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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 9/30/25 has been entered.
Claims 7 and 18-21 are pending.
Claims 7, 18, and 19 have been amended by Applicant.
Claims 7 and 18-21 are currently under consideration.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This Office Action contains New Rejections.
Rejections Withdrawn
All previous rejections are withdrawn.
New Rejections
Claim Rejections - 35 USC § 103
Claims 7 and 18-21 are rejected under 35 U.S.C. 103(a) as being unpatentable over Reck et al (Clinical Lung Cancer, 2017, 19(3): 213-220) in view of Robichaux et al (Nat Med, 2018, 24(5): 638-646), Heymach et al (Journal of Thoracic Oncology, 2018, 13(10)(OA02.06)S323-S324), Insercji et al (Pneumonol. Alergol. Pol., 2013, 81: 294-297), Chuang et al (Journal of Thoracic Oncology, 2017, 12(5): 833-842), and Ma et al (Biol. Pharm. Bull. 2019, 42: 873-876; 2/22/22 IDS).
Reck et al teaches a method of treating subjects with NSCLC comprising administering to the subjects the VEGFR2 inhibitor ramucirumab in combination with the HER2 and EGFR tyrosine kinase inhibitor (TKI) erlotinib results encouraging clinical activity (Conclusion of Abstract, in particular). Subjects of Reck et al are treatment-naïve metastatic NSCLC patients (right column on page 1526, in particular).
Reck et al does not specifically teach administering the HER2 and EGFR inhibitor poziotinib monohydrochloride to a subject that has been determined to have a CNS metastases. However, these deficiencies are made up in the teachings of Robichaux et al, Heymach et al, Insercji et al, Chuang et al, and Ma et al.
Robichaux et al teaches the majority of patients with NSCLC whose tumors have ‘classical’ sensitizing mutations (including deletions in exon 19) TKIs, such as erlotinib, provide dramatic clinical benefit with an approximately 70% response rate and improved quality of life as compared to being administered chemotherapy alone (page 2, in particular). In contrast, Robichaux et teaches historical data for patients with EGFR exon 20 insertion mutations have shown overall response rates of approximately 3-8% to tyrosine kinase inhibitors (TKIs) such as erlotinib and afatinib and that EGFR exon 20 insertion mutations are found in about 12% of EGFR-mutant NSCLC tumors (page 2, in particular). Robichaux et al further teaches insertions at Exon20 of HER2 and EGFR lead to an active EGFR that is resistance to first generation tyrosine kinase inhibitors (paragraph spanning pages 2-3, in particular) and finds erlotinib does not substantially inhibit p-EGFR (see paragraph spanning pages 3-4 and one of skill in the art would recognize p-EGFR is an indication of activated EGFR, in particular). Robichaux et al further hypothesized, based on the structure of the TKI poziotinib, that poziotinib may effectively bind and inhibit HER2 and EGFR exon 20 insertion mutants (paragraph spanning pages 4-5, in particular). Robichaux et al further teaches poziotinib selectively inhibits HER2 and EGFR exon 20 mutants (page 5 and paragraph spanning pages 6-7, in particular) and inhibited HER2 and EGFR-mutant NSCLC more potently than afatinib (page 6, in particular). Robichaux et al further teaches administration of poziotinib to subjects with NSCLC tumors comprising HER2 or EGFR Exon20 insertions resulted in a reduction in tumor volume and concludes poziotinib inhibits EGFR- and HER2-mutant NSCLC in vivo more potently than afatinib (paragraph spanning pages 6-7 and paragraph spanning pages 7-8, in particular).
Heymach et al teaches both Tyrosine Kinase Inhibitor (TKI)-naïve and TKI-refractory patients with metastatic NSCLC with HER2 or EGFR Exon 20 insertion mutation therapeutically benefit from administration of poziotinib (see Result and Conclusion, in particular).
Insercji et al teaches an NSCLC patient with an exon 20 HER2 insertion mutation and CNS metastases (right column on page 296, in particular).
Chuang et al teaches an NSCLC patient with an exon 20 HER2 insertion mutation and CNS metastases that demonstrated resistance to CNS-active chemotherapy (see Patient 4 at pages 835-836, in particular).
Ma et al teaches d3-poziotinib, the “monohydrochloride salt form” of poziotinib, has a longer half time than poziotinib (Abstract, in particular), which is indicative of d3-poziotinib being more stable than poziotinib (right column on page 875, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of treating subjects having NSCLC harboring an HER2 or EGFR Exon 20 insertion mutation comprising determining whether the subjects have NSCLC harboring an HER2 or EGFR Exon insertion 20 mutation and treating subjects that have NSCLC harboring an HER2 or EGFR Exon insertion 20 mutation by performing the method of Reck et al comprising administering to the subjects a therapeutically effective amount of the VEGFR2 inhibitor ramucirumab in combination with a therapeutically effective amount of the HER2 and EGFR tyrosine kinase inhibitor (TKI) poziotinib of Robichaux et al in place of the HER2 and EGFR TKI erlotinib of Reck et al due to the presence of an HER2 or EGFR Exon 20 insertion mutation because administering poziotinib in place of erlotinib to NSCLC patients of the combined method that have an HER2 or EGFR Exon 20 insertion mutation would predictably provide therapeutic benefit because patients with EGFR exon 20 insertion mutations have historically shown an overall response rates of approximately only 3-8% to TKIs such as erlotinib of Reck et al, Robichaux et al teaches the HER2 and EGFR TKI poziotinib may effectively bind and inhibit HER2 and EGFR exon 20 insertion mutants based on the structure of poziotinib, and Robichaux et al teaches that poziotinib demonstrates therapeutic benefit upon administering poziotinib to subjects with NSCLC with HER2 or EGFR Exon 20 insertion mutation. This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. This is further an example of a simple substitution of one known element (the TKI poziotinib that is particularly effective at treating NSCL in the presence of HER2 or EGFR exon 20 insertion mutations) in place of another (the TKI erlotinib that is not particular effective at treating NSCLC in the presence of EGFR mutations) to yield predictable results (therapeutic benefit upon treating a NSCLC patient with an HER2 or EGFR exon 20 insertion mutation with the TKI poziotinib that is particularly effective at treating NSCL in the presence of HER2 or EGFR exon 20 insertion mutations).
Further, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method wherein (i) the poziotinib is d3-poziotinib and (ii) wherein the subjects are just any subjects having NSCLC harboring a HER2 or EGFR Exon 20 insertion mutation (including TKI-naïve and TKI-refractory metastatic NSCLC subjects of Heymach et al with HER2 or EGFR Exon 20 insertion mutation; including NSCLC patients like the NSCLC patient of Insercji et al with an exon 20 HER2 insertion mutation and CNS metastases; and including NSCLC patient like the NSCLC patient with an exon 20 HER2 insertion mutation and CNS metastases that demonstrated resistance to CNS-active chemotherapy of Chuang et al) because (i) Ma et al teaches d3-poziotinib, the “monohydrochloride salt form” of poziotinib, has a longer half time than poziotinib (Abstract, in particular), which is indicative of d3-poziotinib being more stable than poziotinib; and (ii) the combined method predictable provides therapeutic benefit to subjects having NSCLC harboring an EGFR or HER2 Exon 20 insertion mutation for the reasons stated above. This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. This is further an example of a simple substitution of one known element (d3-poziotinib) in place of another (poziotinib) to yield predictable results (a more stable therapeutic).
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Conclusion
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/SEAN E AEDER/Primary Examiner, Art Unit 1642