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 .
Election/Restriction
Applicant's election with traverse of Invention II and the species STM3480 in the reply filed on 17AUG2026 is acknowledged.
Upon further consideration, the invention of group II (i.e., claim(s) 14-15 and 18-24) as set forth in the restriction requirement mailed 18JUN2026 has been rejoined to groups I and III (i.e., claim(s) 1-4, 6, 8-9, 11-13, and 16). In view of the withdrawal of the restriction requirement, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Claim Status
Claims 1-4, 6, 8-9, 11-16, and 18-24 have been amended.
Claims 5, 7, 10, and 17 have been canceled.
Claims 1-4, 6, 8-9, 11-16, and 18-24 are pending and examined on the merits in the instant application (i.e., Claims 1, 14, and 16 are independent).
Priority
The present application is a 371 National Stage of PCT International Application No. PCT/GB2022/051400, filed 01JUN2022, which claims foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy of United Kingdom Application No. 2107907.4 filed on 02JUN2021 has been received and is acknowledged.
Specification
The disclosure is objected to because of the following informalities:
¶0023 has a typographical error in the last line of the paragraph.
At least ¶005 and ¶0090 references WO 2020/050898 with regards to Formula I; however, WO 2020/050898 is drawn to a wearable device having regions of varying stiffness.
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.
The lengthy specification has not been checked to the extent necessary to determine the presence of and to catalog all possible minor errors. Applicant’s assistance and cooperation in finding and correcting any errors of which the applicant may become aware of in the specification is appreciated.
Appropriate correction is required.
Claim Objections
Claims 1-2 and 14 are objected to because of the following informalities:
Claims 1-2 contain the acronyms METTL3, BCL2, FLT3, ICOS, GITR, A2AR, etc.. While acronyms are permissible as shorthand in the claims, the first recitation of the term should include the full recitation followed by the acronym in parentheses.
Claim 2 contains a typographical error: “conisting” should be corrected to “consisting” in line 2 of the claim.
Claim 14 contains a typographical error: “adminisering” should be corrected to “administering” in line 1 of the claim.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-4, 6, 8-9, 11-13, 15-16, 18-23 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, 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.
The term “combination” in claim 1, with the recitation of “an immune oncology agent or therapy” renders the claim indefinite because it is unclear as to whether the invention is directed to a product (i.e., pharmaceutical product) or a method (i.e., a method of combining therapies as a therapeutic strategy or a method to produce a pharmaceutical product). Claim 3 has a similar issue (i.e., “treatment” is action-oriented). Claims 2-4, 6, 8-9, and 11-13 are also rejected since they depend from claim 1, but do not remedy this deficiency.
Regarding claim 2, the use of “e.g.,” renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. Per MPEP §2173.05(d) description of examples or preferences should be properly set forth in the specification rather than the claims.
Claims 2, 4, 6, 9, 11, 15-16, and 18 appear to recite a Markush group, but the group of alternatives are not closed as required by a proper Markush group in MPEP §2173.05(h). In this instance, claim 2 recites Markush-type claims without reciting proper Markush-type language such as “selected from the group consisting of” and an “and” between the last two species. For example, in claim 2, an “and” should replace the “and/or” between “…vaccines” and “CAR-T….” Claims 4, 6, 9, 11, 15-16, and 18 recite “…is selected from” and “or” between the last two species and if amended to “…is selected from the group consisting of” and “and” between the last two species would obviate the rejection.
Claims 11, 15, 18-20, and 22-23 are dependent claims which start the claim with the indefinite article “A….” rather than the definite article “The….” The use of the definite article “The” shows that the claims are modifying an element already introduced in an earlier claim and particularly points out and distinctly claims the subject matter.
Claim 15 recites the limitation "immune checkpoint inhibitor" which is dependent on method claim 14, which recites an immune oncology agent or therapy. Therefore, there is insufficient antecedent basis for this limitation in the claim. Amending claim 15 to “…is administered in combination with an immune oncology agent or therapy, wherein the immune oncology agent is an immune checkpoint inhibitor…” or something of a similar nature would obviate this rejection.
Claim 20 recites the limitation "venetoclax" which is dependent on method claim 14, which recites a BCL2 inhibitor. Therefore, there is insufficient antecedent basis for this limitation in the claim. Claim 21 is also rejected since it depends from claim 20 but does not remedy this deficiency. Amending claim 20 to “…is administered in combination with a BCL2 inhibitor, wherein the BCL2 inhibitor is venetoclax …” or something of a similar nature would obviate this rejection.
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.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
Claims 1-4, 6, 8-9, 11-16, and 18-24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling and having support for:
“A pharmaceutical product comprising a METTL3 inhibitor or a pharmaceutically acceptable salt thereof and
an immune checkpoint inhibitor;
a BCL2 inhibitor or a pharmaceutically acceptable salt thereof;
an anthracycline topoisomerase II inhibitor or a pharmaceutically acceptable salt thereof;
a hypomethylating agent or a pharmaceutically acceptable salt thereof; or
a FLT3 inhibitor or a pharmaceutically acceptable salt thereof;
wherein the METTL3 inhibitor is selected from the group consisting of STM3480, STM3675, and STM3006 and pharmaceutically acceptable salts thereof; and
wherein the immune checkpoint inhibitor is selected from the group consisting of BMS-986016/relatlimab, TSR-033, REGN3767, MGDO13 (bispecific DART binding PD-1 and LAG-3), GSK2831781, LAG525, MDX-010/Ipilimumab, AGEN1884, and CP-675,206/tremelimumab, pembrolizumab, nivolumab, atezolizumab, avelumab and durvalumab;
wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof;
wherein the anthracycline topoisomerase II inhibitor is selected from the group consisting of daunorubicin, doxorubicin, epirubicin and idarubicin and pharmaceutically acceptable salts thereof;
wherein the hypomethylating agent is selected from the group consisting of 5-azacitidine or decitabine and pharmaceutically acceptable salts thereof; or
wherein the FLT3 inhibitor is selected from the group consisting of sorafenib, lestaurtinib, midostaurin, quizartinib, crenolanib, and gilteritinib, and pharmaceutically acceptable salts thereof.” (claims 1-4, 6, 8-9, and 11-12);
-AND-
“A pharmaceutical composition comprising a pharmaceutical product of claim 1 and one or more pharmaceutically acceptable excipients.” (amended claim 1 and claim 13);
-AND-
“A method of treating cancer, the method comprising administering a therapeutically effective amount of a METTL3 inhibitor or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of
an immune checkpoint inhibitor;
a BCL2 inhibitor or a pharmaceutically acceptable salt thereof;
an anthracycline topoisomerase II inhibitor or a pharmaceutically acceptable salt thereof;
a hypomethylating agent or a pharmaceutically acceptable salt thereof; or
a FLT3 inhibitor or a pharmaceutically acceptable salt thereof;
wherein the cancer is selected from the group consisting of acute myeloid leukaemia (AML), chronic lymphocytic leukaemia (CLL), small lymphocytic lymphoma (SLL) and myelodysplastic syndromes (MDS);
wherein the METTL3 inhibitor is selected from the group consisting of STM3480, STM3675, and STM3006 and pharmaceutically acceptable salts thereof; and
wherein the immune checkpoint inhibitor is selected from the group consisting of BMS-986016/relatlimab, TSR-033, REGN3767, MGDO13 (bispecific DART binding PD-1 and LAG-3), GSK2831781, LAG525, MDX-010/Ipilimumab, AGEN1884, and CP-675,206/tremelimumab, pembrolizumab, nivolumab, atezolizumab, avelumab and durvalumab;
wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof;
wherein the anthracycline topoisomerase II inhibitor is daunorubicin or a pharmaceutically acceptable salt thereof;
wherein the hypomethylating agent is 5-azacitidine or a pharmaceutically acceptable salt thereof; or
wherein the FLT3 inhibitor is quizartinib or a pharmaceutically acceptable salt thereof. (i.e., claims 14-15, 18-24);
-AND-
“A method of treating a solid tumor, the method comprising administering a therapeutically effective amount of a METTL3 inhibitor or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of an immune checkpoint inhibitor;
wherein the METTL3 inhibitor is selected from the group consisting of STM3480, STM3675, and STM3006 and pharmaceutically acceptable salts thereof and
wherein the immune checkpoint inhibitor is selected from the group consisting of BMS-986016/relatlimab, TSR-033, REGN3767, MGDO13 (bispecific DART binding PD-1 and LAG-3), GSK2831781, LAG525, MDX-010/Ipilimumab, AGEN1884, and CP-675,206/tremelimumab, pembrolizumab, nivolumab, atezolizumab, avelumab and durvalumab. (i.e., claim 16)
does not reasonably provide enablement or support for more.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims nor does it provide sufficient description to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, at the time the application was filed had possession of the claimed invention.
It is common technical knowledge that it is difficult to grasp a compound structure given the function, such as “inhibitor,” “agent,” “therapy” or in the instance of antibodies the antigen. For example, the number of METTL3 inhibitors encompassed by instant claim 1 is in the hundreds which are referenced in lists I and II of the instantly filed specification and is expanded to include any variety of METTL3 inhibitors as taught by Wu, et al., in instant claim 14 (Wu, et al., Exp Opin on Ther Patents, 2025, 35, 305-320, see entire document). Similarly, for each category of immune checkpoint inhibitors, BCL2 inhibitors, anthracycline topoisomerase II inhibitors, hypomethylating agents, or FLT3 inhibitors there is a breadth of structures in the art (Xu, et al., Cancers (Basel), 2023, 15, 1-24; El-Shorbagi, et al., Biomed Pharma J, 2024, 17, 1347-1364; Auni, et al., Life Sci, 2025, 363, 1-13; etc.). Therefore, a skilled artisan would be unable to envisage the METTL3 inhibitor and immune checkpoint inhibitor, BCL2 inhibitor, anthracycline topoisomerase 2 inhibitor, hypomethylating agent, or FLT3 inhibitor a priori given the current state of the art.
The specification discloses in vitro and in vivo studies, utilizing three of the hundreds of the METTL3 inhibitors listed in the specification in combination with at most a handful of compounds from the breadth of possibilities in each category (i.e., immune checkpoint inhibitor, BCL2 inhibitor, anthracycline topoisomerase 2 inhibitor, hypomethylating agent, or FLT3 inhibitor). The in vitro studies are comprised of:
STM3480 and pembrolizumab or avelumab, wherein the combination reduced tumor viability more than individual agents (Example 1);
STM3480, STM3006, or STM3675 and venetoclax, wherein the combination shows synergistic effects in two different AML cell lines (Example 3); and
STM3480 or STM3006 and daunorubicin, cytarabine, 5-azacitidine, or quizartinib, wherein the combination shows additive interaction in AML cell lines (Example 4).
The in vivo study evaluated the combination of STM3480 and an anti-PD1 antibody for its efficacy in an A20 lymphoma model, EMT6 breast cancer model, and CT26 colorectal cancer model, wherein the combination achieved the highest tumor regression compared to single agents (Example 2). Thus, the specification supports a combination of a specific METTL3 inhibitor and specific immune checkpoint inhibitor or specific BCL2 inhibitor resulting in a significantly improved effect over the individual inhibitors. Therefore, claims 1-4, 6, 8-9, 11-16, and 18-24 as presently claimed are rejected because the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims nor does it provide sufficient description to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, at the time the application was filed had possession of the claimed invention.
Double Patenting
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 1-4, 11, 13-16, and 24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 12,195,458 B2 (Blackaby, et al.,), herein referred to as “the ‘458 patent” in view of Wang, et al., (EMBO J, 2020, 39, 1-15), herein referred to as “Wang.”
Issued claims of the ‘458 patent:
Instant Application patent claims, underline corresponds to direct mapping to claim 1 of the ‘458 patent and italics corresponds to the additional claim limitations.
PNG
media_image1.png
417
250
media_image1.png
Greyscale
PNG
media_image2.png
715
230
media_image2.png
Greyscale
PNG
media_image3.png
702
237
media_image3.png
Greyscale
PNG
media_image4.png
392
223
media_image4.png
Greyscale
PNG
media_image5.png
86
234
media_image5.png
Greyscale
….
PNG
media_image6.png
46
244
media_image6.png
Greyscale
PNG
media_image7.png
273
228
media_image7.png
Greyscale
A combination comprising a METTL3 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the METTL3 inhibitor is a compound of formula I, II, VI or VII defined herein, or a pharmaceutically acceptable salt thereof, and: a. an immune oncology agent or therapy; b. a BCL2 inhibitor, or a pharmaceutically acceptable salt thereof; c. an anthracycline topoisomerase 2 inhibitor, or a pharmaceutically acceptable salt thereof; d. cytarabine, or a pharmaceutically acceptable salt thereof; e. a hypomethylating agent, or a pharmaceutically acceptable salt thereof; or f. a FLT3 inhibitor, or a pharmaceutically acceptable salt thereof.
The combination according to claim 1, wherein the immune oncology agent or therapy is selected from the group consisting of immune checkpoint inhibitors (e.g. a PD1, PD-L1 inhibitor, LAG3, CTLA-4, TIGIT, TIM3, or VISTA inhibitor), STING agonists, TLR agonists, anti-CD137 antibodies, CD28 antibodies, OX40 stimulators, CD40 antibodies, ICOS agonists, GITR agonists, A2AR antagonists, Bispecific T cell engagers (BiTE), oncolytic viruses, cancer vaccines, and/or CAR-T cell therapy.
The combination according to claim 1, wherein the immune oncology agent or therapy is treatment with an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof.
The combination according to claim 2, wherein the immune checkpoint inhibitor is selected from a PD1, PD-L1 inhibitor, a LAG3 inhibitor and a CTLA-4 inhibitor.
11. A combination according to claim 1, wherein the METTL3 inhibitor is selected from STM3480, STM3675 or STM3006, or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comprising a combination according to claim 1 and one or more pharmaceutically acceptable excipients.
14. A method of treating cancer, the method comprising administering a therapeutically effective amount of a METTL3 inhibitor or a pharmaceutically acceptable salt thereof to a patient in combination with: a. an immune oncology agent, b. a BCL2 inhibitor….
15. A method of treating cancer according to claim 14, wherein the METTL3 inhibitor is administered in combination with an ICI, wherein the METTL3 inhibitor is selected from STM3480, STM3675 or STM3006, or a pharmaceutically acceptable salt thereof.
16. A method of treating a solid tumour, the method comprising administering a therapeutically effective amount of a METTL3 inhibitor to a patient in combination with an ICI, wherein the METTL3 inhibitor is selected from STM3480, STM3675 or STM3006, or a pharmaceutically acceptable salt thereof.
24. The method of treating cancer according to claim 14, wherein the METTL3 inhibitor is administered to a patient in combination with an immune oncology agent.
The claimed METTL3 inhibitor structure, N-[(2-{[(cyclobutylmethyl)amino]methyl}-1 H-indol-6-yl)methyl]-4- oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide, of the ‘458 patent and the method of treatment comprising administering the METTL3 inhibitor structure, N-[(2-{[(cyclobutylmethyl)amino]methyl}-1 H-indol-6-yl)methyl]-4- oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide, of the ‘458 patent are the same as STM3480 of the instant claims.
The main difference is that the instant claims combine the METTL3 inhibitor, STM3480, with a second therapeutic. Specifically, the instant claims combine the METTL3 inhibitor, STM3480, and an immune checkpoint inhibitor (i.e., anti-PD1), a BCL2 inhibitor, an anthracycline topoisomerase II inhibitor, a hypomethylating agent, cytarabine or a FLT3 inhibitor or treat cancer by administering a therapeutically effective amount of the METTL3 inhibitor, STM3480, with an immune checkpoint inhibitor (i.e., anti-PD1), a BCL2 inhibitor, an anthracycline topoisomerase II inhibitor, a hypomethylating agent, cytarabine or a FLT3 inhibitor.
Wang teaches the inhibition of N6-methyladenosine mRNA modification by depletion of METTL3, enhanced response to anti-PD1 treatment in solid tumors (i.e., colorectal and melanoma) (see entire document, specifically see abstract and p2, col 1, last paragraph to col 2). In this instance, the in vivo efficacy of an anti-PD1 antibody was evaluated in METTL3-positive tumors and METTL3-depleted tumors, wherein in the METTL3-positive tumors the anti-PD1 antibody had a negligible effect on tumor growth or overall survival, whereas in METTL3-depleted tumors, the anti-PD1 antibody slowed tumor growth and prolonged survival (Fig 1).
It would have been obvious to artisans to modify the issued products of the METTL3 inhibitor and issued methods of administering a METTL3 inhibitor to treat cancer as claimed by the ‘458 patent to include an anti-PD1 antibody in the pharmaceutical composition and to use the combination of a METTL3 inhibitor in combination with an anti-PD1 antibody to treat cancer, as taught by Wang. This is because Wang teaches by depleting METTL3 in tumors (i.e., inhibiting METTL3) the solid tumors became responsive to anti-PD1 antibody administration. One would have been motivated to do so, given the direction by the ‘458 patent that the METTL3 inhibitors could be formulated into a pharmaceutical composition, and administered to a patient to treat lung cancer, AML, etc.. There would have been a reasonable expectation of success, given the knowledge that by modifying the METTL3 inhibitor and pharmaceutical composition thereof as well as the methods of treatment taught by the ‘458 patent by including an anti-PD1 antibody as taught by Wang would lead to a more effective pharmaceutical composition and method of treating cancer or a method of treating a solid tumor wherein METTL3 is inhibited.
Claims 1, 8-9, 11, 13-14, 18-23 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 12,195,458 B2 (Blackaby, et al.,), herein referred to as “the ‘458 patent” in view of Vu, et al., (Nat Med, 2017, 23, 1369-1376), herein referred to as “Vu;” Pollyea, et al., (Blood Adv, 2019, 3, 4326-4335), herein referred to as “Pollyea;” and Zhou, et al., (Drug Des, Dev Ther, 2019, 13, 1117-1125), herein referred to as “Zhou.”
Issued claims of the ‘458 patent:
Instant Application patent claims, underline corresponds to direct mapping to claim 1 of the ‘458 patent and italics corresponds to the additional claim limitations.
PNG
media_image1.png
417
250
media_image1.png
Greyscale
PNG
media_image2.png
715
230
media_image2.png
Greyscale
PNG
media_image3.png
702
237
media_image3.png
Greyscale
PNG
media_image4.png
392
223
media_image4.png
Greyscale
PNG
media_image5.png
86
234
media_image5.png
Greyscale
….
PNG
media_image6.png
46
244
media_image6.png
Greyscale
PNG
media_image7.png
273
228
media_image7.png
Greyscale
A combination comprising a METTL3 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the METTL3 inhibitor is a compound of formula I, II, VI or VII defined herein, or a pharmaceutically acceptable salt thereof, and: a. an immune oncology agent or therapy; b. a BCL2 inhibitor, or a pharmaceutically acceptable salt thereof; c. an anthracycline topoisomerase 2 inhibitor, or a pharmaceutically acceptable salt thereof; d. cytarabine, or a pharmaceutically acceptable salt thereof; e. a hypomethylating agent, or a pharmaceutically acceptable salt thereof; or f. a FLT3 inhibitor, or a pharmaceutically acceptable salt thereof.
The combination according to claim 1, wherein the BCL2 inhibitor, which is venetoclax or a pharmaceutically acceptable salt thereof.
The combination according to claim 1, a. the anthracycline topoisomerase 2 inhibitor is selected from daunorubicin, doxorubicin, epirubicin or idarubicin, or a pharmaceutically acceptable salt thereof; b. the hypomethylating agent is selected from 5-azacitidine or decitabine, or a pharmaceutically acceptable salt thereof; or c. the FLT3 inhibitor is selected from sorafenib, lestaurtinib, midostaurin, quizartinib, crenolanib, or gilteritinib, or a pharmaceutically acceptable salt thereof.
11. A combination according to claim 1, wherein the METTL3 inhibitor is selected from STM3480, STM3675 or STM3006, or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comprising a combination according to claim 1 and one or more pharmaceutically acceptable excipients.
14. A method of treating cancer, the method comprising administering a therapeutically effective amount of a METTL3 inhibitor or a pharmaceutically acceptable salt thereof to a patient in combination with: a. an immune oncology agent, b. a BCL2 inhibitor….
18. A method of treating cancer according to claim 14, wherein the METTL3 inhibitor is administered in combination with a BCL2 inhibitor, wherein the METTL3 inhibitor is selected from STM3480, STM3675 or STM3006, or a pharmaceutically acceptable salt thereof.
19. A method of treating cancer according to claim 18, wherein the METTL3 inhibitor is administered in combination with venetoclax or a pharmaceutically acceptable salt thereof.
20. A method of treating cancer according to claim 14, wherein the cancer is selected from AML, CLL, SLL, MDS, and wherein the METTL3 inhibitor is STM3480 and is administered to a patient in combination with venetoclax or a pharmaceutically acceptable salt thereof.
21. The method of treating cancer according to claim 20, wherein the cancer is AML.
22. A method of treating cancer according to claim 14, wherein the METTL3 inh is administered in combination with a. an anthracycline topo 2 inh, b. cytarabine, c. a hypomethylating agent, or d. a FLT3 inh.
23. A method of treating cancer according to claim 22, wherein the METTL3 inhibitor is STM3480.
The claimed METTL3 inhibitor structure, N-[(2-{[(cyclobutylmethyl)amino]methyl}-1 H-indol-6-yl)methyl]-4- oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide, of the ‘458 patent and the method of treatment comprising administering the METTL3 inhibitor structure, N-[(2-{[(cyclobutylmethyl)amino]methyl}-1 H-indol-6-yl)methyl]-4- oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide, of the ‘458 patent are the same as STM3480 of the instant claims. The main difference is that the instant claims combine the METTL3 inhibitor, STM3480, with a second therapeutic. Specifically, the instant claims combine the METTL3 inhibitor, STM3480, and an immune checkpoint inhibitor, a BCL2 inhibitor (i.e., venetoclax), an anthracycline topoisomerase II inhibitor, a hypomethylating agent, cytarabine or a FLT3 inhibitor (i.e., quizartinib) or treat cancer by administering a therapeutically effective amount of the METTL3 inhibitor, STM3480, with an immune checkpoint inhibitor, a BCL2 inhibitor (i.e., venetoclax), an anthracycline topoisomerase II inhibitor, a hypomethylating agent, cytarabine or a FLT3 inhibitor.
Vu teaches that AML cells show elevated abundance of METTL3 as compared to normal hematopoietic cells and that METTL3 depletion (i.e., inhibition) induces apoptosis in leukemia cells but not in normal hematopoietic cells (see last paragraph of the Main section). Additionally, Vu teaches that METTL3 depleted cells initially resulted in depleted BCL2; however, after four days, BCL2 protein levels increased suggesting that translation of BCL2 is no longer be repressed by m6A (Fig 4). Lastly, Vu teaches that inhibition of METTL3 could be exploited as a therapeutic strategy for myeloid malignancies, in combination with current and emerging therapeutic agents such as chemotherapy, FLT3, and IDH inhibitors (see last paragraph of the Main section).
In view of the teachings of Vu, wherein it appears that BCL2 finds an alternative translation mechanism following the depletion of METTL3, Pollyea teach that venetoclax is a specific BCL2 inhibitor that can restore activation of apoptosis in malignancies, such as AML (see abstract).
Furthermore, given the teaching of Vu to combine a METTL3 inhibitor with an FLT3 inhibitor, Zhou teaches that quizartinib is an effective therapy for patients with FLT3-ITD AML by continuing to inhibit the activity of FLT3 leading to apoptosis of tumor cells.
It would have been obvious to artisans to modify the issued products of the METTL3 inhibitor and issued methods of administering a METTL3 inhibitor to treat cancer as claimed by the ‘458 patent to include venetoclax or quizartinib in the pharmaceutical composition and to use the combination of a METTL3 inhibitor in combination with venetoclax or quizartinib to treat cancer, as taught by Vu, Pollyea, and Zhou. This is because Vu teaches by depleting METTL3 (i.e., inhibiting METTL3) that BCL2 translation is only transiently inhibited and the combination of METTL3 inhibitors with chemotherapeutics (i.e., venetoclax) or FLT3 inhibitor (i.e., quizartinib) would provide an effective therapeutic strategy. One would have been motivated to do so, given the direction by the ‘458 patent that the METTL3 inhibitors could be formulated into a pharmaceutical composition, and administered to a patient to treat lung cancer, AML, etc.. There would have been a reasonable expectation of success, given the knowledge that by modifying the METTL3 inhibitor and pharmaceutical composition thereof as well as the methods of treatment taught by the ‘458 patent by including venetoclax or quizartinib would lead to a more effective pharmaceutical composition and method of treating AML when METTL3 is inhibited.
Claims 1-4, 11, 13-16, and 24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 12,358,915 B2 (Blackaby, et al.,), herein referred to as “the ‘915 patent” in view of Wang, et al., (EMBO J, 2020, 39, 1-15), herein referred to as “Wang.”
Issued claims of the ‘915 patent:
Instant Application patent claims, underline corresponds to direct mapping to claim 1 of the ‘915 patent and italics corresponds to the additional claim limitations.
PNG
media_image8.png
338
299
media_image8.png
Greyscale
PNG
media_image9.png
708
214
media_image9.png
Greyscale
PNG
media_image10.png
704
226
media_image10.png
Greyscale
PNG
media_image11.png
700
226
media_image11.png
Greyscale
PNG
media_image12.png
703
239
media_image12.png
Greyscale
PNG
media_image13.png
554
223
media_image13.png
Greyscale
PNG
media_image14.png
192
233
media_image14.png
Greyscale
…
PNG
media_image15.png
32
227
media_image15.png
Greyscale
….
PNG
media_image16.png
47
236
media_image16.png
Greyscale
A combination comprising a METTL3 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the METTL3 inhibitor is a compound of formula I, II, VI or VII defined herein, or a pharmaceutically acceptable salt thereof, and: a. an immune oncology agent or therapy; b. a BCL2 inhibitor, or a pharmaceutically acceptable salt thereof; c. an anthracycline topoisomerase 2 inhibitor, or a pharmaceutically acceptable salt thereof; d. cytarabine, or a pharmaceutically acceptable salt thereof; e. a hypomethylating agent, or a pharmaceutically acceptable salt thereof; or f. a FLT3 inhibitor, or a pharmaceutically acceptable salt thereof.
The combination according to claim 1, wherein the immune oncology agent or therapy is selected from the group consisting of immune checkpoint inhibitors (e.g. a PD1, PD-L1 inhibitor, LAG3, CTLA-4, TIGIT, TIM3, or VISTA inhibitor), STING agonists, TLR agonists, anti-CD137 antibodies, CD28 antibodies, OX40 stimulators, CD40 antibodies, ICOS agonists, GITR agonists, A2AR antagonists, Bispecific T cell engagers (BiTE), oncolytic viruses, cancer vaccines, and/or CAR-T cell therapy.
The combination according to claim 1, wherein the immune oncology agent or therapy is treatment with an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof.
The combination according to claim 2, wherein the immune checkpoint inhibitor is selected from a PD1, PD-L1 inhibitor, a LAG3 inhibitor and a CTLA-4 inhibitor.
11. A combination according to claim 1, wherein the METTL3 inhibitor is selected from STM3480, STM3675 or STM3006, or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comprising a combination according to claim 1 and one or more pharmaceutically acceptable excipients.
14. A method of treating cancer, the method comprising administering a therapeutically effective amount of a METTL3 inhibitor or a pharmaceutically acceptable salt thereof to a patient in combination with: a. an immune oncology agent, b. a BCL2 inhibitor….
15. A method of treating cancer according to claim 14, wherein the METTL3 inhibitor is administered in combination with an ICI, wherein the METTL3 inhibitor is selected from STM3480, STM3675 or STM3006, or a pharmaceutically acceptable salt thereof.
16. A method of treating a solid tumour, the method comprising administering a therapeutically effective amount of a METTL3 inhibitor to a patient in combination with an ICI, wherein the METTL3 inhibitor is selected from STM3480, STM3675 or STM3006, or a pharmaceutically acceptable salt thereof.
24. The method of treating cancer according to claim 14, wherein the METTL3 inhibitor is administered to a patient in combination with an immune oncology agent.
The claimed METTL3 inhibitor structure, 6-bromo-4-[1- ({6-[(4,4-di methylpiperidin-1-yl)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-1 H-1,2,3-triazol-4- yl]-1 H-indazole of the ‘915 patent is the same as STM3006 of the instant claims. The main difference is that the instant claims combine the METTL3 inhibitor structures with a second therapeutic. Specifically, the instant claims combine the METTL3 inhibitor structures and an immune checkpoint inhibitor, a BCL2 inhibitor, an anthracycline topoisomerase II inhibitor, a hypomethylating agent, cytarabine or a FLT3 inhibitor or treat cancer by administering a therapeutically effective amount of the METTL3 inhibitor structures with an immune checkpoint inhibitor, a BCL2 inhibitor, an anthracycline topoisomerase II inhibitor, a hypomethylating agent, cytarabine or a FLT3 inhibitor.
Wang teaches the inhibition of N6-methyladenosine mRNA modification by depletion of METTL3, enhanced response to anti-PD1 treatment in solid tumors (i.e., colorectal and melanoma) (see entire document, specifically see abstract and p2, col 1, last paragraph to col 2). In this instance, the in vivo efficacy of an anti-PD1 antibody was evaluated in METTL3-positive tumors and METTL3-depleted tumors, wherein in the METTL3-positive tumors the anti-PD1 antibody had a negligible effect on tumor growth or overall survival, whereas in METTL3-depleted tumors, the anti-PD1 antibody slowed tumor growth and prolonged survival (Fig 1).
It would have been obvious to artisans to modify the issued products of the METTL3 inhibitor as claimed by the ‘915 patent to include an anti-PD1 antibody and to use the combination of a METTL3 inhibitor in combination with an anti-PD1 antibody to treat cancer, as taught by Wang. This is because Wang teaches by depleting METTL3 in tumors (i.e., inhibiting METTL3) the solid tumors became responsive to administration of an anti-PD1 antibody (i.e., a method of treating cancer or a method of treating a solid tumor). One would have been motivated to do so, given the direction by the ‘915 patent that the METTL3 inhibitors could be formulated into a pharmaceutical composition, which would presumably be administered to a patient. There would have been a reasonable expectation of success, given the knowledge that by modifying the METTL3 inhibitor and pharmaceutical composition thereof taught by the ‘915 patent by including an anti-PD1 antibody as taught by Wang would lead to an effective pharmaceutical composition and method of treating cancer or a method of treating a solid tumor wherein METTL3 is inhibited.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMANTHA L. HOPKINS whose telephone number is (703)756-4666. The examiner can normally be reached Mon-Thurs 6:00 AM to 4:00 PM EST.
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, Misook Yu can be reached at (571)272-0839. 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.
/SAMANTHA LAKE HOPKINS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
