MTA-Cooperative PRMT5 Inhibitors

§112 §DOUBLEPATENT

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 Claims Claims 1-2, 5, 7, 9-14, 24-27, 28-30, 33-35 are pending. Priority Instant application 18/549,864, filed 09/08/2023 claims priority as follows: PNG media_image1.png 118 643 media_image1.png Greyscale Information Disclosure Statement All references from IDS(s) received 09/08/2023, 11/15/2024, 12/11/2025 have been considered unless marked with a strikethrough. Election/Restrictions Applicant’s election without traverse of Group I, claims 1-2, 5, 7, 9-14, 24-25, 28-30, and 33-35; and the species compound 4-184 in the reply filed on 01/30/2026 is acknowledged. Claims 26-27 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 01/30/2026. Examination will begin with the elected species. In accordance with MPEP 803.02, if upon examination of the elected species, no prior art is found that would anticipate or render obvious the instant invention based on the elected species, the search of the Markush-type claim will be extended. If prior art is then found that anticipates or renders obvious the non-elected species, the Markush-type claim will be rejected. It should be noted that the prior art search will not be extended unnecessarily to cover all non-elected species. Should Applicant overcome the rejection by amending the claim, the amended claim will be examined again. The prior art search will be extended to the extent necessary to determine patentability of the Markush-type claim. In the event prior art is found during further examination that renders obvious or anticipates the amended Markush-type claim, the claim will be rejected and the action made final. The elected species compound 4-184 was searched and applicable prior art was not identified (though double patenting references were identified). Therefore, the search was extended to the full scope of pending claims 1-2, 5, 7, 9-14, 24-5, 28-30, 33-35 and applicable prior art was not identified (though double patenting references were identified). Claim Interpretation Claim 14 recites systematic chemical names. The systematic chemical names chemical names are being interpreted according to the following table: NAME STRUCTURE 2-{4-[4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl]-1-methyl-1H-pyrazol-5-yl}-1-benzothiophene-3-carbonitrile PNG media_image2.png 200 400 media_image2.png Greyscale 2-{4-[4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl]-1-methyl-1H-pyrazol-5-yl}thieno[2,3-b]pyridine-3-carbonitrile PNG media_image3.png 200 400 media_image3.png Greyscale 2-{4-[4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl]-1-methyl-1H-pyrazol-5-yl}-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile PNG media_image4.png 200 400 media_image4.png Greyscale 2-{4-[4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl]-1-methyl-1H-pyrazol-5-yl}-6-cyclopropoxy-3-fluoro-4-methylbenzonitrile PNG media_image5.png 200 400 media_image5.png Greyscale 2-{4-[4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl]-1-methyl-1H-pyrazol-5-yl}-3-chloro-6-cyclopropoxybenzonitrile PNG media_image6.png 200 400 media_image6.png Greyscale 2-{4-[4-(aminomethyl)-8-chloro-1-oxo-1,2-dihydrophthalazin-6-yl]-1-methyl-1H-pyrazol-5-yl}-6-cyclopropoxy-3-fluoro-4-methylbenzonitrile PNG media_image7.png 200 400 media_image7.png Greyscale 2-{4-[4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl]-1-methyl-1H-pyrazol-5-yl}-6-cyclopropoxy-3-fluorobenzonitrile PNG media_image8.png 200 400 media_image8.png Greyscale Claim Objections Claims 1, 11, 24, and 33 are objected to because of the following informalities: In claim 1, the definition for R6 ends with “oxetane and THF”. The word “and” appears to be a typographical error and should be replaced with the word “or”. The same error also appears in claim 11. Claims 1 and 2 recites the group “-X-arC1-C3alkyl” under the definitions of R2 and R5. The group “arC1-C3alkyl” is defined on page 7, para. [0033] as an “aryl group covalently linked to a C1-C3 alkyl”. While applicant can act as their own lexicographer, the term “-X-arC1-C3alkyl” is unclear without reference to the specification, and claims should be complete in themselves. The examiner recommends amending the phrase “-X-arC1-C3alkyl” to read “-X-arylC1-C3alkyl” for clarity and consistency. See also claim 26, where the phrase is recited as PNG media_image9.png 27 148 media_image9.png Greyscale for the group R22. Claim 1 recites “each R9 is independently H or C1-C3 alkyl, halogen or haloalkyl”. The comma-separated structure is ambiguous as to whether R9 can by any one of H, C1-C3 alkyl, halogen, or haloalkyl; or whether the claim intends two alternatives “H or C1-C3 alkyl” versus “halogen or haloalkyl”. This is being interpreted as a typographical error and claim 1 is being interpreted as reading: “each R9 is independently H, C1-C3 alkyl, halogen, or haloalkyl”. Claim 24 reads: PNG media_image10.png 80 743 media_image10.png Greyscale PNG media_image11.png 163 734 media_image11.png Greyscale Because the strikethrough above cancels the compound structure, the claim does not recite any compound. This is being interpreted as a typographical error. Claim 33 contains multiple typographical errors that should be corrected: “medukloblastoma” should read “medulloblastoma” “endometrial wcarcinoma” should read “endometrial carcinoma” “osteochronfroma” should read “osteochondroma” Appropriate correction is required. Claim Rejections - 35 USC § 112(b) 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 1-2, 5, 11, 14, and 33-34 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. Claims 1 and 2 recite the group “-X-arC1-C3alkyl substituted with cyano”. The phrase “-X-arC1-C3alkyl substituted with cyano” is ambiguous because an arC1-C3alkyl group has two distinct structural components (the aryl ring or the alkyl chain), and the claim does not specify which part bears the cyano which substituent. A person having ordinary skill cannot determine with reasonable certainty the metes and bounds of this limitation in the claims. Accordingly, claims 1 and 2 are indefinite. Claims 5, 7, 9-13, 28-30, and 33-35 depend from claim 1 and fail to resolve the issue, therefore these claims are also rejected as indefinite. Claim 2 recites that R10 is selected from a list that includes “C1-C6 heterocycloalkyl”. Claim 1 defines R10 as including “C3-C7 heterocycloalkyl”. It is unclear if claim 2 actually intends to recite “C1-C6 heterocycloalkyl,” or if that is a typographical error and the limitation should read “C3-C7 heterocycloalkyl”. This inconsistency between the claim 1 definition and claim 2 definitions of R10 renders claim 2 indefinite. Claim 5 depends from claim 1 and recites “wherein W is CR9”. However, claim 1 defines W as “CR10 or N”, where R10 has its own definition (H, C1-C3 alkyl, halogen, haloalkyl, or C3-C7 heterocycloalkyl) that is broader than R9. It is unclear whether claim 5 intends to narrow W to only those substituents within the definition of R9, or whether R9 is a typographical error for R10. Accordingly, claim 5 is indefinite. Claim 11 recites that R6 is selected from a list that includes “-CF2”. The recited group “CF2” is not a chemically valid terminal substituent on a ring; it is a radical that requires further bonding. As written, a person of ordinary skill cannot determine what substituent is claimed, rendering claim 11 indefinite. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present claims, claim 14 recites a definition of R51 which includes “R51 and R52 together with atoms to which they are attached form a C4-C6 heterocycloalkyl (e.g., hydrofuranyl). The claim therefore contains a broad recitation “C4-C6 heterocycloalkyl,” and the claim also contains “e.g., hydrofuranyl” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Additionally, claim 33 recites an extensive Markush group of cancers, each major organ category followed by parenthetical subtypes. For example, “Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma)…”. The extensive use of parentheticals raises the question of whether the parenthetical terms are part of the Markush group (i.e., additional claimed species) or merely exemplary of the preceding broader term. For example, in the sarcoma recitation above, it is unclear whether only those four sarcomas are claimed, or whether any cardiac sarcoma falls within the claims. This ambiguity is present for each of the parenthetical groupings in the claim. Claim 34 is indefinite because the term “MTAP-associated cancer” is not meaningfully defined in the claims or the specification, and has no single art-recognized meaning. The specification provides a vague definition at para. [0021], stating: “An MTAP-associated disease or disorder” as used herein refers to diseases or disorders associated with or mediated by or having a loss of MTAP activity resulting in sensitizing the disorder to selective inhibition of PRMT5 activity”. The definition therefore includes the cancers “associated with” a loss of MTAP activity. A cancer could be “associated with” MTAP loss if, for example, MTAP deletions are observed at a higher-than-background frequency in that cancer type, even if most tumors of that type are MTAP-intact. Approximately 15% of all human cancers harbor MTAP deletions according to the specification (para. [0004]). Does that mean that all cancer types where any MTAP deletion has ever been observed are “MTAP-associated”? What threshold of frequency makes a cancer type “associated with” MTAP loss? Is a cancer “associated with” MTAP loss only if the individual patient’s tumor harbors the deletion, or is it enough that the cancer type is statistically associated with MTAP loss at the population level? The specification provides no guidance for resolving these questions. Applicant is invited to amend claim 34 to recite, for example, “wherein the cancer is an MTAP-deficient cancer”. The phrase “MTAP-deficient” has clearer meaning and is used throughout the specification (e.g. [0006]-[0007]). Claim Rejections - 35 USC § 112(a) 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 1-2, 5, 7, 9-13, 28-30, and 33-35 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The specification, while being enabling for the compound formulas recited in claim 14 or the specific compounds recited in claim 25, does not reasonably provide enablement for the full scope of the claimed genus. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims. Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), enablement is assessed under the following factors to determine whether undue experimentation is required: (1) The breadth of the claims, (2) The nature of the invention, (3) The state of the prior art, (4) The level of one of ordinary skill, (5) The level of predictability in the art, (6) The amount of direction provided by the inventor, (7) The existence of working examples and (8) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. Breadth of the claims: Claim 1 recites a Markush genus comprising six scaffold formulae (IIA, IIA-1, IIB, IIB-1, IIC, IIC-1) and a set of independently variable substituents. The size of the Markush genus in claim 1 is conservatively estimated to be on the order of billions of compounds, and likely many orders of magnitude larger due to the unbounded generic terms “heterocyclyl,” “heteroaryl,” “aryl,” and “cycloalkyl”. Dependent claims 2, 5, 7, and 9-13 recite limitations that narrow the genus only marginally and still read on many orders of magnitude more compounds than the specification exemplifies. Nature of the invention: The invention relates to a class of small-molecule inhibitors of the PRMT5:MEP50 enzyme complex, disclosed as binding cooperatively in the presence of methylthioadenosine (MTA). State of the prior art and predictability in the art: The prior art previously disclosed the synthetic lethality between MTAP deletion and PRMT5 inhibition. See, for example, FIRESTONE (Journal of the American Chemical Society, vol. 139, no. 39, Oct. 2017, pp. 13754–60; cited at para. [0004]); MARJON (Cell Reports, vol. 15, no. 3, Apr. 2016, pp. 574–87); and MAVRAKIS (Science, vol. 351, no. 6278, Mar. 2016, pp. 1208–13). At the priority date, multiple selective PRMT5 inhibitors spanning several chemotypes had been disclosed in the prior art. See WANG (Journal of Medicinal Chemistry, vol. 61, no. 21, Nov. 2018, pp. 9429–41), which reviewed PRMT5 inhibitor chemotypes including the tool compound EPZ015666 and clinical candidate GSK3326595. Clinical-stage PRMT5 inhibitors had also advanced into first-in-human studies. GSK3326595 was evaluated in the METEOR-1 Phase I trial in advanced solid tumors. See SIU (Annals of Oncology, vol. 30, Oct. 2019, p. v159). JNJ-64619178 was evaluated in a first-in-human Phase I trial in patients with advanced cancers. See VILLAR (Annals of Oncology, vol. 31, Sept. 2020, p. S470). However, the PRMT5 inhibitors in the prior art were structurally distinct from the instant genus. The prior art did not establish a structure-activity principle from which a person of ordinary skill could predict, without synthesis and testing, which members of the vast claimed genus would possess MTA-cooperative PRMT5-inhibitory activity at therapeutically useful potency. Pharmacological activity in general is a very unpredictable area. Note also that in cases involving physiological activity, such as the instant case, “the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved.” See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). Moreover, the unpredictability of the art is evidenced by Applicant’s own data in Table A1 of the specification, which reports PRMT5-biochemical IC50 values (with 2 uM MTA) for the disclosed example compounds. The reported values span more than three orders of magnitude from single digit nanomolar potencies (e.g. 4-37) to greater than 100,000 nM. (e.g. 4-33). The structures of 4-37 and 4-33 are shown below: PNG media_image12.png 136 249 media_image12.png Greyscale PNG media_image13.png 162 262 media_image13.png Greyscale Other representative entries include Example 3-12 (210,000 nM), Example 1-4 (39,000 nM), and Example 1-8 (10,000 nM) contrasted with Example 3-40 (6 nM) and 3-16 (13 nM). Similarly, Table B reports cellular IC50 values in HCT116 MTAP-knockout cells spanning from single-digit nanomolar to values greater than 10,000 nM. Applicant’s own data therefore demonstrate that a substantial subset of the claimed Markush genus is inoperative for the recited utility, and a sufficient correlation is not disclosed to enable the skilled artisan to predict which of the myriad of claimed genus members are operative. Level of ordinary skill in the art: The person of ordinary skill is a team comprising medicinal chemists, biochemists, molecular biologists, and or pharmacologists experienced in enzyme and cell-based assays, collaborating with a clinician. This is a high level of skill, but it does not eliminate the unpredictability of pharmacological activity. The amount of direction provided: The specification provides extensive synthetic procedures for roughly 630 individual compounds distributed across 23 example series (Examples 1 through 23), and reports activity data for approximately 580 unique compounds in Tables A1-A3 and B. It describes two activity assays (Example A and Example B). However, the specification provides no structure-activity rule that would permit a POSITA to predict, without making and testing each candidate, which of the > 109 claimed compounds possess MTA-cooperative PRMT5-inhibitory activity. Existence of working examples: Approximately 580 compounds are specifically exemplified with activity data in Tables A1-A3 and/or B, and a subset of these compounds were tested in Tables A1 and B. However, even taking the larger figure of ~630 synthesized compounds, the exemplified subset is an miniscule fraction of the > 109 compounds within the claimed genus, and the wide range of activities within the exemplified set of compounds establishes that the examples do not reasonably represent the entire claimed genus. Quantity of experimentation needed to use the invention based on the content of the disclosure: The quantity of experimentation needed is undue experimentation. To practice the claims across their full scope, a POSITA would be required to synthesize and test a statistically representative sample of > 109 compounds in the disclosed biochemical and cellular assays. Given the activity spread of three or more orders of magnitude demonstrated in Applicant’s own Tables A1-3 and B, and the absence of any predictive structure-activity relationship, this effort represents undue experimentation. Therefore, in view of the factors discussed above, claims 1-2, 5, 7, 9-13, 28-30, and 33-35 are rejected as failing to comply with the enablement requirement. Claims 30 and 33-35 are additionally rejected under 35 U.S.C. 112(a) as failing to comply with the enablement requirement because the specification, while being enabling for inhibiting PRMT5 activity and inhibiting proliferation of MTAP-deficient cells in culture, does not reasonably provide enablement for methods of “treating cancer” as recited in claim 30 or for the specific cancers recited in dependent claims 33, 34, and 35. The specification does not enable any person skilled in the art to use the invention commensurate in scope with these claims. Breadth of the claims: Claim 30 recites “a method for treating cancer comprising administering to a patient having cancer a therapeutically effective amount of a compound according to claim 1.” Under BRI, the term “cancer” reads on any human or mammalian cancer and includes MTAP-intact cancers. Claim 33 recites a Markush list of essentially all known cancers, spanning cardiac, pulmonary, gastrointestinal, genitourinary, hepatic, biliary, osseous, nervous-system, gynecological, hematological, cutaneous, and adrenal categories; the list additionally includes benign neoplasms (lipoma, fibroma, hemangioma, osteoid osteoma, adenomatoid tumors, keloids, dermatofibroma, moles/dysplastic nevi, hamartoma) and psoriasis, which are not cancers. Claim 34 limits the cancer to a “MTAP-associated cancer” which is indefinite as set forth above. Claim 35 lists hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, and head and neck cancer. State of the prior art and predictability in the art: At the priority date, no MTA-cooperative PRMT5 inhibitor had been approved, and the art lacked extensive clinical validation. The publicly available clinical record for other PRMT5 inhibitors consisted of Phase I first-in-human studies of a limited number of compounds in advanced cancer populations. See, for example, SIU (Annals of Oncology, vol. 30, Oct. 2019, p. v159) and VILLAR (Annals of Oncology, vol. 31, Sept. 2020, p. S470). The state of the prior art did not establish that PRMT5 inhibition alone is sufficient to treat the enormous range of cancers recited in claims 30 and 33. Further, the prior art did not provide a basis from which a person of ordinary skill could extrapolate efficacy from applicant’s single in vitro MTAP-deleted colorectal model (HCT116 MTAP Knockout, Example B) to the approximately 150 cancers of claim 33, the seven cancers of claim 35, or the indefinite scope of “MTAP-associated cancer” in claim 34. Cancer therapeutics is an unpredictable art. The issues with predictability are compounded here by the factors identified above concerning the chemical genus, and by the absence of in vivo tumor-efficacy data of any kind in the instant application. The leap from enzyme inhibition to cell-based activity to in vivo cancer treatment introduces additional unpredictability at each stage. The relationship between in vitro PRMT5 inhibition and clinical efficacy against the dozens of cancer types listed in claim 33 is highly unpredictable. Existence of working examples: The specification presents evidence of in vivo efficacy (e.g. no xenograft, patient-derived xenograft, genetically-engineered mouse model, or any other animal tumor-efficacy data are provided). The sole cellular efficacy data (Example B, Table B) are limited to the colorectal HCT116 parental vs. HCT116 homozygous MTAP knockout. No data are presented in any of the other cancers recited. No data are presented concerning benign lesions or psoriasis. The specification further provides no pharmacokinetic, ADMET, or human-dose data for any compound. The POSITA accordingly has no basis in the specification to select a compound, a dose, a route, or a schedule for administration to “a patient having cancer”. Quantity of experimentation needed to use the invention based on the content of the disclosure: The quantity of experimentation needed is undue experimentation. To practice the claims across their full scope, a POSITA would be required to undertake preclinical tumor-efficacy and pharmacology studies in each of the approximately 150 cancers of claim 33 and the seven cancers of claim 35, followed by human clinical development to establish a “therapeutically effective amount” in each. This effort represents undue experimentation. Therefore, in view of the factors discussed above, claims 30 and 33-35 are rejected as failing to comply with the enablement requirement. 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. US 11,492,351 B2 Claim 1-2, 5, 7, 9-14, 24-25, 28-30, 33-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 of U.S. Patent No. 11,492,351 (“the reference patent”). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the reference patent recite compounds of Formula (I-D) useful for inhibiting PRMT5 activity in a cell: PNG media_image14.png 342 506 media_image14.png Greyscale which read on the instant claims. As (non-exhaustive) examples, claim 20 of the reference patent recites the elected species compound: PNG media_image15.png 168 203 media_image15.png Greyscale ; and claim 22 recites the compound: PNG media_image16.png 160 224 media_image16.png Greyscale . Both compounds are recited in instant claim 25. US 11,479,551 B2 Claim 1-2, 5, 7, 9-14, 24-25, 28-30, 33-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 11,479,551 (“the reference patent”). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the reference patent recite a method for inhibiting PRMT5 activity in a cell or a method for treating cancer comprising administering a compound of Formula (I-D): PNG media_image14.png 342 506 media_image14.png Greyscale which read on the instant claims. As (non-exhaustive) examples, claim 22 of the reference patent recites the elected species compound: PNG media_image15.png 168 203 media_image15.png Greyscale ; and claim 23 recites the compound: PNG media_image16.png 160 224 media_image16.png Greyscale . Both compounds read on the instant claims and are explicitly recited in instant claim 25. US 12,128,048 B2 Claim 1-2, 5, 7, 9-14, 24-25, 28-30, 33-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 of U.S. Patent No. 12,128,048 (“the reference patent”). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the reference patent recite a method for treating lung cancer comprising administering a compound of the formula: PNG media_image17.png 473 836 media_image17.png Greyscale . The above compound reads on the rejected claims. While the proviso in instant claim 14 specifically excludes the above compound, and claim 25 does not appear to recite the compound, these claims are rejected because the proviso does not exclude obvious variants of the above compound, such as those arrived at through a simple substitution of one halo substituent for another. For example, replacing the -fluoro substituent in the above compound with a -chloro (a halogen in the same period of the periodic table, expected to have similar properties to -fluoro) produces the compound: PNG media_image18.png 166 222 media_image18.png Greyscale recited in claim 14. US 12,171,765 B2 Claim 1-2, 5, 7, 9-14, 24-25, 28-30, 33-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 12,171,765 (“the reference patent”). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the reference patent recite a method for treating lung cancer comprising administering a compound of the formula: PNG media_image17.png 473 836 media_image17.png Greyscale . The above compound reads on the rejected claims. While the proviso in instant claim 14 specifically excludes the above compound, and claim 25 does not appear to recite the compound, these claims are rejected because the proviso does not exclude obvious variants of the above compound, such as those arrived at through a simple substitution of one halo substituent for another. For example, replacing the -fluoro substituent in the above compound with a -chloro (a halogen in the same period of the periodic table, expected to have similar properties to -fluoro) produces the compound: PNG media_image18.png 166 222 media_image18.png Greyscale recited in claim 14. Conclusion Claims 1-2, 5, 7, 9-14, 24-25, 28-30, and 33-35 are rejected. Claims 26-27 are withdrawn. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kyle Nottingham whose telephone number is (571)270-0640. The examiner can normally be reached M-F from 10:00 am - 6:00 pm. 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, Clinton Brooks can be reached at (571) 270-7682. 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. /K.N./Examiner, Art Unit 1621 /CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621