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 .
Election/Restrictions
Applicant’s election without traverse of Group II, claims 11-17, in the reply filed on 11/24/2025 is acknowledged. The election of species as a compound of Formula II set forth on page 4 of the Response is also acknowledged.
Claims 1-19 are pending, of which claims 1-10, 18 and 19 are withdrawn from consideration at this time as being directed to a non-elected invention. Claims 11-17 encompass the elected invention and are examined herein on the merits for patentability.
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.
Claim(s) 11-17 are rejected under 35 U.S.C. 103 as being unpatentable over Choi et al. (US 2007/0225306) in view of Kallergi et al. (Breast Cancer Research, 2009, 11, R84).
The instant claims are directed to a method to inhibit the proliferation and/or decrease the survivability of circulating tumor cells (CTCs) comprising contacting the CTCs with a compound of Formula 1.
Choi teaches a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly diseases or disorders that involve abnormal activation of the FAK, Abl, BCR-Abl, PDGF-R, c-Kit, NPM-ALK, Flt-3, JAK2 and c-Met kinases (abstract). The novel compounds of this invention inhibit the activity of one or more protein kinases and are, therefore, expected to be useful in the treatment of kinase-associated diseases (paragraph 0005).
In one aspect, the present invention provides compounds selected from Formulae Ia, Ib, Ic, Id and Ie (paragraph 0006),
The invention provides a pharmaceutical composition which contains a compound of Formula I or a N-oxide derivative, individual isomers and mixture of isomers thereof; or a pharmaceutically acceptable salt thereof, in admixture with one or more suitable excipients.
The present invention provides a method of treating a disease in an animal in which inhibition of kinase activity, particularly FAK, Abl, BCR-Abl, PDGF-R, c-Kit, NPM-ALK, Flt-3, JAK2 and/or c-Met activity, can prevent, inhibit or ameliorate the pathology and/or symptomology of the diseases, which method comprises administering to the animal a therapeutically effective amount of a compound of Formula I or a N-oxide derivative, individual isomers and mixture of isomers thereof, or a pharmaceutically acceptable salt thereof.
Focal adhesion kinase (FAK), a non-receptor protein-tyrosine kinase, is localized to cell substratum-extracellular matrix (ECM) contact sites that function as part of a cytoskeletal-associated network of signaling proteins. In adherent cells, FAK is often associated with integrins at focal adhesions. Phosphorylation of FAK results in activation of the mitogen-activated protein kinase pathway. Overexpression of FAK is involved in cancer progression. High levels of FAK correlate with invasiveness and metastatic potential in colon tumors, breast tumors and oral cancers. The role of FAK in cell migration has led to the speculation that it may be relevant in other diseases such as embryonic development dysfunctions and angiogenic disorders (paragraph 0033).
Compounds of the present invention inhibit abl kinase, especially v-abl kinase. The compounds of the present invention also inhibit wild-type BCR-Abl kinase and mutations of BCR-Abl kinase and are thus suitable for the treatment of Bcr-abl-positive cancer and tumor diseases, such as leukemias (especially chronic myeloid leukemia and acute lymphoblastic leukemia, where especially apoptotic mechanisms of action are found), and also shows effects on the subgroup of leukemic stem cells as well as potential for the purification of these cells in vitro after removal of said cells (for example, bone marrow removal) and reimplantation of the cells once they have been cleared of cancer cells (for example, reimplantation of purified bone marrow cells) (paragraph 0035).
PDGF (Platelet-derived Growth Factor) is a very commonly occurring growth factor, which plays an important role both in normal growth and also in pathological cell proliferation, such as is seen in carcinogenesis and in diseases of the smooth-muscle cells of blood vessels, for example in atherosclerosis and thrombosis. Compounds of the invention can inhibit PDGF receptor (PDGFR) activity and are, therefore, suitable for the treatment of tumor diseases, such as gliomas, sarcomas, prostate tumors, and tumors of the colon, breast, and ovary.
Compounds of the present invention, can be used not only as a tumor-inhibiting substance, for example in small cell lung cancer, but also as an agent to treat non-malignant proliferative disorders, such as atherosclerosis, thrombosis, psoriasis, scleroderma and fibrosis, as well as for the protection of stem cells, for example to combat the hemotoxic effect of chemotherapeutic agents, such as 5-fluoruracil, and in asthma. Compounds of the invention can especially be used for the treatment of diseases, which respond to an inhibition of the PDGF receptor kinase (paragraph 0036-7).
An exemplary compound is compound 85 (page 33):
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3-{3-[2-(3,4,5-Trimethoxy-phenylamino)-pyrrolo[2,3-d]pyrimidin- -7-yl]-phenyl}-propionitrile (example 85) has an IC50 of 16 nM for FLT3-ITD (paragraph 0123).
Accordingly, while Choi teaches that compounds of the invention modulate the activity of protein tyrosine kinases and, as such, are useful for treating diseases or disorders in which protein tyrosine kinases, particularly FAK, etc., Choi does not specifically recite that inhibitition of the proliferation and/or a decrease the survivability of circulating tumor cells.
Kallergi teaches that the development of metastasis is mainly responsible for can cer-related death. Malignant cells detached from the primary tumor possessing advantageous biological characteristics are presumed to generate distant disease sites. Indeed, it has been shown that metastasis is associated with the presence of circulating (CTCs) and disseminated (DTCs) tumor cells in peripheral blood and bone marrow, respectively, of otherwise metastasis-free patients.
Recent studies have shown that in patients with metastatic breast cancer, the assessment of CTCs is an earlier and more reliable marker than that of DTCs, associated with disease prognosis and suit able for monitoring of tumor response to chemotherapy (page 1).
Our group has recently demonstrated that FAK as well as PI 3 and Akt kinases are phosphorylated and thus activated in CTCs of breast cancer patients [18,19]. Since FAK is implicated in the angiogenesis process and induces the expression of VEGF, it was of interest to evaluate whether CTCs from breast cancer patients have activated the angiogenesis path way by expressing HIF-1α and VEGF. This could be an impor tant mechanism associated with the metastatic potential of these cells and therefore could bear important therapeutic implications (page 2).
The expression of pFAK, HIF-1α, VEGF and VEGF2 in CTCs of patients with metastatic breast cancer could explain the metastatic potential of these cells and may provide a therapeutic target for their elimination.
The data reported in the present study demonstrate that CTCs from patients with metastatic breast cancer express VEGF both at mRNA and protein level. The production of VEGF is probably under the regulation of HIF-1α and/or pFAK as suggested by the observed significant correlation between the expression of these molecules (page 10).
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide a compound of Formula I as inhibiting or decreasing the survivability of circulating tumor cells in a subject upon administration, for treating a disease in an animal in which inhibition of kinase activity, particularly FAK, Abl, BCR-Abl, PDGF-R, c-Kit, NPM-ALK, Flt-3, JAK2 and/or c-Met activity, which can prevent, inhibit or ameliorate the pathology and/or symptomology of the diseases when the teaching of Choi is taken in view of Kallergi. One would have been motivated to do so because Choi teaches that high levels of FAK correlate with invasiveness and metastatic potential in colon tumors, breast tumors and oral cancers, and it is known from Kallergi that CTCs from patients with metastatic breast cancer express VEGF both at mRNA and protein level. The production of VEGF is probably under the regulation of HIF-1α and/or pFAK as suggested by the observed significant correlation between the expression of these molecules. Further, Kallergi teaches that the expression of pFAK, HIF-1α, VEGF and VEGF2 in CTCs of patients with metastatic breast cancer could explain the metastatic potential of these cells and may provide a therapeutic target for their elimination (page 1).
Conclusion
No claims are allowed at this time.
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/LHS/
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618