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 .
Claim Status
Claims 10, 30, 32, 34, 45, 51, 58, 81, 98, 115, 117, 127, 161, 164, 167-168, 173, 177, 180, 187, 227 are pending and under examination.
Information Disclosure Statement
The information disclosure statement filed 09/13/2024 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. The information disclosure statement filed 09/13/2024 has been placed in the application file, but the information referred to as “CN102816734A”, “EP2925329A1”, “CN106244538A”, CN106591232A”, “EP3188740A1”, “CN107384867A”, “EP3365434A1”, “EP3368659A1”, and “EP3487990A1” have not been submitted.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 34, 45, 51, 81, 98, 115, 117, 127, 161, 164, 168, 173, 177, 180, 187, and 227 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 34, 45, 51, 81, 98, 115, 117, 127, 161, 164, 168, 173, 177, 180, 187, and 227, the phrase "optionally" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
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 10, 30, 32, 34, 51, 58, 81, 98, 115, 117, 127, 161, 164, 167-168, 173, 177, 180, 187, 227 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chartier-Courtaud (WO2019/136459A1, published 07/11/2019, effectively filed 01/08/2018) in view of Reed (US2017/0291934A1, published 10/12/2017, effectively filed 09/21/2015) and Hinrichs (US2021/0052647A1, published 02/25/2021, effectively filed 02/09/2018).
The disclosure of Chartier-Courtaud is directed to improved processes and methods for reprogramming TILs in order to prepare therapeutic populations of tumor-infiltrating lymphocytes (TILs) with increased therapeutic efficacy.
Regarding claim 10, pertaining to a method of expanding TILs into a therapeutic population of TILs, Chartier-Courtaud recites the method steps (a)-(f) verbatim ([0006]-[0007]).
Regarding claim 81, wherein the modifying is carried out on TILs from the first expansion, or TILs from the second expansion, Chartier-Courtaud teaches an electroporation step performed on the second population of TILs (Pg. 292, claim 58(h).
Regarding claim 98, wherein the cell culture medium of the first expansion further comprises a cytokine selected from the disclosed list of cytokines, Chartier-Courtaud teaches a triple cocktail first expansion step comprising IL-2/IL-15/IL-21 (Fig. 10, [00143], Lines 1-5).
Regarding claim 115, wherein the first expansion step and the second expansion step are each individually performed within a period of 11 days, Chartier-Courtaud teaches a rapid expansion protocol wherein the first and second expansion are each 11 days (Fig. 10, [00143], Lines 1-5).
Regarding claim 117, wherein the modified TILs further comprise a genetic modification that causes expression of one or more immune checkpoint genes to be silenced or reduced in at least a portion of the therapeutic population of TILs, Chartier-Courtaud teaches delivery of a siRNA for inhibiting the expression of PD-1 (Pg. 285, claim 53(j)).
Regarding claim 167, wherein the modified TILs are transfected with the nucleic acid encoding the fusion protein using microfluidic device to temporarily disrupt the cell membranes of TILs, Chartier-Courtaud teaches a sterile microfluidic membrane disruption step on the second TIL population that mediates the transfer of mRNA (Pg. 286, claim 54).
Regarding claim 168, wherein the method further comprises activating the TILs by incubation with an anti-CD3 agonist before transfection, Chartier-Courtaud teaches incubation of the second population with anti-CD3 mAb clone OKT-3 (Pg. 277, claim 1) and transfection of the second population of cells (Pg. 286, claim 54).
Chartier-Courtaud does not teach: (1) modifying the portion of TILs such that each of the modified TILs comprises an immunomodulatory composition associated with its surface membrane or (2) wherein the TILs comprise a first membrane anchored moiety and a second membrane anchored moiety.
These deficiencies are taught by Reed and Hinrichs.
Reed:
The disclosure of Reed is directed to modified forms of IL-12, including heterodimeric p35/p40, and membrane bound forms of IL-12 (see Abstract). Hinrich teaches IL-12 enhances production of cytotoxic lymphocytes and production of pro-inflammatory cytokines, however systemic administration of IL-12 is toxic ([0007], Lines 1-11).
Regarding the method step of claim 10(h), wherein the method comprises modifying TILs such that they comprise an immunomodulatory composition associated with its surface membrane, Reed teaches membrane tethered IL-12 (Fig. 6 and Fig. 7).
Regarding claims 30, 32, 34, and 173, wherein the immunomodulatory composition comprises one or more membrane anchored immunomodulatory fusion proteins each comprising one or more immunomodulatory agents and a cell membrane anchor moiety (claim 30), wherein the one or more immunomodulatory agents comprise one or more cytokines, wherein the one or more cytokines comprise IL-12 (claim 32, 173), and wherein the IL-12 comprises a human IL-12 p35 subunit attached to a human IL-12 p40 subunit (claim 34), Reed teaches single chain IL-12 configuration comprising p35 and p40 (Fig. 2) and a fusion protein comprising the IL-12 configuration linked to a transmembrane domain CD80 or a GPI anchor (Fig. 7).
Regarding claim 51 and 180, wherein the membrane immunomodulatory fusion protein has the formula of a signal peptide, immunomodulatory agent, linker and cell membrane anchor moiety (S-IA-L-C), Reed teaches the fusion protein comprising the Igκ signal peptide, IL-12, carbohydrate-containing linker, and GPI anchor (Fig. 7, with linker described in [0035]).
Regarding claim 58 and 161, wherein the modifying comprises introducing a heterologous nucleic acid encoding the fusion protein into the portion of the TILs and expressing the fusion protein on the surface of the modified TILs (claim 58), and wherein the modified TILs are modified by transfecting the TILs with a nucleic acid encoding the fusion protein (claim 161), Reed teaches the modified IL-12 constructs are encoded in nucleic acids and provides vectors encoding the nucleic acids ([0002], Lines 1-7) and the vectors transfected into cells using standard high-throughput transfection methods ([0354], Lines 1-10).
Regarding claim 127, wherein the modified TILs are modified to transiently express the immunomodulatory composition on the cell surface, Reed teaches regulation of IL-12 expression is regulated by a ligand inducible gene switch (Reed claim 17, [0269], Lines 1-3) allowing for regulation of gene expression by addition or removal of a specific ligand ([0228], Lines 1-5).
Regarding claim 164, wherein the TILs are transfected with the mRNA with electroporation, Reed teaches vectors may be introduced into host cells by methods known in the art including electroporation ([0091], Lines 1-3).
Regarding claim 227, wherein the modified TILs express the one or more membrane anchored immunomodulatory fusion proteins under the control of the NFAT promoter, Reed teaches
Hinrichs:
The disclosure of Hinrichs is directed to nucleic acids and polypeptides that encode tethered IL-21 and 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).
Regarding claim 177 and 187, wherein the modified TILs comprise a first membrane anchored immunomodulatory fusion protein and a second membrane anchored immunomodulatory fusion protein (claim 177) and wherein the one or more membrane anchored immunomodulatory fusion proteins are independently according to the formula, from N- to C-terminus: S1-IA1-L1-C1-L2-S2-IA2-L3-C2, wherein S1 and S2 are each independently a signal peptide, IA1 and IA2 are each independently an immunomodulatory agent, L1-L3 are each independently a linker, and C1 and C2 are each independently a cell membrane anchor moiety (claim 187), Hinrichs teaches the same formula, written in the following format: S1-N1-L1-C1a-L2-S2-N2-L3-C2b, wherein each S is a signal sequence, each N is independently an interleukin N1 IL-21 and N2 IL-15, each L1 and L3 are linkers and L2 is a cleavable linker, and each C is transmembrane intracellular amino acid sequence. Exemplary fusion proteins using this formula is shown in Hinrichs Table 6A (Pg. 13).
It would have been prima facie obvious to one having ordinary skill in the art at the time of filing to modify the TILs generation method of Chartier-Courtaud with (1) the membrane anchor IL-12 as taught by Reed and (2) further expression of another cytokine such as IL-15 as taught by Hinrichs. One would have been motivated to do so because Reed’s membrane-bound IL-12 provides site specific and ligand inducible delivery of IL-12 and Hinrichs teaches the membrane-tethered dual cytokine autocrine expression on adoptively transferred cells overcomes the issues associated with cytokine administration which is constrained by dose-limiting cytotoxicity and the need for repeated administration ([0034], Lines 1-8). There would be an expectation of success in modifying the TILs of Chartier-Courtaud with the membrane tethered cytokines of Reed and Hinrichs because both Reed and Hinrichs demonstrate their modifications on cells and teach methods of performing the modification using methods routinely used in the art at the time of filing.
Claims 10, 30, 32, 34, 45, 51, 58, 81, 98, 115, 117, 127, 161, 164, 167-168, 173, 177, 180, 187, 227 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chartier-Courtaud (WO2019/136459A1, published 07/11/2019, effectively filed 01/08/2018) in view of Reed (US2017/0291934A1, published 10/12/2017, effectively filed 09/21/2015) and Hinrichs (US2021/0052647A1, published 02/25/2021, effectively filed 02/09/2018) as applied to claims 10, 30, 32, 34, 51, 58, 81, 98, 115, 117, 127, 161, 164, 167-168, 173, 177, 180, 187, 227 above, and further in view of Kuhn (Cancer Cell. 2019 Mar 18;35(3):473-488.e6).
The combined teachings of Chartier-Courtaud, Reed, and Hinrichs teach a method of expanding TILs into a therapeutic population of TILs, comprising modifying a portion of the TILs such that each of the modified TILs comprises an immunomodulatory composition associated with its surface membrane.
The disclosure of Chartier-Courtaud does not teach wherein the one or more immunostimulatory agents comprise a CD40 agonist.
This deficiency is taught by Kuhn.
The disclosure of Kuhn is directed to engineered tumor-targeted CAR T cells to express the immune-stimulatory molecule CD40L and their efficacy in different mouse cancer molecules (Abstract).
Regarding claim 45, wherein the one or more immunomodulatory agents comprise a CD40 agonist, Kuhn teaches after adoptive cell transfer, the CD40L+ CAR T cells displayed superior antitumor efficacy, licensed antigen-presenting cells, enhanced recruitment of immune effectors, and mobilized endogenous tumor-recognizing T cells (Abstract, seen for example in Fig. 2).
It would have been prima facie obvious to one having ordinary skill in the art at the time of filing to modify the method of expanding and modifying TILs of Chartier-Courtaud, Reed, and Hinrichs with the addition of a membrane anchored CD40L as taught by Kuhn. One would have been motivated to do so because Kuhn teaches the addition of CD40L to tumor-specific adoptively transferred T cells increased the antitumor efficacy of the cells. There would be an expectation of success in modifying the methods of Chartier-Courtaud, Reed, and Hinrichs with the membrane anchored CD40L because Kuhn distills to practice the genetic modification of lymphocytes to express the CD40L using methods routinely used in the art at the time of filing.
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.
Nonprovisional
Claims 10, 30, 32, 34, 45, 51, 58, 81, 98, 115, 117, 127, 161, 164, 167-168, 173, 177, 180, 187, 227 are rejected on the ground of nonstatutory double patenting as being unpatentable over the U.S. Patents listed below in view of Reed (US2017/0291934A1, published 10/12/2017, effectively filed 09/21/2015), Hinrichs (US2021/0052647A1, published 02/25/2021, effectively filed 02/09/2018) and Kuhn (Cancer Cell. 2019 Mar 18;35(3):473-488.e6).
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Each of the patents listed above teach the rapid TIL expansion comprising a first and second expansion step in a closed system. It would have been prima facie obvious to one having ordinary skill in the art at the time of filing to modify the TIL expansion methods with: (1) the membrane anchor IL-12 as taught by Reed, (2) further expression of another cytokine such as IL-15 as taught by Hinrichs, and (3) the addition of a membrane anchored CD40L as taught by Kuhn.
One would have been motivated to do so because: (1) Reed’s membrane-bound IL-12 provides site specific and ligand inducible delivery of IL-12, (2) Hinrichs teaches the membrane-tethered dual cytokine autocrine expression on adoptively transferred cells overcomes the issues associated with cytokine administration which is constrained by dose-limiting cytotoxicity and the need for repeated administration, and (3) Kuhn teaches the addition of CD40L to tumor-specific adoptively transferred T cells increased the antitumor efficacy of the cells. As all of the reference patents teach a method of preparing TILs for adoptive transfer for treatment of cancer, then it would be obvious to modify the therapeutic TILs using known techniques to yield predictable results.
There would be an expectation of success in modifying the TILs of the reference patents with the membrane tethered cytokines of Reed and Hinrichs because both Reed, Hinrichs, and Kuhn demonstrate their modifications on cells and teach methods of performing the modification using methods routinely used in the art at the time of filing.
Provisional
Claims 10, 30, 32, 34, 45, 51, 58, 81, 98, 115, 117, 127, 161, 164, 167-168, 173, 177, 180, 187, 227 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the copending applications listed below in view of Reed (US2017/0291934A1, published 10/12/2017, effectively filed 09/21/2015), Hinrichs (US2021/0052647A1, published 02/25/2021, effectively filed 02/09/2018) and Kuhn (Cancer Cell. 2019 Mar 18;35(3):473-488.e6).
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Each of the co-pending applications listed above teach the rapid TIL expansion comprising a first and second expansion step in a closed system. It would have been prima facie obvious to one having ordinary skill in the art at the time of filing to modify the TIL expansion methods with: (1) the membrane anchor IL-12 as taught by Reed, (2) further expression of another cytokine such as IL-15 as taught by Hinrichs, and (3) the addition of a membrane anchored CD40L as taught by Kuhn.
One would have been motivated to do so because: (1) Reed’s membrane-bound IL-12 provides site specific and ligand inducible delivery of IL-12, (2) Hinrichs teaches the membrane-tethered dual cytokine autocrine expression on adoptively transferred cells overcomes the issues associated with cytokine administration which is constrained by dose-limiting cytotoxicity and the need for repeated administration, and (3) Kuhn teaches the addition of CD40L to tumor-specific adoptively transferred T cells increased the antitumor efficacy of the cells. As all of the reference patents teach a method of preparing TILs for adoptive transfer for treatment of cancer, then it would be obvious to modify the therapeutic TILs using known techniques to yield predictable results.
There would be an expectation of success in modifying the TILs of the co-pending applications with the membrane tethered cytokines of Reed and Hinrichs because both Reed, Hinrichs, and Kuhn demonstrate their modifications on cells and teach methods of performing the modification using methods routinely used in the art at the time of filing.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CAROL ANN CHASE whose telephone number is (571)270-0934. The examiner can normally be reached Monday-Friday 9:00am-6:00pm.
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/CAROL ANN CHASE/Examiner, Art Unit 1646
/HONG SANG/Primary Examiner, Art Unit 1646