DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
1. Claims 2, 3, 7-11, 22, 23, and 27-31 have been withdrawn. Claims 1, 6, 19-21, and 26 have been amended.
Claims 1, 4-6, 12-21, 24-26, and 32-34 are under examination.
2. The objection to the specification is withdrawn in response to the amendment filed on 11/26/2025.
Claim Rejections - 35 USC § 103
3. 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.
4. Claims 1, 4-6, 12-21, 24-26, and 32-33 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, 12-16, 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, 4-6, 19, 20, 24-26). 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 (see Abstract; p. 6, last paragraph). Furthermore, 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 p. 6, second paragraph). 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 1first 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 T-cells as recited in claim 18.
Thus, the claimed invention was prima facie obvious at the time it was made.
5. Claims 1, 4-6, 12-21, 24-26, and 32-33 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, 4-6, 12-21, 24-26, and 32-33. 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.
6. Claims 1, 4-6, 12-21, 24-26, and 32-33 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, 4-6, 12-21, 24-26, and 32-33. 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
7. The applicant argues that Inozume teaches TIM-3 and Lag-3 did not show any correlation with tumor-specific reactivity.
This argument is not material to the rejection because the rejection is not based on using TIM-3 and Lag-3 for selection.
The applicant argues that Inozume teaches 4-1BB showed a correlation only at day 5 of culture.
However, Inozume’s CD8+ T-cells were cultured in the absence of tumor cells. Vardegaal teaches it is the contact with the tumor which induces 4-1BB on CD8+ T-cells. One of skill in the art would have reasonably concluded that the in vivo contact with the tumor cells within the tumor would induce 4-1BB on the tumor infiltrating CD8+ T-cells and that 4-1BB could be used for selecting tumor reactive CD8+ T-cells from the bulk population T-cells freshly isolated from a tumor sample.
The argument that Inozume discloses that using 4-1BB as marker would require antigen-stimulated bulk peripheral lymphocytes is not found persuasive. In teaching this, Inozume cites Wolfl (Blood, 2007, 110: 201-210; IDS filed on 08/28/2025). Wolfl teaches that 4-1BB remains upregulated for 12 to up to 5 days after antigen stimulation (see p. 201). This is consistent with Inozume’s teaching that tumor-reactive TILs express 4-1BB until culture day 5 in the absence of antigen-stimulation (see Abstract; p. 958, column 1 and Fig. 1). Please note that the legend for Fig. 1 in the reference of record does not actually describe the results in Fig. 1. The correct legend for Inozume’s Fig. 1 is shown below (see Inozume, J. Immunother., 2010, 33: 1-17; attached):
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766
776
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The data in Inozume 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 applicant argues Vardegaal teaches obtaining tumor-reactive T-cells from blood.
While this is true, the fact that T-cells from blood and tumors have different phenotypes is not evidence for non-obviousness. TILs are T-cells which have migrated from blood into the tumor, i.e., blood T-cells coming into contact with the tumor cells.
Vardegaal provides evidence that 4-1BB is induced by the contact with tumor cells. Inozume’s data shows that 4-1BB is induced in CD8+ T-cells via the contact with tumor cells in vivo. One of skill in the art would have reasonably concluded that the in vivo contact with the tumor cells would induce 4-1BB on the tumor infiltrating CD8+ T-cells.
The argument that modifying Dudley would not have been obvious and the argument of lack of reasonable expectation of success are not found persuasive because they are just arguments not supported by any evidence.
The argument that Kim and Borkner do not remedy the deficiencies of Inozume and Vardegaal is not found persuasive because there is no deficiency to be remedied in the combined teachings of Inozume and Vardegaal.
The argument of unexpected results is not found persuasive. As evidenced by Fig. 1 in Inozume, using only PD-1 for selection would have selected a population comprising a significant amount of tumor-nonreactive CD8+ T-cells. Since the cited prior art teaches that both PD-1 and 4-1BB are upregulated and could be used to isolate TILs, one of skill in the art would have reasonably expected that using an additional selection marker (4-1BB) would provide higher frequency of tumor-reactive CD8+ T-cells compared to population selected by using either marker alone or to populations not expressing these markers.
Conclusion
8. THIS ACTION IS MADE FINAL. 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.
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/ILEANA POPA/Primary Examiner, Art Unit 1633