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 .
2. Applicant’s response filed on 08/03/2026 is acknowledged.
3. Claims 2-21 are pending.
4. Applicant's election with traverse of Group I and the species of
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in the reply filed on 08/03/2026 is acknowledged. The traversal is on the ground(s) that
With respect to all claims, Applicant respectfully submits that the Examiner has not shown a requisite search burden. Restriction of claims pursuant to 35 U.S.C. § 121 is improper unless there is a serious search burden. M.P.E.P. § 803(I). Here, the Examiner has not cited evidence showing that the present claims have achieved a separate status in the art or would require a different field of search. See id. § 808.02. As such, the Examiner has not established that a serious burden exists so as to authorize restriction pursuant to 35 U.S.C. § 121.
This is not found persuasive because as every scientist knows nucleic acids, T cells and NK cells are different. A piece of art which teaches the cells and not the nucleic acids could not be used to reject the nucleic acids. A piece of art that does not teach nucleic acids cannot be used to reject the claims directed to a method of introducing nucleic acids into cells. In addition to these basic facts, the claims have different considerations under 112. The mere suggestion that the full scope of these claims would not be a burden to search implies a misunderstanding of how claims are searched and the time and resources allowed for searching of claims at the US Patent Office. STIC searches 10 total sequences per application at a time. The elected invention is 18 sequences.
The requirement is still deemed proper and is therefore made FINAL.
5. Claims 13-16 and 20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected Groups, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 08/03/2026.
6. Claims 2-12, 17-19 and 21 are currently under consideration as they read on the elected species and the species of the prior art cited.
7. Applicant’s IDS documents filed on 04/27/2023, 11/10/2023, 02/08/2024 and 08/03/2026 have been considered.
8. REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The incorporation by reference paragraph required by 37 CFR 1.834(c)(1), 1.835(a)(2), or 1.835(b)(2) is missing, defective or incomplete.
Required response - Applicant must:
Amend the date in the incorporation by reference paragraph since the XML file was amended on 08/07/2023.
• Provide a substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
9. The drawings are objected to because
A. Figures 9A-9D, Figures 20A-20C, Figure 29A, Figure 30A, Figure 31A, Figure 32A, Figure 32B, Figure 33A-33B, and Figure 34A are illegible.
B. Figure 107D does not show required information. The brief description of the drawing discloses “Figure 107D shows the concentration of secreted IL-15 assayed by R&D Systems Quantikine IL-15 ELISA kit according to the manufacturer's instructions. [00654] The results show comparable # of CD8+TCR+ T cells transduced with Construct #5 and #6 as compared to TCR-only transduced controls. T cells transduced with Construct #5 were particularly efficient at producing sIL15 (see FIG. 107D).” but the actual drawing is not labeled in any way.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
10. 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.
11. Claims 2-12, 17-19 and 21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 and 21-27 of copending Application No. 18/309,080 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1-13 and 21-27 are directed to A nucleic acid encoding a polypeptide comprising SEQ ID NO: 311, 313, or 315 or a polypeptide at least about 95% identical to SEQ ID NO: 311, 313, or 315, said nucleic acid optionally comprising SEQ ID NO: 312, 314, or 316, or a sequence at least about 95% identical to SEQ ID NO: 312, 314, or 316 of claim 1; encoding (i) a polypeptide comprising SEQ ID NO: 307 fused directly or indirectly to an N terminus of a polypeptide comprising any of SEQ ID NO: 311, 313, or 315, or (ii) a polypeptide at least about 95% identical to SEQ ID NO: 307 fused directly or indirectly to a polypeptide at least about 95% identical to any of SEQ ID NO: 311, 313, or 315 of claim 2; encoding a polypeptide comprising SEQ ID NO: 317, 321, 325, 327, 329, 331, or 333, or a polypeptide at least about 95% identical to SEQ ID NO: 317, 321, 325, 327, 329,331, or 333,wherein the nucleic acid optionally comprises SEQ ID NO: 318, 320, 322, 324, 326, 328, 330, 332, or 334 or a sequence at least about 95%at least about 98%2 or a polypeptide at least about 95% 2 or a sequence at least about 95% identical to SEQ ID NO: 338, 342, 346, 348, 350, 352, or 354 of claim 6; further comprising a nucleic acid encoding (a) at least one TCR polypeptide comprising an a chain and a p chain,(b) at least one CD8 polypeptide comprising (i) an a chain, (ii) a p chain, or (iii) both an a chain and a p chain, or (c) at least one TCR polypeptide comprising an a chain and a 3 chain and at least one CD8 polypeptide comprising (i) an a chain, (ii) a p chain, or (iii) both an a chain and a p chain of claim 7; comprising a nucleic acid at least about 95% identical to the nucleic acid of SEQ ID NO: 267, 269, 271, 273, 275, 277, 279, 281, 283, 285, 287, 289, 291, 295, 297, 299, 301, 438, 439, 440, 441, 442, 443, 444, 445, 446, or 447 of claim 8; wherein the TCR a chain and the TCR 3 chain are selected from SEQ ID NO: 15 and 16, 17 and 18, 19 and 20, 21 and 22, 23 and 24, 25 and 26, 27 and 28, 29 and 30, 31 and 32, 33 and 34, 35 and 36, 37 and 38, 39 and 40, 41 and 42, 43 and 44, 45 and 46, 47 and 48, 49 and 50, 51 and 52, 53 and 54, 55 and 56, 57 and 58, 59 and 60, 61 and 62, 63 and 64, 65 and 66, 67 and 68, 69 and 70, 71 and 303, 304 and 74, 75 and 76, 77 and 78, 79 and 80, 81 and 82, 83 and 84, 85 and 86, 87 and 88, 89 and 90, and 91 and 92;wherein the CD8a chain is SEQ ID NO: 7, 258, 259, 262, or a variant thereof; and wherein, if present, the CD83 chain is SEQ ID NO: 8, 9, 10, 11, 12, 13, or 14 of claim 9; vector comprising Formula III or Formula TV:5'-N1-L1-N2-L2-N3-L3-N4-L4-NS-3' [III] 5'-NS-L1-N1-L2-N2-L3-N3-L4-N4 -3' [IV], wherein N1 comprises a nucleic acid encoding a CD83 chain and is present or absent, wherein, if present, the CD83 chain is SEQ ID NO: 8, 9, 10, 11, 12, 13, or 14, N2 comprises a nucleic acid encoding a CD8a chain, wherein the CD8a chain is SEQ ID NO: 7, 258, 259, 262, or a variant thereof, N3 comprises a nucleic acid encoding a TCR3 chain, N4 comprises a nucleic acid encoding a TCRa chain, wherein the TCR a chain and the TCR 3 chain are selected from SEQ ID NO:15 and 16, 17 and 18, 19 and 20, 21 and 22, 23 and 24, 25 and 26, 27 and 28, 29 and 30, 31 and 32, 33 and 34, 35 and 36, 37 and 38, 39 and 40, 41 and 42, 43 and 44, 45 and 46, 47 and 48, 49 and 50, 51 and 52, 53 and 54, 55 and 56, 57 and 58, 59 and 60, 61 and 62, 63 and 64, 65 and 66, 67 and 68, 69 and 70, 71 and 303, 304 and 74, 75 and 76, 77 and 78, 79 and 80, 81 and 82, 83 and 84, 85 and 86, 87 and 88, 89 and 90, and 91 and 92, and NS comprises a nucleic acid encoding an IL-15/IL-15Ra fusion polypeptide comprising SEQ ID NO: 317, 321, 325, 327, 329, 331, or 333s or a polypeptide at least about 95% identical to SEQ ID NO:317, 321, 325, 327, 329, 331, or 333, and wherein L1-L4 each comprises a nucleic acid encoding at least one linker, wherein each of L1-L4 is independently the same or different, and wherein each of L1-L4 is independently present or absent of claim 10; wherein the vector is a viral vector or a non-viral vector of claim 11; wherein the viral vector is selected from adenoviruses, poxviruses, alphaviruses, arenaviruses, flaviviruses, rhabdoviruses, retroviruses, lentiviruses, herpesviruses, paramyxoviruses, picornaviruses, and any combination thereof of claim 12; method of preparing T cells and/or natural killer cells for immunotherapy comprising: isolating T cells and/or natural killer cells from a blood sample of a human subject, activating the isolated T cells and/or natural killer cells, transducing the activated T cells and/or natural killer cells with the nucleic acid of transducing the activated T cells and/or natural killer cells with the nucleic acid of expanding the transduced T cells and/or natural killer cells of claim 13; wherein the polypeptide comprises SEQ ID NO: 311, 313, or 315 of claim 21; wherein the polypeptide comprises SEQ ID NO: 307 fused directly or indirectly to an N terminus of a polypeptide comprising any of SEQ ID NO: 311, 313, or 315 of claim 22; wherein the polypeptide comprises SEQ ID NO: 317, 321, 325, 327, 329, 331, or 333 of claim 23; wherein the nucleic acid encodes a signal peptide directly or indirectly fused to an N terminus of SEQ ID NO: 317, 321, 325, 327, 329, 331, or 333 of claim 24; wherein the signal peptide comprises SEQ ID NO: 367, or wherein the nucleic acid comprises SEQ ID NO: 368 of claim 25; wherein the polypeptide comprises SEQ ID NO: 337, 341, 345, 347, 349, 351, or 353 of claim 26; comprising SEQ ID NO: 267, 269, 271, 273, 275, 277, 279, 281, 283, 285, 287, 289, 291, 295, 297, 299, 301, 438, 439, 440, 441, 442, 443, 444, 445, 446, or 447 of claim 27;
Instant SEQ ID NO:311 is 100% sequence identical to reference SEQ ID NO:305 and they are both wild-type IL-15. Reference SEQ ID NO:307 is the mature wild type IL-15 polypeptide corresponding to amino acids 49-162 of instant SEQ ID NO:311/reference SEQ ID NO:2. It would have been obvious to have encoded the full length wild type IL-15 rather than the mature wild type IL-15 in view of the reference teachings.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
12. Claims 2-12, 17-19 and 21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent 11,975,025 (PTO-892; Reference A) in view of WO 2021/040736 (PTO-892; Reference N).
A vector comprising a nucleotide sequence Si encoding a CD8a polypeptide, a nucleotide sequence S2 encoding a CD8p3 polypeptide, a nucleotide sequence S3 encoding a T cell receptor (TCR)a polypeptide, and a nucleotide sequence S4 encoding a TCRp3 polypeptide, wherein the nucleotide sequences are arranged in tandem in a 5' to 3' orientation of S2-S 1-S4-S3 of claim 1; wherein the CD8a polypeptide comprises the amino acid sequence of SEQ ID NO: 11 and the CD8p3 polypeptide comprises the amino acid sequence of SEQ ID NO: 12 of claim 2; further comprising a nucleotide sequence S5 encoding a 2A peptide and a nucleotide sequence S6 encoding a linker peptide, wherein S5 and S6 are positioned between 51 and S2, 51 and S4, and/or S3 and S4 of claim 3; wherein the 2A peptide is selected from P2A (SEQ ID NO: 3), T2A (SEQ ID NO: 4), E2A (SEQ ID NO: 5), or F2A (SEQ ID NO: 6) of claim 4; wherein the linker peptide is GSG or SGSG (SEQ ID NO: 8) of claim 5; further comprising a nucleotide sequence S7 encoding a furin peptide (SEQ ID NO: 2), wherein S7 is positioned between 51 and S2, 51 and S4, and/or S3 and S4 of claim 6; a method of preparing T cells for immunotherapy comprising isolating T cells from a blood sample of a human subject, activating the isolated T cells, transducing the activated T cells with the vector of transducing the activated T cells with the vector of expanding the transduced T cells of claim 7; wherein the T cells are isolated from a leukapheresis human sample of claim 8; wherein the T cells are activated in the presence of an aminobisphosphonate and wherein the aminobisphosphonate is optionally selected from pamidronic acid, alendronic acid, zoledronic acid, risedronic acid, ibandronic acid, incadronic acid, a salt of any of the foregoing and/or a hydrate thereof of claim 9; wherein the activating is further in the presence of human recombinant interleukin 2 (IL-2) and human recombinant interleukin 15 (IL-15) of claim 10; wherein the expanding is in the presence of IL-2 and IL- 15 of claim 11; wherein the T cells are yS T cells of claim 12; further comprising a nucleotide sequence S5 encoding a 2A peptide and a nucleotide sequence S6 encoding a linker peptide, wherein S5 and S6 are positioned between Si and S2, Sl and S4, and/or S3 and S4 of claim 12; wherein the 2A peptide is selected from P2A (SEQ ID NO: 3), T2A (SEQ ID NO: 4), E2A (SEQ ID NO: 5), or F2A (SEQ ID NO: 6) of claim 13; wherein the linker peptide is GSG or SGSG (SEQ ID NO: 8) of claim 14; and further comprising a nucleotide sequence S7 encoding a furin peptide (SEQ ID NO: 2), wherein S7 is positioned between S1 and S2, S1 and S4, and/or S3 and S4 of claim 15.
The claimed invention differs from the prior art in the recitation of the nucleic acid of instant SEQ ID NO:310 encoding instant SEQ ID NO:9.
WO 2021/040736 teaches transducing T cells with the nucleic acid of reference SEQ ID NO:852 encoding IL-12 as the payload which comprises instant SEQ ID NO:310 to treat cancer. (In particular, paragraph [0296], whole document).
It would have been obvious one of ordinary skill in the art at the time of invention to have added instant SEQ ID NO:310 to the nucleic acid to treat cancer.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary
13. Claims 2-12, 17-19 and 21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18/590,008 (reference application) in view of WO 2021/040736 (PTO-892; Reference N).
Claims 1-20 of 18/590,008 are directed to a T cell transduced with a vector comprising a nucleotide sequence S1 encoding a CD8α polypeptide, a nucleotide sequence S2 encoding a CD8β polypeptide, a nucleotide sequence S3 encoding a T cell receptor (TCR)α polypeptide, and a nucleotide sequence S4 encoding a TCRβ polypeptide, wherein the nucleotide sequences are arranged in tandem in a 5’ to 3’ orientation of S2-S1-S4-S3; further comprising a nucleotide sequence S5 encoding a 2A peptide and a nucleotide sequence S6 encoding a linker peptide, wherein S5 and S6 are positioned between S1 and S2, S1 and S4, and/or S3 and S4; wherein the 2A peptide is selected from P2A (SEQ ID NO: 3), T2A (SEQ ID NO: 4), E2A (SEQ ID NO: 5), or F2A (SEQ ID NO: 6); wherein the linker peptide is GSG or SGSG (SEQ ID NO: 8); further comprising a nucleotide sequence S7 encoding a furin peptide (SEQ ID NO: 2), wherein S7 is positioned between S1 and S2, S1 and S4, and/or S3 and S4; wherein the T cell comprises an αβ T cell, a γδ T cell, and/or a natural killer T cell; a composition comprising the T cell of claim 1; further comprising an adjuvant selected from anti-CD40 antibody, imiquimod, resiquimod, GM-CSF, cyclophosphamide, sunitinib, bevacizumab, atezolizumab, interferon-alpha, interferon-beta, CpG oligonucleotides and derivatives, poly-(I:C) and derivatives, RNA, sildenafil, particulate formulations with poly(lactide co-glycolide) (PLG), virosomes, interleukin (IL)-1, IL-2, IL-4, IL-7, IL-12, IL-13, IL-15, IL-21, and IL-23; wherein the adjuvant is IL-2; wherein the adjuvant is IL-15; a method of treating a patient who has cancer, comprising administering to the patient a composition of claim 7, and wherein the T cell kill cancer cells that present a peptide in a complex with an MHC molecule on the surface, wherein the cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, melanoma, liver cancer, breast cancer, uterine cancer, Merkel cell carcinoma, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, urinary bladder cancer, kidney cancer, leukemia, ovarian cancer, esophageal cancer, brain cancer, gastric cancer, and prostate cancer; a method of eliciting an immune response in a patient who has cancer, comprising administering to the patient a composition of claim 7, wherein the T cell kill cancer cells that present a peptide in a complex with an MHC molecule on the surface, wherein the cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, melanoma, liver cancer, breast cancer, uterine cancer, Merkel cell carcinoma, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, urinary bladder cancer, kidney cancer, leukemia, ovarian cancer, esophageal cancer, brain cancer, gastric cancer, and prostate cancer; a method of preparing a T cell for immunotherapy, comprising activating the T cell in the presence of a statin, transducing the activated T cell with a vector comprising a nucleotide sequence S1 encoding a CD8α polypeptide, a nucleotide sequence S2 encoding a CD8β polypeptide, a nucleotide sequence S3 encoding a T cell receptor (TCR)α polypeptide, and a nucleotide sequence S4 encoding a TCRβ polypeptide, wherein the nucleotide sequences are arranged in tandem in a 5’ to 3’ orientation of S2-S1-S4-S3, and expanding the transduced T cell; further comprising a nucleotide sequence S5 encoding a 2A peptide and a nucleotide sequence S6 encoding a linker peptide, wherein S5 and S6 are positioned between S1 and S2, S1 and S4, and/or S3 and S4; wherein the 2A peptide is selected from P2A (SEQ ID NO: 3), T2A (SEQ ID NO: 4), E2A (SEQ ID NO: 5), or F2A (SEQ ID NO: 6); wherein the linker peptide is GSG or SGSG (SEQ ID NO: 8); further comprising a nucleotide sequence S7 encoding a furin peptide (SEQ ID NO: 2), wherein S7 is positioned between S1 and S2, S1 and S4, and/or S3 and S4; wherein the T cell comprises an αβ T cell, a γδ T cell, and/or a natural killer T cell; and wherein the vector is pseudotyped with an envelope protein of vesicular stomatitis virus (VSV-G).
The claimed invention differs from the prior art in the recitation of the nucleic acid of instant SEQ ID NO:310 encoding instant SEQ ID NO:9.
The claimed invention differs from the prior art in the recitation of the nucleic acid of instant SEQ ID NO:310 encoding instant SEQ ID NO:9.
WO 2021/040736 teaches transducing T cells with the nucleic acid of reference SEQ ID NO:852 encoding IL-12 as the payload which comprises instant SEQ ID NO:310 to treat cancer. (In particular, paragraph [0296], whole document).
It would have been obvious one of ordinary skill in the art at the time of invention to have added instant SEQ ID NO:310 to the nucleic acid to treat cancer.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary
14. Claims 2-12, 17-19 and 21 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush groupings of the claims is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: T cells and NK cells transduced with nucleic acids encoding IL-15, IL-12, and IL-18 of SEQ ID NOs 311, 305, 307, 309 and 315 do not have the same structure or significant structural similarity and do not have a common use. The same can be said for the alternative nucleic acids encoding SEQ ID NOs 311, 305, 307, 309 and 315 of in claim 2; the alternatives in claims 3-5 do not have the same structure or common use; and the “adjuvants” alternatives in claim 19 do not have the same structure or common use particularly because the molecules recited have no common effect induced.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
15. 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.
16. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
17. 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.
18. Claims 2-12, 17-19 and 21 are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over US Patent Application Publication 2020/376031 (PTO-892; Reference B)
US Patent Application Publication 2020/376031 teaches in the claims
a vector comprising a nucleotide sequence S1 encoding a CD8a polypeptide, a nucleotide sequence S2 encoding a CD8P polypeptide, a nucleotide sequence S3 encoding a T cell receptor (TCR)a polypeptide, and a nucleotide sequence S4 encoding a TCR3 polypeptide, wherein the nucleotide sequences are arranged in tandem in a 5' to 3' orientation selected from S1-S2-S3-S4, S1-S2-S4-S3, S2-S1-S3-S4, S2-S1-S4-S3, S3-S4- S1-S2, S3-S4-S2-S1, S4-S3-S1-S2, and S4-S3-S2-S1.
wherein the nucleotide sequences are arranged in tandem in a 5' to 3' orientation selected from S1-S2-S3-S4, S1-S2-S4-S3, S2-S1-S3-S4, and S2-S1-S4- S3.
wherein the nucleotide sequences are arranged in tandem in a 5' to 3' orientation of S2-S1-S4-S3.
wherein the CD8aP polypeptides comprise amino acid sequences at least 90% identical to SEQ ID NO: 11 and at least 90% identical to SEQ ID NO: 12.
wherein the TCRaP polypeptides comprise amino acid sequences at least 90% identical to the amino acid sequences selected from SEQ ID NO: 13 and 14, 15 and 16, 17 and 18, 19 and 20, 21 and 22, 23 and 24, 25 and 26, 27 and 28, 29 and 30, 31 and 32, 33 and 34, 35 and 36, 37 and 38, 39 and 40, 41 and 42, 43 and 44, 45 and 46, 47 and 48, 49 and 50, 51 and 52, 53 and 54, 55 and 56, 57 and 58, 59 and 60, 61 and 62, 63 and 64, 65 and 66, 67 and 68, 69 and 70, 71 and 72, 73 and 74, 75 and 76, 77 and 78, 79 and 80, 81 and 82, 83 and 84, 85 and 86, 87 and 88, or 89 and 90.
wherein the TCRap polypeptides comprise a amino acid sequences at least 90% identical to SEQ ID NO: 13 and at least 90% identical to SEQ ID NO:14.
further comprising a nucleotide sequence S5 encoding a 2A peptide and a nucleotide sequence S6 encoding a linker peptide, wherein S5 and S6 are positioned between S1 and S2, S1 and S3, S1 and S4, S2 and S3, S2 and S4, and/or S3 and S4.
wherein the 2A peptide is selected from P2A (SEQ ID NO: 3), T2A (SEQ ID NO: 4), E2A (SEQ ID NO: 5), or F2A (SEQ ID NO: 6).
wherein the linker peptide is GSG or SGSG (SEQ ID NO: 8).
further comprising a nucleotide sequence S7 encoding a furin peptide (SEQ ID NO: 2), wherein S7 is positioned between S1 and S2, S1 and S3, S1 and S4, S2 and S3, S2 and S4, and/or S3 and S4.
a vector comprising a first nucleotide sequence S1 encoding a protein Z1, a second nucleotide sequence S2 encoding a protein Z2, a third nucleotide sequence S3 encoding a protein Y1, and a fourth nucleotide sequence S4 encoding a protein Y2, wherein Z1 and Z2 form a first dimer and Y1 and Y2 form a second dimer, wherein the first dimer Z1 Z2 is structurally different from the second dimer Y1 Y2, wherein the vector is in a gene delivery system that is used for adaptive cellular therapy.
wherein the S1, S2, S3, and S4 are arranged in tandem in a 5' to 3' orientation selected from S1-S2-S3-S4, S1-S2-S4-S3, S1-S3-S2-S4, S1-S3-S4-S2, S1-S4-S3-S2, S1-S4-S2-S3, S2-S1-S3-S4, S2-S1-S4-S3, S2-S3-S1-S4, S2-S3-S4-S1, S2- S4-S3-S1, S2-S4-S1-S3, S3-S1-S2-S4, S3-S1-S4-S2, S3-S2-S1-S4, S3-S2-S4-S1, S3-S4- S1-S2, S3-S4-S2-S1, S4-S1-S2-S3, S4-S1-S3-S2, S4-S2-S1-S3, S4-S2-S3-S1, S4-S3-S1- S2, or S4-S3-S2-S1.
further comprising a fifth nucleotide sequence S5 encoding a 2A peptide and a sixth nucleotide sequence S6 encoding a linker peptide, wherein S5 and S6 are positioned between S1 and S2, S1 and S3, S1 and S4, S2 and S3, S2 and S4, and/or S3 and S4.
wherein the 2A peptide is selected from P2A (SEQ ID NO: 3), T2A (SEQ ID NO: 4), E2A (SEQ ID NO: 5), or F2A (SEQ ID NO: 6).
wherein the linker peptide is GSG or SGSG (SEQ ID NO: 8).
further comprising a post-transcriptional regulatory element (PRE) sequence selected from a Woodchuck PRE (WPRE) or a hepatitis B virus (HBV) PRE (HPRE).
further comprising a promoter sequence that controls the transcription of the S2-S7, wherein the promoter sequence is selected from cytomegalovirus (CMV) promoter, phosphoglycerate kinase (PGK) promoter, myelin basic protein (MBP) promoter, glial fibrillary acidic protein (GFAP) promoter, modified MoMuLV LTR containing myeloproliferative sarcoma virus enhancer (MNDU3), Ubiqitin C promoter, EF-1 alpha promoter, or Murine Stem Cell Virus (MSCV) promoter.
wherein the orientation is S2-S1-S4-S3.
comprising the sequence selected from PTE WPRE (SEQ ID NO: 91), TPE WPRE (SEQ ID NO: 92), or PTE fn WPRE (SEQ ID NO: 93).
wherein the orientation is S4-S3-S2-S1.
comprising the sequence PTE CD8 TCR WPRE (SEQ ID NO: 94).
a viral vector selected from adenoviruses, poxviruses, alphaviruses, arenaviruses, flaviruses, rhabdoviruses, retroviruses, lentiviruses, herpesviruses, paramyxoviruses, or picornaviruses.
wherein the vector is pseudotyped with an envelope protein of a virus selected from the native feline endogenous virus (RD114), a chimeric version of RD114 (RD114TR), gibbon ape leukemia virus (GALV), a chimeric version of GALV (GALV-TR), amphotropic murine leukemia virus (MLV 4070A), baculovirus (GP64), vesicular stomatitis virus (VSV-G), fowl plague virus (FPV), Ebola virus (EboV), or baboon retroviral envelope glycoprotein (BaEV), lymphocytic choriomeningitis virus (LCMV).
a method of preparing T cells for immunotherapy comprising isolating T cells from a blood sample of a human subject, activating the isolated T cells in the presence of an aminobisphosphonate, transducing the activated T cells with the vector and expanding the transduced T cells.
wherein the T cells are isolated from a leukapheresis human sample.
wherein the activating is further in the presence of human recombinant interleukin 2 (IL-2) and human recombinant interleukin 15 (IL-15).
wherein the expanding is in the presence of IL- 2 and IL-15.
wherein the T cells are yb T cells.
wherein the first dimer Z1 Z2 and the second dimer Y1Y2 are co-expressed on the surface of the expanded T cells.
a population of expanded T cells prepared by the methods
a method of treating a patient who has cancer, comprising administering to the patient a composition comprising the population of expanded T cells of claim 34, wherein the T cells kill cancer cells that present a peptide in a complex with an MHC molecule on the surface, wherein the peptide is selected from SEQ ID NO: 98-255, wherein the cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, melanoma, liver cancer, breast cancer, uterine cancer, Merkel cell carcinoma, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, urinary bladder cancer, kidney cancer, leukemia, ovarian cancer, esophageal cancer, brain cancer, gastric cancer, and prostate cancer.
wherein the composition further comprises an adjuvant.
wherein the adjuvant is selected from anti-CD40 antibody, imiquimod, resiquimod, GM-CSF, cyclophosphamide, sunitinib, bevacizumab, atezolizumab, interferon-alpha, interferon-beta, CpG oligonucleotides and derivatives, poly- (1:C) and derivatives, RNA, sildenafil, particulate formulations with poly(lactide co-glycolide) (PLG), virosomes, interleukin (IL)-1, IL-2, IL-4, IL-7, IL-12, IL-13, IL-15, IL-21, and IL-23.
A method of eliciting an immune response in a patient who has cancer, comprising administering to the patient a composition comprising the population of expanded T cells of claim 34, wherein the T cells kill cancer cells that present a peptide in a complex with an MHC molecule on the surface, wherein the peptide is selected from SEQ ID NO: 98-255, wherein the cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, melanoma, liver cancer, breast cancer, uterine cancer, Merkel cell carcinoma, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, urinary bladder cancer, kidney cancer, leukemia, ovarian cancer, esophageal cancer, brain cancer, gastric cancer, and prostate cancer.
wherein the composition further comprises an adjuvant.
wherein the adjuvant is selected from anti-CD40 antibody, imiquimod, resiquimod, GM-CSF, cyclophosphamide, sunitinib, bevacizumab, atezolizumab, interferon-alpha, interferon-beta, CpG oligonucleotides and derivatives, poly- (1:C) and derivatives, RNA, sildenafil, particulate formulations with poly(lactide co-glycolide) (PLG), virosomes, interleukin (IL)-1, IL-2, IL-4, IL-7, IL-12, IL-13, IL-15, IL-21, and IL-23.
a method of preparing T cells for immunotherapy comprising activating the T cells, transducing the activated T cells with the vector of any one of claims 11-26, and expanding the transduced T cells.
wherein the T cells comprise ap T cells, yb T cells, and/or natural killer T cells.
wherein the T cells comprise ap T cells.
wherein the activating is in the presence of an anti-CD3 antibody and an anti-CD28 antibody.
wherein the expanding is in the presence of IL-7 and IL- 15.
[00107] Some embodiments of the present disclosure may include viral vectors containing sequences encoding TCR alpha chain and TCR beta chain and sequences encoding other proteins, such as cytokines (including, but not limited to, IL-1, IL-2, IL-6, IL- 7, IL-10, IL-12, IL-15, IL-18, and IL-21), IL-15/IL-15 receptor (IL-15R) fusion protein, dominant-negative TGF beta receptor (DN TGFbRII), and/or extracellular domain of a transforming growth factor-beta receptor. In some embodiments, these coding sequences may be driven by a promotor or bidirectional promoters.
FIG. 8A shows an inducible NFAT promoter with minimal IL-2 promoter positioned at the 5' end of the sequences encoding IL-12, e.g., IL-12alpha(p35)/IL- 12beta(p40) fusion protein (SEQ ID NO: 261) to drive the expression of 12alpha(p35)/IL- 12beta(p40) fusion protein in a viral vector shown in FIG. 7.
FIG. 8B shows an inducible CD69 promoter with CNS1 and CNS2 enhancer elements positioned at the 5' end of the sequences encoding IL-12, e.g., IL-12alpha(p35)/IL-12beta(p40) fusion protein (SEQ ID NO: 262) to drive the expression of 12alpha(p35)/IL-12beta(p40) fusion protein in a viral vector shown in FIG. 7.
[00129] The ability of yb T cells to recognize a broad spectrum of antigens can be enhanced by genetic engineering of the yb T cells. In an aspect, yb T cells can be engineered to provide a universal allogeneic therapy that recognizes an antigen of choice in vivo. Genetic engineering of the yb T-cells may include stably integrating a construct expressing a tumor recognition moiety, such as ap TCR, yb TCR, chimeric antigen receptor (CAR), which combines both antigen-binding and T-cell activating functions into a single receptor, an antigen binding fragment thereof, or a lymphocyte activation domain into the genome of the isolated yb T-cell(s), a cytokine (for example, IL-15, IL-12, IL-2. IL-7. IL-21, IL-18, IL-19, IL-33, IL-4, IL-9, IL-23, or IL1P) to enhance T-cell proliferation, survival, and function ex vivo and in vivo. Genetic engineering of the isolated yb T-cell may also include deleting or disrupting gene expression from one or more endogenous genes in the genome of the isolated yb T-cells, such as the MHC locus (loci).
Reference SEQ ID NOs 261 and 262 comprise instant SEQ ID NO:310 which encodes IL-12 of instant SEQ ID NO:9.
The reference teachings anticipate the claimed invention.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
19. No claim is allowed. It does appear that the elected species is free of the art.
20. 1. Any inquiry concerning this communication or earlier communications from the examiner should be directed to NORA MAUREEN ROONEY whose telephone number is (571)272-9937. The examiner can normally be reached on M-F from 8:00am to 4:30pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner' s supervisor, Misook Yu, can be reached at telephone number (571) 272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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September 30, 2026
/Nora M Rooney/
Primary Examiner, Art Unit 1641
