DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The present application is a continuation application of PCT/US2022/073884 filed 2022-07-19 which claims benefit of provisional application 63223926 2021-07-20.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 01/19/2024 and 03/03/2026 comply with the provisions of 37 CFR 1.97, 1.98, and MPEP § 609. Accordingly, they have been placed in the application file and the information therein has been considered on the merits. See attached copy of PTO-1449.
Status of the claims
Claims 1-22 are pending and are currently examined.
Claim Objections
Claims 11, 12, 17, 18, and 22 are objected to because of the following informalities:
The recitation and wording of FOLFIRI and FOLFOX is unclear and inconsistent throughout the claims (e.g., claim 11, 22). An example of how it could be written is “…with a creatine transporter inhibitor, a combination comprising leucovorin, 5-fluorouracil, and irinotecan hydrochloride (FOLFIRI), and/or bevacizumab…” or “…with a creatine transporter inhibitor, a combination comprising FOL – folinic acid (leucovorin), F – fluorouracil (5-FU), and IRI – irinotecan (FOLFIRI), and/or bevacizumab…”.
Claim Interpretation
Claim 2 recites “wherein the creatine transporter is SLC6A8 or is selected from those listed in Table 2”. Examiner notes that claim 1 recites “a creatine transporter inhibitor” and not a creatine transporter and Table 2 lists creatine transporter inhibitors. Furthermore, the instant specification discloses methods for contacting a cancer cell with a creatine transporter inhibitor, and, therefore, it is unclear how a cancer cell would be contacted with a creatine transporter. Thus, for the sake of searching, this claim is being examined as it reads on any creatine transport inhibitor of Table 2 (e.g.,, β-GPA).
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 2 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
(A). Claim 2 recites “is selected from those listed in Table 2”. Examiner points to MPEP 2173.05(s) regarding referencing figures or tables in claims. Table 2 or its contents should be properly incorporated into claim 2. Appropriate correction by incorporation into the claim is required.
(B). Claim 2 recites the limitation " the creatine transporter" however claim 1 recites “a creatine transporter inhibitor”. There is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 102
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.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim 16 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Martinez et al., (WO 2016/176636 A1, published 2016-03-11).
Regarding claim 16, Martinez teach treatment of colon cancer by inhibition of the SLC6A8 creatine transporter via administration of β-GPA alone or in combination with other chemotherapeutic agents (e.g., 5'-Fluorouracil). For example, “administration of β-GPA to mice injected with LvM3b colon cancer cells resulted in inhibition of colon cancer metastasis to the liver after two weeks of treatment” (see pg. 151, Example 12, Figures 1e and 2). Additionally, “β-GPA enhanced the cytotoxic activity of 5'Fluorouracil on Ls-LvM3b colon cancer cells” when cell viability was assessed using various concentrations of 5'-Fluorouracil with and without 10 mM of β-GPA for 48 hours (see pg. 153, Example 16, Figure 7).
Thus, claim 16 is anticipated in view of Martinez.
Claim Rejections - 35 USC § 103
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.
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.
The factual inquiries 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.
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.
Claims 1-6, 8 and 13 and 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Martinez et al., (WO 2016/176636 A1, published 2016-03-11), and in view of Amodio et al., “EGFR blockade reverts resistance to KRASG12C inhibition in colorectal cancer”, Cancer Discov 2020;10:1129–39, DOI:10.1158/2159-8290.CD-20-0187.
Regarding claims 1-4, and 8 and 14, Martinez teach treatment of colon cancer by inhibition of the SLC6A8 creatine transporter via administration of β-GPA alone or in combination with other chemotherapeutic agents. For example, “administration of β-GPA to mice injected with LvM3b colon cancer cells resulted in inhibition of colon cancer metastasis to the liver after two weeks of treatment” (see pg. 151, Example 12, Figures 1e and 2). Additionally, “β-GPA enhanced the cytotoxic activity of 5'Fluorouracil on Ls-LvM3b colon cancer cells” when cell viability was assessed using various concentrations of 5'-Fluorouracil with and without 10 mM of β-GPA for 48 hours (see pg. 153, Example 16, Figure 7).
Regarding claim 13, Martinez further disclose the use of β-GPA in combination with additional antiproliferative agents (e.g., fluorouracil, FOLFOX (5-FU, leucovorin, and Eloxatin), FOLFIRI (5-FU, leucovorin, and Camptosar) (see pg. 65, lines 4-6).
Although Martinez et al. teach treatments of colorectal cancer using combinations of β-GPA with other chemotherapeutic agent, it does not explicitly teach that the combination treatment comprise a creatine transporter inhibitor and a KRAS inhibitor and an EGFR inhibitor.
Regarding claims 1, 5-6 and 15, in the same field of endeavor of treatment of colorectal cancer treatments, Amodio teach treatment of colorectal with KRAS inhibitors (i.e., AMG510, also known as Sotorasib and MRTX849, also known as adagrasib). For example, Amodio disclose that “[s]everal clinical trials testing the efficacy of KRASG12C-targeted drugs are currently ongoing, and early results from the first two trials using AMG510 and MRTX849 have documented promising outcomes in the clinic (see Introduction, para. 4). Amodio further teach “combinatorial targeting of EGFR and KRASG12C is highly effective in colorectal cancer cells and patient-derived organoids and xenografts” (see Abstract). Specifically, Amodio demonstrates that “Cetuximab [EGFR inhibitor] Sensitizes KRASG12C Colorectal Cancer Cell Lines to AMG510 ” which resulted in a cytotoxic effect measured by cell death and arrest of cell proliferation (see Results, pg. 1133, para. 2; Figure 3d). Amodio further demonstrated in a KRASG12C xenograft mouse model that “[c]ombination treatment [cetuximab and AMG510] induced massive or even complete tumor shrinkage in the treated animals” (see Results, pg. 1135, para. 1; Figure 4d-e).
It would have been obvious to a person of ordinary skill in the art at the time of filing of the instant application to combine the teachings of Martinez and Amodio. See MPEP 2143 (I) (A) regarding combining prior art elements according to known methods to yield predictable results. The prior art teach each individual component (i.e., the creatine transporter inhibitor, the KRAS inhibitor, the EGFR inhibitor, the additional chemotherapeutic agent) as components with known benefit for the treatment of colorectal cancer. Furthermore, the prior art teach that each of the individual components discussed above are found in combination with other known colorectal cancer treatments/therapeutic agents and have synergistic therapeutic efficacy. Thus, one of skill in the art in the same endeavor of colorectal cancer therapeutics would have been motivated to combine the components of instant claims by known methods with no change in their respective functions (i.e., providing a benefit in colorectal cancer), and the combination would yield nothing more than predictable results of a treatment for colorectal cancer. See KSR, 550 U.S. at 416, 82 USPQ2d at 1395.
Thus claims 1-6, 8,13 and 14-15 are obvious in view of Martinez and Amodio.
Claims 7 and 9-10 are rejected under 35 U.S.C. 103 as being unpatentable over Martinez et al., (WO 2016/176636 A1, published 2016-03-11) and in view of Amodio et al., “EGFR blockade reverts resistance to KRASG12C inhibition in colorectal cancer”, Cancer Discov 2020;10:1129–39, DOI:10.1158/2159-8290.CD-20-0187 as applied to claims 1-6, 8 and 13, discussed above, and in view of Hallin et al., “Abstract LB-098: The anti- tumor activity of the KRAS G12C inhibitor MRTX849 is augmented by cetuximab in CRC tumor models”, Cancer Res (2020) 80 (16_Supplement): LB-098, DOI: 10.1158/1538-7445.AM2020-LB-098.
Regarding claims 7 and 9-10, as discussed above, although Amodio does not explicitly demonstrate the use of KRAS inhibitor MRTX849 (i.e., adagrasib), it does disclose that MRTX849 is being tested in the context of colorectal cancer and demonstrate the use of other known KRAS inhibitors (i.e., Sortorasib) in combination with an EGFR inhibitors. In the same field of endeavor of colorectal cancer combination treatments comprising KRAS and EGFR inhibitors, Hallin teach the use of KRAS inhibitor MRTX849 and EGFR inhibitors cetuximab in colorectal cancer. Specifically, Hallin demonstrate that MRTX849 was evaluated in models of colorectal cancer to “identify combination strategies that might optimize anti-tumor activity” and “[t]he combination of MRTX849 plus cetuximab demonstrated the best anti-tumor activity in multiple models” (e.g., cell line and patient-derived xenograft (PDX) models).
Based on the disclosure of Amodio and the teachings of Hallin, one of skill in the art of colorectal cancer treatment and KRAS inhibitors would have been motivated to substitute one known KRAS inhibitor (e.g., AMG510/sotorasib ) with another known KRAS inhibitor (e.g., MRTX849/adagrasib) with a reasonable expectation of success (see MPEP §2143 (I)(B)).
Therefore, the use of adagrasib would have been obvious over Martinez and Amodio in view of Hallin.
Thus claims 7 and 9-10 are obvious in view of Martinez and Amodio and in further view of Hallin.
Claims 11-12 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Martinez et al., (WO 2016/176636 A1, published 2016-03-11) and in view of NCT03829410 “Onvansertib in Combination With FOLFIRI and Bevacizumab for Second Line Treatment of Metastatic Colorectal Cancer Patients With a KRAS Mutation”, published 2021-04-28.
Regarding claims 11-12 and 17, as discussed above, Martinez teach treatment of colon cancer via administration of β-GPA alone or in combination with other chemotherapeutic agent FOLFIRI (see pg. 65, lines 4-6). Martinez does not explicitly teach the method comprising the creatine transporter inhibitor, FOLFIRI and/or bevacizumab.
However, in the same field of endeavor of colorectal cancer treatment, NCT03829410 disclose phase 1 and phase 2 studies that teach FOLFIRI and bevacizumab are used in combination with other cancer chemotherapeutic agents to treat colorectal cancer. Specifically, adult patients with metastatic colorectal cancer with KRAS mutation were treated with onvansertib and “in combination with FOLFIRI (180 mg/m2 irinotecan, 400 g/m2 leucovorin, 400 mg/m2 bolus 5-fluorouracil (5-FU), and 2400 mg/m2 continuous intravenous infusion 5-FU) [and] 5 mg/kg bevacizumab” (see Arms and Interventions).
As discussed above, one of skill in the art would be motivated to combine two or more known individual treatments for colorectal cancer (i.e., β-GPA, FOLFIRI, and bevacizumab) for an additive or synergistic effect when they are known in the prior art to be used alone and in combination with each other or other chemotherapeutic agents. See MPEP 2143 (I) (A).
Thus claims 11-12 and 17 are obvious in view of Martinez and NCT03829410.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Martinez et al., (WO 2016/176636 A1, published 2016-03-11)
Regarding claim 18, Martinez teach treatment of colon cancer by inhibition of the SLC6A8 creatine transporter via administration of β-GPA alone or in combination with other chemotherapeutic agents. For example, Martinez teach the use of β-GPA in combination with additional antiproliferative agents (e.g., FOLFOX comprising 5-FU, leucovorin, and Eloxatin) (see pg. 65, lines 4-6).
Thus, claim 18 is obvious in view of Martinez.
Claims 19-21 are rejected under 35 U.S.C. 103 as being unpatentable over Martinez et al., (WO 2016/176636 A1, published 2016-03-11), and in view of Amodio et al., “EGFR blockade reverts resistance to KRASG12C inhibition in colorectal cancer”, Cancer Discov 2020;10:1129–39, DOI:10.1158/2159-8290.CD-20-0187.
Regarding claims 19-21, as discussed above, Martinez teach treatment of colon cancer by inhibition of the SLC6A8 creatine transporter via administration of β-GPA and Amodio teach treatment of colorectal cancer with KRAS inhibitors (i.e., AMG510, also known as Sotorasib). Martinez additionally disclose that method of treating cancer includes identifying subjects with “the expression level of KCB and/or SLC6a8 is above a predetermined reference value” (see 64, line 24), which reads on the limitation of increased levels of creatine recited in claim 19. Martinez is silent on mutations of KRAS, HRAS, or NRAS in colorectal cancer.
However, Amodio, disclose recent developments in the art to target KRAS-mutant alleles (e.g., G12C) (see Introduction, para. 2). Amodio further demonstrate efficacy of KRAS inhibitor AMG510 in combination with an EGFR inhibitor in KRASG12C mutant cells and patient-derived organoids and xenografts (see pg. 1133, para. 2; Figure 3d; pg. 1135, para. 1; Figure 4d-e), which reads on the limitation of the cancer comprising a KRAS mutation recited in claim 19.
As discussed above, one of skill in the art would be motivated to combine two or more known individual treatments for colorectal cancer (i.e., β-GPA, KRAS inhibitor, EGFR inhibitor) for an additive effect when they are known in the prior art to be used in combination with each other or other chemotherapeutic agents and then use the method of the combined teachings in a subject that has increased creatine levels or a KRAS G12C mutation. See MPEP 2143 (I) (A).
Thus claims 19-21 are obvious in view of Martinez and Amodio.
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Martinez et al., (WO 2016/176636 A1, published 2016-03-11), and in view of Kurth et al., “Therapeutic targeting of SLC6A8 creatine transporter inhibits KRAS mutant and wildtype colon cancer and modulates human creatine levels”, bioRxiv (2021), DOI:10.1101/2021.04.26.441371.
Regarding claim 22, as discussed above, Martinez teach treatment of colon cancer via administration of β-GPA alone or in combination with other chemotherapeutic agent FOLFIRI (see pg. 65, lines 4-6). Martinez does not explicitly teach dosages or dosing schedules used of β-GPA.
However, in the same field of endeavor of creatine transporter inhibition for the treatment of colorectal cancer, Kurth teach dosing regimens from human clinical studies. Specifically, Kurth teach that β-GPA was administered to male and female adult patients with colorectal cancer enrolled in a Phase 1 a/b open-label study to “determine the maximum-tolerated dose, or maximum tested dose at which multiple dose-limiting toxicities (DLTs) are not observed” (see pg. 23, Patient Details; pg. 24, Clinical Study Design). Kurth further teach that “[p]atients were treated with RGX-202 [β-GPA] at 600 mg, 1200 mg, 2400mg or 3600 mg twice/day continuous dosing” (see pg. 24, Clinical Study Design).
Therefore, based on the teachings of Martinez and Kurth it would be prima facia obvious to one of skill in the art at the time of filing of the instant application to make a method of treatment comprising amounts of β-GBA in combination with FOLFIRI that read on the claimed dosing regimen of instant claim 22.
Thus claim 22 is obvious in view of Martinez and Kurth.
Conclusion
Claims 1-22 are rejected. No claims are allowed in this action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALAN JEROME FOWLER whose telephone number is (571)272-0195. The examiner can normally be reached Monday - Friday 9-5PM EST.
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/ALAN J FOWLER/ Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691
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