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 .
Claim Status
Claims 1-19 are pending an under examination in the instant office action.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings are objected to because The chosen symbols, shades, and pixelation in Fig. 1 graphs mean that not all of the groups listed in the legend can be discerned from one another (e.g. the cJun ROR1 Regnase1 KO High line cannot be distinguished in Fig. 1A). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 2 objected to because of the following informalities: the preamble recites the three elements of "A method of increasing T cell function, reducing T cell exhaustion, increasing T cell survival" without a conjunction of "and" or "or". Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)- Scope of Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 17-19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating: 1) cancer, wherein the subject has cancer; 2) comprising administering the cells of claim 6, wherein the human T cell further comprises a recombinant engineered TCR or CAR or wherein the T cell comprises a tumor-targeting TCR (e.g. a TIL); and 3) wherein the method of administering human T cells comprising one or more expression vectors encoding human c-Jun and wherein the expression level of Regnase-1 is reduced comprises administering the modified T cells at a dose of 2.5x105 cells
does not reasonably provide enablement for a method of treating: 1) any subject in need thereof for any unspecified disease; 2) comprising administering a human T cell with no additional elements; and 3) comprising administering any dose of human T cells comprising one or more expression vectors encoding human c-Jun, wherein the expression level of Regnase-1 is reduced due to a null mutation in the Regnase-1 gene or due to RNA interference or an antisense oligonucleotide targeting Regnase-1.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Scope of the claimed genus and nature of the invention
The instant invention is in the field of adoptive T cell therapy.
Regarding claim 17, the claim is directed towards a method of treating a subject in need thereof, comprising administering to the subject the cell of claim 1. The cells of claim 1 are a human T cell comprising one or more expression vectors encoding human c-Jun, wherein expression level of Regnase-1 or PTPN2 in the cell is reduced due to a null mutation in the Regnase-1 or PTPN2 gene or due to RNA interference or an antisense oligonucleotide targeting Regnase-1 or PTPN2 mRNA.
Regarding claim 18, the claim recites the method of claim 17 wherein the cell is an autologous or allogeneic T cell. This restricts the subjects to human subjects because the T cell is required to be human but does not further modify the structure or components of the human T cell or the particulars of the method, such as the scope of diseases treated.
Regarding claim 19, the claim recites the method of claim 17 wherein the subject has cancer. This partially resolves the scope of enablement because it limits the scope of the diseases treated, but it does not further require any additional structure to the scope of the T cell (e.g. comprising a recombinant CAR or TCR) or any particular dose of the c-Jun/REGNASE-1 KO T cells.
State of the Relevant Art; level of one of ordinary skill; and level of predictability of the art
Regarding adoptive T cell therapy and methods of increasing expansion and persistence of T cells, this is a very active area in the field of T-cell therapy. For example, Chan, Jack D., et al. "Cellular networks controlling T cell persistence in adoptive cell therapy." Nature Reviews Immunology 21.12 (2021): 769-784 reviews the different cellular networks to increase T-cell persistence and discusses gene modifications that have been shown to improve T-cell fitness. Chan et. al. states that “The antitumour activity of ACT is highly dependent on the expansion, persistence and continued activity of adoptively transferred cells. Although T cell products that are dominated by effector-type cells have greater cytotoxic potential, these cells are also predisposed to terminally differentiate and become dysfunctional”. Chan et. al. teaches that the known ways to regulate therapeutic outcomes include modulating CAR affinity, targeting receptor transgenes to the TRAC locus, selection and modification of co-stimulatory motifs, cytokines and media in ex vivo culture (e.g. PI3K inhibitors, WNT activators, targeting transcription factors, modulating epigenetic states, targeting immune checkpoint receptors and phosphatases, and targeting T-cell metabolism. Chan et. al. states “Modulation of transcription factor activity may be readily achieved through CRISPR–Cas9 knockout, short hairpin RNA-mediated knockdown or viral transduction for overexpression”. Chan et. al. teaches that the transcriptions factors that mediate T-cell expansion and effector differentiation are also involved in T cell exhaustion: “In particular, NFATC1, IRF4 and BATF and the NR4A family of transcriptional regulators are drivers of T cell exhaustion under conditions of prolonged TCR engagement, as observed during chronic infection and in tumours” (“Targetting transcriptional regulators” section, ¶3). Chan et. al. teaches that “Overexpression of JUN targeted nuclear factor of activated T cells (NFAT) signaling, thereby increasing CAR T cell maintenance […]The decreased differentiation status of JUN-overexpressing cells enabled improved control of osteosarcoma tumours” (“Targetting transcriptional regulators” section, ¶4). Regarding overcoming immunosuppression, Chan et. al. teaches “Protein tyrosine phosphatase non-receptor type 2 (PTPN2) is a known negative regulator of TCR signalling and was recently shown to drive T cell exhaustion[…] PTPN2 targeting is particularly promising as PTPN2-knockout CAR T cells of a TCM-like phenotype exhibit improved in vivo antitumour function compared with wild-type central memory CAR T cells” (“Overcoming immunosuppression” section, ¶7). Chan et. al. teaches “An important area of inquiry will be to determine a patient’s suitability of the proposed strategies owing to different cancer types, particularly within the context of solid cancers, in which CAR T cells may potentially require a combination of approaches to overcome additional challenges such as the immunosuppressive TME and antigen heterogeneity to increase their therapeutic efficacy in the clinic” (“Concluding remarks” ¶1).
Regarding methods of treating tumors with T cells that do not comprise an anti-tumor TCR or CAR, there are no methods currently of record. Even early studies of adoptive cell therapy (ACT) focused on populations of anti-tumor lymphocytes for the treatment of cancer. For example, Rosenberg, Steven A., and Mark E. Dudley. "Adoptive cell therapy for the treatment of patients with metastatic melanoma." Current opinion in immunology 21.2 (2009): 233-240 teaches “Melanoma appears to be unique among human cancers because of its ability to induce significant numbers of lymphocytes with anti-tumor activity during the natural course of tumor growth [1]. Thus, tumor infiltrating lymphocytes (TIL) or peripheral lymphocytes repeatedly stimulated in vitro with autologous melanoma cells often demonstrate in vitro recognition of melanoma cells based on assays of lysis or cytokine secretion […] Effective cancer immunotherapy is dependent on the presence of large numbers of anti-tumor lymphocytes with appropriate homing and effector functions that enable them to seek out and destroy cancer cells in vivo” (Introduction ¶1-2). Thus, a person of ordinary skill in the art would not predictably be able to treat any cancer with generic human T cells that may or may not have the ability to recognize the tumor being treated.
Regarding combining overexpression with c-Jun and knockout or knockdown of either PTPN2 or REGNASE-1, there is no specific guidance about methods of treating with this combination in the art to guide dosing or toxicity information, and therefore a person of ordinary skill in the art must rely only on the guidance in the specification as described below.
Summary of Species disclosed in the original specification; the amount of direction provided by the inventor, existence of working examples; and quality of experimentation needed to make or use the invention based on the content of the disclosure.
The instant specification teaches genetic knockout of Regnase-1 and PTPN2 in human T-cells further comprising a vector overexpressing human c-Jun and further comprising a ROR1 CAR against an NSG model of ROR1-positive NSCLC (Example 1; also see materials and methods [0068-0076]). The instant specification teaches administration to the mice of the ROR1 CAR/REGNASE-1 KO/c-JUN T cells and the ROR1 CAR/PTPN2 KO/c-JUN T cells at a dose of 1x106 or 2.5x105 cells. The inventors measured anti-tumor activity and treatment-related toxicity and states that: “The data show that at a dose of 1x106 CAR T cells, control ROR1 CAR T cells were ineffective at reducing tumor burden or extending survival (FIGs. 1A and 1B). ROR1 CAR T cells overexpressing c-Jun significantly reduced tumor burden and extended survival. ROR1 CAR T cells overexpressing c-Jun in a VHL or XBP1 knockout background lost the ability to control tumor growth and did not extend animal survival (FIGs. 1A and 1B). Some mice receiving ROR1 CAR T cells overexpressing c-Jun in a Regnase-1 knockout background exhibited body weight loss and had to be taken off study, all surviving animals were able to control tumor growth (FIG. 1A). ROR1 CAR T cells overexpressing c-Jun in a PTPN2 knockout background had prolonged anti-tumor activity without any signs of toxicity (FIG. 1A)”. However, regarding Fig. 1A, the cJun ROR1 Regnase 1 KO High group cannot be distinguished from the groups where there is no improvement in tumor treatment and there is no evidence of the tumor treatment effect. Additionally, Fig. 1b shows that the cJun ROR1 Regnase1 KO High mice started dying first and the total deaths appears to be equivalent to the mock or ineffective T cell groups. It is unclear, as described in the drawings objection above, whether the Regnase 1 KO group in the low dose in the group showed tumor control or life extension because both the cJun ROR1 Control KO and the cJun ROR1 Regnase1 KO Low group have similar symbols on the graph. However, the instant specification states that those two groups that show tumor control are the cJun ROR1 Regnase1 Low and cJun ROR1 PTPN2 Low groups, and therefore it is considered that the the cJun ROR1 Regnase1 human T cells were shown to be effective at treating tumor at a low dose (2.5x105 cells) but not high dose. There is no additional guidance on what caused the toxicity or whether this toxicity would be expected in other subjects such as human subjects. There is no evidence of tumor control at the higher dose where toxicity was observed.
Regarding subjects in need thereof and how it may be assessed that the subject has a disease suitable for administering the T cells of the invention, the specification does not offer any additional examples or guidance other than cancer (e.g. [0012]). The inventors only demonstrate the working example of a single human donor against a single model of NSCLC. There are no examples of tumor targeting in the absence of a tumor specific recombinant receptor (e.g. a TCR or CAR).
Conclusion
Applicant does not have enablement for a method of treating any generic subject in need thereof comprising administering the claimed human T cells comprising one or more vectors encoding human c-Jun wherein the level of Reganse-1 or Ptpn2 is reduced and without any additional tumor-targeting receptor (e.g. without a recombinant CAR or TCR, or endogenous anti-tumor TCR) and wherein the cJun/ REGNASE-1 KO human T cells are administered at any dose. Due to the state of the art and the teachings of the specification, it would take undue experimentation to determine 1) which unspecified diseases may be treated with the instant T cells because the art and the specification teach targeting of tumor antigens wherein 2) the T cells do not comprise an endogenous TCR or a chimeric CAR or TCR targeting a tumor antigen because the art and the specification do not teach generic boosting of T cells; and 3) wherein the cJun/REGNASE-1 KO human T cells are at a particular dose, because the instant specification teaches that cJun/REGNASE-1 KO/ROR1 CAR T cells were not effective as treating the tumor and caused toxicity at higher doses and therefore outside the disclosed effective low dose a person of ordinary skill in the art would not know which doses were effective to treat tumors.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claim(s) 1-8, 10-17, and 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO2019118902 to Mackall et. al. published 10 June 2019 (IDS dated 4/19/2024) in view of Wei, Jun, et al. "Targeting REGNASE-1 programs long-lived effector T cells for cancer therapy." Nature 576.7787 (2019): 471-476 (IDS dated 4/19/2024).
Regarding claim 1, Mackall et. al. teaches human T cells that overexpress the AP-1 transcription factor c-Jun (e.g. p. 3 lines 1-14; p. 62 lines 31-33). The cell overexpress c-Jun via retroviral vector transduction (e.g. p. 63 lines 7-13; Example 2 p. 69 lines 15-22; Example 5 p. 70 lines 21-33). Mackall et. al. teaches that the cells may optionally (e.g. “and/or”) comprise a decrease in an inhibitor of the AP-1 pathway (e.g. p. 3 lines 23-30).
Regarding claims 5-6, Mackall et. al. teaches the cell wherein the human T cell further comprises an expression cassette for a chimeric antigen receptor (reads on recombinant antigen receptor and CAR) (e.g. Example 5 p. 70 lines 21-33). Regarding claim 7, Mackall et. al. teaches c-Jun co-expressed with 8 different CARs targeting tumor antigens such as CD19 (e.g. Example 5 p. 70 lines 21-33). Regarding claim 8, Mackall et. al. teaches that the T cells were transduced with a bicistronic expression cassette expressing human c-Jun and a CAR (e.g. Example 5 p. 70 lines 21-33).
Regarding claim 10, Mackall et. al. teaches the T cells comprising wildtype Jun OE (e.g. see p. 79 lines 1-7).
Regarding claims 11 and 12, Mackall et. al. teaches the T cells comprising a mutant Jun OE wherein the c-Jun comprises alanine substitutions at Ser63 and Ser73 (e.g. see p. 78 lines 31-33 and 79 lines 1-7).
Regarding claims 13 and 14, Mackall et. al. teaches the cells are both CD4+ and CD8+ T cells (e.g. see p. 75 lines 9-25; p. 71 lines 8-10).
Regarding claim 15, Mackall et. al. teaches that in some embodiments the T cells are tumor-infiltrating lymphocytes (e.g. p. 4 lines 27-30).
Regarding claim 16, Mackall et. al. teaches compositions comprising the modified T cells of the invention and a pharmaceutically acceptable carrier (e.g. p. 10 lines 12-14).
Regarding claims 17 and 19, Mackall et. al. teaches a method of treating or delaying the progression of cancer in a patient comprising administering to the patient a therapeutically effective amount of the c-Jun vector expressing T cells (e.g. p. 10 lines 15-20; p. 46 lines 21-p. 47 line 16)).
Regarding claim 2, Mackall teaches a method of preventing exhaustion of engineered T cells and enhancing T cell function against cancer or infectious disease (Abstract). Mackall teaches that engineering CAR T cells to overexpress an AP-1 factor (e.g., c-Jun) renders them exhaustion resistant (e.g. p. 3 lines 10-14). Mackall teaches introducing into a human T cell an expression vector for expressing a human c-Jun, wherein the T cell overexpresses human c-Jun compared to a reference cell without the vector and that this introduction reduced exhaustion and T cell function (e.g. Example 11; also see p. 31 lines 12-13: “Lentiviral vectors or retroviral vectors may be used (e.g., to introduce DNA encoding one or more AP-1 transcription factors and/or a CAR construct into cells (e.g., T cells))”).
Mackall et. al. also teaches knockdown of c-Jun inhibitory complex members such as IRF4. Mackall et. al. teaches that “while JunB and BATF3 knockout improved functionality in some donors, IRF4 knockout dramatically improved IL-2 secretion in stimulated HA-28z CAR T cells (left and middle) in all donors tested. IRF4-KO CAR T cells even showed improved baseline section of IL-2 from tonic signaling” (Example 16).
Mackall et. al. does not teach the human T cells wherein the expression level of Regnase-1 or PTPN2 in the cell is reduced due to a null mutation in the Regnase-1 or PTPN2 gene or due to RNA interference or an antisense oligonucleotide targeting Regnase-1 or PTPN2 mRNA or a method of preventing exhaustion or increasing T cell function by providing a human T cell comprising an expression vector for expressing human c-Jun and introducing a null mutations to one or both alleles of the Regnase-1 or PTPN2 gene in the cell.
This deficiency is resolved by Wei et. al.
Wei et. al. teaches that in a CRIPSR/Cas9 mutagenesis screen for T cells with long-lived effector function and better persistence, REGNASE-1 knockout was the most highly enriched gene (Fig. 1, “Screen for metabolic regulators of ACT section”). Wei et. al. teaches that loss of REGNASE-1 improves adoptive cell transfer (ACT) against several tumor models including melanoma and leukemia (Fig. 2, “Loss of REGNASE-1 improves ACT efficiency section”). Wei et. al. teaches that genes that were repressed by REGNASE-1 null were enriched in memory-like CD8+ T cells in chronic infection (Fig. 3 “REGNASE-1 loss reprograms T cells in TME section) including decreased Irf4. Wei et. al. teaches that “although tumour-infiltrating CD8+ T cells that lack REGNASE-1 acquire better persistence and a survival advantage, they retain potent effector function” (“REGNASE-1 loss reprograms T cells in TME” section).
It would have been obvious, at the time of filing, for a person of ordinary skill in the art to make an improved human T-cell with increased persistence and effector function by combination c-Jun overexpression with knockdown of REGNASE-1 in order to benefit from the metabolic reprogramming including decreased expression of IRF4 as taught by Wei et. al. in the background of a c-Jun overexpressing human T cell with prophetically recited decrease of an additional inhibitor of the AP-1 pathway as taught by Mackall et. al. A person of ordinary skill in the art would expect to benefit from the improvement to anti-tumor T cell activity as taught by both Mackall et. al. and Wei et. al. This would have a reasonable expectation of success because Mackall et. al. suggests combing c-Jun overexpression with knockdown or knockout of another gene negatively regulating the AP-1 pathway and both Mackall et. al. and Wei et. al. suggest that IRF4 overexpression contributes to T-cell exhaustion via dysregulation of c-Jun/c-Fos heterodimers; in addition, a person of ordinary skill in the art would have a reasonable expectation that combining two different modifications that have both been shown to improve T-cell effector function and persistence would result in a T-cell with improved persistence.
Regarding claim 2, as described above, it would have been obvious, at the time of filing, for a person of ordinary skill in the art to introduce a null mutation in REGNASE-1 as taught by Wei et. al. into the human T cell comprising c-Jun expression vector as taught by Mackall et. al.
Regarding claims 3-4, Wei et. al. teaches generation of a null mutation in REGNASE-1 by CRISPR Cas-9 editing (see e.g. Methods, Lentiviral sgRNA metabolic library CRISPR-Cas9 mutagenesis screening section; Extended data Fig. 1).
Claim(s) 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO2019118902 to Mackall et. al. published 10 June 2019 (IDS dated 4/19/2024) in view of Wei, Jun, et al. "Targeting REGNASE-1 programs long-lived effector T cells for cancer therapy." Nature 576.7787 (2019): 471-476 (IDS dated 4/19/2024) as applied to claims 1 and 5 above, and further in view of US 20160318988 A1 to Knox published 3 Nov. 2016.
The teachings of Mackall et. al. in view of Wei et. al. in regard to claims 1 and 5 are in the 103 rejection above and are incorporated by reference herein.
In regard to claim 9, Wei et. al. further teaches the REGNASE-1 null T cells showed stronger effects than wildtype T cells when combined with the pme-1 TCR that recognize the endogenous melanoma antigen gp100 (“Loss of REGNASE-1 improves ACT efficiency” section ¶1).
Mackall et. al. in view of Wei et. al. does not teach human T cell comprising an expression cassette for expressing a recombinant antigen receptor wherein the T-cell comprises a tri-cistronic expression cassette for expressing the human c-Jun and the alpha and beta chains, or gamma and delta chains, of an engineered TCR.
This deficiency is resolved by Knox.
Knox teaches a vector capable of expressing a transcription factor (in the case of Knox, Foxp3) and a TCR of the invention wherein the TCR alpha and beta chains are expressed together with the transcription factor from a tricistronic retroviral vector using 2A and IRES in order to ensure that the TCR and the transcription factor are not dissociated from one another (e.g. [0065]).
It would have been obvious, at the time of filing, for a person of ordinary skill in the art to use a tricistronic expression vector as taught by Knox in order to express a tumor-targeting TCR in combination with c-Jun ovexpression and REGNASE-1 knockout as taught by Mackall et. al. in view of Wei et. al. in order to ensure that the anti-tumor activity of the TCR is not separated from the T-cell activity boosting function of c-Jun as taught by Knox. This would have a reasonable expectation of success because a person of ordinary skill in the art would have been able to modify known expression vectors in order to get the desired expression of different components in the T cell population.
Claim(s) 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO2019118902 to Mackall et. al. published 10 June 2019 (IDS dated ) in view of Wei, Jun, et al. "Targeting REGNASE-1 programs long-lived effector T cells for cancer therapy." Nature 576.7787 (2019): 471-476 as applied to claims 1 and 17 above, and further in view of Depil, S et al. "‘Off-the-shelf’allogeneic CAR T cells: development and challenges." Nature reviews Drug discovery 19.3 (2020): 185-199.
The teachings of Mackall et. al. and Wei et. al. in regard to claim 1 and 17 are in the 103 rejection above and are incorporated herein.
Mackall et. al. in view of Wei et. al. do not explicitly teach that the method of treating may comprise administration of autologous or allogeneic human T cells.
This deficiency is resolved by Depil et. al.
Depil et. al. teaches that “From an immunological point of view, autologous CAR-T cell therapy is associated with the absence of allogeneic reaction, and the engineered T cells can thus persist for a long time. However, autologous CAR T cell therapies require a bespoke manufacturing process for every patient after leukapheresis” (p. 185 left column ¶2-right column ¶1). Depil et. al. teaches that autologous T cells also have downsides and that, “The ability to use cells from healthy donors, referred to as ‘off-the-shelf’ allogeneic CAR T cells, could potentially address these issues. Allogeneic CAR T cells have many potential advantages, such as a decreased cost due to the implementation of industrialized and scaled-up manufacturing processes, in which a high number of CAR T cells can be produced from a single donor” (p. 185 right column ¶2-p. 186 right column).
It would have been obvious, at the time of filing, for a person of ordinary skill in the art to perform a method of treating cancer comprising the modified human T cells comprising an expression vector expressing c-Jun and a knockout of REGNASE-1 as taught by Mackall et. al. in view of Wei et. al. by using either autologous or allogeneic human CAR T cells because Depil et. al. teaches that these are the two options for treating human patients and they both have advantageous and disadvantageous. This would have a predictable result because a person of ordinary skill in the art would be able to choose autologous or allogeneic human T cells based on the available T cells and donors as well as the condition of patient T cells as suggested by Depil et. al and there are only two common solutions for T cell sources for human therapy.
Conclusion
No claims are allowed.
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/KATHLEEN CUNNINGCHEN/ Examiner, Art Unit 1646
/GREGORY S EMCH/ Supervisory Patent Examiner, Art Unit 1678
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