DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 1-20 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 Statements
One IDS(s) received on 01/25/2024 has been considered unless marked with a strikethrough. Three of foreign references (i.e., JP2012180329A, CN102686568A, and JP6121597B1) have not been considered due to the insufficient provided English translations.
Claim Interpretation
The claims recite the functional limitation that “wherein the effective amount is sufficient to induce the production of reactive oxygen species in polymorphonuclear leukocytes.” The specification defines an “effective amount” as an amount sufficient to support or affect a metabolic process or to treat or prevent a disease (paragraph [0020]). The specification further explains that “an effective amount is capable of inducing the production of reactive oxygen species (ROS), and preferably comprises 20 or 25 mg of L-ergothioneine or a pharmaceutically acceptable salt thereof when administered orally once daily.” Accordingly, the specification demonstrates that the claimed functional limitation is satisfied by the disclosed dosage amounts, which a person of ordinary skill in the art would understand to be sufficient to induce ROS production in polymorphonuclear leukocytes and thereby improve immune response to microbial infection.
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 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Repine et al. (WO 2019/089878 A1, pub’d 05/09/2019), in view of Yoshida et al. (“The Anti-Oxidant Ergothioneine Augments the Immunomodulatory Function of TLR Agonists by Direct Action on Macrophages” PLoS One, 2017, 12(1), e0169360, pub’d 01/23/2017).
With respect to independent claim 1, the claim recites a method of improving a mammal’s immune response to a microbial infection comprising orally administering to the mammal an effective amount of L-ergothioneine or a pharmaceutically acceptable salt thereof, wherein the effective amount is sufficient to induce the production of reactive oxygen species in polymorphonuclear leukocytes.
Repine teaches 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). Repine further teaches 1) ERGO is L isomer (claim 2); 2) orally administration for the mammal (page 10, lines 23-27, and page 6, lines 1-3); 3) administering ERGO to improve antibacterial activity for microbial infection (claim 1 and page 8 lines 15-20).
Repine fails to teach that the administered L-ergothioneine induces the production of reactive oxygen species (ROS) in polymorphonuclear leukocytes.
Yoshida teaches the L-ergothioneine (ERGO) modules the immune system and enhances immune cell activation, including stimulation of macrophages and increased production of immune mediators involved in host defense responses (introduction section). Yoshida further teaches that ERGO enhances innate immune responses through activation of immune cells responsible for pathogen clearance (introduction section).
It would have been obvious to a PHOSITA at the time of the invention to administer ERGO in the method of Repine in view of the teachings of Yoshida in order to enhance immune cell activation and antimicrobial defense response, including reactive oxygen species production by polymorphonuclear leukocyte. The immune activating properties of EGRO taught by Yoshida provide motivation to use EGRO in methods that enhance oxidative antimicrobial responses because polymorphonuclear leukocytes such as neutrophils generate reactive oxygen species during immune activation and phagocytosis as part of the host defense mechanism (introduction section). Such combination would have been improved the host immune response against microbial infection and thereby enhance antimicrobial efficacy relative to the method of Repine. Yoshida further teaches that the immune-activating function of EGRO that is exerted under TLR (toll-like receptor) stimulation, and murine macrophages express various TLRs and respond to pathogen associated molecular patterns to induce cytokines and modulate inflammation (discussion section). Therefore, combining the antimicrobial treatment method of Repine with the immune enhancing activity of ERGO described by Yoshida would have reasonably been expected to provide improved immune mediated pathogen clearance.
The references is directed to the same field of endeavor and address related to the application. The Supreme Court in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham.
Examples of rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Applying KSR example rationale (A) in the claim 1, it would have been prima facie obvious to combine the immune activation properties of ERGO taught by Yoshida in the infection treatment method of Repine in order to enhance host immune response to microbial infection. Accordingly, the claimed modification would have provided the advantages of improving host immune response against microbial infection by stimulating immune cell activity associated with antimicrobial defense mechanisms, yielding predictable results. (see MPEP 2141)
With respect to claims 2 and 15, the claims recite ERGO compositions comprising L-ergothioneine comprises 0% D-ergothioneine, 0% nucleic acids, 0% amino acids, and less than 2% total impurities.
Repine teaches administration of ERGO in pharmaceutically acceptable forms suitable for therapeutic use (page 5 lines 30-34). Repine further teaches that ERGO compounds may undergo final isolation and purification during preparation, including preparation of pharmaceutical acceptable salts during the final isolation and purification od the compounds (page 10 lines 13-16). Repine continually teaches that “ERGO is made in relatively few organisms, notably Actinobacteria, Cyanobacteria, and certain fungi. ERGO is available commercially in purified form.” (page 5 lines 11-13). Yoshida also demonstrates that ERGO is obtained from a commercial supplier (i.e., Tetrahedron, Paris, France, Cell isolation and culture section), indicating that purified ERGO materials were conventionally available and used in the art. The instant specification is indicated “Various sources of L-ergothioneine are marketed commercially, including a mushroom extract marketed by Blue California (Tomas, RSM, CA) and a chemically synthesized compound manufactured by Tetrahedron, Vincennes, France (US 8,399,500 B2)” (paragraph [0004]).
Repine does not explicitly disclose ERGO compositions having less than 2% total impurities. However, it would have been prima facie obvious to one having ordinary skill in the art to further ERGO using known purification techniques in order to obtain a higher purity pharmaceutical product suitable for human administration. Optimization of impurity levels in a known pharmaceutical compound through purification constitutes routine optimization of a results-effective variable and routine experimentation. Such routine purification would reasonably have resulted in ERGO compositions having minimal impurities, including impurity levels of less than 2%. (see MPEP 2144.05)
With respect to claims 3, 7, 12 and 16, the claims recite that the method is used for improving the mammal’s immune response to a microbial infection, and the microbial infection is selected from the group consisting of bacterial infections, viral infections, fungal infections, and protozoal infections, and the mammal is a human.
Repine teaches administering ERGO for treatment of the microbial infection including an antibiotic-resistant bacterial infection in a mammal that is including a human or non-human (claim 8, 14, and page 6, lines 1-3).
Applying KSR example rationale (C), it would have been prima facie obvious to apply the antimicrobial treatment method of Repine and other microbial infections such as viral fungal and protozoal infections because these pathogens represent well known classes of microorganisms responsible for infectious disease. Extending the treatment of microbial infection to additional pathogen classes would have been a predictable use of the prior art method, yielding predictable results. (see MPEP 2141)
.
With respect to 4-6, 8, 10 and 17-19, the claims recite specific dosage amounts and oral dosage forms of ERGO, including ranges such as 1-100 mg/day, 1-50 mg/dosage form, and specific amounts such as about 20 mg or about 25 mg for an oral dosage form.
Repine teaches the daily therapeutically effective or prophylactically effective amount of the ERGO administered to a patient in single or divided doses range from about 0.01 to about 750 milligram per kilogram of body weight per day (mg/kg/day) (page 15, lines 7-9). For example, for typical adult body weights (i.e., 70 kg), a daily dose of the instant claimed 1-100 mg/day translates to approximately 0.01-1.4 mg/kg/day, which lies within the range of 0.01-750 mg/kg/day. Repine further teaches ERGO is administered by a route selected from oral, topical, buccal, intravenous, subcutaneous, intramuscular, intradermal, and intrathecal administration, and a composition comprising ERGO and another anti-microbial and/or anti-inflammatory agent, and optionally one or more excipients, in a pharmaceutical carrier for the treatment of a condition related to microbial infections or inflammation wherein the ERGO comprises at least 50% (w/v) or at least 90% (w/v) of the composition. (claims 53, and 60-62)
The claimed dose ranges and dosing regimens overlap with those disclosure by Repine. Where the claimed range overlaps with a range disclosed in the prior art, the claimed subject matter is prima facie obvious.
With respect to claims 9, 11, 13, 14 and 20, the claims recite that a method of inducing the production of reactive oxygen species in polymorphonuclear leukocytes in a mammal comprising orally administering to the mammal an effective amount of L-ergothioneine or a pharmaceutically acceptable salt thereof, and the mammal is a human.
Repine teaches orally administering ERGO to treat microbial infection for the mammal that is including a human or non-human, as required in claim 20 (claim 8, 14, and page 6, lines 1-3). Repine further teaches solid dosage forms for oral administration include capsules, tablets, pills, powders and granules, as required in claim 9 (page 10, lines 25-26).
Yoshida teaches that ERGO activates immune cells and enhances innate immune responses involved in pathogen defense. Because polymorphonuclear leukocytes generate reactive oxygen species during immune activation as part of the host antimicrobial defense, the immune activating effects of ERGO suggest enhancement of oxidative antimicrobial mechanisms (introduction section). Reactive oxygen species production by polymorphonuclear leukocytes during phagocytosis is a well-established antimicrobial defense mechanism in innate immunity.
Applying KSR example rationale (A), it would have been prima facie obvious to administer ERGO to induce oxidative antimicrobial response associated with immune activation because activation of innate immune cells during pathogen clearance antimicrobial treatment method of Repine with the immune activation taught by Yoshida would have predictably resulted in induction of oxidative antimicrobial responses in immune cells. (see MPEP 2141)
Conclusion
Claims 1-20 are rejected.
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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/SEONG JONG KIM/ Examiner, Art Unit 1621
/CLINTON A BROOKS/ Supervisory Patent Examiner, Art Unit 1621