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 .
DETAILED ACTION
Claim Status
Applicant’s amendment filed June 16, 2025 has been received and entered.
Claims 20, 60, 63-67, 80-85, and 87 have been amended.
Claims 1 and 8 have been canceled.
Claims 2-7, 9-19, 21-59, 68-79, 86, and 88-95 were previously canceled.
Claims 20, 60-67, 80-85, and 87 are pending and under consideration.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant’s remarks received June 16, 2025 pointing out the particular places within Provisional Application Nos. 63/146,425 and 63/127,060 that disclose the specific limitations of claims 1, 8, and 20 were found persuasive. Accordingly, Applicant has perfected the priority of the instant application as follows:
This application is a 371 of PCT/US21/63910 filed on December 16, 2021, which claims the benefit of U.S. Provisional Application 63/277,371 filed on November 9, 2021, which claims the benefit of U.S. Provisional Application 63/146,425 filed on February 5, 2021, which claims the benefit of U.S. Provisional Application 63/127,060 filed on December 17, 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on June 16, 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
In view of the Applicant’s amendment, the previous claim objections are withdrawn.
Claim Rejections
In view of the Applicant’s claim amendments and perfection of priority as set forth above, the previous grounds of rejection are withdrawn. The following are new grounds of rejection necessitated by Applicant’s claim amendments and perfection of priority.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 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 20, 60-62, 64-67, 84-85, and 87 are rejected under 35 U.S.C. 103 as being unpatentable over Chesney et al. (Poster No. 290a, ASCO 2019 Annual Meeting: May 31-June 4, 2019) (“Chesney”), in view of Wardell et al. (US 2018/0207201 A1) (“Wardell”).
The instant claims are drawn to a method of treating checkpoint inhibitor naïve cancer by administering tumor infiltrating lymphocytes (TILs) and a PD-1 inhibitor or PD-L1 inhibitor, without administering a CTLA-4 inhibitor. The first population of TILs from a resected tumor is processed into multiple tumor fragments and the therapeutic population of TILs are generated as recited in claim 20 subparagraphs (b) to (f). The therapeutic population of TILs is administered to the patient, followed by administration of a PD-1 inhibitor or PD-L1 inhibitor. The method further comprises treating the patient with a non-myeloablative lymphodepletion regimen comprising cyclophosphamide at a dose of 60 mg/m2/day for two days followed by administration of fludarabine at a dose of 25 mg/m2/day for five days prior to TIL treatment, followed by a high-dose IL-2 regimen comprising 600,000 or 720,000 IU/kg of aldesleukin administered as a 15-minute bolus intravenous infusion every eight hours starting on the same day or day after administration of a therapeutically effective amount of the population of TILs, wherein IL-2 is administered 3-24 hours after completion. The PD-1 inhibitor is pembrolizumab administered at a dose of about 200 mg to about 500 mg every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, or every 6 weeks beginning 1-5 days after IL-2 administration.
Chesney discloses administration of autologous tumor infiltrating lymphocytes (TIL) in combination with pembrolizumab for the treatment of patients with metastatic melanoma, head and neck squamous cell carcinoma (HNSCC), or non-small cell lung cancer (NSCLC) solid tumors. TIL therapy has been previously shown to be effective against tumors with a high mutational burden, and the presence of TIL in the tumor microenvironment (TME) is correlated with long term response and survival. Addition of pembrolizumab to TIL therapy further enhances treatment prior and post TIL infusion by assisting trafficking into the tumor and dampening TME suppressor mechanisms, respectively [Background].
Chesney discloses the treatment protocol for Cohort 1 (melanoma), Cohort 2 (HNSCC), and Cohort 3A (NSCLC) comprising TIL + pembrolizumab administration in patients that are checkpoint inhibitor naïve [Study Design, Fig. 2].
Chesney further discloses the patients are treated with a nonmyeloablative lymphodepletion regimen (NMA-LD) one to seven days prior to TIL transfer comprising cyclophosphamide (60 mg/kg x 2 days) and fludarabine (25 mg/m2 x 5 days). Following TIL transfer, patients receive 6 doses of IL-2 (600,000 IU/kg) starting at Day 1 through Day 4. Patients receive 200 mg IV pembrolizumab every 3 weeks (Q3W) following IL-2 completion for 24 months or until disease progression or unacceptable toxicity [Study Flowchart].
In addition, Chesney teaches an abbreviated protocol for TIL manufacturing with a processing time of ≤ 22 days, comprising removing a patient’s tumor via surgical resection, fragmenting the tumor and placing in media for TIL to leave the tumor and enter the media, and exponentially expanding the TIL ex vivo via IL-2 + OKT3. Fig. 1 shown below, shows the TILs are kept in a closed system during processing before cryopreservation. The cryopreserved TIL infusion product is delivered to the patient for infusion. Fig. 1 clearly shows a patient being administered the TILs from an infusion bag.
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The teachings of Chesney differ from the instant invention, in that even though TIL + pembrolizumab therapy for the treatment of PD-1/PD-L1 naïve cancer patients, including steps for TIL manufacturing are taught, the number of days for each expansion are not. In addition, Chesney teaches the high-dose IL-2 regimen starting at day 1 as recited in the instant claims, but does not explicitly teach can be administered the day after TIL transfer or that it is administered as a 15-minute bolus infusion every 8 hours.
Wardell teaches improved and shortened methods expanding tumor infiltrating lymphocytes (TILs) into a therapeutic population of TILs comprising: (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; (b) adding the tumor fragments into a closed system; (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, and wherein the transition from step (b) to step (c) occurs without opening the system; (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 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; (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; and (f) transferring the harvested TIL to an infusion bag; and further comprising the step of cryopreserving the infusion bag comprising the harvested TIL using a cryopreservation process.
In addition, Wardell teaches the high-dose IL-2 regimen comprising 600,000 IU/kg of aldesleukin administered on the day after administration of the TIL cells as a I5-minute bolus intravenous infusion every eight hours until tolerance [0068].
It would have been obvious at the time of filing the instant invention to combine the protocols of Chesney with those of Wardell. Chesney teaches administering TIL in combination with pembrolizumab for treating melanoma in anti-PD-1/PD-L1 naïve patients, however, does not provide timing or duration of IL-2 administration or a detailed protocol for TIL production. Methods for treatment with autologous TIL that include IL-2 administration post transfer were known in the art at the time of filing, and a skilled artisan would easily be able to obtain detailed protocols for TIL production and transfer as evidenced by Wardell, and both Chesney and Wardell teach methods for IL-2. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claims 20, 60-61, 63, and 83 are rejected under 35 U.S.C. 103 as being unpatentable over Clinical Trial No. NCT02621021 (ver. 55: 2019-06-01) (“Trial ‘021”), in view of Wardell et al. (US 2018/0207201 A1) (“Wardell”).
The instant claims are drawn to a method of treating checkpoint inhibitor naïve cancer by administering tumor infiltrating lymphocytes (TILs) and a PD-1 inhibitor or PD-L1 inhibitor, without administering a CTLA-4 inhibitor. The first population of TILs from a resected tumor is processed into multiple tumor fragments and the therapeutic population of TILs are generated as recited in claim 20 subparagraphs (b) to (f). The therapeutic population of TILs is administered to the patient, followed by administration of a PD-1 inhibitor or PD-L1 inhibitor, where the PD-1 inhibitor is pembrolizumab administered at a dose of 0.5 mg/kg to 10 mg/kg further comprising the step of treating the patient with a non-myeloablative lymphodepletion regimen prior to administering the TILs comprising administration of cyclophosphamide at a dose of 60 mg/m2/day for two days followed by administration of fludarabine at a dose of 25 mg/m2/day for five days, wherein the cyclophosphamide is administered with mesna.
Trial ‘021 teaches a randomized and Phase 2 trial for treating metastatic melanoma using adoptive cell therapy with tumor infiltrating lymphocytes (TIL) plus IL-2 and pembrolizumab. Trial ‘021 teaches two experimental cohorts for treatment of metastatic melanoma, wherein Cohort 2 comprises a non-myeloablative conditioning regimen, TIL, and high-dose IL-2 in combination with pembrolizumab in patients with metastatic melanoma who have not received prior anti-PD-1/PD-L1 therapy (Detailed Description).
The protocol for Cohort 2 comprises a non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine, wherein cyclophosphamide is administered at a dose of 60 mg/m2/day with mesna and fludarabine is administered at a dose of 25 mg/m2/day daily for five days. IL-2 is administered at 720,000 IU/kg IV over 15 minutes beginning within 24 hours of cell infusion. Pembrolizumab is administered at a dose of 2 mg/kg every three weeks.
Trial ‘021 does not teach TIL manufacturing protocols.
Wardell teaches TIL manufacturing protocols as set forth in the rejection above.
Protocols for non-myeloablative lymphodepletion were readily available at the time of filing the instant invention. The skilled artisan would have a reasonable expectation of success in treating PD-1/PD-L1 naïve patients with a treatment that includes mesna, because Trial ‘021 teaches the method for use in melanoma patients that are PD-1/PD-L1 naïve undergoing TIL + pembrolizumab therapy, including dosing based on body weight. As such, the combination of prior art references provided a prima facie case of obviousness.
Claims 20 and 81-82 are rejected under 35 U.S.C. 103 as being unpatentable over Clinical Trial No. NCT03215810 (ver. 14: 2019-11-08) (“Trial ‘810”), in view of Wardell et al. (US 2018/0207201 A1) (“Wardell”).
The instant claims are drawn to a method of treating checkpoint inhibitor naïve cancer by administering tumor infiltrating lymphocytes (TILs) and a PD-1 inhibitor or PD-L1 inhibitor, without administering a CTLA-4 inhibitor. The first population of TILs from a resected tumor is processed into multiple tumor fragments and the therapeutic population of TILs are generated as recited in claim 20 subparagraphs (b) to (f). The therapeutic population of TILs is administered to the patient, followed by administration of a PD-1 inhibitor or PD-L1 inhibitor, wherein the PD-1 inhibitor is nivolumab that is administered at a dose of about 200 mg to about 500 mg every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, or every 6 weeks.
Trial ‘810 teaches the benefits of tumor-infiltrating lymphocytes (TILs) when they are given with nivolumab (Brief Summary) for the treatment of stage IV or recurrent non-small cell lung cancer (NSCLC) in patients that have not had any previous treatment with a PD-1 or PD-L1 inhibitor (Eligibility). A sample of the participant's tumor tissue that is surgically removed, and cells will be grown in the laboratory using interleukin-2 (IL-2) during part of the process. The TILs are given back to the participant by an infusion in their veins. The use of TILs involves two types of chemotherapy drugs, fludarabine and cyclophosphamide which are used for lymphodepletion. The purpose of lymphodepletion is to temporarily reduce the number of normal lymphocytes circulating in the body before TIL transfer so that there will be more "space" for the TILs that will be infused. IL-2 is used to help the body's response to treatment on the immune system, and a high dose regimen of IL-2 is given after the infusion of the TILs (Detailed Description).
Trial ‘810 teaches the protocol wherein tumor cells are harvested for TIL growth in the lab. Nivolumab is administered intravenously at a fixed dose of at a fixed dose of 480 mg every 4 weeks after TIL administration (Arms and Interventions).
Trial ‘810 does not teach TIL manufacturing protocols.
Wardell teaches TIL manufacturing protocols as set forth in the rejection above.
It would have been obvious to one of ordinary skill in the art to obtain dosing protocols for nivolumab from those available in the art and tested in clinical trials, including a flat 480 mg dose as taught by Trial ‘810. One would have a reasonable expectation of success in utilizing this dose to treat PD-1/PD-L1 naïve cancers with TIL + nivolumab therapy because Trial ‘810 teaches this regimen for PD-1/PD-L1 naïve NSCLC. As such, the combination of prior art references provided a prima facie case of obviousness.
Claims 20 and 80 are rejected under 35 U.S.C. 103 as being unpatentable over Clinical Trial No. NCT03215810 (ver. 14: 2019-11-08) (“Trial ‘810”), in view of Wardell et al. (US 2018/0207201 A1) (“Wardell”), as applied to claim 20 above, and in further view of Nivolumab FDA Office of Clinical Pharmacology Review; June 18, 2018.
The instant claims are drawn to a method of treating checkpoint inhibitor naïve cancer by administering tumor infiltrating lymphocytes (TILs) and a PD-1 inhibitor or PD-L1 inhibitor, without administering a CTLA-4 inhibitor. The first population of TILs from a resected tumor is processed into multiple tumor fragments and the therapeutic population of TILs are generated as recited in claim 20 subparagraphs (b) to (f). The therapeutic population of TILs is administered to the patient, followed by administration of a PD-1 inhibitor or PD-L1 inhibitor, wherein the PD-1 inhibitor is nivolumab that is administered at a dose of about 0.5 mg/kg to about 10 mg/kg
The teachings of Trial ‘810 and Wardell are set forth above.
Trial ‘810 and Wardell do not teach a mg/kg dose for nivolumab.
The FDA reviewed dosing for nivolumab in 2018, approving a 480 mg IV dosage every two weeks in addition to the original approved nivolumab dosage regimen of 3 mg/kg every two weeks.
Accordingly, at the time of filing the instant invention it was known in the art that nivolumab can be administered in flat 480 mg dose as taught by Trial ‘810 or as a 3 mg/mL dose as evidenced by the FDA review. As such, the combination of prior art references provided a prima facie case of obviousness.
Response to Arguments
Applicant’s arguments with respect to claims 20, 60-67, 80-85, and 87 have been considered but are moot because the new grounds of rejection do not rely on Clinical Trial No. NCT02621021 ver. 71 or Fardis et al. (WO 2020/096989) as the primary reference applied in the prior rejections of record for any teaching or matter specifically challenged in the argument.
Double Patenting - Maintained
Pursuant to 37 CFR 1.78(f), when two or more applications filed by the same applicant or assignee contain patentably indistinct claims, elimination of such claims from all but one application may be required in the absence of good and sufficient reason for their retention during pendency in more than one application. Applicant is required to either cancel the patentably indistinct claims from all but one application or maintain a clear line of demarcation between the applications. See MPEP § 822.
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 20, 60-67, 80-85, and 87 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of following copending applications in view of the references set forth in the rejections above.
Although the claims at issue are not identical, they are not patentably distinct from each other because the applications have overlapping subject matter that either anticipates or renders obvious the instant claimed invention in view of the references set forth in the rejections above.
These are provisional nonstatutory double patenting rejections.
COPENDING APPLICATION No.
COPENDING CLAIMS
17/290,639
21-27, and 30
18/674,562
96-97, 99, 103-108, and 114-117
18/849,440
At least claims 1-3 of claims 1-329
18/886,988
1, 6-15, 20, and 22-27
Double Patenting – Withdrawn
The previous nonstatutory double patenting rejections over copending Application Nos. 16/211,159 (US Patent No. 11433097B2), 18/247,877, 18/256,853, 18/262,365, 18/674,755, 18/832,493, and 18/832,901 have been withdrawn after further consideration and/or amendments to the instant claims or copending claims.
Conclusion
No claim is allowed.
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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAUREEN DRISCOLL whose telephone number is (571)270-0730. The examiner can normally be reached Monday through Friday.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Daniel Kolker can be reached on (571) 272-3181. The fax phone number for the organization where this application or proceeding is assigned is (571) 273-8300.
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/MAUREEN VARINA DRISCOLL/ Examiner, Art Unit 1644
/DANIEL E KOLKER/Supervisory Patent Examiner, Art Unit 1644