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 17/821,931
This Office Action is responsive to the amended claims and the Applicant remarks of 03/18/20206. Claims 37, 40, 42-45, 49-55, 59, and 80-82 are pending. Claims 54-55 and 59 are rejoined. Claims 37, 40, 42-45, 49-55, 59, and 80-82 have been examined on the merits.
Priority
The instant application is a continuation of U.S. Application No. 16/461,992, filed May 17, 2019, which is a national phase entry of PCT/US2017/062326, filed November 17, 2017, which claims the benefit of priority to U.S. Provisional Application No. 62/423,732, filed November 17, 2016, U.S. Provisional Application No. 62/427,692, filed November 29, 2016, and U.S. Provisional Application No. 62/572,716, filed October 16, 2017.
Response to Applicant Remarks and Amendments
In response to the object to the drawings filed on 04/14/2023, Applicants have submitted new drawings that are clear and legible. These drawings are found in the DRW.SUPP submission of 04/28/2026. In view of this submission, the previous objection to the drawings is withdrawn.
Applicants have corrected a claim dependency issue in claim 50. This amendment renders the previous rejection moot. The rejection is withdrawn.
In response to the rejections under 35 U.S.C. §103 over the references Cha and Herter-Sprie, Applicants contend that the method of instant claim 37 requires one or more HER2 exon 20 mutations comprising a point mutation, an insertion, and/or a deletion of 1-6 amino acids between amino acids 770-785. Each of these mutations are at residues S779 or P780 and are selected from the group consisting of A775insV G776C, G776V, G776C V777insV, G776C V777insC, G776del insVV, G776del insVC, and P780insGSP. Applicants allege that Cha teaches that poziotinib exhibits inhibition of EGFR, HER2, and HER4, and more specifically, that poziotinib is an inhibitor of EGFR exon 20 mutation T790M. This amino acid position is outside the claimed range of 770-785 and does not occur on residues S779 or P780. Herter-Sprie teaches that subjects bearing A775insYVMA mutations may be treated with HER2 inhibitors. Applicants have amended the claims to remove the A775insYVMA mutation. Herter-Sprie is silent regarding the limitations of instant claim 37. Therefore, there is no nexus between the use of poziotinib in the treatment of the claimed mutations of HER2 exon 20. Applicants further argue that reference Bianco fails to teach the claimed mutations of HER2 exon 20 of base claim 37. These arguments have been fully considered and are found persuasive. The previous rejections over the references discussed above are withdrawn.
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 37, 40, 51-53 and 80-82 are rejected under 35 U.S.C. 103 as being unpatentable over Cha (Cha, Mi Young et al. “Antitumor activity of HM781-36B, a highly effective pan-HER inhibitor in erlotinib-resistant NSCLC and other EGFR-dependent cancer models.” International journal of cancer vol. 130,10 (2012): 2445-54. doi:10.1002/ijc.26276, found in IDS submitted 02/24/2024) in view of Cappuzzo (WO 2005/117553 A2) and Herter-Sprie (Herter-Sprie, Grit S et al. “Activating Mutations in ERBB2 and Their Impact on Diagnostics and Treatment.” Frontiers in oncology vol. 3 86. 23 Apr. 2013, doi:10.3389/fonc.2013.00086).
Cha teaches that HM781-36B (poziotinib) is a novel, small-molecule, irreversible pan HER tyrosine kinase inhibitor (TKI) exhibiting potent inhibition of EGFR, HER2, and HER4. (pg. 2446, left col., first para., Tables 1-3). The reference demonstrates that poziotinib shows strong HER2 directed activity and excellent antitumor efficacy in HER2-dependent xenograft tumors (pg 2447-2448 ,Tables 1, 2, and 3). Cha further discloses that poziotinib exhibits excellent in vitro and in vivo antitumor activity against EGFR-mutant tumor models (Results, pgs. 2447-2451). Although, Cha does not specify specific individual HER2 mutations, including particular exon 20 insertion mutations, the reference teaches poziotinib’s efficacy broadly in HER2-dependent tumors. This does not exclude tumors whose HER2 dependence stems from such mutations.
Cappuzzo teaches diagnostic methods and assay kits for identifying cancer patients likely to benefit from EGFR inhibitor therapy based on biomarker levels in a patient population (Abstract). The reference explicitly teaches that HER2 biomarker status was evaluated in advanced NSCLC patients treated with gefitinib. The reference discloses measuring HER2 gene copy number by FISH, measuring HER2 protein levels by immunohistochemistry, and evaluating mutations in HER2 exon 20 in a cohort of advanced NSCLC patients (pgs. 65-67). These teachings demonstrate that detecting specific HER2 mutations in patient tumor samples, including HER2 20 exon mutations, was known in the art and would have been within the ordinary skill of the artisan seeking to identify HER2 status for improved patient treatment.
Herter-Sprie teaches that HER2 exon 20 insertion mutations represent activating ERBB2 kinase mutations (pg. 3, left col., first para). The reference teaches that these HER2 exon 20 mutations drive ERBB2-dependent oncogenic signaling, and that irreversible ERBB-directed TKIs (such as afatinib) show preclinical and early clinical activity against tumors harboring these specific HER2 exon 20 mutations (pg. 1, first and second para. of Introduction). Herter-Sprie establishes HER2 exon 20 insertion mutations as a recognized HER2 cancer subgroup amenable to treatment with irreversible pan-ERBB inhibitors.
Herter-Sprie teaches that HER2 exon 20 insertion mutations are both responsible for oncogenic signaling and that they are responsive to irreversible ERBB inhibitors. This underscores the suitability of irreversible ERBB inhibitors for targeting tumors harboring such mutations. Cha discloses poziotinib as an especially potent irreversible pan-HER inhibitor suitable for treating HER2-dependent cancer, possessing strong HER2 inhibitory activity and robust antitumor efficacy in HER2-dependent xenograft models. Cha also demonstrates that poziotinib achieves clinically relevant exposure levels in humans, addressing a known limitation of other HER-targeted inhibitors. Cappuzzo further supports the rationale for patient sleeciton because it teaches evaluating HER2 status in advanced NSCLC patients including HER2 exon mutations to guide treatment selection. The art therefore recognized both the clinical relevance of HER2 biomarkers and the feasibility of detecting HER2 mutations in patient tumor samples.
Based on these disclosures, the artisan would have been motivated to evaluate poziotinib in patients whose tumors harbor HER2 exon 20 insertion mutations, as these mutations are recognized HER2-driven tumor subset and poziotinib represents a potent and bioavailable member of the same inhibitor class already shown to be active against such tumors. The art presents a finite and identified field of predictable solutions (irreversible pan-ERBB inhibitors) for treating HER2 exon 20-driven cancers, and poziotinib would have been an obvious candidate to try due to its advantageous pharmacokinetic and pharmacodynamic properties. The above art identifies a promising class of compounds and a recognized molecular target. It would have been obvious to the artisan to try the agent of this class with the best potency and pharmacokinetic properties.
Claims 37 and 42-45 are rejected under 35 U.S.C. 103 as being unpatentable over Cha Cappuzzo and Herter-Sprie in view of Bianco ((Bianco, R et al. “Inhibition of mTOR pathway by everolimus cooperates with EGFR inhibitors in human tumors sensitive and resistant to anti-EGFR drugs.” British journal of cancer vol. 98,5 (2008): 923-30. doi:10.1038/sj.bjc.6604269).
The teachings of Cha, Cappuzzo, and Herter-Sprie are discussed above and are incorporated by reference into this rejection. The combined teachings of the references teach the limitations of instant claim 37. These references do not disclose combination therapies.
Bianco teaches that activation of the mTOR pathway promotes cancer cell proliferation and resistance to EGFR-targeted therapies, identifying mTOR inhibition as a complementary strategy for enhancing EGFR/HER-pathway inhibitors (Abstract). The reference teaches that everolimus is active in both EGFR-sensitive and EGFR-resistant tumor models and can restore or enhance responsiveness to EGFR-directed agents (pg 925, right col, final para). Bianco further teaches that everolimus is orally bioavailable, supporting its use in clinical combination regimens (pg. 924, left col, first para).
The artisan would be familiar with cancer biology, HER-family signaling, and the mechanisms of action of targeted therapeutics, including tyrosine kinase and mTOR inhibitors. The artisan would have experience evaluating preclinical efficacy data and would understand common drug resistance pathways. The artisan would understand the principles of combination therapy and would have experience developing and modifying treatment regimens to target specific disease states commensurate with what is known in the art.
Based on the teachings of the references above, the artisan would have recognized that tumors harboring HER2 exon 20 insertion mutations represent a patient subpopulation expected to respond to irreversible pan-HER inhibition and that poziotinib offers an especially potent means of targeting this biology. The art identifies mTOR signaling as a parallel survival pathway that contributes to reduced responsiveness to HER inhibitors and that inhibiting mTOR with everolimus can enhance and/or restore the antitumor effects of EGFR/HER-directed therapies. Given these complementary mechanisms and the known feasibility of administering both agents orally, the artisan would have viewed combing poziotinib with everolimus as an obvious to try treatment regimen to achieve greater pathway suppression and potentially improved therapeutic outcomes in patients whose tumors harbor HER2 exon 20 mutations.
.
Examiner’s Note
In the interest of compact prosecution the Examiner suggests the following amendment to base claim 37 to remove unnecessary where clauses. Such amendment would more clearly describe the claimed invention. The following is the Examiner’s suggestion: “A method of treating cancer in a subject comprising administering an effective amount of poziotinib to the subject, where the subject has a tumor that has been determined to have one or more HER2 exon 20 mutations selected from the group consisting of A775insV…. And P780insGSP.” Dependent claims should be similarly amended to parallel this concise structure.
Conclusion
No claims are allowed.
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/C.K.E./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625
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