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
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 04/27/2026 has been entered.
Claims 1-20, 22, and 24 are pending.
Claim 1 is amended.
Claims 25 and 26 are canceled.
Claims 1-20, 22, and 24 are under examination on the merits.
Rejections Maintained
35 U.S.C. 103
The rejection of claims 1-14, 17, 20, 22, and 24 under 35 U.S.C. 103 as being unpatentable over Dudley et al. (US 2011/0052530, publication date: 03/03/2011, IDS) in view of Ochoa et al. (US PAT 5,443,983, publication date: 08/22/1995, IDS), Carrasco et al. (WO 0165998, international publication date: 09/13/2001, IDS), and Singh et al. (US PG PUB 2010/0167945, publication date: 07/01/2010) is maintained. Claims 25 and 26 are canceled.
The rejection of claims 15 and 16 under 35 U.S.C. 103 as being unpatentable over Dudley et al. (US 2011/0052530, publication date: 03/03/2011, IDS) in view of Ochoa et al. (US PAT 5,443,983, publication date: 08/22/1995, IDS), Carrasco et al. (WO 0165998, international publication date: 09/13/2001, IDS), and Singh et al. (US PG PUB 2010/0167945, publication date: 07/01/2010), as applied to claims 1-14, 17, 20, 22, and 24, and further in view of Maeurer (WO 2015/189356, international publication date: 12/17/2015, IDS) is maintained.
The rejection of claims 18 and 19 under 35 U.S.C. 103 as being unpatentable over Dudley et al. (US 2011/0052530, publication date: 03/03/2011, IDS) in view of Ochoa et al. (US PAT 5,443,983, publication date: 08/22/1995, IDS), Carrasco et al. (WO 0165998, international publication date: 09/13/2001, IDS), and Singh et al. (US PG PUB 2010/0167945, publication date: 07/01/2010), as applied to claims 1-14, 17, 20, 22, and 24-26, and further in view of Bozzetti et al. (J Thorac Oncol., 3:18–22, 2008) is maintained.
Nonstatutory Double Patenting
The nonstatutory double patenting rejections of record have been maintained.
Response to Arguments
In Applicant Arguments, dated 04/27/2026, Applicant asserts that “[c]laim 1, as amended, requires the two-step expansion process to produce a therapeutic population of TILs comprising from about 1 X 109 to about 10x1010 cells, a therapeutically effective dosage, from an FNA or small biopsy starting material, within 3-11 days per expansion step (17-22 days total per claims 5-8). The cited references do not provide the skilled artisan with a reasonable expectation that this output can be achieved under these conditions.”
These arguments have been fully considered but are not deemed persuasive. First as indicated at p. 12-14 of the Final Rejection, dated 11/25/2025, the prior art teaches or suggests a method for expanding tumor infiltrating lymphocytes (TILs) into a therapeutic population of TILs using a two-step expansion process comprising: (i) performing a first expansion (Pre- Rapid Expansion Process, pre-REP) of a first population of TILs by culturing a fine needle aspirate (FNA) tumor biopsy comprising the first population of TILs in a first cell culture medium to obtain a second population of TILs, wherein the first culture medium comprises IL-2, OKT-3, and antigen presenting cells (APCs), and wherein the first expansion is performed for about 12 days; and (ii) performing a second expansion (Rapid Expansion Process, REP) by culturing the second population of TILs in a second culture medium comprising IL-2, OKT-3, and APCs (PBMCs), to produce a third population of TILs, wherein the second expansion is performed for about 12 days, wherein the third population of TILs is the therapeutic population of TILs. This method comprises all of the active steps of the instant claim 1, and as such the instantly claimed invention and that of the prior art would be expected to yield similar numbers of TILs.
Applicant further asserts that “Carrasco, the only reference in the combination that quantifies an FNA yield, describes cells that are methanol-fixed in CytoLyt solution upon collection and saponin-permeabilized for diagnostic intracellular antibody staining. These cells are non-viable and have zero proliferative capacity… The question is whether those [Carrasco’s] cells can seed a successful pre-REP/REP TIL expansion to therapeutic scale, as required by Dudley’s own teachings. Carrasco’s cells cannot, because Carrasco’s cells are dead.” Applicant also asserts that “[n]either Dudley nor Carrasco provide any teaching, suggestion, motivation that an FNA can supply the viable lymphocyte content Dudley’s own Figure 5A identifies as critical.”
These arguments have been fully considered but are not deemed persuasive. It is initially noted that the claims do not require a particular lymphocyte content prior to pre-REP/REP TIL expansion. The claims only require a step of “performing a first expansion step of a first population of TILs by culturing a fine needle aspirate (FNA) tumor biopsy or a small biopsy comprising the first population of TILs in a first cell culture medium to obtain a second population of TILs…” Further as indicated at p. 9-11 of the Final Rejection, dated 11/25/2025, Dudley et al. teach a pre-REP/REP TIL expansion protocol, and Carrasco et al. is used to demonstrate that tumor samples may be isolated via FNA using a 22-gauge needle. At p. 20, Carrasco et al. teach that “[a] multidirectional fine-needle aspiration biopsy (FNAB) from the tumor was performed with a 22-gauge needle connected to a 20 ml plastic syringe that was attached to a metal holder. The aspirate was resuspended and fixed in CytoLyt solution (Cyto Corporation, Boxborough, MA), maintained at 4° C, and analyzed within 24-48 hr. The cells which were resuspended in the CytoLyt solution were then passed through a 35-mm nylon mesh, centrifuged at 500 g, and resuspended and permeabilized in PBS (phosphate buffered saline) containing 0.1% BSA (bovine serum albumin) and 0.2% saponin (PBSAP). 200,000 cells/tube were incubated for 1 hr at room temperature in 100 ml PBSAP containing 10-80 nM of one of the two affinity-purified anti-NIS antibodies raised against the intracellular C-terminal end of NIS...” Although the cells of Carrasco are ultimately fixed, this passage from Carrasco et al. suggests that approx. 200,000 viable cells/tube may be acquired via FNA using a 22-gauge needle, and one of ordinary skill in the art would reason that said viable cells are appropriate for a variety of laboratory or clinical uses, including TIL manufacturing.
Furthermore at [0004] and [0026], Dudley et al. teach “a method of promoting regression of a cancer in a mammal comprising (i) culturing autologous T cells; (ii) expanding the cultured T cells using OKT3 antibody, IL-2, and feeder lymphocytes, wherein the cultured T cells are enriched for CD8+ T cells prior to expansion of the T cells; (iii) administering to the mammal nonmyeloablative lymphodepleting chemotherapy; and (iv) after administering nonmyeloablative lymphodepleting chemotherapy, administering to the mammal the expanded T cells… An embodiment of the method comprises expanding cultured T cells. The cultured T cells are pooled and rapidly expanded.” At [0076], Dudley et al. teach “several options for the initial cell preparation for culturing tumor infiltrating lymphocytes: a fine needle aspirate from the tumor tissue; tumor fragments, cut with a scalpel or scissors to 1-1.5 min in each of 3 dimensions; a mechanically dispersed, single-cell suspension; and an enzymatically generated single-cell suspension (emphasis added).” These teachings provide additional evidence that fine needle aspirates provide ample cells for initiating the expansion of therapeutic T cells.
Applicant also asserts that “Dudley’s pre-REP and REP manufacturing timelines are weeks-long, not compressible to 3-11 day windows.”
This argument has been fully considered but is not deemed persuasive. One of ordinary skill in the art would have been motivated to experiment with different expansion times in order to determine which expansion time provides an optimal or desired number of TILs, because culture time is a critical variable for any cell expansion protocol. Furthermore Dudley et al. teach that the primary culture of TILs is between 5 and 21 days, which encompasses a window of 3-11 days, see [0025]. At [0026], Dudley et al. state that while 14 days is a preferable culture time for the second expansion step, i.e., the rapid expansion step, Dudley also states that rapid expansion of TILs generally occurs over a range from about 10 to about 14 days, which overlaps with a window of 3-11 days.
Applicant further asserts that “Singh therefore does not address, let alone resolve, the critical question: whether an FNA or small biopsy can yield a sufficient number of viable lymphocytes to support therapeutic-scale TIL expansion within the claimed compressed timeline. Singh's needle-gauge teaching is incidental to its diagnostic purpose and provides no information about TIL content, viability, or expansion potential from biopsy-derived material.”
These arguments have been fully considered but are not deemed persuasive. As indicated above Carrasco et al. suggest that approx. 200,000 viable cells/tube may be acquired via FNA using a 22-gauge needle, and one of ordinary skill in the art would reason that said viable cells are appropriate for a variety of laboratory or clinical uses, including TIL manufacturing. Furthermore the FNA methods of Carrasco et al. could be repeated if additional starting material is desired.
Applicant further points out that Maurer does not teach or suggest the claimed pre-REP/REP TIL expansion protocol, and Bozetti et al. do not teach obtaining viable lymphocytes from FNA-derived material; however as indicated above, these teachings are provided by Dudley et al. and Carrasco et al.
Therefore the rejections of the claims under 35 U.S.C. 103 have been maintained. The obviousness-type double patenting rejections of record have likewise been maintained.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NELSON B MOSELEY II whose telephone number is (571)272-6221. The examiner can normally be reached on M-F, 9:00-6:00 EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis, can be reached at 571-270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642
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