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 .
Applicant’s amendments, filed 6/17/2026, is acknowledged.
Claims 2-9 and 12-20 are cancelled.
Claims 1, 10, 11, and 21-23 are currently pending.
Claims 1 and 10 stand withdrawn, and newly added claim 23 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions and/or Species.
Claims 11, 21, and 22 are under examination.
In view of the amendments and remarks filed on 6/17/2026, the following rejections remain.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 11, 21, and 22 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventors, at the time the application was filed, had possession of the claimed invention. This is a new grounds of rejection necessitated by Applicant’s amendments.
Instant claim 11 has been amended to recite a method of killing renal cell carcinoma comprising administration of a cytotoxic immune cell genetically modified with a nucleic acid sequence encoding a BTSS that binds either AXL or CDH6 and a nucleic acid encoding a CAR that recognizes the other antigen, wherein the nucleic acid encoding the CAR is operably linked to a regulatory sequence that is responsive to the BTSS, wherein binding of the BTSS triggers expression of the CAR.
Claims 11, 21, and 22 encompass methods of killing renal cell carcinoma comprising administration of cytotoxic immune cells genetically modified with a broad genus of nucleic acids encoding anti-CDH6 or anti-AXL binding triggered transcriptional switches with no recited structure (claims 11 and 22), or transcriptional activators with no recite structure (claim 21) with the recited function of “binding of the BTTS to the first antigen activates expression of the chimeric antigen receptor”.
Claims 11, 21, and 22 additionally encompass methods of killing renal cell carcinoma comprising administration of cytotoxic immune cells genetically modified with a broad genus of regulatory sequences operably linker to a CAR with no recited structure and the function of “responsive to the BTTS”.
Claim 21 additionally encompasses methods of killing renal cell carcinoma comprising administration of cytotoxic immune cells genetically modified with a broad genus of nucleic acids encoding a BTTS with domains with no recited structure and the function of “protease cleavage domain”.
However, the specification fails to provide adequate written description support for methods of treating RCC comprising administration of a cytotoxic immune cells genetically modified with a genus of nucleic acids encoding anti-CDH6 or anti-AXL binding triggered transcriptional switches with no recited structure (claims 11 and 22), or transcriptional activators with no recite structure (claim 21) with the recited function of “binding of the BTTS to the first antigen activates expression of the chimeric antigen receptor”; broad genus of regulatory sequences with no recited structure and the function of “responsive to the BTTS” (claims 11, 21, and 22); or a broad genus of nucleic acids encoding a BTTS with domains with no recited structure and the function of “protease cleavage domain” (claim 21).
The claims are not supported by a description that satisfies 35 U.S.C. § 112(a) or 35 U.S.C. § 112, first paragraph. "[T]he test for sufficiency [of the written description] is whether the disclosure of the application relied upon reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date." Ariad Phanns., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en bane).
A "sufficient description of a genus ... requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can 'visualize or recognize' the members of the genus." Id. at 1350. "[A]n adequate written description requires a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials." Id.
"[F]unctional claim language can meet the written description requirement when the art has established a correlation between structure and function." Id. "But merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing that one has invented a genus and not just a species." Id.
"A sufficient description of a genus ... requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus" (AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69) (emphasis added).
The specification discloses a general scheme for dual targeting system comprising a synthetic notch receptor fused to a transcription factor, which when bound to its target antigen drives the expression of a chimeric antigen receptor (Fig. 7A):
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The specification discloses a dual antigen receptor system to target renal cell carcinoma (¶[00244]-[00255], Fig. 4). An anti-AXL synthetic notch receptor was designed that has an anti-AXL scFv fused to a notch TM domain and a GAL4-VP64 transcription factor which, when bound to AXL, leads to self-cleavage of the protein and release of the GAL4-VP64 transcription factor to drive the expression of a second receptor, which is an anti-CD70 chimeric antigen receptor (¶[00247]): “[t]o create a T cell that recognizes AXL AND CD70, a synNotch receptor (Morsut et al., 2016) was used using an a-AXL scFv recognition domain fused to the Notch transmembrane domain and an orthogonal transcription factor (GAL4-VP64). It was found that T cells expressing an a-AXL synNotch that are co-cultured with RCC cells activate a synNotch GFP reporter; in contrast, the same T cells co-cultured with Raji B cells, which do not express AXL, do not activate the AXL synNotch receptor. AND gate T cells were engineered in which an a-AXL synNotch drives expression of a CD70 CAR. This AND circuit was found to cause the specific lysis of RCC cells, but not of Raji B cells…”
The specification discloses a second dual antigen receptor system in which an anti-Cadherin 6 synNotch drives the expression of an anti-AXL CAR to lead to specific lysis of RCC cancer cells (¶[00248]): “[a] synNotch receptor targeting CDH6 was generated by screening four potential CDH6 scFv's fused to the synthetic notch core receptor. It was found that a-CDH6 synNotch receptors expressed in human primary T cells would specifically drive GFP reporter activity when cocultured with an RCC cell line, but not with CDH6 negative lung epithelium cells (Beas2B). When an AND-gate T cell was constructed with a-CDH6 synNotch driving expression of an a-AXL CAR, it ws found that specific lysis was only seen for the RCC cell line, and not the lung epithelial cell…”
With respect to representative number of species, see AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc. (Fed. Cir. 2014). Also, see MPEP 2163 Il(A)(3)(a))(ii):
A representative number of species means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See Abb Vie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.").
Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date." See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014) (Holding that claims to all human antibodies that bind IL-12 with a particular binding affinity rate constant (i.e., koff) were not adequately supported by a specification describing only a single type of human antibody having the claimed features because the disclosed antibody was not representative of other types of antibodies in the claimed genus, as demonstrated by the fact that other disclosed antibodies had different types of heavy and light chains, and shared only a 50% sequence similarity in their variable regions with the disclosed antibodies.).
Regarding the claimed methods of treatment comprising administration of a cytotoxic immune cell genetically modified with a genera of nucleic acids encoding anti-CDH6 or anti-AXL binding triggered transcriptional switches with no recited structure (claims 11 and 22), or transcriptional activators with no recite structure (claim 21) with the recited function of “binding of the BTTS to the first antigen activates expression of the chimeric antigen receptor”, the instant specification discloses that the an scFv fused to the Notch TM domain and a GAL4-VP6 transcription factor can undergo Notch domain proteolysis upon ligand binding, leading to release of the transcription factor which binds to a nucleic acid sequence and drive the expression of a CAR, but provides no examples of specific structures, defined by their amino acid sequences, with the broadly recited function of “binding of the BTTS to the first antigen activates expression of the chimeric antigen receptor”. This does not sufficiently represent the broadly claimed genus of methods of treating RCC comprising administration of a cytotoxic immune cell genetically modified to contain a broad genus of nucleic acids with no recited structure and the claimed function.
Regarding the claimed methods of treatment comprising administration of a cytotoxic immune cell genetically modified broad genus of regulatory sequences with no recited structure and the function of “responsive to the BTTS” (claims 11, 21, and 22), the specification does not disclose any structures with this function other than generic “DNA binding domain target sequence” (¶[00221]), which does not sufficiently represent the broadly claimed genus of methods of treating RCC comprising administration of a cytotoxic immune cell genetically modified to contain a broad genus of nucleic acids with no recited structure and the claimed function.
Regarding the claimed methods of treatment comprising administration of a cytotoxic immune cell genetically modified with broad a broad genus of nucleic acids encoding a BTTS with domains with no recited structure and the function of “protease cleavage domain” (claim 21), the specification discloses the Notch TM domain can act as a protease cleavage domain in a BTTS (i.e., a synNotch receptor, ¶[00244]-[00245]), however this one example does not sufficiently represent the broadly claimed genus of methods of treating RCC comprising administration of a cytotoxic immune cell genetically modified to contain a broad genus of nucleic acids with no recited structure and the claimed function of “protease cleavage domain”.
Moreover, there is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed methods of treating RCC comprising administration of cytotoxic immune cells genetically modified to contain a broad genus of nucleic acids encoding anti-CDH6 or anti-AXL binding triggered transcriptional switches with no recited structure (claims 11 and 22), or transcriptional activators with no recite structure (claim 21) with the recited function of “binding of the BTTS to the first antigen activates expression of the chimeric antigen receptor”; broad genus of regulatory sequences with no recited structure and the function of “responsive to the BTTS” (claims 11, 21, and 22); or a broad genus of nucleic acids encoding a BTTS with domains with no recited structure and the function of “protease cleavage domain” (claim 21), to demonstrate possession. Also, see Amgen Inc. v. Sanofi, Aventisub LLC, No. 2017-1480 (Fed. Cir. 2017). The Court reiterated that adequate written description must “contain enough information about the actual makeup of the claimed products . . . .” The Court simultaneously suggested that the “newly characterized antigen” test “flouts” section 112 because it “allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen.” The Court concluded that for written description of an antibody to be adequate when presented with “functional” terminology, there must be an established correlation in the art between structure and function.
Given the broadly claimed methods of treating RCC comprising administration of cytotoxic immune cells genetically modified to contain a broad genus of nucleic acids with the functions recited in the claims, and in the absence of sufficient disclosure of relevant identifying characteristics for the broadly claimed methods of treating RCC comprising administration of cytotoxic immune cells genetically modified to contain a broad genus of nucleic acids with the functions recited in the claims, the patentee must establish “a reasonable structure-function correlation” either within the specification or by reference to the knowledge of one skilled in the art with functional claims. AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc. (Fed. Cir. 2014), MPEP 2163.
The specification does not disclose any relationship between a protein’s structure, as defined by its amino acid sequence, and the functions of “binding of the BTTS to the first antigen activates expression of the chimeric antigen receptor” (claims 11 and 21-13) or “protease cleavage domain” (claim 21) that can be used in the broadly claimed methods of treatment. The specification only discloses two methods of treatment, both of which use cytotoxic T-cells genetically modified to express a chimeric synNotch receptor comprising an scFv that specifically binds to either AXL or CDH6, a Notch TM domain, and a Gal4-VP64 transcription factor. All three of these domains are required for the function of “binding of the BTTS to the first antigen activates expression of the chimeric antigen receptor”, as upon antigen binding, the Notch domain undergoes proteolytic cleavage to release the Gal4-VP64 transcription factor, which will then specifically bind to a particular DNA sequence to drive expression of a CAR. Other that these two specific examples of treating RCC, there is no disclosed structure function relationship.
Additionally, the specification does not disclose any relationship between a DNA sequence and the function of “responsive to the BTTS”, other than to list that there exists DNA elements that Gal4-VP64 can bind to and be utilized in the claimed method of treatment.
Furthermore, the prior art teaches that there is a specific structural relationship between a polypeptide’s amino acid sequence and a specific DNA sequence that allows a transcription factor to bind to DNA and drive gene expression. For example, Reece et al. (Science. 1993 Aug 13;261(5123):909-11. doi: 10.1126/science.8346441. PMID: 8346441) teaches that a specific cysteine rich motif and the linker and part of the dimerization domain of the Gal4 transcription factor are responsible for binding to DNA, and the specific sequence of these domains determines whether the transcription factor will target Gal4 binding targets, or other binding targets such as those recognized by the PUT3 or PPR1 transcription factors (Abstract): “…zinc clusters of these proteins work interchangeably to recognize the conserved triplets and that the region 19 amino acids to the carboxyl-terminal side of the zinc cluster, comprising the linker and the beginning of a dimerization element as inferred from the GAL4 crystal structure, directs the protein to its preferred site”. Additionally, Liang et al. (Mol Cell Biol. 1996 Jul;16(7):3773-80. doi: 10.1128/MCB.16.7.3773) teaches that the DNA binding site for GAL4 is a consensus sequence, and changing the length of this sequence or the ends of it significantly alters GAL4 binding (Introduction): “…Examination of 16 known natural sites reveals a 17-bp pseudo-palindromic consensus sequence...This consensus site is a high-affinity binding site for GAL4…The site has highly conserved palindromic CGG sequences at its ends separated by 11 bp.”
Additionally, the prior art teaches that the Notch receptor sequence not only has protease cleavage sites, it is folded in a way to mask these cleavage sites until mechanical force is applied via ligand binding and mechanical tension, leading to protease cleavage sites and release of the intracellular signaling domain. Gordon et al. (Dev Cell. 2015 Jun 22;33(6):729-36. doi: 10.1016/j.devcel.2015.05.004. Epub 2015 Jun 4) teaches that mechanical tension exposes protease cleavage sites, leading to release of the intracellular signaling domain (Fig. 2).
The prior art teaches that there is unpredictability in a protein’s amino acid sequence and the function of binding to a particular DNA segment, and alterations in either the DNA or protein sequence can alter this binding. Furthermore, the prior art teaches that the Notch receptor sequence gives rise to a structure that masks proteolytic cleavage domains until ligand binding and mechanical tensions is applied, leading to proteolysis and release of an intracellular domain. Therefore, there is even greater unpredictability in combining these elements together to develop a polypeptide that binds to CDH6 or AXL, which leads to tension to expose notch proteolysis domains, leading to proteolytic cleavage and release of a transcription factor such as Gal4-VP64, which then binds to a specific DNA sequence to drive expression of a chimeric antigen receptor that is specific for the other antigen of CDH6 or AXL, leading to targeted killing of renal cell carcinoma by a cytotoxic cell.
Possession is not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. Sufficient description to show possession of such a genus may be achieved by means of a recitation of a representative number of methods of treating RCC comprising administration of cytotoxic cells genetically modified to contain a genus of nucleic acids encoding anti-CDH6 or anti-AXL binding triggered transcriptional switches with no recited structure (claims 11 and 22), or transcriptional activators with no recite structure (claim 21) with the recited function of “binding of the BTTS to the first antigen activates expression of the chimeric antigen receptor”; broad genus of regulatory sequences with no recited structure and the function of “responsive to the BTTS” (claims 11, 21, and 22); or a broad genus of nucleic acids encoding a BTTS with domains with no recited structure and the function of “protease cleavage domain” (claim 21) thereof falling within the scope of the genera or of a recitation of structural features common to members of the genera, which features constitute a substantial portion of the genus. See Eli Lilly, 119F.3d at 1568, 43 USPQ2d at 1406.
Claims 11, 21, and 22 do not meet the requirements of 35 U.S.C. 112(a) for written description.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the written description inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.). Consequently, Applicant was not in possession of the instant claimed invention. See University of California v. Eli Lilly and Co. 43 USPQ2d 1398.
Applicant is invited to point to clear support or specific examples of the claimed invention in the specification as-filed. This is a new grounds of rejection necessitated by Applicant’s amendments.
Claims 11, 21, and 22 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claims contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. This is a new grounds of rejection necessitated by Applicant’s amendments.
Claim 11 and newly added claims 21 and 22 are rejected for the same reasons set forth in the Office Action mailed on 3/17/2026. Briefly, the claims are directed to methods of treating renal cell carcinoma in an individual, regardless of expression status of CDH6 and AXL, comprising administration of a cytotoxic immune cell genetically modified to contain nucleic acid encoding a broad genus of binding-triggered transcriptional switch that is specific for CDH6 or AXL with no recited structure, while the instant specification only discloses one specific example of an antigen binding domain with the function of “binds to CDH6” and one specific example of an antigen binding domain with the function of “binds to AXL”.
The instant claims are directed to classes of polypeptides that include “a ‘vast’ number” of additional structures with defined amino acid sequences in which the instant specification fails to describe. It would be necessary to first generate and then screen each candidate CAR and/or BTTS polypeptide to determine whether it met the functional limitations of “binds to CDH6” and/or “binds to AXL”. The Federal Circuit concluded that there was a lack of enablement, which was affirmed by the Supreme Court in Amgen.
Applicant argues that the amendments to the instant claims obviated the previous rejection, however for the reasons set forth in the Office Action mailed on 3/17/2026 and supra, the claims are not enabled.
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 11, 21, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Morsut et al. (Cell. 2016 Feb 11;164(4):770-9. doi: 10.1016/j.cell.2016.01.011. Epub 2016 Jan 28) in view of Bailucha et al. (Cancer Discov 1 September 2017; 7 (9): 1030–1045. Doi: 10.1158/2159-8290.CD-16-1414, in Office Action mailed on 3/17/2026), Chaudhary et al. (WO2017172981, in Office Action mailed on 3/17/2026), Yu et al. (Br J Cancer. 2015 Aug 11;113(4):616-25. doi: 10.1038/bjc.2015.237. Epub 2015 Jul 16), and Cho et al. (Sci Rep. 2018 Mar 1;8(1):3846. doi: 10.1038/s41598-018-22252-6, in Office Action mailed on 3/17/2026). This is a new grounds of rejection necessitated by Applicant’s amendments.
Claim 11 recites a method of killing renal cell carcinoma in a subject comprising administration of a engineered cytotoxic immune cell that is genetically modified to contain a nucleic acid encoding a binding-triggered transcriptional switch that is specific for AXL or CDH6, that when activated binds to a regulatory sequence operably linked to a nucleic acid encoding a CAR that is specific for the other of AXL or CDH6 to drive the expression of said CAR.
Morsut et al. teaches a dual receptor CAR-T circuit comprising a synNotch specific for a first target on a tumor cell, which leads to Notch-driven proteolytic release of a transcription factor that drives the expression of a CAR specific for a second target on the same tumor cell, leading to targeted killing of the tumor cell with reduced killing of normal cells that express either of the targets alone (Graphical Abstract):
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Morsut et al. further teaches (Summary): “[a] powerful way to
enhance ON-target activity of therapeutic T cells is to engineer them to require combinatorial antigens. Here, we engineer a combinatorically activated T cell circuit in which a synthetic Notch receptor for one antigen induces the expression of a CAR for a second antigen. These dual receptor AND-gate T cells are only armed and activated in the presence of dual antigen tumor cells. These T cells show precise therapeutic discrimination in vivo—sparing single antigen ‘‘bystander’’ tumors while efficiently clearing combinatorial antigen ‘‘disease’’ tumors. This type of precision dual-receptor circuit opens the door to immune recognition of a wider range of tumors.”
Morsut et al. teaches methods of treating cancer comprising administration of these cells to an individual to target and kill the cancer (pg. 772): “[a]fter giving the tumors 10 days to implant, we injected primary CD4+ and CD8+ human T cells equipped with the a-GFP synNotch Gal4VP64 receptor, the corresponding response elements controlling the expression of the a-CD19 4-1BBz CAR…”
Morsut et al. does not teach methods of treating renal cell carcinoma specifically comprising administration of cytotoxic T-cells expressing this dual-targeting system adapted to target renal cell carcinoma, where the synNotch is specific for AXL or CDH6 and the CAR is specific for the other antigen.
Bailucha et al., in the same field of endeavor, teaches that renal cell carcinomas have increased cadherin-6 expression (Introduction and Fig 1A, cropped below): “[w]e also noticed extensive expression of CDH6 in renal clear cell and papillary carcinoma…”
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Bailucha et al. further teaches that targeting CDH6 with a therapeutic (in this case, a CDH6 ADC) reduces tumor volume in a mouse renal cell cancer model (Fig. 6C, “”HKT288”):
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Bailucha et al. teaches that renal cell carcinoma expresses CDH6, and targeting CDH6 can successfully lead to inhibition of tumor growth.
Chaudhary et al., in the same field of endeavor, teaches an anti-CDH6 chimeric antigen receptor (claim 12, Table 19, ¶[0060]): “…comprising conventional CAR I and K13-vFLIP, wherein the antigen specific domain of the CAR targets CDH6…”.
Chaudhary et al. teaches that the cells express the CAR through vectors comprising nucleic acids encoding the anti-CDH6 CAR (¶[0086]): “…herein are vectors comprising nucleic acid sequences encoding the conventional CARs or novel backbones (comprising conventional CARs and accessory modules) described herein. In exemplary embodiments, the vector is any of a DNA vector, an RNA vector, a plasmid, a lentivirus vector, an adenoviral vector or a retrovirus vector. In an embodiment, the vector is a lentivirus vector as described herein…” Chaudhary et al. teaches that the vectors also comprise a promoter that can be induced by a transcription factor from a synthetic notch receptor (¶[0086]): “…the vector further comprises a promoter…the promoter is an inducible promoter that provides a molecule switch capable of turning on expression of the polynucleotide sequence encoding conventional CARs… a combinatorially activated T cell circuit can be engineered in which a synthetic Notch receptor for one antigen induces the expression of a conventional CAR or backbones 1-62 targeting a second antigen as described recently for controlling the activity of CARs…”
Chaudhary et al. additionally teaches methods of treating CDH6 expressing cancer cells comprising administration of immune effector cells such as T-cells engineered to express an anti-CDH6 CAR (claims 1 and 12, ¶[00535]): “[i]n one aspect, the present invention provides methods of treating or preventing a disease by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express a CDH6-specific conventional CAR…wherein the disease causing or disease associated cells express CDH6. In one embodiment, the disease to be treated or prevented is a cancer. In one embodiment, the cancer to be treated or prevented is a solid tumor.” Chaudhary et al. teaches that the cancer can be renal cell carcinoma (¶[00520]).
Yu et al., in the same field of endeavor, teaches that AXL is highly expressed in renal cell carcinoma and is a therapeutic target for treatment, and an anti-Axl antibody therapeutic could reduce tumor growth (Abstract): “[w]e have determined by immunohistochemistry (IHC) that Axl is expressed in 59% of RCC array samples with moderate to high in 20% but not expressed in normal kidney tissue. Western blot analysis of 11 pairs of tumour and adjacent normal tissue show high Axl expression in 73% of the tumours but not normal tissue. Axl is also expressed in RCC cell lines in which Axl knockdown reduces cell viability and PI3K/Akt signalling. The Axl antibody hMAb173 significantly induced RCC cell apoptosis in histoculture and inhibited the growth of RCC tumour in vivo by 78%. The hMAb173-treated tumours also had significantly reduced Axl protein levels, inhibited PI3K signalling, decreased proliferation, and induced apoptosis… Axl is highly expressed in RCC and critical for RCC cell survival. Targeting Axl is a potential approach for RCC treatment”
Cho et al., in the same field of endeavor, teaches an anti-AXL CAR SynNotch receptor and cytotoxic T-cells expressing the receptor (i.e., “a BTTS”; Cho et al. Abstract): “…an anti-Axl synNotch generated using the same scFv can be activated with Axl expressing tumor cells.” (pg. 3): “[t]he Axl synNotch receptor is composed of the Axl scFv as the extracellular domain and notch core region fused to engineered transcription factor (tTA). Jurkat T cells were engineered to stably express Axl synNotch receptor using electroporation…”
Cho et al. further teaches that cytotoxic T-cells expressing the anti-AXL CAR receptor target and kill cancer cells (Fig. 3D), and cells expressing the AXL-SynNotch successfully bind and activate upon binding to either AXL or cells expressing AXL (Fig. 4C and 4E). Cho et al. additionally teaches that both of these receptors are made with the same extracellular domain (Methods): “Axl CAR was designed by fusing humanized Axl scFv to the hinge region of the human CD8α chain and transmembrane and cytoplasmic regions… Axl synNotch receptor was designed by fusing humanized Axl scFv to the notch core intracellular domain…” Cho et al. further teaches (Discussion): “…we developed a humanized Axl scFv from previously reported Axl monoclonal antibody by fusing variable region of heavy and light chain via a polypeptide linker. Using this Axl scFv, we successfully created the first Axl CAR and synNotch receptor, which can be valuable therapeutic reagents since Axl is overexpressed in many cancers…” Also see Fig. 4A:
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Cho et al. further teaches that the cytotoxic T-cells are engineered to express the anti-AXL CAR or synNotch through lentiviral transduction of a nucleic acid encoding the construct (“Lentiviral Transduction of Human T cells”), which are genetically modified cytotoxic cells containing a nucleic acid encoding the CAR or synNotch.
It would have been obvious to one with ordinary skill in the art, before the effective filing date of the instant application, to have combined the references of Morsut et al., Bailucha et al., Chaudhary et al., Yu et al., and Cho et al. to adapt the dual receptor CAR-T circuit of Morsut et al. to target RCC by targeting AXL with a functional anti-AXL synNotch to drive expression of an anti-CDH6 CAR with a reasonable expectation of success because Morsut et al. teaches the general outline of this system, Bailucha et al., and Yu et al. teach that both CDH6 and AXL are tractable targets to treat RCC, Cho et al teaches an anti-AXL synNotch, and Chaudhary et al. teaches an anti-CDH6 CAR that one with ordinary skill in the art would be able to develop into a dual receptor CAR-T circuit. One would have been motivated to do so for the purposes of developing a CAR-T system that targets RCC with less off-target effects, as taught by Morsut et al.
This combination of references would generate a method of killing RCC comprising administration of cytotoxic T-cells engineered to comprise a nucleic acid encoding an anti-AXL synNotch (i.e., expressing the receptor) that will, upon binding to AXL, lead to release of a transcription factor that binds to a promoter operably linked to a nucleic acid encoding the anti-CDH6 CAR (taught by Chaudhary et al.), driving expression of the CAR, meeting the limitations of instant claim 11.
Regarding claim 21, Cho et al. teaches the anti-AXL synNotch comprises an anti-AXL scFv, a notch core with a TM domain and protease cleavage sites, and a transcriptional activator that is release upon binding to drive expression (see, for example Fig, 4A supra), meeting the claim limitations.
Regarding claim 22, Morsut et al. teaches the cell used in the dual-targeting system and methods of treating cancer using the system is a cytotoxic T-cell, meeting the claim limitations.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 11, 21, and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18/708,921 (App ‘921, in Office Action mailed on 3/17/2026). Although the claims at issue are not identical, they are not patentably distinct from each other. This is a new ground of rejection necessitated by Applicant’s amendments.
App ‘921 claims engineered immune cells comprising nucleic acids encoding a BTTS and a CAR that each recognize different antigens (claims 1, 2, and 4). App ‘921 additionally claims cells comprising the BTTS and CAR that recognize antigens selected from Table 1 (claims 8 and 9). Table 1 is relied upon in the disclosure to determine which antigens are encompassed by the instant claims (specification pg. 21 and 11), and the antigens CDH6 and AXL are both included.
App ‘921 claims that the BTTS drives expression of the CAR to kill the target cell (claims 1 and 17).
App ‘921 claims the engineered cell can be a T-cell (i.e., “cytotoxic immune cell”; App ‘921 claim 15).
App ‘921 additionally methods of treating a subject with cancer (i.e., “killing a target cancer cell in an individual”) comprising administration of the engineered cell (claim 18), including kidney (i.e., “renal”) cancer (claims 19 and 20).
It would have been obvious to one of ordinary skill in the art to have used the claimed immune cells of App ‘921 in the claimed method of treating a subject with renal cancer with a reasonable expectation of success, as one with ordinary skill in the art would appreciate that the engineered immune cells can be used to treat cancer. One would have been motivated to do so to treat renal cancer with the claimed immune cells.
Regarding instant claim 21, App ‘921 claims the BTTS comprises an extracellular binding domain, a TM domain, two protease cleavage sites, and a transcription factor that drives CAR expression (claim 12), meeting the claim limitations.
Regarding instant claim 22, App ‘921 claims the engineered cells are cytotoxic T-cells (claim 15), meeting the claim limitations.
Therefore, the invention encompassed by App ‘921 is a prima facie obvious variant of the invention encompassed by the instant claim. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEC JON PETERS whose telephone number is (703)756-5794. The examiner can normally be reached Monday-Friday 8:30am - 6:00pm EST.
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/ALEC JON PETERS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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