DETAILED ACTION
All rejections and objections not mentioned below have been withdrawn.
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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 03/23/2026 has been entered.
Priority
Acknowledgment is made of applicant’s claim for priority in parent Application No. 62/981,204, filed on 2/25/2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/25/2022 is being considered by the examiner.
Claim Interpretation
Since the specification does not indicate what is specifically required to provided “wherein the administration improves cardiac function by inducing cardiomyocyte proliferation sufficient to increase cardiac contractile force or increase the thickness of the myocardium” other than the generic method of claim 1 the claims are interpreted as any method of claim 1 would have these effects inherently. This is the broadest reasonable interpretation of the claims.
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, 4-13, and 22 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.
The term “about” in claims 1, 4-13, and 22 is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The term about is a relative term and one of ordinary skill in the art would not know the extent of the scope of the claim. For example about could encompass ±10, ±20, ±30, etc. The specific does not provide a definition for the term “about” because paragraph [0031] states, “The term "about" as used herein generally refers to plus or minus 10% of the indicated number”, only a general rule that is not cover all cases.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 7 and 9-10 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claims 7 and 9-10 all depend on claim 1 and do not further limit the scope of claim 1 because all the limitations listed in these claims are recited in claim 1.. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Applicant is advised that should claims 1 be found allowable, claims 7 and 9-10 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).
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.
Claim(s) 1, 4-5, 7-11 is/are rejected under 35 U.S.C. 102((a)(1)) as anticipated by Li ( Li et al., Uptake and Protective Effects of Ergothioneine in Human Endothelial Cells, J Pharmacol Exp Ther 350:691–700, September 2014).
The reference Li teaches “In summary, ergothioneine is taken up by endothelial cells via OCTN-1, where the compound then protects against oxidative stress, curtailing endothelial dysfunction”(abstract) and “Endothelial dysfunction is associated with a number of cardiovascular disease processes, including hyper tension, atherosclerosis, heart failure, coronary syndrome, and stroke (Fèlètou and Vanhoutte, 2006)”(page 691). The instant application defines cardiovascular disease as “Cardiovascular disease or disorder or condition is intended to include all disorders
characterized by insufficient, undesired or abnormal cardiac function, e.g., arrhythmia, ischemic
heart disease…”[0046]. Thus any abnormal cardiac function such as endothelial dysfunction would be considered a cardiovascular disease.
PNG
media_image1.png
157
285
media_image1.png
Greyscale
The reference Li teaches “Endothelium-Dependent Relaxations. To study endothelium-dependent relaxations, rat basilar arteries were contracted with the thromboxane-prostanoid receptor agonist U46619 (100 nM) and exposed to increasing concentrations of acetylcholine. Ergothioneine itself had no effect on acetylcholine-induced relaxations. Preincubation with pyro gallol (100 mM), hypoxanthine (1 mM) plus xanthine oxidase (10 mU), or glucose (25 mM) impaired the acetylcholine induced relaxations (Fig. 9). This impairment in relaxation was inhibited by ergothioneine in a concentration-dependent manner, and this effect was comparable to that of tiron (10 mM). Streptozotocin-induced diabetes resulted in a blunting of the maximal relaxation by acetylcholine of the basilar artery to 33%(Fig.10). Chronic treatment with ergothioneine(100 or 1000mg/kg per day) did not affect the response to acetylcholine of basilar arteries of control rats. Ten and 100 mg/kg per day of ergothioneine also had no significant effect on acetylcholine induced relaxations in preparations of streptozotocin-treated rats. However, when the streptozotocin-treated rats were fed with a higher dosage of ergothioneine (1000 µg/kg per day) for 6 weeks, the maximal relaxation by acetylcholine averaged 73%(Fig. 10). This effect was significantly greater than that of vitamin C (1000 mg/kg per day) and comparable to that of apocynin (16 mg/kg per day) (Fig. 10)” (page 694) and “Consistent with earlier work on endothelial dysfunction, the present study shows that relaxations by the endothelium dependent vasodilator acetylcholine (Furchgott and Zawadzki, 1980) were dampened by ROS producers (pyrogallol, hypoxanthine/ xanthine oxidase) (Abrahamsson et al., 1992; Kamata et al., 2006) and hyperglycemic conditions (25 mM glucose in vitro, streptozotocin-induced diabetes in vivo) (Pieper et al., 1995; Guoetal., 2000; Leo et al., 2011). This oxidative stress–associated impairment of relaxations was prevented by ergothioneine. Importantly, ergothioneine was more potent than vitamin C in protecting the endothelial integrity and vascular function, reflecting the potential beneficial effects of the substance in regard to vascular health. Ergothioneine has long been recognized as an antioxidant amino acid present in food (especially in mushrooms) (Kawano et al., 1982). The compound is rapidly cleared from the circulatory system and retained in the body with minimal metabolism (Mayumi et al., 1978). The absence of toxicity, high potency, and broad spectrum antioxidant properties, together with the high water solubility and stability at physiologic pH, make ergothioneine, especially when compared with existing conventional antioxidants, a very attractive candidate for protecting endothelial cells against oxidative stress and, thus, for the treatment and/or prevention of oxidative stress associated cardiovascular diseases”(page 699).
Since the specification does not indicate what is specifically required to provided “wherein the administration improves cardiac function by inducing cardiomyocyte proliferation sufficient to increase cardiac contractile force or increase the thickness of the myocardium” other than the generic method of claim 1 the claims are interpreted as any method of claim 1 would have these effects inherently. This is the broadest reasonable interpretation of the claims.
This anticipates claims 1, 4-5, 7-11.
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.
Claim(s) 1, and 12-13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Li ( Li et al., Uptake and Protective Effects of Ergothioneine in Human Endothelial Cells, J Pharmacol Exp Ther 350:691–700, September 2014) in view of Matsuzawa(Matsuzawa et al., Age‐Dependent Predictive Value of Endothelial Dysfunction for Arrhythmia Recurrence Following Pulmonary Vein Isolation, Journal of the American Heart Association, Volume 5, Issue 9, September 2016).
The reference Li has been discussed supra (and is incorporated herein by reference) and does not disclose the specific diseases of claims 12-13.
The reference Matsuzawa teaches “Atrial fibrillation (AF) is the most common type of sustained cardiac arrhythmia encountered in clinical practice and is associated with an increased risk of all-cause mortality and morbidity including stroke, heart failure, dementia, embolic events, hospitalization, and impaired quality of life”(page 1) and “Our findings imply that endothelial dysfunction might not only result from AF risk factors including hypertension but also directly cause AF”(page 10).
This helps to teach claims 12-13.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified Li with Matsuzawa because Li teaches curtailing endothelial dysfunction and Matsuzawa suggests endothelial dysfunction can cause AF. One have a reasonable expectation of success because ergothioneine was shown to treat endothelial dysfunction and one would be motivated to do so because ergothioneine’s absence of toxicity, high potency, and broad spectrum antioxidant properties, together with the high water solubility and stability at physiologic pH.
Claim(s) 1, and 6 is/are rejected under 35 U.S.C. 103 as being unpatentable over Li ( Li et al., Uptake and Protective Effects of Ergothioneine in Human Endothelial Cells, J Pharmacol Exp Ther 350:691–700, September 2014) in view of Matsuzawa(Matsuzawa et al., Age‐Dependent Predictive Value of Endothelial Dysfunction for Arrhythmia Recurrence Following Pulmonary Vein Isolation, Journal of the American Heart Association, Volume 5, Issue 9, September 2016) further in view of Trujillo (Trujillo et al., Antiarrhythmic Agents Drug Interactions of Clinical Significance, Drug Safety 2000 Dec; 23 (6): 509-532).
The reference Li and Matsuzawa has been discussed supra (and is incorporated herein by reference) and does not disclose the use of the antiarrhythmic agent of claim 6.
The reference Trujillo teaches “The management of cardiac arrhythmias has grown more complex in recent years. Despite the recent focus on nonpharmacological therapy, most clinical arrhythmias are treated with existing antiarrhythmics”(abstract) and “A drug interaction is defined as a reaction between 2 or more drugs that acts to enhance or inhibit the predicted response. An interaction between 2 or more agents maybe either beneficial or harmful, depending on the desired outcome”(page 512).
This helps to teach claim 6.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified Li and Matsuzawa with Trujillo because Matsuzawa suggests endothelial dysfunction can cause AF and Trujillo teaches most clinical arrhythmias are treated with existing antiarrhythmics. One would be motivated to do so because a combination effect may enhance the treatment of antiarrhythmics and one would have a reasonable expectation of success because the drugs have suggested to treat cardiovascular diseases separately.
Claim(s) 1, 13 and 22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Li ( Li et al., Uptake and Protective Effects of Ergothioneine in Human Endothelial Cells, J Pharmacol Exp Ther 350:691–700, September 2014) in view of WATANABE (WATANABE et al., JP 2014223051 A (2014), previously provided) further in view of Shiekh ( Shiekh et al., Engineering Bioinspired Antioxidant Materials Promoting Cardiomyocyte Functionality and Maturation for Tissue Engineering Application, ACS Appl. Mater. Interfaces 2018, 10, 3260−3273, previously provided).
The reference Li has been discussed supra (and is incorporated herein by reference) and does not disclose the specific disease of claims 13 and 22.
The reference WATANABE teaches “The food containing the ergothioneine produced by the production method of the present invention or the composition of the present invention exhibits high antioxidant action, and therefore suppresses the production of active oxygen in the body, and the production of injuries due to active oxygen and the formation of lipid peroxides. And arteriosclerosis, hypertension, myocardial infarction, angina pectoris, cerebral infarction, cerebral hyperemia, diabetes, cancer, dementia, decreased immunity, metabolic syndrome and the like due to these can be expected”(page 5). This helps to teach claims 13 and 22.
The reference Shiekh teaches “Oxidative stress has been also implicated in progression of various diseases, such as chronic wound inflammation, cardiovascular diseases, such as atherosclerosis and myocardial infarction… ”(page 3260-3261).
This helps to teach claims 13 and 22.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified Li with WATANAB and Shiekh because Li teaches ergothioneine, especially when compared with existing conventional antioxidants is a very attractive candidate for protecting endothelial cells against oxidative stress and, thus, for the treatment and/or prevention of oxidative stress associated cardiovascular diseases and WATANAB suggests ergothioneine for treatment of myocardial infarction caused by oxidative stress and Shiekh teaches this is a cardiovascular disease. One would be motivated to do so to treat myocardial infarction with ergothioneine because of its absence of toxicity, high potency, and broad spectrum antioxidant properties, together with the high water solubility and stability at physiologic pH. One would have a reasonable expectation of success both because it is suggested to treat cardiovascular diseases and because it is an antioxidant.
Response to Arguments
Applicant’s arguments with respect to claim(s) 1, 4-13 and 22 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
The applicant also argues unexpected results. This argument was not considered persuasive because the unexpected results are not commensurate in scope with the claims. For example the claims cover all cardiovascular diseases not just the stroke model tested, the declaration does not provide any data to show that the unexpected results are over the full dose ranges or any time frame larger than 30 days, additionally no data is provided for combinations of all antiarrhythmic drugs under claim 6, or any combination of ingredients claimed due to the comprising language of claim 1. Thus the claims are not commensurate in scope with the unexpected results.
Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (Claims were directed to a process for removing corrosion at "elevated temperatures" using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100C). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F .2d 731,741,218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.). To establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range. In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960).
Additionally, claims 1, 4-5, 7-11 are rejected over 102 and thus cannot be overcome by unexpected results.
Conclusion
Claims 1, 4-13 and 22 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALISON AZAR HASTINGS whose telephone number is (703)756-4584. The examiner can normally be reached Mon-Thurs 7:30am-5pm EST Friday 7:30-4pm EST (every other Friday off).
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 (571) 270-5239. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/A.A.H./ Examiner, Art Unit 1627
/Kortney L. Klinkel/ Supervisory Patent Examiner, Art Unit 1627
Prosecution Insights