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 .
DETAILED ACTION
Amendments
In the reply filed 10/13/2025, Applicant has amended claims 13, 15, 16, 24, 25, 30, 34 and 36, canceled claims 1-12 and 14, and added new claims 37-41.
Claim Status
Claims 13 and 15-41 are pending.
Claims 20-23, 29, 33 and 35 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to non-elected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/05/2025.
Claims 13, 15-19, 24-28, 30-32, 34 and 36-41 are considered on the merits.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10/07/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. The corresponding signed and initialed PTO form 1449 has been mailed with this action.
New Claim Objections
Claims 13 and 24-25 are objected to because of the following informalities:
Claim 13, claim 24 and claim 25 recite the phrase “at least not less than”, in which the phrase “at least” and the phrase “not less than” are repetitive. It is recommended to remove one.
Appropriate correction is required.
Withdrawn Claim Rejections - 35 USC § 112
The prior rejection of claims 13, 15-19, 24-28, 30-32, 34 and 36 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn in light of Applicant’s amendment to the claims.
New 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.
Claims 40-41 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.
Claim 40 recites the limitation “the test subject” in line 2. There is insufficient antecedent basis for this limitation in the claim because the base claim 13 does not recite a test subject. Claim 41 is rejected as being dependent from claim 40 but not resolving the ambiguity.
Withdrawn Claim Rejections - 35 USC § 102 and 103
The prior rejections of claims 13, 15-19, 24-28, 30-32, 34 and 36 under 35 U.S.C. 102 (a)(1) and 103 set forth in the prior Office action mailed on 07/15/2025 have been withdrawn in light of Applicant’s amendment to claims 13, 24 and 25 to recite new limitation wherein T cells constituting the master cell bank of T cells or working cell bank of T cells can be proliferated at least not less than 1010 times by expansion culture of not more than 5 times”.
New 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.
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.
Rejection of TCR-iPSC-derived T cells
Claims 13, 18, 24, 26, 28, 37 and 39-41 are rejected under 35 U.S.C. 103 as being unpatentable over Minagawa et al., (Cell Stem Cell. 2018 November 15; 23: 850-858. Prior art of record), as evidenced by Nishimura et al., (Cell Stem Cell. 2013; 12: 114-126. Prior art of record) and in view of Leen et al., (Blood. 2013;121(26):5113-5123. Prior art of record).
With respect to independent claim 13 and independent claim 24, Minagawa teaches a method for transducing iPSCs with an antigen-specific TCR to make a TCR-iPSC, and teaches this TCR-iPSC is differentiated into CD8αβ T cells that show monoclonal expression of the transduced TCR (see e.g. abstract, also see Fig 3), thus teaches a method for producing a T cell product comprising CD8αβ T cells that are derived from a TCR-transduced iPSC in claim 13, and teaches a method comprising (1) a process of differentiating an iPSC free of a CAR gene into a T cell and (3) a process of characterization of the differentiated T cell in claim 24. Minagawa further teaches the induced CD8 T cells can be frozen and defrosted (see Fig 4F for the “frozen” sample and p. e4, para “Subcutaneous tumor animal model #4”), thus teaches (2) a process of stocking the differentiated T cell in claim 24.
Minagawa teaches two types of TCR-iPSCs that can be differentiated into two types of antigen-specific CD8αβ T cells (GPC3 and WT1, see e.g., p. 854, right col, para 1). Minagawa teaches these TCR-stabilized, regenerated CD8αβ T cells effectively inhibit tumor growth in xenograft cancer models and these approaches could contribute to safe and effective regenerative T cell immunotherapies (see e.g., abstract).
However, Minagawa is silent on constructing a master cell bank of T cells in claims 13 and 24.
Leen teaches a method for constructing a master cell bank of 32 virus-specific T cell (VST) lines for treating viral infection by cryopreserving the cell lines (abstract, see e.g., p. 5113, last para “Third-party T-cell bank” – p. 5114, right col, para 1). Leen teaches constructing and storing a bank of T cell lines with antigen-specificity is a feasible and safe approach that enables immediate and multicenter use for T cell therapy (p. 5113, right col, para 1 and abstract).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method for producing and providing a T cell product comprising T cells derived from a TCR-transduced iPSC and stocking the T cells disclosed by Minagawa, by combining the teaching of Leen to construct a master cell bank of the differentiated antigen-specific T cells with a reasonable expectation of success. Since Minagawa teaches the TCR-stabilized, regenerated CD8αβ T cells can be frozen and defrosted (see Fig 4F) and can effectively inhibit tumor growth in xenograft cancer models (see e.g., abstract), and since Leen teaches constructing and storing a bank of T cell lines with antigen-specificity is a feasible and safe approach that enables immediate and multicenter use for T cell therapy (p. 5113, right col, para 1 and abstract), one of ordinary skill in the art would have had a reason to construct and store a master cell bank of the TCR-stabilized, regenerated CD8αβ T cells of Minagawa in order to enable immediate use in multicenter to rapidly treat patients.
Regarding the new limitation that the T cells can be proliferated at least not less than 1010 times by expansion culture of not more than 5 times, it is noted that the limitation “be proliferated at least not less than 1010 times” is being examined as “be expanded at least 1010 folds”, and the limitation “expansion culture of not more than 5 times” is being examined as “expansion culture of not more than 5 stimulations” according to instant Figs 7-9 showing “fold expansion” in y-axis and figure legends indicating “arrows show the day when stimulation was started”).
Although Minagawa performs a proliferation assay of iPSC-derived CD8 T cells by a single stimulation (see Fig 3E), Minagawa is silent on assaying iPSC-T cell expansion capacity by multiple stimulations.
Nishimura discloses a method for reprogramming antigen-specific CD8+ T cells to pluripotency and redifferentiating the iPSCs into CD8+ T cells that have a high proliferative capacity and elongated telomeres (e.g., abstract). Regarding the proliferative capacity of the iPSC-derived T cells, Nishimura discloses “fewer than 105 T lineage cells were obtained” from iPSCs, “they could be expanded to >108 cells with the first stimulation”. “We assessed the expansion rate induced by the second stimulation” and “these cells expanded from 100-fold to 1,000-fold” (p. 119, last para. “Generation of Highly Proliferative T Cells through T-iPSCs”). Thus, Nishimura discloses the derivative T cells are expanded 103 – 104 folds by the first stimulation (>108 / fewer than 105), and are expanded another 100-fold to 1,000-fold by the second stimulation, i.e., the iPSC-derived T cells are expanded 105 – 107 folds by expansion culture of 2 stimulations. Nishimura discloses that “even after 100-to-1,000-fold expansions, some cells still expressed central memory T cell markers” and “with passage through the iPSC state, wherein telomerase activity is quite high, re-elongation of shortened telomeres… gives the redifferentiated T cells high replicative potential” (p. 119, last para. “Generation of Highly Proliferative T Cells through T-iPSCs”).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have immediately expected that the iPSC-derived T cells of Minagawa could likely be expanded at least 1010 folds by expansion culture of not more than 5 stimulations as evidenced by Nishimura with a reasonable expectation of success. Since Minagawa teaches the T cells are derived from an iPSC, and since Nishimura evidences that iPSC-derived T cells are expanded 105 – 107 folds by expansion culture of just 2 stimulations because “with passage through the iPSC state, wherein telomerase activity is quite high, re-elongation of shortened telomeres gives the redifferentiated T cells high replicative potential” (see above), one of ordinary skill in the art would have had a reasonable expectation of success in appreciating that the iPSC-derived T cells of Minagawa could be expanded 105 – 107 folds by expansion culture of just 2 stimulations as evidenced by Nishimura, and thus could likely be expanded at least 1010 folds by expansion culture of 4 to 5 stimulations.
With respect to claim 18 directed to a step of expansion culturing a T cell, Minagawa teaches the generated CD8αβ T cells are sorted and expanded (p. e3, para “T cell differentiation from iPSCs”).
With respect to claim 26 directed to the iPSC having an exogenous TCR gene, as stated supra, Minagawa teaches the iPSC are transduced with an exogenous antigen-specific TCR (see abstract and p. 854, right col, para 1).
With respect to claim 28 directed to the T cell expressing CD8αβ, as stated supra, Minagawa teaches the T cell express CD8αβ (see e.g. abstract).
With respect to claim 37 directed to the T cell product comprising two or more kinds, as stated supra, Minagawa teaches two types of TCR-iPSCs that are differentiated into two types of antigen-specific CD8αβ T cells (GPC3 and WT1, see e.g., p. 854, right col, para 1).
With respect to claim 39 directed to a step of constructing a T cell product collection comprising two or more kinds of T cell products by collecting T cell products, as stated supra, Minagawa teaches two types of TCR-iPSCs that are differentiated into two types of antigen-specific CD8αβ T cells (GPC3 and WT1, see e.g., p. 854, right col, para 1), thus teaches a step of constructing a T cell product collection.
With respect to claim 40 directed to s step of identifying a tumor-associated antigen expressed in a tumor of a test subject, Minagawa teaches an in vivo assay in a xenograft tumor model by inoculating lung cancer PC9 cells that overexpress WT1 (PC9/WT1) in an NSC mouse and teaches WT1 is a well-known tumor-associated antigen that is expressed on various tumor cells (see e.g., p. 854, right col, para 1-2).
With respect to claim 41 directed a step of selecting a T cell product expressing an exogenous TCR that recognizes and binds to the identified antigen from a T cell product collection, as stated supra, Minagawa teaches treating the tumor by injecting WT1-TCR iCD8 T cells (see e.g., p. 854, right col, para 2) and teaches the WT1-TCR iCD8 T cells recognize and bind to the WT-1 antigen (see e.g., Fig 3B). Thus, Minagawa teaches selecting a T cell product expressing an exogenous TCR (the WT1-TCR iCD8 T cells) that recognizes and binds to the identified WT-1 antigen from a T cell product collection (i.e., a collection that comprises at least two T cell product of WT1-TCR iCD8 T cells and GPC3-TCR iCD8 T cells).
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 10/13/2025 are acknowledged.
Applicant argues that the new limitation “a T cell derived from an iPSC” in claim 13 overcomes the prior 102 rejection and the new limitation the T cells “can be proliferated at least not less than 1010 times by expansion culture of not more than 5 times” in claims 13 and 24-25 overcomes the prior 103 rejections (Remarks, p. 8-9).
Applicant’s arguments have been fully considered and they are persuasive. Therefore, the prior rejections have been withdrawn. However, as necessitated by amendment, prior art Nishimura has been cited in the instant Office action, who makes obvious the claimed proliferative capacity of iPSC-derived T cells as discussed above.
Applicant further argues that the present Application demonstrates particular advantages by expanding T cells by 1010-1012 or more with just three to five cultures.
Applicant’s arguments have been fully considered but they are not persuasive. As stated supra, Nishimura discloses the iPSC-derived T cells are expanded 105 – 107 folds by expansion culture of mere 2 stimulations. Additionally, Nishimura discloses that “even after 100-to-1,000-fold expansions, some cells still expressed central memory T cell markers” (which present high proliferative capacities), and “with passage through the iPSC state, wherein telomerase activity is quite high, re-elongation of shortened telomeres… gives the redifferentiated T cells high replicative potential” (p. 119, last para. “Generation of Highly Proliferative T Cells through T-iPSCs”). Thus, Nishimura teaches that iPSC-derived T cells can be expanded by 105 – 107 with just 2 cultures, and the cells still preserve Tcm markers. Therefore, based on the teaching of Nishimura, one of ordinary skill in the art would have expected that the iPSC-derived T cells would likely be expanded by 1010 with not more than five cultures as claimed (i.e., the cells of Nishimura being further expanded by 103 – 105 with additional 3 cultures). Therefore, the purported particular advantages demonstrated by present Application would be reasonably expected by Nishimura.
Rejection of iPSC-derived T cells transduced with a CAR
Claims 13, 16-18, 24-25, 28, 30-31, 34, 36-37 and 39-41 are rejected under 35 U.S.C. 103 as being unpatentable over Panch et al., (Molecular Therapy. 2019 July; 27(7):1275-1285, supple. 1-13. Prior art of record) in view of Leen et al., (Blood. 2013;121(26):5113-5123. Prior art of record) and Nishimura et al., (Cell Stem Cell. 2013; 12: 114-126. Prior art of record).
With respect to independent claims 13, 24 and 25, Panch investigates the effects of cryopreservation on CAR-T cell characteristics in clinical applications (abstract). Panch teaches manufacturing CARTs using cryopreserved peripheral blood T cells as the starting fraction in 70 applications (see e.g., p. 1276, right col, para 1-2). Panch teaches that PBMNC cryopreservation did not affect final CART fold expansion, transduction efficiency, CD3%, or CD4:CD8 ratios (see e.g., abstract). Panch teaches the starting material is often cryopreserved to allow for flexibility in scheduling manufacturing (p. 1275, right col, para 2). Panch teaches some patients need more than one infusion (i.e., more than one CART cultures, see p. 1276, left col, last para). Thus, Panch teaches a method for manufacturing CART cells comprising a process of cryopreserving the starting material peripheral blood T cells in 70 applications.
However, Panch is silent on constructing a master cell bank of T cells in claims 13, 24 and 25.
Leen teaches a method for constructing a master cell bank of 32 virus-specific T cell (VST) lines for treating viral infection by cryopreserving the cell lines (abstract, see e.g., p. 5113, last para “Third-party T-cell bank” – p. 5114, right col, para 1). Leen teaches constructing and storing a bank of T cell lines is a feasible and safe approach that enables immediate and multicenter use for T cell therapy (p. 5113, right col, para 1 and abstract).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method for producing a CAR-T cell product comprising a process of stocking the starting material T cells in multiple applications disclosed by Panch, by combining the teaching of Leen to construct a master cell bank of the starting material T cells with a reasonable expectation of success. Since Panch teaches some patients need more than one infusion (i.e., more than one CART cultures, see p. 1276, left col, last para) and cryopreservation at either end of CART manufacture (i.e., storing starting material T cells or final product CART cells) is a viable strategy (p. 1282, left col, last para), and since Leen teaches constructing and storing a bank of T cell lines is a feasible and safe approach that enables immediate and multicenter use for T cell therapy (p. 5113, right col, para 1 and abstract), one of ordinary skill in the art would have had a reason to construct and store a master cell bank of the starting material T cells in the multiple applications of Panch in order to enable an immediate CAR-T manufacturing for the second infusion.
However, Panch and Leen are silent on the T cells being derived from an iPSC in claim 13, nor teach processes of differentiating an iPSC into a T cell, stocking the differentiated T cell and characterization of the differentiated T cell expressing CD8αβ in claims 24-25 and 28, or the claimed proliferative capacity in claims 13 and 24-25.
Nishimura teaches a method for reprogramming CD8+ T cells to pluripotency and redifferentiating the iPSCs into CD8+ T cells that have a high proliferative capacity and elongated telomeres (e.g., abstract). It is noted that Nishimura’s iPSC does not comprise a chimeric antigen receptor or an exogenous T cell receptor (see p. 123, last section “Generation of T-iPSCs”), related to claims 24-25. Thus, Nishimura teaches a T cell that is derived from an iPSC in claim 13. Nishimura teaches (1) a process of differentiating the iPSC into a T cell (see abstract), (2) a process of stocking the differentiated T cell (to “preserve” the T cells, see e.g., p. 123, right col, para 2), and (3) a process of characterization of the differentiated T cell (e.g., the T cells possessing antigen-specific killing, see abstract), and teaches the differentiated T cell expresses CD8αβ (see abstract for CD8+ T cells, see e.g., p. 119, left col, last 5 lines for TCRA and TCRB analysis), related to claims 24, 25 and 28.
Regarding the new limitation that the T cells can be proliferated at least not less than 1010 times by expansion culture of not more than 5 times in claims 13 and 24-25, it is noted that the limitation “be proliferated at least not less than 1010 times” is being examined as “be expanded at least 1010 folds”, and the limitation “expansion culture of not more than 5 times” is being examined as “expansion culture of not more than 5 stimulations” according to instant Figs 7-9 showing “fold expansion” in y-axis and figure legends indicating “arrows show the day when stimulation was started”).
Nishimura teaches “fewer than 105 T lineage cells were obtained” from iPSCs, “they could be expanded to >108 cells with the first stimulation”. “We assessed the expansion rate induced by the second stimulation” and “these cells expanded from 100-fold to 1,000-fold” (p. 119, last para. “Generation of Highly Proliferative T Cells through T-iPSCs”). Thus, Nishimura teaches the derivative T cells are expanded 103 – 104 folds by the first stimulation (>108 / fewer than 105), and are expanded another 100-fold to 1,000-fold by the second stimulation, i.e., the iPSC-derived T cells are expanded 105 – 107 folds by expansion culture of 2 stimulations. Nishimura teaches that “even after 100-to-1,000-fold expansions, some cells still expressed central memory T cell markers” and “with passage through the iPSC state, wherein telomerase activity is quite high, re-elongation of shortened telomeres… gives the redifferentiated T cells high replicative potential” (p. 119, last para. “Generation of Highly Proliferative T Cells through T-iPSCs”). Nishimura teaches exhaustion of antigen-specific T cells represents a major challenge to adoptive immunotherapy for combating cancer and the method of reprogramming and redifferentiation obtains ‘‘rejuvenated’’ T cells with high replicative potential (see e.g., abstract and above).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method for producing, providing and constructing a CART cell product comprising a master cell bank of starting material peripheral blood T cells suggested by Panch in view of Leen, by combining the reprogramming and redifferentiating steps to obtain ‘‘rejuvenated’’ T cells as the starting material T cells as suggested by Nishimura with a reasonable expectation of success. Since Nishimura teaches exhaustion of antigen-specific T cells represents a major challenge to adoptive immunotherapy for combating cancer and the method of reprogramming and redifferentiation obtains ‘‘rejuvenated’’ T cells with high replicative potential (see e.g., abstract and above), one of ordinary skill in the art would have had a reason to combine a process of reprogramming, redifferentiation and characterization as taught by Nishimura in the method of Panch in view of Leen in order to obtain ‘‘rejuvenated’’ T cells with high replicative potential as the starting material T cells for adoptive immunotherapy to overcome the challenge of T cell exhaustion.
Furthermore, since Nishimura teaches that iPSC-derived T cells are expanded 105 – 107 folds by expansion culture of just 2 stimulations and “even after 100-to-1,000-fold expansions, some cells still expressed central memory T cell markers” (see above), one of ordinary skill in the art would have had a reasonable expectation of success in appreciating that the iPSC-derived T cells in Panch in view of Leen and Nishimura could likely be expanded at least 1010 folds by expansion culture of 4 to 5 stimulations.
With respect to claims 16-17 directed to a step of introducing a nucleic acid comprising an exogenous CAR gene into a T cell prepared from the master cell bank, as stated supra, Panch teaches the thawed starting material T cells are transduced with a CAR construct (see e.g., p. 1276, left col, last para, also see diagram in Fig 1).
With respect to claim 18 directed to a step of expansion culturing a T cell, Panch teaches a step of expansion culturing in the CAR-T manufacturing (see e.g., p. 1275, right col, para 1).
With respect to claim 30, as stated supra, Panch, in view of Leen and Nishimura, suggests a method for producing a T cell product expressing a CAR comprising (1) a process of preparing a T cell from the master cell bank of the starting material T cells derived from iPSCs, (2) a process of introducing a CAR gene into the prepared T cell (transducing a CAR into the thawed starting material T cells, see e.g., Panch, diagram in Fig 1), and (3) a process of expansion culturing the T cell into which the CAR gene has been introduced (see e.g., Panch, p. 1275, right col, para 1).
With respect to claim 31 directed to the CAR recognizing and binding to a tumor-associated antigen, as stated supra, Panch teaches the CARs recognize and bind to tumor-associated antigens, such as a CD19, BCMA or GD2 (see Table 1 in p. 1276 for the CART type and also see p. 1276, left col, last para).
With respect to claim 34, as stated supra, Panch, in view of Leen and Nishimura, suggests a method for constructing a T cell product collection comprising two or more kinds of T cell products, comprising a process of collecting the T cell product (see Panch teaching constructing a collection of multiple types of CAR-T cells, such as CD19-CART, BCMA-CART or GD2-CART in Table 1 in p. 1276 for the CART type and also see p. 1276, left col, last para).
With respect to claim 36, as stated supra, Panch teaches a method for providing a T cell product suitable for a test subject (i.e., CAR-T therapy in cancer patients). Panch teaches identifying the tumor types in patients for applying respective CAR T cells (see Table 1 in p. 1276), thus teaches (1) a process of identifying tumor-associated antigen expressed in the tumor of the test subject. Panch teaches selecting respective CAR-T cells for treating patients according to the type of tumors (see Table 1 in p. 1276 for patient information and also see p. 1276, left col, last para), thus teaches (2) a process of selecting a T cell product that expresses a CAR that recognizes and binds to the identified antigen from the T cell product collection.
With respect to claim 37 directed to the T cell product comprising two or more kinds, as stated supra, Panch teaching multiple types of CAR-T cells, such as CD19-CART, BCMA-CART or GD2-CART in Table 1 in p. 1276 for the CART type and also see p. 1276, left col, last para).
With respect to claim 39, as stated supra, Panch, in view of Leen and Nishimura, suggests a method for constructing a T cell product collection comprising two or more kinds of T cell products by collecting the T cell products (see Panch teaching constructing a collection of multiple types of CAR-T cells, such as CD19-CART, BCMA-CART or GD2-CART in Table 1 in p. 1276 for the CART type and also see p. 1276, left col, last para).
With respect to claim 40, as stated supra, Panch teaches a method for providing CAR-T therapy in cancer patients. Panch teaches identifying the tumor types in patients for applying respective CAR T cells (see Table 1 in p. 1276 for patient information), thus teaches a step of identifying tumor-associated antigen expressed in the tumor of the test subject.
With respect to claim 41, Panch teaches selecting respective CAR-T cells for treating patients according to the type of tumors (see Table 1 in p. 1276 for patient information and also see p. 1276, left col, last para), thus teaches a step of selecting a T cell product that expresses a CAR that recognizes and binds to the identified antigen from the T cell product collection.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 10/13/2025 are acknowledged and have been discussed above.
Claims 15 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Panch et al., (Molecular Therapy. 2019 July; 27(7):1275-1285, supple. 1-13. Prior art of record) in view of Leen et al., (Blood. 2013;121(26):5113-5123. Prior art of record) and Nishimura et al., (Cell Stem Cell. 2013; 12: 114-126. Prior art of record), as applied to claims 13 and 24 above, and further in view of Torikai et al., (Blood. 2013;122(8):1341-1349. Cited in IDS 04/22/2024).
Claim 15 is directed to the master cell bank of T cells comprising a T cell with suppressed expression of at least one kind of HLA gene. Claim 27 is directed to at least one kind of HLA gene being deleted in the iPSC.
However, Panch, Leen and Nishimura are silent on the T cell with suppressed expression of at least one kind of HLA gene in claim 15 or at least one kind of HLA gene being deleted in the iPSC.
Torikai teaches a method of eliminating HLA class I expression to generate universal cells from allogeneic donors (see abstract). Torikai teaches genetic editing by nucleases permanently and completely eliminates expression of HLA-A expression on human T cells, and these HLA-A negative T cells can evade lysis by HLA-restricted cytotoxic T-cell clones or by natural killer cells (see e.g., abstract), thus teaches at least one kind of HLA gene is deleted in the T cell, and the T cell has suppressed expression of at least one kind of HLA gene. Torikai teaches HLA-A disruption from donor cells provide a foundation whereby cells from a single donor can be administered to multiple recipients and it is a step toward generating allogeneic cells as an off-the-shelf therapeutic (see abstract and Key Points in p. 1341).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method comprising constructing a master cell bank of rejuvenated T cells by reprogramming donor T cells into iPSCs and redifferentiating the iPSCs into rejuvenated T cells suggested by Panch in view of Leen and Nishimura, by combining a step of HLA-A deletion in the donor T cells as taught by Torikai with a reasonable expectation of success. Since Torikai teaches the HLA-A negative T cells can evade lysis by HLA-restricted cytotoxic T cells or by natural killer cells and thus can expand donor compatibility to be used as an off-the-shelf therapeutic (see e.g., abstract and Key Points in p. 1341), one of ordinary skill in the art would have had a reason to add a step of HLA-A deletion in the donor T cells before the steps of reprogramming and redifferentiation so as to obtain HLA-A-deleted iPSCs and HLA-A-deleted rejuvenated T cells in order to take advantage of the expanded donor compatibility to produce an off-the-shelf therapeutic. One of ordinary skill in the art would have appreciated that the HLA-A-deleted rejuvenated T cell in the master cell bank would have suppressed expression of one kind of HLA gene in claim 15, and one kind of HLA gene would be deleted in the HLA-A-deleted iPSC in claim 27.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 10/13/2025 are acknowledged and have been discussed above.
Claims 19, 32 and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Panch et al., (Molecular Therapy. 2019 July; 27(7):1275-1285, supple. 1-13. Prior art of record) in view of Leen et al., (Blood. 2013;121(26):5113-5123. Prior art of record) and Nishimura et al., (Cell Stem Cell. 2013; 12: 114-126. Prior art of record), as applied to claims 13, 18, 24 and 30 above, and further in view of Smith et al., (Cell. 1993; 73: 1349-1360. Prior art of record).
Claim 19 is directed to the step of expansion culturing comprising a process of stimulating the cell with a CD30 agonist. Claim 32 is directed to the process (3) of expansion culturing the T cell introduced with the CAR gene comprising a process of stimulating the T cell with a CD30 agonist.
As stated supra, Panch teaches a process of expansion culturing T cells after introduction of CAR gene. Panch teaches the T cells are stimulated with CD3/CD28 antibodies bound to paramagnetic beads in the expansion culturing and the beads are removed on the day of harvest (see e.g., supplemental p. 6, para 1).
However, Panch, Leen and Nishimura are silent on expansion culturing comprising a process of stimulating the cell with a CD30 agonist in claims 19 and 32.
Smith teaches CD30 ligand (CD30L) and an immobilized CD30 monoclonal antibody M44 both induce proliferation of CD3-activated T cells (p. 1354, left col, section “Biological activities of human CD30L”, para 1, see Fig 8A and 8B. It is noted that Smith teaches the CD30 monoclonal antibody M44 has agonist characteristics, see p. 1354, right col, para 1). Thus, Smith teaches a CD30 agonist, i.e., a CD30L or an agonistic CD30 mAb, induces proliferation of activated T cells, related to claims 19 and 32.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method for producing a T cell product comprising a process of expansion culturing the T cells in the presence of anti-CD3/CD28 antibodies suggested by Panch in view of Leen and Nishimura, by combining a CD30 agonist to stimulate the T cells as suggested by Smith with a reasonable expectation of success. Since Smith teaches a CD30 agonist, i.e., a CD30L or an agonistic CD30 mAb, induces proliferation of CD3-antibody-activated T cells (p. 1354, left col, section “Biological activities of human CD30L”, para 1, see Fig 8A and 8B), one of ordinary skill in the art would have had a reason to combine a CD30 agonist in the expansion culturing CD3/CD28-stimulated T cells of Panch in view of Leen and Nishimura in order to induce proliferation of the activated T cells by the CD30 agonist to obtain a large amount of CAR-T cells for cancer treatment.
With respect to claim 38 directed to a step of producing a frozen T cell product comprising the expansion cultured T cell, Panch teaches the expansion cultured CART cells are cryopreserved (see e.g., Fig 1 diagram and p. 1277-1278).
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 10/13/2025 are acknowledged and have been discussed above.
Withdrawn Provisional Double Patenting Rejections
The prior provisional double patenting rejection has been withdrawn in light of Applicant amendment to recite new limitation directed to proliferative capacity of T cells.
New Provisional Double Patenting Rejections
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 be 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 13, 15-19, 24-28, 30-32, 34 and 36-41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending claims 1-27 of copending Application No. 18/285,023 in view of Nishimura et al., (Cell Stem Cell. 2013; 12: 114-126. Prior art of record), Xu et al., (Cell Stem Cell. 2019 April; 24: 566-578. Prior art of record) and Smith et al., (Cell. 1993;73:1349-1360. Prior art of record). Although the claims at issue are not identical, they are not patentably distinct from each other.
Copending claims recite a method for producing T cell formulations comprising providing the cell bank according to claim 1 and producing a T cell formulation from the cell bank (copending claim 27), the cell bank composed of cells for transfecting a TCR gene wherein the cells are one or more of iPSCs, immature T cells or mature T cells (copending claim 1), the cells further transfected with a CAR (copending claim 2), the transfection of TCR gene into the mature T cells using genome editing techniques (copending claim 6), the iPSCs are differentiated into mature T cells (copending claim 7, thus the mature T cells are differentiated from iPSCs), the cells are cryopreserved (copending claim 8), the mature T cells express a TCR that does not recognize non-tumor cells derived from a subject different from a subject from which the mature T cells are derived (copending claim 11), the mature T cells recognize a single antigen (copending claim 12), the immature or mature T cells are CD8 αβ chain double positive (copending claims 15-16), the TCR is from T cells from a subject and has reactivity to tumor-related antigen (copending claims 17-19), the tumor-related antigen is selected from GPC3 or WT1 or others (copending claims 20-21). Thus, copending claims recite a method of producing or constructing a master cell bank of T cells with the claimed steps of the instant claims.
However, copending claims are silent on the T cells having the newly claimed proliferative capacity.
Regarding the new limitation that the T cells can be proliferated at least not less than 1010 times by expansion culture of not more than 5 times, it is noted that the limitation “be proliferated at least not less than 1010 times” is being examined as “be expanded at least 1010 folds”, and the limitation “expansion culture of not more than 5 times” is being examined as “expansion culture of not more than 5 stimulations” according to instant Figs 7-9 showing “fold expansion” in y-axis and figure legends indicating “arrows show the day when stimulation was started”).
Nishimura teaches a method for reprogramming antigen-specific CD8+ T cells to pluripotency and redifferentiating the iPSCs into CD8+ T cells that have a high proliferative capacity and elongated telomeres (e.g., abstract). Nishimura teaches “fewer than 105 T lineage cells were obtained” from iPSCs, “they could be expanded to >108 cells with the first stimulation”. “We assessed the expansion rate induced by the second stimulation” and “these cells expanded from 100-fold to 1,000-fold” (p. 119, last para. “Generation of Highly Proliferative T Cells through T-iPSCs”). Thus, Nishimura teaches the derivative T cells are expanded 103 – 104 folds by the first stimulation (>108 / fewer than 105), and are expanded another 100-fold to 1,000-fold by the second stimulation, i.e., the iPSC-derived T cells are expanded 105 – 107 folds by expansion culture of 2 stimulations. Nishimura teaches that “even after 100-to-1,000-fold expansions, some cells still expressed central memory T cell markers” and “with passage through the iPSC state, wherein telomerase activity is quite high, re-elongation of shortened telomeres… gives the redifferentiated T cells high replicative potential” (p. 119, last para. “Generation of Highly Proliferative T Cells through T-iPSCs”).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have immediately expected that the iPSC-derived T cells in copending claims (e.g., copending claim 7) could likely be expanded at least 1010 folds by expansion culture of not more than 5 stimulations as suggested by Nishimura with a reasonable expectation of success. Since copending claims recite the mature T cells are derived from an iPSC, and since Nishimura teaches that iPSC-derived T cells are expanded 105 – 107 folds by expansion culture of just 2 stimulations because “with passage through the iPSC state, re-elongation of shortened telomeres gives the redifferentiated T cells high replicative potential” (see above), one of ordinary skill in the art would have had a reasonable expectation of success in appreciating that the iPSC-derived T cells in copending claims could be expanded 105 – 107 folds by expansion culture of just 2 stimulations as taught by Nishimura, and thus could likely be expanded at least 1010 folds by expansion culture of 4 to 5 stimulations.
However, copending claims are silent on the cells having at least one kind of HLA gene being suppressed or deleted, nor teach the expansion culturing comprising stimulating T cells with a CD30 agonist.
Regarding HLA being deleted, Xu teaches a method for deleting HLA-A and HLA-B biallelically and retaining a single haplotype of HLA-C to generate HLA-C-retained iPSCs (e.g., p. 567, left col, para 2). Xu teaches the HLA-C-retained iPSCs could evade T cells and NK cells in vitro and in vivo while maintains antigen presentation and greatly expands donor compatibility and facilitates iPSC-based medicine applications (e.g., see abstract).
Regarding stimulating T cells with a CD30 agonist, Smith teaches CD30 ligand (CD30L) and an immobilized CD30 monoclonal antibody M44 both induce proliferation of CD3-activated T cells (p. 1354, left col, section “Biological activities of human CD30L”, para 1, see Fig 8A and 8B. It is noted that Smith teaches the CD30 mAb M44 has agonist characteristics, see p. 1354, right col, para 1). Thus, Smith teaches a CD30 agonist, i.e., a CD30L or a CD30 mAb M44, induces proliferation of activated T cells.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method recited in the copending claims of ‘023, by substituting with HLA-A and HLA-B-deleted iPSCs and by combining a CD30 agonist in the expansion culturing as suggested by Xu and Smith with a reasonable expectation of success. Since Xu teaches HLA-A/B-deleted iPSC greatly expands donor compatibility and since Smith teaches a CD30 agonist, i.e., a CD30L or an agonistic CD30 mAb, induces proliferation of activated T cells (see above), one of ordinary skill in the art would have had a reason to substitute with HLA-A/B-deleted iPSCs and to combine a CD30 agonist in the expansion culturing as suggested by Xu and Smith in order to expand donor compatibility of the cell bank and to induce proliferation of T cells in the cell bank for producing a T cell formulation.
Since the instant application claims are obvious over cited application claims, in view of Nishimura, Xu and Smith, said claims are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims in the copending application have not in fact been patented.
Response to Traversal:
Applicant’s argument filed on 10/13/2025 requests that the double patenting rejections be held in abeyance until allowable subject matter is identified. This is not found persuasive. Applicant is reminded that a complete response to a nonstatutory double patenting (NSDP) rejection is either a reply by applicant showing that the claims subject to the rejection are patentably distinct from the reference claims, or the filing of a terminal disclaimer. Such a response is required even when the nonstatutory double patenting rejection is provisional. See MPEP 804.I.B.1.
The prior double patenting rejection has been withdrawn and a ground of double patenting rejection has been made as necessitated by amendment as discussed above.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jianjian Zhu whose telephone number is (571)272-0956. The examiner can normally be reached M - F 8:30AM - 4PM (EST).
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/JIANJIAN ZHU/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631