DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Continued Examination Under 37 CFR 1.114
1. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 08/07/2026 has been entered.
Claims 2-11, 14, 20, 22-31 have been cancelled. Claims 1, 13, 18, 19, 21, and 33 have been amended.
Claims 1, 12, 13, 15-19, 21, and 32-34 are pending and under examination.
Claim Rejections - 35 USC § 103
2. 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 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 pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
3. Claims 1, 12, 13, 16-19, 21, and 32-34 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Dudley et al. (US 2011/0052530), in view of both Inozume et al. (J. Immunother., 2010, 33: 956-964) and Vardegaal et al. (Cancer Immunol. Immunother., 2011, 60: 953-963).
Dudley et al. teach a method of treating cancer in a mammalian subject, the method comprising: obtaining bulk autologous T-cells from a tumor sample (tumor infiltrating lymphocytes) obtained from the subject, where the bulk autologous T-cells are not non-specifically stimulated; selecting for CD8+ expression to obtain a population enriched for CD8+ T-cells without screening for autologous tumor recognition; expanding the selected CD8+ T-cells in a medium comprising IL-2 or Il-15 or by stimulation with the tumor antigen; administering to the subject nonmyeloablative chemotherapy, followed by the administration of the expanded CD8+ T-cells (claims 1, 12, 13, 16, 21, 32, and 33) (see [0023]; [0025]-[0027]; [0033]-[0034]; [0036]; [0044]; [0064]; [0130]-[0131]). Dudley et al. teach administering 1.0-13x1010 T-cells (claim 34) (see [0033]). Dudley et al. teach modifying the CD8+ T-cells with a nucleic acid encoding IL-12 (claim 17) (see [0038]).
Dudley et al. do not teach specifically selecting CD8+ T-cells expressing 4-1BB and PD-1 from the bulk population of T-cells (claims 1 and 19). However, using 4-1BB and PD-1 as selection markers is suggested by the prior art. For example, Inozume et al. teach that tumor infiltrating CD8+T-cells express high levels of PD-1; selecting CD8+ PD-1+ T-cells from the bulk of the fresh tumor infiltrating lymphocytes enriches for tumor-reactive CD8+ T-cells. Inozume et al. teach that 4-1BB was used in the prior art as a selection marker for the enrichment of the antigen-stimulated T-cells (see Abstract; p. 858, Fig. 1; p. 962, paragraph bridging columns 1 and 2; paragraph bridging p. 962 and 963). Vardegaal et al. teach that contacting the CD8+ T-cells with tumor cells in vitro induces 4-1BB on CD8+ T-cells and that the 4-1BB-expressing CD8+ T-cells are useful for adoptive transfer in human patients (see Abstract; p. 954; paragraph bridging p. 954 and 955; p. 955, column 1, first full paragraph; p. 958, Fig. 3; p. 959, column 2, last paragraph). Based on these teachings, one of skill in the art would have reasonably concluded that the in vivo contact with the tumor cells within the tumor microenvironment would induce 4-1BB on the tumor infiltrating CD8+ T-cells and that 4-1BB could be used for selection. One of skill in the art would have found obvious to modify the method of Dudley et al. by specifically selecting the CD8+ PD-1+4-1BB+ T-cells from the bulk population of T-cells with the reasonable expectation that doing so would result in a population enriched in tumor reactive CD8+T-cells suitable for enhanced therapy. By doing so, one of skull in the art would have obtained a population of T-cells capable of lysing an autologous tumor, as recited in claims 1 and 18.
Thus, the claimed invention was prima facie obvious at the time it was made.
4. Claims 1, 12, 13, 15-19, 21, and 32-34 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Dudley et al. taken with both Inozume et al. and Vardegaal et al., in further view of Kim et al. (J. Immunol., 2012, 188: 1-23).
The teachings of Dudley et al., Inozume et al., and Vardegaal et al. are applied as above for claims 1, 12, 13, 16-19, 21, and 32-34. Dudley et al., Inozume et al., and Vardegaal et al. do not teach an Akt inhibitor (claim 15). Kim et al. teach that using Akt inhibitors increases the number of effector memory CD8+ T-cells (p. 1; p. 7, second full paragraph; p. 9, second full paragraph). Thus, culturing the enriched CD8+ T-cells with an Akt inhibitor would have been obvious to one of skill in the art to achieve the predictable result of obtaining a composition suitable to treat cancer.
Thus, the claimed invention was prima facie obvious at the time it was made.
5. Claims 1, 12, 13, 16-19, 21, and 32-34 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Dudley et al. taken with both Inozume et al. and Vardegaal et al., in further view of Borkner et al (Cancer Immunol. Immunother., 2010, 59: 1173-1183).
The teachings of Dudley et al., Inozume et al., and Vardegaal et al. are applied as above for claims 1, 12, 13, 16, 18, 19, 21, and 32-34. Dudley et al., Inozume et al., and Vardegaal et al. do not teach the elected species of anti-PD-1 siRNA (claim 17). Borkner et al. teach that using siRNAs targeting PD-1 improves immune functions of tumor-specific T-cells; Borkner et al. teach that using an anti-PD-1 siRNA represents a promising approach to achieve long-lasting enhancement of tumor-specific T cell function in adoptive T-cell therapy (Title; Abstract; p. 1182; paragraph bridging p. 1182 and 1183). One of skill in the art would have found obvious to modify the teachings of Dudley et al., Inozume et al., and Vardegaal et al. by further using an anti-PD-1 siRNA to achieve the predictable result of obtaining a composition suitable for enhanced cancer therapy.
Thus, the claimed invention was prima facie obvious at the time it was made.
Response to Arguments
6. The arguments and the 132 Declaration have been considered but not found persuasive.
The statement in the 132 Declaration that one of skill in the art would not have assumed that 4-1BB can be used as a marker based the mere expression following contact with the tumor cells is not found persuasive for the reasons set forth in the rejection.
The 132 Declaration states that Baitsch found that 4-1BB was not upregulated in TILs from lymph nodes compared to bystander virus-reactive T-cells.
The comparison with virus-reactive T-cells is not material to the rejection. It is also noted that the examiner was unable to find the teaching in Baitsch that the virus-reactive T-cells and lymph nodes TILs express comparable 4-1BB levels.
Importantly, Baitsch teaches that 4-1BB is upregulated in TILs from lymph nodes, which is consistent to the Vardegaal’s teaching that the contact with tumor cells induces 4-1BB on CD8+ T-cells.
The 132 Declaration states that chronically stimulated TILs are highly exhausted and that the ability to expand exhausted TILs can also be impaired. Sakuishi does not provide any evidence to this effect. Inozume teaches that chronically stimulated TILs can be successfully expanded.
The 132 Declaration states that Treg constitutively express 4-1BB, and thus, it could not have been assumed that 4-1BB could be used as a selection marker for cells capable of lysing autologous tumor cells.
This is not found persuasive because the prior art teaches selecting for CD8+ T-cells before the step of selecting with PD-1 and 4-1BB.
The 132 Declaration refers to Fig. 1 in Inozume. As previously noted, Fig. 1 shows that the isolated tumor-reactive TILs express both PD-1 and 4-1BB at day 0 until culture day 5, in the absence of antigen stimulation. One of skill in the art would have reasonably expected PD-1 and 4-1BB to remain upregulated in the freshly isolated TILs during the isolation procedure, which takes place in the absence of antigen stimulation. Thus, using both PD-1 and 4-1BB markers to select for tumor-reactive TILs would have been obvious.
The 132 Declaration states that it would have reasonably expected that the cells expressing both PD-1 and 4-1BB would be the most exhausted (the most impaired to expand) or would exhibit the immunosuppressive characteristics of Treg.
This is not found persuasive. The assertion that the exhausted TILs would exhibit the immunosuppressive characteristics of Treg is not supported by any evidence.
With respect to the statement that the TILs expressing both PD-1 and 4-1BB would be the most exhausted, it is noted that 4-1BB is a marker of TIL activation, not exhaustion. 4-1BB is expressed when TILs are activated by the contact with the tumor cells, as also demonstrated by Verdegaal (see p. 955, paragraph bridging columns 1 and 2; p.958, Fig. Fig. 3).
Furthermore, the prior art teaches that, once removed from tumors, TILs recover their function and can be successfully expanded in vitro (see for example Inozume, Abstract; p. 958, column 2; p. 962, column 1, last paragraph).
The applicant argues that Verdegaal and Wolfl do not show that 4-1BB can be used as a selection marker.
However, Verdegaal and Wolf do not have to show using 4-1BB as a selection marker. The test for obviousness under 35 U.S.C. 103(a) is not the express suggestion of the claimed invention in any of the references, but what the references taken collectively would suggest to those of skill in the art presumed to be familiar with them. The combined teachings of Inozume and Verdegaal suggest using 4-1BB as a selection marker.
The argument that Inozume teaches away is not found persuasive. The teaching indicated by the applicant only relates to the approach of firstly stimulating the TILs with the tumor cells, as taught by Wolfl. There is no teaching in Inozume against using 4-1BB to isolate TILs from tumors. Fig. 1 in Inozume shows that the isolated tumor-reactive TILs express both PD-1 and 4-1BB at day 0 until culture day 5, suggesting to one of skill in the art that both PD-1 and 4-1BB could be used for selection.
7. No claim is allowed. No claim is free of prior art.
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/ILEANA POPA/Primary Examiner, Art Unit 1633
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