DETAILED ACTION
Applicant’s response of 12/22/2025 has been received and entered into the application file.
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 .
Priority
The instant application is a national stage entry under 35 USC 371 of PCT/CN21/088303 (filed
02/26/2021). Acknowledgement is made of Applicants’ claim for priority to PCT/CN21/088303 (filed 02/26/2021).
Copies of the certified copies of the priority documents have been received in this National Stage application from
the International Bureau (PCT Rule 17.2(a)).
Status of Prior Rejections/Response to Arguments
RE: Rejection of claims 5-7 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph:
Applicants’ amendments, filed on 12/22/2025, overcome the indefiniteness rejection. Applicants have specifically amended claim 5, such that it depends from the method of making claim (i.e. claim 3). The rejection is therefore withdrawn.
RE: Rejection of claims 1-2, 5, and 7 under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Markel et al. (WO2011013129A1):
Applicants’ amendments, filed on 12/22/2025, overcome the anticipation rejection. Applicants have specifically amended claim 1 to recite that the TILs are produced from donor tumor cells with elevated gene expression of CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13. The rejection is therefore withdrawn.
RE: Rejection of claims 1-9 under 35 U.S.C. 103 as being unpatentable over Markel et al. (WO2011013129A1), in view of Mulé et al. (US10041129B2):
Applicants have traversed the rejection asserting that Mulé et al. does not teach or suggest that tumor-infiltrating lymphocytes (TILs) in patients with tertiary lymphoid structures (TLSs) have enhanced reactivity - only that these TLSs can predict survival in these patients and therefore be used to select optimal treatments. Applicants specifically argue that none of the cited references, alone or in combination, implicate TILs are enhanced in patients with TLSs.
Applicants cite Chung et al. (Submitted as Exhibit A) that teaches that even though the presence of TLSs is a predictor of favorable immunotherapy response, the TILs in these patients have a more exhausted T cell signature and therefore, there was no reason in the art to presume that TILs from patients with TLSs would have enhanced tumor reactivity. Applicants further cite Cinnamon et al. (Submitted as Exhibit B) that teaches that while TLSs have been correlated with better prognosis and response to immunotherapy in some cases, other TLSs are pro-tumorigenic as they harbor tumor progenitor cells and support their growth.
Applicants further argue that the Office is therefore using impermissible hindsight to conclude that one of ordinary skill in the art would presume that the presence of TLSs in a subject (e.g. predicted by chemokine signature) provides a reasonable expectation that TILs produced from that subject.
Applicant's arguments filed on 12/22/2025 have been fully considered but they are not persuasive.
In response to applicants’ arguments that none of the cited references implicate TILs have enhanced reactivity nor the prior art cited by applicants (such as Exhibits A and B) teach that TILs from patients with TLSs would have enhanced tumor reactivity, although none of the cited references specifically teach that the TILS have enhanced reactivity in patients, primary reference Markel et al. actually teaches that the tumor infiltrating lymphocytes selected for cancer treatments are actually cells that migrate towards the cancer cells; thus, tumor-infiltrating lymphocytes may have tumor specificity (see Markel et al. teachings in Abstract, claims 1-7, and page 8, lines 19-22). Additionally, Markel et al. teaches expressing at least one chemokine receptor, such as CCL4 and CXCL9 in TILs of the subject, said chemokine receptor being a target for a chemokine, wherein an expression of said chemokine is upregulated above a predetermined level in cells of the cancer as compared to expression in cells of a non-related cancer to generate genetically modified TILs. This reads on TILs with enhanced reactivity in these patients. Also, Mule et al. reference was only used to cure the deficiency of Markel et al. to teach the limitation of
determining gene expression levels of all 12 CD-GES (CCL2, CCL3, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL10, CXCL11, and CXCL13) in patients’ tumor cells.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). The rejection is therefore maintained.
New/Maintained Grounds of Rejection
Claim Rejections - 35 USC § 103
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.
Claim(s) 1-9 are rejected under 35 U.S.C. 103 as being unpatentable over Markel et al. (WO2011013129A1, filed on 07/29/2010, and published on 02/03/2011), in view of Mulé et al. (US10041129B2, filed on 06/02/2016, and published on 08/07/2018).
Regarding claim 1, Markel et al. teaches a method of selecting lymphocytes for the treatment of cancer and, more particularly, for the treatment of melanoma (page 7, lines 10-12 and page 16, lines 18-20). Markel et al. specifically teaches a method of selecting tumor infiltrating lymphocytes (TILs) for treating cancer of a subject, the method comprising selecting the TILs that migrate towards the cancer cells, thereby selecting TILs for treating cancer (page 8, lines 12-18). TILs that migrate towards the cancer cells reads on tumor-infiltrating lymphocytes (TILs) with enhanced tumor reactivity. Markel et al. also teaches that for TILs isolated from a melanoma, they have a tendency to migrate towards four chemokines in particular - including CCL4 and CXCL9. The method comprises expressing at least one chemokine receptor in TILs of the subject, said chemokine receptor being a target for a chemokine, wherein an expression of said chemokine is upregulated above a predetermined level in cells of the cancer as compared to expression in cells of a non-related cancer to generate genetically modified TILs and administering a therapeutically effective amount of said TILs to the subject, thereby treating cancer, wherein said at least one chemokine receptor is selected from the group consisting of CCL4 and CXCL9 (Claims 11 and 12 of Markel et al.). This reads on the claimed method of treating tumors in a subject, comprising administering to the subject an effective amount of a composition comprising Tumor-infiltrating lymphocytes (TILs) with enhanced tumor reactivity, wherein the TILs are produced from donor tumor cells with elevated gene expression of CCL4 and CXCL9.
However, Markel et al. fails to teach determining gene expression levels of CCL2, CCL3, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL10, CXCL11, and CXCL13 in tumor cells.
However, Mulé et al. teaches in claim 1 a method of treating a subject who has melanoma, the method comprising obtaining cells from the melanoma; determining gene expression levels of chemokine (C-C motif) ligand 2 (CCL2), CCL3, CCL4, CCL5, CCL8, chemokine (C-C motif) ligand 18 (pulmonary and activation-regulated) (CCL18), CCL19, CCL21, chemokine (C-X-C motif) ligand 9 (CXCL9), CXCL10, CXCL11, and CXCL13 in the melanoma cells; comparing the melanoma gene expression levels to reference gene expression levels; identifying a subject who has melanoma gene expression levels above the reference gene expression levels.
Mulé et al. further teaches the reference levels can represent levels in a subject who has lymphoid like structures present in the tumor, or is predicted to respond to immunotherapy. Alternatively, reference levels can represent levels in a subject who lacks tumor lymphoid structures, or is predicted to have no or a poor response to immunotherapy (column 10, lines 48-53).
Therefore, it would have been prima facie obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to have further determined the gene expression levels of CCL2, CCL3, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL10, CXCL11, and CXCL13 in the melanoma cells of Markel et al. with a reasonable expectation of success. One would have been motivated to have done so as testing for these extra markers provides the benefit of using a gene signature panel associated with tumors that respond to immunotherapy, so that the TILs will migrate towards and bond with such a tumor that is expressing those markers that is likely to respond to the treatment.
Regarding claim 2: Following discussion of claim 1 above, Markel et al. teaches that the method of selecting lymphocytes is for the treatment of melanoma (page 7, lines 10-12 and page 16, lines 18-20).
Regarding claim 3, Markel et al. teaches a method of selecting tumor infiltrating lymphocytes (TILs) for killing cancer cells (page 14, lines 13-22). This reads on a method for producing TILs with enhanced tumor reactivity. Markel et al. teaches in claims 10 and 12 that the method comprises analyzing an expression of a plurality of chemokines in the cancer cells, wherein the chemokine is selected from the group consisting of CCL4 and CXCL9. This reads on claimed step (a) determining gene expression levels of CCL4….. and CXCL9 in tumor cells.
Markel et al. also teaches that the method comprises comparing the expression of a chemokine in a particular cancer cell with the expression of a chemokine in a non- related cancer cell (page 13, lines 20-22). This reads on claimed step (b) comparing the tumor gene expression levels to reference gene expression levels. Markel et al. further teaches in claim 10 identifying at least one chemokine of said plurality of chemokines in the cancer cells, wherein an expression of said at least one chemokine is upregulated to a significant level compared with an expression in cells of a non-related cancer. This reads on claimed step (c) identifying tumor cells with gene expression levels above the reference gene expression levels. Markel et al. teaches that the TILs are isolated from a patient with a melanoma (page 11, lines 18-20). This reads on claimed step (d) producing TILs from the tumor cells.
However, Markel et al. fails to teach determining gene expression levels of CCL2, CCL3, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL10, CXCL11, and CXCL13 in tumor cells.
However, Mulé et al. teaches in claim 1 a method of treating a subject who has melanoma, the method comprising obtaining cells from the melanoma; determining gene expression levels of chemokine (C-C motif) ligand 2 (CCL2), CCL3, CCL4, CCL5, CCL8, chemokine (C-C motif) ligand 18 (pulmonary and activation-regulated) (CCL18), CCL19, CCL21, chemokine (C-X-C motif) ligand 9 (CXCL9), CXCL10, CXCL11, and CXCL13 in the melanoma cells; comparing the melanoma gene expression levels to reference gene expression levels; identifying a subject who has melanoma gene expression levels above the reference gene expression levels.
Mulé et al. further teaches the reference levels can represent levels in a subject who has lymphoid like structures present in the tumor, or is predicted to respond to immunotherapy. Alternatively, reference levels can represent levels in a subject who lacks tumor lymphoid structures, or is predicted to have no or a poor response to immunotherapy (column 10, lines 48-53).
Therefore, it would have been prima facie obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to have further determined the gene expression levels of CCL2, CCL3, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL10, CXCL11, and CXCL13 in the melanoma cells of Markel et al. with a reasonable expectation of success. One would have been motivated to have done so as testing for these extra markers provides the benefit of using a gene signature panel associated with tumors that respond to immunotherapy, so that the TILs will migrate towards and bond with such a tumor that is expressing those markers that is likely to respond to the treatment.
Regarding claim 4: Following discussion of claim 3 above, Markel et al. teaches that the method of selecting lymphocytes is for the treatment of melanoma (page 7, lines 10-12 and page 16, lines 18-20).
Regarding claim 5, Markel et al. teaches a method of selecting lymphocytes for the treatment of cancer and, more particularly, for the treatment of melanoma (page 7, lines 10-12 and page 16, lines 18-20). The treating comprises adoptive cell transfer (ACT) therapy (claim 20 of Markel et al.). Adoptive cell transfer (ACT) therapy is an enhanced immunotherapy. The method comprises administering a therapeutically effective amount of said TILs to the subject, thereby treating cancer (Claim 11 of Markel et al.). Regarding the recitation “TILs produced by the method of claim 2”, it is a product-by-process limitation. MPEP 2113 states “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). In the instant case, as set forth under Claim Rejections - 35 USC § 112 (b) above, TILs produced by the method of claim 2 is interpreted to as TILs produced from donor melanoma cells that have elevated expression of CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, CXCL13, or any combination thereof.
Regarding claim 6: Following discussion of claim 5 above, Markel et al. fails to teach that the treatment comprises a checkpoint inhibitor selected from an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, or a combination thereof.
However, Mulé et al. teaches in claims 9-12 that the method of treatment comprises immunotherapy which comprises administering to the subject an anti-cancer antibody, wherein the antibody is anti-programmed death-1 receptor (PD1), or anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4).
Therefore, it would have been prima facie obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to have combined the treatment method of Markel et al. by administering TILs to the cancer patient with the method of Mulé et al. by administering a checkpoint inhibitor, such as administering to the subject an anti-cancer antibody, wherein the antibody is anti-programmed death-1 receptor (PD1), or anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4). One would have expected the combined therapy to
provide persistent positive therapeutic results in terms of treating melanoma and responding to immunotherapy as taught by Markel et al. and Mulé et al. As discussed in In re Kerkhoven 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980), and then upheld in KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (U.S. 2007), the combination of multiple elements (in this case therapies), each taught in the prior art as effective for the same purpose, to yield a combination with predictable results (e.g. the combined effect of each individual element) is prima facie obvious.
Regarding claim 7: Following discussion of claim 5 above, Markel et al. teaches that the method of selecting lymphocytes is for the treatment of melanoma (page 7, lines 10-12 and page 16, lines 18-20).
Regarding claim 8, Markel et al. teaches a method of selecting tumor infiltrating lymphocytes (TILs) for killing cancer cells (page 14, lines 13-22). This reads on a method of treating a tumor in a subject. Markel et al. teaches isolating cells from a patient with a melanoma (page 11, lines 18-20). This reads on claimed step (a) obtaining cells from the tumor. Markel et al. teaches in claims 10 and 12 that the method comprises analyzing an expression of a plurality of chemokines in the cancer cells, wherein the chemokine is selected from the group consisting of CCL4 and CXCL9. This reads on claimed step (b) determining gene expression levels of CCL4….. and CXCL9 in tumor cells. Markel et al. also teaches that the method comprises comparing the expression of a chemokine in a particular cancer cell with the expression of a chemokine in a non- related cancer cell (page 13, lines 20-22). This reads on claimed step (c) comparing the tumor gene expression levels to reference gene expression levels. Markel et al. further teaches in claim 10 identifying at least one chemokine of said plurality of chemokines in the cancer cells, wherein an expression of said at least one chemokine is upregulated to a significant level compared with an expression in cells of a non-related cancer. This reads on claimed step (d) identifying tumor cells with gene expression levels above the reference gene expression levels. Markel et al. further teaches that the method comprises administering a therapeutically effective amount of the TILs to the subject, thereby treating cancer (Claim 11 of Markel et al.). This reads on claimed step (e) administering to the subject an effective amount of a composition comprising Tumor-infiltrating lymphocytes (TILs) with enhanced tumor reactivity.
However, Markel et al. fails to teach that determining gene expression levels of CCL2, CCL3, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL10, CXCL11, and CXCL13 in tumor cells.
However, Mulé et al. teaches in claim 1 a method of treating a subject who has melanoma, the method comprising obtaining cells from the melanoma; determining gene expression levels of chemokine (C-C motif) ligand 2 (CCL2), CCL3, CCL4, CCL5, CCL8, chemokine (C-C motif) ligand 18 (pulmonary and activation-regulated) (CCL18), CCL19, CCL21, chemokine (C-X-C motif) ligand 9 (CXCL9), CXCL10, CXCL11, and CXCL13 in the melanoma cells; comparing the melanoma gene expression levels to reference gene expression levels; identifying a subject who has melanoma gene expression levels above the reference gene expression levels.
Mulé et al. further teaches the reference levels can represent levels in a subject who has lymphoid like structures present in the tumor, or is predicted to respond to immunotherapy. Alternatively, reference levels can represent levels in a subject who lacks tumor lymphoid structures, or is predicted to have no or a poor response to immunotherapy (column 10, lines 48-53).
Therefore, it would have been prima facie obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to have further determined the gene expression levels of CCL2, CCL3, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL10, CXCL11, and CXCL13 in the melanoma cells of Markel et al. with a reasonable expectation of success. One would have been motivated to have done so as testing for these extra markers provides the benefit of using a gene signature panel associated with tumors that respond to immunotherapy, so that the TILs will migrate towards and bond with such a tumor that is expressing those markers that is likely to respond to the treatment.
Regarding claim 9: Following discussion of claim 8 above, Markel et al. teaches that the method of selecting lymphocytes is for the treatment of melanoma (page 7, lines 10-12 and page 16, lines 18-20).
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HANAN ISAM ABUZEINEH whose telephone number is (571)272-9596. The examiner can normally be reached Mon- Fri 8:30-5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, CHRISTOPHER BABIC can be reached at (571)272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Hanan Isam Abuzeineh
/H.I.A./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633