DETAILED ACTION
This office action is in response to applicant’s filing dated March 19, 2026.
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 allowance or after an Office action under Ex Parte Quayle, 25 USPQ 74, 453 O.G. 213 (Comm'r Pat. 1935). 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, prosecution in this application has been reopened pursuant to 37 CFR 1.114. Applicant's submission filed on March 19, 2026 has been entered.
Status of claims
Claims 6 - 24 are pending in the instant application. Acknowledgment is made of Applicant’s amendments filed March 19, 2026. Acknowledgment is made of Applicant’s addition of new claims 20 – 24.
Priority
The present application was filed on April 18, 2023 and claims the benefits of priority of U.S Provisional Application No. 63/484,135, filed February 9, 2023 and U.S. Provisional Application No. 63/363,296, filed April 20, 2022.
Claim Rejections - 35 USC § 103
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.
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.
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.
Claims 6 - 24 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al (US 8,748,453 B2, hereinafter Zhang) in view of Heigener et al (The Oncologist 2015;20:1167–1174, hereinafter Heigener).
Regarding claims 6, 9, 10, 18 and 19 - 24, drawn to a method for treating a non-small cell lung cancer (NSCLC), characterized by a presence of a rare EGFR mutation such as L861Q, G719X, or S768I, or any combination thereof, comprising: administering to a subject in need thereof a therapeutically effective amount of a compound (E)-N-(3-cyano-7- ethoxyl-4-(3-ethynylphenylamino)quinoline-6-yl)-4-(dimethylamino)but-2-enamide (
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(specification page 3, [0012])) maleate, or a solvate thereof. The compound, shown above, can be also taken in the form of a hemihydrate or monohydrate. Additionally, the said method is useful for treatment of non-small cell lung cancer where the rare EGFR mutation further comprises an additional rare EGFR mutations such as an EGFR exon 20 mutation of S768I or T790M, and where the additional rare EGFR mutations is other than exon 19 deletion and L858R mutation. The compound of instant claims acts as tyrosine kinase inhibitor (EGFR-TKI).
Zhang teaches methods for treating or preventing an EGFR and/or ErbB2 mediated disorder or treating neoplasia, comprising administering to a mammalian subject in need thereof a therapeutically effective amount of a compound of (C)
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and where the neoplasia is a non-small cell lung cancer (column 8, line 46). The method, taught by Zhang, utilizes compound (C) in the form of pharmaceutically acceptable salt, wherein the salt is formed by reacting the free base form of the compound with a pharmaceutically acceptable organic acid, such as maleic acid (column 10, lines 19 – 23) (Examiner notes: salt of maleic acid is called maleate), as well as in the form of a solvate (column 8, lines 7 – 12). Similarly, the compound (C) can be taken in the forms of hemi- or monohydrate of the compounds, salts and derivatives thereof (column 10, lines 57 – 59).
Zhang teaches method for treating non-small cell lung cancer, where the compound (C) irreversibly inhibits a number of mutants of tyrosine kinase epidermal growth factor receptors (column 8, lines 63 – 65), and is useful in treatment of any tumor or cancers having one or more mutations in EGFR (column 14, lines 1 - 2). Zhang represents experimental data of effectiveness of compound (C) on NCI-H1975 cell line (lung adenocarcinoma), expressing the EGFR mutant L858R and T790M (column 33, lines 61 – 62). Thus, the method, taught by Zhang is applicable for treatment of EGFR mutation-mediated non-small cell lung cancer, where cancer has one or more mutations in EGFR gene, and where the drug (Sutetinib), used in said method, inhibits a number of mutants of tyrosine kinase epidermal growth factor receptors (e.g., erbB1, erbB2, erbB3 and erbB4).
Zhang does not explicitly teach the method for treatment of non-small cell lung cancer characterized by a presence of L861Q, G719X, or S768I EGFR mutations, or any combination thereof, or additional EGFR mutation, such as exon 20 mutations (e.g. S768I or T790M).
However, Heigener teaches a method for treatment of non-small cell lung cancer patients with uncommon EGFR mutations, using irreversible ErbB family (ErbB1 (EGFR), ErbB2 (HER2) and ErbB4) blocker afatinib (page 1167, summary). The patients with uncommon EGFR mutations carried: T790M mutations (T790M alone, T790M plus exon 19, T790M plus exon 21) G719X mutations ( G719A, G719C, G719S, G719A plus E709A, G719C plus E709A, G719C plus L861Q), L861Q mutations (alone, plus T790M and each one plus G719C or L858M), E709X mutations (E709K plus L858R, E709A plus G719X), and insertions in exon 20. Further mutations included A702S, A750V, deletion and insertion (delins) exon 19, G753S, point mutation exon 19, S768I plus V769L, R776H plus L858R, L858M, L858M plus L861Q, G857E, and G861L plus T790M (page 1168, “Uncommon EGFR Mutations” and page 1170, Fig. 1). The study demonstrated that afatinib is clinically active in patients with NSCLC harboring uncommon EGFR mutations. Afatinib features acrylamide group in the molecule, which group allows afatinib to irreversibly bind specific residues in EGFR, in contrast to gefitinib and erlotinib. Afatinib is a structural analog of instantly claimed Sutetinib.
Thus, since Zhang teaches a method for treatment non-small cell lung cancer (NSCLC) mediated by one or more mutations in EGFR with a compound (C) (Sutetinib), where the compound (C) inhibits a number of mutants of tyrosine kinase epidermal growth factor receptors, and since Heigener teaches a method for treatment of patients suffering from non-small cell lung cancer, harboring uncommon EGFR mutations, such as G719X, L861Q, and S768I or combination thereof with structural analog afatinib, where afatinib demonstrated efficacy in treatment of patients with uncommon mutations, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present invention to try to apply a known in the art drug, acting as irreversible EGFR-TKI, and useful in treatment of NSCLC with one or more mutation in EGFR to the method of treatment of patients suffering from NSCLC with rare EGFR mutations, since the prior art teaches its known structural analog is an effective agent in targeted therapy of non-small cell lung cancer patients with uncommon EGFR mutations. The one of ordinary skills would be motivated to do so in search of an effective method for treatment of patients harboring rare EGFR mutations with the reasonable expectation of success.
Regarding claims 7, 8 and 11 – 17, drawn to a method, where the therapeutically effective amount is from 50 to 250 mg per day; or wherein the therapeutically effective amount is about 100 mg per day; wherein the therapeutically effective amount is daily dose/body weight from 0.01 to 500 mg/kg; or wherein the therapeutically effective amount is daily dose/body weight from 0.01 to 50 mg/kg; or wherein the therapeutically effective amount is daily dose/body weight from 0.01 to 30 mg/kg or daily dose/body weight from 0.01 to 10 mg/kg or daily dose/body weight from 0.5 to 3 mg/kg, and wherein the administering comprises administering about 100 mg of the compound or the solvate thereof daily, for 28 days.
The method, taught by Zhang, proposes the daily dose of about 0.01 to 500 mg/kg, advantageously between about 0.01 and about 50 mg/kg, more advantageously about 0.01 and about 30 mg/kg, even more advantageously between about 0.1 and about 10 mg/kg, and even more advantageously between about 0.25 and about 1 mg/kg body weight. The daily dose can be administered in one to four doses per day (column 15, lines 43 – 51), wherein formulations for oral administration such us tablets or capsules contain an amount of active ingredient from about 1 to 2000 mg, advantageously from about 1 to 500 mg, and typically from about 5 to 150 mg (column 17, lines 33 – 41). All the dosages of instant claims are within the ranges or overlapping with dosages, taught by Zhang. MPEP 2144.05 states: In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Even a slight overlap in range establishes a prima facie case of obviousness. In re Peterson, 65 USPQ2d 1379, 1382 (Fed. Cir. 2003).
With regards to the limitation claimed in instant claim 17 which claims administering about 100 mg of the compound or the solvate thereof daily, for 28 days. Zhang does not specifically teach the exact duration of administration of the drug claimed in instant claim 17. However, it would be within the skill of an ordinary artisan to be able to modify the duration of drug administration in order to obtain the desirable therapeutic effect. It is noted that "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Therefore, taking all together, taught by prior art, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made,
as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant argues:
- the Office failed to address at least the following arguments presented by Applicant: combining the teaching of Zhang and Chiu requires the presence of efficacy data of Sutetinib against rare EGFR mutations. Cancer treatment is complex and unpredictable; possible EGFR mutants are in the thousands, if not in the millions; each mutant may have different protein structure; and many attributes of an experimental drug or its intended biological target (metabolism of the drug, off-target effects, (toxicity), adverse side effects, or resistant mutations of the target) can derail a successful clinical trial for the experiment drug to treat the target disease. Thus, a person skilled in the art cannot simply substitute one drug for another sua sponte to treat a cancer disease with a reasonable expectation of success absent considerable trial-and-error research confirming the clinical efficacy of the experiment drug against the targeted cancer disease.
- According to the declaration Dr. Dawei ZHANG, in terms of possible EGFR mutations, the core tyrosine kinase domain (having approximately 188 amino acids) of the EGFR protein may allow "3,572 distinct possible single amino acid substitution variants" or "over 6.3 million distinct double substitution variants" within the kinase domain alone. Applicant submits that the "obvious to try" rationale does not apply to claims 6-19 of the present application since there are not a finite number of solutions to apply the method of Zhang.
- It is unquestioned with clear and convincing evidence that a drug's success in treating one type of cancer (e.g., NSCLC mediated by the T790M mutation) does not necessarily translated to success in treating a different type of cancer (e.g., NSCLC mediated by other EGFR mutations including rare EGFR mutations) due to the fact that EGFR mutations exhibit mutation-specific structural and functional differences. Thus, NSCLC mediated by the T790M mutation is a different disease from NSCLC mediated by other EGFR mutations, therefore, drug that is effective to treat one type of EGFR mutation in NSCLC may be ineffective to treat another type of EGFR mutation in NSCLC.
- The status of some TKIs that are effective against T790M mutation in cell-based assays, but failed to show clinically acceptable efficacy and safety against PACC (e.g. L861Q, G719X, or S768I) mutations in patients; and that have been discontinued, shown in Table 1 (Remarks, page 11). This is another clear and convincing evidence to show the unpredictability in finding effective clinical compounds against rare EGFR mutants in patients.
- Sutetinib demonstrated unexpected, durable antitumor activity and acceptable toxicity in patients with NSCLC harboring EGFR mutations G719X, S768I, and/or L861Q in open-label Phase II clinical trial after administering oral Sutetinib monotherapy at 80 or 64 mg/day (Chinese trial register CTR20190681)".
- The evidence to support an alleged obviousness rejection should come from the closest prior art embodiment existing in the prior art, not the hindsight gained from the disclosure found in the specification of the present application.
Examiner’s response:
Applicant's arguments and the Declaration of Dr. Zhang have been fully considered but they are not persuasive because: as set forth above, the prior art reference of Zhang, applied in the rejection, teaches the method for treatment of NCSLC, mediated by mutations in EGFR with the drug Sutetinib, acting as EGFR-TKI, where, according to the reference, the drug is effective against a number of mutants of tyrosine kinase epidermal growth factor receptors. Thus, Zhang teaches Sutetinib effectively inhibits multiple mutants of EGFR.
Examiner notes: Chiu’s reference has not been applied in the present office action.
However, Heigener teaches a method for treatment of patients suffering from non-small cell lung cancer, harboring uncommon EGFR mutations, such as G719X, L861Q, and S768I or combination thereof with afatinib, where afatinib is an EGFR-TK inhibitor, irreversibly binding to ErbB1 (EGFR), ErbB2 (HER2) and is a structural analog of instantly claimed sutetinib. Although sutetinib itself was not previously tried on uncommon EGFR mutations, since sutetinib is a known active agent against multiple common mutations in EGFR, and it is known that its structural analog afatinib is effective against common and uncommon (e.g. G719X, L861Q, and S768I) mutations in EGFR according to preclinical and clinical studies, it would give to the skilled artisan reasonable expectation of success to try the effectiveness of sutetinib against certain identified mutants in EGFR. MPEP 2145.X(B): An "obvious to try" rationale may support a conclusion that a claim would have been obvious where one skilled in the art is choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success. " [A] person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that product [was] not of innovation but of ordinary skill and common sense.
Regarding the argument that “obvious to try” rational is not applicable herein is not persuasive, because, as set forth above, combined prior art clearly supports “obvious to try rational” since there are: two comparable, known, structurally analogous drugs, suitable in the method of treatment of EGFR mediated NSCLC, where both drugs have similar mechanism of action and effective against common EGFR mutations, where one of them (afatinib) has been also clinically proven to treat NSCLC mediated by uncommon mutations in EGFR, it is obvious to try another drug (sutetinib) to treat NSCLC mediated by the same uncommon mutations in EGFR with the reasonable expectation of success, since its structural analog demonstrated efficacy in treating patients suffering from NSCLC mediated by uncommon EGFR mutations. In fact, it is a well-established practice in pharmaceutical research. MPEP 2144.08.II states:[…]However, obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988).
Regarding the argument about status of some TKIs, which were effective against some common mutations in EGFR but failed to treat uncommon mutations in EGFR is not persuasive because, considering TKIs, listed in Table 1 (Remarks, page 11) or The Declaration (page 7 – 8), some of them either do not have data on uncommon EGFR mutations or were discontinued for the reasons, that are not relevant to the present discussion. Furthermore, MPEP 716.02 (b) states: “It is the Applicant's burden to present clear and convincing factual evidence of nonobviousness or unexpected results, i.e., side-by-side comparison with the closest prior art in support of nonobviousness for the instant claimed invention over the prior art. The claims must be commensurate in the scope with any evidence of unexpected results.” “If the Applicant provides a DECLARATION UNDER 37 CFR 1.132, it must compare the claimed subject matter with the closest prior art in order to be effective to rebut a prima facie case of obviousness. See MPEP 716.02 (e). The exemplary EGFR-TKIs, listed in the Table1 do not represent the closets prior art, as required by MPEP. In fact, the reference of Heigener, used in the present office action, which teaches afatinib, structural analog of instantly claimed sutetinib, is the closest prior art reference. According to Heigener’s teachings, afatinib is an effective agent against NSCLC mediated by uncommon mutations in EGFR.
Regarding Applicant’s argument that examiner’s conclusion of obviousness is based on hindsight reasoning, MPEP 2145.X(A) states: "[a]ny judgment on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper." In re McLaughlin, 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971).
Therefore, Applicant’s arguments are not persuasive and the rejection of claims 6 - 24 as obvious over teachings of Zhang and Heigener is maintained.
.
Conclusion
Claims 6 - 24 are rejected. No claim is allowed.
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/E.V.V./Examiner, Art Unit 1691
/SAVITHA M RAO/Primary Examiner, Art Unit 1691
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