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 without traverse of the following species in the reply filed 07/07/2026 is acknowledged:
Modified TIL population: the second population of TILs
Additional genetic modification that reduces expression of immune checkpoint genes: CLTA-4
Additional genetic modification that causes expression of one or more immune checkpoint genes to be enhanced: IL-15
Genetic modification method: TALE method
Digest composition: neutral protease
Claim Status
Claims 19, 46, 89-98, and 101-107 are pending. Claims 96-97 and 103-104 and 106 are withdrawn for being directed to a non-elected species.
Claims 19, 46, 89-95, 98, 101-102, 105, and 107 are under examination.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on Pgs. 238, 339 and 516. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the terms GlutaMax® and gentleMACS® (for example, on Pg. 149), which are trade names or a marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim 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 19, 46, 89-91, 94-95, 98, 101-102, 105, and 107 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Simpson-Abelson (WO2020/096986A2, published 05/14/2020, effectively filed 11/05/2018).
The disclosure of Simpson-Abelson is directed to methods of preselecting TILs based on PD-1 expression as well as methods for expanding the preselected PD-1 positive TILs to produce therapeutic populations of TILs with enhanced cytotoxicity (see Abstract).
Regarding claims 19 and 46, pertaining to a method for expanding tumor infiltrating lymphocytes (TILs) into a therapeutic population of TILs comprising (a) selecting PD-1 positive TILs from a first population of TILs, (b) performing a priming first expansion, (c) performing a rapid second expansion, (d) harvesting the therapeutic TIL population, (e) transferring the harvested therapeutic TIL population to an infusion bag and (f) genetically modifying the second population of TILs to reduce the expression of PD-1, Simpson-Abelson teaches a method for expanding TILs that is coextensive with the instant method (Pg. 429, claim 1). The method is as follows:
obtaining and/or receiving a first population of TILs from a tumor resected from a subject by processing a tumor sample obtained from the subject into multiple tumor fragments;
selecting PD-1 positive TILs from the first population of TILs in (a) to obtain a PD-1 enriched TIL population;
performing a priming first expansion by culturing the PD-I enriched TIL population in a cell culture medium comprising IL-2, OKT-3, and antigen presenting cells (APCs) to produce a second population of TILs, wherein the priming first expansion is performed in a container comprising a first gas permeable surface area, wherein the priming first expansion is performed for first period of about 7/8 days to obtain the second population of TILs, wherein the second population of TILs is greater in number than the first population of TILs;
performing a rapid second expansion by supplementing the cell culture medium of the second population of TILs with additional IL-2, OKT-3, and APCs, to produce a third population of TILs, wherein the number of APCs added in the rapid second expansion is at least twice the number of APCs added in step (b ), wherein the rapid second expansion is performed for a second period of about 1 to 11 days to obtain the third population of TILs, wherein the third population of TILs is a therapeutic population of TILs, wherein the rapid second expansion is performed in a container comprising a second gas-permeable surface area;
harvesting the therapeutic population of TILs obtained from step (d); and
transferring the harvested TIL population from step (e) to an infusion bag.
the method further comprises a method of genetically modifying a population of TILs e.g. a first population, a second population and/or a third population.. In an embodiment, a method of genetically modifying a population of TILs includes the step of stable incorporation of genes for production or inhibition (e.g., silencing) of one or more proteins ([001076], Lines 1-5).
silencing or permanently inhibiting inhibitory checkpoint molecules, including PD-1 ([001091], Lines 1-2)
Regarding claims 89 and 90, wherein the genetically modified TILs of the method of claim 19 further comprises an additional genetic modification that reduces the expression of CTLA-4, Simpson-Abelson teaches the method further comprises silencing or inhibiting the inhibitory checkpoint molecule CTLA-4 ([001091], Lines 1-2).
Regarding claim 91, wherein the genetically modified TILs of the method of claim 19 further comprises an additional genetic modification that causes the expression of IL-15 to be enhanced, Simpson-Abelson teaches the method further comprises enhancing or permanently gene-editing pro-inflammatory molecules including IL-15 ([001092], Lines 1-3).
Regarding claims 94-95, and 98, wherein the genetically modifying step is performed using a programmable nuclease that mediates the generation of a double- strand or single-strand break at the PD-1 gene (claim 94) and wherein the genetically modifying step is performed using a TALE method (claims 95 and 98), Simpson-Abelson teaches the permanent gene-editing is performed using a TALE method ([001091], Lines 1-2; [001092], Lines 1-3).
Regarding claims 101-102 and 105, wherein the enzymatic digest medium comprises a mixture of enzymes (claim 101) and wherein the enzymatic digest medium comprises a neutral protease (claims 102 and 105), Simpson-Abelson teaches the tissues are digested in a cocktail comprising neutral protease ([001706], Lines 1-2).
Regarding claims 107, wherein the tumor sample or plurality of tumor fragments are subjected to mechanical dissociation, Abelson-Simpson teaches tissue processing using a combined enzymatic and mechanical dissociation method using Miltenyi gentleMACS® Dissociator ([001707], Lines 1-3).
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 19, 46, 89-95, 98, 101-102, 105, and 107 are rejected under 35 U.S.C. 103 as being unpatentable over Simpson-Abelson (WO2020/096986A2, published 05/14/2020, effectively filed 11/05/2018) as applied to claims 19, 46, 89-91, 94-95, 98, 101-102, 105, and 107 above, and further in view of Chartier-Courtaud (WO2019/210131, published 10/31/2019, effectively filed 04/27/2018 ).
The disclosure of Simpson-Abelson teaches a method for expanding TILs into a therapeutic composition comprising selecting PD-1 positive TILs and further comprising a genetic modification that reduces the expression of PD-1.
The disclosure of Simpson-Abelson does not teach: (a) restimulating the second population of TILs with OKT-3 for about 2 days before performing the genetic modification step or (b) resting the modified second population of TILs for about 1 day before initiation of the second expansion or rapid second expansion.
These deficiencies are taught by Chartier-Courtaud.
Chartier-Courtaud is directed to improved and/or shortened methods for expanding TILs and producing therapeutic populations of TILs, including novel methods for expanding TIL populations in a closed system (see Abstract). The method of Chartier-Courtaud is mostly co-extensive with the method of Simpson-Abelson and provides additional teaching pertaining to the genetic modification methods.
Regarding claim 92, wherein the genetic modification step is performed on the second population of TILs and wherein the method comprises restimulating the second population of TILs with OKT-3 for about 2 days before performing the genetic modification step, Chartier-Courtaud teaches stimulating the TILs with OKT-3 for 1-3 days prior to electroporation (Pg. 245, claim 177(d)).
Regarding claim 93, wherein after the genetic modification step, the modified second population of TILs is rested for about 1 day before initiation of the second expansion or rapid second expansion, Chartier-Courtaud teaches resting the second population of TILs for about 1 day after electroporation (Pg. 245, claim 177(f)).
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 Simpson Abelson by (1) stimulating the second TIL population with OKT-3 about 2 days before genetic modification and (2) resting the TILs about 1 day after genetic modification before expansion as taught by Chartier-Courtaud. One would have been motivated to do so because Chartier-Courtaud teaches known methods for effective genetic modification of TILs. Integration of the teachings of Chartier-Courtaud constitutes combining prior art elements according to known methods to yield predictable results. There would be an expectation of success in incorporating the genetic modification method of Chartier-Courtaud to the method of Simpson-Abelson because both methods are directed to modification of TILs for therapeutic purposes and Chartier-Courtaud’s methods could readily be incorporated into the comparable methods of Simpson-Abelson.
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 19, 46, 89-95, 98, 101-102, 105, and 107 are rejected on the ground of nonstatutory double patenting as being unpatentable over the U.S. Patents listed below in view of Fernandez-Poma (Cancer Res. 2017 Jul 1;77(13):3672-3684)
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Each of the patents listed above teach the rapid TIL expansion method of the instant invention comprising a first and second expansion step in a closed system. The distinguishing feature of the instant application is the selection for PD-1+ TILs from a first population of TILs and subsequent genetic modification of the expanded PD-1+ TILs to reduce the expression of PD-1.
This limitation is obvious in view of Fernandez-Poma.
The disclosure of Fernandez-Poma is directed to evaluating the antitumor activity of PD-1–selected TILs in vivo.
Pertaining to the generation of therapeutic TILs, Fernandez-Poma teaches a major hurdle is isolating tumor-specific T cells from unrelated T cells present in the tumor infiltrate without knowing the specific antigen targets. Inhibitory checkpoint molecule PD-1 is induced upon T cell activation and it is known that isolation of PD-1+ cells selects for tumor-specific TIL subsets (Pg. 3673, Left column, Lines 1-3). Their study found that PD-1 in primary tumor cells can be used to isolate the full repertoire of tumor-reactive CD8+ TILs without needing to know epitope specificity (Fig. 2). Importantly, they showed that tumor-specificity was maintained in the CD8+ TILs expanded from the PD-1+ compartment; this was demonstrated through in vitro ELISPOT and ELISA assays (Fig. 5) and in vivo treatment of large established tumors in mice (Fig. 7). As the PD-1+ TILs maintained high expression of PD-1 after expansion, PD-1/PD-L1 blockade was added and was shown to increase the anti-tumor efficacy of the transferred cells (Fig. 7E-F, described Pg. 3680, Left column, Full paragraph 2). This points to the obviousness of modifying the TIL population to have reduced PD-1 expression.
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 of the cited patents by enriching for PD-1 TILs from the primary tumor digest and subsequently genetically modify the TILs to reduce the expression of PD-1.
One would have been motivated to do so because Fernandez-Poma teaches that isolating the PD-1+ CD8+ T cells in the tumor tissue effectively isolates the population of TILs that is activated and tumor antigen-specific. Fernandez-Poma also teaches inhibition of PD-1/PD-L1 improves the anti-tumor efficacy of the TILs. There would be an expectation of success in modifying the therapeutic TIL expansion method of the reference patents with the teachings of Fernandez-Poma because Fernandez-Poma demonstrates enriching/selecting for PD-1+ TILs produces therapeutic TILs with superior anti-tumor efficacy. The methods for doing so were performed readily at the time of filing.
Provisional
Claims 19, 46, 89-95, 98, 101-102, 105, and 107 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the copending applications listed below in view of Fernandez-Poma (Cancer Res. 2017 Jul 1;77(13):3672-3684)
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Each of the co-pending applications listed above teach the rapid TIL expansion method of the instant invention comprising a first and second expansion step in a closed system. The distinguishing feature of the instant application is the selection for PD-1+ TILs from a first population of TILs and subsequent genetic modification of the expanded PD-1+ TILs to reduce the expression of PD-1.
This limitation is obvious in view of Fernandez-Poma.
The disclosure of Fernandez-Poma is directed to evaluating the antitumor activity of PD-1–selected TILs in vivo.
Pertaining to the generation of therapeutic TILs, Fernandez-Poma teaches a major hurdle is isolating tumor-specific T cells from unrelated T cells present in the tumor infiltrate without knowing the specific antigen targets. Inhibitory checkpoint molecule PD-1 is induced upon T cell activation and it is known that isolation of PD-1+ cells selects for tumor-specific TIL subsets (Pg. 3673, Left column, Lines 1-3). Their study found that PD-1 in primary tumor cells can be used to isolate the full repertoire of tumor-reactive CD8+ TILs without needing to know epitope specificity (Fig. 2). Importantly, they showed that tumor-specificity was maintained in the CD8+ TILs expanded from the PD-1+ compartment; this was demonstrated through in vitro ELISPOT and ELISA assays (Fig. 5) and in vivo treatment of large established tumors in mice (Fig. 7). As the PD-1+ TILs maintained high expression of PD-1 after expansion, PD-1/PD-L1 blockade was added and was shown to increase the anti-tumor efficacy of the transferred cells (Fig. 7E-F, described Pg. 3680, Left column, Full paragraph 2). This points to the obviousness of modifying the TIL population to have reduced PD-1 expression.
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 of the cited co-pending applications by enriching for PD-1 TILs from the primary tumor digest and subsequently genetically modify the TILs to reduce the expression of PD-1.
One would have been motivated to do so because Fernandez-Poma teaches that isolating the PD-1+ CD8+ T cells in the tumor tissue effectively isolates the population of TILs that is activated and tumor antigen-specific. Fernandez-Poma also teaches inhibition of PD-1/PD-L1 improves the anti-tumor efficacy of the TILs. There would be an expectation of success in modifying the therapeutic TIL expansion method of the reference patents with the teachings of Fernandez-Poma because Fernandez-Poma demonstrates enriching/selecting for PD-1+ TILs produces therapeutic TILs with superior anti-tumor efficacy. The methods for doing so were performed readily 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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gregory Emch can be reached at 571-272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CAROL ANN CHASE/Examiner, Art Unit 1646
/HONG SANG/Primary Examiner, Art Unit 1646
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