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 .
Claims 1, 3-6, and 8-14, submitted on 13 June 2023, represent all claims currently under consideration.
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.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. The effective filing date is 14 December 2020.
Information Disclosure Statement
Two Information Disclosure Statements (IDSs), submitted on 13 June 2023 and 2 October 2024, are acknowledged and have been considered.
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, 3-6, and 8-14 are rejected under 35 U.S.C. 103 as being unpatentable over Li (Oncogene, 2020, 39:6203-6217; Published online: 21 August 2020) in view of Almagthali (Diabetes & Metabolic Syndrome: Clinical Research and Reviews, 13 (2019) 36-39), Bachovchin (WO 2018/049008; Publication Date: 15 March 2018) and Yang (Cancers, 2020, 12, 2459, Published: 20 August 2020).
Li (See IDS, 13 June 2023) teaches the link between ApoC1, STAT3 activation, and renal cell carcinoma. Renal cancer samples exhibit an upregulation of ApoC1, which is accompanied by ccRCC progression. A high level of ApoC1 is closely related to poor survival time in ccRCC patients. Furthermore, ApoC1 is over-expressed in highly invasive ccRCC cells as compared to that in low-invasive ccRCC cells. ApoC1 promoted metastasis of ccRCC cells via EMT pathway, whereas depletion of ApoC1 alleviated these effects. ApoC1 as a novel pro-metastatic factor facilitates activation of STAT3 and enhances metastasis of ccRCC cells. The metastatic potential of ccRCC cells driven by ApoC1 was suppressed by DPP-4 inhibition (Abstract). The plasma ApoC1 concentration is increased in patients with type 2 diabetes, and the elevated ApoC1 can be cleaved using FDA-approved DPP-4 inhibitors indicated for the treatment of type 2 diabetes. The authors showed that DPP-4 suppression by siRNA inhibited expression of ApoC1 and activation of STAT3 in ccRCC cells. DPP-4 deletion suppressed migratory and invasive abilities promoted by ApoC1 in the ccRCC cells. The authors then used the DPP-4 inhibitor linagliptin and found that it significantly abolished STAT3 activation and the invasive capacity of ccRCC cells harboring high ApoC1 expression. The authors conclude by stating that DPP-4 might be a potential target to suppress ApoC1 promoted metastasis and DPP-4 inhibitors could be attractive therapeutic agents for treating metastatic ccRCC patients (Page 6211).
Almagthali provides a review of dipeptidyl peptidase (DPP-4) inhibitors and their anti-cancer activity. DPP4 or CD26 is a serine exopeptidase belonging to the S9B protein family that cleaves X-proline dipeptides from the N-terminus of polypeptides, such as chemokines, neuropeptides, and peptide hormones. In a new study, researchers showed that inhibiting DPP4 is responsible for the degradation of key immune signals, and increases the number of immune cells within the tumor microenvironment, leading to an efficient anti-tumoral response. DPP4 degrades the chemokine CXCL10, which is responsible for targeting T-cells into diseased tissues. Researchers showed that inhibiting the activity of DPP4 improves immune efficacy, particularly against tumors. The team confirmed that DPP4 activity in vivo limited immune cells’ migration towards tumors and other inflammatory locations within the body. Upon inhibition of DPP4 activity in mice using the specific DPP4 inhibitor sitagliptin, researchers observed that blocking this enzyme preserved the biological activity of the CXCL10 chemokine, resulting in an increase of the respective T-cells into the tumor environment, inhibiting tumor growth (3. Role of DPP4 inhibitors in increasing immunity against tumors). The authors conclude by stating that inhibition of DPP4 is responsible for the degradation of key immune signals, increases the number of immune cells within the tumor microenvironment, leading to an efficient anti-tumoral response (6. Conclusion).
Li and Almagthali fail to teach the treatment of renal cell carcinoma using tyrosine kinase inhibitors in conjunction with DPP4 inhibition.
Bachovchin discloses potent immuno-DASH inhibitors and their use in the treatment of cell proliferative diseases (Abstract). Mammalian post-proline cleaving enzymes for a sub-family of serine proteases called dipeptidyl peptidase (DPP)-4 and/or structural homologs (DASH enzymes). DASH comprises DPP4, DPP2, DPP8, DPP9, fibroblast activation protein (FAP), and prolyl endopeptidase (Paragraph 0002). DPP4 is a validated drug target for human type II diabetes (Paragraph 0003). It has previously been reported that pharmacological inhibition of the enzymatic activity of DPP4 with dipeptide boronic acids can mediate tumor regression in an immune mediated manner. In the clinic, a DASH inhibitor PT_100 (Talabostat) achieved some partial and complete responses but has since been discontinued due to dose-limiting toxicity (Paragraph 0004). Recently, a paper published suggested that Sitagliptin, a highly selective DPP4 inhibitor relative to inhibition of DPP8 and DPP9 could be used in a triple combination with PD-1 and CTLA-4 inhibitors to cause a regression of tumors (Paragraph 0005). The present invention is based on the finding that potent DPP8/DPP9 inhibitors, which are also multimediator inhibitors of DPP4, can be used in combination with other agents to treat tumors, and when tumor regression is achieved, the consequences also include the induction of immunological memory selectively for the tumor (Paragraph 0006). One aspect of the present invention relates to compositions of matter for enhancing cell-mediated immune response against a cancer and specially to “immuno-DASH inhibitors” which are characterized as (a) the immuno-DASH inhibitor has a pharmacokinetic profile of being an inhibitor of DPP8, DPP9, and DPP4 when administered at a therapeutically effective amount and (b) the immuno-DASH inhibitor has an in vivo IC50 for DPP4 inhibition of less than 10 nM, and an intracellular IC50 for DPP8 and DPP9 inhibition less than 10 nM (Paragraph 0007). In certain embodiments, the subject immuno-DASH inhibitor can be administered as part of a therapy involving one or more other chemotherapeutic agents, immuno-oncology agents, or radiation (Paragraph 0043). Particularly preferred is the combination of immuno-DASH inhibitor or pharmaceutically acceptable salt thereof, with erlotinib, sorafenib, axitinib, bosutinib, cediranib, crizotinib, dasatinib, gefitinib, imatinib, canertinib, lapatinib, lestaurtinib, neratinib, nilotinib, semaxanib, sunitinib, vatalanib, and vandetanib, and even more particularly in the treatment of cancer selected from lung cancer, sarcoma, prostate cancer, pancreas carcinoma, gastric carcinoma, ovarian cancer, hepatoma, breast cancer, colorectal cancer, kidney cancer and brain cancer (Paragraph 00389).
Bachovchin fails to specifically teach that the cancer is resistant to tyrosine kinase inhibition.
Yang teaches the relationship between STAT3 and chemotherapeutic resistance. STAT3, an oncogene, contributes to insensitivity to chemotherapy and radiotherapy in tumor, reducing clinical efficacy. STAT3 may become a potential target to overcome chemoresistance. The authors focus on exploring the role of STAT3 in resistance to receptor tyrosine kinase inhibitors and radiotherapy, outlining the potential of targeting STAT3 to overcome resistance and improving clinical outcomes. STAT3 regulates vital biological process such as cell proliferation and cell growth, and is constitutively activated in various cancers and limits the application of chemoradiotherapy (Abstract). The development of small-molecule inhibitors has significantly improved progression-free survival agonist receptor tyrosine kinases, but disappointing outcomes remain due to the emergence of drug resistance. Erlotinib, an RTK inhibitor, increases STAT3 phosphorylation in EGFR-mutant non-small cell lung cancer cells through an autocrine loop, whereas knockdown of STAT3 decreases erlotinib-resistant colony numbers in the presence of erlotinib. This suggests that the interruption of STAT3 feedback loop blocks chemotherapy resistance. A similar result was reported for HER2-overexpressing breast and gastric cancers, where hyperactivated STAT3 signaling mediated trastuzumab resistance. Moreover, MEK inhibitor induced STAT3 feedback activation, leading to resistance in KRAS mutant lung cancer cells. MEK blockage has poor clinical outcome in KRAS-mutant colorectal cells, and siRNA mediated knockdown of macrophage inhibitor factor restored sensitivity to refametinib by decreasing STAT3 phosphorylation. Clearly, a combination of STAT3 pathway inhibitors and receptor tyrosine kinases may offer a promising strategy to improve chemotherapeutic efficacy (2. Feedback Loop Leading to STAT3 Activation). Activated STAT3 binds to DNA sequences in target genes and usually correlates with an enhanced expression of anti-apoptotic proteins, prevention of cell cycle arrest, and promotion of cell proliferation. The authors demonstrated that blocking of the transcriptional activation of STAT3α by STAT3 isoform STAT3β sensitized esophageal squamous cell carcinoma cels to chemotherapeutic agents, namely, cisplatin and 5-FU both in vitro and in vivo (4. STAT3 Target Genes Impact Chemoresistance and Radioresistance). Current evidence indicates that STAT3 is an oncogene, is constitutively activated in a variety of cancers, and regulates resistance to chemotherapy and radiotherapy. Targeting the STAT3 pathway alone or in combination with other drugs can reverse resistance to chemotherapy or radiotherapy to significantly improve the effectiveness of therapy (7. Conclusions and Future Perspectives).
Li, Almagthali, Bachovchin, and Yang are considered analogous to the claimed invention as all are involved in the treatment of cancer. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to specifically treat tyrosine kinase inhibitor resistant renal cancer using a tyrosine kinase inhibitor and a DPP4 inhibitor. Li demonstrates that renal cancer is sensitive to inhibition of DPP4 and results in a significant reduction in STAT3 signaling and activation , while Almagthali establishes that DPP4 inhibition using commercially available DPP4 inhibitors modulates the tumor environment, improving the immune response towards the tumor. Bachovchin discloses the treatment of cancers, including kidney cancer, using DASH inhibitors in combination with tyrosine kinase inhibitors, with Yang establishing that STAT3 activation contributes significantly to the insensitivity and resistance towards receptor tyrosine kinase inhibitors, and proposes that targeting STAT3 is a target to overcome this resistance. The combination of these teachings to arrive at the claimed invention is prima facie obvious combination of prior art elements according to known methods to yield predictable results (See MPEP § 2143 I (A)); the prior art teaches the inhibition of DPP4 in conjunction with the claimed tyrosine kinase inhibitors for the treatment of cancer, and also teaches that DPP4 inhibition ablates STAT3 in renal cancer and mitigates tumor metastasis, and that DPP4 inhibition is known to be useful for modulation of the tumor immune response. STAT3 is also implicated in drug resistance, and because DPP4 inhibition in renal cancer has been shown to result in reduction in STAT3 signaling and activation, the artisan would have a reasonable expectation of success in combining these teachings to arrive at the claimed invention.
Regarding Claim 6, the prior art teaches that DPP4 inhibition reduces STAT3 activation, which contributes to drug resistance. It flows from this teaching that co-administration of a DPP4 inhibitor with a tyrosine kinase inhibitor would result in an enhanced therapeutic effect in the treatment of renal cancer.
Regarding Claims 5, 10, 12, and 14, the prior art does not disclose the use of a double-stranded nucleic acid molecule inhibiting expression of a DPP4 gene, DNA including a base sequence encoding the double-stranded nucleic acid molecule, or a vector including the DNA. However, as the prior art establishes that both siRNA knockdown of DPP4 (Li) and pharmacological inhibition of DPP4 (Li, Almagthali, Bachovchin) is effective in the treatment of cancer, it would be prima facie obvious to substitute these gene-based treatments for the pharmacological inhibitors as these are equivalents known for the same purpose (See MPEP § 2144.06 II).
Conclusion
Claims 1, 3-6, and 8-14 are rejected.
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/P.M.R./ Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625