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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 02/19/2026 has been entered.
Election/Restrictions
Claims 52, 63, 66-73, 77, 81-83, 104 and 114-115 are pending in the instant application.
Applicant has previously elected without traverse of Group III, drawn to a method for manufacturing anti-BCMA CAR T cells comprising:
(a) activating a population of T cells and stimulating the population of T cells to proliferate;
(b) transducing the T cells with a lentiviral vector encoding an anti-BCMA CAR that comprises the amino
acid sequence set forth in SEQ ID NO: 1;
(c) culturing the transduced T cells to proliferate for a period of about 5 to about 7 days wherein:
(I) the gene expression of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or all of (i) NR4A2, LY9, LIN7A, WNT5B, BCL6,
EGR1, EGR2, ATF3, CCL1, IL-IA, and CCL5 or (ii) CCL1, NR4A2, ATF3, CCL5, and WNTSB is at least 1.5-fold
or at least two-fold greater in the cultured T cells of step (c) compared to T cells transduced according to step (b)
and cultured to proliferate for a period of about 10 days (i.e. a first method of making said first product), in the reply
filed on 04/24/2025.
Claims 52, 63, 66-73, 77, 81-84, 104 and 114-115 were pending. Claim 84 is now cancelled. Therefore, claims 52, 63, 66-73, 77, 81-83, 104, 114-115 are pending and under examination in the instant application.
Status of Prior Rejections/Response to Arguments
RE: Rejection of claims 52, 63, 66-73, 77, 81-84, 104 and 114-115 under 35 U.S.C. 103 as being unpatentable over Morgan et al. in view of Wang et al.:
Applicants have traversed the rejection asserting that Wang et al. teaches methods for generating a structurally distinct cell. Applicant specifically argues that Wang et al. discloses T cells expressing a CAR and a T cell receptor specific for CMV, i.e., a bi-specific T cell, while the pending claims are directed to a method of manufacturing anti-BCMA CAR T cells, including transducing T cells with a lentiviral vector encoding an anti-BCMA CAR. In response, this is not persuasive because Wang et al. actually teaches in paragraph 0009 that the CAR is selective for BCMA antigen. Wang et al. was relied upon to cure the deficiency of the primary reference Morgan et al. and teach the limitation that the CAR T cells comprise at least CD27+ T-cells (See paragraph 0045).
Applicants also argue that While Wang discloses the stimulated cells express CD27, this population of cells is noted to "no longer express the central memory markers of the originally selected cells" (see paragraph [0045] of Wang). This is not persuasive because Wand et al. teaches in this same paragraph that levels of CD27 remained high, suggesting a greater proliferative potential that has been associated with greater clinical efficacy. Applicants further argue that the CD27 expressing cells of Wang decline after in vivo administration, while the cells made by the instant claimed method are demonstrated as more potent, persistent, and effective T cell population, improved ability to regulate tumor growth and sustain a clinical response 6 months after treatment, and robust expansion in vivo. In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., improved ability to regulate tumor growth, and sustain a clinical response 6 months after treatment, and robust expansion in vivo) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Instant claim 52 is directed to a method of manufacturing the anti-BCMA CAR T cells not to the method of using the manufactured cells or administering them in vivo. Also, although independent claim 104 is directed to a method for increasing the therapeutic efficacy of anti-BCMA CAR T cells, the active method steps require that the anti-BCMA CAR T cells are contacted ex vivo with a PI3K inhibitor for about 5 to about 7 days. None of the instant claims requires using the manufactured cells in vivo.
Applicant's arguments filed 02/19/2026 have been fully considered but they are not persuasive for the reasons set forth above. The rejection is therefore maintained.
New/Maintained Grounds of Rejection
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 52, 63, 66-73, 77, 81-83, 104, and 114-115 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as failing to set forth 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.
Regarding claims 52 and 104, they both recite “…wherein the anti-BCMA CAR T cells comprise at least 10%, at least 15%, at least 20%, at least 25%, or at least 30% CD27+, and LEF1+, CCR7+, TCF1+, or any combination thereof T cells”. The article “and” after “CD27+” introduces ambiguity as it is unclear if the anti-BCMA CAR T cells comprise at least 10%, at least 15%, at least 20%, at least 25%, or at least 30% CD27+ and at least 10%, at least 15%, at least 20%, at least 25%, or at least 30% LEF1+, CCR7+, and/or TCF1+ or that the anti-BCMA CAR T cells comprise at least 10%, at least 15%, at least 20%, at least 25%, or at least 30% CD27+, and are at least positive for at least one of LEF1, CCR7, and/or TCF1. However, in the interest of combat prosecution, claims 52 and 104 are interpreted as: the anti-BCMA CAR T cells comprise at least 10%, at least 15%, at least 20%, at least 25%, or at least 30% CD27+, and the anti-BCMA CAR T cells also comprise at least one T cell that is positive for LEF1, CCR7 and/or TCR1. Claims 63, 66-73, 77, 81-83, and 115 that directly or indirectly depend from claims 52 and 104 are similarly rejected.
Regarding claim 114, it recites “The method of claim 84, wherein the anti-BCMA CAR T cells comprise an anti-BCMA CAR that comprises the amino acid sequence set forth in SEQ ID NO: 1.” However, claim 84 is now cancelled. So it is unclear what claim 114 does actually depend from. Claim 114 depending from a cancelled claim introduces ambiguity and renders the claim indefinite. It is unclear what anti-BCMA CAR T cells are meant to comprise the amino acid sequence set forth in SEQ ID NO: 1. It is unclear if the claimed anti-BCMA CAR T cells are the same cells made in previous independent claims by transducing the T cells with a lentiviral vector or with a non-viral vector or any other transduction method. Therefore, the metes and bounds of the claim cannot be determined. However, in the interest of combat prosecution, claim 114 is interpreted as being dependent from claim 104.
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.
Claim(s) 52, 63, 66-73, 77, 81-83, 104 and 114-115 are rejected under 35 U.S.C. 103 as being unpatentable over Morgan et al. (the US Patent Application Publication US20180085444A1, filed on 12/07/2015, and published on 03/29/2018), in view of Wang et al. (the US Patent Application Publication US20180214527A1, filed on 03/28/2016, and published on 08/02/2018).
Regarding claim 52, Morgan et al. teaches a method of generating an immune effector cell comprising a CAR (paragraph 0060). Morgan et al. also teaches improved chimeric antigen receptors (CARs) comprising murine anti-BCMA antibodies or antigen binding fragments thereof, immune effector cells genetically modified to express these CARs (Paragraph 0003). This reads on a method for manufacturing anti-BCMA CAR T-cells. Morgan et al. also teaches that T cells are modified after stimulation and activation in the presence of an inhibitor of a PI3K cell signaling pathway (paragraph 0338), which is comparable to step (a) of the instant claimed method. Morgan et al. further teaches that the immune effector cell is transduced with a retroviral vector, e.g., a lentiviral vector, encoding the CAR. For example, an immune effector cell is transduced with a vector encoding a CAR that comprises a murine anti-BCMA antibody or antigen binding fragment thereof that binds a BCMA polypeptide (paragraph 0258). Morgan et al. teaches that the anti-BCMA CAR comprises the amino acid sequence set forth in SEQ ID NO: 9 (paragraph 0031), which is 100% identical to instant SEQ ID NO: 1. This is comparable to step (b) of the instant claimed method. Morgan et al. further teaches that after T cells are activated, the cells are cultured to proliferate. T cells may be cultured for at least 5, 6, or 7 days (paragraph 0339), which is comparable to step (c) of the instant claimed method. Morgan et al. further teaches that the resulting T cell compositions are enriched in developmentally potent T cells that have the ability to proliferate and express CD27 (paragraph 0336). Morgan et al. further teaches in paragraph 0336, that the resulting T cell compositions are enriched in developmentally potent T cells that have the ability to proliferate and express CCR7.
Although Morgan et al. does not specifically teach that the gene expression of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or all of (i) NR4A2, LY9, LIN7A, WNT5B, BCL6, EGR1, EGR2, ATF3, CCL1, IL-1A, and CCL5 or (ii) CCL1, NR4A2, ATF3, CCL5, and WNT5B is at least 1.5-fold or at least two-fold greater in the cultured T cells of step (c) compared to T cells transduced accordingly step (b) and cultured to proliferate for a period of about 10 days, Morgan et al. actually teaches the exact same method steps (a)-(c) as instantly recited in claim 52. Since the steps of the claimed method of manufacturing anti-BCMA CAR T cells and the method steps taught by Morgan et al. are the same, the claimed change in gene expression of the claimed genes after culturing for 7 days is inherently and necessarily present in Morgan et al. When the prior art method is the same as a method described in the specification for carrying out the claimed method, it can be assumed the method will inherently perform the claimed process. See In re Best, 562 F. 2d, 1252, 1255, 195 USPQ 430, 433 (CCPA 1977) and Ex parte Novitski, 26 USPQ 2d 1389 (Bd. Pat. App. & inter. 1993). There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of the invention, but only that the subject matter is in fact inherent in the prior art reference. See Schering Corp. v. Geneva Pharm. Inc, 339 F.3d 1373, 1377, 67, USPQ2d 1664, 1668 (Fed. Cir. 2003). See also Toro Co. v. Deere & Co. 355 F.3d 1313, 1320, 69 USPQ2d 1584, 1590 (Fed. Cir. 2004). See MPEP 2112.02.
Also, Morgan et al. fails to specifically teach that the anti-BCMA CAR T-cells comprise at least 10%, at least 15%, at least 20%, at least 25%, or at least 30% CD27+ T-cells.
However, Wang et al. teaches a method for preparing T cells expressing a chimeric antigen receptor (CAR), the method comprising providing PBMC and transducing at least a portion of the enriched population of cells with a vector expressing a CAR, thereby preparing T cells expressing a CAR (claim 1 of Wang et al.). Wang et al. further teaches that the CAR is selective for BCMA antigen (paragraph 0009). Wang et al. also teaches that levels of CD27 remained high, suggesting a greater proliferative potential that has been associated with greater clinical efficacy (paragraph 0045). Fig. 2A of Wang et al. actually shows 66.3% CD27 expression levels.
Therefore, it would have been prima facie obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to have modified the method of Morgan et al. to include generating a population of CAR T cells with at least 30% CD27 expression levels with a reasonable expectation of success. One would have been motivated to have optimized the CD27 expression level of the anti-BCMA CAR to ensure sufficiently high number of CD27+ CAR T cells for greater proliferative potential that has been associated with greater clinical efficacy and since Wang et al. establishes that expressing high levels of CD27 biomarker would have required only routine experimentation.
Regarding claim 63: Following discussion of claim 52 above, Wang et al. teaches that the enriched population of cells is CD8 positive, and CD4 positive (claim 8 of Wang et al.).
Regarding claim 66: Following discussion of claim 52 above, Morgan et al. teaches that the T cells used for CAR T cell production may be autologous (paragraph 0346).
Regarding claim 67: Following discussion of claim 52 above, Morgan et al. teaches that the T cells are isolated from peripheral blood mononuclear cells (PBMCs) (paragraph 0319).
Regarding claim 68: Following discussion of claim 67 above, Morgan et al. teaches that the (PBMCs) are obtained from a patient diagnosed with B cell malignancy (paragraph 0331). Morgan et al. further teaches that the B cell malignancy can be multiple myeloma. Morgan et al. teaches compositions comprising CAR-modified T cells are used in the treatment of hematologic malignancies, including but not limited to B cell malignancies such as, for example, multiple myeloma (MM) (paragraph 0456).
Regarding claim 69: Following discussion of claim 68 above, Morgan et al. teaches that variant forms of multiple myeloma include overt multiple myeloma, smoldering multiple myeloma, plasma cell leukemia, non-secretory myeloma, IgD myeloma, and osteosclerotic myeloma (paragraph 0457). Although Morgan et al. fails to specifically teach that the PBMC cells are isolated from a subject that has relapsed/refractory multiple myeloma, it would have been prima facie obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to have obtained PBMCs from a patient diagnosed with relapsed/refractory multiple myeloma with a reasonable expectation of success. One would have been motivated to have done so because the compositions comprising CAR-modified T cells of Morgan et al. can be used in the treatment of hematologic malignancies, including that are not limited to B cell malignancies such as multiple myeloma (MM).
Regarding claim 70: Following discussion of claim 52 above, Morgan et al. further teaches a method of storing genetically modified murine, CAR protein expressing immune effector cells which target a BCMA protein, comprising cryopreserving the immune effector cells such that the cells remain viable upon thawing (paragraph 0334). Although Morgan et al. fails to specifically teach that the PBMCs are cryopreserved before activation and stimulation, it would have been prima facie obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to have cryopreserved the PBMCs before activation and stimulation with a reasonable expectation of success. One would have been motivated to have done so such that the PBMCs remain viable upon thawing.
Regarding claim 71: Following discussion of claim 52 above, Morgan et al. further teaches a method of storing genetically modified murine, CAR protein expressing immune effector cells which target a BCMA protein, comprising cryopreserving the immune effector cells such that the cells remain viable upon thawing (paragraph 0334).
Regarding claim 72: Following discussion of claim 52 above, Morgan et al. further teaches that T cells are modified within 12 hours or 24 hours of stimulation and activation in the presence of an inhibitor of a PI3K cell signaling pathway (paragraph 0338).
Regarding claim 73: Following discussion of claim 52 above, Morgan et al. further teaches that the method further comprises stimulating the immune effector cell and inducing the cell to proliferate by contacting the cell with antibodies that bind CD3 (paragraph 0061).
Regarding claim 77: Following discussion of claim 52 above, Morgan et al. further teaches that the method further comprises stimulating the immune effector cell and inducing the cell to proliferate by contacting the cell with antibodies that bind to CD28 (paragraph 0061).
Regarding claim 81: Following discussion of claim 52 above, Morgan et al. further teaches that the immune effector cell is transduced with a retroviral vector, e.g., a lentiviral vector, encoding the CAR (paragraph 0258), wherein the lentivirus is HIV type 1 (paragraph 0261).
Regarding claim 82: Following discussion of claim 52 above, Morgan et al. teaches that the anti-BCMA CAR comprises the polynucleotide sequence set forth in SEQ ID NO: 10 (claim 66 of Morgan et al.), which is 100% identical to instant SEQ ID NO: 2.
Regarding claim 83: Following discussion of claim 52 above, Morgan et al. teaches that the PI3K inhibitor is ZSTK474 (paragraph 0058).
Regarding claim 104, Morgan et al. discloses a method for increasing the therapeutic efficacy of anti-BCMA CAR T cells by specifically teaching a method of generating an immune effector cell comprising a CAR (paragraph 0060). Morgan et al. also teaches improved chimeric antigen receptors (CARs) comprising murine anti-BCMA antibodies or antigen binding fragments thereof, immune effector cells genetically modified to express these CARs (Paragraph 0003). Morgan et al. also teaches that T cells are modified after stimulation and activation in the presence of an inhibitor of a PI3K cell signaling pathway (paragraph 0338). Morgan et al. also teaches methods for administering cell compositions that results in reintroduction of ex vivo genetically modified immune effector cells that directly express the CAR of the invention in the subject (paragraph 0478). This reads on contacting anti-BCMA CAR T cells ex vivo with a PI3K inhibitor. Morgan et al. further teaches that the immune effector cell is transduced with a retroviral vector, e.g., a lentiviral vector, encoding the CAR. For example, an immune effector cell is transduced with a vector comprising a polynucleotide encoding a CAR that comprises a murine anti-BCMA antibody or antigen binding fragment thereof that binds a BCMA polypeptide (paragraph 0258). Morgan et al. further teaches that after T cells are activated, the cells are cultured to proliferate. T cells may be cultured for at least 5, 6, or 7 days (paragraph 0339). Morgan et al. also teaches that the polynucleotide encoding the CAR encodes a polypeptide that provides a therapeutic effect in the treatment or prevention of a disease or disorder (paragraph 0221). Morgan et al. further teaches that the resulting T cell compositions are enriched in developmentally potent T cells that have the ability to proliferate and express CD27 (paragraph 0336). Morgan et al. further teaches in paragraph 0336, that the resulting T cell compositions are enriched in developmentally potent T cells that have the ability to proliferate and express CCR7.
Although Morgan et al. does not specifically teach that the gene expression of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or all of (i) NR4A2, LY9, LIN7A, WNT5B, BCL6, EGR1, EGR2, ATF3, CCL1, IL-1A, and CCL5 or (ii) CCL1, NR4A2, ATF3, CCL5, and WNT5B is at least 1.5-fold greater in the anti-BCMA CAR T cells compared to anti-BCMA CAR T cells contacted ex vivo with a PI3K inhibitor for about 10 days, Morgan et al. teaches the exact same method step of contacting anti-BCMA T cells ex vivo with the PI3K inhibitor as instantly recited in claim 104. Since the steps of the claimed method and the method steps taught by Morgan et al. are the same, the claimed change in gene expression of the claimed genes after culturing for 10 days is inherently and necessarily present in Morgan et al. When the prior art method is the same as a method described in the specification for carrying out the claimed method, it can be assumed the method will inherently perform the claimed process. See MPEP 2112.02.
Also, Morgan et al. fails to specifically teach that the anti-BCMA CAR T-cells comprise at least 10%, at least 15%, at least 20%, at least 25%, or at least 30% CD27+ T-cells.
However, Wang et al. teaches a method for preparing T cells expressing a chimeric antigen receptor (CAR), the method comprising providing PBMC and transducing at least a portion of the enriched population of cells with a vector expressing a CAR, thereby preparing T cells expressing a CAR (claim 1 of Wang et al.). Wang et al. further teaches that the CAR is selective for BCMA antigen (paragraph 0009). Wang et al. also teaches that levels of CD27 remained high, suggesting a greater proliferative potential that has been associated with greater clinical efficacy (paragraph 0045). Fig. 2A of Wang et al. actually shows 66.3% CD27 expression levels.
Therefore, it would have been prima facie obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to have modified the method of Morgan et al. to include generating a population of CAR T cells with at least 30% CD27 expression levels with a reasonable expectation of success. One would have been motivated to have optimized the CD27 expression level of the anti-BCMA CAR to ensure sufficiently high number of CD27+ CAR T cells for greater proliferative potential that has been associated with greater clinical efficacy and since Wang et al. establishes that expressing high levels of CD27 biomarker would have required only routine experimentation.
Regarding claim 114: Following discussion of claim 104 above, Morgan et al. teaches that the anti-BCMA CAR comprises the amino acid sequence set forth in SEQ ID NO: 9 (paragraph 0031), which is 100% identical to instant SEQ ID NO: 1.
Regarding claim 115: Following discussion of claim 104 above, Morgan et al. teaches that the anti-BCMA CAR comprises the amino acid sequence set forth in SEQ ID NO: 9 (paragraph 0031), which is 100% identical to instant SEQ ID NO: 1.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HANAN ISAM ABUZEINEH whose telephone number is (571)272-9596. The examiner can normally be reached Mon- Fri 8:30-5:00.
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Hanan Isam Abuzeineh
/H.I.A./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633