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 .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-4, 6, 8, 10, 12, 19-21, and 34) and the below-listed species in the reply filed on 02/05/2026 is acknowledged.
Elected Species:
A DPP6-binding domain comprising SEQ ID NOs: 16-18 as the CDRs and SEQ ID NO: 10 as the variable region;
An IgG4 hinge;
A CD28 transmembrane domain;
A CD28 costimulatory domain;
A CD3zeta activation domain;
A chimeric antigen receptor (CAR) scaffold (i.e., hinge, transmembrane, and intracellular domains) comprising SEQ ID NO: 25;
A full CAR (i.e., the CAR scaffold plus the DPP6-binding domain) comprising SEQ ID NO: 28 without the optional tag (i.e., [X]n).
Claim Status
Claims 5, 7, 9, 11, 13-18, 25-26, and 31-33 have been cancelled and claims 22-24 have been amended, as requested in the preliminary amendment filed on 11/22/2023. Following the amendment, claims 1-4, 6, 8, 10, 12, 19-24, 27-30 and 34-35 are pending in the instant application.
Claims 22-24, 27-30, and 35 stand as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention in the Response filed 02/05/2026, there being no allowable generic or linking claim.
Claims 1-4, 6, 8, 10, 12, 19-21, and 34 are under examination in the instant office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Claims 1-4, 6, 8, 10, 12, 19-21, and 34 have an effective filing date of October 29, 2020 corresponding to PRO 63/107,110.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 11/22/2023 and 02/05/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Specification
The specification is objected to because the use of the terms (i) nanobody and/or nanobodies, (ii) BD FACSAria, and (iii) FlowJo, which are trade names or marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Interpretation
With regard to claim language regarding sequences, the following are noted:
The limitation of, for example, “a CDR1 of SEQ ID NO:16” is being interpreted as closed claim language such that the full-length sequence corresponding to SEQ ID NO:16 is required to meet the limitation. Such language pertains to claim 2.
The limitation of, for example, “comprises the amino acid sequence of SEQ ID NO:10” is being interpreted as closed claim language such that the full-length sequence corresponding to SEQ ID NO:10 is required to satisfy the claim limitation. Such language pertains to claims 3, 12, and 19.
The limitation of, for example, “an amino acid sequence sharing at least 90%, 95% or 99% identity with SEQ ID NO:10” is being interpreted such that sequences having at least 90% identity with full-length SEQ ID NO:10 are required to meet the limitation. Such language pertains to claims 3, 12, and 19.
Art-Free Subject Matter
It is noted that the instantly elected CAR species (as pertains to claims 2-4, 6, 8, 10, 12-21, and 34), which comprises a DPP6-binding domain comprising (i) full-length SEQ ID NOs: 16-18 as the CDRs; (ii) corresponding full-length SEQ ID NO: 10 or an amino acid sequence having at least 90% identity thereto as the variable region; (iii) the CAR scaffold (i.e., hinge, transmembrane, and intracellular domains) comprising SEQ ID NO: 25; and (iv) the full CAR (i.e., the CAR scaffold plus the DPP6-binding domain) comprising SEQ ID NO: 28 without the optional tag (i.e., [X]n) has been thoroughly searched and is free of the prior art. However, it is noted that independent claim 1 is rejected under 35 USC § 103, and claims 2-4, 6, 8, 10, 12, 19-21, and 34 are rejected under 35 USC § 112(b) as detailed below.
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.
Claims 2-4, 6, 8, 10, 12, 19-21, and 34 are 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.
Claim 2 contains the trademark/trade name “nanobody”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a single domain antibody (i.e., a sdAb or VHH) and, accordingly, the identification/description is indefinite. Claims 3-4, 6, 8, 10, 12, 19-21, and 34 are included in this rejection as they all depend from and/or incorporate claim 2.
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.
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.
Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/157440 A1 (provided by Applicant as foreign patent citation #1 of 11/22/2023 IDS; herein after referred to as "Sentman") in view of non-patent literature by Yu et. al. (Inflammation, 2012, 35(6), 1773-1780; previously cited on PTO-892; herein after referred to as "Yu"), non-patent literature by Balhuizen et. al. (Scientific Reports, 2017, 7(15130), 1-13; provided by Applicant as non-patent literature citation #1 of 11/22/2023 IDS; herein after referred to as "Balhuizen"), and non-patent literature by Radichev et. al. (Cellular Immunology, Available September 2020, 358(104224), 1-8; previously cited on PTO-892; herein after referred to as “Radichev”).
Sentman teaches chimeric antigen receptors ("CARs"), modified regulatory T cells (Tregs) expressing such CARs, compositions containing such modified Tregs, and methods of use thereof as therapeutics, in particular in the context of treating neurodegenerative diseases (Abstract). CAR-expressing cells may comprise immune cells, preferably wherein said CAR-expressing immune cells comprise Tregs such as FOXP3+ Tregs (Paragraph 0013). In some
embodiments, a CAR of the invention comprises at least an extracellular antigen binding domain (AB domain), a transmembrane domain (TM domain) and a cytoplasmic signaling domain (also referred to as an intracellular signaling (ICS) domain) comprising a functional signaling domain derived from a stimulatory molecule and/or costimulatory molecule (Paragraph 0071). Sentman provides an exemplary embodiment wherein CARs comprised by modified Tregs may be
targeted to Aβ peptides, and may comprise anti-Aβ CARs using single chain variable
fragment (scFv) sequences from antibodies, e.g., human and/or humanized antibodies, with
different binding specificities to Aβ, e.g., oligomeric Aβ; in exemplary embodiments, said
scFvs may be fused to human CD28 hinge, transmembrane, and cytoplasmic domains (i.e., costimulatory domain), followed by a human CD3ζ cytoplasmic domain (i.e., activation domain) wherein said CARs may trigger both primary (CD3ζ) and co-stimulatory (CD28) signaling upon antigen binding and cross-linking (Paragraph 00127).
However, Sentman does not explicitly teach a Treg that is CD4+CD25+CD127low/− nor a CAR comprising a DPP6-binding domain. These deficiencies are remedied by the combination of Yu, Balhuizen, and Radichev.
Yu compared four staining profiles of Tregs, including CD4+CD25high T cells, CD4+CD39+ T cells, CD4+CD73+ T cells, and CD4+CD25+CD127low/− T cells; the authors found that (i) CD4+CD25+CD127low/− T cells expressed the highest level of Foxp3 and had the strongest correlation with CD4+CD25+Foxp3+ T cells, the accepted identifying characteristics for “real” nTreg cells and (ii) functional data showed that CD4+CD25+CD127low/− T cells could effectively suppress the proliferation of CD4+CD25− T cells, suggesting that compared with the other three populations, CD4+CD25+CD127low/− T cells best fit the definition of naturally occurring regulatory T cells in human peripheral blood (Abstract).
Balhuizen teaches that Dipeptidyl-Peptidase 6 (DPP6) was identified as a target whose mRNA expression is at least 25-fold higher in human pancreatic islets as compared to surrounding tissues and is not changed by proinflammatory cytokines and at the protein level, DPP6 localizes only in beta and alpha cells within the pancreas; the authors generated a high-affinity camelid single-domain antibody (nanobody) targeting human DPP6 (Abstract). The authors identified DPP6 as a biomarker for the endocrine pancreas, expressed preferentially in human beta and alpha cells as well as insulinomas (Page 9, First Full Paragraph); DPP6 was identified as a new potential islet biomarker and a novel nanobody tracer that targets it was generated wherein the tracer displays high specificity for DPP6 and its in vivo properties were validated in mice xenografted with either human insulin secreting cells or a neuronal derived tumor that spontaneously expresses DPP6 (Page 9, Paragraph 7).
Radichev teaches that Type 1 Diabetes (T1D) is an autoimmune disease marked by direct elimination of insulin-producing β cells by autoreactive T effectors, and recent T1D clinical trials utilizing autologous Tregs transfers to restore immune balance and improve disease prompted the authors to design a novel Tregs-based antigen-specific T1D immunotherapy; the authors engineered a Chimeric Antigen Receptor (CAR) expressing a single-chain Fv (scFv) recognizing the human pancreatic endocrine marker, HPi2 (Abstract). CAR Tregs have great potential to be used as a treatment against autoimmunity including T1D, therefore, exploring target-specific
CARs is crucial for developing new therapeutics; anti-HPi2-driven CAR was unsuccessful because the anti-HPi2 antibody appeared not to be exclusively specific for human pancreatic islets, but the authors suggest that using alternative islet-specific targets should be explored, and with the recent advancement of 10x single cell sequencing technology into β cell biology field, different reports suggested that NTPDase3, DPP6, and (FXYD2)γa could be such potential pancreatic β cell markers (Page 7, Column 1, Paragraph 2).
Thus, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to develop Tregs engineered to express a CAR wherein said CAR comprises a binding domain linked via hinge and transmembrane domain to an intracellular domain further comprising a costimulatory domains and an activation domain (as taught by Sentman), wherein said Tregs are CD4+CD25+CD127low/− (as taught by Yu) and further wherein the binding domain is DPP6 specific (e.g., a DPP6 nanobody as taught by Balhuizen), an islet-specific target that could have therapeutic applications in CAR-based therapeutics for T1D (as suggested by Radichev), because combining prior art elements according to known methods would be expected to yield predictable results with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to combine the teachings of the cited references to arrive at human Tregs engineered to express a DPP6-reactive CAR wherein the Tregs are CD4+, CD25+, CD127-/lo and wherein the CAR comprises a DPP6-binding domain linked via hinge and transmembrane domain to an intracellular domain further comprising a costimulatory domains and an activation domain in order to develop Tregs expressing a CAR specific for islets in order to develop a therapeutic directed at T1D, wherein the specificity of the CAR for DPP6 would reasonably be expected to be a successful therapeutic approach for T1D because (i) Tregs engineered to express CARs are known in the art as disclosed by Sentman, (ii) Yu indicates that , CD4+CD25+CD127low/− T cells best fit the definition of naturally occurring regulatory T cells in human peripheral blood; (iii) Radichev teaches that CAR Tregs have great potential to be used as a treatment against autoimmunity including T1D and suggests that DPP6 is a potential pancreatic β cell marker; and (iv) targeting DPP6 is further supported by Balhuizen which teaches that DPP6 localizes only in beta and alpha cells within the pancreas.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim1 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, and 8-11 of U.S. Patent No. 12,421,302 (herein after referred to as "reference patent") in view of WO 2019/157440 A1 (provided by Applicant as foreign patent citation #1 of 11/22/2023 IDS; herein after referred to as "Sentman") in view of non-patent literature by Yu et. al. (Inflammation, 2012, 35(6), 1773-1780; previously cited on PTO-892; herein after referred to as "Yu"), non-patent literature by Balhuizen et. al. (Scientific Reports, 2017, 7(15130), 1-13; provided by Applicant as non-patent literature citation #1 of 11/22/2023 IDS; herein after referred to as "Balhuizen"), and non-patent literature by Radichev et. al. (Cellular Immunology, Available September 2020, 358(104224), 1-8; previously cited on PTO-892; herein after referred to as “Radichev”).
Claim 1 of the reference patent is drawn, generally, to a chimeric antigen receptor (CAR) comprising an antigen specific binding domain, a hinge domain, a transmembrane domain, a co-stimulatory domain, and a CD3zeta signaling domain, wherein: (i) the antigen specific binding domain specifically binds to antigens comprising citrullinated-vimentin (CV) polypeptides or peptides thereof, (ii) the co-stimulatory domain comprises a CD28 or 4-1BB polypeptide, and (iii) the antigen specific binding domain comprises a single chain variable fragment (scFv) which specifically binds to CV. Thus, the reference patent reads on a CAR comprising an antigen specific binding domain, a hinge, a transmembrane domain, and an intracellular domain (i.e., a co-stimulatory and activation/signaling domain). Claim 5 of the reference patent is drawn to an isolated T cell that is modified to express: a chimeric antigen receptor (CAR) comprising an antigen specific binding domain, a hinge domain, a transmembrane domain, a co-stimulatory domain, and a CD3zeta signaling domain, wherein: (i) the antigen specific binding domain specifically binds to antigens comprising citrullinated-vimentin (CV) polypeptides or peptides thereof, (ii) the co-stimulatory domain comprises a CD28 or 4-1BB polypeptide, and (iii) the antigen specific binding domain comprises a single chain variable fragment (scFv) which specifically binds to CV. Thus, the reference patent also reads on a T cell engineered to express said CAR. Reference patent claim 8 further limits the isolated T cell to a mammalian Treg and claim 9 further limits the mammalian Treg to CD4+CD25+CD127-FOXP3+ Tregs. Reference patent claims 10 and 11 are drawn to (1) an expression vector encoding a chimeric antigen receptor (CAR) comprising an antigen specific binding domain, a hinge domain, a transmembrane domain, a co-stimulatory domain, and a CD3zeta signaling domain, wherein: (i) the antigen specific binding domain specifically binds to antigens comprising citrullinated-vimentin (CV) polypeptides or peptides thereof, (ii) the co-stimulatory domain comprises a CD28 or 4-1BB polypeptide, and (iii) the antigen specific binding domain comprises a single chain variable fragment (scFv) which specifically binds to CV; and (2) a host cell comprising said expression vector, respectively. Thus, the reference patent reads on a mammalian Treg cell engineered to express a CAR comprising an antigen specific binding domain, a hinge, a transmembrane domain, and an intracellular domain (i.e., a co-stimulatory and activation/signaling domain). However, the reference patent does not explicitly read on human Tregs that are CD4+CD25+CD127-/lo, nor an extracellular DPP6-binding domain. These deficiencies are remedied by Sentman, Yu, Balhuizen, and Radichev.
Sentman teaches chimeric antigen receptors ("CARs"), modified regulatory T cells (Tregs) expressing such CARs, compositions containing such modified Tregs, and methods of use thereof as therapeutics, in particular in the context of treating neurodegenerative diseases (Abstract). CAR-expressing cells may comprise immune cells, preferably wherein said CAR-expressing immune cells comprise Tregs such as FOXP3+ Tregs (Paragraph 0013). In some
embodiments, a CAR of the invention comprises at least an extracellular antigen binding domain (AB domain), a transmembrane domain (TM domain) and a cytoplasmic signaling domain (also referred to as an intracellular signaling (ICS) domain) comprising a functional signaling domain derived from a stimulatory molecule and/or costimulatory molecule (Paragraph 0071). Sentman provides an exemplary embodiment wherein CARs comprised by modified Tregs may be
targeted to Aβ peptides, and may comprise anti-Aβ CARs using single chain variable
fragment (scFv) sequences from antibodies, e.g., human and/or humanized antibodies, with
different binding specificities to Aβ, e.g., oligomeric Aβ; in exemplary embodiments, said
scFvs may be fused to human CD28 hinge, transmembrane, and cytoplasmic domains (i.e., costimulatory domain), followed by a human CD3ζ cytoplasmic domain (i.e., activation domain) wherein said CARs may trigger both primary (CD3ζ) and co-stimulatory (CD28) signaling upon antigen binding and cross-linking (Paragraph 00127).
Yu compared four staining profiles of Tregs, including CD4+CD25high T cells, CD4+CD39+ T cells, CD4+CD73+ T cells, and CD4+CD25+CD127low/− T cells; the authors found that (i) CD4+CD25+CD127low/− T cells expressed the highest level of Foxp3 and had the strongest correlation with CD4+CD25+Foxp3+ T cells, the accepted identifying characteristics for “real” nTreg cells and (ii) functional data showed that CD4+CD25+CD127low/− T cells could effectively suppress the proliferation of CD4+CD25− T cells, suggesting that compared with the other three populations, CD4+CD25+CD127low/− T cells best fit the definition of naturally occurring regulatory T cells in human peripheral blood (Abstract).
Balhuizen teaches that Dipeptidyl-Peptidase 6 (DPP6) was identified as a target whose mRNA expression is at least 25-fold higher in human pancreatic islets as compared to surrounding tissues and is not changed by proinflammatory cytokines and at the protein level, DPP6 localizes only in beta and alpha cells within the pancreas; the authors generated a high-affinity camelid single-domain antibody (nanobody) targeting human DPP6 (Abstract). The authors identified DPP6 as a biomarker for the endocrine pancreas, expressed preferentially in human beta and alpha cells as well as insulinomas (Page 9, First Full Paragraph); DPP6 was identified as a new potential islet biomarker and a novel nanobody tracer that targets it was generated wherein the tracer displays high specificity for DPP6 and its in vivo properties were validated in mice xenografted with either human insulin secreting cells or a neuronal derived tumor that spontaneously expresses DPP6 (Page 9, Paragraph 7).
Radichev teaches that Type 1 Diabetes (T1D) is an autoimmune disease marked by direct elimination of insulin-producing β cells by autoreactive T effectors, and recent T1D clinical trials utilizing autologous Tregs transfers to restore immune balance and improve disease prompted the authors to design a novel Tregs-based antigen-specific T1D immunotherapy; the authors engineered a Chimeric Antigen Receptor (CAR) expressing a single-chain Fv (scFv) recognizing the human pancreatic endocrine marker, HPi2 (Abstract). CAR Tregs have great potential to be used as a treatment against autoimmunity including T1D, therefore, exploring target-specific
CARs is crucial for developing new therapeutics; anti-HPi2-driven CAR was unsuccessful because the anti-HPi2 antibody appeared not to be exclusively specific for human pancreatic islets, but the authors suggest that using alternative islet-specific targets should be explored, and with the recent advancement of 10x single cell sequencing technology into β cell biology field, different reports suggested that NTPDase3, DPP6, and (FXYD2)γa could be such potential pancreatic β cell markers (Page 7, Column 1, Paragraph 2).
Thus, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the CAR and Tregs engineered to express said CAR of the reference patent wherein the Tregs are engineered to express a CAR wherein said CAR comprises a binding domain linked via hinge and transmembrane domain to an intracellular domain further comprising a costimulatory domains and an activation domain (as taught by Sentman), wherein said Tregs are CD4+CD25+CD127low/− (as taught by Yu) and further wherein the binding domain is DPP6 specific (e.g., a DPP6 nanobody as taught by Balhuizen), an islet-specific target that could have therapeutic applications in CAR-based therapeutics for T1D (as suggested by Radichev), because combining prior art elements according to known methods would be expected to yield predictable results with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to combine the teachings of the cited references to arrive at human Tregs engineered to express a DPP6-reactive CAR wherein the Tregs are CD4+, CD25+, CD127-/lo and wherein the CAR comprises a DPP6-binding domain linked via hinge and transmembrane domain to an intracellular domain further comprising a costimulatory domains and an activation domain in order to develop Tregs expressing a CAR specific for islets in order to develop a therapeutic directed at T1D, wherein the specificity of the CAR for DPP6 would reasonably be expected to be a successful therapeutic approach for T1D because (i) Tregs engineered to express CARs are known in the art as disclosed by Sentman, (ii) Yu indicates that , CD4+CD25+CD127low/− T cells best fit the definition of naturally occurring regulatory T cells in human peripheral blood; (iii) Radichev teaches that CAR Tregs have great potential to be used as a treatment against autoimmunity including T1D and suggests that DPP6 is a potential pancreatic β cell marker; and (iv) targeting DPP6 is further supported by Balhuizen which teaches that DPP6 localizes only in beta and alpha cells within the pancreas.
Claim 1 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the pertinent claims of the below-listed copending Application Nos. (herein after collectively referred to as “reference applications”) in view of WO 2019/157440 A1 (provided by Applicant as foreign patent citation #1 of 11/22/2023 IDS; herein after referred to as "Sentman") in view of non-patent literature by Yu et. al. (Inflammation, 2012, 35(6), 1773-1780; previously cited on PTO-892; herein after referred to as "Yu"), non-patent literature by Balhuizen et. al. (Scientific Reports, 2017, 7(15130), 1-13; provided by Applicant as non-patent literature citation #1 of 11/22/2023 IDS; herein after referred to as "Balhuizen"), and non-patent literature by Radichev et. al. (Cellular Immunology, Available September 2020, 358(104224), 1-8; previously cited on PTO-892; herein after referred to as “Radichev”).
Application No.
Brief Description of the Invention
Pertinent Claims
17635054
CAR Comprising Antigen Specific Binding Domain Specific for Antigen Comprising Acetylated Laminin, Hinge Domain, Transmembrane Domain, Co-Stimulatory Domain, and Primary Signaling Domain, Isolated T Cell, Expression Vector, and Pharmaceutical Composition Thereof
1, 6, 9-10, 15, 18, 34, 36
18044772
Chimeric Polypeptide Comprising Extracellular Domain Having Binding Affinity for an Antigen, Hinge Domain, CD28 Transmembrane Domain, and Intracellular Signaling Domain, CAR, Nucleic Acid Construct, Recombinant Cell, Pharmaceutical Composition, and Kit Thereof
1-2, 11-16, 20, 22-23, 26-29, 31-32, 56
18682764
CAR-Treg Comprising Exogenous Nucleic Acid Encoding a CAR comprising Human Anti-HLA-A2 Antibody, Hinge Domain, Transmembrane Domain, and Intracellular Signaling Domain, Vector, and Method of Generating CAR-Tregs Thereof
1, 3-7, 11, 19, 33
19314531
CAR Comprising Antigen Specific Binding Domain Specific for Antigen Comprising Vimentin Polypeptides and Peptides Thereof, Hinge Domain, Transmembrane Domain, Co-Stimulatory Domain, and CD3zeta Signaling Domain, Isolated T Cell, and Pharmaceutical Composition Thereof
1, 3, 6, 19-20, 29-32, 48, 50-51
18043716
Chimeric Receptor Comprising Extracellular Antigen-Binding Domain Capable of Binding Target Antigen, Transmembrane Domain, and Intracellular Signal Transduction Domain, Nucleic Acid, Recombinant Immune Cell, Pharmaceutical Composition, and Kit Thereof
1, 4, 14, 18, 20, 25, 49, and 53
16981168
CAR Comprising Antigen Specific Binding Domain, Spacer Domain, Transmembrane Domain, Primary Signaling Domain, and Second Signaling Domain, and Isolated CD4+CD25+CD127-FOXP3+Helios+ Treg Cell Thereof
1-2, 5, 11-14, 20, 25-26, 28
Claim 1 is rendered obvious by the combined teachings of the prior art above as discussed in the 103 section, the 103 being incorporated here. The addition of the copending claims of the reference applications over related subject matter only further supports this obviousness.
It is specifically noted that all of the above-listed reference applications are drawn to chimeric polypeptides, chimeric receptors, and/or CARs thereof and recombinant cells engineered to express said chimeric polypeptides, chimeric receptors, and/or CARs, wherein the wherein the claims of the reference applications generally disclose the structural components of the chimeric polypeptides, chimeric receptors, and/or CARs comprise (i) an antigen-binding domain; (ii) a spacer/hinge region; (iii) a transmembrane domain; and (iv) an intracellular signaling domain. However, it is noted that the above-listed reference applications do not explicitly claim human Tregs that are CD4+CD25+CD127-/lo, nor an extracellular DPP6-binding domain. These deficiencies are addressed by the cited references, as provided by the teachings specified in the 103 section.
Thus, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify chimeric polypeptides, chimeric receptors, and/or CARs thereof and recombinant cells engineered to express said chimeric polypeptides, chimeric receptors, and/or CARs of the reference applications wherein Tregs are engineered to express a CAR wherein said CAR comprises a binding domain linked via hinge and transmembrane domain to an intracellular domain further comprising a costimulatory domains and an activation domain (as taught by Sentman), wherein said Tregs are CD4+CD25+CD127low/− (as taught by Yu) and further wherein the binding domain is DPP6 specific (e.g., a DPP6 nanobody as taught by Balhuizen), an islet-specific target that could have therapeutic applications in CAR-based therapeutics for T1D (as suggested by Radichev), because combining prior art elements according to known methods would be expected to yield predictable results with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to combine the teachings of the cited references to arrive at human Tregs engineered to express a DPP6-reactive CAR wherein the Tregs are CD4+, CD25+, CD127-/lo and wherein the CAR comprises a DPP6-binding domain linked via hinge and transmembrane domain to an intracellular domain further comprising a costimulatory domains and an activation domain in order to develop Tregs expressing a CAR specific for islets in order to develop a therapeutic directed at T1D, wherein the specificity of the CAR for DPP6 would reasonably be expected to be a successful therapeutic approach for T1D because (i) Tregs engineered to express CARs are known in the art as disclosed by Sentman, (ii) Yu indicates that , CD4+CD25+CD127low/− T cells best fit the definition of naturally occurring regulatory T cells in human peripheral blood; (iii) Radichev teaches that CAR Tregs have great potential to be used as a treatment against autoimmunity including T1D and suggests that DPP6 is a potential pancreatic β cell marker; and (iv) targeting DPP6 is further supported by Balhuizen which teaches that DPP6 localizes only in beta and alpha cells within the pancreas.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Claims 1-4, 6, 8, 10, 12, 19-24, 27-30 and 34-35 are pending. Claims 22-24, 27-30, and 35 are withdrawn. Claims 1-4, 6, 8, 10, 12, 19-21, and 34 are rejected. No claims are allowed.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642