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 December 29, 2025, in response to the Office Action of August 29, 2025, is acknowledged.
Response to Arguments
Applicant has amended the claims to require a 3-fold higher ALP in a subject compared to baseline. The examiner notes that the prior art teaches a linear correlation of daily UDCA dose and ALP level at doses from 700 mg to 1750 mg. The prior art also teaches HTD1801 for treating PSC at a dose of 500 mg and 1000 mg BID and the subjects initially had a serum ALP of at least 1.5 x the upper limit of normal (ULN). The prior art also teaches that after treatment with UDCA, ALP levels improved and that higher doses can effectuate a greater reduction in ALP with a dose linear correlation of ALP and UDCA up to 1750 mg.
The examiner notes that it is not clear why having a higher level of ALP, which is common, and is taught to be mitigated with a claimed drug would somehow not be administered to lower ALP if the levels are 3-fold higher rather than at least 1.5 fold higher as explicitly taught by the prior art. Moreover, as evidenced by Trivedi et al., “Inter- and Intra-individual Variation, and Limited Prognostic Utility, of Serum Alkaline Phosphatase in a Trial of Patients With Primary Sclerosing Cholangitis,” Clinical Gastroenterology and Hepatology 2021;19:1248–1257: subjects with PSC were shown to commonly have ALP levels above 3-fold ULN, including 12.5% at 1 year, and 17.9% at 2 years.
With regard to the DP rejections, the examiner notes:
Applicant argues that the 11,685,735 patent are compositions claims and methods claims. The examiner notes that these claims are directed to treating inflammatory and a liver disease, and a metabolic disorder. Further, claim 8 is directed to cholestatic liver disease. PSC is a cholestatic liver disease.
Applicant argues that the 11,976,063 patent are composition claims directed to a treating some conditions. The examiner notes that the claims include methods for treating a cholestatic liver disease, inflammation, and a metabolic disorder. See prior art claim 6.
Applicant argues that the 12,138,258 patent does not teach a method for treatment. The examiner notes that the compound produced by the ‘258 patent in view of the other cited prior art would be use to treat subjects with PSC, including with elevated ALP, as discussed above.
Applicant argues that the 10,988,471 patent does not teach administering BUDCA for ALP as claimed. The claims of ‘471 patent are directed to a method of treating liver conditions, metabolic disorders, cholestasis, hyperlipidemia and diabetes with the claimed product. Claim 7 is directed to cholestatic liver disease. Yu and Van Tomme provide the motivation and reasonable expectation of success that such product can be used for the claimed purposes as expounded on more in the rejection above.
Applicant argues that the 10,301,303 patent is directed to products. The examiner notes that the claims of ‘303 patent are directed to the products claimed for use in the claimed methods. Yu and Van Tomme provide the motivation and reasonable expectation of success that such product can be used for the claimed purposes as expounded on more in the rejection above.
Applicant argues that application serial number 17/966,782 does not teach the claimed ALP and subject population. in view of Yu et al., (WO2018/205987), in view of Van Tomme et al., (EP3653214). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘782 application are directed to treating the same subject with the same agent. The instant claims provide for also treating diabetes and hyperlipidemia secondary to PSC.
Status of the Claims
Claims 1-3, 5-13, 15, 26-32 are pending and examined.
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 1-3, 5-13, 15, 26-32 are rejected under 35 U.S.C. 103 as being unpatentable over Yu et al., (WO2018/205987), in view of Van Tomme et al., (EP3653214).
Yu teaches berberine ursodeoxycholate for therapeutic uses to treat metabolic disorders and liver diseases among others. See par. 2. These diseases include fatty liver, NAFLD, NASH, cholestatic liver diseases, and improving liver functions in chronic viral associated liver diseases. See par. 8. Form A is taught to include XRPD peaks that are identical those in the instant Specification at par. 77. See prior art par. 9. Other diseases include primary sclerosing cholangitis, diabetes, and hyperlipidemia. See par. 36. In another aspect, the compound can be a hemi-nonahydrate. See par. 20. In one embodiment a tablet can range from 1 mg to 1000 mg, 50 to 500 mg and a tablet can be 50, 100, 150, in 50 mg increments up to 1000 mg. See par. 228.
Van Tomme teaches improved dosage regimen for treating cholestatic liver diseases with UDCA. See par. 1. After UDCA treatment, liver function indices such as ALP were improved. See par. 10. For a dose of 500 to 750 mg/day, a significant reduction of ALP was noted. ALP is currently used as a marker for cholestasis and response to UDCA in those with PSC. See par. 11. Van Tomme provides for administering a dose that can be optimized to decrease ALP levels. Doses can be higher to effectuate a larger reduction in ALP. See par. 22. The liver disease can be PSC. See par. 26. An extremely high level of ALP would require a higher dose of UDCA. Figure 1 shows a linear correlation of daily UDCA dose and ALP level at doses from 700 mg to 1750 mg.
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990); Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985); and 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. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). If a level of ALP is too high, treatment would be optimized. The result of treatment would be a reduction in level of ALP. This is an optimizable parameter with a clear roadmap as to how to achieve such result.
It would have been prima facie obvious to a POSA prior to the filing of the instant application to combine the teachings of Yu and Van Tomme to arrive at the claimed methods. One would be motivated to do so because the claimed agent is taught to be administered to the claimed subject population at a dose that overlaps the claimed dosage. Further, the mitigation of an increased ALP, e.g., is known to be dose-proportionate to the administration of UDCA and Van Tomme has provided a roadmap for optimization of a known result effective variable with linear and correlative pharmacokinetics with respect to ALP and dosage of UDCA administered. Even further, the claimed combination is known to treat PSC as well as diabetes and hyperlipidemia. There is no reason to avoid treating a subject that has already received UDCA or is UDCA naïve. As such, there is a reasonable and predictable expectation of success in arriving at the claimed methods in view of the combination of teachings from the cited prior art as a whole.
Claims 1-3, 5-13, 15, 26-32 are rejected under 35 U.S.C. 103 as being unpatentable over NCT03333928 (study start date February 2, 2019) (study first posted November 11, 2017), in view of Yu et al., (WO2018/205987), and in view of Van Tomme et al., (EP3653214).
NCT03333928 teaches HTD1801 for treating PSC at a dose of 500 mg and 1000 mg BID. The subjects initially had a serum ALP of at least 1.5 x the upper limit of normal (ULN). ALP was used as an outcome measure in the first 6 weeks, weeks 6 to 12, and weeks 12 to 18.
Yu teaches berberine ursodeoxycholate for therapeutic uses to treat metabolic disorders and liver diseases among others. See par. 2. These diseases include fatty liver, NAFLD, NASH, cholestatic liver diseases, and improving liver functions in chronic viral associated liver diseases. See par. 8. Form A is taught to include XRPD peaks that are identical those in the instant Specification at par. 77. See prior art par. 9. Other diseases include primary sclerosing cholangitis, diabetes, and hyperlipidemia. See par. 36. In another aspect, the compound can be a hemi-nonahydrate. See par. 20. In one embodiment a tablet can range from 1 mg to 1000 mg, 50 to 500 mg and a tablet can be 50, 100, 150, in 50 mg increments up to 1000 mg. See par. 228.
Van Tomme teaches improved dosage regimen for treating cholestatic liver diseases with UDCA. See par. 1. After UDCA treatment, liver function indices such as ALP were improved. See par. 10. For a dose of 500 to 750 mg/day, a significant reduction of ALP was noted. ALP is currently used as a marker for cholestasis and response to UDCA in those with PSC. See par. 11. Van Tomme provides for administering a dose that can be optimized to decrease ALP levels. Doses can be higher to effectuate a larger reduction in ALP. See par. 22. The liver disease can be PSC. See par. 26. An extremely high level of ALP would require a higher dose of UDCA. Figure 1 shows a linear correlation of daily UDCA dose and ALP level at doses from 700 mg to 1750 mg.
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990); Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985); and 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. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). If a level of ALP is too high, treatment would be optimized. The result of treatment would be a reduction in level of ALP. This is an optimizable parameter with a clear roadmap as to how to achieve such result.
It would have been prima facie obvious to a POSA prior to the filing of the instant application to combine the teachings of NCT03333928, Yu and Van Tomme to arrive at the claimed methods. One would be motivated to do so because the claimed agent is taught to be administered to the claimed subject population at a dose that overlaps the claimed dosage. Further, the mitigation of an increased ALP, e.g., is known to be dose-proportionate to the administration of UDCA and Van Tomme has provided a roadmap for optimization of a known result effective variable with linear and correlative pharmacokinetics with respect to ALP and dosage of UDCA administered. Even further, the claimed combination is known to treat PSC as well as diabetes and hyperlipidemia. There is no reason to avoid treating a subject that has already received UDCA or is UDCA naïve. As such, there is a reasonable and predictable expectation of success in arriving at the claimed methods in view of the combination of teachings from the cited prior art as a whole.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3, 5-13, 15, 26-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 10,959,999, in view of Yu et al., (WO2018/205987), in view of Van Tomme et al., (EP3653214). The claims of ‘999 patent are directed to the product claimed for use in the claimed methods. Yu and Van Tomme provide the motivation and reasonable expectation of success that such product can be used for the claimed purposes as expounded on more in the rejection above.
Claims 1-3, 5-13, 15, 26-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 12,138,258, in view of Yu et al., (WO2018/205987), in view of Van Tomme et al., (EP3653214). The claims of ‘258 patent are directed to a method of preparing the product claimed for use in the claimed methods. Yu and Van Tomme provide the motivation and reasonable expectation of success that such product can be used for the claimed purposes as expounded on more in the rejection above.
Claims 1-3, 5-13, 15, 26-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 11,976,063, in view of Yu et al., (WO2018/205987), in view of Van Tomme et al., (EP3653214). The claims of ‘063 patent are directed to a method of treating liver conditions, metabolic disorders, and others with the claimed product. Yu and Van Tomme provide the motivation and reasonable expectation of success that such product can be used for the claimed purposes as expounded on more in the rejection above.
Claims 1-3, 5-13, 15, 26-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 11,685,735, in view of Yu et al., (WO2018/205987), in view of Van Tomme et al., (EP3653214). The claims of ‘735 patent are directed to a method of treating liver conditions, metabolic disorders, and others, as well as the claimed product. Yu and Van Tomme provide the motivation and reasonable expectation of success that such product can be used for the claimed purposes as expounded on more in the rejection above.
Claims 1-3, 5-13, 15, 26-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 10,988,471, in view of Yu et al., (WO2018/205987), in view of Van Tomme et al., (EP3653214). The claims of ‘471 patent are directed to a method of treating liver conditions, metabolic disorders, cholestasis, hyperlipidemia and diabetes with the claimed product. Yu and Van Tomme provide the motivation and reasonable expectation of success that such product can be used for the claimed purposes as expounded on more in the rejection above.
Claims 1-3, 5-13, 15, 26-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 10,301,303, in view of Yu et al., (WO2018/205987), in view of Van Tomme et al., (EP3653214). The claims of ‘303 patent are directed to the product claimed for use in the claimed methods. Yu and Van Tomme provide the motivation and reasonable expectation of success that such product can be used for the claimed purposes as expounded on more in the rejection above.
Claim 1-3, 5-13, 15, 26-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-5, 8, 9, 11, 12, 24-26, 29-33, 35, 37, 38, and 41of copending Application No. 17/966,782, in view of Yu et al., (WO2018/205987), in view of Van Tomme et al., (EP3653214). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘782 application are directed to treating the same subject with the same agent. The instant claims provide for also treating diabetes and hyperlipidemia secondary to PSC. Further, the claimed agent is known to treat liver fibrosis and mitigate elevated enzymes as a result secondary to administration.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
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