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 .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 133-138 and 141-149) in the reply filed on 06/09/2025 is acknowledged.
The withdrawn claims, 139-140, have been canceled by Applicant in the amendments filed 14 October 2025.
Claim Status
Claims 1-132 were previously canceled, claims 139-140 and 148-149 are newly canceled, claims 133-138 and 141-147 have been amended, and claims 133-138 and 141-149 have been considered on their merits.
Withdrawn Rejections/Objections
The claim objections have been withdrawn due to Applicant’s amendments to the claims.
The claim rejections under 35 U.S.C. § 112(b) have been withdrawn due to Applicant’s
amendments to the claims.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 133-138, 141, and 146-147 are rejected under 35 U.S.C. 103 as being unpatentable over Maus et al. (WO2019157533, published 08/15/2019, IDS ref., of record) in view of Luehrsen et al. (WO2011053465, published 05/5/2011, of record).
This rejection is repeated with regard to claims 133-138, 141, and 146-147 for the same reasons of record as set forth in the Official action mailed 01 July 2025. The rejections of claims 148 and 149 have been removed as these claims have been canceled. A response to applicant's traversal follows the reiterated rejection below.
Regarding claim 133, Maus et al. teach an immune cell engineered to express a chimeric antigen receptor (CAR) polypeptide including an extracellular domain including a first antigen binding domain that binds to a first antigen and a second antigen-binding domain that binds to a second antigen (Abstract). Maus teach any cell-surface moiety can be targeted by a CAR (p. 33, line 3). Maus teach the target will be a cell-surface polypeptide that may be differentially or preferentially expressed on a cell that one wishes to target tumors or cancer cells, antibody domains can be targeted against EGFRvIII (p. 33, lines 3-8). Maus teach targeting tumor antigens or tumor-associated antigens specific to the tumors, to include EphA3, can provide a means to target tumor cells while avoiding or at least limiting collateral damage to non-tumor cells or tissues (p. 33, lines 8-14). Maus et al. teach glioblastoma (GBM) is a cancer with extremely poor prognosis and is known to express surface antigens that may be targeted for effective antitumor immunity, including EGFRvIII, IL-13Ra2, EGFR, HER2, and ephrins (p. 76, lines 14-16). Maus et al. teach, to date, responses of GBM to CAR-T cells directed against single antigens such as EGFRvIII or IL-13Ra2 have been limited, in part due to antigen escape (p. 76, lines 16-17). Maus et al. teach to address antigen escape, a second-generation CAR was designed comprised of two or more antigen-binding domains and has the capacity to be activated by engagement with two or more different antigens, for example, EGFRvIII and IL-13Ra2, wherein the humanized anti-EGFRvlll binding domain comprising a heavy chain immunoglobulin variable region and a light chain immunoglobulin variable region wherein the anti-EGFRvIII binding domain is fused in tandem to a hinge region, a transmembrane domain; and an intracellular signaling domain comprising a costimulatory domain and an activation domain (p. 76, lines 18-35). The teachings of Maus et al. suggest the use of both (dual targeting) EGFRvIII and EphA3 as binding domains for CAR-T cell. Maus et al. teach Construct 12 (Tandem CAR) comprising IL-13 zetakine linker, EGFRvIII scFv, CD8 hinge/transmembrane, 4-1BB intracellular signaling domain/costimulatory domain, and CD3ζ activation domain (SEQ ID NO: 100, pp. 92-93). SEQ ID NO: 100 of Maus et al. comprise both the heavy and light chain immunoglobulin variable regions CDR1, CDR2, and CDR3 sequences as required by the second CAR construct of instant claim 133 (instant SEQ ID NO: 31-SEQ ID NO: 36).
Maus et al. teach ephrins are surface antigens expressed in glioblastoma and suggests the use of human Eph receptor A3 (EphA3) in combination with humanized anti-EGFRvIII binding domain, however, Maus et al. are silent to the specific first CAR construct which binds to human EphA3 and the heavy and light chain sequences of EphA3.
Luehrsen et al. teach an anti-EphA3 antibody for the use of treating an EphA3-dependent disease (Abstract). Luehrsen et al. teach Ephs are known to be over-expressed on human solid tumors and have been shown to play a role in vascular development and have been observed to contribute to tumor invasion, metastasis, and neo-angiogenesis (para. [0003]). Luehrsen et al. teach the anti-EphA3 antibody comprises the VH CDR1, CDR2, and CDR3 and VL CDR1, CDR2, and CDR3 (para. [0010-0011] and Figure 1). SEQ ID NO: 5 and SEQ ID NO: 13 correspond to instant SEQ ID NO: 1 and SEQ ID NO: 2 respectively, as indicated in the sequence search results 20250402_071457_us-17-774-834-1.rag (result 1, AZH76391) and 20250402_071457_us-17-774-834-2.rag (result 1, AZH76399) with 100% identity using the A_Geneseq database. Luehrsen et al. teach antibodies include VH-VL dimers, including single chain antibodies (antibodies that exist as a single polypeptide chain), such as single chain Fv antibodies (sFv or scFv) in which a variable heavy and a variable light region are joined together (directly or through a peptide linker) to form a continuous polypeptide (para. [0042]). Luehrsen et al. teach humanization of an antibody which comprise immunoglobulin molecule in CDRs from a donor antibody grafted onto human framework sequences (para. [0050]). Luehrsen et al. teach the heavy chain of the Fab' is a Fd' fragment generated by fusion of a VH region of to human heavy chain constant region sequences, the first constant (CH1) domain and hinge region and the antibody can include a human Fc region (para. [0110-0111]).
Therefore, it would have been obvious to one of ordinary skill in the art to utilize the anti-EphA3 antibody of Luehrsen et al. with the dual targeting CAR-T cell of Maus et al. with a reasonable expectation of success because Maus et al. teach the second-generation CAR was designed of two or more antigen-binding domains (p. 76, example 14, lines 10-25). Additionally, both EGFRvIII and EphA3 are both known in the art to be expressed by GBM. One would have been motivated to utilize the anti-EphA3 antibody of Luehrsen et al. with the dual targeting CAR construct of Maus et al. because Maus et al. teach the target of the CAR-T cell will be a cell-surface polypeptide that may be differentially or preferentially expressed on a cell that one wishes to target tumors or cancer cells, antibody domains can be targeted against EGFRvIII and targeting tumor antigens or tumor-associated antigens specific to the tumors, to include EphA3, can provide a means to target tumor cells while avoiding or at least limiting collateral damage to non-tumor cells or tissues.
Regarding claim 134, Maus et al. teach the humanized scFv of monoclonal antibody clone 3C10, the amino acid sequence SEQ ID NO: 103 is 100% identical to instant SEQ ID NO: 37, therefore, reads on the limitations of the claim.
Regarding claim 135, Maus et al. teach a (c) transmembrane domain comprising the amino acid sequence, SEQ ID NO: 100 comprises instant SEQ ID NO: 38; (d) a hinge region comprising amino acid sequence, SEQ ID NO: 104 comprises instant SEQ ID NO: 39; and (e) an intracellular signaling domain comprising a costimulatory domain and a primary signaling domain, wherein the costimulatory domain comprises a 4-1BB costimulatory domain amino acid sequence, SEQ ID NO: 105 is identical to instant SEQ ID NO: 9.
Regarding claims 136 and 137, Maus et al. teach a CD3 zeta primary signaling domain, SEQ ID NO: 106 (Db), which is a different isoform than the instant SEQ ID NO: 41 (Qy), see alignment below:
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189
592
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However, the NCBI Reference Sequence NM_000734.3 listed in claim 136 and 137 translates to the amino acid sequence displayed below:
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62
386
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the highlighted sequence is 100% identical to SEQ ID NO: 106 of Maus et al., which reads on the limitation of claims 136 and 137 wherein the primary signaling domain comprises the amino acid sequence NCBI Reference Sequence NM_000734.3. Additionally, while the SEQ ID NOs are not identical, the sequence of Maus et al. would serve the same function of the claimed SEQ ID NO: 41 as both are CD3 zeta domains, thus, would be an obvious substitution, absent evidence to the contrary. See M.P.E.P. § 2144.06 (II).
Regarding claim 138, Maus et al. teach a pharmaceutical composition including activated CAR-T cells as described in the rejection of claim 133 and optionally a pharmaceutically acceptable carrier wherein the pharmaceutically acceptable carriers for cell-based therapeutic formulation include saline and aqueous buffer solutions, Ringer's solution, and serum component, such as serum albumin, HDL and LDL (p. 48, lines 31-39).
Regarding claim 141 directed to a method of treating a solid tumor cancer comprising the pharmaceutical composition of claim 138 wherein the solid tumor cancer is GBM, Maus et al. teach a treatment wherein mice were infused once with CAR-T cells (1 x 106 CAR-transduced T cells per mouse) via tail vein to overcome tumor heterogeneity and immunosuppression in glioblastoma (p. 56, lines 23-35). Maus et al. teach EGFRvIII CAR-T cells mediated antitumor activity in subcutaneous models of human GBM xenograft, wherein bulky tumors responded to CART-EGFRvIII (Figures 2A and 2B; CART-EGFRvIII treats EGFRvIII expressing tumor (U87vIII) in a subcutaneous model of human glioma; and p. 56-57, results).
Regarding claim 146, Maus et al. teach their activated CAR-T cells can be used in combination with a checkpoint inhibitor, to include anti-PD-1 inhibitor Pembrolizumab (p. 51, lines 36-40).
Regarding claim 147 directed to an autologous EphA3-targeting CAR T-cell, Maus et al. teach a T cell can be obtained from a subject using standard techniques known in the art and may be isolated from peripheral blood taken from a donor or patient (p. 46, lines 16-21). T cells isolated from peripheral blood taken from a patient suggests the use of autologous T cells, therefore suggests the dual targeting CAR T-cell taught by Maus et al. in view of Luehrsen et al. is an autologous EphA3-targeting CAR T-cell.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Response to Traversal:
Applicant's arguments filed 14 October 2025 have been fully considered but they are not persuasive.
Applicant argues the dual targeting CAR construct of Maus et al. does not meet all of the limitations of independent claim 133. The language of claim 133 does not distinguish itself from that of the dual targeting CAR construct of Maus et al., in that, only “a first CAR” is described as possessing being fused in tandem to a hinge region, a transmembrane domain, and an intracellular signaling domain comprising a costimulatory domain and an activation domain. The phrase “a second CAR” of claim 133 step (2) does not add structure to the claimed dual targeting CAR-T cell. As indicated in the rejection above, the CAR-T cell disclosed by Maus et al. in view of Luehrsen et al. read on the limitations of the claim.
Applicant argues at the bottom of page 8 and top of page 9 of the response, independent claim 133 recites particular sequences for each CAR. The combination of references, Maus et al. in view of Luehrsen et al., do in fact provide all of the required SEQ ID NOs of instant claim 133.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In response to applicant's argument that the unexpected results provide evidence of non-obviousness, on page 9 of the response, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
Claims 142-145 are rejected under 35 U.S.C. 103 as being unpatentable over Maus et al. (WO2019157533, published 08/15/2019, IDS ref., of record) in view of Luehrsen et al. (WO2011053465, published 05/5/2011, of record) as applied to claims 133-138, 141, and 146-147 above, and further in view of Ma et al. (Int. J. Biol. Sci. 2019, Vol. 15, published 09/07/2019, of record) and Sachdeva et al. (J. Biol. Chem. (2019) 294(14), published 02/25/2019, of record) as evidenced by Crotti et al. (Drug Design, Development and Therapy, published 01/13/2017, of record).
This rejection is repeated with regard to claims 142-145 for the same reasons of record as set forth in the Official action mailed 01 July 2025. A response to applicant's traversal follows the reiterated rejection below.
Regarding claims 142 and 143, Maus et al. in view of Luehrsen et al. are silent to administering a human GM-CSF (hGM-CSF) antagonist.
Ma et al. teach solid tumors generally consist of a large number of immune suppressor cells, such as myeloid-derived suppressor cells (MDSCs) and blocking granulocyte-macrophage colony stimulating factor (GM-CSF) dependent MDSC expansion and PD-L1 expression on MDSC may be a potential approach to enhance the anti-tumor effects of CAR-T cells (p. 2551, 3.1 Immune suppressor cells). Ma et al. teach MDSC depletion in a mouse model, the antitumor activity of CAR-T cells was rescued and during MDSC recruitment, tumor cells secrete high levels of GM-CSF in vivo, which suggests GM-CSF neutralization may be an alternative method to inhibit MDSC expansion (p. 2553, 6.2 Reversal of the immunosuppressive microenvironment). The teachings of Ma et al. suggest the addition of GM-CSF neutralizing agent could improve the anti-tumor effects of CAR-T cells.
Sachdeva et al. teach GM-CSF secretion by tumor-activated CAR T-cells play a key role in monocyte activation and in the secretion of cytokine release syndrome (CRS) (p. 5430, 2nd column). Sachdeva et al. teach therapeutic strategies for preventing the biogenesis of CRS directed toward GM-CSF because it is specifically up-regulated in a CAR-dependent manner and is known as a pro-inflammatory cytokine using a neutralizing antibody against GM-CSF (p. 5431, Neutralization of GMCSF decreases monocyte-dependent inflammatory cytokines). Sachdeva et al. teach the GM-CSF receptor has been shown to be highly expressed by microglia, brain macrophages, and astrocytes, suggesting these cells can respond to the cytokines which would further increase resistant immune cells (p. 5431, Neutralization of GMCSF decreases monocyte-dependent inflammatory cytokines). Sachdeva et al. teach GMCSF levels are low in normal healthy individuals, yet activated lymphocytes produce elevated GM-CSF levels under pathological conditions such as infection (p. 5431, Neutralization of GMCSF decreases monocyte-dependent inflammatory cytokines). Sachdeva et al. teach the neutralizing Ab was able to decrease GM-CSF secretion at low doses, with barely any GM-CSF detected at higher doses suggesting CAR T-cell-induced GM-CSF can be neutralized by higher antibody doses (p. 5431, 2nd column and Figure 1). Sachdeva et al. teach the mAb against GM-CSF, Namilumab, and an antibody against GM-CSF receptor, Mavrilumumab, has been used in multiple clinical trials against inflammatory disease (p. 5434, 1st column). Sachdeva et al. teach the GM-CSF neutralization antibody used was MAB215, a human GM-CSF antibody (p. 5434, Antibodies and reagents). Namilumab and Lenzilumab are known monoclonal antibodies which target GM-CSF and mavrilimumab is a known antibody against GM-CSF receptors, as evidenced by Crotti et al. (p. 214, 1st column and p. 219, GM-CSF pathway blockade in RA beyond mavrilimumab).
Therefore, it would have been obvious to one of ordinary skill in the art to include an anti-human GM-CSF antibody as taught by Ma et al. in view of Sachdeva et al. with the dual targeting CAR-T cell as taught by Maus et al. in view of Luehrsen et al. with a reasonable expectation of success because Maus et al. and Ma et al. both teach methods for treating solid tumor cancer with CAR T-cell therapy and Ma et al. suggest the use of a GM-CSF antibody to improve CAR T-cell therapy. Sachdeva et al. teach GM-CSF neutralizing antibodies decreases monocyte-dependent inflammatory cytokines. While these references do not specifically teach the use of Lenzilumab as the anti-human GM-CSF antibody, it would be obvious to substitute MAB215 taught by Sachdeva et al. with Lenzilumab because Lenzilumab and MAB215 are both anti-human GM-CSF antibodies which would result in the predictable result of neutralizing the human GM-CSF. See M.P.E.P § 2144.06 (II). One would have been motivated to include an anti-human GM-CSF antibody as taught by Ma et al. in view of Sachdeva et al. with the dual targeting CAR-T cell as taught by Maus et al. in view of Luehrsen et al. because Ma et al. suggest the addition of GM-CSF neutralizing agent could improve the anti-tumor effects of CAR-T cells and Sachdeva et al. teach GM-CSF secretion by tumor-activated CAR T-cells play a key role in monocyte activation and in the secretion of CRS which is a known negative side-effect of CAR-T cell immunotherapy toxicity (Ma et al. p. 2551, 4.1 On-target/on-tumor toxicity).
Regarding claim 144 directed to wherein the administration of Lenzilumab reduces incidence of immunotherapy-related toxicity, which is cytokine release syndrome, in the subject, Ma et al. suggest the addition of GM-CSF neutralizing agent could improve the anti-tumor effects of CAR-T cells and Sachdeva et al. teach GM-CSF secretion by tumor-activated CAR T-cells play a key role in monocyte activation and in the secretion of CRS which is a known negative side-effect of CAR-T cell immunotherapy toxicity (Ma et al. p. 2551, 4.1 On-target/on-tumor toxicity).
Regarding claim 145, anti-human GM-CSF antibody as taught by Ma et al. in view of Sachdeva et al. with the dual targeting CAR-T cell as taught by Maus et al. in view of Luehrsen et al. suggest the anti-human GM-CSF antibody as taught by Ma et al. in view of Sachdeva et al. would silence the GM-CSF which would have been present on the activated dual targeting CAR-T cell as taught by Maus et al. in view of Luehrsen et al. because Sachdeva et al. teach the neutralizing Ab was able to decrease GM-CSF secretion at low doses, with barely any GM-CSF detected at higher doses suggesting CAR T-cell-induced GM-CSF can be neutralized (silenced) by higher antibody doses (p. 5431, 2nd column and Figure 1). Ma et al. suggest the addition of GM-CSF neutralizing agent could improve the anti-tumor effects of CAR-T cells and Sachdeva et al. teach GM-CSF secretion by tumor-activated CAR T-cells play a key role in monocyte activation and in the secretion of CRS which is a known negative side-effect of CAR-T cell immunotherapy toxicity (Ma et al. p. 2551, 4.1 On-target/on-tumor toxicity).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Response to Traversal:
Applicant did not provide any arguments in the response filed 14 October 2025, regarding the rejection of claims 142-145.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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.
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/N.A.H./Examiner, Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631
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