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 .
Claims 4-53, 56-60, 62-71, 75-135, 144-149 have been canceled. Claims 1-3, 54, 55, 61, 72-74, 136-143 remain pending.
Election/Restrictions
Applicant’s elected Group I, claims 1-3, 136, 137, without traverse in the reply filed on 8-4-25.
Claims 54, 55, 61, 72-74, 138-143 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1-3, 136, 137 remain under consideration.
Applicant's arguments filed 4-14-26 have been fully considered but they are not persuasive.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Objections
The phrase “heavy chain variable region (VH)” in claim 1 should be “heavy chain variable (VH) region
The VH and VL “regions” within a protein in claim 1 are referred to as domains, not “regions”. This is to distinguish the protein domains from the VH and VL “gene segments”.
Claim 10 fails to say the “heavy [or light] chain variable region[s]” are “immunoglobulin” VH or VL domains (as opposed to T-cell receptor domains).
The structure of the extracellular domain in claim 1 should be up front with the first mention of the extracellular domain.
The phrase “or a population of said cells” in claim 1 is redundant because the claim encompasses one or more cells.
The phrase “the isolated engineered NK cell” in line 2 of claim 1 lacks antecedent basis. The end of the claim says the cell is isolated which should be up front in the preamble.
The term “engineered” in claim 10 does not capture the fact that the cells contain a nucleic acid sequence encoding the CAR or are genetically modified, e.g. pg 107, paragraph bridging pg 144-145, 146, 149, 150. Setting forth the structure of the exogenous sequence encoding the CAR and saying that the NK cells express the CAR would be clearer.
Claim 1 no longer says the cells are human.
The phrase “antigen comprising an nucleophosmin 1c (NPM1c) neoepitope in complex with a class I [MHC I protein] in claim 1 is misleading because an NPM1c epitope is the antigen; it may be presented by an MHC I protein, but the combination of an NPM1c epitope in context of/presented by an MHC I protein is not an “antigen” per se.
The phrase “an nucleophosmin” in claim 1 is grammatically incorrect and should be ---a nucleophosmin---.
The metes and bounds of “neoepitope” in claim 1 are unclear, so if it encompasses any epitope, then just say epitope. If “neo” infers some limitation beyond any “epitope”, then the metes and bounds of how “neo” further limits any NPM1c “epitope” cannot be determined.
It is unclear why/whether the CAR must bind an NPM1c epitope in context of an MHC class I molecule or if the CAR is capable of binding any NPM1c epitope in context of MHC molecule.
Including the SEQ ID NO and the amino acid sequence itself is redundant. Just use the SEQ ID NOs.
The sequence of each CDR should be upfront with the first mention of each, e.g. ---[CDR1] comprising the amino acid sequence of…---.
Claim 1 can be written more clearly as ---An isolated genetically modified mammalian natural killer (NK) cell comprising an exogenous nucleic acid sequence encoding a chimeric antigen receptor (CAR) that binds a nucleophosmin 1c (NPM1c) antigen in complex with a major histocompatibility complex class I (MHC class I) protein, wherein the CAR comprises an intracellular domain, a transmembrane domain, and an extracellular domain comprising:
i) an immunoglobulin (Ig) heavy chain variable (VH) domain comprising a complementarity determining region 1 (CDR1) comprising the amino acid sequence of SEQ ID NO: 9, a CDR2 comprising the amino acid sequence of SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 11;
ii) an Ig light chain variable (VL) domain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO: 6, a CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 8,
wherein the NK cells express the CAR---.
Claim 2 can be written more simply as ---wherein the extracellular binding domain does not bind to the MCH class I protein alone or to an NY-ESO-1 antigen or influenza virus M1 antigen in complex with the MHC class protein---.
Claim 3 can be written more clearly as ---wherein the NPM1c antigen comprises the amino acid sequence of SEQ ID NO: 1---.
Specification
The title has been changed to ---NATURAL KILLER CELLS CONTAINING A CHIMERIC ANTIGEN RECEPTOR THAT TARGETS MUTANT NPM1c FOUND IN ACUTE MYELOID LEUKEMIA---.
Claim Rejections - 35 USC § 112
Written Description
Claims 1-3, 136, 137 remain 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.
Claim 1 is drawn to an “natural killer (NK} cell or a population of said cells, wherein the isolated engineered NK cell or population of said cells expresses a chimeric antigen receptor (CAR) polypeptide comprising an intracellular domain, a transmembrane domain and an extracellular binding domain, wherein the extracellular binding domain specifically binds to an antigen comprising an nucleophosmin 1 c(NPMlc) neoepitope in complex with a class I major histocompatibility complex (MHC class I) protein, wherein the extracellular domain comprises: a heavy chain variable region (VH) comprising a VH complementarity determining region (CDR)1, a VH CDR2 and a VH CDR3, wherein the VH CDR1 has the amino acid sequence GFTFSSYA (SEQ ID NO: 9), the VH CDR2 has the amino acid sequence ISGSGGST (SEQ ID NO: 10), and the VH CDR3 has the amino acid sequence ARLGYPTTTLLPFDY (SEQ ID NO: 11), and a light chain variable region (VL) comprising VL complementarity determining region (CDR)1, VL CDR2 and VL CDR3, wherein the VL CDR1 has the amino acid sequence QSISSY (SEQ ID NO: 6), the VL CD2 has the amino acid sequence AAS (SEQ ID NO: 7), and the VL CD3 has the amino acid sequence QQSYSTPLT (SEQ ID NO: 8), wherein the engineered cell or the population of said cells is isolated.”
Claim 1 as newly amended encompasses any species of NK cells. The specification lacks written description for any species of NK cells as broadly encompassed by claim 1 other than human NK cells. The specification does not correlate human NK cells to any plant, insect, invertebrate, fish, amphibian, reptile, bird, or non-human mammalian NK cell.
The metes and bounds of a [extracellular binding domain of the] CAR that “specifically” binds “an antigen comprising an NPM1c neoepitope” in complex with an MHC Class I protein in claim 1 cannot be determined. The specification and the art do not teach when a CAR “specifically” binds an NPM1c antigen complexed with an MHC Class I protein. It is also unclear when an NPM1c protein is a “neoepitope”. The phrase “NPM1c neoepitope” appears to be jargon that fails to further limit the structure of the NPM1c protein in claim 1 in any meaningful way; therefore, it is unclear what structure/function the CAR must have.
The end of claim 1 limits the NK cell to an isolated cell. This should be in the preamble and not at the end of the claim (see claim objection).
Example 1 (pg 136) discusses a scFv specific for AIQ-HLA-A2 bound to a specific NPM1c with a mutation. The specification does not teach the structure of the mutant NPM1c or any tumors or cells that naturally express the mutant NPM1c.
Example 2 (pg 138) describes identifying scFvs with “high affinity binding” to the AIQ-HLA-A2 – mutant NPM1c complex.
Example 3 (pg 139) describes making CARs using the scFvs with “high affinity binding” to the AIQ-HLA-A2 – mutant NPM1c complex.
Example 4 (pg 140) describes transfecting T-cells to express the CARs and using them to kill acute myeloid leukemia (AML) cells that express the mutant NPM1c in vitro.
Example 5 (pg 142) describes introducing T-cells that express the CARs into mice with acute myeloid leukemia (AML) cells that express the mutant NPM1c in vivo.
Example 6 (pg 143) describes using CAR T-cells for treating leukemic cells in different tissues in vivo.
The specification does not teach making/using NK cells comprising the CAR as required in claim 1, specifically “memory-like” NK cells. However, those of skill would have been able to transfect any NK with the CAR described by Xie (Nature Biomed. Engineering, 2021, Vol.
The specification does not teach the NPM1c “neoepitope” in claim 1 or a mutant NPM1c antigen for treating disease as contemplated in the specification. Claim 3 says the NPM1c neoepitope has the amino acid sequence of SEQ ID NO: 1; however, the specification does not teach SEQ ID NO: 1 is a mutant NPM1c or a “neoepitope”. The specification does not correlate SEQ ID NO: 1 with any NPM1c “neoepitope” as required in claim 1. Griffioen (WO 2019/004831) taught various NPM1c mutants on AML (pg 2-3), but they do not correlate to any NPM1c “neoepitope” in claim 1.
The examples are limited to CARs that target a mutant NPM1c peptide in context of an AIQ-HLA-A2 protein. AIQ-HLA-A2 does not correlate to any other MHC Class I protein as broadly encompassed by claim 1. The specification does not correlate AIQ-HLA-A2 to any other HLA-A proteins or any HLA-B or HLA-C proteins as broadly encompassed by claim 1.
Claims 136 and 137 lack written description for a CAR that targets any NPM1c neoepitope for reasons set forth above.
Claim 137 requires the NK cell of claim 136 “wherein in the presence of a target cell presenting the NPM 1 c neoepitope in complex with a MHC class I protein, (i) has increased expression of IFNgamma; (ii) has increased expression of granzyme B relative to a control population of NK cells; (iii) has increased expression of one or more activation markers relative to a control population of NK cells, wherein the one or more activation markers are selected from: CD25, CD107a, CD69, ICOS, CD226, and CD62L;(iv) has increased expression of one or more activating receptors relative to a control population of NK cells, wherein the one or more activating receptors are selected from: NKp30, NKG2D, NKp44;(v) has increased expression of one or more maturation markers relative to a control population of NK cells, wherein the one or more maturation markers are selected from: CD56 and NKG2A;(vi) has decreased expression of CD57 relative to a control population of NK cells; (vii) has increased expression of TIGIT relative to a control population of NK cells; and/or (viii) has decreased expression of TRAIL relative to a control population of NK cells; optionally wherein the control population of NK cells is an untransduced population of cytokine- induced ML NK cells”. It is wholly unclear whether applicants are attempting to give a function to the NK or whether they are trying to say the NK cell is in the presence of a “targeting cell”. If applicants are attempting to give the NK cells a function, that function cannot be determined. It is unclear whether the NK cells or the “target cell” has increased expression of IFNgamma, granzyme B, CD25, CD107a, CD69, ICOS, CD226, CD62L, NKp30, NKg2D, NKp44, CD56, NKG2A, CD57, TIGIT, or TRAIL. The specification is limited to a “target cell” that is an acute myeloid leukemia that express a mutant NPM1c protein that matches the target mutant NPM1c protein recognized by the CAR – this is missing from claim 137, and the breadth of “target cell” is massive compared to this limited embodiment. Accordingly, claim 137 lacks written description.
Response to arguments
Applicants argue the amendment overcomes the rejection. Applicants’ argument is not persuasive for reasons set forth above.
Indefiniteness
Claims 1-3, 136, 137 remain 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.
The metes and bounds of a [extracellular binding domain of the] CAR that “specifically” binds “an antigen comprising an NPM1c neoepitope” in complex with an MHC Class I protein in claim 1 and 136 cannot be determined. In particular, it is unclear when a CAR “specifically” binds an NPM1c antigen complexed with an MHC Class I protein. It is also unclear when an NPM1c protein is a “neoepitope”. The phrase “NPM1c neoepitope” appears to be jargon that fails to further limit the structure of the NPM1c protein in claim 1 or 136 in any meaningful way; therefore, it is unclear what structure/function the CAR must have. This phrasing makes the claim indefinite, and those of skill would not be able to determine whether they were infringing on the claim.
Response to arguments
Applicants argue the amendment overcomes the rejection. Applicants’ argument is not persuasive for reasons set forth above.
Claim 137 requires the NK cell of claim 136 “wherein in the presence of a target cell presenting the NPM 1 c neoepitope in complex with a MHC class I protein, (i) has increased expression of IFNgamma; (ii) has increased expression of granzyme B relative to a control population of NK cells; (iii) has increased expression of one or more activation markers relative to a control population of NK cells, wherein the one or more activation markers are selected from: CD25, CD107a, CD69, ICOS, CD226, and CD62L;(iv) has increased expression of one or more activating receptors relative to a control population of NK cells, wherein the one or more activating receptors are selected from: NKp30, NKG2D, NKp44;(v) has increased expression of one or more maturation markers relative to a control population of NK cells, wherein the one or more maturation markers are selected from: CD56 and NKG2A;(vi) has decreased expression of CD57 relative to a control population of NK cells; (vii) has increased expression of TIGIT relative to a control population of NK cells; and/or (viii) has decreased expression of TRAIL relative to a control population of NK cells; optionally wherein the control population of NK cells is an untransduced population of cytokine- induced ML NK cells”. It is wholly unclear whether applicants are attempting to give a function to the NK or whether they are trying to say the NK cell is in the presence of a “targeting cell”. If applicants are attempting to give the NK cells a function, that function cannot be determined. It is unclear whether the NK cells or the “target cell” has increased expression of IFNgamma, granzyme B, CD25, CD107a, CD69, ICOS, CD226, CD62L, NKp30, NKg2D, NKp44, CD56, NKG2A, CD57, TIGIT, or TRAIL. The specification is limited to a “target cell” that is an acute myeloid leukemia that express a mutant NPM1c protein that matches the target mutant NPM1c protein recognized by the CAR – this is missing from claim 137, and the breadth of “target cell” is massive compared to this limited embodiment. This makes claim 137 indefinite, and those of skill would not be able to determine whether they were infringing on the claim.
Response to arguments
Applicants argue the amendment overcomes the rejection. Applicants’ argument is not persuasive for reasons set forth above.
Claim Rejections - 35 USC § 103
The rejection of claims 1-3, 136, 137 under 35 U.S.C. 103 as being unpatentable over Berrien-Elliott (Blood, 2019, Vol. 134, Suppl. 1, pg 869) in view of Greiner (Blood, 2012, Vol. 120, pg 1282-1289) has been withdrawn. Berrien-Elliott taught human “memory-like” NK cells comprising a CAR that targets a protein specific to AML. Greiner taught an antigen of NPM1c (AIQDLCLAV) found in ALM that is presented by the most common HLA-A*0201 allele (in ~50% of the human population) (abstract). The combined teachings of Berrien-Elliott and Greiner did not teach a CAR comprising an extracellular domain comprising:
i) an immunoglobulin (Ig) heavy chain variable (VH) domain comprising a complementarity determining region 1 (CDR1) comprising the amino acid sequence of SEQ ID NO: 9, a CDR2 comprising the amino acid sequence of SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 11;
ii) an Ig light chain variable (VL) domain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO: 6, a CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 8.
The art at the time of filing did not reasonably teach or suggest an NK cell that expresses a CAR comprising an extracellular domain comprising:
i) an immunoglobulin (Ig) heavy chain variable (VH) domain comprising a complementarity determining region 1 (CDR1) comprising the amino acid sequence of SEQ ID NO: 9, a CDR2 comprising the amino acid sequence of SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 11;
ii) an Ig light chain variable (VL) domain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO: 6, a CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 8.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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Michael C. Wilson
/MICHAEL C WILSON/
Primary Examiner, Art Unit 1638
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