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
This action is FINAL.
Status of Claims
Claims 1, 3, 5-7, and 9 are pending.
Priority
This application is filed 01/25/2024 and claims the benefit of domestic priority as below:
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Information Disclosure Statement
One IDS(s) received 05/30/2023 have been considered unless marked with a strikethrough. Two of foreign references (i.e., CN102686568A, and JP6121597B1) have not been considered due to the insufficient provided English translations. No additional IDS(s) is/are provided.
Response to Arguments
Applicants’ arguments/amendments filed on 6/18/2026, and in the amendments, claims 1, 6 and 9 are amended; and claims 2, 4, 8, and 10-20 are cancelled. No new matter has been added. The Applicant's arguments of the rejection of claims under 35 U.S.C 103 have been considered but are moot in view of the new ground of rejections for the amended claims 1, 3, 5-7 and 9. The previous rejections of record are withdrawn in view of the amendment.
Response to DECLARATION UNDER 37 CFR 1.132
DECLARATION UNDER 37 CFR 1.132 was filed on 6/18/2026. In summary, the declaration explains that 1) Repine does not disclose or suggest that L-ergothioneine promotes ROS production in PMNs or otherwise teaches the claimed immunological effect; 2) Yoshida's study focuses on macrophages rather than neutrophils and reports that L-ergothioneine scavenges reactive oxygen species. Thus, Yoshida’s finding contradicts the present invention, suggesting that the effects are specific to the cell type and unpredictable; and 3) the claimed dosage range is critical and yields unexpected results, and this claim is supported by the experimental data in Example 1, which shows a statistically significant increase in ROS production in human PMNs.
The Declaration has been fully considerate but is insufficient to overcome the present rejection. The arguments relate to Yoshida including the alleged teaching away, the distinction between macrophage and PMNs, and the asserted cell type specific unpredictability, are moot in view of the new ground of rejection. The remaining arguments regarding Repine in the Declaration, regarding the dosage range, criticality, experimental evidence of Example 1, and unexpected results, are not sufficient to overcome the new grounds for rejection.
The new ground of rejection relies on Ayabe for enhancing a host mediated antimicrobial immune response, Repine for oral administration of L-ergothioneine to treat microbial infection, and EFSA for high purity L-ergothioneine and oral daily amounts within the claimed range. The Declaration is insufficient to overcome the new ground of rejection because its arguments concerning Repine, dosage range criticality, and unexpected results do not establish that the claimed subject matter would have been nonobvious over the teachings relied upon in the present rejection. See the new ground of rejection.
The Declaration is also insufficient to establish critical or unexpected results for the claimed dosage range of 1-500 mg/day. Example 1 concerns vitro exposure at 1.25, 2.5 and 5 g/L and does not establish that oral administration within the claimed range produces comparable concentrations or the asserted ROS-enhancing effect across the full scope of the range. Moreover, EFSA taches oral administration at 20 and 30 mg/day, which falls within the claimed range. See the new ground of rejection.
Therefore, the Declaration is insufficient to overcome the prima facie case of obviousness.
New Ground of Rejections
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 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, 3, 5-7, and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Ayabe et al. (JP2012180329A, pub’d 09/20/2012, IDS cited) in view of Repine et al. (WO 2019/089878 A1, pub’d 05/09/2019, IDS cited), and further in view of EFSA Panel on Dietetic Products et al. (Scientific opinion on the safety of synthetic l-ergothioneine (Ergoneine®) as a novel food pursuant to Regulation (EC) No 258/97. EFSA Journal, 14(11), 4629, pub’d 11/18/2016, herein “EFSA”).
With respect to the independent claim 1, the claim recites that a method of improving a mammal's innate immune response to a microbial infection by promoting production of reactive oxygen species in polymorphonuclear leukocytes, comprising orally administering to the mammal an effective amount of L-ergothioneine or a pharmaceutically acceptable salt thereof, wherein the effective amount comprises from 1 to 500 mg/day of the L-ergothioneine or the pharmaceutically acceptable salt thereof, and the L-ergothioneine or the pharmaceutically acceptable salt thereof comprises 0% D-ergothioneine, 0% nucleic acids, 0% amino acids, and less than 2% total impurities.
Ayabe teaches 1) an agent that promotes the production and/or secretion of an antimicrobial substance in a panel cell, and contains ergothioneine extracted from sputum and/or sputum as an active ingredient; 2) stimulation activates host immunity; and 3) may be used to prevent or treat diseases associated with microorganisms (abstract, and page 9 in Machine Translated (MT) reference).
Ayabe fails to teach orally administering L-ergothioneine in the claimed dose range.
Repine teaches 1) a method for treating a microbial infection in a subject in need of treatment thereof, comprising administering to the subject a therapeutically effective amount of ergothioneine (ERGO), a precursor of ERGO, a salt thereof, or a biologically active analog, or prodrug thereof (claim 1); 2) ERGO is L isomer (claim 2); 3) orally administration for the mammal (page 10, lines 23-27, and page 6, lines 1-3); 4) administering ERGO to improve antibacterial activity for microbial infection (claim 1 and page 8 lines 15-20); and 5) therapeutically or prophylactically effective daily amount ranging from about 0.01 to about 750 mg/kg/day.
Ayabe and Repine fail to teach the claimed high purity L-ergothioneine preparation.
EFSA teaches 1) synthetic L-ergothioneine suitable for human oral consumption having at least ≥99.5% chemical purity by HPLC, and ≥ 99% chemical purity by 1H NMR (table 1); and 2) oral administration of L-ergothioneine at 30 mg/day in adults and 20 mg/day in children, both of which fall the claimed range of 1 to 500 mg/day (Anticipated intake/extent of use of the NF section).
It would have been obvious to a PHOSITA at the time of the invention to use the standardized high purity L-ergothioneine taught by EFSA in the oral antimicrobial treatment suggested by Ayabe and Repine. Ayabe teaches benefits associated with enhancing the host's antimicrobial immunity. Refine teaches an oral L-ergothioneine treatment regimen for microbial infections, including dosage adjustments. EFSA teaches a standardized L-ergothioneine suitable for oral administration to humans at daily intake levels within the claimed range. Therefore, the combination of teachings is expected to have yielded an oral antimicrobial therapeutic agent offering advantages such as enhanced host antimicrobial defense, convenient oral administration, reduced impurity levels, improved compositional consistency, and suitability for human use.
The combination teachings of Ayabe, Repine, and ESFA fail to teach the limitation “by promoting production of reactive oxygen species in polymorphonuclear leukocytes,” However, the limitation recites a physiological result or mechanism associated with the claimed administration rather than a separate treatment step. (see MPEP 2111 and 2114) Repine teaches that intracellular killing of bacteria by neutrophils depends on free radical generation, including toxic free radicals generated by NADPH oxidase. (page 7, lines 22-33) Thus, read together with the disclosure identifying ROS as free radical (page 5, lines 3-8), it indicates that ROS generated by neutrophils participate in the intracellular killing of bacteria. Moreover, the instant specification evaluates ROS formation only after PMNs are stimulated with the bacterial peptide fMLP, indicating that the asserted effect concerns enhancement of an activated antimicrobial response rather than independent imitation of ROS production by L-ergothioneine (example 1). Thus, if the obvious administration of L-ergothioneine naturally enhances ROS production in activated polymorphonuclear leukocytes, recognition of that physiological effect does not distinguish the claimed method from the prior arts. (see MPEP 2112 and 2114)
With respect to the claimed purity profile, EFSA teaches a synthetic, stereochemical defined L-ergothioneine preparation having at least 99.5% chemical purity and less than 0.8% total impurities for human oral consumption. The batch-to-batch analyses show average 99.83% chemical purity (Table 2). Moreover, the instant specification acknowledges that known prior-art manufacturing methods may be used, and indicates that the absence of D-ergothioneine, nucleic acids, and amino acids represents further control over impurity levels in high-purity L-ergothioneine products. (paragraphs [0004] and [0031]- [0032]). Given the known high-purity substances and manufacturing methods, optimizing impurity content would have constituted routine purification and quality control activities, absent evidence that a specifically defined impurity profile yielded different or unexpected technical effects.
With respect to the Applicant’s evidence (i.e., DECLARATION UNDER 37 CFR 1.132) of unexpected results and criticality, the submitted data do not establish that the claimed oral dosage range of 1-500 mg/day is critical for promoting ROS production in polymorphonuclear leukocytes. Example 1 exposes human blood in vitro to L- ergothioneine concentrations of 0.01-5 g/L for 24 hours and subsequently stimulates ROS formation with fMLP. A pharmacokinetic correlation between relevant in vitro concentrations and oral doses of 1–500 mg per day has not been established. Furthermore, it has not been demonstrated that an effect of increasing ROS occurs across the entire range of oral doses presented. Furthermore, the specification states that “the L-ergothioneine is preferably administered as an oral dosage form comprising 1-500 mg, 1-300 mg, 1-100 mg, 1-50 mg, 3-50 mg, 5-50 mg, 10-50 mg, 10-30 mg of L-ergothioneine.”, without demonstrating that the endpoints of 1 and 500 mg/day produce a critical change in kind or effect (paragraph [0033]). Accordingly, the evidence does not establish unexpected results or criticality commensurate in scope with claim 1 and is insufficient to overcome the prima facie case of obviousness. See MPEP 716.02(d)
With respect to claims 3 and 7, the claims recite that the microbial infection is selected from the group consisting of bacterial infections, viral infections, fungal infections, and protozoal infections in claim 3 and the mammal is a human in claim 7.
Ayabe teaches bacteria, fungi, protozoa, and viruses among the microorganisms against which its ergothioneine mediated antimicrobial response may be directed (page 7-8 in Machine Translated (MT) reference). Ayabe further teaches humans among the mammals having Paneth cells to which its immune activating teaching applies (page 7 in Machine Translated (MT) reference). Thus, claim 3 would have been obvious for the same reasons discussed above with respect to claim 1.
With respect to claims 5 and 6, the claims recite that the L-ergothioneine is administered as
an oral dosage form comprising from 15 to 50 mg of L-ergothioneine, specifically 20 mg and 25 mg of L-ergothioneine.
EFSA teaches oral L- ergothioneine supplementation at 30 mg/day for adults. In addition, EFSA further teaches oral administration of L- ergothioneine at 20 mg/day for children older than three years (Anticipated intake/extent of use of the NF section). Thus, claims 5-6 would have been obvious for the same reasons discussed above with respect to claim 1.
With respect to claim 9, the claim recites that the oral dosage form is in the form of a tablet, a capsule, a powder sachet, or a liquid.
Repine teaches solid dosage forms for oral administration include capsules, tablets, pills, powders and granules, as required in claim 9 (page 10, lines 25-26). Thus, claim 9 would have been obvious for the same reasons discussed above with respect to claim 1.
Conclusion
Claims 1, 3, 5-7, and 9 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 nonprovisional extension fee (37 CFR 1.17(a)) 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 SEONG JONG KIM whose telephone number is (571)272-6918. The examiner can normally be reached 7:00am-3:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton A. Brooks can be reached at 571-270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SEONG JONG KIM/Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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