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 .
Status of Claims
Claims 1-31 were previously pending in this application. By the amendment filed on 28 January 2025, claims 2-3, 6-10, and 15-20 are cancelled. Claims 1, 4-5, 11-14, and 21-31 have been amended. New claims 32-33 have been added. As a result, claims 1, 4-5, 11-14, and 21-33 are pending, with claim 1 being the sole independent claim.
Priority
This application, filed 8 August 2024, is a National Stage entry from International Application No. PCT/EP2023/053386, filed 10 February 2023, which claims priority under 35 U.S.C. 119 or 365 to Great Britain Application No. 2201819, filed on 11 February 2022. The certified copy of the foreign application has been received.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 28 January 2025 has been acknowledged and considered.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 4-5, 11-12, 14, 21-22, 25-26, 29-30, 32-33 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Horn et al., Cancer Res (2016) 76 (23): 6950–6963 (“Horn”), evidenced by Niedermaier et al., Scientific Reports volume 9, Article number: 18207 (2019) (“Niedermaier”) and Sanmartin-Salinas et al., J Mol Hist 49, 39–49 (2018) (“Salinas”).
Regarding claims 1, 4-5, 11, 12, 14, 21-22, 30, and 33, Horn teaches a method of administering linsitinib (IGFR/IR) and MK-2206 (AKT) to the LS-180 colorectal cancer cell line which carries a KRAS mutation (Figure 2A, Supplementary Tables S1-S2 and S4). The LS-180 cell line is the same one used in Examples 3 and 4 of the instant specification (Spec., pp. 30-31), and is evidenced by Niedermaier to carry an ARID1A mutation (Figure 1A).
Regarding claims 25-26, 29-30, and 32-33 Horn teaches a method of administering linsitinib and MK-2206 to the RKO colorectal cancer cell line, which are evidenced by Niedermaier to carry an ARID1A mutation (Figure 1A) and evidenced by Salinas to carry the IRS4 wild-type gene (Fig 2E).
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.
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, 4-5, 11-14, 21-22, 25-26, 29-33 are rejected under 35 U.S.C. 103 as being unpatentable over Horn in view of EP3879269 (“Laing”) and WO2012015741 (“Narayanan”), evidenced by Niedermaier and Salinas.
Horn teaches a method of administering linsitinib (IGFR/IR) and MK-2206 (AKT) to the LS-180 colorectal cancer cell line which carries both a KRAS mutation (Figure 2A, Supplementary Tables S1-S2, and S4) and an ARID1A mutation evidenced by Niedermaier (Figure 1A). Horn also teaches a method of administering linsitinib and MK-2206 to the RKO colorectal cancer cell line (Figure 2A, Supplementary Tables S1-S2, Supplementary Table S4), which is evidenced by Niedermaier to carry an ARID1A mutation (Figure 1A) and evidenced by Salinas to carry the IRS4 wild-type gene (Fig 2E).
Horn does not teach administration of a competitive Akt inhibitor like, capivasertib, afuresertib, and ipatasertib in combination with an IFG1R inhibitor like linsitinib.
Laing teaches an assessment of multiple signaling pathways in a subject’s cancer cells can further involve the selection of multiple targeted therapeutics for administration to the subject (i.e., a combination of targeted therapeutics for combination therapy). For example, targeting of the AKT and IGF-1R pathways (¶¶[0156]), [0182]-[0183]; claims 5-6). Furthermore, the use of rational combinatorial targeted therapy has been proposed as a solution to the ongoing challenge of cancer drug resistance (¶ [0160]). Laing also teaches that one of the targeted therapeutic that is administered to a subject is linsitinib, AZD5363 (i.e., capivasertib), MK-2206, afuresertib, ipatasertib, etc., and the cancer is selected from breast, colorectal, ovarian, etc. (¶¶[0162], [0166], claims 1 and 4).
With respect to claim 31, Laing fails to explicitly teach separate administration of an IGF-1R inhibitor and an Akt inhibitor.
Narayan teaches a method of treating cancer by administering an IGF-1R specific antibody in combination with an Akt Pathway inhibitor (Abstract). Examples of the inhibitors taught are the IGF-1R inhibitor dalotuzumab, that specifically binds to human Insulin-Like Growth Factor Receptor Type 1 (IGF-1R) and the Akt inhibitor, MK-2206 (p. 3, lines 8-12). The IGF-1R inhibitor and the Akt inhibitor can be formulated in the same formulation for simultaneous administration, or can be in two separate dosage forms, which may be administered simultaneously or sequentially (p. 53, lines 12-14) for the treatment of cancer, for example endometrium cancer, colorectal carcinoma, or ovarian cancer (p. 16, lines 23-27).
Horn and Laing are analogous art because they are in the same field of administering IGF-1R and Akt inhibitors to subjects having cancer like colorectal cancer. Therefore, it would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) to combine the teachings of Horn and Laing to arrive at the claimed invention. Following the teachings of Horn, administration of an IGF-1R inhibitor, like linsitinib, and an Akt inhibitor like MK-2206, and Laing, to patients having colorectal cancer or ovarian cancer, would have led to predictable results for a PHOSITA, because they are both in the same field of targeting multiple signaling pathways, like IGF-1R and Akt, with one or more targeted therapeutics (MPEP §2143(A)). Furthermore, a PHOSITA would have had a reasonable expectation of success in substituting the inhibitor MK-2206, an allosteric Akt inhibitor, for another Akt inhibitor, like AZD5363, afuresterib, or ipatasertib, all competitive Akt inhibitors, because they are implicitly taught as equivalents since they are grouped with MK-2206 as a desired targeted therapeutic. In other words, AZD5363 (i.e., capivasertib), MK-2206, afuresertib, ipatasertib are all Akt inhibitors and the teachings of Laing acknowledged this by grouping them sequentially (MPEP §§2143(B), 2144.06(II)).
Regarding claims 21-22, 25-26, 29-30, 32-33, Horn explicitly teaches a method of administering linsitinib and MK-2206 to LS-180 colorectal cancer cell lines which bear ARID1A and KRAS mutations. Horn also explicitly teaches administration of linsitinib and MK-2206 to RKO colorectal cancer cell lines which bear an ARID1A mutations and the IRS4 wild type gene. It would have been prima facie obvious to a PHOSITA to follow the express teachings of Horn and arrive at the claimed invention.
Regarding claim 31, Narayan teaches the IFG1R inhibitor, dalotuzumab, and the Akt inhibitor, MK-2206, can be administered in two separate dosage forms to treat a subject having cancer, for example endometrium cancer, colorectal carcinoma, or ovarian cancer (vide supra). It would have been prima facie obvious to combine the teachings of Horn and Laing, to administer an IGF-1R inhibitor, like linisitinib, in combination with an Akt inhibitor, like MK-2206, AZD5363 (i.e., capivasertib), MK-2206, afuresertib, or ipatasertib, and administer this combination sequentially as taught by Narayan to yield reasonably predictable results and arrive at the claimed invention (MPEP §2143(A)).
Claims 23-24 are rejected under 35 U.S.C. 103 as being unpatentable over Horn in view of Bala et al., Oncogene (2021) 40:863–874 (“Bala”), evidenced by Niedermaier and Salinas.
The teachings of Horn and the evidentiary references Niedermaier and Salinas are discussed above and are incorporated by reference herein.
Regarding claims 23-24, Horn does not teach administration of a combination of IGF-1R inhibitors and Akt inhibitors to subjects having ARID1A and/or ARID2 mutations.
Bala teaches the tumorigenic potential and functional relevance of TP53, KRAS, APC, PIK3R1, SMAD4, and ARID1A have been extensively studied in CRC. ARID2 is a subunit of the PBAF SWI/ SNF chromatin remodeling complex and its inactivating mutation are identified in some cancer types, but is studied only in hepatocellular carcinoma hitherto (p. 870, 2nd column). Figure 2b shows early-onset sporadic rectal cancer (EOSRC) cells, a predominant form of colorectal cancer (Abstract), IN-2769 and -2409, bear both ARID1A and ARID2 mutations, and cells IN-2603, -2549, and -2397, bear only the ARID2 mutation. Figure 4C shows ARID2 loss at protein level was observed in 27% of EOSRC samples (p. 870, 2nd column). Bala further teaches: “Considering the recent interest to develop targeted therapy against SWI/SNF-deficient cancer, it is interesting to determine whether the tumor suppressor role of ARID2 in CRC is dependent on its transcription regulatory or DNA repair function(s). Given the recalcitrance of advanced colorectal tumors to conventional therapies and the identification of PBAF inactivation association with increased susceptibility to killing by cytotoxic T cells, our identification of ARID2 loss in a significant proportion of EOSRC, a poorly studied CRC subtype, is of significance.” (p. 870, 2nd column).
Horn and Bala are considered analogous art because they are both in the same field of analyzing important signaling pathways implicated in colorectal cancer. Therefore, it would have been prima facie obvious to a PHOSITA to administer linsitinib and MK-2206 as taught by Horn to subjects having colorectal cancer bearing the ARID1A and/or ARID2 mutations as taught by Bala, because Bala suggests the recalcitrance of advanced colorectal tumors, like EOSRC, to conventional therapies, is in part because of the lack of attention given to the loss of ARID2 in said tumors (vide supra). Thus, a PHOSITA would have been motivated to administer the linistinib and MK-2206 to EOSRC subjects to arrive at the methods instantly claimed (MPEP §2143(G)).
Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over Horn in view of Wang et al., Mol Cancer Ther (2005) 4 (8): 1214–1221 (“Wang”) and Hirai et al. Mol Cancer Ther (2010) 9 (7): 1956–1967 (“Hirai”), evidenced by Niedermaier, Salinas, and Kwan et al., Oncotarget. 2016; 7:56933-56943 (“Kwan”).
The teachings of Horn and the evidentiary references Niedermaier and Salinas are discussed above and are incorporated by reference herein.
Regarding claims 27, Horn does not teach administration of a combination of IGF-1R inhibitors and Akt inhibitors to subjects having ovarian cancer bearing an ARID1A mutation.
Wang teaches a fully human anti-IGF-1R monoclonal antibody 19D12 administered to xenograft mouse models injected with A2780 human ovarian carcinoma cells.
Wang does not teach administration of an Akt inhibitor in combination with 19D12.
Hirai teaches administration of MK-2206 in A2780 ovarian tumor cells in distinct combination with five different chemotherapeutic agents (Table 3).
As evidenced by Kwan, the A2780 ovarian cancer cells bear an ARID1A mutation (Figure 1).
It would have been prima facie obvious to a PHOSITA to administer a combination of an IGF-1R inhibitor and an AKT inhibitor, as taught by Horn, to the A2780 ovarian cancer cell lines, as taught by Wang and Hirai, because Wang and Hirai teach administration of an IGF-1R and an Akt inhibitor, respectively, to the same ovarian cancer cell line bearing an ARID1A mutation. The teachings of Horn, Wang, and Hirai are all in the same field of administering IGF-1R and AKT inhibitors to ovarian cancer cells bearing an ARID1A mutation, and therefore their combined teachings, to a PHOSITA, would yield reasonably predictable results (MPEP §§2143(A), 2144.06(I)).
Claim 28 is rejected under 35 U.S.C. 103 as being unpatentable over Horn in view of Wang et al., Cancer Biology & Therapy, 20(3), 295–306 (“Guo”) and Engel 1 al., European Journal of Obstetrics & Gynecology and Reproductive Biology, Volume 141, Issue 1, 2008, Pages 64-69 (“Jia”), evidenced by Niedermaier, Salinas, and Kwan.
The teachings of Horn and the evidentiary references Niedermaier and Salinas are discussed above and are incorporated by reference herein.
Regarding claims 28, Horn does not teach administration of a combination of an IGF-1R inhibitor and Akt inhibitor to subjects having endometrial cancer bearing an ARID1A mutation.
Guo teaches IGF-1R is upregulated in endometrial cancer (EC) cells (p. 295, Results). The cell lines tested for inhibiting IGF-1R were HEC-1A and Ishikawa (Figure 1(D)). The knockdown of IGFR-1 with short hairpin IGF-1R (sh-IGF-1R) showed a decrease in IGF-1R and apoptosis of the EC cells (Figures 2(F) and 3(B); p. 298, 2nd column).
Guo does not teach administration of an Akt inhibitor in combination with 19D12.
Engel teaches administration of perifosine, an Akt inhibitor, to human EC cells, namely Ishikawa and HEC-1A cells. Administration of persifone in HEC-1A and Ishikawa cells led to a decrease in Akt phosphorylation and inhibition of tumor cell proliferation, which was more pronounced at longer treatment times (Figures 1 and 2; p. 66, 2nd column).
As evidenced by Kwan, the HEC-1A EC cells bear an ARID1A mutation (Figure 1).
It would have been prima facie obvious to a PHOSITA to administer a combination of an IGF-1R inhibitor and an AKT inhibitor, as taught by Horn, to the HEC-1A endometrial cancer cell lines, as taught by Guo and Engel, because Guo and Engel teach administration of an IGF-1R and an Akt inhibitor, respectively, to the same EC cell line bearing an ARID1A mutation. The teachings of Horn, Guo, and Engel are all in the same field of administering IGF-1R and AKT inhibitors to endometrial cancer cells bearing an ARID1A mutation, and therefore their combined teachings, to a PHOSITA, would yield reasonably predictable results (MPEP §§2143(A), 2144.06(I)).
Conclusion
No claims are allowed.
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/SAHIL CHANDER AGGARWAL/Examiner, Art Unit 1623
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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