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 .
Current Status of 18/835,778
This Office Action is responsive to the amended claims of 08/05/2024. Claims 1-3, 5-6, 10-11, 14, 17-18, 21, 27-28, 30, 32, 34, 36, 38-39, and 41 are pending and have been examined on the merits.
Priority
The instant application is a national stage entry of PCT/US2023/061726, filed 02/01/2023, which claims priority to U.S. Provisional Patent Application No. 63/267,563, filed 02/04/2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/05/2024 submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings are objected to because the compounds of Figures 12 and 13 are grainy and difficult to read. The axes and labels of Figures 7I and 14 are grainy and difficult to read. Submission of new figures where these images are clear and legible will render these objections moot. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 38, 39, and 41 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating prostate cancer, pancreatic cancer, breast cancer, and non-small cell lung cancer, does not reasonably provide enablement for the treatment of all disease as claimed in claim 38 nor does it provide enablement for the other species of cancer listed in claim 39 or the metabolic disorders of claim 41. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure meets the enablement requirements of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir., 1988). The court in Wands states, “Enablement is not precluded by the necessity for some experimentation, such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue’, not ‘experimentation’” (Wands, 8 USPQ2sd 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations” (Wands, 8 USPQ2d 1404). Among these factors are: (1) the nature of the invention; (2) the breadth of the claims; (3) the state of the prior art; (4) the predictability or unpredictability of the art; (5) the relative skill of those in the art; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
(1) The nature of the invention and (2) the breadth of the claims:
The claims are drawn to a method of treating any disease or disorder comprising administering any compound of claim 1. Thus, the claims taken together with the specification imply that any compound of Formula I, including those that are not found in the disclosure, are capable of treating any disease or disorder. Thus, the scope of the claims is extremely broad.
(3) The state of the prior art and (4) the predictability or unpredictability of the art:
The prior art teaches that PIM kinases are oncogenic serine/threonine kinases that regulate tumorigenesis by phosphorylating substrates involved in cellular processes (see Luszczak et al. and Toth et al.). PIM kinases are known to be overexpressed in multiple cancers and to promote resistance to multiple type of anticancer therapies (see Luszczak et al. and Toth et al.). However, the art recognizes that PIM inhibitor monotherapy has limited clinical utility because of compensatory signaling and the potential for acquired resistance.
The PI3K/Akt/mTOR signaling pathway is recognized as a cancer-relevant pathway and is frequently targeted in the treatment of various types of cancer (see Zou et al.). The prior art shows that mTOR inhibitors may have utility, especially in combination with other antitumor agents. However, the prior art also recognizes the complexity of mTOR signaling and their side effects (see Zou et al.). PIM and mTOR signaling are promising therapeutic targets in certain cancers, but the prior art does not establish that inhibition of these pathways would predictably treat all disease or disorders as claimed.
The prior art establishes that PIM and mTOR inhibitors are promising therapeutic approaches for the treatment of some forms of cancer, but is a still developing field. The art does not provide a general expectation that these inhibitors would be effective across unrelated disease or disorders. The complexity and the uncertainty of these signaling pathways make therapeutic outcomes unpredictable.
(5) The relative skill of those in the art:
The artisan would have experience in developing and evaluating small molecule kinase inhibitors, including kinase inhibitors of Pim and mTOR. The artisan would be familiar with the role of Pim and mTOR kinases in the phosphorylation of EDC3 and the associated cancer signaling pathways. The artisan would be familiar with similar inhibitors used for treatment of cancer and disorders associated with these signaling pathways.
(6) The amount of direction or guidance presented and (7) the presence or absence of working examples:
The specification has provided guidance for some of the disclosed compounds in cancer models, including prostate cancer, pancreatic cancer, T-cell acute lymphoblastic leukemia, lung cancer, and breast cancer cells ([0334]). However, the mTORC substrate phosphorylation assay was only performed on a limited subset of analogs including VBT-1-31, VBT-1-34, VBT-1-35, VBT-1-60, VBT-1-94, VBT-1-104, and VBT-1-127. Of the tested compounds, only VBT-1-31, VBT-1-34, VBT-1-35, and VBT-1-104 appear to show the desired inhibition of phosphorylation of mTORC substrates (FIGs 19-20). VBT5445 is more extensively characterized in assays relating to Pim/EDC3 phosphorylation, P-body formation, cancer cell growth inhibition, and mTOR-related signaling (FIG 7A-7I).
However, the specification does not provide evidence that the compounds of Formula I are capable of treating all forms of disease and disorders as claimed.
(8) The quantity of experimentation necessary:
Considering the state of the art as discussed by the references above, particularly with regards to the lack of evidence demonstrating that all compounds of Formula I are capable of treating all forms of disease or disorders and the high unpredictability in the art as evidenced therein, and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to practice the invention commensurate in the scope of the claims.
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 1-3, 5-6, 11, 14, 17, and 21 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by PubChem CID 26342358 (found in IDS submitted 08/05/2024).
Applicants have supplied a copy of PubChem CID 26342358 in the IDS filed 08/05/2024 which indicates a creation date of 05/28/2009. The compound has the following structure
PNG
media_image1.png
236
196
media_image1.png
Greyscale
. This compound reads on the indicated claims with the following substitutions: R1a-1b and 1d are H; R1c is Cl; m is 2; Z is O; R2 is aryl; X is NR3, R3 is H; W is CH2, n is 1; Ar is substituted C6 aryl, A, U, T, V, Y, are each C, R4a-4d are each H, R4e is alkoxy.
Claims 1-3, 5-6, 11, and 14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by PubChem CID 26352206 (found in IDS submitted 08/05/2024).
Applicants have supplied a copy of PubChem CID 26342358 in the IDS filed 08/05/2024 which indicates a creation date of 05/28/2009. The compound has the following structure
PNG
media_image2.png
241
178
media_image2.png
Greyscale
. This compound reads on the indicated claims with the following substitutions: R1a-1b and 1d are H; R1c is Cl; m is 2; Z is O; R2 is aryl; X is NR3, R3 is H; W is CH2, n is 1; Ar is substituted heteroaryl.
Claims 1-3, 5-6, 11, 14, 17, 18, 21, and 28 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gnawali (Gnawali, Giri R., et al. "Synthesis of 2-oxoquinoline derivatives as dual pim and mTORC protein kinase inhibitors." Medicinal Chemistry Research 31.7 (2022): 1154-1175.).
Gnawali teaches the following compound
PNG
media_image3.png
147
207
media_image3.png
Greyscale
. This compound reads on the indicated claims with the following substitutions: R1a-1b and 1d are H; R1c is Cl; m is 2; Z is O; R2 is aryl; X is NR3, R3 is H; W is CH2, n is 1; Ar heteroaryl, A, U, T, Y, are each C, R4a-4d are each H, R4e is alkoxy, V is N. The reference also teaches that the compound is an inhibitor of both Pim and mTORC protein kinases (Abstract).
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.
Claims 1, 10, and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Gnawali in view of Patani (Patani, George A., and Edmond J. LaVoie. "Bioisosterism: a rational approach in drug design." Chemical reviews 96.8 (1996): 3147-3176.).
The teachings of Gnawali are discussed above and are incorporated by reference into this rejection. The references teaches the limitations of claim 1. Gnawali does not teach that the position corresponding to position X in the instant application can be O.
Patani teaches that bioisosteric replacement is a well-known and routine tool used for lead compound modification. The reference also teaches that O is an isostere of NH (Table 2, pg. 3148). The reference also teaches that classic isosteric substitutions when applied to ring systems result in different heterocyclic analogs that can be effective bioisosteres (pg. 3158, Ring Equivalents, first para.). The reference also teaches that the use of classic bioisosteres such as benzene, thiophene, and pyridine produced analogs with retention of biological activity within different pharmacological agents (pg. 3158, Ring Equivalents, first para.). The reference
The artisan would have experience in organic chemistry, medicinal chemistry, pharmaceutical science, or a related field and would have experience in the synthesis and development of small-molecule kinase inhibitors. The artisan would be familiar with known strategies for lead compound modification, including bioisosteric replacements.
The artisan would have been motivated to substitute the -NH- for -O- in Gnawali’s compound as part of routine lead compound modification. The artisan would have recognized -O- as a common isosteric replacement of -NH- and would have expected that substitution would preserve the biological activity of the core compound while potentially improving other properties, such as ADME characteristics.
The artisan would have been further motivated to modify the pyridine ring of Gnawali’s compound by varying the position of the ring nitrogen atom as part of routine lead-compound optimization. The artisan would expect that such pyridyl regioisomer screening would preserve the desired biological activity of the core compound while potentially improving other properties, such as ADME characteristics. Modification of Gnawali’s compound with the above teachings would afford the following compound
PNG
media_image4.png
92
187
media_image4.png
Greyscale
of the instant disclosure. As discussed above, replacement of -NH- for -O- and regioisomer screening of the pyridine ring are obvious in view of the teachings of the disclosed references.
Conclusion
Claims 1-3, 5-6, 10,11, 14, 17-18, 21, 27-28, 38-39, and 41 are rejected.
Claims, 30, 32, 34, and 36 are objected to for being dependent upon a rejected base claim.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CONNOR KENNEDY ENGLISH whose telephone number is (571)270-0813. The examiner can normally be reached Monday Friday, 8 a.m. 5 p.m. ET..
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Andrew Kosar can be reached at (571)272-0913. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/C.K.E./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625
Prosecution Insights