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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 04/08/2026 has been entered.
Claim Status
1. Claims 7 – 9 and 11 – 12 remain pending and are under consideration.
Withdrawn Claim Rejections
2. The rejection of claims 7 – 9 under 35 U.S.C. 103 is withdrawn in view of Applicant’s amendment to claim 7.
3. The rejection of claims 11 and 12 under 35 U.S.C. 103 is withdrawn in view of Applicant’s amendment to claim 7.
New Claim Rejections
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.
4. Claims 11 and 12 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.
5. Regarding claims 11 and 12, it is unclear how the limitations of these claims relates to the scope of independent claim 1 that recites “a method for preparing CAR-T cells” because the scope of claims 11 and 12 is a method of treating and not a method of preparing CAR-T cells.
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.
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.
6. Claim(s) 7 – 9 are rejected under 35 U.S.C. 103 as being unpatentable over Escriba-Garcia (Escriba-Garcia, L., et. al. Haematologica: 22nd Congress of the European-Hematology-Association; Madrid, Spain; June 22 – 25, 2017, p. 336, S816; previously cited), hereinafter Escriba-Garcia in view of Alvarez (Alvarez-Fernández, Carmen, et al. Journal of translational medicine 14.1 (2016): 214; previously cited), hereinafter Alvarez as evidenced by StemCell (StemCell: (09/25/2016). "EasySep Human Naïve CD4+ T Cell Isolation Kit." https://www.stemcell.com/easysep-human-naive-cd4-t-cell-isolation-kit.html,. Accessed 06/02/2026.), hereinafter StemCell in view of Zoon (Zoon CK, et. al. Int J Mol Sci. 2015 Apr 20;16(4):8744-60), hereinafter Zoon.
Regarding step (a) of claim 7, Escriba-Garcia teaches a method for generating CAR-T cells comprising obtaining naïve T cells from healthy donors (page 336, left col. S816, Methods). Escriba-Garcia does not teach the naïve T cells were obtained from PBMCs “with exclusion of γ/[Symbol font/0x64] T cells or that the Tn cells comprise CCR7+CD45RA+ but references the teachings of Alvarez.
Regarding step (b) of claim 7, Escriba-Garcia teaches activating and culturing the naïve T cells in IL-7, IL-15, and IL-21 to obtain a Tscm cells (page 336, left col. S816, Methods). Escriba-Garcia does not teach the concentration of IL7, IL15, or IL21 but references the teachings of Alvarez.
Regarding step (c) of claim 7 and “viral transduction” of claim 8, Escriba-Garcia teaches transducing the cultured cells with a lentiviral vector (“performing engineering modification” of claim 7 and “viral transduction” of claim 8) encoding CD30-CAR after culturing with IL-7, IL-15, and IL-21 to prepare CAR-T cells (page 336, left col. S816, Methods).
Escriba-Garcia does not teach naïve T cells were obtained from PBMCs or “with exclusion of γ/[Symbol font/0x64] T cells” or that the naïve T cells comprise CCR7+CD45RA+ cells of step (a) or a concentration of IL15, IL7 or IL21 in the recited ranges of step (b) of claim 7 or a concentration of IL15, IL7, or IL21 in the recited ranges of claim 9. However, Escriba-Garcia teaches the CD30-CAR expression in the CAR-T cells was greater than 75% and the CD8+ CAR-T cells conferred specific cytolytic activity in vitro compared to untransduced T cells (page 336, left col. S816, Results). Escriba-Garcia teaches the method produces CAR-TSCM cells with potent antitumor efficacy against peripheral T-cell lymphoma (PTCL) in vitro suggesting the potential to improve the outcome of patients with CD30+ PTCL through adoptive therapy (page 336, right col. para. 1). Escriba-Garcia teaches PTCL represents the most aggressive form among non-Hodgkin lymphomas with a very poor prognosis (5 year survival of 30%) demanding innovative novel treatment strategies (page 336, left col. S816, Background). Escriba-Garcia teaches application of adoptive immunotherapy with CAR-T cells remains a challenge for PTCL because of a lack of truly tumor-specific antigens that are not expressed on normal T cells (page 336, left col. S816, Background). Escriba-Garcia teaches using TSCM cells to promote engraftment and persistence after transfer (page 336, left col. S816, Background).
Regarding enriching naïve T cells from PBMCs, “with exclusion of γ/[Symbol font/0x64] T cells”, and naïve T cells comprise CCR7+CD45RA+ cells of step (a) of claim 7, Alvarez teaches PBMCs were obtained from healthy donors and naïve T cells were enriched with an on demand T-cell enrichment kit from Stem Cell (page 2, left col. last para.). The enrichment kit excludes γ/[Symbol font/0x64] T cells and retains CCR7+ and CD45RA+ cells from PBMCs as evidenced by StemCell (page 4, para. 1). Therefore, the naïve T cells of Escriba-Garcia and Alvarez do not contain γ/[Symbol font/0x64] T cells but do contain CCR7+CD45RA+ naïve T cells.
Alvarez teaches culturing activated naïve T cells with low doses of IL7, IL15, and IL21 at 25 ng/mL each to generate and expand Tscm cells (page 2, right col. para. 4; page 7, left col.; page 9, left col. last para.) but does not teach the concentrations of IL15, IL7, or IL21 of step (b) of claim 7 or claim 9. However, Alvarez teaches the combination of IL7/15/21 results in 0.7 x 106 TSCM cells which may have relevant clinical implications for the generation of TSCM for adoptive cell therapy of patients with cancer (Abstract). Alvarez teaches studies have demonstrated the generation and expansion of CD8+ TSCM from naïve T cells through CD3/CD28 costimulation in combination with IL7 and IL15 , and IL21 acts synergistically with IL7 and IL15 to promote proliferation and survival of both memory and naïve T cells (page 2, left col. para. 2 – 3). Alvarez teaches identification of reproducible methods to generate and expand large numbers of TSCM for adoptive T cell therapy (ACT) of cancer remains a clinical priority (page 2, left col. para. ). Alvarez ACT therapy is a highly promising strategy to treat cancer and memory stem T cells, due to their enhanced antitumor and self-renewal capacity have become potential candidate for ACT of cancer (page 1, left col.; Abstract). Alvarez teaches TSCM have greater antitumor effect in vivo compared to other more differentiated T cell subsets (page 2, left col. para. 1). One would have been motivated to combine the teachings of Escriba-Garcia and Alvarez because Escriba-Garcia references Alvarez for obtaining naïve T cells and culturing with IL7, IL15, and IL21 to prepare CAR-T cells.
Regarding 5 ng/ml of IL15, IL17, and IL21 of step (b) of claim 7 and “about 10 ng/mL” and “a concentration of 3 ng/mL – 10 ng/mL” of claim 9, Zoon teaches a method of expanding naïve T cells by culturing with 5 ng/mL each of IL7, IL15, and IL21 (page 8755, para. 1). Zoon teaches T cells expanded in this concentration of IL7/15/21 have a large proliferative capacity, which show great promise for producing large numbers of effective anti-tumor T cells for future human trials (Abstract; page 8746, para. 2; page 8748; page 8756, para. 3). Zoon teaches 628 million naïve T cells could be obtained by culturing with IL7/15/21 (page 8748; page 8749, para. 1; Figure 4b). Zoon teaches adoptive immunotherapy has demonstrated promising results in multiple murine tumor models but a regimen that optimizes both T cell expansion as well as tumor regression for human therapy remains elusive (page 8745, para. 1). Zoon teaches naïve T cells could be expanded with exposure to IL7 and IL15 and these T cells cure melanoma metastases and are similar to CAR T cells (page 8745, para. 2).
It would have been obvious prior to the effective filing date of the invention as claimed for the person or ordinary skill in the art to combine the teachings of Escriba-Garcia regarding a method of producing CAR-T cells comprising culturing activated naïve T cells in IL7, IL15, and IL21 to obtain Tscm cells and transducing the cultured cells with a lentiviral vector encoding a CAR with the teachings of Alvarez regarding a method of enriching CCR7+CD45RA+ cells and excluding γ/[Symbol font/0x64] T cells from PBMCs and culturing activated naïve T cells in IL7, IL15, and IL21 to generate and expand TSCM cells with the teachings of Zoon regarding a method of expanding naïve T cells by activating and culturing with 5 ng/mL each of IL7, IL15, and IL21 to arrive at the claimed method for preparing CAR-T cells, the method comprising: (a) enriching naive T (Tn) cells with exclusion of γ/[Symbol font/0x64] T cells from peripheral blood mononuclear cells (PBMCs) to generate a Tn cell-rich cell population, wherein the Tn cells comprise CCR7+CD45RA+ cells; (b) amplifying the Tn cell-rich cell population in the presence of IL15, IL7 and IL21 to obtain cultured T cells, wherein IL15 is at a concentration of 5 ng/ml - 10 ng/ml, IL 7 is at a concentration of 1 ng/ml -10 ng/ml, and IL21 is at a concentration of 5 ng/ml -10 ng/ml; and (c) performing engineering modification on the cultured T cells after step (b) to prepare CAR-T cells. One would have been motivated to combine the teachings of Escriba-Garcia, Alvarez, and Zoon in a method to produce a large quantity of CAR-T cells for cancer therapy as Escriba-Garcia teaches application of adoptive immunotherapy with CAR-T cells remains a challenge and Alvarez teaches identification of reproducible methods to generate and expand large numbers of TSCM for adoptive T cell therapy of cancer remains a clinical priority and Zoon teaches adoptive immunotherapy has demonstrated promising results in multiple murine tumor models but a regimen that optimizes both T cell expansion as well as tumor regression for human therapy remains elusive. One would have a reasonable expectation of success in combining the teachings as Escriba-Garcia teaches the method produces CAR-TSCM cells with potent antitumor efficacy against PTCL in vitro suggesting the potential to improve the outcome of patients with CD30+ PTCL through adoptive therapy and Alvarez teaches the combination of IL7/15/21 results in 0.7 x 106 TSCM cells which may have relevant clinical implications for the generation of TSCM for adoptive cell therapy of patients with cancer and Zoon teaches 628 million naïve T cells could be obtained by culturing with IL7/15/21 and Zoon teaches naïve T cells could be expanded with exposure to IL7 and IL15 and these T cells cure melanoma metastases and are similar to CAR T cells.
7. Claim(s) 11 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Escriba-Garcia (Escriba-Garcia, L., et. al. Haematologica: 22nd Congress of the European-Hematology-Association; Madrid, Spain; June 22 – 25, 2017, p. 336, S816; previously cited), hereinafter Escriba-Garcia in view of Alvarez (Alvarez-Fernández, Carmen, et al. Journal of translational medicine 14.1 (2016): 214; previously cited), hereinafter Alvarez as evidenced by StemCell (StemCell: (09/25/2016). "EasySep Human Naïve CD4+ T Cell Isolation Kit." https://www.stemcell.com/easysep-human-naive-cd4-t-cell-isolation-kit.html,. Accessed 06/02/2026.), hereinafter StemCell in view of Zoon (Zoon CK, et. al. Int J Mol Sci. 2015 Apr 20;16(4):8744-60), hereinafter Zoon as applied to claims 7 – 9 above, and further in view of Wang (Wang, Chun-Meng, et al. Clinical Cancer Research 23.5 (2017): 1156-1166; previously cited), hereinafter Wang.
Escriba-Garcia in view of Alvarez and Zoon make obvious the limitations of claim 7 as set forth above.
Escriba-Garcia teaches the CD8+ CD30 CAR-TSCM cells conferred specific cytolytic activity in vitro with tumor cell death 92.6% versus untransduced TSCM (page 336, left col. S816, Results). Escriba-Garcia teaches CD30 is expressed lymphomas and by activated normal cells but no other healthy tissues (page 336, left col. Background). Zoon teaches adoptive immunotherapy with the expanded T cells by infusing the cells obtained from mice into the mice (“administered” of claim 11 and “autologous or allogeneic” of claim 12) and the T cells are similar to CAR T cells (page 8745, para. 2; page 8755, para. 2) but does not teach the cells are CAR-T cells or are obtained from PBMCs.
Regarding “CAR-T cells are administered to a patient” of claim 11 and “autologous” of claim 12, Wang teaches administering CD30 CAR-T cells to patients (claim 11) with relapsed or refractory Hodgkin lymphoma where the CD30 CAR T-cells were generated from the PBMCs of each patient (claim 12) (Abstract; page 1157, left col. para. 1 – 2 and right col. para. 1; page 1158, right col. para. 2). Wang teaches of 18 patients who received CD30 CAR-T cells, 7 achieved partial remission and 6 had stable disease (page 1162, right col.; Table 2). Wang teaches CD30 CAR-T cells were well tolerated, without severe toxicity, can traffic to tumor sites, and yields a high clinical benefit to some extent for patients (page 1165, left col. para. 2). Wang teaches patients with Hodgkin lymphoma who are refractory to or relapse after the first-line treatment or autologous stem cell transplantation, the prognosis is rather poor and so it is imperative to develop novel approaches to improve the prognosis for these patients (page 1156, right col. para. 1). Wang teaches CD30 is selectively overexpressed in malignant Hodgkin and Reed-Sternberg cells and exhibits very low expression in normal tissues, rendering CD30 a promising target for novel treatment strategy (page 1156, right col. para. 2).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Escriba-Garcia regarding a method of producing CAR-T cells comprising culturing activated naïve T cells in IL7, IL15, and IL21 to obtain Tscm cells and transducing the cultured cells with a lentiviral vector encoding a CAR with the teachings of Alvarez regarding a method of enriching CCR7+CD45RA+ cells and excluding γ/[Symbol font/0x64] T cells from PBMCs and culturing activated naïve T cells in IL7, IL15, and IL21 to generate and expand TSCM cells with the teachings of Zoon regarding a method of expanding naïve T cells by activating and culturing with 5 ng/mL each of IL7, IL15, and IL21 and administering the expanded T cells to a subject with the teachings of Wang regarding administering autologous CD30 CAR T-cells to patients with relapsed or refractory Hodgkin lymphoma to arrive at the claimed method where CAR-T cells from autologous or allogeneic PBMCs are administered to a patient. One would have been motivated to combine the teachings of Escriba-Garcia, Alvarez, Zoon and Wang in a method to produce CAR-T cells for cancer therapy as Wang teaches in patients with Hodgkin lymphoma who are refractory to or relapse after the first-line treatment or autologous stem cell transplantation, the prognosis is rather poor and so it is imperative to develop novel approaches to improve the prognosis for these patients. One would have a reasonable expectation of success in combining the teachings as Wang teaches CD30 CAR-T cells were well tolerated, without severe toxicity, can traffic to tumor sites, and yield a high clinical benefit to some extent for patients.
Applicant’s Arguments/ Response to Arguments
8. Applicant Argues: Applicant asserts that the Examiner has failed to establish a case of obviousness because the cited references fail to teach amended claim 7.
Response to Argument: This is not found persuasive because Alvarez teaches the method of isolating naïve T cells excludes γ/[Symbol font/0x64] T cells as evidenced by StemCell.
Applicant Argues: Applicant asserts that a skilled artisan would not have been motivated to combine Escriba-Garcia and Alvarez with Xu.
Response to Argument: The previous rejection of claims 7 – 9 citing the teachings of Xu has been withdrawn in view of the amendment to claim 7 narrowing the concentration range of cytokines used for culturing. In the new rejection set forth above, Zoon teaches culturing naïve T cells with 5 ng/mL each of IL7, IL15, and IL21 (page 8755, para. 1) and this results in 628 million naïve T cells (page 8748; page 8749, para. 1; Figure 4b), while Alvarez teaches the combination of IL7/15/21 results in 0.7 x 106 TSCM cells. Therefore, a skilled artisan would be motivated to combine Escriba-Garcia, Alvarez, and Zoon to produce more naïve T cells/Tscm cells for cancer therapy as Escriba-Garcia teaches application of adoptive immunotherapy with CAR-T cells remains a challenge and Alvarez teaches identification of reproducible methods to generate and expand large numbers of TSCM for adoptive T cell therapy of cancer remains a clinical priority and Zoon teaches adoptive immunotherapy has demonstrated promising results in multiple murine tumor models but a regimen that optimizes both T cell expansion as well as tumor regression for human therapy remains elusive.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZANNA M BEHARRY whose telephone number is (571)270-0411. The examiner can normally be reached Monday - Friday 8:45 am - 5:45 pm.
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/ZANNA MARIA BEHARRY/Examiner, Art Unit 1632
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