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 18/685,798
This Office Action is responsive to the amended claims and Applicant remarks of 05/20/2026. Claims 1, 5-6, 8, 10, 12-14, 23, 25, 28-29, 31, 35-38, and 43-44 are pending. Claims 8, 36, 43, and 44 are withdrawn from consideration pursuant to the restriction requirement of 03/20/2026. Claims 1, 5-6, 10, 12-14, 23, 25, 28-29, 31, 35, and 37-38 have been examined on the merits.
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 05/20/2026 is acknowledged. Applicant’s election without traverse of compound 66
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for the species election is acknowledged. A search for the elected species did not retrieve any pertinent prior art. The search was expanded to the full scope of the compound of Formula (I) or claim 1. The species election is withdrawn.
Priority
The instant application is a national stage entry of PCT/US2022/041218, filed 08/23/2022, which claims priority to U.S. Provisional Patent Application No. 63/236,581, filed 08/24/2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 07/11/2024, 06/27/2025, and 05/20/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
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, 37, and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Jung (US 2005/0096332 A1) in view of Lee (WO 2008/150118, found in IDS filed 07/11/2024).
Jung teaches compounds that are kinase inhibitors for the treatment of inflammatory diseases of the lungs and teaches pharmaceutical compositions comprising the compounds (Title, Abstract).The reference describes lung-indication testing where the inhibition of cigarette smoke-induced influx of neutrophilic granulocytes into the lung tissue by the above mentioned EGF-receptor kinase inhibitor [0089] and further states that treatment of animals with the EGFR kinase inhibitor A resulted in significant inhibition of smoke-induced accumulation of granulocytes [0092]. Compounds A-M were tested and the results are shown in the Table of [0096]. Compound F exhibited approximately a 6.5-fold lower effective dose than compound A. Compound F is compound (27), 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline which has the following structure:
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. (27) reads on the instantly claimed compound of Formula (I) where R1 is C6 aryl substituted with two R9, each R9 is halogen; R2-R4 are each H; R5 is OR10, where R10 is C1 alkyl; X is a C6 cycloalkylene; and R7 is hydrogen. Jung teaches compound (27) and shows that it is a promising EGFR inhibitor. Jung’s (27) differs from the instantly claimed compounds due to the lack of an acrylamide functionality at the position corresponding to R6 of the instant compound (I).
Lee teaches that irreversible inhibitors of EGFR BIBW-2992, HKI-272, and AV-412
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contain acrylamide functional groups at C-6 of the quinazoline or cyanoquinoline group because the acrylamide forms a covalent bond with Cystein773 positioned at an ATP domain of EGFR. This blocks autophosphorylation of EGFR and inhibits the signal transfer of cancer cells (pg. 3, lines 1-20).
The artisan would have experience in organic chemistry, medicinal chemistry, pharmaceutical science, or a related field. The artisan would recognize quinazoline derivatives as a known class of small-molecule EGFR inhibitors useful in the treatment of cancer. The artisan would also understand that the incorporation of an acrylamide functionality onto a quinazoline EGFR-inhibitor would enable a covalent interaction with a cysteine residue of EGFR.
Based on the teachings of the references above, the artisan would have been motivated to begin with a quinazoline core when developing an EGFR inhibitor, as these scaffolds are well established as small-molecule EGFR inhibitors. Lee teaches that incorporating an acrylamide functionality into EGFR inhibitors bearing similar quinazoline cores is a common strategy in the development of irreversible EGFR inhibitors. The artisan would have been motivated to incorporate an acrylamide functionality into a lead compound containing a quinazoline scaffold with a reasonable expectation that the acrylamide would provide a handle for covalent inhibition of a cys773 of the ATP domain of EGFR, thereby blocking EGFR autophosphorylation and inhibiting downstream cancer cell signaling.
Claims 1, 5, 6, 10, 12, 13, 23, 25, 28, 31 and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Jung and Lee in view of Ward (Kinase Drug Discovery: Modern Approaches).
The teachings of Jung and Lee are discussed above and are incorporated by reference into this rejection. The combined teachings of the references teach the limitations of claim 1. The references do not teach modifying the ring size of the cycloalkylene of X to be a cyclobutyl group. However, modification of linker length and geometry near the acrylamide warhead of covalent EGFR inhibitors, including incorporation of cyclic linkers of various size, is a known strategy in the art. Ward teaches that compound containing different linear linkers and four-, five-, six-, or seven-membered rings were prepared and tested for time-dependent inhibition of EGFR DM (pg. 72, second para). Ward further teaches that ring size was an important factor in positioning the acrylamide warhead in the appropriate position to react covalently with the Cys797 residue (pg. 72, second para). From these teachings, the artisan would have understood that linker/ring-size modifications near the acrylamide warhead is a viable strategy for optimizing placement of the acrylamide near cysteine residues for covalent inhibition of EGFR inhibitors.
The artisan would have experience in organic chemistry, medicinal chemistry, pharmaceutical science, or a related field. The artisan would recognize quinazoline derivatives as a known class of small-molecule EGFR inhibitors useful in the treatment of cancer. The artisan would also understand that the incorporation of an acrylamide functionality onto a quinazoline EGFR-inhibitor would enable a covalent interaction with a cysteine residue of EGFR. The artisan would also be familiar with known strategies used to optimize acrylamide warhead positioning for improved covalent interaction with cysteine residues.
As discussed above, the artisan would have been motivated to incorporate an acrylamide warhead onto the EGFR inhibitor of Jung based on the known ability of these warheads to form covalent bonds with cysteine residues. The artisan would have been motivated to improve the covalent interactions of the acrylamide warhead through known structure-optimization techniques, including incorporation of cyclic linker moieties of varying size to improve positioning of the warhead for enhanced inhibitory activity. The artisan would have reasonably expected that modifying the linker near the acrylamide warhead would alter the distance and orientation of the acrylamide relative to the cysteine residue, providing a predictable means of optimizing covalent bond formation while retaining the EGFR-inhibiting quinazoline core.
The above discussion shows that the artisan would have been motivated to incorporate and acrylamide warhead into Jung’s compound (27) and would have been further motivated to optimize the position of the warhead through modifications to the linker bearing the warhead, including incorporating cyclic groups in the linker. The resulting compound of these modifications corresponds to compound 85 of the instant application
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. The claimed compound would have been obvious because the prior art provided both a reason to make the structural changes to arrive at the instantly claimed compound and a reasonable expectation that the resulting compound would function as a covalent EGFR inhibitor.
Claims 1, 5, 6, and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Jung, Lee, and Ward in view of Shindo (Shindo, Naoya, and Akio Ojida. “Recent progress in covalent warheads for in vivo targeting of endogenous proteins.” Bioorganic & medicinal chemistry vol. 47 (2021): 116386. doi:10.1016/j.bmc.2021.116386).
The teachings of Jung, Lee, and Ward are discussed above and are incorporated by reference into this rejection. These references teach the limitations of claims 1, 5, and 6. These references do not teach propynamide warheads. Shindo teaches that a,b-unsaturated amide-type Michael acceptors, such as propynamides, are the most successful class of targeted covalent inhibitors design, especially in the field of kinase inhibitors for the treatment of cancer (pg. 1, right col., first para). Table 1 and Figure 1 of Shindo disclose propynamide warheads including acalabrutinib
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(Figure 1).
The artisan would have experience in organic chemistry, medicinal chemistry, pharmaceutical science, or a related field. The artisan would recognize quinazoline derivatives as a known class of small-molecule EGFR inhibitors useful in the treatment of cancer. The artisan would also understand that the incorporation of an acrylamide functionality onto a quinazoline EGFR-inhibitor would enable a covalent interaction with a cysteine residue of EGFR. The artisan would also be familiar with other covalent warheads used in covalent EGFR inhibitor, including a,b-unsaturated amide-type Michael acceptors.
Based on the teachings discussed above, substitution of one a,b-unsaturated amide-type Michael acceptor warhead for another represents a predictable selection of a known alternative form a recognized class of electrophilic covalent warheads. The artisan would expect that the resulting compound would retain covalent warhead functionality.
Conclusion
Claims 1, 5-6, 10, 12-13, 23, 25, 28-29, 31, 35, and 37-38 are rejected.
Claim 14 is objected to for depending 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..
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/C.K.E./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625
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