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 .
Status of the Claims
Claims 1-11 are currently pending and under examination.
Priority
The instant application 18/849,136 filed on September 20, 2024 is a 371 of
PCT/CN2023/083444 filed on 03/23/2023, which claims priority to, and the benefits of CN Application No. CN202210321879.4 filed on March 25, 2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 9/20/2024. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 6-7 and 11 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 6 recites “the mass-to-volume ratio of the OB1 to the solvent,” but claim 1 defines the compound as OB-1. It is unclear whether “OB1” is intended to refer to the same compound as “OB-1” or a different compound.
Regarding claim 7, the phrases “a protection of ethylene glycol” and “a de-protection of ethylene glycol” are unclear. Ethylene glycol itself is not being protected or deprotected. The claim should clarify that compound OB-4 is subjected to ketal protection with ethylene glycol and that the ethylene-glycol ketal of compound OB-2 is deprotected to obtain compound OB-1. Claim 7 step b also recites two alternative reactions in a manner that makes the scope unclear. The Wittig reaction alternative and the Knoevenagel condensation alternative should be separately and clearly recited.
Claim 11 depends from claim 7 and is indefinite for at least the same reasons.
Therefore, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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 1-7 and 9-11 are rejected under 35 U.S.C. 103 as being unpatentable over Qiu et al. (US12441759B2) in view of Weymouth-Wilson et al. (WO2017199033A1).
Regarding claim 1, Qiu et al. teaches a process for preparing bile-acid compounds from a BA-derived steroid intermediate (see e.g. col. 1 line 15). Qiu et al. teaches oxidizing BA to an aldehyde intermediate, extending the side chain by a Wittig-type or Knoevenagel-type reaction to provide an unsaturated ester intermediate, protecting the ketone as an ethylene-glycol ketal, conducting allylic oxidation, deprotecting the ketal, and conducting catalytic hydrogenation under hydrogen in the presence of a hydrogenation catalyst (see e.g. col. 9 line 5). Qiu et al. teaches hydrogenation catalysts including Raney Ni, Pd/C, and teaches carrying out the hydrogenation in organic solvents (see e.g. col. 14 line 1, col. 36 line 65).
Regarding claim 2, Qiu et al. teaches alkyl ester bile-acid intermediates R is a C1-C20 alkyl group in the same BA-derived steroid route (see e.g. claim 2). C1-C20 alkyl ester groups such as methyl, ethyl, propyl, and tert-butyl were conventional carboxylic-acid protecting groups for bile-acid intermediates.
Regarding claims 3 and 10, claim 3 recites that the reaction is performed in the presence of a catalyst, claim 10 further recites that the catalyst is selected from a Raney Ni catalyst, a Pd/C catalyst, a Pt/C catalyst, or a Ru/C catalyst. Qiu et al. teaches catalytic hydrogenation using hydrogenation catalysts including Raney Ni, Pd/C.
Regarding claim 7, claim 7 recites a method for preparing OB-1 from BA through oxidation to OB-5, side-chain extension to OB-4 by Wittig reaction or Knoevenagel condensation, ethylene-glycol ketal protection to OB-3, oxidation to OB-2, and ketal deprotection to OB-1. Qiu et al. teaches the same general BA-derived steroid route. Specifically, Qiu et al. teaches oxidation of BA to an aldehyde intermediate, conversion of that aldehyde intermediate to an unsaturated ester side-chain intermediate by Wittig-type or Knoevenagel-type chemistry, ketal protection with ethylene glycol, allylic oxidation, and ketal deprotection to provide the corresponding hydrogenation substrate.
Regarding claim 9, claim 9 recites that R1 is methyl, ethyl, n-propyl, or tert-butyl.
As discussed above for claim 2, lower alkyl esters are conventional carboxylic-acid protecting groups in bile-acid synthesis.
Regarding claim 11, claim 11 depends from claim 7 and recites that the phosphonoacetate reagent is triethyl phosphonoacetate. Qiu et al. teaches side-chain extension of the BA-derived aldehyde intermediate by Wittig-type chemistry using a phosphonoacetate reagent to form the unsaturated ester side-chain intermediate. Triethyl phosphonoacetate was a conventional Horner-Wadsworth-Emmons/Wittig-type reagent for preparing α,β-unsaturated esters from aldehydes. Selection of triethyl phosphonoacetate would have been obvious because it predictably forms the claimed unsaturated ester side chain, and the use of such phosphonoacetate reagents is expressly within the side-chain homologation chemistry taught by Qiu et al.
Qiu et al. does not expressly teach performing the hydrogenation of the OB-1 type intermediate in an amide solvent.
Weymouth-Wilson et al. teaches intermediates and methods for preparing bile-acid derivatives, particularly obeticholic acid and analogues, from steroid/bile-acid intermediates (see e.g. p. 1 line 2). Weymouth-Wilson et al. teaches that the reduction may be catalytic hydrogenation and that suitable hydrogenation catalysts include Pd/C, Pd/CaCO₃, Pd/alumina, Pt/Pd, and Raney nickel (see e.g. p. 20 line 20). Weymouth-Wilson et al. further teaches that the hydrogenation may be carried out in organic solvents including N,N-dimethylformamide (DMF) (see e.g. p. 20 line 24)., and identifies DMF with Pd/C as a particularly suitable solvent/catalyst combination for hydrogenation of steroid bile-acid intermediates (see e.g. p. 21 line 10).
Weymouth-Wilson et al. also teaches working examples in which closely related steroid bile-acid intermediates are hydrogenated in DMF using Pd/C and hydrogen. For example, Weymouth-Wilson et al. teaches hydrogenating a 7-hydroxy-3-oxo-4-choleno steroid nitrile in DMF using 10% Pd/C under hydrogen to give the corresponding saturated 5β steroid product in 74% yield (see e.g. p. 80 line 20).
Regarding claim 4, claim 4 recites that the mass ratio of OB-1 to the catalyst is (2–20):1.
Weymouth-Wilson et al. teaches hydrogenating a steroid bile-acid intermediate by charging 350 mg substrate and 83 mg of 10% Pd/C, corresponding to a substrate:catalyst mass ratio of about 4.2:1 (see e.g. p. 80 line 20), which falls within the claimed range. Weymouth-Wilson et al. also teaches another DMF/Pd-C hydrogenation using 3.1 g substrate and 0.79 g Pd/C, corresponding to about 3.9:1, also within the claimed range (see e.g. p. 86 line 25). The claimed ratio would have been an obvious result-effective process variable for catalytic hydrogenation. A person of ordinary skill would have routinely adjusted catalyst loading to obtain acceptable conversion, reaction rate, selectivity, and impurity profile.
Regarding claim 5, claim 5 recites that the amide solvent is selected from at least one of N,N-dimethylformamide, N,N-dimethylacetamide, formamide, N-methylpyrrolidone, N-methylformamide, N-methylacetamide, and N,N-dimethylpropyleneurea. Weymouth-Wilson et al. expressly teaches DMF as an organic solvent for catalytic hydrogenation of steroid bile-acid intermediates and identifies DMF/Pd-C as a particularly suitable solvent/catalyst combination. Because DMF is one of the solvents recited in claim 5, the limitation is taught by the applied art.
Regarding claim 6, claim 6 recites that the mass-to-volume ratio of OB-1 to the solvent is 1:(1–20) g:mL. Weymouth-Wilson et al. teaches hydrogenating 350 mg of steroid substrate in 2.1 mL DMF, corresponding to a substrate:solvent ratio of about 1:6 g:mL, within the claimed range. Weymouth-Wilson et al. also teaches hydrogenating 3.1 g substrate in 54.5 mL DMF, corresponding to about 1:17.6 g:mL, also within the claimed range. The claimed solvent loading would have been an obvious optimization of a known process variable, because substrate concentration in catalytic hydrogenation is routinely adjusted to balance solubility, mixing, reaction rate, and workup efficiency.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the hydrogenation step of Qiu et al. by using an amide solvent, such as DMF, and Pd/C/H₂ hydrogenation conditions, as taught by Weymouth-Wilson et al. The motivation would have been to use known solvent/catalyst conditions that Weymouth-Wilson et al. teaches are suitable for catalytic hydrogenation of closely related steroid/bile-acid intermediates. Qiu et al. already teaches preparation of a BA-derived hydrogenation substrate and catalytic hydrogenation of that substrate, but does not expressly teach the claimed amide solvent. Weymouth-Wilson et al. cures that deficiency by teaching hydrogenation of structurally related cholane/steroid bile-acid intermediates in DMF using Pd/C and hydrogen. A person of ordinary skill in the art would have had a reasonable expectation of success because both references are directed to catalytic hydrogenation of closely related steroid/bile-acid intermediates, and Weymouth-Wilson et al. demonstrates that DMF/Pd-C/H₂ conditions successfully hydrogenate such substrates. The use of DMF as the amide solvent would have been no more than applying a known solvent/catalyst system for its known purpose in a closely related steroid hydrogenation reaction.
The catalyst loading of claim 4 and solvent amount of claim 6 would also have been obvious because Weymouth-Wilson et al. teaches working examples within the claimed ranges, and catalyst amount and solvent loading are result-effective process variables routinely optimized to obtain acceptable conversion, reaction rate, selectivity, solubility, mixing, and workup efficiency.
Claims 1-11 are rejected under 35 U.S.C. 103 as being unpatentable over Qiu et al. (WO2021109791A1), in view of Weymouth-Wilson et al. (WO2017199033A1, and further in view of Jiang et al. (CN110437296B).
Claims 1-7 and 9-11 are unpatentable over Qiu et al. in view of Weymouth-Wilson et al. for the reasons set forth above.
Regarding claim 8, claim 8 recites preparing 7-ketolithocholic acid by preparing OB according to claim 1 and hydrolyzing OB to obtain 7-ketolithocholic acid. Qiu et al. teaches preparing bile-acid ester intermediates and converting ester intermediates to free bile-acid products. Hydrolysis of a lower alkyl ester to the corresponding carboxylic acid was a routine and predictable transformation. But Qiu et al. does not expressly teach performing the hydrolyzing OB to obtain 7-ketolithocholic acid.
Jiang et al. teaches that a 7-ketolithocholic acid intermediate can be used to prepare 7-ketolithocholic acid and specifically teaches hydrolyzing an intermediate under alkaline conditions to obtain target 7-ketolithocholic acid (see e.g. p. 8 [0040]). It would have been obvious to hydrolyze the OB alkyl ester prepared by the method of claim 1 to obtain 7-ketolithocholic acid, because hydrolysis of an alkyl ester to the corresponding free acid is a conventional final step in bile-acid synthesis, and Jiang et al. expressly teaches alkaline hydrolysis of 7-ketolithocholic acid intermediates to obtain 7-ketolithocholic acid.
Jiang et al. also teaches 7-ketolithocholic acid intermediates in which R1 may be methyl, ethyl, isopropyl, n-propyl, tert-butyl, n-butyl, or isobutyl (see e.g. p. 6 [0015]) . Therefore, claim 2 would have been obvious. Claim 9 recites that R1 is methyl, ethyl, n-propyl, or tert-butyl, as discussed above for claim 2, lower alkyl esters are conventional carboxylic-acid protecting groups in bile-acid synthesis. Jiang et al. expressly teaches 7-ketolithocholic acid intermediates in which R1 may be methyl, ethyl, isopropyl, n-propyl, tert-butyl, n-butyl, or isobutyl. Therefore, claim 9 would have been obvious.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the hydrogenation step of Qiu et al. by using the DMF/Pd-C/H₂ hydrogenation conditions taught by Weymouth-Wilson et al., and to further hydrolyze the resulting OB alkyl ester to 7-ketolithocholic acid as taught by Jiang et al. The motivation would have been to use known hydrogenation conditions suitable for closely related steroid/bile-acid intermediates and then convert the resulting ester intermediate to the desired free bile acid product. A person of ordinary skill in the art would have had a reasonable expectation of success because Weymouth-Wilson et al. demonstrates successful DMF/Pd-C/H₂ hydrogenation of related cholane/steroid bile-acid substrates, and Jiang et al. demonstrates alkaline hydrolysis of related 7-ketolithocholic acid intermediates to obtain 7-ketolithocholic acid. Thus, the claimed process would have involved applying known reaction conditions to closely related steroid/bile-acid intermediates for their known purposes, with predictable results.
Therefore, the claimed invention is obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
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 1–11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1–3, 5, 8, and 11–14 of copending U.S. Application No. 18/849,000, published as US20250206771A1.
Although the claims at issue are not identical, they are not patentably distinct. The copending application claims a method of preparing a compound of formula I by hydrogenating compound I-1 in the presence of a catalyst, wherein R1 is H or alkyl. The copending application further claims that the reaction is performed in an amide solvent, including N,N-dimethylformamide, N,N-dimethylacetamide, formamide, N-methylpyrrolidone, N-methylformamide, N-methylacetamide, and N,N-dimethylpropyleneurea, and further claims alkyl embodiments including C1-6 alkyl, methyl, ethyl, n-propyl, and tert-butyl. The presently claimed OB-1 and OB correspond to the same hydrogenation substrate and product framework, with R1 limited to alkyl and with the amide solvent expressly required.
It would have been obvious to one of ordinary skill in the art to practice the presently claimed OB-1-to-OB hydrogenation using the amide solvent and catalyst selections claimed in the copending application, because the copending claims already encompass the same hydrogenation of the same steroid intermediate framework and expressly recite the amide solvent and catalyst selections used in the present claims. The present claims therefore would unjustifiably extend protection for patentably indistinct subject matter.
This is a provisional nonstatutory double patenting rejection because the reference application is copending.
Conclusion
No claims are allowed.
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/G.S./ Examiner, Art Unit 1628
/AMY L CLARK/Supervisory Patent Examiner, Art Unit 1628
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