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 .
Claims 1-4, 9-19, 22-31 are pending.
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 1-4, 9-19, 22-31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 19309299 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims contain overlapping subject matter.
Claim 1 of 19309299:
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The disease treated, the active ingredient and the (human) patient treated are same in the conflicting claims. The dependent claims also contain overlapping subject matter with regards to effective dose and duration of treatment and other.
Double Patenting
A rejection based on double patenting of the “same invention” type finds its support in the language of 35 U.S.C. 101 which states that “whoever invents or discovers any new and useful process... may obtain a patent therefor...” (Emphasis added). Thus, the term “same invention,” in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co., 151 U.S. 186 (1894); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Ockert, 245 F.2d 467, 114 USPQ 330 (CCPA 1957).
A statutory type (35 U.S.C. 101) double patenting rejection can be overcome by canceling or amending the claims that are directed to the same invention so they are no longer coextensive in scope. The filing of a terminal disclaimer cannot overcome a double patenting rejection based upon 35 U.S.C. 101.
Claim 1 is provisionally rejected under 35 U.S.C. 101 as claiming the same invention as that of claim 1 of copending Application No. 19309299 (reference application). This is a provisional statutory double patenting rejection since the claims directed to the same invention have not in fact been patented.
Claim 1 of 19309299:
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Instant Claim 1:
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The term ‘patient’ includes ‘human patient’.
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.
Claims 1-4, 9-19, 22-31 are rejected under 35 U.S.C. 103 as being unpatentable over Hong, New England Journal of Medicine 2020, Vol. 383 pages 1207-1217; Canon 2019 Nature Vol. 575 pages 217-223; Yamamoto, 2019 Journal of Thoracic Oncology Vol. 14 pages E97-E99. Lin, Lancet Oncology 2015, Vol. 16 pages 270-278; and Cui, Lung Cancer 2020, Vol. 146 pages 310-317, Patel, Clinical Pharmacokinetics (2020) 59:447–462.
Hong teaches that KRAS mutant metastatic non-small cell lung cancer and colorectal carcinoma patients do not benefit from standard anti-EGFR therapies and have poorer progression-free survival and overall survival compared to wild type KRAS patients (page 1216 left col). Hong teaches that considering the poor prognosis in patient with metastatic disease and the lack of effective treatments in this population, controlling tumor burden with oral therapies may be meaningful (page 1216 left col.). Hong teaches the method of treating metastatic KRAS G12C mutant non-small cell lung cancer and metastatic KRAS G12C colorectal carcinoma in a subject in need comprising orally administering sotorasib in doses ranging from 180 mg to 960 mg to said subject (abstract, page 1208 right col., page 1209 right col.).
As shown in Table 3, 35% of said metastatic non-small cell lung cancer patients treated with 960 mg of sotorasib yielded a tumor reduction and 91% of said patients comprised disease control (page 1213 left col.). In addition, 66% of said metastatic colorectal carcinoma patients comprised stabilized disease upon receiving 960 mg of sotorasib (page 1213, page 1215 right col., Table 3). As shown in Figure 1, doses ranging from 180 mg to 960 mg were effective at yielding tumor reduction in the afflicted neoplastic patient. The above read on the limitations of claims 1, 30 and 31.
Metastatic patients previously treated with anti-PD-1 immunotherapies and platinum-based chemotherapies were embraced within the patient population treated with sotorasib (page 1209 right col.). All patients were previously treated with platinum-based chemotherapies (Table 1). Regarding the conditional language limitation wherein the patient also underwent treatment with an EGFR, ALK or ROS1 inhibitor if the cancer also exhibited a mutation in EGFR, ALK or ROS1, Hong is silent as to these mutations in the mutant KRAS G12C non-small cell lung cancer patient population. As such, treatment of said patients with sotorasib and who had previously been treated with platinum-based chemotherapies embodied within Hong reads on the limitations of claims 1, 30, 31.
Hong Abstract:
No therapies for targeting KRAS mutations in cancer have been
approved. The KRAS p.G12C mutation occurs in 13% of
non-small-cell lung cancers (NSCLCs) and in 1 to 3% of
colorectal cancers and other cancers. Sotorasib is a small mol.
that selectively and irreversibly targets KRASG12C. methods We conducted a
phase 1 trial of sotorasib in patients with advanced solid tumors
harboring the KRAS p.G12C mutation. Patients received sotorasib
orally once daily. The primary end point was safety. Key secondary end
points were pharmacokinetics and objective response, as assessed according
to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.
results A total of 129 patients (59 with NSCLC, 42 with colorectal
cancer, and 28 with other tumors) were included in dose escalation and
expansion cohorts. Patients had received a median of 3 (range, 0 to 11)
previous lines of anticancer therapies for metastatic disease. No
dose-limiting toxic effects or treatment-related deaths were obsd. A
total of 73 patients (56.6%) had treatment-related adverse events; 15
patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC,
32.2% (19 patients) had a confirmed objective response (complete or
partial response) and 88.1% (52 patients) had disease control (objective
response or stable disease); the median progression-free survival was 6.3
mo (range, 0.0+ to 14.9 [with + indicating that the value includes patient
data that were censored at data cutoff]). In the subgroup with
colorectal cancer, 7.1% (3 patients) had a confirmed response, and
73.8% (31 patients) had disease control; the median progression-free
survival was 4.0 mo (range, 0.0+ to 11.1+). Responses were also obsd. in
patients with pancreatic, endometrial, and appendiceal cancers and
melanoma. conclusions Sotorasib showed encouraging anticancer
activity in patients with heavily pretreated advanced solid tumors
harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related
toxic effects occurred in 11.6% of the patients.
Canon teaches the method of treating human patients comprising orally administering AMG-510 to KRAS G12C mutant non-small cell lung cancer.
As evidenced by paragraph [0011] of the instant specification, compound AMG-510 is art-recognized as sotorasib. As shown in Figure 3b, a significant reduction in tumor burden was achieved with the administered 360 mg dose. Regarding claims 15-16, said patients were previously treated with carboplatin and anti-PD-1 (nivolumab) prior to administration of compound AMG-510 (page 220 left col. Figure 3, Extended Data Figure 5). Canon also teaches that AMG-510 is synergistic with the MEK inhibitor trametinib inhibiting KRAS G12C non-small cell cancer tumor growth (NCI-H373) and KRAS G12C colorectal cancer tumor growth (pages 220-221; Figure 4a).
The difference between the methodologies of Hong and Canon and that of the present claims is that neither Hong nor Cannon specifically teaches treating said KRAS G12C mutant non-small cell cancer patient wherein the KRAS G12C metastatic non-small cell lung cancer patient treated with sotorasib comprises active brain metastases.
Yamamoto (Journal of Thoracic Oncology Vol. 14 pages E97-E99 published 2019) teaches treating non-small cell lung cancer patients with active brain metastases comprising administration of a therapeutically effective amount of trametinib and dabrafenib along with radiation therapy. As shown in Figures 2-3, Yamamoto teaches that said trametinib-dabrafenib-radiation regimen is efficacious for the treatment of non-small cell lung cancer with intracranial metastases.
Therefore, one of ordinary skill in the art of treating KRAS G12C mutant metastatic non-small cell lung cancer and metastatic colorectal carcinoma, knowing that administration of sotorasib is efficacious at treating metastatic KRAS G12C mutant non-small cell lung cancer and colorectal cancer in a subject in need as taught by Hong, coupled with the knowledge that sotorasib is synergistic with the MEK inhibitor trametinib in reducing KRAS G12C non-small cell lung cancer and KRAS G12C colorectal tumor burden as taught by Canon, said skilled artisan would have found it prima facie obvious to administer sotorasib in combination with the MEK inhibitor trametinib, dabrafenib and radiation therapy to treat KRAS G12C non-small cell lung cancer and KRAS G12C colorectal carcinoma patients with active brain metastases in view of Yamamoto.
Motivation to administer the MEK inhibitor trametinib, radiation therapy and dabrafenib in combination with the art-recognized KRAS G12C mutant non-small cell lung cancer and colorectal cancer treating sotorasib of Hong and Canon to KRAS G12C mutant non-small cell lung cancer and colorectal cancer patients with active brain metastases logically flows from the fact that Yamamoto teaches that trametinib, radiation therapy and dabrafenib combination is efficacious at inhibiting growth of non-small cell lung cancer patients with active brain metastasis. Considering that sotorasib is synergistic with the MEK inhibitor trametinib in reducing KRAS G12C non-small cell lung cancer and KRAS G12C colorectal tumor burden as taught by Canon, said artisan would have readily predicted that administration of the combination of sotorasib, the MEK inhibitor trametinib, radiation therapy and dabrafenib to the KRAS G12C mutant non-small cell lung cancer and colorectal cancer patients with active brain metastases would have effectively inhibited primary and metastatic tumor growth in the afflicted neoplastic patient and the active brain metastases. Reduction of the primary lung tumor hinders the capacity of the primary tumor to metastasize to the brain, thereby decreasing new tumor formation and treating the disease as recited in [0070] of the specification.
Regarding the limitation wherein the daily dose of sotorasib administered to the metastatic non-small cell lung cancer or colorectal carcinoma patient is 960 mg 480 mg or 240 mg (claims 2-4), the optimum dose of sotorasib administered to the metastatic non-small cell lung cancer (claim 9) or colorectal carcinoma (claim 10) patient with active brain metastases would have been a matter well within the insight of one of ordinary skill in the art. Such a determination would have been made in accordance with a variety of factors, such as the route of administration, pharmacological considerations, such as activity, efficacy, pharmacokinetics and toxicology profiles of the combined regimen, as well as the age, weight, sex, diet and severity of the medical condition of the patient. Thus, the dosing of sotorasib that would have been employed would have varied widely and, in the absence of evidence to the contrary, the current claimed specific administration regimen is not seen to be inconsistent with one that would have been determined by the skilled artisan. Moreover, as shown in Figure 1 of Hong, doses ranging from 180 mg to 960 mg were effective at yielding tumor reduction in the afflicted neoplastic patient. Furthermore, absent and evidence demonstrating a patentable difference between the compositions administered and the criticality of the claimed frequency and dosing cycles, the determination of the optimum or workable frequency of administration given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan. Please see MPEP 2144.05 [R-2](II)(A) and In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)(”[W]here the general conditions of the claim are disclosed in the prior art, it is not inventive to discover the workable ranges by routine experimentation.”)
Lin teaches assessment criteria for active brain metastases. Lin teaches that measurable disease is defined as a contrast-enhancing lesion that can be accurately measured in at least one dimension with a minimum size of 10 mm (page 271 left col.) Lin states that for studies wherein the CNS objective response is the primary endpoint, it is highly recommended that there is a cutoff of 10 mm to limit the study to measurable disease (page 271 right col.)
Cui teaches mutant KRAS G12C metastatic non-small cell lung cancer patients and colorectal carcinoma patients comprising active brain metastases. Cui teaches that there is a poorer prognosis in both patient classes compared to KRAS wild type tumors (pages 310-311). Cui also teaches that there is a high incidence of KRAS mutant G12C non-small cell lung cancer developing brain metastatic lesions. Cui teaches that 28% of patients diagnosed with KRAS G12C metastatic non-small cell lung cancer comprise active brain metastases and that 40% of said KRAS G12C metastatic non-small cell lung cancer patients will develop active brain metastases during follow up (page 313-314). Cui teaches that in this distinct patient population, treatments with good intracranial penetration is important for long-term disease control (page 314 right col.).
Therefore, one of ordinary skill in the art of treating patients comprising mutant KRAS G12C non-small cell lung cancer and colorectal cancer and further comprising active brain metastases comprising administering a therapeutically effective amount of the art-recognized KRAS G12C inhibitor sotorasib in combination with trametinib, radiation therapy and dabrafenib as taught by the combination of Hong, Canon and Yamamoto above, said skilled artisan would have found it prima facie obvious to administer said sotorasib, trametinib, radiation therapy and dabrafenib therapeutic regimen to said KRAS mutant G12C non-small cell lung cancer patient or colorectal carcinoma patient with an metastatic cranial lesion of greater than 10 mm in view of Cui and Lin.
Considering Lin teaches that measurable disease of an active brain metastasis is defined as a contrast-enhancing lesion that can be accurately measured in at least one dimension with a minimum size of 10 mm, said skilled artisan would have readily predicted that administering the sotorasib, trametinib and dabrafenib regimen to a patient with an active brain metastasis includes a patient with measurable disease, and thus embraces a patient with a contrast-enhancing lesion that can be accurately measured in at least one dimension with a minimum size of 10 mm. Further, considering Cui teaches that there is a high incidence of KRAS mutant G12C non-small cell lung and colorectal cancer patients developing brain metastatic lesions along with poorer prognosis of said patients compared to wild type disease, said skilled artisan would have been motivated to administer the sotorasib, trametinib and dabrafenib regimen in order to improve the therapeutic outcome in the poorer prognosed patient class. Note that obviousness can 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.
The teachings of Patel is invoked here with respect to the limitations of claims 11-19. 22-29: These claims are drawn to combination of the active ingredient sotorasib with acid reducing agents, claims 11-14), PPI or H2RA (claims 15-18), CYP3A4 inducer (claims 19, 22-26) and P-gp (claims 27-29). According to Patel at column A, top of page 448, gastric acid-reducing agents (ARAs) are commonly used among patients across all fields of medicine and are often recommended to treat conditions related to gastrointestinal disease. The teaching(s) of Patel is invoked here for the coadministration of such agents in treatment of diseases. Coadministration of each of these additional agents are discussed in the Systematic Review of Gastric Acid‑Reducing Agent‑Mediated Drug–Drug Interactions with Orally Administered Medications. Note that by definition, a scientific review is a comprehensive, critical synthesis of existing research on a specific topic, designed to summarize, analyze, and interpret the current state of knowledge, often highlighting trends, gaps, and future directions. Unlike primary research, these are secondary publications that organize literature into a cohesive narrative, providing valuable insights for researchers and novices alike. Applicant is encouraged to point out data for secondary consideration with respect to these claims.
Therefore nothing unobvious is seen in the claims.
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 1-4, 9-19, 22-31 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 5-6, 9-10, 16-17 of U.S. Patent No. 11426404 in view of the combined teachings of Hong, New England Journal of Medicine Vol. 383 pages 1207-1217; Canon Nature Vol. 575 pages 217-223; Yamamoto, Journal of Thoracic Oncology Vol. 14 pages E97-E99. Lin, Lancet Oncology Vol. 16 pages 270-278; and Cui, Lung Cancer Vol. 146 pages 310-317, Patel, Clinical Pharmacokinetics (2020) 59:447–462.
Although the claims at issue are not identical, they are not patentably distinct from each other because of the following. Claims 1-47 of U.S. Patent No. 11426404 are directed to treating a human patient comprising KRAS G12C mutant non-small cell lung cancer comprising administering once-a-day a dose of 960 mg of Formula (I). Claims 11426404 are directed to treating a human patient comprising KRAS G12C mutant colorectal carcinoma comprising administering once-a-day a dose of 960 mg of Formula (I).
The difference between the present claims and that of claims of 111426404 is that the base claim of 111426404 , do not specifically teach wherein the KRAS G12C mutant non-small cell lung cancer patient or KRAS G12C mutant colorectal carcinoma patient comprises brain metastases. The teachings of Hong, Canon, Yamamoto, Lin and Cui are invoked for the obviousness of this difference.
Hong teaches that KRAS mutant metastatic non-small cell lung cancer and colorectal carcinoma patients do not benefit from standard anti-EGFR therapies and have poorer progression-free survival and overall survival compared to wild type KRAS patients (page 1216 left col). Hong teaches that considering the poor prognosis in patient with metastatic disease and the lack of effective treatments in this population, controlling tumor burden with oral therapies may be meaningful (page 1216 left col.). Hong teaches the method of treating metastatic KRAS G12C mutant non-small cell lung cancer and metastatic KRAS G12C colorectal carcinoma in a subject in need comprising orally administering sotorasib in doses ranging from 180 mg to 960 mg to said subject (abstract, page 1208 right col., page 1209 right col.).
As shown in Table 3, 35% of said metastatic non-small cell lung cancer patients treated with 960 mg of sotorasib yielded a tumor reduction and 91% of said patients comprised disease control (page 1213 left col.). In addition, 66% of said metastatic colorectal carcinoma patients comprised stabilized disease upon receiving 960 mg of sotorasib (page 1213, page 1215 right col., Table 3). As shown in Figure 1, doses ranging from 180 mg to 960 mg were effective at yielding tumor reduction in the afflicted neoplastic patient. The above read on the limitations of claims 1, 30 and 31.
Metastatic patients previously treated with anti-PD-1 immunotherapies and platinum-based chemotherapies were embraced within the patient population treated with sotorasib (page 1209 right col.). All patients were previously treated with platinum-based chemotherapies (Table 1). Regarding the conditional language limitation wherein the patient also underwent treatment with an EGFR, ALK or ROS1 inhibitor if the cancer also exhibited a mutation in EGFR, ALK or ROS1, Hong is silent as to these mutations in the mutant KRAS G12C non-small cell lung cancer patient population. As such, treatment of said patients with sotorasib and who had previously been treated with platinum-based chemotherapies embodied within Hong reads on the limitations of claims 1, 30, 31.
Hong Abstract:
No therapies for targeting KRAS mutations in cancer have been
approved. The KRAS p.G12C mutation occurs in 13% of
non-small-cell lung cancers (NSCLCs) and in 1 to 3% of
colorectal cancers and other cancers. Sotorasib is a small mol.
that selectively and irreversibly targets KRASG12C. methods We conducted a
phase 1 trial of sotorasib in patients with advanced solid tumors
harboring the KRAS p.G12C mutation. Patients received sotorasib
orally once daily. The primary end point was safety. Key secondary end
points were pharmacokinetics and objective response, as assessed according
to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.
results A total of 129 patients (59 with NSCLC, 42 with colorectal
cancer, and 28 with other tumors) were included in dose escalation and
expansion cohorts. Patients had received a median of 3 (range, 0 to 11)
previous lines of anticancer therapies for metastatic disease. No
dose-limiting toxic effects or treatment-related deaths were obsd. A
total of 73 patients (56.6%) had treatment-related adverse events; 15
patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC,
32.2% (19 patients) had a confirmed objective response (complete or
partial response) and 88.1% (52 patients) had disease control (objective
response or stable disease); the median progression-free survival was 6.3
mo (range, 0.0+ to 14.9 [with + indicating that the value includes patient
data that were censored at data cutoff]). In the subgroup with
colorectal cancer, 7.1% (3 patients) had a confirmed response, and
73.8% (31 patients) had disease control; the median progression-free
survival was 4.0 mo (range, 0.0+ to 11.1+). Responses were also obsd. in
patients with pancreatic, endometrial, and appendiceal cancers and
melanoma. conclusions Sotorasib showed encouraging anticancer
activity in patients with heavily pretreated advanced solid tumors
harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related
toxic effects occurred in 11.6% of the patients.
Canon teaches the method of treating human patients comprising orally administering AMG-510 to KRAS G12C mutant non-small cell lung cancer.
As evidenced by paragraph [0011] of the instant specification, compound AMG-510 is art-recognized as sotorasib. As shown in Figure 3b, a significant reduction in tumor burden was achieved with the administered 360 mg dose. Regarding claims 15-16, said patients were previously treated with carboplatin and anti-PD-1 (nivolumab) prior to administration of compound AMG-510 (page 220 left col. Figure 3, Extended Data Figure 5). Canon also teaches that AMG-510 is synergistic with the MEK inhibitor trametinib inhibiting KRAS G12C non-small cell cancer tumor growth (NCI-H373) and KRAS G12C colorectal cancer tumor growth (pages 220-221; Figure 4a).
The difference between the methodologies of Hong and Canon and that of the present claims is that neither Hong nor Cannon specifically teaches treating said KRAS G12C mutant non-small cell cancer patient wherein the KRAS G12C metastatic non-small cell lung cancer patient treated with sotorasib comprises active brain metastases.
Yamamoto (Journal of Thoracic Oncology Vol. 14 pages E97-E99 published 2019) teaches treating non-small cell lung cancer patients with active brain metastases comprising administration of a therapeutically effective amount of trametinib and dabrafenib along with radiation therapy. As shown in Figures 2-3, Yamamoto teaches that said trametinib-dabrafenib-radiation regimen is efficacious for the treatment of non-small cell lung cancer with intracranial metastases.
Therefore, one of ordinary skill in the art of treating KRAS G12C mutant metastatic non-small cell lung cancer and metastatic colorectal carcinoma, knowing that administration of sotorasib is efficacious at treating metastatic KRAS G12C mutant non-small cell lung cancer and colorectal cancer in a subject in need as taught by Hong, coupled with the knowledge that sotorasib is synergistic with the MEK inhibitor trametinib in reducing KRAS G12C non-small cell lung cancer and KRAS G12C colorectal tumor burden as taught by Canon, said skilled artisan would have found it prima facie obvious to administer sotorasib in combination with the MEK inhibitor trametinib, dabrafenib and radiation therapy to treat KRAS G12C non-small cell lung cancer and KRAS G12C colorectal carcinoma patients with active brain metastases in view of Yamamoto.
Motivation to administer the MEK inhibitor trametinib, radiation therapy and dabrafenib in combination with the art-recognized KRAS G12C mutant non-small cell lung cancer and colorectal cancer treating sotorasib of Hong and Canon to KRAS G12C mutant non-small cell lung cancer and colorectal cancer patients with active brain metastases logically flows from the fact that Yamamoto teaches that trametinib, radiation therapy and dabrafenib combination is efficacious at inhibiting growth of non-small cell lung cancer patients with active brain metastasis. Considering that sotorasib is synergistic with the MEK inhibitor trametinib in reducing KRAS G12C non-small cell lung cancer and KRAS G12C colorectal tumor burden as taught by Canon, said artisan would have readily predicted that administration of the combination of sotorasib, the MEK inhibitor trametinib, radiation therapy and dabrafenib to the KRAS G12C mutant non-small cell lung cancer and colorectal cancer patients with active brain metastases would have effectively inhibited primary and metastatic tumor growth in the afflicted neoplastic patient and the active brain metastases. Reduction of the primary lung tumor hinders the capacity of the primary tumor to metastasize to the brain, thereby decreasing new tumor formation and treating the disease as recited in [0070] of the specification.
Regarding the limitation wherein the daily dose of sotorasib administered to the metastatic non-small cell lung cancer or colorectal carcinoma patient is 960 mg 480 mg or 240 mg (claims 2-4), the optimum dose of sotorasib administered to the metastatic non-small cell lung cancer (claim 9) or colorectal carcinoma (claim 10) patient with active brain metastases would have been a matter well within the insight of one of ordinary skill in the art. Such a determination would have been made in accordance with a variety of factors, such as the route of administration, pharmacological considerations, such as activity, efficacy, pharmacokinetics and toxicology profiles of the combined regimen, as well as the age, weight, sex, diet and severity of the medical condition of the patient. Thus, the dosing of sotorasib that would have been employed would have varied widely and, in the absence of evidence to the contrary, the current claimed specific administration regimen is not seen to be inconsistent with one that would have been determined by the skilled artisan. Moreover, as shown in Figure 1 of Hong, doses ranging from 180 mg to 960 mg were effective at yielding tumor reduction in the afflicted neoplastic patient. Furthermore, absent and evidence demonstrating a patentable difference between the compositions administered and the criticality of the claimed frequency and dosing cycles, the determination of the optimum or workable frequency of administration given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan. Please see MPEP 2144.05 [R-2](II)(A) and In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)(”[W]here the general conditions of the claim are disclosed in the prior art, it is not inventive to discover the workable ranges by routine experimentation.”)
Lin teaches assessment criteria for active brain metastases. Lin teaches that measurable disease is defined as a contrast-enhancing lesion that can be accurately measured in at least one dimension with a minimum size of 10 mm (page 271 left col.) Lin states that for studies wherein the CNS objective response is the primary endpoint, it is highly recommended that there is a cutoff of 10 mm to limit the study to measurable disease (page 271 right col.)
Cui teaches mutant KRAS G12C metastatic non-small cell lung cancer patients and colorectal carcinoma patients comprising active brain metastases. Cui teaches that there is a poorer prognosis in both patient classes compared to KRAS wild type tumors (pages 310-311). Cui also teaches that there is a high incidence of KRAS mutant G12C non-small cell lung cancer developing brain metastatic lesions. Cui teaches that 28% of patients diagnosed with KRAS G12C metastatic non-small cell lung cancer comprise active brain metastases and that 40% of said KRAS G12C metastatic non-small cell lung cancer patients will develop active brain metastases during follow up (page 313-314). Cui teaches that in this distinct patient population, treatments with good intracranial penetration is important for long-term disease control (page 314 right col.).
Therefore, one of ordinary skill in the art of treating patients comprising mutant KRAS G12C non-small cell lung cancer and colorectal cancer and further comprising active brain metastases comprising administering a therapeutically effective amount of the art-recognized KRAS G12C inhibitor sotorasib in combination with trametinib, radiation therapy and dabrafenib as taught by the combination of Hong, Canon and Yamamoto above, said skilled artisan would have found it prima facie obvious to administer said sotorasib, trametinib, radiation therapy and dabrafenib therapeutic regimen to said KRAS mutant G12C non-small cell lung cancer patient or colorectal carcinoma patient with an metastatic cranial lesion of greater than 10 mm in view of Cui and Lin.
Considering Lin teaches that measurable disease of an active brain metastasis is defined as a contrast-enhancing lesion that can be accurately measured in at least one dimension with a minimum size of 10 mm, said skilled artisan would have readily predicted that administering the sotorasib, trametinib and dabrafenib regimen to a patient with an active brain metastasis includes a patient with measurable disease, and thus embraces a patient with a contrast-enhancing lesion that can be accurately measured in at least one dimension with a minimum size of 10 mm. Further, considering Cui teaches that there is a high incidence of KRAS mutant G12C non-small cell lung and colorectal cancer patients developing brain metastatic lesions along with poorer prognosis of said patients compared to wild type disease, said skilled artisan would have been motivated to administer the sotorasib, trametinib and dabrafenib regimen in order to improve the therapeutic outcome in the poorer prognosed patient class.
The teaching(s) of Patel is invoked here with respect to the limitations of claims 11-19. 22-29: These claims are drawn to combination of the active ingredient sotorasib with acid reducing agents, claims 11-14), PPI or H2RA (claims 15-18), CYP3A4 inducer (claims 19, 22-26) and P-gp (claims 27-29). Coadministration of each of these additional agents are discussed in the Systematic Review of Gastric Acid‑Reducing Agent‑Mediated Drug–Drug Interactions with Orally Administered Medications. Applicant is encouraged to point out data for secondary consideration with respect to these claims.
Therefore, one of ordinary skill in the art prior to the time of the invention knowing that administration of sotorasib is efficacious at treating KRAS G12C mutant non-small cell lung cancer and colorectal carcinoma in a subject in need as taught by claims of 11426404 said skilled artisan would have found it prima facie obvious to administer sotorasib to said KRAS G12C mutant non-small cell lung cancer and colorectal carcinoma patient comprising active brain metastases
Reentering the discussion, that is the same arguments from Claim Rejections - 35 USC § 103 in the obviousness analysis\, is as per Examination guidelines. The following rejections avoids this redundancy.
Claims 1-4, 9-19, 22-31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 18503009.
Although the claims at issue are not identical, they are not patentably distinct from each other because of the following.
Claim 1 of copending Application 18503009 is directed to the method of treating cancer in a subject in comprising administering once a day 960 mg of Formula (I).
The pictured compound in claim 1 of 18503009 is sotorasib. The methodology of the present claims lies inside the methodology of claim 1 of copending Application 18503009:
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The difference is that the claim 1 of 18503009 does not recite brain metastases. The position taken is that the subjects being treated with the above method does not exclude the patients of instant claim KRAS G12C mutation in a patient with active brain metastases
Claims 1-4, 9-19, 22-31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 19097649.
Although the claims at issue are not identical, they are not patentably distinct from each other because of the following.
Claim 1 of copending Application 19097649 is directed to the method of treating cancer in a subject in comprising administering once a day 960 mg of Formula (I).
The pictured compound in claim 1 of 19097649 is sotorasib. The methodology of the present claims lies inside the methodology of claim 1 of copending Application 19097649:
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The difference is that the claim 1 of 19097649 does not recite brain metastases. The position taken is that the subjects being treated with the above method does not exclude the patients of instant claim KRAS G12C mutation in a patient with active brain metastases.
References made of record and not relied upon is considered pertinent to applicant's disclosure:
Feldman, Understanding ‘Evergreening’ : Making Minor Modifications Of Existing Medications To Extend Protections, Health Affairs June 2022 41:6, 801-804
Dwivedi, Evergreening: A deceptive device in patent rights, Technology in Society 32, (2010) 324–330.
US 10519146 and US Applications 17696758, 18689716 and 18270581 in the use of sotorasib for treating cancer wherein the cancer is a KRAS G12C mutated cancer.
Copending Applications
A large number of issued patents and pending Applications are found in the PTO database for related subject matter. Applicant is encouraged to check for additional copending applications and issued patents for overlapping subject matter in the claims and file terminal disclaimers.
MPEP 2001.06(b) Information Relating to or From Copending United States Patent Applications [R-08.2012]: The individuals covered by 37 CFR 1.56 have a duty to bring to the attention of the examiner, or other Office official involved with the examination of a particular application, information within their knowledge as to other copending United States applications which are “material to patentability” of the application in question. As set forth by the court in Armour & Co. v. Swift & Co., 466 F.2d 767, 779, 175 USPQ 70, 79 (7th Cir. 1972):
[W]e think that it is unfair to the busy examiner, no matter how diligent and well informed he may be, to assume that he retains details of every pending file in his mind when he is reviewing a particular application . . . [T]he applicant has the burden of presenting the examiner with a complete and accurate record to support the allowance of letters patent.
Emphasis added by the Examiner.
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/NIZAL S CHANDRAKUMAR/Primary Examiner, Art Unit 1625