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
In the reply filed 10 December 2025, Applicant has amended cancelled claims 1-227 and added new claims 228-230. Therefore, claims 228-230 are herein pending.
Priority
This application was filed 10/31/2022 and is a 371 application of PCT/US21/30655 filed on 05/04/2021, which claims benefit to the Provisional Application 63146400 filed on 02/05/2021 followed by Provisional Application 63019907 filed on 05/04/2020. Thus, the earliest possible priority for the instant application is 05/04/2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 07/18/2025, 12/10/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn Objections
In the reply filed 10 December 2025, Applicant has filed amended abstract and submitted it as a single paragraph on a separate sheet as required. Therefore, the objection to abstract is withdrawn.
The objection to Claims 2, 7, and 160 have been withdrawn due to applicant’s amendment and cancelled the claims.
In the reply filed 10 December 2025, Applicant has filed amended to specification and delete the embedded hyperlink and/or other form of browser-executable code. Therefore, Therefore, the objection to specification is withdrawn.
Withdrawn Rejections
The prior rejection of claims 2, 7 and 160 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the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention is withdrawn. The withdrawn is in light of Applicant’s amendment of claims and canceled claims 2, 7, and 160.
The prior rejection of Claims 2, 7, and 160 under 35 U.S.C. 103 as being unpatentable over Wardell et al. (US20180282694A1; published in Oct. 4, 2018; cited in PTO892; hereinafter “Wardell-964”), in view of Gros et al. (WO2016179006A1; published on Nov. 10, 2016; cited in PTO892; hereinafter “Gros”) is withdrawn. The withdrawn is in light of Applicant’s amendment of claims and cancelled claims 2, 7, and 160.
The prior rejection of Claims 2, 7, and 160 are rejected under 35 U.S.C. 103 as being unpatentable over US Wardell et al. (20180325954A1; published on Nov. 15, 2018; cited in PTO892; hereinafter “Wardell-954”), in view of Gros et al. (WO2016179006A1; published on Nov. 10, 2016; cited in PTO892; hereinafter “Gros”) is withdrawn. The withdrawn is in light of Applicant’s amendment of claims and cancelled claims 2, 7, and 160.
The prior rejection of Claims 2, 7, and 160 on the ground of nonstatutory double patenting as being unpatentable over the claims of the U.S. Patents set forth below in view of Gros et al. (WO2016179006A1; published on Nov. 10, 2016; cited in PTO892; hereinafter “Gros”) is withdrawn. The withdrawn is in light of Applicant’s amendment of claims and cancelled claims 2, 7, and 160.
The prior rejection of Claims 2, 7, and 160 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of the co-pending applications set forth below in view of Gros et al. (WO2016179006A1; published on Nov. 10, 2016; cited in PTO892; hereinafter “Gros”) is withdrawn. The withdrawn is in light of Applicant’s amendment of claims and cancelled claims 2, 7, and 160.
New 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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 228-230 are newly rejected under 35 U.S.C. 103 as being unpatentable over Wardell et al. (US20180282694A1; published in Oct. 4, 2018; cited in PTO892 (filed on 07/10/2025); hereinafter “Wardell-694”), in view of Gros et al. (J Clin Invest. 2014;124(5):2246–2259; cited in IDS filed 07/18/2025; hereinafter “Gros”). The new rejection is necessitated by applicant’s claim amendments.
Regarding claims 228-230, Wardell-694 teaches a method for expanding tumor infiltrating lymphocytes (TILs) into a therapeutic population of TILs comprising ([0006] of Wardell-694):
(a) obtaining a first population of TILs from a tumor resected from a patient by processing a tumor sample obtained from the patient into multiple tumor fragments ([0007] of Wardell-694);
(b) adding the tumor fragments into a closed system ([0008] of Wardell-694);
(c) performing a first expansion by culturing the first population of TILs in a cell culture medium comprising IL-2 to produce a second population of TILs, wherein the first expansion is performed in a closed container providing a first gas-permeable surface area, wherein the first expansion is performed for about 3-14 days to obtain the second population of TILs, wherein the second population of TILs is at least 50-fold greater in number than the first population of TILs, and wherein the transition from step (b) to step (c) occurs without opening the system ([0009] of Wardell-694);
(d) performing a second expansion by supplementing the cell culture medium of the second population of TILs with additional IL-2, OKT-3, and antigen presenting cells (APCs), to produce a third population of TILs, wherein the second expansion is performed for about 7-14 days to obtain the third population of TILs, wherein the third population of TILs is a therapeutic population of TILs, wherein the second expansion is performed in a closed container providing a second gas-permeable surface area, and wherein the transition from step (c) to step (d) occurs without opening the system ([0010] of Wardell-694);
(e) harvesting the therapeutic population of TILs obtained from step (d), wherein the transition from step (d) to step (e) occurs without opening the system ([0011] of Wardell-694); and
(f) transferring the harvested TIL population from step (e) to an infusion bag, wherein the transfer from step (e) to (f) occurs without opening the system ([0012] of Wardell-694);
(g) administering a therapeutically effective dosage of the TILs from step (e) to the subject ([0052] of Wardell-694).
Wardell-694 teaches that the first period in step (c) and the second period in step (e) are each individually performed within a period of 10 days, 11 days, or 12 days ([0029] – [0030] of Wardell-694).
With respect to claims 289-230, Wardell-694 does not teach to selecting the PD-1, LAG3 and/or TIM3 enriched TIL population for the expansion and the using of OKT-3 (anti-CD3) in the first expansion step. However, such was known in the prior art.
Regarding claims 228-230, Gros teaches a method for expanding tumor infiltrating lymphocytes (TILs) into a therapeutic population of TILs comprising;
a) obtaining population of TILs from a tumor resected from a subject by processing a tumor sample obtained from the subject into multiple tumor fragments (p. 2255 2nd ¶ of Gros);
b) isolated cells from 6 independent fresh tumors based on expression of PD-1, LAG-3, and TIM-3, expanded them in vitro for 15 days with IL-2, anti-CD3 (OKT-3) stimulation (p. 2249 2nd ¶ “Expression of PD-1, LAG-3, and TIM-3 in the tumor identifies tumor reactive T cells” of Gros). Therefore, POSITA would recognize that Gros disclose is obvious to selecting PD-1, LAG3, and TIM3 positive TILs from the population of TILs to obtain a PD-1, LAG3, and/or TIM3 enriched TIL population.
MPEP 2143 (A) states that combining prior art elements according to known methods to yield predictable results. The rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395. Accordingly, it would have been obvious to practice the TIL culture method of Wardell-694 and include selecting the PD-1, LAG3 and/or TIM3 enriched TIL population with OKT3 and IL-2 in the medium as taught by Gros with a reasonable expectation of success. The POSITA would have been motivated at the time of filing to do so as taught by Gros because expression of PD-1 on CD8+ TILs from tumor subject accurately identifies the repertoire of clonally expanded tumor-reactive, mutation-specific lymphocytes and suggest that cells derived from this population play a critical role in tumor regression after TIL administration (p. 2248 1st ¶ of Gros), and OKT-3 and IL-2 are routinely used for TIL expansion (p. 2249 2nd ¶ of Gros). The POSITA would have had a reasonable expectation of success in combining the teachings of Wardell-694 in view of Gros because each of these teachings both successfully expanding tumor TILs. Therefore, the products and method as taught by Wardell-694 in view of Gros would have been prima facie obvious over the method and products of the instant application. In regard to the reasonable expectation of success in doing so, isolating PD-1, LAG3 and/or TIM3 enriched TIL population and include the OKT-3, IL-2 in the cell culture medium of Gros had a reasonable expectation of success since the steps thereof required no more than pipetting the appropriate protein concentration and cell culture technology.
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Claims 228-230 are newly rejected under 35 U.S.C. 103 as being unpatentable over Wardell et al. (20180325954A1; published on Nov. 15, 2018; cited in PTO892 (filed on 07/10/2025); hereinafter “Wardell-954”), in view of Gros et al. (J Clin Invest. 2014;124(5):2246–2259; cited in IDS filed 07/18/2025; hereinafter “Gros”). The new rejection is necessitated by applicant’s claim amendments.
Regarding claims 2228-230, Wardell-954 teaches a method for expanding tumor infiltrating lymphocytes (TILs) into a therapeutic population of TILs comprising ([0006] of Wardell-954):
(a) obtaining a first population of TILs from a tumor resected from a patient by processing a tumor sample obtained from the patient into multiple tumor fragments ([0007] of Wardell-954);
(b) adding the tumor fragments into a closed system ([0008] of Wardell-954);
(c) performing a first expansion by culturing the first population of TILs in a cell culture medium comprising IL-2, and optionally OKT-3, to produce a second population of TILs, wherein the first expansion is performed in a closed container providing a first gas-permeable surface area, wherein the first expansion is performed for about 3-14 days to obtain the second population of TILs, wherein the second population of TILs is at least 50-fold greater in number than the first population of TILs, and wherein the transition from step (b) to step (c) occurs without opening the system ([0009] of Wardell-954);
(d) performing a second expansion by supplementing the cell culture medium of the second population of TILs with additional IL-2, OKT-3, and antigen presenting cells (APCs), to produce a third population of TILs, wherein the second expansion is performed for about 7-14 days to obtain the third population of TILs, wherein the third population of TILs is a therapeutic population of TILs, wherein the second expansion is performed in a closed container providing a second gas-permeable surface area, and wherein the transition from step (c) to step (d) occurs without opening the system ([0010] of Wardell-954);
(e) harvesting the therapeutic population of TILs obtained from step (d), wherein the transition from step (d) to step (e) occurs without opening the system ([0011] of Wardell-954);
(f) transferring the harvested TIL population from step (e) to an infusion bag, wherein the transfer from step (e) to (f) occurs without opening the system ([0012] of Wardell-954).
(g) administering a therapeutically effective dosage of the TILs from step (e) to the subject ([0052] of Wardell-594).
Furthermore, Wardell-954 discloses that the first period in step (c) and the second period in step (e) are each individually performed within a period of 10 days, 11 days, or 12 days ([0029] – [0030] of Wardell-954).
Wardell-954 teaches as set forth above, but with respect to claims 289-230, Wardell-954 does not teach using OKT-3 in the first expansion step or selecting the PD-1, LAG3 and/or TIM3 enriched TIL population for the expansion. However, such was known in the prior art.
Regarding claims 228-230, Gros teaches a method for expanding tumor infiltrating lymphocytes (TILs) into a therapeutic population of TILs comprising;
a) obtaining population of TILs from a tumor resected from a subject by processing a tumor sample obtained from the subject into multiple tumor fragments (p. 2255 2nd ¶ of Gros);
b) isolated cells from 6 independent fresh tumors based on expression of PD-1, LAG-3, and TIM-3, expanded them in vitro for 15 days with IL-2, anti-CD3 (OKT-3) stimulation (p. 2249 2nd ¶ “Expression of PD-1, LAG-3, and TIM-3 in the tumor identifies tumor reactive T cells” of Gros). Therefore, POSITA would recognize that Gros disclose is obvious to selecting PD-1, LAG3, and TIM3 positive TILs from the population of TILs to obtain a PD-1, LAG3, and/or TIM3 enriched TIL population.
MPEP 2143 (A) states that combining prior art elements according to known methods to yield predictable results. The rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395. Accordingly, it would have been obvious to practice the TIL culture method of Wardell-954 and include selecting the PD-1, LAG3 and/or TIM3 enriched TIL population with OKT3 and IL-2 in the medium as taught by Gros with a reasonable expectation of success. The POSITA would have been motivated at the time of filing to do so as taught by Gros because expression of PD-1 on CD8+ TILs from tumor subject accurately identifies the repertoire of clonally expanded tumor-reactive, mutation-specific lymphocytes and suggest that cells derived from this population play a critical role in tumor regression after TIL administration (p. 2248 1st ¶ of Gros), and OKT-3 and IL-2 are routinely used for TIL expansion (p. 2249 2nd ¶ of Gros). The POSITA would have had a reasonable expectation of success in combining the teachings of Wardell-694 in view of Gros because each of these teachings both successfully expanding tumor TILs. Therefore, the products and method as taught by Wardell-694 in view of Gros would have been prima facie obvious over the method and products of the instant application. In regard to the reasonable expectation of success in doing so, isolating PD-1, LAG3 and/or TIM3 enriched TIL population and include the OKT-3, IL-2 in the cell culture medium of Gros had a reasonable expectation of success since the steps thereof required no more than pipetting the appropriate protein concentration and cell culture technology.
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Response to Traverses
Applicant's arguments filed on 10 December 2025 are acknowledged.
Applicant argue that the Skilled Artisan Would Not Be Motivated to Select PD-1 + TILs for Expansion Because of Their Well-Known Exhaustion Phenotype. Gros (cited in prior office action mailed on 07/10/2025; WO2016179006, hereinafter “Gros-006”) itself underscores the notion that PBMCs and TILs are not equivalent. See remark p. 10 paragraph B.
Applicant arguments have been fully considered but they are not persuasive because the new ground of rejection relies on amendment claims and references applied in the prior rejection of record for any teaching or matter specifically challenged in the argument. In the new rejection, Wardell-694 et al. and in view of Gros et al. addressed the method for expanding tumor infiltrating lymphocytes (TILs) into a therapeutic population of TILs comprising a) obtaining population of TILs from a tumor resected from a subject by processing a tumor sample obtained from the subject into multiple tumor fragments (p. 2255 2nd ¶ of Gros). Furthermore, b) isolated cells from 6 independent fresh tumors based on expression of PD-1, LAG-3, and TIM-3, expanded them in vitro for 15 days with IL-2, anti-CD3 (OKT-3) stimulation (p. 2249 2nd ¶ “Expression of PD-1, LAG-3, and TIM-3 in the tumor identifies tumor reactive T cells” of Gros), therefore, POSITA would recognize that Gros disclose is obvious to selecting PD-1, LAG3, and TIM3 positive TILs from the population of TILs in (a) to obtain a PD-I, CD39, CD38, CD103, CD IOI, LAG3, TIM3 and/or TIGIT enriched TIL population. Accordingly, it would have been obvious to practice the TIL culture method of Wardell-954 and include selecting the PD-1, LAG3 and/or TIM3 enriched TIL population with OKT3 and IL-2 in the medium as taught by Gros with a reasonable expectation of success. The POSITA would have been motivated at the time of filing to do so as taught by Gros because expression of PD-1 on CD8+ TILs from tumor subject accurately identifies the repertoire of clonally expanded tumor-reactive, mutation-specific lymphocytes and suggest that cells derived from this population play a critical role in tumor regression after TIL administration (p. 2248 1st ¶ of Gros), and OKT-3 and IL-2 are routinely used for TIL expansion (p. 2249 2nd ¶ of Gros).
Applicant argues the present claims provide unexpected results showing that PD-1 preselection does not impose an expansion penalty under the claimed two-step process. When the claimed manufacturing protocol is applied, the fold expansion of PD1-preselected TILs during the second expansion phase is comparable to that of unselected TILs (see Figure 21, lower panel, reproduced below). See remark p. 12.
Applicant arguments have been fully considered but they are not persuasive because the new ground of rejection relies on amendment claims and references applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
MPEP 2112.01 states that “Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established,” In re Best (195 USPQ 430) and In re Fitzgerald (205 USPQ 594) discuss the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to "prove that subject matter shown to be in the prior art does not possess characteristic relied on" (205 USPQ 594, second column, first full paragraph). it is noted that the claimed wherein clauses do not recite any additional active method steps, but simply state a function, characterization or measurement of the results of product positively recited (e.g., enhanced target cell killing). In here, In the new rejection, Wardell-694 et al. and in view of Gros et al. addressed the method for expanding tumor infiltrating lymphocytes (TILs) into a therapeutic population of TILs, so the method for expanding TILs would have been obvious. Accordingly, at the time of the invention POSITA would have obvious expectation PD-1 enriched TIL cell population produced by Wardell-694 et al. and in view of Gros et al. as like instant claimed. Therefore, the claimed therapeutic population of TILs have the same structure as the therapeutic population of TILs of Wardell-694 et al. and in view of Gros et al. MPEP 2112.01(II) recites that if the composition is physically the same, it must have the same properties: "Products of identical chemical composition cannot have mutually exclusive properties. In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Accordingly, the therapeutic population of TILs of Wardell-694 will exhibit a significantly enhanced target cell killing, and are not unexpected.
New 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.
Claims 228-230 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of the U.S. Patents set forth below in view of Gros et al. (J Clin Invest. 2014;124(5):2246–2259; cited in IDS filed 07/18/2025; hereinafter “Gros”). The new rejection is necessitated by applicant’s claim amendments.
Claims 228-230 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of the co-pending applications set forth below in view of Gros et al. (J Clin Invest. 2014;124(5):2246–2259; cited in IDS filed 07/18/2025; hereinafter “Gros”). The new rejection is necessitated by applicant’s claim amendments.
The conflicting patented and co-pending claims are drawn to or include the steps of a method for expanding tumor infiltrating lymphocytes (TTLs) into a therapeutic population of TILs comprising some or all of : a) obtaining and/or receiving a first population of TTLs from a tumor resected from a subject by processing a tumor sample obtained from the subject into multiple tumor fragments; b) selecting PD-1 positive TILs from the first population of TILs in (a) to obtain a PD-1 enriched TIL population; c) performing a priming first expansion by culturing the PD-1 enriched TIL population in a cell culture medium comprising IL-2, or OKT-3, and optionally comprising antigen presenting cells (APCs), to produce a second population of TILs, wherein the priming first expansion is performed for a first period of about 11 days to obtain the second population of TILs, wherein the second population of TILs is greater in number than the first population of TILs; d) performing a rapid second expansion by contacting the second population of TILs with a cell culture medium comprising IL-2, OKT-3, and APCs, to produce a third population of TILs, wherein the rapid second expansion is performed for a second period of about 11 days to obtain the third population of TILs, wherein the third population of TILs is a therapeutic population of TILs; e) harvesting the therapeutic population of TILs obtained from step (d) and/or using gas-permeable surfaces and/or an infusion bag; and (g) administering a therapeutically effective dosage of the TILs from step (e) to the subject.
Wardell-694 teaches as set forth above, but does not teach selecting the PD-1, LAG3 and/or TIM3 enriched TIL population for the expansion and using OKT-3 in the first expansion step.
Gros teach as set forth above.
Accordingly, it would have been obvious to practice the TIL culture method of Wardell-954 and include selecting the PD-1, LAG3 and/or TIM3 enriched TIL population with OKT3 and IL-2 in the medium as taught by Gros with a reasonable expectation of success. The POSITA would have been motivated at the time of filing to do so as taught by Gros because expression of PD-1 on CD8+ TILs from tumor subject accurately identifies the repertoire of clonally expanded tumor-reactive, mutation-specific lymphocytes and suggest that cells derived from this population play a critical role in tumor regression after TIL administration (p. 2248 1st ¶ of Gros), and OKT-3 and IL-2 are routinely used for TIL expansion (p. 2249 2nd ¶ of Gros). The POSITA would have had a reasonable expectation of success in combining the teachings of Wardell-694 in view of Gros because each of these teachings both successfully expanding tumor TILs. Therefore, the products and method as taught by Wardell-694 in view of Gros would have been prima facie obvious over the method and products of the instant application. In regard to the reasonable expectation of success in doing so, isolating PD-1, LAG3 and/or TIM3 enriched TIL population and include the OKT-3, IL-2 in the cell culture medium of Gros had a reasonable expectation of success since the steps thereof required no more than pipetting the appropriate protein concentration and cell culture technology.
No.
Patent
Claims
1
10,130,659
1,3,14-18
2
10,166,257
1, 19-20
3
10,272,113
1
4
10,363,273
1, 16
5
10,398,734
1
6
10,420,799
1
7
10,463,697
1
8
10,639,330
1
9
10,646,517
1
10
10,695,372
1
11
10,894,063
1
12
10,918,666
1
13
10,925,900
1
14
11,713,446
1
15
11,384,337
1, 2
16
11,007,225
1
17
11,007,226
1,
18
11,013,770
1
19
11,026,974
1
20
11,040,070
1
21
11,052,115
1
22
11,052,116
1
23
11,168,303
1
24
11,168,304
1
25
11,058,728
1
26
11,083,752
1
27
11,123,371
1
28
11,141,438
1, 2
29
11,179,419
1, 14-15
30
11,202,803
1
31
11,202,804
1
32
11,241,456
1
33
11,254,913
1, 15
34
11,266,694
1
35
11,273,180
1
36
11,273,181
1-3
37
11,291,687
1, 3
38
11,293,009
1
39
11,304,979
1
40
11,304,980
1
41
11,311,578
1-3
42
11,337,998
1-5
43
11,344,579
1
44
11,344,580
1, 2, 5
45
11,344,581
1, 3
46
11,351,197
1, 3
47
11,351,198
1
48
11,351,199
1, 3
49
11,364,266
1, 3
50
11,369,637
1, 3
51
11384337
1
52
11401507
1
53
11433097
1
54
11517592
1
55
11529372
1-23
56
11541077
1
57
11026974
1-2
58
10517894
1
61
11529372
1
62
11713446
1
63
11857573
1-2
64
11865140
1, 3
65
10130659
1, 3, 16, 18
66
10166257
1
67
10272113
1, 3
68
11969444
1, 3
69
10363273
1, 3, 16, 18
70
10398734
1
71
10463697
1
72
10646517
1, 3
73
10695372
1, 3
74
10894063
1
75
10925900
1
76
11007225
1
77
11013770
1, 3
78
11052115
1
79
11052116
1
80
11058728
1
81
11083752
1
82
11123371
1
83
11141438
1, 2
84
11202803
1
85
11202804
1
86
11241456
1
87
11254913
1, 15
88
11266694
1
89
11273181
1
90
11304980
1
91
11311578
1
92
11337998
1
93
11344579
1
94
11344580
1, 2
95
11344581
1,3,12-13
96
11351197
1, 3
97
11364266
1, 3
98
11369637
1, 3, 17-23
99
11433097
1
100
11517592
1
101
11529372
1, 2, 4, 6
102
11541077
1
103
11026974
1-5
104
10517894
1, 12-13
105
11351198
1, 3
106
11351199
1, 3
107
12104172
1-7
108
12031157
1, 23-28
109
12024718
1, 23-28
110
12121541
1, 15
111
11939596
1, 14-15, 20-28
112
11998568
1, 3, 18-23
113
11975028
1, 10-11
No.
Application
Claims
1
17/771723
1, 69, 159
2
17/050552
65
3
17/610671
367-3369
4
17/415175
1-6, 103
5
17/290639
1
6
17/810540
1
7
17/778309
1-3
8
17/110179
1, 17
9
17/147080
1, 22, 24
10
17/147096
1
11
17/817207
1, 3
12
17/817217
1, 18-19
13
17/817226
1, 2, 18-21
14
17/817239
1, 3, 18-22
15
17/817247
1, 2, 15-19
16
17/817273
1, 15-18
17
17/817276
1, 18-20
18
17/819209
1, 2, 12-15, 17-21
19
17/819214
1, 16-22
20
17/819219
1, 3
21
17/819910
1
22
17/823419
1
23
17/823448
1
24
17/823454
1
25
17/829087
1, 7, 15-17, 19-22
26
17/856793
1
27
17/856806
1
28
17/819909
1-2, 15-21
29
16/969362
1, 52
30
18/410900
285, 296-299
31
17/997731
30-31, 50-67, 73-75
32
18/256798
20, 60
33
18/256853
86
34
18/262365
10
35
18/411991
285
36
18/555513
2
37
18/693508
121-122
38
18/745958
71
39
18/781928
12
40
18/832493
242
41
18/832901
9, 85, 155
42
18/262843
1, 10, 33, 156
43
18/560,898
19, 46
44
18/247,877
2, 7,
45
18/477,810
19
46
17/271601
1
47
17/290710
81
48
17/290708
1
RESPONSE TO ARGUMENTS
Applicant's arguments filed on October 9, 2012 are acknowledged.
Applicant argues that the the cited U.S. patent claims have a step of PD-1 preselection during the expansion of the TILs. As described above, Gros would not motivate the skilled artisan to incorporate a PD-1 pre-selection step into the TIL expansion processes recited by any of the claims of the cited patents. Thus, the Applicant respectfully requests that the non-statutory double patenting rejection be withdrawn. See remark p. 14 5th ¶.
Applicant arguments have been fully considered but they are not persuasive because the new ground of rejection addresses the new limitations. Therefore, the references applied in the prior rejection of record for any teaching or matter specifically challenged in the argument. In the new rejection, Wardell-694 et al. and in view of Gros et al. addressed the method for expanding tumor infiltrating lymphocytes (TILs) into a therapeutic population of TILs comprising a) obtaining population of TILs from a tumor resected from a subject by processing a tumor sample obtained from the subject into multiple tumor fragments (p. 2255 2nd ¶ of Gros). Furthermore, b) isolated cells from 6 independent fresh tumors based on expression of PD-1, LAG-3, and TIM-3, expanded them in vitro for 15 days with IL-2, anti-CD3 (OKT-3) stimulation (p. 2249 2nd ¶ “Expression of PD-1, LAG-3, and TIM-3 in the tumor identifies tumor reactive T cells” of Gros), therefore, POSITA would recognize that Gros disclose is obvious to selecting PD-1, LAG3, and TIM3 positive TILs from the population of TILs in (a) to obtain a PD-I, CD39, CD38, CD103, CD IOI, LAG3, TIM3 and/or TIGIT enriched TIL population.
Pertinent References
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure is the following:
Flens et al. (Efficient expansion of tumor-infiltrating lymphocytes from solid tumors by stimulation with combined CD3 and CD28 monoclonal antibodies. Cancer Immunology, Immunotherapy, 1993, 37(5), pp.323-328) provides the teaching of combined CD3 and CD28 mAb are superior to rIL-2 with respect to the initiation of expansion of CD8+ cytolytic TIL from solid tumors. Stimulation with specific tumor antigens at a later stage of culturing may further augment the expansion of tumor-specific cytolytic T cells (abstract).
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MASUDUR RAHMAN whose telephone number is (571)272-0196. The examiner can normally be reached M-F 8-5 (EST).
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/MASUDUR RAHMAN/ Patent Examiner, Art Unit 1633
/JEREMY C FLINDERS/ Primary Examiner, Art Unit 1684