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 .
Status of the Claims
Claims 83-85, 87, 89-90, 92-94, 96-97, 99, 101, 103-104, 106-108, 112 and 117-126 are pending in the instant application and subject to examination herein.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 03/12/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements is being considered by the examiner.
Claim Rejections - 35 USC § 112(d) – Withdrawn
The prior rejection of claim 117 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends, is withdrawn in response to Applicant’s amendment of claim 117.
Claim Rejections - 35 USC § 102 – Withdrawn
The prior rejection of claims 83-84, 86 and 88 under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Miyazaki_2018 (US 2018/0009818 A1) is withdrawn in response to Applicant’s amendment of claim 83.
Applicant has traversed the prior rejection on the grounds that Miyazaki_2018 does not specifically disclose a combination of Vepafestinib1 and the treatment of non-small cell lung cancer (NSCLC):
Applicant alleges that Miyazaki_2018 does not particularly point out or suggest Vepafestinib for use in a treatment method, but instead mentions Vepafestinib “merely as one of those many compounds” that fall within the scope of Miyazaki_2018’s Formula (I);
Applicant alleges that Miyazaki_2018 does not particularly point out NSCLC as a cancer to be treated, but rather “NSCLC is mentioned merely as one of those many general cancer types” listed by Miyazaki_2018 in paragraph [1254]; and
Applicant alleges that Miyazaki_2018 does not provide any examples of administering the claimed compound(s) to humans. Only administration to mice is described.
Applicant’s traverse has been considered, but is not found persuasive, based on the following observations:
As noted in the prior rejection, Miyazaki_2018 mentions Vepafestinib by its IUPAC name (paragraph [1076]) in, as Applicant notes, a list of compound names, which, as Applicant has overlooked, is described by Miyazaki_2018 as a list of “Preferred examples of the present invention” (paragraph [1068]); Additionally, Vepafestinib, as “compound 85” disclosed by Miyazaki_2018, is included in all of Miyazaki_2018’s in vitro and in vivo assays, including those wherein only a few compounds (<10) out of >200 prepared compounds were assayed, for example Miyazaki_2018’s Evaluation of Cell Growth Inhibitory Effect (Test Example 7, paragraphs [1585]-[1587]) that includes only 6 assayed compounds, including compound 85, and Miyazaki_2018’s in vivo treatment of mice bearing xenograft tumors (Test Example 10, paragraphs [1594]-[1597]) that includes only 4 compounds, including compound 85;
Miyazaki_2018’s list of cancers to be treated does not merely include NSCLC, but narrows down to a list of just 4 cancer types, including NSCLC, that are “particularly preferably” the target cancer(s) to be treated (paragraph [1254]);
Regarding whether Miyazaki_2018 discloses Vepafestinib for human NSCLC cancer treatment, while Applicant notes that the only in vivo administration of compounds that is exemplified by Miyazaki_2018 is with mice, Applicant has overlooked that the mice so tested were grafted with xenografts of human thyroid cancer cells. Additionally, Miyazaki_2018’s in vitro assays of compounds disclosed therein as inhibitors of RET kinase and other kinases (e.g., SRC protein, LCK protein, EGFR protein, AURB protein) all use human recombinant protein in each and every instance, and Miyazaki_2018 assays compound 85 in a select group of compounds as inhibitors of cell growth of human LC-2/ad cells (paragraphs [1585]-[1587]), which is a known cell line for non-small cell lung cancer, as known in the art: see, for example Matsubara (Matsubara, et al.; Journal of Thoracic Oncology, v7, pp1872-1876; 2012), who teaches a study of 39 non-small cell lung cancers, including LC-2/ad cells, and identifies LC-2/ad as the only cell line that showed sensitivity to Vandetinib, a known RET inhibitor, thus revealing LC-2/ad as a RET-fusion positive lung adenocarcinoma (Abstract, page 1872). Thus, Miyazaki_2018 clearly evaluates Vepafestinib for treatment of human non-small cell lung cancer;
Regarding the medical parameters of administration of Vepafestinib to human subjects, Examiner notes that, as discussed in the prior rejection, Miyazaki_2018 discloses that the dose of the medicine depends on the condition, body weight, age, gender, etc., of the patient. . . and may be generally 0.5 to 5000 mg and preferably 0.1 to 1000 mg. Thus, Miyazaki_2018 discloses an understanding that dosing is a result-effective variable that is understood in the art, and a person of ordinary skill in the art would not discount the relevance of Vepafestinib to human cancer treatment solely due to the absence of human clinical trial results exemplified in a patent application.
Claim Rejections - 35 USC § 102 – Necessitated by Amendment(s)
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 –
(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.
(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.
Claims 83-84, 120, and 122-123 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Miyazaki_2018 (US 2018/0009818 A1).
Claim 83 is drawn to a method of treating a human patient with non-small cell lung cancer (NSCLC) having a RET gene abnormality comprising administering to the human patient a composition comprising an effective amount of Vepafestinib2, or a salt thereof, wherein the human patient is administered a dosage equivalent to about 40-3000 mg of free base Vepafestinib per day and the effective amount is a dosage equivalent to about 40-3000 mg of free base Vepafestinib per day.
Miyazaki_2018 discloses a genus of pyrrolopyrimidine compounds (“Formula (I)”) that encompasses Vepafestinib, as shown in the table below (paragraph [0048]), and further discloses a list of specific preferred compounds within the scope of Formula (I) that includes Vepafestinib by IUPAC name (paragraph 1076]).
Claim Number(s) of Instant Application
Instant Application
Miyazaki_2018
1
A method of treating a human patient with non-small cell lung cancer (NSCLC) having a RET gene abnormality comprising administering to the human patient a composition comprising [Vepafestinib], wherein the human patient is administered an effective amount of [Vepafestinib].
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Miyazaki_2018 further discloses a method for preventing or treating a malignant tumor, comprising administering the compound or a salt thereof of the invention disclosed therein, which is directed to a mammal, wherein the malignant tumor is a malignant tumor with enhanced activation of RET (paragraph [1116]), and Miyazaki_2018 clarifies that, in the invention disclosed therein, “RET” includes human and non-human mammal RET, preferably human RET (paragraph [1237]), and further provides a Markush group of applicable cancers to be treated, that, upon twice narrowing to just 4 cancers, includes “particularly preferably non-small cell lung cancer” (paragraph [1254]). Miyazaki_2018 further discloses that the dose of the medicine “depends on the condition, body weight, age, gender, etc., of the patient and cannot be generalized. For example, the daily dose of the compound of the present invention for an adult (body weight: 50 kg) may be generally 0.05 to 5000 mg, and preferably 0.1 to 1000 mg; and is preferably administered in one dose, or in two to three divided doses, per day” (paragraph [1260]).
Thus, claim 83 is anticipated by the disclosure of Miyazaki_2018.
Claim 84 further limits claim 83 to wherein the patient has a locally advanced or metastatic non-small cell lung cancer and the effective amount of Vepafestinib is a dosage equivalent in the range of 40-1000 mg. As discussed above, Miyazaki_2018 discloses a method for the treatment of malignant tumors, and a person of ordinary skill in the art would at once recognize that a malignant tumor meets the limitation of “locally advanced or metastatic”, as this limitation is inherent in the property of a tumor being malignant, as evidenced by NCI-Cancer Terms (National Cancer Institute: Cancer Terms, https://training.seer.cancer.gov/disease/cancer/terms.html, accessed via the Internet Archive Wayback Machine, site data archived on 20Oct2020 and retrieved on 22Oct2025), which teaches cancer terms, including teaching that “a malignant tumor is composed of cells that invade the basement membrane and invade or spread to other parts of the body.”
Thus, claim 84 is anticipated by the disclosure of Miyazaki_2018.
Claim 120 further limits claim 83 to wherein the composition is administered orally. Miyazaki_2018 discloses pharmaceutical compositions comprising compound(s) disclosed therein, and states that oral preparations are preferred (paragraph [1255]) and further discloses that “When a solid preparation for oral administration is prepared, optionally an excipient, a binder, a disintegrator, a lubricant, a colorant, a sweetener, and the like may be added to the compound of the present invention; and the resulting mixture may be formulated into tablets, coated tablets, granules, powders, capsules, etc., according to an ordinary method” (paragraph [1257]).
Thus, claim 120 is anticipated by the disclosure of Miyazaki_2018.
Claim 122 further limits claim 83 to wherein the composition to be administered comprises the dihydrochloride salt of Vepafestinib. Miyazaki_2018 discloses that salts of the compounds disclosed therein can include acid addition salts to an amino or basic heterocyclic group, such as hydrochloride (paragraphs [1235]-[1236]). While Miyazaki_2018 does not specifically point out or suggest a double acid addition salt, a person of ordinary skill in the art (POSITA) would at once envisage that a compound that possesses two amino and/or basic heterocyclic groups would form a double acid addition salt, and a POSITA would at once recognize that Vepafestinib, shown in the table above, has two amino groups: the morpholino amine and the anilinic amine.
Claim 123 further limits claim 83 to wherein the composition is administered once per day (QD) or twice per day (BID), and is met by the rejection above.
Thus, claims 122-123 are anticipated by the disclosure of Miyazaki_2018.
Double Patenting - Maintained
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.
The prior rejection of claims 83-85, 87, 89-90, 92-94, 96-97, 99, 101, 103-104, 106-108, 112 and 117 on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 10,155,768 B2 (hereafter referred to as “Taiho”) is maintained. Applicant has traversed this rejection on the same grounds as the traverse of the prior 102 rejection of claims over Miyazaki_2018 (US 2018/0009818 A1) (see “Claim Rejections - 35 USC § 102 – Withdrawn” section above), including that Taiho did not exemplify human treatment of NSCLC with Vepafestinib. Applicant’s traverse has been considered, but is not found persuasive, because the NSDP rejection relates to the invention that is claimed by Taiho in comparison to the instant claims: Taiho claims a genus of compounds that includes the compound Vepafestinib and distinctly claims the compound Vepafestinib that is required as the agent to be administered in every one of the instant claims.
Reiterated Rejection:
Claims 83-85, 87, 89-90, 92-94, 96-97, 99, 101, 103-104, 106-108, 112 and 117-126 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 10,155,768 B2 (Hereafter referred to as “Taiho”). Although the claims at issue are not identical, they are not patentably distinct from each other because Taiho claims 1-7 anticipate the instant claim set by prior claiming a genus of compounds that includes the compound Vepafestinib3 and/or distinctly claiming the compound Vepafestinib that is required as the agent to be administered in every one of the instant claims.
Claim 1 of Taiho claims a genus of compounds that encompasses the instant compound Vepafestinib, as shown in the table below:
Claim Number(s) of Instant Application
Instant Application
U.S. Patent No. 10,155,768 B2 (“Taiho”)
1
A method of treating a human patient with non-small cell lung cancer (NSCLC) having a RET gene abnormality comprising administering to the human patient a composition comprising [Vepafestinib], wherein the human patient is administered an effective amount of [Vepafestinib].
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wherein:
Claims 2-6 of Taiho further limit the genus of Taiho’s claim 1, each to a narrower genus that still encompasses Vepafestinib. Claim 7 claims a Markush group of specific compounds that includes Vepafestinib (compound 8 of the listed group).
Claims 118-126 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of Taiho. The claims of Taiho are discussed in the rejection above and hereby incorporated into the instant rejection. Instant claims 118-126 all require the compound Vepafestinib that is claimed by Taiho.
The prior rejection of claims 85 and 87 on the ground of nonstatutory double patenting as being unpatentable over claims 29-37 of copending Application No. 18/253,273 (hereafter referred to as “Miyazaki_2024”) in view of Tan (Tan, et al.; International Journal of Molecular Sciences, v21, Article 1416, pp.1-12; 2020) is maintained. Applicant has traversed the rejection on the grounds that neither Miyazaki_2024 nor Tan provide example(s) of administering Vepafestinib to humans at the dosage level required in instant claim 83, from which claims 85 and 87 depend. Applicant’s traverse has been considered but is not found persuasive, because the NSDP is based on what is claimed by Miyazaki_2024 in comparison to the instant claims, not what is exemplified by the disclosure of Miyazaki_2024. While the claims of Miyazaki_2024 are not identical to the instant claims, the respective claims are not patentably distinct for the reasons provided in the prior rejection and reiterated below.
Reiterated Rejection:
Claim 85 further limits claim 83 that regards a method of treating a human patient with non-small cell lung cancer (NSCLC) having a RET gene abnormality comprising administering an effective amount of Vepafestinib, to wherein the patient has metastatic NSCLC having a RET gene abnormality with brain and/or leptomeningeal metastases.
Claim 87 further limits claim 85 to wherein the brain and/or leptomeningeal metastases is asymptomatic.
Miyazaki_2024 claim 29 claims a method for treating a subject having a tumor with enhanced activation of RET, comprising administering a brain-penetrable antitumor agent comprising an effective amount of a compound represented by a genus of pyrrolopyrimidine compounds (“Formula (I)”) that encompasses Vepafestinib as shown in the table below:
Claim Number(s) of Instant Application
Instant Application
copending Application No. 18/253,273 (“Miyazaki_2024)”
1
A method of treating a human patient with non-small cell lung cancer (NSCLC) having a RET gene abnormality comprising administering to the human patient a composition comprising [Vepafestinib], wherein the human patient is administered an effective amount of [Vepafestinib].
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29. A method for treating a subject having a tumor with enhanced activation of RET, comprising administering a brain-penetrable antitumor agent comprising an effective amount of a compound represented by Formula (I) below or a salt thereof to the subject:
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wherein:
While Miyazaki_2024’s claim 29 does not claim that the tumor of the patient to be treated is an NSCLC tumor with brain and/or leptomeningeal metastases, a person of ordinary skill in the art would have a reasonable expectation of success in applying the method of Miyazki_2024’s claim 29 to the treatment of a patient having an NSCLC tumor with brain and/or leptomeningeal metastases, because it was known in the art that NSCLC cancer is susceptible to gene fusion, including RET gene fusion, that can drive tumorigenesis and brain metastases, per the teaching of Tan.
Tan teaches that non-small cell lung cancer is a leading cause of cancer death globally and is characterized by a high prevalence of brain metastases of up to 50% during the course of the disease, and that the presence of brain metastases portends a poor prognosis, both in terms of survival and response to systemic therapies, and has associated morbidity, including from the side effects of treatment (Abstract). Tan also teaches that novel therapies may have variable intracranial efficacy, and typically only patients with stable asymptomatic brain metastases are enrolled in clinical trials or may be excluded altogether, particularly in the setting of leptomeningeal carcinomatosis (Abstract, pages 1-2, bridging paragraph). Tan additionally teaches that a number of molecular subtypes and therapeutically targetable oncogenic drivers have been discovered for NSCLC, including some gene fusion drivers, including of the ‘rearrangement during transfection’ (RET) gene (Abstract, pages 1-2, bridging paragraph). Tan further teaches that the incidence of brain metastases in RET fusion-positive NSCLC at diagnosis has been estimated at 25% based on a combined multi-institutional registry and bi-institutional dataset cohort of 133 patients, and the lifetime prevalence of brain metastases in this study was 46% (page 3). Regarding the biological mechanism of brain metastases forming from gene fusion NSCLS cancer, Tan teaches that many oncogenic kinases within driver fusions such as ALK and RET are known to constitutively activate the PI3K/Akt/mechanistic target of rapamycin (mTOR) pathway, including in response to treatment, resulting in tumorigenesis, thus implicating the PI3K/Akt/mTOR pathway as a mechanism by which gene fusion driven non-small cell lung cancers develop brain metastases (page 2). Regarding treatment of brain metastases, Tan teaches that multikinase RET tyrosine kinase inhibitors (TKIs) have shown poor intracranial response, while selective RET TKIs have shown improved intracranial response (page 3 and page 6 – Table 1). Tan further teaches that the blood-brain barrier hinders the ability of drugs to penetrate the central nervous system, and that while the blood-brain barrier may have increased permeability in the presence of brain metastases, achieving sufficient drug concentrations for anti-tumor efficacy remains a challenge (page 2).
Applicant’s invention is unpatentable over claim 29 of Miyazaki_2024 in view of the teaching of Tan, because a person of ordinary skill in the art would have a reasonable expectation of success in applying the method of Miyazaki_2024’s claim 29, comprising treating a subject having a tumor with enhanced activation of RET comprising a brain-penetrable compound of a genus that encompasses Vepafestinib to the treatment of an NSCLC tumor with brain and/or leptomeningeal metastases, because it was known in the art that some NSCLCs exhibit RET gene fusion that can drive brain metastasis and, while some selective RET TKIs show better intracranial response than multikinase TKIs in clinical trials (which only include patients with asymptomatic brain metastases), brain permeability remains a challenge in the treatment of RET-driven brain metastases.
Miyazaki_2024’s claims 30-34 further narrow claim 29, each to a narrower genus that still encompasses Vepafestinib. Miyazaki_2024’s claims 35 and 36 each further limit claim 29 to a Markush group of specific compounds, and each includes Vepafestinib by IUPAC name (compound 2 in each listing). Miyazaki’s claim 37 further limits claim 29 to the treatment of a primary or metastatic brain tumor.
This is a provisional nonstatutory double patenting rejection.
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 W. JUSTIN YOUNGBLOOD whose telephone number is (703)756-5979. The examiner can normally be reached on Monday-Thursday from 8am to 5pm. The examiner can also be reached on alternate Fridays.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S. Lundgren, can be reached at telephone number (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/W.J.Y./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 4-amino-N-[4-(methoxymethyl)phenyl]-7-(l-methylcyclopropyl)-6-(3-morpholinoprop-1-yn-1-yl)-7H-pyrrolo[2, 3-d]pyrimidine-5-carboxamide;
2 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinoprop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
3 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinoprop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
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