CTNF 18/668,774 CTNF 85407 Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. DETAILED ACTION 12-151 AIA 26-51 12-51 Status of Claims Claims 1, 4-10, 14-15, and 17-26 are pending and under examination in the instant office action. Claim Objections Claim 1 is objected to because of the following informalities: typographical errors. It appears that “the patient” is missing after “administering” in line 2. Claim Rejections - 35 USC § 103 07-20-aia AIA 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 of this title, 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. 07-20-02-aia AIA 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. 07-23-aia AIA The factual inquiries set forth in Graham v. John Deere Co. , 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows: 1. Determining the scope and contents of the prior art. 2. Ascertaining the differences between the prior art and the claims at issue. 3. Resolving the level of ordinary skill in the pertinent art. 4. Considering objective evidence present in the application indicating obviousness or nonobviousness. 07-21-aia AIA Claim s 1, 4-10, 14-15, and 17-26 are rejected under 35 U.S.C. 103 as being unpatentable over US2017/0015678 (hereafter, BRAUN) in view of Khan et al . (The Oncologist 2016; 21:855–860) and Leone et al. (Advances in Nutrition and Cancer 159; pp 355–376, 2014) . BRAUN teaches GDC-0077 ( PNG media_image1.png 168 211 media_image1.png Greyscale , (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d] [1,4]oxazepin-9-yl)amino)propenamide) or pharmaceutically acceptable salts thereof as phosphoinositide-3 kinase (PI3K) modulation activity (PI3K alpha inhibitor) and a method of treating cancer in a patient having cancer comprising administering to said patient a therapeutically effective amount of the compound (abstract, [0013]-[0019], p9, Table 1, Compound #101, p12, Table 2A, and claims 1 and 4). BRAUN further teaches a dose to treat human patients may range from about 1 mg to about 1000 mg, typically 10 mg to 300 mg and a dose may be administered once a day (QID) (p52, lines 11-18). BRAUN teaches that the cancer includes breast cancer, non-small cell lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and uterine cancer ([0037] and [0116]). BRAUN specifically teaches that the cancer is selected from breast cancer and non-small cell lung cancer (solid tumor) and the cancer expresses a PIK3CA mutant selected from E542K, E545K, Q546R, H1047L and H1047R (claim 14 and 19). BRAUN also discloses that the cancer is breast cancer wherein the breast cancer is estrogen receptor positive (ER+) (hormone-receptor positive) breast cancer or HER2 negative (claims 16 -17, 21-22). BRAUN further teaches that about 35-40% of hormone receptor positive (HR+) breast cancer tumors harbor a PIK3CA mutation ([0006]). BRAUN further discloses that the Compound 101 is more efficacious than GDC-0032 (Taselisib), which was developed as a treatment for patients with oestrogen receptor (ER)-positive, HER2-negative metastatic breast cancer (mBC) and non-small cell lung cancer (NSCLC), in a PI3K mutant tumor model ([0009] and [0104]-[0108]). BRAUN teaches that the compound may be employed alone or in combination with additional therapeutic agents wherein the additional therapeutic may be a Bcl-2 inhibitor, a JAK inhibitor, an anti-inflammatory agent, an immunomodulatory agent, chemotherapeutic agent, an apoptosis-enhancer, a neurotropic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an antiviral agent, an agent for treating blood disorders, an agent for treating diabetes , and an agent for treating immunodeficiency disorders ([0142]). In a particular embodiment, the additional therapeutic agents include 5-FU, docetaxel, eribulin, gemcitabine, cobimetinib, ipatasertib, paclitaxel, tamoxifen, fulvestrant , GDC-0810, dexamethasone, palbociclib , bevacizumab, pertuzumab, trastuzumab emtansine, trastuzumab and letrozole (p63, lines 1-4 and claim 15). Palbociclib is a selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6 disclosed in the Specification ([0038]) and fulvestrant is a selective estrogen receptor down-regulator (SERD) disclosed in the Specification ([0035]). BRAUN further teaches that the combination therapy may be administered as a simultaneous or sequential regimen and when administered sequentially, the combination may be administered in two or more administrations ([0143]). In addition, BRAUN teaches that the combined administration includes coadministration, using separate formulations or a single pharmaceutical formulation, and consecutive administration in either order, wherein preferably there is a time period while both (or all) active agents simultaneously exert their biological activities ([0143]). BRAUN does not specifically disclose that the patient has been previously treated with metformin and the dose or regimen of metformin is adjusted to moderate, stabilize, or diminish hyperglycemia in the patient prior to administration of GDC-0077. Also, BRAUN does not specifically disclose the narrower range of effective amount of GDC-0077. In addition, the prior art does not specifically teach that the patient is obese or pre-diabetic recited in claim 15 Khan et al . teach that dysregulation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway is implicated in human cancer growth and progression (abstract). Khan et al . further teach that while hyperglycemia is common in patients treated with PI3K/AKT/mTOR inhibitors due to interaction with the insulin-glucose regulatory axis, it is manageable with conventional treatment such as metformin (abstract and p857, col 2, “Treatment of Hyperglycemia”). Khan et al . suggest that identifying the predictive factors for hyperglycemia in patients treated with these agents may help direct future management (abstract) and early and regular glucose monitoring and early intervention achieve early and lasting control of hyperglycemia (p858, col 1, para 1). Also, one of ordinary skill in the art would have recognized that cancer patients may also have diabetes because diabetic patients were known to be at increased risk of cancer as evidenced by Leone et al. (p361, para 2-3). Leone et al. teach that hyperglycemia and prediabetic status might represent risk factors for pancreatic cancer and that insulin plays a prominent role in promoting cancer progression (p361, para 5). Also, Leone et al. teach that metformin is an inexpensive, well-tolerated oral agent that is commonly used in the first line treatment for type 2 diabetes (abstract). Leone et al. disclose that metformin exerted anticancer protective effects in a dose-dependent manner (p365, para 2). Leone et al. further disclose that the use of metformin reduced the occurrence of metastatic disease and improved chemotherapeutic outcomes in diabetic patients with lung cancer and similarly, metformin increased the pathological complete response in breast cancer patients receiving neoadjuvant chemotherapy (p365, para 4). In addition, Leone et al. disclose that metformin, when administered at a standard dose (1,500 mg/day), reduced insulin levels in non-diabetic breast cancer survivors by 22 % without relapse (p370, para 3). Furthermore, Leone et al. disclose that the antitumor activity of metformin appears to be elicited by both direct and indirect mechanisms, through lowering insulin levels and by directly affecting the tumor tissues via both AMPK-dependent and AMPK-independent mechanisms. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use GDC-0077 in combination with metformin for a cancer patient who has been previously treated with metformin because of the following reasons. BRAUN explicitly teaches the use of PI3K inhibitor such as GDC-0077 for treating cancer and already suggest the use of GDC-0077 with an agent for treating diabetes. The skilled artisan would have recognized that the target cancer patient of BRAUN would encompass those patients who has been previously treated with metformin and those previously treated with metformin might be diabetic or pre-diabetic patients. Also, it was known in the art that metformin as the first line therapy for treating diabetes also has anti-cancer protective activity and reduced occurrence of metastatic disease and improved chemotherapeutic outcomes in diabetic patients with lung cancer as evidenced by Leone et al. In addition, Khan et al . teach and suggest that common hyperglycemic effects of PI3K inhibitors should be monitored for its early and lasting control and is manageable with conventional treatment such as metformin. Thus, the skilled artisan would have been motivated to administer metformin before or with the treatment of GDC-0077 for those who have a higher risk of hyperglycemia (e.g., prediabetic or diabetic patients) on the reasonable expectation that metformin would provide additional anti-cancer effects while mitigating or minimizing potential hyperglycemia which is a common side effect of PI3K inhibitors as evidenced by Khan et al . and Leone et al. In the alternative, the skilled artisan would have been motivated to use GDC-0077 in combination with metformin on the reasonable expectation that metformin would provide additional anti-cancer effects while mitigating or minimizing hyperglycemia for cancer patients who are diabetic or prediabetic and thus has been previously treated with metformin. As to the dose of GDC-0077, BRAUN teaches the range which overlaps those claimed. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim , 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff , 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Also, a rejection under 35 USC §103 is proper for that portion of the range that overlaps as it would have been prima facie obvious to have selected the overlapping portion of the range. See MPEP 2144.05. As to the dose and regimen of metformin recited in claims 18-22, Leone et al. disclose that a standard dose of metformin is 1,500 mg/day, which falls within the claimed range. Also, Khan et al . suggest that early and regular glucose monitoring and early intervention achieve early and lasting control of hyperglycemia in the treatment of cancer with PI3K/AKT/mTOR inhibitors. In addition, BRAUN taches that the combination therapy may be administered as a simultaneous or sequential regimen. Thus, it would have been obvious to adjust the dose of metformin based on the standard dose disclosed in Leone et al. and to administer metformin with or prior to the treatment of GDC-0077 for minimizing or managing hyperglycemia. The skilled artisan would have been motivated to stabilize or manage the blood sugar level in a diabetic or pre-diabetic patient by administering metformin for sufficient period of time before administering GDC-0077 for cancer treatment on the reasonable expectation that it would minimize or prevent the potential toxicities related with GDC-0077 treatment. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller , 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.) Double Patenting Rejections 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp. Claims 1, 4-10, 14-15, and 17-26 are ejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-23 of US patent 9650393 in view of Leone et al. (Advances in Nutrition and Cancer 159; pp 355–376, 2014). Although the conflicting claims are not identical, they are not patentably distinct from each other because the claims of the patent are also drawn to a method of treating cancer in a patient having cancer comprising administering a compound formula I including the claimed compound, wherein the cancer expresses a PIK3CA mutant selected from E542K, E545K, Q546R, H1047L and H1047R, the cancer include breast cancer and non-small cell lung cancer, and the breast cancer is estrogen receptor positive (ER+) (hormone-receptor positive) breast cancer or HER2 negative. Also, the claims of the patent recite that the method further comprises administering to the patient an additional therapeutic agent such as palbociclib and fulvestrant. The claims of the patent do not specifically disclose that the patient has been previously treated with metformin or is administered about 15 days before administering GDC-0077 or beginning with the first dose of GDC-0077. However, one of ordinary skill in the art would have recognized that the cancer patient may also be pre-diabetic or diabetic because diabetic patients were known to be at increased risk of cancer as evidenced by Leone et al. (p361, para 2-3). Leone et al. further teach that hyperglycemia and prediabetic status might represent risk factors for pancreatic cancer and that insulin plays a prominent role in promoting cancer progression (p361, para 5). Also, Leone et al. teach that metformin is an inexpensive, well-tolerated oral agent that is commonly used in the first line treatment for type 2 diabetes (abstract). Leone et al. disclose that metformin exerted anticancer protective effects in a dose-dependent manner (p365, para 2). Leone et al. further disclose that the use of metformin reduced the occurrence of metastatic disease and improved chemotherapeutic outcomes in diabetic patients with lung cancer and similarly, metformin increased the pathological complete response in breast cancer patients receiving neoadjuvant chemotherapy (p365, para 4). In addition, Leone et al. disclose that metformin, when administered at a standard dose (1,500 mg/day), reduced insulin levels in non-diabetic breast cancer survivors by 22 % without relapse (p370, para 3). Furthermore, Leone et al. disclose that the antitumor activity of metformin appears to be elicited by both direct and indirect mechanisms, through lowering insulin levels and by directly affecting the tumor tissues via both AMPK-dependent and AMPK-independent mechanisms. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use GDC-0077 in combination with metformin for a cancer patient who has been previously treated with metformin because metformin as the first line therapy for treating diabetes also has anti-cancer protective activity and reduced occurrence of metastatic disease and improved chemotherapeutic outcomes in diabetic patients with lung cancer as evidenced by Leone et al. Also, one of ordinary skill in the art would have recognized that the cancer patient may also have diabetes because diabetic patients were known to be at increased risk of cancer as evidenced by Leone et al. Thus, the skilled artisan would have been motivated to use GDC-0077 in combination with metformin on the reasonable expectation that metformin would provide additional anti-cancer effects while mitigating or minimizing hyperglycemia for cancer patients who are diabetic or prediabetic and thus has been previously treated with metformin. As to the dose and regimen of metformin recited in claims 16 and 18-22, Leone et al. disclose that a standard dose of metformin is 1,500 mg/day, which falls within the claimed range. Thus, it would have been obvious to adjust the dose of metformin based on the standard dose disclosed in Leone et al. and to administer metformin with or prior to the treatment of GDC-0077 for minimizing or managing hyperglycemia. The skilled artisan would have been motivated to stabilize or manage the blood sugar level in a diabetic or pre-diabetic patient by administering metformin for sufficient period of time before administering GDC-0077 for cancer treatment on the reasonable expectation that it would minimize or prevent the potential toxicities related with GDC-0077 treatment. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller , 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.) As such, the instant claims would have been obvious over the claims of the patent in view of Leone et al. Claims 1, 4-10, 14-15, and 17-26 are ejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-17 of US patent 11760753 in view of Leone et al. (Advances in Nutrition and Cancer 159; pp 355–376, 2014). Although the conflicting claims are not identical, they are not patentably distinct from each other because the claims of the patent are also drawn to a method of treating cancer in a patient having cancer comprising administering a compound formula I including the claimed compound, wherein the cancer expresses a PIK3CA mutant selected from E542K, E545K, Q546R, H1047L and H1047R, the cancer include breast cancer and non-small cell lung cancer, and the breast cancer is estrogen receptor positive (ER+) (hormone-receptor positive) breast cancer or HER2 negative. Also, the claims of the patent recite that the method further comprises administering to the patient an additional therapeutic agent such as palbociclib and fulvestrant. The claims of the patent do not specifically disclose that the patient has been previously treated with metformin. However, one of ordinary skill in the art would have recognized that the cancer patient may also have diabetes because diabetic patients were known to be at increased risk of cancer as evidenced by Leone et al. (p361, para 2-3). Leone et al. further teach that hyperglycemia and prediabetic status might represent risk factors for pancreatic cancer and that insulin plays a prominent role in promoting cancer progression (p361, para 5). Also, Leone et al. teach that metformin is an inexpensive, well-tolerated oral agent that is commonly used in the first line treatment for type 2 diabetes (abstract). Leone et al. disclose that metformin exerted anticancer protective effects in a dose-dependent manner (p365, para 2). Leone et al. further disclose that the use of metformin reduced the occurrence of metastatic disease and improved chemotherapeutic outcomes in diabetic patients with lung cancer and similarly, metformin increased the pathological complete response in breast cancer patients receiving neoadjuvant chemotherapy (p365, para 4). In addition, Leone et al. disclose that metformin, when administered at a standard dose (1,500 mg/day), reduced insulin levels in non-diabetic breast cancer survivors by 22 % without relapse (p370, para 3). Furthermore, Leone et al. disclose that the antitumor activity of metformin appears to be elicited by both direct and indirect mechanisms, through lowering insulin levels and by directly affecting the tumor tissues via both AMPK-dependent and AMPK-independent mechanisms. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use GDC-0077 in combination with metformin for a cancer patient who has been previously treated with metformin because metformin as the first line therapy for treating diabetes also has anti-cancer protective activity and reduced occurrence of metastatic disease and improved chemotherapeutic outcomes in diabetic patients with lung cancer as evidenced by Leone et al. Also, one of ordinary skill in the art would have recognized that cancer patients may also be pre-diabetic or diabetic because diabetic patients were known to be at increased risk of cancer as evidenced by Leone et al. Thus, the skilled artisan would have been motivated to use GDC-0077 in combination with metformin on the reasonable expectation that metformin would provide additional anti-cancer effects while mitigating or minimizing hyperglycemia for cancer patients who are diabetic or prediabetic and thus has been previously treated with metformin. As to the dose and regimen of metformin recited in claims 16 and 18-22, Leone et al. disclose that a standard dose of metformin is 1,500 mg/day, which falls within the claimed range. Thus, it would have been obvious to adjust the dose of metformin based on the standard dose disclosed in Leone et al. and to administer metformin with or prior to the treatment of GDC-0077 for minimizing or managing hyperglycemia. The skilled artisan would have been motivated to stabilize or manage the blood sugar level in a diabetic or pre-diabetic patient by administering metformin for sufficient period of time before administering GDC-0077 for cancer treatment on the reasonable expectation that it would minimize or prevent the potential toxicities related with GDC-0077 treatment. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller , 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.) As such, the instant claims would have been obvious over the claims of the patent in view of Leone et al. Claims 1, 4-10, 14-15, and 17-26 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-20 of US co-pending application 18/967059 in view of Leone et al. (Advances in Nutrition and Cancer 159; pp 355–376, 2014). Although the conflicting claims are not identical, they are not patentably distinct from each other because the claims of the patent are also drawn to a method of treating hormone receptor positive and HER2 negative locally advanced or metastatic breast cancer in a patient having PIK3CA mutated, hormone receptor positive and HER2 negative locally advanced or metastatic breast cancer, the method comprising administering to the patient a combination therapy comprising: (i) inavolisib; (ii) palbociclib; and (iii) fulvestrant. Inavolisib is the same compound as claimed GDC-0077 (see [0098]). The claims of the ‘059 application do not specifically disclose that the patient has been previously treated with metformin. However, one of ordinary skill in the art would have recognized that the cancer patients may have diabetes because diabetic patients were known to be at increased risk of cancer as evidenced by Leone et al. (p361, para 2-3). Leone et al. further teach that hyperglycemia and prediabetic status might represent risk factors for pancreatic cancer and that insulin plays a prominent role in promoting cancer progression (p361, para 5). Also, Leone et al. teach that metformin is an inexpensive, well-tolerated oral agent that is commonly used in the first line treatment for type 2 diabetes (abstract). Leone et al. disclose that metformin exerted anticancer protective effects in a dose-dependent manner (p365, para 2). Leone et al. further disclose that the use of metformin reduced the occurrence of metastatic disease and improved chemotherapeutic outcomes in diabetic patients with lung cancer and similarly, metformin increased the pathological complete response in breast cancer patients receiving neoadjuvant chemotherapy (p365, para 4). In addition, Leone et al. disclose that metformin, when administered at a standard dose (1,500 mg/day), reduced insulin levels in non-diabetic breast cancer survivors by 22 % without relapse (p370, para 3). Furthermore, Leone et al. disclose that the antitumor activity of metformin appears to be elicited by both direct and indirect mechanisms, through lowering insulin levels and by directly affecting the tumor tissues via both AMPK-dependent and AMPK-independent mechanisms. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer the combination comprising GDC-0077 with metformin for a cancer patient who has been previously treated with metformin because metformin as the first line therapy for treating diabetes also has anti-cancer protective activity and reduced occurrence of metastatic disease and improved chemotherapeutic outcomes in diabetic patients with lung cancer as evidenced by Leone et al. Also, one of ordinary skill in the art would have recognized that cancer patients may also be pre-diabetic or diabetic because diabetic patients were known to be at increased risk of cancer as evidenced by Leone et al. Thus, the skilled artisan would have been motivated to use GDC-0077 in combination with metformin on the reasonable expectation that metformin would provide additional anti-cancer effects while mitigating or minimizing hyperglycemia for cancer patients who are diabetic or prediabetic and thus has been previously treated with metformin. As to the dose and regimen of metformin recited in claims 16 and 18-22, Leone et al. disclose that a standard dose of metformin is 1,500 mg/day, which falls within the claimed range. Thus, it would have been obvious to adjust the dose of metformin based on the standard dose disclosed in Leone et al. and to administer metformin with or prior to the treatment of GDC-0077 for minimizing or managing hyperglycemia. The skilled artisan would have been motivated to stabilize or manage the blood sugar level in a diabetic or pre-diabetic patient by administering metformin for sufficient period of time before administering GDC-0077 for cancer treatment on the reasonable expectation that it would minimize or prevent the potential toxicities related with GDC-0077 treatment. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller , 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.) As such, the instant claims would have been obvious over the claims of the ‘059 application in view of Leone et al. Conclusion No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to BONG-SOOK BAEK whose telephone number is 571-270-5863. The examiner can normally be reached 9:00AM-6:00PM Monday-Friday. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bethany Barham can be reached on 571-272-6175. The fax phone number for the organization where this application or proceeding is assigned is (571) 273-8300. Information regarding the status of an application may be obtained from Patent Center. Status information for published applications may be obtained from Patent Center. Status information for unpublished applications is available through Patent Center for authorized users only. Should you have questions about access to Patent Center, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) Form at https://www.uspto.gov/patents/uspto-automated- interview-request-air-form. /BONG-SOOK BAEK/Primary Examiner, Art Unit 1611 Application/Control Number: 18/668,774 Page 2 Art Unit: 1611 Application/Control Number: 18/668,774 Page 3 Art Unit: 1611 Application/Control Number: 18/668,774 Page 4 Art Unit: 1611 Application/Control Number: 18/668,774 Page 5 Art Unit: 1611 Application/Control Number: 18/668,774 Page 6 Art Unit: 1611 Application/Control Number: 18/668,774 Page 7 Art Unit: 1611 Application/Control Number: 18/668,774 Page 8 Art Unit: 1611 Application/Control Number: 18/668,774 Page 9 Art Unit: 1611 Application/Control Number: 18/668,774 Page 10 Art Unit: 1611 Application/Control Number: 18/668,774 Page 11 Art Unit: 1611 Application/Control Number: 18/668,774 Page 12 Art Unit: 1611 Application/Control Number: 18/668,774 Page 13 Art Unit: 1611 Application/Control Number: 18/668,774 Page 14 Art Unit: 1611 Application/Control Number: 18/668,774 Page 15 Art Unit: 1611 Application/Control Number: 18/668,774 Page 16 Art Unit: 1611 Application/Control Number: 18/668,774 Page 17 Art Unit: 1611 Application/Control Number: 18/668,774 Page 18 Art Unit: 1611 Application/Control Number: 18/668,774 Page 19 Art Unit: 1611
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