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 .
Priority
Acknowledgment is made of applicant’s claim for priority based on a foreign priority application filed as GB2114871.3 on 10/18/2021.
All claims are given the priority date of 10/18/2021.
Application Status
Receipt is acknowledged of amendment, filed 04/12/2024. Claims 1-28 are currently pending.
Information Disclosure Statement
Receipt of acknowledgment of the information disclosure statement filed on 04/12/2024 has been received and all references have been considered.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code, specifically on pages 3 and 18. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claims 6, 7, 9 and 19 are objected to because of the following informalities:
Claim 19 recites “a SLAM-associated protein (SAP) protein”. It would be remedial to remove the second recitation of the term “protein”.
Claim 6 recites “A guide RNA according to claim 1”. It would be remedial to amend the claim to recite “The guide RNA according to claim 1”.
Claim 7 recites “A guide RNA according to claim 1”. It would be remedial to amend the claim to recite “The guide RNA according to claim 1”.
Claim 9 recites “A guide RNA according to claim 1”. It would be remedial to amend the claim to recite “The guide RNA according to claim 1”.
Appropriate correction is required.
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.
Claims 1-7, 10-12, 15, 16, 20-23, and 25-28 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by Benson et al (WO 2019/178422 A1) as evidenced by ENSEMBL- SH2D1A gene transcript (ENSEMBL Human GRCh38.p14 Transcript ENST00000371139.9 SH2D1A exon 1; Accessed Sept. 2026; Pg. 1/1-1/1).
Regarding claims 1 and 3, Benson teaches a gRNA complexed to Cas9 in an RNP format and delivered via electroporation for targeting SH2D1A for anti-tumor CAR-T therapy [00523]. Benson teaches the gRNA sequence of SEQ ID NO: 1253 which is 100% identical to instant SEQ ID NO: 9 which is shown to target within exon 1 of SH2D1A (See Appendix I and [0087]). ENSEMBL is only cited to show the specific sequence of exon 1 and that the gRNA sequence is complementary to exon 1 of the SH2D1A gene (Page 1/1).
Regarding claim 2, Benson teaches a gRNA complexed to Cas9 in an RNP format and delivered via electroporation for targeting SH2D1A for anti-tumor CAR-T therapy [00523]. Benson teaches the gRNA sequence of SEQ ID NO: 1253 which is 100% complementary to instant SEQ ID NO: 4 which is shown to target within exon 1 of SH2D1A (Page 218 to 219, Table 6C; and See Appendix II). ENSEMBL is only cited to show the specific sequence of exon 1 and that the gRNA sequence is complementary to exon 1 of the SH2D1A gene (Page 1/1).
Regarding claim 4, Benson teaches a gRNA complexed to Cas9 in an RNP format and delivered via electroporation for targeting SH2D1A for anti-tumor CAR-T therapy [00523].
Regarding claim 5, Benson teaches “gRNAs” used in all experiments are single-molecule gRNAs (sgRNAs) [00453]. Benson teaches a gRNA complexed to Cas9 in an RNP format and delivered via electroporation for targeting SH2D1A for anti-tumor CAR-T therapy [00523].
Regarding claims 6 and 7, Benson teaches a gRNA complexed to Cas9 in an RNP format and delivered via electroporation for targeting SH2D1A for anti-tumor CAR-T therapy [00523]. Benson teaches the gRNA sequence of SEQ ID NO: 1253 which is 100% identical to instant SEQ ID NO: 9 which is shown to target within exon 1 of SH2D1A (See Appendix I and [0087]). ENSEMBL is only cited to show the specific sequence of exon 1 and that the gRNA sequence is complementary to exon 1 of the SH2D1A gene (Page 1/1).
Regarding claims 10 and 11, Benson teaches a gRNA complexed to Cas9 in an RNP format and delivered via electroporation for targeting SH2D1A for anti-tumor CAR-T therapy [00523]. Benson teaches all of the Cas9 proteins used are derived from S. pyogenes [00454]. Benson teaches the gRNA sequence of SEQ ID NO: 1253 which is 100% identical to instant SEQ ID NO: 9 which is shown to target within exon 1 of SH2D1A (See Appendix I and [0087]). ENSEMBL is only cited to show the specific sequence of exon 1 and that the gRNA sequence is complementary to exon 1 of the SH2D1A gene (Page 1/1).
Regarding claim 12, Benson teaches Cas9 nickase mutant is co-expressed with a nucleic acid repair template to facilitate the incorporation of an exogenous nucleic acid sequence by homology directed repair [00338].
Regarding claim 15, Benson teaches a gRNA complexed to Cas9 in an RNP format and delivered via electroporation for targeting SH2D1A for anti-tumor CAR-T therapy [00523].
Regarding claim 16, a kit is a collection of items and therefore, if the reference teaches all of the listed items, then it teaches the kit.
Benson teaches a gRNA complexed to Cas9 in an RNP format and delivered via electroporation for targeting SH2D1A for anti-tumor CAR-T therapy [00523]. Benson teaches all of the Cas9 proteins used are derived from S. pyogenes [00454]. Benson teaches Cas9 nickase mutant is co-expressed with a nucleic acid repair template to facilitate the incorporation of an exogenous nucleic acid sequence by homology directed repair [00338].
Regarding claims 20-23, Benson teaches a gRNA complexed to Cas9 in an RNP format and delivered via electroporation for targeting SH2D1A for anti-tumor CAR-T therapy in human CD8 T cells [00523]. Benson teaches all of the Cas9 proteins used are derived from S. pyogenes [00454]. Benson teaches Cas9 nickase mutant is co-expressed with a nucleic acid repair template to facilitate the incorporation of an exogenous nucleic acid sequence by homology directed repair [00338].
Regarding claim 25, Benson teaches the culture medium is serum free [00399].
Regarding claim 26, Benson teaches a gRNA complexed to Cas9 in an RNP format and delivered via electroporation for targeting SH2D1A for anti-tumor CAR-T therapy [00523]. Benson teaches all of the Cas9 proteins used are derived from S. pyogenes [00454]. Benson teaches Cas9 nickase mutant is co-expressed with a nucleic acid repair template to facilitate the incorporation of an exogenous nucleic acid sequence by homology directed repair [00338].Benson teaches administering the composition to a subject for purposes such as gene therapy, e.g. to treat a disease, for use as an antiviral, for use as an anti-pathogenic, for use as an anti-cancer therapy, or for biological research [00434].
Regarding claims 27 and 28, the recitation of intended use does not result in a structural difference between the product from prior art and the claimed product.
Benson teaches a gRNA complexed to Cas9 in an RNP format and delivered via electroporation for targeting SH2D1A for anti-tumor CAR-T therapy [00523]. Benson teaches all of the Cas9 proteins used are derived from S. pyogenes [00454]. Benson teaches Cas9 nickase mutant is co-expressed with a nucleic acid repair template to facilitate the incorporation of an exogenous nucleic acid sequence by homology directed repair [00338].Benson teaches administering the composition to a subject for purposes such as gene therapy, e.g. to treat a disease, for use as an antiviral, for use as an anti-pathogenic, for use as an anti-cancer therapy, or for biological research [00434].
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.
Claims 8, 9, 13, 14, 17 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Benson et al (WO 2019/178422 A1) as evidenced by ENSEMBL- SH2D1A gene transcript (ENSEMBL Human GRCh38.p14 Transcript ENST00000371139.9 SH2D1A exon 1; Accessed Sept. 2026; Pg. 1/1-1/1) in view of Chen et al (WO 2022/036180 A1; filed on 08/13/2021).
The teachings of Benson as described and applied as above.
Regarding claims 8, 9 13 and 14, Claim 13 is interpreted that “a sequence” means two or more consecutive amino acids/nucleotides and not the entirety of the sequence.
Benson teaches a gRNA complexed to Cas9 in an RNP format and delivered via electroporation for targeting SH2D1A for anti-tumor CAR-T therapy [00523]. Benson teaches the CRISPR protein can be Cas12a [00325].
Benson does not teach the specific sequence of SEQ ID NO: 13 as well as the specific use of a mutant asCas12a.
Chen teaches a guide RNA for targeting the SH2D1A gene within exon 1 as SEQ ID NO: 9836 which is 100% identical to nucleotides 1-20 of the 21 long guide RNA of instant SEQ ID NO: 13 (Page 27, Lines 20-23; Page 108, Table 2; See Appendix III). Chen teaches the length of the guide RNA can vary between 10-60 nucleotides (Page 49, Lines 22-32; Page 50, Lines 18-31). Chen teaches the use of enAsCpf1, an engineered or mutant Cas12a derived from Acidaminococcus sp. BV3L6, as the cas enzyme for targeting editing (Page 6, Lines 1-8; Page 32, Lines 4-16).
ENSEMBL is only cited to show the specific sequence of exon 1 and that the gRNA sequence is complementary to exon 1 of the SH2D1A gene (Page 1/1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the guide RNA and Cas9 of Benson for the guide RNA and Cas12 as taught by Chen because Benson teaches it is within the ordinary skill in the art to use a guide RNA 21 nucleotides in length complexed to Cas9 in an RNP format and delivered via electroporation for targeting SH2D1A for anti-tumor CAR-T therapy and Chen teaches guide RNAs of varying lengths for targeting the SH2D1A gene with enAsCpf1.
One would have been motivated to make such a modification in order to receive the expected benefit of using the specific guide RNA sequence of SEQ ID NO: 13 complexed with enAsCpf1 for targeting the Sh2D1A gene as taught by Chen.
Regarding claims 17 and 18, Benson teaches the CAR and engineered TCR expression constructs described were then inserted into a plasmid comprising a human or a murine (depending on the species the T cells were derived from) U6 promoter driving expression of one or more sgRNAs for delivery to the T cells [00461].
Benson does not teach the use of an AAV6 viral vector.
Chen teaches the Descartes library and/or individual gene targeting CLASH vectors were packaged by AAV6 serotype vectors to target human T cells after electroporation with Cas 12a mRNA (Page 9, Lines 4-6; Page 48, Lines 23-30; Page 113, Lines 14-20).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the lentiviral vector of Benson for the AAV6 viral vector as taught by Chen because Benson teaches it is within the ordinary skill in the art to use the CAR and engineered TCR expression constructs described were then inserted into a plasmid comprising a human or a murine (depending on the species the T cells were derived from) U6 promoter driving expression of one or more sgRNAs for delivery to the T cells and Chen teaches the Descartes library or individual gene targeting CLASH vectors were packaged by AAV6 serotype vectors to target human T cells after electroporation with Cas 12a mRNA.
One would have been motivated to make such a modification in order to receive the expected benefit of using AAV6 as the viral vector for delivering the guide RNA complexed with Cas 12a and donor sequence as taught by Chen.
Claims 19, 24, 27 and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Benson et al (WO 2019/178422 A1) as evidenced by ENSEMBL- SH2D1A gene transcript (ENSEMBL Human GRCh38.p14 Transcript ENST00000371139.9 SH2D1A exon 1; Accessed Sept. 2026; Pg. 1/1-1/1) in view of Rivat et al (Blood. 2012 Dec 5;121(7):1-13).
The teachings of Benson as described and applied as above.
Regarding claim 19, Benson teaches a gRNA complexed to Cas9 in an RNP format and delivered via electroporation for targeting SH2D1A for anti-tumor CAR-T therapy within CAR T cells [00523]. Benson teaches all of the Cas9 proteins used are derived from S. pyogenes [00454]. Benson teaches Cas9 nickase mutant is co-expressed with a nucleic acid repair template to facilitate the incorporation of an exogenous nucleic acid sequence by homology directed repair [00338].
Benson does not specifically teach the donor sequence encodes for a SLAM-associated protein (SAP).
Rivat teaches Sap-/- murine HSCs were transduced with lentiviral vectors containing a sequence encoding SAP before transplantation into irradiated recipients (Page 1, Abstract). Rivat teaches NKT-cell development was significantly higher and NK-cell cytotoxicity restored to wild-type levels in mice receiving the SAP vector in comparison to control mice (Page 1, Abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Benson to include the donor sequence encoding a SAP protein as taught by Rivat because Benson teaches it is within the ordinary skill in the art to use a guide RNA complexed to Cas9 and donor sequence in an RNP format and delivered via electroporation for targeting SH2D1A for anti-tumor CAR-T therapy within CAR T cells and Rivat teaches NKT-cell development was significantly higher and NK-cell cytotoxicity restored to wild-type levels in mice receiving the SAP vector in comparison to control mice.
One would have been motivated to make such a modification in order to receive the expected benefit of restoration of SAP levels in deficient subjects when the donor sequence encodes SAP as taught by Rivat.
Regarding claim 24, Benson teaches a gRNA complexed to Cas9 in an RNP format and delivered via electroporation for targeting SH2D1A for anti-tumor CAR-T therapy within CAR T cells [00523].
Benson does not teach the use of hematopoietic stem cells.
Rivat teaches Sap-/- murine HSCs were transduced with lentiviral vectors containing a sequence encoding SAP before transplantation into irradiated recipients (Page 1, Abstract). Rivat teaches NKT-cell development was significantly higher and NK-cell cytotoxicity restored to wild-type levels in mice receiving the SAP vector in comparison to control mice (Page 1, Abstract). Rivat teaches that SAP gene transfer into Sap-/- HSCs is able to reconstitute major defects in cellular and humoral immunity seen in Sap-/- mice, specifically, the mechanisms of reconstitution after gene transfer are due to the expression of SAP in several specific cell lineages, which now allows SAP interaction with specific SLAM family receptors, especially 2B4 and Ly108 (Page 8, 2nd Paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Benson to include the use of hematopoietic stem cells as taught by Rivat because Benson teaches it is within the ordinary skill in the art to use a guide RNA complexed to Cas9 and donor sequence in an RNP format and delivered via electroporation for targeting SH2D1A for anti-tumor CAR-T therapy within CAR T cells and Rivat teaches SAP gene transfer into Sap-/- HSCs is able to reconstitute major defects in cellular and humoral immunity seen in Sap-/- mice, specifically, the mechanisms of reconstitution after gene transfer are due to the expression of SAP in several specific cell lineages, which now allows SAP interaction with specific SLAM family receptors, especially 2B4 and Ly108.
One would have been motivated to make such a modification in order to receive the expected benefit of restoration of SAP activity by delivering the vector via HSCs as taught by Rivat.
Regarding claims 27 and 28, Benson does not specifically teach the use of the kit for the treatment of an SAP-mediated disease, such as X-linked lymphoproliferative disease.
Rivat teaches Sap-/- murine HSCs were transduced with lentiviral vectors containing a sequence encoding SAP before transplantation into irradiated recipients (Page 1, Abstract). Rivat teaches NKT-cell development was significantly higher and NK-cell cytotoxicity restored to wild-type levels in mice receiving the SAP vector in comparison to control mice (Page 1, Abstract). Rivat teaches that SAP gene transfer into Sap-/- HSCs is able to reconstitute major defects in cellular and humoral immunity seen in Sap-/- mice, specifically, the mechanisms of reconstitution after gene transfer are due to the expression of SAP in several specific cell lineages, which now allows SAP interaction with specific SLAM family receptors, especially 2B4 and Ly108 (Page 8, 2nd Paragraph). Rivat teaches the first time a proof of concept for a HSC gene strategy approach for correction of the different immunologic abnormalities seen in XLP1 (Page 9, 1st Paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Benson to include the use of hematopoietic stem cells comprising the donor sequence encoding SAP for the treatment of XLP1 as taught by Rivat because Benson teaches it is within the ordinary skill in the art to use a guide RNA complexed to Cas9 and donor sequence in an RNP format and delivered via electroporation for targeting SH2D1A for anti-tumor CAR-T therapy within CAR T cells and Rivat teaches SAP gene transfer into Sap-/- HSCs is able to reconstitute major defects in cellular and humoral immunity seen in Sap-/- mice, specifically, the mechanisms of reconstitution after gene transfer are due to the expression of SAP in several specific cell lineages, which now allows SAP interaction with specific SLAM family receptors, especially 2B4 and Ly108.
One would have been motivated to make such a modification in order to receive the expected benefit of restoration of SAP activity by delivering the vector via HSCs for the treatment of XLP1 as taught by Rivat.
Conclusion
No claims are allowed.
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/ALEXANDRA ROSE LIPPOLIS/Examiner, Art Unit 1637
/CELINE X QIAN/Primary Examiner, Art Unit 1637
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