DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Receipt is acknowledged of response to the Restriction Requirement, filed on 12/22/2025.
Claims 1-17 are pending.
Election/Restrictions
Applicant’s election without traverse of Group I, and the species of costimulatory domain, 41BB, in the reply filed on 12/22/2025 is acknowledged.
Claim(s) 13-17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 12/22/2025.
Claims 1-12 are under consideration.
Priority
Acknowledgement is made of Applicant’s claim for priority based on a provisional application filed as 63/327,189 on 04/04/2022.
All claims are given the priority date of 04/04/2022.
Information Disclosure Statement
Receipt of information disclosure statements, filed on 04/03/2023 and 12/22/2025 is acknowledged.
Specification
The disclosure is objected to because of the following informalities: paragraph [0038] at line 13, “(Hi) a costimulatory domain…”, should recite “(iii) a costimulatory domain…”. Applicant is listing CAR domains and the provided list is in roman numerals.
Appropriate correction is required.
The use of the term(s) listed below, which is/are a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
List of trade name or a mark used in the instant application:
Incucyte [0008], [0009], [0010], [0011];
Glutamax [0069];
RosetteSep [0070];
Countess [0070], [0074];
ImmunoCult [0070], [0071], [0074], [0080], [0083];
AMPure [0072], [0079], [0082];
“NanoPhotemeter” [0072] (misspelled, should be NanoPhotometer);
Nanodrop [0072];
Nucleovuvette [0074];
Nucleofector [0074];
Ghost Dye [0075];
FCS Express 7 Software [0075];
Q5 (both TM and ® listed, see comment below) [0072], [0076];
Of note: Applicant uses both “TM” or ® interchangeably for various registered trade-marked reagents, materials, and/or systems (e.g., Q5® in paragraph [0072], then uses Q5TM in paragraph [0076]). It would be remedial to apply these marks appropriately to their respective goods.
The disclosure is objected to because of the following informalities: “NanoPhotemeter” in paragraph [0072] should be “NanoPhotometer”.
Appropriate correction is required.
Claim Objections
Claim 1 is objected to because of the following abbreviations/acronyms are not spelled out prior to introduction:
“HDR” (third word in);
“HA” in line(s) 4, 10, 12, 18, 20, and 26;
“SA” in line(s) 4, 12, and 20;
“IRES” in line(s) 4, 7, 9, 12, 15, 17, 20, 23, and 24;
“uPAR” in line(s) 5, 12, and 20;
It is noted that “HA”, “SA”, “IRES” are spelled out later in the claim, however, it would be remedial to spell each out first, followed by the abbreviation for clarity.
Claim 2 is objected to because of the following informalities: For clarity purposes, “cutsite” should be “cleavage site” as referenced in independent claim 1. Appropriate correction is required.
Claim 5 is objected to because of the following informalities: claim 5 recites … a single-chain variable fragment comprising a heavy variable fragment and a light chain variable fragment. The “heavy variable fragment” is also a “chain” thus, it would be remedial to recite “…, a single-chain variable fragment comprising a heavy chain variable fragment and a light chain variable fragment. Appropriate correction is required.
Claim 8 is objected to because of the following informalities: “41BB” should be recited as “4-1BB”. Appropriate correction is required.
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.
Claim(s) 1, 3-12 are rejected under 35 U.S.C. 103 as being unpatentable over Muller et al (The CD28-Transmembrane Domain Mediates Chimeric Antigen Receptor Heterodimerization With CD28, frontiers in Immunology, Vol 12, Article 639818, pages 1-13, March 23, 2021) in view of Chen et al, (WO 2020/092057 A1), in further view of Sadelain et al (WO 2020/160518 A1, publication date 08/06/2020).
Regarding claim 1, Muller et al teaches, the impact of CD28-TMD on 19-
CARs in human T cells (page 2, column 1, paragraph 3). Muller et al discloses generating 19-CARs constructs (reading on templates) by differing only in their hinge domain (CD8, CD29, or IgG4) and/or their transmembrane domain (CD8 vs. CD28), which all have been used to engineer CAR T cells for clinical applications (page 4, column 2, paragraph 3; and, Figure 1A). More specifically, Muller et al teaches a homology-directed repair (HDR) construct with the following components located in Figure 5A:
A left homology arm (HA);
A T2A;
A CAR gene (in this case, CD19);
A hinge domain (CD28 or CD8);
A transmembrane domain;
An intracellular domain;
A PolyA; and,
A right homology arm (HA).
Regarding claim 3, Muller et al teaches a T2A (Figure 5).
Regarding claim 6, claim 7, and claim 8, Muller et al teaches a transmembrane domain and an intracellular domain. More specifically, Muller et al teaches a CD28 transmembrane domain, and CD3-zeta (Figure 5A). Muller et al further teaches a costimulatory domain as part of the intracellular signaling domain, and is situated between the CD28 and CD3-zeta (Figure 5A). Muller et al teaches that the costimulatory domain is 4-1BB (Figure 5A).
Claim 1 is drawn to an embodiment where the first and second secreted factors are optional. Dependent claim 9 recites, “The template of claim 1, wherein the first and second secreted factors are each independently a pro-regenerative secreted factor, a pro-memory secreted factor, growth factor, or a factor that attracts pro-regenerative immune cells.” Claim 9 limits the optional secreted factors of claim 1 but does not make them a requirement of the claim. Thus, the secreted factors remain optional and need not be taught by the prior art. The teachings of Muller et al apply to claim 9 as they are described with regard to claim 1 above.
Claim 1 is drawn to an embodiment where the first and second selection marker polynucleotides are optional. Dependent claim 10 recites, “The template of claim 1, wherein the first selection marker, second selection marker or both are a coding sequence for a fluorescent protein.” Claim 10 limits the optional selection markers but does not make them a requirement of the claim. Thus, the selection markers remain optional and need not be taught by the prior art. The teachings of Muller apply to claim 10 as they are described with regard to claim 1 above.
Regarding claim 11, Muller et al teaches a vector encoding the HDR templates utilized throughout the manuscript (page 2, column 2, paragraph 2).
Muller et al does not teach that the CAR gene is a uPAR binding fragment (antibody fragment or scFv fragment) and contains a splice acceptor (SA) between the left HA and T2A.
Chen et al teaches HDR templates that contain a splice acceptor. More specifically, Chen et al teaches, “…one or more HDR templates can contain a sequence that encodes a reporter gene, a chimeric antigen receptor (CAR), another gene of interest, or combinations thereof, and one or more sequences homologous to one or more target sites. The HDR template can further include one or more regulatory elements, e.g., a promoter, enhancer, silencer, 5’ or 3’ untranslated region (UTR), splice acceptor, IRES, 2 A self-cleaving peptides (e.g., F2A, E2A, P2A and T2A), triple helix, polyadenylation signal, or combinations thereof, operationally linked to each reporter gene, CAR, or combination thereof.”, (Page 55, lines 20-27). Chen et al explains that “One of skill in the art would understand that in some cases it can be advantageous for a transgene (being targeted for integration) to be kept under the control of an endogenous promoter (e.g., a promoter at or near the site of integration). For example, the HDR template (e.g., provided by the AAV vector) can contain a splice acceptor/donor, 2A peptide, and/or internal ribosome entry site (IRES) operationally linked to a transgene (e.g., reporter gene, CAR) to allow expression of the transgene in frame with a gene at the site of integration and/or under the control of the promoter at the site of integration.”, (page 46, lines 14-21).
Regarding claim 1, 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 HDR CAR construct of Muller et al to incorporate a splice acceptor. One would have been motivated to make such a modification in order to receive the expected benefit of allowing for expression of the transgene to be in frame with a gene at the site of integration and/or under control of the promoter at the site of the integration as taught by Chen et al.
Chen et al does not teach that the CAR gene is a uPAR binding fragment (antibody fragment or scFv).
Sadelain et al teaches, “…that the uPAR surface protein is commonly upregulated in a broad range of in vitro and in vivo mammalian models for senescence. As demonstrated in the Examples herein, upregulation of uPAR occurred in response to all tested senescence triggers: replication induced senescence, drug induced senescence (e.g., combined MEK and CDK4/6 inhibition or Doxorubicin), and oncogene induced senescence (oncogenic Ras). Indeed, soluble uPAR (suPAR) plasma levels were positively correlated with the load of senescent cells present in the organism. Furthermore, the engineered immune cells of the present technology selectively targeted senescent cells, while leaving normal proliferating cells unaffected.”, (paragraph [0063]). Sadeline et al discloses an isolated nucleic acid molecule that “encodes an anti-uPAR-targeted CAR comprising (a) an uPAR binding fragment (e.g., an anti-uPAR scFv or uPA fragment) that specifically binds to a uPAR antigen, (b) a transmembrane domain comprising a CD8 polypeptide or CD28 polypeptide, and (c) an intracellular domain comprising a CD3ζ polypeptide, and optionally one or more of a co-stimulatory signaling region disclosed herein, a P2A self-cleaving peptide, and/or a reporter or selection marker (e.g., GFP, LNGFR)...”, (see paragraph [00229]). Furthermore, Sadeline et al teaches, “...the polynucleotides encoding an extracellular antigen-binding fragment that specifically binds to a uPAR antigen (e.g., human uPAR antigen) (e.g, an scFv (e.g, a human scFv), a Fab, or a (Fab)2), CD3, CD8, CD28 can be modified by codon optimization. Codon optimization can alter both naturally occurring and recombinant gene sequences to achieve the highest possible levels of productivity in any given expression system…”, (paragraph [00271]).
Therefore, regarding claim 1, 4, and 5, 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 CD19 CAR-T gene of the HDR template of Muller et al with a uPAR binding fragment (antibody fragment of claim 4 or scFv of claim 5) to yield the predictable outcome of selectively targeting senescent cells with the ability to codon optimize the extracellular binding antigen fragment to achieve the highest possible levels of productivity in any given expression system as taught by Sadeline et al.
Regarding claim 12, Muller et al and Chen et al teach a plasmid containing the HDR template as taught by the combination of references in regard to instant claim 1, however, Muller et al and Chen et al do not explicitly teach a virus-free plasmid.
Sadeline et al teaches, “For example, a polynucleotide encoding the uPAR-specific CAR can be cloned into a retroviral vector and expression can be driven from its endogenous promoter, from the retroviral long terminal repeat, or from an alternative internal promoter. Non-viral vectors or RNA may be used as well.”, (paragraphs [00259] and [00260]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize a non-viral vector (reading on a virus-free plasmid), as taught by Sadeline et al. One would be motivated to utilize such a plasmid to reduce immunogenicity, increase safety, and lower cost of production.
Thus, claims 1 and 3-12 are unpatentable over Muller et al, in view of Chen et al, in further view of Sadeline et al.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Muller et al and Chen et al in view of Sadeline et al as applied to claim(s) 1 and 3-12 above, and further in view of Gottschalk et al (WO 2021263075 A1, publication date of 12-30-2021).
In combination, Muller et al, Chen et al, and Sadeline et al teach the DNA HDR template of claim 1, for which claim 2 depends upon. Despite Muller et al utilizing the TRAC locus known in the art, i.e., exon 1, referencing Eyquem et al (Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection, Nature, Vol 543, pages 112-117, 2017; NPL citation #6 from the top of IDS filed 12/22/2025), Muller et al, Chen et al, and Sadeline et al, do not explicitly teach any given length of homology arms for the HDR template upstream and downstream the TRAC locus.
Gottschalk et al discloses methods of genetically modifying an immune cell such that the immune cell expresses a transgene in an activation dependent manner (abstract). More specifically, Gottschalk teaches varying the lengths of homology arms upstream and downstream the TRAC locus exon 1, also referencing Eyquem et al (2017) in Figure 2B. Figure 2C of Gottschalk et al teaches 400bp of a right homology arm and 400bp of a left homology arm. Moreover, example 1 of Gottschalk et al teaches, “To optimize knock-in conditions the TRAC locus was targeted for gene insertion, which has been previously explored for the knock-in of several genes. … For successful integration of a large transgene, the following elements have to be considered: (i) target site and guide RNAs (gRNAs), (ii) transgene design, (iii) donor DNA length, type (ssDNA, dsDNA or plasmid) and delivery, (iv) detection and efficiency of the knock-in and (v) T cell viability (Figure 1).”, (see paragraph [00259]). Lastly, “… It was next evaluated if longer HA length results in improved knock-in efficiency. To test this, the IL-15.E2A.mClover3 transgene was used flanked by 100, 200, 300, 400bp HAs. As shown in Figure 4C, an average of 21.5%, 26.6%, 24.8% or 27.7% GFP+ cells was obtained respectively, with no statistically significant difference between groups. In addition, different HA length did not affect T cell viability (Figure 4C, right panel). Taken together, these results indicate that knock-in efficiency of a large transgene is not dependent on HA length tested.”, (see paragraph [00266]).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date to take the combined teachings of the DNA HDR template from claim 1, and modify the template to include TRAC homology arms of 383 to 588 (LHA) and 391 to 499 (RHA), upstream and downstream of the target cleavage site, respectively, to yield the predictable results of a knock-in efficiency or T cell viability that is not dependent on homology arm lengths for the TRAC locus between 100-400 base pairs, as taught by Gottschalk et al.
Accordingly, claim 2 is unpatentable over Muller et al, Chen et al, and Sadeline et al, in further view of Gottschalk et al.
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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Claim(s) 1-5 and 11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim(s) 4, 6, 8, and 11-12 of copending Application No. 19/316,786 (Reference application - herein after the ‘786 application) in view of Gottshalk et al (WO 2021263075 A1, publication date of 12-30-2021) and further view of Sadeline et al (WO 2020/160518 A1, publication date 08/06/2020).
Claim 8 of the ‘786 application is drawn to “A DNA template plasmid for generating genome modified immune cells, comprising a plasmid backbone, a first insert, and a second insert; wherein the first insert comprises a transgene, wherein the transgene is flanked by left and right homology arms that are complementary to sequences on both sides of a cleavage site in a target expressed gene in an unmodified immune cell; wherein the second insert comprises a cleavage target comprising a protospacer sequence defining the cleavage site in the target expressed gene, and a protospacer adjacent motif sequence (PAM) for recognition by a Cas9 ribonucleoprotein complex (Cas9-RNP); wherein the Cas9-RNP comprises a Cas9 polypeptide and a single guide RNA (sgRNA) comprising a sequence complementary to the protospacer sequence; and wherein the Cas9-RNP binds the second insert and linearizes the DNA template plasmid by Cas9-RNP-directed cleavage at the cleavage site,” “wherein the transgene of the first insert comprises a chimeric antigen receptor (CAR),” and wherein the CAR comprises an extracellular domain linked to an intracellular domain through a first transmembrane domain, wherein the first extracellular domain comprises an antigen recognition domain.”
Claim 11 of the ‘786 application depends from claim 8 and requires, “wherein the transmembrane domain comprises CD4, CD8, CD-8 alpha, CD8-beta, CD3-epsilon, CD3-beta, CD28, 4-1BB, OC40, PD-1, LAG-3, CH2CH3 or NKG2D, IgG, CD3-zeta…”.
Claim 12 of the ‘786 application depends from claim 8 and requires, “wherein the intracellular domain comprises a costimulatory domain selected from 2B4, CD27, CD28, CD137, CD154, CD244, CD278, and combinations thereof, and a signaling domain selected from CD16, DAP10, DAP12, CD28, ICOS, CD27, OX40, CD40L, CD3-zeta, and combinations thereof.”
Claims 8, 11, and 12 of the ‘786 application do not require a splice acceptor (SA), a 2A, a uPAR fragment, a hinge domain, and a polyA terminator. However, Gottshalk et al teaches a construct scheme in FIG. 2C containing a LHA, SA, P2A, a CAR transgene, a polyA, and an RHA. More specifically, Gottshalk et al teaches, “There are no universal guidelines on how to design a donor/template DNA for HDR mediated gene insertion when using CRISPR-Cas9 mediated knock-in. Donor DNA consists of a gene of interest (GOI) flanked by left and right homology arms (LHA and RHA) which are sequences homologous to the target locus (Figure 2A). In addition, the donor DNA can also include other elements such as a promoter, enhancer, 2 A or IRES sequence at the 5’ and poly(A) signal at the 3’ end. HAs are designed to flank the Cas9 cutting site, with equal length HAs of up to 800 bp per side (Figures 2A, 2B). Based on these rules, the final donor DNA for the TRAC locus contains the following parts: 400bp LHA, spliced acceptor (SA), P2A, IL-15, E2A, mClover3, poly(A) (bovine growth hormone polyadenylation signal) and 400bp RHA (Figure 2C). A P2A sequence was included at the 5’ end to separate the transgene from a possible fusion to the endogenous gene, and a poly(A) sequence at the 3’ end for efficient termination as simple STOP codon might not be sufficient.”, (see paragraph [00260]). Moreover, Gottshalk teaches, “A hinge domain is usually required to provide more flexibility and accessibility between the antigen-binding moiety and the transmembrane domain.”, (see paragraph [00102]). Gottshalk et al does not teach that the CAR transgene contains a uPAR extracellular antigen binding fragment.
Sadeline et al teaches, “…that the uPAR surface protein is commonly upregulated in a broad range of in vitro and in vivo mammalian models for senescence. As demonstrated in the Examples herein, upregulation of uPAR occurred in response to all tested senescence triggers: replication induced senescence, drug induced senescence (e.g., combined MEK and CDK4/6 inhibition or Doxorubicin), and oncogene induced senescence (oncogenic Ras). Indeed, soluble uPAR (suPAR) plasma levels were positively correlated with the load of senescent cells present in the organism. Furthermore, the engineered immune cells of the present technology selectively targeted senescent cells, while leaving normal proliferating cells unaffected.”, (paragraph [0063]). Sadeline et al discloses an isolated nucleic acid molecule that “encodes an anti-uPAR-targeted CAR comprising (a) an uPAR binding fragment (e.g., an anti-uPAR scFv or uPA fragment) that specifically binds to a uPAR antigen, (b) a transmembrane domain comprising a CD8 polypeptide or CD28 polypeptide, and (c) an intracellular domain comprising a CD3ζ polypeptide, and optionally one or more of a co-stimulatory signaling region disclosed herein, a P2A self-cleaving peptide, and/or a reporter or selection marker (e.g., GFP, LNGFR)...”, (see paragraph [00229]).
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 DNA template of the ‘786 application with the construct scheme of Gottschalk et al to include a splice accepter and 2A 5’ of the transgene insert and a polyA terminator and hinge domain 3’ of the transgene insert for the predictable results of being able to separate the transgene from a possible fusion to the endogenous gene, to provide more flexibility and accessibility between the antigen-binding moiety and the transmembrane domain (hinge domain), and for efficient termination as taught by Gottshalk et al. Regarding the template taught by the ‘786 application as modified by Gottschalk et al, it would have been obvious to one of ordinary skill in the art before the effective filing date to substitute the CAR gene of the ‘786 application with a uPAR binding fragment (antibody fragment of instant claim 4 or scFv of instant claim 5) to yield the predictable outcome of selectively targeting senescent cells with the ability to codon optimize the extracellular binding antigen fragment to achieve the highest possible levels of productivity in any given expression system as taught by Sadeline et al.
Accordingly, instant claims 1, 4-5, and 11 are not patentably distinct from claims 8, 11 and 12 of the ‘786 application.
Claim 4 of the ‘786 application is drawn to “The DNA template plasmid of claim 1, wherein the right and left homology arms are each independently 50 to 3000 nucleotides in length.”, (see claim 1’s recitation above). Claim 4 does not require that the homology arms be upstream or downstream of the TRAC locus cutsite despite Fig. 1A and Fig. 2B of the ‘786 application explicitly target the TRAC locus. Moreover, Gottschalk teaches varying the lengths of homology arms upstream and downstream the TRAC locus exon 1, also referencing Eyquem et al (2017) in Figure 2B. Figure 2C of Gottschalk et al teaches 400bp of a right homology arm and 400bp of a left homology arm. Gottschalk further teaches that “In addition, different HA length did not affect T cell viability (Figure 4C, right panel). Taken together, these results indicate that knock-in efficiency of a large transgene is not dependent on HA length tested.”, (see paragraph [00266]).
It would have been obvious to one of ordinary skill in the art to modify the left and right homology arms of the DNA template plasmid of the ‘786 application to contain any amount of between 50 and 3000 nucleotides in length, to yield the predictable results of a knock-in efficiency or T cell viability that is not dependent on homology arm lengths for the TRAC locus between 100-400 base pairs, as taught by Gottschalk et al.
Accordingly, instant claim 2 is not patentably distinct from claim 4 of the ‘786 application.
Claim 6 of the ‘786 application is drawn to “The DNA template plasmid of claim 1 (as recited above) “wherein first insert comprises a splice acceptor site (SA), encodes a self-cleaving peptide (2A), includes a terminator sequence that defines the end of a transcriptional sequence (polyA), or a combination thereof”, wherein 2A comprises a coding sequence for a porcine teschovirus-1 (P2A) peptide, a Thoseasigna virus (T2A) peptide, an equine rhinitis A virus (E2A) peptide, or a foot-and-mouth disease virus (F2A) peptide. Claim 6 requires all the limitations of instant claim 3.
Accordingly, instant claim 3 is not patentably distinct from claim 6 of the ‘786 application.
This is a provisional nonstatutory double patenting rejection.
Claim(s) 6-8 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 12 of copending Application No. 19/316,786 (Reference application - herein after the ‘786 application) in view of Gottshalk et al (WO 2021263075 A1, publication date of 12-30-2021) and Sadeline et al (WO 2020/160518 A1, publication date 08/06/2020) and further view of Muller et al (The CD28-Transmembrane Domain Mediates Chimeric Antigen Receptor Heterodimerization With CD28, frontiers in Immunology, Vol 12, Article 639818, pages 1-13, March 23, 2021).
In combination, the ‘756 application, Gottschalk et al, and Sadeline et al teach the DNA HDR template of instant claim 1, for which instant claim(s) 6-8 depend upon.
Claim 12 of the ‘786 application is drawn to, “The DNA template plasmid of claim 1 (as recited above) “wherein the transgene of the first insert comprises a chimeric antigen receptor (CAR)” “wherein the CAR comprises an extracellular domain linked to an intracellular domain through a first transmembrane domain, wherein the first extracellular domain comprises an antigen recognition domain” “wherein the intracellular domain comprises a costimulatory domain selected from 2B4, CD27, CD28, CD137, CD154, CD244, CD278, and combinations thereof, and a signaling domain selected from CD16, DAP10, DAP12, CD28, ICOS, CD27, OX40, CD40L, CD3-zeta, and combinations thereof.”
Claim 12 does not require that the costimulatory domain be located between the transmembrane domain and intracellular domain and that the costimulatory domain is explicitly 4-1BB.
Muller et al teaches in Figure(s) 1a and 5a that the HDR CAR T template design can have a costimulatory domain (4-1BB or CD28), between a transmembrane domain (CD8 or CD28) and the intracellular domain (CD3-zeta, also known as zeta).
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 orientation of the DNA template of the ‘786 application (as taught in combination of Gottschalk et al and Sadeline et al) with the template design of Muller et al to include the costimulatory domain between the transmembrane domain and the intracellular domain for the predictable results of having the costimulatory domain on the inside of the cell for proper persistence and proper T Cell functionality.
Accordingly, instant claim(s) 6-8 are not patentably distinct from claim 12 of the ‘786 application.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/L.M.T./Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637