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 .
Status of Application/Claims
The preliminary amendment, filed 12/04/2025, is acknowledged. Claims 2-8, 12, 14, 17-18, 22, and 24-25 are canceled. Claim 1 is currently amended. Claims 1, 9-11, 13, 15-16, 19-21, and 23 are currently pending and are examined on the merits herein.
Information Disclosure Statement
No new IDSs are submitted.
Withdrawn Rejections
Regarding the requirement for submission of an English translation to receive the priority of foreign application CN201910741624.1, applicant has submitted a translated document and priority is perfected.
Regarding the rejections for claim 8 under 35 U.S.C. 103 for obviousness: Claim 8 has been canceled and the rejection is withdrawn.
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.
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.
Claims 1, 9-11, 13, 15-16, 20-21, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Kenderian et al. Chimeric antigen receptor T cells and hematopoietic cell transplantation: How not to put the CART before the horse. Biology of Blood and Marrow Transplantation (2017), 23, p.235-246 (herein referred to as Kenderian); further in view of Guedan et al. Enhancing CAR T cell persistence through ICOS and 4-1BB costimulation. JCI Insight (2018), 3:1, p.1-17, herein referred to as Guedan; further view of Frost and Onuffer. Chimeric antigen receptors against AXL or ROR2 and methods of use thereof (WO2018/136570) (herein referred to as Frost); further view of Hutloff, et al. ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature (1999), 497:21, p.263-266 (herein referred to as Hutloff); and, in further view of Zhou et al. Characteristics of human homologue of 4-1BB and its ligand. Immuno. Lett. (1995), 45, p.1-2 (herein referred to as Zhou).
Kenderian teaches a chimeric antigen receptor (CAR) wherein the CAR comprises an extracellular domain that includes a heavy chain variable region and a light chain variable region of a single chain antibody fragment and CD8 hinge region that recognizes antigen (p.235, column 1, [1]; Figure 1). Kenderian also teaches a CAR comprising a transmembrane domain/TM that includes an immune co-stimulator transmembrane domain/ICTM (i.e., CD28, p.240, column 1, [6]; Figure 1). Kenderian further teaches a CAR comprising an intracellular domain that includes an immune co-stimulator intracellular segment/ICIS and CD3ζ chain (p.235, Figure 1) (instant claim 1).
Kenderian teaches that the TM domain can be CD8 or CD28, and that the ICIS domain can include one or more co-stimulatory molecules that can comprise 4-1BB, CD28, CD27, ICOS, and/or OX-40. Kenderian explains that third- and fourth-generation CAR construct development included CARs with more than one co-stimulatory molecule (p.235, column 2, [3]). Thus, Kenderian teaches a CAR wherein the ICTM is CD8, and the ICIS is 4-1BB and ICOS or OX-40 (Figure 1; instant claim 2); a CAR with domains that can be expressed in the order of CD8 (TM)-ICOS/4-1BB (ICIS)-CD3ζ (Figure 1; instant claim 1).
Kenderian teaches that viral vector (i.e., nucleic acid) constructs encoding the above-described CARs (instant claim 10) can be introduced into lymphocytes, thus producing a transgenic lymphocyte (instant claim 16). Kenderian also specifically teaches the use of retroviral and lentiviral vectors for clinical use of gene transfer into T cells, which allows for integration into the genome and has been shown to be safe when transducing primary T cells (p.236, column 1, [3]; p.236, column 2, [1]; instant claims 13 and 23). Kenderian further teaches that using adoptive transfer of less-differentiated T cells results in better antitumor activity compared with more-differentiated cells (i.e., improving effectiveness of lymphocyte therapy, instant claim 23; p.236, column 2, [5]). Kenderian also teaches that CD4 or CD8 CAR T cells derived from naïve T cells or central memory T cells have more potent antitumor activity compared with effector T cells (i.e., improving effectiveness of lymphocyte therapy, instant claim 23; p.236, column 2, [5]). Kenderian teaches that other T cell subsets, such as Th17 cells, have demonstrated superior proliferation, persistence, and antitumor activity compared with Th1 cells (p.237, column1, [1]; instant claim 23).
Kenderian also teaches a preparation method for generating a transgenic lymphocyte which comprises the following steps (p.236, column 1, [2]; instant claim 20):
(1) The patient undergoes leukapheresis;
(2) T cells may be enriched from peripheral blood mononuclear cells (PBMCs) using magnetic or mechanical techniques;
(3) T cells are stimulated in culture using beads, cytokines, or artificial antigen-presenting cells;
(4) the CAR transgene is introduced into the T cells;
(5) the T cells are further expanded in culture over several days to weeks; and
(6) the CART cells are reinfused into patients (often after lymphodepletion chemotherapy), where they are intended to proliferate, traffic to tumor sites, recognize their target antigen, and release cytotoxic molecules, resulting in tumor death.
Kenderian teaches the above-described CARs wherein the target antigen is CD19, CD20, CD123, or BCMA (Table 1; instant claim 9). Kenderian also teaches several instances where transgenic lymphocytes harboring CARs have been used for in clinical trials involving therapeutic CAR administration for cancer, including hematopoietic/hematologic malignancies such as acute lymphoblastic leukemia/ALL, non-Hodgkin lymphoma/NHL, Hodgkin lymphoma/HL, multiple myeloma/MM, chronic lymphocytic leukemia/CLL, and acute myelogenous leukemia/AML (Table 1; instant claim 21).
While Kenderian teaches CARs comprising CD8 (TM)-ICOS/4-1BB (ICIS)-CD3ζ (Figure 1), Kenderian does not specify that the order of the co-stimulator intracellular segment domains is CD8 (TM)-ICOS (ICIS)-4-1BB (ICIS)-CD3ζ ; and, does not provide a motivation for the order (i.e., ICOS proximal to the membrane/41BB distal to the membrane; instant claim 1). Kenderian also does not teach a construct with a promoter operably connected with the nucleic acid molecule wherein the promoter comprises at least one selected from CMV, EF-1, and ESV (instant claim 11). The disclosure recites “…the promoter comprises at least one selected from CMV, EF-1α, RSV” and EF-1 is a broader genus. Thus, the examiner interprets EF-1α (of the disclosure) to be encompassed by the broader EF-1 genus (listed in the claim).
Guedan teaches CARs comprising both ICOS ICIS and 41BB ICIS, including the following construct comprising in order from N-terminus to C-terminus: CD8 TM – ICOS ICIS – 41BB ICIS – CD3ζ (Figure 1A, bottom construct; instant claim 1). Guedan further teaches that ICOS proximity to the cell membrane is key to enhancing antitumor effects, whereas incorporation of 41BB in CD8+ T cells is required to enhance proliferation and elevate the CD8+/CD4+ ratio in vivo (p.9, para.1; instant claim 1). Guedan also teaches expression of various CAR constructs as well as the effects of different promoters on cell surface and fold change in CAR expression; T cell volume during ex vivo expansion in the absence of cognate antigen; expression, activation, differentiation, and exhaustion markers 14 days following stimulation; and tumor volume (Figure 4). Guedan teaches that EF-1α promoter driven expression of BBz (a CAR construct comprising a CD8 TM, 41BB ICIS, and CD3ζ chain), compared to a BBz construct driven by a pGK300 promoter, increased cell surface and fold change CAR expression, T cell volume and differentiation, higher levels of IL-2 receptor α (i.e., CD25) and inhibitory receptors (i.e., PD1, TIM-3, and CD200), and reduced tumor volume.
Regarding the order of the ICIS domains and the promoter: It would have been prima facie obvious for one of ordinary skill in the art to combine the teachings of Kenderian with the teachings of Guedan by modifying the CAR, as taught by Kenderian, that comprises an extracellular single chain antibody fragment and a CD8 hinge region, a CD8 transmembrane domain/TM that includes an immune co-stimulator transmembrane domain/ICTM, and an intracellular domain that includes an immune co-stimulator intracellular segment/ICIS and CD3ζ chain to be arranged in the order of CD8 TM – ICOS ICIS – 41BB ICIS – CD3ζ where the ICOS ICIS is the membrane-proximal ICIS (as taught by Guedan), in order to receive the expected benefit, as taught by Guedan, that positioning the ICOS ICIS proximal to the membrane would provide for enhanced anti-tumor effects. One would also be motivated to include the 41BB ICIS because Guedan teaches that the 41BB ICIS enhances proliferation of CD8+ T cells. One of ordinary skill in the art would have a reasonable expectation of success because Kenderian teaches the components of the CAR domains, including ICOS and 41BB, and Guedan teaches the benefits of the membrane-proximal ICOS ICIS and inclusion of the 41BB ICIS.
Thus, it would also be obvious for one of ordinary skill in the art to use a viral vector that comprises a nucleic acid (taught by Kenderian) encoding the CAR (as taught by the combination of Kenderian/Guedan) for introduction of the vector into lymphocytes (as taught by Kenderian) to express the CAR (instant claim10). One skilled in the art would also be motivated to use the EF-1/EF-1α promoter to express the CAR to predictably enhance the anti-tumor and inhibitory characteristics of the CAR that would also provide the benefit of reduced tumor volume (as taught by Guedan). Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to construct a CAR with the domain order of CD8 TM – ICOS ICIS – 41BB ICIS – CD3ζ (as taught by Kenderian/Guedan) and to use an EF-1/EF1-α promoter (according to Guedan) to drive expression of a CAR in lymphocytes transduced via viral vector-mediated delivery of a CAR-encoding nucleic acid (as taught by Kenderian) to enhance the expression and anti-tumor effects of the CAR (instant claim 11).
Regarding instant SEQ ID NO: 1 of instant claim 1: The combination of Kenderian and Guedan does not teach the amino acid of SEQ ID NO: 1 which encodes for the immune co-stimulator transmembrane domain connected with the immune co-stimulator intracellular segments (i.e., CD8 TM – ICOS ICIS – 41BB ICIS – CD3ζ).
Frost teaches CAR receptors, as well as the specific domain amino acid sequence for instant application CD8 TM fragment from applicant SEQ ID NO: 1 (p.14, [126-a], Frost SEQ ID NO: 46) .
Hutloff teaches the human ICOS ICIS co-stimulator amino acid sequence that shares 100% identity with applicant’s ICOS fragment from SEQ ID NO: 1 (Figure 1d).
[AltContent: textbox (Sequence Alignment 1: Applicant SEQ ID NO: 1 vs.
CD8 TM (Frost) / ICOS ICIS (Hutloff) / 41BB ICIS (Zhou)
[img-media_image1.png])]Zhou teaches the 41BB ICIS sequence fragment of applicant SEQ ID NO: 1 (see sequence alignment 1; Zhou, NP_001552.2; see sequence alignment 1 below: CD8 TM = solid box, ICOS ICIS = bold underline; 41BB ICIS = dashed box).
It would have been prima facie obvious for one of ordinary skill before the effective filing date to further combine the teachings of Kenderian and Guedan with the teachings of Frost, Hutloff, and Zhou by using the CD8 TM amino acid sequence taught by Frost, the ICOS ICIS amino acid sequence taught by Hutloff, and the 41BB ICIS amino acid sequence taught by Zhou to encode the CAR CD8 TM – ICOS ICIS – 41BB ICIS – CD3ζ construct (as taught by the combination of Kenderian/Guedan) because the combination of prior art elements according to known methods results in a predictable result of producing the CAR of the instantly claimed invention. One of ordinary skill in the art would have a reasonable expectation of success because the prior art teaches the exact amino acid sequences for the construct.
Regarding instant claim 15: The combination of Kenderian and Guedan teaches a CAR that comprises an extracellular domain, transmembrane domain/TM, and immune co-stimulator transmembrane domain(s)/ICTM with the specified order CD8 TM – ICOS ICIS – 41BB ICIS – CD3ζ as applied to instant claim 1.
Kenderian also teaches viral vectors (i.e., nucleic acid) constructs that can be introduced into lymphocytes, thus producing a transgenic lymphocyte as described for instant claims 10 and 16 above. Kenderian also specifically teaches the use of lentiviral vectors for clinical use of CAR gene transfer into T cells, which allows for integration into the genome and has been shown to be safe when transducing primary T cells (p.236, column 1, [3]; p.236, column 2, [1]) as described for instant claims 13 and 23 above (instant claim 15).
Kenderian does not teach that the lentivirus carries a nucleic acid molecule having a nucleotide sequence of SEQ ID NO: 7. SEQ ID NO: 7 of the instant application is a nucleotide sequence that encodes the for a three-domain (CD8 TM – ICOS ICIS – 41BB ICIS) fusion CAR polypeptide (i.e., CAR3 of applicant disclosure (nucleotide sequence-p.5, [28]; amino acid sequence-p.3, [017]).
Reverse translation shows that SEQ ID NO: 7 encodes the amino acid polypeptide of instant claim 1/applicant SEQ ID NO: 1, which is taught by the combination of Kenderian/Guedan/Frost/Hutloff/Zhou as described for instant claim 1 above. Nucleotide sequences for each of the CD8 TM, ICOS ICIS, and 41BB ICIS domains are highlighted below (also see SEQ ID NO: 1 amino acid sequence above; [AltContent: textbox (Applicant SEQ ID NO: 7 nucleic acid CD8 TM (underlined), ICOS ICIS (no underline), and 41BB ICIS (dashed underline)
[img-media_image2.png])]instant claim 15).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to combine the teachings of Kenderian/Guedan with the teachings of Frost, Hutloff, and Zhou by using a lentivirus carrying a nucleic acid molecule (as taught by Kenderian) expressing the CAR to arrive at the instantly claimed invention because a reverse translation of the CAR amino acid sequence taught by the combination of Kenderian/Guedan/Frost/Hutloff/Zhou predictably produces the instantly claimed CAR as described for instant claim 1 above. One of ordinary skill in the art would have a reasonable expectation of success because the reverse translation produces instant SEQ ID NO: 7 which encodes for the polypeptide of instant claim 1 taught by the combination of prior art elements.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Kenderian, Guedan, Frost, Hutloff, and Zhou, as applied to instant claims 1, 10, and 16 above; and, further in view of Simon et al. The generation of CAR-transfected natural killer T cells for the immunotherapy of melanoma. Intl. J. Mol. Sci. (2018), 19:2365, p.1-15, herein referred to as Simon.
The combination of Kenderian/Guedan/Frost/Hutloff/Zhou teaches a CAR that comprises an extracellular domain, transmembrane domain/TM, and immune co-stimulator transmembrane domain(s)/ICTM with the specified order CD8 TM – ICOS ICIS – 41BB ICIS – CD3ζ and is encoded by instant SEQ ID NO: 1 as applied to instant claim 1. The combination of Kenderian/Guedan/Frost/Hutloff/Zhou also teaches the nucleic acid molecule encoding the CAR of SEQ ID NO: 1 as applied to instant claim 10 and a transgenic lymphocyte expressing the CAR of instant claim 1.
The combination of Kenderian/Guedan/Frost/Hutloff/Zhou does not teach that the transgenic lymphocyte is a natural killer T cell (instant claim 19).
Simon teaches the generation of CAR-transfected natural killer T cells (NKT; title). Simon teaches that NKT cells transfected with CARs can attack tumor cells antigen-specifically via the CAR and additionally through its endogenous TCR (abstract). Simon further teaches that CAR-NKT cells exhibit maintained cytotoxicity while preserving their intrinsic cytotoxic activity, thus providing a valuable alternative to conventional CAR-T cell cancer immunotherpy (abstract; Figure 5).
It would have been prima facie obvjous for one of ordinary skill in the art before the effective filing date to further combine the teachings of Kenderian/Guedan/Frost/ Hutloff/Zhou with the teachings of Simon by using a natural killer T cell (as taught by Simon) as the transgenic lymphocyte (taught by Kenderian) expressing the CAR (taught by Kenderian/Guedan/Frost/Hutloff/Zhou) to arrive at the instantly claimed invention because the combination of prior art elements results in a predictable result of producing a natural killer T cell that expresses the instantly claimed CAR. Further, one would be motivated to do so because Simon teaches that NKT cells transfected with CARs can attack tumor cells.
Response to Arguments
Regarding the rejections for claims 1, 9-11, 13, 16, 20-21, and 23 under 35 U.S.C. 103 for obviousness: The examiner respectfully thanks applicant for highlighting the typo on p.9 of the Non-Final office action filed 09/04/2025 and agrees with applicant’s interpretation and assessment that “Kenderian does not specify” the order of the ICIS domains ICOS and 4-1BB. Regarding the rejection, applicant argues that Kenderian and Guedan each teach several possible CAR designs and that it is not clear that a person of ordinary skill in the art at the time of filing and that one would not predict the beneficial effects of the claimed CAR. The examiner respectfully disagrees and does not find this argument persuasive. Kenderian as the primary reference teaches a limited number of ICIS domains: 41BB, CD28, CD27, ICOS, and OX40. Further, Kenderian teaches that the CAR can comprise one or more ICIS domains. Guedan teaches the importance of membrane-proximal positioning of the ICOS domain with the motivation that such positioning enhances antitumor effects (p.10 of Non-Final filed 09/04/2025). Guedan further teaches incorporation of 41BB with the motivation that this enhances CD8+ T cell proliferation. Given that claim 1 recites that the CAR comprises the recited ICOS and 41BB ICIS domains, a CAR that also comprises any additional or any additional combination of the remaining ICIS domains taught by Kenderian also reads on claim 1. The examiner also points out that given the limited number of ICIS combinations, it would additionally be obvious to try the remaining different combinations of ICIS domains wherein the CAR comprises a proximal ICOS domain and a 41BB domain, along with the absence or presence of the other limited combinations in order to optimize the CAR.
Regarding applicant arguments pertaining to claim 8 which has been cancelled and wherein the limitations of claim 8 have been included in amended instant claim 1: Applicant argues that Guedan reports a construct wherein a CAR comprising an ICOS TM domain performed better than a CAR with a CD8 TM domain (applicant remarks filed 12/04/2025, p.7-8) and states that this disclosure is contrary to the technical effects demonstrated by the claimed CARs and highlights a comparison between CAR5 (comprising an ICOSTM domain) and CAR3 (comprising a CD8TM). The examiner respectfully disagrees and does not find this argument persuasive. The combination of Kenderian and Guedan teaches the CAR of instant claim 1 (as well as other CARs not recited in claim 1) as described above. Further, the references Frost, Hutloff, and Zhou provide the amino acid sequences for the CD8 TM, ICOS ICIS, and 41BB ICIS domains, respectively. As the CAR taught by the combination of Kenderian and Guedan teaches the same CAR with the same domains in the orientation recited in claim 1, and the amino acid sequences for the TM and ICIS domains are provided by Frost/Hutloff/Zhou, the CAR taught by prior art possesses the same structure as the recited CAR. Thus, the CAR necessarily possesses the same properties as the CAR of amended instant claim 1 (previously instant claims 1 and 8). Thus, following applicant’s amendment filed 12/04/2025, the rejection for amended claim 1, and for claims9-11, 13, 16, 20-21, and 23 are maintained in modified form.
Regarding the rejections for claim 15 under 35 U.S.C. 103 for obviousness: Claim 15 is dependent on instant claim 1. The rejection for claim 1 is maintained as described above; thus, the rejection for claim 15 is also maintained in modified form.
Regarding the rejections for claim 19 under 35 U.S.C. 103 for obviousness: Claim 19 is dependent on instant claim 1. The rejection for claim 1 is maintained as described above; thus, the rejection for claim 19 is also maintained in modified form.
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.
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.
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/JAMI MICHELLE GURLEY/Examiner, Art Unit 1647
/JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647