DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
2. 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
3. The response filed on 31 August, 2023 has been entered in full. These are the amended claims of the original claim set received on 29 June, 2023. In the amendment, claims 4, 5, 12, 13, 15, 16, 18, 19, and 21-23 are amended and claims 14, 20, and 24-66 are cancelled. Therefore, claims 1-13, 15-19, and 21-23 are pending and are the subject of this Office Action.
Information Disclosure Statement
4. The information disclosure statement (IDS) submitted on 08 September, 2023 has been considered by the examiner.
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.
5. Claims 1-5, 8, 9, 12, 15-19, 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).
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, 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).
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, (and) 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. 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 and Sagi 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.
6. Claims 6, 7, 10, 11, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Ptꞻčkovꞻ in view of Sagi 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 and Sagi 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 and Sagi 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 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, 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+ and CD8+ T cells.
7. Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Ptꞻčkovꞻ in view of Sagi 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 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 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, 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.
Conclusion
8. 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 7am to 4:30pm and Fridays from 7am to 11am.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama, can be reached at telephone number (571)272-2911. 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