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 2, 3, 5, 7, 11-18, 21-26, 30, 33, 34, 40, 43 have been canceled. Claims 1, 4, 6, 8-10, 19, 20, 27-29, 31, 32, 35-39, 41, 42 are pending.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1, 4, 6, 8-10, 19, 20, 27-29, 31; PDL1; SEQ ID NO: 1; CTL; CAR; SEQ ID NO: 12 in the reply filed on 9-3-25 is acknowledged.
Claims 32, 35-39, 41, 42 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 9-3-25.
Claims 1, 4, 6, 8-10, 19, 20, 27-29, 31 are under consideration.
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, 4, 6, 8-10, 19, 20, 27-29, 31 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 an isolated mammalian cytotoxic T-cell comprising an exogenous nucleic acid sequence encoding PDL1 that expresses the PDL1 and an MHC molecule, does not reasonably provide enablement for the claims as broadly written. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make/use the invention commensurate in scope with these claims.
A) The specification lacks written description for a modified therapeutic cell comprising a first heterologous nucleic acid sequence encoding PDL1, wherein the therapeutic cell expresses a Major Histocompatibility Complex (MHC) molecule as being examined in claim 1 other than an isolated mammalian cell comprising an exogenous nucleic acid sequence encoding PDL1. The specification and the art at the time of filing are limited to an isolated mammalian cell comprising an exogenous nucleic acid sequence encoding PDL1. Nagy (CN 110869494) taught isolated mouse ES cells comprising an exogenous nucleic acid sequence encoding PDL1 (para 19). Themeli (AU 20140248119) taught mammalian cells transfected with a vector comprising an exogenous nucleic acid sequence encoding PDL1 and a CAR (claim 29). The cells inherently MUST express MHC as required in claim 1 because they are nucleated cells. PDL1 is the immune checkpoint ligand in claim 1. The specification and the art do not correlate isolated cells to cells in vivo. The specification and the art do not correlate expressing PDL1 in mammalian cells to expressing PDL1 in plant, invertebrate, insect, amphibian, reptile, or bird cells as broadly encompassed by claim 1. Therefore, the claim lacks written description except for isolated mammalian cells.
B) The specification lacks written description for any “variant thereof” of SEQ ID NO: 1 having at least about 85% identity to SEQ ID NO: 1 as broadly encompassed by claim 8 other than SEQ ID NO: 1.
SEQ ID NO: 1 was the species of PDL1 elected by applicants.
Claim 8 requires the “ICL comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 1-8 or variants thereof comprising an amino acid sequence that is at least about 85% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 1-8”.
The specification does not teach any assay to determine whether any fragment of SEQ ID NO: 1 is a functional variant of SEQ ID NO: 1. The specification does not teach any assay to determine whether any fragment of SEQ ID NO: 1 that shares at least about 85% identity to SEQ ID NO: 1 is a functional variant of SEQ ID NO: 1. The specification does not teach how to use any fragment of SEQ ID NO: 1 is not functional in a “modified therapeutic cells” as encompassed by claim 8. Accordingly, claim 8 lacks written description other than SEQ ID NO: 1.
C) The specification lacks written description for a cell comprising a first heterologous nucleic acid sequence encoding PDL1 and a second heterologous nucleic acid sequence encoding a chimeric antigen receptor (CAR) (elected in claims 19, 20), that are “present in a vector” as required in claim 27, “fused” “via a third nucleic acid sequence encoding a self-cleavable linker” as required in claim 28, or a first heterologous nucleic acid sequence encoding PDL1 and a second heterologous nucleic acid sequence encoding the amino acid sequence of SEQ ID NO: 12 as required in claim 29.
SEQ ID NO: 12 was the elected species in claim 29.
The art at the time of filing taught isolated mammalian T-cells and NK comprising a nucleic acid sequence encoding a CAR that targets PDL1 (CN 109161532; CN 109576307; CN 110079502), but SEQ ID NO: 12 encodes PDL1.
Fig. 1A shows a vector comprising a first heterologous nucleic acid sequence encoding an “ICP ligand” which can be PDL1.
Fig. 1B shows a vector encoding a CAR (“antigen-binding domain; hinge + transmembrane; costimulatory; CD3z”) and an ICP ligand (which can be PDL1 – pg 6, para 26).
SEQ ID NO: 12 comprises SEQ ID NO: 1 (amino acids 1-209) which encodes PLD1 (pg 37, para 131) plus amino acids 210-798 of a non-disclosed structure. Pg 69, lines 4-8, contemplates using SEQ ID NO: 12; however, the function of SEQ ID NO: 12 is not disclosed.
The specification does not teach how to use a cell that encodes PDL1 (SEQ ID NO: 1) and a CAR (SEQ ID NO: 12) that encodes PDL1 as required in claims 19, 20, 27, 28, 29. The specification does not teach SEQ ID NO: 12 is a CAR. Assuming it IS a CAR, the function of a CAR encoding PDL1 cannot be determined, and the function of expressing PDL1 along with a CAR encoding PDL1 is not disclosed and cannot be envisioned from the specification or the art at the time of filing. The specification does not teach how to use any plant, invertebrate, insect, fish, amphibian, reptile, bird, or mammalian cell encoding PDL1 and a CAR as broadly encompassed by claims 19, 20, 27-29. The specification does not correlate the function of SEQ ID NO: 12 to any other CARs as broadly encompassed by claims 12, 20, 27-29. The specification does not correlate the function of SEQ ID NO: 12 to SEQ ID NO: 12-27 in claim 29.
Given the lack of guidance in the specification taken with the art at the time of filing, the concept lacks written description.
Enablement
Claims 1, 4, 6, 8-10, 19, 20, 27-29, 31 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 an isolated mammalian cell comprising an exogenous nucleic acid sequence encoding PDL1, does not reasonably provide enablement for the claims as broadly written. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make/use the invention commensurate in scope with these claims.
A) The specification does not enable making/using a modified therapeutic cell comprising a first heterologous nucleic acid sequence encoding PDL1, wherein the therapeutic cell expresses a Major Histocompatibility Complex (MHC) molecule as being examined in claim 1 other than an isolated mammalian cell comprising an exogenous nucleic acid sequence encoding PDL1. The specification and the art at the time of filing are limited to an isolated mammalian cell comprising an exogenous nucleic acid sequence encoding PDL1. Nagy (CN 110869494) taught isolated mouse ES cells comprising an exogenous nucleic acid sequence encoding PDL1 (para 19). Themeli (AU 20140248119) taught mammalian cells transfected with a vector comprising an exogenous nucleic acid sequence encoding PDL1 and a CAR (claim 29). The cells inherently MUST express MHC as required in claim 1 because they are nucleated cells. PDL1 is the immune checkpoint ligand in claim 1. The specification and the art do not correlate isolated cells to cells in vivo. The specification and the art do not correlate expressing PDL1 in mammalian cells to expressing PDL1 in plant, invertebrate, insect, amphibian, reptile, or bird cells as broadly encompassed by claim 1. Given the lack of guidance in the specification taken with the art at the time of filing, it would have required those of skill undue experimentation to determine how to make/use any species of cell in vivo or in vitro as broadly encompassed by claim 1 other than isolated mammalian cells.
B) The specification does not enable making/using a cell comprising a first heterologous nucleic acid sequence encoding PDL1 and a second heterologous nucleic acid sequence encoding a chimeric antigen receptor (CAR) (elected in claims 19, 20), that are “present in a vector” as required in claim 27, “fused” “via a third nucleic acid sequence encoding a self-cleavable linker” as required in claim 28, or a first heterologous nucleic acid sequence encoding PDL1 and a second heterologous nucleic acid sequence encoding the amino acid sequence of SEQ ID NO: 12 as required in claim 29.
SEQ ID NO: 12 was the elected species in claim 29.
The art at the time of filing taught isolated mammalian T-cells and NK comprising a nucleic acid sequence encoding a CAR that targets PDL1 (CN 109161532; CN 109576307; CN 110079502), but SEQ ID NO: 12 encodes PDL1.
Fig. 1A shows a vector comprising a first heterologous nucleic acid sequence encoding an “ICP ligand” which can be PDL1.
Fig. 1B shows a vector encoding a CAR (“antigen-binding domain; hinge + transmembrane; costimulatory; CD3z”) and an ICP ligand (which can be PDL1 – pg 6, para 26).
SEQ ID NO: 12 comprises SEQ ID NO: 1 (amino acids 1-209) which encodes PLD1 (pg 37, para 131) plus amino acids 210-798 of a non-disclosed structure. Pg 69, lines 4-8, contemplates using SEQ ID NO: 12; however, the function of SEQ ID NO: 12 is not disclosed.
The specification does not teach how to use a cell that encodes PDL1 (SEQ ID NO: 1) and a CAR (SEQ ID NO: 12) that encodes PDL1 as required in claims 19, 20, 27, 28, 29. The specification does not teach SEQ ID NO: 12 is a CAR. Assuming it IS a CAR, the function of a CAR encoding PDL1 cannot be determined, and the function of expressing PDL1 along with a CAR encoding PDL1 is not disclosed and cannot be envisioned from the specification or the art at the time of filing. The specification does not teach how to use any plant, invertebrate, insect, fish, amphibian, reptile, bird, or mammalian cell encoding PDL1 and a CAR as broadly encompassed by claims 19, 20, 27-29. The specification does not correlate the function of SEQ ID NO: 12 to any other CARs as broadly encompassed by claims 12, 20, 27-29. The specification does not correlate the function of SEQ ID NO: 12 to SEQ ID NO: 12-27 in claim 29.
Given the lack of guidance in the specification taken with the art at the time of filing, it would have required those of skill undue experimentation to determine how to make/use any cell as required in claims 19, 20, 27-29.
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, 4, 6, 9, 10, 19, 20, 27, 28, 31 are rejected under 35 U.S.C. 102a1 as being anticipated by Nagy (CN 110869494).
Nagy taught isolated mouse ES cells comprising an exogenous nucleic acid sequence encoding PDL1 (para 19); the cells inherently MUST express MHC as required in claim 1 because they are nucleated cells. PDL1 is the immune checkpoint ligand in claim 1.
Nagy did not teach modifying the B2M gene as required in claim 4.
Nagy taught PDL1 as required in claim 6.
The cells are immune cells, e.g. T-cells, B-cells, natural killer cells, dendritic cells, peripheral blood lymphocytes (para 28 et al), as required in claims 9 and 10.
Nagy taught the cell further comprised an exogenous nucleic acid sequence encoding an engineered receptor (para 353, 397, 403) as required in claim 19.
Nagy taught the receptor was an Fc-receptor fusion protein (para 403) which is a “chimeric antigen receptor” (CAR) as required in claim 20.
The exogenous sequence encoding the receptor can be operably linked to the first exogenous sequence in a vector (para 353) as required in claims 27, 28.
The cell is a pharmaceutically composition as required in claim 31 because it is in pH balanced culture medium.
Claims 1, 4, 6, 9, 10, 19, 20, 27, 28, 31 are rejected under 35 U.S.C. 102a1 as being anticipated by Themeli (AU 20140248119).
Themeli taught isolated cells transfected with a vector comprising an exogenous nucleic acid sequence encoding PDL1 and a CAR (claim 29). The cells inherently MUST express MHC as required in claim 1 because they are nucleated cells. PDL1 is the immune checkpoint ligand in claim 1.
Themeli modifying or not modifying the B2M gene (claim 1 vs. 15). Not modifying the B2M gene as encompassed by Themeli is equivalent to claim 4.
Themeli taught PDL1 (claim 29) as required in claim 6.
The cells are immune cells, e.g. T-cells, B-cells, natural killer cells, dendritic cells, peripheral blood lymphocytes (claim 16), as required in claims 9 and 10.
Themeli taught the cell further comprised an exogenous nucleic acid sequence encoding an engineered receptor (claim 1) as required in claim 19.
Themeli taught the receptor was an (CAR) (claim 1) as required in claim 20.
Themeli taught exogenous sequence encoding the CAR can be operably linked to another exogenous coding sequence in a vector (Fig. 4) as required in claims 27, 28.
The cell is a pharmaceutically composition as required in claim 31 because it is in pH balanced culture medium.
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.
A) Claims 1, 4, 6, 8, 9, 10, 19, 20, 27, 28, 31 are rejected under 35 U.S.C. 102a1 as being unpatentable over Nagy (CN 110869494) in view of Freeman (J. Exp. Med., 2000. Vol. 192, pg 1027-1034).
Nagy taught ES cells comprising an exogenous nucleic acid sequence encoding PDL1 (para 19); the cells inherently MUST express MHC as required in claim 1 because they are nucleated cells. PDL1 is the immune checkpoint ligand in claim 1.
Nagy did not teach the PDL1 had an amino acid sequence that is at least 85% identical to SEQ ID NO: 1 as required in claim 8.
However, Freeman taught an amino acid sequence encoding human PDL1 that is at least 85% identical to SEQ ID NO: 1 (Fig. 1).
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to make cells comprising an exogenous nucleic acid sequence encoding PDL1 that inherently express endogenous MHC as described by Nagy wherein the PDL1 was human and had an amino acid sequence that is at least 85% identical to SEQ ID NO: 1 as described by Freeman. Those of ordinary skill in the art at the time of filing would have been motivated to express human PDL1 to humanize the mouse cell, to study “negative regulation of lymphocyte activation” in vitro as described by Freeman (title; pg 1028, 1st full paragraph).
Claims 1, 4, 6, 9, 10, 19, 20, 27, 28, 31 have been included for reasons set forth above under anticipation.
Thus, Applicants' claimed invention as a whole is prima facie obvious in the absence of evidence to the contrary.
B) Claims 1, 4, 6, 8, 9, 10, 19, 20, 27, 28, 31 are rejected under 35 U.S.C. 102a1 as being unpatentable over Themeli (AU 20140248119) in view of Freeman (J. Exp. Med., 2000. Vol. 192, pg 1027-1034).
Themeli taught cells transfected with a vector comprising an exogenous nucleic acid sequence encoding PDL1 and a CAR (claim 29). The cells inherently MUST express MHC as required in claim 1 because they are nucleated cells. PDL1 is the immune checkpoint ligand in claim 1.
Themeli did not teach the PDL1 had an amino acid sequence that is at least 85% identical to SEQ ID NO: 1 as required in claim 8.
However, Freeman taught an amino acid sequence encoding human PDL1 that is at least 85% identical to SEQ ID NO: 1 (Fig. 1).
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to make cells comprising an exogenous nucleic acid sequence encoding PDL1 that inherently express endogenous MHC as described by Nagy wherein the PDL1 was human and had an amino acid sequence that is at least 85% identical to SEQ ID NO: 1 as described by Themeli. Those of ordinary skill in the art at the time of filing would have been motivated to express human PDL1 to humanize the mouse cell, to study “negative regulation of lymphocyte activation” in vitro as described by Freeman (title; pg 1028, 1st full paragraph).
Claims 1, 4, 6, 9, 10, 19, 20, 27, 28, 31 have been included for reasons set forth above under anticipation.
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