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 .
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. CN202110280575.3, filed on 16 March 2021. The effective filing date is 16 March 2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 13 September 2023, 14 July 2025, and 29 January 2026 are being considered by the examiner.
Status of Application, Amendments, and/or Claims
Claims 14, 16, 22, 23, 29, 31, 36, 38, 45, 50, 52, 53, 63-67, 72, 73, and 75 were the subject of the 08 April 2026 office action. In the amendment of 08 July 2026, claims 14, 16, and 22 were cancelled, claims 23, 29, 31, 45, 50, 52, 65, 66, and 75 were amended, and claim 87 was added. Claims 23, 29, 31, 36, 38, 45, 50, 52, 53, 63-67, 72, 73, 75, and 87 are pending and the subject of this office action.
Withdrawn Objection/Rejections
In the office action of 08 April 2026, claims 23, 36, 38, 45, 63, 66, 67, and 73 were rejected under 35 U.S.C. 102(a)(1) as being anticipated by Valton J, et al. (2015) A Multidrug-resistant Engineered CAR T Cell for Allogeneic Combination Immunotherapy. Mol Ther. 2015 Sep;23(9):1507-18 (herein Valton). Independent claim 23 has been amended to include limitations further defining the nature of the bioactive molecule and cell activity inhibitor, which overcome the previous rejections claim 23 and the cited dependent claims. Thus, the 35 U.S.C. 102(a)(1) rejections of claims 23, 36, 38, 45, 63, 66, 67, and 73 have been withdrawn.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 87 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. The claim references a cell expressing a chimeric antigen receptor, as defined in claim 23, wherein the intracellular signaling domain of the CAR comprises a CD3z signal transduction domain, a CD28 co-stimulatory domain, and optionally either hIL-7 and CCL19 or IL2RB and an IL-7R alpha mutant, as described in claim 65. Claim 87 further defines the amino acid sequences of the various domains referenced. However, the claim provides conflicting definitions of the CD3z domain (SEQ ID NO: 48 and SEQ ID NO: 81), an alignment of the referenced CD3z segments is provided below. As a result, it is unclear what subject matter is being claimed, regarding the referenced CAR comprising CD3z, CD28, and the optional pairing of IL2RB and the IL7R mutant.
SEQ ID NO: 48 RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYN 60
SEQ ID NO: 81 RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYN 60
************************************************************
SEQ ID NO: 48 ELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 112
SEQ ID NO: 81 ELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDAYRHQALPPR 112
******************************************* : ******
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
WRITTEN DESCRIPTION
Claim 87 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. The claim, as written, reference cells expressing a chimeric antigen receptor, as defined in claim 23, wherein the intracellular signaling domain of the CAR comprises a CD3z signal transduction domain, a CD28 co-stimulatory domain, and optionally either hIL-7 and CCL19 or IL2RB and an IL-7R alpha mutant, as described in claim 65. Claim 87 further defines the amino acid sequences of the various domains referenced. The specification is vague, regarding the structure of receptors comprising these optional elements (Figure 42 and Example 24). The provided amino acid sequences for the hIL-7 (SEQ ID NO: 79), CCL19 (SEQ ID NO: 80), and the mutant IL7R alpha segments (SEQ ID NO: 81) include signal peptides, and, in the case of the IL7R alpha, complete extracellular and transmembrane domains, and as such it is unclear how the referenced sequences could be contained within an intracellular signaling domain, when using the standard interpretation of “intracellular”.
Additionally, CCL19 and IL-7 are known to be soluble/secreted cytokines that interact with extracellular receptors, and it is unclear how the inclusion of such sequences within the intracellular domain of the receptor would have any effect on the characteristics of the claimed cells. Regarding the cells of claim 65 and 87, which comprise the optional inclusion of IL-7 and CCL19, the specification does describe that the anti-CD19 and anti-CD5 CARs comprise a T2A sequence following the CD3z domain ([0233] and [0346]). For the sake of completeness, the examiner has extended prior art search parameters to encompass CAR T cells that express soluble IL-7 and CCL19, see 35 U.S.C. 103 rejection of claim 87.
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.
Claims 23, 29, 31, 36, 38, 45, 50, 52, 53, 63, 64, 65, 66, 67, 72, 73, and 75 are rejected under 35 U.S.C. 103 as being unpatentable over Valton J, et al. (2015) A Multidrug-resistant Engineered CAR T Cell for Allogeneic Combination Immunotherapy. Mol Ther. 2015 Sep;23(9):1507-18 (herein Valton) in view of Lee KC, et al. (2010) Lck is a key target of imatinib and dasatinib in T-cell activation. Leukemia. 2010 Apr;24(4):896-900 (herein Lee), Mestermann K, et al. (2019) The tyrosine kinase inhibitor dasatinib acts as a pharmacologic on/off switch for CAR T cells. Sci Transl Med. 2019 Jul 3;11(499) (herein Mestermann), and Azam M, et al. (2008) Activation of tyrosine kinases by mutation of the gatekeeper threonine. Nat Struct Mol Biol. 2008 Oct;15(10):1109-18 (herein Azam).
In regard to claims 23, 29, 31, 50, 52 and 72, Valton teaches genetically engineered allogeneic anti-CD19 CAR T cells, that are resistant to lymphodepletive agents, PNAs (abstract). The authors used TALEN-mediated dual gene processing to simultaneously disrupt the DCK and TRAC genes in primary T cells (figure 1, figure 2, and results sections 1-3). The engineered T cells, after undergoing transduction with a lentiviral vector comprising a CD19-specific CAR element, were then shown to be resistant to PNAs (clofarabine, fludarabine, and cytarabine), as demonstrated by their ability to proliferate. in the presence of clinically relevant concentrations of the PNAs (figure 4 and results section 4). This proliferative capacity was not shared with wild-type cell, under the same conditions. In the absence of PNA treatment, the engineered CAR T cells are also shown to possess comparable killing potential towards CD19+ cells to that of wild-type cells (figure 5 and results section 6). Ultimately, it was shown that the engineered CAR T cells, when combined with PNA treatment, were able to generate a 50% drop in tumor cell viability, which is significantly more efficacious than either PNA treatment alone or engineered CAR T cells alone (figure 7 and results section 7). The collective teaching of Valton discloses a method of preparing and utilizing an engineered T cell that possesses an engineered form of a bioactive molecule, that is insensitive to cell activity inhibitors, which inhibit normal T cells. It is also disclosed that these CAR T cells possess cytotoxicity, even in the presence of the cell activity inhibitor (Relevant to instant 23, 36, 45, 64, 66, and 73). Voltan also teaches that this strategy provides a “therapeutic window during which allogeneic CAR T cells could engraft and eradicate tumors before being rejected by the patient immune system” (Discussion section 3).
Valton does not teach that the bioactive molecule is an Lck protein tyrosine kinase, comprising a T316I mutation. Lee, Mestermann, Kantor, and Azam teach these deficiencies.
Lee teaches that dasatinib is an (ATP)-competitive tyrosine kinase inhibitor capable of suppressing T cell function (paragraphs 1 and 2). It is taught that Lck inhibits multiple Src kinases, Lck, Fyn, and Src (paragraph 3). Lee teaches that dasatinib inhibits Lck in T cells, as shown by decreased levels of pY394 Lck in primary human T cells, following dasatinib treatment, relative to untreated cells (figure 2 and paragraph 4). It is also shown that dasatinib binds directly to Lck, and that the inhibitor’s accesses to its binding pocket can be blocked by modifications to a gatekeeper residue, T316 (paragraph 3). By introducing a plasmid, encoding the mutant T316M Lck, into COS-7 cells, it is shown that the mutated Lck is resistant to dasatinib inhibition (figures 3c and 3d, and paragraph 5). Taken as a whole, Lee effectively teaches a T cell in which at least one bioactive molecule, Lck, is engineered to be to be insensitive a cell activity inhibitor, dasatinib, and demonstrates that the inhibitor can inhibit a normal T cell, as shown in figure 3. Lee also suggests that Lck is an attractive target for selective suppression of T-cell responses, given its restricted expression profile and essential role in T-cell activation (Page 899 paragraph 4). Additionally, Lee suggests that Lck inhibitors are expected to have superior safety profiles, when used in the treatment of inflammatory diseases or after organ transplantation (i.e. patients at risk of HvG), compared to standard immunosuppressive agents, which have off-target activity (Page 899 paragraph 4). Lee does not teach this system in the context of a CAR cell.
Mestermann teaches the use of a combination dasatinib and either anti-CD19-CAR/CD28-CD3[Symbol font/0x7A] T or anti-CD19-CAR/4-1BB-CD3[Symbol font/0x7A] immune therapy (abstract). Mestermann demonstrates that use of dasatinib inhibits CAR T signaling upon administration and shows that the effect is rapidly reversed upon cessation of treatment (results section 8). The author goes on to suggest that dasatinib may be used to steer the activity of CAR T cells, effectively acting as an on/off switch (results section 6). Additionally, it is shown that when CAR T cells are inhibited, immediately after transplantation, the frequency of lethal cytokine release syndrome dramatically decreases (results section 8 and figure 6). Of special relevance to the current disclosure, Mestermann teaches that in addition to the CAR T cells, endogenous innate immune cells and endogenous T cells are also inhibited by dasatinib (discussion paragraph 7).
It would have been obvious to one skilled in the art to combine the teachings of Valton (CAR expressing T cells that have been engineered to lack sensitivity to cell activity inhibitors) with the dasatinib-insensitive Lck mutant taught by Lee and the combination dasatinib-anti-CD19 CAR T therapy taught by Mestermann. As taught by Valton, this general strategy provides a therapeutic window, during which allogenic CAR T cells can engraft and attack tumors, before being rejected by the patient’s immune system. Lee provides motivation for the selection of Lck as a target, that being a restricted expression profile, which limits the effects of Lck inhibitors to lymphoid cells (Page 899 pragraph 4). Furthermore, Lee also suggests that Lck inhibitors are expected to have superior safety profiles, when used in the treatment of inflammatory diseases or after organ transplantation (i.e. patients at risk of HvG), compared to standard immunosuppressive agents, which have off-target activity (Page 899 paragraph 4). Lee as well as Mestermann provide technical guidance to modify Voltan’s method, in such a way as to comprise a CAR-T cells comprising a dasatinib-insensitive Lck mutant can function when exposed dasatinib. One of ordinary skill in the art at the time of filing would have been motivated to incorporate the inhibitor-insensitive Lck mutant into CAR T cells, due to the previously established selective inhibition of endogenous immune cells, which would allow for the engineered CAR T cells to act/persist without interference from endogenous innate immune cell or T cell populations. Furthermore, by combining these pre-existing elements, the instant application discloses a claimed invention that behaves in a predictable manner, based on the prior art describing each element individually. The combined teachings of Voltran, Lee, and Mestermann teach the use of T316M Lck mutant, that is resistant to dasatinib and imatinib but does not teach the use of a T316I mutant. This deficiency is taught by Azam.
The teachings of Azam regard structural studies that provide an explanation for imatinib-resistance in CML patients carrying a T315I mutation in the type 1a isoform of c-ABL (whole document). It is taught that many tyrosine kinases share a conserved “gatekeeper” residue, residing in a hinge region between the N and C lobes of the kinases, and that this residue controls access to the hydrophobic pocket proximal to the catalytic machinery of the enzyme (results section 1). The authors then demonstrate that by mutating this residue, in multiple different tyrosine kinases, enzymatic activity could be modified (results sections 1-3). The authors note that substituting the wild-type threonine with an amino acid containing a bulky hydrophobic side-chain, such as isoleucine or methionine, results in abnormally active mutant kinases (discussion paragraph 4, figures 1-3). The author’s analysis of inactive and active states of various homologous tyrosine kinases teaches that the activated form of these kinases undergoes a conformational rearrangement, in which a “hydrophobic spine” is formed and aligns the catalytic residues, enabling catalysis (results section 4). The gatekeeper residue is located at the top of this spine, and acts to stabilize the active site. Azam teaches that by mutating this residue, to an amino acid with a bulky hydrophobic side-chain, the spine is stabilized to such a degree that ATP-competitive inhibitors (i.e. imatinib or nilotinib, dasatinib, or ponatinib), which normally act by preventing the formation of the hydrophobic spine, are unable to overcome the higher free energy requirement needed to destabilize the hydrophobic spine (results section 8). Support for this hypothesis is provided in the author’s comparison of the active sites of wild-type Lck and a gatekeeper variant of c-SRC, both kinases being in the activated state and bound to ATP analogs (results section 6). The presence of an isoleucine at position 341 of the c-SRC (corresponding to position 316 in Lck numbering) led to conformational differences in the active site lysine. This conformation has the lysine more closely pack against the gatekeeper residue and allows for an additional hydrogen bond between the lysine and the alpha phosphate of the ATP analog. These teachings, when taken as a whole, make amino substitutions (T->M or T->I) at the gatekeeper residue, within related tyrosine kinases, abundantly obvious to one skilled in the art.
It would have been obvious to one skilled in the art to combine the teachings of Valton, Lee, and Mestermann (CAR expressing T cells that have been engineered to lack sensitivity to Lck inhibitors) with the T->I gatekeeper residue mutation taught by Azam. One of ordinary skill in the art at the time of filing would have been motivated to generate mutant immune cells containing a LCK gene, that encodes a T316I mutant, because Azam disclosed that there were differences in the extent to which the various T->I or T->M tyrosine kinases gatekeeper variants responded in terms of relative activity compared to the wild-type enzymes (results section 1). Despite the existence of an experimentally validated Lck gatekeeper variant, T316M, taught by Lee, one would have been motivated to experiment with alternative mutations, taught by Azam, to optimize the intended function within confines of the experimental/therapeutic system taught by Valton, Lee, and Mestermann.
In regard to claim 38, Valton teaches that the engineered T cells, have a disrupted TRAC gene (figure 1, figure 2, and results sections 1-3).
In regard to claim 63, Valton, Lee, Mestermann, and Azam teach a combination therapy of dasatinib and CAR therapy, in which the CAR cells contain genetic modifications to the LCK and TRAC genes, as discussed above.
Mesternann teaches that innate immune cells (i.e. NK cells) as well as T cells are inhibited by dasatinib (discussion paragraph 7). Furthermore, it is taught that T cells and NK proliferation is paused in the presence of the inhibitor (results section 1). It would have been obvious to contact the NK or T cell population undergoing genetic modification, to bestow insensitivity to drug that otherwise inhibits activity of the cell, as it would allow for the targeted proliferation of only the cells that have successfully been modified.
In regard to claim 65, Valton, Lee, Mestermann, and Azam teach a combination therapy of dasatinib and CAR therapy, in which the CAR cells contain genetic modifications to the LCK and TRAC genes, as discussed above.
Mestermann further teaches a CAR element that has a CD3z stimulatory domain and a CD28 co-stimulatory domain (abstract).
In regard to claim 67, Valton suggests that the CAR T cells, described in regard to claim 23, may be used in an allogeneic combination therapy with inhibitors (abstract and conclusion). Additionally, it is taught that the engineered CAR T cells in combination with the cell activity inhibitor prevent alloreactivity in vitro (results paragraph 5).
In regard to claim 75, Valton, Lee, Mestermann, and Azam teach a combination therapy of dasatinib and CAR therapy, in which the CAR cells contain genetic modifications to the LCK and TRAC genes, as discussed above.
The pairing of the two components is taught and a pharmaceutical kit comprising the cells and the inhibitor would have been prima facie obvious at the time of filing.
Claim 53 is rejected under 35 U.S.C. 103 as being unpatentable over Valton J, et al. (2015) A Multidrug-resistant Engineered CAR T Cell for Allogeneic Combination Immunotherapy. Mol Ther. 2015 Sep;23(9):1507-18 (herein Valton), Lee KC, et al. (2010) Lck is a key target of imatinib and dasatinib in T-cell activation. Leukemia. 2010 Apr;24(4):896-900 (herein Lee), Mestermann K, et al. (2019) The tyrosine kinase inhibitor dasatinib acts as a pharmacologic on/off switch for CAR T cells. Sci Transl Med. 2019 Jul 3;11(499) (herein Mestermann), and Azam M, et al. (2008) Activation of tyrosine kinases by mutation of the gatekeeper threonine. Nat Struct Mol Biol. 2008 Oct;15(10):1109-18 (herein Azam) in view of Kantor A, et al. (2020) CRISPR-Cas9 DNA Base-Editing and Prime-Editing. Int J Mol Sci. 2020 Aug 28;21(17):6240 (herein Kantor) and Komor AC, et al. (2016) Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature. 2016 May 19;533(7603):420-4 (herein Komor).
Valton, Lee, Mestermann, and Azam do not teach the use of ABE or CBE base editors as a method for modifying the genes of the targeted cells or the use of sgRNA comprising nucleotide sequences set forth in and of SEQ ID Nos: 5-8. These deficiencies are taught by Kantor and Komor.
Kamor teaches an approach for editing targeted DNA bases in genomic DNA, without the requirement of double stand breaks (abstract).
Kantor reviews the development of several base-editing techniques and discusses the advantages and limitations of the various techniques (abstract). Kantor teaches that base-editing techniques have several advantages over more traditional technologies (section 3: DNA Base-Editing, paragraph 1). Chief among them is a lower indel frequency as compared to more traditional techniques, due to the mechanism lacking DNA double strand breaks (section 3.1 Cytosine Base-Editors, paragraph 1).
Komor teaches a strategy for modifying targeted bases within genomic DNA, without the requirement of double-stranded DNA cleavage (abstract). This pioneering study discloses the overall strategy for genomic base-editing techniques, which were widely-used at the time the current application was filed (figure 1). In fact, the design of gRNA would have been trivial, prior to the submission of the current application, as there were numerous publicly available resources to aid in their design. One such tool, Benchling (benchling.com), which was available prior to the submission of the instant application and references the teaching of Komor, was able to predict the sgRNA corresponding to numerous gRNA sequences listed in the instant application. One example, when using a 20-nt sequence length and an NGG PAM sequence, is SEQ ID NO: 6, which targets exon 9 of the LCK gene. Use of this gRNA would be obvious to one of average skill in the art, as this gRNA was predicted by a publicly available algorithm and has favorable base-editing scores and off-target scores.
It would have been obvious to one skilled in the art to combine the teachings of Valton, Lee, Mestermann (CAR T cells that have genetic modifications to TRAC and LCK), and Azam with the base-editing techniques taught by Kantor and the sgRNA design taught by Komor. One of ordinary skill in the art at the time of filing would have been motivated to incorporate the techniques taught by Kantor and Komor into the method of preparing the genetically modified CAR cells, taught by Vantor Mestermann, Lee, and Azam, due to the lower error frequency associated with ABE and CBE. Furthermore, by combining these pre-existing elements, the instant application discloses a claimed invention that behaves in a predictable manner, based on the prior art describing each element individually.
Claim 87 is rejected under 35 U.S.C. 103 as being unpatentable over Valton J, et al. (2015) A Multidrug-resistant Engineered CAR T Cell for Allogeneic Combination Immunotherapy. Mol Ther. 2015 Sep;23(9):1507-18 (herein Valton), Lee KC, et al. (2010) Lck is a key target of imatinib and dasatinib in T-cell activation. Leukemia. 2010 Apr;24(4):896-900 (herein Lee), Mestermann K, et al. (2019) The tyrosine kinase inhibitor dasatinib acts as a pharmacologic on/off switch for CAR T cells. Sci Transl Med. 2019 Jul 3;11(499) (herein Mestermann), and Azam M, et al. (2008) Activation of tyrosine kinases by mutation of the gatekeeper threonine. Nat Struct Mol Biol. 2008 Oct;15(10):1109-18 (herein Azam) in view of Adachi K, et al. (2018) IL-7 and CCL19 expression in CAR-T cells improves immune cell infiltration and CAR-T cell survival in the tumor. Nat Biotechnol. 2018 Apr;36(4):346-351 (herein Adachi) with Duan D, et al. (2021) The BCMA-Targeted Fourth-Generation CAR-T Cells Secreting IL-7 and CCL19 for Therapy of Refractory/Recurrent Multiple Myeloma. Front Immunol. 2021 Mar 5;12:609421 (herein Duan) providing additional evidentiary value.
Valton, Lee, Mestermann, and Azam teach a combination therapy of dasatinib and CAR/CD28-CD3[Symbol font/0x7A] T therapy, in which the CAR cells contain genetic modifications to the LCK and TRAC genes, as discussed above for the 35 U.S.C. 103 rejection of claim 65. Valton, Lee, Mestermann, and Azam do not teach CAR/CD28-CD3[Symbol font/0x7A] cells, in which the intracellular domain further comprises i) hIL-7 (SEQ ID NO: 79) and CCL19 (SEQ ID NO: 80), or ii) IL2RB (SEQ ID NO: 81) and IL7Ra (SEQ ID NO: 82). Adachi teaches these deficiencies.
Adachi relates to a study investigating the effect of IL-7 and CCL19 expression in anti-CD20 CAR T cells, in terms of immune cell infiltration, CAR T cell survival, and anti-tumor activity (Abstract). IL-7 is taught to be a known T cell proliferation and survival enhancer (Paragraph 4). CCL19 is taught to be chemoattractant of for T cells and DCs (Paragraph 5). Adachi teaches that IL-7 and CCL19 produced by T-cell zone fibroblastic reticular cells are “essential for the formation and maintenance of the T-cell zone in lymphoid organs, where both T cells and DCs are recruited from the periphery” (Paragraph 2). Based on this teaching, the authors sought to develop CAR-T cells, that produce IL-7 and CCL19, to recruit T cells and DCs to tumor tissues, which could improve the therapeutic effects of CAR-T cells against solid tumors. The CAR cells disclosed in this article, comprise a tandem construct encoding an anti-hCD20-CAR molecule- 2A peptide - IL-7- 2A peptide- CCL19 (Paragraph 3 and Supplementary Figure 1a). These CAR T cells were shown to effectively secrete both cytokines (Paragraph 3 and Supplementary Figure 1c). The cells displayed enhanced proliferation and persistence as compared to conventional CAR T cells (Paragraph 4 and Figures 1a and 1b). Additionally, when co-incubated with responder T cells, in a transwell migration assay, the CAR T cells, expressing Il-7 and CCL19, caused a significant increase in responder T cell migration, compared to that caused by conventional T cells (Paragraph 5 and Figure 1c). In vivo experiments, using mouse models with human CD20 tumors (P815-hCD20 and 3LL-hCD20), showed that CPA pre-treatment combined with CAR T therapy, comprising expression of CCL19 and IL-7, induced complete tumor regression, which was a significant improvement to similar experiments with conventional CAR T cells (Figures 2a, 2b, Supplementary Figures 10a, and Paragraphs 8 and 11). Histopathological analysis also showed that treatment with the CAR T cells, expressing CCL19 and Il-7, induced massive T-cell infiltration into the tumor tissue, which was not observed for conventional CAR T cell treatment (Paragraph 14, Figure 3b, and Supplementary Figure 14a).
It would have been obvious to combine the teachings of Valton, Lee, Mestermann, and Azam (combination therapy of dasatinib and CAR/CD28-CD3[Symbol font/0x7A] T therapy, in which the CAR cells contain genetic modifications to the LCK and TRAC genes) with those of Adachi (CAR T cells, expressing CCL19 and IL-7). Adachi demonstrates that CAR T cells that express CCL19 and IL-7 have superior proliferation, persistence, infiltration, and anti-tumor efficacy, compared to conventional CAR T cells, which provides clear motivation to incorporate the teachings of Adachi. Adachi also demonstrates that this strategy works in various CAR configurations (i.e. second-generation 4-1BB CAR cells, second generation CD28 CAR cells, as well as third generation CARs) and with varied CAR-specificities, as they also show that CARs comprising anti-mesothelin scFv also benefit from the disclosed design strategy (Paragraphs 10-12). Thus, Adachi has shown that this strategy is adaptable to multiple configurations, which would lead one skilled in the art to have reasonable expectation of success for its incorporation into varied designs. It should be noted that Adachi teaches CAR T cells expressing mouse IL-7 and CCL19, due to nature of the experimental system (mouse). The use of the human forms of these proteins/nucleic acids, such as those referenced in instant claim 87 (SEQ ID NOs: 79 and 80). would have been obvious to one skilled in the art, if the intended model system or subject was human, as evidenced by Duan, which refers to clinical trial in which 4th generation CAR T cells, expressing human IL-7 and CCL19, were administered to human subjects.
Response to Arguments
Applicant’s arguments filed in response of 08 April 2026 have been fully considered in so far as they apply to the rejections of the instant application but were not persuasive. With regard to the rejection of claim 23 under 35 U.S.C. 103, the applicant argues the claimed chimeric antigen receptor would not have obvious of Valton in view of Lee and Mestermann. The applicant’s response is drawn to the following core arguments:
“Use of TKI to suppress the recipient’s immune cells is not obvious”
“The introduction of T316I mutation is not obvious”
Regarding argument 1), the applicant argues that the combination of Lee and Valton would not have been obvious, due to the fac that Valton teaches CAR-T cells that are resistant to conventional lymphodepletion drugs, and Lee teaches T cells that resistant to dasatinib. This argument was found to be uncompelling, because as stated by Lee suggests “Lck is an attractive target for the selective suppression of T-cell responses, given its restricted expression profile and essential role in T-cell activation. Drugs that selectively inhibit Lck would benefit patients with inflammatory diseases or after organ transplantation, and are expected to have an improved safety profile over currently used immunosuppressive agents that also target nonlymphoid cells.” This quotation directly counters the applicant’s argument that TKI are known as anti-tumor drugs (Page 9 paragraph 1). Furthermore, this quotation provides clear motivation for the use of Lck inhibitors as immunosuppressive agents for combating HvG, which is a shared complication for both organ transplantation and allogenic CAR T cell therapy. Thus, there is clear motivation to combine the teachings of Valton and Lee, as Lee suggest the Lck inhibitors, such as dasatinib, are expected to have superior safety profiles to conventional immunosuppressive agents.
It is also argued that it would not have been obvious to combine the teachings of Valton and Lee with Mestermann, as Mestermann’s method is aimed at regulating the function of CAR T cells, rather than suppressing the recipient’s immune cells. This is found to be uncompelling, because Mestermann teaches that, in a combination therapy, dasatinib inhibits endogenous T cells, which is a crucial factor for the method taught by the prior art and claimed in the current application.
In regard to argument 2), that the use of T316I is not obvious, the rejection of the claim 23 has been modified to contain the examiner’s previous 35 U.S.C. 103 rejection of claim 52. This obviousness rejection incorporates the teachings of Azam, relating to a detailed structural analysis of imatinib-resistance in CML patients carrying a T315I mutation. In short, this study teaches that substituting the wild-type threonine with an amino acid containing a bulky hydrophobic side-chain, such as isoleucine or methionine, results in abnormally active mutant kinases (discussion paragraph 4, figures 1-3). Thus, the effect of a T316I mutation in Lck was known in the prior art, before the effective filing date, and is predictable, due to extensive structural studies.
Conclusion
No claims allowed.
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MATTHEW CURRAN METCALF whose telephone number is (571)272-5520. The examiner can normally be reached 7:30AM-5:00PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama, can be reached at (571)272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/MATTHEW CURRAN METCALF/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
Prosecution Insights