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 .
Applicants’ response filed 10/06/2025 to the non-final rejection mailed 07/22/2025 has been received. All previous “objections” are withdrawn in view of applicant’s amendments. Claims 57-66 are pending and are currently under consideration.
Rejections Withdrawn
The prior rejections (paragraphs 8 and 9) under 35 USC 112, 2nd paragraph in the non-final mailed 07/22/2025 are withdrawn in view of applicant’s amendments.
The prior rejection (paragraph 10) under 35 USC 112, 1st paragraph (written description) in the non-final mailed 07/22/2025 is withdrawn in view of applicant’s amendments.
New Rejections
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.
Claim(s) 57-59 are rejected under 35 U.S.C. 103 as being unpatentable over US 20140004121 (Fanslow III et al, Jan 2, 2014, Applicant’s IDS) in view of US Patent 9272002 (Powell et al. March 1, 2016) and Park et al (Scientific Reports volume 7, Article number: 14366, 2017)
Fanslow et al. teach methods (page 149, claim 42) of treating cancer comprising the administration of antibodies that specifically bind the tumor associated antigen mesothelin. In particular, Fanslow et al. teach a variable heavy chain comprising the three claimed CDRs (SEQ ID Nos: 3, 4, and 5) and a variable light chain comprising the three claimed CDRs (SEQ ID Nos: 6, 7, and 8):
Variable Heavy Chain of Fanslow (SEQ ID NO: 94) with claimed CDRs matches 100% to VH chain of applicant’s SEQ ID NO:9
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Variable Light Chain of Fanslow (SEQ ID NO: 83) with claimed CDRs matches 100% to VL chain of applicant’s SEQ ID NO:10.
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Fanslow et al. specifically claim the above Vh and Vl chains:
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Fanslow terms this antibody, “Ab1.51” or 151. According to Figure 4, Antibody 151 had the lowest affinity (Kd=1/ka) for soluble human mesothelin and for native (cellular) human mesothelin at 17400 and 30, respectively.
US Patent 9272002 teaches methods of treating cancer comprising engineering chimeric antigen receptors that target mesothelin. These CARs include a transmembrane domain, a cytoplasmic domain comprising a CD3 zeta signaling domain and a co-stimulatory domain (see Fig 1 and summary of the invention). The patent further teaches (column 17, lines 6+) that the antigen binding domain can be any domain that binds to the antigen including but not limited to monoclonal antibodies, polyclonal antibodies, synthetic antibodies, human antibodies, humanized antibodies, and fragments thereof.
One of ordinary skill in the art at the time of filing would consider it prima facie obvious to incorporate Fanslow’s Vh and Vl chains together with a CD3 zeta signaling and co-stimulatory domain to make a chimeric antigen receptor T-cell because engineering patients’ T cells with chimeric antigen receptor (CAR) provides for tumor-specific T cells. In this case, targeting tumors that overexpress mesothelin would provide for an added immunotherapeutic to target solid tumors as shown by US Patent 9272002.
Further, one of ordinary skill would be motivated to use the lower affinity Vh and Vl chains of the 151 antibody because Park et al. (Scientific Reports volume 7, Article number: 14366, 2017) summarize studies that emphasize the need to reconsider the criteria used to determine optimal CAR affinities to achieve enhanced therapeutic indices. For example, many commonly targeted solid tumor antigens, such as human epidermal growth factor receptor 2 (ErbB2), epidermal growth factor receptor (EGFR), mucin 1 (MUC1), prostate-specific membrane antigen (PSMA), and disialoganglioside (GD2), are also expressed by non-tumor tissues, albeit at lower levels. CAR molecules with high affinity to such antigens can lead to collateral targeting of healthy tissues resulting in on-target, off-tumor toxicity, a major limiting factor to the progress of CAR T cell therapy to date. The affinity and avidity of a CAR for its target antigen also influences T cell cytokine release, the rate of tumor killing, and T cell persistence. Studies using engineered TCRs with pMHC affinities significantly above their natural range caused T cells to exhibit rapid exhaustion and poor persistence in vivo. The authors further teach that high affinity and avidity interactions by CAR can reduce T cells’ propensity for serial killing, potentially causing exhaustion or increased susceptibility to activation-induced cell death (AICD).
Claim(s) 60-61, 63 are also rejected under 35 U.S.C. 103 as being unpatentable over the prior art as set forth above and as applied to claim 59 above, in view of Zhao et al. (Journal of Hematology & Oncology (2018) 11:132).
The claims are drawn to the engineered immune cell according to claim 59 “wherein expression of TCR is reduced or suppressed” (Claim 60) or “wherein said immune cell is mutated to confer resistance to an anti-CD52 antibody” (Claim 61), or “wherein said immune cell has been mutated in a gene encoding HLA or B2m” (Claim 63).
Zhao et al. teach that TALE (transcription activator-like effector nuclease) technology or zinc finger nuclease technology in CAR therapy can help prevent graft vs. host disease (GVHD) by disrupting the TCR gene or the HLA gene. Further, to abolish the possibility of any remaining alloreactive T cells and facilitate the engraftment of third-party CAR T cells, the CD52 gene in the CAR T cells can also be disrupted by TALEN (Fig. 5). Zhao et al. teach that these modifications help to establish a process for the large-scale manufacturing of healthy readily available “off-the-shelf” T cells deficient in expression of both T cell receptor and CD52.
Thus, one of ordinary skill in the art at the time of filing would consider it prima facie obvious to include these CAR modifications because all of these modifications to CAR therapy were previously known and the prior art expressly teaches that they provide therapeutic advantages in CAR therapy; such as helping to prevent GVHD. Further, since this technology was well-known, one of ordinary skill in the art would have a reasonable expectation of success that said modifications would operate successfully. Additionally, KSR International Co. V. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that that "the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results". For the same reason, if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond his or her skill. MPEP 2141 I.
Claim(s) 60-66 are also rejected under 35 U.S.C. 103 as being unpatentable over the prior art as set forth above and as applied to claim 59 above, in view of (PG-PUB 20250034641 (Sourdive et al., July 2, 2018)
The applied reference has a common applicant and inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Claims 60-65 are all individually dependent from claim 59 and incorporate known modifications or advantages to improving CAR-T directed therapies as taught by Sourdive et al.
As to claim 60, wherein expression of TCR is reduced or suppressed in the immune cell, Sourdive et al. teach [0010] that T cells from one individual when transferred to another individual can be detrimental to the host resulting in graft versus host disease (GvHD) and leading to potentially serious tissue damage and death. The molecular mechanisms responsible for acute or chronic GVHD have been at least partially identified. Recognition of MHC disparities between the donor and recipient through specific TCR(s) that can lead to T cells proliferation and to the development of GvHD in recipients of allogeneic cells. To overcome this problem, new techniques of gene editing have been used to reduce the expression of TCR genes encoding the various subunits of the endogenous TCR.
As to claim 61, wherein the immune cell is mutated to confer resistance to an anti-CD52 antibody, Sourdive et al teach [1400] the immune cells can be further genetically engineered to improve their resistance to immunosuppressive drugs or chemotherapy treatments, which are used as standard care for treating positive malignant cells. For instance, CD52 and glucocorticoid receptors (GR), which are drug targets of Campath (alemtuzumab) and glucocorticoids treatments, can be inactivated to make the cells resistant to these treatments and give them a competitive advantage over patient's own T-cells.
As to claim 62, wherein the immune cell has been further mutated to confer resistance to a purine analogue drug, Sourdive et al. teach [1603-1604] that immune cells of the invention are further engineered to be resistant to drugs used either to deplete T cells in the patient or as part of the treatment that is in combination with immune cells of the invention. In other words, the expression of the drug resistance gene in a cell permits survival and proliferation of the cells in the presence of the agent to a greater extent than the proliferation of a corresponding cell without the drug resistance gene. A drug resistance gene of the invention can encode resistance to anti-metabolite, methotrexate, vinblastine, cisplatin, alkylating agents, Purine nucleotide analogs (PNA), proteasome inhibitors anthracyclines, cytotoxic antibiotics, anti-immunophilins, their analogs or derivatives, and the like.
As to claim 63 and 66, wherein said immune cell has been mutated in a gene encoding HLA or B2m and wherein said CAR is co-expressed with an exogenous genetic sequence selected from an NK cell inhibitor selected from HLAG, HLAE or ULBP1, Sourdive et al. teach [0337-0348] the inclusion of exogenous polynucleotide sequences to be integrated at a selected locus and encode at least one NK cell inhibitor. In a preferred embodiment, the method comprises integrating an exogenous sequence into a gene selected from TCR, PD1 CD25, B2M wherein said exogenous sequence encodes a NK inhibitor, preferably said exogenous sequence encoding a NK inhibitor comprise sequences encoding non polymorphic class I molecules, such as HLA-F, HLA-G or HLA-E or fragment(s) thereof comprising an heavy chain epitope thereof, more preferably said exogenous sequence when integrated at p32m endogenous locus, results into the expression of a fusion of a HLA-E or HLA-G or fragment thereof with β2m. Also see [1317 and 1319].
As to claims 64-65, wherein said CAR is co-expressed with an exogenous genetic sequence encoding an inhibitor or decoy of TGFbeta receptor having at least 80% identity with SEQ ID NO:24 (also known as TGFbeta II receptor) or wherein said cell has at least one TGFbeta receptor gene expression reduced or inactivated, Sourdive et al. teach [0559] the present invention provides allogeneic T-cells (less or no alloreactive) expressing a CAR or a TCR, in particular any of the CAR described above, wherein at least one gene expressing one or more component of T-cell receptor (TCR) is inactivated and/or one gene selected from the genes CTLA4, PPP2CA, PPP2CB, PTPN6, PTPN22, PDCD1, LAG 3, HAVCR2, BTLA, CD160, TIG IT, CD96, CRTAM, LAIR1, SIGLEC7, SIGLEC9, CD244, TNFRSF10B, TNFRSF10A, CASP8, CASP10, CASP3, CASP6, CASP7, FADD, FAS, TGFBRII, TGFBRI. This “inactivation” can be performed by homologous recombination mediated gene targeting [see 1391] which can comprise introduction into cells of an exogeneous nucleic acid comprising at least a sequence homologous to a portion of the target nucleic acid sequence.
Thus, one of ordinary skill in the art at the time of filing would consider it prima facie obvious to include these CAR modifications because all of these modifications to CAR therapy were expressly taught by Sourdive et al. thus providing one of ordinary skill in the art with a reasonable expectation of success. Additionally, KSR International Co. V. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that that "the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results". For the same reason, if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond his or her skill. MPEP 2141 I.
Applicants argue (Response, 10/06/2025, page 8) that it was “unpredictable” to use antibody 1.51 to make a CAR because this antibody was presented as the worst. Applicants refer to Figure 4 and indicate that the highest values mean the least efficiencies. This argument was considered and not found persuasive because of the teachings of Park et al. set forth above.
No claim is currently allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GARY B NICKOL, Ph.D. whose telephone number is (571)272-0835. The examiner can normally be reached M-F 9AM-5:30PM.
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/GARY B NICKOL/Primary Examiner, Art Unit 1643