CORRECTED 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 .
Response to Amendment
The rejections of claims 16, 18 and 27 are moot in view of the cancelation of the claims.
The rejection of claim 45 under 35 USC 112(b) is withdrawn in view of the amendment removing reference to monitoring.
The rejections of claims 31, 32, 38-41 and 45 under 35 USC 112(a), for lack of enablement for the full scope of the claims, and claims 31, 32, 38-40 and 45 under 35 USC 112(a), for lacking written description, are withdrawn in view of the amendment to claim 31 adding that the antibody has at least one of ADCC or ADCP, which would reasonably be expected to provide antitumor activity.
The rejection of claims 16 and 27 under 35 USC 102(a)(2) as being anticipated by US 2021/0277129 A1 (McGrath, cited in the IDS filed 5/16/20204) in light of CN 118852430 A is withdrawn in view of the cancelation of the claims.
The rejection of claims 16, 18, 27, 31, 32, 38 and 39 on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 12,065,497 (‘497) in view of Lin et al. (Oncotarget, 8(48):83986-83994, 2017) is withdrawn in view of Applicant’s argument that the instant invention is a divisional ultimately of application 17/358,841, which issued as US 12,065,497, and in which the invention of the patent (Group VIII) was restricted from the invention elected in the instant application (Group VII).
The rejection of claims 31, 32, 38 and 39 on the ground of provisional nonstatutory double patenting as being unpatentable over claims 1, 2, 4, 6, 8, 13, 14, 16-18 and 25 of copending Application No. 19/110,032 (‘032) in view of Lin et al. (Oncotarget, 8(48):83986-83994, 2017) is withdrawn in view of Applicant’s argument that the instant claims as amended are patentably distinct (see restriction referenced in immediately preceding paragraph). Further, the copending application has a later patent term filing date and the rejection would have been withdrawn were all instant claims otherwise in condition for allowance.
The provisional rejection of claims 16, 18, 31, 32 and 38-39 on the ground of nonstatutory double patenting as being unpatentable over claims 17, 24, 31, 33, 38, 40, 42, 43, 45, 48, 51 and 53 of copending Application No. 18/666,512 (‘512) in view of Lin et al. (Oncotarget, 8(48):83986-83994, 2017) is withdrawn in view of Applicant’s argument that the instant invention is a divisional ultimately of application 17/358,841 (now US 12,065,497) in which the present subject matter and that of ‘512 was restricted.
Claim Objections
Claim 31 (end), 39, 40 and 46 are objected to because of the following informalities: In claims 31, 39, 40 and line 2 of claim 46, there should be an “or” between the alternatives because the listing is preceded by “selected from” instead of “selected from the group consisting of”. (Compare 40 and end of claim 46).
Similarly, claim 31 is also objected to because it recites “having at least one of …ADCC… and … ADCP. Because it recites “at least one of”, the selection should be listed in the alternative with “or” between. [This is different from ‘at least one of A and B’, wherein A and B are each groups and which would mean choosing at least one from A and at least one from B.]
Appropriate correction is required.
New
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 31 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 31 is indefinite because section c. recites “the subject”, however, there is no “subject” previously mentioned in the claim as amended. As a result, the claim is confusing and it is unclear if the tumor or tumor sample used in step a. was from the subject.
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 (i.e., changing from AIA to pre-AIA ) 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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 31, 32, 38 and 39 remain and claims 40 and 46 are rejected under 35 U.S.C. 103 as being unpatentable over US 20210277129 Al (McGrath, cited in the IDS filed 5/16/20204) and further in view of Juneja et al. (J. Exp. Med., 214(4):895-904, 2017) for the reasons set forth in the previous Office action and as recast here to better address the claims as amended and Applicant’s response.
US 20210277129 Al (McGrath) teaches treatment of cancer with anti-CCR8 human IgG1 chimeric antibodies 1-K17 and 7-B16 that possess ADCC activity (Fig. 6). This Fc effector function is required for efficient in vivo killing of TIL (tumor-infiltrating) regulatory T cells (Treg), as shown in a mouse MC38 syngeneic tumor model ([0054] and Figs. 8A-8C). It teaches that CCR8 is preferentially expressed on TIL Tregs, which are immune suppressing cells found in the tumor microenvironment that generally suppress induction and proliferation of effector T cells ([0049], [0132] and Figs. 3A-3B). Suppressor Tregs have relative high expression of CD4, FoxP3 and CD25, and Tregs from cancer patients compared to healthy subjects express CCR4 and CCR5, which helps migration into tumors in response to their ligands derived from the tumor microenvironment ([0132]). It teaches treatment of solid cancers having tumor-infiltrating Tregs that express CCR8 by administering to a subject with the cancer an effective amount of anti-CCR8 antibody 1-K17 or 7-B16 ([0299]). The antibody may be administered in conjunction with another anti-cancer treatment, including an inhibitory immune checkpoint blocker or inhibitor such as an antibody binding PD-1 or PD-L1, including pembrolizumab, nivolumab or atezolizumab ([0044], [0316], [0331], [0337]). An anti-mouse CCR8 monoclonal antibody that was Fc-competent caused depletion of TIL Tregs and reduced tumor growth in an in vivo MC38 syngeneic mouse model ([0054]-[0055]). Figs. 8A-8B show that in that system intratumoral Treg depletion was at least 50%. While McGarth teaches determining the level of a biomarker in a tumor or tumor sample comprising Tregs, e.g., DDR4 or CCR5, it does not teach wherein the level of the biomarker determines whether or not to administer an anti-CCR8 antibody having ADCC and/or ADCP activity.
Juneja et al. showed that PD-L1 is expressed on tumor cells, and that PD-1 expression on TILs from MC38 tumors was rapidly up-regulated with T cell activation (p. 896, col. 1, second paragraph, and p. 898, end of col. 2). Administration of an anti-PD-L1 blocking antibody to mice with MC38 tumor cells resulted in tumor clearance in most mice (p. 899, col. 2, first paragraph). It is stated that PD-L1 expression on tumors can correlate with a higher response frequency to PD-1 blockade in the clinic (p. 901, sentence bridging cols. 1-2). It is concluded (p. 902, col. 1, end of first full paragraph), “[P]atients whose tumors express high levels and percentages of PD-L1 are more sensitive to PD-1 blockade: tumor PD-L1 may render CD8+ TILs sensitive to PD-1 signaling, which can then be blocked therapeutically. Together, our work demonstrates that PD-L1 on tumor cells can exert functionally significant suppressive effects that inhibit antitumor immunity, and is far more than a marker of an ineffective immune response.” Further, it is reported that (p. 895, col. 1, first paragraph), “PD-1 is commonly highly expressed on tumor-infiltrating lymphocytes (TILs; Ahmadzadeh et al., 2009). Blocking the interaction of PD-1 with its ligands, PD-L1 and PD-L2, leads to impressive antitumor responses and clinical benefit in a subset of patients (Ribas, 2012; Alme et al., 2016).” “In cancer patients, clinical responses to PD-1 immunotherapy positively correlate with tumor PD-L1 expression,…” (p. 895, col.2, middle) The understanding that the PD-1 pathway is responsible for dampening effector T cell responses and inhibiting the initial activation of T cells is noted. Also, “tumors often express PD-1 ligands.” This knowledge provided the rationale for targeting the PD-1 pathway for antitumor therapy (p. 895, paragraph bridging cols. 1-2).
It would have been obvious to the artisan of ordinary skill before the effective filing date of the instant application to have treated a tumor with an anti-CCR8 antibody, especially antibody 7-B16, that possessed ADCC activity as taught by McGrath, who showed that Fc effector function is required by the anti-CCR8 antibodies for efficient in vivo killing of the immunosuppressive TIL Tregs. It further would have been obvious based on the teachings of Juneja et al. relating to the expression of PD-1 ligands, and especially PD-L1, on tumor cells and the successful use of PD-1/PD-L1 inhibitors in the treatment of cancers, to have treated tumors with an anti-CCR8 antibody capable of killing tumor cells after detecting tumors expressing PD-L1 by comparing the level of PD-L1 in a tumor sample to a reference control in view of the teachings of McGrath and Juneja et al., which also taught that TILs express PD-1. Because anti-CCR8 antibodies have therapeutic application in killing TIL Tregs as shown by McGarth, it would have been obvious to determine the presence of TILs, e.g., by determining the expression level of PD-1, before administration of the anti-CCR8 antibody to increase odds of successful treatment using the antibody. It would have been obvious to have looked at the biomarker’s presence in the tumor microenvironment, including by determining the level of PD-1 or PD-L1 using a common immunoassay with a suitable antibody such as pembrolizumab, nivolumab or atezolizumab. Alternatively, it would have been obvious to have determined the expression level of Treg biomarkers CD4, FoxP3, CD25, CCR4 and/or CCR5, to support use of the anti-CCR8 antibody that targets Tregs to produce an antitumor response (see McGarth).
Applicant argues (p. 12 or REMARKS) that the instant claims do not recite combination therapy of an anti-CCR8 antibody and immune checkpoint inhibitor antibody, but instead administration of an anti-CCR8 antibody if a tumor biomarker, e.g., an immune checkpoint protein, level is high compared to a reference. While Juneja discusses that blocking PD-1 creates a stronger response in tumors expressing PD-L1, there is no similar correlation with CCR8. McGrath does not disclose or suggest tumors expressing PD-L1 will be more responsive to CCR8. “This correlation was not appreciated before the work described in the present application,” which identified “predictive biomarkers for patient stratification” through “extensive experiments”. McGrath provides no motivation to measure PD-L1 before treating with an anti-CCR8 antibody. There is no suggestion that anti-CCR8 antibody efficacy is variable, dependent on the additional therapeutic targets. The argument has been fully considered but is not persuasive. First, the claims are not limited to wherein the biomarker is PD-L1. As recited at the end of claim 31, the biomarker may be an immune cell checkpoint protein, immune cell marker or Treg infiltration marker, for example. As Applicant’s remarks relate to a “correlation” between tumors expressing PD-L1 and response to anti-CCR8 antibody, this is not persuasive for two reasons. In 12.6.7, it was shown that a syngeneic tumor model with intratumoral T cells expressing PD-1 and PD-L1 that were not responsive to antibodies binding either immune checkpoint protein, only showed improved efficacy when the PD-1 antibody was combined in treatment with anti-CCR8 antibody TPP-15285, while monotherapies did not. The combination also was associated with an increased CD8/Treg ratio (Table 12.6.7). However, as pointed out by Applicant, the instant claims do not recite treatment with an immune checkpoint inhibitor. Further, it was found by the instant inventors that expression of PD-L1 as well as other specific genes (e.g., interferon-gamma and FOXP3) correlated with response to anti-CCR8 antibodies TPP-14099 or TPP-15285 in 21 syngeneic mouse models judged by tumor volume/control of tumor volume at study end (T/C; Example 12.7.2). The legend for Table 12.7.2.1 states, “Suitable biomarkers correlating with anti-tumor response achieved with inventive anti-CCR8 antibodies.” (See also Table 12.7.2.2) The instant antibodies, i.e., the inventive anti-CCR8 antibodies, used in the experiments and correlating with biomarker expression prior to treatment had particular characteristics which the antibodies of the claimed method are not required to have. Those of the instant examples with anti-tumor activity were glycosylated and as a result led to a reduction in intratumoral immunosuppressive Tregs, whereas unglycosylated forms did not (p. 17, lines 1-8). Antibody TPP-14099 also produced proinflammatory activity, increased infiltration of macrophages, induction of cytotoxic T cell infiltration and/or proliferation and higher levels of NK cells (p. 19, line 32, through p. 19, line 8). Anti-CCR8 surrogate antibodies TPP-14099 and TPP-15285 specifically bind the N-terminal region of CCR-8, with at least for TPP-14099 binding only sulfated and not non-sulfated CCR-8 peptides ([1917]) and with TPP-15285 being a fucosylated IgG antibody with high ADCC and ADCP activity that binds the TRD region of CCR-8 (e.g., Table 10.3.3.2.1 and 10.3.4.2.1). There is no reasonable expectation that the genus of generic anti-CCR8 antibodies encompassed by the claimed method would necessarily show antitumor activity dependent on expression of an additional target. That is, either any CCR8 antibody would have the correlated activity with the increased biomarker expression, such as PD-L1 expression, or there is(are) some property(ies) particular to the antibodies shown to have activity in the specification to which Applicant refers. If it is the former, in response to Applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, the prior art together shows that anti-CCR8 antibodies can be used to treat cancer and that PD-1 and PD-L1, for example, are cancer biomarkers. Therefore, it is maintained that it would have been obvious to treat cancer with an antibody which the artisan of ordinary skill would reasonably have expected to have antitumor efficacy in a PD-L1-expressing tumor. Additionally, the prior art taught that both PD-1 and CCR8 are highly and/or preferentially expressed on TILs. Therefore, expression of PD-1on TILs would have been expected to correlate with antitumor activity of an anti-CCR8 antibody, which would have targeted the TILs for killing. Also, it is stated that PD-L1 expression on tumors can correlate with a higher response frequency to PD-1 blockade in the clinic (Juneja et al.). In the latter case, as discussed in MPEP 716.02(d) (see In re Clements, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)): “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.”” In this instance, the broad scope of encompassed antibodies would not be commensurate in scope with antibodies shown in the examples to have any special property to which Applicant refers. Further, claim 31 refers to comparison of the level of a biomarker in a tumor or tumor sample compared to the level in a reference sample or value, but the specification does not clearly define a reference sample or value (e.g., p. 183, lines 7-9). The reference is not limited to one in which, for example, the tumor is not responsive to anti-CCR8 antibody therapy or the reference is from a sample from corresponding healthy tissue.
New
Claim(s) 31, 45 and 46 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/181425 A1 (Filarsky, cited in the IDS filed 05/16/2024, English machine translation attached as an appendix to this Office action).
Filarsky teaches a method of treating cancer with an antibody that binds CCR8 and efficiently induces antibody-dependent cell-mediated cytotoxicity (ADCC) and/or antibody-dependent cell-mediated phagocytosis (ADCP) (Abstract). Anti-mouse CCR8 antibody SA21414G2 can induce ADCC as shown in Figs. 8 and 9 (see also [0063]). It is further stated that the antibody can remove tumor infiltrating Treg cells or macrophages ([0039], [0041]-[0042]). Administration of this antibody to mice bearing colorectal cancer-derived CD26 tumors led to a decrease in tumor volume and nearly complete disappearance by 17 days (see Figs. 20 and 21 and Example 12). “Based on these results, it was concluded that administration of anti-mCCR8 antibodies suppressed the function of mCCR8 expressed in Treg and monocytes/macrophages, which are identified as immunosuppressive cells, or by killing (removing these expressing cells) through antibody ADCC activity, thereby enhancing tumor immunity and leading to tumor regression and extinction” (end of [0076]) It is further taught that Treg cells constitutively express FoxP3. By examining the expression levels of FoxP3 gene in fractions F2 and F3 of PBMCs in tumor infiltrating cells, it is possible to confirm the presence of tumor-infiltrating Tregs cells ([0058], see also [0055]). Additionally, CD25 is a marker of mouse Treg cells ([0077]).
The FoxP3 gene has been identified as a gene that is specifically expressed in Treg cells and is not expressed in tumor cells or most normal human cells. As so-called marker genes expressed only in specific cells, such as the FoxP3 gene as a marker for Treg cells, the CD3G gene as a marker for T cells and NK cells, and the CD8A gene as a marker for CD8-positive T cells, these are known. Regarding the FoxP3 gene, a marker gene for Treg cells, it has been reported that measuring the mRNA expression level of FoxP3 within each tumor can serve as an indicator of the proportion of Treg cells present within the tumor (Cell, 2015, Vol. 160, pp. 48-61).
In other words, by analyzing marker gene expression in RNA-Seq data of tumor masses, it is possible to identify tumor infiltrating cells. Furthermore, the expression amount of marker genes in tumor masses can be understood as the product of the number of expressing cells corresponding to the specific cell corresponding to the infiltrating marker gene and the expression amount of each expressing cell. ([0083])
It was found that CCR8 and CD3G mRNA are expressed at background levels in a variety of cancer cell lines, however, their mRNA expression is higher in infiltrating cells present in tumor masses (end of [0084]). Patients with kidney, prostate or bladder cancer had lower survival rates when they had higher proportion of CCR8-expressing cells in tumor-infiltrating T cells. “From this, it is suggested that, just as anti-mCCR8 antibody administration in mice has anti-tumor effects, in humans, specifically removing or killing intratumor-expressing CCR8 cells in some way may enhance tumor immunity and improve survival rates.” ([0086]) The anti-CCR8 antibody significantly reduced tumor volume in a mouse tumor model transplanted with tumors from mouse renal cancer cell-derived cells (Example 23, [0092]). Similar results were shown using breast cancer-derived tumor transplants (Example 21, [0090]), cutaneous fibrosarcoma transplants (Example 20, [0089]) and osteosarcoma transplants (Example 19, [0088]).
It would have been obvious to the artisan of ordinary skill before the effective filing date of the instant application to have determined the level of a Treg biomarker, such as FoxP3, CD25 or CD3G, in a tumor or tumor sample compared to a reference, wherein increased levels of the biomarker(s) indicates the presence of Treg cells in the tumor. Alternatively, it would have been obvious wherein the biomarker was CCR8 (a TIL Treg marker) itself in order to show the expectation of success of treatment with the anti-CCR8 antibody. Showing the presence of Tregs in a subject’s tumor would have motivated the artisan of ordinary skill to have treated the tumor with an anti-CCR8 antibody, since CCR8 was expressed by Treg cells and monocytes/macrophages and the antibody was shown by Filarsky to reduce tumor size and suggested to improve survival rates. Additionally, it would have been obvious to determine the level of the biomarker not only prior to treatment to determine the presence of Tregs and/or macrophages, but also after treatment as an indicator of the effectiveness of treatment and to provide information relevant to further anti-CCR8 antibody treatment.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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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Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
July 28, 2026
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