CTNF 18/263,341 CTNF 97575 Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia 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 Election/Restriction Applicant’s election without traverse: 1) Group II invention, drawn to a method of treating a subject for cancer having EGFR mutation; and 2) method species of treating a subject having lung cancer with a P-loop aC-helix compressing (PACC) EGFR mutation, specifically G719A, comprising administering afatinib , a second-generation EGFR inhibitor, in the reply filed on 05/11/2026 is acknowledged. Applicant identified claims 187, 188, 189, 190, 191, and 192 read on the elected invention and species. Claims 117 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention. Claims 196, 197, and 201-208 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species. 12-151 AIA 26-51 12-51 Status of Claims Claims 117, 187-192, 196, 197, and 201-208 are pending in the instant application. Claims 117, 196, 197, and 201-208 are withdrawn. Claims 187-192 are currently under examination. Priority The instant application 18/263,341 filed on 07/27/2023 is 371 of PCT/US2022/014367 01/28/2022, which claims priority benefit of US provisional application No. 63/244,169 filed on 09/14/2021 and 63/143,710 filed on 01/29/2021 . Information Disclosure Statement The information disclosure statements filed 04/11/2024, 06/20/2024, 01/22/2025, 04/14/2025, 07/01/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the reference listed in IDS are being considered by the Examiner. 06-49-06 AIA However, the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered. Claim Objections Claims 187 and 189 are objected to because of following informalities: Claim 187 recites the subject determined to have variety of EGFR mutation. There are no punctuation marks following ii) a T790M-like-3S EGFR mutation and v) a exon 20 far-loop insertion EGFR mutation. Claim 189 recites variety of EGFR inhibitors. The names of EGFR inhibitors should be uniform, lower case or capitalized. “ abivertinib” is recited twice in claim 189. Drawings 06-22 AIA The drawings are objected to because Figs. 1, 2, 3A-B, 4A, 4C, 6A, 7A, 7E, 7G, 8A-D, 8F, and 11 contain text which is unclear or difficult to read . 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. Specification Page 27, [0084], “abivertinib” is recited twice in the same sentence, “In some embodiments, the TKIs are third-generation EGFR TKIs, which include but are not limited to Osimertinib, Nazartinib, Olmutinib, Rocelitinib, Naquotinib, Lazertinib, WZ4002, almonertinib, furmonertinib, abivertinib, alflutinib, mavelertinib, abivertinib , olafertinib, and rezivertinib”. Instant specification contain vast variety of EGFR mutation biomarkers and EGFR inhibitors. The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification. Claim Rejections - 35 USC § 112 07-30-01 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. Claims 187, 188, 189, 190, 191, and 192 are rejected under 35 U.S.C. 112(a) first paragraph, as failing to comply with the enablement requirement. The claims contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims. The specification, while be enabling for method of treating certain cancer with certain EGFR inhibitor in subjects with certain mutation, e.g. afatinib treating non-small cell lung cancer with G719 mutation, etc., does not reasonably provide enablement for treating any cancer with any recited EGFR inhibitor in subjects with variety of EGFR mutations. This is a scope of enablement rejection . To be enabling, the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright , 999 F.2d 1557, 1561 (Fed. Cir. 1993). The determination that "undue experimentation" would have been needed to practice the claimed invention in full scope is not a single, simple factual determination. As stated in the MPEP 2164.01(a), “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." In In re Wands , 8 USPQ2d 1400 (1988), factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have need described. They are: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. Keeping that in mind, the Wands factors are relevant to the instant application for the following reasons: The Breadth of The Claims/ Nature of The Invention Instant claims are directed to method of treating cancer with variety of EGFR inhibitors in patients with vast variety of mutations, while the first-generation, second-generation or third generation EGFR inhibitors have different chemical structures, different pharmacological activity/ efficacy and different toxicological profile. The cancer of claim 187 is construed under BRI as any cancer that has different etiology, symptoms, different treatment mechanism and targeted outcome, etc. Claim 187 and 190 recite subject with vast variety of mutations. The nature of instant invention is method of treating variety of cancers with vast variety of agents in variety of subjects, thus, the scope of instant claims are extremely broad. The State of the Prior Art and the Predictability or Lack Thereof in the Art It is well known that treating cancer is highly unpredictable, especially for subjects with mutations. Different cancer/tumor has different etiology, symptoms, different treatment mechanism and targeted outcome, etc. The efficacies of treating cancer vary greatly due to a lot factors including the subjects to be treated, the structures/ physical properties of the agents, mechanism of action, delivery route, dosage regimen, etc. Activity by in-vitro experiment does not necessarily translate into efficacy in animals and/or humans. The in-vitro efficacy at certain dosage regimen might lead to toxicologic effect in in-vivo study. When agents display in-vitro activity, the efficacy/effectiveness of treatment needs to be evaluated/validated through animal study and/or clinical study to provide accurate evidence for effective and safe treatments in mammals /human which are not disclosed in instant specification. With respect to treating lung cancer in patient with mutations, EGFR mutations in lung cancer are extremely complicated and each mutation appears to have unique characteristics. Kobayashi (2016, submitted by Applicant on 03/08/2024) teaches not all EGFR mutations in lung cancer are equal and different subjects respond differently to different EGFR-tyrosine kinase inhibitors (See Table 1-4): Targeted therapy for these lung cancers has been established based on evidence regarding mainly common mutations; that is, exon 19 deletions (Del19) and L858R. EGFR-tyrosine kinase inhibitors (TKI), gefitinib, erlotinib or afatinib showed high objective response rates (ORR) of approximately 60%. On the other hand, it has been difficult to establish evidence for other less common mutations, accounting for 12% of all EGFR mutations, because there are many variants and many studies have excluded patients with these uncommon mutations. However, recent studies revealed that these rare genotypes could be targetable if appropriate TKI are selected. For example, G719X (X denotes A, S, C and so on), Del18, E709K, insertions in exon 19 (Ins19), S768I or L861Q showed moderate sensitivities to gefitinib or erlotinb with ORR of 30%– 50%. However, afatinib appeared to be especially effective for these tumors. It is important to precisely detect targetable mutations, to select the most appropriate TKI for each mutation, and to continue investigating in vitro studies and collecting clinical data on even rare mutations” (See Abstract). Russo (2019, submitted by Applicant on 03/08/2024) teaches heterogeneous responses to EGFR Tyrosine Kinase Inhibitors (TKIs) in patients with uncommon EGFR mutations: “the sensitivity of uncommon EGFR mutations to the different classes of EGFR TKIs may significantly vary, since some have increased sensitivity to second-generation EGFR TKIs (i.e., exon 18 mutations and S768I exon 20 point mutation), whereas others are unresponsive to first-/second-generation EGFR TKIs, but sensitive to mutant-selective EGFR inhibitors, such as osimertinib and poziotinib (i.e., exon 20 insertions). The highly heterogeneous nature of these mutations, encompassing the complete spectrum of sensitivity to EGFR TKIs, suggests that each of these rare variants should be analyzed separately in clinical studies and that clinical recommendations should be made on a case-by-case basis” (See whole article, Conclusion, Abstract, Table 1-4). More generally, the invention is directed toward medicine and is therefore physiological in nature. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity (e.g., cancer prevention) is generally considered an unpredictable factor. See In re Fisher , 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The Amount of Direction Present and Presence or Absence of Working Examples The specification does not provide sufficient guidance/protocols for a skilled artisan to practice the claimed method of treating cancer that have different etiology/mechanisms, symptoms/signs, different mutations, etc. with any recited EGFR inhibitor in its full scope . Instant specification disclose tumor DNA mutation detection and classification of EGFR mutation, especially non-small cell lung cancer, into groups. Instant specification discloses responses/sensitivity profile of cells with EGFR mutation to certain EGFR inhibitor, e.g. gefitinib, afatinib, etc. (See Table 1 to 5) and selection of the TKIs treatment based on the response profile. However, EGFR mutations in NSCLC are highly diverse as shown in instant specification, and many mutations do not have positive response to the TKIs to be established as effective treatment. For example, instant Table 5 discloses response of cells comprising PACC EGFR mutations to first, second and third generation of TKIs, while some TKIs are ineffective. Due to the high unpredictably of treating cancer in subjects with different mutations, instant specification does not support instant claimed of method of treating cancer in subjects with vast variety of EGFR mutation in full scope. The level of one of ordinary skill in the art The level of skill required to make and/or use the instant invention would likely require many years of professional experience conducting research in the art (e.g., medicine, pharmaceutical science, biology, biochemistry, medicinal chemistry, etc.) as well as an advanced educational degree (e.g., M.D. and/or Ph.D.) commensurate in level with the advanced techniques involved in the preparation and/or use of the instant invention. The quantity of experimentation needed An unduly extensive amount of experimentation would be required for one of ordinary skill in the art to develop protocols for the claimed method of treating cancer that have different etiology/mechanisms, symptoms/signs, etc. with any instantly claimed EGFR inhibitor in subjects with vast variety of mutations . Working examples would be needed to determine the therapeutically effective dose for different type of cancer with different agent in different subjects with different mutations. The therapeutically effective amount may vary depending on many factors, such as the subjects being treated , the efficacy of the agent, administration route, the disease condition and intended treatment income, etc. The specific dosage may vary depending on the agent selected, the dosing regimen to be followed, administration route, the toxicological profile, etc. Therefore, it would be a great burden for one of ordinary skill in the art to carry out undue experimentation to use the claimed invention for claimed method of treating a variety of cancers with vast variety of agents in patients with variety of mutations in full scope. Conclusion MPEP 2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright , 999 F.2d 1557,1562,27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here with respect to the claimed method of treating cancers with variety of agents in subjects with variety of mutations in full scope, in view of the analysis above pursuant to In re Wands . In other words, one skilled in the art could not practice the claimed invention without undue experimentation. The following is a quotation of 35 U.S.C. 112(b): (b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention. Claim 188 is rejected under 35 U.S.C. 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 188 recites an EGFR inhibitor specific to mutations associated with EGFR exon 20. The limitation “specific to mutations associated with EGFR exon 20” is indefinite. An ordinary skilled in the art would not know what EGFR inhibitor is determined to be specific to EGFR exon 20 mutation in absence of efficacy data, thus the boundaries of the claim scope is unclear . Claim Rejections - 35 USC § 102 07-06 AIA 15-10-15 In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status. 07-07-aia AIA 07-07 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 – 07-08-aia AIA (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. 07-12-aia AIA (a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention. 07-15 AIA Claim s 187-192 are rejected under 35 U.S.C. 102( a)(1 ) as being anticipated by Robichaux et al. (hereafter “ Robichax 2018 ”, Nature medicine, 2018, 24(5), pp.638-646, submitted by Applicant on 03/08/2024, “Mechanisms and clinical activity of an EGFR and HER2 exon 20–selective kinase inhibitor in non–small cell lung cancer”) . Robichax 2018 discloses a method of treating cancer (e.g. non–small cell lung cancer) in a subject comprising administering EGFR inhibitors ( poziotinib or afatinib) to the subject, wherein the subject has been determined to have one or more EGFR exon 20 insertion mutations (See whole article; abstract; page 4-5, section “Poziotinib is a potent inhibitor of EGFR and HER2 exon 20 insertion mutants in vitro” ). Regarding limitation of P-loop a-C helix, Robichax 2018 teaches exon 20 of EGFR contains two major regions, the a-C helix (residues 762-766 in EGFR) and the loop following the a-C helix (residues 767-774 in EGFR), and shifts of phosphate-binding loop P-loop and the a-C helix into the binding pocket result in steric hindrance, reducing the size of the binding pocket in EGFR and HER2 exon 20 mutants (See page 4, EGFR and HER2 exon 20 insertion mutations cause steric hindrance of the drug-binding pocket; Figure 1). Robichax 2018 also teaches other EGFR mutations (See page 17-18, Fig 1b, Fig. 2). Regarding afatinib , Robichax 2018 teaches “Consistent with results from our aforementioned in vitro testing, 3D modeling supported the observation that afatinib inhibits exon 20 insertions more effectively than osimertinib... afatinib has a smaller 1-chloro-2-flurobenzene ring terminal group indirectly linked to a quinazoline core via a secondary amine group, enabling afatinib to fit into the sterically hindered binding pocket ( See page 4, EGFR and HER2 exon 20 insertion mutations cause steric hindrance of the drug-binding pocket ). Robichax 2018 teaches cell viability of afatinib and poziotinib on cell lines with EGFR A767dupASV and EGFR N771delinsFH (See page 18, Fig. 2). Regarding poziotinib , Robichax 2018 teaches poziotinib inhibits EGFR- and HER2-mutant NSCLC in vivo more potently than afatinib, wherein poziotinib (10mg/ kg) and afatinib (20 mg/kg) administered to mice with lung tumors harboring EGFR D770insNPG ( See page 6,last para). Robichax 2018 teaches poziotinib reduced tumor by 50%-56% in xenograft model of a patient-derived cell line harboring an EGFR N771 delinsFH mutation, >85% in the PDX model LU0387 bearing an EGFR H773insNPH exon 20 insertion ( page 6, last para, Fig.2, 3g, 3h; page 7, first para). Robichax 2018 teaches poziotinib is a clinically active inhibitor of NSCLC with EGFR exon 20 mutations (NCT03066206) (See page 7, 3rd para). Robichax 2018 teaches poziotinib is a relatively selective inhibitor of EGFR exon 20 mutants over EGFR T790M mutants, wherein poziotinib was 65 times more potent in inhibiting cell lines with EGFR exon 20 insertions than EGFR T790M mutant cell lines (See page 5; page 9, 2 nd para). Robichax 2018 teaches “poziotinib demonstrated greater activity than approved EGFR TKls in vitro and in patient-derived xenograft models of EGFR or HER2 exon 20 mutant NSCLC and in genetically engineered mouse models of NSCLC. In a phase 2 trial, the first 11 patients with NSCLC with EGFR exon 20 mutations receiving poziotinib had a confirmed objective response rate of 64%. These data identify poziotinib as a potent, clinically active inhibitor of EGFR and HER2 exon 20 mutations and illuminate the molecular features of TKls” (See abstract; page 9, 3 rd para). Robichax 2018 teaches a method of treating non-small cell cancer with EGFR inhibitors (afatinib and poziotinib) in subjects with exon 20 mutations. Thus, Robichax 2018 anticipates instant claimed invention . 07-15 AIA Claim s 187-192 are rejected under 35 U.S.C. 102( a)(1 ) as being anticipated by Yang et al. (Journal of Thoracic Oncology, 2020; 15, 803-815, https://doi.org/10.1016/j.jtho.2019.12.126 Afatinib for the Treatment of NSCLC Harboring Uncommon EGFR Mutations: A Database of 693 Cases) . Yang reviews clinical data for EGFR tyrosine kinase inhibitors (EGFR TKIs) (e.g. afatinib) in patients with NSCLC harboring uncommon EGFR mutations categorized as (1) T790M; (2) exon 20 insertions; (3) “major” uncommon mutations (G719X, L861Q, and S768I, with or without any other mutation except T790M or an exon 20 insertion); (4) compound mutations; and (5) other uncommon mutations (See whole article, Abstract, Results, Table 2 and 3, Figure 2). Yang teaches afatinib demonstrated clinical activity across a broad range of uncommon mutations including E709_T710>D, E709X, T725M, V717A, K739_I744dup6, L747_P753>Q, L747P, Q787Q, R776H, V765M, L861P, L858M, H870R, and Exon21Del that are documented in database(See page 807, right column, first para, Supplementary Table 1). Yang and incorporated reference teaches afatinib demonstrated durable responses in some patients with certain exon 20 insertions, e.g. A767delinsASVD39 and A767_S768insSVA (See page 807, right column; page 811, left column ). Yang teaches activity of afatinib observed in patients with NSCLC tumors harboring a major uncommon mutation is consistent with findings from the LUX-Lung trials, wherein the response rate in patients with NSCLC tumors harboring G719X (n = 18), L861Q (n= 16), and S768I (n= 8) was 77.8%, 56.3%, and 100.0%, respectively...(See, page 808, right column; Table 2 and 3, Figure 2). Yang concludes afatinib has clinical activity in NSCLC against major uncommon EGFR mutations and broad activity against other uncommon EGFR mutations and some exon 20 insertions (See page 804, left column, first and second para). Thus, Yang anticipates instant claimed invention . 07-15 AIA Claim s 187-192 are rejected under 35 U.S.C. 102( a)(1) and (a)(2 ) as being anticipated by Robichaux et al. ( WO2018094225A1, hereafter “ Robichax ’225 ”, family member of US11446302B2) . Robichax ’225 discloses a method of treating cancer (e.g. non-small cell lung cancer ) in a subject comprising administering an effective amount of third-generation tyrosine kinase inhibitor (afatinib or poziotinib) in a patient determined to have one or more EGFR exon 20 mutations (See abstract, [0007], [0012]-[0013], [0075], Figures 1-10; claims 1-78). Robichax ’225 teaches the activity of afatinib and poziotinib on different cell lines with variety of mutation, e g. EGFR D770insNPG, EGFR N771del insFH, etc. (See [0027]-[0029], Figs 2- 10). Robichax ’225 teaches exon 20 of EGFR and HER2 contains two major regions, the c -helix (residues 762- 766 in EGFR and 770-774 in HER2) and the loop following the c-helix (residues 767- 774 in EGFR and 775-783 in HER2), and shifts of the P- loop and the α-c-helix into the binding pocket result in an overall reduction in the size of the binding pocket (See [0006], [0026]) . Regarding instant claim 190, Robichax ’225 discloses one or more exon 20 mutations, e.g. A763, A767, S768 , V769, D770, N771, P772, A763insFQEA, A767insASV, S768dupSVD, V769insASV, D770insSVD, D770insNPG, H773insNPH, N771del insGY, N771del insFH, and N771dupNPH(See [0008], [0012], claim 5 and 7). Regarding claims 191 and 192, Robichax ’225 teaches the cancer is non-small cell lung cancer (See [0017], claims 18 and 52) Robichax ’225 teaches a method of treating cancer (e.g. non-small cell lung cancer ) with EGFR inhibitors (afatinib or poziotinib) in subjects with EGFR exon 20 mutations. Thus, Robichax ’225 anticipates instant claimed invention. Claim Rejections - 35 USC § 102/103 07-06 AIA 15-10-15 In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status. 07-07-aia AIA 07-07 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 – 07-08-aia AIA (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. 07-12-aia AIA (a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention. 07-20-aia AIA 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. 07-23-aia AIA 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. 07-20-02-aia AIA This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention. 07-15 AIA Claim s 187-192 are rejected under 35 U.S.C. 102 ( a)(1) and (a)(2 ) as being anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Robichaux et al. ( WO2018094225A1, “ Robichax ’225 ”, family member of US11446302B2) . The collective teachings of Robichax ’225 are elaborated in previous 102 rejections and applied as before. Robichax ’225 teaches a method of treating cancer (e.g. non-small cell lung cancer ) with EGFR inhibitors (afatinib or poziotinib) in subjects with EGFR exon 20 mutations. Even if instantly recited mutation in claim 190 are slight different from Robichax ’225 , the differences between what is disclosed in prior art and what is claimed are considered to be obvious within the meaning of 103 rejection. Please note the biological activity of compound is the property of active compound and products of identical or similar composition cannot exert mutually exclusive properties when administered under the same or similar circumstances. If the prior art teaches and/or suggests the same or similar method step as instantly claimed (i.e. administering an effective amount of an EGFR inhibitor to a subject in need of cancer treatment), the method of the prior art would have achieved instant intended results if instant claimed method works as claimed . It’s common practice to explore an effective drug in different patient populations. In search for more effective treatment for non-small cell lung cancer tumors, a skilled artisan would be motivated to explore and identify different mutations in different subjects based on combined beneficial teachings of prior art and general knowledge of cancer treatment. Accordingly, the claimed invention as a whole was at least prima facie obvious, if not anticipated by the cited reference, especially in the absence of sufficient, clear, and convincing evidence to the contrary. The burden of proof is shifted to the Applicant to show that the subject matter of the prior art does not possess the characteristic relied on whether the rejection is based on inherency under 35 U.S.C.102 or obviousness under 35 U.S.C. 103. Double Patenting 08-33 AIA The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg , 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman , 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi , 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum , 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel , 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington , 418 F.2d 528, 163 USPQ 644 (CCPA 1969). A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b). The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13. The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA/25, or PTO/AIA/26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer. Claims 187-192 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 11446302 B2. Reference claims are directed to a method of for treating cancer in a subject comprising administering an effective amount of poziotinib to the subject, wherein the subject has a tumor that has been determined to have one or more EGFR exon 20 insertion mutations. Reference claims 2-6 recite subjects determined to have variety of EGFR mutation exon 20 insertion mutation, e.g. A763, A767, S768, V769, D770, N771, P772, and H773, A763insFQEA, A767insASV, S768dupSVD, V769insASV, D770insSVD, D770insNPG, H773insNPH, N771del insGY, N771del insFH, and N771dupNPH. Reference claim 15 recites non-small cell lung cancer. Poziotinib is a EGFR inhibitor treating non-small cell lung cancer in subjects with exon 20 mutations. Thus, reference claims anticipates instant claimed invention. Although poziotinib is not recited in instant claim 189, the disclosure of U.S. Patent No. 11446302 B2 disclosed method of treating cancer in a patient comprising administering an effective amount of poziotinib or afatinib to the subject, wherein the subject has been determined to have one or more EGFR and/or HER2 exon 20 mutations, such as an insertion mutation (See abstract, Col. 3, line 67, etc.). As stated in MPEP 804(II)(B)(1): “those portions of the specification which provide support for the reference claims may also be examined and considered when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the reference patent or application (as distinguished from an obvious variation of the subject matter disclosed in the reference patent or application). In re Vogel, 422 F.2d 438, 441-42, 164 USPQ 619, 622 (CCPA 1970).” The instant application shares at least one common inventor/applicant with the reference patent. , and no 35 USC 121 shield exists. Claims 187-192 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6-9, 14, 19, 30, 35-36, 38-39, 54-55 and 84 of copending U.S. application No. 17/604,560, in view of Robichaux et al. ( WO2018094225A1, “ Robichax ’225 ”). Although the claims at issue are not identical, they are not patentably distinct from each other Reference claims are directed to a method of treating cancer in a subject comprising administering an effective amount of poziotinib to the subject, wherein the subject has been determined to have one or more epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistant mutations, wherein the one or more EGFR TKI resistant mutations comprise: (a) one or more point mutations, insertions, and/or deletions of 3-18 nucleotides between amino acids 688-728 of exon 18;(b) one or more EGFR exon 19 mutations located at one or more residues selected from the group consisting of I744, L747, K754, A755, K757, and/or D761;(c) one or more EGFR exon 20 mutations located at one or more residues selected from the group consisting of C775, S784, L792, G796, and S811; or (d) one or more EGFR exon 21 mutations located at one or more residues selected from the group consisting of L833, V834, G836, T854, L861, L862, L844 and L858, Reference claims 6-9 and 14 recite EGFR mutation that read on classical-like mutation. Reference claim 19 recite one or more EGFR exon 20 mutations, Reference claim 30 and 35 recites the subject has a G719A mutation (that reads on instant elected species). Reference claim 55 recites non-small cell lung cancer. Poziotinib is a EGFR inhibitor treating non-small cell lung cancer in subjects with and classical-like and exon 20 mutations. Thus, reference claims anticipates instant claims 187-188, 190-192. Although poziotinib is not recited in instant claim 189, Robichax ’225 teaches method of treating cancer (e.g. non-small cell lung cancer ) with EGFR inhibitors (afatinib or poziotinib) in subjects with EGFR exon 20 mutations. It would have been obvious to one of the ordinary skilled in the art to further explore afatinib for treating cancer (e.g. non-small cell lung cancer with mutations based on the combined teachings of reference claims and Robichax ’225. A skilled artisan would be motivated to do so with reasonable expectation of success because Robichax ’225 teaches method of treating cancer (e.g. non-small cell lung cancer ) with afatinib or poziotinib in subjects with EGFR exon 20 mutations. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. Claims 187-192 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 10, 12, 14-15, 17, 19, 49 and 50 of copending U.S. application No. 17/604,689. Although the claims at issue are not identical, they are not patentably distinct from each other Reference claims are directed to a method of treating cancer in a subject comprising administering an effective amount of a quinazolinamine derivative tyrosine kinase inhibitor (TKI) to the subject, wherein the subject has been determined to have one or more epidermal growth factor receptor (EGFR) TKI resistant mutations,... (c) one or more EGFR exon 20 mutations located at one or more residues selected from the group consisting of A763, S768, H773, D770, C775, L792, G796, C797, S811, and R776, or wherein the one or more EGFR exon 20 mutations are selected from the group consisting of A763insLQEA, C775Y, and H773insAH... Regarding instant claim 189, reference claim 6 recites quinazolinamine TKI is sapatinib, AZD3759, Varlitinib, TAK-285, or gefitinib . Regarding instant claims 191 and 192, reference claim 50 recites non-small lung cancer. Reference claims teaches a method of treating non-small cell lung cancer with TKIs (e.g. gefitinib) in subjects with exon 20 mutations. Thus, reference claims anticipates instant invention. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. Claims 187-192 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 31-40, 42 and 52 of copending U.S. application No. 18/263,340, in view of Robichaux et al. ( WO2018094225A1, “ Robichax ’225 ”). Reference claims are directed to a method of treating a subject for cancer, the method comprising administering an effective amount of poziotinib to a subject determined, from analysis of tumor DNA from the subject, to have: i) a classical-like EGFR mutation; ii) a exon 20 near-loop insertion EGFR mutation; or iii) a P-loop αC-helix compressing EGFR mutation. Reference claim 34 recites non-small cell lung cancer that read on instant claims 191and 192. Reference claim 32 recites classical-like EGFR mutation, Reference claims 42 and 52 recite exon20 near loop insertion EGFR mutation and P-loop αC-helix compressing EGFR mutation that read on instant claim 190. Poziotinib is a EGFR inhibitor treating non-small cell lung cancer in subjects with and classical-like and exon 20 mutations. Thus, reference claims anticipates instant claims 187-188, 190-192 . Although poziotinib is not recited in instant claim 189, Robichax ’225 teaches method of treating cancer (e.g. non-small cell lung cancer ) with EGFR inhibitors (afatinib or poziotinib) in subjects with EGFR exon 20 mutations. It would have been obvious to one of the ordinary skilled in the art to further explore afatinib for treating cancer (e.g. non-small cell lung cancer) with mutations based on the combined teachings of reference claims and Robichax ’225. A skilled artisan would be motivated to do so with reasonable expectation of success because Robichax ’225 teaches method of treating cancer (e.g. non-small cell lung cancer ) with afatinib or poziotinib in subjects with EGFR exon 20 mutations. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. Conclusion No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LIYUAN MOU whose telephone number is (571)270-1791. The examiner can normally be reached Mon-Fri 9:00-5:30. 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, Amy L Clark can be reached on (571)272-1310. 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. /L.M./Examiner, Art Unit 1628 /JARED BARSKY/Primary Examiner, Art Unit 1628 Application/Control Number: 18/263,341 Page 2 Art Unit: 1628 Application/Control Number: 18/263,341 Page 3 Art Unit: 1628 Application/Control Number: 18/263,341 Page 4 Art Unit: 1628 Application/Control Number: 18/263,341 Page 5 Art Unit: 1628 Application/Control Number: 18/263,341 Page 6 Art Unit: 1628 Application/Control Number: 18/263,341 Page 7 Art Unit: 1628 Application/Control Number: 18/263,341 Page 8 Art Unit: 1628 Application/Control Number: 18/263,341 Page 9 Art Unit: 1628 Application/Control Number: 18/263,341 Page 10 Art Unit: 1628 Application/Control Number: 18/263,341 Page 11 Art Unit: 1628 Application/Control Number: 18/263,341 Page 12 Art Unit: 1628 Application/Control Number: 18/263,341 Page 13 Art Unit: 1628 Application/Control Number: 18/263,341 Page 14 Art Unit: 1628 Application/Control Number: 18/263,341 Page 15 Art Unit: 1628 Application/Control Number: 18/263,341 Page 16 Art Unit: 1628 Application/Control Number: 18/263,341 Page 17 Art Unit: 1628 Application/Control Number: 18/263,341 Page 18 Art Unit: 1628 Application/Control Number: 18/263,341 Page 19 Art Unit: 1628 Application/Control Number: 18/263,341 Page 20 Art Unit: 1628
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