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 .
Current Status of 17/749,491
The rejections of record have been withdrawn below.
This Office Actions is responsive to the amended claims of 4/28/2026.
Claims 1-4, 8-9, 11-15, 17-18, 20-21, 30-31, 33-34, and 36-38 are examined on the merits.
Priority
The instant application claims priority to U.S. provisional application 63/191,826, filed 05/21/2021.
The instant claims find support from the provisional application. Therefore, the effective filing date is 05/21/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 04/21/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Response to Arguments
Applicants’ claim amendments and Remarks of 4/28/2026 are acknowledged and have been considered.
Any rejection and/or objection not specifically addressed or modified below is herein withdrawn.
Claims 10, 19, and 35 are canceled. Claims 1-4, 11, 13-14, 20, 30-31, and 36-37 are amended.
In regard to the obviousness rejection, this rejection is withdrawn. Applicant’s remarks with Examiner’s Comments are summarized below:
Applicants amended the biguanide to Metformin. Applicants also narrowed the scope for the chronic liver diseases or disorder.
The current rejection of record is no longer within the scope of the instant claims.
Applicants point out that Matafome did not observe hepatic steatosis and fibrosis in the high fat diet.
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Applicants pointed out the points above. All of which are persuasive in showing how Matafome is different from the amended claims.
Applicants reiterate the unexpected results is commensurate with scope of the instant claims.
Surprisingly, CLD patients with NASH and diabetes exhibited significantly better liver function and less portal-systemic shunting in the cholate liver function tests including DSI and SHUNT compared to non-NASH and non-diabetes subjects.
Examiner has reviewed Figures 1, 6, 7B, 8B-13B, and 15A-17B again. Applicants submit that for subjects taking both an anti-diabetic drug therapies and a statin, the mean difference in DSI was -3.6 and the mean difference in SHUNT was -7.6% (table 6 on page 12 of Remarks of 03/27/2026). Examiner now better understands that a lower DSI indicates better hepatic function; lower SHUNT indicates less portal-hepatic shunting.
Examiner reviewed Instant Table 6 and Applicant’s comments. In subjects taking both anti-diabetic drug therapies and a statin, had better liver function and decreased portal-systemic shunting than subjects taking either drug or neither drug (this was shown with DSI and mean difference in SHUNT).
Applicants submit additional data for the unexpected results (submitted the reference called Rahimi published in 2026 after the effective filing date).
Rahimi discusses the SHUNT-V study linking DSI to risk of varices. Rahimi surprisingly found that subjects with MASLD/MASH or DM had better liver function as judged by lower DSI and less severe portal-systemic shunting as judged by lower SUNT% (page 5).
Rahimi found that statins demonstrated statistical significance, but metformin trended toward significance (table 5). Overall the combination of both provides a greater significance benefit and is detectable only by DSI. Rahimi provides statistical data to support these claims.
Rahimi is published after the effective filing date.
While this rejection is withdrawn, a new/different obviousness rejection is made below for the following reasons. Meformin and statins are known in the prior art to treat NAFLD. The instant claims are broader than their arguments and the unexpected results are just not convincing, particularly for the breadth of statins and diseases. The prior art is clear in suing both compounds for treating multiple liver diseases, and the combination would be obvious using Kerkhoven logic. The instant claims have a generic test and the DSI test is well-established for liver diseases like NAFLD (e.g. WO 2014075072 A1, para [0026], [00104], [00120], [00123], [00288], figures 11 and table 12). Furthermore, the instant claims have no specific cutoff and “predetermined” which is vague at best. However, the art provides enough guidance that it would have been obvious to have used this test to ascertain the liver disease and the combination of treatment falls in there.
The second obviousness rejection is withdrawn due to claim amendments. Applicants also additionally point out that Chen teaches away from using metformin (table 1, page 5, right col).
Response to Amendment
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, 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 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.
Claim(s) 1-4, 8-9, 11-14, 17-18, 20-21, 30-31, 33-34, 36-38 are rejected under 35 U.S.C. 103 as being unpatentable over DIMARCHI (US9783592B2) in view of JIROUSEK (WO 2015073901 A1) and EVERSON2 (WO2014075082A1), in view of Pinyopornpanish (Pinyopornpanish et al., “Effects on Metformin on Hepatic Steatosis in Adults with Nonalcoholic Fatty Liver Disease and diabetes”, Gut and Liver, February 17, 2021), and in view of EVERSON (Gregory Everson, “The HepQuant SHUNT Test for Monitoring Liver Disease and Treatment Effects by Measuring Liver Function and Physiology”, HepQuant LLC, May 15, 2018).
DIMARCHI teaches as Metformin being used to treat NAFLD in a subject (paragraph [00884]). This teaches claim 1’s limitation c.
JIROUSEK teaches that Statins (for example atorvastatin paragraph [00115]) are used for treating NAFLD in a subject (claim 12). This teaches claim 1’s and 2’s limitation c. This teaches claims 8 and 33.
JIROUSEK administered 45 mg of atorvastatin per day (paragraph [00159]). This helps teach claims 9, 34, and 37.
EVERSON2 teaches the DSI test is well-established for liver diseases like NAFLD (para [0026], [00104], [00120], [00123], [00288], figures 11 and table 12).
EVERSON2 teaches that the DSI can be used for defining disease severity in patients with NAFLD (paragraph [00123]). This helps teach claim 1’s and 2’s limitation a and d.
EVERSON2 teaches that a DSI can be used for assessment of liver function for a number of specific clinical applications (paragraph [00125]). EVERSON also teaches that DSI having cutoff values and an optimum value to compare to (paragraph [00288]). This helps teach claim 1’s limitation b.
Pinyopornpanish teaches metformin dosages from 3 mg per kg per day to 300 mg per kg per day (table 1). This helps teach claims 9, 11, 18, 20, 34, 36 and 37.
Pinyopornpanish teaches Gliclazide, a drug in sulfonylurea class, was able to decrease hepatic fat content for diabetic NAFLD patients (page 837 left col). This teaches claims 12, 21, and 38.
EVERSON teaches the disease severity index (DSI) is for monitoring liver disease (NASH) and seeing how effective treatments are (page 8). EVERSON teaches that to determine a baseline DSI, performed prior to the treatment (page 8). This teaches step a of claims 1 and 2.
EVERSON teaches a criteria for evaluation for the treatment effect, which the DSI value is compared to (page 8). This teaches step b of claim 1.
EVERSON additionally teaches that Disease severity in NAFLD and NASH is based upon clinical, laboratory, and histologic criteria (page 29). A higher DSI value means a worse disease condition (page 20 DSI bullet point). This teaches step c of claim 1.
EVERSON teaches measuring DSI “serially” (page 36). This teaches claim 2’s c. EVERSON teaches the change in DSI (relative to baseline, during the placebo/treatment and post-treatment follow-up periods of the study) (page 36). This teaches claim 2’s step d and step f of claim 3.
EVERSON teaches “If treatment is effective the ∆DSI of the treatment arm should be negative – implying a lowering of disease severity and improvement in liver function and physiology” (page 18). This teaches claim 2’s step e.
It is prima facie obvious to combine one NAFLD treatment with another in order to form a composition to be used for the very same purpose. In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). See MPEP 2144.06(I). This teaches claim 1’s limitation 1, 4, 8, and claims 12-14, 21.
The claims as currently written have no specific cutoff value. However, EVERSON2 and EVERSON provide enough guidance that it would have been obvious to have used the DSI test to ascertain the liver disease and the combination of treatment falls in there.
The method steps of using the DSI test to measure/watch the progression of liver disease and the effect of treatment is known (EVERSON pages 8, 18, 20, 29, and 36). This teaches claim 1’s steps a and b, and claim 2’s steps a, c, d, e, and claim 3’s step f. The artisan would have been motivated to combine the DSI testing from EVERSON with the combination treatment. The artisan would expect the DSI test would be compatible and be effective at measuring the severity of liver disease when using a metformin/ atorvastatin/ sulfonylurea drug combination. This teaches claims 1-3.
The artisan would be motivated to experiment with dose ranges of metformin and atorvastatin to find the optimal dosage range in order to increase therapeutic efficacy of metformin and atorvastatin in a patient. The artisan would be expected to optimize the dosage of 3-500 mg/kg/day of metformin (Pinyopornpanish) to 45 mg/ day (JIROUSEK) to arrive at the instantly claimed dosages. An artisan would have been expected to optimize the doses for humans. See MPEP 2144.05 (II)(A): “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical”. Neither the specification nor the claims indicate the dosages of metformin and atorvastatin of the instant claims is critical. This teaches claims 9, 11, 18, 20, 34, 36, and 37.
Conclusion
Claim 15 is objected to for depending on a rejected base claim.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/G.A.H./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625
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