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 maintained below.
The Markush searches are 1) Chronic Liver disease (NASH), 2) cholate liver function test (DSI), 3) Statin (atorvastatin), 4) Biguanide (Metformin), and 5) additional agent (sulfonylurea).
This Office Action is responsive to the amended claims of 8/22/2025.
Claims 1-4, 7-15, 17-21, 30-31, and 33-42 have been examined on the merits.
Claims 5, 16, and 32 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 9/14/2023.
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.
Response to Arguments
Applicants’ claim amendments and Remarks of 8/22/2025 are acknowledged and have been considered.
Applicants have amended claim 1 to specify the cholate liver function test disease severity index value.
In regard to the 103 rejection, this rejection is maintained. Applicant’s remarks with Examiner’s reply are summarized below;
MATAFOME does not disclose a method to improve cholate liver function test value or a cholate liver function disease severity index test.
EVERSON teaches the disease severity index (DSI, the elected species of cholate liver function test). MATAFOME is not used to teach DSI/cholate liver function test.
Applicants submit that Matafome does not alter hepatic lipids (Table 3 of Matafome, and page 9 of Remarks).
In response to applicant's argument that improvement of liver function, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
Matafome still teaches a combined treatment of Metformin and atorvastatin, which protects the liver in type 2 diabetes with hyperlipidemia (title and Discussion page 59, and paragraph 18 of the Nonfinal). When the claim recites using an old composition or structure and the “use” is directed to a result or property of that composition or structure, then the claim is anticipated. See MPEP 2112.02(II).
The base claims have not been narrowed to exclude Metformin and atorvastatin.
Applicants submit unexpected results.
This data (instant example 1, Figure 18, Table 6, Figure 20, Table 8, and the corresponding paragraphs in the specification) has been previously cited in past remarks.
Applicants describe that the SHUNT% was significantly lower and DSI was significantly lower for subjects having NASH for a different patient population (table 8 and paragraphs [00237], [00239], and [00240]).
Examiner is unsure how Table 8 and Figure 20 are supporting Applicants’’ claim of unexpected results. Additionally, the scope of the unexpected results (NASH and diabetes) given are not commensurate with the scope of the instant claims (all diseases listed in the wherein clause of claim 1).
Applicants submit that surprisingly 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).
Examiner is unsure how Applicants comment that both drugs have a mean difference in SHUNT value of -7.6%, while the table seems to be labeled for just STATINS. Additionally, the mean difference for metformin is -7.4%, which compared to the -7.6% value, does not seem unexpected.
Applicants submit that the instant claims improved liver function in subjects administered a statin and co-administered a biguanide, as surprisingly found in diabetic and NASH patients.
In regard to the unexpected results (all the data described above), the unexpected results focus on the diabetic and NASH patients (see Applicant’s underlined remarks summarizing this on top of page 13 of Remarks). The scope of the unexpected results given are not commensurate with the scope of the instant claims.
In regard to the 103 rejection over Chen, Helmke, and Lee, Examiner maintains this rejection. Applicants’ remarks are not persuasive. Applicants submit that the combinations of references does not teach a method for treating a chronic liver disease to improve liver function comprising administering a statin and co-administering a biguanide. Examiner disagrees. There is motivation and reasonable expectation of success (see Paragraph 54 in the Nonfinal).
Response to Amendments
Claim Rejections - 35 USC § 103- MAINTAINED
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.
Claims 1-4, 7-15, 17-21, 30-31, and 33-42 are rejected under 35 U.S.C. 103 as being unpatentable over:
MATAFOME (MATAFOME et al., “Metformin and atorvastatin combination further protect the liver in type 2 diabetes with hyperlipidemia”, Diabetes and Metabolism Research and Reviews, Volume 27, Issue 1, January 2011),
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),
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).
Determining the scope and contents of the prior art
MATAFOME teaches a combined treatment of Metformin and atorvastatin, which protects the liver in type 2 diabetes with hyperlipidemia (title and Discussion page 59). Examiner understands type 2 diabetes with hyperlipidemia as a chronic liver disease of claim 13 because type 2 diabetic and dyslipidemia patients develop hepatic complications, namely NAFLD (Introduction page 54). Examiner also understands MATAFOME would also treat “liver damage due to progressive fibrosis” of claim 13. This teaches claim 13.
MATAFOME teaches atorvastatin (elected species of statin) (title). This teaches claim 17.
MATAFOME teaches metformin (elected species of biguanide). This teaches claim 19.
MATAFOME teaches administering the combined metformin/ atorvastatin using high fat diet (hd) as a carrier (page 55). Examiner interprets the high fat diet as a pharmaceutically acceptable carrier. This teaches claims 30, 33, and 35.
Examiner also understands MATAFOME would also treat “liver damage due to progressive fibrosis”.
MATAFOME teaches that NASH is an aggravated state of NAFLD and that NASH has higher liver nitrotyrosin levels and isoprostane levels (page 55 left col). This helps teach claims 4, 14, 15, and 31.
MATAFOME teaches that the combined metformin/ atorvastatin treatment lowered isoprostane levels (Figure 3B). This helps teach claims 4, 14, 15, and 31.
MATAFOME teaches the daily dose of metformin is 60 mg/kg/day (dose for a rat) (page 55). This helps teach claims 11, 20, 36, and 37.
MATAFOME teaches the daily dose of atorvastatin is 10 mg/kg/day (dose for a rat) (page 55). This helps teach claims 9, 18, 34, 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, the elected species of cholate liver function test from claim 7) 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.
Ascertaining the differences between the prior art and the claims at issue
While MATAFOME teaches a combined metformin/ atorvastatin treatment (titl) and that that NASH is an aggravated state of NAFLD and that NASH has higher liver nitrotyrosin levels and isoprostane levels (page 55 left col), and dosages, MATAFOME does not teach the method of instant claims 1 and 2. MATAFOME does not teach sulfonylurea.
While Pinyopornpanish teaches Gliclazide, a drug in sulfonylurea class, was able to decrease hepatic fat content for diabetic NAFLD patients (page 837 left col), Pinyopornpanish does not teach the combination treatment.
While EVERSON teaches the disease severity index (DSI, the elected species of test from claim 7) (page 8), and EVERSON teaches the methods of claims 1-3 (pages 8, 18, 20, 29, and 36), EVERSON does not teach the combination treatment, or sulfonylurea.
Resolving the level of ordinary skill in the pertinent art:
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the chronic liver disease, and possesses the technical knowledge necessary to make adjustments to the therapeutics to optimize the doses of treatments for chronic liver diseases. Said artisan has also reviewed the problems in the art as regards to bioavailability of these therapeutics and understands the solutions that are widely-known in the art.
Considering objective evidence present in the application indicating obviousness or nonobviousness:
The instant claims 1-4, 7-15, 17-21, 30-31, and 33-42 are prima facie obvious in light of the combination of references.
Because of the MATAFOME’s successful animal model testing, the artisan would have been motivated and expected to give MATAFOME’s method to human patients. MATAFOME (title, Discussion page 59, and page 55) teaches claims 13, 17, 19, 30, 33, and 35. This also teaches the human subject in claims 1, 2, 13, and 30.
Matafome still teaches a combined treatment of Metformin and atorvastatin, which protects the liver in type 2 diabetes with hyperlipidemia (title and Discussion page 59, and paragraph 18 of the Nonfinal). When the claim recites using an old composition or structure and the “use” is directed to a result or property of that composition or structure, then the claim is anticipated. See MPEP 2112.02(II). This teaches the “improved liver function” of claims 1, 2, 13, and 30.
The artisan would have been motivated to administer the combination treatment of metformin and atorvastatin to treat NASH. MATAFOME teaches NASH has higher isoprostane levels (page 55 left col). The artisan would expect that the combination treatment to lower isoprostane levels, thus treating NASH (figure 3B). This teaches treating NASH from claims 4, 14, 15, and 31.
The artisan would have been motivated to add Gliclazide, a drug in sulfonylurea class (the elected species), in order to treat NASH. MATAFOME teaches that NASH is an aggravated/more developed version of NAFLD (page 55 left col). Gliclazide is a known treatment of NAFLD (a less severe NASH) (Pinyopornpanish page 837 left col). The artisan would expect Gliclazide to be effective at treating NASH since they share a pathogenesis. The artisan would further expect that combining a treatment of NASH (a type of sulfonylurea) with another NASH treatment (metformin/atorvastatin) would produce a functional combination treatment used for the same purpose (treating NASH). This teaches claims 12, 21, and 38.
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 60 mg/kg/day of metformin (MATAFOME page 55) and 10 mg/kg/day (MATAFOME page 55) to arrive at the instantly claimed dosages. MATAFOME teaches these dosages for rats, not humans. 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.
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 taught from MATAFOME and Pinyopornpanish. 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 further expect that a successfully treated subject with improved liver function to also have a decrease in cholate liver function over time of claims 39-42.
Claims 1-3, 7-13, 17-21, 30, and 33-42 are rejected under 35 U.S.C. 103 as being unpatentable over:
CHEN (Chen et al., “Combination Therapy of Metformin and Statin May Decrease Hepatocellular Carcinoma Among Diabetic Patients in Asia”, Medicine, June 2015)
In view of
HELMKE (Helmke et al., “Non-Invasive Assessment of Liver Function”, Curr Opin Gastroenterol, May 2015),
In view of
LEE (Lee et al., “Comparison of Hepatocellular carcinoma risk between patients treatment with glimepiride and gliclazide”, Diabetes and Metabolism, January 2019).
Determining the scope and contents of the prior art
Chen teaches a method of using/administering metformin and statins (simvastatin, atorvastatin, pravastatin, fluvastatin, lovastatin, and rosuvastatin) to treat hepatocellular carcinoma in a patient (Abstract). Hepatocellular carcinoma is one of the chronic liver diseases of claim 1. This teaches claims 13, 17, 19, 30, 33, and 35.
HELMKE teaches that the cholate test is an improvement (minimally or noninvasive test) for testing liver function and physiology (abstract’s purpose of review). HELMKE teaches that there was a “long felt need” (abstract). HELMKE’s test (QLFT the dual cholate test) has good results across numerous liver diseases (Disease Severity Index). HELKME also teaches comparing DSI scores (“cutoffs” in Disease Severity Index). This teaches claim 1 and helps teach claims 2-3 and 39-42.
HELMKE teaches comparing cutoff values throughout the stages of liver disease (figure 3).
LEE teaches that the use of gliclazide, a drug in sulfonylurea class, was associated with a significantly lower risk of HCC (page 84 left col). This teaches claims 12, 21, and 38.
Ascertaining the differences between the prior art and the claims at issue
While Chen teaches a method of using/administering metformin and statins to treat hepatocellular carcinoma in a patient (Abstract), Chen does not teach instant steps a and b.
While HELMKE teaches that the cholate test is an improvement (minimally or noninvasive test) for testing liver function and physiology (abstract’s purpose of review), HELMKE does not teach administering metformin and a statin.
While LEE teaches that the use of gliclazide, a drug in sulfonylurea class, was associated with a significantly lower risk of HCC (page 84 left col), LEE does not teach administering metformin and a statin.
Resolving the level of ordinary skill in the pertinent art:
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the chronic liver disease, and possesses the technical knowledge necessary to make adjustments to the therapeutics to optimize the doses of treatments for chronic liver diseases. Said artisan has also reviewed the problems in the art as regards to bioavailability of these therapeutics and understands the solutions that are widely-known in the art.
Considering objective evidence present in the application indicating obviousness or nonobviousness:
The instant claims are prima facie obvious in light of the combination of references.
When the claim recites using an old composition or structure and the “use” is directed to a result or property of that composition or structure, then the claim is anticipated. See MPEP 2112.02(II). This teaches the “improved liver function” since the administered compounds remain the same.
The artisan would have found it obvious to identify patients using HELMKE’s liver function test in order to administer CHEN’s combination of metformin and a statin. The artisan would have been motivated by HELKME’s teaching that there is a long felt need for a minimally or noninvasive liver function test (Abstract). HELKME teaches instant claim 1’s steps a and b (determining and comparing DSI scores; “cutoffs” in Disease Severity Index). Chen teaches a method of using/administering metformin and statins to treat hepatocellular carcinoma in a patient (Abstract). Hepatocellular carcinoma is one of the chronic liver diseases of claim 1. This teaches claim 1.
The artisan would have found it obvious to determine a second cholate liver function test value in at least one time point after the administration of metformin and a statin. HELMKE teaches comparing cutoff values throughout the stages of liver disease (figure 3). The artisan would have been motivated and found it obvious to confirm that the treatment was improving the patient’s condition. This teaches claims 2-3 and 39-42. The artisan would further expect that a successfully treated subject with improved liver function to also have a decrease in cholate liver function over time of claims 39-42.
The artisan would be motivated to experiment with dose ranges of metformin and statin to find the optimal dosage range in order to increase therapeutic efficacy of metformin and statin in a patient. 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 statin of the instant claims is critical. This teaches claims 9, 11, 18, 20, 34, 36, and 37.
The artisan would have been motivated to add another compound useful in treating HCC. LEE teaches that the use of gliclazide, a drug in sulfonylurea class, was associated with a significantly lower risk of HCC (page 84 left col).”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 2144.06(I).This teaches claims 12, 21, and 38.
Conclusion
No claims are allowed.
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/G.A.H./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625