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 .
Election/Restrictions
This action is in response to the papers filed on 02/18/2026. Claims 1-21 are
currently pending as per claims filed on 02/18/2026.
Applicant’s election without traverse of Group 1, claims 1-11 in the
reply filed on 02/18/2026 is acknowledged.
Claims 12-21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 02/18/2026.
Claim 12 has been amended and claim 22 has been cancelled by Applicants’ amendment filed on 02/18/2026. No new claims were added.
The requirement is still deemed proper and is therefore made FINAL.
Therefore, claims 1-11 are subject to examination to which the following grounds of rejection are applicable.
Priority
The instant application claims domestic benefit to US provisional patent
application number 63/388,129 filed on 07/11/2022 and US provisional patent
application number 63/401,014 filed on 08/25/2022. Thus, the earliest possible priority
for the instant application is 07/11/2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10/069/2024 was filed after the mailing date of the current office action. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Interpretation
The term "longevity" used in claim 1 is not specifically defined in the specification and there is no established meaning in the art. It is interpreted that “longevity” means persistence, ability to repopulate, and/or lifespan of a viable cell population.
Claim Objections
Claim 1 is objected to because abbreviations such as mTOR and ULK1 should be spelled out at the first encounter in the claims. Appropriate correction is required.
Claim 9 is objected to because abbreviations such as Rg2 should be spelled
out at the first encounter in the claims. Appropriate correction is required.
Claim Rejections - 35 USC § 102
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 1, 4-7, 10, and 11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lee et al (Biology of Blood and Marrow Transplantation, 2014, pages 1282-1289) as evidenced by Kim et al (Nature Cell Biology, 2011, pages 132-142; hereinafter “Kim 2011”).
Lee teaches a method of enhanced long-term repopulation capacity of hematopoietic stem/progenitor cells (HSPCs) by pre-conditioning (i.e. culturing/stimulating/exposing) with an agent which is a small molecule AMPK activator (AICAR) (abstract, page 1). With regard to claims 1, 4, 10, and 11, claim 1 recites a method of stimulating mTOR-independent ULK1-mediated autophagy, claim 4 recites an agent which stimulates mTOR-independent ULK-1-mediated autophagy, claim 10 recites an AMPK activator that is a direct activator, and claim 11 recites the agent is an activator of ULK1, it is noted that the claims are reciting functional properties/activities of the AMPK activator which are an inherent characteristic or result based on the properties of the AMPK activator AICAR. While Lee does not explicitly recite that the AMPK activator AICAR stimulates mTOR-independent ULK-1 mediated autophagy, it was known that AMPK activation causes autophagy through phosphorylation (i.e. activation) of ULK1 in an mTOR-independent manner, as evidenced by Kim 2011 who teaches AMPK promotes autophagy by directly activating Ulk1 through phosphorylation of Ser 317 and Ser 777 (page 1, abstract). It is noted that In re Best (195 USPQ 430) and In re Fitzgerald (205 USPQ 594) discuss the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to "prove that subject matter shown to be in the prior art does not possess characteristic relied on" (205 USPQ 594, second column, first full paragraph) As such the functional limitations would be present in the identical compounds taught by Lee and would therefore elicit these effects whenever it is administered to the cell population.
Thus, by teaching all the limitations of the claims as written, Lee as evidenced by Kim 2011 anticipates the instant invention as claimed.
Claim 1, 4-7, 10, and 11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ting-Ting et al (Biochemical and Biophysical Research Communications, 2019, pages 826-834).
Ting-Ting teaches in vitro culturing a population of AC16 human myocardial cells with a small molecule AMPK direct activator GSK621, and that GSK621 inhibits oxygen glucose deprivation-re-oxygenation-induced viability reduction (i.e. increased cell survival/longevity) (abstract, page 1). Moreover, Ting-Ting teaches that activated AMPK directly phosphorylates (i.e. activates) ULK1, independently from mTOR, to cause cell autophagy (page 826, right col, para 1). Thus, by teaching all the limitations of the claims as written, Ting-Ting anticipates the instant invention as claimed.
Claim 1, 4-6, and 11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ouyang et al (J. of Medicinal Chem., 2018, pages 2776-2792).
Ouyang teaches a small molecule ULK1 activator 33i (BL-918) which induces autophagy in cultured SH-SY5Y cells and that the activator displays cytoprotective effects on 1-methyl-4-phenylpyridinium (MPP+)- treated cells as well as protection against loss of dopaminergic neurons by targeting ULK1-modulated autophagy in mouse models of Parkinson’s disease (abstract, page 1). More specifically, Ouyang teaches that the ULK1 activator 33i was added to a population of SH-SY5Y cells during in vitro culture and showed cytoprotective effects through increased cell viability (i.e. increased longevity) (Figure 6A; page 2780, left col, para 2)). Thus, by teaching all the limitations of the claims as written, Ouyang anticipates the instant invention as claimed.
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.
Claim(s) 1-11 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al (Biology of Blood and Marrow Transplantation, 2014, pages 1282-1289) in view of Jiang et al (Stem Cells and Development, 2015, pages 2740-2745; cited in IDS) and Fan et al (Autophagy, 2017, pages 41-56), Kim 2011 (Nature Cell Biology, 2011, pages 132-142) and Kim et al (Experimental & Molecular Medicine, 2016, pages 1-12; hereinafter “Kim 2016”).
Lee teaches a method of enhanced long-term repopulation capacity of hematopoietic stem/progenitor cells (HSPCs) by pre-conditioning (i.e. culturing/stimulating/exposing) with a small molecule AMPK activator (AICAR) (abstract, page 1). With regard to claims 1, 4, 10, and 11, which recite wherein an agent stimulates mTOR-independent ULK-1-mediated autophagy, is an AMPK activator that is a direct activator, and the agent is an activator of ULK1, it is noted that the claims are reciting functional properties/activities of the AMPK activator which are an inherent characteristic or result based on the properties of the AMPK activator AICAR. While Lee does not explicitly recite that the AMPK activator AICAR stimulates mTOR-independent ULK-1 mediated autophagy, it was known that AMPK activation causes autophagy through phosphorylation (i.e. activation) of ULK1 in an mTOR-independent manner, as evidenced by Kim 2011 who teaches AMPK promotes autophagy by directly activating Ulk1 through phosphorylation of Ser 317 and Ser 777 (page 1, abstract). It is noted that In re Best (195 USPQ 430) and In re Fitzgerald (205 USPQ 594) discuss the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to "prove that subject matter shown to be in the prior art does not possess characteristic relied on" (205 USPQ 594, second column, first full paragraph). Further, reliance upon inherency is not improper even though rejection is based on Section 103 instead of Section 102. In re Skoner, et al. 186 USPQ 80 (CCPA). As stated in MPEP 2112, The express, implicit, and inherent disclosures of a prior art reference may be relied upon in the rejection of claims under 35 U.S.C. 102 or 103. "The inherent teaching of a prior art reference, a question of fact, arises both in the context of anticipation and obviousness." In re Napier, 55 F.3d 610, 613, 34 USPQ2d 1782, 1784 (Fed. Cir. 1995). See also In re Grasselli, 713 F.2d 731,739, 218 USPQ 769, 775 (Fed. Cir. 1983).. As such the functional limitations would be present in the identical compounds taught by Lee and would therefore elicit these effects whenever it is administered to the cell population.
The teachings of Lee do not teach wherein the cell population comprises cells derived from induced pluripotent stem cells (iPSCs) (claim 2) or induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) (claim 3).
Jiang teaches overexpression of the SIRT1 gene via lentiviral vector transfection in iPSC-ECs maintains EC phenotype, function, and proliferative capacity by overcoming early cell senescence (abstract, page 1). Moreover, Jiang teaches there are many challenges associated with iPSC-ECs in culture including “instability of the endothelial phenotype and limited cell proliferative capacity over time. Early senescence (i.e. decreased longevity) is believed to be the primary mechanism underlying these limitations” (abstract, page 1).
It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to use the teachings and motivation provided by Jiang to decrease senescence and thereby increase longevity in iPSC-ECs with the teachings of Lee for increasing longevity of cells by culturing cells in the presence of AICAR to arrive at the claimed invention of increasing the longevity of iPSC-ECs by culturing in the presence of AICAR with a reasonable expectation of success.. One would be motivated to do so since iPSC-ECs, which are valuable in drug discovery and developing patient-specific treatments, have limited proliferative capacity and would benefit from methods that increase their longevity without use of a lentivirus vector. As culturing of iPSC-ECs and methods to increase cell viability in cultured cells is known in the art, one would have a reasonable expectation of success.
The teachings of Lee and Jiang do not teach wherein the AMPK activator is an indirect activator (claim 8) and the indirect activator is Rg2 (claim 9).
Fan teaches pharmacological strategies to activate autophagy are needed to treat disease and many compounds are difficult and highly costly to synthesize (page 41, left col, para 1). Moreover, Fan teaches that using plant compounds is a desirable alternative as they are “a natural reservoir of molecules for drug discovery” (page 41, right col, para 1) and Rg2, a ginsenoside, “is a novel AMPK activator and induces autophagy through activation of the AMPK-ULK1 pathway, but not by inhibition of mTOR” (i.e. mTOR-independent) (abstract, page 41). Additionally, it is noted that claims 8 and 9 are directed Rg2 being an indirect activator which is an inherent property of the AMPK activator Rg2. As taught by Kim 2016, ginsenosides, including Rg2, have been reported to activate AMPK (left col, para 1, page 6) and “these compounds are likely to activate AMPK via AMP-dependent mechanisms” (i.e. indirect activation; ginsenosides are listed in as indirect activators in Table 1 Indirect AMPK activators). It is noted that In re Best (195 USPQ 430) and In re Fitzgerald (205 USPQ 594) discuss the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to "prove that subject matter shown to be in the prior art does not possess characteristic relied on" (205 USPQ 594, second column, first full paragraph). Reliance upon inherency is not improper even though rejection is based on Section 103 instead of Section 102. In re Skoner, et al. 186 USPQ 80 (CCPA). As stated in MPEP 2112, The express, implicit, and inherent disclosures of a prior art reference may be relied upon in the rejection of claims under 35 U.S.C. 102 or 103. "The inherent teaching of a prior art reference, a question of fact, arises both in the context of anticipation and obviousness." In re Napier, 55 F.3d 610, 613, 34 USPQ2d 1782, 1784 (Fed. Cir. 1995). See also In re Grasselli, 713 F.2d 731,739, 218 USPQ 769, 775 (Fed. Cir. 1983).As such the functional limitations would be present in the identical compounds taught by Fan and would therefore elicit these effects whenever it is administered to the cell population.
It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to modify the teachings of increasing the cell population longevity with mTOR-independent ULK-1 mediated autophagy as taught by Lee with the teachings of using Rg2 as an indirect activator of AMPK for inducing autophagy as taught by Fan to generate a method of increasing the cell population longevity with mTOR-independent ULK-1 mediated autophagy that uses a plant-derived compound capable of inducing autophagy in the cells. One would be motivated to do so to increase the longevity of a cell population using a compound that does not require costly synthesis and is found naturally in a plant. Since Rg2 is known to induce autophagy in cells, one would have a reasonable expectation of success.
Conclusion
Claims 1-11 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Juliana Candelaria whose telephone number is (571)272-5488. The examiner can normally be reached Monday - Friday 8am - 5pm.
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, Maria Leavitt can be reached at (571) 272-1085. 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.
/JULIANA IRENE CANDELARIA/Examiner, Art Unit 1634
Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
Prosecution Insights