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 .
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.
Priority
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed applications, Application No. 62/858,302 and 62/884,592, fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The earliest support for a method of inducing quiescence of a cardiomyocyte appears in provisional application 62/933,962. Therefore, claims 106-124 are accorded an earliest priority date of 11/11/19.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Status
Claims 106-124 are currently pending and examined on the merits.
Claim Objections
Claim 107 is objected to because of the following informalities. Appropriate correction is required.
Claim 107 contains a misspelling of the term “upregulator”.
Applicant is advised that should claim 106 be found allowable, claims 115 and 120 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 115 purports to further limit claim 106 by including the limitation “wherein the quiescent cardiomyocyte is a mature cardiomyocyte”. This same limitation is present in claim 106. Similarly ). Claim 120 purports to further limit claim 106 by including the limitation “wherein the mature cardiomyocyte exhibits increased expression of REST and/or GATA4 as compared to an immature cardiomyocyte”, the same limitation as present in claim 106. Therefore, claims 115 and 120 are considered to be substantial duplicates.
Claim Interpretation
Claim 106 contains the limitation “wherein the mature cardiomyocyte exhibits increased expression of REST and/or GATA4 as compared to an immature cardiomyocyte”. This wherein clause recites the intended result of the method rather than requiring an additional, active method step be performed. MPEP § 2111.04 states “[c]laim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed” and that such a clause ‘"in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.” Therefore, since this claim only recite the results of the actively recited method steps (resultant marker expression pattern), art reading on the method of claim 106, necessarily results in the same expression profile in the absence of evidence to the contrary.
Claims 111-114, and 116-122 each contain a wherein clause which recites the intended result of the method of claim 106 rather than requiring an additional, active method step be performed. MPEP § 2111.04 states “[c]laim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed” and that such a clause ‘"in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.” Therefore, since these claims only recite the results of the actively recited method steps (resultant marker expression pattern, beating rate, or mature cardiomyocyte species), art reading on the method of claim 106, necessarily results in the same expression profile in the absence of evidence to the contrary.
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.
Claim 122 is 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.
Claim 122 contains the limitation “wherein the mature cardiomyocyte is an electrically mature cardiomyocyte, a contractility mature cardiomyocyte and/or a metabolically mature cardiomyocyte”. The use of “and/or” in this limitation renders it unclear which limitations are required, and which are optional. For examination purposes this limitation is interpreted as “wherein the mature cardiomyocyte is selected from at least one of the group consisting of an electrically mature cardiomyocyte, a contractility mature cardiomyocyte, and[[/or]] a metabolically mature cardiomyocyte
Claim Rejections - 35 USC § 103
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.
Claim(s) 106-107, 110-124 is/are rejected under 35 U.S.C. 103 as being unpatentable over Avolio et al., (2014) Ex vivo molecular rejuvenation improves the therapeutic activity of senescent human cardiac stem cells in a mouse model of myocardial infarction. Stem Cells, 32(9): 2373-2385 (hereinafter Avolio) in view of Khan et al., (2006) Rapamycin confers preconditioning-like protection against ischemia-reperfusion injury in isolated mouse heart and cardiomyocytes. Journal of Molecular and Cellular Cardiology, 41: pp. 256-264 (hereinafter Khan).
Regarding claims 106-107, 110, Avolio discloses methods of altering cardiac stem cell (CSC) senescence with rapamycin (Abstract). Avolio explains that mTOR inactivation converts cellular senescence into quiescence (Introduction). Avolio discloses that rapamycin treatment inhibits mTOR, thereby converting cellular senescence into quiescence (Introduction).
Avolio discloses isolating cardiomyocytes from pathological human hearts (Human CSC isolation and culture, Mouse model of MI). The pathological CSCs display typical senescence features (CSC isolated from failing hearts are senescent). Avolio discloses treating the isolated CSCs with between 1 nM to 1 µM rapamycin (Rapamycin and resveratrol cooperatively reduce E-CSC senescence). Avolio discloses that a combination of 10 nM rapamycin and resveratrol reduces the fraction of senescent CSCs without cytotoxic effects, attenuated TORC1 signaling activation, and modifies the secretory profile of the cells (Rapamycin and resveratrol cooperatively reduce E-CSC senescence, Fig. S5, S8).
Regarding claim 123-124, Avolio discloses administering CSCs treated with rapamycin and resveratrol to mouse model of myocardial infarction (In vitro pharmacologic pretreatment of senescent CSC improves their in vivo reparative potential). Avolio concludes that conditioning senescent CSCs with antiaging drugs restores reparative potential to levels observed with normal CSCs (Discussion). Avolio suggests that this allows for use of autologous therapeutic treatments and a reduces risks associated with other treatment modalities (Discussion).
Avolio does not disclose that the cells are cardiomyocytes.
Khan examines the protective effects of rapamycin in adult cardiomyocytes subjected to ischemia (Abstract). Khan discloses isolating adult, rat cardiomyocytes, culturing with between 0 to 100nM rapamycin, and subjecting the cells to simulated ischemia (2.6). Treated cardiomyocytes demonstrate improved viability, protection against apoptosis (3.4, Fig. 5-6). Khan concludes that rapamycin produces a protective effect in adult cardiomyocytes (Discussion, Conclusion).
As both Avolio and Khan are directed to methods of treating cardiac cells with rapamycin, it would be obvious to one of ordinary skill in the art that the references could be combined. A skilled artisan would understand that cardiomyocytes of Khan could be used in the methods of Avolio as a simple substitution of one type of cardiac cell responsive to rapamycin for another with a reasonable expectation that a portion of the cells would likewise transition into quiescence.
The combination is silent as to increased expression of REST and/or GATA4 as compared to an immature cardiomyocyte as recited in claim 106. The combination also does not disclose that the quiescent cardiomyocyte exhibits increased expression of certain quiescence markers, decreased expression of certain proliferative markers, increased expression of certain sarcomeric proteins, increased expression of certain ion channel genes, displays certain physical traits as recited in claims 111-122. However, the claims each contain a wherein clause that recites the intended result of the method rather than requiring an additional, active method step be performed. MPEP § 2111.04 states “[c]laim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed” and that such a clause ‘"in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.” Therefore, since these claims only recite the results of the actively recited method steps (resultant marker expression pattern), art reading on the method of claim 106, necessarily results in the same expression profile in the absence of evidence to the contrary, including unexpected results.
Further, the Patent and Trademark Office is not equipped to conduct experimentation in order to determine whether or not the quiescent cardiomyocyte produced by the methods of the prior art differ, and if so to what extent, from applicant’s quiescent cardiomyocytes. The prior art discloses quiescent cardiomyocytes which are similar to applicant’s quiescent cardiomyocytes for these reasons: the prior art discloses methods of contacting senescent cardiomyocytes with a cardiomyocyte maturation factor which is an mTOR inhibitor such that quiescence is induced in the cardiomyocyte. Where an examiner cannot determine whether or not the reference inherently possesses properties which anticipate, or render obvious, the claimed invention a rejection under §§102/103 is appropriate. See MPEP §§ 2112-2112.02.
The cited art taken as a whole demonstrates a reasonable probability that the resultant quiescent cardiomyocyte of the prior art is either identical or sufficiently similar to the claimed resultant quiescent cardiomyocyte that whatever differences exist, they are not patentably significant. Therefore, the burden of establishing novelty or unobviousness by objective evidence is shifted to applicants. See MPEP § 2112(v). Clear evidence that the quiescent cardiomyocyte of the cited prior art does not possess a critical characteristic that is possessed by the claimed resultant quiescent cardiomyocyte would advance prosecution and might permit allowance of claims to applicant’s method. Applicant is requested to specifically point out the support for any amendments made to the disclosure and arguments in response to this Office Action, including the claims. See MPEP §§ 714.02 and 2163.06. Applicant is also requested to refer to pages and line numbers in the as-filed specification. It is noted that other art may be applicable under 35 U.S.C. § 102 or 35 U.S.C. § 103(a) once the aforementioned issue(s) is/are addressed.
Claim(s) 108-109 is/are rejected under 35 U.S.C. 103 as being unpatentable over Avolio in view of Khan as applied to claims 106-107, 110-124 above, and in further view of Torin1. Datasheet [online]. Tocris, 2019 [retrieved on 2026-03-21]. Retrieved from the Internet: <URL: Torin 1 Supplier | CAS 1222998-36-8 | Torin1 | Tocris Bioscience> (hereinafter Torin1)., and Korotchkina et al., (2010) The choice between p53-induced senescence and quiescence is determined in part by the mTOR pathway. Aging, 2(6): pp244-352 (hereinafter Korotchkina).
Regarding claims 108-109, the combination does not disclose that the maturation factor is Torin1 or a combination of Torin1 and nutlin-3a.
Torin1 explains that Torin1 is a potent and selective mTOR inhibitor (Biological activity for Torin1). A skilled artisan would be motivated to try Torin1 in the methods of the combination as choosing one of a finite number of identified compositions which are known to inhibit the mTOR pathway, thereby converting senescence to quiescence.
Korotchkina explains that upregulation of p53 in certain cells inhibits the mTOR pathway, suppressing senescence and converting to quiescence (Abstract, Introduction, Discussion). Korotchkina explains that nutlin-3a induces quiescence and inhibit the mTOR pathway (Abstract, Introduction). A skilled artisan would be motivated to try nutlin-3a in the methods of the combination as choosing one of a finite number of identified compositions which are known to convert senescence into quiescence via inhibition of the mTOR pathway.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KARA D JOHNSON whose telephone number is (571)270-1414. The examiner can normally be reached Monday-Friday 8:00-4:00 CT.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached at (571) 272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KARA D JOHNSON/Primary Examiner, Art Unit 1632
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