DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restriction
Applicant's election with traverse of Invention III and the species of SEQ ID NO: 36 in the reply filed on 09MAR2026 is acknowledged. Upon further consideration the invention of groups I-II and VII-VIII (i.e., claim(s) 1-11, 13-14, 19, 67-83) as set forth in the restriction requirement mailed 09DEC2025 has been rejoined to group III and the election of species has been withdrawn. In view of the withdrawal of the restriction requirement, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Claim Status
Claim 15 has been amended.
Claims 12 and 20-66 have been canceled.
Claims 72-83 are new.
Claims 1-11, 13-19, and 67-83 are pending in the instant application and examined on the merits (i.e., Claim(s) 1, 15, and 67 is/are independent).
Priority
The present application is a 371 National Stage of PCT International Application No. PCT/US2021/058138 filed 04NOV2021, which claims the benefit of US Provisional Patent Application No. 63/109829, filed 04NOV2020 and US Provisional Patent Application No. 63/172891, filed 09APR2021. Applicant’s claim for the benefit of prior-filed application is acknowledged.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 13NOV2023 and 09MAR2026 is/are acknowledged and the references cited therein have been considered.
Claim Objections
Claims 3-5, 9, 11, 17, 73-75, 79, and 81 are objected to because of the following informalities:
Claims 3-5, 9, 11, 17, 73-75, 79, and 81 contain acronyms not readily known (e.g., EGFIR, Foxpl, CIS, etc.). While acronyms are permissible as shorthand in the claims, the first recitation of the term should include the full recitation followed by the acronym in parentheses.
Claims 3 and 73 contains duplicates of EGFRvIII and EGFR-VIII and ERBB2 and HER2 are equivalent. For consistency and clarity purposes, a single name of the tumor antigen should be listed.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 1, 4-5, 8-9, 15, 18, 67-68, 74-75, and 79 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claims 1, 15, and 67 recite the broad recitation of 80% identity to SEQ ID NOs: 36-41, and the claim also recites 99% identity to SEQ ID NOs: 36-41 which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claims 4(iv), 8(b), 8(c), 18(c)(ii), and 74(iv), recite the phrase "optionally," which renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(h)(II).
Claims 5 and 75 contain a reference to Table 1. Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.” Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted). See MPEP § 2173.05(s). In this instance, Table 1 (p 88-91) referenced in claims 5 and 75, includes genotypes of the cell or population thereof, which is 130 genotype species. The genotypes can be defined so that the claims are complete in themselves. Additionally, the extensiveness of Table 1, does not clearly define the metes and bounds of the patent protection desired.
Claims 9 and 79 recites the limitation "wherein the CPI" which are dependent upon claim 7 or 77, respectively, which are dependent on claims 5 and 75, respectively which recite “…further comprising one or more of: ….(iv) an exogenous CD16 or a variant thereof;…(viii)….a CPI,….” In this instance, it is unclear whether the cell populations “further comprise” introduction of a CPI or whether claims 9 and 79 were to be dependent on claims 5 and 75, respectively.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 68 recites the broad recitation 1-229 amino acid hinge peptide, and the claim also recites 1-80 amino acid hinge peptide which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
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.
Written Description
Claims 1-11, 13-19, and 67-83 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.
Scope of the claimed genus:
Applicant has broadly claimed a cell or a population thereof, wherein the cell comprises a polynucleotide encoding a CAR targeting a B7H3 tumor antigen wherein the CAR comprises a binding domain comprising: (i) an amino acid sequence that is at least 80-99% identity to SEQ ID NOs: 36-41; (ii) an amino acid sequence represented by a variant of SEQ ID NO: 36, and wherein the variant has one or more mutations at positions comprising 1, 40, 46, 79, 87, 88, 89, 97, 98, and 117 of SEQ ID NO: 36; (iii) an amino acid sequence represented by a variant of SEQ ID NO: 36, wherein the variant has one or more substitutions comprising Q1E, T40A, E46V, G79L, K87R, P88A, D89E, V97A, S98R, and Q117L according to SEQ ID NO: 36; or (iv) an amino acid sequence represented by any of SEQ ID NOs: 36, 37, 38, 39, 40, and 41; and wherein the cell is an eukaryotic cell, an animal cell, a human cell, an immune cell, an induced pluripotent cell (iPSC), or a derivative cell differentiated therefrom (i.e., claim 1); or a composition comprising a cell or population thereof and one or more therapeutic agents (i.e., claim 15); or said CAR (i.e., claim 67). In this instance, the CAR of claims 1, 15, and 67, section (i) of each claim do not require specific CDRs and therefore the binding domains encompass CARs with potential CDR mutations and/or substitutions relative to the claimed sequences, but neither the claims nor the specification define where the up to 20% mutation can occur that will maintain the claimed specificity; section (ii) of each claim is extraordinarily broad resulting in an extreme number of possibilities of SEQ ID NO: 36; section (iii) of each claim is more limited, but still results in a variety of potential sequences of SEQ ID NO: 36; section (iv) of each claim recites, “an amino acid sequence represented by any of SEQ ID NOs: 36-41” which limits the scope of the claim to comprising the full-length sequence or any portion of SEQ ID NOs: 36-41; and none of the sections provide a full-length structure of the CAR (i.e., binding domain-hinge region-transmembrane domain-signaling domain). Claims 2-11, 13-14, 16-19, and 68-83 are also rejected since they depend on claims 1, 15, or 67, but do not remedy this deficiency.
Specifically, claims 2 and 72 recite that the cell or population thereof further comprises one or more polynucleotides encoding an engager and optionally a CFR, which lack a definitive structure (i.e., SEQ ID NO or other method of identification) to envisage what an engager and a CFR encompasses, with exception of Figure 15, which shows a TCR-/- CAR T cell expressing a B73H CAR and a BiTE or TRiKE (i.e., Bispecific T cell engager or Tri-specific killer engagers, respectively specific to secondary TAAs) or said CART cell expressing a B73H CAR, said BiTE or TRiKE, and a surface triggering receptor for the BiTE (i.e., includes, but is not limited to a CFR) (¶000339). Furthermore, there is no evidence that any combination of bispecific/trispecific engager and optionally any vaguely defined CFR would enhance the tumor efficacy of a B7H3 CAR construct rather than interfere with the function.
Claims 3 and 73, recite that the engager comprises a first binding domain comprising specificity to any one of a long list of antigens and second binding domain having different specificity of the first binding domain or a cytokine or a variant of the first and second binding domain. In this instance, there is no evidence of the specific structures of the engager and instead the engager is defined by the antigen which the engager binds.
Claims 4 and 74, recite that the CFR comprises an ectodomain fused to a transmembrane domain, which is operatively connected to an endodomain and do not comprise any ER retention or endocytosis signals; however, the specification lacks an exemplary combination of structures defined by SEQ ID NOs or otherwise to envisage the structure and the function of the CFR (which is optional).
Claims 5 and 75, recite that the cell or population thereof further comprises one or more of: (i) CD38 knockout;… (vi) at least one of the genotypes of Table 1;….(viii) introduction of at least one of HLA-E,…antigen-specific TCR, Fc receptor, an antibody or functional variant or fragment thereof, a CPI, and surface triggering receptor (for example, a CFR, but not limited to a CFR) for coupling with an agonist, in comparison to its counterpart primary cell, which lacks support from the specification of the breadth of the cell or cell population further comprising one or more of (i)-(viii) as it appears only one of the combination of 130 potential genotypes of Table 1 (i.e., examples of genotypes inclusive of one or more of (i)-(viii)) was exemplified in Example 6. Furthermore, it is unclear what the scope of exogenous CD16 or a variant thereof of (iv) and an antibody or functional variant or fragment thereof of (viii) encompasses and the specification lacks support for these additional structures within the cell or population thereof. Dependent claims 7-8 and 77-78 are also rejected because they depend from claims 5 and 75, but do not remedy this deficiency.
In the instance of claims 6 and 76, which recite that the cell or a population thereof has therapeutic properties comprising one or more of: (i) increased cytotoxicity,…and (ix) ability to avoid fratricide, in comparison to its counterpart primary cell obtained from peripheral blood, umbilical cord blood, or any other donor tissues, there is no demonstration of the breadth of CAR structures which are able to function to increase cytotoxicity in comparison to its counterpart primary cell (i.e., only three CARs of specific structure are supported in the specification).
State of the relevant art:
In the instance of single domain antibodies, the formation of an intact antigen-binding site requires the association of three CDRs rather than the six present in conventional VH/VL antibodies (Henry, et al., MAbs, 2018, 10, 815-826, see entire document, specifically the abstract). Gordon teaches that the CDR3 loop contributes most to sdAb-antigen binding specificity and is typically longer than the CDR-H3 loop of a conventional antibody (Gordon, et al., Front Immunol, 2023, 14, 1-18, see entire document, specifically see p 2, col 1). Asaadi, et al., teach that the sdAbs evolved with an extra disulfide bond between CDR1, CDR2, or FR2, which in addition to the other structural features of a sdAb increases paratope diversity and allows for a wide variety of geometrical loop structures that deviate fundamentally from the canonical loop structures defined for conventional antibodies (Asaadi, et al., Biomarker Res, 2021, 9, 1-20, see entire document, specifically see p 3, col 1). Therefore, the specific combination of CDRs 1-3 affects structure within the sdAb and specific antigen binding. Thus, based upon the prior art, skilled artisans would reasonably understand that it is the organization of the three CDRs in a specific combination, in a single domain antibody, which gives rise to the functional property of antigen binding to in this instance, B7H3.
Furthermore, it is well-known in the art that the structure of a CAR minimally comprises an extracellular binding domain, linked to a transmembrane domain, and an endodomain, with structures spanning five or more structural generations, each becoming more technically evolved (Tokarew, et al., Br J Canc, 2019, 120, 26-37, see entire document, specifically see Fig 1). In addition to the B7H3 VHH binding domain not being fully defined by CDRs 1-3, the claimed CAR structures lack structural definition to function (i.e., transmembrane domain and endodomain structures). Accordingly, the skilled artisan would be unable to envisage the CAR that functions to bind B7H3 and function therapeutically thereof a priori given the current state of the CAR arts.
Artisans are well aware that knowledge of a given antigen (for instance a specific epitope of ADGRE2, CAIX, CCR1, etc. of claims 3 and 73) provides no information concerning the sequence/structure of antibodies that bind the given antigen. For example, Edwards et al. teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences spanning almost the entire heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines, and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well (Edwards, et al., J Mol Biol, 2003, 334, 103-118, see entire document). Goel et al. disclose the synthesis of three monoclonal antibodies that bind to the same short (12-mer) peptide and found that the sequences of these antibodies which bound the same epitope exhibited diverse V gene usage indicating their independent germline origin (Goel, et al., J Immunol, 2004, 173, 7358-7367, see entire document). Further, it should be noted that degenerate binding of the same structural motif by antibodies does not require the existence of sequence homology or identity at any of their CDRs or other chemical similarities at the antigen-binding sites; side chain mobility of epitope residues can confer steric and electrostatic complementarity to differently shaped combining sites, allowing functional mimicry to occur (Lescar et al., J Biol Chem, 1995, 270, 18067-18076, see entire document, in particular Abstract and Discussion). As such, it does not seem possible to predict the sequence/structure of an antibody that binds a given antigen as there does not appear to be any common or core structure present within all antibodies that gives rise to the function of antigen binding. Further, given data such as that of Edwards et al. indicating the diversity of sequences in a population of antibodies that bind to a given antigen, no number of species appears to reasonably represent the breadth of the genus of antibodies that bind the given antigen in the instant application.
Description of representative species in the specification:
MPEP § 2163 states that “a representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., 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.
To support such broad claims, the specification teaches three CARs, wherein the binding region is a single domain anti-B7H3 (i.e., camB7H3) and the transmembrane, costimulatory and signaling domains are NKG2D-2B4-CD3z, respectively, and the hinge between the VHH and transmembrane domain is varied (i.e., short, medium, and long sequence lengths) shown in Example 6 and Figure 8 (¶000334-000335). In this instance, the short and medium hinge region sequence length performed better than the long sequence, however all three CARs were able to induce cytotoxicity (¶000335). However, given the immense breadth of the claims and the depth and diversity of the CAR repertoire as described above, such a disclosure would not reasonably be considered representative of the genus: a CAR, which is only described by its binding target.
Identifying characteristics and structure/function correlation:
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.
In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted:
“A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”
The court has further stated that “Adequate written description requires a precise definition, such as by structure, formula, chemical name or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.” Id. at 1566, 43 USPQ2d at 1404 (quoting Fiers, 984 F.2d at 1171, 25 USPQ2d at 1606). Also see Enzo-Biochem v. Gen-Probe 01-1230 (CAFC 2002). Recent court cases have emphasized the need for correlation between a well-defined structure and recited functional limitations. For example, the courts have indicated that recitation of an antibody which has specific functional properties in the absence of knowledge of the antibody sequences that give rise to said functional properties do not satisfy the requirements for written description. See for example AbbVie Deutschland GmbH v. Janssen Biotech. Inc. 759 F.3d 1285 (Fed. Cir. 2014) as well as Amgen v. Sanofi, (Fed Cir, 2017-1480. 10/5/2017). In Amgen v. Sanofi, the court indicates that that it is improper to allow patentees to claim antibodies by describing something that is not the invention, i.e., the antigen, as knowledge of the chemical structure of an antigen does not give the required kind of structure-identifying information about the corresponding antibodies, with the antibody-antigen relationship be analogized as a search for a key on a ring with a million keys on it. As such, knowledge of where an antibody binds provides no information as to what such an antibody necessarily looks like (i.e., its primary amino acid structure).
It should also be noted that the USPTO has released a Memo on the Clarification of Written Description Guidance For Claims Drawn to Antibodies and Status of 2008 Training Materials, 02/22/2018. See https://www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf. This Memo clarifies the applicability of USPTO guidance regarding the written description requirement of 35 U.S.C. § 112(a) concerning the written description requirement for claims drawn to antibodies and states: “In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional.” Further, the courts have indicated that the enablement and written description requirements of 35 USC 112 are separable as can be seen in for example Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111.
To meet this requirement in the instant case, the specification must describe structural features that the skilled artisan as of the effective filing date would have expected to convey the claimed B7H3 binding activity.
The specification discloses SEQ ID NOs: 36-41, but because of the variability recited in claims 1, 15, and 67, without defining three CDRs for the anti-B7H3 VHH binding domain, the specification lacks structural features that the skilled artisan as of the effective filing date would function appropriately.
Claim analysis:
In this instance, the prior art supports three defined CDRs for a VHH binding domain, and defined structures for the engager and the surface triggering receptor. As presently written, the claims recite that up to 20% mutation of SEQ ID NOs: 36-41 inclusive of CDRs functions to bind B7H3 and with any transmembrane or signaling domain functions as a therapeutic CAR T cell. However, the specification and the working examples fail to disclose any data indicating that the breadth of structures (i.e., mutations within the CDRs, substitutions within SEQ ID NO: 36, overall CAR structures, etc.) encompassed by the language of the instant claims will have the same function (i.e., bind B7H3 and effectively induce cytotoxicity with any CAR components). Therefore, as presently written, the claimed broad genus of a cell population comprising a polynucleotide which encodes a CAR or said CAR lacks adequate written description because there does not appear to be any correlation between the structure of the up to 20% mutations of SEQ ID NOs: 36-41 inclusive of the CDRs combined with any combination of CAR construct components and the ability to bind B7H3 and effectively induce cytotoxicity. Thus, one of ordinary skill in the art would reasonably conclude that the applicant was not in possession of the full breadth of the claimed genus of a cell or population thereof comprising a polynucleotide that encodes a CAR or said CAR that bind to B7H3 and induces cytotoxicity at the time the instant application was filed.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 5-6, 9, 14-19, 67, 69-70, 75-76, and 79 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US 2023/0203166 A1 (Felices, et al., Provisional Application No. 63/033989, filed 03JUN2020, which includes the specific sequences that bind B7H3), herein referred to as “’166.”
‘166 teaches CARs that bind B7H3 (i.e., the binding domain of SEQ ID NO: 2 is 100% query match to SEQ ID NO: 36 of the instant application, see OA.APPENDIX and genotype 1 of Table 1), methods of use, and methods of making (see entire document, ¶0003, ¶0033). The immune cell is a T cell or NK cell (¶0006) and the NK cell engager domain may include anti-PD1/PDL1, and/or any other inhibition blocking domain (¶0064). The nucleic acid constructs may be introduced into a host cell to be altered thus allowing expression of the chimeric protein within the T cell or NK cell, thereby generating a genetically engineered cells (i.e., introduced following differentiation) (¶0083-0085). The cell population of NK cells expressing the CAR may be stimulated and expanded in vivo for administration and treatment (¶0096).
Therefore, the prior art anticipates the invention as presently claimed.
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.
Claims 2-3, 13, 68, 71-73, and 83 are rejected under 35 U.S.C. 103 as being unpatentable over US 2023/0203166 A1 (Felices, et al., Provisional Application No. 63/033989, filed 03JUN2020), herein referred to as “’166” as applied to claims 1, 5-6, 9, 14-19, 67, 69-70, 75-76, and 79 and in further view of US 2021/0038646 A1 (Maus, et al., PCT/US2019/017727 filed 12FEB2019), herein referred to as “’646.”
The teachings of ‘166 are summarized above.
However, they do not teach: wherein the cell or population thereof further comprises one or more polynucleotides encoding an engager; or wherein the engager comprises a first and second binding domain (i.e., ADGRE2, CAIX, CCR1, CEA, CD3, …EGFRvIII, ERB-B2, ERB-B3, ERB-B4, EGFR, etc.) that are not B7H3 and are not the same or comprises a cytokine or a variant thereof between the first and second binding domains; or wherein the iPSC is a clonal iPSC, a single cell dissociated iPSC,…or wherein the derivative cell comprises a derivative CD34+ cell,…a derivative T lineage cell,…or a derivative effector cell having one or more functional features that are not present in a counterpart primary T, NK, NKT, and/or B cell; or wherein the CAR further comprises a hinge peptide that comprises no more than 80 amino acids, between 80-180 amino acids, or no more than 229 amino acids.
Nevertheless, ‘646 teaches an immune cell engineered to express (a) CAR polypeptide including an extracellular domain, including a first and second antigen binding domain and (b) a BiTE, wherein the BiTE binds to a target antigen and a T cell antigen, pharmaceutical compositions including the immune cell and treating a subject with cancer (see entire document, specifically see abstract section). Specifically, ‘646 teaches that a CAR T cell that secretes an immune-modulating antibody, such as a BiTE enhances the efficacy of CAR T cells within tumor microenvironments (e.g., to overcome immune regulation by Tregs), can be used to complement one another, and protect against tumor progression via antigen escape (¶0368, ¶0409, and ¶0411). Furthermore, the hinge/transmembrane domain of an immunoglobulin like protein, CD28, CD8, or 4-1BB may be used, for example any one of SEQ ID NOs: 4,10, 16, 22, 28, etc. (i.e., SEQ ID NOs: 4, 10, 16, 22, and 28 are all less than 80 amino acids in length) (¶0247). Regarding the BiTE, ‘646 further teaches that the BiTE target antigen is a glioblastoma-associated antigen selected from one of EGFR, EGFRvIII, CD19, CD79b, CD37, PSMA,…HER2, etc. and the T cell antigen is CD3 (e.g., the first binding site could be EGFRvIII and the second binding site could be CD3 for the BiTE construct) (¶0020). Additionally, ‘646 teaches that the CAR may be expressed in naïve T cells, central memory T cells, effector memory T cells or combinations thereof (i.e., derivative T lineage cells or derivative cells after pluripotent stem cell differentiation) (¶0221), and that CARs with BiTES promoted expansion/enrichment of the less differentiated central memory T cells (¶0409).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the CAR constructs that bind B7H3 (i.e., the binding domain of SEQ ID NO: 2 is 100% query match to SEQ ID NO: 36 of the instant application, see OA.APPENDIX) disclosed by ‘166 by further expressing a BiTE that binds to a target antigen and a T cell antigen, wherein the target antigen is a glioblastoma-associated antigen selected from one of EGFR, EGFRvIII, CD19, CD79b, CD37, PSMA,…HER2, etc. and the T cell antigen is CD3, or wherein the CAR is expressed in a naïve T cell, central memory T cell, effector memory T cell or combinations thereof, disclosed by ‘646. This is because a CAR T cell that secretes an immune-modulating antibody, such as a BiTE enhances the efficacy of CAR T cells within tumor microenvironments (e.g., to overcome immune regulation by Tregs), can be used to complement one another, and protect against tumor progression via antigen escape and because CARs with BiTES promoted expansion/enrichment of the less differentiated central memory T cells. One would have been motivated to do so, given the teachings of ‘646 that a CAR T cell which also expresses a BiTE (i.e., engager) enhances the efficacy of cancer therapy. There would have been a reasonable expectation of success, given the knowledge that a CAR T cell which also expresses a BiTE protects against tumor progression via antigen escape, as taught by ‘646.
Thus, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time of filing.
Claims 10-11 and 80-82 are rejected under 35 U.S.C. 103 as being unpatentable over US 2023/0203166 A1 (Felices, et al., Provisional Application No. 63/033989, filed 03JUN2020), herein referred to as “’166” as applied to claims 1, 5-6, 9, 14-19, 67, 69-70, 75-76, and 79 and in further view of Eyquem, et al., (Nature, 2017, 543, 113-117), herein referred to as “Eyquem.”
The teachings of ‘166 are summarized above.
However, they do not teach: wherein the derivative cell comprises one or more exogenous polynucleotides integrated in a safe harbor locus or a selected gene locus; or more than two exogenous polynucleotides integrated in different safe harbor loci or two or more selected gene loci; or wherein the safe harbor locus comprises at least one of AAVS1, CCR5,…; and/or wherein the integration of the exogenous polynucleotides knocks out expression of the gene in the locus; or wherein the TCR locus is a constant region of the TRAC and/or TRBC.
Nevertheless, Eyquem teaches genome editing via CRISPR/Cas9 to enable efficient sequence-specific interventions in human cells, including targeted gene delivery to the CCR5 and AAVS1 loci and in this instance by specifically disrupting the TRAC locus by placing a CAR resulted in uniform CAR expression in T cells and enhanced potency (see entire document, specifically see p 113, col 1 and 2 and Fig 1a). Furthermore, they were able to show that the modification resulted in precise and targeted insertion without altering the T cells native machinery (p 113, col 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the CAR constructs that bind B7H3 (i.e., the binding domain of SEQ ID NO: 2 is 100% query match to SEQ ID NO: 36 of the instant application, see OA.APPENDIX) disclosed by ‘166 by utilizing a CRISPR/Cas9 for specific gene editing of safe harbor locus disclosed by Eyquem because by knocking out for instance TRAC and replacing it with a CAR resulted in uniform CAR expression in T cells and enhanced potency. One would have been motivated to do so, given the teachings of Eyquem that safe harbor locus gene editing has resulted in precise and targeted insertion without altering the T cells native machinery. There would have been a reasonable expectation of success, given the knowledge that precisely knocking out TRAC would lead to a more uniformly expressed CAR that was more potent than conventionally generated CARs, as taught by Eyquem.
Thus, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time of filing.
Claims 4, 7, 74, and 77 are rejected under 35 U.S.C. 103 as being unpatentable over US 2023/0203166 A1 (Felices, et al., Provisional Application No. 63/033989, filed 03JUN2020), herein referred to as “’166” as applied to claims 1, 5-6, 9, 14-19, 67, 69-70, 75-76, and 79 and in further view of Kudo, et al., (Canc Res, 2014, 74, 93-103), herein referred to as “Kudo.”
The teachings of ‘166 are summarized above.
However, they do not teach: wherein the exogenous CD16 or a variant thereof comprises at least one of: (a) a high affinity non-cleavable CD16, ….; and (h) transmembrane, signaling, and stimulatory domains that are not originated from CD16 and are originated from a same or different polypeptide.
Nevertheless, Kudo teaches transfection of a high-affinity CD16 V158 variant, CD8α hinge/transmembrane domain, and CD3 and 4-1BB signaling domains (i.e., exogenous CD16 with transmembrane/signaling domains that are not originated from CD16 and are originated from different polypeptides) for effective ADCC mediated cancer cell killing and as a potential universal (i.e., off the shelf) T cell therapy (see entire document, specifically abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the CAR constructs that bind B7H3 (i.e., the binding domain of SEQ ID NO: 2 is 100% query match to SEQ ID NO: 36 of the instant application, see OA.APPENDIX) disclosed by ‘166 by incorporating a secondary CD16 receptor structure to improve ADCC induced cancer cell killing disclosed by Kudo. One would have been motivated to do so, given the teachings of Kudo that by incorporating a high affinity CD16 receptor allows for a potential universal T cell, which would be obvious to further modify. There would have been a reasonable expectation of success, given the knowledge that incorporation of an exogenous CD16 receptor lead to an effective T cell therapy.
Thus, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time of filing.
Claims 8 and 78 are rejected under 35 U.S.C. 103 as being unpatentable over US 2023/0203166 A1 (Felices, et al., Provisional Application No. 63/033989, filed 03JUN2020), herein referred to as “’166” as applied to claims 1, 5-6, 9, 14-19, 67, 69-70, 75-76, and 79 and in further view of Batra, et al., (Canc Immunol Res, 2020Mar, 8, 309-320), herein referred to as “Batra.”
The teachings of ‘166 are summarized above.
However, they do not teach: wherein the cell surface expressed exogenous cytokine or receptor thereof: (a) comprises at least one of IL2, IL4,…IL15, IL18, IL21, and its respective receptor(s);…; and optionally, (d) is transiently expressed.
Nevertheless, Batra teaches a CAR T cell which co-expresses IL15 and IL21, promotes T cell expansion, survival and function and improves antitumor properties of T cells (see entire document, specifically abstract). Specifically, Batra teaches that incorporation of IL15 and IL21 in a CAR T cell resulted in effective in vitro and in vivo expansion and persistence and provided the most robust antitumor activity in vivo (see abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the CAR constructs that bind B7H3 (i.e., the binding domain of SEQ ID NO: 2 is 100% query match to SEQ ID NO: 36 of the instant application, see OA.APPENDIX) disclosed by ‘166 by co-expressing IL15 and IL21 in the CAR T cell disclosed by Batra. One would have been motivated to do so, given the teachings of Batra that by incorporating IL15 and IL21 in a CAR T cell, promotes T cell expansion, survival and function and improves antitumor properties of CAR T cells. There would have been a reasonable expectation of success, given the knowledge that incorporation of IL15 and IL21 in a CAR T cell lead to effective in vitro and in vivo expansion and persistence and provided the more robust antitumor activity in vivo.
Thus, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time of filing.
Conclusion
No claims are allowed.
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/SAMANTHA LAKE HOPKINS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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