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 .
Status of the Application
Receipt is acknowledged of Applicants’ amendment and remarks, filed on 10/13/2025, in which claims 7, 9, 16-19, and 21 are amended and claims 25-27 are newly added, and claims 1-6, 8, 10, 20, and 22 are canceled.
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.
Rejections Withdrawn
Applicant’s amendment and remarks, filed 10/13/2025, with respect that claims 9, 16-18, and 21 are rejected under 35 U.S.C. 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention has been fully considered and is persuasive, as claims 9 and 21 have been amended to clarify that the salt or isomer is selected from a list of options, and claims 16-18 have been amended to remove the phrase preferably. This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 10/13/2025, with respect that claims 16-24 are rejected under 35 U.S.C. 112(a), because the specification, while being enabling for treating diabetes mellitus and/or a diabetic complication does not reasonably provide enablement for preventing diabetes mellitus and/or a diabetic complication has been fully considered and is persuasive, as claims 16-19 have been amended to remove the phrase preventing. This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 10/13/2025, with respect that claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Yano in view of Lu as applied to claim 7, further in view of Dash has been fully considered and is persuasive, as claim 10 is canceled. This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 10/13/2025, with respect that claims 8, 20, and 22 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 the claims are canceled. This rejection has been withdrawn.
The following are maintained or new grounds of rejection necessitated by Applicant’s amendment, in which claims 25-27 are newly added.
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) in view of Lu et al. (WO2016107222A1; PTO-892 and English translation 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 Pema-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 Yano does not teach a compound of instant Formula (I) (instant claims 7-14 and 16-24).
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]:
PNG
media_image1.png
259
317
media_image1.png
Greyscale
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].
It would have been prima facie obvious to combine the teachings of Yano and Lu before the effective filing date of the claimed invention by administering the PPAR-α modulator of Lu and an SGLT-2 inhibitor such as tofogliflozin to treat 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 exchange the pemafibrate in the combination of Yano with the PPAR-α modulator of Lu because both compounds are taught as PPAR-α modulators useful for the treatment of metabolic disorders. 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 combination because Lu teaches that PPAR-α modulators are useful for treating fatty liver disease and that the compound is a PPAR-α modulator useful for the treatment of diabetes and metabolic syndromes and furthermore teaches that it may be administered with other pharmaceutically active ingredients.
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. It would have been prima facie obvious to optimize the dosage of PPAR-α modulator and SGLT-2 inhibitor in the compositions of Yano and Lu 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.
The instant specification has been reviewed for evidence of unexpected results. However, the instant specification does not provide the sample size of the treatment groups or data showing that there is a statistically significant difference between the results of the combination therapy as compared to the results of each of the components administered singly. Thus the disclosure does not allow for comparison with the closest prior art, which discloses the administration of the compounds singly, and as a result the disclosure does not overcome the rejection.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Yano et al. (Clinical Diabetes/Therapeutics, 2018; PTO-892) in view of Lu et al. (WO2016107222A1; PTO-892 and English translation PTO-892) as applied to claim 14 above, further in view of ASHP Statement on Unit Dose Drug Distribution (Am J Hosp Pharm., 1989; PTO-892)
The combined teachings of Yano and Lu are as above.
The combined teachings of Yano and Lu 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 Yano and Lu 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 Yano teaches that the compound may be formulated as a capsule or tablet and discloses administration of the compound orally as a pill, which is a single unit in a ready-to-administer form and would be useful as a unit dose.
Response to Arguments
Applicant's arguments filed 10/13/2025 have been fully considered but they are not persuasive.
Applicant argues that Yano discloses efficacy only for the specific combination of tofogliflozin and pemafibrate in STAM mice, a diabetic NASH-to-HCC model. Yano does not teach or suggest that any SGLT2 inhibitor ( e.g., empagliflozin, dapagliflozin) would exhibit synergistic effects with any selective PPARα modulator (Remarks, page 9, paragraph 4). This is not persuasive.
As discussed in that above grounds of rejection, 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. Thus Yano teaches and suggests that this combination may be effective as a strategy for further drug combinations.
Applicant further argues that because the compound of Lu targets multiple PPAR subtypes including PPARα, PPARγ, and PPARδ, which enables it to modulate various metabolic pathways such as lipid metabolism, energy expenditure, and inflammation, it is therefore fundamentally different from the single-target action of PPARα agonists, such as pemafibrate, such that one of ordinary skill in the art would not have exchanged the pemafibrate in the combination of Yano with the compound of Lu (Remarks, page 10, paragraph 1). This is not persuasive.
As discussed in the above grounds of rejection, Yano teaches and suggests that the effect of modulation by an agonist of PPARα in combination with an SGLT2 inhibitor produces a desired effect. Lu teaches a compound that selectively activates PPAR-α, PPAR-γ and PPAR-δ, and can be used to treat diseases related to metabolic syndrome, such as diabetes. Thus the compound of Lu has the biological activity of being a PPAR-α agonist, and would be expected to act synergistically with the SGLT2 inhibitor of Yano. That the compound of Lu has additional biological activity would not prevent it from acting in its disclosed function of a PPAR-α agonist.
Finally, Applicant argues that the pharmaceutical composition comprising the components recited in claim 7 achieves an unexpected result in which it synergistically reduces blood glucose in db/db diabetic mice and alleviates the weight gain induced by chiglitazar sodium (paragraph bridging pages 10-11 to paragraph 1 on page 11). This is not persuasive.
Specifically, Applicant argues that instant application demonstrates that the combination of chiglitazar sodium with the SGLT2 inhibitors empagliflozin or dapagliflozin can synergistically reduce blood glucose in diabetic mice and alleviate the weight gain induced by chiglitazar sodium (paragraph bridging pages 10-11). Using the Bliss independence model, Applicant provides an analysis of the effect of the combination therapy of Chiglitazar sodium and Empagliflozin (using the data from instant Figure 3) and of Chiglitazar sodium and Dapagliflozin (using the data from instant Figure 4) on triglyceride levels. The analysis is provided on pages 12-13 of the Remarks. This analysis demonstrates that the provided data suggests a synergistic effect by these combination therapies. The Examiner further notes that the scope of the instant claims has been amended to be commensurate with this data. However, as discussed in the above grounds of rejection, the instant specification does not provide the sample size of the treatment groups and demonstrate that there is a statistically significant difference between the results of the combination therapy as compared to the results of each of the components administered singly. In this case, indication of statistical significance is particularly important because the error bars of the cited figures overlap, such that statistical data is needed to identify the relevance of any synergistic effect of the combination therapies. MPEP 716.02(b)(I) states that the evidence relied upon should establish that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance. In this case the instant specification has not demonstrated that the differences in results are of statistically meaningful significance, and the claims are obvious over the combined teachings of Yano and Lu.
Because Applicant’s arguments are not persuasive, the instant claims are rejected for the reasons of record.
Conclusion
No claims are allowed.
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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sarah Grace Hibshman whose telephone number is (703)756-5341. The examiner can normally be reached Monday-Thursday 7:30am-5:30pm (EST). Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Scarlett Goon can be reached on (571) 270-5241. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/S.G.H./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693