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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/16/2025 was filed after the mailing date of the non-final on 10/01/2025. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Status of the Claims
Claims 63-91 are pending in this application. Claims 1-62 have been cancelled by the applicant.
Claim Interpretations
Claim interpretations, as presented in non-final action filed 10/01/2025, have been reproduced herein for convenience.
Regarding the dosage of 380 mg/ m2 cited in claims 63, 70, 76, and 84, an online calculator was used to determine the dose amount for a subject 55 in tall, and weighing 32 kg (average weight and height for a 10 year old boy – Obtained from disabled-world.com [Retrieved on September 8th, 2025] <URL: https://www.disabled-world.com/disability/publications/printables/boys-weight-chart.php> - previously cited), and using the Mosteller BSA formula – as described in the specification (page 39, [0091], lines 2-3).
Using these parameters (as shown below), a dosage amount of about 423 mg was obtained, which equals about 13.2 mg/ kg, for a person with the parameters indicated. This value will be considered for the purposes of applying art (Obtained from reference.medscape.com [Retrieved on September 8th, 2025] <URL: https://reference.medscape.com/calculator/692/body-surface-area-based-dosing> - previously cited).
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Regarding the ages of the treated subjects, as recited in claims 63, 72-74, 76, 82-84, and 90-91, the specification discloses their study included “pediatric patients” aged 6 months to about 25 years of age ([0015], line 2). In agreement with this definition, Williams et al., from Community Health Centers (Obtained from Chcfl.org) defines the term “pediatric” as encompassing the ages of birth to about 18 to 21 years of age (page 2, second to last para. [Retrieved on September 8th, 2025] <URL: https://www.chcfl.org/what-age-is-considered-pediatric/> - previously cited).
Thus, for the purposes of applying art, the term “pediatric” will be interpreted as pertaining to any subject aged between 6 months to about 25 years of age. Therefore, pediatric low-grade glioma will be interpreted as low-grade glioma affecting subjects between 6 months and about 25 years of age.
Regarding all the instant claims, which speak to pediatric low-grade glioma (pLGG), the cited art refers to pediatric low-grade astrocytoma (PLGA). Astrocytoma is known in the art to be a type of glioma (page 1, last para.; Brennan et al.; Obtained from mdanderson.org [Retrieved on September 8th, 2025, <URL: https://www.mdanderson.org/cancerwise/what-is-astrocytoma--and-how-is-it-different-from-glioblastoma.h00-159694389.html> - previously cited).
Claim 63 speaks to a method of treating pLGG comprising administration of Compound A ((R)-2-(1-(6-amino-5-chloropyradine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridine-2-yl)thiazole-5-carboxamide), which corresponds to the compound below (page 12, [0047] of the specification).
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This compound is also known as DAY101, formally TAK-580, BIIB024, or MLN2480 ([0047], page 12).
Claims 73, 82, and 90 speak to the treatment wherein the subject is an adolescent. The specification does not define the intended ages to be encompassed by “adolescence.” The World Health Organization defines adolescents as individuals between 10 and 19 years of age [Retrieved on September 8th, 2025] <URL: https://www.who.int/southeastasia/health-topics/adolescent-health#:~:text=WHO%20defines%20'Adolescents'%20as%20individuals,age%20range%2010%2D24%20years.> - previously cited).
Claims 72, 82, and 90 speak to the treatment wherein the subject is a child. The specification does not define the intended ages to be encompassed by “child.” Based on The World Health Organization’s definition of adolescence, it will be understood that a child is any subject from birth to 9 years of age.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 63-91 are rejected under 35 U.S.C. 103 as being unpatentable over Sun et al. (Neuro-Oncology; 19, 2017, 774-785 – cited in IDS – previously cited) (“Sun”); in view of Brake et al. (US 2017/0173033 A1 – cited in IDS – previously cited) (“Brake”).
Regarding claims 63, 70, 76, and 84, Sun discloses structural rearrangements in BRAF are identified in roughly 75% of all pediatric low-grade astrocytomas (PLGAs) (reading on pediatric low-grade glioma (PLGG) harboring an activating BRAF alteration). Sun identifies MLN2480 (a.k.a. TAK-580 or instant Compound A) as a type II RAF inhibitor that serves as an equipotent antagonist of BRAF V600E, KIAA1549: BRAF (a truncation/fusion BRAF oncoprotein), and other noncanonical BRAF oncoproteins (abstract – results and conclusion). Sun further discloses MLN2480 maximum tolerated doses based on human trials being about 2500 mg/ kg (page 776, col. 1, end of para. 1). Sun also teaches administration of MLN2480 to mice, orally, at 10 mg/kg resulted in significant accumulation in the CNS (page 779, col. 1, para. 2, line 4) – therefore, Sun actually discloses a dosage range or 10-2500 mg/kg, which overlaps with the instant claims.
Regarding the instantly claimed ranges of 380 mg/ m2 once weekly (about 13.2 mg/ kg or about 423 mg doses – see claim interpretation) in claims 63, 70, 76, and 84, Sun actually discloses a dosage range or 10-2500 mg/kg, which overlaps with the instant claims.
Regarding the ages of the treated subjects, as recited in claims 63, 72-74, 76, 82-84, and 90-91, Sun teaches MLN2480 may be an effective therapeutic for BRAF mutant pediatric astrocytomas (encompassing ages ranging from 6 months to 25 years of age – see claim interpretation for “pediatric”) (abstract – conclusion) and that cancers of the brain have become the number one cause of cancer-related death in children (ages ranging from birth to 9 years of age – see claim interpretation of “child”) (Importance of the study – box in page 775).
Regarding claims 64, 77, and 85, Sun discloses mice were dosed liquid suspensions of MLN1480 via oral gavage (page 776, col. 1, para. 2, lines 1-3).
Regarding claims 67, 81, and 89, Sun discloses MLN2480 (a.k.a. TAK-580 or instant Compound A) (abstract – conclusion).
Regarding claims 68 and 71, Sun discloses MLN2480 (a.k.a. TAK-580 or instant Compound A) as a type II RAF inhibitor, effective in mouse models of PLGA, that serves as an equipotent antagonist of BRAF V600E, KIAA1549: BRAF (a truncation/fusion BRAF oncoprotein), and other noncanonical BRAF oncoproteins (abstract – results and conclusion).
While Sun et al. does not specifically teach: (i) relapsed/ refractory pediatric low-grade gliomas (claims 63, 70, 76, and 84); (ii) weekly administration of the dosage form (claims 63, 69-70, 76, 80, 84, and 87); or (iii) administration of a tablet dosage form (claims 65, 78, and 86); the teachings of Brake are relied upon for these disclosures.
Brake discloses compositions comprising the instant compound A and methods of treating cancer comprising administration of these compositions intermittently [0003]. Brake discloses Compound A is an inhibitor of wild-type and mutant Raf kinases currently in Phase 1 clinical trials in patients with relapsed or refractory solid tumors followed by a dose expansion in patients with BRAF mutation-positive cancers (reading on relapsed or refractory pLGG and PLGA) [0006]. Brake discloses pharmaceutical compositions in the form of a tablet comprising 5-100 mg of instantly claimed compound A (Embodiments 8-11, page 4). Brake discloses a method of treating cancer in a patient comprising administration of the pharmaceutical compositions of embodiments 8-11, according to an intermittent dosing regimen, comprising administration once a week, in an amount ranging from 400-1000 mg of compound A (Embodiment 189, page 19). Brake discloses the method of embodiment 189, wherein the cancer is brain cancer, such as astrocytoma (Embodiment 240, page 22).
Therefore, regarding claims 63, 70, 76, and 84, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer Sun’s oral suspension dosage of MLN2480 (instant Compound A) for the treatment of pediatric low-grade glioma (pLGG) in a subject up to 25 years of age with relapsed or refractory glioma, in view of Brake. One of ordinary skill would have been motivated to do so in view of Sun’s teachings that MLN2480 is a type II RAF inhibitor effective in mouse models of PLGA, serving as an equipotent antagonist of BRAF V600E, KIAA1549: BRAF, and other noncanonical BRAF oncoproteins. One of ordinary skill would have had a reasonable expectation of success in view of Sun’s disclosure of MLN2480 dosage amounts (ranging from 10-2500 mg/kg) and maximum tolerated doses; further in view of Brake’s disclosure that MLN2480 is currently in Phase 1 clinical trials in patients with relapsed or refractory solid tumors followed by a dose expansion in patients with BRAF mutation-positive cancers (reading on pLGG and PLGA).
Regarding maximum weekly doses of 600 mg, administration once weekly, or administration as a single dose per week after the initial dose, as recited in instant claims 63, 66, 69-70, 75-76, 79-80, 84, and 87-88, Brake discloses a method of treating cancer in a patient comprising administration of the pharmaceutical compositions comprising Compound A (MLN2480), according to an intermittent dosing regimen comprising administration once a week, with a 6 day rest period in between administrations, in an amount ranging from 400-1000 mg of compound A (Embodiment 189 and 193, pages 19-20). Thus, Brake’s 400-1000 mg dose/week reads on the instant dose of 423 mg/week or maximum of 600 mg per week (for an average 10-year-old weighing 32 kg) – see claim interpretation for 380 mg/m2.
Regarding administration in the form of a tablet, as recited in instant claims 65, 78, and 86, Brake discloses pharmaceutical compositions in the form of a tablet comprising instantly claimed compound A (Embodiments 8-11, page 4).
Regarding the claimed dosages and ages, Applicant is advised that the courts have stated that where the claimed ranges overlap or lie inside the ranges disclosed by the prior art and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. See In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990); Titanium Metals Corp. of America v. Banner, 778 F2d 775. 227 USPQ 773 (Fed. Cir. 1985) (see MPEP 2144.05.01). The courts have also found that where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05-II.
Therefore, the claimed dosage and age ranges merely represent an obvious variant and/or routine optimization of the values of the cited prior art.
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 63-91 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6, 8, 10, 12-16, 19, 23, 32, 36, 42, 45, 49, 53-54, 56-57, 60, and 66 of copending Application No. 18/450,638 (Copending ‘638); in view of Sun et al. (Neuro-Oncology; 19, 2017, 774-785 – cited in IDS); and Brake et al. (US 2017/0173033 A1 – cited in IDS). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant claims 63, 67, 70, 76, 81, 84, and 89, Copending ‘638 claims a method of treating a subject suffering from cancer, comprising administration of instant Compound A (MLN2480) (Copending ‘638’s claim 1); in an amount ranging from 100 to about 600 mg/ m2 per week (reading on instant 380 mg/ m2 weekly) (Copending ‘638’s claims 2-3, 13, and 45). Copending ‘638 further discloses treatment of glioma and malignant brain cancer (Copending ‘638’s claim 56); and treatment wherein the subject has received at least one prior therapy that is considered standard of care prior to the administration of Compound A (reading on relapsed or refractory cancer) (Copending ‘638’s claim 60).
Regarding instant claims 68, 71, 76, and 84, Copending ‘638 discloses treatment of a cancer wherein the subject is identified as having the following fusions KIAA1549: BRAF, BRAF V600E, etc. (Copending ‘638’s claims 6, 16, and 32).
Regarding instant claims 66, 69, 75, 79-80, and 87-88, Copending ‘638 discloses administration of 50 to about 800 or 200 to about 600 mg of Compound A per week (Copending ‘638’s claim 2-3).
Regarding the claimed amounts, Applicant is remined that the courts have stated that where the claimed ranges overlap or lie inside the ranges disclosed by the prior art and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. The courts have also found that where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.
Therefore, the claimed dosage amount merely represents an obvious variant and/or routine optimization of the values of the cited prior art.
While Copending ‘638 does not specifically teach: (i) treatment of pediatric low-grade glioma (pLGG) (all instant claims); (ii) treatment wherein the subject is 6 months to 25 years old, a child, or an adolescent (instant claims 63, 70, 72-74, 76, 82-84, and 90-91); or (iii) wherein Compound A is administered as a liquid suspension or a tablet (instant claims 63-65, 77-78, and 85-86); the teachings of Sun and Brake et al. are relied upon for these disclosures.
Sun discloses structural rearrangements in BRAF are identified in roughly 75% of all pediatric low-grade astrocytomas (PLGAs) (reading on pediatric low-grade glioma (PLGG)). Sun identifies MLN2480 as a type II RAF inhibitor that serves as an equipotent antagonist of BRAF V600E, KIAA1549: BRAF (a truncation/fusion BRAF oncoprotein), and other noncanonical BRAF oncoproteins (abstract – results and conclusion). Sun discloses mice were dosed liquid suspensions of MLN1480 via oral gavage (page 776, col. 1, para. 2, lines 1-3).
Brake discloses pharmaceutical compositions in the form of a tablet comprising 5-100 mg of instantly claimed compound A (Embodiments 8-11, page 4).
Therefore, regarding the treatment of pLGG by administering Copending ‘638’s Compound A to a subject between 6 months and 25 years of age, as recited in instant claims 63, 70, 72-74, 76, 82-84, and 90-91, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application, as taught by Copending ‘638’s in view of Sun. One of ordinary skill in the art would have been motivated to do so, with a reasonable expectation of success in view of Copending ‘638’s disclosure of Compound A (MLN2480) as a therapeutic agent for the treatment of cancers, including gliomas harboring fusions KIAA1549: BRAF and BRAF V600E (taught by Sun to be present in PLGAs); further in view of Sun’s teachings that Compound A is a type II equipotent antagonist of BRAF V600E, KIAA1549: BRAF, suitable for the treatment of pediatric cancers of the brain (reading on cancers in subjects of ages 6 months to 25 years of age – see claim interpretation for “pediatric”).
Regarding instant claims 64, 77, and 85, Sun discloses an oral liquid suspension comprising MLN2480 (Compound A) (page 776, col. 1, para. 2, lines 1-3).
Regarding instant claims 65, 78, and 86, Brake discloses a pharmaceutical composition comprising Compound A, in the form of a tablet for oral administration (Embodiments 8-11, page 4).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer Copending ‘638’s Compound A as a tablet in view of Brake. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Copending ‘638’s disclosure of the compound A for the treatment of cancers, such as glioma; Sun’s teachings that compound A can treat PLGA; and Brake’s disclosure of an oral tablet formulation of compound A.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 63-91 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 15 of copending Application No. 18/696,942 (Copending ‘942); in view of Sun et al. (Neuro-Oncology; 19, 2017, 774-785 – cited in IDS); and Brake et al. (US 2017/0173033 A1 – cited in IDS). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant claims 63, 70, 73-74, 76, 82-84, and 90-91, Copending ‘942 claims a method of treating cancer comprising administering a Raf kinase inhibitor to a subject in need thereof, wherein the subject has a BRAF gene fusion, wherein the Raf kinase inhibitor is instant Compound A, and wherein the subject is at least 18 years of age (reading on adolescents and subjects up to about 25 years old) (Copending ‘942’s claim 15).
Regarding the instantly claimed age ranges, Applicant is remined that the courts have stated that where the claimed ranges overlap or lie inside the ranges disclosed by the prior art and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. The courts have also found that where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.
Therefore, the claimed ages merely represent an obvious variant and/or routine optimization of the values of the cited prior art.
Regarding instant claims 67, 81, and 89, Copending ‘942 discloses Compound A (MLN2480) (Copending ‘942’s claim 15).
While Copending ‘942 does not specifically teach: (i) treatment of pediatric low-grade glioma (pLGG) (all instant claims); (ii) treatment wherein the subject is a child (instant claim 72); or (iii) wherein Compound A is administered as a liquid suspension or a tablet (instant claims 63-65, 77-78, and 85-86); (iii) administration of amount 380 mg/ m2 of Compound A once a week (instant claims 63, 70, 76, and 84); (iv) wherein the initial weekly dose does not exceed 600 mg (instant claims 66, 75, 79, and 88); (v) wherein the pLGG harbors a BRAF fusion or BRAF V600 mutation (instant claims 68, 71, 76, and 84); or (vi) wherein Compound A is administered as a single dose per week after the initial dose (claims 69, 80, and 87); the teachings of Sun and Brake et al. are relied upon for these disclosures.
Sun discloses structural rearrangements in BRAF are identified in roughly 75% of all pediatric low-grade astrocytomas (PLGAs) (reading on pediatric low-grade glioma (PLGG) harboring an activating BRAF alteration). Sun identifies MLN2480 (a.k.a. TAK-580 or instant Compound A) as a type II RAF inhibitor that serves as an equipotent antagonist of BRAF V600E, KIAA1549: BRAF (a truncation/fusion BRAF oncoprotein), and other noncanonical BRAF oncoproteins (reading on BRAF fusion) (abstract – results and conclusion). Sun further discloses MLN2480 dosing at 30 mg/ kg, and maximum tolerated doses based on human trials being about 2500 mg/ kg (page 776, col. 1, end of para. 1). Sun discloses mice were dosed liquid suspensions of MLN1480 via oral gavage (reading on oral administration) (page 776, col. 1, para. 2, lines 1-3).
Brake discloses compositions comprising the instant compound A and methods of treating cancer comprising administration of these compositions intermittently [0003]. Brake discloses Compound A is an inhibitor of wild-type and mutant Raf kinases currently in Phase 1 clinical trials in patients with relapsed or refractory solid tumors followed by a dose expansion in patients with BRAF mutation-positive cancers (reading on pLGG and PLGA) [0006]. Brake discloses pharmaceutical compositions in the form of a tablet comprising 5-100 mg of instantly claimed compound A (Embodiments 8-11, page 4). Brake discloses a method of treating cancer in a patient comprising administration of the pharmaceutical compositions of embodiments 8-11, according to an intermittent dosing regimen, comprising administration once or twice a week, in an amount ranging from 400-1000 mg of compound A (Embodiment 189, page 19). Brake discloses the method of embodiment 189, wherein the cancer is brain cancer, such as astrocytoma (Embodiment 240, page 22).
Therefore, regarding the treatment of pLGG by administering Copending ‘942’s Compound A to a child or an adolescent, as recited in instant claims 63, 68, 70-74, 76, 82-84, and 90-91, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application, as taught by Copending ‘942’s in view of Sun and Brake. One of ordinary skill in the art would have been motivated to do so, with a reasonable expectation of success in view of Copending ‘942’s disclosure of Compound A (MLN2480) as a therapeutic agent for the treatment of subjects harboring a BRAF gene fusion (taught by Sun to be present in PLGAs); further in view of Sun’s teachings that Compound A is a type II equipotent antagonist of BRAF V600E, KIAA1549: BRAF, suitable for the treatment of pediatric cancers of the brain (reading on cancers in subjects of ages 6 months to 25 years of age – see claim interpretation for “pediatric”); and Brake’s disclosure of a method of treating cancer (including brain cancer and astrocytomas) in a patient, comprising administration of the pharmaceutical compositions of Compound A according to an intermittent dosing regimen, comprising administration once a week.
Regarding: (i) administration of amount 380 mg/ m2 of Compound A once a week; (ii) wherein the initial weekly dose does not exceed 600 mg; and (iii) wherein Compound A is administered as a single dose per week after the initial dose; as recited in instant claims 63, 66, 69-70, 75-76, 79-80, 84, and 87-88, Sun discloses MLN2480 dosing at 30 mg/ kg, and maximum tolerated doses based on human trials being about 2500 mg/ kg (page 776, col. 1, end of para. 1). Brake discloses a method of treating cancer (including brain cancer and astrocytomas) in a patient comprising administration of the pharmaceutical compositions of Compound A, once a week, in an amount ranging from 400-1000 mg of compound A (Embodiment 189, page 19).
Regarding the claimed amounts, Applicant is remined that the courts have stated that where the claimed ranges overlap or lie inside the ranges disclosed by the prior art and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. The courts have also found that where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.
Therefore, the claimed dosage amount merely represents an obvious variant and/or routine optimization of the values of the cited prior art.
Regarding instant claims 64, 77, and 85, Sun discloses an oral liquid suspension comprising MLN2480 (Compound A) (page 776, col. 1, para. 2, lines 1-3).
Regarding instant claims 65, 78, and 86, Brake discloses a pharmaceutical composition comprising Compound A, in the form of a tablet for oral administration (Embodiments 8-11, page 4).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 63-91 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 5, 13, 15, 27, 50, 60-61, 64, 85-86, 89, 92, 96-98, 100, 102, 104, 107, 123-124, 126-127, 131, 135, and 162 of copending Application No. 18/332,906 (Copending ‘906); in view of Sun et al. (Neuro-Oncology; 19, 2017, 774-785 – cited in IDS); and Brake et al. (US 2017/0173033 A1 – cited in IDS). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant claims 63, 70, 73-74, 76, 82-84, and 90-91, Copending ‘906 claims a method of treating pediatric low grade glioma (pLGG) comprising administering Compound A (Copending ‘906’s claims 131 and 135).
Regarding instant claims 67, 81, and 89, Copending ‘942 discloses Compound A (MLN2480) (Copending ‘906’s claims 1-2, 5, 13, 15, 27, 50, 60-61, 64, 85-86, 89, 92, 96-98, 100, 102, 104, 107, 123-124, 126-127).
While Copending ‘942 does not specifically teach: (i) treatment wherein the subject is a child (instant claim 72); or (ii) wherein Compound A is administered as a liquid suspension or a tablet (instant claims 63-65, 77-78, and 85-86); (iii) administration of amount 380 mg/ m2 of Compound A once a week (instant claims 63, 70, 76, and 84); (iv) wherein the initial weekly dose does not exceed 600 mg (instant claims 66, 75, 79, and 88); (v) wherein the pLGG harbors a BRAF fusion or BRAF V600 mutation (instant claims 68, 71, 76, and 84); or (vi) wherein Compound A is administered as a single dose per week after the initial dose (claims 69, 80, and 87); the teachings of Sun and Brake et al. are relied upon for these disclosures.
Sun discloses structural rearrangements in BRAF are identified in roughly 75% of all pediatric low-grade astrocytomas (PLGAs) (reading on pediatric low-grade glioma (PLGG) harboring an activating BRAF alteration). Sun identifies MLN2480 (a.k.a. TAK-580 or instant Compound A) as a type II RAF inhibitor that serves as an equipotent antagonist of BRAF V600E, KIAA1549: BRAF (a truncation/fusion BRAF oncoprotein), and other noncanonical BRAF oncoproteins (reading on BRAF fusion) (abstract – results and conclusion). Sun further discloses MLN2480 dosing at 30 mg/ kg, and maximum tolerated doses based on human trials being about 2500 mg/ kg (page 776, col. 1, end of para. 1). Sun discloses mice were dosed liquid suspensions of MLN1480 via oral gavage (reading on oral administration) (page 776, col. 1, para. 2, lines 1-3).
Brake discloses compositions comprising the instant compound A and methods of treating cancer comprising administration of these compositions intermittently [0003]. Brake discloses Compound A is an inhibitor of wild-type and mutant Raf kinases currently in Phase 1 clinical trials in patients with relapsed or refractory solid tumors followed by a dose expansion in patients with BRAF mutation-positive cancers (reading on pLGG and PLGA) [0006]. Brake discloses pharmaceutical compositions in the form of a tablet comprising 5-100 mg of instantly claimed compound A (Embodiments 8-11, page 4). Brake discloses a method of treating cancer in a patient comprising administration of the pharmaceutical compositions of embodiments 8-11, according to an intermittent dosing regimen, comprising administration once or twice a week, in an amount ranging from 400-1000 mg of compound A (Embodiment 189, page 19). Brake discloses the method of embodiment 189, wherein the cancer is brain cancer, such as astrocytoma (Embodiment 240, page 22).
Therefore, regarding the treatment of pLGG by administering Copending ‘906’s Compound A to a child or an adolescent, as recited in instant claims 63, 68, 70-74, 76, 82-84, and 90-91, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application, as taught by Copending ‘906’s in view of Sun and Brake. One of ordinary skill in the art would have been motivated to do so, with a reasonable expectation of success in view of Copending ‘906’s disclosure of Compound A (MLN2480) as a therapeutic agent for the treatment of pLGG; further in view of Sun’s teachings that Compound A is a type II equipotent antagonist of BRAF V600E, KIAA1549: BRAF, suitable for the treatment of pediatric cancers of the brain (reading on cancers in subjects of ages 6 months to 25 years of age – see claim interpretation for “pediatric”); and Brake’s disclosure of a method of treating cancer (including brain cancer and astrocytomas) in a patient, comprising administration of the pharmaceutical compositions of Compound A according to an intermittent dosing regimen, comprising administration once a week.
Regarding: (i) administration of amount 380 mg/ m2 of Compound A once a week; (ii) wherein the initial weekly dose does not exceed 600 mg; and (iii) wherein Compound A is administered as a single dose per week after the initial dose; as recited in instant claims 63, 66, 69-70, 75-76, 79-80, 84, and 87-88, Sun discloses MLN2480 dosing at 30 mg/ kg, and maximum tolerated doses based on human trials being about 2500 mg/ kg (page 776, col. 1, end of para. 1). Brake discloses a method of treating cancer (including brain cancer and astrocytomas) in a patient comprising administration of the pharmaceutical compositions of Compound A, once a week, in an amount ranging from 400-1000 mg of compound A (Embodiment 189, page 19).
Regarding the claimed amounts, Applicant is remined that the courts have stated that where the claimed ranges overlap or lie inside the ranges disclosed by the prior art and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. The courts have also found that where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.
Therefore, the claimed dosage amount merely represents an obvious variant and/or routine optimization of the values of the cited prior art.
Regarding instant claims 64, 77, and 85, Sun discloses an oral liquid suspension comprising MLN2480 (Compound A) (page 776, col. 1, para. 2, lines 1-3).
Regarding instant claims 65, 78, and 86, Brake discloses a pharmaceutical composition comprising Compound A, in the form of a tablet for oral administration (Embodiments 8-11, page 4).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Claims
No claim amendments were made.
Specification
Amendments to the specification are acknowledged and have been entered. Objections to the specification have been withdrawn.
Claim Rejections - 35 USC § 103
Applicant's arguments filed 12/16/2025 have been fully considered but they are not persuasive.
Applicant argues that claimed dosage range of about 380 mg/m2 (13.2 mg/kg or 423 mg dose – calculated for a 10-year-old boy, 55 in tall, weighing 32 kg in the claim interpretation section of non-final filed 10/01/2025) does not lie inside Sun’s range and is not “close enough” to be obvious. Applicant states Sun’s range does not read on the instant claims and does not teach or suggest the instant claims. Applicant states MPEP 2144.05 II recites ranges and amounts within a difference in single digit percentages or fractions while Sun’s range is 30-2500 mg/kg. Applicant states the Office fails to provide a rationale why one of ordinary skill would reduce Sun’s dosage range to arrive at the claimed invention. Applicant states that Sun exemplifies 30 mg/kg twice daily, which is a 20-fold increase in the claimed dosage. Applicant further states that there is no motivation to modify Sun’s dosage to arrive at the instant claims, and that Sun suggests the feasibility of increasing the dosage if permitted by solubility, citing page 776, col. 1 of Sun. Applicant states that Brake does not cure the deficiencies of Sun, because Brake teaches using the highest possible dosage of Compound A and lacks motivation to lower the dosage taught in Sun. Applicant states that the Office has not provided any reason why those skilled in the art would be motivated to lower the dosage in order to arrive at the claimed invention with a reasonable expectation of success.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
In this case, Sun teaches that the maximum tolerated doses based on human trials being about 2500 mg/ kg (page 776, col. 1, end of para. 1). Sun also teaches administration of MLN2480 to mice, orally at 10 mg/kg, led to significant accumulation in the CNS (page 779, col. 1, para. 2, line 4) – therefore, Sun actually discloses a dosage range or 10 - 2500 mg/kg, which overlaps with the instant claims.
Applicant is advised that the courts have stated “[A] prior art reference must be considered in its entirety, i.e., as a whole” W.L. Gore & Associates, Inc. v. Garlock, Inc., 721 F.2d 1540, 220 USPQ 303 (Fed. Cir. 1983) (see MPEP 2141.02 VI). Thus, while the rejections listed above present a modified interpretation of the teachings of the previously cited prior solely for the purpose of clarity, the claims remain rejected over the prior art of record.
Brake discloses a method of treating cancer in a patient comprising administration of the pharmaceutical compositions comprising Compound A (MLN2480), according to an intermittent dosing regimen comprising administration once a week, with a 6-day rest period in between administrations, in an amount ranging from 400-1000 mg of compound A (Embodiment 189 and 193, pages 19-20). Thus, Brake’s 400-1000 mg dose/week reads on the instant dose of 423 mg/week or maximum of 600 mg per week (for an average 10-year-old weighing 32 kg) – see claim interpretation for 380 mg/m2).
Therefore, not only does Sun disclose that administration of Compound A at 10 mg/kg resulted in significant accumulation in the CNS, but they state that in view of these positive results, instant compound A was singled out for closer scrutiny as a potential therapeutic for PLGAs.
Furthermore, Brake discloses administration of compound A once a week, with a 6-day rest period between administrations, dosing at 400-1000 mg per week, which overlaps with the instant claims of 423 mg/week or maximum doses of 600 mg/week.
Applicant is reminded that the courts have stated that where the claimed ranges overlap or lie inside the ranges disclosed by the prior art and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. The courts have also found that where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.
Therefore, the claimed dosage and age ranges merely represent an obvious variant and/or routine optimization of the values of the cited prior art.
In response to applicant’s statement that Brake states “it is desirable to administer compound 1 at the highest possible dose” in [0007]; Brake states that “the efficacy of Compound 1 correlates with drug exposure. Accordingly, it is desirable to be able to administer Compound 1 at the highest possible dose” ([0007], lines 11-13); Sun states “following oral (10 mg/kg) drug administration, MLN2480 had a plasma:brain ratio of 24% and area under the curve (brain) of 41.6 h•μM following the oral dose, suggesting significant accumulation in the CNS”, suggesting that a dose of 10 mg/kg was sufficient for “significant accumulation in the CNS” (page 779, col. 1, para. 2, line 4). Therefore, the claimed ranges are obvious in view of the cited art.
Double Patenting
Applicant's arguments filed 12/16/2025 have been fully considered but they are not persuasive.
Applicant requests obviousness-type double patenting rejections be held in abeyance until allowable subject matter is indicated.
This is not persuasive. Claims stand rejected by the obviousness-type double patenting rejections presented herein.
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.
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/JACKSON J HERNANDEZ/Examiner, Art Unit 1627
/SARAH PIHONAK/Primary Examiner, Art Unit 1627