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 .
DETAILED ACTION
Election/Restriction
Applicant’s election, without traverse, of Group II, claims 26, 29, 30, 33, 40, 42, 44, 50, 55, 86, 87, 110, 129 and 146, drawn to a method of producing multiple genome edits in a cell, delivering LNP compositions to a population of cells, gene editing in a population of cells, or producing multiple genome edits in a T cell, in the reply filed on 11/25/2025 is acknowledged.
Claims 1, 5, 15, 19, 20, 170 and 172 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claim Status
Claims 1, 5, 15, 19, 20, 26, 29, 30, 33, 40, 42, 44, 50, 55, 86, 87, 110, 129, 146, 170 and 172 are pending.
Claims 1, 5, 15, 19, 20, 170 and 172 are withdrawn.
Claims 26, 29, 30, 33, 40, 42, 44, 50, 55, 86, 87, 110, 129 and 146 are considered on the merits.
Claims 26, 33, 40 and 55 are independent claims.
Priority
This application is a CON of PCT/US2021/029446 (filed on 04/27/2021), which claims benefits from applications 63/176,221 (filed on 04/17/2021), 63/165,619 (filed on 03/24/2021), 63/130,100 (filed on 12/23/2020), 63/124,058 (filed on 12/11/2020), 63/121,781 (filed on 12/04/2020) and 63/016,913 (filed on 04/28/2020). The priority claim of the instant application has been granted and the earliest benefit date is 04/28/2020 from the application 63/016,913.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 02/01/2024, 03/07/2025 and 07/10/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner. The corresponding signed and initialed PTO forms 1449 have been mailed with this action.
Specification Objections
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (e.g., p. 18 and 85). Applicant is required to amend or delete the embedded hyperlink and/or other form of browser-executable code. For example, “www” can be replaced with “world wide web”. See MPEP § 608.01.
Claim Objections
Claim 42 is objected to because of the following informalities:
Claim 42 recites “the first genome editing tool or the first genome editing tool”, which contains a typographical error. It seems to refer to “the first genome editing tool or the second genome editing tool”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claim 33 is 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.
Claim 33 recites the limitations in step c (i) “the population of cells … after the last contact with an LNP composition”, and (ii) “d. expanding the population of cells”. There is insufficient antecedent basis for the limitations in the claim because there are multiple populations of cells recited prior to the limitations, such as a population of cells before contacting with any LNP composition, a population of cells after contacting with a first LNP composition, and a population of cells after contacting with a second LNP composition. Thus, it is not clear which population of cells the limitations in step c (i) and (ii) are referring to.
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 26, 40, 42, 44 and 87 are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Ju et al., (Biomaterials. 2019; 217:119298, p. 1-14, IDS 03/07/2025).
With respect to independent claims 26 and 40, it is noted that under the broadest reasonable interpretation, the limitation of contacting the cell/the population of cells with a first LNP composition and a second LNP composition is being examined as contacting the cell/cells with a mixture of a first LNP composition and a second LNP composition.
Ju teaches a multiplexed gene editing system applicable for suspension cells (see e.g., title and abstract), thus teaches the preambles of claims 26 and 40.
In regard to step (a) contacting the cell/the population of cells in vitro with a mixture of a first LNP composition and a second LNP composition, Ju teaches treating EG7 cells with multiple Cas9 RNPs targeting both PD-L1 and PD-L2, “Specifically, lipofectamine-mediated multiple sgRNAs deliveries obtains 64% and 61% of the reduction in gene expression of PD-L1 and PD-L2, respectively (Fig. 4C)” (p. 7, left col., see Fig 4A-C). Ju also teaches a complexation of Cas9 proteins with two sgRNAs (e.g., p. 2, right col, para 1) and lipofectamine 2000-mediated transfection (see p. 2, right col, para 2.4 “Cell culture and transfection”). It is noted that liposomes (e.g., lipofectamine 2000) are one type of lipid nanoparticles (LNPs). Thus, Ju teaches step (a) contacting the cell/the population of cells in vitro with a mixture of a first LNP composition and a second LNP composition (i.e., the complexation of Cas9 proteins with two sgRNAs mediated by lipofectamine 2000), and teaches the first LNP composition comprises a first gRNA directed to a first target sequence (i.e., PD-L1) and a first nucleic acid genome editing tool (i.e., the Cas9 protein) and the second LNP composition comprises a second gRNA directed to a second target sequence (i.e., PD-L2) and a second nucleic acid genome editing tool (i.e., the Cas9 protein) in claims 26 and 40.
In regard to step (b) or (b-1) expanding the cell/the population of cells in vitro, Ju teaches the expression of PD-L1 and PD-L2 is evaluated by T7E1 assay, western blotting assay, and flow cytometric analysis after lipofectamine-mediated multiple RNPs deliveries (p. 7, left col., see Fig 4A-C), and teaches the assays are performed at 48 h post incubation (p. 4, left col, para 3.2 evaluating targeting efficiencies). Thus, Ju teaches the cell or the population of cells are cultured and expanded in vitro for at least 48 hours after transfection, thereby producing multiple genome edits in the cell or editing the population of cells in claims 26 and 40.
With respect to claim 42, claim 44 and claim 87, as stated supra, Ju teaches the LNP compositions (i.e., lipofectamine-incubated RNPs) comprise a complexation of Cas9 proteins with sgRNAs (e.g., p. 2, right col, para 1), thus teaches the genome editing tools comprise a guide RNA (i.e., a single-guide RNA, sgRNA) in claim 42 and an RNA-guided DNA binding agent (i.e., a Cas9 protein) in claims 44 and 87.
Accordingly, Ju anticipates instant claims.
Claim 33 is rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Shang et al., (Laboratory Investigation. 2004; 84: 332-341).
With respect to claim 33, Shang teaches a method of preparing a stable cell line expressing a mutant β-catenin by lipofectamine-mediated transfection (see e.g., p. 333, last para “Cell transfection”. It is noted that lipofectamine is a type of lipid nanoparticle), thus teaches the preamble a method of delivering lipid nanoparticle (LNP) compositions to a population of in vitro-cultured cells.
In regard to step (a), Shang teaches AML12 cells are contacted with lipid-DNA complex formed by incubating lipofectamine with a plasmid encoding a mutant β-catenin (see e.g., p. 333, last para “Cell transfection”), thus teaches contacting a population of cells in vitro with a first LNP composition (i.e., lipid-DNA complex) comprising a first nucleic acid (i.e., a plasmid encoding a mutant β-catenin), thereby producing a contacted population of cells.
In regard to step (b), Shang teaches the transfected cells are cultured for 20 days and then selected and amplified (p. 333, last para – p. 334, first 2 lines, referred to as “AML12S33Y”), thus teaches culturing the contacted population of cells in vitro, thereby producing a population of cultured contacted cells.
In regard to step (c), Shang teaches the stable clonal cells are transiently transfected with a plasmid encoding reporter gene TOPFLASH using lipofectamine (e.g., p. 334, right col, para “Luciferase Assay” and p. 335, right col, “Results” para 1), thus teaches contacting the population of cultured contacted cells (i.e., “AML12S33Y”) in vitro with a second LNP composition comprising a second nucleic acid (lipofectamine-mediated transfection of plasmid encoding a reporter gene TOPFLASH), wherein the second nucleic acid is different from the first nucleic acid (i.e., a plasmid encoding a mutant β-catenin vs. a plasmid encoding a reporter gene).
In regard to the wherein clause in (i) directed to at least 70% of the cells are viable 24 hours after contact with an LNP composition, it must be noted that this wherein clause does not recite an active step in the claimed method, but only the results of contacting the population of cells with an LNP composition as taught by Shang. MPEP 2111.04 I states a whereby clause (or a wherein clause) “in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.” Therefore, this wherein clause does not provide any patentable weight in determining patentability of the claimed method.
Accordingly, Shang anticipates instant claim 33.
Claim Rejections - 35 USC § 103
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 26, 29, 30, 40, 42, 44, 50, 55, 86, 87, 110, 129 and 146 are rejected under 35 U.S.C. 103 as being unpatentable over Kalaitzidis et al., (WO 2019/097305 A2, published May 2019, cited in IDS 07/10/2025) in view of Ho et al., (WO 2019/067999, published on April 4, 2019, cited in IDS 03/07/2025).
With respect to independent claims 26, 40 and 55, it is noted that under the broadest reasonable interpretation, the limitations of contacting the cell/the population of cells/the T cell with at least a first LNP composition and a second LNP composition or additional LNP compositions in claim 26 (a), claim 40 (a) and claim 55 (a) and (c), encompass the scope of contacting the cell/cells/T cell with a mixture of LNP compositions. Furthermore, it is noted that the claims merely recite the limitation “comprising the steps of”, thus encompass the steps being carried out in any order and being carried out simultaneously. Accordingly, claim 55 is examined as the method comprising performing step (b) first, and then steps (a) and (c) simultaneously thereafter, and step (d) the last. It is noted that since steps (a) and (c) are carried out simultaneously, i.e., contacting the activated T cell with two LNP compositions recited in (a) and two recited in (c), steps (a) and (c) in claim 55 are examined as contacting the activated T cell with a mixture of four LNP compositions.
Kalaitzidis teaches a method of producing multiple genome edits in an in vitro-cultured T cell or a population of T cells (see e.g., abstract and the figure in the front page), thus teaches the preamble of claims 26, 40 and 55.
In regard to step (b) of claim 55 directed to activating the T cell in vitro, Kalaitzidis teaches primary human T cells are isolated and incubated with Human T-Activator CD3/CD28 Dynabeads (Example 2, p. 153, last para), thus teaches activating the T cell in vitro.
In regard to step (a) in claim 26, step (a) in claim 40, and steps (a) & (c) in claim 55, directed to contacting the activated T cell with a mixture of four compositions comprising different gRNAs, Kalaitzidis teaches the activated T cells are electroporated with ribonucleoproteins (RNPs) comprising Cas9 and sgRNAs (Example 2, p. 154, para 2). Kalaitzidis teaches for the knockout of 2 or more genes and their protein products in the same cell (multiplex editing), each of Cas9 pre-complexed individually with sgRNAs is added to the nucleofection mix (p. 160, Example 6 “Multiplex editing in cells), and teaches the gRNAs are directed to multiple targets including TRAC, B2M, CD3ε, CD52, CIITA and AAVS1, and exemplifies a triple gene knockout TRAC, B2M, and CIITA (Example 6, p. 160-161). Thus, Kalaitzidis teaches or suggests a step of contacting the activated T cell with a mixture of four RNP compositions comprising four different gRNAs targeting four different genes.
However, Kalaitzidis does not use lipid nanoparticle compositions to deliver the genome editing compositions in the working examples.
Nevertheless, Kalaitzidis teaches polynucleotides, such as guide RNA, sgRNA and mRNA encoding an endonuclease, and endonuclease polypeptide, may be delivered to a cell by a lipid nanoparticle (LNP) (p. 82, para 2 and para 4), thus suggests lipid nanoparticles may be used to deliver the genome editing compositions.
Ho teaches an in vitro method of delivering genome editing compositions using lipid nanoparticles and teaches the disclosure relates to modifying a gene sequence using a CRISPR-Cas9 complex that is delivered by lipid nanoparticles (e.g., abstract and example of LNP Transfection of Human CD34+ Bone Marrow Cells in p. 65). Ho teaches the LNP transfection may reduce HSPC or CD34+ cell death as compared to known technologies like electroporation, and post-transfection cell survival is at least 60%, 70%, 80%, 90%, or 95% ([0023]).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method for producing multiple genome edits in in vitro-cultured T cells by electroporation-mediated delivery of genome editing compositions as suggested by Kalaitzidis, by substituting the electroporation technology with lipid nanoparticle-mediated delivery of CRISPR-Cas9 complex as suggested by Kalaitzidis and Ho with a reasonable expectation of success. Since Kalaitzidis contemplates the use of lipid nanoparticle in delivering the genome editing compositions, and since Ho teaches the LNP transfection may reduce cell death as compared to known technologies like electroporation with post-transfection cell survival being up to 95% ([0023]), one of ordinary skill in the art would have had a reason to substitute with LNP-mediated delivery of genome editing compositions in order to reduce cell death and promote post-transfection cell survival.
In regard to step (b) in claim 26, step (b-1) in claim 40, and step (d) in claim 55, directed to expanding the cell/cells in vitro, Kalaitzidis teaches the BCMA-CAR-T cells that are TCR and B2M double knockout (TCR-/ B2M-/ CAR+) are expanded in cell culture medium in the presence of cytokines (see Fig. 53 and p. 17 Fig. 53 legend), thus teaches the T cells are expanded thereby producing multiple genome edits in the T cell.
With respect to claim 29, Kalaitzidis teaches mRNA (or DNA) encoding an endonuclease (e.g., p. 74, para 3; p. 76, para 2) and teaches mRNA encoding an endonuclease may be delivered to a cell by a LNP (p. 82, para 4). Ho teaches LNP compositions that include a Cas nuclease mRNA (e.g., [0042]). Thus, both Kalaitzidis and Ho teach one of the nucleic acid genome editing tools comprises a nucleic acid (e.g., mRNA) encoding an RNA-guided DNA binding agent (i.e., a Cas nuclease).
With respect to claim 30 directed to a donor nucleic acid for insertion in a target sequence, claim 86 directed to the genome editing tool comprising a donor nucleic acid, and claim 110 directed to contacting the cell with a donor nucleic acid that comprises regions having homology with corresponding regions of a TRAC locus, Kalaitzidis teaches the method comprises delivering to a T cell a composition comprising a RNA-guided nuclease, a gRNA targeting a TRAC gene, a gRNA targeting a B2M gene, and a vector comprising a donor template that comprises a nucleic acid encoding a CAR, wherein the nucleic acid encoding the CAR is flanked by left and right homology arms to the TRAC gene locus (e.g., p. 4, para 2, reference claim 66, and Fig 13B “KO TCR/KI CAR”), thus teaches a donor nucleic acid (a CAR template) for insertion in a target sequence (e.g., the TRAC locus) in claim 30, the genome editing tool comprises a donor nucleic acid in claim 86 and the donor nucleic acid has flanking homology arms in claim 110.
With respect to claim 42 directed to the genome editing tool comprising a guide RNA, claim 44 directed to the LNP compositions comprising an RNA-guided DNA binding agent, and claim 87 directed to the genome editing tool comprising an RNA-guided DNA binding agent, as stated supra, Kalaitzidis teaches the T cells are transfected with ribonucleoproteins comprising Cas9 (i.e., an RNA-guided DNA binding agent) and sgRNAs (Example 2, p. 154, para 2).
With respect to claim 50 directed to a T cell, as stated supra, Kalaitzidis teaches the T cells undergo genome editing (Example 2, p. 154, para 2).
With respect to claim 129 directed to the cells being T cells and at least 95% of the cells comprising a genome edit of an endogenous TCR, as stated supra, Kalaitzidis teaches the cells are T cells (Example 2, p. 154, para 2), and in one embodiment, Figure 51 shows flow cytometry graphs demonstrating that 95.5% of the gene edited cells are TCR negative before further enrichment (Figure 51 and legend in p. 17), thus teaches at least 95% of the cells comprising a genome edit of an endogenous TCR.
With respect to claim 146 directed to the LNP composition comprising an amine lipid, a helper lipid and a PEG lipid, Kalaitzidis teaches the LNPs may be made from cationic, anionic, or neutral lipids, and that neutral lipids, such as DOPE or cholesterol, may be included in LNPs as 'helper lipids' to enhance transfection activity and nanoparticle stability (p. 82, lines 24-26). Kalaitzidis teaches examples of cationic lipids such as DLin-MC3-DMA which is an amine lipid, and teaches examples of PEG-modified lipids such as PEG-DMG, thus teaches a PEG lipid (p. 83, para 1). Thus, Kalaitzidis suggests the LNP composition comprising an amine lipid, a helper lipid and a PEG lipid. Ho teaches an LNP composition comprising the mRNA, an amine lipid, a helper lipid, a neutral lipid, and a PEG lipid (e.g., p. 3, para 1). Thus, both Kalaitzidis and Ho teach or suggest an LNP composition comprising an amine lipid, a helper lipid and a PEG lipid.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Double Patenting Rejections
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 26, 29, 30, 33, 40, 42, 44, 50, 55, 86, 87, 110, 129 and 146 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 27-38 and 52-53 of US Patent No. 12,037,583 B2 (‘583) in view of Ho et al., (WO 2019/067999, published on April 4, 2019, cited in IDS 03/07/2025). Although the claims at issue are not identical, they are not patentably distinct from each other.
Patented claims of ‘583 recite a method of altering a target sequence of a cell, comprising contacting the cell with a gRNA and a Cas9 molecule or a nucleic acid encoding a Cas9 molecule (reference claim 27), and if present, the one or more additional gRNA molecule(s) and template nucleic acid are introduced into the cell by electroporation (reference claim 29, related to multiple genome edits in instant claims 26, 29, 33, 40, 42, 44, 55 and 87, and donor nucleic acid in instant claims 30, 86 and 110), the cell is a T cell (reference claim 32, related to instant claims 55, 50 and 129), a method of modifying cells by reducing or eliminating expression of TCR and B2M and expanding said cells, and further eliminating CIITA (reference claims 52-53, related to instant claims 26, 33, 40 and 55, and claims 110 and 129). It is noted that the multiple genome edits recited in reference claims 29 and 52-53 encompass the scope of contacting the cells with multiple genome editing compositions and encompass the scope of contacting different compositions sequentially as being encompassed in instant claims 33 and 55).
However, reference claims are silent on using lipid nanoparticles to deliver the genome editing compositions, nor teach the composition of the lipid nanoparticles in instant claim 146.
Ho teaches an in vitro method of delivering genome editing compositions using lipid nanoparticles and teaches the disclosure relates to modifying a gene sequence using a CRISPR-Cas9 complex that is delivered by lipid nanoparticles (e.g., abstract and example of LNP Transfection of Human CD34+ Bone Marrow Cells in p. 65). Ho teaches an LNP composition comprising the mRNA, an amine lipid, a helper lipid, a neutral lipid, and a PEG lipid (e.g., p. 3, para 1, related to instant claim 146). Ho teaches the LNP transfection may reduce HSPC or CD34+ cell death as compared to known technologies like electroporation, and post-transfection cell survival is at least 60%, 70%, 80%, 90%, or 95% ([0023]).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method for producing multiple genome edits in in vitro-cultured T cells by electroporation-mediated delivery of genome editing compositions as recited in reference claims, by substituting the electroporation technology with lipid nanoparticle-mediated delivery of CRISPR-Cas9 complex as suggested by Ho with a reasonable expectation of success. Since Ho teaches the LNP transfection may reduce cell death as compared to known technologies like electroporation with post-transfection cell survival being up to 95% ([0023]), one of ordinary skill in the art would have had a reason to substitute with LNP-mediated delivery of genome editing compositions in order to reduce cell death and promote post-transfection cell survival. Furthermore, it would have also been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have performed the contacting cells with genome editing compositions sequentially as encompassed by reference claims since it is one of the only two options (sequentially or simultaneously), thus one of ordinary skill in the art would have immediately envisioned the taught option of sequentially contacting the cells with the compositions among the limited genus of options as encompassed by the reference claims.
Since the instant application claims are obvious over cited patent claims, in view of Ho, said claims are not patentably distinct.
Provisional Double Patenting Rejections
Claims 26, 29, 30, 33, 40, 42, 44, 50, 55, 86, 87, 110, 129 and 146 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 5, 7-9, 11-14, 16, 18, 23, 26, 31, 33, 71, 76, 80 and 82 of US Application No. 18/980,643 (‘643) in view of Kalaitzidis et al., (WO 2019/097305 A2, published May 2019, cited in IDS 07/10/2025) and Ho et al., (WO 2019/067999, published on April 4, 2019, cited in IDS 03/07/2025). Although the claims at issue are not identical, they are not patentably distinct from each other.
Copending claims in ‘643 recite a method of genetically modifying a cell, comprising (a) contacting the cell with a first genome editing tool comprising a first genomic editor and a gRNA that targets a genomic locus, and (b) contacting the cell with a second genome editing tool comprising a second genomic editor and a gRNA that targets a genomic locus, thereby producing at least two genomic edits in the cell (reference claim 1), the genomic editor comprising a cleavase, a nickase (reference claim 5), being Cas9 (reference claims 23, 26) the method further comprising contacting the cell with a nucleic acid encoding an exogenous gene (reference claim 8), further comprising culturing the cell thereby producing a population of cells comprising at least two genomic edits per cell (reference claim 12), the gRNA comprising at least two, at least three, at least four, at least five gRNAs that target different genomic loci (reference claim 33), the genomic editor and one, two, three, four, five or six of the at least one gRNA are contained in the same lipid nanoparticles (LNP). It is noted that the contacting a cell with different genome editing tools encompasses the scope of contacting different compositions sequentially as being encompassed in instant claims 33 and 55. Furthermore, it would have been obvious for one of ordinary skill in the art to have prepared separate lipid nanoparticles containing the genomic editor and each gRNA for the convenience of mixing and matching.
However, the copending claims are silent on the cell being a T cell, or the composition of the LNP.
Nevertheless, copending claims cited a method for treating cancer by administering to a subject the cell of claim 76.
Kalaitzidis teaches a method of producing multiple genome edits in an in vitro-cultured T cell or a population of T cells for universal cancer immunotherapy (see e.g., abstract and the figure in the front page).
Ho teaches an in vitro method of delivering genome editing compositions using lipid nanoparticles-mediated delivery of a CRISPR-Cas9 complex (e.g., abstract and example of LNP Transfection in p. 65). Ho teaches an LNP composition comprising the mRNA, an amine lipid, a helper lipid, a neutral lipid, and a PEG lipid (e.g., p. 3, para 1, related to instant claim 146). Ho teaches the LNP transfection may reduce HSPC or CD34+ cell death as compared to known technologies like electroporation, and post-transfection cell survival is at least 60%, 70%, 80%, 90%, or 95% ([0023]).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method for producing multiple genome edits in in vitro-cultured cells by LNP-mediated delivery of genome editing compositions for cancer therapy as recited in reference claims, by choosing T cells and the LNP with instantly recited compositions as suggested by Kalaitzidis and Ho with a reasonable expectation of success. Since Kalaitzidis teaches a method of producing multiple genome edits in an in vitro-cultured T cell or a population of T cells for universal cancer immunotherapy (see e.g., abstract and the figure in the front page), and since Ho reduces to practice the LNP with the instantly recited compositions may reduce cell death and promote cell survival, one of ordinary skill in the art would have had a reason to choose T cells to have genome edits for using as universal cancer immunotherapy as suggested by Kalaitzidis and choose the LNP of Ho in order to reduce cell death and promote cell survival.
Since the instant application claims are obvious over cited application claims, in view of Kalaitzidis and Ho, said claims are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims in the copending application have not in fact been patented.
Claims 26, 29, 30, 33, 40, 42, 44, 50, 55, 86, 87, 110, 129 and 146 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 60, 63, 65, 67, 75, 94, 116 and 130 of US Application No. 18/287,239 (‘239) in view of Kalaitzidis et al., (WO 2019/097305 A2, published May 2019, cited in IDS 07/10/2025). Although the claims at issue are not identical, they are not patentably distinct from each other.
The reference claims recite a lipid nanoparticle composition comprising an amine lipid, a helper lipid, a neutral lipid, and a PEG lipid (reference claim 1), further comprising mRNA encoding an RNA-guided DNA-binding agent Cas9 (reference claims 60, 63), a guide RNA (reference claim 65), a method of gene editing, a method of delivering a bioactive agent to a cell comprising contacting the cell with the lipid composition (reference claim 75), the cell is an immune cell (reference claim 94, it is noted that one of ordinary skill in the art would have immediately envisioned a T cell as an immune cell), a method of producing multiple genome edits in a cell or a population of cells comprising contacting the cell in vitro with at least a first lipid composition and a second lipid composition, that each comprises a gRNA and a genome editing tool thereby producing multiple genome edits in the cell or the population of cells. It is noted that the contacting a cell with different genome editing tools encompasses the scope of contacting different compositions sequentially as being encompassed in instant claims 33 and 55.
However, reference claims are silent on a donor nucleic acid for insertion into the immune cell in a target locus.
Kalaitzidis teaches a method of producing multiple genome edits in an in vitro-cultured T cell or a population of T cells for universal cancer immunotherapy (see e.g., abstract and the figure in the front page). Kalaitzidis teaches the method comprises delivering to a T cell a composition comprising a RNA-guided nuclease, a gRNA targeting a TRAC gene, a gRNA targeting a B2M gene, and a vector comprising a donor template that comprises a nucleic acid encoding a CAR, wherein the nucleic acid encoding the CAR is flanked by left and right homology arms to the TRAC gene locus (e.g., p. 4, para 2, Kalaitzidis claim 66, and Fig 13B “KO TCR/KI CAR”), thus teaches a donor nucleic acid (a CAR template) for insertion in a target sequence (e.g., the TRAC locus) in instant claim 30, the genome editing tool comprises a donor nucleic acid in instant claim 86, and the donor nucleic acid has flanking homology arms in instant claim 110. Kalaitzidis teaches the cells are T cells (Example 2, p. 154, para 2), and in one embodiment, Figure 51 shows flow cytometry graphs demonstrating that 95.5% of the gene edited cells are TCR negative before further enrichment (Figure 51 and legend in p. 17), thus teaches at least 95% of the cells comprising a genome edit of an endogenous TCR in instant claim 129.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method for producing multiple genome edits in in vitro-cultured immune cells by LNP-mediated delivery of genome editing compositions as recited in reference claims, by choosing T cells and by combining a donor nucleic acid such as a CAR for insertion into the TRAC locus as suggested by Kalaitzidis with a reasonable expectation of success. Since Kalaitzidis teaches a method of producing multiple genome edits in an in vitro-cultured T cell or a population of T cells for universal cancer immunotherapy by inserting CAR into TRAC locus (see e.g., abstract and the figure in the front page), one of ordinary skill in the art would have had a reason to choose T cells and to combine a CAR inserted into the TRAC locus in order to obtain universal cancer immunotherapy as suggested by Kalaitzidis.
Since the instant application claims are obvious over cited application claims, in view of Kalaitzidis, said claims are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims in the copending application have not in fact been patented.
Claims 26, 29, 30, 33, 40, 42, 44, 50, 55, 86, 87, 110, 129 and 146 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 51, 62, 65, 67, 69, 74, 76, 77 and 118 of US Application No. 18/287,229 (‘229) in view of Kalaitzidis et al., (WO 2019/097305 A2, published May 2019, cited in IDS 07/10/2025). Although the claims at issue are not identical, they are not patentably distinct from each other.
The reference claims recite a lipid nanoparticle composition comprising an amine lipid, a helper lipid, a neutral lipid, and a PEG lipid (reference claim 1), in the form of LNPs (reference claims 51 and 76), further comprising mRNA encoding an RNA-guided DNA-binding agent Cas9 (reference claims 62, 65), a guide RNA (reference claims 67, 74), a method of gene editing, a method of delivering a bioactive agent to a cell comprising contacting the cell with the lipid composition (reference claim 77), a method of producing multiple genome edits in a cell or a population of cells comprising contacting the cell in vitro with at least a first lipid composition and a second lipid composition, that each comprises a gRNA and a genome editing tool thereby producing multiple genome edits in the cell or the population of cells (reference claim 118). It is noted that the contacting a cell with different genome editing tools encompasses the scope of contacting different LNP compositions sequentially as being encompassed in instant claims 33 and 55.
However, reference claims are silent on the cell being a T cell, or a donor nucleic acid for insertion into the cell in a target locus.
Kalaitzidis teaches a method of producing multiple genome edits in an in vitro-cultured T cell or a population of T cells for universal cancer immunotherapy (see e.g., abstract and the figure in the front page). Kalaitzidis teaches the method comprises delivering to a T cell a composition comprising a RNA-guided nuclease, a gRNA targeting a TRAC gene, a gRNA targeting a B2M gene, and a vector comprising a donor template that comprises a nucleic acid encoding a CAR, wherein the nucleic acid encoding the CAR is flanked by left and right homology arms to the TRAC gene locus (e.g., p. 4, para 2, Kalaitzidis claim 66, and Fig 13B “KO TCR/KI CAR”), thus teaches a donor nucleic acid (a CAR template) for insertion in a target sequence (e.g., the TRAC locus) in instant claim 30, the genome editing tool comprises a donor nucleic acid in instant claim 86, and the donor nucleic acid has flanking homology arms in instant claim 110. Kalaitzidis teaches the cells are T cells (Example 2, p. 154, para 2), and in one embodiment, Figure 51 shows flow cytometry graphs demonstrating that 95.5% of the gene edited cells are TCR negative before further enrichment (Figure 51 and legend in p. 17), thus teaches at least 95% of the cells comprising a genome edit of an endogenous TCR in instant claim 129.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method for producing multiple genome edits in in vitro-cultured cells by LNP-mediated delivery of genome editing compositions as recited in reference claims, by choosing T cells and by combining a donor nucleic acid such as a CAR for insertion into the TRAC locus as suggested by Kalaitzidis with a reasonable expectation of success. Since Kalaitzidis teaches a method of producing multiple genome edits in an in vitro-cultured T cell or a population of T cells for universal cancer immunotherapy by inserting CAR into TRAC locus (see e.g., abstract and the figure in the front page), one of ordinary skill in the art would have had a reason to choose T cells and to combine a CAR inserted into the TRAC locus in order to obtain universal cancer immunotherapy as suggested by Kalaitzidis.
Since the instant application claims are obvious over cited application claims, in view of Kalaitzidis, said claims are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims in the copending application have not in fact been patented.
Conclusion
No claims are allowed.
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/JIANJIAN ZHU/Examiner, Art Unit 1631