ETAILED 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 .
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.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on August 31, 2026 has been entered.
The amendment filed August 31, 2026 has been entered. The terminal disclaimers filed August 31, 2026 were disapproved.
The terminal disclaimers were disapproved for naming the inventor and not the applicant.
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Applicant’s arguments filed August 31, 2026 were fully considered but they were not persuasive. Rejections and response to arguments as they currently apply are addressed below.
Claims 1-7, 9-19, and 21-26 are pending in this application.
Priority
This application is a 371 of PCTT/US2022/045737 filed October 5, 2022 and claims benefit of US provisional application 62/252,859 filed October 6, 2021.
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 1-7, 9-10, 12-19, 21-22, 24, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Brunicardi (WO 2018/044369, cited in previous action) in view of Bardou (Gut, 2010, cited in previous action), and De Falco (Diagnostics, 2021, cited in previous action).
Regarding claims 1-7, 9-10, 12-19, 21-22, 24, and 26: Brunicardi teaches a method comprising contacting the cancer with a combination therapy that comprises: metformin, simvastatin, and digoxin (pg. 27, lines 16-22). Digoxin as a cardiac glycoside (pg. 17, lines 1-2) Typically, the composition comprises 5-80 milligrams po of simvastatin; 500-2550 milligrams po of metformin; and 0.125-0.250 milligrams po of digoxin (i.e. combined into one dose, pg. 17, lines 22-24). In one specific implementation, the composition is given orally once per day indefinitely (pg. 22, lines 4-5). In some embodiments, the methods can further comprise observing the population of human cells for evidence of growth inhibition and/or cell death (pg. 4, lines 10-12). Brunicardi teaches all 9 major types of cancers (i.e. breast cancer, brain cancer, colon cancer, gastric cancer, liver cancer, lung cancer, pancreatic cancer, renal cancer, prostate cancer) overexpress BIRC5 (pg. 23, lines 9-12). Thus, the triple drug combination described herein, which suppresses BIRC5 (a target of the three drug therapy), may be used as part of a therapy for all 9 major types of cancers (pg. 23, lines 12-14). Brunicardi analyzed mRNA expression of 9 major cancers and established BIRC5 as one of the network geneses that can be treated (suppressed mRNA) with the combination therapy (pg. 27, lines 11-16). Determination of treating patients that overexpress BIRC5 as an effective strategy thereby anticipates the active step of determining overexpression as recited by instant claim 26. Brunicardi teaches the composition can also comprise a pharmaceutically acceptable carrier, typically one selected to facilitate the oral delivery of metformin, simvastatin, and digoxin (pg. 3, lines 3-5). In illustrative embodiments of the invention, the composition is formed as a time release formulation and is disposed in a capsule or tablet (pg. 3, lines 5-6). In short, Brunicardi teaches the triple drug combination comprising metformin or a metformin analog, a statin such as simvastatin, and a cardiac glycoside such as digoxin can inhibit pancreatic cancer growth by inhibiting genes involving cell proliferation and energy metabolism, and the predominant drug in these effects are the statins (pg. 14, lines 11-15). Brunicardi teaches that such combination is also beneficial in reducing tumor size in pancreatic cancer mouse models that express mutant constitutively active KRAS G12D (pg. 30, lines 3-14, drawings pg. 2, figure 1).
Although Brunicardi teaches colon cancer as part of a genus of cancers that can be treated with the formulation, the express teaching relating BIRC5 suppression as a viable target for colon cancer (colorectal adenomas, pg. 45, table 4B), would yield a reasonable expectation of success to a person of ordinary skill in treating these cancer types. A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments (See MPEP 2123 (I)).
Taken together, it would have been prima facie obvious to one of ordinary skill in the art to apply the method of treating pancreatic cancers as taught by Brunicardi to the treatment of colorectal cancer as claimed. One of ordinary skill in the art would have had the motivation to do so as Brunicardi teaches the method is effective against cancers with elevated BIRC5 levels and suggests that the triple drug combination may be used as part of a therapy for these cancers.
Brunicardi does not teach wherein colorectal cancer is microsatellite stable and has a G12D KRAS Mutation.
However, Bardou teaches statins have been shown to be effective against familial adenomatous polyposis in colorectal cancer (pg. 1574, col. 2, para. 4). Bardou teaches that combination therapies including simvastatin in metastatic colorectal cancer exhibited promising antitumor activity and statins generally can interfere with colorectal cancer by inhibiting the ability of cancer cells to metastasize (pg. 1581, col. 1, para. 2, pg. 1582, col. 1, paras. 1-3). Additionally, De Falco teaches colorectal cancer patients with G12D mutations in KRAS gene are known in the art and are in need of treatment (abstract). De Falco teaches these patients with this mutation were microsatellite stable (pg. 8, para. 5). De Falco further teaches KRAS mutations are a hallmark of worse prognosis of CRC with metastatic profile (pg. 6, para. 3).
Taken together it would have been prima facie obvious to one of ordinary skill in the art to apply the method of Brunicardi to the treatment of colorectal cancer or metastatic colorectal cancer that is microsatellite stable and has a G12D KRAS mutation as taught by Bardou and De Falco. One of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success given that combination therapies comprising statins are known in the art as effective treatments for these types of cancer and both Brunicardi suggest them to be viable treatment options for a G12D KRAS mutation, Bardou establishes statins are effective for colorectal cancers, and De Falco discloses that these patients exist and are in need of treatment.
Claims 11, 23, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Brunicardi (WO 2018/044369, cited in previous action), Bardou (Gut, 2010, cited in previous action), and De Falco (Diagnostics, 2021, cited in previous action) as applied to 1-7, 9-10, 12-19, 21-22, 24, and 26 above in view of Jimenez-Fonseca (Clin. Transl. Oncol., 2015, cited in previous action).
Regarding claims 11, 23, and 25: As discussed above Brunicardi, Bardou, and De Falco render obvious the methods of claims 1, 12, and 26. Brunicardi teaches in addition to the triple drug combination of metformin, simvastatin, and digoxin, the composition/methods may further include therapeutic compounds/regimens commonly used in first-line and/or second-line treatments for pancreatic cancer (pg. 19, lines 25-28). In one or more embodiments, the composition further includes a gemcitabine (gemzar), 5-fluorouracil (5-FU), irinotecan (camptosar), oxaliplatin The method can further include (eloxatin), albumin-bound paclitaxel (abraxane), capecitabine (xeloda), cisplatin, paclitaxel (taxol), docetaxel (taxotere), irinotecan liposome (onivyde), or combinations thereof, including FOLFOX (folinic acid, fluorouracil, oxaliplatin) and FOLFIRINOX (folinic acid, fluorouracil, irinotecan, oxaliplatin) (pgs. 19-20, bridging para.). Additionally, Bardou teaches that 5-fluorouracil have been used in combination therapies with statins in both drug-sensitive and drug resistant cell lines (pgs. 1581-1582, bridging para.).
Brunicardi does not explicitly teach that these additional therapeutics (gemcitabine/capecitabine) would be effective against other cancers, such as colorectal cancer.
However, Jimenez-Fonseca teaches a proportion of patients with metastatic colorectal cancer (mCRC) are still able to continue with active therapy after their progression to fluoropyrimidines, oxaliplatin, and irinotecan regimens (abstract). Studies suggest that gemcitabine and fluoropyrimidines are synergic antimetabolites (abstract). Gemcitabine-capecitabine is a tolerable and feasible regimen, associated with clinical benefit in non-selected, heavily pretreated, mCRC patients (abstract). Additionally, in vitro studies in CRC have demonstrated the synergy of gemcitabine with 5-FU, and phase I and phase II trials have evaluated doses, efficacy, and toxicity of this combination in patients with refractory tumors, especially in those with pancreatic and colorectal cancers (pg. 390, col. 2, para. 2).
Taken together it would have been prima facie obvious to one of ordinary skill in the art to modify the composition of Brunicardi by including gemcitabine and/or capecitabine as suggested by Brunicardi and Jimenez-Fonseca for the purpose of treating colorectal cancer in a subject. One of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success given that compositions comprising gemcitabine and capecitabine are effective in treating colorectal cancers. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." (See MPEP 2144.06 (I)).
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 1-7, 9-10, 12-19, 21-22, 24, and 26 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 10,813,909 (IDS filed March 20, 2024) in view of Brunicardi (WO 2018/044369, cited in previous action), Bardou (Gut, 2010, cited in previous action), and De Falco (Diagnostics, 2021, cited in previous action).
Regarding claims 1-7, 9-10, 12-19, 21-22, 24, and 26: The patented claims teach the following composition:
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. Although the claims are directed towards a composition, the recitation of the intended uses, for treatment of cancer/inhibition of cancer cells, render obvious a method comprising administration of the composition for the treatment of cancer.
The patented claims differ from the instant claims in that the patented claims do not teach a method for the treatment of the specific cancers recited by instant claims 1 and 12. The patented claims do not teach wherein the composition is effective to inhibit the expression of BIRC5 mRNA or activity in the cancer.
However, Brunicardi teaches a method comprising contacting the cancer with a combination therapy that comprises: metformin, simvastatin, and digoxin (pg. 27, lines 16-22). Digoxin as a cardiac glycoside (pg. 17, lines 1-2) Typically, the composition comprises 5-80 milligrams po of simvastatin; 500-2550 milligrams po of metformin; and 0.125-0.250 milligrams po of digoxin (i.e. combined into one dose, pg. 17, lines 22-24). In one specific implementation, the composition is given orally once per day indefinitely (pg. 22, lines 4-5). In some embodiments, the methods can further comprise observing the population of human cells for evidence of growth inhibition and/or cell death (pg. 4, lines 10-12). Brunicardi teaches all 9 major types of cancers (i.e. breast cancer, brain cancer, colon cancer, gastric cancer, liver cancer, lung cancer, pancreatic cancer, renal cancer, prostate cancer) overexpress BIRC5 (pg. 23, lines 9-12). Brunicardi teaches that such combination is also beneficial in reducing tumor size in pancreatic cancer mouse models that express mutant constitutively active KRAS G12D (pg. 30, lines 3-14, drawings pg. 2, figure 1). Thus, the triple drug combination described herein, which suppresses BIRC5 (a target of the three drug therapy), may be used as part of a therapy for all 9 major types of cancers (pg. 23, lines 12-14). Brunicardi analyzed mRNA expression of 9 major cancers and established BIRC5 as one of the network geneses that can be treated (suppressed mRNA) with the combination therapy (pg. 27, lines 11-16). Determination of treating patients that overexpress BIRC5 as an effective strategy thereby renders obvious the active step of determining overexpression as recited by instant claim 26.
Taken together, it would have been prima facie obvious to one of ordinary skill in the art to apply the method of treating pancreatic cancers as taught by the patented claims to the treatment of breast, colorectal, prostate cancer as taught by Brunicardi. One of ordinary skill in the art would have had the motivation to do so as Brunicardi teaches the method is effective against cancers with elevated BIRC5 levels and suggests that the triple drug combination may be used as part of a therapy for these cancers.
The method taught by the patented claims further differ in that they do not teach wherein the colorectal cancer is microsatellite stable and has a G12D KRAS Mutation.
However, Bardou teaches statins have been shown to be effective against familial adenomatous polyposis in colorectal cancer (pg. 1574, col. 2, para. 4). Bardou teaches that combination therapies including simvastatin in metastatic colorectal cancer exhibited promising antitumor activity and statins generally can interfere with colorectal cancer by inhibiting the ability of cancer cells to metastasize (pg. 1581, col. 1, para. 2, pg. 1582, col. 1, paras. 1-3). Additionally, De Falco teaches colorectal cancer patients with G12D mutations in KRAS gene are known in the art and are in need of treatment (abstract). De Falco teaches these patients with this mutation were microsatellite stable (pg. 8, para. 5). De Falco further teaches KRAS mutations are a hallmark of worse prognosis of CRC with metastatic profile (pg. 6, para. 3).
Taken together it would have been prima facie obvious to one of ordinary skill in the art to apply the method of the patented claims and Brunicardi to the treatment colorectal cancer or metastatic colorectal cancer that is microsatellite stable and has a G12D KRAS mutation as taught by Bardou and De Falco. One of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success given that combination therapies comprising statins are known in the art as effective treatments for these types of cancer and both Brunicardi suggest them to be viable treatment options for a G12D KRAS mutation, Bardou establishes statins are effective for colorectal cancers, and De Falco discloses that these patients exist and are in need of treatment.
Claims 11, 23, and 25 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 10,813,909 (IDS filed March 20, 2024) and Brunicardi (WO 2018/044369, cited in previous action), Bardou (Gut, 2010, cited in previous action), and De Falco (Diagnostics, 2021, cited in previous action) as applied to claims 1-7, 9-10, 12-19, 21-22, 24, and 26 above in view of Jimenez-Fonseca (Clin. Transl. Oncol., 2015, cited in previous action).
Regarding claims 11, 23, and 25: As discussed above the patented claims and Brunicardi render obvious the method of claims 1 and 12. Brunicardi further teaches in addition to the triple drug combination of metformin, simvastatin, and digoxin, the composition/methods may further include therapeutic compounds/regimens commonly used in first-line and/or second-line treatments for pancreatic cancer (pg. 19, lines 25-28). In one or more embodiments, the composition further includes a gemcitabine (gemzar), 5-fluorouracil (5-FU), irinotecan (camptosar), oxaliplatin The method can further include (eloxatin), albumin-bound paclitaxel (abraxane), capecitabine (xeloda), cisplatin, paclitaxel (taxol), docetaxel (taxotere), irinotecan liposome (onivyde), or combinations thereof, including FOLFOX (folinic acid, fluorouracil, oxaliplatin) and FOLFIRINOX (folinic acid, fluorouracil, irinotecan, oxaliplatin) (pgs. 19-20, bridging para.).
The method rendered obvious over the patented claims and prior art further differ from the instant claims in that the patented claims and prior art do not teach that these additional therapeutics (gemcitabine/capecitabine) would be effective against other cancers, such as colorectal cancer.
However, Jimenez-Fonseca teaches a proportion of patients with metastatic colorectal cancer (mCRC) are still able to continue with active therapy after their progression to fluoropyrimidines, oxaliplatin, and irinotecan regimens (abstract). Studies suggest that gemcitabine and fluoropyrimidines are synergic antimetabolites (abstract). Gemcitabine-capecitabine is a tolerable and feasible regimen, associated with clinical benefit in non-selected, heavily pretreated, mCRC patients (abstract). Additionally, in vitro studies in CRC have demonstrated the synergy of gemcitabine with 5-FU, and phase I and phase II trials have evaluated doses, efficacy, and toxicity of this combination in patients with refractory tumors, especially in those with pancreatic and colorectal cancers (pg. 390, col. 2, para. 2).
Taken together it would have been prima facie obvious to one of ordinary skill in the art to further modify the method of the patented claims in view of the prior art by including gemcitabine and/or capecitabine as suggested by Brunicardi and Jimenez-Fonseca for the purpose of treating colorectal cancer in a subject. One of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success given that compositions gemcitabine and capecitabine are effective in treating colorectal cancers.
Claims 1-7, 9-10, 12-19, 21-22, 24, and 26 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 11,197,844 in view of Brunicardi (WO 2018/044369, cited in previous action), Bardou (Gut, 2010, cited in previous action), and De Falco (Diagnostics, 2021, cited in previous action).
Regarding claims 1-7, 9-10, 12-19, 21-22, 24, and 26: The patented claims teach the following method:
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The patented claims differ from the instant claims in that the patented claims do not teach a method for the treatment of the colorectal cancer.
However, Brunicardi teaches a method comprising contacting the cancer with a combination therapy that comprises: metformin, simvastatin, and digoxin (pg. 27, lines 16-22). Digoxin as a cardiac glycoside (pg. 17, lines 1-2) Typically, the composition comprises 5-80 milligrams po of simvastatin; 500-2550 milligrams po of metformin; and 0.125-0.250 milligrams po of digoxin (i.e. combined into one dose, pg. 17, lines 22-24). In one specific implementation, the composition is given orally once per day indefinitely (pg. 22, lines 4-5). In some embodiments, the methods can further comprise observing the population of human cells for evidence of growth inhibition and/or cell death (pg. 4, lines 10-12). Brunicardi teaches all 9 major types of cancers (i.e. breast cancer, brain cancer, colon cancer, gastric cancer, liver cancer, lung cancer, pancreatic cancer, renal cancer, prostate cancer) overexpress BIRC5 (pg. 23, lines 9-12). Brunicardi teaches that such combination is also beneficial in reducing tumor size in pancreatic cancer mouse models that express mutant constitutively active KRAS G12D (pg. 30, lines 3-14, drawings pg. 2, figure 1). Thus, the triple drug combination described herein, which suppresses BIRC5 (a target of the three drug therapy), may be used as part of a therapy for all 9 major types of cancers (pg. 23, lines 12-14). Brunicardi analyzed mRNA expression of 9 major cancers and established BIRC5 as one of the network geneses that can be treated (suppressed mRNA) with the combination therapy (pg. 27, lines 11-16). Determination of treating patients that overexpress BIRC5 as an effective strategy thereby renders obvious the active step of determining overexpression as recited by instant claim 26.
Taken together, it would have been prima facie obvious to one of ordinary skill in the art to apply the method of treating pancreatic cancers as taught by the patented claims to the treatment of breast, colorectal, prostate cancer as taught by Brunicardi. One of ordinary skill in the art would have had the motivation to do so as Brunicardi teaches the method is effective against cancers with elevated BIRC5 levels and suggests that the triple drug combination may be used as part of a therapy for these cancers.
The method taught by the patented claims further differ in that they do not teach wherein the colorectal cancer is microsatellite stable and has a G12D KRAS Mutation.
However, Bardou teaches statins have been shown to be effective against familial adenomatous polyposis in colorectal cancer (pg. 1574, col. 2, para. 4). Bardou teaches that combination therapies including simvastatin in metastatic colorectal cancer exhibited promising antitumor activity and statins generally can interfere with colorectal cancer by inhibiting the ability of cancer cells to metastasize (pg. 1581, col. 1, para. 2, pg. 1582, col. 1, paras. 1-3). Additionally, De Falco teaches colorectal cancer patients with G12D mutations in KRAS gene are known in the art and are in need of treatment (abstract). De Falco teaches these patients with this mutation were microsatellite stable (pg. 8, para. 5). De Falco further teaches KRAS mutations are a hallmark of worse prognosis of CRC with metastatic profile (pg. 6, para. 3).
Taken together it would have been prima facie obvious to one of ordinary skill in the art to apply the method of the patented claims and Brunicardi to the treatment colorectal cancer or metastatic colorectal cancer that is microsatellite stable and has a G12D KRAS mutation as taught by Bardou and De Falco. One of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success given that combination therapies comprising statins are known in the art as effective treatments for these types of cancer and both Brunicardi suggest them to be viable treatment options for a G12D KRAS mutation, Bardou establishes statins are effective for colorectal cancers, and De Falco discloses that these patients exist and are in need of treatment.
Claims 11, 23, and 25 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 11,197,844, Brunicardi (WO 2018/044369, cited in previous action), Bardou (Gut, 2010, cited in previous action), and De Falco (Diagnostics, 2021, cited in previous action) as applied to claims 1-7, 10, 12-19, 22, 24, and 26 above in view of Jimenez-Fonseca (Clin. Transl. Oncol., 2015, cited in previous action).
Regarding claims 11, 23, and 25: As discussed above the patented claims and Brunicardi render obvious the method of claims 1 and 12. Brunicardi further teaches in addition to the triple drug combination of metformin, simvastatin, and digoxin, the composition/methods may further include therapeutic compounds/regimens commonly used in first-line and/or second-line treatments for pancreatic cancer (pg. 19, lines 25-28). In one or more embodiments, the composition further includes a gemcitabine (gemzar), 5-fluorouracil (5-FU), irinotecan (camptosar), oxaliplatin The method can further include (eloxatin), albumin-bound paclitaxel (abraxane), capecitabine (xeloda), cisplatin, paclitaxel (taxol), docetaxel (taxotere), irinotecan liposome (onivyde), or combinations thereof, including FOLFOX (folinic acid, fluorouracil, oxaliplatin) and FOLFIRINOX (folinic acid, fluorouracil, irinotecan, oxaliplatin) (pgs. 19-20, bridging para.).
The method rendered obvious over the patented claims and prior art further differ from the instant claims in that the patented claims and prior art do not teach that these additional therapeutics (gemcitabine/capecitabine) would be effective against other cancers, such as colorectal cancer.
However, Jimenez-Fonseca teaches a proportion of patients with metastatic colorectal cancer (mCRC) are still able to continue with active therapy after their progression to fluoropyrimidines, oxaliplatin, and irinotecan regimens (abstract). Studies suggest that gemcitabine and fluoropyrimidines are synergic antimetabolites (abstract). Gemcitabine-capecitabine is a tolerable and feasible regimen, associated with clinical benefit in non-selected, heavily pretreated, mCRC patients (abstract). Additionally, in vitro studies in CRC have demonstrated the synergy of gemcitabine with 5-FU, and phase I and phase II trials have evaluated doses, efficacy, and toxicity of this combination in patients with refractory tumors, especially in those with pancreatic and colorectal cancers (pg. 390, col. 2, para. 2).
Taken together it would have been prima facie obvious to one of ordinary skill in the art to further modify the method of the patented claims in view of the prior art by including gemcitabine and/or capecitabine as suggested by Brunicardi and Jimenez-Fonseca for the purpose of treating colorectal cancer in a subject. One of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success given that compositions gemcitabine and capecitabine are effective in treating colorectal cancers.
Response to Arguments
Applicant’s arguments filed August 31, 2026 have been fully considered but they are not persuasive as they currently apply.
On page 7 of Applicant’s response, Applicant argues that the amended claims include the limitation that the colorectal cancer is microsatellite stable and has a G12D KRAS mutation (para. 2). Applicant argues these cancers are not candidates for immunotherapy and are KRAS G12D mutation positive. Applicant argues that while Brunicardi is enabling for pancreatic cancer would require undue experimentation for any other cancer generally, and not colorectal cancers that are microsatellite stable and has a G12D KRAS mutation as claimed (para. 2). Applicant argues that Bardou merely teaches that statins may have an effect on colorectal cancers, but not on a colorectal cancer that is microsatellite stable and has a G12D KRAS mutation (para. 2). Applicant argues Brunicardi does not demonstrate a synergistic combination of the three components against the specifically claimed colorectal cancer (para. 2).
However, Brunicardi recognizes the synergistic effects of the three drugs the instant claims are directed to, and there is no teaching that the synergistic effect is cancer dependent (pg. 14, lines 11-19). Additionally, as discussed above, Brunicardi teaches that such combination is also beneficial in reducing tumor size in pancreatic cancer mouse models that express mutant constitutively active KRAS G12D (pg. 30, lines 3-14, drawings pg. 2, figure 1). One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references (See MPEP 2145 (IV)). De Falco teaches colorectal cancer patients with G12D mutations in KRAS gene are known in the art and are in need of treatment (abstract). De Falco teaches these patients with this mutation were microsatellite stable (pg. 8, para. 5). Given that Brunicardi teaches the combination is effective in patients with G12D mutations in the KRAS gene, and De Falco discloses such patients with colorectal cancer exhibiting this gene that are microsatellite stable and are in need of treatment, a person of ordinary skill in the art would have had a reasonable expectation of success in applying the method to colorectal patients with this mutation, absent a showing of unexpected results. The claim of unexpected synergy cannot be considered unexpected when Brunicardi clearly teaches the combination has a synergistic effect. There is no teaching that a person of ordinary skill in the art would expect a different outcome when applied to other cancer/cancer subtypes. A person of ordinary skill would be capable of applying the method of Brunicardi to the treatment of other cancers that are expressly taught in the reference, absent evidence that applying the method of Brunicardi to other types of cancers would not be seen as a viable treatment plan to a person of ordinary skill in the art. Applicant’s argument that Bardou solely teaches statins are beneficial in colorectal adenomas and does not account for the inclusion of digoxin or metformin, given that both Brunicardi and Bardou teach treatment of colorectal adenomas with compositions comprising statins, a person of ordinary skill in the art would have had a reasonable expectation of success in the formulation of Brunicardi being beneficial to this patient population given that both Bardou and Brunicardi are directed towards cancer treatment with combination therapies.
On page 7 of Applicant’s response, Applicant argues De Falco merely teaches that two patients with colorectal cancer has mutations of KRAS at G12D need treatment for colorectal cancer, but does not teach or suggest using the claimed composition to treat a colorectal cancer that is microsatellite stable and has a G12D KRAS mutation (para. 4). Applicant argues DeFalco does not teach a reasonable expectation of success in targeting this specific colorectal cancer and that the claimed combination has the surprising and unexpected results obtained (para. 4). Applicant argues that para 00074 of the instant specification demonstrates that the combination and amounts yielded a cancer that was metastatic at 565 days that was both colorectal cancer, microsatellite stable, and had a G12D KRAS mutation (para. 4) On page 7 of Applicants, response, Applicant summarizes that the combination of references fails to teach every element of the invention with a reasonable expectation of success in treating colorectal cancer, that is microsatellite stable, and has a G12D KRAS mutation (para. 5).
However, as discussed above, Brunicardi teaches that such combination is beneficial in reducing tumor size in pancreatic cancer mouse models that express mutant constitutively active KRAS G12D (pg. 30, lines 3-14, drawings pg. 2, figure 1). De Falco teaches colorectal cancer patients with G12D mutations in KRAS gene are known in the art and are in need of treatment (abstract). De Falco teaches these patients with this mutation were microsatellite stable (pg. 8, para. 5). Given that Brunicardi teaches the combination is effective in patients with G12D mutations in the KRAS gene, and De Falco discloses such patients with colorectal cancer exhibiting this gene that are microsatellite stable and are in need of treatment, a person of ordinary skill in the art would have had a reasonable expectation of success in applying the method to colorectal patients and expect a similar synergy as is achieved by Brunicardi.
On page 8 of Applicant’s response, Applicant argues Jimenez-Fonseca does cure the deficiencies described above (para. 4). Applicant argues Jimenez-Fonseca does not teach a synergistic combination of three components against a colorectal cancer that is microsatellite stable and has a G12D KRAS mutation (para. 4).
However, see response to arguments above, where prior art renders obvious treating this subtype with the claimed composition.
On pages 9-10 of Applicant’s response, Applicant argues that the terminal disclaimer overcomes the double patenting rejections.
However, the terminal disclaimers filed August 31, 2026 were disapproved. The terminal disclaimers were disapproved for naming the inventor and not the applicant.
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Applicant’s reply is considered to be a bona fide attempt at a response and is being accepted as a complete response. The 35 USC § 103 and double patenting rejections are maintained for reason of record and foregoing discussion.
Conclusion
No claims are allowed in this action.
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/S.L.G./ Examiner, Art Unit 1693
/ANDREA OLSON/ Primary Examiner, Art Unit 1693
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