DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The claim listing filed July 17, 2023 is pending.
Claims 2, 4, 6-8, 15-17, 19, 20, 23, 24, 35, 37, 45, 46, 48, 50, 51, 54, 59, and 84-90 are canceled.
Claims 1, 3, 5, 9-14, 18, 21, 22, 25-34, 36, 38-44, 47, 49, 52, 53, 55-58, and 60-83 are pending.
Claims 1, 34, and 71 are independent claims.
Election/Restriction
The Applicant’s election without traverse to Invention I (claims 1, 3, 5, 9-14, 18, 21, 22, 25-34, 36, 38-44, 47, 49, 52, 53, 55-58, 60-77 and 83, drawn to a polynucleotide encoding a chimeric polypeptide comprising an extracellular domain, a transmembrane domain, and one or more intracellular domains, a vector, engineered immune cells, a method of making an engineered immune cell, a chimeric polypeptide, a population of cells, and a composition); and the species of SEQ ID NO: 75 as the single chimeric polypeptide, a DLL3 CAR as the single CAR of the single engineered immune cell, and a T cell as the single engineered immune cell in the reply filed on May 8, 2026 is acknowledged.
Claims 3, 5, 13, 14, 18, 21, 22, 27, 28, 36, 38, 43, 44, 47, 49, 52, 53, 56, 60, 69, 70, and 78-82 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Claims 1, 9-12, 25, 26, 29, 30-34, 39-42, 55, 57, 58, 61-68, 71-77, and 83 are currently under consideration.
Claim Interpretation
It is noted that the Applicant’s elected species of a single chimeric polypeptide as SEQ ID NO: 75 comprises a wildtype PD-1 extracellular domain (SEQ ID NO: 9), a truncated CD28 extracellular domain (SEQ ID NO: 16) as the hinge region, a wildtype CD28 transmembrane domain (SEQ ID NO: 17), and a wildtype CD28 intracellular signaling domain (SEQ ID NO: 18). It is further noted that the chimeric polypeptide of SEQ ID NO: 75 does not comprise a signal peptide.
Claim Objections
Claims 26 is objected to because of the following informalities:
Claims 26 recites “optionally the polypeptide further comprises a signal peptide” where it should recite “optionally wherein the polypeptide further comprises a signal peptide” in lines 3 and 4.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
Indefinite Language
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 25, 26, 32, 57, 58, 64-68, and 72-77 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.
Claims 25, 26, 57, and 58 recite “the polypeptide” in lines 1 or 2. Claims 25 and 26 depend on claim 1 and claims 57 and 58 depend on claim 34. Claims 1 and 34 only recite “a chimeric polypeptide” not “a polypeptide.” Therefore, the limitation of “the polypeptide” in claims 25, 26, 57, and 58 lacks antecedent basis and renders the claims indefinite.
Amending claims 25, 26, 57, and 58 to recite “the chimeric polypeptide” instead of “the polypeptide” would obviate this part of the rejection.
Claim 32 recites “the vector” in line 2. Claim 32 depends on claim 31 which recites “a vector.” However, claim 32 recites “the vector” and “a viral vector” in line 1. Therefore, it is unclear which vector the limitation of “the vector” in line 2 of claim 32 is referring to. Therefore, the limitation of “the vector” in line 2 of claim 32 lacks antecedent basis and renders the claims indefinite.
Amending claim 32 to recite “the viral vector” in line 2 would obviate this part of the rejection.
Claims 64, 67, and 73-77 recite “the cell,” “the immune cell,” or “cells” in lines 1 or 2. Claims 64 and 73-77 depend on claim 63 and claim 67 depends on claim 64. Claim 63 recites “an engineered immune cell” bur not “a cell,” “an immune cell,” or “cells.” Therefore, the limitations of “the cell,” “the immune cell,” or “cells” in claims 64, 67, and 73-77 lack antecedent basis and render the claims indefinite.
Amending claims 64, 67, and 73-77 to recite “the engineered immune cell” instead of “the cell,” “the immune cell,” or “cells” would obviate this part of the rejection.
Claim 68 recites “wherein the CCR is constitutively active or inducible” in lines 1 and 2. However, a skilled artisan would readily recognize that a protein itself cannot be constitutively active or inducible only its expression from a particular gene can be. In fact, the Applicant defines a promoter as an "expression control sequence" or a nucleic acid sequence that directs transcription of a nucleic acid (e.g. see [0093]). Furthermore, the Applicant discloses that the promoter can be a constitutive or an inducible promoter which is operably linked to the nucleic acid sequence to be transcribed (e.g. see [0093]).
Therefore, claim 68 is indefinite because it is unclear how the CCR, which is a protein, can be
constitutively active or inducible. A skilled artisan would readily recognize that only the gene which encodes the CCR could be constitutively active or inducible, not the protein itself.
Amending claim 68 to recite “wherein expression of the CCR is constitutively active or inducible” in lines 1 and 2 would obviate this part of the rejection.
Claim 72 recites “wherein the engineered immune cell comprises or expresses a polypeptide comprising the amino acid sequence of SEQ ID NO: 74, with or without the signal peptide” in lines 1-3. Claim 72 depends on claim 71 which is drawn to a engineered immune cell comprising or expressing a DLL3 CAR that comprises the amino acid sequence of SEQ ID NO: 73 or 165, and a CCR that comprises the amino acid sequence of SEQ ID NO:162. Furthermore, it is noted that SEQ ID NO: 74 comprises SEQ ID NOs: 73, 162, and 165. SEQ ID NOs: 73 and 165 comprise identical DLL3 Car amino acid sequences, however, SEQ ID NO: 73 also comprises an N-terminal CD8 signal sequence (e.g. see table 3).
Thus, it is unclear if the “polypeptide” of claim 72 is in addition to the proteins already recited in claim 71 or if the “polypeptide” is meant to comprise the proteins already recited in claim 71.
Amending claim 72 to recite “wherein the engineered immune cell further comprises or expresses a polypeptide comprising the amino acid sequence of SEQ ID NO: 74, with or without the signal peptide” would obviate this part of the rejection.
Written Description
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 that 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 that 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 1, 9-12, 25, 26, 29, 30-34, 39-42, 55, 57, 58, 61-68, 73-77, and 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 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.
In view of the Applicant’s species election (see claim interpretation above), the instant claims are drawn to (1) a polynucleotide encoding a chimeric polypeptide and (2) a chimeric polypeptide comprising an extracellular domain, a transmembrane domain, and one or more intracellular domains, wherein the extracellular domain comprises a PD-1 extracellular domain, and optionally wherein the PD-1 extracellular domain comprises the amino acid sequence of SEQ ID NO:9; and (3) an engineered immune cell comprising or expressing a DLL3 CAR that comprises the amino acid sequence of SEQ ID NO: 73 or 165, and a CCR that comprises the amino acid sequence of SEQ ID NO:162.
The Applicant’s invention is drawn to chimeric switch receptors (CSRs) which can be fusion proteins comprising an ectodomain and/or transmembrane domain derived from an inhibitory receptor (e.g. PD1 or TGFbR2) fused to the transmembrane domain and/or intracellular signaling domain derived from one or more costimulatory proteins (e.g. CD2, CD28, MyD88, DAP10 or ICOS) (e.g. see [0006] and [0216]). Chimeric switch receptors can compete with endogenous inhibitory receptors (e.g. PD1 or TGFbR) for ligand binding to subvert immunosuppression, and transmit a costimulatory signal in PDL1/2- or TGFb-enriched environments (e.g. see [0216]).
Individual intracellular costimulatory domains may be optimized to reduce vector cargo size and/or enhance or modulate functional activity by the removal of non-signaling intervening sequences or negative regulatory sequences (e.g. CD2short) or by mutating key residues involved in signal transduction (e.g. CD28.YMFM and CD28.AYAA, which are amino acid substitution variants from YMNM and PYAP of the CD28 intracellular domain, respectively) (e.g. see [0220]).
The Applicant has disclosed several chimeric polypeptides that comprise a wildtype PD-1 extracellular domain (SEQ ID NO: 9) all of which comprise only one intracellular signaling domain, specifically costimulatory domains (e.g. see Figure 1A). The specific amino acid sequences of the chimeric polypeptides that comprise a wildtype PD-1 extracellular domain include SEQ ID NOs: 75-83 (e.g. see pages 60 and 61 of Table 3).
All of SEQ ID NOs: 75-83 comprise only one intracellular signaling domain, such as the costimulatory domains WT CD28 (SEQ ID NO: 18), CD28.YMFM (SEQ ID NO: 19), CD28.AYAA (SEQ ID NO: 20), CD2 full (SEQ ID NO: 13), CD2 short (SEQ ID NO: 24), WT DAP10 (SEQ ID NO: 27), WT ICOS (SEQ ID NO: 29), WT CD40 (SEQ ID NO: 31), or WT OX40 (SEQ ID NO: 33) (e.g. see pages 60 and 61 of Table 3). Furthermore, the transmembrane domains of the chimeric polypeptides of SEQ ID NOs: 75-83 are either WT CD28 (SEQ ID NO: 17), WT CD2 (SEQ ID NO: 22), the D57N DAP10 mutant (SEQ ID NO: 26), WT ICOS (SEQ ID NO: 28), WT CD40 (SEQ ID NO: 30), or WT OX40 (SEQ ID NO: 31). It is further noted that only the chimeric polypeptides of SEQ ID NOs: 75-80 comprise a hinge domain wherein the hinge domains are either a truncated CD28 ECD (SEQ ID NO: 16), truncated CD2 ECD (SEQ ID NO: 21), or DAP10 ECD (SEQ ID NO: 25). The chimeric polypeptides of SEQ ID NOs: 81-83 do not comprise hinge domains (e.g. see pages 60 and 61 of Table 3).
Regarding the claims that are drawn to a CAR, the Applicant has only disclosed two CARs, 2G1 (SEQ ID NO: 73 (with CD8 signal peptide) and SEQ ID NO: 165 (without CD8 signal peptide)), which is an anti-DLL3 CAR (e.g. see pages 59 and 60 of Table 3), and an anti-CD70 CAR (SEQ ID NO: 178 (without safety switch) and SEQ ID NO: 178 (with safety switch)) (e.g. see pages 65 and 66 of Table 3).
When given the broadest reasonable interpretation in light of specification, (1) the chimeric polypeptides of the instant invention are defined broadly to be any chimeric polypeptide comprising any PD-1 extracellular domain, any transmembrane domain, and any number of any intracellular domains; and (2) the engineered immune cells of the instant invention are defined broadly to be any engineered immune cell comprising the chimeric polypeptide of claim 34 and any CAR that comprises any intracellular signaling domain comprising any number of a CD3𝞯 signaling domain, a CD28 signaling domain, and a 4-1 BB signaling domain (claim 65), or any CAR that comprises any extracellular ligand-binding domain specifically recognizes or binds to DLL3 (claim 66).
It is noted that the broadest claims do not recite sufficient structure for the genera of chimeric polypeptides comprising a PD-1 extracellular domain, a transmembrane domain, and one or more intracellular domains (claims 1 and 34) or for the genera of engineered immune cells that comprise a CAR comprising any one or more of a CD3𝞯 signaling domain, a CD28 signaling domain, and a 4-1 BB signaling domain (claim 65) or an extracellular ligand-binding domain specifically recognizes or binds to DLL3 (claim 66).
While independent claims 1 and 34 appear to recite sufficient structure (SEQ ID NO: 9) for the PD-1 extracellular domain, this is only within an “optionally” clause, meaning, that the PD-1 extracellular domain is not necessarily required to have that structure.
Dependent claims 9 and 39 limit the one or more intracellular domains to that which comprises one or more intracellular signaling domains, optionally wherein the one or more intracellular signaling domains is a CD28 intracellular signaling domain.
Dependent claims 10 and 40 limit the one or more intracellular domains to that which comprises the amino acid sequence of SEQ ID NO: 18.
Dependent claims 11 and 41 limit the transmembrane domain to that which comprises a CD28 transmembrane domain.
Dependent claims 12 and 42 limit the transmembrane domain to that which comprises SEQ ID NO: 17.
Dependent claims 25 and 57 limit the chimeric polypeptide to that which further comprises a hinge domain located between the extracellular domain and the transmembrane domain.
Dependent claims 26 and 58 limit the chimeric polypeptide to that which comprises SEQ ID NO: 75 or an amino acid sequence that is at least 90% identical to SEQ ID NO: 75.
Dependent claim 55 limits the transmembrane domain to that which comprises a CD28 transmembrane domain, optionally wherein the CD28 transmembrane domain comprises the amino acid sequence of SEQ ID NO: 17 or an amino acid sequence that is at least about 90% identical to the amino acid sequence of SEQ ID NO: 17.
It is noted that independent claim 71 and dependent claim 72 recite sufficient structure for the anti-DLL3 and the CCR and are therefore not included in this part of the rejection.
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by reduction to drawings, or 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 genus (Federal Register, Vol. 66, No. 4, pages 1099-1111, January 5, 2001, see especially page 1106 column 3). 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.”
Rane et al. 2025 (Front. Immunol. 16:1662238, 1-13) teach that while CAR T cell therapy has shown remarkable clinical success, particularly in hematological malignancies, its efficacy in solid tumors remains limited due to multiple challenges, including antigen heterogeneity, physical barriers, and most notably, the immunosuppressive tumor microenvironment (TME) that inhibits T cell activation and function (e.g. see page 2, left column, first paragraph). One promising strategy to overcome these limitations involves chimeric switch receptors (CSRs), engineered receptors that convert inhibitory signals into activating ones within the TME (e.g. see page 2, paragraph spanning left and right columns). Under physiological conditions, immune checkpoint receptors such as PD-1 serve as negative regulators of T cell activity by engaging ligands like PD-L1, thereby maintaining immune homeostasis and preventing autoimmunity. Many solid tumors exploit these pathways by upregulating such ligands, leading to chronic inhibitory signaling, T cell exhaustion, and diminished anti-tumor responses. CSRs counteract this suppression by fusing the extracellular domains of inhibitory receptors with intracellular signaling domains of costimulatory molecules like cluster of differentiation 28 (CD28) and 4-1BB (CD137). This design enables T cells to transform immunosuppressive signals into costimulatory cues, thereby enhancing T cell activation and persistence in the hostile TME (e.g. see page 2, paragraph spanning left and right columns).
Regarding the structure of the PD-1 extracellular domain of a CSR, Zak et al. 2015 (Structure 23, 2341–2348) teach that the protein interaction hotspot of PD-1 for proper binding to PD-L1 are mostly hydrophobic and comprises Asn66, Tyr68, Gly124, Ile126, Leu128, Ile134, and Glu136 located in the front sheet of hPD-1 (e.g. see page 2345, right column, second paragraph). The most distinctive feature of this segment is the hydrophobic cleft at Gly124. The interface here relies on the steric complementarity between the PD-1 cleft and the hydrophobic face of the hPD-L1 and, in particular, on LTyr123, which inserts deep in the Gly124 cleft. With the aromatic ring of Tyr68 on one side and the backbone of Glu136 on the other side of the groove, the cleft is a perfect spot for anchoring an aromatic ring (e.g. see page 2345, right column, second paragraph).
Thus, based upon the prior art, skilled artisans would reasonably understand that these interaction hotspots are essential for proper binding to PD-L1 and in turn proper CSR function.
This applies to the instant invention which is drawn to genera of chimeric polypeptides that comprise any PD-1 extracellular domain.
Regarding CSRs and CARs with any number of intracellular signaling domains, the art does not teach CARs with more than three intracellular domains (one CD3𝞯 intracellular signaling domain and up to two costimulatory domains) (e.g. see Weinkove et al. 2019. Clin Transl Immunol, 8(e1049), 1-14, Figures 3A-E) and the art does not teach CSRs with more than two intracellular, specifically costimulatory, domains (Rane et al. 2025. Front. Immunol. 16:1662238, 1-13, Figures 2 and 3).
Regarding the claims drawn to any CD28 intracellular signaling domain structure (claims 9, 39, and 65), Esensten et al. 2016 (Immunity 44, 5, 973-988) teach that CD28 engagement by ligands initiates signal transduction events that are dependent on specific associations of proteins with the cytoplasmic tail of CD28 (e.g. see page 975, right column, first column and Figure 1). Despite having no intrinsic enzymatic activity, the 41 amino acid cytoplasmic tail of human CD28 contains highly conserved tyrosine-based signaling motifs that are phosphorylated in response to TCR or CD28 stimulation and bind targets with SH2 domains in a phosphotyrosine-dependent manner. Proline-rich sequences within the cytoplasmic tail also bind SH3-domain-containing proteins. In particular, the membrane proximal YMNM motif and the distal PYAP motif have been shown to complex with several kinases and adaptor proteins, and some proteins are able to bind to either or both motifs via SH2 and/or SH3 domain interactions. These motifs are important for IL2 transcription, which is mediated by the CD28-dependent activation of NFAT, AP-1, and NF-κB family transcription factors (e.g. see page 975, right column, first column and Figure 1).
Regarding the claims being drawn to any transmembrane domain structure, Bernard and Evgin 2025 (Front. Immunol. 16:1664403, 1-9) teach that not only are transmembrane domains actively involved in regulating surface expression, but they are also capable of mediating interactions with endogenous proteins (e.g. see page 5, right column, second paragraph). For example, CARs with a CD28 transmembrane domain, but not those with a CD8α transmembrane domain, were shown to heterodimerize with endogenous CD28, which elicited CAR-dependent proliferation. This phenomenon was attributed to four polar amino acids found in the CD28 transmembrane domain, and disruption of these amino acids abrogated the interaction (e.g. see page 5, right column, second paragraph). Bernard and Evgin also teach that the hinge/transmembrane domain can tune the threshold for antigen recognition to enhance efficacy against antigen low targets. Bernard and Evgin also teach that previous studies propose that selecting CARs with reduced cytokine release profiles, a property that has in part been attributed to the transmembrane domain, may represent a favorable design strategy (e.g. see page 6. Left column, second paragraph).
Regarding the claims being drawn to any hinge domain structure, Bernard and Evgin teach that the properties of the hinge, including its identity and length, shape how the CAR responds to antigen density and epitope position, ultimately affecting sensitivity and signaling strength (e.g. see page 3, right column, second paragraph).
The hinge domain retains features of the native molecule, which affect the functional properties of the CAR. (e.g. see paragraph spanning pages 3 and 4). For example, CD28 typically exists as a homodimer due to an interdomain disulfide bond and the critical cysteine at position 123 is incorporated into the CAR hinge domain. A series of CD19 FMC63-based CARs incorporating various hinge and transmembrane domains identified that the cysteine in the CD28 hinge domain can stabilize a heterodimer of the CAR and endogenous CD28 (e.g. see paragraph spanning pages 3 and 4).
The length of the hinge also contributes to the overall functionality of a CAR in an antigen- and epitope-specific manner (e.g. see paragraph spanning pages 4 and 5). Given the implications on activation, together with knowledge of the target epitope location and antigen density, the length of the hinge can be manipulated to fine-tune CAR sensitivity (e.g. see page 5, left column, second paragraph). The selection of shorter hinges can promote antigen-driven activation of CARs targeting membrane distal epitopes. Conversely, shortening the hinge length is a useful method to attenuate the activation of a CAR targeting a membrane-proximal epitope of an overexpressed but not cancer-specific antigen. Other structural or steric factors, such as restricted flexibility or suboptimal binding domain orientation when the hinge is too short, may influence activation (e.g. see page 5, left column, second paragraph).
Ultimately, Bernard and Evgin teachings underscore that there is not a one-size-fits-all approach to hinge engineering and that optimization is required for each CAR (e.g. see page 5, paragraph spanning left and right columns). Nonetheless, understanding the properties of the binding domain (i.e. affinity, oligomerization propensity), the position of the target epitope on the antigen and its proximity to the membrane, as well as overall antigen density may help to predict a ‘goldilocks’ hinge identity and length (e.g. see page 5, paragraph spanning left and right columns).
Taken together, the art cited above ultimately teaches that: (1) CSRs do not comprise more than two intracellular, specifically costimulatory, domains (Rane et al.); (2) CARs do not comprise more than three intracellular domains, specifically, one CD3𝞯 intracellular signaling domain and up to two costimulatory domains (Weinkove et al.); (3) a CD28 intracellular signaling domain minimally requires its 41 amino acid cytoplasmic tail comprising the membrane proximal YMNM motif and the distal PYAP motif for proper functionality (Esensten et al.); and (4) there is not a one-size-fits-all approach to hinge and transmembrane domain engineering and that optimization is required for each specific CAR (Bernard and Evgin).
Although the last two points were made in the context of a CAR, given the similarities in the hinge, transmembrane, and intracellular domain structure and function between CARs and CSRs, a skilled artisan would readily recognize that these teachings would also be applicable to CSR structure.
These teachings apply to the instant invention which is drawn to genera and subgenera of CSRs and CARs that comprise any transmembrane domain and any number of any intracellular domains.
Regarding claim 66 which is drawn to an anti-DLL3 CAR, it is well known that antigen binding domains of CARs fall in three general categories, either single chain variable fragments (scFvs) derived from antibodies, Fab’s selected from libraries, or natural ligands that engage their cognate receptor (e.g. see Sadelain et al. Cancer Discov. 2013;3(4):388–398, page 389, left column, second paragraph under “CAR TARGETING”). Successful examples in each of these categories have been reported. scFvs derived from murine immunoglobulins are commonly used, as they are easily derived from well-characterized monoclonal antibodies. They, however, may prove to be more immunogenic than Fab’s derived from human libraries or invariant human ligands (e.g. see Sadelain et al. Cancer Discov. 2013;3(4):388–398, page 389, left column, second paragraph under “CAR TARGETING”).
Given that CARs generally comprise antibody-derived antigen binding domains, the following argument still applies to the instant invention. Artisans are well aware that knowledge of a given antigen (for instance DLL3) provides no information concerning the sequence/structure of CARs that bind the given antigen. For example, Edwards et al. (J. Mol. Biol., 2003, 334:103-118) 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, see entire document).
As such, it does not seem possible to predict the sequence/structure of a CAR that binds a given antigen, as there does not appear to be any common or core structure present within all antigen binding molecules 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 representative of the breadth of the genus of antibodies or antigen binding molecules that bind the given antigen.
It should be pointed out that it is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antigen binding molecule to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (Janeway Jr et al., Immunology, 3rd Edition, 1997 Garland Publishing Inc., pages 3:1-3:11.see entire selection).
Thus, based upon the prior art, skilled artisans would reasonably understand that it is the structure of the CDRs within CAR which gives rise to the functional property of antigen binding, the epitope to that which said CDRs bind is an inherent property which appears to necessarily be present due to conservation of critical structural elements, namely the CDR sequences themselves.
This applies to the instant invention which is drawn to genera of anti-DLL3 CARs that do not have any structure.
As noted above, the Applicant has disclosed nine WT PD-1-based chimeric polypeptides (SEQ ID NOs: 75-83). These chimeric polypeptides sufficiently describe the structure for the PD-1 extracellular domain, the hinge domain, and the transmembrane domain, and sufficiently define the number and structure of the intracellular signaling domain(s). All of SEQ ID NOs: 75-83 comprise the wildtype PD-1 extracellular domain (SEQ ID NO: 9) and only one intracellular signaling domain, particularly WT CD28 (SEQ ID NO: 18), CD28.YMFM (SEQ ID NO: 19), CD28.AYAA (SEQ ID NO: 20), CD2 full (SEQ ID NO: 13), CD2 short (SEQ ID NO: 24), WT DAP10 (SEQ ID NO: 27), WT ICOS (SEQ ID NO: 29), WT CD40 (SEQ ID NO: 31), or WT OX40 (SEQ ID NO: 33). Furthermore, the transmembrane domains of the chimeric polypeptides of SEQ ID NOs: 75-83 are either WT CD28 (SEQ ID NO: 17), WT CD2 (SEQ ID NO: 22), the D57N DAP10 mutant (SEQ ID NO: 26), WT ICOS (SEQ ID NO: 28), WT CD40 (SEQ ID NO: 30), or WT OX40 (SEQ ID NO: 31) and the hinge domains are either a truncated CD28 ECD (SEQ ID NO: 16), truncated CD2 ECD (SEQ ID NO: 21), or DAP10 ECD (SEQ ID NO: 25) for SEQ ID NOs: 75-80, while SEQ ID NOs: 81-83 do not comprise hinge domains.
However, such a disclosure does not serve to provide sufficient written description of the claimed to genera of PD-1-based chimeric polypeptides that comprise any PD-1 extracellular domain, any transmembrane domain, and any number of any intracellular domains. The disclosure does not identify sufficient structural features or combination of features which give rise to the proper function of the chimeric polypeptides, which, in view of the specification, are chimeric switch receptors. Additionally, there does not appear to be any reasonable shared structure present in the genera of chimeric polypeptides which gives rise to their functional activity. Ultimately, identifying a chimeric polypeptide on the basis of functioning as a chimeric switch receptor rather than by identifying the sequence/structure of the PD-1 extracellular domain, hinge domain, transmembrane, and intracellular domain(s) of the chimeric polypeptides in question is generally insufficient to provide written description.
Thus, based on the art cited above which teaches that: (1) CSRs do not comprise more than two intracellular, specifically costimulatory, domains; (2) a CD28 intracellular signaling domain minimally requires its 41 amino acid cytoplasmic tail comprising the membrane proximal YMNM motif and the distal PYAP motif for proper functionality; and (3) there is not a one-size-fits-all approach to hinge and transmembrane domain engineering and that optimization is required for each specific CSR, artisans would reasonably conclude that applicant was not in possession of the full breadth of chimeric polypeptides as encompassed by the claims at the time the instant application was filed.
This reasoning further applies to claims 26, 55, and 58 which recite “wherein the polypeptide comprises the amino acid sequence of any one of SEQ ID NOS: 75-115 or an amino acid sequence that is at least 90% identical to any one of SEQ ID NOS: 75-115” (claims 26 and 55) and “wherein the CD28 transmembrane domain comprises the amino acid sequence of SEQ ID NO: 17 or an amino acid sequence that is at least about 90% identical to the amino acid sequence of SEQ ID NO: 17” (claim 58). Claims 26, 55, and 58 do not satisfy the written description requirement because the claim language allows for up to 10% variability in the amino acid sequence structure of the chimeric polypeptides, inclusive of the PD-1 extracellular domain, hinge domain, transmembrane, and intracellular domain(s), which would be expected to impact the functional activity of the chimeric switch receptor based on the state of the art. Claims 26, 55, and 58 are drawn to a broad genus of chimeric polypeptides which are functionally defined as chimeric switch receptors without reciting a corresponding structure expected to correlate with this ability as supported by Applicant’s disclosure.
Furthermore, this reasoning also applies to the claimed genera of CARs which comprise that comprises any intracellular signaling domain comprising any number of a CD3𝞯 signaling domain, a CD28 signaling domain, and a 4-1 BB signaling domain.
Based on the art cited above which teaches that: (1) CARs do not comprise more than three intracellular domains, specifically, one CD3𝞯 intracellular signaling domain and up to two costimulatory domains; (2) a CD28 intracellular signaling domain minimally requires its 41 amino acid cytoplasmic tail comprising the membrane proximal YMNM motif and the distal PYAP motif for proper functionality; and (3) there is not a one-size-fits-all approach to hinge and transmembrane domain engineering and that optimization is required for each specific CAR, artisans would reasonably conclude that applicant was not in possession of the full breadth of CARs as encompassed by the claims at the time the instant application was filed.
Regarding the anti-DLL3 CARs that do not have any recited structure in the claims, as noted above, the Applicant has only disclosed one anti-DLL3 CAR, 2G1 (SEQ ID NO: 165). Such a disclosure does not serve to provide sufficient written description of the claimed genera of anti-DLL3 CARs. The disclosure does not identify sufficient structural features or combination of features which give rise to the function of DLL3 recognition or binding. Additionally, there does not appear to be any reasonable shared structure present in the genera of recited anti-DLL3 CARs which gives rise to their functional activity. Ultimately, identifying an CAR on the basis of recognition or binding to DLL3 rather than by identifying the sequence/structure, namely a complete set of six CDRs, of the CARs in question is generally insufficient to provide written description.
Therefore, in view of the breadth of the claims and the limited disclosure, artisans would reasonably conclude that applicant was not in possession of the full breadth of anti-DLL3 CARs as encompassed by the claims at the time the instant application was filed.
Amending the claims to recite: (1) sufficient structure, not in an optionally clause or with variability within required domains, for the PD-1 extracellular domain, the hinge domain (if present), the transmembrane domain, and the intracellular domain(s), and to recite no more than two intracellular domains for the chimeric polypeptide; (2) the intracellular domain of the CAR comprises one CD3𝞯 intracellular signaling domain and up to two costimulatory domains (CD28 and/or 4-1BB); and (3) a complete set of six CDRs for the anti-DLL3 CAR, would obviate this part of the rejection.
Enablement
Claims 61 and 83 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for engineered immune cell comprising a vector comprising the polynucleotide of claim 1 and a method of making an engineered immune cell comprising the step of introducing a vector comprising the polynucleotide of claim 1 into an immune cell; does not reasonably provide enablement for an engineered immune cell comprising the polynucleotide of claim l or a method of making an engineered immune cell comprising the step of introducing the polynucleotide of claim 1 into an immune cell. The specification does not enable any person skilled in the art to that which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The factors considered in determining whether a disclosure would require undue experimentation include:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP § 2164.01.
Nature of the invention/Breadth of the claims
The claims are drawn an engineered immune cell comprising the polynucleotide of claim l (claim 61) and method of making an engineered immune cell comprising the step of introducing the polynucleotide of claim l into an immune cell (claim 82).
State of the prior art/Predictability of the art
The art teaches that recombinant proteins are produced by first generating a plasmid by cloning the DNA encoding the protein into parent plasmids for expression and purification from a variety of cells (e.g. see DeLuca et al. STAR Protocols. 2022, 3, 101915, 1-17; page 1, paragraph under “Before you begin”). Many plasmids have been generated for the purpose of expressing and purifying proteins from human cells, however, the proteins sequences can be cloned into any plasmid appropriate for expression of high levels of recombinant protein in mammalian cells (e.g. see page 1, paragraph under “Before you begin”). Any plasmid designed for a high level of protein expression in mammalian cells (e.g., driven by a CMV promotor) can be used to generate the parent heavy and light chain plasmids (e.g. see note on page 8).
Thus, the art teaches that in order for the protein to be produced (or expressed) by a host cell, the DNA encoding the protein needs to be inserted into an appropriate plasmid backbone that has all of the elements required for protein expression (i.e. promoter, origin of replication, selectable marker). This plasmid can then be used to transform a host cell for protein expression.
Working examples/ Guidance in the specification
The chimeric polypeptides of the instant invention were expressed in T cells using lentivirus transduction (e.g. see Example 2, page 95). The lentivirus was prepared by mixing together lentiviral packaging vectors 1.5ug psPAX2, 0.5ug pMD2G, and 0.5ug of the appropriate CAR vector or chimeric switch receptor vector in 250uL Opti-MEM (Gibco) per well of the 6-well plate ("DNA mix") (e.g. see [0225]).
Amount of experimentation necessary
The instant specification discloses that chimeric polypeptides of the instant invention were expressed in T cells using lentivirus transduction (vectors). There is insufficient objective evidence that the specific method disclosed in the specification can be extrapolated to provide guidance and direction for use any nucleic acid to transform a host cell for production of the claimed chimeric polypeptides. As it is known in the art, producing a protein generally involves culturing a cell that has been transformed with a DNA plasmid comprising the protein gene and critical elements required for protein expression (i.e. promoter, origin of replication, selectable marker). These plasmids are optimized for independent replication, controlled expression, and high yield. While the Applicant has disclosed how to make the instantly claimed chimeric polypeptides by transforming a cell with a vector comprising a nucleic acid encoding the amino acid sequences of the chimeric polypeptides, the Applicant has not disclosed how to make chimeric polypeptides by transforming a cell with any nucleic acid encoding the amino acid sequences of the chimeric polypeptides.
Thus, based on the content of the disclosure in view of the prior art, a skilled artisan, through extensive trial-and-error experimentation, would have to transform a host cell with any nucleic acid encoding the chimeric polypeptide with a reasonable expectation of success. This quantity of experimentation goes beyond what is considered “a reasonable degree of experimentation” and constitutes undue further experimentation in order to enable a skilled artisan to make and/or use an engineered immune cell comprising the polynucleotide of claim l and a method of making an engineered immune cell comprising the step of introducing the polynucleotide of claim 1 into an immune cell for the breadth of what is claimed.
Thus, the specification does not enable one of ordinary skill in the art to make and/or use the entire genus of engineered immune cells and the method of making an engineered immune cell as it is currently claimed. Therefore, claims 61 and 83 rejected under 35 U.S.C. 112(a).
Canceling claim 61 and amending claim 83 to recite “a method of making an engineered immune cell comprising the step of introducing a vector comprising the polynucleotide of claim 1 into an immune cell” would obviate this part of the rejection.
Claim Rejections - 35 USC § 102
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 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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 9-12, 26, 31-34, 39-42, 55, 58, 61-63, 73-75, 77, and 83 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Noonan et al. 2019 (US20190330306A1).
In view of the Applicant’s election, independent claim 1 is drawn to a polynucleotide encoding a chimeric polypeptide comprising an extracellular domain, a transmembrane domain, and one or more intracellular domains, wherein the extracellular domain comprises a PD-1 extracellular domain, optionally wherein the PD-1 extracellular domain comprises the amino acid sequence of SEQ ID NO:9.
Independent claim 34 is drawn to a chimeric polypeptide comprising an extracellular domain, a transmembrane domain, and one or more intracellular domains, wherein the extracellular domain comprises a PD-1 extracellular domain, optionally wherein the PD-1 extracellular domain comprises the amino acid sequence of SEQ ID NO:9.
Dependent claims 9 and 39 limit the one or more intracellular domains to that which comprises one or more intracellular signaling domains, optionally wherein the one or more intracellular signaling domains is a CD28 intracellular signaling domain.
Dependent claims 10 and 40 limit the one or more intracellular domains to that which comprises the amino acid sequence of SEQ ID NO: 18.
Dependent claims 11 and 41 limit the transmembrane domain to that which comprises a CD28 transmembrane domain.
Dependent claims 12 and 42 limit the transmembrane domain to that which comprises SEQ ID NO: 17.
Dependent claims 26 and 58 limit the chimeric polypeptide to that which comprises SEQ ID NO: 75 or an amino acid sequence that is at least 90% identical to SEQ ID NO: 75.
Dependent claim 31 is drawn to a vector comprising the polynucleotide of claim 1.
Dependent claim 32 limits the vector to a viral vector, optionally wherein the vector is a lentiviral vector.
Dependent claim 33 is drawn to a chimeric polypeptide encoded by the polynucleotide of claim l.
Dependent claim 55 limits the transmembrane domain to that which comprises a CD28 transmembrane domain, optionally wherein the CD28 transmembrane domain comprises the amino acid sequence of SEQ ID NO: 17 or an amino acid sequence that is at least about 90% identical to the amino acid sequence of SEQ ID NO: 17.
Dependent claim 61 is drawn to an engineered immune cell comprising the polynucleotide of claim l.
Dependent claim 62 is drawn to an engineered immune cell comprising the vector of claim 31.
Dependent claim 63 is drawn to an engineered immune cell comprising or expressing the chimeric polypeptide of claim 34.
Dependent claim 73 limits the engineered immune cell of claim 63 to a T cell.
Dependent claim 74 limits the engineered immune cell of claim 63 to an autologous T cell.
Dependent claim 75 limits the engineered immune cell of claim 63 to an allogeneic T cell.
Dependent claim 77 is drawn to a composition comprising the cell of claim 63 and a pharmaceutically acceptable carrier.
Dependent claim 83 is drawn to a method of making an engineered immune cell comprising the step of introducing the polynucleotide of claim l into an immune cell.
Regarding claims 1, 9-12, 34, 39-42, 55, Noonan et al. teach a chimeric polypeptide, called a PD-1 switch receptor, comprising a WT PD-1 extracellular domain (instant SEQ ID NO: 9), a WT CD28 transmembrane domain (instant SEQ ID NO: 17), and a WT CD28 intracellular domain (instant SEQ ID NO: 18) and a nucleic acid encoding this chimeric polypeptide (e.g. see SEQ ID NO: 23 and SEQ ID NO: 24, respectively, on page 6). See sequence alignment below.
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Alignment of Noonan et al.’s SEQ ID NO: 23 and instant SEQ ID NOs: 9, 17, and 18:
Regarding claims 26 and 58, it is noted that SEQ ID NO: 23 is at least 90% identical to instant SEQ ID NO: 75. See sequence alignment below.
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Alignment of Noonan et al.’s SEQ ID NO: 23 and instant SEQ ID NO: 75:
Regarding claims 31-33, 61-63, 73, and 83, Noonan et al. teach that their PD-1 switch receptors were expressed in lentivirus transduced Jurkat leukemia cell line, an immortalized line of human T cells (e.g. see [0090]). Jurkat cells were transduced with lentiviruses carrying the PD-1 switch receptor (e.g. see [0090]).
Regarding claims 74 and 75, Noonan et al. also teach that the cell that is transfected may be obtained from a subject, for example a cell that is autologous or allogenic to the subject (e.g. see [0075] and [0079]).
Regarding claim 77, Noonan et al. also teach that the chimeric switch receptor-bearing cells can be delivered as a pharmaceutically acceptable composition or as compositions with pharmaceutically acceptable vehicles or carriers (e.g. see [0083]).
As such, claims 1, 9-12, 26, 31-34, 39-42, 55, 58, 61-63, 73-75, 77, and 83 are anticipated by Noonan et al.
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 that 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 25, 29, 30, 57, and 64-66 are rejected under 35 U.S.C. 103 as being unpatentable over Noonan et al. 2019 (US20190330306A1) in view of Zhao et al. 2021 (WO2021008610) and Fujiwara et al. 2020 (Cells. 9(5), 1182).
Dependent claims 25 and 57 limit the chimeric polypeptide to that which further comprises a hinge domain located between the extracellular domain and the transmembrane domain.
Dependent claim 29 recites that the polynucleotide further encodes a second polypeptide, optionally wherein the second polypeptide comprises a chimeric cytokine receptor (CCR) or a chimeric antigen receptor (CAR) and claim 30 limits the CCR to that which is constitutively active or inducible.
Dependent claim 64 limits the engineered immune cell of claim 63 to that which further comprises or expresses a CAR, wherein the CAR comprises an extracellular ligand-binding domain, a transmembrane domain, and an intracellular signaling domain.
Claim 65 limits the CAR intracellular signaling domain comprises any one or more of a CD3𝞯 signaling domain, a CD28 signaling domain, and a 4-1 BB signaling domain.
Claim 66 limits the CAR extracellular ligand-binding domain specifically recognizes or binds to DLL3.
The teachings of Noonan et al. are outlined in the 102 rejection above.
Noonan et al. do not teach that: (1) the chimeric polypeptide further comprises a hinge domain located between the extracellular domain and the transmembrane domain; (2) the polynucleotide further encodes a CAR or that the engineered immune cell which further comprises or expresses a CAR; or (3) the CAR binds to DLL3.
Regarding claims 25 and 57, Zhao et al. teach a PD-1 chimeric switch receptor which comprises a PD-1 extracellular domain, a WT CD28 transmembrane domain, a WT CD28 intracellular domain, and a truncated CD28 ECD as the hinge domain connecting the PD-1 ECD to the transmembrane domain (e.g. see SEQ ID NO: 524).
Regarding claims 29 and 64-66, Zhao et al. also teach that CSRs were created to reverse the outcomes of its original signaling pathway in order to confer an immune cell (e.g., a CAR T cell) with a desired activity, such as, the ability to overcome the immunosuppressive tumor microenvironment and to allow it to have greater in vivo persistence (e.g. see [0144]). A CSR can exploit the inhibitory molecules expressed by a cancer cell to further stimulate the CAR T cell. A CAR T cell can be engineered to express a CSR composed of the extracellular ligand binding domain of the human inhibitory receptor programmed cell death protein 1 (PD-1) fused to the transmembrane and cytoplasmic co-stimulatory signaling domains of CD28. When the CAR T cell is administrated into a subject with a cancer expressing DLL3 and programmed cell death ligand 1 (PD-L1) , the expressed CAR can bind to the DLL3 and the expressed switch receptor can bind to PD-L1. The nature of the PD-1/CD28 chimeric switch receptor fusion protein prevents the normal PD1/PD-L1-mediated T-cell suppression and, instead, promotes signaling through the CD28 domain, which results in the stimulation of the CAR T cell. Thus, exchanging the transmembrane and intracellular domain of PD-1 with that of CD28 converts PD-L1 into a co-stimulation ligand of the CAR T cell. This will induce enhanced toxicity against PD-L1-expressing cancer cells (e.g. see [0144]).
Zhao et al. specifically teach PD-1 Chimeric Switch Receptor (PD-1CSR) armored DLL3 CARs (e.g. see SEQ ID NO: 522; [0614], [0617], and [0618]; and figure 10B). It is noted that SEQ ID NO: 522 comprises SEQ ID NO: 524 which is more than 90% identical to instant SEQ ID NO: 75 (see second sequence alignment in 102 rejection above). The PD-1 CSR armored CAR-T cells showed a strong expansion capability and cytotoxic potency against SHP-77/PD-L1 cells (overexpressing human PD-L1 in SHP-77 cells) (e.g. see [0624]).
Zhao et al. also teach that DLL3 has been found to be clinically associated with various proliferative disorders, including tumors exhibiting neuroendocrine features, such as small-cell lung cancer (SCLC) (e.g. see [0004]). SCLC, originating from neuroendocrine progenitor cells, comprises approximately 15%of all lung cancers, and has one of the lowest 5-year survival rates at 6%. This is because it is highly aggressive, with about two-thirds of patients having metastatic diseases at diagnosis, and is highly refractory to conventional treatment (e.g., platinum-based chemotherapy). (e.g. see [0004]). Therefore, there is a need for improved therapeutic approaches to treat SCLC and other DLL3-expressing cancers.
Further regarding claims 64 and 65, it is noted that Zhao et al. also teach that the anti-DLL3 CAR comprises an extracellular ligand-binding domain, a transmembrane domain, and an intracellular signaling domain, wherein the intracellular signaling domain comprises any one or more of a CD3𝞯 signaling domain, a CD28 signaling domain, and a 4-1 BB signaling domain (e.g. see Figure 10B).
Further regarding claims 25 and 57, Fujiwara et al. teach that hinge domain modification may adjust the functional strength of CAR-T cells without impairing the antigen binding properties of the extracellular antigen recognition domain and the signaling properties of the intracellular signal transduction domain to modify T cell functions (e.g. see paragraph spanning pages 11 and 12). Fujiwara et al. teach that the hinge domain plays a role in the control of the modality of CAR expression and membrane transport efficiency of CAR, and the definition of the CAR signaling threshold (e.g. see page 14, fourth paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Noonan et al. to incorporate the teachings of Zhao et al. and Fujiwara et al. to include that (1) the chimeric polypeptide further comprises a hinge domain located between the extracellular domain and the transmembrane domain; (2) the polynucleotide further encodes a CAR or that the engineered immune cell which further comprises or expresses a CAR; and (3) the CAR binds to DLL3. This is because (1) hinge domains are known to play a role in CAR expression, transport efficiency, and function (Fujiwara et al.); (2) CSRs can exploit the inhibitory molecules expressed by a cancer cell to further stimulate CAR T cells (Zhao et al.); and (3) there is a need for improved therapeutic approaches to treat SCLC and other DLL3-expressing cancers (Zhao et al.).
Regarding the claims drawn to the chimeric polypeptide further comprising a hinge domain, given that hinge domains are known to play a role in CAR expression, transport efficiency, and function (Fujiwara et al.) and Zhao et al. teach a PD-1 chimeric switch receptor that comprises a truncated CD28 ECD hinge domain, a PD-1 extracellular domain, a WT CD28 transmembrane domain, and a WT CD28 intracellular domain and confers strong expansion capability and cytotoxic potency against PD-L1 overexpressing cells for a PD-1CSR armored CAR; it would have been obvious to a skilled artisan, with the goal of fine tuning the expression, transport efficiency, and function of the PD-1-CSR taught by Noonan et al., to experiment with including the truncated CD28 ECD as the hinge domain in the PD-1-CSR with a reasonable expectation of success. Given that Zhao et l’s PD-1CSR armored CAR, which comprises a PD-1-CSR that is more than 90% identical to Noonan et al.’s PD-1CSR but further comprises a hinge domain, demonstrated strong expansion capability and cytotoxic potency against PD-L1 overexpressing cells; a skilled artisan would have reasonably concluded that the addition of a hinge may further enhance the function of Noonan et al.’s PD-1CSR.
Regarding the claims that are drawn to the polynucleotide further encoding a CAR and the engineered immune cell further comprising or expressing a CAR, given that a CSR can exploit the inhibitory molecules expressed by a cancer cell to further stimulate the CAR T cell; it would have been obvious to a skilled artisan to modify the PD-1-CSR-expressing T cell taught by Noonan et al.’s to further include a CAR with a reasonable expectation of success. When a CAR T cell is engineered to express a PD-1-CSR and is administrated into a subject with a cancer expressing PD-L1, the expressed CAR can bind to its target and the expressed CSR can bind to PD-L1 thereby preventing the normal PD1/PD-L1-mediated T-cell suppression and, instead, promoting signaling through the CD28 domain, which results in the stimulation of the CAR T cell (Zhao et al.). Therefore, a skilled artisan would reasonably expect that the addition of a CAR to a T cell expressing a PD-1-CSR would enhance the efficacy of the CAR in immunosuppressive environments where PD-L1 is overexpressed.
Regarding claims that are specifically drawn to a DLL3 CAR, given that DLL3 has been found to be clinically associated with various proliferative disorders, including SCLC which highly aggressive and refractory; there is a need for improved therapeutic approaches to treat SCLC and other DLL3-expressing cancers; and PD-1CSR armored DLL3 CAR T cells have already been successfully designed and applied in this context; it would have been obvious to a skilled artisan to specifically select an anti-DLL3 CAR as the CAR to be incorporated into the PD-1-CSR-armored CAR T cells with a reasonable expectation of success.
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.
Claims 67, 68, 71, 72, 76 are rejected under 35 U.S.C. 103 as being unpatentable over Noonan et al. 2019 (US20190330306A1) in view of Zhao et al. 2021 (WO2021008610) and Fujiwara et al. 2020 (Cells. 9(5), 1182), as applied to claims 64-66, and further in view of Lin et al. 2021 (US20210061881A1) and Zhang et al. 2020 (WO2020180591).
Claim 67 limits the engineered immune cell of claim 64 to that which further comprises or expresses a chimeric cytokine receptor (CCR).
Claim 68 limits the CCR to that which is constitutively active or inducible.
Independent claim 71 is drawn to an engineered immune cell comprising or expressing a DLL3 CAR that comprises the amino acid sequence of SEQ ID NO: 73 or 165, and a CCR that comprises the amino acid sequence of SEQ ID NO:162.
Dependent claim 72 limits the engineered immune cell of claim 71 to that which comprises or expresses a polypeptide comprising the amino acid sequence of SEQ ID NO: 74, with or without the signal peptide.
Dependent claim 76 is drawn to a population of cells comprising at least about 1x104, 1x105, 1x106, 1x107, or 1x108 cells of claim 63.
The combined teachings of Noonan et al. in view of Zhao et al. and Fujiwara et al. pertaining to claims 64-66, and the rationale for combining them are outlined in the 103 rejection above.
The combined reference teachings do not teach that the engineered immune cell further comprises or expresses a chimeric cytokine receptor (CCR), the CCR is constitutively active or inducible, the CCR comprises SEQ ID NO:162 and the DLL3 CAR that comprises SEQ ID NO: 73 or 165, or that the CCR and DLL3 CAR are joined by a P2A self-cleaving peptide as found in SEQ ID NO: 74.
Lin et al. teach that CAR T-cell proliferation, cytotoxic potency, and persistence is driven by signal transduction pathways including CD3zeta activation (Signal 1) and co-stimulation (Signal 2), and, in some cases, cytokine-induced cytokine receptor signaling (Signal 3) may be desirable but has been met with significant limitations (e.g. see [0004]). One approach to provide cytokine support is based on introducing a constitutively activated dimerized cytokine receptor to the T cell directly or indirectly with the CAR (e.g. see [0005]).
Lin et al. also teach the CCRs comprising instant SEQ ID NO: 162 (e.g. see SEQ ID NO: 164 (without CD8 signal sequence) and 167 (with CD8 signal sequence) on page 26 of table 6) See sequence alignment below. SEQ ID NOs: 164 and 167 comprise dimerization mutations in the transmembrane domain of TPOR/MPLR (S505N, W515K, see SEQ ID NO:60) and the recruiting domain, “IL2YY” refers to IL2Rb (393-433, 518-551, SEQ ID NO: 111), joined in tandem to mimic signaling from IL2Rb (e.g. see [163]). The CCR was fused to a CAR by a P2A self-cleaving peptide (e.g. see Figure 11A). The P2A self-cleaving peptide is disposed between the CCR and the CAR to permit stoichiometric co-expression of the chimeric cytokine receptor and the CAR (e.g. see [0152]).
T cells expressing the CCR-P2A-CAR fusion were generated (CAR T cells expressing the TGFβR2.IL2YY chimeric cytokine receptor) (e.g. see [0163]). Lin et al. teach that the CCR comprising TPOR/MPLR (SEQ ID NO:60) and IL2YY (SEQ ID NO: 111) performed very well in CAR T cell production and STAT 5 phosphorylation assays (e.g. see [0163] and [0164]; and Figures 11C-E. Furthermore, CAR T cells expressing the TGFβR2.IL2YY chimeric cytokine receptor exhibited an enriched population of stem cell-like (stem) memory T cell (CD62L.sup.hiCD45RO.sup.low), a desirable T cell phenotype that has been associated with better clinical outcome (e.g. see [0165] and Figures 11F and D). This is in comparison to CAR T cells expressing the TGF-βR2.IL7IL12 chimeric cytokine receptor which largely differentiated into central memory T cells (CD62L.sup.hiCD45RO.sup.hi) (e.g. see [0165] and Figures 11F and D).
Regarding claim 76, Lin et al. also teach that a population of cells (bearing the chimeric cytokine receptors and CARs of the disclosure) can comprise about 104 to about 109 cells per kg body weight of a patient receiving said population of cells (e.g. see [0140]).
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Alignment of Lin et al.’s SEQ ID NO: 164 and instant SEQ ID NO: 162:
Zhang et al. teach a DLL3 CAR-T cells comprising one of three anti-DLL3 scFv, 2G1, 4H8, and 10G1-K (e.g. see [0292]). It is noted that the scFv of 2G1 (SEQ ID NO: 117) is identical to instant SEQ ID NO: 165. See sequence alignment below. It is noted that the 2G1-based anti-DLL3 CAR T cells has the highest percentage of cells expressing each anti-DLL3 CAR (e.g. see Figure 9B) and showed the greatest cytotoxicity (e.g. see Figure 9C).
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Alignment of Zhang et al. SEQ ID NO: 117 and instant SEQ ID NO: 165:
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the combined teachings of Noonan et al. in view of Zhao et al. and Fujiwara et al. as applied to claims 64-66, and incorporate the teachings of Lin et al. and Zhang et al. to include that the engineered immune cell further comprises or expresses a chimeric cytokine receptor (CCR), the CCR is constitutively active or inducible, the CCR comprises SEQ ID NO:162 and the DLL3 CAR that comprises SEQ ID NO: 73 or 165, and the CCR and DLL3 CAR are joined by a P2A self-cleaving peptide as found in SEQ ID NO: 74. This is because one approach to provide cytokine support to CAR T cells, which is critical for their efficacious proliferation, cytotoxic potency, and persistence, is based on introducing a constitutively activated dimerized cytokine receptor to the T cell directly or indirectly with the CAR.
Given that the introduction of constitutively activated dimerized cytokine receptors to a T cell is meant to provide cytokine support in order to enhance CAR T-cell proliferation, cytotoxic potency, and persistence; a CCR comprising instant SEQ ID NO: 162 was able to markedly enhance STAT 5 phosphorylation and CAR T cell production, specifically the stem memory T cell population which is a desirable T cell phenotype that has been associated with better clinical outcome; an anti-DLL3 CAR comprising instant SEQ ID NO: 165 outperformed other anti-DLL3 CARs with different anti-DLL3 scFv binding domains; and the P2A self-cleaving peptide permits stoichiometric co-expression of the chimeric cytokine receptor and the CAR when expressed from the same construct; it would have been obvious to a skilled artisan to modify the PD-1CSR armored DLL3 CAR T cells taught by Noonan et al. in view of Zhao et al. and Fujiwara et al. to further include a constitutively activated CCR and specifically include the CCR and the anti-DLL3 CAR in a fusion protein (instant (SEQ ID NO: 74) comprising instant SEQ ID NO: 162, a P2A self-cleaving peptide, and instant SEQ ID NO: 165 with a reasonable expectation of success.
A skilled artisan would have reasonably expected, given the success of a CCR(instant SEQ ID NO:162)-P2A-CAR fusion protein for the stoichiometric expression of the CCR and a CAR and its enhancement of proliferation, cytotoxic potency, and persistence of the underlying CAR T cell, that introducing such a construct to the PD-1CSR armored DLL3 CAR T cells taught by Noonan et al. in view of Zhao et al. and Fujiwara et al. would have would permit a similar level of success at enhancing the proliferation, cytotoxic potency, and persistence of the PD-1CSR armored DLL3 CAR T cells.
Furthermore, 2G1 is a known DLL3 binder that has shown significant success in a CAR T cell. Therefore, a skilled artisan would have readily expected that the 2G1 scFv would be successful in the PD-1CSR armored DLL3 CAR T cells.
It is noted that the only difference between fused instant SEQ ID NOs: 162 and 165 and instant SEQ ID NO: 74 is the P2A self-cleaving peptide joining these two sequence. It would have been obvious to a skilled artisan to include this element between these two proteins to allow for stoichiometric expression of the CCR and a CAR with a reasonable expectation of success.
Combining prior art elements according to known methods to yield predictable results is obvious to one of ordinary skill in the art (see MPEP § 2143(A)). From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
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.
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Claims 1, 9-12, 25, 26, 29, 30-34, 39-42, 55, 57, 58, 61-68, 71-77, and 83 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-34 and 40 of U.S. Patent No. 12,528,856 (the ‘856 Patent) in view of Lin et al. 2021 (US20210061881A1), Zhao et al. 2021 (WO2021008610), Zhang et al. 2020 (WO2020180591), and Noonan et al. 2019 (US20190330306A1), Fujiwara et al. 2020 (Cells. 9(5), 1182).
The instant claims are drawn to a polynucleotide encoding a chimeric polypeptide comprising an extracellular domain, a transmembrane domain, and one or more intracellular domains, wherein the extracellular domain comprises a PD-1 extracellular domain, optionally wherein the PD-1 extracellular domain comprises the amino acid sequence of SEQ ID NO:9; a chimeric polypeptide comprising an extracellular domain, a transmembrane domain, and one or more intracellular domains, wherein the extracellular domain comprises a PD-1 extracellular domain, optionally wherein the PD-1 extracellular domain comprises the amino acid sequence of SEQ ID NO:9; and an engineered immune cell comprising or expressing a DLL3 CAR that comprises the amino acid sequence of SEQ ID NO: 73 or 165, and a CCR that comprises the amino acid sequence of SEQ ID NO:162.
The claims in the ‘856 Patent are drawn to a chimeric cytokine receptor comprising: a) a binding domain comprising an extracellular portion of a TGF-β receptor, or a TGF-β antigen binding domain; b) a transmembrane domain; c) an intracellular Janus Kinase (JAK)-binding domain; and d) an intracellular recruiting domain, wherein the transmembrane domain and the intracellular JAK-binding domain is a fragment of a variant of the full-length thrombopoietin receptor/myeloproliferative leukemia protein receptor (TPOR/MPLR) as shown in SEQ ID NO: 26, wherein the fragment is selected from the group consisting of SEQ ID NO: 30-71, 73-79, 160, and 217-234, and wherein the intracellular recruiting domain is not from TPOR/MPLR.
The claims in the ‘856 Patent differ from the instant invention by failing to recite that the chimeric cytokine receptor (CCR) is comprised in a CAR-CSR-CCR fusion protein or that the CAR-CSR-CCR fusion protein is expressed on a T cell.
The teachings of Lin et al., Zhao et al., Zhang et al., Noonan et al., and Fujiwara et al. are outlined in the 103 rejection above.
It would be obvious to one of ordinary skill in the art to modify the claims in the ‘856 Patent and to incorporate the teachings of Lin et al., Zhao et al., Noonan et al., Fujiwara et al., and Zhang et al. to include that the chimeric cytokine receptor (CCR) is comprised in a CAR-CSR-CCR fusion protein or that the CAR-CSR-CCR fusion protein is expressed on a T cell. This is because approaches for improving CAR T-cell proliferation, cytotoxic potency, and persistence include providing cytokine support by introducing a constitutively activated dimerized cytokine receptor (CCR) to the T cell directly or indirectly with the CAR (Lin et al.) and engineering a CAR T cell to also express a CSR that can exploit the inhibitory molecules expressed by a cancer cell to further stimulate the CAR T cell (Zhao et al.).
It is well known that strategies for overcoming the limitations of CAR T cell therapy, especially for solid cancers, are needed. Given that CCRs, such as those claimed in the ‘856 Patent, have been expressed as fusion proteins comprising a CCR, a P2A self-cleaving peptide, and a CAR have proven successful in enhancing CAR T-cell proliferation, cytotoxic potency, and persistence (Lin et al.) and PD-1CSR armored CAR T cells show improved expansion capability and cytotoxic potency against PD-L1-overexpressing cancer cells when compared to CAR T cells lacking the PD-1-CSR; it would be obvious to a skilled artisan to modify the CCR of the ‘865 Patent to be a CCR comprised in a CSR-CCR-armored CART cell with a reasonable expectation of success. A skilled artisan would reasonably expect that a CAR T cell further comprising a PD-1 CSR and a CCR would have enhanced efficacy in immunosuppressive environments where PD-L1 is overexpressed.
Regarding claims that are specifically drawn to a DLL3 CAR, given that DLL3 has been found to be clinically associated with various proliferative disorders, including SCLC which highly aggressive and refractory; there is a need for improved therapeutic approaches to treat SCLC and other DLL3-expressing cancers; and PD-1CSR armored DLL3 CAR T cells have already been successfully designed and applied (Zhao et al.); it would be obvious to a skilled artisan to specifically select an anti-DLL3 CAR and the CAR to be incorporated into the PD-1CSR-CCR armored CAR T cells with a reasonable expectation of success.
Furthermore, 2G1 is a known DLL3 binder that has shown significant success in a CAR T cell (Zhang et al). Therefore, a skilled artisan would readily expect that the 2G1 scFv would be successful in the PD-1CSR armored DLL3 CAR T cells.
It is noted that the only difference between fused instant SEQ ID NOs: 162 and 165 and instant SEQ ID NO: 74 is the P2A self-cleaving peptide joining these two sequence. It would be obvious to a skilled artisan to include this element between these two proteins to allow for stoichiometric expression of the CCR and a CAR with a reasonable expectation of success.
Therefore, the claims in the ‘856 Patent would render the instant claims obvious.
Claims 1, 9-12, 25, 26, 29, 30-34, 39-42, 55, 57, 58, 61-68, 71-77, and 83 are (provisionally) rejected on the ground of nonstatutory double patenting as being unpatentable over the claims in the following U.S. Patents and Application in view of Lin et al. 2021 (US20210061881A1), Zhao et al. 2021 (WO2021008610), Zhang et al. 2020 (WO2020180591), and Noonan et al. 2019 (US20190330306A1), Fujiwara et al. 2020 (Cells. 9(5), 1182) for similar reasons to the ‘856 Patent above.
The instant claims are drawn to a polynucleotide encoding a chimeric polypeptide comprising an extracellular domain, a transmembrane domain, and one or more intracellular domains, wherein the extracellular domain comprises a PD-1 extracellular domain, optionally wherein the PD-1 extracellular domain comprises the amino acid sequence of SEQ ID NO:9; a chimeric polypeptide comprising an extracellular domain, a transmembrane domain, and one or more intracellular domains, wherein the extracellular domain comprises a PD-1 extracellular domain, optionally wherein the PD-1 extracellular domain comprises the amino acid sequence of SEQ ID NO:9; and an engineered immune cell comprising or expressing a DLL3 CAR that comprises the amino acid sequence of SEQ ID NO: 73 or 165, and a CCR that comprises the amino acid sequence of SEQ ID NO:162.
Claims 1-8 of U.S. Patent No. 12,163,169 are drawn to an inducible chimeric cytokine receptor comprising at least two identical polypeptide monomers each comprising an N-terminal to C-terminal orientation of: an FK506 Binding Protein (FKBP) extracellular dimerization domain comprising the amino acid sequence of SEQ ID NO:218; an intracellular tyrosine kinase activating domain comprising the wild-type thrombopoietin receptor (TPOR/MPLR) tyrosine kinase activating domain amino acid sequence of SEQ ID NO: 96; and an intracellular tyrosine effector domain comprising at least two STAT-activation domains obtained from two cytokine receptors, wherein the at least two STAT-activation domains comprise the interleukin-7 receptor (IL7R) amino acid sequence of SEQ ID NO: 134 and the interleukin-12 receptor b2 (IL12Rb2) amino acid sequence of SEQ ID NO: 155 in tandem.
Claims 1-37 of U.S. Patent No. 12,043,655 are drawn to a constitutively active chimeric cytokine receptor (CACCR) composed of two monomers, each monomer comprising: a. a transmembrane domain; b. a Janus Kinase (JAK)-binding domain; and c. a recruiting domain, wherein the monomers are constitutively dimerized and wherein the transmembrane domain and JAK-binding domain comprises amino acids 478-582 of SEQ ID NO: 6 and comprises amino acid substitutions S505N and W515K.
Claims 1-13 and 19-32 of U.S. Patent No. 12,036,243 are drawn to an engineered immune cell comprising an anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) and a constitutively active chimeric cytokine receptor (CACCR), wherein the CACCR comprises two monomers, each monomer comprising: a transmembrane domain; a Janus Kinase (JAK)-binding domain; and a recruiting domain comprising the amino acid sequence of SEQ ID NO: 78, wherein the transmembrane domain and JAK-binding domain are present in a polypeptide (TM/JAK polypeptide) that comprises the amino acid sequence of SEQ ID NO: 12, wherein the CACCR does not comprise an extracellular ligand-binding domain, wherein the anti-BCMA CAR comprises an extracellular ligand-binding domain, a transmembrane domain, and an intracellular signaling domain, wherein the extracellular ligand-binding domain specifically recognizes and binds to human BCMA and comprises a single chain variable fragment (scFv), wherein the scFv comprises a heavy chain variable (VH) region and a light chain variable (VL) region; and wherein the VH region comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 146, 147, or 148; a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 149 or 150; and a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 151; and the VL region comprises a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 152; a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 153; and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 154.
Claims 1-33 of U.S. Patent No. 11,786,553 are drawn to a PD-1 chimeric cytokine receptor comprising: a. a PD-1 ectodomain or an antigen binding domain of an anti-PD-L1 or an anti-PD-L2 antibody; b. a transmembrane domain; c. a Janus Kinase (JAK)-binding domain; and d. a recruiting domain comprising a STAT-recruiting domain from IL2Rb, wherein the transmembrane domain and JAK-binding domain comprise SEQ ID NO: 40, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, or SEQ ID NO: 27.
Claims 1-11 of U.S. Patent Application No. 19/551,160 are drawn to a PD-1 chimeric cytokine receptor comprising: a. a PD-1 ectodomain or a PD-L1 antigen binding domain of an anti-PD-L1 or an anti-PD-L2 antibody; b. a transmembrane domain and a Janus Kinase (JAK)-binding domain comprising SEQ ID NO: 40, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, or SEQ ID NO: 27; and c. a STAT recruiting domain comprising a STAT-recruiting domain from a receptor selected from the group consisting of BLNK, IL2RG, EGFR, EpoR, GHR, IFNAR1, IFNAR2, IFNAR1/2, IFNLR1, IL10R1, IL12Rb1, IL12Rb2, IL21R, IL2small, IL7R, IL7Ra, IL9R, IL15R, and IL21R.
Claims 111-130 of U.S. Patent Application No. 18/917,035 are drawn to an inducible chimeric cytokine receptor comprising:(a) an extracellular dimerization domain;(b) a tyrosine kinase activating domain comprising a thrombopoietin receptor (TpoR) transmembrane domain and TpoR Janus Kinase (JAK) binding domain; and(c) a tyrosine effector domain; wherein the tyrosine effector domain comprises at least one STAT-activation domain of a receptor, wherein the receptor is not a TpoR.
The claims in the above U.S. Patents and Application differ from the instant invention by failing to recite that the chimeric cytokine receptor (CCR) is comprised in a CAR-CSR-CCR fusion protein or that the CAR-CSR-CCR fusion protein is expressed on a T cell.
The teachings of Lin et al., Zhao et al., Zhang et al., Noonan et al., and Fujiwara et al. are outlined in the 103 rejection above.
It would be obvious to one of ordinary skill in the art to modify the claims in the above U.S. Patents and Application and to incorporate the teachings of Lin et al., Zhao et al., Noonan et al., Fujiwara et al., and Zhang et al. to include that the chimeric cytokine receptor (CCR) is comprised in a CAR-CSR-CCR fusion protein or that the CAR-CSR-CCR fusion protein is expressed on a T cell. This is because approaches for improving CAR T-cell proliferation, cytotoxic potency, and persistence include providing cytokine support by introducing a constitutively activated dimerized cytokine receptor (CCR) to the T cell directly or indirectly with the CAR (Lin et al.) and engineering a CAR T cell to also express a CSR that can exploit the inhibitory molecules expressed by a cancer cell to further stimulate the CAR T cell (Zhao et al.).
It is well known that strategies for overcoming the limitations of CAR T cell therapy, especially for solid cancers, are needed. Given that CCRs, such as those claimed in the above U.S. Patents and Application, have been expressed as fusion proteins comprising a CCR, a P2A self-cleaving peptide, and a CAR have proven successful in enhancing CAR T-cell proliferation, cytotoxic potency, and persistence (Lin et al.) and PD-1CSR armored CAR T cells show improved expansion capability and cytotoxic potency against PD-L1-overexpressing cancer cells when compared to CAR T cells lacking the PD-1-CSR; it would be obvious to a skilled artisan to modify the CCR of the above U.S. Patents and Application to be a CCR comprised in a CAR-CSR-CCR fusion protein or that the CAR-CSR-CCR fusion protein is expressed on a T cell with a reasonable expectation of success. A skilled artisan would reasonably expect that a CAR T cell further comprising a PD-1 CSR and a CCR would have enhanced efficacy in immunosuppressive environments where PD-L1 is overexpressed.
Regarding claims that are specifically drawn to a DLL3 CAR, given that DLL3 has been found to be clinically associated with various proliferative disorders, including SCLC which highly aggressive and refractory; there is a need for improved therapeutic approaches to treat SCLC and other DLL3-expressing cancers; and PD-1CSR armored DLL3 CAR T cells have already been successfully designed and applied (Zhao et al.); it would be obvious to a skilled artisan to specifically select an anti-DLL3 CAR and the CAR to be incorporated into the PD-1CSR-CCR armored CAR T cells with a reasonable expectation of success.
Furthermore, 2G1 is a known DLL3 binder that has shown significant success in a CAR T cell (Zhang et al). Therefore, a skilled artisan would readily expect that the 2G1 scFv would be successful in the PD-1CSR armored DLL3 CAR T cells.
It is noted that the only difference between fused instant SEQ ID NOs: 162 and 165 and instant SEQ ID NO: 74 is the P2A self-cleaving peptide joining these two sequence. It would be obvious to a skilled artisan to include this element between these two proteins to allow for stoichiometric expression of the CCR and a CAR with a reasonable expectation of success.
Therefore, the claims in the above U.S. Patents and Application would render the instant claims obvious.
This is a provisional nonstatutory double patenting rejection for the co-pending Application because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
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/GRACE H LUNDE/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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