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 rejection of claims 2, 3, 6, 46-48 and 58 are moot in view of the cancelation of the claims.
The rejection of claims 1-3, 6, 7, 20-23 and 29-49 under 35 U.S.C. 112(a), as failing to comply with the written description requirement, is withdrawn in view of the cancelation of claims and the amendment to claims 1 and 7 that brings the HVR sequences from claim 58 into the independent claims.
The rejection of claims 1-3, 6, 7, 20-23, 29, 44-49 and 67 under 35 U.S.C. 112(a), for lacking enablement, is withdrawn in view of the cancelation of claims and the amendment to claims 1 and 7 that brings the HVR sequences from claim 58 into the independent claims.
The rejection of claim(s) 1-2, 7, 20, 21, 29 and 46-49 under 35 U.S.C. 102(a)(1) as being anticipated by Tolcher et al. (Clin Cancer Res (2017) 23 (18): 5349–5357, cited in the IDS filed 8/11/2023) and Applicant’s admission in the specification in Figures 1A-1C is withdrawn in view of the cancelation of claims and of the amendment to claims 1 and 7 including the limitation of previous claim 58 that brings the HVR sequences into the independent claims.
The rejection of claim(s) 1, 2, 20-23, 29, 44-49 and 67 under 35 U.S.C. 102(a)(1) as being anticipated by US 2019/0055314 A1 (‘314, cited in the IDS filed 8/11/2023) is withdrawn in view of the cancelation of claims and of the amendment to claims 1 and 7 including the limitation of claim 58 that brings the HVR sequences into the independent claims. Antibody AG10131 of ‘314 does not have the HVRs of the antibody of the instant claims. However, the new and amended claims are rejected below as anticipated by US 2019/0055314.
The rejection of claim(s) 1-3 and 6, 20-23, 29, 44-48 and 67 under 35 U.S.C. 102(a)(2) as being anticipated by US 2020/0377608 A1 (cited in the IDS filed 8/11/2023) is withdrawn in view of the amendment to claims 1 and 7 including the limitation of claim 58 that brings the HVR sequences into the independent claims.
The rejection of claims 1-3, 20-21, 29 and 44-49 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 19, 9, 13, 15 and 17-19 of U.S. Patent No. 11,242,395 B2 (‘395) in view of Tolcher et al. (Clin Cancer Res (2017) 23 (18): 5349–5357, cited in the IDS filed 8/11/2023) is withdrawn in view of the amendment to the instant claims bringing the HVRs into the independent claims and changing the dosage and biomarker limitations. The rejection has been replaced by a new one addressing the amendments.
The provisional rejection of claims 1-3, 6, 7, 20-23, 29, 44-48, 58-60 and 67 on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6, 19, 20, 27, 28, 31, 32, 44-48 and 55 of copending Application No. 18/011,801 (‘801) in view of US 8,673,855 B2 and US 10,875,894 B2 is withdrawn in view of the amendment to the instant claims bringing the HVRs into the independent claims and changing the dosage and biomarker limitations. The rejection has been replaced by a new one addressing the amendments.
The provisional rejection of claims 1-3, 20-23, 29, 44-48 and 58-60 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 39, 42 and 56 of copending Application No. 18/842,313 (‘313) in view of Tolcher et al. (Clin Cancer Res (2017) 23 (18): 5349–5357, cited in the IDS filed 8/11/2023) is withdrawn in view of the amendment to the instant claims bringing the HVRs into the independent claims and changing the dosage and biomarker limitations, as well as the amendment to claims of the copending application requiring a variant IgG Fc region.
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 § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 20, 22, 23, 44, 45, 49, 59, 60 remain and new claim 76 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by ClinicalTrials.gov Study NCT03802955 (version 1, https://clinicaltrials.gov/study/NCT03802955?intr=ADG106&rank=7&tab=history&a=1#version-content-panel>, 01/11/2019) and Applicant’s in admission in the specification on pp. 226-top of p. 227, [409] and in Figures 1A-1C for the reasons set forth in the previous Office action and in light of Nair et al. (J. Basic Clin. Pharm. 7(2):27-31, 2016) as recast here to address the amendment to the claims.
NCT03802955 is briefly entitled, “Study of ADG106 With Advanced or Metastatic Solid Tumors and/or Non-Hodgkin Lymphoma”. It teaches administration of anti-CD137 antibody ADG106 to patients with advanced or metastatic solid tumors and/or relapsed/refractory non-Hodgkin lymphoma (Brief Summary, first paragraph). Patients are treated by intravenous infusion of a doses of 0.1 mg/kg, 0.5 mg/kg, 1.5 mg/kg, 3.0 mg/kg, 5.0 mg/kg, 7.5 mg/kg, or 10 mg/kg ADG106 (Arms). Infusion is on Day 1 of each cycle, with two cycles being 42 days, i.e.¸ each cycle is 21 days (Arms and Interventions: Assigned Interventions, and Outcome Measures: Primary Outcome Measures). The method further comprises subsequently determining a level of one or more of circulating T cells or NK cells (Outcome Measures: Secondary Outcome Measures:17.).
On page 226 through the top of p. 227 of the specification, antibody ADG106 is disclosed as having the HVR-H1-3 of SEQ ID NO: 2-5 and HVR-L103 of SEQ ID NO:5-6, VH/VL of SEQ ID NO:7/8 and heavy and light chain of SEQ ID NO:10 and 11. Figures 1A-1C of the instant application shows antibody ADG106 binds one or more amino acid residues 51, 53, 62-73, 83, 89, 92, 95-104 and 112-116 of SEQ ID NO: 1. ADG106 is a fully human IgG4 antibody ([409]). This reference is not necessary for anticipation, but only cited to show the immunoglobulin isotype and sequence of antibody ADG106 and that it binds one or more amino acid residues of CD137 as recited in the instant claims.
Nair et al. teaches the reference human weight is 60 kg (Table 1). Therefore, 5 mg/kg is the same as 300 mg for a 60 kg human and 7.5 mg/kg is the same as 450 mg for an average human. The doses taught by Study NCT03802955 meet the limitations of instant claim 1.
Applicant argues (section V.1. of REMARKS) the claims are now allowable because independent claims 2 and 3 have been canceled and independent claims 1 and 7 have been amended to recite HVR sequences and claim 1 has added that dose is between 300 mg to 500 mg, while claim 7 has removed recitation of “CD8+ effector memory T (Tmem) cells, regulatory T (Treg) cells, and NK cells.” Also, NCT03802955 does not disclose the dosage limitation of claim 1 or determination step of claim 7. The argument has been fully considered but is not persuasive in part. Claim 7 and claims dependent thereon are no longer rejected under 35 USC 102, but are rejected under 35 USC 103. As to claim 1, the clinical study teaches administration of dosages that include two between 300 and 500 mg, assuming an average human weight of 60 kg as set forth in Nair et al. (supra). Because the antibody used in the clinical trial inherently has the HVR, VH/VL and heavy and light chain (HC/LC) sequences of the antibody as instantly claimed, NCT03802955 anticipates the claims.
Claim(s) 1, 20, 22, 23, 44, 45, 49, 59, 60 remain and 76 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by ClinicalTrials.gov Study NCT03707093 (version 1, <https://clinicaltrials.gov/study/NCT03707093?intr=ADG106&rank=8&tab=history&a=1&b=2#version-content-panel>, 10/12/2018) and Applicant’s admission in the specification on pp. 226-top of p. 227, [409] and in Figures 1A-1C for the reasons set forth in the previous Office action and in light of Nair et al. (J. Basic Clin. Pharm. 7(2):27-31, 2016) as recast here to address the amendment to the claims.
NCT03707093 is briefly entitled, “Study of CD137 Agonist ADG106 With Advanced or Metastatic Solid Tumors and/or Non-Hodgkin Lymphoma”. It teaches administration of anti-CD137 antibody ADG106 to patients with advanced or metastatic solid tumors and/or relapsed/refractory non-Hodgkin lymphoma (Brief Summary, first paragraph). Patients are treated by intravenous infusion of a doses of 0.1 mg/kg, 0.5 mg/kg, 1.5 mg/kg, 3.0 mg/kg, 5.0 mg/kg, 7.5 mg/kg, or 10 mg/kg ADG106 (Arms). Infusion is on Day 1 of each cycle, with two cycles being 42 days, i.e., each cycle is 21 days (Arms and Interventions: Assigned Interventions, and Outcome Measures: Primary Outcome Measures).
On page 226 through the top of p. 227 of the specification, antibody ADG106 is disclosed as having the HVR-H1-3 of SEQ ID NO: 2-5 and HVR-L103 of SEQ ID NO:5-6, VH/VL of SEQ ID NO:7/8 and heavy and light chain of SEQ ID NO:10 and 11. Figures 1A-1C of the instant application shows antibody ADG106 binds one or more amino acid residues 51, 53, 62-73, 83, 89, 92, 95-104 and 112-116 of SEQ ID NO: 1. ADG106 is a fully human IgG4 antibody ([409]). This reference is not necessary for anticipation, but only cited to show the sequence of antibody ADG106 and that it binds one or more amino acid residues of CD137 as recited in the instant claims.
Nair et al. teaches the reference human weight is 60 kg (Table 1). Therefore, 5 mg/kg is the same as 300 mg for a 60 kg human and 7.5 mg/kg is the same as 450 mg for an average human. The doses taught by Study NCT03802955 meet the limitations of instant claim 1.
Applicant’s arguments (section V.2.) directed to anticipation by ClinicalTrials.gov Study NCT03707093 are the same as for NCT03802955 addressed above. The arguments have been fully considered but are not persuasive for the same reasons, particularly that the dose used by the study includes two between 300 and 500 mg (300 and 450 mg) and the antibody is the same as that of the instant application. Claim 7 and claims dependent thereon are no longer rejected.
Claim(s) 1, 20-23, 44-45, 49, 59, 60 and 76 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 2019/0055314 A1 (‘314, cited in the IDS filed 8/11/2023) in light of Nair et al. (J. Basic Clin. Pharm. 7(2):27-31, 2016).
'314 claims a method of treating cancer in a subject comprising administering an antibody that binds the extracellular domain of human CD137 and comprises a heavy and light chain of SEQ ID NO:657 and 658, respectively (claims 18, 24-27 and 54). Other anti-CD137 antibodies were tested in mouse models for treatment of breast cancer, liver and colon cancer and in and cynomolgus monkey for safety and pharmacokinetic and in mouse and rat for pharmacokinetic profile (Examples 10, 13 and 14). Administration to monkeys and rats was intravenously. The antibody maybe administered at a dose of 5 mg/kg ([0198] and with a frequence of once every three weeks ([0199]). In syngeneic mouse models of liver, colon and breast cancer, the antibody showed anti-tumor activity (Examples 10a-c). Cancers that can be treated by the disclosed method include non-Hodgkin's lymphoma, as well as solid tumors such as lung, breast cancer, head and neck cancer, and cholangiocarcinoma, for example [0187]). The CD137 antibody induced infiltration of CD8+ T cell into tumors ([0054]) and T cell proliferation ([0117]).
Nair et al. teaches the reference human weight is 60 kg (Table 1). Therefore, 5 mg/kg is the same as 300 mg for an average human. The dose taught by ‘314 meets the limitations of instant claim 1.
Applicant argues (section V.4.) the instantly claimed method requiring a dose of 300 to 500 mg is not disclosed by ‘314. The argument has been fully considered but is not persuasive. ‘314 teaches a range of dosages, including 5 mg/kg which corresponds to about 300 mg for a human dosage.
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) 1, 7, 20-23, 44, 45, 49, 59, 60 and 71-77 is/are rejected under35 U.S.C. 103 as being unpatentable over ClinicalTrials.gov Study NCT03802955 (version 1, https://clinicaltrials.gov/study/NCT03802955?intr=ADG106&rank=7&tab=history&a=1#version-content-panel>, 01/11/2019) and Applicant’s in admission in the specification on pp. 226-top of p. 227, [409] and in Figures 1A-1C in light of Nair et al. (J. Basic Clin. Pharm. 7(2):27-31, 2016) as applied to claims 1, 20, 22, 23, 44, 45, 49, 59, 60 and 76 above and further in view of US 2019/0331682 A1 (Zitvogel) and Chester et al. (Blood. 2018;131(1):49-57).
NCT03802955 is briefly entitled, “Study of ADG106 With Advanced or Metastatic Solid Tumors and/or Non-Hodgkin Lymphoma”. It teaches administration of anti-CD137 antibody ADG106 to patients with advanced or metastatic solid tumors and/or relapsed/refractory non-Hodgkin lymphoma (Brief Summary, first paragraph). Patients are treated by intravenous infusion of a doses of 0.1 mg/kg, 0.5 mg/kg, 1.5 mg/kg, 3.0 mg/kg, 5.0 mg/kg, 7.5 mg/kg, or 10 mg/kg ADG106 (Arms). Infusion is on Day 1 of each cycle, with two cycles are 42 days, i.e., each cycle is 21 days (Arms and Interventions: Assigned Interventions, and Outcome Measures: Primary Outcome Measures). The method further comprises subsequently determining a level of one or more of circulating T cells or NK cells (Outcome Measures: Secondary Outcome Measures:17.). The method further comprises initially determining, i.e., during screening, a level of PD-L1, CD137, CD138_L and MSI (Eligibility: Inclusion Criteria:4.). NCT03802955 does not teach determining the level of a biomarker which is CD137 or Ki67 after treatment with the anti-CD137 antibody or wherein the treatment is for a particular solid cancer.
On page 226 through the top of p. 227 of the instant specification, antibody ADG106 is disclosed as having the HVR-H1-3 of SEQ ID NO: 2-5 and HVR-L103 of SEQ ID NO:5-6, VH/VL of SEQ ID NO:7/8 and heavy and light chain of SEQ ID NO:10 and 11. Figures 1A-1C of the instant application shows antibody ADG106 binds one or more amino acid residues 51, 53, 62-73, 83, 89, 92, 95-104 and 112-116 of SEQ ID NO: 1. ADG106 is a fully human IgG4 antibody ([409]). This reference is not necessary for anticipation, but only cited to show the immunoglobulin isotype and sequence of antibody ADG106 and that it binds one or more amino acid residues of CD137 as recited in the instant claims.
Nair et al. teaches the reference human weight is 60 kg (Table 1). Therefore, 5 mg/kg is the same as 300 mg for a 60 kg human and 7.5 mg/kg is the same as 450 mg for an average human. The doses taught by Stud NCT03802955 meet the limitations of instant claim 1.
Zitvogel teaches methods of predicting sensitivity of immunotherapy as well as response to immunotherapy by determining the expression of a biomarker(s) ([0106]). These biomarkers were discovered using blood and tumor samples of patients with stage III melanoma ([0021]). It is taught that expression of biomarker Ki67 on T, NK and Treg cell populations allows for proliferation monitoring ([0111]). It is reported ([0223]) that expression of CD137 on CD8+ T cells was significantly associated with lack of relapse in unresectable MMel (metastatic melanoma) in patients treated with ipilimumab plus nivolumab, and the identification of a biomarker predictive of response (i.e., lack of relapse) is “an urgent unmet clinical need.” In the same paragraph it is stated that the use of CD137 as a biomarker is based on the following data:
(i) circulating T lymphocytes expressing CD137 could be found in the blood of patients with no evidence of disease at 13 months who received the combination in an adjuvant setting (and not in those where nivolumab was administered alone); (ii) the finding from the ex vivo mLN assay that CD137 is upregulated in CD4.sup.+ and CD8.sup.+ TILs in lesions qualifying as “responding” to ex vivo stimulation with the combination of anti-PD-1+anti-CTLA-4 mAbs (and not to anti-PD-1 mAb or to other combinatorial regimens). It is therefore conceivable that this combinatorial stimulation leads to the engagement of the CD137/CD137L co-stimulatory pathway, required for T cell fitness and recirculation in the blood of responders (47). However, this pathway did not appear responsible for immediate tumor rejection mediated by the combination regimen in mouse models, although the addition of an agonistic CD137 mAb to the combination therapy further delayed tumor outgrowth in a therapeutic MCA-induced sarcoma model (MJS, unpublished data). This data confirms a previous study performed in mouse ovarian carcinomas, where agonistic anti-CD137 mAb augmented the impact of anti-PD-1+anti-CTLA-4 mAb therapy (61).
Chester et al. discusses that anti-4-1BB (anti-CD137) antibodies have shown promise in the treatment of lymphoma (e.g., p. 51, col. 2, last paragraph). It teaches (p. 50, col. 2),“[T]he capacity of 4-1BB expression to identify tumor antigen–experienced T cells is unique.“ Further (p. 51, col. 1, first full paragraph), “4-1BB is expressed on DC, activated monocytes, and NK cells, neutrophils, eosinophils, and mast cells.34-37 NK cells are of particular interest given their role in tumor control and conflicting reports on the effects of agonizing 4-1BB in this population. Upon Fc-receptor triggering, NK cells upregulate 4-1BB and increase cytotoxic function in response to 4-1BB agonism.” It had been shown that (p. 51, col. 1, last paragraph), “[I]n vivo microscopy experiments revealed that anti-4-1BB mAb treatment can increase the intratumor persistence of tumor-specific cytotoxic T cells resulting in enhanced tumor cell killing.51”
It would have been obvious to one of ordinary skill before the effective filing date of the instant invention to use membrane bound CD137 on T cells, particularly tumor-infiltrating lymphocytes (TILs), as a marker for reduced likelihood of relapse, as suggested by Zitvogel for melanoma. Further, Chester et al. report that agonistic 4-1BB antibody therapy upregulates CD137 on NK cells and increases cytotoxic response, and verification of this response would be valuable for determination of anti-4-1BB antibody treatment success. Further or alternatively, it would have been obvious and desirable to determine whether antitumor cytotoxic cells, e.g., NK cells and/or T lymphocytes, were proliferating, which would have been expected to have been indicative or a productive antitumor immune response by the artisan of ordinary skill. It would have been obvious wherein the cancer to be treated with the anti-CD137 antibody was Non-Hodgkin’s lymphoma as taught by NCT03802955 or a solid tumor, such as a sarcoma or ovarian carcinoma (see NCT03802955 and Zitvogel).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 20-23, 44, 45, 49, 59, 60 and 71-77 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 13, 15, 21, 22, 28 and 29 of U.S. Patent No. 11,242,395 B2 (‘395) in view of ClinicalTrials.gov Study NCT03802955 (version 1, https://clinicaltrials.gov/study/NCT03802955?intr=
ADG106&rank=7&tab=history&a=1#version-content-panel>, 01/11/2019, cited in the PTO-892 mailed 8/20/2025), Nair et al. (J. Basic Clin. Pharm. 7(2):27-31, 2016) and Chester et al. (Blood. 2018;131(1):49-57).
Independent claim 1 is drawn to a method of treating cancer in a subject comprising administering an anti-CD137 antibody that binds human CD137 and comprises HVR-H1-3 of SEQ ID NO:2-4 and HVR-L1-3 of SEQ ID NO:5-7, wherein the anti-CD137 antibody is administered at a dose of 300 mg to 500 mg. Independent claim 7 has the same structural limitation for the antibody used in the method but instead of reciting a limiting dose, requires determining a level of one or more biomarkers selected from the group consisting of total CD137, membrane bound or soluble CD137, CD137_L or Ki67 in a sample from the subject after initial treatment with the anti-CD137 antibody. Claims 44-45 further limit the dose to 300-400 mg. Claims 49 and 73 specify administration is intravenously. Claims 76 and 77 limit administration to about once every three weeks. Claims 20-23 and 71-72 limit the cancer to one which is a solid cancer or liquid cancer, e.g., non-Hodgkin’s lymphoma. Claims 59-60 and 74-75 further define the antibody of claims 1 and 7, respectively, as having the VH/VL of SEQ ID NO:8/9 or HC/LC of SEQ ID NO:10/11. The specification defines the antibody having the HC/LC of SEQ ID NO:10/11 as ADG106 (pp. 226-227).
US 11,242,395 B2 claims an antibody that binds the extracellular domain of human CD137 and has the heavy and light chain sequences of SEQ ID NO:657 and 658, respectively (claim 22), which are identical to instant SEQ ID NO:10 and 11 and comprise the same HVRs and variable domains as the instant claims (claims 1 and 21 of ‘395). A pharmaceutical composition comprising the anti-CD137 antibody is claimed (claims 15, 28 and 29). ‘395 does not claim a method of treating cancer.
NCT03802955 is briefly entitled, “Study of ADG106 With Advanced or Metastatic Solid Tumors and/or Non-Hodgkin Lymphoma”. It teaches administration of anti-CD137 antibody ADG106 to patients with advanced or metastatic solid tumors and/or relapsed/refractory non-Hodgkin lymphoma (Brief Summary, first paragraph). Patients are treated by intravenous infusion of a doses including 5.0 mg/kg and 7.5 mg/kg ADG106 (Arms). Infusion is on Day 1 of each cycle, with two cycles are 42 days, i.e., each cycle is 21 days (Arms and Interventions: Assigned Interventions, and Outcome Measures: Primary Outcome Measures). The method further comprises subsequently determining a level of one or more of circulating T cells or NK cells (Outcome Measures: Secondary Outcome Measures:17.). The method further comprises initially determining, i.e., during screening, a level of PD-L1, CD137, CD138_L and MSI (Eligibility: Inclusion Criteria:4.).
Nair et al. teaches the reference human weight is 60 kg (Table 1). Therefore, 5 mg/kg is the same as 300 mg for a 60 kg human and 7.5 mg/kg is the same as 450 mg for an average human.
Chester et al. discusses that anti-4-1BB (anti-CD137) antibodies have shown promise in the treatment of lymphoma (e.g., p. 51, col. 2, last paragraph). It teaches (p. 50, col. 2), “[T]he capacity of 4-1BB expression to identify tumor antigen–experienced T cells is unique.“ Further (p. 51, col. 1, first full paragraph), “4-1BB is expressed on DC, activated monocytes, and NK cells, neutrophils, eosinophils, and mast cells.34-37 NK cells are of particular interest given their role in tumor control and conflicting reports on the effects of agonizing 4-1BB in this population. Upon Fc-receptor triggering, NK cells upregulate 4-1BB and increase cytotoxic function in response to 4-1BB agonism.” It had been shown that (p. 51, col. 1, last paragraph), “[I]n vivo microscopy experiments revealed that anti-4-1BB mAb treatment can increase the intratumor persistence of tumor-specific cytotoxic T cells resulting in enhanced tumor cell killing.51”
The copending application does not claim a method of treating cancer. Using the claimed antibody to treat cancer, either a solid tumor or liquid, such as non-Hodgkin’s lymphoma, would have been obvious in view of clinical study NCT03802955 using the same agonist anti-CD137 antibody to treat non-Hodgkin’s lymphoma and solid cancers by intravenous infusion every three weeks (21 days). In view of human body weight set forth by Nair et al, it would have been obvious wherein the antibody dose was 300 or 450 mg, corresponding to 5 mg/kg or 7.5 mg/kg, understanding that different body weights would yield different total mg/subject. It would have been obvious to determine the proliferation status of NK cells by measuring Ki67 after treatment and/or the level of CD137 on T cells to determine the activity of cytotoxic immune cells as supported by Chester et al. to evaluate the potential success of treatment at a time point before stable, partial or complete response could otherwise be evaluated.
Applicant’s arguments that relate to the new rejection above necessitated by amendment to the claims are addressed here:
Applicant argues (paragraph bridging pp. 16-17 of REMARKS) that there were unexpected effects that support non-obviousness. These are the effects of a dose of 300 mg and 400 mg, which were safe and effective, and up to 500 mg. The argument has been fully considered but is not persuasive. The copending application recites a dose of no more than 500 mg, which includes 300 mg to 500 mg, making those doses and any in between obvious. If Applicant is arguing that the results are surprising because the subjects were refractory or relapsed after prior therapy but were effectively treated after with the anti-CD137 antibody, it is noted that the feature upon which Applicant relies (i.e., subjects being treated with the anti-CD137 antibody who were refractory or relapsed after prior therapy) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Claim 1, 7, 20-23, 44, 45, 59, 59, 60 and 71-77 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 6, 27, 36, 44, 47, 48 and 55 of copending Application No. 18/011,801 (‘801) in view of US 10,875,894 B2 and Chester et al. (Blood. 2018;131(1):49-57).
Independent claim 1 is drawn to a method of treating cancer in a subject comprising administering an anti-CD137 antibody that binds human CD137 and comprises HVR-H1-3 of SEQ ID NO:2-4 and HVR-L1-3 of SEQ ID NO:5-7, wherein the anti-CD137 antibody is administered at a dose of 300 mg to 500 mg. Independent claim 7 has the same structural limitation for the antibody used in the method but instead of reciting a limiting dose, requires determining a level of one or more biomarkers selected from the group consisting of total CD137, membrane bound or soluble CD137, CD137_L or Ki67 in a sample from the subject after initial treatment with the anti-CD137 antibody. Claims 44-45 further limit the dose to 300-400 mg. Claims 49 and 73 specify administration is intravenously. Claims 76 and 77 limit administration to about once every three weeks. Claims 20-23 and 71-72 limit the cancer to one which is a solid cancer or liquid cancer, e.g., non-Hodgkin’s lymphoma. Claims 59-60 and 74-75 further define the antibody of claims 1 and 7, respectively, as having the VH/VL of SEQ ID NO:8/9 or HC/LC of SEQ ID NO:10/11. The specification defines the antibody having the HC/LC of SEQ ID NO:10/11 as ADG106 (pp. 226-227).
The claims of 18/011,801 are drawn to a method of treating cancer in a subject comprising administering the same antibody, i.e., one that binds the heavy and light chain HVR1-3 of SEQ ID NO:2-4 and 5-7, respectively, but also administration of an effective amount of an agent, including IL-2, that induces expression of CD137 on an immune cell and/or expression of CD137L on a cancer cell of the subject, wherein the cancer is melanoma or lymphoma (claim 1). Claim 2 further defines the immune cell as a CD8+ Treg, NK and NK-T cell. Claim 6 limits the agent to IL-2. Claim 27 define the cancer as a lymphoma, e.g., non-Hodgkin’s lymphoma or T cell lymphoma (compare to instant claims 21-23 and 72). Claim 36 limits the dose to no more than 500 mg and/or no more than about 10 mg/kg (see instant claims 1, 2 and 44-48). Claims 44 and 47-48 further define the antibody structure (see instant claims 58-60). Claim 55 specifies the anti-CD137 antibody comprise a human IgG4 Fc region (see instant claim 67). The VH and VL sequences as well as heavy and light chain sequences are set forth in claims 47-48 and identical to those of the instant claims. ‘801 does not claim wherein the level of total CD137, membrane bound CD137, CD137L and/or Ki67 is determined.
US 10,875,894 B2 teaches that IL-2-activated NK cells express CD137 (col. 34, line 48).
Chester et al. discusses that anti-4-1BB (anti-CD137) antibodies have shown promise in the treatment of lymphoma (e.g., p. 51, col. 2, last paragraph). It teaches (p. 50, col. 2), “[T]he capacity of 4-1BB expression to identify tumor antigen–experienced T cells is unique.“ Further (p. 51, col. 1, first full paragraph), “4-1BB is expressed on DC, activated monocytes, and NK cells, neutrophils, eosinophils, and mast cells.34-37 NK cells are of particular interest given their role in tumor control and conflicting reports on the effects of agonizing 4-1BB in this population. Upon Fc-receptor triggering, NK cells upregulate 4-1BB and increase cytotoxic function in response to 4-1BB agonism.” Chester et al. also teaches 4-1BB signaling leads to increased IL-2 secretion and other proteins that protect against activation-induced T cell death (p. 50, col. 2). Anti-4-1BB antibody treatment can restore function of CD8+ TILs (tumor infiltrating lymphocytes) that have lost their capacity to secrete IL-2 (p. 51, col. 1, middle of last paragraph). It had been shown that (p. 51, col. 1, last paragraph), “[I]n vivo microscopy experiments revealed that anti-4-1BB mAb treatment can increase the intratumor persistence of tumor-specific cytotoxic T cells resulting in enhanced tumor cell killing.51”
It would have been obvious to treat cancer by administration of the same anti-CD137 antibody of claims of both applications and determine the amount of CD137 expression on immune cells, e.g., NK cells, and/or of CD137L on cancer cells of the subject, including after treatment, since claim 1 of ‘801 in view of the patents provides the expectation that treatment with IL-2 increases CD137 expression on immune cells, including T reg and NK cells, and Chester et al. taught that anti-CD137 treatment increases expression on NK cells. The dosage of ‘801 is within the range of the instant claims. It would have been obvious wherein administration was intravenously because this was the routine and well-known means of administering cancer therapeutics.
This is a provisional nonstatutory double patenting rejection.
Applicant notes (section VI. 2.) that the copending application has a later effective fling date and the rejection should be held in abeyance until the instant claims are otherwise allowable. The argument has been fully considered but is not persuasive. While it is agreed the instant application has an earlier patent term filing date and the rejection would be withdrawn if it were the only remaining rejection, the rejection cannot be held in abeyance.
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