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 Application
1. Claims 1-3, 5-13, and 36-37 are pending and subject to examination on the merits. Claims 12-13 and 37 are withdrawn for being drawn to non-elected species. Therefore, claims 1-3, 5-11, and 36 are under examination.
Election/Restrictions
2. Applicant’s election without traverse of Group I, claims 1-3, 5-13 and 36-37, in the reply filed on 11 February 2026 is acknowledged. Additionally, in a follow-up call on 20 April 2026, Applicant confirmed the election of Species 1a: LCA, 1b: SEQ ID NO: 32, and 1c: SEQ ID NO: 33 also without traverse. Therefore, claims 12-13 and 37 are withdrawn, since they are drawn to non-elected subject matter.
Priority
3. Acknowledgment is made for the Applicant’s claim for domestic priority based on the US provisional application PRO 63/119,188 filed 30 November 2020.
Information Disclosure Statement
4. The information disclosure statements (IDS) submitted on 22 May 2023, 20 December 2023, and 20 December 2023 have been considered by the examiner. See initialed and signed PTO/SB/08’s.
Drawings
5. The drawings are objected to because Fig. 1A-C has no x-axis label; Fig. 5 has no y-axis label; Fig. 6 has no y-axis label; Fig. 7 has no y-axis label; Fig. 8 has no y-axis label; and Fig. 9 has no x-axis label. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
6. The use of the term Waters XSelect™ and Waters Agilent™ (p. 29, “Analysis of culture extracts”), which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
7. The disclosure is objected to because of the following informalities: “SEQ ID NO.” should be amended to “SEQ ID NO:”. See MPEP 2422.
Appropriate correction is required.
Claim Objections
8. Claim 1 is objected to because of the following informalities: “LCA,” “3-KCA,” “UDCA”, and “3-KUDCA” should be defined before being used as an acronym. Appropriate correction is required.
9. Claim 5 is objected to because of the following: in line 3, “(“CYP”) enzyme, the CYP…” should be “(“CYP”) enzyme, wherein the CYP…” to improve grammar.
10. Claims 6-9 are objected to because of the following informalities: periods in claims are not permitted except at the end of the claim and when used for abbreviations (See MPEP 608.01(m)). Thus, it is suggested to replace, for example, “a.” with “(a)” or “a)”, etc. and “i.” with “(i)” or “i)”, etc. It is noted, the preferred format for sequence identifiers is “SEQ ID NO:” – see MPEP 2422.01 and 37 C.F.R. 1821(c) and (d).
Appropriate corrections are required.
FOR SEQ ID NO: - – See MPEP 2422.01 and 37 C.F.R. 1.821(c) and (d)
Claim Rejections - 35 USC § 112(b)
11. 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.
12. Claims 5 and 10 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.
13. Claim 5 recites the limitation "7β-hydroxylation system" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim.
14. Regarding claim 10, the phrases "preferably" and “most preferably” render the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim Rejections - 35 USC § 103
15. 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.
16. 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.
17. Claims 1-3 and 5-11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yang et al (Yang et al., 2020, Biotechnol Lett—cited on the IDS filed 22 May 2023) as evidenced by Glewen et al (Glewen et al., 2010, ”Dealing with High Yeast Levels in High Moisture Corn and Corn Silage” downloaded 15 May 2026 from <https://sheboygan.extension.wisc.edu/files/2010/10/DealingwithHighYeastLevelsinHighMoistureCornandCornSilage.pdf> as a PDF--cited herein), and further in view of Huang et al (Huang et al., 2014, Pharmaceutical Bioprocessing—cited herein)..
Regarding claim 1, drawn to a method of converting LCA to UDCA with a 7β-hydroxylase system in the presence of a yeast, wherein the 7β-hydroxylase system is not native to the yeast, Yang et al. teaches the 7β-hydroxylation of LCA to produce UDCA by exposing the yeast Gibberella zeae to LCA and determining the upregulated enzymes annotated as a hydrolase or CYP450, where specifically, Yang et al. determined 12 enzymes involved in the 7β-hydroxylation system (abstract, Table 1), where Gibberella zeae resides on corn with other strains of yeast, such as Cryptococcus sps., Thadotorala sps., and Sporabolomyces sps as evidenced by Glewen et al (“Mechanism”). Regarding claim 5, drawn to the 7β-hydroxylase system comprising P450 oxidoreductase (CPR) and a P450 7β-hydroxylase (CYP) enzymes, where the CYP and CPR enzymes are not native to yeast, Yang et al. teaches the 7β-hydroxylase system in Gibberella zeae, which comprises both CYP and CPR enzymes (abstract, Table 1), where the yeast cohabitates with other yeasts on corn as evidenced by Glewen et al (“Mechanism”). Regarding claim 6, drawn to the CYP enzyme encoded by SEQ ID NO: 32, Yang et al. teaches a G. zeae enzyme, where said enzyme is encoded by SEQ ID NO: 32 (Table 1, See also supplemental file 20250926_163221_us-18-038-203-32.rng, entry 1). Regarding claim 7, drawn to a CPR enzyme encoded by SEQ ID NO: 5, Yang et al. teaches a G. zeae enzyme, where said enzyme is encoded by SEQ ID NO: 5 (Table 1, See also supplemental file 20250926_162730_us-18-038-203-5.rng, entry 1). Regarding claim 8, drawn to a CYP enzyme comprising SEQ ID NO: 33, Yang et al. teaches a G. zeae CYP enzyme comprising SEQ ID NO: 33 (Table 1, See also supplemental file 20250926_163215_us-18-038-203-33.rag, entry 1). Regarding claim 9, drawn to a CPR enzyme comprising SEQ ID NO: 33, Yang et al. teaches a G. zeae CPR enzyme comprising SEQ ID NO: 33 (Table 1, See also supplemental file 20250926_162736_us-18-038-203-3.rag, entry 1). Regarding claim 10, drawn to P450 7β-hydroxylase system comprising a CYP enzyme native to Gibberella zeae, Yang et al. teaches multiple CYP enzymes comprising the 7β-hydroxylase system (Table 1). Regarding claim 11, comprising utilizing SEQ ID NO: 33 to produce UDCA from LCA, Yang et al. teaches a G. zeae CPR enzyme comprising SEQ ID NO: 33 converting LCA to UDCA (abstract, Table 1).
Yang et al. as evidenced by Glewen et al. does not teach the utilization of the yeast Saccharomyces cerevisiae (claims 2-3) or the utilization of a heterologous protein system for the conversion of LCA to UDCA. Huang et al. teaches, “the yeast Saccharomyces cerevisiae is one of these preferred cell factories as it meets many of the requirements. There are several reports on improvement of recombinant protein production by S. cerevisiae through rational engineering of different stages of the protein secretion pathway” (abstract).
Therefore, it 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 combine the teachings of Yang et al. as evidenced by Glewen et al. and Huang et al. to produce UDCA utilizing a 7β-hydroxylase system from G. zeae to utilize butchery wastes, such as LCA to prevent it from being discarded as taught by Yang et al (p. 415, Introduction, paragraph 2). One would be motivated to combine these teachings to arrive at the instant claims to produce UDCA, since it is the clinical first-line drug to treat primary biliary cirrhosis as taught by Yang et al (p. 415, Introduction, paragraph 1). There would be reasonable expectation of success, yielding no surprising results when combining the teachings of Yang et al. as evidenced by Glewen et al. and Huang et al. to produce UDCA in S. cerevisiae utilizing the 7β-hydroxylase system from G. zeae, since Huang et al teaches S. cerevisiae as a cell factory for recombinant protein production (abstract).
18. Claim 36 are rejected under 35 U.S.C. 103 as being unpatentable over as applied to claim 1-3 and 5-11 above, Yang et al (Yang et al., 2020, Biotechnol Lett—cited on the IDS filed 22 May 2023) as evidenced by Glewen et al (Glewen et al., 2010, ”Dealing with High Yeast Levels in High Moisture Corn and Corn Silage” downloaded 15 May 2026 from <https://sheboygan.extension.wisc.edu/files/2010/10/DealingwithHighYeastLevelsinHighMoistureCornandCornSilage.pdf> as a PDF--cited herein), further in view of Huang et al (Huang et al., 2014, Pharmaceutical Bioprocessing—cited herein), and further in view of Colombo et al (Colombo et al., 1992, Hepatology—cited herein).
The teachings of Yang et al. as evidenced by Glewen et al. are discussed above and incorporated into the instant rejection.
Yang et al. as evidenced by Glewen et al. does not teach the processing of UDCA into a finished dosage form. Colombo et al. teaches the utilization of 5-15mg/kg body wt/day to treat liver disease patients (p. 924, abstract).
Therefore, it 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 combine the teachings of Yang et al. as evidenced by Glewen et al. and Colombo et al. to process UDCA to a dosage ready form from UDCA produced by a 7β-hydroxylase system from G. zeae to utilize to treat patients with liver disease as taught by Colombo et al. One would be motivated to combine these teachings to arrive at the instant claims to formulate UDCA in dosage from to treat liver patients who have bile acid malabsorption as taught by Colombo et al (abstract). here would be reasonable expectation of success, yielding no surprising results when combining the teachings of Yang et al. as evidenced by Glewen et al. and Huang et al. to produce UDCA in S. cerevisiae utilizing the 7β-hydroxylase system from G. zeae and formulate it into a dosage ready form, since Colombo teaches the dosages of UDCA.
Conclusion
19. All claims are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CIARA A MCKNIGHT whose telephone number is (703)756-4791. The examiner can normally be reached M-F 8:00am-4:30pm.
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/CIARA A MCKNIGHT/Examiner, Art Unit 1656
/SUZANNE M NOAKES/Primary Examiner, Art Unit 1656
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