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 .
Detailed Action
The Amendments and Remarks filed 4/6/26 in response to the Office Action of 10/8/25 are acknowledged and have been entered.
Claims 7 and 19-21 are pending.
Claim 7 has been amended by Applicant.
Claims 7 and 19-21 are currently under examination.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Rejections Maintained
Claim Rejections - 35 USC § 103
Claims 7 and 19-21 remain 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 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 describes poziotinib as “potently” inhibiting EGFR and HER20 exon 20 insertion mutants (Figure 2, 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 (Figure 3 and paragraph spanning pages 6-7 and paragraph spanning pages 7-8, in particular). See Figure 3b:
PNG
media_image1.png
293
380
media_image1.png
Greyscale
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 “In heavily pre-treated population with EGFR and HER2 exon 20 mutant NSCLC, poziotinib demonstrated encouraging anti-tumor activity activity in both TKI-naïve and -refractory patients, and manageable toxicity profile” at 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.
Response to Arguments
In the Reply of 4/6/26, Applicant indicates that a response rate of 3-8% with a specific chemotherapeutic to first-line therapy cannot be considered as predictable as to the use of other chemotherapy combinations with cancer that is refractory to chemotherapy or radiotherapy, resistant to chemotherapy, or has relapsed. Applicant further indicates the claims are not drawn to d3-pozioitinib. Applicant further cites Xiuning et al and indicates the claims are non-obvious because poziotinib exhibited meaningful CNS activity in patients with EGFR or HER2 exon 20 mutations.
The amendments to the claims and the arguments found in the Reply of 4/6/26 have been carefully considered, but are not deemed persuasive. In regards to the indication that a response rate of 3-8% with a specific chemotherapeutic to first-line therapy cannot be considered as predictable as to the use of other chemotherapy combinations with cancer that is refractory to chemotherapy or radiotherapy, resistant to chemotherapy, or has relapsed, the combined method is not directed a method that demonstrates a response rate of 3-8%.
In regards to the indication the claims are not drawn to d3-pozioitinib, the claims are drawn to “poziotinib monohydrochloride.” The instant specification does not define “poziotinib monohydrochloride” as something that does not encompass d3-poziotinib. Page 6 of the specification defines poziotinib as having the following structure:
PNG
media_image2.png
218
374
media_image2.png
Greyscale
Chart 1 of Ma et al teaches d3-poziotinib as having the above structure with a single hydrochloride:
PNG
media_image3.png
157
264
media_image3.png
Greyscale
Therefore, d3-poziotinib is a claimed “poziotinib monochloride.”
In regards to the citation of Xiuning et al and indication claims are non-obvious because poziotinib exhibited meaningful CNS activity in ZENITH20 Cohorts 1-3 patients with EGFR or HER2 exon 20 mutations, the examiner disagrees. It is first noted that that “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support” (see MPEP 716.02(d)). the ZENITH20 Cohorts 1-3 patients with EGFR or HER2 exon 20 mutations is not limited to patients that are “refractory to chemotherapy or radiotherapy, resistant to chemotherapy, or has relapsed.” In fact, previous treatment with an EGFR or HER2 exon 20 insertion mutation-selective TKI excluded patients from being ZENITH20 Cohorts 1-3 patients (see: https://clinicaltrials.gov/study/NCT03318939). Further, therapeutic benefit from poziotinib in patients with EGFR or HER2 exon 20 mutations is expected because Robichaux et al describes poziotinib as “potently” inhibiting EGFR and HER20 exon 20 insertion mutants (Figure 2, in particular), Robichaux et al teaches that poziotinib demonstrates therapeutic benefit of reduction in tumor volume upon administering poziotinib to subjects with NSCLC with HER2 or EGFR Exon 20 insertion mutation (Figure 3 and paragraph spanning pages 6-7 and paragraph spanning pages 7-8, in particular), and 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 “In heavily pre-treated population with EGFR and HER2 exon 20 mutant NSCLC, poziotinib demonstrated encouraging anti-tumor activity activity in both TKI-naïve and -refractory patients, and manageable toxicity profile” at Conclusion, in particular).
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEAN E AEDER whose telephone number is (571)272-8787. The examiner can normally be reached M-F 9am-6pm 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, Samira Jean-Louis can be reached at (571)270-3503. 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.
/SEAN E AEDER/Primary Examiner, Art Unit 1642
Prosecution Insights