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 .
Priority
This application is a U.S. national phase of International Application No. PCT/US2021/027204, filed on 04/14/2021, which claims domestic benefit to US provision application 63/059,534, filed 07/31/2020, and 63/009,761, filed 04/14/2020.
Claim Status
The Amendment, filed on 12/22/2025, is acknowledged in which:
Claims 3-6, 9-12, 18, 20-24, 31-36, 39-42, 44-48, 51-53, 55-63, 66-70, 72-90, 93-100, and 103-106 are canceled.
Claims 1, 7-8, 19, 43, 71, and 101-102 are currently amended.
Claims 2, 13-14, 16-17, 25, 29, 37, 49, 54, 64-65, and 91-92 were previously presented.
Claims 30, 38, 50 are original.
Claims 107-115 are new.
Claims 1-2, 7-8, 13-14, 16-17, 19, 25, 29-30, 37-38, 43, 49-50, 54, 64-65, 71, 91-92, 101-102, and 107-115 are pending in the instant application and are examined on the merits herein.
Withdrawn Objections and Rejections
In the office action dated 08/20/2025,
The specification was objected to for informalities in the text and tradenames or marks used in commerce without appropriate symbols. Applicant’s submission of an amended specification with appropriate corrections has overcome the objections and the objections are withdrawn.
All previous rejections regarding claims 6, 9, 10, and 21-23 have been rendered moot in view of claim cancellation.
Claim 19 was rejected under 35 USC 112(a) for reciting sequences without sufficient written description. Applicant’s amendment to the claim to recite full identity to claimed sequences has overcome the rejection and the rejection is withdrawn.
Claims 1, 2, 14, 25, 29-30, 49-50, 54, 64-65, 71, 91-92, and 101-102 were rejected under 35 USC 102(a)(2) as being anticipated by Spencer. Applicant’s amendment to the narrow the scope of the claim to recite “wherein the target molecule is secreted by an immune cell expressing the chimeric MyD88 receptor” has overcome the rejection and the rejection as previously stated is withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Rafiq as evidenced by Raphael as discussed below.
Claims 1, 7-8, 13, 16, 37-38, 43, and 64-65 were rejected under 35 USC 102(a)(2) as being anticipated by Roth. Applicant’s amendment to the claims to remove PD-L1 targeting domains has overcome the rejection and the rejection is withdrawn.
Claims 7-8 were rejected under 35 USC 103 as being unpatentable over Spencer in further view of Rafiq and Suzuki. Applicant’s amendment to the base claim has overcome the rejection and the rejection as previously stated is withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of modified base claim rejection with new evidentiary reference Raphael as discussed below.
Claims 17 and 19 were rejected under 35 USC 103 as being unpatentable over Spencer in further view of Rafiq, Suzuki, and CN217. Applicant’s amendment to the base claim and to instant claim 19 to recite full identity to respective anti-IL13 scFv sequences has overcome the rejection and the rejection as previously stated is withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of modified base claim rejection with new evidentiary reference Raphael and secondary reference Rao as discussed below.
Claims 1, 2, 13-14, 25, 29-30, 37-38, 49-50, 54, 64-65, 71, 91-92, and 101-102 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending Application No. 17/056,181. Applicant’s amendment to the base claim and to instant claim 19 to recite full identity to respective anti-IL13 scFv sequences has overcome the rejection and the rejection is withdrawn.
The following grounds of objections and/or rejections are either maintained or necessitated by applicant’s amendment to the claims.
New Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 7 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Base claim 1 has been amended to recite “…the target molecule is secreted by an immune cell expressing the chimeric MyD88 receptor…” However the instant claim recites target molecules species that are transmembrane proteins (i.e. would not be considered secreted protein) - OX40 and ICOS (as evidenced by UniProt entries P43489 and Q9Y6W8, respectively).
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Modified Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 2, 9-10, 13-14, 25, 29-30, 37-38, 49-50, 54, 64-65, 71, 91-92, and 101-102, 107-115 are rejected under 35 U.S.C. 103 as being anticipated by US 10,888,608 B2 (herein Spencer) and Rafiq (Nat Rev Clin Oncol. 2020;17(3):147-167) as evidenced by Raphael (Cytokine. 2015;74(1):5-17).
Regarding claims 1, 2, 9-10, 13-14, 25, 29-30, 37-38, 49-50, 54, 64-65, 71, 91-92, and 101-102, 107-109, Spencer teaches retroviral constructs encoding (i.e. polynucleotides within retroviral vector) chimeric antigen receptors with an extracellular antigen binding moiety (scFv), a CD8 hinge and transmembrane domain, a cytoplasmic domain comprising MyD88 (SEQ ID NO: 214 within 80% identity to instant SEQ ID NO: 9), and an additional iCaspase-9 safety switch (column 181, ¶ 1) operationally linked via self-cleaving peptide (2A sequence which induces ribosome skipping upon translation; column 35-36 spanning ¶) and a signal sequence (S) [e.g. SEQ ID NO: 311 with 100% identity to human immunoglobin heavy chain variable region (see alignment below) leading the extracellular domain (i.e. leader sequence) (Figures 37D and 37E - shown below; Claims 1-4).
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Spencer further teaches transduction of T cells with aforementioned CAR vector (Claims 11-12, column 181, ¶ 2) and injected into tumor engrafted immune deficient (NSG) mice (column 181, lines 30-47). Spencer teaches methods for treating a subject having a disease or condition associated with elevated expression of a target antigen, comprising administering to the subject an effective amount of a modified cell comprising MyD88-CAR (column 9, lines 54-62). Specifically, treatment of tumor engrafted NSG mice with injected T-cells expressing MyD88/CD40 (MC) based CARs (scFv targeting CD19 or HER2 expressed on cancer cells - i.e. cells not expressing the chimeric receptor) enhanced T-cell proliferation, cytokine production, and antitumor efficacy in vivo (i.e. tumor killing) (Figures 39 and 40). Spencer teaches where clinical applications are contemplated, it will be necessary to prepare pharmaceutical compositions containing transduced cells appropriate for intended applications (e.g. injectable solutions of cells in diluent rendered isotonic with sufficient saline or glucose - i.e. pharmaceutically acceptable carrier) (column 73, ¶ 2; column 75, ¶ 2).
Spencer does not explicitly teach the antigen as a target molecule secreted by the immune cell expressing the chimeric MyD88 receptor as recited in the instant claim.
Rafiq teaches the modular nature of CAR components (Figure 1). Rafiq teaches that while CARs classically contain scFvs targeting extracellular antigens of cell-surface proteins expressed by cancer cells, CARs have also been engineered to bind to soluble ligands (e.g. TGFβ; secreted by Tregs as evidenced by Raphael (Figure 1)) in order to convert an immunosuppressive signal to a potent T cell activator (pg 148, left column ¶ 1). Rafiq also teaches the use of chimeric receptors with cytokine receptor ectodomain fusions (I.e. extracellular domains of a cell surface receptor) targeting a secreted cytokine (i.e. found within tumor microenvironment; chimeric cytokine receptors) can augment CAR T cell activity in tumor tissue (Figure 3D). These cytokine binding chimeric receptors can act as dominant-negative receptors that act a sink for immunosuppressive cytokines, thereby enhancing CAR T cell function in the TME, or they can act as switch receptors to functionally convert inhibitory signals present in the TME into proinflammatory signals (page 159, column 1, last ¶).
A skilled artisan would recognize the modular nature of CARs and the benefits of cytokine switch receptors in altering an otherwise immunosuppressive signal to instead aid in T-cell persistence as taught by Rafiq. Therefore, a skilled artisan would be motivated to modify the MyD88 chimeric receptor as taught by Spencer to target a secreted molecule found in the TME (e.g. TGFβ, a cytokine secreted by Tregs as evidenced by Raphael (i.e. population of suitable cells for MyD88 CAR transfection as recited in the instant claims)) as a method to redirect an otherwise immunosuppressive signal as taught by Rafiq with a reasonable expectation of enhancing host cell cytotoxic function in the context of adoptive transfer therapies.
Regarding claims 110-115, the combined teachings of Spencer and Rafiq as evidenced by Raphael teach an isolated host cell within scope of claim 71.
Rafiq further teaches the merit of multiprong strategies to overcome antigen escape or heterogeneity via targeting multiple antigens using strategies including dual CAR T cells and BiTE expression (i.e. CARs and BiTEs that direct the host cell to a tumor-associated antigen expressed on the target cell) (Figure 4A). Rafiq also references several clinical studies in which CD19 is a common target for these therapies (pg 155, right column, ¶ 1-2).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to combine a chimeric receptor as taught by the combined teachings of Spencer and Rafiq with additional targeting elements (e.g. secondary CAR and/or BiTE) as taught by Rafiq because this would have a reasonable expectation of improving the efficiency of the respective CAR-T cells for malignancies prone to antigen escape or heterogeneity as taught by Rafiq.
Claims 7, 8, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Spencer, Rafiq, and Raphael applied to claim 1 above, and further in view of Suzuki (Cytokine. 2015;75(1):79-88).
The combined teachings of Spencer and Rafiq as evidenced by Raphael teach claim 1 as discussed above.
However, none of the aforementioned references teach IL-13 as the target molecule.
Suzuki teaches IL-13, secreted predominantly by T cells, is a pleotropic cytokine that has a key regulatory role in cancer without directly affecting resting or activated T cells (page 79, column 2, ¶ 1-2; receptors for IL-13 are not expressed in T cells - Figure 3). IL-13 receptors are overexpressed in a variety of human solid cancers, and have been linked to activation of tumor-associated macrophages and myeloid-derived suppressor cells that mediate pro-tumor activity (e.g. correlation between IL-13Rα2 expression and metastasis) (page 79-80, page spanning ¶; page 82, column 1, ¶ 3).
One of ordinary skill in the art would recognize that blockade or redirecting IL-13 signaling in cancers that overexpress the IL-13 receptor would likely improve prognosis. Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify an scFv-based chimeric receptor as taught by the combined teachings of Spencer and Rafiq (as evidenced by Raphael) to target IL-13 in order to switch immunosuppressive IL-13 signaling within the TME as taught by Suzuki to proinflammatory signals (i.e. switch chimeric receptor).
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Spencer, Rafiq, Raphael, and Suzuki applied to claim 17 above, and further in view of US 8,388,965 B2 (herein Rao) and Chen (Adv Drug Deliv Rev. 2013;65(10):1357-1369).
The combined teachings of Spencer, Rafiq, Raphael, and Suzuki teach claim 17 as discussed above.
While Spencer teaches a targeting moiety comprising an scFv (Figure 37), Spencer does not teach an IL-13 specific scFv.
Rao teaches an IL-13 antibody (Table 3; “huB-B13 VL3 x VH2”) with VH/VL sequences (SEQ ID NOs: 2 and 1, respectively) identical to those within the instantly claimed SEQ ID NO:3 (see alignment below). Rao also teaches scFv antibodies can be generated using VH and VL domains of an antibody linked by flexible peptide (column 14, ¶ 2).
Instant SEQ ID NO: 3 aligned with Rao SEQ ID NOs: 1-2:
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Halford teaches “GATCTC” (the nucleotide sequence that encodes the DL overhang in instant SEQ ID NO:3 as evidenced by nucleic acid sequence SEQ ID NO:4) is a residual restriction enzyme cleavage site used in plasmids (i.e. used in methods of molecular cloning) (abstract).
Chen teaches (GGGGS)3 as a common flexible peptide linker used in scFv construction (Table 3).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention that VH/VL domains from a known antibody for IL-13 as taught by Rao, having residual restriction residues as taught by Halford, can be engineered into an scFv via flexible linker as taught by the combined teachings of Rao and Chen via methods known in the art with a reasonable expectation of success. Therefore, it would have also been obvious that said scFv for IL-13 can be used to modify the a chimeric MyD88 receptor as taught by the combined teachings of Spencer, Rafiq, Rahael, and Suzuki, arming CAR-T cells against immunosuppressive IL-13 found the in TME as a strategy to enhance CAR T cell antitumor activity.
Response to Arguments - 35 USC § 103
Applicant's arguments filed 12/22/2025 have been fully considered in so far as they apply to the new/modified rejections discussed above, but they are not persuasive.
Applicant states:
“…the closest construct discussed in Spencer to that of claim 1 is in the context of a CAR.
The CARs of Spencer, however, do not target a molecule produced by the cell in which its CAR is expressed, especially not a secreted molecule as required by claim. Further, one of ordinary skill in the art would understand that CARs do not target a molecule secreted by the cell in which the CAR is expressed, or this would result in death of the cell expressing the CAR. Therefore, a person of skill in the art reviewing Spencer, would not be motivated to design a chimeric MyD88 receptor comprising an extracellular domain that targets a molecule that is secreted by an immune cell that expresses the chimeric MyD88 receptor.
Rafiq and Suzuki fail to remedy the deficiencies of Spencer. Rafiq generally discloses use of chimeric cytokine receptor targeting a tumor secreted cytokine to target CART cell activity in tumor tissue. Suzuki discloses IL13 and IL13 receptor signaling in cancers; however, Suzuki does not disclose or suggest chimeric cytokine receptors comprising a cytoplasmic domain comprising a MyD88 polypeptide.” (Remarks, page 12, ¶ 2-3)
In response to applicant’s argument regarding the individual teachings of Spencer, as applicant’s amendment has altered the scope of the claims, new grounds of rejection
are made in view of Rafiq that teaches CARs can target soluble factors within scope of the currently amended claim as discussed above. Subsequent arguments regarding the deficiencies of Spencer in combination with Rafiq are therefore also considered not persuasive.
Furthermore, In response to applicant's argument that Suzuki does not disclose a chimeric cytokine receptor comprising a MyD88 domain, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). Briefly, Spencer teaches MyD88 receptors, Rafiq teaches the feasibility of targeting soluble molecules (i.e. cytokines) using CARs, and Suzuki teach IL-13 to be a cytokine involved in pro-tumor signaling within the TME. Therefore, a skilled artisan would be able to combine these teachings to arrive at a CAR within scope of the instant claims.
Allowable Subject Matter
Claim 43 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims as prior art does not teach nor fairly suggest a sequence encoding a CAR comprising the recited amino acid sequences (SEQ ID NOs: 15 or 17), nucleic acid sequences (SEQ ID NOs: 16 or 18), nor at least 80% identity to said sequences.
Conclusion
No claims are allowed.
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.
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/HANNAH SUNSHINE/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647