DETAILED ACTION
Applicant’s amendment and response received on 10/14/25 has been entered. Claim 128 has been canceled. Claims 117-127, and 129-135 are currently pending and under examination in the instant application. An action on the merits follows. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Those sections of Title 35, US code, not included in this action can be found in a previous office action.
37 CFR 1.121
The claim listing filed on 10/14/25 fails to comply with 37 CFR 1.121(c). Claim 128, identified as canceled, includes the text of the claimed with marking lining through the text. 37 CFR 1.121(c)(4)(i) states that no claim text shall be presented for any claim in the claim listing with the status of “canceled”.
In the interests of compact prosecution, the claim listing has been entered. However, future claim listing must comply fully with 37 CFR 1.121(c) or risk non-entry.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10/14/25 is in compliance with the provisions of 37 CFR 1.97 and 1.98. Accordingly, the information disclosure statement has been considered by the examiner and an initialed and signed copy of the 1449 is attached to this action.
Claim Rejections - 35 USC § 103
Pending claims 117-127, and 129-135 remain rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (2008) Anal. Chem., Vol. 80, 2118-2124, in view of WO 2012/129514 (September, 2012), hereafter referred to as Riddell et al., Milone et al. (2009) Mol. Ther., Vol. 17 (8), 1453-11464, doi.org/10.1038/mt.2009.83, pages 1-20, WO 2013/188427 (Dec. 19, 2013), hereafter referred to as Wilson, and U.S. Patent 5,773,224 (1998), hereafter referred to as Grandics et al. Note that claim 128, previously rejected, has been canceled. Applicant’s amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
The applicant argues that the claims have been amended to recite the limitation previously recited in claim 128, now canceled, wherein, “the CD4+ cells to CD8+ cells in the culture-initiating composition are combined at a ratio of 5:1 to 1:5”. The applicant argues that the cited references do not individually or in combination teach or suggest combining the CD4+ and CD8+ cells at a particular ratio of 5:1 to 1:5 as now claimed prior to introduction of an engineered antigen receptor as now required by all the claims. In particular, the applicant argues that although Wang et al. teaches methods of selecting two cell populations in a series or in tandem from the same starting cell population, Wang et al. does not teach or suggest to select CD4+ and CD8+ T cells or to combine the two separated populations prior to genetically engineering the cells. Riddell et al., according to the applicants, teaches the separate selection and genetic engineering of separated CD4+ and CD8+ T cells prior to combining the separated populations at a 1:1 ratio. Regarding Milone et al., the applicant argues that Milone et al. does not teach to transduce a combined population of CD4+ and CD8+ T cells or to transduce the combined cells with a vector encoding a CAR as claimed. The applicant also states that neither Wilson nor Grandics provides the missing teachings. Thus, the applicant concludes that none of the references cited teach to transduce a specific ratio of combined selected CD4+ and CD8+ T cells with a vector encoding a CAR.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). Further, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
In this case, Wang et al. was cited for teaching multiple cell type purification using open-tubular capillary cell affinity chromatography where multiple capillaries are attached either in parallel or in a series to allow for the isolation of two or more different cell types based on either positive or negative selection of cell surface markers on the target cells from a single peripheral blood sample (Wang et al., pages 2118-2119). Wang et al. teaches that the capillaries are coated with biotin, then with neutravidin (a streptavidin analog with reduced nonspecific binding properties) (Wang et al., page 2120). The capillaries were then either coated with biotin conjugated mouse anti-human antibody specific for the target cell to create a surface for cell capture, or used directly to bind cells pre-incubated with the biotin-antibody conjugate (Wang et al., pages 2120 and 2124). Wang et al. further shows that pre-incubation with antibody allows for the use of antibodies with insufficient affinities to capture cells under flow shear forces when bound to the capillary surface, i.e. suboptimal yield conditions (Wang et al., page 2124). Wang et al. demonstrates the use of a closed system of two capillaries either in parallel or in a series to separate and enrich for separate populations of CD4+ lymphocytes and either CD19 B cells or CD14 positive monocyte where a lysed blood sample is either applied directly to the system of parallel or serial capillaries using either continuous flow, or stop flow to allow for an extended contact time of the cells with the capillary surface (Wang et al., pages 2122-2124). Wang et al. teaches that positively selected cells retained in the capillaries can be recovered using bubble induced or shear flow detachment of the captured cells, or by the use of a soluble competitive agent in the buffer (Wang et al., page 2119). Wang et al. teaches that a laser beam can be incorporated to count cells eluting from the column, and that the number of cells eluting from the capillary can be changed based on the shear force of the elution buffer used (Wang et al., page 2121-2122). Wang et al. further teaches that the cells were separated and recovered in a sterile manner allowing for subsequent reculture (Wang et al., page 2122). Thus, Wang et al. teaches a system that can be used to select two different cells populations where one is a CD4+ T cells and the other is a different type of cell. Riddell et al. was cited to supplement Wang et al. by teaching the benefits of generating a combined population of isolated CD4+ and CD8+ T lymphocytes for adoptive immunotherapy of cancer. Specifically, Riddell et al. teaches compositions for adoptive immunotherapy of cancer comprising a combination of isolated CD4+ and CD8+ T cells at CD4/CD8 ratios including 2:1, 1:1, and 1:2 (Riddell et al., pages 36-37). Riddell et al. teaches that the CD4 and CD8 cell populations were isolated from human peripheral blood mononuclear cells (PBMC), stimulated with anti-CD3 antibody, and transduced with lentivirus encoding a cancer specific chimeric antigen receptor (CAR) (Riddell et al., pages 30-33). Riddell et al. further teaches to isolate specific subpopulations of CD4+ T cells, and in particular a central memory (CM) CD4+ T cells with the phenotype CD45RA- CD45RO+ CD62L+ and to combine these CM CD4+ T cells with CD8+ T cells at a 1:1 ratio (Riddell et al., pages 37-39). Riddell et al. demonstrates that the combination of CD4+ T cells, either bulk or the CM fraction augments CD8+ CTL activity (Riddell et al., pages 36-37). Thus, Riddell et al. provides specific motivation to isolate and combine CD4+ and CD8+ T cells and to further transduce the cells with a vector encoding a CAR. The applicant is correct that as stand alone references, neither reference teaches to combine the separated CD4 and CD8 T cells in a specific ratio prior to their stimulation and transduction. However, these references are not considered individually, but as part of the larger rejection that combines the teachings of these references with the teachings of Milone et al.
Milone et al. was cited to supplement Wang et al. and Riddell et al. by teaching alternative methods of producing a genetically modified combined population of CD4+ T cells and CD8+ T cells in which CD4+ T cells and CD8+ T cells. While Milone et al., like Riddell et al., teaches that separated CD4 and CD8 T cells can be separately stimulated with alpha CD3/alphaCD28 aAPCs and transduced with a lentiviral vector encoding a gene of interest prior to their combination at a 1:1 ratio, Milone et al. also teaches an alternate protocol where separated CD4 and CD8 T cells are first mixed in a 1:1 ratio and then stimulated and transduced (Figure 1 vs Figure S1). While Milone used a lentiviral vector encoding GFP and not a CAR in those experiments where CD4 and CD8 T cells were mixed at a 1:1 ratio prior to their stimulation and transduction, Milone et al. clearly shows that there are two equally valid methods for producing a mixed population of transduced CD4 and CD8 T cells which express a gene of interest. As such, the skilled artisan reading Milone et al. would have been equally motivated to use either methodology to generate a mixed population of transduced CD4 and CD8 T cells expressing a CAR with a reasonable expectation of success as both methods successfully resulted in a transduced mixed population of CD4 and CD8 T cells which express the gene present in the introduced vector and there is no teaching or suggestion in any of the prior art references that the nature of the protein encoded by the gene used to transduce the CD4 and CD8 T cells affects the transduction efficiency or expression efficiency of the gene in the T cells. Therefore, it is maintained that in view of the specific motivation provided by both Riddell et al. and Milone et al. for making a mixed population of CAR expressing transduced CD4+ T cells and CD8+ T cells using isolated CD4+ T cells and CD8+ T cells for use in cancer immunotherapy, and the further specific teachings of Milone et al. for a successful method of transducing a mixed population of CD4+ T cell and CD8+ T cells, which includes mixing untransduced isolated CD4+ T cells and CD8+ T cells at a 1:1 ratio, stimulating the mixed population, and transducing the mixed population with a vector encoding a gene, it would have been prima facie obvious to the skilled artisan at the time of filing utilize the methodology of Wang et al. to isolate CD4+ and CD8+ T cells and to then combine them in a 1:1 ratio prior to stimulation and transduction with a vector encoding a CAR with a reasonable expectation of success in producing an output mixed composition of CD4+ and CD8+ T cells transduced with a vector encoding a CAR.
Double Patenting
Pending claims 117-127, and 129-135 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of U.S. Patent No.11,400,115, hereafter referred to as the ‘115 patent. The applicant requests that the rejection be held in abeyance until the indication of allowable subject matter. However, the instant rejection may not be held in abeyance. As set forth in MPEP 804, only objections or requirements as to form not necessary for further consideration of the claims may be held in abeyance until allowable subject matter is indicated. A complete response to a nonstatutory double patenting (NDP) 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 in accordance with 37 CFR 1.321 in the pending application(s) with a reply to the Office action (MPEP 804 (B)(1)).
Thus, since a terminal disclaimer has not been filed and since the applicant has not traversed the grounds of rejection, the rejection of record stands.
No claims are allowed.
THIS ACTION IS MADE FINAL. 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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
Any inquiry concerning this communication from the examiner should be directed to Anne Marie S. Wehbé, Ph.D., whose telephone number is (571) 272-0737. If the examiner is not available, the examiner’s supervisor, Maria Leavitt, can be reached at (571) 272-1085. For all official communications, the technology center fax number is (571) 273-8300. Please note that all official communications and responses sent by fax must be directed to the technology center fax number. For informal, non-official communications only, the examiner’s direct fax number is (571) 273-0737. For any inquiry of a general nature, please call (571) 272-0547.
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Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634