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 .
Status of the Claims
The following Office Action is in response to Applicant’s communication dated 3/16/2026.
Claims 367-382, and 386-396 are pending.
Claims 367, 378 are amended.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 3/26/2026 has been entered.
Response to Arguments
Applicant’s arguments, filed 3/16/2026 with respect to Cohen’s deficiencies in teaching the sorting or removal of TIL based on IFN-gamma expression, the have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground of rejection is made in view of Miltenyi.
Applicant is correct to point out that Cohen does not sort or otherwise isolate/remove TILS based on their expression of IFN-gamma. Cohen’s method instead consists of 1) exposing TILs to mutant polypeptide, 2) Sorting those cells based on the TIL’s ability to bind a specific antigen via a fluorescent tetramer, 3) expansion of those cells under REP, and finally, 4) later verification that the previously sorted cells are expressing/secreting IFN-gamma measured via ELISA in the culture supernatant, which also would not verify that each and every sorted cell was excreting interferon gamma, only that at least some of them are. This appears reasonable since IFN-gamma is excreted, and not membrane bound. Cohen’s method of sorting relies entirely on FACS/flow cytometry, and the sorting in this way using a fluorophore directed to IFN-gamma would, at least for FACS, appear to be of limited to no use in determining which cells were expressing IFN-gamma.
However, the claim limitation requires that the maker consists of IFN-gamma. So, this claim would read on a method that sorted cells based on the expression of IFN-gamma, or IFN-gamma and PD-1, and any number of other markers. Cohen was only sorting initially based on the presence of an antigen specific marker, but f Cohen could have sorted based on IFN-gamma as well as their more specific antigen binding marker (fluorescent tetramer), they may have been motivated to do so in order to remove the extra confirmation step. Miltenyi as explained in the rejection below is a protocol for a publicly available kit, which was designed to label viable IFN-gamma producing cells for sensitive detection by flow cytometry (i.e, sorting and removal of cells expressing IFN-gamma).
Wickstrom, Cohen and Miltenyi
Claims 367-380 and 386-396 are rejected under 35 U.S.C. 103 as being unpatentable over:
Cohen (Cohen, Cyrille J., et al. "Isolation of neoantigen-specific T cells from tumor and peripheral lymphocytes." The Journal of clinical investigation 125.10 (2015): 3981-3991.) (of record),
Wickström, S., Lövgren, T. (2019). Expansion of Tumor-Infiltrating Lymphocytes from Melanoma Tumors. In: Pico de Coaña, Y. (eds) Immune Checkpoint Blockade. Methods in Molecular Biology, vol 1913. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-8979-9_7 (22 January 2019) (of record), and
Miltenyi (IFN-γ Secretion Assay – Detection Kit (PE) package insert)
Regarding claim 367 and 378, Cohen teaches a method of producing a therapeutic population of TILs that recognize a mutant polypeptide of a patient, wherein the mutant polypeptide comprises mutations not present in a normal tissue of the patient. (Cohen, Abstract). Cohen teaches incubation of TILs from a patient with mutant polypeptides using MHC tetramers. Cohen teaches that T cells were incubated for 60 minutes with fluorophore-conjugated Abs or Tetramers (mutant polypeptides), and T cells were then isolated using a cell sorter and collected. These cells were then expanded to large numbers using a rapid expansion protocol (REP) with IL-2, anti-CD3 Ab and irradiated feeder cells. (I.e., the claimed priming first expansion step). (Cohen, pg.3990, sorting and rapid expansion protocol). Cohen demonstrates that by using their method, T cells specific for neoantigens can be sorted and expanded in vitro by a factor of 1,000-fold or more. (Cohen, 3982, introduction, last para).
IFN-gamma - Miltenyi
Regarding the IFN-gamma biomarker, Cohen teaches that IFN-gamma was used to later identify /confirm that their sorted TILs were activated. (Cohen, 3983, “Isolation of tetramer-reactive T cells from treatment TIL cultures”). But Cohen fails to teach sorting (“removing based on a biomarker specific antibody”) TILS based on IFN-gamma expression. Instead, Cohen just later verifies that the previously sorted cells were indeed secreting IFN-gamma.
The key issue then becomes whether sorting of T cells by IFN-gamma production was known in the art already, and if so, would there be some motivation for Cohen to just sort the cells by IFN-gamma as well as the specifically-bound tetramer at the same time, instead of just confirming activation status later.
Miltenyi is a package insert for a commercially available kit for the detection of IFN-gamma secretion, and more importantly, specifically designed for detection by flow cytometry. Miltenyi accomplishes this by first stimulating the T cells with antigen, subsequently capturing secreted IFN-gamma on the cell surface, and then directing a (labeled) IFN-gamma detection antibody. Miltenyi teaches that their kit allows for sensitive detection by flow cytometry of viable cells, and that the kit is specially developed for the detection and isolation of antigen-specific T cells. (Miltenyi 1.1).
It would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date of the application to Miltenyi’s kit to label IFN-gamma in Cohen’s method. One of ordinary skill in the art would have been motivated to do so, since Cohen still recognized the necessity to identify activated TILS, Cohen just waited until after the sorting step to do so. The skilled artisan would be motivated to sort based on IFN-gamma as well, since if Cohen could just sort those same cells based on both antigen specificity (tetramers) and cell activation status (IFN-gamma using a commercially available Miltenyi kit), at the same time, Cohen could save the later step of having to confirm that those cells were indeed activated.
One of ordinary skill in the art would have had a reasonable expectation of success, since Miltenyi advertises that their assay is effective for the highly sensitive detection and isolation of antigen-specific T cells.
Regarding the publication date of the Miltenyi kit insert, this appears to be the latest kit insert, but the citations (According to the Document properties, the Detection kit Assay protocol was created on July 2, 2021. The last page indicates a copyright of 2021. The priority date for this application is 11/11/2021. In any event, the citations page of the Miltenyi website (attached as Miltenyi website) refers to publications dating back to 2001 that used this kit. Thus, it is reasonable to believe that this kit was publicly available before the priority date.
Wickstrom’s resting step and rapid expansion protocol reads on steps (b) and (c)
Steps (b) and (c) appear to read on a rapid expansion protocol which is taught by Cohen and described in more detail by Wickstrom. Regarding step (b), Cohen teaches that their responsive TIL are submitted to a rapid expansion protocol (REP) with IL-2, anti-CD3 Ab (OKT-3), and irradiated feeder cells (APC). (Cohen, pg.3990, sorting and rapid expansion protocol). Cohen does not describe the REP in detail, as it appears to be a protocol that is well known in the art. Wickstrom teaches that the REP consists of expanding TIL in the presence of irradiated PBMC (i.e. irradiated feeder cells of Cohen), IL-2, anti-CD3 antibody (OKT-3), serum, with additional IL-2 added at day 5, 9, and 12 with a total cell culture length of 9-14 days. Wickstrom teaches that the REP may take place in a GREX flask, i.e. a flask with a gas-permeable membrane. (Wickstrom, Fig. 1). Wickstrom teaches the refreshing of the culture media at day 7 and additional IL-2 at day 5, 9, and 12, reading on the IL-2 supplementation limitation of step c.
The claim as written appears to require three distinct steps. (1) Culture and sorting of responsive TIL. (2) Expanding those sorted TIL in the presence of IL-2 for at least one day. (3) supplementing the cell culture medium of step 2 with the claimed components.
Wickstrom’s optional resting step only includes IL-2 and reads on step (b)
Wickstrom teaches an optional IL-2 only resting step before REP is started if the TIL were frozen after the first expansion step (Wickstrom 3.2 steps 1-6). Wickstrom teaches that it would apparently be routine to freeze TIL after the initial expansion (sorted or otherwise) and if that freezing step is carried out, that an initial IL-2 only resting step should take place before REP begins. Cohen teaches expanding TIL, followed by immediately sorting those TIL, followed by REP. Thus, if Cohen were motivated to freeze the sorted cells prior to REP as a routine practice, then Cohen would also be motivated to culture the thawed, sorted, responsive TIL in IL-2 only for 1-2 days before REP is started as taught by Wickstrom (which would read on step (b)) and then continuing on to REP with IL-2, OKT-3, and APCs (step (c)).
It would have been obvious to the skilled artisan to use Wickstrom’s REP protocol as the REP protocol in Cohen’s TIL sorting and expansion method, including Wickstrom’s thawing/resting step.
One of ordinary skill in the art would have been motivated to do so, since Cohen’s method includes a REP step after the initial TIL expansion and sorting step. Wickstrom provides a detailed protocol for REP of TILs, including a resting step in the event that the expanded TIL are frozen which is evidently routine enough for instructions for that eventuality being included in the protocol. So, the skilled artisan of Cohen would, after routinely freezing their sorted and responsive TIL prior to REP, would be motivated to use Wickstrom’s detailed REP protocol, which includes a step for resting frozen TIL in IL-2 only media for a time, followed by conventional REP protocol, reading on steps (b) and (c) in particular.
One of ordinary skill in the art would have had a reasonable expectation of success, since Cohen essentially teaches the first identifying and sorting neoreactive TIL prior to the claimed expansion method, which is described in more detail in Wickstrom.
There are also slight differences in culture times between Wickstrom’s method and the claimed methods.
Claim 367’s time period for the first expansion is 1 to 7 or 8 days. Claim 378’s time period for the first expansion is 3-14 days. Wickstrom teaches that their initial expansion step takes place for about 2-4 weeks, with periodic assessments of TIL outgrowth during that time, and with a shorter time period being preferable. (Wickstrom pg 110). Claim 367’s second expansion is 1-11 days. Claim 378’s time period for the second expansion is 7-14 days. Wickstrom teaches that the second expansion step may take place for up to 14 days, with the cells being harvested on day 14 at the latest. (Wickstrom pg 112). In any event these culture periods overlap, and thus would be obvious to the skilled artisan. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In reWertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976) (MPEP 2144.05(I).
Wickstrom teaches the use of GREX containers (G containers), which are containers comprising a gas permeable surface area, as part of their protocol. (Wickstrom pg. 106-107).
Regarding claim 368, Cohen teaches the transfer of TILs to an infusion bag (Cohen Fig. 6).
Regarding claim 369, Cohen teaches the expansion of neoantigen specific TILs after the initial sorting and expansion step. (Cohen, 3990, left col.).
Regarding claim 370-371, Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Selection of a particular seeding density would be arrived at through routine optimization of a cell culture protocol, and thus would be obvious to the skilled artisan.
Regarding claim 372, Wickstrom teaches that the cell culture medium supplemented with 6000 IU/ml IL-2 during REP (Wickstrom, 3.2 step 6).
Regarding claim 373, Wickstrom teaches that their optional resting step (claimed priming first expansion step) takes place for about 1-2 days. (Wickstrom 3.2). However, the claimed time period is at least 5 days. Wickstrom’s resting step does not appear to be constrained to only about 2 days, and reasonably the skilled artisan would be able to extend this resting period as a part of routine optimization, for example if the cells upon observation are still stressed and require a longer resting period. Another reason to extend this step may be if the cell culture needs to be extended for simple convenience reasons, for example resting the cells over a holiday weekend to begin REP at the beginning of the next week. [W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Regarding claim 374, Wickstrom teaches that the second expansion step (REP) may take place for 9 to 14 days. (Wickstrom pg 112, Fig. 1).
Regarding claim 375, Wickstrom’s entire protocol appears to take anywhere from less than 4 weeks to up to 6 weeks. But again, Wickstrom appears to suggest moving cells onto the next step and harvesting them as soon as they are ready instead of rigidly adhering to their protocol’s timeframe. A prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of Americav.Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985)
Regarding claim 376-377, Cohen teaches that it is feasible to use their method to isolate T cells specific for mutated epitopes in patients with metastatic melanoma and lay the groundwork for designing novel and personalized immunotherapeutic strategies for the treatment of advanced cancers. Cohen does not specifically teach what an exact therapeutic dose would be, but still teaches that their process would result in a therapeutically effective population of TILs. The selection of a specific dosage of these cells that would be therapeutically effective would be arrived at through routine optimization by the skilled artisan, as the skilled artisan would adjust the number of TILs to arrive at a therapeutically effective dose as needed, and thus would be obvious to the skilled artisan. (MPEP2144 (II)(A)).
Regarding claim 379-380, Cohen identifies cytokines, including IFN-γ by ELISA in their (already sorted) population. It is noted that here the term “identifies” is interpreted to have a different meaning than “removed”. That is, this identification step may occur anytime in the protocol, either before or after removal/sorting of TILS expressing IFN-gamma (Cohen, 3990)
Regarding claim 386-389, Cohen teaches positive/negative cell sorting, including the use of fluorescent tags (Cohen 3982 left column, 3989-3990 bridging para.).
Regarding claim 390-391, Cohen teaches that their TILS may be either CD8+ or CD4+ (Cohen Fig. 3 D)
Regarding claim 392, Wickstrom teaches the use of irradiated PBMC as feeder cells as part of a cell culture protocol for expansion of tumor-infiltrating lymphocytes.
Regarding claim 393, Wickstrom teaches that their feeder cells are irradiated autologous or allogenic PBMC. (Wickstrom pg. 106, last para.)
Regarding claim 394, Wickstrom teaches adding feeder cells in the rapid expansion protocol step. Wickstrom teaches that the initial expansion of TIL from tumor material is dependent on a few factors including the amount of tumor received, efficacy of TIL outgrowth, and the number of G-rex flasks used. Wickstrom teaches that this initial expansion usually takes between 2 and 4 weeks, and a shorter timeframe is preferable. (Wickstrom pg 110, first para). These cells are then harvested and used in the rapid expansion protocol, which takes place in the presence of the PBMC feeder cells. (Wickstrom pg 110).
So, Wickstrom teaches that the PBMCs (i.e., step (c)) may be added to the cell culture on day 14 of cell culture.
Regarding claim 395, Wickstrom teaches that artificial APC may be used as well. (Wickstrom pg 114 para # 5).
Regarding claim 396, Wickstrom is more concerned with culturing TILs from tumor resections, and does not specify an initial cell seeding density. However, generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Selection of a particular seeding density would be arrived at through routine optimization of a cell culture protocol, and thus would be obvious to the skilled artisan.
Wickstrom, Cohen, Miltenyi, and Chen
Claims 367-384, and 386-396 are rejected under 35 U.S.C. 103 as being unpatentable over:
Wickström, S., Lövgren, T. (2019). Expansion of Tumor-Infiltrating Lymphocytes from Melanoma Tumors. In: Pico de Coaña, Y. (eds) Immune Checkpoint Blockade. Methods in Molecular Biology, vol 1913. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-8979-9_7 (22 January 2019) (of record)
Cohen (Cohen, Cyrille J., et al. "Isolation of neoantigen-specific T cells from tumor and peripheral lymphocytes." The Journal of clinical investigation 125.10 (2015): 3981-3991.) (of record)
Miltenyi (IFN-γ Secretion Assay – Detection Kit (PE) package insert)
Chen (Chen, Fangjun, et al. "Neoantigen identification strategies enable personalized immunotherapy in refractory solid tumors." The Journal of clinical investigation 129.5 (2019): 2056-2070.) (of record)
Claims 367-380 and 386-396 are maintained as obvious in view of Wickstrom, Cohen, and Miltenyi.
Regarding claim 381-382, Cohen teaches the measurement of cytokines in the already sorted TIL population, particularly IFN-gamma, but does not specifically teach the measurement of TNF-alpha or beta, or PD-1 to identify these TILs stimulatory activity.
Chen describes methods for identifying neoantigens, and the activation of T cells in response to those neoantigens. (Chen, Title, Abstract). Regarding using TNF as a marker specifically to identify activated lymphocytes, Chen teaches the identification of neoantigen reactive T cells by measuring TNF. (Chen, Abstract, pg. 2062, left col. First para.).
It would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date of the application to use TNF, as a marker of TIL stimulatory activity as taught by Chen, with the TIL sorting/expansion method taught by Cohen and Wickstrom. One of ordinary skill in the art would have been motivated to do so, since this combination would be combining prior art elements according to known methods (TNF as a marker for lymphocyte stimulation) to yield predictable results (identification of stimulated lymphocytes). Cohen already teaches sorting TIL based on certain markers, but just does not specify that TNF is one of those markers. Chen however teaches that TNF is such a marker.
One of ordinary skill in the art would have had a reasonable expectation of success, since Chen demonstrates identification of stimulated lymphocytes based on a TNF marker.
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.
U.S. Patent No. 11337998, and Cohen
Claims 367-371, 373-380, and 386-391 are rejected on the ground of nonstatutory double patenting as being unpatentable over:
Claim 1 of U.S. Patent No. 11337998, application 17/480,596 (hereinafter “998”) (of record)
Cohen (Cohen, Cyrille J., et al. "Isolation of neoantigen-specific T cells from tumor and peripheral lymphocytes." The Journal of clinical investigation 125.10 (2015): 3981-3991.) (of record)
Regarding claim 367 and 378, -998’s claim 1 discloses a population of expanded TILs that are obtainable by a method comprising isolating a first population of TILS form tumor resected tissue. Then the TILs undergo a first expansion, in a closed container with a gas-permeable surface area, in a cell culture medium comprising IL-2, for about 3-11 days to obtain a second population of TILs. 596 then performs a second expansion of the first population by supplementing the medium with additional IL-2, OKT-3, and APC for a period of 7-11 days to obtain a third population of TILs. These cells are then harvested.
There are only a few notable differences between claim 1 of 596 and the present claim 367. Generally, the present claim 367 appears to be narrower in scope than the method disclosed in claim 1 of the 596 application. These differences are namely:
(1) The separation step, step (a). This application requires the separation from the patient TILS that are activated by a mutant polypeptide from those that are not activated by the mutant polypeptide to form a first population of responsive TILS. -998 appears to not require separation of TILs based on activation status, but they do use TILs from “dissociated tumor materials” comprising their first population of TILs. It is reasonable that at least some of the TILS in that resected tumor tissue may be reactive to that mutant tissue/peptide, but 596 does not specifically teach, in the claims, that their first population of TILs would necessarily be reactive to mutant peptides in that resected tissue, nor that these TILs need to be separated from non-reactive TILs prior to expansion.
This step is taught by Cohen. Cohen teaches the identification, isolation, and expansion of neoantigen reactive TILs prior to immune therapy, which Cohen teaches will potentially provide the basis for designing personalized immunotherapies to treat patients with advanced cancer. (Cohen, Abstract). Cohen’s expansion method also includes an initial expansion of TILs in the presence of IL-2, (Cohen, pg. 3989 “Subjects and cell lines” section) identification and isolation of reactive TILs, and then a second rapid expansion in the presence of IL-2, and irradiated feeder cells (APCs) (Cohen pg. 3990, left column, “Sorting and Rapid Expansion”).
It would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date of the application to use the primary and secondary expansion method disclosed in claim 1 of -998, with the initial identification and sorting step for TILs prior to expansion as taught by Cohen. One of ordinary skill in the art would have been motivated to do so, since Cohen provides a teaching, suggestion, or motivation that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Specifically, Cohen’s expansion method reads on the claimed expansion method almost directly, with the exception of the “gas permeable” container limitations which are instead taught by the reference application. The substantive culture steps, as well as the initial identification and sorting of neoantigen reactive TIL however are taught by Cohen
One of ordinary skill in the art would have had a reasonable expectation of success, since Cohen essentially teaches the first identifying and sorting neoreactive TIL prior to the claimed expansion method.
(2) Culture time differences. There are small differences in culture times. -998’s first expansion period is 3-11 days, while this app’s first expansion period is 1 to 7, or 1 to 8 days. -998’s second expansion step is 7-11 days, while this app’s second expansion is 1-11 days. In any event these culture periods overlap, and thus would be obvious to the skilled artisan. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In reWertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976) (MPEP 2144.05(I).
Regarding claim 368, Cohen teaches the transfer of TILs to an infusion bag (Cohen Fig. 6).
Regarding claim 369, Cohen teaches the expansion of neoantigen specific TILs after the initial sorting and expansion step. (Cohen, 3990, left col.).
Regarding claim 370-371, Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Selection of a particular seeding density would be arrived at through routine optimization of a cell culture protocol, and thus would be obvious to the skilled artisan.
Regarding claim 373-375, -998’s first expansion period is 3-11 days, while this app’s first expansion period is 1 to 7, or 1 to 8 days. -998’s second expansion step is 7-11 days, while this app’s second expansion is 1-11 days. In any event these culture periods overlap, and thus would be obvious to the skilled artisan. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In reWertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976) (MPEP 2144.05(I).
Regarding claim 376-377, Cohen teaches that it is feasible to use their method to isolate T cells specific for mutated epitopes in patients with metastatic melanoma and lay the groundwork for designing novel and personalized immunotherapeutic strategies for the treatment of advanced cancers. Cohen does not specifically teach what an exact therapeutic dose would be, but still teaches that their process would result in a therapeutically effective population of TILs. The selection of a specific dosage of these cells that would be therapeutically effective would be arrived at through routine optimization by the skilled artisan, as the skilled artisan would adjust the number of TILs to arrive at a therapeutically effective dose as needed, and thus would be obvious to the skilled artisan. (MPEP2144 (II)(A)).
Regarding claim 378, and the inclusion of OKT-3 in step c, the reference patent includes OKT-3 in the second expansion in claim 1.
Regarding claim 379-380, Cohen measures cytokines, including IFN-γ. (Cohen, 3990)
Regarding claim 386-389, Cohen teaches positive/negative cell sorting, including the use of fluorescent tags (Cohen 3982 left column, 3989-3990 bridging para.).
Regarding claim 390-391, Cohen teaches that their TILS may be either CD8+ or CD4+ (Cohen Fig. 3 D)
U.S. Patent No. 11337998, Cohen, and Chen
Claims 367-371, 373-382, and 386-391 are rejected on the ground of nonstatutory double patenting as being unpatentable over:
Claim 1 of U.S. Patent No. 11337998, application 17/480,596 (hereinafter “998”) (of record)
Cohen (Cohen, Cyrille J., et al. "Isolation of neoantigen-specific T cells from tumor and peripheral lymphocytes." The Journal of clinical investigation 125.10 (2015): 3981-3991.) (of record)
Chen (Chen, Fangjun, et al. "Neoantigen identification strategies enable personalized immunotherapy in refractory solid tumors." The Journal of clinical investigation 129.5 (2019): 2056-2070.) (of record)
Claims 367-371, 373-380, and 386-391 are maintained as obvious in view of Claim 1 of U.S. Patent No. 11337998 and Cohen.
Regarding claim 381-382, Cohen teaches the measurement of cytokines in the initial sorted TIL population, particularly IFN-gamma, but does not specifically teach the measurement of TNF-alpha or beta, or PD-1 to identify these TILs stimulatory activity.
Chen however at least teaches the identification of neoantigen reactive T cells by measuring TNF. (Chen, Abstract, pg. 2062, left col. First para.). Regarding using TNF as a marker specifically to identify activated lymphocytes, Chen teaches the identification of neoantigen reactive T cells by measuring TNF. (Chen, Abstract, pg. 2062, left col. First para.).
It would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date of the application to use TNF, as a marker of TIL stimulatory activity as taught by Chen, with the TIL sorting/expansion method taught by Cohen and Wickstrom. One of ordinary skill in the art would have been motivated to do so, since this combination would be combining prior art elements according to known methods (TNF as a marker for lymphocyte stimulation) to yield predictable results (identification of stimulated lymphocytes). Cohen already teaches sorting TIL based on certain markers, but just does not specify that TNF is one of those markers. Chen however teaches that TNF is such a marker.
One of ordinary skill in the art would have had a reasonable expectation of success, since Chen demonstrates identification of stimulated lymphocytes based on a TNF marker.
U.S. Patent No. 11337998, Cohen, and Wickstrom
Claims 367-380, and 386-396 are rejected on the ground of nonstatutory double patenting as being unpatentable over:
Claim 1 of U.S. Patent No. 11337998, application 17/480,596 (hereinafter “998”) (of record)
Cohen (Cohen, Cyrille J., et al. "Isolation of neoantigen-specific T cells from tumor and peripheral lymphocytes." The Journal of clinical investigation 125.10 (2015): 3981-3991.) (of record)
Wickström, S., Lövgren, T. (2019). Expansion of Tumor-Infiltrating Lymphocytes from Melanoma Tumors. In: Pico de Coaña, Y. (eds) Immune Checkpoint Blockade. Methods in Molecular Biology, vol 1913. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-8979-9_7 (22 January 2019) (of record)
Claims 367-371, 373-380, and 386-391 are maintained as obvious in view of U.S. Patent No. 11337998, and Cohen.
Regarding claim 372, Cohen does not specify that the containers are necessarily GREX containers. Wickstrom’s method is very similar to the claimed method, and like Cohen appears to read on the claimed method except for the initial identification and sorting step. Wickstrom teaches the use of GREX containers as part of their protocol. (Wickstrom pg. 106-107).
Regarding claim 392, Cohen teaches the use of irradiated feeder cells, but does not specify that those cells are necessarily PBMC. Wickstrom teaches the use of irradiated PBMC as feeder cells as part of a cell culture protocol for expansion of tumor-infiltrating lymphocytes.
It would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date of the application to use PBMC feeder cells as taught by Wickstrom in Cohen’s method. One of ordinary skill in the art would have been motivated to do so, since Wickstrom essentially teaches the same method, but just specifies that the feeder cells are in fact PBMC.
One of ordinary skill in the art would have had a reasonable expectation of success, since Wickstrom teaches a method for expanding TILs, and the successful use of PBMC feeder cells.
Regarding claim 393, Wickstrom teaches that their feeder cells are irradiated autologous or allogenic PBMC. (Wickstrom pg. 106, last para.)
Regarding claim 394, Wickstrom teaches adding feeder cells in the rapid expansion protocol step. Wickstrom teaches that the initial expansion of TIL from tumor material is dependent on a few factors including the amount of tumor received, efficacy of TIL outgrowth, and the number of G-rex flasks used. Wickstrom teaches that this initial expansion usually takes between 2 and 4 weeks, and a shorter timeframe is preferable. (Wickstrom pg 110, first para). These cells are then harvested and used in the rapid expansion protocol, which takes place in the presence of the PBMC feeder cells. (Wickstrom pg 110).
So, Wickstrom teaches that the PBMCs (i.e., step (c)) may be added to the cell culture on day 14 of cell culture.
Regarding claim 395, Wickstrom teaches that artificial APC may be used as well. (Wickstrom pg 114 para # 5).
Regarding claim 396, Wickstrom is more concerned with culturing TILs from tumor resections, and does not specify an initial cell seeding density. However, Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Selection of a particular seeding density would be arrived at through routine optimization of a cell culture protocol, and thus would be obvious to the skilled artisan.
Conclusion
Claims 367-382, and 386-396 are rejected.
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/THOMAS R. AMICK/ Examiner, Art Unit 1638
/Tracy Vivlemore/ Supervisory Primary Examiner, Art Unit 1638
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