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 .
Application Status
The Response to the Election of Species Requirement mailed on April 28, 2026 is acknowledged. Applicant’s elections of (1) a composition comprising a first chimeric antigen receptor (CAR) comprising an anti-CD19 extracellular ligand-binding domain (with traverse), a CD28 transmembrane domain (with traverse), and a LAT (SEQ ID NO: 185) intracellular signaling domain (without traverse), and a second CAR comprising an anti-HER2 extracellular ligand-binding domain (with traverse), a CD8 transmembrane domain (with traverse), and a SLP-76 (SEQ ID NO: 106) intracellular signaling domain (without traverse), reading on claims 102-111, and (2) a chimeric antigen receptor polypeptide comprising .
While Applicant has traversed specific elements of the Election of Species Requirement, Applicant did not distinctly and specifically point out supposed errors in the restriction requirement as set forth in MPEP § 818.01(a). The Election of Species Requirement is maintained for the reasons set forth in the Office Action mailed April 28, 2026.
The amended claims filed July 24, 2026 are acknowledged. Claims 102-121 are pending. Claims 102 and 118-121 are amended. No claims are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 102-121 are under examination herein.
Claim Objections
Claim 120 is objected to because of the following informalities: For consistency of language, it is suggested that “the cell expresses the CAR” in line 2 be amended to “the T cell expresses the CAR”, in line with the remainder of the claim. In addition, the claim language could be clearer that the ligand contacted with the T cell is the same ligand that is bound by the extracellular ligand-binding domain of the CAR polypeptide.
Appropriate correction is requested.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 106, 108-109, 115, 119, and 121 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 106 recites the limitation, “…wherein the cell expressing both CAR polypeptides…” in lines 1-2. There is insufficient antecedent basis for this limitation in the claim. The claim depends from claim 102, which recites a composition, but not a cell.
Claim 108 recites the limitation, “The cell expressing the composition of claim 102”. There is insufficient antecedent basis for this limitation in the claim. The instant claim does not earlier recite “A cell” to which this limitation may refer.
Claim 109 recites the limitation, “A method of expressing the composition of claim 102 in the cell…”. There is insufficient antecedent basis for this limitation in the claim. Neither the instant claim nor claim 102 recite a cell to which this limitation refers.
It is suggested that the claim be amended to recite “a cell” instead of “the cell.”
Claim 111 recites the limitations of “the cell expressing the composition” in lines 6 and 10 and “the cancer cells” in lines 7 and 10-11. There is insufficient antecedent basis for these limitations in the claim. Neither the instant claim nor earlier claim 102 recite “a cell” expressing the composition or one or more cancer cells to which these limitations refer.
Regarding claim 112 and dependent claims 115-121, claim 112 recites that the numbering of the at least one mutation present in the ZAP70 fragment corresponds to the numbering of full-length human ZAP70. However, neither the claim nor Applicant's disclosure appear to provide a standard (e.g., an amino acid sequence) for ascertaining what is considered to be the sequence of a full-length ZAP70 in humans. For example, it is noted that the entry for Accession AAH39039.1 published in October 2003 reports a 493-residue sequence for human ZAP70, which not only excludes the claimed mutation positions of 597 and 598 but also contains different residues in at least positions 292 and 492 than recited in the claim. Furthermore, Accession XP_054188971 published August 2025 which is after the effective filing date reports a 707-residue sequence for full-length human ZAP70, which also contains different residues in at least some of the positions 292 and 492 recited in the claim. See Office Action appendix.
Accordingly, it is apparent that full-length human ZAP70 can vary such that it is unclear what numbering should be used for full-length human ZAP70 in claim 112 and its dependents.
It is suggested that one way this rejection could be obviated is by canceling part (c) of claim 112 and amending the claim to recite “wherein the intracellular signaling domain comprises an amino acid sequence selected from SEQ ID NOs: 107-110, 163, 165, 167, and 169”. Furthermore, while the scope of the claim is unclear, in the interests of compact prosecution, Zhao (Molecular and Cellular Biology (1999) 19(1): 948-956) which discloses a human ZAP70 Y292F mutation is being applied as below prior art that appears to meet this limitation, absent a showing otherwise.
Regarding claim 115, the claim recites the limitation, “activating the T cell expressing the CAR polypeptide” in list item (a). There is insufficient antecedent basis for this limitation in the claim. Neither the instant claim nor earlier claim 102 recite “a T cell” to which this limitation may refer.
Regarding claim 119, the claim recites the limitation, “A method of expressing the CAR polypeptide in a T cell” in the preamble. There is insufficient antecedent basis for this limitation in the claim. The claim does not earlier recite “a CAR polypeptide” to which this limitation may refer.
Regarding claim 121, the claim recites the limitations of “the cancer cells” in line 6 and “a ligand”/”the ligand” in lines 6-7 which is expressed on the surface of said cancer cells. There is insufficient antecedent basis for these limitations in the claim. With respect to “the cancer cells”, neither the instant claim nor claim 112 earlier specifically recite one or more cancer cells to which this limitation may refer. With respect to “a ligand”/”the ligand” expressed on the cancer cells, the construction of the claim does not make sufficiently clear that the ligand expressed on the cancer cells is in fact the same ligand which is bound by the extracellular ligand-binding domain of the CAR polypeptide of claim 112.
Claim Rejections - 35 USC § 112(a)
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 103-104 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 claim(s) contains 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 inventor(s), at the time the application was filed, had possession of the claimed invention.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991).
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or it may be satisfied by the disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. “Functional” terminology may be used “when the art has established a correlation between structure and function” 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 one has invented a genus and not just a species. Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010).
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). “[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.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention. For example, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural "stepping stone" to the corresponding chimeric antibody, but not to human antibodies. Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875 (Fed. Cir. 2011).
The claimed invention. The nature and scope of the claimed invention at issue is a “mutant” or “variant” thereof of the intracellular signaling domains selected from the group consisting of LAT, SLP-76, CD28, CD2, 4-1BB, and CD6, as set forth in claim 103. Claim 104 further sets forth the further condition that first intracellular signaling domain comprises an LAT mutant or variant thereof comprising a sequence “at least 80% identical to” SEQ ID NO: 1851 and that the second intracellular signaling domain comprises a SLP-76 mutant or variant thereof comprising a sequence “at least 80% identical to” SEQ ID NO: 1062. These limitations fail to satisfy the written description requirement because neither Applicant's disclosure nor the prior art provide sufficient evidence that all possible variants and mutants that are conceivable from the claim language would function effectively as a CAR intracellular signaling domain as claimed.
State of the prior art. The broad goal of cancer immunotherapy is to enhance the immune response against tumor cells. As taught by Harris (Trends in Pharmacological Sciences (2016) 37(3): 220-230), adoptive T cell therapies such as T cell receptors (TCRs) and chimeric antigen receptors (CARs) have great potential for harnessing the tumor-killing properties of T cells through genetic engineering (Abstract). CAR-based adoptive T cell therapies have shown great promise and have gained the interest of biotechnology and pharmaceutical companies (e.g., Abstract; Introduction, first paragraph). Harris teaches that CARs are synthetic constructs typically comprising a single-chain antibody fragment (scFv, VH-linker-VL, or VL-linker-VH), an extracellular stalk (hinge) region, a transmembrane domain, and one or more intracellular signaling domains (e.g., page 223, “Chimeric Antigen Receptor: Structure and Signaling”). The scFv enables the CAR to respond to cell surface antigens independent of MHC. Per Harris, “The hinge region of a CAR typically comprises either immunoglobulin-like CH2-CH3 (Fc) domains from the constant region of immunoglobulin G (IgG) or the spacer domain from either CD4 or CD8.” Lengthening or shortening the extracellular domain can optimize activity of an individual CAR (e.g., page 223). Various transmembrane regions incorporated into CARs include CD3 zeta, CD28, OX40, and others (e.g., pages 223-224). The intracellular signaling domains of a CAR are derived from CD3 zeta and a co-stimulatory molecule (typically CD28 or 4-1BB) (e.g., Figure 1). Harris teaches that these intracellular signaling domains have received the most attention in terms of their impact on T cell activity, T cell persistence, and efficacy. Second-generation CARs comprising co-stimulatory signaling components in concert with CD3 zeta have shown improved clinical efficacy and persistence (e.g., page 224).
Compositions containing CAR constructs that comprise an intracellular signaling domain derived from SLP-76 and/or LAT have previously been set forth in the art. See, for example, Balagopalan (WO 2020/190771 A1; cited in IDS) and Sadelain (WO 2020/172177 A1; cited in IDS).
Scope of species disclosed in original specification. The disclosure describes selected examples of SLP-76 and LAT mutant or variant intracellular signaling domains (e.g., figures (thoughout); ¶ 00178-00179; Table 1). Specific point mutations and deletions in SLP-76 and LAT are summarized in the excerpt from the specification below:
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Relevant to the elected invention, the activity of exemplary CAR constructs “CD19-28H/TM-LAT”, “CD19-28H/TM-LAT2YF”, “CD19-28H/TM-LAT200-262 del”, “CD19-28H/TM-LAT3YF”, “CD19-28H/TM-LAT28-90 del, 200-262 del”, “CD19-28H/TM-LAT28-130 del, 200-262 del”, “HER2-8H/TM-SLP76”, and “HER2-8H/TM-SLP76224-244 del” are shown in Figures 28-29, 32, 38, and 47-48.
MPEP § 2163 states that 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. In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics; i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
As shown above, the disclosure describes several specific embodiments of anti-CD19 CARs having variant LAT intracellular signaling domains comprising selected point mutations or deletions and anti-HER2 CARs having variant SLP-76 intracellular signaling domains comprising selected deletions. However, the teachings of the disclosure do not broadly support that Applicant possesses all of the many possible variant or mutant LAT or SLP-76 intracellular signaling domains encompassed by the scope of the instant claims.
Conclusion. For all of the reasons presented above, one of skill in the art would not know which of the countless other CAR constructs encompassed by the highly general structural requirements of the claims would also possess the required functional activity. Given the lack of shared structural properties that provide the claimed binding activity, the limited number of species described, and the fact that the species that were described cannot be considered representative of the broad genus, the Applicant did not possess the full genus of CAR constructs as broadly claimed at the time the application was filed.
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.
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.
(1)
Claims 102-103 and 106-111 are rejected under 35 U.S.C. 103 as being unpatentable over Balagopalan (WO 2020/190771 A1; cited in IDS) in view of Powell (US 2019/0125797 A1; cited in IDS) and Grada (Molecular Therapy - Nucleic Acids (2013) 2: e105).
Balagopalan describes chimeric polypeptides (“CAPs”) comprising (a) an extracellular targeting domain (e.g., a CD19-targeting domain or a HER2-targeting domain), (b) a transmembrane domain (e.g., a CD28 transmembrane domain or a CD8 transmembrane domain), (c) an intracellular domain comprising SLP-76 or LAT, and (d) an intracellular ZAP70 domain3, as well as modified T cells or natural killer (NK) cells transduced or transfected with expression vectors comprising a nucleic acid encoding a CAP of the invention and compositions comprising the same (e.g., Abstract; pages 1-2, 8-9, 14-27; claims 1-4, 9-15, 27-28, 31-40). Balagopalan teaches that the modified T cells or modified NK cells of the invention may comprise more than one of the disclosed nucleic acids or vectors (e.g., pages 11-12), such that a composition of the invention could reasonably comprise a first CAP comprising a LAT intracellular signaling domain and a second CAP comprising an SLP-76 intracellular signaling domain, pertinent to claims 102-103 and 107-108. Relevant to claim 109, Balagopalan discloses methods in which cells (e.g., T cells) isolated using art-recognized methods are transduced or transformed with a vector including a CAP(s) of the invention (e.g., pages 34-37).
Relevant to claims 106 and 110, Balagopalan describes a method in which PBMCs (which comprise T cells) transduced with constructs CAP1, CAP2, or CAP3 were cultured with Nalm6 and K652 CD19 cells and displayed high levels of cytokine release (e.g., Example 3, page 39; Figures 7-8). Relevant to claim 111, Balagopalan discloses methods of treating a subject with cancer that comprise administering an isolated cell or composition of the invention to said subject (e.g., pages 2, 31-35).
However, Balagopalan does not expressly teach that binding of a first and second ligand to a first and second extracellular ligand-binding domain activates the first and second intracellular signaling domains, wherein activation of one but not the other does not activate the cell. Balagopalan also does not teach a specific embodiment in which CD19 and HER2 are co-targeted.
Powell describes compositions comprising trans-signaling CAR-T cells comprising a first CAR having a first signaling module and a second CAR having a second signaling module, as well as methods of stimulating a T cell-mediated immune response to a target cell population by administering a cell comprising said first and second CARs (e.g., Abstract; ¶ 0007-0016). Powell teaches embodiments in which activation of the T cell in which the CARs are expressed is dependent on the binding of the first CAR to its corresponding target and the binding of the second CAR to its corresponding target and the cell exhibits anti-tumor activity upon binding (e.g., ¶ 0029-0030; claims 11-15). Powell teaches that “it may be beneficial to effectively control and regulate CAR T cells such that they kill tumor cells while not affecting normal bystander cells” (¶ 0029).
Grada describes the generation of a bispecific tandem (tan)CAR which simultaneously targets CD19 and HER2 (e.g., Abstract; Results). Grada teaches that bispecific CAR-T cells could offset tumor escape and “could enable simultaneous targeting of tumor cells and elements in the tumor microenvironment thereby augmenting T cell activation and function by increasing avidity and by broadening their therapeutic reach” (Introduction). Grada teaches that in cocultures, tanCAR T cells secreted IFN-γ and IL-2 upon encountering HER2+ or CD19+ target cells (e.g., page 4). Grada further tested the ability of the tanCAR T cells to simultaneously target both antigens using a Daoy.TET.CD19 xenograft model and observed that the tanCAR T cells displayed enhanced cytolytic activity upon simultaneous recognition of both antigens (e.g., Results, pages 4-5; Figures 5-6).
In view of these teachings, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to arrive at a composition comprising a first CAR (e.g., a CAR comprising an extracellular CD19 ligand-binding domain, a CD28 transmembrane domain, and a LAT intracellular signaling domain) and a second CAR (e.g., a CAR comprising an extracellular HER2 ligand-binding domain, a CD8 transmembrane domain, and a SLP-76 intracellular signaling domain), each having a separate intracellular signaling domain which does not comprise an ITAM, based on the teachings of Balagopalan, Powell, and Grada. The skilled artisan would have been motivated to do so because such a strategy would allow for regulation of the CARs such that they kill tumor cells without affecting normal bystander cells (as taught by Powell) and because targeting multiple tumor-associated antigens simultaneously could help to offset the known issue of tumor escape and broaden the therapeutic reach of the CAR-expressing cell compositions (as taught by Grada). There would have been a reasonable expectation of success because at least Powell provides a proof-of-concept that simultaneous expression of two CAR constructs, each having separate intracellular signaling domains, in a T cell results in potent anti-tumor activity, tumor localization, and persistence in vivo while minimizing activity against normal tissues (e.g., Example 1).
(2)
Claims 102 and 105 are rejected under 35 U.S.C. 103 as being unpatentable over Balagopalan (WO 2020/190771 A1; cited in IDS) in view of Powell (US 2019/0125797 A1; cited in IDS) and Grada (Molecular Therapy - Nucleic Acids (2013) 2: e105) as applied to claims 102-103 and 106-111 above, further in view of Bethune (US 2022/0023346 A1; earliest priority date: July 21, 2020).
The teachings of Balagopalan are recited in the 35 U.S.C. § 103 rejection above.
However, Balagopalan does not expressly teach that a CAP of the invention comprises a LAT intracellular signaling domain comprising the amino acid sequence of instant SEQ ID NO: 185.
The teachings of Powell and Grada are recited in the 35 U.S.C. § 103 rejection above.
Bethune describes recombinant antigen receptors (e.g., CARs) having modified cytoplasmic domains that provide improved signaling and, by extension, improved performance and safety (e.g., Abstract). In an aspect of the invention, Bethune teaches an engineered immune cell comprising a first recombinant antigen receptor (a CAR) and a second recombinant receptor comprising an intracellular domain that comprises a downstream mediator of T cell signaling, e.g., LAT, comprising an amino acid sequence of SEQ ID NO: 8 (for which residues 91-199 share 100% sequence identity to instant SEQ ID NO: 185) (e.g., claims 26-29 and 32; ¶ 0036-0042; Table 1). Examples 2-3 disclose that overexpression of LAT in combination with a first CAR improved efficacy compared to several other tested constructs (e.g., Figure 3).
In view of the further teachings of Bethune, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to substitute into a CAP construct taught by Balagopalan a LAT intracellular signaling domain comprising the amino acid sequence of instant SEQ ID NO: 185. The skilled artisan would have been motivated to do so because Bethune teaches that the modified cytoplasmic domains of the invention including LAT improve CAR signaling and efficacy. There would have been a reasonable expectation of success because one of ordinary skill in the art would recognize that the LAT intracellular signaling domain described by Bethune is suitable for use in a CAR construct and that the construct taught by Bethune is an equivalent known for the same purpose.
(3)
Claims 112-113 and 115-121 are rejected under 35 U.S.C. 103 as being unpatentable over Balagopalan (WO 2020/190771 A1; supra) in view of Zhao (Molecular and Cellular Biology (1999) 19(1): 948-956) and Jin (The Journal of Biological Chemistry (2004) 279(41): 42818-42825).
Balagopalan describes chimeric polypeptides (“CAPs”) comprising (a) an extracellular targeting domain (e.g., a CD19-targeting domain), (b) a transmembrane domain (e.g., a CD28 transmembrane domain), (c) an optional intracellular domain comprising SLP-76 or LAT, and (d) an intracellular ZAP70 domain (e.g., Abstract; pages 1-2, 8-9, 14-27; claims 1-4, 9-15). Pertinent to claims 112-113, the ZAP70 domain comprised in the CAPs includes a combination of ZAP70 kinase domain (KD) and a ZAP70 interdomain B (e.g., pages 1-2). As shown by Zhao, interdomain B span residues 254-337 of wild-type ZAP70 and the kinase domain spans residues 338-593 of wild-type ZAP70 (e.g., Figure 1). Balagopalan states that linkers (spacers) may be present between any of the components of the disclosed CAPS to allow proper folding and/or function (e.g., pages 2, 25). Relevant to claims 115 and 118, Balagopalan teaches isolated cells (e.g., T cells or natural killer (NK) cells) expressing the CAPs of the invention as well as compositions comprising said cells (e.g., page 2). Balagopalan states that “ZAP70 … plays a critical role in the events involved in initiating T-cell responses by the antigen receptor” (page 9; see also pages 24-25).
Relevant to claims 116-117, Balagopalan describes expression vectors comprising nucleic acids encoding the CAPs of the invention (e.g., page 2). Relevant to claim 119, Balagopalan discloses methods in which cells (e.g., T cells) isolated using art-recognized methods are transduced or transformed with a vector including a CAP of the invention (e.g., pages 34-37).
Relevant to claim 120, Balagopalan describes a method in which PBMCs (which comprise T cells) transduced with constructs CAP1, CAP2, CAP3, and CAP4 (which comprise ZAP70 intracellular signaling domains) were cultured with Nalm6 and K652 CD19 cells and displayed high levels of cytokine release (e.g., Example 3, page 39; Figures 7-8). Relevant to claim 121, Balagopalan discloses methods of treating a subject with cancer that comprise administering an isolated cell or composition of the invention to said subject (e.g., pages 2, 31-35).
However, Balagopalan does not expressly teach that the ZAP70 fragment comprised in the intracellular signaling domain comprises residues 255-600 and at least a Y292 mutation.
In addition to the teachings above, Zhao further teaches that residue Y292 in interdomain B of ZAP70 negatively regulates ZAP70 function (e.g., Discussion). Zhao further sets forth that the Y292F mutation enhances ZAP70 function in TCR induction of NF-AT activity in TAg-Jurkat cells (e.g., Discussion).
Jin teaches, “The ZAP-70 tyrosine kinase plays a critical role in T cell activation and the immune response and therefore is a logical target for immunomodulatory therapies” (Abstract). Jin implemented systematic N- and C-terminal truncations to determine how selected portions of the structure of ZAP70 are involved in the function of regulating kinase activity (e.g., pages 42818-42819, 42821; Figure 1). Figure 1 generally illustrates that ZAP70 fragments that don’t comprise at least residues 599-606 together with a portion of the ZAP70 interdomain B (i.e., the portion after the second SH2 domain) do not show kinase activity.
Taken together, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the CAR polypeptide of Balagopalan, which comprises an extracellular ligand-binding domain (e.g., anti-CD19), a transmembrane domain (e.g., CD28), and an intracellular signaling domain comprising a ZAP70 fragment (IB + KD), such that the ZAP70 fragment comprises at least residues 255-600 and a Y292F mutation, based on the further teachings of Zhao and Jin. The skilled artisan would have been motivated to do so because Jin generally teaches that ZAP70 fragments comprising at least residues 255-606 retain kinase activity and because Zhao teaches that the Y292F mutation enhances ZAP70-mediated TCR activation. There would have been a reasonable expectation of success because these residues generally correspond to the ZAP70 IB and KD, which are present in the CAPs disclosed by Balagopalan.
Conclusion
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/Brad Duffy/Primary Examiner, Art Unit 1643
1 Corresponding to the LAT intracellular signaling domain elected by Applicant in the Response filed July 24, 2026.
2 Corresponding to the SLP-76 intracellular signaling domain elected by Applicant in the Response filed July 24, 2026.
3 As evidenced by the instant specification, SLP-76, LAT, and ZAP-70 do not comprise an ITAM.
Prosecution Insights