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 .
DETAILED ACTION
1. The Amendment filed February 23, 2026 in response to the Office Action of September 23, 2025 is acknowledged and has been entered. Claims 2-5 have been cancelled. Claims 1 and 6-10 have been amended. New claims 11-17 have been added.
2. Claims 1 and 6-17 are currently being examined.
New Grounds of Rejection
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.
3. Claim(s) 1, 6-10 and 12-17 are rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0346541 A1 (Wong et al. Dec. 6, 2018, of record), “Wong” in view of WO 2019/199689 (Powell et al. Oct. 17, 2019, IDS), “Powell”.
Wong teaches a composition comprising a multi-component chimeric antigen receptor (CAR); the multi-component CAR comprising: a) a first recognition polypeptide comprising 1) an antibody reagent specific for a first target ligand and 2) a protein interaction domain; and b) a signaling polypeptide comprising 1) an extracellular protein interaction domain that can bind specifically with the protein interaction domain of the first recognition polypeptide and 2) an intracellular T cell receptor (TCR) signaling domain. In some embodiments of any of the aspects, the protein interaction domains are leucine zipper domains. In some embodiments of any of the aspects, one leucine zipper domain is BZip (RR) and the second leucine zipper domain is AZip (EE). See ¶¶ 0012, 0015, 0016, 0023 and Figs. 1-6, 8, 12, 13A and 16.
Wong teaches that the signaling polypeptide comprises a transmembrane domain. See ¶¶ 0053, 0054, and 0057.
Wong teaches nucleic acid vectors encoding the multi-component CAR. See ¶¶ 0138-0141, 0201, 0220 and 0449.
Wong teaches that the multi-component CAR cell, the recognition and/or signaling polypeptide can be under the control of an inducible and/or repressible promoter. Such promoters allow the expression of the polypeptide to be increased or decreased as desired and are in contrast to constitutive promoters. See ¶ 0077.
Wong teaches the term “inducible promoter” refers to a promoter of a gene which can be expressed in response to a given signal, for example addition or reduction of an agent. Non-limiting examples of an inducible promoter are promoters that are regulated in a specific tissue type, a promoter regulated by a steroid hormone, by a polypeptide hormone (e.g., by means of a signal transduction pathway), or by a heterologous polypeptide (e.g., the tetracycline-inducible systems, “Tet-On” and “Tet-Off”. See ¶ 0077.
Wong teaches expression of the polypeptide can be precisely regulated, for example, by using an inducible regulatory sequence that is sensitive to certain physiological regulators, e.g., circulating glucose levels, or hormones. Such inducible expression systems, suitable for the control of expression in cells or in mammals include, for example, regulation by ecdysone, by estrogen, progesterone, tetracycline, chemical inducers of dimerization, and isopropyl-beta-D1-thiogalactopyranoside (IPTG). A person skilled in the art would be able to choose the appropriate regulatory/promoter sequence based on the intended use of the polypeptide. See ¶ 0077.
Wong teaches an engineered cell expressing the multi-component CARs of the invention. Wong teaches that the cell is a T cell, NK cell, or NKT cell. ¶ 0021
Wong teaches ZipCARs can be introduced into primary T cells (i.e., CD4 and CD8) via lentiviral transduction. See ¶ 0220.
Wong teaches two jurkat T cell lines were transduced with two different lentivirus vectors. One jurkat cell line expressed zipCAR with signaling domain (CD3 zeta) fused to mCherry. The other jurkat cell lines expressed zipCAR with cognate leucine zipper and did not have a signaling domain (CD3 zeta). See ¶ 0449.
Wong teaches transducing primary CD4 T cells with a CAR composed the BZip (RR) as the extracellular domain and signaling domain from CD28, 41BB, and CD3z as the intracellular domains. Jurkat T cell lines expressing either the AZip (EE) or BZip (RR) leucine zipper domains on the surface were also generated. When the cell lines were mixed together, the engineered CD4 T cells expressing zipCAR were able to activate and initiate signaling pathway by interacting with Jurkat T cells expressing the AZip (EE) domain on the surface. See ¶ 0463 and Fig. 4.
Wong teaches BZip CAR (RR) can be activated by anti-Her2-zipper fusion proteins in primary CD4+ T cells (measured secreted cytokines) when mixed with Her2 expressing K562 tumor cells. See ¶¶ 0034 and 0464 and Fig. 5.
Wong teaches BZip CAR (RR) can be activated by anti-Her2-zipper fusion proteins in CD8 expressing CD8 T-cells and mediate tumor cell killing in vitro and in vivo. See ¶¶ 0042-0044, 0200-0207 and 0499 and Figs. 13-15.
Wong teaches one or more multi-component CARs as described herein can be present in/on a T cell, NK cell, or NKT cell or secreted into the extracellular space. See ¶¶ 0075-0076 and 0080.
Wong teaches making CARs against Her2 and Axl. See ¶¶ 0046, 0212-0216 and 0220.
Regarding claims 7-10, the recitation of the (a) inducible gene expression system in a first immune cell and (b) the nucleic acid encoding the CAR in a second immune cell does not exclude the inducible gene expression system from being in the second immune cell and does not exclude the CAR from being in the first immune cell.
Wong teaches as set forth above, but does not teach wherein the antigen-activated inducible promoter expresses the adapter when the immune cells comprising the antigen-activated inducible gene expression system are activated by an activating antigen, wherein the activating antigen that activates the immune cell is not the same antigen that binds to the first (poly)peptide of said adapter.
Powell teaches a single viral vector comprising: a first polynucleotide comprising a constitutive promoter operably linked to a nucleic acid encoding at least one transgene, wherein one of the at least one transgenes encodes a receptor or receptor subunit, a receptor fusion protein or a fluorescent marker; and a second polynucleotide comprising an inducible promoter operably linked to a nucleic acid encoding an effector. In some embodiments, the transgene encodes a receptor fusion protein. See Abstract and p. 2-lines 10-20.
Powell teaches that the viral vector system allows for in situ expression. See p. 35-lines 29-34 and p. 37-lines 13-15.
Powell teaches the transgene can be a T-cell receptor (TCR) or CAR. See p. 2-lines 20-31.
Powell teaches the inducible promoter can be a NFAT or STAT3 promoter; promoters that are responsive to activating antigen increased transcriptional factors as claimed. See p. 3-lines 16-20.
Powell teaches the inducible promoter is activated by the CAR/TCR engagement or tumor microenvironment antigens. See p. 11-lines 14-34, p. 30-lines 8-10, p. 31-lines 1-5, p. 35-lines 24-27, p. 40-lines 20-32, p. 64-lines 20-32, and Figures 1 and 2.
Powell teaches the that the inducible promoters were induced by TCR signaling pathways in T-cell lines (Jurkat) and primary T cells. See Examples 2-4 and Figs. 3-5..
Powell teaches that the exemplified reporter gene eGFP under control of the inducible promoter may be exchanged by the effector of choice to increase safety and efficacy of immunotherapy. See p. 11-lines 30-34 and Figure 2.
Powell teaches an advantage of the all-in-one system is its simplified modular assembly, where only one virus need be produced to achieve constitutive expression of a transgene, for example a CAR or TCR or TCR subunit, and inducible expression of an effector. See p. 36-lines 23-25.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Wong and Powell and use the inducible promoters of Powell to express the recognition polypeptide of Wong because Wong teaches that the multi-component CAR cell, the recognition and/or signaling polypeptide can be under the control of an inducible and/or repressible promoter and Powell teaches that an effector of choice may be placed under control of the inducible promoter to limit expression to the tumor microenvironment to increase safety and efficacy of immunotherapy. One would have been motivated to use the inducible promoter expression system of Powell to express the recognition polypeptide of Wong because Powell teaches the advantages of the simplified all in one vector system and to limit expression to the tumor microenvironment to increase safety and efficacy of immunotherapy.
4. Claim(s) 11 is rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0346541 A1 (Wong et al. Dec. 6, 2018, of record), “Wong” in view of WO 2019/199689 (Powell et al. Oct. 17, 2019, IDS), “Powell” as applied to claims 1, 6-10 and 12-17 above, and further in view of JP 2014224065 A (Onizuka, K. Dec. 4, 2014), “Onizuka”.
Wong and Powell teach as set forth above, but do not teach where the second polypeptide of the adaptor is at least 4 amino acids and not more than 30 amino acids.
Wong additionally teaches that leucine zipper domains can include FOS leucine zippers. See ¶ 0059.
Onizuka teaches a short peptide of less than 30 residues (28 residues) that forms a leucine zipper structure and associates with a 28-residue peptide having the same sequence as the 28-residue sequence in the leucine zipper region of FOS of human bZIP, i.e. SEQ ID NO: 1 (anti-FOS) and SEQ ID NO: 2 (FOS28), See Abstract, p. 1-Technical Field, Example and Figs. 1 and 2. .
Onizuka teaches that the peptides could be used for therapeutic purposes. See p. 4-Industrial Applicability.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Wong, Powell and Onizuka and use the short FOS leucine zipper regions of Onizuka as the binding domains of the adaptor protein and CAR of the multi-component CAR of Wong because Wong teaches that leucine zipper domains can include FOS leucine zippers and Onizuka teaches that the anti-FOS and FOS28 leucine zipper peptides effectively bind to each other. One would have been motivated to use the short FOS leucine zipper regions of Onizuka because they would be less likely to cause steric interference with the first polypeptide antigen binding domain of the adapter protein or the other CAR domains than larger domains and Onizuka teaches that the anti-FOS and FOS28 leucine zipper peptides effectively bind to each other.
Claim Objections
5. Claim 14 is objected to because of the following informalities: the article “a” should be inserted between “is” and “SP1” on line 1. Appropriate correction is required.
Conclusion
6. All other objections and rejections recited in the Office Action of September 23, 2025 are withdrawn in view of Applicant’s amendments and arguments.
7. No claims allowed.
8. 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 extension fee 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 date of this final action.
9. Any inquiry concerning this communication or earlier communications from the examiner should be directed to PETER J REDDIG whose telephone number is (571)272-9031. The examiner can normally be reached on M-F 8:30-5:30 Eastern Time
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/Peter J Reddig/
Primary Examiner, Art Unit 1642
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