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 .
Claims 44-49, 51-57, 63-66, of record 5/12/2026, are pending and subject to prosecution. Claims 44 and 46-49 are amended. Claims 65-66 are newly added.
Declaration of Dr. Martinez-Llordella
A declaration under 37 CFR 1.132 was submitted on 5/12/2026 by Dr. Martinez-Llordella. The declaration asserts that:
One of ordinary skill in the art would not expect a CAR comprising a STAT5 association motif and JAK1- and/or JAK2-binding motif to be effective in providing a pro-survival signal when expressed in Tregs (Declaration, page 2).
IL-2 signaling pathways and responses should not be assumed to be similar in Teffs and Tregs, given their different functions (Declaration, page 2-4).
Unexpected results were observed in the form of higher activation in response to A2 antigen in CARs comprising a STAT5 association motif and JAK1- and/or JAK2-binding motif versus CARs comprising a STAT5 association motif, JAK1- and/or JAK-2 binding motif, and JAK3 binding motif (Declaration, page 2 and 5).
The declaration under 37 CFR 1.132 filed 5/12/2026 is insufficient to overcome the rejection of claims 44-49, 51-57, and 63-66 based upon Tanaka et al. in view of Stephan and Antov et al., as set forth in the last Office action.
That Teffs and Teffs have different functions and differences surrounding IL-2 signaling is not at issue, and arguments directed thereto are not productive. Dr. Martinez-Llordella asserts that, post-antigen-binding, the effects of the claimed CAR in a Treg cannot be predicted (Declaration, page 4). However, multiple groups had expressed CARs in Tregs for modulating immune responses (See Zhang et al., of record, table 1 and fig. 1), demonstrating that the same CARs used in Teffs could be applied to Tregs. Further, antigen binding of CARs comprising JAK-STAT signaling domains has been demonstrated to result in STAT phosphorylation in Teffs in an antigen-dependent manner (See Kagoya et al., page 324, col. 1, ¶1), and STAT5 phosphorylation (which does not strictly require IL-2) is known to promote Treg survival (See Wuest et al., Abstract). Given that, like Teffs, Tregs comprise JAK kinases and STAT proteins, and given that phosphorylation of STAT by various means positively impacts Treg viability, it would be entirely reasonable for one of ordinary skill in the art to expect that a) a CAR having a STAT5 association motif and JAK1- and/or JAK2-binding motifs could be functional in Tregs b) for signaling through JAK-STAT pathways c) with an effect of promoting Treg survival.
While the argument directed toward higher CAR activation in the absence of a JAK3-binding motif is compelling, the supporting results are not commensurate with the scope of the claims, as detailed below.
Status of Prior Rejections/Response to Arguments
RE: Rejection of claims 44-49, 53, 57, and 64 under 35 U.S.C. 103 over Tanaka et al. (WO 2016127257 A1) in view of Stephan (WO 2014153114 A1) and Antov et al. (Journal of Immunology, 2003):
RE: Rejection of claims 44-49, 51, 53, 57, and 64 under 35 U.S.C. 103 over Tanaka et al. (WO 2016127257 A1) in view of Stephan (WO 2014153114 A1) and Antov et al. (Journal of Immunology, 2003), further in view of Bradner et al. (US 11311609 B2):
RE: Rejection of claims 44-49, 52-54, 57, and 64 under 35 U.S.C. 103 over Tanaka et al. (WO 2016127257 A1) in view of Stephan (WO 2014153114 A1) and Antov et al. (Journal of Immunology, 2003), further in view of Riley et al. (US 11827705 B2):
RE: Rejection of claims 44-49, 52-54, 56-57, and 64 under 35 U.S.C. 103 over Tanaka et al. (WO 2016127257 A1) in view of Stephan (WO 2014153114 A1) and Antov et al. (Journal of Immunology, 2003), further in view of Riley et al. (US 11827705 B2), further in view of Chaudhary (WO 2017172981 A2):
RE: Rejection of claims 44-49, 53, 55, 57, and 64 under 35 U.S.C. 103 over Tanaka et al. (WO 2016127257 A1) in view of Stephan (WO 2014153114 A1) and Antov et al. (Journal of Immunology, 2003), further in view of Forman et al. (WO 2017079528 A1):
The applicant asserts that:
Tanaka et al. and Stephan et al. do not teach or suggest that the claimed CAR provides a STAT5-mediated pro-survival signal in Tregs upon antigen binding and that Antov et al. teach away from the claimed invention in disclosing that JAK3 signals were required to maintain Treg self-tolerance and numbers in peripheral organs (Applicant Remarks, page 7-8 and 16-18).
There would not be a reasonable expectation of success in expressing the claimed CAR in a Treg because Tanaka et al. focus on Teffs and their functions and mention Tregs only in a “long” list of cell types (Applicant Remarks, page 9-11).
The applicant’s arguments have been fully considered but are not found persuasive. The arguments involving Dr. Martinez-Llordella’s declaration are addressed above.
The prospect of CAR expression in a Treg is not a “speculative, unsubstantiated possibilit[y]”, as the applicant describes it, because a number of studies demonstrating the efficacy of CAR-Tregs for different conditions had been published prior to the filing date of the claimed invention (See Zhang et al., table 1, for a review of these works), and a person of ordinary skill in the art would have been aware of this. Inclusion of “a regulatory T cell” in a listing of cells in which the CAR of Tanaka et al. can be expressed (See ¶0121) indicates that a Treg comprising a CAR having STAT5 association motif and JAK1- and/or JAK2-binding motif had already been envisaged, regardless of the general focus of Tanaka et al. on Teffs.
Regarding the teachings of Antov et al. regarding JAK3, JAK3 signaling was found to be indispensable for normal Treg functions (See Antov et al., page 3436, col. 2, full ¶4). Because Tregs inherently express JAK3-binding motifs on various receptor chains, though, this requirement for JAK3 signaling would be satisfied without any need for a CAR to feature a JAK3-binding motif, and the CAR in question is not activated by IL-2, which circumvents the need for JAK3 involvement as with the native IL-2 receptor. Antov et al. therefore do not teach away from the exclusion of such a motif from a Treg-expressed CAR, and their findings still support a role for STAT5 signaling in promoting Treg survival, even in an IL-2-independent manner (See page 3436, col. 1, full ¶1 and fig. 2 and 5).
With respect to the assertion of unexpected results, fig. 7 of the instant application provides valid evidence that inclusion of a JAK3-binding motif can lead to decreased CAR activation in Tregs, as seen via CD69 and CD137 expression, which is not suggested by the prior art. However, for a showing of unexpected results to overcome a finding of obviousness, the experimental conditions used to achieve the results must be fully commensurate with the scope of the claims. See MPEP 716.02(d). For instance, the constructs used in the applicant’s examples comprised an HLA-A2-specific scFv; the instant claims do not limit the CAR targeting moiety, and the applicant has not provided evidence that similar results would be observed with any other targeting moieties that would be encompassed by the full scope of the claims.
The rejections are therefore maintained in modified form to address amended limitations and newly added claims.
New/Maintained Objections/Rejections
Claim Objections
Claim 44 and 66 are objected to because of the following informalities:
In lines 7-8 of claim 44 and line 1 of claim 66, the limitations “IL-28β endodomain” and “IL2Rβ” should be replaced with “IL-2Rβ”.
Appropriate correction is required.
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.
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 44-49, 53, 57, and 64-66 are rejected under 35 U.S.C. 103 as being unpatentable over Tanaka et al. (WO 2016127257 A1), of record, in view of Stephan (WO 2014153114 A1), of record, and Antov et al. (Journal of Immunology, 2003), of record.
Regarding claims 44-45, 57, 64, and 66: Tanaka et al. teach CARs that can comprise an intracellular STAT5 association motif and a JAK1-binding motif (See ¶0003 and 0068). In an embodiment, the cytoplasmic domain of the CAR comprises at least a STAT5 association motif, optionally a STAT5 association motif and a JAK binding motif (which reads on “the CAR endodomain does not comprise a JAK3 binding motif”) (See ¶0066-0067). The motifs can be derived from an IL-2Rβ chain, and the interleukin receptor chain cytoplasmic domain can be a truncated fragment minimally comprising a JAK-binding motif and STAT5 association motif (See ¶0016, 0069, 0084, and 0131). Tanaka et al. teach that the claimed CAR can be expressed in Tregs (See ¶0121). Tanaka et al. teach administering the CAR-T cells to a subject for treating inflammatory or autoimmune diseases such as asthma or eczema (which reads on “treating an autoimmune or allergic disease”) (See ¶0117). Tanaka et al. teach that the CAR-expressing T cell may have an increased proliferation rate and/or increased survivability (See ¶0040) but do not expressly teach that the CAR provides a STAT5-mediated pro-survival signal to the cell upon antigen binding. Tanaka et al. also do not teach an embodiment wherein a Treg expresses the CAR for the treatment of atopic dermatitis, inflammatory bowel disease, systemic lupus erythematosus, or diabetes mellitus.
Stephan teaches the use of CAR-T cells for targeting autoimmune markers expressed by on the surface of cells in autoimmune or allergic conditions (See ¶0008, 0081, 0083, and 0086-0087). The T cells can be Tregs (See ¶0006). The conditions include atopic dermatitis, Crohn’s disease, and cutaneous lupus erythematosus (See ¶0081).
Antov et al. teach that STAT5 signaling is associated with homeostasis and cell survival in Tregs and that it is essential for maintaining peripheral Treg populations (See Abstract; page 3436, col. 1, full ¶1; page 3439, col. 2, full ¶1 and 3; and page 3440, col. 1, full ¶1).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Tanaka et al. to comprise use of the CAR-T reg cells for treating the conditions named by Stephan. One would be motivated to make this modification because Stephan teaches that CAR-T cells, such as CAR-expressing Tregs, can be used to protect cells from autoimmune attack or reduce immune system activity in an area (See ¶0006 and 0083). Naturally occurring regulatory T cells constitutively express FoxP3, thereby reading on “FoxP3+”. There would be a reasonable expectation of success in making this modification because Tanaka et al. teach that the claimed CAR can be expressed in Tregs (See ¶000121).
It also would have been obvious to one having ordinary skill in the art that the CAR of Tanaka et al., if expressed in Tregs, would be reasonably expected to provide a STAT-5 mediated pro-survival signal, as Antov et al. demonstrate that STAT5 is associated with Treg homeostasis and survival (See Abstract; page 3436, col. 1, full ¶1; page 3439, col. 2, full ¶1 and 3; and page 3440, col. 1, full ¶1).
Regarding claims 46 and 65: Following the discussion of claims 44-45, 57, 64, and 66, Tanaka et al. teach that the CAR endodomain can comprise but does not require the STAT3 association motif YXXQ (See Abstract and ¶0068). The CAR of Tanaka et al. therefore reads on “does not comprise a STAT3 association motif” and “does not comprise the amino acid sequence YXXQ”.
Regarding claim 47: Following the discussion of claims 44-45, 57, 64, and 66, Tanaka et al. teach that the CAR intracellular domain can have multiple STAT5 association motifs (which reads on “two or more STAT5 association motifs”) (See ¶0076). The STAT5 association motif can be derived from the cytoplasmic portion of an interleukin receptor such as IL2Rβ (which reads on “is from an interleukin receptor… endodomain” and “is from IL2Rβ”) (See ¶0006 and 0016). The STAT5 association motif can comprise sequence YXXL, YLSL, YCTF, YFFF, and/or YLSLQ (which reads on “comprises the amino acid motif YXXF/L (SEQ ID NO: 8)”, “comprises one or more of the amino acid motifs YCTF (SEQ ID NO: 9), YFFF (SEQ ID NO: 10), YLSL (SEQ ID NO: 11), and/or YLSLQ (SEQ ID NO: 12)”, “comprises the amino acid motif YLSLQ (SEQ ID NO: 12”, “comprises a first STAT5 association motif comprising the amino acid motif YLSLQ (SEQ ID NO: 12) and a second STAT5 association motif comprising the amino acid motif YCTF (SEQ ID NO: 9) or YFFF (SEQ ID NO: 10)”, and “comprises the following STAT5 association motifs: YLSLQ (SEQ ID NO: 12), YCTF (SEQ ID NO: 9), and YFFF (SEQ ID NO: 10)”) (See ¶0070 and 0097).
Regarding claim 48: Following the discussion of claim 44-45, 57, 64, and 66, Tanaka et al. teach a truncated portion of the IL-2Rβ chain that comprises instant SEQ ID NO 13 (which reads on “the JAK-binding domain is a JAK1-binding motif being the amino acid motif shown as SEQ ID NO: 13; or a variant which has at least 80% identity to SEQ ID NO: 13”) (See ¶0079, SEQ ID NO 5 and alignment below).
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Regarding claim 49: Following the discussion of claims 44-45, 57, 64, and 66, Tanaka et al. teach a human IL-2RB fragment having a sequence identical to that of instant SEQ ID NO 1 (which reads on “the IL2Rβ endodomain comprises an amino acid sequence as set forth in SEQ ID NO: 1; or a variant which has at least 80% sequence identity to SEQ ID NO: 1”) (See ¶0064, SEQ ID NO 11 and alignment below (first 120 bp displayed)).
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Regarding claim 53: Following the discussion of claims 44-45, 57, 64, and 66, Tanaka et al. teach that the CAR can bind the surface molecule of an inflammatory cell that appears in an autoimmune disease (which reads on “an antigen whose expression is upregulated during… tissue inflammation”) (See ¶0046).
Claims 44-49, 51, 53, 57, and 64-66 are rejected under 35 U.S.C. 103 as being unpatentable over Tanaka et al. (WO 2016127257 A1), of record, in view of Stephan (WO 2014153114 A1), of record, and Antov et al. (Journal of Immunology, 2003), of record, further in view of Bradner et al. (US 11311609 B2), of record.
The teachings of Tanaka et al., Stephan et al., and Antov et al. are set forth in the rejections above and are incorporated herein in their entirety.
Regarding claim 51: Following the discussion of claims 44-49, 53, 57, and 64-66, Tanaka et al., modified by Stephan and Antov et al., teach the generation of Tregs expressing a CAR and their administration to a subject (See ¶0030 and 0036) but do not expressly teach the generation of CAR-T cells from a regulatory T cell-enriched sample.
Bradner et al. teach the generation of CAR-T cells from cells, such as regulatory T cells, and their use in treating autoimmune conditions (See Abstract; col. 42, line 60-64; and col. 81, line 56-60). The starting population of T cells can be enriched for or positively selected for regulatory T cells on the basis of CD4, CD25, CD62, GITR, and FoxP3 expression (See col. 83, line 25-28).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Tanaka et al., modified by Stephan and Antov et al., to comprise an enrichment step, such as that taught by Bradner et al., prior to transfection or transduction. One would be motivated to make this modification in order to obtain a desired cell population for therapeutic use. There would be a reasonable expectation of success in doing so because the cells of Tanaka et al., modified by Stephan and Antov et al., could be readily subjected to enrichment by immunosorting before deliver of a CAR-encoding polynucleotide.
Claims 44-49, 52-54, 57, and 64-66 are rejected under 35 U.S.C. 103 as being unpatentable over Tanaka et al. (WO 2016127257 A1), of record, in view of Stephan (WO 2014153114 A1), of record, and Antov et al. (Journal of Immunology, 2003), of record, further in view of Riley et al. (US 11827705 B2), of record.
The teachings of Tanaka et al., Stephan, and Antov et al. are set forth in the rejections above and are incorporated herein in their entirety.
Regarding claims 52 and 54: Following the discussion of claims 44-49, 53, 57, and 64-66, Tanaka et al., modified by Stephan and Antov et al., teach the CAR-T cells can be used to treat to a subject receiving a transplant but do not expressly teach the subject as undergoing immunosuppressive therapy or the CAR as specific for an HLA antigen present in the graft donor but not the recipient.
Riley et al. teach regulatory T cells expressing a CAR specific for HLA-A2 (which reads on “capable of specifically binding to a HLA antigen” and “capable of specifically binding to the HLA antigen HLA-A2”) (See Abstract). Riley et al. teach that the CAR suppresses alloresponses provoked by donor-MHC class molecules expressed by allografts (which reads on “antigen that is present in the graft donor but not the graft recipient”) (See col. 16, line 4-11). The subject can be administered immunosuppressive drugs in addition to the CAR-T cells (which reads on “undergoing immunosuppression therapy”) (See col. 59, line 28-30). The transplanted tissue can be liver, kidney, heart, lung, pancreas, intestine, or skin (See col. 59, line 19-25).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Tanaka et al., modified by Stephan and Antov et al., to use a host antigen-specific CAR, such as that taught by Riley et al., for administration to a transplant recipient. It also would have been obvious to use immunosuppressive drugs, as taught by Riley et al., in conjunction with CAR-T cell therapy. One would be motivated to make these modifications in order to reduce adverse immune responses following transplantation. There would be a reasonable expectation of success in doing so because the CAR construct of Tanaka et al. could be readily modified to comprise an HLA-A2-specific binding moiety and because immunosuppressive drugs could be readily administered to the subject.
Claims 44-49, 52-54, 56-57, and 64-66 are rejected under 35 U.S.C. 103 as being unpatentable over Tanaka et al. (WO 2016127257 A1), of record, in view of Stephan (WO 2014153114 A1), of record, and Antov et al. (Journal of Immunology, 2003), of record, further in view of Riley et al. (US 11827705 B2), of record, further in view of Chaudhary (WO 2017172981 A2), of record.
The teachings of Tanaka et al., Stephan, Antov et al., and Riley et al. are set forth in the rejections above and are incorporated herein in their entirety.
Regarding claim 56: Following the discussion of claims 44-49, 53, 57, and 64-66, Tanaka et al., modified by Stephan, Antov et al., and Riley et al., render obvious the use of CAR-T cells for targeting an HLA-A2 moiety but do not expressly teach the sequences of instant SEQ ID NOs 93-95 and 105-107.
Chaudhary teaches SEQ ID NO 1932 and SEQ ID NO 2173 as VL and VH fragments for binding HLA-A2 (See tables 4 and 6). SEQ ID NO 2173 comprises instant SEQ ID NOs 93-95 (which reads on “an antigen binding domain comprising SEQ ID NOs: 93-95”) (See alignments below).
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SEQ ID NO 1932 comprises instant SEQ ID NOs 105-107 (which reads on “an antigen binding domain comprising… SEQ ID NOs: 105-107”) (See alignments below).
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It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Tanaka et al., modified by Stephan, Antov et al., and Riley et al., to comprise the heavy and light chains taught by Chaudhary. One would be motivated to make this modification because Chaudhary teaches SEQ ID NOs 1932 and 2173 as exemplary sequences for targeting HLA-A2. There would be a reasonable expectation of success in doing so because Chaudhary teaches that these sequences can be used in a CAR (See ¶0021).
Claims 44-49, 53, 55, 57, and 64-66 are rejected under 35 U.S.C. 103 as being unpatentable over Tanaka et al. (WO 2016127257 A1), of record, in view of Stephan (WO 2014153114 A1), of record, and Antov et al. (Journal of Immunology, 2003), of record, further in view of Forman et al. (WO 2017079528 A1), of record.
The teachings of Tanaka et al., Stephan, and Antov et al. are set forth in the rejections above and are incorporated herein in their entirety.
Regarding claim 55: Following the discussion of claims 44-49, 53, 57, and 64-66, Tanaka et al., modified by Stephan and Antov et al., teach a CAR comprising a CD8 transmembrane domain but do not expressly teach a CD8α transmembrane domain.
Forman et al. teach CAR-T cells wherein the CAR comprises a CD8α transmembrane domain (See ¶007 and table 2, SEQ ID NO 17). The CD8α transmembrane domain is identical to the sequence of instant SEQ ID NO 87 (which reads on “the CAR comprises a CD8α transmembrane domain” and “comprising the amino acid sequence of SEQ ID NO: 87, or a variant which is at least 80% identical to SEQ ID NO: 87”) (See table 2, SEQ ID NO 17 and alignment below).
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It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the CAR of Tanaka et al., modified by Stephan and Antov et al., to substitute the transmembrane domain taught by Forman et al. Substitution of one known element for another known element is considered to be prima facie obvious, absent a showing that the result of the substitution yields more than predictable results.
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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
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/J.S.S./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633
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