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 .
Election/Restrictions
Applicant's election with traverse of Group I (claims 1-36, which are directed to a method of preparing a population of modified unstimulated immune cells) in the reply filed on 16 Oct, 2025 is acknowledged. The traversal is on the ground(s) that the search and examination of the three Groups does not present an undue burden to the Office.
This is not found persuasive because the searching of the three groups would require the consideration of different prior art, for instance, as the modified unstimulated immune cells of Invention I requires ribonucleoprotein complex Cas9 gene editing via homology-directed repair on TRAC locus while Invention II and III are directed to product-by-process claims wherein the modified unstimulated or stimulated immune cells can be generated using materially different method such as vector delivery as it is product-by-process claims.
Therefore, the requirement is still deemed proper and is therefore made FINAL.
Claim Status
Claims 1-47 are currently pending. Claims 37-47 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Accordingly, claims 1-36 are examined herein.
Information Disclosure Statement
The information disclosure statement filed 23 Feb, 2023 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein has not been considered.
Priority
Acknowledgment is made of applicant's claim for domestic priority based on a US provisional application No. 63/071,236 filed on 27 Aug, 2020.
Specification
This application does not contain an abstract of the disclosure as required by 37 CFR 1.72(b). An abstract on a separate sheet is required.
Claim Rejections - 35 USC § 102
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 1-18, 26-18, 30-36 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Roth (WO 2018/232356 A1; Published Date: 20 Dec, 2018).
Regarding claim 1, Roth teaches a method of editing the genome of naïve T cells (i.e., unstimulated immune cells), obtained from a biological sample ([0023]) by delivering RNP complexes comprising a Cas9 nuclease, a guide RNA, and a HDR template ([0010], [0068]), wherein the Cas9 nuclease and guide RNA form a complex to generate a double-stranded break at a target site and wherein the HDR template facilitates HDR at the target site to generate modified immune cells ([0058]). Roth further teaches the HDR template can encode a polypeptide or fragment thereof ([0058]), and this method can be used for generation of recombinant T cells (0089] wherein “the T cell receptor can be replaced with a heterologous T cell receptor, with a polypeptide having a different receptor domain, such as an antibody or antibody fragment” ([0065]), and with a chimeric antigen receptor ([0065]). Thus, Roth’s method comprises a HDR template encodes an antigen-binding polypeptide. Roth further teaches RNP complexes were introduced into the cells via transfection (claim 13) and the cells were cultured under non-expansion conditions for one day ([0100]).
Regarding claim 2, Roth’s teachings is discussed in claim 1 and applied here. Roth further teaches T cells were enriched by magnetic negative selection prior to transfection and gene editing [0100], and more than 10% of the T cells were modified ([0073] and Fig 12b).
Regarding claim 3, Roth’s teachings is discussed in claim 1 and applied here.
Regarding claim 4, Roth’s teachings is discussed in claim 1 and applied here.
Regarding claim 5, Roth’s teachings is discussed in claim 2 and applied here.
Regarding claim 6, Roth further teaches the immune cell is a T cell, a naïve T cell, a CD4+, CD8+, or CD4+ and CD8+ T cell ([0010]) and these cells are enriched by magnetic negative selection ([0100]).
Regarding claim 7, Roth further the Cas9 RNP complex was introduced into about 1 x 105 to about 2 x 106 cells ([0010]) after cell enrichment and stimulation, which was performed using a STEMCELL EasySep Human T Cell Isolation Kit (0100]) designed for processing 1 x 1010 cells (Product Information Sheet, pg. 2). Therefore, if Roth was to modify a population of naïve T cells (i.e., unstimulated immune cells), the population would have comprised a population recited in the instant claim.
Regarding claim 8, Roth further teaches wherein the method provide a transfection efficiency of at least about 20% to 99%, or higher ([0073]).
Regarding claim 9, Roth further teaches wherein the method provides a cell viability at least about 20% to 99%, or higher ([0076]).
Regarding claim 10, Roth further teaches wherein the HDR template is at a concentration of about 2.5 pM to about 25 pM (claim 18 and [0078]).
Regarding claim 11, Roth further teaches the molar ratio of RNP to HDR template is from about 5:1 ([0009]).
Regarding claim 12, Roth further teaches wherein the complex is a RNP complex ([0005]).
Regarding claim 13, Roth further teaches the hematopoietic cell is an immune cell, such as a T cell, B cell, macrophage, a natural killer (NK) cell or dendritic cell ([0063]), a naïve T cell, a regulatory T cell, an effector T cell, a CD4+, CD8+, or CD4+ and CD8+ T cell ([0010]).
Regarding claims 14 and 15, Roth teaches performing gene-editing in CD4+ and CD8+ T cells (discussed in claim 13) that were previously enriched by magnetic selection using EasySep Human T Cell Isolation Kit (discussed in claim 6), thus the enriched population comprises about 99% CD4+ and CD8+ T cells as evidenced by the Kit’s Product Information Sheet’s data demonstrating the purity of final enriched T cells is 98.8% (pg. 4).
Regarding claim 16, the EasySep Human T Cell Isolation Kit further teaches cells are incubated in media containing 2% fetal bovine serum (FBS), which comprises albumin (Product Information Sheet, pg. 2).
Regarding claim 17, Roth’s teachings on culturing cells under non-expansion conditions are discussed above and applied to claim 1. Roth further teaches cells are resuspended in Bambanker freezing medium (i.e., cryopreservant solution) ([0100]).
Regarding claim 18, Roth further teaches wherein the transfection method comprises electroporation (claim 13).
Regarding claim 26-28, Roth further teaches all of the elements of the instant claims, wherein the HDR template comprises a 5’ and 3’ ends with sequences homologous to genomic sequences flanking the insertion site ([005]), is a double-stranded DNA template ([0022]), the length of the HDR template ranges from 200 bp to 5.0 kb ([0078]), and is delivered by electroporation (claim 13).
Regarding claims 30, Roth’s teachings on method comprising a Cas9 nuclease is discussed above and applied to claim 1.
Regarding claim 31, Roth further the gene-editing nuclease comprises a Streptococcus pyogenes Cas9 nuclease ([0056]), and the Cas9 nuclease and guide RNA form into a RNP complex ([0005]) from outside a cell to inside the cell (i.e. prior to and after delivering into the cells) ([0059]).
Regarding claim 32, Roth further teaches wherein at least two RNP complexes containing one or more additional guide RNAs are delivered ([0008]).
Regarding claim 33, Roth further teaches primary T cells isolated from blood or various other sources including apheresis samples (Fig 15 and [0023]).
Regarding claim 34, it is interpreted to include the “optional” expansion step. Roth further teaches T cells were stimulated, followed by expansion (Fig 12)
Regarding claim 35, Roth further teaches cells were cultured under expansion conditions for 4-12 days (Fig 12a).
Regarding claim 36, Roth’s teachings on immune cells types are discussed above and applied to claim 13.
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.
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 19-25, and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Roth (WO 2018/232356 A1; Published Date: 20 Dec, 2018) in view of Brandt (WO 2019/070541 A1; Published Date: 11 Apr, 2019).
Regarding claims 19, Roth’s teachings on antigen-binding polypeptide is discussed above and applied to claim 1. Roth further teaches the antigen-binding polypeptide comprises a chimeric antigen receptor (CAR) ([0065]).
Roth does not teach wherein the antigen-binding polypeptide comprises (a) an antigen-binding domain, (b) a CAR, (c) a cell surface receptor ligand; or (d) a T-cell receptor (TCR); and/or (e) binds to a tumor antigen.
Brandt teaches a method of modifying T cells using CRISPR Cas9 gene-editing and HDR templates to express antigen-binding polypeptides such as antigen receptor (i.e., antigen-binding domain), cell surface receptor, recombinant CARs, TCR-like CARs, and CD19 marker ([0428] and [0364]), which is a tumor antigen associated with hematologic malignancy.
It would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to modified Roth’s method with the antigen-binding polypeptides taught by Brandt because it would have merely amounted to a simple substitution of Roth’s recombinant CAR with Brandt’s different recombinant polypeptides according to known methods to yield predictable results. One would have been motivated to have done so for the advantage of obtaining modified T cells expressing various types of antigen-binding polypeptides for uses in adoptive cell therapy, such as treatment of diseases and disorders associated with HPV 16 E6 or E7 expression as taught by Brandt and not Roth. One would have had a reasonable expectation of success in doing so because both Roth and Brandt teaches methods of modifying T cells using CRISPR Cas9 nuclease and HDR insertions.
Regarding claim 20, Roth further teaches the antigen-binding domain comprises an antibody fragment (i.e., antigen-binding fragment), and the CAR comprises a targeting domain (i.e., antigen-binding domain), a transmembrane domain, and an intracellular domain ([0065]).
Regarding claims 21-23, the use of multiple “and/or” renders the determination of the exact scope of the claims difficult. Considering that second generation of CARs comprise an antigen-binding domain, a transmembrane domain, and an intracellular domain with a costimulatory and a cytoplasmic signaling domain, claims 21-23 are interpreted as the CAR comprising of i) an antigen-binding domain, ii) a transmembrane domain selected from an alpha, beta, or zeta chain of a T cell receptor, and iii) an intracellular domain with a 4-1BB costimulatory and a human CD3 zeta chain cytoplasmic signaling domain. The teachings of Roth on CARs are discussed above in claim 20 and applied here.
However, Roth does not teach wherein ii) a transmembrane domain selected from an alpha, beta, or zeta chain of a T cell receptor, and iii) an intracellular domain with a 4-1BB costimulatory and a human CD3 zeta chain cytoplasmic signaling domain.
Brandt teaches the transmembrane domain are derived from alpha, beta or zeta chain of the T-cell receptor ([0411]), and an intracellular domain with a 4-1BB costimulatory ([0423]) and a CD3 zeta chain cytoplasmic signaling domain ([0418]) that mediates T-cell activation and cytotoxicity.
The obviousness to modify Roth’s method with the antigen-binding polypeptide taught by Brandt is discussed above and applied to claim 19. One would have been motivated to have done so for the advantage of obtaining modified T cells expressing CARs comprising of these specific domains for the advantage of improving T-cell activation and target efficiency. One would have had a reasonable expectation of success in doing so because both Roth and Brandt teaches methods of modifying T cells using CRISPR Cas9 nuclease and HDR insertions.
Regarding claim 24, the obviousness of modifying T cells with CD19 marker that binds to tumor antigen associated with hematologic malignancy is discussed above as applied to claim 19.
Regarding claim 25, the teachings of Roth on antigen-binding polypeptide is discussed above as applied to claim 19 and 20.
However, Roth does not teach wherein the TCR comprises a TCR alpha chain and a TCR beta chain, and/or is selected from a wild-type TCR, a high affinity TCR, and a chimeric TCR.
Brandt teaches a TCR comprising an alpha chain and a beta chain ([0992]) and recombinant TCRs as chimeric TCRs contain a mouse constant region ([1042]).
The obviousness of modifying T cells with TCRs comprising these features is discussed above as applied to claim 19 and 21-23.
Regarding claim 29, Roth teaches wherein in the target site is in the RAB11A locus.
Roth does not explicitly teach wherein the target site is in the TRAC locus.
Brandt teaches the target site is at or near TRAC locus ([0581]), and specifically between the most 5’ nucleotide of exon 1 and upstream of the most 3’ nucleotide of exon 1 ([0629]).
It would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to modified Roth’s method to target the TRAC locus because it would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. One would have been motivated to have done so for the advantage of eliminating the endogenous TCR expressed from the TRAC locus to prevent cross pairing between the exogenous and endogenous TCRs. One would have had a reasonable expectation of success in doing so because both Roth and Brandt teaches methods of targeting a specific locus in T cells using CRISPR Cas9 nuclease and HDR insertions.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to QIWEN SU-TOBON whose telephone number is (571)272-0331. The examiner can normally be reached Monday - Friday, 8:00am-4:30pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammel can be reached at 571-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
QIWEN SU-TOBON
Examiner
Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636