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 1-3, 54, 55, 61, 72-74, 136-143 are pending.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-3, 136, 137, in the reply filed on 8-4-25 is acknowledged.
Claims 54, 55, 61, 72-74, 138-143 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 8-4-25.
Claims 1-3, 136, 137 are under consideration.
Claim Objections
The terms “NK” and NPM1c” should be spelled out before being abbreviated.
Specification
The title will have to be changed to more accurately reflect the claimed subject matter, e.g. ---NATURAL KILLER CELLS CONTAINING A CHIMERIC ANTIGEN RECEPTOR THAT TARGETS MUTANT NPM1c FOUND IN ACUTE MYELOID LEUKEMIA---.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description
Claims 1-3, 136, 137 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 is drawn to an “engineered cytokine-induced memory-like human NK cell or a population of said cells, wherein the 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 NPM1c neoepitope in complex with a class I major histocompatibility complex (MHC class I) protein.”
The metes and bounds of a cytokine-induced memory-like human NK cell in claim 1 cannot be determined. Berrien-Elliott (Blood, 2019, Vol. 134, Suppl. 1, pg 869) described “chimeric antigen receptor modified memory-like” NK cells but did not define when they are “memory-like”. The specification does not define when NK cells are “memory-like”. It is unclear what the NK cells are “remembering” or how well they must “remember”. This appears to be jargon that refers to the ability of NK target certain cells, but the phrase “memory-like” has no defined metes and bounds in context of the function of NK cells.
It is also unclear how the phrase “cytokine-induced” further limits the structure or function of NK cells. The phrase appears to attempt to invoke product-by-process language, but the phrase does not further limit the NK cells because ALL NK cells are influences by cytokines whether they are in vivo or in vitro. This too appears to be jargon that fails to further limit the NK cells in claim 1 in any meaningful way.
Saying that the CAR has intracellular, transmembrane, and extracellular binding domains in claim also fails to meaningfully further limit the structure of the CAR because all CARs MUST have intracellular, transmembrane, and extracellular binding domains.
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. 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 in any meaningful way; therefore, it is unclear what structure/function the CAR must have.
Claim 1 encompasses NK cells in vivo or in vivo. Claim 1 encompasses engineering the NK cells in vivo or in vivo.
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 mutant NPM1c neoepitope required for targeting AML cells. Claim 3 says the NPM1c neoepitope has an amino acid sequence XiX2X3X4X5X6X7X8X9, wherein Xi is selected from A, V, L or I, wherein X2 is selected from A, T, S, V, L, I, M or Q, wherein X3 is selected from Q or N, wherein X4 is selected from D or E, wherein Xs is selected from L, I, V, M, A or F, wherein X6 is selected from C, S, or A, wherein X7 is selected from L, I, V, M, A, or F, wherein Xs is selected from A, V, L or I, and wherein X9 is selected from L, I, V, MorA. However, the specification does not teach any mutant NPM1c within the metes and bounds of claim 3. Griffioen (WO 2019/004831) taught various NPM1c mutants on AML (pg 2-3), but they do not correlate to the peptides in claim 3, the breadth of peptides in claim 3, or the breadth of 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 MHC Class II 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.
While those of skill could use the NK in vivo, the specification does not correlate genetically modifying an NK cell in vivo as broadly encompassed by claim 1. Therefore, the claims should be limited to isolated NK cells.
Accordingly, the NK of claim 1 lacks written description.
Claim 3 lacks written description for any NPM1c “neoepitope” for reasons set forth above in relationship to those disclosed by Griffioen (WO 2019/004831).
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.
Indefiniteness
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-3, 136, 137 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.
The metes and bounds of a cytokine-induced memory-like human NK cell in claim 1 cannot be determined. Berrien-Elliott (Blood, 2019, Vol. 134, Suppl. 1, pg 869) described “chimeric antigen receptor modified memory-like” NK cells but did not define when they are “memory-like”. The specification does not define when NK cells are “memory-like”. It is unclear what the NK cells are “remembering” or how well the they must “remember”. This appears to be jargon that refers to the ability of NK target certain cells, but the phrase “memory-like” has no defined metes and bounds in context of the function of NK cells. Those of skill would not be able to determine whether they were infringing on the claim.
It is also unclear how the phrase “cytokine-induced” further limits the structure or function of NK cells in claim 1. The phrase appears to attempt to invoke product-by-process language, but the phrase does not further limit the NK cells because ALL NK cells are influences by cytokines whether they are in vivo or in vitro. This too appears to be jargon that fails to further limit the NK cells in claim 1 in any meaningful way. This makes the claim indefinite, and those of skill would not be able to determine whether they were infringing on the claim.
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.
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.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3, 136, 137 are rejected 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).
Berrien-Elliott taught human “memory-like” NK cells comprising a CAR that targets a protein specific to AML. Berrien-Elliott did not teach the protein was NPM1c complexed with an MHC Class I protein as required in claim 1 or 136.
However, 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).
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to make an NK cell comprising a CAR that targets a AML as described by Greiner wherein the CAR targets an NPM1c protein in context of an HLA-A protein as described by Greiner. Those of ordinary skill in the art at the time of filing would have been motivated to obtain an NK capable of killing AML that expresses an NPM1c containing that peptide.
Claim 2 has been included because the CARs obtained is specific to the NPM1c-HLA-A complex.
The peptide described by Greiner is within the metes and bounds of the peptide in claim 3.
Claim 137 has been included because the NK cell MUST inherently increase expression of IFNgamma, granzyme B, and the other proteins listed upon binding a target cell because it has the exact same structure claimed.
Thus, Applicants' claimed invention as a whole is prima facie obvious in the absence of evidence to the contrary.
Conclusion
No claim is allowed.
Inquiry concerning this communication or earlier communications from the examiner should be directed to Michael C. Wilson who can normally be reached at the office on Monday through Friday from 9:30 am to 6:00 pm at 571-272-0738.
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Michael C. Wilson
/MICHAEL C WILSON/
Primary Examiner, Art Unit 1638