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 .
DETAILED ACTION
The office acknowledges Applicants filing of the claim amendments on 11/12/2024. Claims 1, 11, 20, 21, 30-32 have been amended, claims 35-41 have been added new, claims 2-3, 5-8, 10, 15-19, 22-29, 31, 33, 34 have been cancelled. For the sake of compact prosecution, Applicants attorney Clark Sullivan was contacted regarding telephonic restriction election requirement. Attorney Sullivan elected Group I, claims 1, 4, 9, 11-14, 35-40 without traverse on 5/28/2026. Claims 1, 4, 9, 11-14, 20, 21, 30, 32, 35-41 are pending. Claims 20, 21, 30, 32 and 41 are withdrawn from further consideration pursuant to 37 C.F.R. 1.142(b), as being drawn to non-elected subject matter. The claims corresponding to the elected subject matter are 1, 4, 9, 11-14, 35-40 and are herein acted on the merits.
Application Priority
This application filed 04/25/2024 is a National Stage entry of PCT/US2022/ 079080, International Filing Date: 11/01/2022, PCT/US2022/079080 Claims Priority from Provisional Application 63274532, filed 11/02/2021.
Information Disclosure Statement
The information disclosure statement(s) (IDS) filed on 4/24/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS is being considered by the Examiner.
Election/Restrictions
Restriction is required under 35 U.S.C. 121 and 372.
REQUIREMENT FOR UNITY OF INVENTION
As provided in 37 CFR 1.475(a), a national stage application shall relate to one invention only or to a group of inventions so linked as to form a single general inventive concept (“requirement of unity of invention”). Where a group of inventions is claimed in a national stage application, the requirement of unity of invention shall be fulfilled only when there is a technical relationship among those inventions involving one or more of the same or corresponding special technical features. The expression “special technical features” shall mean those technical features that define a contribution which each of the claimed inventions, considered as a whole, makes over the prior art.
The determination whether a group of inventions is so linked as to form a single general inventive concept shall be made without regard to whether the inventions are claimed in separate claims or as alternatives within a single claim. See 37 CFR 1.475(e).
When Claims Are Directed to Multiple Categories of Inventions:
As provided in 37 CFR 1.475 (b), a national stage application containing claims to different categories of invention will be considered to have unity of invention if the claims are drawn only to one of the following combinations of categories:
(1) A product and a process specially adapted for the manufacture of said product; or
(2) A product and a process of use of said product; or
(3) A product, a process specially adapted for the manufacture of the said product, and a use of the said product; or
(4) A process and an apparatus or means specifically designed for carrying out the said process; or
(5) A product, a process specially adapted for the manufacture of the said product, and an apparatus or means specifically designed for carrying out the said process.
Otherwise, unity of invention might not be present. See 37 CFR 1.475 (c).
This application contains the following inventions or groups of inventions which are not so linked as to form a single general inventive concept under PCT Rule 13.1.
In accordance with 37 CFR 1.499, applicant is required, in reply to this action, to elect a single invention to which the claims must be restricted.
Group I, claim(s) 1, 4, 9, 11-14, 35-40 are drawn to a compound of formula I.
Group II, claim 20 is drawn to making a UDCA pharmaceutical dosage form comprising the compound of formula I
Group III, claim 21 is drawn to a method of producing the compound of claim 1 through a DKCA intermediate.
Group IV, claim(s) 30, 32 and 41 are drawn to salts of DKCA and in an isolated state.
The groups of inventions listed above do not relate to a single general inventive concept under PCT Rule 13.1 because, under PCT Rule 13.2, they lack the same or corresponding special technical features for the following reasons:
Groups I-IV lack unity of invention because the groups do not share the same or corresponding technical feature. The technical feature for Groups I-III is the compound of formula I and Groups III-IV is DKCA. Individually the compound of formula I (see Wang, Steroids, 157, 2020) and DKCA is known in the art. In conclusion, there is a lack of unity of inventions, and therefore restriction for examination purposes is proper.
During a telephone conversation with attorney Sullivan on 5/28/2026 a provisional election was made without traverse to prosecute the invention of Group I, claims 1, 4, 9, 11-14, 35-40. Affirmation of this election must be made by applicant in replying to this Office action. Claims 20, 21, 30, 32 and 41 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
The examiner has required restriction between product or apparatus claims and process claims. Where applicant elects claims directed to the product/apparatus, and all product/apparatus claims are subsequently found allowable, withdrawn process claims that include all the limitations of the allowable product/apparatus claims should be considered for rejoinder. All claims directed to a nonelected process invention must include all the limitations of an allowable product/apparatus claim for that process invention to be rejoined.
In the event of rejoinder, the requirement for restriction between the product/apparatus claims and the rejoined process claims will be withdrawn, and the rejoined process claims will be fully examined for patentability in accordance with 37 CFR 1.104. Thus, to be allowable, the rejoined claims must meet all criteria for patentability including the requirements of 35 U.S.C. 101, 102, 103 and 112. Until all claims to the elected product/apparatus are found allowable, an otherwise proper restriction requirement between product/apparatus claims and process claims may be maintained. Withdrawn process claims that are not commensurate in scope with an allowable product/apparatus claim will not be rejoined. See MPEP § 821.04. Additionally, in order for rejoinder to occur, applicant is advised that the process claims should be amended during prosecution to require the limitations of the product/apparatus claims. Failure to do so may result in no rejoinder. Further, note that the prohibition against double patenting rejections of 35 U.S.C. 121 does not apply where the restriction requirement is withdrawn by the examiner before the patent issues. See MPEP § 804.01.
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 1, 4, 9, 11-14, 30, 32, 35, 36 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 1 is directed to:
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Claim 11 is directed to:
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There is only one compound in formula I. It is not clear how a compound can be selected from a single compound. Further a compound cannot comprise δ13C value. Appropriate correction is required. It is suggested that the claims be amended as ‘A compound of ursodeoxycholic acid of formula I and its pharmaceutical salts having a δ13C value’.
Claims 1, 4, 9, 11-14, 35, 36 recite a limitation of the ‘compound further comprising’ or compound comprising (claims 1, 11). Claim 1 is to a compound. Specifically, the phrase "comprising" renders the products indefinite as the phrase "comprising" can be considered open-ended language when not clearly defined and therefore is including additional subject matter in the derivative of claim 1 that is not described in the instant specification and is not particularly pointed out or distinctly claimed. A claim to a chemical compound cannot be open-ended, but must be claimed with precision. Appropriate correction is required.
Claim 4 recites a limitation of abbreviation LCA. Applicants have not defined what LCA is in the specification. For examination purposes LCA has been interpreted as ‘lithocholic acid’ based on the subject matter and prior art. Clarification is required.
Claims 30, 32 recite a limitation of ‘substantially’. The term substantially is a relative term which renders the claims indefinite. The term, substantially, is not defined by the claims, the specification does not provide an adequate standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the metes and bounds of the invention. Appropriate correction is required.
Claim Objections
Claims 30, 32 are objected to because of the following informalities: The claims recite a limitation of ‘Pattern’ (line 2). It is suggested that it is changed to ‘pattern’ (with lower case ‘p’). Appropriate correction is required.
Claim Rejections - 35 USC § 102/103
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 4 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by or in the alternative, under 35 U.S.C. 103 as being unpatentable over Pellicciari et al. (IDS: WO 2017019524).
Pellicciari teachings are directed to the synthesis of bile acids (BAs) from diosgenin, a naturally occurring steroid sapogenin found in abundance in various plant species and to the synthesis of ursodeoxycholic acid (UDCA); the synthesis of the present application advantageously do not rely on microorganisms; hence they are free of toxins and contaminants associated with preparation of bile acids from mammalian and microbial organisms (p 27, lines 13-18, p 28, lines 1-5). It is taught that bile acids and bile acid derivatives are useful in the treatment and prevention of diseases (See p 1, lines 1-2). Bile acids are often isolated from mammalian and microbial organisms that naturally produce them. However, bile acids isolated from such organisms may contain toxins and contaminants. Moreover, methods of preparing bile acid derivatives by using microorganisms can lead to contamination of the final product (See p 1, para 3).
Pellicciari et al. teach preparing compounds of Formula (I) or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, R1 is H, α-OH, β-ΟΗ, or an oxo group.
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The references teaches compound,
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and its composition (See abstract, claims 1, 5), for oral adminstration, e.g. tablet and its use in cholestatic liver disease, NASH etc. (See p 44 last para and p 45, last para). The reference teach the composition can be prepared by admixing the compound with liqiud or solid carriers to arrive at the tablet (see p 45, para 1-2). The refernece teaches isolation and purificaiton of the products and intermediates (see p 28, lnes 3-5, examples). The reference teaches that the compound of formula I has a purity greater than 98%, e.g. 99.9% (See p 44, lines 1-19).
Pellicaciari teachings anticipate the claimed ursodecylic acid (UDCA) with a δ13C vlaue corresponding to a plant derived molecule with the impurity profile as claimed because the reference teaches preparation of UDCA from plant material diosgenin and the purity greater than 98%, addressing the limitations of the impurities (hydroxysteroids, steroids, LCA, DKCA). Thus claims 1, 4 are anticipated.
From Pellicciari a person skilled in the art before the effective filing date of the invention would have arrived at the claimed compound or its salt. A person skilled in the art would have been motivated to arrive at the claimed compound with a reasonable expectation of success and to use it in treating diseases like NASH. As to the limitations of δ13C vlaue, and impurity profile characterization for e.g. less than 5%, the reference teaches the preparation of UDCA from plant material diosgenin and the purity of the compound greater than 98%, addressing the limitations of the impurities (hydroxysteroids, steroids, LCA, DKCA). Thus claims 1, 4 would have been obvious over Pellicciari.
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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 4, 9, 11-14, 35-40are rejected under 35 U.S.C. 103 as being unpatentable over Pellicciari et al. (IDS: WO 2017019524).
Pellicciari et al. as discussed above.
From Pellicciari a person skilled in the art before the effective filing date of the invention would have arrived at the claimed compound or its salt. A person skilled in the art would have been motivated to arrive at the claimed compound with a reasonable expectation of success and to use it in treating diseases like NASH. As to the limitations of δ13C vlaue, and impurity profile characterization for e.g. less than 5%, the reference teaches the preparation of UDCA from plant material diosgenin and the purity of the compound greater than 98%, addressing the limitations of the impurities (hydroxysteroids, steroids, LCA, DKCA). Thus claims 1, 4 would have been obvious over Pellicciari.
As to claims 9, 11-14, 35, 36, Pellicciari teach the purity of the compound can be 99.9%. A skilled artisan would have found it obvious to prepare UDCA compounds with 99.9% purity or 100% purity (with no impurity). A person skilled in the art would have been motivated to arrive at the claimed compound with 99.9% purity or 100% purity (addressing the limitations of the impurities (hydroxysteroids, steroids, LCA, DKCA)) with a reasonable amount of success and for drug stability and therapeutic efficiency. As to claim 37, the UDCA compound has been prepared from the plant derived compound diosgenin and hence will have the same δ13C profile as claimed. As to claims, 38 and 40, the instant specification state that ‘By isolated form is meant that the compound is preferably present as a solid, and that it is substantially free of any compounds other than the recited compound (i.e. < 10%, 5%, 3%, or 1% other compounds)’. It is noted that the compound obtained of Pellicciari is solid and the purity can be 99.9%, hence in isolated state as claimed.
Note: As per the instant specification, UDCA is urosodeoxycholic acid (p 1, para 3, line 7), DKCA has been defined as 3,7-diketo-5β-cholanic acid (see page 7, line 3) and VPDB as Vienna Pee Dee Belemnite (See p 7, last para). LCA has been interpreted as ‘lithocholic acid’ based on the subject matter for examination purposes.
Claims 1, 4, 9, 11-14, 35-40 are rejected under 35 U.S.C. 103 as being unpatentable over Qiu et al. (IDS: WO 2021109791, English translation) and Singh et al. (World J Pharmacy and Pharmaceutical Sciences, 2017, 6, 10, 1337-1354).
Qiu teachings relates to a method for synthesizing ursodeoxycholic acid (UDCA) using plant material, in particular 21-hydroxy-20-methylpregna-4-en-3-one (BA) (Abstract, claims). The reference teach that at present, there are mainly two methods for preparing ursodeoxycholic acid: animal bile extraction and artificial synthesis. However, the source of animal bile extraction is limited and it is difficult to meet medical needs (See Abstract, p 2, para 3)The raw material 21-hydroxy-20-methylpregn-4-en-3-one ((20S)-21-hydroxy-20-methylpregn-4-en-3-one) used in the present invention is also called BA (Bisnoralcohol) is derived from the fermentation of phytosterols, leftovers from the oil and fat process; it is raw green material of plant origin (page 4, lines 5-8). It is taught that UDCA is the first-line treatment drug for primary biliary cirrhosis (PBC) approved by the US FDA. It can also effectively treat gallstone diseases and chronic liver diseases in clinical practice (See p 2, para 2).
Singh in detail reviews the types of impurities, detection, isolation and purification of the active pharmaceutical agents. Singh teaches that “Pharmaceutical impurities are those substances which co-exist with the API or they may develop during synthesis or ageing of both API and formulation. The presence of these impurities even in minor amounts can influence the efficacy and safety of drug. The safety of drug is dependent not only on the toxicological properties of active drug substance itself, but also on impurities that it contains” (see p 1338, para 1). Further taught is chromatography as one of the techniques for the purification of the active agents and for isolation of the impurities (See p 11, 6.1, 6.12, 6. 2).
From Qiu a person skilled in the art before the effective filing date of the invention would have arrived at the claimed compound. A person skilled in the art would have been motivated to arrive at the claimed compound with a reasonable expectation of success and to use it in treating diseases like biliary cirrhosis. As to the limitations of δ13C vlaue, and impurity profile characterization for e.g. less than 5%, the reference teaches the preparation of UDCA from plant material BA. From Singh a person skilled in the art would have found it obvious that impurities are associated with pharmaceutical agents and they affect the efficacy and safety of drug and there are techniques well known to identify and purify the compounds. A person skilled in the art would have been motivated to isolate the impurities and obtain a purified compound of formula I for its therapeutic efficacy and safety for use in medical conditions. One skilled in the art would be able to arrive at compound of formula I or its salt with little (e.g. 0.01%) or no impurity (0%) and arrive at the impurity profile as in the instant claims with a reasonable amount of success. Thus Qiu and Singh claims 1, 4, 11-14, 35-36 would have been obvious over the prior art teachings. As to claims 37, 39 the UDCA compound has been prepared from the plant derived compound Bisnoralcohol (as in the instant specification) and hence will have the same δ13C profile as claimed. As to claims, 38 and 40, the instant specification state that ‘By isolated form is meant that the compound is preferably present as a solid, and that it is substantially free of any compounds other than the recited compound (i.e. < 10%, 5%, 3%, or 1% other compounds)’. It is noted that the compound obtained from Qiu is solid and can be purified by known methods to have limited or free of any impurities, hence in isolated state as claimed.
Note: The prior art made of record and not relied upon is considered pertinent to
applicant's disclosure Wang et al. (Steroids, 157, 2020, p 1-6) teach synthesis of UDCA from plant source (20S)-21-hydroxy-20-methylpregn-4-en-3-one (bisnoralcohol). Chen teach synthesis of UDCA from plant source dehydroepiandrosterone (IDS: Chen, Steroids, 172, 2021).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to UMAMAHESWARI RAMACHANDRAN whose telephone number is (571)272-9926. The examiner can normally be reached M-F- 8:30-5:00 PM (PST).
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, Kortney Klinkel can be reached at 5712705239. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Umamaheswari Ramachandran/ Primary Examiner, Art Unit 1627
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