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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 January 20, 2026 has been entered.
Application Status
The claims filed on January 20, 2026 are acknowledged. Claims 1 and 28 have been amended. Claims 26-27 and 34 have been canceled. Claims 35-42 and 45 remain withdrawn from consideration pursuant to a Restriction Requirement.
Claims 1-14, 16-25, 28-33, 35-42, and 45 are pending. Claims 1-14, 16-25, and 28-33 are under examination herein.
Claim Rejections Withdrawn
All prior rejections of claims 26-27 and 34 are rendered moot by the cancellation of the claims.
MAINTAINED CLAIM REJECTIONS
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.
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.
(1)
Claims 1-2, 5-7, 9-10, 12-14, 16-19, 21, 23-25, 28-31, and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Enoki (US 2010/0068192 A1; cited in PTO-892 mailed April 11, 2024) in view of Podack (Annals New York Academy of Sciences (2002) 975: 101-113; cited in IDS), Kennedy (Immunology (2006) 118(2): 143-152), and Alvarez-Fernández (Journal of Translational Medicine (2016) 14: 214; cited in IDS). This rejection has been updated to reflect Applicant's claim amendments.
Enoki discloses a method for preparing a T cell population expressing CD45RA and CCR7 (also known as CD197), wherein the method includes the step of culturing a T cell population in the presence of fibronectin or a fragment thereof and an anti-CD3 antibody (Abstract; ¶ 0017; claims 1-2 and 5-6), relevant to instant claims 1, 24, and 28. Enoki teaches that CD45RA and CCR7 are cell surface antigen markers of lymphocytes known to be expressed in undifferentiated cells, e.g., naïve T cells (¶ 0072). Such CD45RA+/CCR7+ T cells can be classified into undifferentiated cells, i.e., naïve T-like cells, before differentiation into memory T cells. Naïve T-like cells have increased survival, proliferation, and tumor accumulation and are useful for cell therapy (¶ 0072). The anti-CD3 antibody (at a final concentration of 5 μg/mL or 5,000 ng/mL) and fibronectin fragment (CH-296; at a concentration of 25 μg/mL) are immobilized on the culture container (Example 1, ¶ 0137-0139; ¶ 0087), relevant to instant claims 10, 13-14, and 16-17. RetroNectin® can be used to improve gene-transducing efficiency (¶ 0100). Enoki discloses, “In the present invention, it is preferable that the culture in the presence of fibronectin, a fragment thereof or a mixture thereof is carried out in the presence of a CD3 ligand, from the viewpoint of effectively stimulating a TCR-CD3 complex with T cells to proliferate the cells” (¶ 0080). The method comprises a subsequent step in which the cell is cultured in the absence of the CD3/TCR complex agonist and fibronectin fragment (¶ 0139), relevant to instant claim 2.
CD8+/CD4- T cells are produced in the method (e.g., Examples 1 and 7; Tables 4-5), relevant to instant claims 6-7. The method disclosed by Enoki further comprises the step of transducing a foreign gene encoding a T-cell receptor (TCR) or a chimeric antigen receptor (CAR) into the cell population (claims 10-11; ¶ 0098, 0107), such that the cell expresses a CAR or TCR, relevant to instant claim 5.
Enoki discloses culturing the cells in a medium containing melanoma antigen MART-1-derived HLA-A2.1 binding peptide (i.e., an HLA/peptide complex; Example 5, ¶ 0191), relevant to instant claims 9 and 12.
Relevant to instant claims 21, 23, 31, and 33, Enoki discloses that the medium used in the method for preparing a T cell population of the present invention is not particularly limited, and known media prepared by mixing components necessary for expanding T cells (e.g., a medium containing cytokines such as IL-12 or IL-7) can be used (¶ 0083).
Enoki additionally teaches that expansion of T cells is carried out in the presence of fibronectin, a fragment thereof, or a mixture thereof (¶ 0075). Enoki discloses a method in which a T cell population is expanded (Example 1 (3), ¶ 0140-0142) in a plate immobilized with an anti-human CD3 antibody or a plate immobilized with an anti-human CD3 antibody and fibronectin. The expansion folds of the T cell population resulting from the culture equipment immobilized with fibronectin were consistently higher than that resulting from culture equipment without fibronectin (Table 1; ¶ 0142).
Enoki further teaches a CD3+ T cell population obtained by the methods of the invention (e.g., claims 16-17), relevant to instant claim 25.
However, Enoki does not disclose culturing a CD3+ cell in the presence of a CD30 agonist or IL-21, nor a second step comprising culturing the CD3+ cell from the previous step in the absence of a CD3/TCR complex agonist and fibronectin and in the presence of a CD30 agonist.
Podack teaches that CD30 regulates CD8 cytotoxic T lymphocyte function and survival during memory responses and is important for proliferation and clonal expansion (Abstract; Figure 1; pages 101-102, text), relevant to the methods of instant claims 1, 26, and 28. Using CD30-Ligand (CD30-L) knockout mice, Podack illustrates that CD30 plays a role in primary clonal expansion of CD8 cytotoxic T lymphocytes (Figure 11; page 109-110, text), relevant to instant claims 6-7 and 28-30. Using an NK like lymphoma line YT that is a useful model for cytotoxic cells, Podack also illustrates that an agonistic anti-CD30 antibody (“C10”) upregulates CCR7 (also called CD197; pages 103-107, text; Figure 7), relevant to instant claims 1, 18-19, and 24.
Further regarding CD30, Kennedy teaches: “Early in vitro studies led to the classification of CD30 as a T-cell ‘costimulatory receptor’ based on observations that immobilized CD30-specific antibodies or CD30L-transfected cells enhance the proliferation of human T cells in response to suboptimal stimulation via the TCR. The physiological relevance of these early findings is not clear, because anti-human or anti-mouse CD30L mAb do not appear to block antigen-presenting cell-dependent T-cell proliferation and/or function in a variety of in vitro systems. As CD30 is expressed on T cells rather late after in vitro activation, it is possible that CD30/CD30L interactions occurring relatively late after antigen encounter promote T-cell survival and/or establishment of strong memory responses” (page 145, right column). Thus, continued stimulation with a CD30 agonist would serve to maintain a population of T cells and to generate memory responses in the T cells, the latter of which could be advantageous for adoptive T cell therapy.
Alvarez-Fernández discloses that a short CD3/CD28 costimulation combined with IL-21 enhances the generation of human memory stem T cells for adoptive immunotherapy. Alvarez-Fernández teaches that the use of less differentiated T cells with extensive replicative capacity, in particular, memory stem T cells (TSCM) that are CCR7+ and CD45RA+, show increased proliferation, self-renewal, persistence, and anti-tumor effect relative to other more differentiated T cell subsets (Background, pages 1-2). Alvarez-Fernández further teaches, “…studies demonstrated the generation and expansion of CD8+ TSCM from naïve T cells through CD3/CD28 costimulation in combination with IL-7 and IL-15 cytokines. However, prolonged in vitro costimulation decrease the expression of memory markers substantially (e.g., CD62L, CCR7 or CD27) leading to a swift [sic] to more differentiated T cells. For these reasons, identification of reproducible methods to generate and expand large numbers of TSCM for [adoptive T cell therapy] of cancer remains a clinical priority” (Background, page 2). To this end, Alvarez-Fernández cultured naïve CD8+ TSCM with IL-7/IL-15 and altered the length of CD3/CD28 costimulation on the maintenance of the TSCM phenotype in vitro, and observed that a short CD3/CD28 costimulation (48h) resulted in significantly greater frequencies of CD8+ TSCM compared with long costimulation (10 days) (Results, page 3; Figure 2b), relevant to instant claims 2, 21, 28, and 31.
Alvarez-Fernández also analyzed the effect of IL-21 on in vitro generation and maintenance of TSCM and observed that IL-21 significantly increased the percentage of CD8+ TSCM cultured under short CD3/CD28 costimulation conditions relative to the long costimulation condition (Results, page 3; Figure 3b), relevant to instant claims 1-2. Alvarez-Fernández also demonstrated that the addition of IL-21 to naïve T cell culture under both CD3/CD28 costimulation conditions (48h and long) significantly increased TSCM expansion, with the combination of short costimulation and IL-21 leading to the greatest expansion of total CD8+ TSCM (Results, page 5; Figure b).
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to carry out a method of enhancing survival of or maintaining enhanced survival of CD3+/CD8+ cells, comprising the steps of culturing the CD3+/CD8+ cell in the presence of a CD3/TCR agonist (e.g., anti-CD3 antibody) and fibronectin (as taught by Enoki), further in the presence of a CD30 agonist (as taught by Podack and Kennedy) and IL-21 (as taught by Alvarez-Fernández). The skilled artisan would have been motivated to do so because:
Culturing CD8+ cells in the presence of an anti-CD3 antibody and fibronectin stimulates cell proliferation and expansion (as taught by Enoki);
Agonism of CD30, e.g., by an anti-CD30 agonist antibody, upregulates CCR7 (CD197) expression (as taught by Podack), which was desired by Enoki, and promotes the proliferation and survival of T cells (as taught by Kennedy), and further, CCR7-expressing TSCM show increased proliferation, self-renewal, persistence, and anti-tumor effect relative to other more differentiated T cell subsets, which is advantageous for adoptive T cell immunotherapies (as taught by Alvarez-Fernández); and
IL-21 increases proliferation and expansion of CD8+ T cells alone and when combined with CD3 co-stimulation (as taught by Alvarez-Fernández).
Further, the skilled artisan would have been motivated to perform a short co-stimulation period with the anti-CD3 antibody (instead of a long co-stimulation period) because shorter CD3 co-stimulation resulted in increased proliferation and expansion of T cells (as taught by Alvarez-Fernández), especially when combined with IL-21. Continued CD30 agonism, e.g., with an anti-CD30 antibody, would serve to promote expansion and maintenance of the T cells.
There would have been a reasonable expectation of success because the prior art recognized the suitability of each of agonism of the CD3/TCR complex (via an anti-CD3 antibody), fibronectin, CD30 agonism (via an anti-CD30 antibody), and IL-21 for the purposes of proliferating and expanding CD3+/CD8+ cells, and because combining equivalents known for the same purpose to be used for the same purpose naturally flows from their having been individually taught in the prior art. See MPEP § 2144.06 and § 2144.07.
Response to Arguments
Applicant's arguments filed January 20, 2026 have been fully considered but they are not persuasive.
Applicant asserts that the presently claimed invention is based in part on “the unexpected discovery that culturing the CD3+ cells in the presence of a CD30 agonist can unexpectedly increase CD197 expression, and unexpectedly increase in vivo survival of the CD3+ cells so cultured, compared to a control CD3+ cells identically culture in the absence of the CD30 agonist”, and that none of the cited references by the Examiner, alone or in combination, teach these technical effects (Remarks at pages 7-8), which are summarized in the excerpt below (from Remarks at page 9):
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Applicant submits that in contrast to the above technical effects, Enoki does not illustrate lasting CD3+ cell survival in vivo when cultured in the presence of a CD30 agonist, fibronectin or a variant thereof, and IL-21 or an apoptotic inhibitor, and that this deficiency is not remedied by any of Podack, Kennedy, or Alvarez-Fernández (Remarks at pages 10-12).
In response to Applicant's arguments regarding the unexpected nature of the observations that culturing CD3+ cells in the presence of a CD30 agonist increase CD197 expression and in vivo survival, it is held that these observations were previously identified by Podack and Kennedy as set forth in the rejection above. Furthermore, Enoki sets forth the following (¶ 0072):
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The excerpt above from Enoki suggests that it was understood in the art before the time of filing of the instantly claimed invention that T cells expressing CD45RA and CCR7 have an increased survival rate and proliferation, as well as properties that make them suitable as anti-tumor agents (i.e., “effect of accumulation to a tumor, production rate of tumor-specific effector cells, in a living body”) when administered in vivo. Enoki also states that such cells are produced in high numbers in the preparation method of the invention. Accordingly, administering a treatment regimen that increases CCR7 expression (e.g., an anti-CD30 agonist) would be expected to confer these advantages, which are presently recited in amended claims 1 and 28.
However, even if Applicant remains unconvinced that any of Enoki, Podack, Kennedy, or Alvarez-Fernández teach or suggest that culturing CD3+ cells in the presence of an anti-CD3 antibody, fibronectin, a CD30 agonist, and an IL-21 inhibitor increases in vivo survival and confers anti-tumor activity, it is further noted that MPEP § 2145 (Il) sets forth the following: “[m]ere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention”. The steps performed in the instantly claimed methods remain the same and were earlier suggested and/or disclosed in the art. It is further noted that MPEP § 2144 (IV) sets forth: “The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006)”.
Further regarding Applicant's assertions regarding unexpected anti-tumor effect and enhanced survival (Remarks at page 10), the methods of claims 1 and 28 do not appear to be entirely commensurate in scope with the corresponding methods described in the disclosure as having a superior anti-tumor effect and enhancing survival. Applicant's disclosure at page 77 (Example 6) states that the groups under comparison in Figure 21 were Nalm6 xenograft mice that were administered one of (1) iPS cell-derived γδ anti-CD19 CAR-T cells that were treated with an anti-CD3 agonist antibody, RetroNectin®, and an anti-CD30 agonist antibody, and transduced with IL-151, and delivered in HBSS buffer, or (2) an equal amount of HBSS buffer (control). Control group mice died within three weeks, whereas the treated mice survived for at least six weeks (page 77). It is not unexpected that animals receiving only a buffer solution (i.e., as in the control group) did not have prolonged survival after xenografting. The independent claims as amended do not require expression of a CAR against a tumor-associated antigen. Of note, the independent claims also recite that the CD3+ cell is cultured in the presence of (i.e., not transduced with) IL-15. Would the stated “anti-tumor effect” still be observed if the T cells administered in the method of the disclosure did not express a CAR? Given the study design, it is not possible to disentangle whether any apparent anti-tumor effect and/or enhanced survival is due to expression of a CAR against a tumor-associated antigen in the T cell, or the exogenous expression of IL-15 (i.e., a factor that enhances CD8+ T cell survival) on the T cell, or the culturing of the T cell with the combination of anti-CD3/RetroNectin®/anti-CD30, or a combination of these variables. Based on the cited references of Zeng (infra), Li (infra), and Brincks (see footnote), the exogenous IL-15 expression and anti-CD30 agonist would each be expected to prolong survival/maintenance of the CD3+ cells. Based on the state of the prior art, the expression of an anti-CD19 CAR would be expected to confer anti-tumor activity.
For these reasons, the rejection is maintained.
(2)
Claims 3-5 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Enoki (US 2010/0068192 A1; supra) in view of Podack (Annals New York Academy of Sciences (2002) 975: 101-113; supra), Kennedy (Immunology (2006) 118(2): 143-152; supra), and Alvarez-Fernández (Journal of Translational Medicine (2016) 14: 214; supra) as applied to claims 1-2, 5-7, 9-10, 12-14, 16-19, 21, 23-26, 28-31, and 33 above, and further in view of Chang (PLOS One, 2014, 9(5): e97335; cited in PTO-892 mailed April 11, 2024).
The teachings of Enoki, Podack, Kennedy, and Alvarez-Fernández are recited in the 35 U.S.C. § 103 rejection above. However, Enoki does not explicitly teach that the CD3+ cell is derived from an induced pluripotent stem (iPS) cell.
Chang discloses antigen-specific T lymphocytes derived from human iPS cells that have a broad TCR repertoire (Abstract). Using in vitro methods, Chang produced mature T cells, derived from human iPS cells, that express CD3, CD8, and TCR-γδ (Abstract; Results, pages 3-5; Figure 2). Chang additionally teaches, “Genetic modification of patient-specific [human iPS cells] followed by differentiation to mature T lymphocytes may provide new treatment options for patients with inherited or acquired immune deficiencies. Also, the addition of chimeric antigen receptor sequences (CARs) to patient-specific [human iPS cells] may provide a method to produce virtually unlimited numbers of T lymphocytes designed to target specific tumor types” (Discussion, page 9).
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to use a CD3+ cell derived from an iPS cell (as taught by Chang) in a method of enhancing in vivo survival that comprises culturing a CD3+ cell in the presence of a CD3/TCR complex agonist, fibronectin, a CD30 agonist, and IL-21, such as collectively taught by Enoki, Podack, Kennedy, and Alvarez-Fernández. The skilled artisan would have been motivated to do so because Chang teaches that patient-specific iPS cells, once further differentiated into mature T lymphocytes, may provide new treatment options for patients with inherited or acquired immune deficiencies. It would be further obvious that some CD3+ cells used in the method, derived from an iPS cell, express TCR-γδ, based on the observations of Chang. There would have been a reasonable expectation of success because the skilled artisan would have recognized the suitability of an iPS cell for carrying out the instantly claimed method of producing a CD3+ cell because iPS cells express CD3.
Response to Arguments
Applicant's arguments filed January 20, 2026 have been fully considered but they are not persuasive.
Applicant submits that the previous Office Action fails to establish a prima facie case of obviousness at least because a motivation to combine the teachings of the cited references with any reasonable expectation of success has not been identified (Remarks at pages 12-13), as summarized in the Response above. Applicant further argues that Chang does not remedy these deficiencies and is “only used by the Office to teach that ‘CD3+ cells are derived from induced pluripotent stem cells (iPSCs)”. Applicant submits that Chang does not teach or suggest that CD3+ cells would survive longer in vivo when produced by culturing in the presence of anti-CD3, fibronectin, a CD30 agonist, and IL-21 (Remarks at page 13).
In response, it is held that Chang discloses a clear utility of using a CD3+ CD8+ cell derived from an iPS cell for the instantly claimed method, specifically that patient-derived iPS cells provide new treatment options for those with inherited or acquired immune deficiencies, and further, since said cells express CD3, it would be recognized by one of ordinary skill in the art that these cells are suitable for a method of increasing survival of a CD3+ cell.
For these reasons, the rejection is maintained.
(3)
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Enoki (US 2010/0068192 A1; supra) in view of Podack (Annals New York Academy of Sciences (2002) 975: 101-113; supra), Kennedy (Immunology (2006) 118(2): 143-152; supra), and Alvarez-Fernández (Journal of Translational Medicine (2016) 14: 214; supra) as applied to claims 1-2, 5-7, 9-10, 12-14, 16-19, 21, 23-26, 28-31, and 33 above, and further in view of Van Wauwe (The Journal of Immunology, 1984, 133(1): 129-132; cited in PTO-892 mailed April 11, 2024).
The teachings of Enoki, Podack, Kennedy, and Alvarez-Fernández are recited in the 35 U.S.C. § 103 rejection above. Enoki further teaches that the CD3 ligand is not particularly limited, and may be exemplified by, for example, an anti-CD3 antibody such as OKT3 (¶ 0081). However, Enoki does not explicitly teach that the anti-CD3 antibody used in the method of the invention is produced from an UCHT1 clone.
Van Wauwe teaches that OKT3 and UCHT1 monoclonal antibodies recognize the same human T cell surface antigen and induce proliferation in T lymphocytes (Abstract). Van Wauwe additionally teaches, “We have previously described that OKT3 and UCHT1 monoclonal antibodies exert mitogenic effects on human blood T cells. The antibodies trigger mitogenesis by interaction with the same antigenic structure on the T cell surface, as evidenced by two-directional co-capping, competitive binding, and immunoprecipitation experiments” (Introduction).
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to substitute an OKT3-derived anti-CD3 antibody with a UCHT1-derived anti-CD3 antibody (as taught by Van Vauwe) in a method of enhancing in vivo survival of a CD3+ cell that comprises culturing a CD3+ cell in the presence of a CD3/TCR complex agonist, fibronectin, a CD30 agonist, and IL-21, such as the method taught by the combined teachings of Enoki, Podack, Kennedy and Alvarez-Fernández. The skilled artisan would have been motivated to do so because of the teachings of Van Vauwe, who discloses that anti-CD3 antibodies derived from OKT3 and UCHT1 both exert mitogenic effects on human blood T cells through their recognition of the same antigenic structure on the T cell surface. There would have been a reasonable expectation of success because both antibodies are in effect functional equivalents being used for the same purpose.
Response to Arguments
Applicant's arguments filed January 20, 2026 have been fully considered but they are not persuasive.
Applicant submits that the previous Office Action fails to establish a prima facie case of obviousness at least because a motivation to combine the teachings of the cited references with any reasonable expectation of success has not been identified (Remarks at pages 13-14), as summarized in the Response above. Applicant further argues that Van Wauwe does not remedy these deficiencies and is “only used by the Office to teach that ‘OKT3 and UCHT1 monoclonal antibodies recognize the same human T cell surface antigen (CD3) and induce proliferation in T lymphocytes’” (Remarks at pages 13-14). Applicant submits that Van Wauwe does not teach or suggest that CD3+ cells would survive longer in vivo when produced by culturing in the presence of anti-CD3, fibronectin, a CD30 agonist, and IL-21 (Remarks at page 14).
In response, it is held that Van Wauwe clearly establishes that OKT3 and UCHT1 are functional equivalents, and accordingly, one of ordinary skill in the art would recognize from these teachings that either anti-CD3 antibody could be used interchangeably to achieve the same desired functional effect, which in the present case is activation of the CD3+ cell.
For these reasons, the rejection is maintained.
(4)
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Enoki (US 2010/0068192 A1; supra) in view of Podack (Annals New York Academy of Sciences (2002) 975: 101-113; supra), Kennedy (Immunology (2006) 118(2): 143-152; supra), and Alvarez-Fernández (Journal of Translational Medicine (2016) 14: 214; supra) as applied to claims 1-2, 5-7, 9-10, 12-14, 16-19, 21, 23-26, 28-31, and 33 above, and further in view of Bowen (The Journal of Immunology, 1993, 151(11): 5896-5906; cited in PTO-892 mailed April 11, 2024).
The teachings of Enoki, Podack, Kennedy, and Alvarez-Fernández are recited in the 35 U.S.C. § 103 rejection above. However, Podack does not explicitly teach that the concentration of the CD30 agonist antibody or binding fragment thereof in the medium is 1-1000 ng/mL.
Bowen recites culturing YT cells under normal culture conditions in the anti-CD30 monoclonal antibody “C10” at concentrations of 1 ng/mL, 10 ng/mL, 100 ng/mL, and 1 μg/mL (e.g., Figure 1). The C10 antibody inhibits YT cytotoxicity for Raji target cells (Abstract; Results; Figure 1).
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to administer an anti-CD30 agonist antibody at a concentration of 1-1000 ng/mL (as taught by Bowen) in a method of enhancing in vivo survival of a CD3+ cell that comprises culturing the CD3+ cell in the presence of a CD3/TCR complex agonist, fibronectin, a CD30 agonist, and IL-21, such as the method taught by the combined teachings of Enoki, Podack, Kennedy, and Alvarez-Fernández. The skilled artisan would have been motivated to do so because Bowen teaches that various concentrations of an agonistic anti-CD30 monoclonal antibody (“C10”) inhibit cytotoxicity in a cell line (“YT”) that is a useful model for cytotoxic cells. There would have been a reasonable expectation of success because CD30 regulates cytotoxicity and facilitates clonal expansion of CD8+ cells.
Response to Arguments
Applicant's arguments filed January 20, 2026 have been fully considered but they are not persuasive.
Applicant submits that the previous Office Action fails to establish a prima facie case of obviousness at least because a motivation to combine the teachings of the cited references with any reasonable expectation of success has not been identified (Remarks at pages 14-15), as summarized in the Response above. Applicant further argues that Bowen does not remedy these deficiencies and is “only used by the Office to teach that ‘culturing YT cells under normal culture conditions in the anti-CD30 monoclonal antibody “C10” at concentrations of 1 ng/ml, 10 ng/ml, 100 ng/ml, and I μg/ml’” (Remarks at pages 14-15). Applicant submits that Bowen does not teach or suggest that CD3+ cells would survive longer in vivo when produced by culturing in the presence of anti-CD3, fibronectin, a CD30 agonist, and IL-21 (Remarks at pages 14-15).
In response, it is held that Bowen establishes that various working concentrations of the anti-CD30 antibody “C10” exert functional effects in a cell line that is useful for modeling cytotoxic cells. Furthermore, it is noted that determining and optimizing a working concentration of antibody for use in the instantly claimed method would be achieved through routine and conventional methods within the technical skill of one of ordinary skill in the art.
For these reasons, the rejection is maintained.
(5)
Claims 21-22 and 28-32 are rejected under 35 U.S.C. 103 as being unpatentable over Enoki (US 2010/0068192 A1; supra) in view of Podack (Annals New York Academy of Sciences (2002) 975: 101-113; supra), Kennedy (Immunology (2006) 118(2): 143-152; supra), and Alvarez-Fernández (Journal of Translational Medicine (2016) 14: 214; supra) as applied to claims 1-2, 5-7, 9-10, 12-14, 16-19, 21, 23-26, 28-31, and 33 above, and further in view of Zeng (Journal of Experimental Medicine (2005) 201(1): 139-148; cited in PTO-892 mailed September 20, 2024) and Li (Journal of Leukocyte Biology, 2007, 82: 142-151; cited in PTO-892 mailed September 20, 2024).
The teachings of Enoki, Podack, Kennedy, and Alvarez-Fernández are recited in the 35 U.S.C. § 103 rejection above. However, although Enoki recites production and expansion methods wherein the culture medium comprises IL-7 (¶ 0083), Enoki does not teach a method wherein the medium comprises the combination of IL-7, IL-15, and IL-18.
Zeng teaches that IL-21 was originally implicated as a regulator of T and B cell proliferation (Introduction, page 139), and that “IL-21 was initially reported to costimulate anti-CD3–activated murine thymocytes and mature murine T cells in vitro and to enhance the proliferative effects of IL-2, IL-7, and IL-15 even without the addition of anti-CD3” (Results, page 140). Zeng presents data illustrating that IL-21 acts synergistically with IL-15 to potently promote the proliferation of CD8+ T cells and augment interferon (IFN)-γ production in vitro (Abstract). Specifically, a marked increase in the proliferation and expansion of T cells is observed after culture with both IL-21 and IL-15 as compared to IL-15 alone, with the majority of expanded cells being CD8+ T cells (Figure 1; Results, page 140-141). By contrast, a similar synergistic effect on CD4+ T cells was not evident (Results, page 141; Figure 1D). Zeng additionally shows that IL-21 acts synergistically with IL-7 in CD8+ T cells but not in CD4+ T cells (Results, page 141; Figure 2). The teachings of Zeng further relate to instant claims 1, 21, and 28-31.
Li examined the role of IL-18 on proliferation and survival of CD8+ T cells. Li teaches that stimulation of T cells through CD3/TCR in the presence of cytokines such as IL-7 results in clonal expansion (Introduction, page 142). Li additionally teaches that IL-18 was previously shown to be involved in the activation, differentiation, and clonal expansion of CD4+ T cells (Introduction, page 142). Li illustrates that IL-18 increases proliferation and survival of CD8+ T cells that have been activated by immobilized anti-CD3 antibody in vitro (Abstract; Figure 2), relevant to instant claims 22 and 32.
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to carry out a method of enhancing or maintaining in vivo survival of a CD3+/CD8+ cell by culturing the cell in the presence of a CD3/TCR agonist (e.g., anti-CD3 antibody) and fibronectin (as taught by Enoki), a CD30 agonist (as taught by Podack and Kennedy), and IL-21 (as taught by Alvarez-Fernández), wherein the medium further comprises IL-7, IL-15, and IL-18 (as collectively taught by Zeng and Li). The skilled artisan would have been motivated to incorporate IL-7 and IL-15 because these cytokines exert synergistic effects on the proliferation and expansion of CD8+ T cells when combined with IL-21 (as taught by Zeng), thus demonstrating an advantage in comparison to IL-21 alone. The skill artisan would have been motivated to incorporate IL-18 because IL-18 increases proliferation and survival of CD8+ T cells that have been activated by an immobilized anti-CD3 antibody in vitro (as taught by Li), thus demonstrating an advantage in methods of proliferation and maintenance when compared to incubation without IL-18. There would have been a reasonable expectation of success because the art recognized the suitability of each of IL-7, IL-15, and IL-18 for the instantly claimed purpose of increasing proliferation and expansion of CD8+ T cells, and one of ordinary skill in the art would have recognized that Zeng and Li teach clear advantages for combining IL-7/IL-15 with IL-21 and combining IL-18 with anti-CD3, respectively.
Response to Arguments
Applicant's arguments filed January 20, 2026 have been fully considered but they are not persuasive.
Applicant submits that the previous Office Action fails to establish a prima facie case of obviousness at least because a motivation to combine the teachings of the cited references with any reasonable expectation of success has not been identified (Remarks at pages 15-16), as summarized in the Response above. Applicant further argues that Zeng does not remedy these deficiencies and is “only used by the Office to teach ‘IL-21 acts synergistically with IL-17 [and IL-15] in CD8+ T cells’”, and that Li is “only used by the Office to teach ‘that IL-18 increases proliferation and survival of CD8+ T cells that have been activated by immobilized anti-CD3 antibody in vitro’”, and “is silent regarding survival of the CD3-positive cells in vivo” (Remarks at pages 15-16). Applicant submits that Zeng and Li do not teach or suggest that CD3+ cells would survive longer in vivo when produced by culturing in the presence of anti-CD3, fibronectin, a CD30 agonist, and IL-21 (Remarks at pages 14-15).
In response, it is held that the teaching that CD3+ cells would survive longer in vivo when produced by culturing in the presence of anti-CD3, fibronectin, a CD30 agonist, and IL-21 are previously supplied by Enoki, Podack, Kennedy, and Alvarez-Fernández for the reasons summarized in the Response above. Zeng and Li are cited for separate motivations related to the dependent claims.
For these reasons, the rejection is maintained.
Citation of Relevant Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Muta (Immunological Research (2013) 57: 151-158) teaches that CD30 is among several co-stimulatory receptors that are activated in T cells upon T cell activation (page 152). Muta discloses, “CD30 signals augment T cell proliferation at low levels of in vitro TCR stimulation. Similar to other members of the TNFR family, CD30 engagement regulates T cell survival. For example, CD30 signaling regulates peripheral T cell responses, controlling T cell survival and down-regulating cytolytic capacity” (page 152).
Telford (Cellular Immunology (1997) 182: 125-136) teaches, “T cells activated by anti-CD3 antibodies for 48 h and then further cultured in the presence of IL-2 but absence of continued CD3/TCR stimulation underwent dramatic cell death approximately 4 days following removal of the TCR stimulus”, largely in the CD8+ T cell subset (Abstract). Telford further teaches that cell death was significantly attenuated when the CD8+ T cells were treated with a CD30 fusion protein comprising an extracellular domain of mouse CD30 joined to a mouse IgG1 at the hinge region (e.g., Abstract; Methods). Telford notes, “CD30 was found to be transiently expressed on CD8 T cells immediately prior to death” (e.g., Abstract).
Conclusion
No claims are allowed.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/Brad Duffy/Primary Examiner, Art Unit 1643
1 Brincks (F1000 Biology Reports (2010) 8(2): 67) teaches that IL-15 controls the maintenance of naïve and memory T cell populations, and promotes the survival of antigen-specific CD8+ T cells.