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 .
Current Status
This action is responsive to the amended claims of 07/17/2026. Claims 1-14 and 20-27 are pending. Claims 20-27 are new. Claims 1-8 and 10-14 are withdrawn.
Claims 9 and 20-27 have been examined on the merits.
Election/Restrictions
Applicant’s election without traverse of Group II (claims 9 and 20-27) and species Formula (I) (i.e., L-ergothioneine) and DAF-16 in the reply filed on 0717/2026 is acknowledged.
A search for the elected species retrieved prior art (see SEARCH 5-6 of the attached search notes). Thus, the search will not be unnecessarily extended to further species in this action, per Markush search practice.
The elected species read on claims 9 and 20-27.
Claims 1-8 and 10-14 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/17/2026.
Priority
The effective filing date is 08/09/2021 for claims 9, 20-25, and 27.
The effective filing date is 02/09/2024 for claim 26.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 05/08/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Applicant is advised that should claim 22 be found allowable, claim 25 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m). In this case, claims 22 and 25 are exact duplicates.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 9 and 20-27 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
MPEP 2163(I) states “The written description requirement has several policy objectives. "[T]he ‘essential goal’ of the description of the invention requirement is to clearly convey the information that an applicant [inventor] has invented the subject matter which is claimed." In re Barker, 559 F.2d 588, 592 n.4, 194 USPQ 470, 473 n.4 (CCPA 1977). Another objective is to convey to the public what the applicant claims as the invention. See Regents of the Univ. of Cal. v. Eli Lilly, 119 F.3d 1559, 1566, 43 USPQ2d 1398, 1404 (Fed. Cir. 1997), cert. denied, 523 U.S. 1089 (1998). "The ‘written description’ requirement implements the principle that a patent must describe the technology that is sought to be patented; the requirement serves both to satisfy the inventor’s obligation to disclose the technologic knowledge upon which the patent is based, and to demonstrate that the patentee [inventor] was in possession of the invention that is claimed." Capon v. Eshhar, 418 F.3d 1349, 1357, 76 USPQ2d 1078, 1084 (Fed. Cir. 2005).”
Factors considered in making the determination as to whether the artisan would recognize that the applicant was in possession of the claimed invention as a whole at the time of filing include: (a) Actual reduction to practice; (b) Disclosure of drawings or structural chemical formulas; (c) Sufficient relevant identifying characteristics such as: (i) Complete structure, (ii) Partial structure, (iii) Physical and/or chemical properties or (iv) Functional characteristics when coupled with a known or disclosed correlation between function and structure; (d) Method of making the claimed invention; (e) Level of skill and knowledge in the art and (f) Predictability in the art.
The Instant Disclosure:
Claims 9 and 20-27 are broadly drawn to a method of administering any possible “pharmaceutically acceptable prodrug” or “pharmaceutically active metabolite” of Formula (I) wherein neither of “prodrug” nor “metabolite” are limited to any defined structural genus. The claimed methods require the “prodrug” and “metabolite” to have pharmacological utility: activation of DAF-16/FOXO genes in general populations (instant claims 9, 20-21, and 27) and those diagnosed with premature ageing diseases (instant claims 22-25) and/or stroke (instant claim 26). This lack of structural definition does not allow the artisan to envisage the “prodrugs” and “metabolites” which are part of the invention (see Factors (b) and (c) above).
The specification does not define either term “prodrug” or “metabolite.” Further, the specification does not provide any synthetic schemes for preparation of prodrugs or metabolite of Formula (I) nor any in vitro or in vivo examples of administration of a prodrug/metabolite thereof. Thus, it is unclear what compounds Applicant considers prodrugs or metabolites of Formula (I), let alone “pharmaceutically acceptable” or “pharmaceutically active” forms of prodrug and metabolite. Thus, Factors (a) and (d), above, are not met.
MPEP 2163(II)(A)(2) states “The disclosure of an element may be critical where those of ordinary skill in the art would require it to understand that inventor was in possession of the invention… Amgen, Inc. v. Chugai Pharm.Co., Ltd., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) ("it is well established in our law that conception of a chemical compound requires that the inventor be able to define it so as to distinguish it from other materials, and to describe how to obtain it").” After review of the specification and claims, the Examiner finds that Applicants have not structurally defined or described how to obtain the prodrug or metabolite of Formula (I). Thus, it has not been demonstrated that the Applicant was in possession of the invention that is claimed (i.e., use any and all prodrugs or metabolites of Formula (I)). Moreover, “prodrug” and “metabolite” attempt to encompass compounds which have not yet been discovered and/or those with uncharacterized metabolic pathways.
Level of Skill and Knowledge in the Art:
The relative skill of those in the art is high, generally that of an M.D. or Ph.D. The artisan using Applicant’s invention would generally be a synthetic chemist and/or health practitioner with several years of professional experience. However, this factor is outweighed by the unpredictable nature of the pharmaceutical art. It is noted that each embodiment of the invention is required to be individually assessed for physiological activity by in vitro or in vivo screening to determine which prodrugs/metabolites exhibit the desired pharmacological activity.
HAN (Han, H., AAPS PharmsciTech., 2000, 2, 1-11) describes that some prodrug forms are not chemically or structurally related to their active form, for example, both glucose
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and hypoxanthine
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are prodrug forms of hydrogen peroxide
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(Pg. 5 Table 1). In view of HAN and the instantly-undefined nature of “prodrug” and “metabolite,” the artisan would not have sufficient guidance as to what a pharmaceutically active “prodrug” or “metabolite” of Formula (I) encompasses.
FDA (FDA Drug Safety Communication: Reduced Effectiveness of Plavix (Clopidogrel) in Patients Who are Poor Metabolizers of the Drug, 2017, pp. 1-2) states that a prodrug, Plavix, was found to have reduced effectiveness in patients who are poor metabolizers of Plavix leading to reduced effectiveness (Pg. 1 P4). As a result, predictability of “prodrug” or “metabolite” efficacy in the art is understood as a challenge facing the artisan.
ZHANG (Zhang & Tang, Acta Pharmaceutica Sinica B, 2018, 8(5), 721-732) discloses, in majority of cases, sites of metabolism are unpredictable and metabolites could have no pharmacological activity (Pg. 725 Right col. ¶2). Thus, the structure and efficacy of a “metabolite” of Formula (I) would be unpredictable to the artisan.
Without guidance as to what structures correspond to viable prodrugs or metabolites of the Formula (I), Factors (e) and (f) are not met.
Conclusions:
Due to the breadth of “prodrug” and “metabolite” of Formula (I), the lack of direction given in the claims/specification regarding embodiments of such which show the desired activity, and the challenges in the art, the artisan would not be able to immediately envisage the breadth of prodrug or metabolite of Formula (I).
Methods of making compounds, in general, are known to the artisan, however the instant disclosure does not inform the artisan of what combination of elements are present in the instant prodrugs/metabolites and if a prodrug/metabolite possesses the required pharmacological activity. As such, the instant specification fails to provide guidance to overcome the complexity and difficulties known to the artisan, as discussed above. Accordingly, the specification fails to provide adequate written description for the genus of the claims and does not reasonably convey to the artisan that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
Thus, claims 9 and 20-27 are rejected as lacking written description for the full scope of “prodrug” and “metabolite” of Formula (I). To overcome this rejection, Applicant is encouraged to strike prodrug and metabolite from the claims.
Claim Rejections - 35 USC § 102
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 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.
Claims 9, 20-23, and 25-27 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by ROTH (WO 2008/089439) as evidenced by: SUN (Sun, X. et al., frontiers in Pharmacology, 8, 2017, 1-8), D’ONOFRIO (D’Onofrio, N. et al., Antioxidants & Redox Signaling, 28(8), 2018, 711-732), and SINGH (Singh, C.K. et al., Antioxidants & Redox Signaling, 28(8), 2018, 643-661).
ROTH teaches methods and compositions involving sirtuin-modulating active compounds used in the treatment of diseases and administered to cells, tissues, organs, organisms, animals, mammals, and humans in vivo or in vitro (Pg. 3 ¶3). The disease is progeria (i.e., Hutchinson-Gilford progeria syndrome) or stroke (Pg. 5 ¶1-3). The sirtuin-modulating compound is administered intravenously, subcutaneously, intratumorally, orally, intrarectally, or transdermally (Pg. 7 last ¶ & Pg. 254-255 bridge ¶). The sirtuin-modulating compound is a sirtuin-activating compound L-ergothioneine (Pg. 94 second to last ¶). Note, L-ergothioneine is the name for the compound of instant Formula (I).
SUN discloses there are four FOXO genes (1, 3, 4, & 6) in mammals and one FOXO gene in invertebrates called DAF-16 (Pg. 2 Left col. ¶4); sirtuin-1 (SIRT1) deacetylates & activates DAF-16/FOXO (Pg. 6 Left col. ¶1).
D’ONOFRIO discloses SIRT1 activity positively regulates activity of FOXO genes (Pg. 714 Fig. 2) including FOXO1 (Pg. 712 Left col. ¶3) and FOXO3 (Pg. 713 Right col. ¶3). The antioxidant ergothioneine increases SIRT1 activity (Pg. 717-718 bridge ¶; Pg. 723 Left col. ¶3).
SINGH also discloses SIRT1 positively regulates FOXO genes (Pg. 647 Fig. 2) and ergothioneine increases SIRT1 activity (Pg. 650 Right col. ¶2).
MPEP 2112.01.I. recites “if a prior art device, in its normal and usual operation, would necessarily perform the method claimed, then the method claimed will be considered to be anticipated by the prior art device. When the prior art device is the same as a device described in the specification for carrying out the claimed method, it can be assumed the device will inherently perform the claimed process.”
Here, the prior art device is ergothioneine which is the same as the instant device (Formula (I)). The evidentiary references show it is a known property of ergothioneine to activate SIRT1 and SIRT1 activates FOXO/DAF-16 genes. Thus, during its normal and usual operation of administration to a biological subject for treatment of progeria or stroke, ergothioneine would necessarily activate SIRT1 and cause downstream activation of FOXO/DAF-16. Thus, the methods of ROTH would necessarily increase the level of activity of DAF-16/FOXO in the cell/subject to which the ergothioneine was administered.
Claims 9, 21-23, and 25 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by LEWIS (US 2016/0106654) as evidenced by: D’ONOFRIO (D’Onofrio, N. et al., Antioxidants & Redox Signaling, 28(8), 2018, 711-732) and SINGH (Singh, C.K. et al., Antioxidants & Redox Signaling, 28(8), 2018, 643-661).
LEWIS teaches exposure of mammalian skin to sunlight/UV wavelengths can result in DNA damage and premature aging of the skin (Pg. 1 ¶5). LEWIS teaches a composition comprising a sunscreen agent and a protein protective antioxidant wherein the antioxidant is L-ergothioneine (Pg. 1 claims 1 & 4-9). The composition is topically applied to human skin to improve skin health (Pg. 8 claim 22). The composition was tested on human skin (Pg. 6 Example 1) and the L-ergothioneine protected the skin against protein carbonylation and repaired DNA damage (Pg. 5 ¶41-42 & Tables 2-3). Thus, the composition comprising ergothioneine treats premature ageing of skin by contacting ergothioneine to a cell/human.
D’ONOFRIO discloses SIRT1 activity positively regulates activity of FOXO genes (Pg. 714 Fig. 2), FOXO1 (Pg. 712 Left col. ¶3), and FOXO3 (Pg. 713 Right col. ¶3); the antioxidant ergothioneine increases SIRT1 activity (Pg. 717-718 bridge ¶; Pg. 723 Left col. ¶3).
SINGH also discloses SIRT1 positively regulates FOXO genes to activate DNA repair (Pg. 647 Fig. 2) and ergothioneine increases SIRT1 activity (Pg. 650 Right col. ¶2).
See the MPEP 2112.01.I. quote above. Here, the prior art device is ergothioneine which is the same as the instant device (Formula (I)). The evidentiary references show it is a known property of ergothioneine to activate SIRT1 and SIRT1 activates FOXO genes. Thus, during its normal and usual operation of administration to a biological subject for treatment of premature skin aging caused by sunlight/DNA damage, ergothioneine would necessarily activate SIRT1 and cause downstream activation of FOXO. Thus, the method of LEWIS would necessarily increase the level of activity of FOXO in the cell/human to which the ergothioneine-composition is administered.
Further, the property of ergothioneine repairing DNA damage taught by LEWIS (Pg. 5 Table 3) aligns with the properties of ergothioneine to activate SIRT1-FOXO and SIRT1 to activate FOXO DNA repair disclosed by the evidentiary reference SINGH.
Claims 9, 20-21, and 26-27 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by BEELMAN (WO 2007/106859) as evidenced by: D’ONOFRIO (D’Onofrio, N. et al., Antioxidants & Redox Signaling, 28(8), 2018, 711-732) and SINGH (Singh, C.K. et al., Antioxidants & Redox Signaling, 28(8), 2018, 643-661).
BEELMAN teaches a method of treating stroke comprising administering to an animal suffering from stroke an effective amount of L-ergothioneine orally, enterally, subcutaneously, or systemically (Pg. 50 claims 9-10). The L-ergothioneine is administered to a human in a dose of 25 ug – 10 g (Pg. 20 Lines 5-14). Further, the L-ergothioneine was administered to cells in vitro and resulted in increased viability of cells (Pg. 42-44 Example 4).
D’ONOFRIO discloses SIRT1 activity positively regulates activity of FOXO genes (Pg. 714 Fig. 2), FOXO1 (Pg. 712 Left col. ¶3), and FOXO3 (Pg. 713 Right col. ¶3); the antioxidant ergothioneine increases SIRT1 activity (Pg. 717-718 bridge ¶; Pg. 723 Left col. ¶3).
SINGH also discloses SIRT1 positively regulates FOXO genes (Pg. 647 Fig. 2) and ergothioneine increases SIRT1 activity (Pg. 650 Right col. ¶2).
See the MPEP 2112.01.I. quote above. Here, the prior art device is ergothioneine which is the same as the instant device (Formula (I)). The evidentiary references show it is a known property of ergothioneine to activate SIRT1 and SIRT1 activates FOXO genes. Thus, during its normal and usual operation of administration to: 1) a cell in vitro (instant claims 9, 20, & 27) or 2) a human for treatment of stroke (instant claims 9, 21, & 26-27), ergothioneine would necessarily activate SIRT1 and cause downstream activation of FOXO. Thus, the methods of BEELMAN would necessarily increase the level of activity of FOXO in the cell/human to which the ergothioneine is administered.
Claims 9 and 20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by D’ONOFRIO (D’Onofrio, N. et al., Antioxidants & Redox Signaling, 28(8), 2018, 711-732) evidenced by BALESTRIERI (Balestrieri, M.L. et al., Free Radical Biology and Medicine, 96, 2016, 211-222).
D’ONOFRIO teaches in endothelial cells (EC) SIRT1 regulates cell physiology by modulating FOXO1 (Pg. 712 Left col. ¶3) and SIRT1 also regulates FOXO3 function (Pg. 713 Right col. ¶3). The SIRT1 positively regulates the FOXO genes (Pg. 714 Fig. 2); i.e., the activation of SIRT1 increases activity of FOXO genes. Ergothioneine inhibits downregulation of SIRT1 in EC resulting in increased activity of SIRT1 (Pg. 717-718 bridge ¶). D’ONOFRIO cites to BALESTRIERI regarding the action of ergothioneine on ECs. BALESTRIERI discloses the ergothioneine experiments were performed on EC’s in vitro (Pg. 213 Right col. Sect. 2.2-2.3).
Thus, contacting a cell, in vitro, with ergothioneine (instant Formula (I)) increases the level of activity of FOXO genes including FOXO1 and FOXO3.
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.
Claims 9 and 21-24 are rejected under 35 U.S.C. 103 as being unpatentable over:
ROTH (WO 2008/089439)
as evidenced by:
D’ONOFRIO (D’Onofrio, N. et al., Antioxidants & Redox Signaling, 28(8), 2018, 711-732) and SINGH (Singh, C.K. et al., Antioxidants & Redox Signaling, 28(8), 2018, 643-661)
as applied to claims 9 and 21-23 above (¶16), and further in view of:
CHEN (WO 2021/158601; effectively filed Feb. 2021 – international filing date)
and in view of:
TRIGUEROS-MOTOS (Trigueros-Motos, L. et al., Frontiers in Bioscience, S3, 2011, 1285-1297).
The instant claims are drawn to administration of L-ergothioneine to activate FOXO genes in a human diagnosed with progeria; the ergothioneine is administered in a dosage of 5 mg to 200 mg daily.
Determining the Scope and Contents of the Prior Art:
ROTH teaches methods of instant claims 9 and 21-23, as evidenced by D’ONOFRIO and SINGH (¶16). ROTH further teaches the effective amount of ergothioneine can be determined by comparison between dosages (Pg. 229 ¶3) – the amount will vary depending on the subject’s size, the dosage form, and the route of administration (Pg. 255 ¶2).
CHEN teaches a method of treating an oxidative stress-related disease comprising administering ergothioneine (Pg. 40 claim 26) wherein the disease is associated with premature ageing (Pg. 40 claim 31) and the ergothioneine is administered at a dose of about 5-25 mg/day (Pg. 40 claims 36-37).
TRIGUEROS-MOTOS teaches Hutchinson-Gilford Progeria Syndrome (HPGS/progeria) is a disease characterized by premature ageing (Pg. 1285 Abstract). Progeria shares features with normal ageing including evidence of oxidative stress (Pg. 1290 Left col. ¶2).
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
ROTH does not teach the dosage of ergothioneine is 5 mg – 200 mg. D’ONOFRIO and SINGH do not teach administration of ergothioneine to a human with a premature ageing disease/progeria/HPGS.
CHEN does not teach the premature ageing disease is progeria/HPGS.
TRIGUEROS-MOTOS does not teach treatment of HPGS with ergothioneine.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development of a method useful for treatment of progeria and possesses the technical knowledge necessary to make adjustments to the method to optimize/enhance the dosage regimen. Said artisan has also reviewed the problems in the art regarding ergothioneine dosages for premature ageing diseases and understands the solutions that are widely-known in the art.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
The instant claims are prima facie obvious in light of the combination of ROTH (evidenced by D’ONOFRIO and SINGH), in view of CHEN, and further in view of TRIGUEROS-MOTOS.
The artisan would have a reasonable expectation of success in increasing the level of activity of FOXO genes (e.g., 1 & 3) by the method of ROTH since D’ONOFRIO and SINGH disclose a known property of ergothioneine is to increase activity of SIRT1 and SIRT1 positively regulates FOXO genes (D’ONOFRIO Pg. 714 Fig. 2, Pg. 712 Left col. ¶3, Pg. 713 Right col. ¶3, & Pg. 717-718 bridge ¶; SINGH Pg. 647 Fig. 2 & Pg. 650 Right col. ¶2).
Regarding claim 24, the artisan would have been motivated to optimize the dosage of ergothioneine for the premature ageing disease progeria/HPGS.
MPEP 2144.05(II)(A) provides guidance about the routine optimization of prior art conditions: "Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.").”
In the instant case, CHEN teaches dosages of 5-25 mg/day (Pg. 40 claims 36-37) which falls within the instantly claimed ~5-200 mg/day. Since ROTH teaches the effective amount of ergothioneine can be determined by comparison between dosages (Pg. 229 ¶3) and will vary depending on the subject’s size, the dosage form, and the route of administration (Pg. 255 ¶2), the artisan would recognize the dosage regimen as a result-effective variable, i.e., a variable that achieves a recognized result. Thus, the dosage is analogous to the “concentration or temperature” recited in the MPEP and may be optimized by routine experimentation. Absent any evidence demonstrating the contrary, the determination of the optimum or workable concentrations of ergothioneine would have been well within the practice of the artisan given the guidance of the prior art.
Moreover, Since CHEN teaches treatment of oxidative-stress related premature ageing disease with ergothioneine (Pg. 40 claim 26 & 31), and since TRIGUEROS-MOTOS teaches HPGS/progeria is a disease characterized by premature ageing (Pg. 1285 Abstract) and oxidative stress (Pg. 1290 Left col. ¶2), the artisan would be motivated to treat progeria with ergothioneine at the dosages taught by CHEN.
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.
Claim 9 is provisionally rejected on the ground of anticipatory nonstatutory double patenting as being unpatentable over claims 1, 4-13, and 22 of copending Application No. 17/904,977 (reference application) as evidenced by: SUN (Sun, X. et al., frontiers in Pharmacology, 8, 2017, 1-8), D’ONOFRIO (D’Onofrio, N. et al., Antioxidants & Redox Signaling, 28(8), 2018, 711-732), and SINGH (Singh, C.K. et al., Antioxidants & Redox Signaling, 28(8), 2018, 643-661). Although the claims at issue are not identical, they are not patentably distinct from each other.
The reference claims teach a method of treating a subject suffering from cardiovascular disease comprising administering the compound of Formula (I)
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or salt thereof at a dose of 10 ug/kg-100 mg/kg for at least 30 days and wherein the administration induces cardiomyocyte proliferation (ref. claim 1, 4-5, & 7-11). The method further comprising administering an antiarrhythmic agent (ref. claim 6) and wherein the cardiovascular disease is selected from a list of species thereof (ref. claims 12-13 & 22).
SUN discloses there are four FOXO genes (1, 3, 4, & 6) in mammals and one FOXO gene in invertebrates called DAF-16 (Pg. 2 Left col. ¶4); sirtuin-1 (SIRT1) deacetylates & activates DAF-16/FOXO (Pg. 6 Left col. ¶1).
D’ONOFRIO discloses, in endothelial cells, SIRT1 activity positively regulates activity of FOXO genes (Pg. 714 Fig. 2) including FOXO1 (Pg. 712 Left col. ¶3) and FOXO3 (Pg. 713 Right col. ¶3). The antioxidant ergothioneine increases SIRT1 activity (Pg. 717-718 bridge ¶; Pg. 723 Left col. ¶3).
SINGH also discloses SIRT1 positively regulates FOXO genes (Pg. 647 Fig. 2) and ergothioneine increases SIRT1 activity (Pg. 650 Right col. ¶2).
See the MPEP 2112.01.I. quote above. Here, the prior art device Formula (I) is the same as the instant device Formula (I). The evidentiary references show it is a known property of ergothioneine to activate SIRT1 and SIRT1 activates FOXO/DAF-16 genes in subjects. Thus, during its normal and usual operation of administration to treat cardiovascular diseases, ergothioneine would necessarily activate SIRT1 and cause downstream activation of FOXO/DAF-16. Thus, the methods of ‘977 would necessarily increase the level of activity of FOXO/DAF-16 in the subject to which Formula (I) is administered.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 9 and 20-27 are provisionally rejected on the ground of obviousness-type nonstatutory double patenting as being unpatentable over:
claims 1, 4-13, and 22 of copending Application No. 17/904,977 (reference application)
evidenced by:
SUN (Sun, X. et al., frontiers in Pharmacology, 8, 2017, 1-8), D’ONOFRIO (D’Onofrio, N. et al., Antioxidants & Redox Signaling, 28(8), 2018, 711-732), and SINGH (Singh, C.K. et al., Antioxidants & Redox Signaling, 28(8), 2018, 643-661),
as applied to claim 9 (above ¶25), further in view of:
NABEL (Nabel, E. G., Transactions of the American Clinical and Climatological Association, 123, 2012, 221-226)
and in view of
ROTH (WO 2008/089439).
The instant claims are drawn to administering Formula (I) to a human diagnosed with Hutchinson-Gilford Progeria Syndrome and/or stroke in order to increase activity level of FOXO/DAF-16 genes.
Determining the Scope and Contents of the Prior Art:
The reference Application no. ‘977, as evidenced by SUN, D’ONOFRIO, and SINGH, teaches the method of instant claim 9 (¶25).
NABEL teaches human Hutchinson-Gilford Progeria Syndrome (HGPS) patients face premature death due to heart attack and/or stroke (Pg. 221 ¶2); i.e., cardiovascular disease. The pathophysiology of cardiovascular disease in HGPS comprises loss of contractile vascular smooth muscle cells (Pg. 222 ¶3-4).
ROTH teaches treatment of progeria (HGPS) or stroke (Pg. 5 ¶1-3) by administering L-ergothioneine (Pg. 94 second to last ¶) intravenously, subcutaneously, intratumorally, orally, intrarectally, or transdermally (Pg. 7 last ¶ & Pg. 254-255 bridge ¶). The ergothioneine is administered to cells in vitro and/or humans in vivo (Pg. 3 ¶3). ROTH further teaches the effective amount of ergothioneine can be determined by comparison between dosages (Pg. 229 ¶3) – the amount will vary depending on the subject’s size, the dosage form, and the route of administration (Pg. 255 ¶2).
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
The reference Application no. ‘977 does not teach the subject is a human with premature ageing/HGPS or stroke, the instant dosages, or in vitro cell conditions.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development of a method useful for treatment of HGPS-related cardiovascular disease/stroke and possesses the technical knowledge necessary to make adjustments to the method to optimize/enhance the outcomes. Said artisan has also reviewed the problems in the art regarding premature ageing and cardiovascular diseases and understands the solutions that are widely-known in the art.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
The instant claims are prima facie obvious in light of the combination of reference Application no. ‘977 (evidenced by SUN, D’ONOFRIO, and SINGH) in view of NABEL and in view of ROTH.
Regarding claims 9, 21-23, and 25-26, The artisan would be motivated to utilize the method of reference Application no. ‘977 to treat HPGS-related cardiovascular disease, since the method of ‘977 induces proliferation of cardiomyocytes (ref. claim 1) and since NABEL teaches HPGS-related cardiovascular disease is characterized by loss of heart muscle cells (Pg. 222 ¶3-4), i.e., loss of cardiomyocytes. Since the method of ‘977 increases cardiomyocyte population, the artisan would have a reasonable expectation of success in treating cardiovascular disease in a human subject diagnosed with HPGS. The artisan would also have motivation, with a reasonable expectation of success, to treat cardiovascular disease in an HPGS patient diagnosed with stroke by the same method since stroke is associated with HPGS and related cardiovascular disease as recognized by NABEL (Pg. 221 ¶2).
Regarding claim 24, see MPEP 2144.05(II)(A) quotation above. The reference Application no. ‘977 teaches dosages of ~0.6-6000 mg (ref. claim 1 - for a ~60 kg human) which overlaps with the instant dosages (5-200 mg). Since ROTH teaches dosages can be optimized based on patient and dosage form parameters (Pg. 229 ¶3; Pg. 255 ¶2), the artisan would recognize the dosage as a results-effective variable. This is equivalent to the “concentration” recited in the MPEP and may be optimized by routine experimentation. Absent any evidence to the contrary, the optimization of the dosage of ergothioneine would be well within the practice of the artisan.
Regarding claim 27, the instant administration routes would be obvious since ROTH teaches such routes are useful for administration of ergothioneine to HPGS/stroke patients (Pg. 7 last ¶ & Pg. 254-255 bridge ¶).
Regarding claim 20, since ROTH teaches administration to cells in vitro (Pg. 3 ¶3) and optimization of ergothioneine through experimentation (Pg. 229 ¶3; Pg. 255 ¶2), the artisan would be motivated to administer the ergothioneine to a cell in vitro as a starting point for dosage optimization.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Claims 9 and 20-27 are rejected.
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/S.E.B./Examiner, Art Unit 1625
/JOHN S KENYON/Primary Patent Examiner, Art Unit 1625
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