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 .
DETAILED ACTION
Amendments
In the reply filed 05/01/2026, Applicant has amended claims 1, 2, 10, 21, 33, 47, 87 and 102, and newly canceled claims 8, 15, 18, 23-25, 39-41, 67, 70-72 and 106.
Claim Status
Claims 1-3, 9-11, 21, 28, 32-33, 36, 38, 46-48, 62, 66, 68, 75, 80, 87-89, 93-100, 102, 104-105 and 107 are pending.
Claims 62, 66, 68, 75, 80, 95-100 and 107 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 11/24/2025.
Claims 1-3, 9-11, 21, 28, 32-33, 36, 38, 46-48, 87-89, 93-94, 102 and 104-105 are considered on the merits.
Withdrawn Specification Objections
The prior objection to the disclosure because of browser-executable code is withdrawn in light of Applicant’s amendment to the specification.
Withdrawn Claim Objections
The prior objection to claim 102 because of informalities is withdrawn in light of Applicant’s amendment to the claim.
New Claim Objections
Claim 87 is objected to because of the following informalities:
Claim 87 (a) recites “a target site within an endogenous T cell stimulation-associated locus”. Since base claim 33 has recited a target site within an endogenous T cell stimulation-associated locus, it is recommended to change the phrase in claim 87 (a) to “the target site within the endogenous T cell stimulation-associated locus”. Similarly, claim 87 recites “a transgene” in line 7. Since base claim 33 (a) has recited a transgene, it is recommended to change this phrase to “the transgene”. Finally, the phrase “a recombinant receptor” in line 8 is recommended to change to “the recombinant receptor”.
Appropriate correction is required.
Withdrawn Claim Rejections - 35 USC § 112
The prior rejection of claims 2, 10, 21, 47, 87 and 89 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn in light of Applicant’s amendments to the claims.
Withdrawn Claim Rejections - 35 USC § 102
The prior rejection of claims 1-3, 9, 21, 33, 36, 46, 87-89 and 93-94 under 35 U.S.C. 102 (a)(1) as being anticipated by Kim et al., (Nature Immunology. 2007;8:191-197. Prior art of record) as evidenced by Pillai et al., (Clinical Immunology. 2007; 123: 18-29) is withdrawn in light of Applicant’s amendment to claim 1 to recite new limitation that the recombinant receptor is a chimeric antigen receptor (CAR), which is not taught by Kim.
The prior rejection of claims 1-3, 9-11, 21, 28, 32-33, 36, 46-48, 87-89, 93 and 104-105 under 35 U.S.C. 102 (a)(1) as being anticipated by Busser et al., (WO 2018/073391. Cited in IDS 07/19/2023) is withdrawn in light of Applicant’s amendment to claim 1 to recite new limitation that the endogenous T cell stimulation-associated locus is FoxP3, which is not specifically taught by Busser.
Withdrawn Claim Rejections - 35 USC § 103
The prior rejection of claims 1-3, 9-11, 21, 28, 32-33, 36, 46-48, 87-89, 93, 102 and 104-105 under 35 U.S.C. 103 as being unpatentable over Busser et al., (WO 2018/073391. Cited in IDS 07/19/2023) is withdrawn in light of Applicant’s amendment to claim 1 to recite new limitation that the endogenous T cell stimulation-associated locus is FoxP3, which is not specifically taught by Busser.
The prior rejection of claims 1-3, 9-11, 21, 28, 32-33, 36, 38, 46-48, 87-89, 93 and 104-105 under 35 U.S.C. 103 as being unpatentable over Busser et al., (WO 2018/073391. Cited in IDS 07/19/2023) in view of Amin et al., (WO 2019/089982, published 2019 May. Cited in IDS 07/19/2023) is withdrawn in light of Applicant’s amendment to claim 1 to recite new limitation that the endogenous T cell stimulation-associated locus is FoxP3, which is not specifically taught by Busser or Amin.
New 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.
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.
Claims 1-3, 9-11, 21, 28, 32-33, 36, 38, 46-48, 87-89, 93 102 and 104-105 are rejected under 35 U.S.C. 103 as being unpatentable over Busser et al., (WO 2018 /073391. Cited in IDS 07/19/2023) in view of Pillai et al., (Clinical Immunology. 2007; 123: 18-29. Prior art of record), Tang et al., (JCI Insight. 2020 February; 5(4): e133977, p. 1-38) and Goodwin et al., (Sci. Adv. 2020 May; 6 : eaaz0571, p. 1-16).
With respect to claim 1, Busser teaches targeted gene insertion for improved immune cells therapy, such as CAR-T cells (e.g., abstract and p. 5, line 13), thus teaches an engineered T cell comprising a transgene encoding a recombinant receptor wherein the recombinant receptor is a chimeric antigen receptor (CAR).
Busser teaches “the invention relies on expressing a chimeric antigen receptor (CAR) at selected gene loci that are upregulated upon immune cells activation” and “the exogenous sequences encoding a CAR can be placed under transcriptional control of the promoter of endogenous genes that are activated by the tumor microenvironment” (p. 5, last full para.), and teaches genetic insertion of exogenous coding sequence(s) under the transcriptional control of endogenous gene promoters that are sensitive to immune cells activation allows the production of safer immune primary cells of higher therapeutic potential (e.g., abstract). Thus, Busser teaches the engineered T cell comprises a modified T cell stimulation-associated locus comprising the transgene encoding the CAR that is integrated into the endogenous T cell stimulation-associated locus of the T cell, wherein the transgene is operably linked to an endogenous transcriptional regulatory element of the endogenous T cell stimulation-associated locus (i.e., “under the transcriptional control of endogenous gene promoters”) and wherein the endogenous transcriptional regulatory element induces or upregulates the expression of the operably linked transgene following a stimulation or activation signal in the T cell (i.e., “gene loci that are upregulated upon immune cells activation”).
However, Busser does not specifically teach the endogenous T cell stimulation-associated locus being FoxP3.
Nevertheless, as stated supra, Busser indicates suitable gene loci include genes that are upregulated upon immune cells activation and that are activated by the tumor microenvironment (p. 5, last full para.).
Pillai teaches that virtually all activated CD4+ and CD8+ T cells transiently upregulate FOXP3, and this activation-induced FOXP3 expression and regulatory activity is a broad T cell phenomenon (e.g., abstract and p. 27, right col., see FoxP3 expression being upregulated in activated CD4+ T cells in Fig 1 and in activated CD8+ T cells in Fig 6a). Thus, Pillai teaches FoxP3 gene locus (i.e., FoxP3 gene expression) is upregulated upon immune cells activation.
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Tang teaches in tumor microenvironment in solid tumors, FOXP3 expression is induced in CAR T cells by TGFβ secreted in the tumor microenvironment (see e.g., “Graphical abstract” in the cover page attached, and see FOXP3 expression being upregulated in CD4+ CAR T cells in Fig 2C and in CD8+ CAR T cells in Fig 2D when exposed to TGF-β1 mimicking the tumor microenvironment). Thus, Tang teaches FoxP3 gene locus (i.e., FoxP3 gene expression) is activated by the tumor microenvironment.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have chosen FoxP3 gene locus as the T cell stimulation-associated locus for CAR integration as suggested by Pillai and Tang with a reasonable expectation of success. Since Busser indicates suitable gene loci include genes that are upregulated upon immune cells activation and that are activated by the tumor microenvironment (p. 5, last full para.), since Pillai teaches FoxP3 gene locus is upregulated upon immune cells activation (see above) and since Tang teaches FoxP3 gene locus is activated by the tumor microenvironment (see above), one of ordinary skill in the art would have had a reason to choose FoxP3 gene locus as the T cell stimulation-associated locus for CAR integration in order to obtain controlled CAR expression upon T cell activation and in the tumor microenvironment (Busser, p. 5, last full para.).
Furthermore, Goodwin teaches a method of CRISPR-based precise editing of FOXP3 gene locus in T cells (see e.g., Fig 1A and legend, showing schematic representation of CRISPR-based editing of the FOXP3 gene showing the CRISPR cut site in first coding exon, homology donor depicted below with arms of homology, exogenous transgene (in this case a wildtype FOXP3 cDNA)). Goodwin teaches the regulation of the integrated exogenous FOXP3 expression in modified T effector cells closely mirrored that in WT controls without statistically significant differences, confirming that endogenous regulation of expression was preserved (p. 6, right col, para 1). Thus, Goodwin reduces to practice a method of targeted integration of an exogenous transgene into the FoxP3 locus that preserves the endogenous regulation on the exogenous transgene expression.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the method of precise editing of the FoxP3 locus as taught by Goodwin in engineering the T cell of Busser in view of Pillai and Tang with a reasonable expectation of success. Since Goodwin reduces to practice a method of targeted integration of an exogenous transgene into the FoxP3 locus that preserves the endogenous regulation on the exogenous transgene expression (see above), one of ordinary skill in the art would have had a reason to combine Goodwin’s method to obtain an engineered T cell comprising an exogenous CAR integrated in the FoxP3 locus in order to take advantage of the endogenous regulation of the FoxP3 locus to obtain controlled CAR expression upon T cell activation and in the tumor microenvironment.
In regard to the last limitation “wherein the endogenous T cell stimulation-associated locus is not produced, or is truncated, or is non-functional in the T cell”, since claim 1 recites “wherein the endogenous transcriptional regulatory element induces or upregulates the expression of the operably linked transgene following a stimulation or activation signal in the T cell”, it is clear that the endogenous T cell stimulation-associated locus is required to be functional in the T cell. Thus, the limitation in the last wherein clause is being examined as “wherein an endogenous gene product of the endogenous T cell stimulation-associated locus is not produced, or is truncated, or is non-functional in the T cell”, which is supported by the instant specification [0010].
Busser teaches “in another aspect, said exogenous sequence is introduced into the genome by deleting or modifying the endogenous coding sequence(s) present at said locus (knock out by knock-in), so that a gene inactivation is combined with transgenesis” (p. 6, lines 15-17), and “if the targeted gene is deemed involved in immune cells inhibition/exhaustion, the insertion procedure is designed to prevent expression of the endogenous gene, preferably by knocking-out the endogenous sequence, while enabling expression of the introduced exogenous coding sequence(s)” (p. 6, lines 22-25). Busser specifically teaches a list of genes involved in immune cell inhibitory pathways that can be inactivated, including FoxP3 (see Table 3 in page 47).
Tang teaches FOXP3-KO CAR T cells (M28z-FKO) and shows that the proliferation suppression abilities of effector cells from the M28z-FKO + TGF-β1 group are much lower than that in M28z + TGF-β1 group (Figure 3B), and “This indicates that FOXP3 played an essential role in the iTreg-like phenotype induced by TGF-β1. In addition, we observed an improvement in the tumor lysis capability of M28z-FKO cells in the presence of TGF-β1” (p. 3, last para – p. 5, para 1).
Furthermore, Goodwin teaches precise editing of FOXP3 gene locus in T cells in which an exogenous transgene (in this case a wildtype FOXP3 cDNA) with a BGH polyadenylation (pA) signal is integrated into the endogenous FOXP3 gene locus (see Fig 1 and legend). Goodwin teaches “A strong Bovine Growth Hormone (BGH) pA signal was positioned after the FOXP3 cDNA, and another pA was included after the tNGFR marker gene …to ensure inactivation of the remaining endogenous FOXP3 locus.” (p. 12, left col, last para). Thus, Goodwin teaches a method of inactivation of the endogenous FOXP3 coding sequence present at said locus (knock out by knock-in).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of Busser and Tang to inactivate the endogenous FOXP3 coding sequence when integrate the CAR into the FOXP3 locus using the method of Goodwin with a reasonable expectation of success. Since Busser specifically teaches FoxP3 is involved in immune cell inhibitory pathways that can be inactivated (see Table 3 in page 47), since Tang teaches FOXP3-KO CAR T cells have much lower proliferation suppression abilities and have improved tumor lysis capability (p. 3, last para – p. 5, para 1), and since Goodwin reduces to practice a method of targeted integration of an exogenous transgene into the FoxP3 locus that inactivates the endogenous FOXP3 gene (p. 12, left col, last para), one of ordinary skill in the art would have had a reason to combine the teaching of Busser, Tang and Goodwin to inactivate the endogenous FOXP3 gene when integrate the CAR into the FOXP3 locus in order to take advantage of the reduced proliferation suppression and the improved tumor lysis capability.
With respect to claim 2, Busser teaches genetic insertion of exogenous coding sequence(s) under the transcriptional control of endogenous gene promoters (see e.g., abstract and p. 5, last full para.), and Goodwin teaches the CRISPR-mediated knock-in uses endogenous FOXP3 promoters and enhancers (e.g., p. 10, last para, also see Fig 1), thus both teach the endogenous transcriptional regulatory element is a promoter, and the transgene is present downstream of the promoter.
With respect to claim 3, as stated supra, Busser teaches genetic insertion of exogenous coding sequence(s) under the transcriptional control of endogenous gene promoters that are upregulated upon immune cells activation (see e.g., abstract and p. 5, last full para.), and Tang teaches FoxP3 gene is upregulated by TGFβ signaling pathway (see e.g., “Graphical abstract” in the cover page), thus both teach the endogenous transcriptional regulatory element comprises a response element recognized by a transcription factor that is activated following the activation signal.
With respect to claim 9, Busser teaches CARs comprise a targeting moiety, such as an antigen-binding domain of a single-chain antibody (p. 3, lines 11-14), thus teaches the CAR comprises an extracellular binding domain. Tang teaches FOXP3-KO CAR T cells (M28z-FKO, see e.g., Fig 3) comprising a mesothelin-CAR that comprises an extracellular binding domain binding mesothelin.
With respect to claim 10 and claim 11, Busser teaches the signaling domains for the CARs are derived from the cytoplasmic region of the CD3zeta (p. 3, lines 16-23), and Tang teaches a M28z (see e.g., Fig 3) that comprises a CD3zeta chain, thus both teach the CAR comprises an intracellular region comprising an intracellular signaling domain of a component of a TCR complex, such as a CD3 chain.
With respect to claim 21, Busser teaches the method of the invention comprises the step of generating a double-strand break (i.e., a genetic disruption) at a locus by expressing sequence-specific nuclease reagents, such as TALEN, ZFN or RNA-guided endonucleases in the presence of a DNA repair matrix set into an AAV6 based vector comprising DNA donor template including two homology arms embedding the exogenous coding sequences (p. 6, para 2). Goodwin teaches a method of CRISPR-based precise editing of FOXP3 gene locus in T cells (see e.g., Fig 1A and legend) comprising inducing a genetic disruption by a CRISPR-Cas9 (see the cut site) that specifically binds to a target site in exon 1 of FoxP3 gene (directed by the guide RNA) and introducing a polynucleotide (i.e., the homology donor) for homology directed repair (see Fig 1A).
With respect to claim 28, Busser teaches the immune cells are further made [TCR]negative for allogeneic transplantation. This can be achieved especially by genetic disruption of at least one endogenous sequence encoding at least one component of TCR, such as TRAC (locus encoding TCRalpha) (p. 7, para 1), thus teaches the T cell further comprises a genetic disruption at an endogenous TRAC gene.
With respect to claim 32, Busser teaches one aspect of the present invention is the transduction of AAV vectors in human primary immune cells (e.g., p. 32, lines 28-29), and Tang teaches T cells are isolated from human donor (p. 14, “Methods” para “CD3+ T cell isolation”), thus both teach the engineered CAR-T cell is a T cell derived from a human subject.
With respect to independent claim 33, the rejection of claim 1 above is incorporated herein. As stated supra, Busser teaches generating a double-strand break at a locus (i.e., a target site within the locus) and a DNA repair matrix comprising a DNA donor template (i.e., a polynucleotide) including two homology arms (i.e., (b) a 5’ homology arm and a 3’ homology arm comprising sequence homologous to a target site within the locus) embedding the exogenous coding sequences (i.e., (a) a transgene encoding the CAR, p. 6, para 2). Goodwin teaches a homology donor comprising a transgene (in this case a FOXP3 cDNA) flanked by 3’ and 5’ homology arms that are homologous to a nucleic acid sequence of a target site within FOXP3 locus (p. 12, left col, last para “FOXP3 homology donor design”).
With respect to claim 36, as stated supra, Busser teaches genetic insertion of exogenous coding sequence(s) under the transcriptional control of endogenous gene promoters (see e.g., abstract and p. 5, last full para.), and Goodwin teaches the target site is in exon 1, downstream of the FOXP3 promoter and enhancer (see Fig 1), thus both teach the target site is downstream of an endogenous transcriptional regulatory element of the locus.
With respect to claim 38, Goodwin teaches a homology donor comprising a transgene (in this case a FOXP3 cDNA) flanked by 3’ and 5’ homology arms that are approximately 600 bp and 650 bp (p. 12, left col, last para “FOXP3 homology donor design”), thus teaches the 5’ homology arm and 3’ homology arm are between 50 and 750 nucleotides.
With respect to claim 46, Busser teaches CARs comprise a targeting moiety, such as an antigen-binding domain of a single-chain antibody (p. 3, lines 11-14), and Tang teaches FOXP3-KO CAR T cells (M28z-FKO, see e.g., Fig 3) comprising a mesothelin-CAR that comprises an extracellular binding domain binding mesothelin, thus both teach the CAR comprises an extracellular binding domain.
With respect to claim 47 and claim 48, Busser teaches the signaling domains for the CARs are derived from the cytoplasmic region of the CD3zeta (p. 3, lines 16-23), and Tang teaches a M28z (see e.g., Fig 3) that comprises a CD3zeta chain, thus both teach the CAR comprises an intracellular region comprising an intracellular signaling domain of a component of a TCR complex, such as a CD3 chain.
With respect to claim 87, as stated supra, Busser teaches the method of the invention comprises the step of generating a double-strand break at a locus by expressing sequence-specific nuclease reagents, such as TALEN, ZFN or RNA-guided endonucleases (i.e., introducing into a T cell one or more agents that induces a genetic disruption at a target site within the locus) in the presence of a DNA repair matrix set into an AAV6 based vector comprising DNA donor template including two homology arms embedding the exogenous coding sequences (i.e., the polynucleotide of claim 33 for homology directed repair) (p. 6, para 2). Goodwin teaches a Cas9 (i.e., an agent inducing genetic disruption, see p. 12, last para) and a homology donor comprising a transgene (in this case a FOXP3 cDNA) flanked by 3’ and 5’ homology arms that are homologous to a nucleic acid sequence of a target site within FOXP3 locus (p. 12, left col, last para “FOXP3 homology donor design”).
With respect to claim 88 and claim 89, Busser teaches a pharmaceutical composition comprising an engineered primary immune cell (e.g., T cell, p. 48, last line) or immune cell population as previously described (e.g., p. 49, lines 18-19).
With respect to claim 93, Busser teaches the populations of cells mainly comprises CD4 and CD8 positive T-cells (e.g., p. 52, lines 6-7).
With respect to claim 102 directed to a kit comprising one or more agents capable of inducing a genetic disruption at the target site and the polynucleotide of claim 33, as stated supra, Busser teaches generating a double-strand break at a locus by expressing sequence-specific nuclease reagents, such as TALEN, ZFN or RNA-guided endonucleases (i.e., one or more agents capable of inducing a genetic disruption at a target site within the locus) in the presence of a DNA repair matrix comprising DNA donor template including two homology arms embedding the exogenous coding sequences (i.e., the polynucleotide of claim 33) (p. 6, para 2). Goodwin teaches a Cas9 (i.e., an agent inducing genetic disruption, see p. 12, last para) and a homology donor comprising a transgene flanked by 3’ and 5’ homology arms that are homologous to a nucleic acid sequence of a target site within FOXP3 locus (p. 12, left col, last para “FOXP3 homology donor design”).
Although Busser does not specifically recite a kit, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have combined said components disclosed by Busser and Goodwin into a kit with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to do so for the purposes of convenience and economy.
With respect to claim 104, Busser teaches integrating exogenous coding sequence at loci, which are specifically transcribed during T-cells activation on a CAR dependent fashion (p. 5, lines 22-24), and Tang teaches binding of antigen (on OVCAR3 cells) to the mesothelin-CAR (M28z) results in inducing a stimulation or activation signal in the T cells that induces and upregulates the FOXP3 expression (see Fig 3A comparing all “M28z” to isotype), thus both teach binding of an agent to the extracellular binding domain of the CAR (i.e., CAR-dependent T-cells activation) results in the inducing or transmitting of the activation signal in the cell, such that the FoxP3 locus is specifically transcribed during T-cells activation.
With respect to claim 105, as stated supra, Busser teaches the signaling domains for the CARs are derived from the cytoplasmic region of the CD3zeta (p. 3, lines 16-23), and Tang teaches a M28z (see e.g., Fig 3) that comprises a CD3zeta chain. One of ordinary skill in the art would have immediately expected that the CD3zeta chain would comprise an ITAM.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 05/01/2026 are acknowledged.
Applicant argues that (1) the subject matter of claim 1 is novel over Kim by reciting new limitation the recombinant receptor is a chimeric antigen receptor (CAR) (remarks, p. 11, last para), (2) the subject matter of claim 1 is novel over Busser by reciting new limitation the endogenous T cell stimulation-associated locus is FoxP3 (remarks, p. 12, section 2 and section VI para 1), (3) Busser does not teach or suggest, inter alia, integrating a transgene encoding a CAR at the endogenous FoxP3 locus. Thus, there is no teaching or suggestion in Busser to integrate a CAR at the endogenous FoxP3 locus. Amin does not cure this deficiency (remarks, p. 14, last para – p. 15, para 2).
Applicant’s arguments have been fully considered and they are persuasive. Therefore, the prior rejections (both 102 and 103 rejections) have been withdrawn. However, as necessitated by amendment, a new ground of rejection has been made over Busser in view of Pillai, Tang and Goodwin.
Specifically, although Busser does not specifically teach the endogenous T cell stimulation-associated locus being FoxP3, Busser indicates suitable gene loci for CAR integration include genes that are upregulated upon immune cells activation and that are activated by the tumor microenvironment (p. 5, last full para.). Pillai teaches FoxP3 gene expression is upregulated upon immune cells activation and Tang teaches FoxP3 gene expression is activated by the tumor microenvironment. Thus, both Pillai and Tang suggest that the FoxP3 locus is a suitable gene locus for CAR integration. Goodwin further reduces to practice a method of precise editing of the FoxP3 locus comprising integrating an exogenous transgene into the FoxP3 locus under the endogenous regulation of FoxP3 while inactivating endogenous FoxP3 gene at the same time.
Claim 94 is rejected under 35 U.S.C. 103 as being unpatentable over Busser et al., (WO 2018 /073391. Cited in IDS 07/19/2023) in view of Pillai et al., (Clinical Immunology. 2007; 123: 18-29. Prior art of record), Tang et al., (JCI Insight. 2020 February; 5(4): e133977, p. 1-38) and Goodwin et al., (Sci. Adv. 2020 May; 6 : eaaz0571, p. 1-16), as applied to claims 88 and 1 above, and further in view of Turtle et al., (J Clin Invest. 2016;126(6):2123-2138).
Claim 94 is directed to the composition comprising CD4+ and CD8+ T cells having a 1:1 ratio.
As stated supra, Busser teaches the populations of cells mainly comprises CD4 and CD8 positive T-cells (e.g., p. 52, lines 6-7), and Tang teaches FOXP3 expression being upregulated in both CD4+ CAR T cells (see Fig 2C) and CD8+ CAR T cells (see Fig 2D) when exposed to TGF-β1 mimicking the tumor microenvironment, thus both teach the composition comprises CD4+ and CD8+ T cells.
However, Busser, Pillai, Tang and Goodwin do not specifically teach the CD4+ and CD8+ CAR T cells are in a 1:1 ratio in the composition.
Turtle teaches using CAR-T cells of defined CD4+:CD8+ composition in treating ALL patients (see e.g., abstract). Turtle teaches a composition comprising the 1:1 ratio of CD4+:CD8+ CAR-T cells was achieved in 27 of 30 patients (e.g., p. 2134, right col, para 2). Turtle teaches the defined composition product was remarkably potent, as 27 of 29 patients (93%) achieved BM remission as determined by flow cytometry (e.g., abstract).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have chosen a composition comprising CD4+ and CD8+ CAR T cells in a 1:1 ratio as suggested by Turtle with a reasonable expectation of success. Since Turtle teaches the defined composition product comprising the 1:1 ratio of CD4+:CD8+ CAR-T cells was remarkably potent, as 27 of 29 patients (93%) achieved BM remission (e.g., abstract), one of ordinary skill in the art would have had a reason to choose the defined composition comprising 1:1 ratio of CD4+:CD8+ CAR-T cells in order to obtain potent therapeutic effect.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 05/01/2026 are acknowledged and have been discussed above.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jianjian Zhu whose telephone number is (571)272-0956. The examiner can normally be reached M - F 8:30AM - 4PM (EST).
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/JIANJIAN ZHU/Examiner, Art Unit 1631
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