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 .
Claim Status
1. The amendment filed 09/16/2025 has been entered. Claims 1 – 6, 8 – 9, 11 – 36, 38, 40, 43, 49, 54, and 58 – 59 remain pending. Claims 7 and 10 have been cancelled.
Election/Restrictions
2. Applicant’s election without traverse of Group I (claims 1 – 7, 18 – 28, 36, and 40) in the reply filed on 05/13/2025 is acknowledged.
3. Claims 8 – 17, 29 – 35, 38, 43, 49, 54, 58, and 59 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 05/13/2025.
4. Claims 1 – 6, 18 – 28, 36, and 40 are under consideration.
Priority
5. This application claims the benefit of U.S. Provisional Patent Application No. 63/171,650
filed April 7, 2021.
Information Disclosure Statement
6. The information disclosure statement (IDS) submitted on 09/16/2025 is acknowledged. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Withdrawn Specification Objection
7. The objection to the specification is withdrawn in view of Applicant’s amendment to the specification to include a proper symbol following trade names or marks used in commerce.
Withdrawn Claim Objections
9. The objection to claim 40 is withdrawn in view of Applicant’s amendment to the claim.
Withdrawn Claim Rejections - 35 USC § 112
10. The rejection of claim 6 is withdrawn in view of Applicant’s amendment to the claim.
11. The rejection of claim 18 is withdrawn in view of Applicant’s amendment to independent claim 1.
12. The rejection of claim 19 is withdrawn in view of Applicant’s amendment to independent claim 1.
13. The rejection of claim 20 is withdrawn in view of Applicant’s amendment to independent claim 1.
14. The rejection of claim 21 is withdrawn in view of Applicant’s amendment to independent claim 1.
15. The rejection of claim 22 is withdrawn in view of Applicant’s amendment to independent claim 1.
16. The rejection of claim 23 is withdrawn in view of Applicant’s amendment to independent claim 1.
17. The rejection of claim 24 is withdrawn in view of Applicant’s amendment to independent claim 1.
18. The rejection of claim 25 is withdrawn in view of Applicant’s amendment to independent claim 1.
19. The rejection of claim 26 is withdrawn in view of Applicant’s amendment to independent claim 1.
20. The rejection of claim 27 is withdrawn in view of Applicant’s amendment to independent claim 1.
21. The rejection of claim 28 is withdrawn in view of Applicant’s amendment to independent claim 1.
Withdrawn Claim Rejections- 35 USC § 103
22. The rejection of claim 7 under 35 U.S.C. 103 is rendered moot by Applicant’s cancellation of the claim.
23. The rejection of claims 1 – 6, 20, 22 – 26, 36, and 40 under 35 U.S.C. 103 is withdrawn in view of Applicant’s amendment to claim 1 to “the rearranged αβ TCR is an exogenously inserted”.
24. The rejection of claims 18 – 19 under 35 U.S.C. 103 is withdrawn in view of Applicant’s amendment to claim 1 to “the rearranged αβ TCR is an exogenously inserted”.
25. The rejection of claim 21 under 35 U.S.C. 103 is withdrawn in view of Applicant’s amendment to claim 1 to “the rearranged αβ TCR is an exogenously inserted”.
26. The rejection of claims 27 – 28 under 35 U.S.C. 103 is withdrawn in view of Applicant’s amendment to claim 1 to “the rearranged αβ TCR is an exogenously inserted”.
Withdrawn Double Patenting Rejection
27. The rejection of claims 1 – 6, 18 – 28, and 36 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 12 – 30 of copending Application No. 17657798 (reference application) is withdrawn in view of Applicant’s remarks on page 19, last paragraph that the reference application recites γ[Symbol font/0x64] TCR and not αβ TCR.
Maintained Rejections
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.
28. Claims 1 – 7, 18 – 28, 36, and 40 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 – 11, 13 – 18, 21 – 23, 29, 30, 38 – 45, and 54 of copending Application No. 18303672 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are generic to (broader than) reference claims 1 – 11, 13 – 18, 21 – 23, 29, 30, 38 – 45, and 54 of the copending application.
Reference claim 1 is drawn to an induced pluripotent stem cell (iPSC) or a derivative cell thereof
comprising: one or more first exogenous polynucleotides encoding: an extracellular polyethylene glycol (PEG) recognition element operably linked to an intracellular signaling domain, and a chimeric antigen receptor (CAR) or T-cell receptor (TCR) targeting a cancer antigen. Instant claim 1 and claim 1 is drawn to an induced pluripotent stem cell (iPSC) comprising: (i) one or more polynucleotides encoding a recombinant rearranged ab T cell receptor (TCR); and (ii) a polynucleotide encoding a chimeric antigen receptor (CAR), wherein the rearranged ab TCR is a public TCR that specifically recognizes a nonhuman
antigen in the context of a specific HLA class I (HLA-1) allele and wherein the rearranged ab TCR supports differentiation of the iPSC to a T cell. Therefore, reference claim 1 is in essence a species of the generic iPSC cell of instant claim 1. It has been held that a generic invention is “anticipated” by a “species” within the scope of the generic invention.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Objections/ Rejections Necessitated by Amendment
Claim Objections
29. Claim 1 is objected to because of the following informalities: in line 8, “the iPSC to a T cell” should read “the iPSC to the T cell” because Applicant has amended the claim to recite “or a T cell derived therefrom”. 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.
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.
30. Claim(s) 1 – 6, 20, 22 – 26, 36, and 40 is/are rejected under 35 U.S.C. 103 as being unpatentable over Minagawa (Minagawa, A. et al. In Vitro Differentiation of T-Cells: Methods and Protocols. New York, NY: Springer New York, 2019. 81-84), hereinafter Minagawa in view of Boyd (WO2017088012-A1; Filed 11/23/2016; Published06/01/2017; previously cited), hereinafter Boyd which is cited on the IDS filed 10/07/2022 in view of Song (Song, InYoung, et al. Nature structural & molecular biology 24.4 (2017): 395-406; previously cited), hereinafter Song.
Regarding claim 1 (i), Minagawa teaches iPSCs (TCR-iPSCs) and T cells derived therefrom (CD8 αβ T cells) comprising a polynucleotide encoding a recombinant TCR (page 81, Introduction; page 82 – 83, 3.1 – 3.2). Minagawa teaches the iPSCs were obtained by transduction with a lentiviral vector encoding a TCR (“exogenously inserted”) and that the αβ TCR supports differentiation of the iPSCs to T cells (page 81, Abstract and Introduction; page 82, 3.1). Minagawa does not teach “rearranged αβ T cell receptor” or “public TCR that specifically recognizes a non-human antigen in the context of a specific HLA class I allele” or (ii) of claim 1. However, Minagawa teaches in combination with antigen-specific receptor transduction, iPSCs are thought to be a good source of cancer antigen-specific T cells for allogeneic cancer immunotherapy (page 81, Introduction).
Regarding “rearranged αβ T cell receptor” of (i) of claim 1 and (ii) of claim 1, Boyd teaches a genetically modified mammalian iPSC or T cell differentiated therefrom where the iPSC has been transduced with rearranged TCR genes and comprises a nucleic acid molecule encoding a CAR (page 34, 00106 – 00108; page 38 – 39, 00120; page 40, 00122; page 71, 00214). Boyd teaches iPSCs comprising a polynucleotide encoding a CAR in Example 7 (page 92, 00299 – 00301). Boyd does not teach “a public TCR” but teaches the TCR is directed to non-self molecules such as would be expected where a cell is infected with a microorganism (e.g., viral proteins) (“recognizes a non-human antigen”) (page 8, 0029; page 56 – 58, 00162; page 58, 00165).
Regarding claim 2, Minagawa teaches expanded T cells differentiated from the TCR-iPSCs (page 82, 3.2; page 83, step 8). Boyd teaches in Example 3 T cells from iPSCs (page 86, 00272 – 00274; page 87; page 88, 00282 – 00287).
Regarding claim 5, Boyd teaches the antigenic determinant to which the TCR is directed includes EBVLmp2 (“EBV”) (page 9, 0034; page 71, 00212).
Regarding claim 6, Boyd teaches iPSCs were produced from donor PBMCs by reprogramming (Figure 3; page 15, 0059; page 35, 00114; page 86, 00270 – 00271). Boyd teaches an iPSC is derived from a cell which expresses a rearranged αβTCR (page 34, 00107).
Regarding claim 20, Boyd teaches the CAR comprises a signal peptide (“(i)”), an extracellular antigen recognition moiety that recognizes and binds to an antigenic determinant of interest (“(ii)”), a spacer region (“(iii)”) a transmembrane domain (“(iv)”) an intracellular signaling domain (“(v)”), and a co-stimulatory domain (“(vi)”) (page 42, 00128 – 00129; page 43, 00129; page 44, 00130 – 00132; page 45, 00133; page 46, 00135).
Regarding claim 22, Boyd teaches the extracellular domain comprises scFV (page 42, 00128 – 00129).
Regarding claim 23, Boyd teaches the hinge region from IgG1 and a traditional CAR comprises a CD8 or CD28 hinge (page 43, 00129).
Regarding claim 24, Boyd teaches the transmembrane domain may be derived from the transmembrane regions of CD28 or CD8 (page 46, 00135).
Regarding claim 25, Boyd teaches the intracellular domain is derived from CD3-zeta signaling domain (page 45, 00132 – 00133).
Regarding claim 26, Boyd teaches the co-stimulatory signaling region comprises CD28, 4-1BB, CD27, OX40, ICOS, or CD40 (page 45, 00133).
Regarding claim 36, Boyd teaches administering the T cells differentiated from the stem cells comprising TCR/CAR to a subject (page 74, 00222 and 00224). Boyd teaches the cells can be administered in the form of a tissue graft or an encapsulated cell suspension and other proteinaceous or non-proteinaceous molecules may be administered with the cells (page 81, 00252; page 82, 00253 – 00254).
Regarding claim 40, Minagawa teaches a method of differentiating the TCR-iPSCs to T cells (page 82, 3.2; page 83, 3.2). Boyd teaches a method for making a T cell that expresses a TCR and CAR (page 72, 00217 – 00218; page 73, 00219; page 86, 00272 – 00274; page 87, page 88, 00282 – 00287). Boyd teaches the method results in mature T cells (page 88, 00285 – 00287).
Minagawa and Boyd do not teach “a public TCR” of claim 1 or “TRAV27”, “TRAJ37”, and “TRAC” of claim 3, or “TRBV19” of claim 4. However, Minagawa teaches the use of iPSCs as a cell source for producing cytotoxic T lymphocytes (CTLs) is expected to have advantages in the antigen specificity, rejuvenation profile, and reproducible number of CTLs (page 81, Introduction). Minagawa teaches in combination with antigen-specific receptor transduction, iPSCs are thought to be a good source of cancer antigen-specific T cells for allogeneic cancer immunotherapy (page 81, Introduction). Boyd teaches the TCR is directed to non-self molecules such as would be expected where a cell is infected with a microorganism (e.g., viral proteins) (page 8, 0029; page 9, 0034; page 71, 00212; page 56 – 58, 00162; page 58, 00165). Boyd teaches there is an urgent and ongoing need to develop improved systemic therapies for cancers (page 3, 0010). Boyd teaches T cells are clearly potentially a major weapon against cancer and the challenges are to increase their ability to detect cancer, numerically expand them and retain or better enhance their powerful cytolytic capacity (page 3, 0011). Boyd teaches CAR expressing T (CAR-T) cells retain the potent, focal, cell lytic capacity and avoid the normal reliance on the intrinsic TCR to detect very rare cancer peptides expressed in HLA clefts (page 4, 0011). Boyd teaches CAR-T cells can be prior selected from donors expressing a homozygous HLA haplotype expressed widely in the population thereby providing a means of generating a bank of cells which exhibit broad donor suitability (page 5, 0013). Boyd teaches generation of an iPSC from a T cell which exhibits TCR specificity directed to an antigen of interest means that the gene rearrangements for that TCR specific for the cancer antigen will be embedded in the iPSC and all T cells induced from that iPSC will retain the anti-cancer TCR specificity (page 5, 0013). Boyd teaches transfecting such iPSCs with a CAR enables the production of T cells with dual specificity for the antigen to which the CAR is directed and a TCR directed to the antigen to which the original T cell was directed to (page 5, 0013). Boyd teaches adoptive transfer of cells directed to “self” antigens may result in outcomes similar to graft versus host disease (page 47, 00139).
Regarding “public TCR” of claim 1, Song teaches expression vectors for public TCRs resulting from influenza A virus infection and stable T cell lines expressing public TCRs (page 395, left col. paragraph 1; page 408, left col. paragraph 1). Song teaches these public TCRs are rearranged TCRs resulting from exposure to influenza A virus HLA-A2-M1 epitope that is presented to HLA-A2*01:01 (page 395, left col. paragraph 1). Song teaches IAV infection results in public TCRs with identical or near-identical patterns of V-region, J-region, and junctional sequences among HLA-A2-matched but otherwise genetically unrelated individuals (page 395, left col. paragraph 1). Song teaches a better understanding of TCR repertoires is becoming increasingly important and ideally vaccines would be able to induce dominant public as well as diverse private responses to provide a resilient repertoire of memory cells (page 405, left col. paragraph 2).
Regarding claims 3 and 4, Song teaches preferential usage of TRAV27 of TCRα in TCRs that respond to HLA-A2-M1 (page 395, paragraph 1). Song teaches TCRs from HLA-A2-M1 T cells contain TCRα-TCRβ gene pairs where TCRα is TRAV27 (“TRAV27” of claim 3) and TCRβ is TRBV19 (“TRBV19” of claim 4) that used TRAJ37 (“TRAJ37” of claim 3) (page 397, left col. paragraph 2 and right col. paragraph 1; Supplementary Figure 2). Song teaches the TCRs comprise constant regions of TRAC (“TRAC” of claim 3) and TRBC (page 407, right col. paragraph 2).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Minagawa regarding iPSCs and T cells derived therefrom comprising an exogenously inserted αβ TCR with the teachings of Boyd regarding an iPSC cell expressing a rearranged αβ TCR that recognizes a non-human antigen and a nucleotide encoding a CAR with the teachings of Song regarding a public TCR to arrive at the claimed iPSC or T cell derived therefrom comprising (i) one or more polynucleotides encoding a recombinant rearranged αβ TCR; and (ii) a polynucleotide encoding a CAR, wherein the rearranged αβ TCR is an exogenously inserted, public TCR that specifically recognizes a non-human antigen in the context of a specific HLA-I allele and wherein the rearranged αβ TCR supports differentiation of the iPSC to the T cell. One would have been motivated to combine the teachings of Minagawa, Boyd and Song for iPSCs that can differentiate to T cells to treat cancer where the T cells do not cause graft-versus-host disease as Minagawa teaches in combination with antigen-specific receptor transduction, iPSCs are thought to be a good source of cancer antigen-specific T cells for allogeneic cancer immunotherapy, Boyd teaches there is an urgent and ongoing need to develop improved systemic therapies for cancers and T cells are clearly potentially a major weapon against cancer and Boyd teaches adoptive transfer of cells directed to “self” antigens may result in outcomes similar to graft versus host disease. One would have a reasonable expectation of success in combining the teachings as Minagawa teaches TCR-iPSCs that can differentiate into T cells and Boyd teaches generation of an iPSC from a T cell which exhibits TCR specificity directed to an antigen of interest means that the gene rearrangements for that TCR specific for the cancer antigen will be embedded in the iPSC and all T cells induced from that iPSC will retain the anti-cancer TCR specificity and Song teaches IAV infection results in public TCRs with identical or near-identical patterns of V-region, J-region, and junctional sequences among HLA-A2-matched but otherwise genetically unrelated individuals.
31. Claim(s) 18 – 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Minagawa (Minagawa, A. et al. In Vitro Differentiation of T-Cells: Methods and Protocols. New York, NY: Springer New York, 2019. 81-84), hereinafter Minigawa in view of Boyd (WO2017088012-A1; Filed 11/23/2016; Published06/01/2017; previously cited), hereinafter Boyd which is cited on the IDS filed 10/07/2022 in view of Song (Song, InYoung, et al. Nature structural & molecular biology 24.4 (2017): 395-406; previously cited), hereinafter Song as applied to claims 1 – 6, 20, 22 – 26, 36, and 40 above, and further in view of Lehner (Lehner, Paul J., et al. The Journal of experimental medicine 181.1 (1995): 79-91; previously cited), hereinafter Lehner.
Minigawa in view of Boyd and Song make obvious the limitations of claim 1 as set forth above. Song teaches T cells use many distinct TCRs to recognize HLA-A2-M1, which enables the use of different structural solutions to the problem of specifically recognizing a relatively featureless influenza M1 peptide (Abstract).
Regarding SEQ ID NO: 85 of claims 18 and 19, Boyd teaches the CDR3 region is important for peptide/MHC recognition (page 34, 00105) but does not teach SEQ ID NO: 84 or 85. Song teaches the CDR3β sequence of the public TCR JM22 is CASSSRSSYEQYF and LS01 is CASSIFGQREQYF (Figure 5). Song teaches the highest frequency of amino acids for CDR3β at amino acids 93 – 105 among public TCRs analyzed comprises CASSIRSSYEQYF in Figure 5b which corresponds to SEQ ID NO: 85 of claim 18 and 19. Minagawa, Boyd, and Song do not teach SEQ ID NO: 84 of claim 18 and 19. However, Song teaches stable T cell lines expressing the canonical public TCR JM22 (page 295, left col. last paragraph; Figure 2b-c; page 399, right col. paragraph 1; Figure 5a-b; page 408, left col. paragraph 2).
Regarding “TRAV27 and TRAJ41” of claim 19, Song teaches a public TCRα chain comprising the amino acid sequence encoded by TRAV38 and TRAJ41 in Figure 1e but does not teach the TRAV27 and TRAJ41 combination. However, Song teaches the TCRα bias is less dramatic but preferential usage of TRAV27 and TRAJ42 for responding to HLA-A2-M1 where M1 peptide is amino acids 58 – 66 of influenza a virus matrix protein (page 395, left col. paragraph 1).
Regarding “TRBV19 and TRBJ2-7” of claim 19, Song teaches a public TCR encoded by TRBV19 and TRBJ1-2 (page 399, left col. paragraph 2) but does not teach TRBJ2-7 or the TRBV19 and TRBJ2-7 combination. However, Song teaches the TCRβ repertoire that responds to HLA-A2-M1 is highly biased toward the use of TBRV19 with a highly conserved CDR3β motif, xR98S99x (page 395, left col. paragraph 1).
Regarding “SEQ ID NO: 84” of claims 18 and 19, Lehner teaches the Vα10 sequence CAGAGSQGNLIF from the public TCR JM22 from a donor presented with the influenza A peptide M58-66 which is the M1 peptide of Song that is SEQ ID NO: 84 (Abstract; Figure 1; page 79, right col.; page 80, left col. paragraph 1). Lehner also teaches the Vβ17 sequence CASSIRSSYEQYF from the public TCR JWUB8 from a donor presented with the influenza A peptide M58-66 which is the M1 peptide of Song that is SEQ ID NO: 85 of claims 18 and 19 (Abstract; Figure 1; page 79, right col.; page 80, left col. paragraph 1). Lehner teaches influenza A is a common viral infection of humans and the majority of adults have serological evidence of previous influenza A exposure (page 79, right col.).
Regarding “TRBJ2-7” of claim 19, Lehner teaches there appears to be relatively little conservation of the Jβ segment, and Jβ2.3 and Jβ2.7 (“TRBJ2-7”) were used in 65% of all transcripts and are amongst the most commonly used in the TCRβ repertoire (page 87, right col. paragraph 3). Lehner teaches TCR comprising the Vβ17 sequence CASSIRSSYEQYF from the public TCR JWUB8 that is SEQ ID NO: 85 comprises Jβ2.7 and the public TCR JM22 comprising Jβ2.7 (Figure 1).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Minagawa regarding iPSCs and T cells derived therefrom comprising an exogenously inserted αβ TCR with the teachings of Boyd regarding an iPSC cell expressing a rearranged αβ TCR that recognizes a non-human antigen and a nucleotide encoding a CAR with the teachings of Song regarding a public TCR comprising TRAJ41, with the teachings of Lehner regarding public TCRs comprising Vα10 sequence CAGAGSQGNLIF and Vβ17 sequence CASSIRSSYEQYF where Jβ2.7 was used in 65% of all transcripts and is amongst the most commonly used in the TCRβ repertoire to arrive at the claimed iPSC cell where the public TCR α chain has TRAV27 and TRAJ41 and CDR3 amino acid SEQ ID NO: 84 and a TCR β chain has TRBV19 and TRBJ2-7 and CDR3 having amino acid SEQ ID NO: 85. One would have been motivated to combine the teachings of Minagawa, Boyd, Song, and Lehner for iPSCs that can differentiate to T cells to treat cancer where the T cells do not cause graft-versus-host disease as Minagawa teaches in combination with antigen-specific receptor transduction, iPSCs are thought to be a good source of cancer antigen-specific T cells for allogeneic cancer immunotherapy and Boyd teaches there is an urgent and ongoing need to develop improved systemic therapies for cancers and T cells are clearly potentially a major weapon against cancer and Boyd teaches adoptive transfer of cells directed to “self” antigens may result in outcomes similar to graft versus host disease and Lehner teaches influenza A is a common viral infection of humans and the majority of adults have serological evidence of previous influenza A exposure. One would have a reasonable expectation of success in combining the teachings as Boyd teaches generation of an iPSC from a T cell which exhibits TCR specificity directed to an antigen of interest means that the gene rearrangements for that TCR specific for the cancer antigen will be embedded in the iPSC and all T cells induced from that iPSC will retain the anti-cancer TCR specificity and Song teaches T cells use many distinct TCRs to recognize HLA-A2-M1 where the TCRβ repertoire is highly biased toward TBRV19 with a highly conserved CDR3β motif, xR98S99x, and less bias for TCRα but preferential usage of TRAV27.
32. Claim(s) 21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Minagawa (Minagawa, A. et al. In Vitro Differentiation of T-Cells: Methods and Protocols. New York, NY: Springer New York, 2019. 81-84), hereinafter Minigawa in view of Boyd (WO2017088012-A1; Filed 11/23/2016; Published06/01/2017; previously cited), hereinafter Boyd which is cited on the IDS filed 10/07/2022 in view of Song (Song, InYoung, et al. Nature structural & molecular biology 24.4 (2017): 395-406; previously cited), hereinafter Song as applied to claims 1 – 6, 20, 22 – 26, 36, and 40 above, and further in view of Valentine (Valentine, Michael, et al. " Frontiers in Bioscience-Landmark 25.2 (2020): 270-282; previously cited), hereinafter Valentine.
Minagawa in view of Boyd and Song make obvious the limitations of claim 1 and 20 as set forth above. Boyd teaches a signal peptide to direct the nascent protein to the endoplasmic reticulum and subsequent surface expression, where the signal peptide is ultimately cleaved (page 42, 00129) but does not teach “the signal peptide is GMCSF signal peptide” of claim 21.
Valentine teaches a CAR construct comprising a GM-CSF signal peptide, scFv, CD28 hinge, CD28 transmembrane and CD28, and CD3 zeta costimulatory domain with or without a transferrin (TF) epitope tag (page 271, right col. last paragraph; Figure 1). Valentine teaches T cells expressing the CARs (CAR-T cells) were positive for the TF tag as determined by flow cytometry (page 273, left col. paragraph 2 – 4; page 274, left col. last paragraph; Figure 2). Valentine teaches CAR-T cells with or without the TF tag killed Raji cells in vitro and decreased Raji xenograft tumors in vivo with similar efficacy (page 275, left col.; Figure 5; page 276, left col. last paragraph and right col. paragraph 1; Figure 7; page 277, left col. paragraph 1). Valentine teaches the cytotoxic effect of CAR-T cells with the TF tag was highly specific and had reduced cytokine secretion suggesting the TF tagged CAR may show superior efficacy and safety in clinical trials (page 280, left col. paragraph 3). Valentine teaches addition of the TF tag may prove useful in clinical studies as it allows assessment of transduction efficiency and monitor CAR-T cells ex vivo (Abstract: page 280, left col. paragraph 3).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Minagawa regarding iPSCs and T cells derived therefrom comprising an exogenously inserted αβ TCR with the teachings of Boyd regarding an iPSC cell expressing a rearranged αβ TCR that recognizes a non-human antigen and a nucleotide encoding a CAR with the teachings of Song regarding a public TCR with the teachings of Valentine regarding a CAR construct comprising GMCSF signal peptide to arrive at the claimed iPSC where the CAR comprises a GMCSF signal peptide. One would have been motivated to combine the teachings of Minagawa, Boyd, Song, and Valentine for iPSCs that can differentiate to T cells to treat cancer where the T cells do not cause graft-versus-host disease as Minagawa teaches in combination with antigen-specific receptor transduction, iPSCs are thought to be a good source of cancer antigen-specific T cells for allogeneic cancer immunotherapy and Boyd teaches there is an urgent and ongoing need to develop improved systemic therapies for cancers and T cells are clearly potentially a major weapon against cancer and Boyd teaches adoptive transfer of cells directed to “self” antigens may result in outcomes similar to graft versus host disease. One would have a reasonable expectation of success in combining the teachings as Boyd teaches a CAR comprises a signal peptide that directs the nascent protein to surface expression and Valentine teaches the CAR construct comprising the GMCSF signal peptide directs surface expression of the TF tag and the CAR-T cells reduce xenograft tumor growth in vivo.
33. Claim(s) 27 – 28 is/are rejected under 35 U.S.C. 103 as being unpatentable over Minagawa (Minagawa, A. et al. In Vitro Differentiation of T-Cells: Methods and Protocols. New York, NY: Springer New York, 2019. 81-84), hereinafter Minigawa in view of Boyd (WO2017088012-A1; Filed 11/23/2016; Published06/01/2017; previously cited), hereinafter Boyd which is cited on the IDS filed 10/07/2022 in view of Song (Song, InYoung, et al. Nature structural & molecular biology 24.4 (2017): 395-406; previously cited), hereinafter Song as applied to claims 1 – 6, 20, 22 – 26, 36, and 40 above, and further in view of Brown (US-20230372483-A1; Filed 01/19/2021; Published 11/23/2023), hereinafter Brown in view of Kochenderfer (Kochenderfer, James N., et al. Journal of immunotherapy 32.7 (2009): 689-702.), hereinafter Kochenderfer in view of Ochi (US-12241061-B2; Filed 02/04/2020; Published 03/04/2025), hereinafter Ochi.
Minagawa in view of Boyd and Song make obvious the limitations of claim 1 and 20 as set forth above. Minagawa and Boyd do not teach SEQ ID NOs: 1, 7, 22, 24, 6, and 20 of claims 27 and 28. However, Boyd teaches the CAR comprises a signal peptide, an extracellular domain that comprises scFV, a hinge region that comprises CD8 or CD28, a transmembrane domain derived from the transmembrane regions of CD28 or CD8, an intracellular signaling domain derived from CD3-zeta signaling domain, and a co-stimulatory domain comprises CD28 (page 42, 00128 – 00129; page 43, 00129; page 44, 00130 – 00132; page 45, 00133; page 46, 00135).
Regarding SEQ ID NOs: 1, 24, and 6 of claims 27 and 28, Brown teaches a CAR sequence comprising the signal peptide sequence MLLLVTSLLLCELPHPAFLLIP that is SEQ ID NO: 1 of claims 27 and 28; the transmembrane domain sequence FWVLVVVGGVLACYSLLVTVAFIIFWV that is SEQ ID NO: 24 of claims 27 and 28, and the intracellular signaling domain sequence RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR that is SEQ ID NO: 6 of claims 27 and 28 (Figure 10A; page 7, 0055; Table 2, SEQ ID NO: 14; Table 3, SEQ ID NO: 21; page 9, 0067 – 0068).
Regarding SEQ ID NO: 22 of claims 27 and 28, the CAR of Figure 10A of Brown includes a spacer comprising the hinge of IgG4 (Table 1). However, Brown teaches a variety of spacers can be used including a CD28 hinge comprising the sequence IEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKP (page 2, 0018; Table 1, SEQ ID NO: 6) that is SEQ ID NO: 22.
Regarding SEQ ID NO: 20 of claims 27 and 28, the CAR of Figure 10A includes a co-stimulatory domain CD28gg (SEQ ID NO: 23) that share 95% sequence identity with SEQ ID NO: 20 (claim 27) as shown below where Sequence 1 is SEQ ID NO: 23 of Brown and Sequence 2 is SEQ ID NO: 20 of claims 27 and 28.
PNG
media_image1.png
98
713
media_image1.png
Greyscale
Brown teaches the co-stimulatory domain can be RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS (page 3, 0024; page 4, 0025, Table 3, SEQ ID NO: 22) that is SEQ ID NO: 20 of claims 27 and 28.
Brown does not teach the extracellular domain comprises SEQ ID NO: 7 of claims 27 and 28. The CAR of Figure 10A of Brown comprises the extracellular domain of IL-13 (page 1, 0005 – 0007). Brown teaches the CAR may be useful for treating cancers where IL12Rα2 is overexpressed using T cells expressing the nucleic acid encoding the CAR (page 1, 0004; page 2, 0009 – 0012). Brown teaches T cells expressing the CAR have antitumor activity in vivo (page 11, 0083; Figure 7 – 8).
Kochenderfer teaches the FMC63-28Z CAR consists of an anti-CD19 scFv (FMC63), a CD28 hinge that comprises SEQ ID NO: 22 of claims 27 and 28, and a CD3 zeta intracellular signaling domain (page 690, left col. paragraph 3; Figure 1A). Kochenderfer teaches in comparison to another FMC63 CAR comprising a CD8 hinge (FMC63-CD828BBZ), FMC63-28Z CAR T-cells produced greater amounts of IFNγ in response to CD19-expressing cells (page 695, right col. paragraph 3). Kochenderfer teaches FMC63-28Z CAR killed allogeneic primary CLL cells (page 696, left col.). Kochenderfer teaches higher expression of the scFv and higher cytokine expression with FMC63-28Z-expressing T cells compared to FMC63-CD828BBZ CAR T-cells (page 698, right col.). Kochenderfer teaches CD19 is a promising target for antigen-specific T cell therapies because CD19 is expressed on most malignant B cells (page 690, left col. paragraph 1; page 700, left col. paragraph 2). Kochenderfer teaches transducing T cells with FMC63-28Z CAR virus and proliferating the resulting cells to obtain sufficient quantities for clinical adoptive T cell transfer can easily be adapted to GMP conditions (page 696, right col. paragraph 1; Figure 3; page 699, right col. paragraph 2; page 700, right col. last paragraph). Kochenderfer does not teach SEQ ID NO:7 of claims 27 and 28.
Regarding SEQ ID NO: 7 of claims 27 and 28, Ochi teaches a FMC63 CAR comprising SEQ ID NO: 201 which is the scFv of the CD19-specific antibody, FMC63HL, in Example 3 (col. 249, lines 15 – 38). SEQ ID NO: 201 of Ochi is SEQ ID NO: 7 of claims 27 and 28.
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Minagawa regarding iPSCs and T cells derived therefrom comprising an exogenously inserted αβ TCR with the teachings of Boyd regarding an iPSC cell expressing a rearranged αβ TCR that recognizes a non-human antigen and a nucleotide encoding a CAR with the teachings of Song regarding a public TCR with the teachings of Brown regarding sequences of a CAR signal peptide, hinge region, transmembrane domain, intracellular signaling domain, and co-stimulatory domain with the teachings of Kochenderfer regarding the FMC63-28Z CAR with the teachings of Ochi regarding the sequence of FMC63 to arrive at the claimed iPSC where the CAR comprises the signal peptide that is SEQ ID NO: 1, the extracellular domain that is SEQ ID NO: 7, the hinge region that is SEQ ID NO: 22, the transmembrane domain that is SEQ ID NO: 24, the intracellular domain that is SEQ ID NO: 6, and the co-stimulatory domain that is SEQ ID NO: 20. One would have been motivated to combine the teachings of Minagawa, Boyd, Song, Kochenderfer, and Ochi for iPSCs that can differentiate to T cells to treat B cell malignancies in large quantities needed for clinical trials where the T cells do not cause graft-versus-host disease as Minagawa teaches in combination with antigen-specific receptor transduction, iPSCs are thought to be a good source of cancer antigen-specific T cells for allogeneic cancer immunotherapy and Boyd teaches there is an urgent and ongoing need to develop improved systemic therapies for cancers and T cells are clearly potentially a major weapon against cancer and Boyd teaches adoptive transfer of cells directed to “self” antigens may result in outcomes similar to graft versus host disease and Kochenderfer teaches CD19 is a promising target for antigen-specific T cell therapies because CD19 is expressed on most malignant B cells. One would have a reasonable expectation of success in combining the teachings as Kochenderfer teaches producing FMC63-28Z CAR-T cells to obtain sufficient quantities for clinical adoptive T cell transfer can easily be adapted to GMP conditions and FMC63-28Z CAR killed primary CLL cells.
Applicant’s Arguments/ Response to Arguments
34. Applicant Argues: On page 16, paragraph 3, Applicant asserts that it is only through hindsight reconstruction that one can come up with the combined features of the present invention and given the highly unpredictable nature of the technology, one skilled in the art would not have a reasonable expectation of success in combining the references to achieve the present invention. Applicant asserts that the mere fact that the references can be combined or modified does not render the resultant combination obvious unless the results would have been predictable to one of ordinary skill in the art.
Response to Argument: Regarding Applicant’s assertion of hindsight reconstruction, this is not found persuasive because it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant’s disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Regarding the predictability of combining the references, Applicant has amended claim 1 to recite “the rearranged αβ TCR is an exogenously inserted, public TCR”. Therefore, the previous rejection has been withdrawn and a new rejection set forth combining the teachings of Minagawa, Boyd, and Song. Minagawa teaches iPSCs and T cells derived therefrom comprising a polynucleotide encoding a TCR and a method for making said cells (page 82 – 83, Methods) and Boyd teaches a genetically modified mammalian iPSC or T cell differentiated therefrom where the iPSC has been transduced with rearranged TCR genes and comprises a nucleic acid molecule encoding a CAR (page 34, 00106 – 00108; page 38 – 39, 00120; page 40, 00122; page 71, 00214) and Boyd teaches transduction of iPSCs with a CAR in Example 7 (page 92, 00299 – 00301). Further, Minagawa teaches in combination with antigen-specific receptor transduction, iPSCs are thought to be a good source of cancer antigen-specific T cells for allogeneic cancer immunotherapy (page 81, Introduction). Solely to rebut Applicant’s argument, Ueda (Ueda, T et. al. In vitro differentiation of T-cells: methods and protocols. New York, NY: Springer New York, 2019. 85-91) teaches a method to generate CAR-engineered iPSCs and differentiate them to T cells (page 86, para. 1; page 89, 3.3 and 3.4; page 90, 3.4). Further, Ueda teaches the importance of selecting the appropriate promoter for engineering iPSCs and for T cell differentiation from iPSCs (page 87, last para; Figure 1; page 88, para. 1). Therefore, an iPSC or a T cell derived therefrom comprising an exogenously inserted nucleic acid encoding a recombinant rearranged αβ T cell receptor and a nucleotide encoding a CAR would have been predictable to one or ordinary skill in the art based on the teachings of Minagawa, Boyd, and Ueda.
Applicant Argues: On page 17, paragraph 1, Applicant asserts that the unexpected aspect of the results presented in Applicant’s disclosure primarily stems from the unpredictability of producing highly functional iPSC derived T cells following gene editing and before the invention no one in the prior art had successfully engineered iPSC cells and differentiated them into functional αβ T cells in the manner of the invention.
Response to Argument: This is not found persuasive because Minagawa teaches iPSCs engineered to express a TCR can be differentiated to functional T cells (page 83, Note 7); Boyd teaches a method of induction of human T cells from iPSCs in Example 3 (page 86, 00272 – 00274; page 87; page 88, 00282 – 00284); and Ueda teaches differentiation of CAR-engineered iPSCs to T cells (page 89 – 90, 3.4). Solely to rebut Applicant’s arguments, Ochi (Ochi, T et. al. In Vitro Differentiation of T-Cells: Methods and Protocols. New York, NY: Springer New York, 2019. 27-39.) teaches to promote both TCR-T-cell therapy and CAR-T-cell therapy and translate them into the clinic, it requires optimal generation of gene-modified T cells and evaluation of their target-specific reactivity in vitro (page 28, para. 2). Ochi teaches a method of genetically engineering antigen-specific receptor-transduced T cells and expansion of these T cells, and that the resulting T cells are functional (page 31, 3.2 and 3.3; Figure 1 – 2). Therefore, engineering iPSCs and differentiating them into functional αβ T cells would have been predictable based on the teachings of Minagawa, Boyd, Ueda, and Ochi.
Applicant Argues: On page 17, paragraph 3 and page 18, paragraph 4 and page 19, paragraph 2 and 4, Applicant asserts that neither Song nor Lehner nor Valentine nor Brown nor Kochenderfer, nor Ochi teach or suggest an iPSC capable of differentiating to a T cell as recited in claim 1. On page 18, para. 1, Applicant asserts that one of ordinary skill in the art would not have been motivated to introduce a public TCR into the iPSCs of Boyd with a reasonable expectation of success to obtain an iPSC that can be used for efficient generation of functional αβ T cells. On page 18, para. 4, Applicant asserts
Response to Argument: This is not found persuasive because in the new rejection set forth above, Minagawa, Boyd, and Song combined make obvious the limitations of amended claim 1. One would have been motivated to combine the teachings of Minagawa, Boyd and Song because Minagawa teaches in combination with antigen-specific receptor transduction, iPSCs are thought to be a good source of cancer antigen-specific T cells for allogeneic cancer immunotherapy and Boyd teaches there is an urgent and ongoing need to develop improved systemic therapies for cancers and T cells are clearly potentially a major weapon against cancer. Further motivation comes from the following: (1) Boyd teaches CAR-T cells can be prior selected from donors expressing a homozygous HLA haplotype expressed widely in the population thereby providing a means of generating a bank of cells which exhibit broad donor suitability (page 5, 0013); (2) Boyd teaches generation of an iPSC from a T cell which exhibits TCR specificity directed to an antigen of interest means that the gene rearrangements for that TCR specific for the cancer antigen will be embedded in the iPSC and all T cells induced from that iPSC will retain the anti-cancer TCR specificity (page 5, 0013); (3) Boyd teaches transfecting such iPSCs with a CAR enables the production of T cells with dual specificity for the antigen to which the CAR is directed and a TCR directed to the antigen to which the original T cell was directed to (page 5, 0013); (4) Boyd teaches adoptive transfer of cells directed to “self” antigens may result in outcomes similar to graft versus host disease (page 47, 00139).
Applicant Argues: On page 20, last paragraph and page 21, paragraph 1, Applicant requests withdrawal of the provisional nonstatutory double patenting rejection upon finding the application otherwise allowable.
Response to Argument: The rejection is maintained because the amended claims are rejected over art as set forth above.
Conclusion
No claims allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZANNA M BEHARRY whose telephone number is (571)270-0411. The examiner can normally be reached Monday - Friday 8:45 am - 5:45 pm.
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, Peter Paras can be reached at (571)272-4517. 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.
/Z.M.B./Examiner, Art Unit 1632
/MARCIA S NOBLE/Primary Examiner, Art Unit 1632