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 .
Claim Status Summary
Claims 1- 26 are pending.
Claims 1- 26 are considered on the merits.
Claims 1- 26 are rejected.
No Claims are allowed.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 12 and 21 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Regarding claim 12, the claim limitation recites “a kit comprising an allogeneic modified immune cell of claim 8.” The specification does not provide a definition for the term “kit”. Accordingly, the term “kit” is interpretated as merely the sum of its contents. Since the only contents specified in the “kit” is “an allogeneic modified immune cell of claim 8”, this claim fails to further limit the subject matter of the claim from which it depends. The instant claim limitation of “a kit” is not further limiting because a kit may comprise only the components of claim 8.
Regarding claim 21, Claim 21 requires a vector and does not require a polypeptide (as required by claim 14). Claim 21 depends from claim 14. However, claim 21 does not require a polypeptide, therefore claim 21 fails to include all of the limitations of the claim from which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Claim(s) 14, 15, 16, 17, 21, and 22 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Conway (Conway WO 2020097188 A1).
Regarding claim 14, Conway teaches “Also provided are molecules identified by the methods described herein… the molecule is a fusion protein comprising the HLA-E and/or HLA-G receptor and a B2M protein, optionally comprising an additional peptide (e.g., nonameric G-derived peptide such as VMAPRTLFL (SEQ ID NO:1)” [0009]. It is worth noting that Conway describes the HLA molecules as “receptors” rather than ligands previously in this same paragraph, “the molecule is endogenous or exogenous to the donor cell, optionally a molecule an endogenous invariant HLA class I molecule (e.g., HLA-E and/or HLA-G receptor).” The instant specification identifies a species of “loading peptide” as having the sequence “VMAPRTLFL” [page 398] which matches Conway’s nonameric G-derived peptide SEQ ID NO 1 100%.
Regarding claim 15, 16, and 17, Conway further teaches their fusion protein is oriented from N-terminus to C-terminus: B2M, loading peptide, and HLA-G as shown in FIG. 4 (shown below). Conway teaches “In certain embodiments, the genetically modified cells of the invention comprise a transgene encoding an HLA-E or HLA-G trimer, which trimer comprises B2M sequences, HLA-E and/or G sequences (wild-type or mutated) and a peptide (e.g., nonameric G-derived peptide) is expressed on the surface of the cells and reduces susceptibility to NK-mediated killing. See, Figure 4. Any peptide sequence can be used including, but not limited to … VMAPRTLFL (SEQ ID NO: 1 )” [0210].
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Claim(s) 18 and 19 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Russell (Russell US 20140134195 A1).
Regarding claim 18, Russell teaches a 500 AA protein SEQ ID No 20 that matches 95.9% with instant SEQ ID No 1015 and residues 1-437 (of SEQ ID NO 1015’s 458 residues) align 100% with residues 1- 437 of Russell’s SEQ ID NO 20 (alignment shown below).
SEQ ID NO 1015 1 MSRSVALAVLALLSLSGLEAVMAPRTLFLGGGGSGGGGSGGGGSIQRTPKIQVYSRHPAE 60
SEQ ID NO 20 1 MSRSVALAVLALLSLSGLEAVMAPRTLFLGGGGSGGGGSGGGGSIQRTPKIQVYSRHPAE 60
SEQ ID NO 1015 61 NGKSNFLNCYVSGFHPSDIEVDLLKNGERIEKVEHSDLSFSKDWSFYLLYYTEFTPTEKD 120
SEQ ID NO 20 61 NGKSNFLNCYVSGFHPSDIEVDLLKNGERIEKVEHSDLSFSKDWSFYLLYYTEFTPTEKD 120
SEQ ID NO 1015 121 EYACRVNHVTLSQPKIVKWDRDMGGGGSGGGGSGGGGSGGGGSGSHSLKYFHTSVSRPGR 180
SEQ ID NO 20 121 EYACRVNHVTLSQPKIVKWDRDMGGGGSGGGGSGGGGSGGGGSGSHSLKYFHTSVSRPGR 180
SEQ ID NO 1015 181 GEPRFISVGYVDDTQFVRFDNDAASPRMVPRAPWMEQEGSEYWDRETRSARDTAQIFRVN 240
SEQ ID NO 20 181 GEPRFISVGYVDDTQFVRFDNDAASPRMVPRAPWMEQEGSEYWDRETRSARDTAQIFRVN 240
SEQ ID NO 1015 241 LRTLRGYYNQSEAGSHTLQWMHGCELGPDGRFLRGYEQFAYDGKDYLTLNEDLRSWTAVD 300
SEQ ID NO 20 241 LRTLRGYYNQSEAGSHTLQWMHGCELGPDGRFLRGYEQFAYDGKDYLTLNEDLRSWTAVD 300
SEQ ID NO 1015 301 TAAQISEQKSNDASEAEHQRAYLEDTCVEWLHKYLEKGKETLLHLEPPKTHVTHHPISDH 360
SEQ ID NO 20 301 TAAQISEQKSNDASEAEHQRAYLEDTCVEWLHKYLEKGKETLLHLEPPKTHVTHHPISDH 360
SEQ ID NO 1015 361 EATLRCWALGFYPAEITLTWQQDGEGHTQDTELVETRPAGDGTFQKWAAVVVPSGEEQRY 420
SEQ ID NO 20 361 EATLRCWALGFYPAEITLTWQQDGEGHTQDTELVETRPAGDGTFQKWAAVVVPSGEEQRY 420
SEQ ID NO 1015 421 TCHVQHEGLPEPVTLRW 437
SEQ ID NO 20 421 TCHVQHEGLPEPVTLRW 437
Furthermore, Russell describes their fusion protein, “Sequences for exemplary single chain fusion HLA class I proteins are provided for HLA-bGBE (SEQ ID NO: … 20)” [0020]. Russell further provides an exemplary image in FIG 3B (shown below).
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Regarding claim 19, Russell teaches the fusion protein as described in the image 3D above. The image highlights a membrane (domain) bound peptide, a β2M domain, and an HLA-E domain.
Regarding claim 20, Russell teaches a 500 AA protein SEQ ID No 20 that matches 95.4% with instant SEQ ID No 1019. Furthermore, bases 1- 447 of the 473 bases of Instant SEQ ID NO 1019 Match 100% with bases 1- 447 of Russell’s SEQ ID NO 20. Russell describes their fusion protein, “Sequences for exemplary single chain fusion HLA class I proteins are provided for HLA-bGBE (SEQ ID NO: … 20)” [0020]. Russell further provides an exemplary image in FIG 3B (shown above).
Regarding claim 21, Conway teaches all of the elements of claim 14.
Conway further teaches “In some embodiments, the molecule [from claim 14 above: fusion protein comprising the HLA-E and/or HLA-G receptor and a B2M protein [0009]] is incorporated (e.g., integrated into the cell episomally or by targeted integration into the genome) in the donor cell and allows the donor cell to have a longer half-life when introduced into the subject.“[0016]. The instant specification teaches episomal vectors, “Vectors include … episomes” [page 91]. Furthermore, Conway teaches, “As noted above, the disclosed methods and compositions can be used in any type of cell including, but not limited to, … mammalian cells and human cells, including T-cells ... Suitable cell lines for protein expression are known to those of skill in the art and include, but are not limited to… CHO” [0020].
Regarding claim 22, Conway teaches all of the elements of claims 14 and 21.
Conway further teaches “Thus, described herein are genetically modified cells (e.g., allogenic or autologous CD8+ T-cells, CD4+ T-cells, or stem cell memory T cells (Tscm), NK cells)” [0208].
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.
Claim(s) 1, 2, 3, 5, 6, 7, 8, 10, 12, and 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Meissner (Meissner US 20190309259 A1, and further in view of Gaudelli (Gaudelli et al. Nat Biotechnol. 2020 Jul;38(7):892-900. Epub 2020 Apr 13.).
Regarding claim 1, 7, 8, and 10, Meissner teaches “universal donor stem cells and related methods of their use and production. The universal donor stem cells disclosed herein are useful for overcoming the immune rejection in cell-based transplantation therapies” [Abstract]; and “Disclosed herein are efficient strategies to overcome immune rejection in cell-based transplantation therapies by the creation of universal donor stem cell lines” [0005]. Here, Meissner teaches the claim limitations “a method for producing a persistent allogeneic modified … cell.” Meissner further teaches “methods for producing hypoimmunogenic stem cells, the method comprising contacting a stem cell with a Cas protein or a nucleic acid sequence encoding the Cas protein” and “and a first pair of ribonucleic acids having sequences selected from the group consisting of [gRNAs] SEQ ID NOs: 36353-81239, thereby editing the NLRC5 gene to reduce or eliminate NLRC5 surface expression and/or activity in the cell” [0018]. Here, Meissner teaches the claim limitations “contacting a cell with a base editor comprising a polynucleotide programmable DNA binding polypeptide (napDNAbp), a deaminase, and one or more guide RNAs (gRNAs) that target the base editor to effect an alteration in a nucleic acid molecule, wherein the 5 nucleic acid molecule encodes a polypeptide and/or comprises a regulatory element associated with expression thereof, and wherein the polypeptide is selected from the group
consisting of … NLRC5.”
Meissner does not teach an “immune" cell” or “the method comprising contacting a cell with … a deaminase.”
However, Meissner further teaches additional altered nucleic acid molecules encoding polypeptides similar to NLRC5 above, “thereby editing the CIITA gene to reduce or eliminate CIITA surface expression” [0019]; and “thereby editing the B2M gene to reduce or eliminate B2M surface expression and/or activity in the cell” [0020].
Gaudelli teaches the deaminase by stating “ABE is a molecular machine comprising an evolved Escherichia coli tRNAARG-modifying enzyme, TadA, covalently fused to a catalytically impaired Cas9 protein (D10A nickase Cas9, nCas9) (Fig. 1a,b, not shown). A single guide RNA (sgRNA) directs the ABE to a target genomic DNA sequence and, upon binding and stable R-loop formation, a short stretch of single stranded nucleotides becomes accessible to TadA, an enzyme that chemically converts adenine to inosine.” (page 892, 1st column, 1st paragraph). Gaudelli further teaches the immune cell by stating “We next evaluated the activities of ABE8 in primary human T cells.” (page 896, 1st column 2nd paragraph). Gaudelli further teaches “We targeted B2M, CIITA, and TRAC, three genes that when disrupted confer reduced cell surface expression of MHC class I, MHC class II, and the T-cell receptor respectively, phenotypes that are proposed to reduce alloreactivity and immune recognition in the context of allogeneic cell therapies.” (page 896, 1st column 2nd paragraph). Gaudelli further teaches a motivation to use their ABE8 in a system like Meisner’s “Approaches using nucleases to introduce indel mutations
in target genes, thereby disrupting their expression in T cells, are effective, but simultaneous creation of multiple DSBs in a target cell can result in genomic rearrangements and toxicities with variable frequencies. Because ABEs function by making single nucleotide genomic changes without creating DSBs, multiplexed base editing with ABE8 is an attractive approach for the creation of genetically modified T cells. To” (page 896, 1st column, 3rd paragraph).
The claim limitation “producing the persistent allogeneic modified immune cell” is merely a summary of the claim and does not further limit the claims. Therefore, it is not given any patentable weight.
It would have been obvious for a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to have incorporated Gaudelli’s ABE (ABE8) base editor-deaminase and T cell immune cell into Meissner’s method for producing a persistent allogeneic modified stem cell because there was some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention (“TSM”). As noted above, Gaudelli explicitly taught both the benefits of their ABE8 system and the challenges of Meissner’s Cas based system. Both Meissner and Gaudelli taught successful methods to make persistent allogeneic modified cells by exploiting nucleic acid guided enzymes targeting similar genes. Gaudelli further showed their method was compatible with immune cells. Therefore, a PHOSITA would have had a reasonable expectation of success using Gaudelli’s T cell and ABE8 base editor in Meissner’s method of producing allogeneic cells.
Regarding claim 2, Meissner teaches the embodiment “wherein the nucleic acid molecule encodes a polypeptide and/or comprises a regulatory element associated with expression thereof, and wherein the polypeptide is selected from the group consisting of beta-2 microglobulin (B2M)” as described above.
Regarding claim 3, Meissner teaches the embodiment “a nucleobase alteration that reduces expression on the cell of a polypeptide selected from the group consisting of HLA-C” by disclosing “the methods disclosed herein further comprise modulating expression of one or more tolerogenic factors by the stem cell. … such tolerogenic factors are selected from the group consisting of HLA-C” [0009].
Regarding claim 5, Meissner further teaches the embodiment “Also disclosed herein are methods of preparing a hypoimmunogenic stem cell, the method comprising modulating expression of one or more tolerogenic factors … In certain embodiments, modulating expression of the tolerogenic factors comprises increasing the expression of the tolerogenic factors… such tolerogenic factors are selected from the group consisting of … HLA-E, HLA-G, PD-L1, … CD47” [0010].
Regarding claim 6, Meissner and Gaudelli teach the preamble and clause (a) of claim 6 as applied to claim 1 above. Meissner further teaches all of the elements of clause (b) of claim 6 as applied to claim 5 above.
Regarding claim 10, Meissner and Gaudelli teach all of the elements of claim 10. In particular, the “composition comprising a guide RNA (gRNA) and a polynucleotide encoding a base editor” are the components in with which Meissner-Gaudelli use in “contacting a stem cell”.
Regarding claim 12, Meissner and Gaudelli teach all of the elements of claim 8. Furthermore, the instant claim limitation of “a kit” is not further limiting, nor does the disclosure on page 11 “the kit contains written instructions” constitute further limiting (see MPEP 2112.01).
Regarding claim 23, Meissner and Gaudelli teach all of the elements of claim 23 as described above in claim 1 except for the limitation “that target the napDNAbp to cleave a target nucleic acid molecule and introduce an alteration in the target nucleic acid molecule”
Meissner teaches this instant limitation by stating, “Also disclosed are hypoimmunogenic stem cells comprising … a first genomic modification in which the CIITA gene has been edited to delete a first contiguous stretch of genomic DNA… wherein the first contiguous stretch of genomic DNA has been deleted by contacting the cell with a Cas protein or a nucleic acid encoding a Cas protein and a first pair of ribonucleic acids.” [0031].
Claim(s) 24 and 25, is/are rejected under 35 U.S.C. 103 as being unpatentable over Meissner (Meissner US 20190309259 A1) and Gaudelli (Gaudelli et al. Nat Biotechnol. 2020 Jul;38(7):892-900. Epub 2020 Apr 13.) as applied to claim 1 above, and further in view of Barnea (Barnea US 20220249603 A1).
Regarding claim 24 and 25, Meissner and Gaudelli teach all of the elements of claim 24 as described above in claim 1 except for the limitation “wherein the persistent allogeneic modified immune cell surface-expresses HLA-C.”
Meissner further teaches this instant limitation by stating, “Also disclosed herein are methods of preparing a hypoimmunogenic stem cell, the method comprising modulating expression of one or more tolerogenic factors … In certain embodiments, modulating expression of the tolerogenic factors comprises increasing the expression of the tolerogenic factors… such tolerogenic factors are selected from the group consisting of HLA-C” [0009].
Barnea teaches they are in the same field of endeavor by stating “This application also describes the use of those compounds [preimplantation factor (PIF) peptides] for improving transplant tolerance, for restoring endocrine function, and for the treatment of transplant recipients of partial endocrine tissue grafts.” [Abstract]. Barnea further teaches “The disclosure also provides a method of inducing transplant tolerance of one or a plurality of donor semi-allogeneic cell and/or cells derived from a species other than the transplant recipient in a recipient subject by increasing expression of HLA-Class I molecules in the subject or on the donor cells to an amount sufficient to increase the likelihood of transplant acceptance of the cells” [0028]. Barnea further teaches one of their embodiments expresses surface HLA-C “In cytotrophoblastic JEG-3 cells PIF increased … surface expression of … HLA-C” [0171].
It would have been obvious for a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to have taken the method of Meissner-Gaudelli and included Barnea’s PIF because it is simply combining prior art elements according to known methods to yield predictable results. Meissner-Gaudelli teach method for producing a persistent allogeneic modified immune cells, including expression of HLA-C. Barnea’s method of PIF is a versatile method that promotes surface-expression of HLA-C. A PHOSITA looking to enhance tolerance (persistence) would have recognized Barnea’s PIF would enhance persistence similarly as, and compatible with, the method of Meissner-Gaudelli. Therefore, a PHOSITA would have predicted the PIF’s of Barnea would successfully enhance immune cells in the method of Meissner-Gaudelli.
Claim(s) 4 is/are rejected under 35 U.S.C. 103 as being unpatentable over Meissner (Meissner US 20190309259 A1) and Gaudelli (Gaudelli et al. Nat Biotechnol. 2020 Jul;38(7):892-900. Epub 2020 Apr 13.) as applied to claim 1 above, and further in view of Hotta (Hotta US 20200407693 A1).
Regarding claim 4, Meissner and Gaudelli teach all of the elements of claim 1.
Meissner and Gaudelli do not teach the limitation “wherein the one or more gRNAs comprise a nucleotide sequence with at least about 85% sequence identity to GCACUCACCCGCCCAGGUCU (SEQ ID NO: 817; TSBTx4190), GACCCGCAUCUCGGCGUCUG (SEQ ID NO: 827; TSBTx4200), CCUUACCCCAUCUCAGGGUG (SEQ ID NO: 820; TSBTx4193), and/or CUUACCCCAUCUCAGGGUGA (SEQ ID NO: 821; TSBTx4194).”
However, Meissner further teaches “The present inventors have successfully employed genome editing tools such as a … CRISPR system … to reduce expression or knock out the highly polymorphic classical MHC-I genes (HLA-A. HLA-B and HLA-C)” [0006].
Hotta teaches their invention is in the same field of endeavor “A method for producing, from a donor cell, a low-antigenic cell in which a rejection reaction is reduced in a case where the cell is allogeneically transplanted into a recipient, the method including: determining human leukocyte antigen (HLA) alleles for the donor cell and the recipient, respectively; specifying an HLA allele that is present in the donor cell but is not present in the recipient; and disrupting or modifying the specified HLA allele to obtain a cell population including a cell not expressing an HLA protein specific to the donor cell, in which the cell not expressing the HLA protein specific to the donor cell is the low-antigenic cell.” [Abstract]. Hotta teaches a 23 base long SEQ ID NO 7482. Bases 2- 21 of Hotta’s SEQ ID NO 7482 pairs 100% with all 20 bases of the instant claimed SEQ ID NO 827. Hotta further teaches the HLA specificity of their SEQ ID NO 7482, “[25] A gRNA targeting, as a target base sequence, a base sequence that is mapped to two or more target HLA haplotypes” [0046]; and “The gRNA according to [25], in which the target base sequence consists of a base sequence set forth in any of SEQ ID NOs: … 2460 to 8013” [0047].
It would have been obvious for a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to have used Hotta’s gRNA SEQ ID NO 7482 with Meissner-Guadelli’s method for producing a persistent allogeneic modified immune cell because it is a simple substitution of one known element for another to obtain predictable results. Meissner-Guadelli’s method utilizes HLA targeted gRNAs. Hotta’s gRNA SEQ ID NO 7482 similarly targets HLA. Therefore, a PHOSITA would have predicted the substitution of Hotta’s HLA targeting gRNA would work successfully in Meissner-Guadelli’s method that also requires HLA targeting gRNAs.
Claim(s) 11, is/are rejected under 35 U.S.C. 103 as being unpatentable over Meissner (Meissner US 20190309259 A1) and Gaudelli (Gaudelli et al. Nat Biotechnol. 2020 Jul;38(7):892-900. Epub 2020 Apr 13.) as applied to claims 1 and 10 above, and further in view of Hotta (Hotta US 20200407693 A1) as applied to claim 4 above.
Regarding claim 11, Meissner and Gaudelli teach all of the elements of claims 1 and 10 and Hotta teaches all of the elements of claims 4.
Based on the teachings of Meissner, Gaudelli, and Hotta as described above, it would have been obvious to a PHOSITA at the time of filing to have used Hotta’s gRNA SEQ ID NO 7482 with Meissner-Guadelli’s composition comprising a guide RNA (gRNA) and a polynucleotide encoding a base editor because it is a simple substitution of one known element for another to obtain predictable results. Meissner-Guadelli’s composition utilizes HLA targeted gRNAs. Hotta’s gRNA SEQ ID NO 7482 similarly targets HLA. Therefore, a PHOSITA would have predicted the substitution of Hotta’s HLA targeting gRNA would work successfully in Meissner-Guadelli’s composition that also requires HLA targeting gRNAs.
Claim(s) 9, 13, and 24 is/are rejected under 35 U.S.C. 103 as being unpatentable over Meissner (Meissner US 20190309259 A1) and Gaudelli (Gaudelli et al. Nat Biotechnol. 2020 Jul;38(7):892-900. Epub 2020 Apr 13.) as applied to claim 8 above, and further in view of Bolen (Bolen US 20200093865 A1).
Regarding claim 9, Meissner and Gaudelli teach all of the elements of claim 8.
Meissner and Gaudelli do not teach the limitation “A pharmaceutical composition comprising an effective amount an allogeneic modified immune cell.”
However, Meissner teaches “Provided herein are novel cells, compositions and methods that are useful for addressing such HLA-based immune rejection of transplanted cells.” [0216]. Meissner further teaches a motivation for pharmaceutical compositions in their background “Needed are novel … compositions … for overcoming immune rejection associated with cell replacement therapies” [0004].
Bolen teaches they are in the same field of endeavor and simultaneously teaches a pharmaceutical composition, “the present disclosure provides methods for treating a hematopoietic malignancy, the method comprising administering to a subject in need thereof (i) a population of the genetically engineered hematopoietic cells described herein, and optionally (ii) a cytotoxic agent such as CAR-T cells that target a lineage-specific cell-surface antigen, the gene of which is genetically edited in the hematopoietic cells such that the cytotoxic agent does not target hematopoietic cells or descendant cells thereof… In some embodiments, the cytotoxic agents and/or the hematopoietic cells may be mixed with a pharmaceutically acceptable carrier to form a pharmaceutical composition, which is also within the scope of the present disclosure.” [0549].
It would have been obvious for a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to have taken Meissner-Gaudelli’s allogeneic modified immune cell of and formulated a pharmaceutical composition as taught by Bolen because there was some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention (“TSM”). Meissner described the need and therefore motivation for compositions of allogeneic modified immune cells. Bolen provided teachings that immune cell compositions, similar to Meissner’s could be successfully formulated into pharmaceutical compositions. Therefore, a PHOSITA combining the cells of Meissner-Gaudelli with the pharmaceutical composition of Bolen would similarly have a reasonable expectation of success.
Regarding claim 13, Meissner-Gaudelli and Bolen teach all of the elements of claims 8 and 9.
Furthermore, Meissner teaches “Humans have three classical MHC-Ia molecules (HLA-A, HLA-B, and HLA-C), which are vital to the detection and elimination of viruses, cancerous cells, and transplanted cells… Provided herein are novel cells, compositions and methods that are useful for addressing such HLA-based immune rejection of transplanted cells.” [0216].
Regarding claim 26, Meissner-Gaudelli teach all of the elements of the methods of claim 24 and 25 as described above. Furthermore, Meissner-Gaudelli and Bolen teach all of the elements of treating cancer as described in claims 8 and 9 above.
Furthermore, Meissner teaches “Humans have three classical MHC-Ia molecules (HLA-A, HLA-B, and HLA-C), which are vital to the detection and elimination of viruses, cancerous cells, and transplanted cells… Provided herein are novel cells, compositions and methods that are useful for addressing such HLA-based immune rejection of transplanted cells.” [0216].
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 1-5, and 7 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 7, 8, 10, 11, 19, 20 of copending Application No. 19/331836 (reference application) and further in view of Yang (Yang et al. Biosci Trends. 2013 Feb;7(1):50-5.), and Meissner (Meissner US 20190309259 A1) and Gaudelli (Gaudelli et al. Nat Biotechnol. 2020 Jul;38(7):892-900. Epub 2020 Apr 13.), and Hotta (Hotta US 20200407693 A1) as applied to the instant claims 1-5 and 7 above. Although the claims at issue are not identical, they are not patentably distinct from each other because claim 1 of the instant application is an obvious variant of the reference application.
Reference application’s claim 7 recites:
“A method for producing a modified allogeneic immune effector cell having increased resistance to an immunosuppressant agent, the method comprising contacting the cell with:
(i) a base editor, or a polynucleotide encoding the base editor, wherein the base editor comprises a programmable DNA binding domain and a deaminase domain; and
(ii) a guide polynucleotide, or a polynucleotide encoding the guide polynucleotide, wherein the guide polynucleotide directs the base editor to effect a nucleobase alteration in a polynucleotide encoding a polypeptide selected from the group consisting of FK506-binding protein 1A (FKBP1A), nuclear receptor subfamily 3, group C, member 1 (NR3C1), and peptidyl-prolyl isomerase A (PPIA)…”
This language is nearly identical to instant claim 1 except for the selection of polypeptides. The instant claim 1 rather offers the following polypeptide selection:
“HLA-A, HLA-B, HLA-C, Transporter Associated with Antigen Processing I (TAP1), Transporter Associated with Antigen Processing II (TAP2), Tapasin/TAP Binding Protein (TAPBP), TAP-Binding Protein-Like (TAPBPL), NLR family CARD domain containing 5 (NLRC5)/MHC class I transactivator (CITA), cluster of differentiation 155 (CD155), MHC class I polypeptide-related sequence A (MICA), MHC class I polypeptide-related sequence B (MICB) polypeptide, nectin cell adhesion molecule 2 (Nectin-2), and UL16 binding protein 1-6 (ULBP).”
However, claim 9 of the reference application presents the same obvious polypeptide option/variant, class II major histocompatibility complex transactivator (CIITA), that is claimed in the instant application’s claim 1. Claim 9 is directed toward a modified persistent allogeneic cell. Yang teaches CIITA is involved in cell immunogenicity “Class II transactivator (CIITA) gene is a chief regulator of major histocompatibility complex class II (MHC II) molecules which contributes to the immunogenicity of Schwann cells.”
Therefore, It would have been obvious for a PHOSITA at the time of filing to have selected the CIITA peptide of claim 9 (reference application) in combination with the modified immune cell of claim 7 (reference application) to arrive at the instant invention of claim 1 because Yang taught CIITA protein expression is a viable target for cell immunogenicity in combination with the immune cell of the reference application.
Regarding claims 2-5, and 7, copending Application No. 19/331836 (reference application) in view of Yang claim all of the elements of claim 1 as described above. Similarly, Meissner and Gaudelli teach all of the claimed elements of claims 2, 3, 5, and 7 as described above. Therefore, for the reasons described above and in view of the reference application’s claim 7 and the teachings of Meissner and Gaudelli, claims 2-5, and 7 would have been obvious for a PHOSITA before the time of filing of the claimed invention.
Likewise, claim 4 would be obvious for a PHOSITA before the time of filing of the claimed invention in view of the reference application’s claim 7 and Hotta’s gRNA SEQ ID NO 7482 as described above.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
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/AARON DUREL WARD/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
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