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/Restriction
Applicant’s election without traverse of Group I claims 1-3, 5, 8-10, 12, 13, 19-20, and 22-27 drawn to an isolated cell comprising reduced MHC class I and or class II and modified to increase expression of CD24 in the reply filed on 08/07/2025 is acknowledged. Claims 28, 62-63, 114, 148, and 160 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08/07/2025.
Priority
Acknowledgement is made of Applicants’ claim for benefit to prior filed US Provisional Application 62/891180, filed on 08/23/2019.
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. PCT/US20/47639, filed on 08/24/2020.
Information Disclosure Statement
The Information Disclosure Statements filed 12/14/2022 and 09/05/2024 have been considered by the Examiner.
Status of Claims
Claims 1-3, 5, 8-10, 12, 13, 19-20, and 22-27 are under examination.
Claims 28, 62-63, 114, 148, and 160 are withdrawn.
Claims 4, 6-7, 11, 14-18, 21, 29-61, 64-113, 115-147, 149-159, and 161-173 are cancelled.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Rejections maintained:
Claims 1-3, 5, 8-10, 12-13, 19-20, 22-27 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Valamehr et al. (US20210024959 A1) as evidenced by UniProt (P25063 · CD24_HUMAN).
Regarding claim 1, Valamehr et al. teach an iPSC cell line with eliminated or substantially reduced expression of both human leukocyte antigen (HLA) class I and HLA class II proteins (page 25, paragraph 0179) which reads on reduced expression of MHC class I and or class II. Valamehr et al. further teach the HLA deficient iPSC is engineered to increase expression of CD24 (page 15, paragraph 0133).
Regarding claim 2, Valamehr et al. teach an iPSC cell line with eliminated or substantially reduced expression of both HLA class I and HLA class II proteins (page 25, paragraph 0179) which reads on reduced expression of MHC class I and class II human leukocyte antigens.
Regarding claim 3, Valamehr et al. teach an iPSC comprising a modification where the cell is CIITA null or low (page 5, paragraph 0031). Valamehr et al. teach targeted editing through the introduction of double strand breaks (DSBs) by specific rare-cutting endonucleases (page 30, paragraph 0208), which would target the CIIITA gene for selective inactivation. Valamehr et al. teach the genetically modified iPSC can further comprise additional genetic modifications to increase expression of HLA-E, CD47, or PD-L1 (page 38, paragraph 0260).
Regarding claim 5, Valamehr et al. teach the genetically modified iPSC comprises introducing a polynucleotide for increasing expression of CD47 (page 38, paragraph 0260). Valamehr et al. teach the endogenous genes for disruption include at least one of B2M or NLRCS (page 2, paragraph 0013). Valamehr et al. teach targeted editing by specific rare-cutting endonucleases (page 30, paragraph 0208), which would target the B2M or NLRCS genes for selective inactivation.
Regarding claim 8, Valamehr et al. teach targeted editing by specific rare-cutting endonucleases (page 30, paragraph 0208). Valamehr et al. further teach a rare-cutting endonuclease is selected from the group consisting of a Cas protein, a zinc finger nuclease (ZFN), a TALE-nuclease, or a homing nuclease (page 7, paragraph 0043).
Regarding claim 9, Valamehr et al. teach an iPSC comprising a modification resulting in CIITA null or low (page 5, paragraph 0031). Valamehr et al. further teach the rare-cutting endonuclease is CRISPR-cas/gNA (guide nucleic acid) (page 7, paragraph 0043), the guide nucleic acid would target the CIITA gene.
Regarding claim 10, Valamehr et al. teach the endogenous gene for disruption comprises at least B2M or NLRCS (page 2, paragraph 0013). Valamehr et al. teach targeted editing by specific rare-cutting endonucleases (page 30, paragraph 0208), which would target the B2M or NLRCS genes for selective inactivation. Valamehr et al. further teach the rare-cutting endonuclease is CRISPR-cas/gNA (guide nucleic acid) (page 7, paragraph 0043), the guide would target the B2M or NLRCS genes.
Regarding claim 12, Valamehr et al. further teach the HLA deficient iPSC is engineered to express CD24 (page 15, paragraph 0133). Valamehr et al. teach an expression vector for introducing the polynucleotide cells (page 7, paragraph 0042).
Regarding claim 13, Valamehr et al. teach the cell of claim 12 however they do not define the CD24 sequence encoding the polypeptide. The sequence for CD24 is well known in the art as evidenced by UniProt database (https://www.uniprot.org/uniprotkb?query=A48996). The CD24 sequence in the UniProT database is the same as SEQ ID NO:28 of present application.
Regarding claim 19, Valamehr et al. further teach the HLA deficient iPSC are engineered to increase expression of CD24 (page 15, paragraph 0133). Valamehr et al. teach introduction of a polynucleotide sequence where the targeted genomic editing a selected site in the cell (page 2, paragraph 0012).
Regarding claim 20, Valamehr et al. teach the cell of claim 19 however they do not define the CD24 sequence encoding the polypeptide. The CD24 sequence is well known in the art as evidenced by UniProt database (https://www.uniprot.org/uniprotkb?query=A48996). The CD24 sequence in the UniProT database is the same as SEQ ID NO:28 of present application.
Regarding claim 22, Valamehr et al teach the genetically modified iPSC can further comprise additional genetically modified modalities comprising introducing a polynucleotide for increasing expression of HLA-E, CD47, or PD-L1 (page 38, paragraph 0260). Valamehr et al. teach the targeted genomic editing a selected site in the cell (page 2, paragraph 0012).
Regarding claim 23, Valamehr et al. teach the genetically modified iPSC comprises introducing polynucleotides to increase expression of CD47 (page 38, paragraph 0260). Valamehr et al. teach the targeted genomic editing a selected site in the cell (page 2, paragraph 0012).
Regarding claim 24, Valamehr et al. teach the iPSC is engineered to express CD24 (page 15, paragraph 0133). Valamehr et al teach the genetically modified iPSC can further comprise additional genetic modifications comprising introduced or increased expression of HLA-E, CD47, or PD-L1 (page 38, paragraph 0260). Valamehr et al. teach the exogenous polynucleotides, where their selected introduction site is a genome safe harbor (page 2, paragraph 0012).
Regarding claim 25, Valamehr et al. teach the genome-engineered iPSC-derived cells comprise one or more desired integration sites comprising AAVS1 , CCR5, or ROSA26(page 37, paragraph 0255).
Regarding claim 26, Valamehr et al. teach the genome-engineered iPSC-derived cells comprise one or more inducible suicide gene integrated, where the genome-engineered iPSC-derived cells further comprise polynucleotides encoding safety switch proteins (page 37, paragraph 0255). The inducible suicide gene integrated and safety switch proteins read on the suicide switch of the present application.
Regarding claim 27, Valamehr et al. teach the genomically edited cell is an induced pluripotent stem cell (iPSC) (page 7, paragraph 0040).
Response to Arguments
Applicant's arguments filed 01/07/2026 have been fully considered but they are not persuasive.
Applicant argues Valamehr fails to provide a single example of an isolated cell comprising "reduced cell surface expression of MHC class I and/or MHC class II human leukocyte antigens and a modification to increase expression of CD24 in the cell, wherein the cell has a reduced susceptibility to macrophage phagocytosis compared to an unmodified cell" as recited in claim 1. Valamehr does not teach increasing the expression of CD24 in order to reduce the susceptibility of the cell to macrophage phagocytosis. What Valamehr teaches is the use of CD24 as a tumor antigen for engaging effector cells expressing hnCD16 in order to kill tumor cells. Thus, the effect of expressing CD24 in Valamehr's proposed system would be to increase killing of the cell, which is inapposite of that of the claimed invention.
Applicant argues Valamehr recites a number of other proteins that may be expressed for a large number of broad and vague purposes, some of which have contradictory effects (e.g., "persistence" and "immune evasion," vs "cellular cytotoxicity").
Examiners response: Valamehr et al. teach an iPSC cell line with eliminated or substantially reduced expression of both human leukocyte antigen (HLA) class I and HLA class II proteins (page 25, paragraph 0179) which reads on reduced expression of MHC class I and or class II. Valamehr et al. further teach the HLA deficient iPSC is engineered to increase expression of CD24 (page 15, paragraph 0133). Valamehr et al. teach various methods and compositions for obtaining functionally enhanced derivative effector cells obtained from directed differentiation of genomically engineered iPSCs. The engineered cells taught by Valamehr et al. deliver improved or enhance therapeutic effects. Valamehr et al. further teach enhanced derivative effector cells alone, or with antibodies or checkpoint inhibitors in combination therapies (cover page, abstract). The section of Valamehr cited by the applicant (page 20, paragraphs 0146 and 0192) is teaching an embodiment for tumor antigen engagement. Valamehr et al. teach enhancement effector cells ability to kill tumor cells with the addition of bi-, tri-, multi- specific engager or binders in one embodiment.
The addition of the cell having reduced susceptibility to macrophage phagocytosis compared to an unmodified cell does not further limit the structure of the cell. The structure of the cell claimed is not materially different than the cell claimed by Valamehr et al. Valamehr et al. teach increasing CD24 expression can be used for immune evasion (page 15, paragraph 0133). While it is in a list, one of ordinary skill in the art would recognize expression of genes which can be utilized for immune evasion. CD24 has been recognized as a “don’t eat me signal” to evade macrophages as evidenced by Barkal et al. (Nature 2019).
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/C.L.M./Examiner, Art Unit 1638
/Anna Skibinsky/
Primary Examiner, AU 1635
Prosecution Insights