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 .
Acknowledgement of Receipt
Applicant’s Response, filed 5/4/2026, in reply to the Office Action mailed 2/2/2026, is acknowledged and has been entered. Claim 11 has been amended. Claims 1-19 are pending, of which claims 1-10 and 18-19 are withdrawn from consideration at this time as being drawn to a non-elected invention. Claims 11-17 encompass the elected invention and are examined herein on the merits for patentability.
Response to Arguments
Applicant’s arguments have been fully considered. Any rejection not reiterated herein has been withdrawn as being overcome by claim amendment. The Examiner’s response to Applicant’s arguments is incorporated below.
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 induce senescence 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).
Aberrant kinase activity has been observed in many disease states including benign and malignant proliferative disorders as well as diseases resulting from inappropriate activation of the immune and nervous systems (paragraph 0004).
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 inhibition of the proliferation and/or inducing senescence of circulating tumor cells.
Kallergi teaches that the development of metastasis is mainly responsible for cancer-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).
Angiogenesis, primarily regulated by vascular endothelial growth factor (VEGF), is a critical event in tumor progression and metastasis. Tumor cells produce and release vascular endothelial growth factor in response to oxygen and nutrients deprivation that in turn stimulates the formation of new vessels and promotes tumor growth and dissemination. Besides its role in new blood formation, VEGF has been also shown to stimulate the proliferation of tumor cells. Indeed, VEGF enhanced the proliferation and the migration of breast cancer cells, whereas siRNA targeting of VEGF in MCF7 breast cancer cell line, effectively inhibited cell proliferation and enhanced apoptosis. Moreover, VEGF expression in breast cancer cells was correlated with decreased response to hormone treatment and with reduced survival in breast cancer patients. Focal adhesion kinase (FAK) and Src catalytic activities are important in promoting VEGF-induced tumor angiogenesis whereas the inhibition of FAK reduces VEGF expression resulting in small avascular tumors in mice (page 2).
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. 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 important 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 proliferation 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 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). Further, VEGF
enhanced the proliferation and the migration of breast cancer cells, whereas siRNA targeting of VEGF in MCF7 breast cancer cell line, effectively inhibited cell proliferation and enhanced apoptosis; and inhibition of FAK reduces VEGF expression; as such it is considered that administration of the kinase inhibitors of Choi would be useful in inhibition of circulating tumor cells, as Choi teaches them to be useful for treating diseases or disorders in which protein tyrosine kinases.
Response to arguments
Applicant argues that the Office's assertion is that the combination of Choi et al. and Kallergi et al. focus on "elimination" or "apoptosis" (cell death). In contrast, the present claims and specification provide that the method achieves senescence - a state where the cell remains viable but permanently loses the ability to divide. The specification provides comparative data in paragraph [0082] stating that the compound of Formula II "induced senescence by at least 3-4 fold greater than CX-4945 (Silmitasertib)." (Emphasis added). Since CX- 4945 is a known kinase inhibitor, the superior and specific induction of senescence by compounds of Formula I to II is an unexpected result that a POSITA would not have predicted from the general teachings of Choi et al.
Applicant’s arguments have been fully considered but are not persuasive. It is respectfully submitted that the claims are not limited to achieving senescence - a state where the cell remains viable but permanently loses the ability to divide, rather include inhibition of proliferation which is addressed by the combined teachings of Choi and Kallergi as set forth above. With regard to the allegation of unexpected results, see MPEP 716.02(d). Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (Claims were directed to a process for removing corrosion at "elevated temperatures" using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100°C). Appellant demonstrated unexpected results via comparative tests with the prior art ion exchange resin at 110°C and 130°C. The court affirmed the rejection of claims 1-7 and 9-10 because the term "elevated temperatures" encompassed temperatures as low as 60°C where the prior art ion exchange resin was known to perform well. The rejection of claim 8, directed to a temperature in excess of 100°C, was reversed.). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.). In the instant case, the claims encompass a large genus of compounds while the results which are stated to be unexpected are directed to a single compound.
Applicant further argues that Kallergi et al. explicitly calls for the "elimination" of CTCs (Kallergi et al. at p. 1). Choi et al. teach "apoptotic mechanisms" ([0035]). Apoptosis and elimination result in the removal of the cell. In contrast, the claimed invention focuses on inducing a specific "arrested state" (senescence) where the cell remains viable but non-metastatic (see, e.g., paragraph [0082]). This is a technically distinct therapeutic strategy that contradicts the "elimination" goal of the cited references, thereby rendering the specific use of Formula I-II for senescence non-obvious.
Applicant’s arguments have been fully considered but are not persuasive. It is respectfully submitted that the claims are not limited to achieving senescence - a state where the cell remains viable but permanently loses the ability to divide, rather include inhibition of proliferation which is addressed by the combined teachings of Choi and Kallergi as set forth above.
Applicant further argues that CTCs are described in the prior art and the specification as being "very rare" and posing an "extreme challenge" for survival and expansion due to high reactive oxygen species (ROS). Kallergi et al. identifies FAK as a target but does not provide evidence that a small molecule inhibitor can effectively penetrate and act upon these fragile, rare cells in the complex environment of a subject. Choi et al.'s data is largely based on standard cell lines (e.g., Ba/F3), which do not exhibit the unique "vulnerability" and "heterogeneity" of CTCs described in paragraph [0033] of the Applicant's specification. Applicant contends that a POSITA would have had a low reasonable expectation of success in specifically targeting CTCs as opposed to primary tumor mass.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g.,In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988). In the instant case, Kallergi teaches pFAK, HIF-1α, VEGF and VEGF2 in CTCs of patients with metastatic breast cancer and metastases and serve as a therapeutic target for their elimination.
Conclusion
No claims are allowed at this time.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/LHS/
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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