DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 05/12/2026 has been entered.
Status of the Application
Receipt is acknowledged of Applicants’ Amendment and Remarks, filed on 05/12/2026, in which claims 7, 12, 14-15, and 19 are amended and claims 1-6, 8, 10, 20, and 22 are cancelled.
Applicant’s declaration of Pan, filed on 05/12/2026, is acknowledged and further discussed below.
Claims 7, 9, 11-19, 21, and 23-27 are pending and are examined on the merits herein.
Priority
The instant application is a 371 of PCT/CN2021/087266, filed on 04/14/2021, which claims foreign priority to CN 202010362374.3, filed on 04/30/2020.
Information Disclosure Statement
The information disclosure statement (IDS) dated 05/21/2026 complies with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, the information disclosure statement has been considered by the examiner.
Rejections Withdrawn
Applicant’s amendment and remarks, filed 05/12/2026, with respect that claims 7, 9, 11-14, 16-19, 21, and 23-27 are rejected under 35 U.S.C. 103 as being unpatentable over Yano in view of Lu has been fully considered and is persuasive, as Yano and Lu do not teach Dapagliflozin.
Applicant’s amendment and remarks, filed 05/12/2026, with respect that claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Yano in view of Lu further in view of ASHP Statement on Unit Dose Drug Distribution has been fully considered and is persuasive, as the cited prior art do not disclose Dapagliflozin.
The following are new grounds of rejection.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 7, 9, 11-14, 16-19, 21, and 23-27 are rejected under 35 U.S.C. 103 as being unpatentable over Yano et al. (Clinical Diabetes/Therapeutics, 2018; PTO-892 07/15/2025) in view of Lu et al. (WO2016107222A1; PTO-892 and English translation PTO-892 07/15/2025) and Tobita et al. (Current Therapeutic Research, 2017; PTO-892).
Yano teaches that NASH is a severe form of nonalcoholic fatty liver disease (NAFLD), and NAFLD is observed in high prevalence in patients with type 2 diabetes (lines 1-2). Yano discloses a method of treating nonalcoholic steatohepatitis (NASH) comprising administering a combination of the SGLT2 inhibitor tofogliflozin and the PPARα modulator pemafibrate to STAM mice as a diabetic animal model of NASH (lines 3-5). Yano discloses the administration of 0.1 mg/kg of pemafibrate and 10 mg/kg of tofogliflozin to STAM mice (line 6). Yano reports that, while blood glucose (BG) level was not altered in pemafibrate-treated group, it lowered significantly with the combination therapy of tofogliflozin and pemafibrate (lines 6-7). The combination of tofogliflozin and pemafibrate exhibited the synergistic effects on lipid droplet size (lines 8-9). Liver triglyceride (TG) content was also decreased in mice with the combination therapy (line 9). The combination of tofogliflozin and pemafibrate significantly improved the survival rates (50%) compared to control group (line 11). Yano concludes that combination therapy of an SGLT2 inhibitor and a selective PPARα modulator would be a potent therapeutic strategy for the treatment of NAFLD and NASH.
The teachings Yano differ from that of the instantly claimed invention in that while Yano teaches a combination of an SGLT2 inhibitor and a selective PPARα modulator Yano does not teach Dapagliflozin or a compound of instant Formula (I).
Lu teaches preparations and uses of 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-carbazol-9-yl)ethoxy)phenyl)propionic acid, which is a phenylalanine compound with therapeutic activity for metabolic diseases [0002] and has the following chemical structure [0003]:
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Specifically, this compound has the ability to selectively activate PPAR-α, PPAR-γ and PPAR-δ, and can be used to treat diseases related to metabolic syndrome, such as diabetes. PPAR-α, PPAR-γ and PPAR-δ are members of the nuclear receptor superfamily and are closely related to the occurrence and development of diseases such as diabetes and fatty liver [0004]. Lu teaches that the sodium and potassium salts of the compound are unexpectedly stable and have significantly improved bioavailability [0010] compared with the free acid for lithium salt [0022]. Lu teaches that the composition may be administered in various solid preparations, such as tablets, capsules or granules, and powders [0023]. Lu discloses a manufacture tablets of a prescription of the compound (Example 5, beginning at [0085]). The tablets contain the compound as well as hydroxypropyl methylcellulose phthalate, microcrystalline cellulose, starch, and sodium bicarbonate [0088], which are recognized as excipients. Lu teaches that the compound may be administered in the form of tablets, capsules, powders and granules (claim 14) and that the pharmaceutical composition may further comprise a second therapeutic agent (claim 13). In a phase IIb clinical trial for the treatment of type 2 diabetes [0116], the compound was administered to patients in the form of oral tablets, containing 32 mg, 40 mg or 48 mg of the compound [0121]. In discussing the results of the clinical trial, Lu teaches that the TC level changes were on average 0.47mmol/L, 0.11mmol/L, and -0.08mmol/L for the 32 mg, 40 mg or 48 mg groups respectively, and thus the tablets showed a dose-dependent reduction trend in total cholesterol (TC) levels. The patients similarly showed a dose dependent reduction in TG and LCL-C levels [0127].
Tobita discloses a clinical trial to assess the efficacy and safety profile of dapagliflozin for the treatment of nonalcoholic steatohepatitis (NASH) associated with type 2 diabetes mellitus (abstract). Nonalcoholic steatohepatitis (NASH) is an active form of nonalcoholic fatty liver disease (NAFLD). NAFLD significantly increases the risk of incident type 2 diabetes mellitus and metabolic syndrome. Significant risk factors for NASH are type 2 diabetes mellitus and obesity (page 13, paragraph 1). Sodium–glucose co-transporter 2 (SGLT2) inhibitors prevent the reabsorption of glucose in the kidney and increase urinary excretion of glucose (page 14, paragraph 1). Dapagliflozin is a potent and selective SGLT2 inhibitor that has been shown to reduce hyperglycemia in patients with type 2 diabetes mellitus and Tobita discloses the effects of dapagliflozin for the treatment of NASH in patients with type 2 diabetes mellitus (page 14, paragraph 2). Tobita teaches that all patients were prescribed once-daily dapagliflozin at a dose of 5 mg/d (page 14, paragraph 5). Tobita discloses that the administration of dapagliflozin, a potent and selective SGLT2 inhibitor, was associated with improvements in liver tests and metabolic laboratory variables in patients with NASH and T2DM over the course of 24 weeks (page 17, paragraph 3). Furthermore, dapagliflozin improved the body composition of patients with NASH associated with T2DM by reducing body fat and was associated with improvements in liver tests and metabolism (paragraph bridging pages 18-19).
It would have been prima facie obvious to combine the teachings of Yano, Lu, and Tobita before the effective filing date of the claimed invention by administering a combination therapy comprising of the compound of Lu and the dapagliflozin of Tobita to diabetic patients with the diabetic complication NASH to arrive at the instantly claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to substitute the pemafibrate in the combination therapy of tofogliflozin and pemafibrate described by Yano with the compound of Lu because both compounds are taught as having the same biochemical effect of modulating PPAR-α for the same purpose of treating metabolic disorders. Similarly, it would have been prima facie obvious for one of ordinary skill in the art to substitute the tofogliflozin in the combination therapy described by Yano with the dapagliflozin of Tobita because both compounds are taught as having the same biochemical effect of inhibiting SGLT2 for the same purpose of treating NASH associated with T2DM. One of ordinary skill in the art would have a reasonable expectation of success in treating diabetes and the diabetic complication NASH by administering the suggested combination therapy because Yano teaches that combination therapy comprising an SGLT2 inhibitor and a selective PPARα modulator would be a synergistic therapeutic strategy for the treatment of NASH associated with T2DM and Lu and Tobita respectively teach compounds having the same biochemical effects of SGLT2 inhibition and PPARα modulation.
Regarding claims 11 and 23, Yano discloses the administration of 0.1 mg/kg of the PPAR-α modulator pemafibrate and 10 mg/kg of the SGLT-2 inhibitor tofogliflozin to STAM mice (line 6). Lu suggests administration of the PPAR-α modulator 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-carbazol-9-yl)ethoxy)phenyl)propionic acid to patients in a dosage of 32 mg and teaches that the dosage of PPAR-α modulator effected the treatment outcome of diabetic patients. Tobita teaches the administration of dapagliflozin at a dose of 5 mg/d It would have been prima facie obvious to optimize the dosage of PPAR-α modulator and SGLT-2 inhibitor in the composition suggested by the combined teachings of Yano, Lu, and Tobita because Lu teaches that the dosage of PPAR-α modulator effected the treatment outcome of diabetic patients. Lu thus teaches that dosage of PPAR-α modulator is a result effective variable such that one of ordinary skill in the art would be motivated to optimize the dosage of PPAR-α modulator and thereby also optimize the dosage of SGLT-2 inhibitor in order to achieve an optimal effect on triglyceride levels and thereby an optimal effect in the treatment of NAFLD and NASH.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Yano et al. (Clinical Diabetes/Therapeutics, 2018; PTO-892 07/15/2025) in view of Lu et al. (WO2016107222A1; PTO-892 07/15/2025 and English translation PTO-892 07/15/2025) and Tobita et al. (Current Therapeutic Research, 2017; PTO-892) as applied to claims 7 and 14 above, further in view of ASHP Statement on Unit Dose Drug Distribution (Am J Hosp Pharm., 1989; PTO-892 07/15/2025)
The combined teachings of Yano, Lu, and Tobita are as above.
The combined teachings of Yano, Lu, and Tobita differ from that of the instantly claimed invention in that they do not teach a kit in which the components are in unit preparations.
The ASHP Statement on Unit Dose Drug Distribution teaches that the unit dose system of medication distribution is a pharmacy-coordinated method of dispensing and controlling medications in organized health-care settings (paragraph 1). In all unit dose systems, medications are contained in single unit packages and are dispensed in as ready-to-administer form as possible (paragraph 2). The inherent advantages of unit doses are, among others, a reduction in the incidence of medication errors, a decrease in the total cost of medication-related activities, and improved overall drug control and drug use monitoring (paragraph 4).
One of ordinary skill in the art would have been motivated to formulate the compounds of the treatment suggested by the combined teachings of Yano, Lu, and Tobita as a unit dose preparation because the ASHP Statement on Unit Dose Drug Distribution teaches that administration of medication as a unit dose decreases medication errors and cost of medication-related activities, as well as improves overall drug control and drug use monitoring. One of ordinary skill in the art would have a reasonable expectation of success because Tobita teaches that all patients were prescribed once-daily dapagliflozin at a dose of 5 mg/d, which would be understood by one of ordinary skill in the art to be a single dosage amount and would be useful as a single unit for unit dosing, and Yano teaches that the compound may be formulated as a capsule or tablet and discloses administration of the compound orally as a pill, which would be understood by one of ordinary skill in the art to be a single unit in a ready-to-administer form and would be useful as a unit dose.
Response to Arguments
Applicant's arguments filed 05/12/2026 have been fully considered but they are not persuasive.
Applicant argues that the combination of chiglitazar sodium and dapagliflozin exerts an unexpected synergistic effect, and accordingly, it would not have been obvious to one of ordinary skill in the relevant art to arrive at the composition recited in claim 7 in view of the cited references (page 9, paragraph 1). Applicant substantiates the argument by reference to Example 2 and Figures 1 and 2 of the instant disclosure (Remarks, page 7, paragraph 4 – page 8, paragraph 1). The Pan declaration provides statistical analysis of the data from the diabetic mouse experiment of Example 2 (Pan declaration, especially paragraph 7). This is not persuasive.
As discussed in the above grounds of rejection, the teachings of Yano disclose that the combination of an SGLT2 inhibitor and a PPARα modulator would be a potent therapeutic strategy for the treatment of NAFLD and NASH. Yano further discloses that the combination of the SGLT2 inhibitor tofogliflozin and the PPARα modulator pemafibrate exhibits significant synergistic effects on lipid droplet size and ballooning and that while blood glucose level was not altered in pemafibrate treated group, but lowered significantly with the combination therapy. Thus Yano, which is the closest prior art, teaches that one of ordinary skill in the art would expect a synergistic result from the combination of an SGLT2 inhibitor and a PPARα modulator in the treatment of NASH.
As a result, Applicant has not demonstrated unexpected results over the teachings of the prior art, which suggests that one of ordinary skill in the art would expect a beneficia synergistic result from the combination of an SGLT2 inhibitor and a PPARα modulator in the treatment of NASH. MPEP 716.02(c)(II) states that expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of nonobviousness thereof.
The closest prior art teaches that one of ordinary skill in the art would expect a synergistic result from the combination of an SGLT2 inhibitor and a PPARα modulator in the treatment of NASH. In order to demonstrate unexpected results, Applicant must demonstrate unexpected and significant results of the claimed combination therapy over other combination therapies comprising an SGLT2 inhibitor and a PPARα modulator, thereby showing the lack of predictability in combination therapies comprising an SGLT2 inhibitor and a PPARα modulator and thus demonstrating the nonobviousness of the claimed invention over the prior art. MPEP 716.02(b)(III) states that evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims.
Although the compound of Lu is taught as activating PPAR-α, PPAR-γ and PPAR-δ, Lu specifically states that this compound has the ability to selectively activate PPAR-α, PPAR-γ and PPAR-δ and can be used to treat diseases related to metabolic syndrome, such as diabetes. Thus one of ordinary skill in the art would expect that the compound of Lu is capable of selectively activating PPAR-α and thus is capable of modulating the same biochemical mechanism of the PPARα modulator pemafibrate of Yano. Thus one of ordinary skill in the art would have a reasonable expectation of success in achieving a synergistic combination therapy for the treatment of the diabetic complication NASH by administering a combination comprising the compound of Lu.
Because Applicant’s arguments are not persuasive, the instant claims are rejected for the reasons of record.
Conclusion
No claims are allowed.
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/S.G.H./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
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