DETAILED ACTION
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 .
Response to Amendments
Applicant’s amendments to the claims of November 4, 2025, in response to the Office Action of August 5, 2025, are acknowledged.
Response to Arguments
Applicant’s amendments to the claims obviate the § 112 rejection. That rejection is withdrawn. With respect to the traversal of the § 103 rejection, Applicant argues that the compound of formula I-1 has significant advantages over HTD1801, citing Tables 1-4. It reduces AST, ALT, ALP, and other histopathological indicators. These are argued to constitute unexpected results.
The examiner notes that Liu teaches treatment to significantly reduce ALT and AST levels when treating treat fatty liver, NAFLD, and fatty liver disease, among many others. Further, berberine is taught to provide a synergistic benefit when combined with pharmacologically organic acids, including analogs and derivatives of UDCA. See par. 164. The synergy is based on the anionic moiety of the UDCA analogue or derivative. Nor-UDCA is a known and almost identical structural compound that would be immediately envisaged for use with berberine within the teachings of Liu. As such, a POSA would expect a synergy when a combination of norUDCA is used with berberine because this is explicitly taught. Further, Fickert teaches norUDCA as a superior anti-inflammatory, anti-fibrotic, and anti-proliferative agent. Moreover, “In each norUDCA group, the relative reduction of serum ALP was statistically significantly superior to placebo in the analysis of the primary endpoint showing dose-dependent reductions by ~12.3%, ~17.3%, and ~26.0% in the 500, 1,000, and 1,500 mg/d norUDCA groups respectively.” Additionally, norUDCA significantly reduced serum AST, ALT, and ALT levels.
Overall, the combination claimed is known to treat the claimed subject population and lower specific parameters of treatment. A synergy is expected based on the prior art and a synergy that is greater than one with UDCA and berberine would be expected in view of the statistically superior effect of norUDCA compared to UDCA. It is not clear how the more efficacious and superior analogue or derivative of UDCA with a single carbon atom difference with an expectation of a synergy when combined with berberine has been shown to be unexpectedly superior as compared to the teachings of the closest prior art.
As such, the examiner cannot conclude at this time that a sufficient and proper showing of unexpected results has been established. This is particularly the case because the claimed dosage and molar ratio is taught by the prior art and a synergy is expected with the claimed combination. To show unexpected results, Applicant would need to show that a level of synergy with norUDCA and berberine is statistically significantly better than the expected synergy when taking into account the higher level of efficacy of norUDCA.
Status of the Claims
Claims 1-4 and 6-12 are pending and examined.
Claim of Foreign Priority
Applicant’s claim of foreign priority and Certified Copy of Foreign Priority Application have been received and are acknowledged by the Office. The examiner acknowledged the English translation of the foreign priority document filed on November 11, 2025.
The examiner did not apply duplicative references published by Liu et al., including, e.g.: 2018/0050048 A1; and 20200188387 A1.
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.
Claims 1-4 and 6-12 are rejected under 35 U.S.C. 103 as being unpatentable over Liu, (US2017/0037043), in view of Fickert et al., “norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis,” Journal of Hepatology, 2017, 67, 549-558, and in view of Traussnigg et al., “Norursodeoxycholic acid versus placebo in the treatment of non-alcoholic fatty liver disease: a double-blind, randomised, placebo-controlled, phase 2 dose-finding trial,” The Lancet Gastroenterology & Hepatology, Vol 4, Issue 10, October 2019, and in view of STN CAS: 1868138-66-2/RN (February 16, 2016).
The examiner notes that claims 6 and 7 are product claims that are examined solely based on the structural limitations claimed. While the term prophylaxis is used, it is not presently considered limiting to the degree that it defines a subject population because a product claim does not have a subject population. If claim 6, .e.g., is amended to require a step for administration to a subject, the examiner may consider a Scope of Enablement rejection for the term prevention unless the Specification and/or state of the art supports the prevention of claimed conditions with the claimed agent. This is all stated in an effort to expedite prosecution on the merits.
Liu teaches a composition comprising berberine and novel salts of ursodeoxycholic acid. In Example 4, a berberine ursodeoxycholate salt is formed. An anionic moiety of UDCA or a derivative or analog thereof can be used. See prior art claim 42, e.g. The synthesis includes steps of dissolving berberine in methanol at room temperature and dissolving UDCA in ethanol at room temperature, wherein the berberine and UDCA can be 1.5 molar equivalents. See par.’s 274-277. Those solutions are mixed and stirred at room temperature. Even further, the efficacy in NAFL mice was evaluated. See par. 279. The compositions can be used to treat fatty liver, NAFLD, and fatty liver disease, among many others. See par.’s 3 and 14. Further, the levels of AST and ALT were significantly elevated compared to a control group. However, after treatment, AST and ALT had shown significantly decline from treatment. See par. 314. Compositions can comprise excipients, carriers, and diluents. See par. 20 and 21. Excipients include buffering agents, lubricants, and others. See par. 79. The dosages administered in Example 6 range from 50 mg/kg to 200 mg/kg. Example 5 includes doses from 30 mg/kg to 300 mg/kg. These doses overlap those claimed. Numerous exemplary UDCA derivatives are provided in Table 3. Liu explains that the examples are intended to illustrate and various embodiments and equivalents thereof can be adapted. See par. 340, “EQUIVALENTS.” Solid and liquid carriers can be used. See par. 79.
Liu does not explicitly teach nor-UDCA.
Fickert teaches “24-norursodeoxycholic acid (norUDCA) is a side chain-shortened C23 homologue of UDCA and was previously shown to be highly effective in preclinical mouse models of cholestatic and fibrotic liver diseases.” See p550, 2nd par. Comparing the effects of UDCA and nor-UDCA, norUDCA is superior as an anti-inflammatory agent, anti-fibrotic, and anti-proliferative. Further, “In each norUDCA group, the relative reduction of serum ALP was statistically significantly superior to placebo in the analysis of the primary endpoint showing dose-dependent reductions by ~12.3%, ~17.3%, and ~26.0% in the 500, 1,000, and 1,500 mg/d norUDCA groups respectively.” See p553, 1st par. and Figure 3. Further, norUDCA significantly reduced serum AST, ALT, and ALT levels. See p553, last par. There was a dose-dependent effect of nor-UDCA and dose was safe and well-tolerated.
Additionally, CAS RN: 1868138-66-2 entered in STN on February 2016, shown below.
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The sole difference between the compound above and that claimed is an extra carbon. In view of the prior art, a POSA would understand that the compound above would work as described by Liu, e.g.
A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious); Aventis Pharma Deutschland v. Lupin Ltd., 499 F.3d 1293, 84 USPQ2d 1197 (Fed. Cir. 2007) (5(S) stereoisomer of ramipril obvious over prior art mixture of stereoisomers of ramipril.).
Further, Traussnigg teaches nor-UDCA is safe and well-tolerated at 500 mg and 1500 mg and resulted in a significant reduction in serum ALT. The study was aimed at evaluating norUDCA treatment in subjects with NAFLD. ALT reduction was a main endpoint of evaluation and this was achieved in a dose-dependent manner. “Norursodeoxycholic acid seems a promising treatment option in patients with NAFLD or NASH.” See Implications of the all the available evidence section.
It would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the instant application to arrive at the claimed invention in view of Lin, Fickert, and Traussnigg. One would be motivated to do so because berberine and UDCA, a homolog of norUDCA, are known and taught for use in treating the claimed subject population. A POSA would immediately envisage the teachings of Liu using an anionic moiety of norUDCA and the claimed compound in light of the teachings of the prior art as a whole. Further, a method of preparing berberine with UDCA is taught by dissolving each agent in claimed alcohol solvents at room temperature prior art mixing solutions comprising berberine and UDCA. In view of the almost identical structure, a POSA would expected that norUDCA can be substituted with UDCA in those compositions taught by Liu. Further and independently, in view of Liu a homolog of a composition would be independently expected to work efficaciously. As an additional motivation to arrive at the claimed compound, a POSA would be motivated to substitute norUDCA with UDCA because norUDCA has been shown to be safe and well-tolerated and efficacious in treating NAFLD as well as having “superior as an anti-inflammatory agent, anti-fibrotic, and anti-proliferative” properties. Moreover, the described efficacy is dose-dependent. In fact, norUDCA significantly reduced serum AST, ALT, and ALT levels. As such, there is a reasonable and predictable expectation of success in preparing the claimed compound and using the claimed compound for purposes set forth in the claims, including ameliorating and treating NAFLD, fatty liver disease, fatty liver, cholestatic and fibrotic liver conditions.
As such, no claim is allowed.
Conclusion
THIS ACTION IS MADE FINAL. 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 mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JARED D. BARSKY whose telephone number is (571)-272-2795. The examiner can normally be reached on Monday through Friday from 8:30 to 5:30. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Amy L. Clark can be reached on 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JARED BARSKY/Primary Examiner, Art Unit 1628