a centrally active agent like naltrexone. The POSA would have had a reasonable expectation of success that the structurally close analog would provide similar activity against NASH or NAFDL but with reduced potential to cause unnecessary CNS effects.
Regarding the oral dose, the REALISTOR® label teaches a clinically available oral MNTX product in the form of a tablet of 150 mg MNTX. It is administered at a recommended oral dose of 450 mg once daily. See RELISTOR® sections 2.2,3, 6.1. The POSA would have further found it obvious to administer RELISTOR® at known oral dose used in the clinical setting. The POSA would have had a reasonable expectation of success that the oral amount of 450 mg as a suitable route and dose for delivery of MNTX to the subject. This meets the limitation of Claim 19.
Claim 13 limits claim 9, wherein the subject is administered (R)-N-methylnaltrexone bromide. Zacny teaches REALISTOR® as the source for MNTX as outlined above. The RELISTOR® label teaches methylnaltrexone bromide as the salt form of MNTX and the chemical name for methylnaltrexone bromide as (R)-N-(cyclopropylmethyl) noroxymorphone methobromide, i.e., (R)-N-methylnaltrexone bromide. The POSA would have understood that (R)-N-methylnaltrexone bromide can be used as a suitable salt form for therapeutic use as it is commercially available for clinical use as described throughout the RELISTOR® label and would have combined it as the MNTX with rifaximin for treating NASH or NAFLD. This also meets the limitations for Claim 18.
Claim 17 limits claim 9, wherein the subject is administered rifaximin orally. Claim 21 limits claim 9, comprising orally administering (i) about 25 mg to about 1000 mg, about 300 mg to about 750 mg, or about 500 mg to about 600 mg of rifaximin; or (ii) about 100 mg/kg to about 700 mg/kg, about 250 mg/kg to about 550 mg/kg or about 350 mg/kg to about 450 mg/kg of rifaximin, or a salt thereof. Rifaximin is an oral medication that was administered to patients at 1100mg/day. See Abdel-Razik, p. 1238, 1st full par. and last par. Abdel-Razik teaches 1100 mg/day rifaximin which meets the claimed limitation of about 25 mg to about 1000 mg.
Claim 38 limits claim 9, wherein the subject is administered (R)-N-methylnaltrexone bromide orally or subcutaneously. RELISTOR is administered as a subcutaneous injection. See RELISTOR® p. 1.
Response to Applicant’s arguments
Applicant's arguments have been fully considered but have not been found to be persuasive. Applicant argues that no reference teaches MNTX for treating NASH/NAFLD and that the POSA would not select a different active ingredient from the naltrexone in Wu, especially given that small structural changes can drastically affect the activity of a drug. This is not persuasive because WU teaches treating NASH/NAFLD with naltrexone “or analog thereof”. See Wu, abstract; 0002; Claims 1, 5-7. MNTX is a recognized analog of naltrexone that maintains antagonist activity against mu-opioid receptor. Thus, the rejection selects an analog the Wu contemplates.
Applicant further asserts unexpected results are obtained. However, generalized assertions of unpredictability does not replace the requirement of objective support as required. Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. MPEP § 716.
Regarding the dose, a new RELISTOR® reference was added to the rejection. It teaches oral dosage amounts that fall squarely within the claimed ranges.
Therefore, the rejection is deemed to still be proper and is, therefore, maintained.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRIS E SIMMONS whose telephone number is (571)272-9065. The examiner can normally be reached M-F: 9:30-6:00p.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James H. Alstrum-Acevedo can be reached at (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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CHRIS E. SIMMONS
Examiner
Art Unit 1622
/CHRIS E SIMMONS/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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