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 .
Application Status
This action is written in response to applicant’s correspondence received 07/13/2026. Claims 55-63 and 66-87 are currently pending and are examined herein. Claims 64-65 were cancelled by the Applicant in the amendments received 07/13/2026. Claims 75-87 are newly added. Claims 55-63 and 66-87 are examined herein.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant' s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Drawings
Substitute drawings were received on 07/13/2026 These drawings are acceptable.
Affidavit/Declaration
The affidavit(s) under 37 CFR 1.130(a) filed 07/13/2026, on the basis that the subject matter disclosed in Buckner et al. (US 2023/0279351) and the claimed invention were owned or subject to assignment to Seattle Children’s Hospital and Benaroya Research Institute not later than the effective filing date of the claimed invention, is sufficient to overcome the rejection of claims 55, 58-59, 61, 63-65 and 67-70 under 35 USC 102(a)(2) over Buckner et al., the rejection of claims 56-57, 62, 66, and 71-72 under 35 USC 103 over Buckner et al., and claim 60 under 35 USC 103 over Buckner et al. in view of WIPO Publication 2019/084552 to Roth et al.
Response to Arguments
Applicant’s arguments, see pages 11-14 of the remarks filed 07/13/2026, with respect to rejection of claims 55-58 and 61-74 under 35 USC 103 over Scharenberg ‘834 in view of Scharenberg ‘541 and Cost (see pages 12-20 of the office action of 04/16/2026) have been fully considered and are persuasive for the reasons that follow.
Applicant argues that, “independent claims 55 and 67 have been amended to recite that each MND promoter is operably linked to a nucleotide sequence that is proximal to the MND promoter and encodes a CISC component” and that, “this arrangement provides unexpectedly enhanced CISC component expression and enrichment of dual-edited cells.”. Applicant provides evidence from Example 15, FIG. 149 and FIG. 150A of the instant specification, which show that, “placing the coding sequence proximal to the promoter (as in 3323) markedly improved the ability to select for dual-edited cells through CISC-mediated signal transduction”. Applicant further argues that, as shown in Example 16 and FIG 151A, “Even the most distal protein encoded by these vectors (mCherry reporter) showed about 9-fold higher expression intensity from the MND promoter.”. Construct 3323, which Applicant argues had unexpectedly and significantly greater enrichment compared to cells transduced with 3323, is a polynucleotide for insertion in a TRAC locus of a genome (TRAC hijack construct) comprising an MND promoter operably linked to a CISC component, the CISC component being proximal to the MND promoter and comprising an extracellular binding and transmembrane domain (FRB) and intracellular signaling domain (IL2Rβ), with a full TCRβ and partial (variable/joining) TCRα coding sequence downstream. Construct 3323 was paired with 3324, a polynucleotide comprising an MND promoter operably linked to a nucleotide sequence encoding FOXP3 and to a CISC component (comprising a FKBP domain and IL-2Rγ domain). These polynucleotides are commensurate in scope with the limitations of the polynucleotides recited in the independent claims. It is also relevant to note that a similar construct, 3354 (with a modified IL2Rβ sequence compared to 3323, see FIG. 150B) similarly outperformed 3243, which had the CISC component placed distal to the MND promoter, when each was paired with the split-CISC FOXP3 polynucleotide 3324 (see FIG. 150D, which showed higher absolute and fold enrichment for the 3324/3323 and 3323/3354 pairs compared to 3324/3243). Additionally, while Ho et al. found that, compared to EF-1A promoters, MND promoters used in lentiviral constructs in CAR T cells enhanced the packaging efficiency, this reference was published in June 2021, after the effective filing date of the instantly claimed invention, and a search of the prior art did not reveal any other direct comparisons between MND and EF-1A promoters in the context of engineered T cells which would have led the ordinary artisan to predict the increased expression observed by the inventors in this application (Ho et al. Promoter usage regulating the surface density of CAR molecules may modulate the kinetics of CAR-T cells in vivo. Mol Ther Methods Clin Dev. 2021 Mar 13;21:237–246.). In combination, the evidence presented by Applicant amounts to objective evidence that the combination of a) the MND promoter and b) the arrangement in which the CISC component is proximal to the MND promoter resulted in unexpectedly superior expression and engineered T cell enhancement compared to what the ordinary artisan would have anticipated based on what was known in the prior art.
In light of the above, the rejection of claims 55-58 and 61-74 under 35 USC 103 over Scharenberg ‘834 in view of Scharenberg ‘541 a\\\\\d Cost has been withdrawn. As the rejections of dependent claims 59 and 60 rely on the same base references, they are likewise withdrawn.
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.
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Claims 55, 58-59, 61-63, 66-72, 75-76, 78-82, 84-87 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 71, 79, 85, 88, 91-92, 96-108, and 110-117 of copending Application No. 17/596,493. Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons.
Regarding instant claim 55, copending claim 79 recites an engineered CD4+ regulatory T (Treg) cell, which is a species within the genus of instantly claimed Treg cells and thus anticipates that limitation of instant claim 55. Copending claim 79 recites the following characteristics of the Treg which anticipate those recited in instant claim 55:
A first inserted nucleic acid in a FOXP3 gene locus (i.e., in the genome of the cell), encoding a first CISC component with a CISC inducer molecule (ligand) binding domains (i.e., extracellular binding domains selected from FKBP and FRB) linked to an activation signal transduction domain (i.e., a cytoplasmic domain selected from IL-2Rβ and IL-2Rγ)
A second inserted nucleic acid in a TRAC gene locus, encoding a second CISC component with a CISC inducer molecule binding domain linked to an activation signal transduction domain selected from those noted above for the first component, the second nucleic acid further encoding various TCRα and TCRβ polypeptides.
Copending claim 79 differs from instant claim 55 in that it does not recite the transmembrane domain, does not recite an MND promoter, and does not recite wherein the CISC component is proximal to the MND promoter. The claim also does recite wherein the ligand is rapamycin. However, it recites wherein a first constitutively active promoter “initiates transcription of the nucleotide sequence encoding the first CISC component”. This is interpreted as an arrangement in which the CISC component is proximal to the first promoter, such that transcription is initiated at the CISC coding sequence (as opposed to transcription being initiated at the FOXP3-encoding sequence and continued into the CISC coding sequence). Further, copending claims 91 and 92 depend from copending claim 79 and specify that the promoter may be a MND promoter. Likewise, copending claim 85, which also depends from copending claim 79, recites specific transmembrane domains of the CISC components. Lastly, copending claim 96 stipulates that the CISC inducer (ligand) is rapamycin.
Regarding instant claim 58, at least copending claim 79 recites that the cell is a CD4+ Treg.
Regarding instant claim 59, at least copending claim 79 recites wherein the promoter is linked to TCR alpha and beta polypeptides, as described above.
Regarding instant claims 61, 79 and 85, the CISC components comprise extracellular, transmembrane, and cytoplasmic domains, which would necessarily have to appear in that order, either in N-to-C or C-to-N, because this is how that series of structures must be arranged relative to the cell (i.e., the extracellular domain must be on the extracellular side of the cell, the cytoplasmic side must be on the cytoplasmic side, and the transmembrane domain must be placed between the two). It would have been obvious to try either of the two possible arrangements and to try arranging the CISC components on one polynucleotide or the other, to optimize its expression and placement.
Regarding instant claim 62, copending claims 71 and 100 teach wherein the promoter is operably linked to a FOXP3 coding sequence (which would include the first exon) and is downstream of a TSDR.
Regarding instant claim 63, at least copending claims 71, 100 and 110 all recite wherein the promoter is operably linked to a FOXP3 gene locus/coding sequence.
Regarding instant claim 66, copending claim 88 recites the cell in a pharmaceutical composition.
Regarding instant claim 67, at least copending claim 71 recites a method for producing an engineered CD4+ Treg comprising the same structural components as those recited in copending claim 79 and discussed above.
Regarding instant claims 68-69, at least copending claim 71 teaches the method of producing the Treg comprising introducing into the cell a CRISPR/Cas nuclease, FOXP3 guide RNA, and TRAC guide RNA (parts iii-v). Claim 68 is interpreted as encompassing embodiments wherein both a ribonucleoprotein comprising a Cas nuclease and TRAC guide RNA and a ribonucleoprotein comprising a second Cas nuclease and FOXP3 guide RNA are introduced into the cell, which is also encompassed by copending claim 71.
Regarding instant claim 70, it would have been obvious to deliver the inducer/ligand to the cell to induce CISC dimerization.
Regarding instant claims 71-72, at least copending claim 90 teaches a method for treating an autoimmune condition comprising administering the engineered Treg.
Regarding instant claim 75, it would have been obvious to administer the inducer/ligand, rapamycin, to the subject to induce the Treg expansion in vivo by inducing CISC dimerization.
Regarding instant claims 76 and 78, at least copending claim 71 recites the TCR alpha and beta polypeptides as in (iv)(a)(2) as discussed above.
Regarding claims 80-81, 84 and 86-87, the copending claims teach the various recited operable linkages and insertions as already discussed above.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 56-57, 73-74, 77 and 83 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 71, 79, 85, 88, 91-92, 96-108, and 110-117 of copending Application No. 17/596,493, as applied to claims 55, 58-59, 61-63, 66-72, 75-76, 78-82, 84-87 above, in view of WO2019210280 A1 to Cost (of record, cited in a previous office action). Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons.
Claims 56, 77 and 83 recite wherein the MND promoter is operably linked to a chimeric antigen receptor. While the copending claims do not recite that limitation, Cost teaches polynucleotides encoding chimeric antigen receptors together with CISC components (para [0051]) to control survival and proliferation of CAR T cells (para [0004]). In paras [0135] and [0136], Cost notes that the T cells may be autologous (relevant to instant claim 73) or allogenic (relevant to instant claim 74). In para [0140], Cost teaches that the T cells comprise CD8+ cells.
It would have been obvious to modify the polynucleotide of the copending claims to comprise a CAR instead of TCRs, and express the construct in CD8+ T cells which are autologous or allogenic to the subject, to produce therapeutic T cells in accordance with the particular disease and treatment required.
Claim 60 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 71, 79, 85, 88, 91-92, 96-108, and 110-117 of copending Application No. 17/596,493, as applied to claims 55, 58-59, 61-63, 66-72, 75-76, 78-82, 84-87 above, in view of WO2019084552 A1 to Roth(of record, cited in a previous office action). Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons.
Claim 60, which depends from claims 55 and 58, recites wherein the second MND promoter is operably linked as in (iv)(b), i.e., a nucleotide sequencing encoding TCRB and a first portion of a TCRa protein comprising the variable and joining regions. While the copending claims do not recite that limitation, Roth teaches antigen-specific T cells comprising heterologous TCRs under control of endogenous TCR promoters (para [0003]), the polynucleotides encoding the heterologous TCRs comprising a nucleotide encoding a full length TCRB chain paired with the variable and joining regions of a TCRa chain (para [0028]). It would have been obvious to modify the copending invention to comprise Roth’s heterologous TCR comprising a TCRB chain and TCRa variable and joining regions to yield a therapeutic T cell which expresses a transgenic TCR under an endogenous promoter while preventing mispairing with endogenous TCR chains.
Conclusion
No claim is allowed at this time.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA M ZAHORIK whose telephone number is (703)756-1433. The examiner can normally be reached M-F 8:00-16:00 EST.
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/AMANDA M ZAHORIK/Examiner, Art Unit 1636
/BRIAN WHITEMAN/Primary Examiner, Art Unit 1636
