DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, 17596493, (PG-Pub US20230279351), filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 71, 79-85, 87-89 and 91-99 are pending. Claims 71 and 89 are withdrawn.
Priority
The filing receipt, mailed 7/18/2025, states that this application, filed 12/10/2021, claims benefit of domestic priority benefit as a 371 of PCT/US2020/039445, filed 06/24/2020, which claims benefit of 62/867,670, filed 06/27/2019 and claims benefit of 62/987,810, filed 03/10/2020.
Election/Restrictions
Applicant’s election without traverse of Group II, Claims 79-88, in the reply filed on 11/4/2025, is acknowledged. Claims 71 and 89 are withdrawn as not in the elected invention.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 8/25/2023 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner, except as follows: The IDS filed 9/1/2023 and 9/8/23, regarding citation #73 and #86, respectively, to Sambrook, and to citation #13, filed 1/13/2025, to Schmidleithner, have been lined out because no publication dates are provided.
Applicant is advised that the date of any re-submission of any item of information contained in this information disclosure statement or the submission of any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the statement, including all certification requirements for statements under 37 CFR 1.97(e). See MPEP § 609.05(a).
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.
Claims 96 and 98, which depend from 79, recite the limitation "the CISC inducer" in 1. These claims are indefinite because it is unclear if said “CISC inducer” is the “first CISC inducer” or the “second CISC inducer”.
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.
1. Claim(s) 79-82, 84, 85, 88, and 91-99 is/are rejected under 35 U.S.C. 103 as being unpatentable over as applied to claims, above, and further in view of Sharenberg, WO 2018080541, (hereinafter “Sharenberg ‘541”) international Publication Date 03 May 2018, US Serial 16345622, now US 11,712,454; Scharenberg, WO 2018111834, hereinafter (“Sharenberg ‘834”), Serial No. 16467013, now US 11,753,460; and Scharenberg, WO2019/210078; (31.10.2019), hereinafter (“Sharenberg ‘078”), US 20210253652, Serial No. 16981213.
Sharenberg ‘541, WO 2018080541 discloses (instant claim 1) an artificial CD4+CD25+ antigen-specific immunoregulatory T (airT) cell (para [0014] - "...providing a cell, wherein the cell comprises a first nucleotide sequence, wherein the first nucleotide sequence comprises a coding strand, the coding strand comprising one or more regulatory elements; and a FOXP3 gene or portion thereof;.....1n some alternatives, the cell is a CD4+ expressing cell."; para [0096] - "As shown in Figure 11, engineered T cells that stably expressed FOXP3 were analyzed by flow cytometry for expression of CD25, CD127, CTLA4 and LAG3. Analogous to natural regulatory T-cells, the engineered cells were shown to express high CD25, low CD127, and high CTLA4 and Lag3."; Figure 10 depicts a Treg expressing CD4 and CD25), comprising: a. an artificial modification of a forkhead box protein 3/winged helix transcription factor, FOXP3 gene (abstract - "Disclosed are methods of making a genetically cell that expressed FOXP3 and methods of treatment. In some embodiments, the method can providing a first nucleotide sequence, wherein the first nucleotide sequence comprises a coding strand, the coding strand comprising one or more regulatory elements and a FOXP3 gene or portion thereof providing a nuclease and performing a gene editing process on the first nucleotide sequence, which edits said one or more regulatory elements, and optionally edits the FOXP3 gene or portion thereof."), wherein the modified gene constitutively expresses a FOXP3 gene product at a FOXP3 expression level that is equal to or greater than the FOXP3 expression level of a naturally occurring regulatory T (Treg) cell (para [0011], [0014] - "In some alternatives, the gene editing process is a gene knock-in process for insertion of a heterologous promoter, a heterologous transcriptional enhancer domain or both. In some alternatives, the heterologous promoter is a constitutive promoter. In some alternatives, the promoter is an EF1 alpha promoter, a PGK promoter, or an MND promoter."; Note, see instant claims 9 and 14, wherein FOXP3 expression is directed by an MND promoter which would inherently provide an expression level of FOXP3 equal to or greater than that of a natural Treg.); and
b. at least one transduced polynucleotide encoding an antigen-specific T cell receptor (TCR) polypeptide (para [0090] - “In some alternatives, the cells can also be further engineered to express a chimeric antigen receptor or a TCR (T cell receptor) or other targeting moiety.....In some alternatives, the targeted tissue has low expression of FOXP3. Allowing a T-cell to express a CAR or TRC would allow the T-cell to target a specific tissue in need for the delivery of cells expressing FOXP3 to a tissue specific site").
Sharenberg ‘541 does not teach CISC first components, CISC second components, rapamycin, the rapamycin analog (rapalog) AP21967, T cell receptor alpha (TRAC) gene locus, and CRISPR/Cas-mediated genomic editing systems.
Scharenberg, WO 2018111834, Sharenberg ‘834), Serial No. 16467013, US 11753460, Sharenberg '834 discloses an artificial CD4+CD25+ antigen-specific immunoregulatory T, airT, cell (para [0034] - "In some embodiments, the cell, such as a mammalian cell, is a precursor T cell or a T regulatory cell. In some embodiments, the cell, such as a mammalian cell, is a hematopoietic stem cell. In some embodiments, the cell is a CD34+, CD8+, or a CD4+ cell."; para [0057], Figure 20, - "Figure 20 shows a FACS assay that is a T-cell marker analysis for CISC V3 expanded cells. Peripheral blood T-cells were activated using anti-CD3/CD28 beads transduced with IL2R-CISC V3 lentivirus, expanded in IL-2 or the indicated IL2R-CISC ligand for 15 days. Cells expanded in IL-2 have generally low expression of CD25, the IL2R alpha subunit, reflecting IL2R turnover in response to IL-2. In contrast, cells expanded through their IL2R-CISC receptors have high CD25 expression, as low media IL-2 promotes minimal turnover of native IL2R."), comprising: a. a transduced nucleic acid sequence encoding a forkhead box protein 3/winged helix transcription factor, FOXP3, gene product (para {0062], Figure 25 - "The described targeting approach integrates a promoter and both components of an IL2R-CISC V3 into the FOXP3 locus in line with a GFP fusion to the native FOXP3 gene"), wherein the cell constitutively expresses the FOXP3 gene product at a FOXP3 expression level that is equal to or greater than the FOXP3 expression level of a naturally occurring regulatory T, Treg, cell (para (0062), Figure 25 - "Figure 25 shows a schematic of the Targeted knock-in of an MND promoter and CISC to enrich/expand gene targeted T-cells. The described targeting approach integrates a promoter and both components of an IL2R-CISC V3 into the FOXP3 locus in line with a GFP fusion to the native FOXP3 gene. This architecture is intended to allow for ligand-induced selection of cells which have undergone an accurate gene targeting event."; Note, see instant claims 91-95, wherein FOXP3 expression is directed by an MND promoter which would inherently provide an expression level of FOXP3 equal to or greater than that of a natural Treg.); and b. at least one transduced polynucleotide encoding an exogenous antigen receptor polypeptide (para [0190] - "In some embodiments, the cell further comprises a chimeric antigen receptor."); wherein the transduced nucleic acid sequence encoding the FOXP3 gene product further comprises a nucleic acid sequence encoding a first chemically inducible signaling complex, CISC, component capable of specifically binding to a CISC inducer molecule (para [0008] - “Some embodiments described herein relate to a protein sequence encoding a chemical-induced signaling complex (CISC)"; para [0062], Figure 25 - "The described targeting approach integrates a promoter and both components of an IL2R-CISC V3 into the FOXP3 locus in line with a GFP fusion to the native FOXP3 gene. This architecture is intended to allow for ligand-induced selection of cells which have undergone an accurate gene targeting event"; para [0056] - "...IL2R-CISC ligand (either rapamycin or AP21967)."); and a second nucleic acid sequence encoding a second chemically inducible signaling complex, CISC, component that is different from the first CISC component and is capable of specifically binding to the CISC inducer molecule (para [0008) - "In some embodiments, the protein sequence comprises a second sequence. In some embodiments, the second sequence encodes a second CISC component. In some embodiments, the second CISC component comprises a second extracellular binding domain or portion thereof, a hinge domain, a transmembrane domain, and a signaling domain or portion thereof. In some embodiments, the first CISC component and the second CISC component are positioned such that when expressed, they dimerize in the presence of a ligand."). Sharenberg '834 does not specifically disclose an exogenous FOXP3 gene product and an exogenous TCR polypeptide. Herzog discloses a transduced nucleic acid sequence encoding an exogenous forkhead box protein 3/winged helix transcription factor, FOXP3, gene product (abstract - "To this end, we first retrovirally transduced FoxP3+ into FVIll-specific CD4+ cells, which resulted in cells that stably express FoxP3, are phenotypically similar to peripherally induced Tregs and are antigen specific suppressors, as judged by in vitro assays."), and at least one transduced polynucleotide encoding an exogenous antigen-specific T cell receptor, TCR, polypeptide (page 4, col 1, para 2 - col 2, para 2 -”...we used DO11.10 Rag2-/- mice, which lack mature B or T lymphocytes or endogenous Tregs but are transgenic for CD4+ T cells with OVA323-339 specificity. Donor FoxP3 transduced CD4+CD25- cells from 0011.10 Rag2-/- mice (FoxP3OVA), when adoptively transferred into recipient wt BALB/c mice and challenged with OVA323-339 peptide, underwent robust proliferation, as observed by dilution of the cell dye label, without compromise in FoxP3 expression.....To test if the observed suppression was antigen specific, the same assay was carried out with freshly isolated thymic Tregs (tTregs, Figure 1D). Because nonspecific polyclonal tTregs failed to suppress the proliferation of OVA323-339 stimulated Teff cells, we conclude that suppression by FoxP3 transduced cells in response to antigen is TCR specific, and not a result of a bystander effect”). It would have been obvious to one of ordinary skill in the art to modify the artificial Treg comprising a modified FOXP3 gene and a first and second chemically inducible signaling complex, as disclosed by Sharenberg '834, to include or instead use an exogenous FOPX3 gene and an exogenous TCR in a Treg, as disclosed by Herzog, as SCH'834 discloses Tregs comprising a modified FOXP3 locus, where T cells may comprise chimeric antigen receptors for directing T cell activity, where a first and second chemically induced signaling complex may be used to allow ligand-induced selection of successfully transformed cells by inserting an CISC component into the respective locus, Herzog discloses integration of an exogenous FOXP3 gene and where Tregs may comprise a TCR for directing T cell activity, and this combination would allow the T cells of SCH'834 with the ability to express an exogenous FOXP3 gene, an exogenous TCR, and to select for these components using the selection CISC selection methods described by Sharenberg '834, affording any improvement in FOXP3 expression and Treg differentiation, any improvement in T cell targeting by use of a TCR, and purity of produced cells, thereby affording any improvement in clinical outcome when used as a therapeutic, such as in adoptive cell therapy.
Scharenberg, WO2019210078; (31.10.2019), hereinafter (“Sharenberg ‘078”), Scharenberg, WO2019/210078; (31.10.2019), US 20210253652, Serial No. 16981213, teaches throughout the publication and abstract, teaches CRISPR/Cas-mediated genome editing, and e.g., at p. 77, para [0265]-p. 82, para [289], CISC components. Scharenberg, ‘078 teaches TRAC, rapamycin, AP21967. Scharenberg, ‘078, teaches throughout the publication and, e.g., para [0008]; rapamycin, e.g., at para [0105], [0124]; the rapamycin analog (rapalog) AP21967 e.g., at para [0124], [0414]; rapalogs, e.g., at para [0413].
It would have been prima facie obvious before the filing date of the instant application for one of ordinary skill in the art to have combined CISC first components, CISC second components, rapamycin, the rapamycin analog (rapalog) AP21967, T cell receptor alpha (TRAC) gene locus, and CRISPR/Cas-mediated genomic editing systems.
One of ordinary skill in the art would have been motivated to use first and second CISC complexes to provide mechanisms for activating signaling within a desired and specifically engineered population of cells, as taught in Sharenberg ‘834, see e.g., para [0003], [0020]. One of ordinary skill in the art would have been motivated to us rapamycin, or the rapamycin analog (rapalog) AP21967 in order to dimerized CISC components. The practitioner would have been motivated to use CRISPR systems for efficient and precise editing of genomes and to insert T cell receptor alpha (TRAC) to modulate the specificity of the created T regulatory cells.
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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
1. Claims 79 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. US 11,712,454 in view of Scharenberg, WO 2018111834, Serial No. 16467013, US 11753460, and Scharenberg, WO2019/210078; (31.10.2019), US 20210253652, Serial No. 16981213.
Claims 1-19 of the ‘454 Patent are drawn to editing a genome of a cell by targeting the FOXP3 gene and inserting a heterologous promoter. The prior art of Scharenberg, WO 2018111834, Serial No. 16467013, US 11753460, and Scharenberg, WO2019/210078; (31.10.2019), US 20210253652, Serial No. 16981213, throughout their specifications, teach promoters into genome edited cells to insert TRAC and CISC inducers, make obvious claim 79 of the instant invention.
2. Claims 79 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No. US 11753460 in view of Scharenberg, WO2019/210078; (31.10.2019), US 20210253652, U.S. Application Serial No. 16981213, and Sharenberg, WO 2018080541, (hereinafter “Sharenberg ‘541”) international Publication Date 03 May 2018, US Serial 16345622, now US 11,712,454.
Claims 1-19 of the ‘460 Patent are drawn to editing a genome of a cell by targeting the FOXP3 gene and inserting a heterologous promoter. The prior art of Scharenberg, WO2019/210078; (31.10.2019), US 20210253652, Serial No. 16981213, and Sharenberg, WO 2018080541, (hereinafter “Sharenberg ‘541”) international Publication Date 03 May 2018, US Serial 16345622, now US 11,712,454, throughout their specifications, teach promoters into genome edited cells to insert TRAC and CISC inducers, make obvious claim 79 of the instant invention.
3. Claims 79 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-57 of Scharenberg, U.S. Application Serial No. 16981213 in view of Scharenberg, WO 2018111834, Serial No. 16467013, US 11753460, and Scharenberg, WO2019/210078; (31.10.2019), and Sharenberg, WO 2018080541, (hereinafter “Sharenberg ‘541”) international Publication Date 03 May 2018, US Serial 16345622, now US 11,712,454.
Claims 1-57 of the ‘460 Patent are drawn to editing a genome of a cell by targeting the FOXP3 gene and inserting a heterologous promoter. The prior art of Scharenberg, WO2019/210078; (31.10.2019), US 20210253652, Serial No. 16981213, and Sharenberg, WO 2018080541, (hereinafter “Sharenberg ‘541”) international Publication Date 03 May 2018, US Serial 16345622, now US 11,712,454, throughout their specifications, teach promoters into genome edited cells to insert TRAC and CISC inducers, make obvious claim 79 of the instant invention.
This is a provisional nonstatutory double patenting rejection.
Conclusion
1. Claims 71, 79-85, 87-89 and 91-99 are pending. Claims 71 and 89 are withdrawn. Claims 79-82, 84, 85, 88, and 91-99 are rejected. Claims 83 and 87 are objected to.
2. Claims 83 and 87 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
3. Claim 83 and 87 are free of the examined prior art. The combination of SEQ ID in engineered CD4+ Treg cells as recited in claim 83 are free of the examined prior art. The closest examined prior art is that of Cerosaletti, 2017, J. Immunol. 199:323-335, (of record, IDS filed 9/1/2023). , throughout the publication and abstract, and at pp. 326-327, bridging paragraph, and Table I, describe expression of C-Peptide and islet Ag peptides in CD4+ memory T cells from DRB1*0401 Class II molecule Type I Diabetes (T1D) subjects and Healthy Controls (HD). Cerosaletti, at pp. 327-328, bridging paragraph, and Table II, report that testing against individual peptides showed that only IGRP 305-324, length 20 amino acids, triggered specific proliferation.
However, Cerosaletti, does not teach T1D2, T1D4 as specific T-cell receptors , as in claim 84, and instead appears to use these terms as designations for individual human subjects. Cerosaletti, at p. 325, para 2, states: “We analyzed a total of 93, 35, and 25 cells from subjects T1D2, T1D4, and TIDS, and 37, 31, and 22 from subjects HC2, HC3, and HCS, respectively. The higher number of cells for subject T1D2 resulted from pooling of profiles from three different visits.”
4. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Mark L Shibuya whose telephone number is (571)272-0806. The examiner can normally be reached M-F, 9AM-4:30PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James (Doug) Schultz, can be reached at (571) 272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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MARK L. SHIBUYA
Primary Patent Examiner
Art Unit 1631
/MARK L SHIBUYA/Primary Patent Examiner, Art Unit 1631