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 .
Priority
The instant application, filed on 07 June, 2023, claims domestic benefit to US provisional application no. 63/350,645, filed on 09 June, 2022.
Status of Application, Amendments, and/or Claims
The response filed on 04 May, 2026 has been entered in full. The response is an amendment to a Non-Final Rejection to the claim set filed on 25 August, 2023. In the amendment claims 1, 12, 16, 21, and 22 are amended, claims 4, 5, 13, 15, 18, 19, and 23 are previously presented, and claims 14, 17, 20, and 24-66 are cancelled. Therefore, claims 1-13, 15, 16, 18, 19, and 21-23 are pending and are the subject of this office action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08 September, 2023 has been considered by the examiner.
The information disclosure statement (IDS) submitted on 04 May, 2026 has been considered by the examiner.
Status of Objections and Rejections
In the office action of 02/02/2026
Claims 1-5, 8, 9, 12, 15, 16, 18, 19, 21, and 23 were rejected under 35 U.S.C. 103 over Ptꞻčkovꞻ et al. in view of Sagi. The amendment of claims 1, 12, and 16 necessitates a modified 103 rejection over Ptꞻčkovꞻ et al. in view of Sagi and Du.
Claim 17 was rejected under 35 U.S.C. 103 over Ptꞻčkovꞻ et al. in view of Sagi. The cancellation of the claim renders the rejection moot.
Claims 6, 7, 10, 11, and 22 were rejected under 35 U.S.C. 103 over Ptꞻčkovꞻ et al. in view of Sagi, and further in view of Xu et al. The amendment of claims 1, 12, and 16 necessitates a modified 103 rejection over Ptꞻčkovꞻ et al. in view of Sagi and Du , and further in view of Xu et al.
Claim 13 was rejected under 35 U.S.C. 103 over Ptꞻčkovꞻ in view of Sagi and further in view of Tian et al. The amendment of claim 1 and 12 necessitates a modified 103 rejection over Ptꞻčkovꞻ et al. in view of Sagi and Du, and further in view of Tian et al.
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.
Claims 1-5, 8, 9, 12, 15, 16, 18, 19, 21, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Ptꞻčkovꞻ et al. (2018) The new approach to CAR T-cell gene engineering and cultivation using piggyBac transposon in the presence of IL-4, IL-7 and IL-21 Cytotherapy (20) 507-520 (hereafter Ptꞻčkovꞻ) in view of Sagi (of record IDS 09/08/2023) and Du et al. (2021) (of record IDS 05/04/2026).
In regards to claim 1 Ptꞻčkovꞻ teaches a method of making a genetically engineering a lymphocyte by exposing the cells to exogenous Interleukin-7 (IL-7) and IL-21 in vitro and further teaches contacting the lymphocyte with a transposon vector with a CAR gene (gene of interest) (Abstract).
In regards to claims 2 and 3 Ptꞻčkovꞻ teaches the lymphocyte being a T-Cell (Abstract).
In regards to claim 4 Ptꞻčkovꞻ teaches contact the T-Cell with an anti-CD3 and anti-CD28 antibody (pg. 509, col 1, lines 40-42).
In regards to claims 5, 8, and 9 Ptꞻčkovꞻ teaches that the T-Cell expresses CD4+ and CD8+ T-cells and further teaches these CD4+ and CD8+ T-cells express CD27+ and CD28+ (Figure 4)
In regards to claims 12 and 15-17 Ptꞻčkovꞻ teaches the T-cell (lymphocyte) expresses a CD19 CAR by transformation with a DNA vector and further teaches the DNA vector is a transposon (pg. 509, col 1, lines 29-39).
In regards to the claim 18 Ptꞻčkovꞻ teaches the benefits of not using IL-2 in the culture when genetically engineering the T-cell (pg. 510, col 2, lines 26-28).
In regards to claim 19 Ptꞻčkovꞻ teaches harvesting the T-cells from patients (subject) with lymphoma (pg. 508, col 2, lines 19-22).
In regards to claim 21 Ptꞻčkovꞻ teaches that the use of a lentiviral vector to genetically engineer T cells is routine (Abstract)
In regards to claim 23 Ptꞻčkovꞻ teaches harvesting the T cell after overnight transformation before stimulation with cytokines (pg. 509, col 1, lines 37-39).
Ptꞻčkovꞻ fails to teach contacting the lymphocyte with an anti-CD81 antibody and the use of a viral vector, as recited in claim 1 from which all claims depend. Sagi, however, teaches the stimulation of T-cells with CD81 and CD3 together activates the T-cells to a naïve phenotype, and further teaches the stimulation with CD81, CD3, and CD28 creates a diverse population of naïve and memory T-cells (Abstract). Sagi also naïve T cells might be useful for the expansion of T cells for adoptive immunotherapy and costimulation with CD28 and CD81 results in an additive effect on T cell activation (Abstract).
Sagi fails to teach the use of a viral vector for the transduction of lymphocytes of claim 1 from which all other claims depend. Du, however teaches the generation of a CAR T cell using lentiviral transduction, and that lentiviral vectors are capable of stably infecting the dividing or non-dividing cells by integrating into the host genome, and are nontoxic to the human body which allows for long term stable gene expression (pg.1, lines 8-11). Du further teaches that IL-21 improves lentiviral transfection efficiency (pg.2, col 1, lines 38-40).
Thus, Ptꞻčkovꞻ discloses a method of making a genetically engineered lymphocyte through contact with IL-7, IL-21 and a transposon vector to express a CD19 CAR which does not need contact with IL-2, Sagi teaches the benefits of T-Cell stimulation with CD81 with or without CD28 to get a naïve phenotype of cells for expansion in adoptive immunotherapy, and Du teaches using lentiviral vectors, for long-term, stable gene expression. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to combine the teachings of Ptꞻčkovꞻ, Sagi, and Du with a reasonable expectation of success to develop a CD19 CAR-T cells with a significant proportion of naïve T cells to improve their effectiveness in adoptive immunotherapy, and further wherein the transposon of Ptꞻčkovꞻ is simple substituted with the lentivirus of Du to allow for stable and long term gene expression for improved adoptive therapy efficacy.
Claims 6, 7, 10, 11, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Ptꞻčkovꞻ in view of Sagi and Du as applied to claims 1 and 5 above, and further in view of Xu et al. (2014) Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15 Blood (123) 24 (hereafter Xu).
In regards to claims 6, 7, 10, and 11 Ptꞻčkovꞻ in view of Sagi and Du fail to teach that the CD4+ and CD8+ T cells express CCR7+ and CD45RA+. Xu, however, uses a very similar method to Ptꞻčkovꞻ (an engineered CAR19 T-cell contacted with IL-7) and teaches that IL-7 in combination with IL-15 promoted a CD45RA and CCR7 expression in both CD4+ and CD8+ T cells when compared to the other commonly used cytokine IL-2 (Supplemental Table 2).
In regards to claim 22 Ptꞻčkovꞻ in view of Sagi and Du fail to teach the use of a retroviral vector, however, Xu uses a retroviral vector to genetically engineer the T cell (pg. 3751, col 1, lines 24-25).
Thus, Ptꞻčkovꞻ in view of Sagi and Du discloses a method of making a genetically engineered T-Cell through contact with IL-7, IL-21, and a vector, as well as outlines the benefits of contacting an anti CD81 antibody wherein the T-Cell expresses CD4+, CD8+, CD27+ and CD28+ and Xu teaches that contact of a T-cell with IL-7 can cause the expression of CD45RA and CCR7 and further teaches the use of a retroviral vector to genetically engineer T-cells. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to try the combination of the teachings of Ptꞻčkovꞻ, Sagi, Du and Xu with a reasonable expectation of success to use a retroviral vector to genetically engineer T-cells and increase the expression CD45RA and CCR7 in CD4+ in CD8+ T cells.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Ptꞻčkovꞻ in view of Sagi and Du as applied to claim 12 above, and further in view of Tian et al. (2020) Gene modification strategies for next-generation CAR T cells against solid cancers Journal of Hematology & Oncology (13) 54 (hereafter Tian).
Ptꞻčkovꞻ in view of Sagi and Du fails to teach the use of a bispecific CAR, however, Tian teaches that bispecific CARs improve CAR T cell antigen recognition (Fig 4) and further teaches a bispecific CAR T cell co-targeting CD19 and HER2 displayed greater antitumor activity in vivo then CAR T cells with a single target (pg. 3, col 2, lines 12-14).
Thus, Ptꞻčkovꞻ in view of Sagi and Du discloses a genetically engineered T-Cell through contact with IL-7, IL-21, and a vector, as well as outlines the benefits of contacting an anti CD81 antibody which further expresses a CAR by vector transformation, and Tian teaches bispecific CARs improve antigen recognition and antitumor activity. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to combine the teachings of Ptꞻčkovꞻ, Sagi, Du, and Tian with a reasonable expectation of success to develop a genetically engineered T -cell which expresses a bispecific CAR to improve its antigen targeting and antitumor activity.
Response to Arguments
Applicant's arguments filed 05/04/2026 have been fully considered but they are not persuasive.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning (Remarks 05/04/2026, pg.6, lines 13 & 26), it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
In response to applicant’s argument that “the office is purposefully omitting one of the required cytokines of Ptꞻčkovꞻ without any reasoning why this critical element of Ptꞻčkovꞻ is not found in the present claims” (Remarks 05/04/2026, pg.6, lines 27-28) and further “the office disregards that IL-7 is disclosed in combination with another critical cytokine”( Remarks 05/04/2026, pg.8, lines 24-25), the examiner recognizes that IL-4 and IL-15 (the “omitted” cytokines) are not expressly stated in the present claims. The use of the language “comprising” is inclusive or open-ended and does not exclude additional elements (See MPEP 2111.03(I)), thus Ptꞻčkovꞻ’s use of IL-4,and Xu use of IL-15 is an additional elements and the use of these cytokines is not omitted by the examiner, but was not discussed as it was not necessary to meet the requirement of the claims which simply must be a method comprising the cytokines IL-7 and IL-21.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references (Remarks 05/04/2026, pg.6, lines 13-15), the examiner recognizes that 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). In this case, Ptꞻčkovꞻ teaches a method of making a genetically engineer lymphocyte to express a CD19 CAR, while Sagi teaches T cell stimulation with CD81 with or without CD28 to generate a naïve phenotype of cells. The motivation to combine these references is stated to be the development of a naïve T cells to improve their effectiveness in adoptive immunotherapy. As highlighted in Sagi, and further known by a person of ordinary skill in the art at the time of the effective filling date, obtaining naïve T cells are an obvious method to improve adoptive cell therapy effectiveness.
In response to applicant's argument that “no reasonable expectation of success has been established for combining such fundamentally different methods” (Remarks 05/04/2026, pg.9, lines 5-6), 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 response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references (Remarks 05/04/2026, pg.8, lines 20-24), the examiner recognizes that 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). In this case, Ptꞻčkovꞻ teaches a method of making a genetically engineer lymphocyte to express a CD19 CAR, while Sagi teaches T cell stimulation with CD81 with or without CD28 to generate a naïve phenotype of cells, and Xu teaches contacting cells with IL-7 to increase the expression of CD45RA and CCR7 better than other cytokines. The motivation to combine these references is stated to be to genetically engineer T-cells and further that the addition of IL-7 would increase the expression of CD45RA and CCR7 in CD8+ T cells. As highlighted in Xu, and further known by a person of ordinary skill in the art at the time of the effective filling date, obtaining CD45RA+ and CCR7+ cells and the use of a retroviral vector a known method of genetic modification are obvious methods to develop and improve adoptive cell therapy effectiveness.
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 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 or earlier communications from the examiner should be directed to DASIA A ALDARONDO whose telephone number is (571)272-1977. The examiner can normally be reached on Mon-Thurs from 8am to 6pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama, can be reached at telephone number (571)272-1977. The fax phone number for the organization where this application or proceeding is assigned is (571)273-8300.
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/D.A.A/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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