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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11/25/2025 has been entered.
Claim Status
Applicant’s reply filed on 11/25/2025 is acknowledged. Claims 1, 8, 10, 14, and 102 have been amended. Claims 7, 13, 15-17, and 59 are cancelled. Claims 1-6, 8, 10, 14, 18-19, 58, 89, and 102 are pending. Claim 3 has been withdrawn from consideration as being drawn to nonelected inventions.
Claims 1-2, 4-6, 8, 10, 14, 18-19, 58, 89, and 102 are under examination.
Rejections Withdrawn
The following rejections are withdrawn in view of applicant’s amendments and arguments dated 11/25/2025:
The rejection of claims 1-2, 4-8, 10, 13-16, 18-19, 58-59, 89, and 102 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 rejection of claims 89 and 102 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because of the scope of enablement.
The rejection of claims 15 and 16 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.
The rejection of claim 18 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.
Rejections Maintained
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2, 4-6, 8, 14, 18-19, 89, and 102 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Ahmed (WO2017/079622A1, published 05/11/2017, effectively filed 11/04/2015), as evidenced by Carrero (Proc Natl Acad Sci U S A. 2019 Jan 8;116(2):599-608).
The disclosure of Ahmed is directed to genetic modification of DNMT3A gene in immune cells for use in adoptive T cell therapies. Ahmed contemplates deleting, changing, or inserting nucleotides within the DNMT3A gene such that the DNMT3A gene product does not function for methylation (see Abstract).
Regarding claim 1, pertaining to a genetically modified immune effector cell, wherein (i) DNA (cytosine-5)-methyltransferase 3A (DNMT3A)-mediated de novo DNA methylation of the cell genome is inhibited relative to a control cell, and (ii) STAT5 signaling pathway is activated by IL-15 wherein the genetically modified immune effector cell is genetically modified to express a chimeric antigen receptor (CAR), an antigen specific T-cell receptor, or a bispecific antibody, Ahmed teaches the following limitations:
Modifying a DNMT3A gene in an isolated CD8+ T cells such that the DNMT3A is not expressed or a non-functional DNMT3A protein is expressed (Pg. 30, claim 1)
The CD8+ T cell further expresses a CAR specific for a tumor-associated antigen (Pg. 30, claim 2)
Administration of the modified CD8+ T cell into a subject, which would necessarily bring the cell into contact with endogenous IL-15 which activates STAT5 (Pg 30, claim 1), as evidenced by Carrero which teaches soluble IL-15 complexes are produced in the tumor microenvironment (Fig. 1) and that soluble IL-15 complexes promote CD8+ T cell and NK cell proliferation in vivo (Pg. 599, Right column).
Regarding claims 2 and 4, wherein the enzymatic activity of the DNMT3A protein is inhibited in the cell (claim 2) and wherein the DNMT3A gene is mutated in DNMT3A catalytic domain so that the enzymatic activity of the DNMT3A protein is inhibited (claim 4), Ahmed teaches the modified CD8+ T cell expresses a non-functional DNMT3A protein (Pg. 30, claim 1) and teaches that the disclosure contemplates the genetic alteration to the DNMT3A gene is in the ADDz active catalytic domain (Pg. 15, Lines 6-8).
Regarding claims 5 and 6, wherein the level of functional DNMT3A protein in the genetically modified cell is decreased by 50% or more (claim 5) and wherein DNMT3A gene is deleted or defective so that no detectable functional DNMT3A protein is produced (claim 6), Ahmed teaches a conditional deletion of DNMT3A, which reads on the level of “functional” DNMT3A decreased by 50% or more (Pg. 23, Lines 6-7).
Regarding claim 8, wherein the genetically modified cell of claim 1 is selected from a list comprising CD8+ T cells, Ahmed teaches the genetically modified cell is a CD8+ T cell (Pg. 30, claim 1).
Regarding claim 14, wherein the STAT5 signaling pathway is activated by IL-15, Ahmed teaches administration of the modified CD8+ T cell into a subject, which would necessarily bring the cell into contact with endogenous IL-15 present in the tumor microenvironment, as evidenced by Carrero (see Fig. 1).
Regarding claim 18, wherein the genetically modified immune effector cell further comprises at least one surface molecule capable of binding specifically to an antigen, the CD8+ T cells were obtained from the subject and would necessarily express endogenous TCR. The claim does not specify that the surface molecule is exogenously introduced.
Regarding claim 19, wherein the antigen is selected from a list comprising a tumor antigen, Ahmed teaches the CAR is specific for tumor associated antigen (Pg. 30, claim 2).
Regarding claim 89, pertaining to a method of treating a disease in a subject in need thereof comprising administering to the subject an effective amount of the genetically modified immune effector cell of claim 1, Ahmed teaches administering the modified CD8+ T cells in to a subject diagnosed with cancer (Pg. 30, claim 1).
Regarding claim 102, pertaining to a method of enhancing an antitumor activity of a T cell comprising: a) modifying a DNMT3A gene or gene product in the genetically modified immune effector cell so that the DNMT3A-mediated de novo DNA methylation of the genetically modified immune effector cell genome is inhibited; and b) activating the STAT5 signaling pathway in the genetically modified immune effector cell by either stimulating the genetically modified immune effector cell with Il-15 or genetically modifying the genetically modified immune effector cell to express IL-15 wherein the genetically modified immune effector is a T cell, and wherein the antitumor activity is enhanced relative to the control cell, Ahmed teaches the following limitations:
Collecting CD8+ T cells from a subject diagnosed with cancer (Pg. 30, claim 1)
Modifying a DNMT3A gene in an isolated CD8+ T cells such that the DNMT3A is not expressed or a non-functional DNMT3A protein is expressed (Pg. 30, claim 1)
The CD8+ T cell further expresses a CAR specific for a tumor-associated antigen (Pg. 30, claim 2)
Administration of the modified CD8+ T cell into a subject, which would necessarily bring the cell into contact with endogenous IL-15 which activates STAT5 (Pg 30, claim 1), as evidenced by Carrero which teaches soluble IL-15 complexes are produced in the tumor microenvironment (Fig. 1) and that soluble IL-15 complexes promote CD8 T cell and NK cell proliferation in vivo (Pg. 599, Right column).
Response to Applicant’s Arguments
Applicant's arguments filed 11/25/2025 have been fully considered but they are not persuasive.
The applicant argues that in patentable contrast to the claimed invention, Ahmed does not teach or disclose activating the STATS pathway by IL-21, IL-15 and/or IL-7, or by expression of an IL-4/IL-7 receptor or an IL-4/IL-2 receptor. The applicant further states that the claimed genetically modified immune effector cells are not known in the art to naturally secrete IL-21, IL-15, and IL-7. The genetically modified immune effector cells, thus, cannot activate the STAT5 pathway themselves. Applicant respectfully disagrees that it is inherent that administering the genetically modified immune effector cells to a subject would necessarily result in activation of the STATS pathway by these cytokines. (Remarks, Pgs. 8-9).
In response, the applicant’s arguments appear to only address STAT5 activation via IL-15 signaling during the manufacturing process of the genetically modified immune effector cells. However, the claims as written do not provide a location or means by which the cells are contacted by IL-15. Carrero (Proc Natl Acad Sci U S A. 2019 Jan 8;116(2):599-608) teaches that IL-15 expression within human tumors is crucial for optimal tumor responses and teaches in a preclinical model that soluble IL-15/IL-15Rα complexes are abundant in interstitial fluid of tumors with expression preceding the infiltration of tumor-infiltrating lymphocytes (see Abstract). Therefore, STAT5 signaling activation would occur in vivo due to contact with cytokines endogenous to the subject. The 35 U.S.C. 102 rejection did not state or imply that the genetically modified cells were the source of STAT5-activating cytokines.
For these reasons, the rejection under 35 U.S.C. 102 is maintained.
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.
Claims 1-2, 4-6, 8, 10, 14, 18-19, 89, and 102 are rejected under 35 U.S.C. 103 as being unpatentable over Ahmed (WO2017/079622A1, published 05/11/2017, effectively filed 11/04/2015). as applied to claims 1-2, 4-6, 8, 14, 18-19, 89, and 102 above, and further in view of Themeli (Nat Biotechnol. 2013 Oct;31(10):928-33).
As described in the 35 USC § 102 rejection above, Ahmed teaches a genetically modified CD8+T cell for adoptive T cell therapy comprising a deleted or disrupted DNMT3 protein and expressing a tumor antigen-specific CAR. The genetically modified cells of Ahmed’s disclosure originate from the subject diagnosed with cancer (Pg. 30, claims 1).
Ahmed does not teach that the genetically modified immune effector cell is an induced pluripotent stem cell.
This deficiency is taught by Themeli.
The disclosure of Themeli seeks to address the lack of readily available, antigen-specific human T lymphocytes for use in adoptive T cell therapy for cancer and infectious diseases (see Abstract). Themeli teaches their method of generating T lymphocytes from T cell lineage iPSCs potentially provides an unlimited source of T lymphocytes targeted to a chosen antigen independent of HLA restriction (Pg. 5, Full paragraph 2) and would be valuable in situations where autologous or allogeneic T cells are not available (Pg. 6, Full paragraph 2).
Regarding claim 10, wherein the stem cell is an induced pluripotent stem cell (iPSC), Themeli teaches generation of iPSCs from peripheral blood T lymphocytes, transduced with a CD19-specific CAR and differentiated to the T-lymphoid lineage (Pg. 2, Full paragraph 2).
It would have been obvious to one having ordinary skill in the art to modify the method of generating a genetically modified immune effector cell of Ahmed with the teachings of Themeli by using an iPSC cell as the starting cell for generation of immune effector cell for therapy instead of the CD8+ T cell from the subject with cancer. One would have been motivated to do so because Themeli teaches that the use of iPSCs as T cell precursors for T cell therapies overcomes the limited availability and time-consuming nature of generating CAR T cells from autologous or donor-derived T cells. There would be an expectation of success in using iPSCs as the precursor cell for the generation of the modified immune cells of Ahmed because Themeli teaches T cells generated from iPSCs can be expanded and maintain their effector phenotype (Pg. 4, Full paragraph 1) and thus would be suitable to be used as the cells of origin to generate genetically modified immune effector cells.
Claims 1-2, 4-6, 8, 14, 18-19, 58, 89, and 102 are rejected under 35 U.S.C. 103 as being unpatentable over Ahmed (WO2017/079622A1, published 05/11/2017, effectively filed 11/04/2015) as applied to claims 1-2, 4-6, 8, 14, 18-19, 89, and 102 above, and further in view of Shum (WO2018/038945A1, published 03/01/2018, effectively filed 08/26/2016).
As described in the 35 USC § 102 rejection above, Ahmed teaches a genetically modified CD8+T cell for adoptive T cell therapy comprising a deleted or disrupted DNMT3 protein and expressing a tumor antigen-specific CAR. Ahmed teaches the modified CAR T cell can be administered in combination with IL-2 (Pg. 18, Lines 4-7).
Ahmed does not teach a pharmaceutical composition comprising the genetically modified immune effector cell.
These deficiencies are taught by Shum.
The disclosure of Shum is directed to methods and compositions for enhancing expansion of immune cells for immunotherapy wherein the immune cells express a constitutively active cytokine receptor (see Abstract).
Regarding claim 58, pertaining to a pharmaceutical composition comprising the genetically modified immune effector cell of claim 1 and a pharmaceutically acceptable carrier and/or excipient, Shum teaches a pharmaceutical composition comprising the genetically modified cell of the disclosure ([0086], Lines 1-2) and a pharmaceutically acceptable carrier or excipient ([0102], Lines 1-4).
It would have been obvious to one having ordinary skill in the art to modify the genetically modified immune cell of Ahmed by formulating the cell in a pharmaceutical composition as taught by Shum. One would have been motivated to do so because both Ahmed and Shum contemplate the use of the genetically modified cells in adoptive T cell therapy administered to a subject and would thus require a pharmaceutical excipient or carrier. There would be an expectation of success in combining the teachings of Ahmed and Shum because they each provide evidence of their respective genetically engineered cells used in the treatment of subjects.
Response to Applicant’s Arguments
The applicant argues that neither Themeli nor Shum cure the deficiencies of Ahmed to render the claimed invention obvious. Themeli is directed to generation of iPSCs and does not provide any guidance or motivation to activate STATS via these cytokines, nor does the reference provide any motivation to alter STAT5 or DNMT3A activity. Shum is directed to constitutively active receptors and discloses that a constitutively active IL-7 receptor activates STAT5. Shum does not provide any guidance or motivation to activate STAT5 via these cytokines, nor does the reference provide any motivation to alter STAT5 or DNMT3A activity. (Remarks, Pgs. 9-10)
In response, Themeli and Shum were not provided for motivation to activate the STAT5 pathway and inhibit DNMT3A-mediated de novo methylation as both of these limitations were addressed in the 35 U.S.C. 102 rejection above. Themeli teaches the ability to generate T lymphocytes from T cell lineage iPSCs. Due to cancellation of claims 15-16, the disclosure of Shum is only used herein to teach a pharmaceutical composition, however, the previous office action dated 08/27/2025 outlines Shum’s teachings pertaining to a constitutively active IL-7 cytokine receptor (“C7R”) and provides evidence that constitutive signaling from C7R activates STAT5 in T cells (Fig. 14A), enhances CAR T cell activity during serial tumor challenge (Figs. 15A-I), and enhances adoptive T cell immunotherapy against metastatic and intracranial malignancies (Figs. 16A-G). Therefore, methods the stimulate STAT5 are known in the art to enhance immune cell therapies.
For these reasons, the rejections under 35 U.S.C. 103 are maintained.
Conclusion
No claims are allowed.
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/CAROL ANN CHASE/Examiner, Art Unit 1646
/HONG SANG/Primary Examiner, Art Unit 1646