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 .
Priority
The instant application, filed November 20th 2023, is a 371 filing of PCT/IB2022/054638, filed May 18th, 2022, and claims domestic benefit to US provisional application 63/190,115, filed May 18th, 2021.
Status of Claims/Application
Claims 1-33, filed on November 20th, 2023, are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 03/27/2024, 02/06/2025, 09/18/2025, and 11/13/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claim Objections
Claim 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33 are objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim should refer to other claims in alternative only and cannot depend on any other multiple dependent claims. See MPEP § 608.01(n). Accordingly, the claims 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33 are not been further treated on the merits. For compact prosecution, only instant claims 1-4 are being examined under the merits herein.
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.
Claims 1-4 are rejected under 35 U.S.C. 103 as being unpatentable over US 2020/0054682 A1, published February 20, 2020 (listed in the IDS), herein “Gojo” and further in view of “Scharping” (Scharping NE, Menk AV, Moreci RS, Whetstone RD, Dadey RE, Watkins SC, Ferris RL, Delgoffe GM. The Tumor Microenvironment Represses T Cell Mitochondrial Biogenesis to Drive Intratumoral T Cell Metabolic Insufficiency and Dysfunction. Immunity. 2016 Aug 16;45(2):374-88. doi: 10.1016/j.immuni.2016.07.009. Epub 2016 Aug 2. Erratum in: Immunity. 2016 Sep 20;45(3):701-703. doi: 10.1016/j.immuni.2016.08.009. PMID: 27496732; PMCID: PMC5207350.) and “Ramanathan”(A. Ramanathan, & S.L. Schreiber, Direct control of mitochondrial function by mTOR, Proc. Natl. Acad. Sci. U.S.A. 106 (52) 22229-22232, https://doi.org/10.1073/pnas.0912074106 (2009))
Regarding instant claim 1, Gojo teaches the method for producing mitochondria replaced T cells from exhausted T cells, the method comprising: incubating exhausted T cells having reduced endogenous mitochondria DNA (mtDNA) copy number with isolated exogenous mitochondria for a sufficient period of time to generate mitochondria replaced T cells (page 2, paragraph 0013, “method of generating a mitochondria replaced cell, comprising: (a) contacting a recipient cell with an agent that reduces endogenous mtDNA copy number; (b) incubating the recipient cell for a sufficient period of time for the agent to partially reduce the endogenous mtDNA copy number in the recipient cell; and (c) co-incubating (1) the recipient cell from step (b) in which the endogenous mtDNA has been partially reduced, and (2) exogenous mitochondria from a healthy donor, for a sufficient period of time to non-invasively transfer exogenous mitochondria into the recipient cell, thereby generating a mitochondria replaced cell” and page 23, paragraph 0269, “In specific embodiments, the T cell is a CD4+ T cell. In other embodiments, the T cell is a CD8+ T cell. In yet further embodiments, the T cell is a chimeric antigen receptor (CAR) T cell. In specific embodiments, the recipient cell is an exhausted or near exhausted T cell in a state or near a state of T cell dysfunction”).
However, Gojo does not teach expression of programmed cell death-1 (PD-1) is decreased by at least 1.1 fold relative to the expression of PD-1 by the exhausted T cells from which the mitochondria replaced T cells were produced, wherein the mitochondria replaced T cells have improved effector function relative to the exhausted T cells.
Scharping teaches that “B16 melanoma is highly enriched for dysfunctional T cells expressing high levels of PD-1, LAG-3, and Tim-3. Mitochondrial loss in the polyclonal T cell response appeared to be progressive, as T cells expressing more co-inhibitory molecules [PD-1 is recited on page 1, column 2 as a co-inhibitory molecule] had decreased mitochondrial mass, as evidenced by MitoTracker FM staining as well as staining for VDAC” and “thus, T cells infiltrating solid tumors showed a progressive loss of mitochondrial mass and function, such that the most exhausted cells show the lowest mitochondrial activity” (page 7, column 2, Loss of mitochondrial mass correlates with upregulation of co-inhibitory molecules). Scharping further teaches that PD-1 plays a role in modulation of metabolism, however, blockade of PD-1 was not sufficient to reverse mitochondrial insufficiency observed in tumor-infiltrating T cells (page 9, column 1). Scharping suggests “that mitochondrial function and mass are dynamically regulated and required to maintain optimal effector function [in T cells]” (page 13, column 1 paragraph 2) and that “reprogramming tumor-specific T cells to favor mitochondrial biogenesis protected them from the loss of function observed in the tumor microenvironment” (page 12, column 1, paragraph 1).
Therefore, it would have been obvious to the person of ordinary skill in the art to use the method of Gojo to produce mitochondria replaced T cells from exhausted T cells to reprogram the dysfunctional metabolism in exhausted T cells as taught by Scharping. One of ordinary skill in the art would be motivated to measure PD-1 expression levels of T cells to measure T cell function as Scharping points out that the PD-1 plays a role in modulation of metabolism and PD-1 is upregulated in exhausted T cells. A skilled artisan would have been able to predict with reasonable expectation of success that the reprogramming of the metabolism of exhausted T cells by substituting the method of replacing mitochondria as taught by Gojo with inducing mitochondrial biogenesis with therapeutic agents as taught by Scharping would result in a revitalization of the exhausted T cells into activated effector T cells and that PD-1 expression would be reduced as the T cells have activated effector functions.
Regarding instant claim 2, Gojo teaches a method for producing mitochondria replaced T cells from exhausted T cells, the method comprising:
(a) electroporating exhausted T cells with a nucleic acid sequence comprising a nucleotide sequence encoding a fusion protein comprising a mitochondrial-targeted sequence (MTS) and XbaIR to reduce exogenous mitochondria DNA (mtDNA) copy number and (page 36, paragraph 0390, “methods of generating a mitochondrial replaced cell described herein that use MTS-XbaI to partially reduce endogenous mitochondria can be effectively used in cells from a subject with a mitochondrial disease or disorder to improve the heteroplasmy level and reduce the amount of mutant mtDNA” and page 40, paragraph 0426, “These results demonstrated that human primary T cells are capable of mitochondria replacement to generate MirC using GMP graded electroporator, such as the electroporator produced by MaxCyte Inc”).
(b) incubating the exhausted T cells having reduced endogenous mitochondria DNA (mtDNA) copy number with isolated exogenous mitochondria for a sufficient period of time to generate a mitochondria replaced T cell in which expression of PD-1 is decreased by at least 1.1 fold relative to the expression of PD-1 by the exhausted T cells from which the mitochondria replaced T cells were produced, wherein the mitochondria replaced T cells have improved effector function relative to the exhausted T cells (page 20, paragraph 0253, “the recipient cell is incubated for a sufficient period of time for the agent to partially reduce the endogenous mtDNA copy number in the recipient cell or partially reduce the endogenous mitochondrial function in the recipient cell, respectively”). As described in instant claim 1, Gojo does not teach that a mitochondria replaced T cell in which expression of PD-1 is decreased by at least 1.1 fold relative to the expression of PD-1 by the exhausted T cells from which the mitochondria replaced T cells were produced, wherein the mitochondria replaced T cells have improved effector function relative to the exhausted T cells. As described above, Scharping teaches that “B16 melanoma is highly enriched for dysfunctional T cells expressing high levels of PD-1, LAG-3, and Tim-3. Mitochondrial loss in the polyclonal T cell response appeared to be progressive, as T cells expressing more co-inhibitory molecules [PD-1 is recited on page 1, column 2 as a co-inhibitory molecule] had decreased mitochondrial mass, as evidenced by MitoTracker FM staining as well as staining for VDAC” and “thus, T cells infiltrating solid tumors showed a progressive loss of mitochondrial mass and function, such that the most exhausted cells show the lowest mitochondrial activity” (page 7, column 2, Loss of mitochondrial mass correlates with upregulation of co-inhibitory molecules). Scharping further teaches that PD-1 plays a role in modulation of metabolism, however, blockade of PD-1 was not sufficient to reverse mitochondrial insufficiency observed in tumor-infiltrating T cells (page 9, column 1). Scharping suggests “that mitochondrial function and mass are dynamically regulated and required to maintain optimal effector function [in T cells]” (page 13, column 1 paragraph 2) and that “reprogramming tumor-specific T cells to favor mitochondrial biogenesis protected them from the loss of function observed in the tumor microenvironment” (page 12, column 1, paragraph 1).
Therefore, it would have been obvious to the person of ordinary skill in the art to use the method of Gojo to produce mitochondria replaced T cells from exhausted T cells to reprogram the dysfunctional metabolism in exhausted T cells as taught by Scharping. One of ordinary skill in the art would be motivated to measure PD-1 expression levels of T cells as a measure for T cell function as Scharping points out that the PD-1 plays a role in modulation of metabolism and PD-1 is upregulated in exhausted T cells. A skilled artisan would have been able to predict with reasonable expectation of success that the reprogramming of the metabolism of exhausted T cells by substituting the method of replacing mitochondria as taught by Gojo with inducing mitochondrial biogenesis with therapeutic agents as taught by Scharping would result in a revitalization of the exhausted T cells into activated effector T cells and that PD-1 expression would be reduced as the T cells have activated effector functions.
Regarding instant claim 3, Gojo teaches the incubation of the exhausted T cells with the isolated exogenous mitochondria occurs in the presence of rapamycin (page 4, paragraph 0035, “The disclosure also provides methods provided herein, further comprising contacting the recipient cell with a second active agent prior to co-incubating the recipient cell with exogenous mitochondria and/or exogenous mtDNA. In certain embodiments, the second active agent is selected from the group consisting of large molecules, small molecules, or cell therapies, and the second active agent is optionally selected from the group consisting of rapamycin”).
Regarding instant claim 4, Gojo does not teach the rapamycin is present at a concentration of 100 nM to 1000 nM. Ramanathan teaches 100 nM rapamycin treatment in cells that changes the mitochondrial metabolism profile of the cells (page 22230, Table 1, “Jurkat cells were treated with 100 nM”
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). Ramanathan further teaches that rapamycin enhances aerobic glycolysis and induces a state of increased dependence on aerobic glycolysis in leukemic cells and therefore is a basis of treatment for certain cancers (page 22232, paragraph 1, “Inhibiting mTOR, which is now the basis of treatment of certain cancers, enhances aerobic glycolysis and induces a state of increased dependence on aerobic glycolysis in leukemic cells”) and that the mTOR has been demonstrated to be sensitive to mitochondrial dysfunction (page 222231, paragraph 2, column 1, “mTOR has been demonstrated to be sensitive to mitochondrial dysfunction”. Therefore, it would have been obvious to the person of ordinary skill in the art to use the dose concentration of 100 nM of rapamycin taught by Ramanathan to induce mitochondrial metabolic changes in the cells and treat mitochondrial dysfunction.
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 b4e 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.
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Copending U.S. Provisional Applications
Claim 1-4 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 2, 4, 5, 6, 11, 16 of copending Application No. 18/924,887, claims filed June 4th, 2026, in view of Gojo (cited previously), Scharping (cited previously) and Ramanathan (cited previously).
Regarding instant claim 1 and 2, App’77 claim 2 recites an in vitro method of preparing a mitochondria replaced cell with improved mitochondrial function compared to that of the cell prior to mitochondrial replacement, comprising:(a) contacting a cell with a polynucleotide encoding a fusion protein comprising an XbaI endonuclease with a mitochondrial targeting sequence (MTS) for a sufficient period of time for the fusion protein to reduce no more than 99% approximately 70% of endogenous mitochondrial DNA (mtDNA) copy number in the cell; and(b) subsequently contacting the cell with exogenous mitochondria comprising exogenous nucleoid or exogenous mtDNA isolated from a healthy donor for a sufficient period of time to non-invasively transfer the exogenous mitochondria, exogenous nucleoid, or exogenous mtDNA into the cell, thereby generating the mitochondria replaced cell with improved mitochondrial function compared to that of the cell prior to mitochondrial replacement, wherein the exogenous nucleoid or exogenous mtDNA lasts for 12 days within the cell. App’887 claim 4 recites the cell is an immune cell. App’887 claim 5 recites the cell is a T cell, App’887 claim 6 recites the T cell is a CD4+ T cell, a CD8+ T cell, or a chimeric antigen receptor T cell. App’887 claim 11 recites the cell is a primary cell. App’887 claim 16 recites the T cell is exhausted.
However, App’887 does not recite electroporating exhausted T cells with a nucleic acid sequence comprising a nucleotide sequence encoding a fusion protein comprising an MTS and XbaIR. Gojo teaches the method of electroporating cells with the nucleotide sequence that encodes MTS and XbaIR fusion protein and that the electroporator can be used in clinical settings which has been cleared the standards of Good Manufacturing Practice and Good Clinical Practice (page 36, paragraph 0390, “methods of generating a mitochondrial replaced cell described herein that use MTS-XbaI to partially reduce endogenous mitochondria can be effectively used in cells from a subject with a mitochondrial disease or disorder to improve the heteroplasmy level and reduce the amount of mutant mtDNA” and page 25, paragraph 0287, “MaxCyte electroporator can be used for mRNA transfection, particularly in the clinical setting, which has cleared the standards of Good Manufacturing Practice and Good Clinical Practice. The transfection can be performed using the MaxCyte electroporator according to the manufacturer's protocol”). Therefore, it would have been obvious to the person of ordinary skill in the art to use the method of electroporation as taught by Gojo to introduce the MTS-XbaIR fusion protein in cells as the method is accepted in clinical setting and GMP approved.
However, App’887 does not recite the expression of PD-1. As described previously, As described above, Scharping teaches that “B16 melanoma is highly enriched for dysfunctional T cells expressing high levels of PD-1, LAG-3, and Tim-3. Mitochondrial loss in the polyclonal T cell response appeared to be progressive, as T cells expressing more co-inhibitory molecules [PD-1 is recited on page 1, column 2 as a co-inhibitory molecule] had decreased mitochondrial mass, as evidenced by MitoTracker FM staining as well as staining for VDAC” and “thus, T cells infiltrating solid tumors showed a progressive loss of mitochondrial mass and function, such that the most exhausted cells show the lowest mitochondrial activity” (page 7, column 2, Loss of mitochondrial mass correlates with upregulation of co-inhibitory molecules). Scharping further teaches that PD-1 plays a role in modulation of metabolism, however, blockade of PD-1 was not sufficient to reverse mitochondrial insufficiency observed in tumor-infiltrating T cells (page 9, column 1). Scharping suggests “that mitochondrial function and mass are dynamically regulated and required to maintain optimal effector function [in T cells]” (page 13, column 1 paragraph 2) and that “reprogramming tumor-specific T cells to favor mitochondrial biogenesis protected them from the loss of function observed in the tumor microenvironment” (page 12, column 1, paragraph 1).
Therefore, it would have been obvious to the person of ordinary skill in the art to use the method of Gojo to produce mitochondria replaced T cells from exhausted T cells to reprogram the dysfunctional metabolism in exhausted T cells as taught by Scharping. One of ordinary skill in the art would be motivated to measure PD-1 expression levels of T cells as a measure for T cell function as Scharping points out that the PD-1 plays a role in modulation of metabolism and PD-1 is upregulated in exhausted T cells. A skilled artisan would have been able to predict with reasonable expectation of success that the reprogramming of the metabolism of exhausted T cells by substituting the method of replacing mitochondria as taught by Gojo with inducing mitochondrial biogenesis with therapeutic agents as taught by Scharping would result in a revitalization of the exhausted T cells into activated effector T cells and that PD-1 expression would be reduced as the T cells have activated effector functions.
However, App’887 does not teach rapamycin and that the concentration is at 100 nM to 1000 nM as recited in instant claim 3 and 4. As previously described, Gojo teaches the incubation of the exhausted T cells with the isolated exogenous mitochondria occurs in the presence of rapamycin (page 4, paragraph 0035, “The disclosure also provides methods provided herein, further comprising contacting the recipient cell with a second active agent prior to co-incubating the recipient cell with exogenous mitochondria and/or exogenous mtDNA. In certain embodiments, the second active agent is selected from the group consisting of large molecules, small molecules, or cell therapies, and the second active agent is optionally selected from the group consisting of rapamycin”).
However, Gojo does not teach the rapamycin is present at a concentration of 100 nM to 1000 nM. Ramanathan teaches 100 nM rapamycin treatment in cells that changes the mitochondrial metabolism profile of the cells (page 22230, Table 1, “Jurkat cells were treated with 100 nM”
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). Ramanathan further teaches that rapamycin enhances aerobic glycolysis and induces a state of increased dependence on aerobic glycolysis in leukemic cells and therefore is a basis of treatment for certain cancers (page 22232, paragraph 1, “Inhibiting mTOR, which is now the basis of treatment of certain cancers, enhances aerobic glycolysis and induces a state of increased dependence on aerobic glycolysis in leukemic cells”) and that the mTOR has been demonstrated to be sensitive to mitochondrial dysfunction (page 222231, paragraph 2, column 1, “mTOR has been demonstrated to be sensitive to mitochondrial dysfunction”. Therefore, it would have been obvious to the person of ordinary skill in the art to use the dose concentration of 100 nM of rapamycin taught by Ramanathan to induce mitochondrial metabolic changes in the cells and treat mitochondrial dysfunction.
This is a provisional nonstatutory double patenting rejection.
Claim 1-4 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 21, 24, 26, 27, 28, and 29 of copending Application No. 18/562,815, claims filed November 20th, 2023, in view of Gojo (cited previously), Ogando (cited previously), and Ramanathan (cited previously).
Regarding instant claim 1 and 3, App’815 claim 1 recites a method for generating mitochondria replaced lymphoid cells in which at least 20% of endogenous mitochondrial DNA (mtDNA) has been replaced with exogenous mtDNA, wherein the method comprises incubating lymphoid cells that have not undergone a procedure to reduce or deplete endogenous mitochondria with isolated exogenous mitochondria and an effective amount of mammalian target of rapamycin (mTOR) inhibitor for a sufficient period of time to non-invasively transfer the exogenous mitochondria to the lymphoid cells, thereby generating mitochondria replaced lymphoid cells in which at least 20% of the endogenous mtDNA has been replaced with exogenous mtDNA.
Regarding instant claim 3 and 4, App’815 claims 2, 3, 4, 5, 6, 7, 8, and 9, recite the mTOR inhibitor is rapamycin and that the concentration is about 100 nM to about 1000 nM.
Regarding instant claim 2, 3, and 4, App’815 claim 11 recites the method for generating mitochondria replaced lymphoid cells, wherein the method comprises incubating lymphoid cells that have not undergone a procedure to reduce or deplete endogenous mitochondria with isolated exogenous mitochondria and about 100 nM to about 1000 nM of rapamycin for a sufficient period of time to non-invasively transfer the exogenous mitochondria to the lymphoid cells, thereby generating a mitochondria lymphoid cells.
Regarding instant claim 2, 3, and 4, App’815 claim 21 recites the method of generating mitochondria replaced lymphoid cells, wherein the method comprises: (a) centrifuging lymphoid cells and isolated exogenous mitochondria under conditions sufficient to generate a cell pellet, wherein the lymphoid cells have not undergone a procedure to reduce or deplete endogenous mitochondria, (b) incubating the lymphoid cells with 100 nM to 1000 nM of rapamycin for approximately 24 hours or more, thereby generating mitochondria replaced lymphoid cells.
Regarding instant claim 1 and 2, App’815 claim 24 recites the lymphoid cells are T cells. App’815 claim 26 recites the T cells comprise exhausted T cells, senescent T cells, or a combination thereof. App’815 claim 27 recites the lymphoid cells are human lymphoid cells.
However, App’815 does not recite electroporating exhausted T cells with a nucleic acid sequence comprising a nucleotide sequence encoding a fusion protein comprising an MTS and XbaIR. Gojo teaches the method of electroporating cells with the nucleotide sequence that encodes MTS and XbaIR fusion protein and that the electroporator can be used in clinical settings which has been cleared the standards of Good Manufacturing Practice and Good Clinical Practice (page 36, paragraph 0390, “methods of generating a mitochondrial replaced cell described herein that use MTS-XbaI to partially reduce endogenous mitochondria can be effectively used in cells from a subject with a mitochondrial disease or disorder to improve the heteroplasmy level and reduce the amount of mutant mtDNA” and page 25, paragraph 0287, “MaxCyte electroporator can be used for mRNA transfection, particularly in the clinical setting, which has cleared the standards of Good Manufacturing Practice and Good Clinical Practice. The transfection can be performed using the MaxCyte electroporator according to the manufacturer's protocol”). Therefore, it would have been obvious to the person of ordinary skill in the art to use the method of electroporation as taught by Gojo to introduce the MTS-XbaIR fusion protein in cells as the method is accepted in clinical setting and GMP approved.
However, App’815 does not recite the expression of PD-1. As described previously, Scharping teaches that “B16 melanoma is highly enriched for dysfunctional T cells expressing high levels of PD-1, LAG-3, and Tim-3. Mitochondrial loss in the polyclonal T cell response appeared to be progressive, as T cells expressing more co-inhibitory molecules [PD-1 is recited on page 1, column 2 as a co-inhibitory molecule] had decreased mitochondrial mass, as evidenced by MitoTracker FM staining as well as staining for VDAC” and “thus, T cells infiltrating solid tumors showed a progressive loss of mitochondrial mass and function, such that the most exhausted cells show the lowest mitochondrial activity” (page 7, column 2, Loss of mitochondrial mass correlates with upregulation of co-inhibitory molecules). Scharping further teaches that PD-1 plays a role in modulation of metabolism, however, blockade of PD-1 was not sufficient to reverse mitochondrial insufficiency observed in tumor-infiltrating T cells (page 9, column 1). Scharping suggests “that mitochondrial function and mass are dynamically regulated and required to maintain optimal effector function [in T cells]” (page 13, column 1 paragraph 2) and that “reprogramming tumor-specific T cells to favor mitochondrial biogenesis protected them from the loss of function observed in the tumor microenvironment” (page 12, column 1, paragraph 1).
Therefore, it would have been obvious to the person of ordinary skill in the art to use the method of Gojo to produce mitochondria replaced T cells from exhausted T cells to reprogram the dysfunctional metabolism in exhausted T cells as taught by Scharping. One of ordinary skill in the art would be motivated to measure PD-1 expression levels of T cells as a measure for T cell function as Scharping points out that the PD-1 plays a role in modulation of metabolism and PD-1 is upregulated in exhausted T cells. A skilled artisan would have been able to predict with reasonable expectation of success that the reprogramming of the metabolism of exhausted T cells by substituting the method of replacing mitochondria as taught by Gojo with inducing mitochondrial biogenesis with therapeutic agents as taught by Scharping would result in a revitalization of the exhausted T cells into activated effector T cells and that PD-1 expression would be reduced as the T cells have activated effector functions.
Conclusion
No Claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Lam Thuy Vi Tran Ho whose telephone number is (571)272-9135. The examiner can normally be reached Monday-Friday 7:30-3.
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/LAM THUY VI TRAN HO/ Examiner, Art Unit 1647 /L.T./Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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