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 .
Response to Amendment / Status of Claims
The Amendments and Remarks filed 04/01/2026 in response to the Office Action of 12/18/2025 are acknowledged and have been entered.
Claims 1-2,4-20,22-27,29-41,43-46 and 49-62 are currently pending.
Claims 1, 2, 20, 26, 27, 29, 31, 33, 35, 36, 41, 46 and 50 have been amended by Applicant.
Claims 1-2,4-20,22-27,29-41,43-46 and 49-62 are currently under examination on the merits.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
This Office Action contains a new rejection necessitated by amendments.
Drawings Objections - Withdrawn
Applicant has amended the drawings of Figs, 10, 11, 12, 13, 15, 17, 19, 22, 29 and 31 and so the objections have been withdrawn.
Specification Objections - Withdrawn
Applicant has amended the specification on Pages 7 and 9 and so the objections have been withdrawn.
Claim Objections - Withdrawn
Applicant has amended claims 20, 22, 36 and 46 and so the objections have been withdrawn.
Claim Rejections - 35 USC § 112(b) - Withdrawn
Given that Applicant has now amended claims 2 and 27 to delete the trademark “nanobody”, the 112(b) rejection of claims 2 and 27 is hereby withdrawn.
Claim Rejections - 35 USC § 103 – Withdrawn
The rejection of claims 46-51, 58 and 59 under 35 U.S.C. 103 (first 103 rejection in Non-Final) as being unpatentable over Rottman (WO 2020191358 A1 Date Published 2020-09-24) in view of Wang et al. (Cancer Immunol Res (2014) 2 (2): 154–166), Gross et al. (US 20200261499 Date Published 2020-08-20; provided in the IDS submitted on 04/11/20124), Busek et al. (Histochem Cell Biol 143, 497–504; 2015) and Duggleby et al. (Front. Immunol. 9:252, Pages 1-13, 2018) is withdrawn. This is because claim 46 has been amended to recite (i) the three CDR amino acid sequences for the CAR having an affinity for DPP6 and (ii) the nucleic acid sequence for the CAR having an affinity for FAP comprising a binding domain. However, it is to be noted that claims 60-62 remain rejected under 35 U.S.C. 103 as being unpatentable over the above references (see 103 rejection maintained below).
The rejection of claims 46-52 and 58-62 under 35 U.S.C. 103 (second 103 rejection in Non-Final) as being unpatentable over Rottman (WO 2020/191358 A1 Date Published 2020-09-24), Wang et al. (Cancer Immunol Res (2014) 2 (2): 154–166), Gross et al. (US 20200261499 Date Published 2020-08-20; provided in the IDS submitted on 04/11/20124) and Busek et al. (Histochem Cell Biol 143, 497–504; 2015) as applied to claims 46-51 and 58-62 above and further in view of NCT02850536 (Record History Version 9 Dat0.e submitted 2020-10-29) is withdrawn. This is because claim 46 has been amended to recite (i) the three CDR amino acid sequences for the CAR having an affinity for DPP6 and (ii) the nucleic acid sequence for the CAR having an affinity for FAP comprising a binding domain. However, it is to be noted that claims 60-62 remain rejected under 35 U.S.C. 103 as being unpatentable over the references of Rottman, Wang et al, Gross, et al. and Busek et al. as stated in the paragraph above (see 103 rejection maintained below).
The rejection of claims 46-51, 54-62 under 35 U.S.C. 103 (third 103 rejection in Non-Final) as being unpatentable over Rottman (WO 2020191358 A1 Date Published 2020-09-24) in view of Wang et al. (Cancer Immunol Res (2014) 2 (2): 154–166), Gross et al. (US 20200261499 Date Published 2020-08-20; provided in the IDS submitted on 04/11/20124), Busek et al. (Histochem Cell Biol 143, 497–504; 2015) and Duggleby et al. (Front. Immunol. 9:252, Pages 1-13, 2018) is withdrawn. This is because claim 46 has been amended to recite (i) the three CDR amino acid sequences for the CAR having an affinity for DPP6 and (ii) the nucleic acid sequence for the CAR having an affinity for FAP comprising a binding domain. However, it is to be noted that claims 60-62 remain rejected under 35 U.S.C. 103 as being unpatentable over the references of Rottman, Wang et al, Gross, et al. and Busek et al. as stated in the first paragraph of this section (see 103 rejection maintained below).
Claim Rejections - Maintained
Claim Rejections - 35 USC § 103 - Maintained
Claims 60-62 remain rejected under 35 U.S.C. 103 as being unpatentable over Rottman (WO 2020191358 A1 Date Published 2020-09-24) in view of Wang et al. (Cancer Immunol Res (2014) 2 (2): 154–166), Gross et al. (US 20200261499 Date Published 2020-08-20; provided in the IDS submitted on 04/11/20124), Busek et al. (Histochem Cell Biol 143, 497–504; 2015) and Duggleby et al. (Front. Immunol. 9:252, Pages 1-13, 2018).
Rottman teaches adoptive cell therapies for the treatment of cancer (Abstract). Rottman teaches the generation of CAR-T cells specific for fibroblast activation protein (FAP) (Pg. 2 lines 19-25, Pg. 4 lines 27-31, Pg. 5 line 7 and Pg. 6 lines 10-19) for treating an animal subject (Pg. 49 lines 17-22).
Rottman also teaches that that the cancer can be pancreatic islet cell tumor. Rottman further teaches a method of treating a cancer in a subject comprising administering to the subject an effective amount of human immune effector cells encoding an engineered antigen receptor (Pg. 2 lines 19 and 23-25), wherein the immune effector cells are autologous to the subject (Pg. 3 line 4) and comprise T cells that are CD4+ (Pg. 3 lines 5-7). They teach the CAR comprises: a CD28 transmembrane domain, a CD28 costimulatory domain, and a CD3ζ primary signaling domain (Pg. 7 lines 1-3).
Rottman further does not specifically teach a method of treating type 1 diabetes in a subject in need thereof, comprising administering to the subject a modified regulatory T cell comprising a chimeric antigen receptor (CAR) having affinity for FAP, wherein the CAR comprises an FAP binding domain, a CD28 transmembrane domain, a CD28 costimulatory domain, and a CD3( intracellular domain, or wherein the modified cell is an autologous cell, or wherein the modified cell is derived from a human.
However, these deficiencies are made up in the teachings of Wang et al., Gross et al. and Busek et al.
Wang et al. teaches CAR-T cells specific for mouse fibroblast activation protein (FAP) that selectively inhibited tumor growth by targeting tumor stroma that is high in FAP expression in mice (Abstract). Wang et al. also teaches that FAP expression was also seen in the pancreas (Pg. 155 column left lines 16-17 and Pg. 163 column right lines 10-18).
Gross et al. teaches effector immune cells comprising CARs and methods for treatment of cancer comprising administering said effector immune cells in mouse models (Abstract, paragraphs [0411] and [0412]). Gross et al. also teaches that the CAR can target FAP (paragraphs [0189] and [0214]).
Busek et al. teaches that fibroblast activation protein (FAP) is expressed in adult human Langerhans islet cells (Abstract). They teach that FAP has been suggested to be involved in the regulation of glucose and lipid metabolism (Pg. 498 column left lines 22-23). Therefore, Busek et al. teaches that FAP is an islet cell antigen.
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of treating cancer in a subject in need thereof, comprising administering to the subject a modified T cell comprising a CAR having affinity for FAP as taught by Rottman and wherein the CAR comprises a CD28 transmembrane domain, a CD28 costimulatory domain, and a CD3ζ intracellular domain also as taught by Rottman, because Wang et al. teaches CAR-T cells specific for FAP can selectively inhibit tumor growth in mouse (Abstract, Pg. 155 column left lines 16-17 and Pg. 163 column right lines 10-18) and Gross et al. teaches that CAR specific for FAP can be used for cancer treatment in a mouse model (Abstract, paragraphs [0189], [0411] and [0412]). In addition, noting that Busek et al. also teaches that FAP is expressed in adult human Langerhans islet cells and may be involved in the regulation of glucose and lipid metabolism (Abstract and Pg. 498 column left lines 22-23), such administering of a FAP binding CAR appears to be equivalent to “prophylactic” treatment of type 1 diabetes “in a subject in need thereof”. Further, Rottman teaches that the immune effector cells encoding CAR specific for FAP can be human immune cells (Pg. 2 lines 19 and 23-25), can be autologous to the subject (Pg. 3 line 4) and can comprise T cells that are CD4+ (Pg. 3 lines 5-7). As taught by Duggleby et al., regulatory T cells are CD4+ T cells (Abstract), thus administering the CD4+ T cells comprising CAR with a binding domain to FAP as taught by Rottman meets the limitation of instant claim 60 of administering a modified regulatory T cell to the subject in need thereof. This is an example of (A) Combining prior art elements according to known methods to yield predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the reply of 04/01/2026, Applicant cites that regarding claims 60-62, the Examiner further alleges that one of ordinary skill in the art would have been motivated, with reasonable expectation of success, to combine the method of treating cancer with anti-FAP CAR T cells as taught by Rottman and Gross with the knowledge that FAP is a human Langerhans cell antigen from Busek with the knowledge that CD4+ regulatory T cells can be used in an adoptive transfer setting as an immunosuppressive therapy as taught by Duggleby. Applicant respectfully disagrees with the asserted grounds for rejection and cites KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 550 USPQ2d 1385 (2007) (hereinafter "KSR") establishes a three-prong test that must be met for a reference or a combination of references to establish a prima facie case of obviousness. The three basic criteria in the KSR test are: first, there must be some suggestion or motivation, either in the references themselves or in the knowledge generally available to one of ordinary skill in the art, to modify the reference or to combine reference teachings; second, there must be a reasonable expectation of success; and third, the prior art reference (or references when combined) must teach or suggest all of the claim limitations.
Applicant continued to cite that regarding claims 60-62, these claims specify the treatment of type I diabetes in a subject using a FAP-specific CAR construct expressed in a regulatory CD4+ T cell. As discussed above, Rottman, Gross, and Wang describe the use of CAR T cells to treat cancer, not an autoimmune disease. There is no disclosure, teaching, or suggestion that the expression of a construct made with signaling domains that activate CD8+ cytotoxic T cells would be able to activate a CD4+ regulatory T cell in a way that would maintain its immunosuppressive function. Moreover, the Duggleby does not remedy this deficiency. While Duggleby describes that polyclonal CD4+ regulatory T cells can be used as cellular therapies to treat autoimmune diseases such as GVHD and Type I diabetes, it does not disclose, teach, or suggest that type-I diabetes can be specifically treated with CAR constructs.
Applicant further cites that at the time of the invention, one of ordinary skill in the art would not have arrived at a method of treating type I diabetes with reasonable expectation of success starting with Rottman, Wang, Gross, Busek, and Duggleby, alone or combined. First, Rottman, Wang, and Gross at best focus exclusively on the use of CAR T cells to treat cancer, not to induce or treat autoimmune diseases. Second, there would be no motivation to combine the teachings of Rottman and Gross with the other references because each of these references describe that optimal CAR T cell function requires unique additional features not taught by the instant invention (e.g., CAR-expressing CD34+ HPCs in Rottman and iCAR/pCAR constructs in Gross).
Examiner’s Response: The arguments found in the Reply of 04/01/2026 have been carefully considered but are not deemed persuasive. As stated above, the rejection of claims 46-51, 58 and 59 have been withdrawn. However, instant claims 60-62 remain rejected because the claims recite "A method of treating diabetes in a subject 'in need thereof', comprising….." rather than just "A method of treating diabetes in a subject, comprising….". Even though the maintained 103 rejection is based on the motivation of administering an FAP-expressing CAR to treat cancer as taught by Rottman, Wang et al. and Gross et al, it is applicable to instant claims 60-62 because instant claim 60, as written or as recited, encompasses prophylactic methods of treating diabetes comprising administering to the subject (who is being treated for cancer), a modified Treg comprising a CAR that comprises an FAP binding domain, a CD28 transmembrane domain, a CD28 costimulatory domain, and a CD3zeta intracellular domain. It is suggested that the phrase “in need thereof” in claim 60 be deleted and the word “therapeutically” be placed after “A method of” in claim 60 so that the claim language would be allowable.
In addition, the instant specification on Pg 22 line 1 discloses that therapeutic can mean a treatment and/or a prophylaxis. Further, on Pg 83 lines 5-6, the instant specification discloses that pharmaceutical compositions of the present invention may be administered in a manner appropriate to the disease to be prevented. Even further, on Pg 85 lines 20-24, the instant specification also discloses that the pharmaceutical composition of some of the embodiments contains cells in amounts effective to prevent the disease and the prophylactic efficacy of said embodiments is monitored by periodic assessment of treated subjects.
Regarding cited references describe that optimal CAR T cell function requires unique additional features not taught by the instant invention (e.g., CAR-expressing CD34+ HPCs in Rottman and iCAR/pCAR constructs in Gross), it should be noted that the method of claim 60 recites “comprising administering to the subject a modified regulatory T cell comprising a chimeric antigen receptor (CAR) having affinity for FAP…..” which means that the recited T cell can comprise an FAP-binding CAR as well as additional features not recited in the instant claim, which can include those taught by Rottman and Gross et al which the Applicant has addressed in the Remarks.
New Claim Objections
Claim 19 is objected to due to a typographical error. The underlined space “_” between the word “wherein” and phrase “the signal peptide” should be deleted.
Claim 49 is objected to due to a typographical error. The underlined space “_” between the word “further” and the word “comprising” should be deleted.
Claim 54 is objected to due to a typographical error. The underlined space “_” between the word “administering” and the phrase “an effective amount of” should be deleted.
Claim 59 is objected to due to a typographical error. The term “type 1” should be inserted before the term “diabetes” so that the claim recites “A non-human primate animal model of type 1 diabetes made by the method of claim 46.
Claims 55-57 are objected to for being dependent upon an objected claim.
New Rejections Necessitated by Amendments
Claim Rejections - 35 USC § 112(b) - New
Claim 50 recites the limitation "the different islet cell antigens”. There is insufficient antecedent basis for "the different islet cell antigens (plural)” in the claim.
Allowable Subject Matter
Claims 1-2,4-18, 20,22-27,29-41,43-46, 51-53, and 58 are allowed.
The DPP6 binding domain comprising a first CDR region comprising the amino acid sequence set forth in SEQ ID NO: 35; a second CDR region comprising the amino acid sequence set forth in SEQ ID NO: 36; and a third CDR region comprising the amino acid sequence set forth in SEQ ID NO: 37, and comprising the variable region comprising the amino acid sequence set forth in SEQ ID NO: 33 are free of prior art.
The DPP binding domain comprising a variable region comprising the nucleic acid sequence set forth in SEQ ID NO: 34 is free of prior art.
The isolated nucleic acid comprising a nucleic acid sequence encoding a chimeric antigen receptor (CAR) having affinity for DPP6, wherein the CAR comprises a DPP6 binding domain, a transmembrane domain, and an intracellular domain, comprising the nucleic acid sequence set forth in SEQ ID NO: 39 is free of prior art.
The FAP binding domain encoded by the nucleic acid sequence of SEQ ID NO: 64 is free of prior art.
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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/YIE-CHIA LEE (TONYA)/Examiner, Art Unit 1642
/SEAN E AEDER/Primary Examiner, Art Unit 1642
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