DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Restriction/Election
Applicant's election with traverse of Group II in the reply filed on 08/03/2026 is acknowledged. The traversal is on the ground(s) that Group I and Group II should not be separated because they are directed to related compositions and the population of gene-edited TILs of Group II are edited by the viral vectors of the independent claim of Group I. This request is found persuasive and the restriction between Group I (claims 1, 4-6, and newly added 27-31) and Group II (claim 7, 9-11, 25 and newly added 32) is herein withdrawn and both Group I and Group II will be examined on the merits.
Claim Status
Claims 1, 4-7, 9-19, 23-32 are pending. Claims 12-19, 23-24, and 26 are withdrawn for being directed to non-elected inventions.
Claims 1, 4-7, 9-11, 25, and 27-32 are under examination.
Claim Rejections - 35 USC § 102
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 –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 4-5, 27-28, and 30-31 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Hinrichs (WO2019/157130A1, published 08/15/2019, effectively filed 09/02/2018).
The disclosure of Hinrichs is directed to nucleic acids and polypeptides that encode tethered IL-21 and/or IL-15 bound to host cell membranes by an anchor moiety. The disclosure is also directed to the associated vectors, host cells, pharmaceuticals and methods of treating cancer using the cells expressing the tethered cytokine (Abstract). Hinrichs teaches tethered interleukins provide autocrine stimulation to therapeutic T cells while preventing systemic toxicity that is caused by administration of soluble interleukins ([0029], Lines 1-12).
Regarding claim 1, pertaining to a lentiviral or retroviral vector comprising a nucleic acid sequence encoding a tethered cytokine comprising a TeIL-15, wherein the lentiviral vector does not comprise a nucleic acid sequence encoding TeIL-21, Hinrichs discloses lentiviral transduction with three different TeIL-15 constructs comprising a signal sequence, an IL-15 mature amino acid sequence, a flexible linker, an a cell membrane anchor moiety ([0124], Lines 1-4 and [0109], Lines 1-6, Fig. 1A). Hinrichs discloses the TeIL-15 construct “TeIL-15 Lr1Ar2” set forth in SEQ ID NO: 31 which comprises human IL-15 (underlined) and human B7-1 transmembrane-intracellular amino acid sequence (bold).
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Regarding claim 4, wherein the nucleic acid encoding the TeIL-15 of claim 1 is set forth in SEQ ID NO: 296, the instant disclosure teaches the nucleic acid sequence SEQ ID NO: 296 corresponds to amino acid sequence SEQ ID NO: 328 (see Specification [00423]). Hinrichs SEQ ID NO: 31 (TeIL-15 Lr1Ar2) is identical to instant SEQ ID NO: 328. The alignment is shown below:
Instant TeIL-15
Hinrichs TeIL-5 “Lr1Ar2”
Nucleotide Sequence: SEQ ID NO: 296
Amino Acid Sequence: SEQ ID NO: 328
Amino Acid Sequence: SEQ ID NO: 31
Instant SEQ ID NO: 328 x Hinrichs SEQ ID NO: 31
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Regarding claim 5, wherein the IL-15 of the viral vector of claim 1 is human IL-15, Hinrichs discloses the human IL-15 portion of the TeIL-15 structure is mature, human IL-15 ([0040], Lines 9-11, human IL-15 sequence in Hinrichs Table 1, SEQ ID NO:3).
Regarding claims 27 and 28, wherein the TeIL-15 of the viral vector of claim 1 comprises a cell membrane anchor moiety (claim 27) and wherein the cell membrane anchor moiety comprises a CD8a transmembrane-intracellular domain, a B7-1 transmembrane domain, a B7-2 transmembrane domain, or a CD8a transmembrane domain (claim 28), Hinrichs discloses that the anchor moiety of the TeIL-15 Lr1Ar2 construct comprises the human B7-1 transmembrane-intracellular amino acid sequence ([0113], Lines 5-7, sequence in Table 3, SEQ ID NO: 5)
Regarding claim 30, wherein the lentiviral vector or retroviral vector of claim 1 is capable of transducing and gene editing TILs to activate the TILs, Hinrichs shows the lentiviral vectors encoding TeIL-15 were able to transduce PBMCs ([0124), Lines 1-5, Fig. 2). Hinrichs further provides evidence that T cells expressing the TeIl-15 are activated by incorporation of the construct as seen in the anti-tumor activity of the TeIL-15 TCR T cells, which delayed tumor growth compared to controls ([0146], Lines 1-5 and Fig. 3).
Regarding claim 31, wherein the TeIL-15 of the viral vector of claim 30 produces the claimed results, these results flow from the inherent properties of IL-15. As evidence of this, Hinrichs demonstrates that PBMCs transduced with TeIL-15 show better proliferation than the control constructs ([0125], Lines 1-3 and Fig. 2).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 7, 9-10, 25, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Hinrichs (WO2019/157130A1) as applied to claims 1, 4-5, 27-28, and 30-31 above, and further in view of Chartier-Courtaud (WO2019/210131A1, published 10/31/2019, effectively filed 04/27/2018, cited in IDS filed 10/30/2024).
The disclosure of Hinrichs is directed broadly to any host cell comprising vectors encoding tethered interleukins, including TeIL-15. Hinrichs teaches the host cell can be tumor infiltrating lymphocytes ([0081], Lines 1-9). Hinrichs teaches the tethered interleukin constructs provide multiple benefits including autocrine stimulation without toxicity seen in free interleukins ([0029], Lines 8-12).
While the disclosure of Hinrichs teaches TILs among a list of potential host cells, Hinrichs does not explicitly teach a population of gene-edited TILs modified by the viral vector comprising a TeIL-15.
This deficiency is taught by Chartier-Courtaud.
The disclosure of Chartier-Courtaud is directed to methods for expanding TILs into a therapeutic population of TILs comprising a gene-editing step.
Regarding claim 7, pertaining to a population of gene-edited TILs modified by the lentiviral or retroviral vector of claim 1, Chartier-Courtaud teaches the method for expanding TILs into a therapeutic population of TILs comprises gene-editing at least a portion of the TILs (Pg. 226, claim 1(g)). Specifically, Chartier-Courtaud teaches in some embodiments the gene-editing causes expression of one or more immune checkpoint genes, including IL-15 ([0058], Lines 1-4).
Regarding claim 9, wherein at least 30% of the TIL population of claim 7 express the TeIL-15, Hinrichs teaches high transduction efficiency using multiple TeIL-15 constructs and in different cell populations. PBMCs transduced with a lentivirus containing TeIL-15 construct resulted in IL-15 expression of 62.3% for their first TeIL-15 construct and 53.2% for a second TeIL-15 construct ([0127], Lines 1-6). Hinrichs also teaches T cells transduced with a retrovirus containing the TeIL-15 Lr1Ar2 construct had 73.1% surface expression of IL-15 (Pg. 39, Table 11). In all, Hinrichs teaches different variations of their TeIL-15 construct in PBMCs and isolated T cells results in 53-73% transduction, which reasonably meets the limitation that the construct has the ability to produce a TIL population with at least 30% of TeIL-15 expression.
Regarding claim 10, wherein the IL-15 of the population of gene-edited TILs of claim 7 is human IL-15, Hinrichs teaches the human IL-15 portion of the TeIL-15 structure is mature, human IL-15 ([0040], Lines 9-11, human IL-15 sequence in Hinrichs Table 1, SEQ ID NO:3).
Regarding claim 25, pertaining to a pharmaceutical composition comprising the population of gene-edited TILs of claim 7 and a pharmaceutically acceptable carrier, Chartier-Courtaud teaches administration of the TILs as a pharmaceutical composition in a suspension in sterile buffer ([00527], Lines 1-3).
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Regarding claim 32, wherein the population of gene-edited TILs does not express a TeIL-21, Hinrichs teaches three constructs comprising only TeIL-15 and teaches transduction of cells with the TeIL-15 construct only. To show that the cells do not also express TeIL-15, with the TeIL-15 only population highlighted in a box.
It would have been prima facie obvious to one having ordinary skill in the art at the time of filing to modify the teachings of Hinrichs with the teachings of Chartier-Courtaud by transducing tumor infiltrating lymphocytes with a viral vector comprising a nucleic acid encoding a TeIL-15. One would have been motivated to do so because: (1) Hinrichs teaches transduction of therapeutic lymphocytes with a tethered IL-15 vector provides autocrine signaling without causing systemic toxicity ([0029], Lines 1-12), but does not specifically teach this modification in TILs and (2) Chartier-Courtaud teaches treatment of bulky, refractory cancer using adoptive transfer of modified TILs in patients with poor prognosis ([0002], Lines 1-3). Chartier-Courtaud specifically teaches TILs can be modified to induce IL-15 expression, which enhances expansion, survival and cytotoxicity of lymphocytes ([00308]-[00309], Interleukins), but does not specifically teach the IL-15 modification is a tethered or membrane-bound IL-15. Since Hinrichs is directed broadly to modification of any cell population with a TeIL-15 construct and Chartier-Courtaud teaches modification of TILs for adoptive transfer to treat patients with poor prognosis, it would be obvious to modify this specific TIL cell population with TeIL-15. There would be an expectation of success in transducing TILs with TeIL-15 because Hinrichs teaches the viral vector can be used to transduce lymphocytes and could readily be used to transduce the specific lymphocyte TIL population.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Hinrichs (WO2019/157130A1) as applied to claims 1, 4-5, 27-28, and 30-31 above, and further in view of Zhu (J Immunol. 2009 Sep 15;183(6):3598-607, cited in IDS filed 10/30/2024).
Hinrichs teaches TeIL-15 constructs comprising the human IL-15 set forth in SEQ ID NO: 3. The IL-15 disclosed in Hinrich is wild-type IL-15 and varies from instant SEQ ID NO: 258 in one position corresponding to a N72D mutation. The alignment is shown below:
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Instant SEQ ID NO: 258 x Hinrichs SEQ ID NO: 3
While the disclosure of Hinrichs discloses the native IL-15 amino acid sequence used in their constructs, Hinrichs does not teach the IL-15 N72D variant set forth in instant SEQ ID NO: 258.
This deficiency is taught by Zhu.
The disclosure of Zhu is directed to the generation of novel human IL-15 muteins generated by site-directed mutagenesis (see Abstract). They identified an N72D hIL-15 mutein with superagonist activity through improved binding to the human IL-15Rβ-chain. This was seen through increased cell proliferation in cells expressing hL-15Rβ compared to that induced with wild-type IL-15, (Figs. 2-4), enhanced signal transduction measured by pJAK1 and pSTAT5 (Fig. 6), and increased cell survival due to reduced apoptosis (Fig. 7).
Regarding claim 6, wherein the human IL-15 of claim 5 has the amino acid sequence of SEQ ID NO: 258, SEQ ID NO: 258 is the product of insertion of the N72D mutation of Zhu into the native IL-15 sequence of Hinrichs.
It would have been prima facie obvious to one having ordinary skill in the art at the time of filing to modify the viral vector of Hinrichs by using the N72D superagonist mutein of Zhu. One would have been motivated to do so because Zhu demonstrates that the mutein provides greater proliferation and activation in T cells compared to the wild-type human IL-15. There would be an expectation of success in combining the teachings of Hinrichs and Zhu because the mutein sequence of Zhu could readily be inserted in place of the wild-type IL-15 sequence in the vector of Hinrichs.
Claim 29 is rejected under 35 U.S.C. 103 as being unpatentable over Hinrichs (WO2019/157130A1) as applied to claims 1, 4-5, 27-28, and 30-31 above, and further in view of Zhang (J Immunother Cancer. 2020 Jan;8(1):e000210).
The disclosure of Hinrichs teaches lentiviral and retroviral vectors comprising the nucleic acid sequence of TeIL-15.
The disclosure of Hinrichs does not teach the nucleic acid sequence of the viral vectors further comprises an NFAT promoter controlling the expression of IL-15.
This deficiency is taught by Zhang.
The disclosure of Zhang is directed to tumor-specific therapeutic T cells genetically engineered to express membrane anchored IL-12 (Abstract). T cells were transduced by a retroviral vector encoding NFAT-inducible IL-12 (“iaIL-12”), producing cells that did not constitutively express IL-12, rather the IL-12 expression was induced with T cell activation (Abstract and Pg. 7 Right column, Lines 2-4).
Regarding claim 29, wherein the nucleic acid sequence further comprises an NFAT promoter controlling the expression of TeIL-15, Zhang teaches that putting a cytokine under control of an NFAT controlling the expression of the cytokine with the use of a small genetic construct and no requirement for administration of an exogenous molecule to activate gene expression (Pg. 10, Left column, Lines 1-14).
It would have been prima facie obvious to one having ordinary skill in the art at the time of filing to modify the teachings of Hinrichs with the teachings of Zhang by putting the tethered IL-15 construct of Hinrichs under control of the NFAT promoter as taught by Zhang. One would have been motivated to do so because Zhang teaches that cytokines under the control of the NFAT promoter are only expressed upon activation of the T cells, ensuring therapeutically administered T cells are activated only in the tumor environment and not promoting inflammation throughout the entire body. There would be an expectation of success in combining the teachings of Hinrichs and Zhang because the NFAT nucleic acid sequence as taught by Zhang could readily be inserted into the TeIL-15 vector of Hinrichs.
Claims 7, 9-11, 25, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Hinrichs (WO2019/157130A1) and Chartier-Courtaud (WO2019/210131A1) as applied to claims 7, 9-10, 25, and 32 above, and further in view of Zhu (J Immunol. 2009 Sep 15;183(6):3598-607).
The combined teachings of Hinrichs and Chartier-Courtaud teach a population of gene-edited TILs expressing a tethered human IL-15. The human IL-15 disclosed by Hinrichs is the native human IL-15.
The combined teachings of Hinrichs and Chartier-Courtaud do not teach the IL-15 N72D variant set forth in instant SEQ ID NO: 258.
This deficiency is taught by Zhu.
The disclosure of Zhu is directed to the generation of novel human IL-15 muteins generated by site-directed mutagenesis (see Abstract). They identified an N72D hIL-15 mutein with superagonist activity through improved binding to the human IL-15Rβ-chain. This was seen through increased cell proliferation in cells expressing hL-15Rβ compared to that induced with wild-type IL-15, (Figs. 2-4), enhanced signal transduction measured by pJAK1 and pSTAT5 (Fig. 6), and increased cell survival due to reduced apoptosis (Fig. 7).
Regarding claim 11, wherein human IL-15 of claim 10 has the amino acid sequence of SEQ ID NO: 258 (claim 11), SEQ ID NO: 258 is the product of insertion of the N72D mutation of Zhu into the native IL-15 sequence of Hinrichs.
It would have been prima facie obvious to one having ordinary skill in the art at the time of filing to modify the genetically modified TIL population of Hinrichs and Chartier-Courtaud by using the N72D superagonist mutein of Zhu. One would have been motivated to do so because Zhu demonstrates that the mutein provides greater proliferation and activation in T cells compared to the wild-type hIL-15. There would be an expectation of success in combining the teachings of Hinrichs, Chartier-Courtaud and Zhu because the mutein sequence of Zhu could readily be inserted in place of the wild-type IL-15 sequence in the vector of Hinrichs.
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.
Application No. 18/262,365
Claims 1, 4-7, 10-11, 25, 27-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 10, 30, 32, 34, 51, 58, 81, 98, 115, 117, 173, 227, and 230-238 of copending Application No. 18/262,365 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the reference patents teaches a method of generating gene-edited TILs that produces the population of TILs of the instant invention.
Regarding claim 1, pertaining to a lentiviral or retroviral vector comprising a nucleic acid sequence encoding TeIL-15, wherein the lentiviral vector does not comprise a nucleic acid sequence encoding TeIL-21, ‘365 claim 58 claims the method of gene-editing the TILs comprises a lentiviral or retroviral vector comprising a nucleic acid encoding TeIL-15.
Regarding claim 4, wherein the nucleic acid sequence encoding the TeIL-15 of claim 1 is set forth in SEQ ID NO: 296, ‘365 claim 230 claims the TeIL-15 of the method for generating TILs is encoded by the nucleic acid set forth in SEQ ID NO: 296, identical to instant SEQ ID NO: 296.
Regarding claims 5 and 6, wherein the IL-15 of claim 1 is human IL-15 (claim 5) and wherein the human IL-15 has the amino acid sequence of SEQ ID NO: 258 (claim 6), ‘365 claim 34 and claim 231 claim the IL-15 is human IL-15 and comprises the amino acid sequence set forth in SEQ ID NO: 258, identical to instant SEQ ID NO: 258.
Regarding claims 27 and 28, wherein the TeIL-15 of claim 1 comprises a cell membrane anchor moiety (claim 27) and wherein the cell membrane anchor moiety comprises a CD8a transmembrane-intracellular domain, a B7-1 transmembrane domain, a B7-2 transmembrane domain, or a CD8a transmembrane domain (claim 28), ‘365 claims 30 and 51 claim the TeIL-15 comprises a cell membrane anchor moiety, wherein the cell membrane anchor moiety comprises a CD8a transmembrane-intracellular domain, a B7-1 transmembrane domain, a B7-2 transmembrane domain, or a CD8a transmembrane domain.
Regarding claim 29, wherein the nucleic acid sequence of claim 1 further comprises a nuclear factor of activated T-cells (NFAT) promoter controlling the expression of the TeIL-15, ‘365 claim 227 claims the TeIL-15 is under the control of the NFAT promoter.
Regarding claim 30, wherein the lentiviral or retroviral vector of claim 1 is capable of transducing and gene-editing TILs to activate the TILs, ‘365 claim 58 claims the modifying of the TILs is performed by the lentiviral or retroviral vector comprising the TeIL-15 nucleic acid sequence.
Regarding claim 31, wherein theTeIL-15 of the viral vector of claim 30 produces the claimed results, ‘365 claim 234 claims the TeIL-15 produces the effects identical to those set forth in the instant claims.
Regarding claim 7, pertaining to a population of gene-edited TILs modified by the lentiviral or retroviral vector of claim 1, ‘365 claim 10 claims a method for producing a population of gene-edited TILs wherein the TILs are edited to comprise TeIL-15 and does not comprise TeIL-21.
Regarding claims 10 and 11, wherein the IL-15 of claim 7 is human IL-15 (claim 10) and wherein the human IL-15 has the amino acid sequence of SEQ ID NO: 258 (claim 11), ‘365 claim 34 and claim 231 claim the IL-15 is human IL-15 and comprises the amino acid sequence set forth in SEQ ID NO: 258, identical to instant SEQ ID NO: 258.
Regarding claim 25, pertaining to a pharmaceutical composition comprising the population of gene-edited TILs of claim 7 and a pharmaceutically acceptable carrier, ‘365 claim 237 claims the TIL population is transferred to an infusion bag and administered therapeutically, which meets the limitation of formulating the TILs in a pharmaceutical composition with a pharmaceutically acceptable carrier.
Regarding claim 32, wherein the population of gene-edited TILs does not express a TeIL-21, ‘365 claim 10 explicitly states that the TILs do not express TeIL-21.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 4-7, 9-11, 25, and 27-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 10, 30, 32, 34, 51, 58, 81, 98, 115, 117, 173, 227, and 230-238 of copending Application No. 18/262,365 as applied to 1, 4-7, 10-11, 25, 27-32 above and further in view of Hinrichs (WO2019/157130A1).
Co-pending ‘365 does not teach that 30% of the population of gene-edited TILs of claim 7 express TeIL-15.
This deficiency is taught by Hinrichs.
The disclosure of Hinrichs is directed to host cells comprising vectors encoding TeIL-15. Hinrichs teaches the host cell can be TILs ([0081], Lines 1-9).
Regarding claim 9, wherein at least 30% of the TIL population of claim 7 express the TeIL-15, Hinrichs teaches high transduction efficiency using multiple TeIL-15 constructs and in different cell populations. PBMCs transduced with a lentivirus containing TeIL-15 construct resulted in IL-15 expression of 62.3% for their first TeIL-15 construct and 53.2% for a second TeIL-15 construct ([0127], Lines 1-6). Hinrichs also teaches T cells transduced with a retrovirus containing the TeIL-15 Lr1Ar2 construct had 73.1% surface expression of IL-15 (Pg. 39, Table 11). In all, Hinrichs teaches different variations of their TeIL-15 construct in PBMCs and isolated T cells results in 53-73% transduction, which reasonably meets the limitation that the construct has the ability to produce a TIL population with at least 30% TeIL-15 expression.
It would have been prima facie obvious to one having ordinary skill in the art at the time of filing to modify the teachings of ‘365 with the teachings of Hinrichs by using the TeIL-15 vectors of Hinrichs for gene-editing the TILs of ‘365. One would have been motivated to do so because Hinrichs teaches high efficiency of viral transduction of lymphocytes with their TeIL-15 constructs. There would be an expectation of success in transducing TILs with TeIL-15 because Hinrichs teaches the viral vector can be used to transduce lymphocytes with high efficiency and could readily be used to transduce the specific lymphocyte TIL population.
This is a provisional nonstatutory double patenting rejection.
Application No. 18/832,493
Claims 1, 4-5, 7, 9-10, 25, and 29-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 226-246 of copending Application No. 18/832,493 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the reference application claims a lentiviral vector comprising a nucleic acid encoding TeIL-15 and a population of TILs edited to express the TeIL-15.
Regarding claim 1, pertaining to a lentiviral or retroviral vector comprising a nucleic acid sequence encoding TeIL-15, wherein the lentiviral vector does not comprise a nucleic acid sequence encoding TeIL-21, ‘493 claims 226 and 234 claim a lentiviral vector comprising a nucleic acid encoding a tethered cytokine, wherein the tethered cytokine is TeIL-15.
Regarding claim 4, wherein the nucleic acid sequence encoding the TeIL-15 of claim 1 is set forth in SEQ ID NO: 296, ‘493 claim 235 claims the nucleic acid sequence encoding TeIL-15 set forth in SEQ ID NO: 296, identical to instant SEQ ID NO: 296.
Regarding claims 5, wherein the IL-15 of claim 1 is human IL-15, the TeIL-15 set forth in SEQ ID NO: 296 is human IL-15.
Regarding claim 29, wherein the nucleic acid sequence of claim 1 further comprises a nuclear factor of activated T-cells (NFAT) promoter controlling the expression of the TeIL-15, ‘493 claim 230 claims the tethered cytokine is under the control of an NFAT promoter.
Regarding claim 30, wherein the lentiviral or retroviral vector of claim 1 is capable of transducing and gene-editing TILs to activate the TILs, ‘493 claims 236 teaches gene-editing of a population of TILs performed by the lentiviral vector of the disclosure.
Regarding claim 31, wherein theTeIL-15 of the viral vector of claim 30 produces the claimed results, these results flow from the inherent properties of IL-15.
Regarding claim 7, pertaining to a population of gene-edited TILs modified by the lentiviral or retroviral vector of claim 1, ‘493 claims 236 and 240 claims a population of gene-edited TILs edited by the lentiviral vector of the disclosure, wherein the TILs express TeIL-15.
Regarding claim 9, wherein at least 30% of the TIL population of claim 7 express the TeIL-15, ‘493 claim 241 claims about 30% of the TILs express TeIL-15.
Regarding claim 10, wherein the IL-15 of claim 7 is human IL-15, the TeIL-15 set forth in SEQ ID NO: 296 is human IL-15.
Regarding claim 25, pertaining to a pharmaceutical composition comprising the population of gene-edited TILs of claim 7 and a pharmaceutically acceptable carrier, ‘493 claim 245 claims a pharmaceutical composition comprising the gene-edited TILs of the disclosure and a pharmaceutically acceptable carrier.
Regarding claim 32, wherein the population of gene-edited TILs does not express a TeIL-21, the vector ‘493 claim 226 encodes a single tethered cytokine (“encoding a tethered cytokine”) and the reference application does not claim modification of the TILs with more than one tethered interleukin.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 4-7, 9-11, 25, 29-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 226-246 of copending Application No. 18/832,493 in view of Zhu (J Immunol. 2009 Sep 15;183(6):3598-607).
Co-pending ‘493 does not teach the IL-15 N72D variant set forth in instant SEQ ID NO: 258.
This deficiency is taught by Zhu.
The disclosure of Zhu is directed to the generation of novel human IL-15 muteins generated by site-directed mutagenesis (see Abstract). They identified an N72D hIL-15 mutein with superagonist activity through improved binding to the human IL-15Rβ-chain. This was seen through increased cell proliferation in cells expressing hL-15Rβ compared to that induced with wild-type IL-15, (Figs. 2-4), enhanced signal transduction measured by pJAK1 and pSTAT5 (Fig. 6), and increased cell survival due to reduced apoptosis (Fig. 7).
Regarding claims 6 and 11, wherein human IL-15 of claims 5 and 10 have the amino acid sequence of SEQ ID NO: 258, SEQ ID NO: 258 is the product of insertion of the N72D mutation of Zhu into the native IL-15 sequence of ‘493.
It would have been prima facie obvious to one having ordinary skill in the art at the time of filing to modify the genetically modified TIL population of ‘493 by using the N72D superagonist mutein of Zhu and producing the amino acid sequence of SEQ ID NO: 258. One would have been motivated to do so because Zhu demonstrates that the mutein provides greater proliferation and activation in T cells compared to the wild-type hIL-15. There would be an expectation of success in combining the teachings of ‘493 and Zhu because the mutein sequence of Zhu could readily be inserted in place of the wild-type IL-15 sequence in the vector of ‘493.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 4-7, 9-10, 25, and 27-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 226-246 of copending Application No. 18/832,493 in view of Hinrichs (WO2019/157130A1).
Co-pending ‘493 does not teach the viral vector of claim 1 comprises a cell membrane anchor moiety.
Regarding claims 27 and 28, wherein the TeIL-15 of the viral vector of claim 1 comprises a cell membrane anchor moiety (claim 27) and wherein the cell membrane anchor moiety comprises a CD8a transmembrane-intracellular domain, a B7-1 transmembrane domain, a B7-2 transmembrane domain, or a CD8a transmembrane domain (claim 28), Hinrichs discloses that the anchor moiety of the TeIL-15 Lr1Ar2 construct comprises the human B7-1 transmembrane-intracellular amino acid sequence ([0113], Lines 5-7, sequence in Table 3, SEQ ID NO: 5)
It would have been prima facie obvious to one having ordinary skill in the art at the time of filing to modify the teachings of ‘365 with the teachings of Hinrichs by using the TeIL-15 vectors comprising an anchor moiety of for gene-editing the TILs of ‘365. One would have been motivated to do so because Hinrichs teaches successful transduction and surface expression of TILs using their TeIL-15 vectors comprising a membrane anchor moiety. There would be an expectation of success in transducing TILs with Hinrichs’ TeIL-15 comprising a membrane anchor moiety because Hinrichs demonstrates that their vectors successfully transduce lymphocytes and could readily be used to transduce the specific lymphocyte TIL population.
This is a provisional nonstatutory double patenting rejection.
Application No. 19/501,582
Claims 1, 4-7, 9-11, 25, 27, 30-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-408 of copending Application No. 19/501,582 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the reference application is directed to a nucleic acid molecule that encodes TeIL-12 and claims the nucleic acid molecules further comprises TeIL-15.
Regarding claim 1, pertaining to a lentiviral or retroviral vector comprising a nucleic acid sequence encoding TeIL-15, wherein the lentiviral vector does not comprise a nucleic acid sequence encoding TeIL-21, ‘582 claims 1, 6, 10, and 13 claim a nucleic acid molecule encodes TeIL-12 and additionally comprises a nucleotide sequence encoding TeIL-15.
Regarding claim 4, wherein the nucleic acid sequence encoding the TeIL-15 of claim 1 is set forth in SEQ ID NO: 296, ‘582 claim 15 claims the TeIL-15 has the amino acid sequence SEQ ID NO: 73. ‘582 SEQ ID NO: 73 corresponds to the identical TeIL-15 set forth in the instantly claimed nucleic acid sequence SEQ NO: 296 (see instant Specification [00423]).
Regarding claims 5 and 6, wherein the IL-15 of claim 1 is human IL-15 (claim 5) and wherein the human IL-15 has the amino acid sequence of SEQ ID NO: 258 (claim 6), ‘582 claim 11 claims the IL-15 is human IL-15 and ‘582 claim 12 discloses the amino acid sequence of SEQ ID NO: 64, identical to instant SEQ ID NO: 258.
Regarding claim 27, wherein the TeIL-15 of claim 1 comprises a cell membrane anchor moiety, ‘582 claim 14 claims the TeIL-15 comprises a membrane anchor.
Regarding claim 30, wherein the lentiviral or retroviral vector of claim 1 is capable of transducing and gene-editing TILs to activate the TILs, ‘582 claim 48 claims the tethered interleukin-expressing TILs are edited by integration of lentiviral DNA into the cell genome.
Regarding claim 31, wherein theTeIL-15 of the viral vector of claim 30 produces the claimed results, these results flow from the inherent properties of IL-15.
Regarding claim 7, pertaining to a population of gene-edited TILs modified by the lentiviral or retroviral vector of claim 1, ‘582 claims 49, 53, 54, 57 claim gene edited TILs expressing TeIL-12 and TeIL-15.
Regarding claim 9, wherein at least 30% of the TIL population of claim 7 express the TeIL-15, ‘582 claim 176 claims 15-60% of the gene-edited TILs express TeIL-15.
Regarding claims 10 and 11, wherein the IL-15 of claim 7 is human IL-15 (claim 10) and wherein the human IL-15 has the amino acid sequence of SEQ ID NO: 258 (claim 11), ‘582 claim 11 claims the IL-15 is human IL-15 and ‘582 claim 12 discloses the amino acid sequence of SEQ ID NO: 64, identical to instant SEQ ID NO: 258.
Regarding claim 25, pertaining to a pharmaceutical composition comprising the population of gene-edited TILs of claim 7 and a pharmaceutically acceptable carrier, ‘582 claim 185 claims a pharmaceutical composition comprising the therapeutic population of gene-edited TILs of the disclosure.
Regarding claim 32, wherein the population of gene-edited TILs does not express a TeIL-21, ‘582 claims addition of single interleukin to the TeIL-12 construct, and thus would not also comprise TeIL-21 in addition to TeIL-15.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 4-7, 9-11, 25, 27-28, 30-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-7, 9-11, 25, 27, 30-32 of copending Application No. 19/501,582 in view of Hinrichs (WO2019/157130A1).
Co-pending ‘493 does not teach the viral vector of claim 1 comprises a cell membrane anchor moiety from the list of claim 28.
Regarding claims 28, wherein the cell membrane anchor moiety of claim 27 comprises a CD8a transmembrane-intracellular domain, a B7-1 transmembrane domain, a B7-2 transmembrane domain, or a CD8a transmembrane domain (claim 28), Hinrichs discloses that the anchor moiety of the TeIL-15 Lr1Ar2 construct comprises the human B7-1 transmembrane-intracellular amino acid sequence ([0113], Lines 5-7, sequence in Table 3, SEQ ID NO: 5)
It would have been prima facie obvious to one having ordinary skill in the art at the time of filing to modify the teachings of ‘365 with the teachings of Hinrichs by using the TeIL-15 vectors comprising an anchor moiety of for gene-editing the TILs of ‘365. One would have been motivated to do so because Hinrichs teaches successful transduction and surface expression of TILs using their TeIL-15 vectors comprising a membrane anchor moiety. There would be an expectation of success in transducing TILs with Hinrichs’ TeIL-15 comprising a membrane anchor moiety can be used to transduce lymphocytes and could readily be used to transduce the specific lymphocyte TIL population.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 4-7, 9-11, 25, 27, 29, 30-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-7, 9-11, 25, 27, 30-32 of copending Application No. 19/501,582 in view of Zhang (J Immunother Cancer. 2020 Jan;8(1):e000210).
Co-pending ‘582 does not teach the nucleic acid sequence of the viral vectors further comprises an NFAT promoter controlling the expression of IL-15.
This deficiency is taught by Zhang.
The disclosure of Zhang is directed to tumor-specific therapeutic T cells genetically engineered to express membrane anchored IL-12 (Abstract). T cells were transduced by a retroviral vector encoding NFAT-inducible IL-12 (“iaIL-12”), producing cells that did not constitutively express IL-12, rather the IL-12 expression was induced with T cell activation (Abstract and Pg. 7 Right column, Lines 2-4).
Regarding claim 29, wherein the nucleic acid sequence of claim 1 further comprises a nuclear factor of activated T-cells (NFAT) promoter controlling the expression of the TeIL-15, Zhang teaches that putting a cytokine under control of an NFAT controlling the expression of the cytokine with the use of a small genetic construct and no requirement for administration of an exogenous molecule to activate gene expression (Pg. 10, Left column, Lines 1-14).
It would have been prima facie obvious to one having ordinary skill in the art at the time of filing to modify the teachings of Hinrichs with the teachings of Zhang by putting the tethered IL-15 construct of Hinrichs under control of the NFAT promoter as taught by Zhang. One would have been motivated to do so because Zhang teaches that cytokines under the control of the NFAT promoter are only expressed upon activation of the T cells, ensuring therapeutically administered T cells are activated only in the tumor environment and not promoting inflammation throughout the entire body. There would be an expectation of success in combining the teachings of Hinrichs and Zhang because the NFAT nucleic acid sequence as taught by Zhang could readily be inserted into the TeIL-15 vector of Hinrichs.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/CAROL ANN CHASE/Examiner, Art Unit 1646
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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