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 .
Priority
The present application, filed on 03/31/23, claims priority over a U.S. provisional application 63/325,991 filed on 03/31/2022.
Status of Claims
Claims 1-4, 7-12, 15,19, 25-26, 35,38,41-43,45-46 and 48-50, amended on 07/18/2023, are pending and examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 07/18/2023 was filed after the mailing date of the present application on 03/31/2023. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-4, 7-12, 15, 19, 25, 26, 35, 38, 41, 43, 45, 46, 49, and 50 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Patent No. 10,780,093 B3, published on 09/22/2020 (herein referred to as Murtie 2020) in view of Cloughesy et al., 2019 (Cloughesy et al. Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma. Nat Med. 2019 Mar;25(3):477-486. doi: 10.1038/s41591-018-0337-7. Epub 2019 Feb 11; listed in the IDS).
Regarding instant claim 1, Murtie 2020 teaches methods of treating an enhancing brain tumor in a patient by administering an effective amount of vorasidenib and one or more additional therapeutic agents one of which the PD-1 inhibitor pembrolizumab (page 5, column 2, line 41-45, "methods of treating a brain tumor in a patient in need thereof comprising administering to the patient a compound described herein and one or more additional therapeutic agents" and (page 11, column 13, line 50-53, "one or more additional therapeutic agents is a checkpoint inhibitor [...] that inhibits an immune checkpoint (e.g., CTLA-4, PD-1/PD-L1). […] examples include [...] pembrolizumab"). Vorasidenib is also known as AG-881 with the chemical formula (6-(6-chloropyridin-2-yl)-N2,N4-bis((R)-1,1,1-trifluoropropan-2-yl)- 1,3,5-triazine-2,4-diamine) as recited in the applicant’s specification (page 4, paragraph 0016). Murtie 2020 teaches the vorasidenib compound with the chemical formula (page 12, column 16, line 3-6, "The compound of formula (I) used in the methods described herein is known as 6-(6-chloropyridin-2-yl)-N.sup.2,N.sup.4-bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine and is referred to in the Examples as Compound A").
Regarding instant claims 2-4, Murtie 2020 teaches the brain tumor is glioma and is an oligodendroglioma or astrocytoma (page 11, column 14, line 20-24, "brain tumor is a glioma, such as astrocytoma, oligodendroglioma […]") and that the brain tumor is recurrent or progressive (page 8, column 7, line 60-65, "methods provided herein increase the time to progression of patients having glioma when treated with an effective amount of the compound of formula").
Regarding instant claims 7-9, Murtie 2020 teaches the enhancing brain tumor is characterized by the presence of an IDH1 mutation, wherein the IDH1 mutation results in an accumulation of R(-)-2-hydrocyglutarate in a patient (page 11, column 14, line 43-46, "the brain tumor (e.g., glioma) to be treated is characterized by the presence of an IDH1 mutation, wherein the IDH1 mutation results in accumulation of R(−)-2-hydroxyglutarate in a patient"). Murtie 2020 further teaches that the IDH1 mutations is an R132X which is an R132H or R132C mutation (page 11, column 14, line 52, " the IDH1 mutation is an R132X mutation”, and page 11, column 14, line 53, " R132X mutation is selected from R132H, R132C").
Regarding instant claims 10-12, Murtie 2020 teaches the enhancing brain tumor is characterized by IDH2 mutation (page 12, column 15, line 1-2 "characterized by the presence of an IDH2 mutation, wherein the IDH2 mutation results in accumulation of R(−)-2-hydroxyglutarate in a patient) which is a R140X or R172X mutation (page 12, column 15, line 8, "IDH2 has an R140X mutation" and line 14 " IDH2 has an R172X mutation"). Murtie further teaches that the R140X and R172X can be R140Q, R140W, R140L. R172K. or R172G mutation (page 12, column 15, line 9-14, "R140Q", "R140W", "R140L" and line 16-17, "R172K", "R172G").
Regarding instant claim 15, Murtie 2020 teaches the enhancing brain tumor is characterized by the presence of IDH1 and IDH2 mutation (page 12, column 15, line 27, "characterized by the presence of an IDH1 mutation and an IDH2 mutation, wherein the IDH1 and IDH2").
Regarding instant claims 19 and 25, Murtie 2020 teaches dosing regimen of the vorasidenib. Murtie 2020 teaches the vorasidenib is administered at a dose of about 40 mg/day (page 9, column 10, line 29, " 30 to 80 mg/day, 40 to 60 mg/day, 45 to 55 mg/day,") as recited in instant claims 19 and 25.
The compound dosage in a composition is clearly a result effective parameter that a person having ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient, i.e., the dosage and dosing regimen, needed to achieve the desired results. The principle of law states from MPEP §§ 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages," (see In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382). Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation," (See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)).
Regarding instant claim 26, Murtie further teaches that the vorasidenib is administered once or twice daily (page 9, column 10, line 56-59, "once per day or more than once per day (e.g., twice per day, three times per day, four times per day, etc.) to achieve administration of the foregoing amounts per day").
Regarding instant claims 35, 38, 41, 43, 45, and 46, while Murtie 2020 teaches dosing regimen for vorasidenib, Murtie does not teach the dosing regimen for the additional therapeutic agent pembrolizumab. Cloughesy et al., 2019 teaches the method of treating recurrent glioblastoma, wherein pembrolizumab is administered 200 mg every three weeks (Q3W) (page 10, Methods, Study design and patients, "pembrolizumab 200 mg intravenous infusions every 3 weeks until tumor progression or an adverse event requiring study drug discontinuation"). Cloughesy et al., 2019 discloses that the dosing regimen resulted in a statistical improvement in overall survival and progression-free survival in patients with recurrent glioblastoma (page 7, discussion).
Therefore, it would have been obvious to the person of ordinary skill in the art to optimize the dosing regimen of pembrolizumab as taught by Cloughesy et al., 2019 and expect reasonable success in improving overall survival and progression-free survival in patients with glioma receiving combination therapy with vorasidenib.
Regarding instant claims 49 and 50, Murtie 2020 teaches the method of claim 1, wherein vorasidenib and pembrolizumab are administered sequentially or concurrently (page 6, column 4, line 48-50, "additional therapeutic agents may be administered concurrently with or sequentially with (prior to or following) the administration of the compound of formula (I)").
Claims 16, 17, 18 is rejected under 35 U.S.C. 103 as being unpatentable over Murtie 2020) as applied to claim 1 above and in further view of Deng et al., 2017 (Deng JH, Lu TB, Sun CC, Chen JM. Dapagliflozin-citric acid cocrystal showing better solid state properties than dapagliflozin. Eur J Pharm Sci. 2017 Jun 15;104:255-261. doi: 10.1016/j.ejps.2017.04.008. Epub 2017 Apr 13).
As described above, Murtie 2020 discloses the method of treating an enhancing brain tumor in a patient in need thereof comprising administering to the patient a therapeutically effective amount of vorasidenib. Murtie 2020 teaches that the vorasidenib is administered in non-salt form (page 6, column 4, line 4, "compound of formula (I) is administered in non-salt (i.e., free base) form) as recited in instant claim 16 and that the vorasidenib is administered as a cocrystal (page 12, column 16, line 17, " any cocrystal thereof") as recited in instant claim 17.
However, Murtie does not teach that the vorasidenib is administered as a cocrystal with citric acid. Deng et al., 2017 teaches a method in making a 1:1 cocrystal between the sodium-glucose contransporter-2 inhibitor and citric acid (page 1, abstract, 1:1 cocrystal between DAP and citric acid (DAP-CA)). Furthermore, Deng et al., 2017 teaches that the cocrystal with citric acid “exhibits superior stability against high temperature and high relative humidity without compromising dissolution and tableting performance” (page 1, abstract).
Therefore, it would have been obvious to the person of ordinary skill in the art to administer vorasidenib as a cocrystal with citric acid to increase stability of the pharmaceutical composition.
Claims 42 and 48 are rejected under 35 U.S.C. 103 as being unpatentable over Murtie 2020) and Cloughesy et al., 2019 (cited previously) as applied to claim 1 above and in further view of FDA drug Keytruda® 2020 (FDA drug label Keytruda® (pembrolizumab), website: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125514s059s064s076s083lbl.pdf, published on 04/2020).
While Murtie 2020 teaches the method of treating enhancing brain tumor using vorasidenib and its dosing regimen and Cloughesy et al., 2019 teaches the dosing regimen of pembrolizumab, they both do not teach that the pembrolizumab is administered every 6 weeks (Q6W) as recited in instant claim 42 and they do not teach that the pembrolizumab is administered at a dose about 400 mg Q3W. The FDA drug label for Keytruda® (pembrolizumab) 2020 discloses approved dosing regimen for a number of different cancers (page 7, Table 1: recommended dosage, “200 mg every 3 weeks or 400 mg every 6 weeks”). The FDA Drug label Keytruda® further teaches that there are no differences in efficacy and safety between the dosing regimen (page 46, 12.2 pharmacokinetics, “no anticipated clinically significant differences in efficacy and safety between pembrolizumab doses of 200 mg or 2 mg/kg every 3 weeks or 400 mg every 6 weeks”) and teaches dose modifications for adverse reactions (page 8, Table 2). The dosing regimen of pembrolizumab is clearly a result effective parameter that a person having ordinary skill in the art would routinely optimize to reduce adverse reactions due to the therapeutic agent. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient, i.e., the dosage and dosing regimen, needed to achieve the desired results. The principle of law states from MPEP §§ 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages," (see In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382). Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation," (See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)).
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.
Claim 1, 2, 4, 7, 8, 9, 10, 11, 12, 15, 16, 17, 18, 19, 25, 26, 35, 38, 41, 42, 43, 45, 46, 48, 49, and 50 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 8, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 of U.S. Patent No. 12,042,497 B2 issued on 07/23/2024 from Servier Pharmaceuticals LLC (herein referred to as Murtie 2024) in view of Murtie 2020 (cited previously); Cloughesy et al., 2019 (cited previously); FDA drug safety label for Keytruda®(cited previously); and Deng et al., 2017 (cited previously).
Regarding instant claim 1, 2, and 4, Murtie 2024 claim 1 recites a method for treating an oligodendroglioma or astrocytoma in a patient in need thereof comprising administering to the patient (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof; and (b) one or more additional therapeutic agents; in amounts effective for treating the oligodendroglioma or astrocytoma. Formula (I) in Murtie 2024 refers to the 6-(6-chloropyridin-2-yl)-N.sup.2,N.sup.4-bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine (Murtie 2024, specification, page 12, column 16, line 4) which is the chemical formula for vorasidenib as specified in the instant application’s disclosure (instant application, specification, page 4, paragraph 0016).
Regarding instant claims 4, 7, 10, and 15, Murtie 2024 claim 17, 20, 25 recite the oligodendroglioma or astrocytoma is characterized by the presence of an IDH1 mutation and/or the presence of an IDH2 mutation, wherein the IDH1 mutation results in accumulation of R(−)-2-hydroxyglutarate in a patient.
Regarding instant claims 8, 9, 11, and 12, Murtie 2024 claims 18, 19, 21, 22, 23, and 24 recite mutations in IDH1 and IDH2 wherein IDH1 mutation is an R132X mutation, R132H or R132C mutation and wherein IDH2 mutation is an R140X mutation (R140Q, R140W, or R140L) or an R172X mutation (R172K or R172G).
Regarding instant claims 19, 25, and 26, Murtie 2024 claim 14, 15, 26, 27, and 28 recite the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered in an amount of from 10 to 50 mg/day, once per day in an amount of 50 mg per administration, administered in an amount of from 15 to 40 mg/day, from 40 to 60 mg/day, and from 10 to 50 mg/day.
Regarding instant claim 16, Murtie 2024 claim 16 recite the compound of formula (I) is administered in non-salt form.
While Murtie 2024 recites a pharmaceutically acceptable salt, Murtie 2024 does not recite the compound formula (I) is administered in a cocrystal with citric acid as recited in instant claims 17 and 18. Deng et al., 2017 teaches a method in making a 1:1 cocrystal between the sodium-glucose contransporter-2 inhibitor and citric acid (page 1, abstract, 1:1 cocrystal between DAP and citric acid (DAP-CA)). Furthermore, Deng et al., 2017 teaches that the cocrystal with citric acid “exhibits superior stability against high temperature and high relative humidity without compromising dissolution and tableting performance” (page 1, abstract).
Therefore, it would have been obvious to the person of ordinary skill in the art to administer vorasidenib as a cocrystal with citric acid to increase stability of the pharmaceutical composition.
Regarding instant claims 1, 35, 38, 41, 42, 43, 45, 46, and 48, Murtie 2024 claim 8 recites one or more additional therapeutic agents is a checkpoint inhibitor.
However, Murtie 2024 does not recite that pembrolizumab is checkpoint inhibitor as recited in instant claim 1. Murtie 2020 (cited previously) recites the additional therapeutic agent includes checkpoint inhibitors one of them is pembrolizumab as recited in instant claim 1 (page 11, column 13, line 50-53, "one or more additional therapeutic agents is a checkpoint inhibitor [...] that inhibits an immune checkpoint (e.g., CTLA-4, PD-1/PD-L1). […] examples include [...] pembrolizumab"). Murtie 2020 further discloses that the checkpoint inhibitor “would prevent immune system attacks on cancer cells, thereby allowing the immune system to attack the cancer cells” (page 11, column 13, line 50). It would have been obvious to the person of ordinary skill in the art to use pembrolizumab to enhance the immune system to attack brain cancer cells.
In addition, Murtie 2024 does not recite dosing regimen for pembrolizumab as recited in instant claims 35, 38, 41, 42, 43, 45, 46 and 48. Cloughesy et al., 2019 teaches the method of treating recurrent glioblastoma, wherein pembrolizumab is administered 200 mg every three weeks (Q3W) (page 10, Methods, Study design and patients, "pembrolizumab 200 mg intravenous infusions every 3 weeks until tumor progression or an adverse event requiring study drug discontinuation"). Cloughesy et al., 2019 discloses that the dosing regimen resulted in a statistical improvement in overall survival and progression-free survival in patients with recurrent glioblastoma (page 7, discussion).
Further, The FDA drug label for Keytruda® (pembrolizumab) 2020 discloses approved dosing regimen for a number of different cancers and one of them is administered at 400mg every 6 weeks (Q6W) as recited in instant claim 42 but they do not teach that the pembrolizumab is administered at a dose about 400 mg Q3W as recited in instant claim 48 (page 7, Table 1: recommended dosage, “200 mg every 3 weeks or 400 mg every 6 weeks”). Keytruda® FDA drug label 2020 further teaches that there are no differences in efficacy and safety between the dosing regimen (page 46, 12.2 pharmacokinetics, “no anticipated clinically significant differences in efficacy and safety between pembrolizumab doses of 200 mg or 2 mg/kg every 3 weeks or 400 mg every 6 weeks”) and teaches dose modifications for adverse reactions (page 8, Table 2). Therefore, the dosing regimen of pembrolizumab is clearly a result effective parameter that a person having ordinary skill in the art would routinely optimize to reduce adverse reactions due to the therapeutic agent. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient, i.e., the dosage and dosing regimen, needed to achieve the desired results. The principle of law states from MPEP §§ 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages," (see In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382). Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation," (See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)).
Therefore, it would have been obvious to the person of ordinary skill in the art to optimize the dosing regimen of pembrolizumab as taught by Cloughesy et al., 2019 and the FDA drug safety label for Keytruda ® 2020 and expect reasonable success in improving overall survival and progression-free survival in patients with glioma receiving combination therapy with vorasidenib.
Regarding instant claims 49 and 50, Murtie 2024 claim 12 and 13 recite the compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents are administered concurrently or sequentially (page 6, column 4, line 48-50, "additional therapeutic agents may be administered concurrently with or sequentially with (prior to or following) the administration of the compound of formula (I)").
Claim 1, 2, 4, 7, 8, 9, 10, 11, 12, 15, 16, 17, 18, 19, 25, 26, 35, 38, 41, 42, 43, 45, 46, 48, 49, and 50 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 16, 17, 18, 19, and 20 of U.S. Patent No. 11, 844,758 B2 issued on 12/19/2023 from Servier Pharmaceuticals LLC (herein referred to as Konteatis 2023) in view of Murtie 2020 (cited previously), Cloughesy et al., 2019 (cited previously), FDA drug safety label for Keytruda (cited previously), and Deng et al., 2017 (cited previously).
Regarding instant claims 1, Konteatis 2023 claim 16 recites a method for treating a glioma characterized by the presence of an isocitrate dehydrogenase 1 (IDH1) mutation comprising administering to a patient in need thereof a therapeutically effective amount of a compound having the Formula:
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227
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(Konteatis 2023, page 257, claim 16 structure) or a pharmaceutically acceptable salt or hydrate thereof. The chemical structure is recited in the instant application’s specification as vorasidenib (AG-811) (page 4, paragraph 0016).
Regarding instant claims 1, 2, 4, 7, 8, 9, 17, and 18, Konteatis 2023 claim 19 recites a method for treating a glioma characterized by the presence of an isocitrate dehydrogenase 1 (IDH1) mutation comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising the chemical structure (Konteatis 2023, shown on page 257, column 500, line 45-55) or a pharmaceutically acceptable salt or hydrate thereof and one or more pharmaceutically acceptable excipients. Further, Konteatis 2023 claim 20 and 17 recite the IDH1 mutation is an R132H or R132C mutation.
However, Konteatis 2023 claims do not recite the brain tumor is characterized by the presence of IDH2 mutation wherein the IDH2 mutation results in accumulation of R(-)-2-hydroxyglutarate in a patient and wherein the IDH2 mutation is either an R140Q, R140W, R140L, R172K or R172G mutation as recited in instant claims 10, 11, 12, and 15. Murtie 2020 recites the vorasidenib is effective in both IDH1 and IDH2 mutations (page 5, column 2, line 35, “6-(6-chloropyridin-2-yl)-N.sup.2,N.sup.4-bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine, which has been shown to act as an inhibitor of mutant IDH1 and IDH2 proteins in biochemical and cellular assays”) and further characterizes the IDH2 mutations described previously (page 12, column 5, line 5-16). Murtie 2020 discloses that since both IDH1 and IDH2 occur in over 70% of diffuse low grade glioma tumors and that inhibitor that only targets IDH1 mutants has resulted in unfavorable clinical outcomes (page 5, column 2, line 15).
Therefore, it would have been obvious to the person of ordinary skill in the art to use the compound formula from Konteatis 2023 and expect a reasonable success at inhibiting IDH2 mutations and improve clinical outcomes since Murtie 2020 teaches the compound formula with the same feature.
In addition, Konteatis 2023 claims do not recite the dosing regimen of the vorasidenib as recited in instant claims 19, 25, and 26. Murtie 2020 describes the dosing regimen of vorasidenib as described above (page 9, column 10, line 29, " 30 to 80 mg/day, 40 to 60 mg/day, 45 to 55 mg/day," and page 9, column 10, line 56-59, "once per day or more than once per day (e.g., twice per day, three times per day, four times per day, etc.) to achieve administration of the foregoing amounts per day").
It would have been obvious to the person of ordinary skill in the art to optimize the dosing regimen as described in Murtie 2020 to improve clinical outcomes patients with glioma. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient, i.e., the dosage and dosing regimen, needed to achieve the desired results. The principle of law states from MPEP §§ 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages," (see In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382).
Regarding instant claims 17 and 18, while Konteatis 2023 recites a pharmaceutically acceptable salt, Konteatis 2023 does not recite the compound formula (I) is administered in a cocrystal with citric acid. Deng et al., 2017 teaches a method in making a 1:1 cocrystal between the sodium-glucose contransporter-2 inhibitor and citric acid (page 1, abstract, 1:1 cocrystal between DAP and citric acid (DAP-CA)). Furthermore, Deng et al., 2017 teaches that the cocrystal with citric acid “exhibits superior stability against high temperature and high relative humidity without compromising dissolution and tableting performance” (page 1, abstract).
Therefore, it would have been obvious to the person of ordinary skill in the art to administer vorasidenib as a cocrystal with citric acid to increase stability of the pharmaceutical composition.
Regarding instant claims 1, 35, 38, 41, 42, 43, 45, 46, and 48, Konteatis 2023 claim 18 recites administering a second therapeutic agent useful in the treatment of cancer. However, Konteatis 2023 does not recite pembrolizumab as the second therapeutic agent useful in the treatment of cancer. As described above, Murtie 2020 (cited previously) recites the checkpoint inhibitors pembrolizumab as recited in instant claim 1 (page 11, column 13, line 50-53). Murtie 2020 further discloses that the checkpoint inhibitor “would prevent immune system attacks on cancer cells, thereby allowing the immune system to attack the cancer cells” (page 11, column 13, line 50). It would have been obvious to the person of ordinary skill in the art to use pembrolizumab to enhance the immune system to attack brain cancer cells.
Konteatis 2023 does not recite dosing regimen for pembrolizumab as recited in instant claims 35, 38, 41, 43, 45, and 46. As described above Cloughesy et al., 2019 teaches the method of treating recurrent glioblastoma, wherein pembrolizumab is administered 200 mg every three weeks (Q3W) (page 10, Methods, Study design and patients). Cloughesy et al., 2019 discloses that the dosing regimen resulted in a statistical improvement in overall survival and progression-free survival in patients with recurrent glioblastoma (page 7, discussion).
Further, as described above, the FDA drug label for Keytruda® (pembrolizumab) 2020 discloses approved dosing regimen for a number of different cancers and one of them is administered at 400mg every 6 weeks (Q6W) as recited in instant claim 42 but they do not teach that the pembrolizumab is administered at a dose about 400 mg Q3W as recited in instant claim 48 (page 7, Table 1: recommended dosage, “200 mg every 3 weeks or 400 mg every 6 weeks”). Keytruda® FDA drug label 2020 further teaches that there are no differences in efficacy and safety between the dosing regimen (page 46, 12.2 pharmacokinetics) and teaches dose modifications for adverse reactions (page 8, Table 2).
Therefore, the dosing regimen of pembrolizumab is clearly a result effective parameter that a person having ordinary skill in the art would routinely optimize to reduce adverse reactions due to the therapeutic agent. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient, i.e., the dosage and dosing regimen, needed to achieve the desired results. The principle of law states from MPEP §§ 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages," (see In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382). Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation," (See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)).
Therefore, it would have been obvious to the person of ordinary skill in the art to optimize the dosing regimen of pembrolizumab as taught by Cloughesy et al., 2019 and the FDA drug safety label for Keytruda ® 2020 and expect reasonable success in improving overall survival and progression-free survival in patients with glioma receiving combination therapy with vorasidenib.
Regarding instant claims 49 and 50, Murtie 2024 claim 12 and 13 recite the compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents are administered concurrently or sequentially (page 6, column 4, line 48-50). As described above, it would have been obvious to the person of ordinary skill in the art to optimize the dosing regimen of the vorasidenib and pembrolizumab to improve survival in patient with glioma receiving vorasidenib and pembrolizumab.
Claims 1, 2, 3, 4, 7, 8, 9, 10, 11, 12, 15, 16, 17, 18, 19, 25, 26, 35, 38, 41, 42, 43, 45, 46, 48, 49, and 50 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 27, 29, 30, and 31 of U.S. Patent No. 11,345,677 B2 issued on 05/31/2022 from Servier Pharmaceuticals LLC (herein referred to as Lane 2022) in view of Murtie 2020 (cited previously), Cloughesy et al., 2019 (cited previously), and FDA drug safety label for Keytruda (cited previously).
Regarding instant claims 1, 7, 15, 17, and 18, Lane 2022 claim 1 recites a cocrystal comprising a compound of formula (I)
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(page 81, column 82, line 50) and citric acid. Formula (I) in Lane 2022 is the chemical structure and formula of vorasidenib which is also recited in the applicant’s disclosure (page 4, paragraph 0016).
Furthermore, Lane 2022 claim 11 and 12 recites a method of treating a cancer characterized by the presence of an IDH1 mutation, IDH2 mutation, or a combination thereof in a patient in need thereof, comprising administering a therapeutically effective amount of the cocrystal of the compound formula (I) to the patient and one or more pharmaceutical excipients.
Regarding instant claims 2, 3, and 4, Lane 2022 claim 21, 22, 23, 24, and 31 recite the cancer is glioma (low grade glioma or a secondary high grade glioma, glioblastoma) and Lane 2022 claim 25 recites the cancer is refractory or relapsed.
Regarding instant claims 8 and 9, Lane 2022 claims 13, 14, and 15, recite the cancer is characterized by the presence of an IDH1 mutation wherein the IDH1 mutation is an R132X mutation (R132H or R132C).
Regarding instant claims 10, 11, and 12, Lane 2022 claims 16, 17, 18, 19, and 20 recite the cancer is characterized by the presence of an IDH2 mutation wherein the IDH2 mutation is an R140X (R140W or R140L) mutation and R172X (R172K or R172G) mutation.
Regarding instant claim 16, while Lane 2022 claims teach the vorasidenib is in a cocrystal with citric acid, Lane 2022 does not teach the vorasidenib in non-salt form. However, Murtie 2020 teaches that the vorasidenib is administered in non-salt form (page 6, column 4, line 4, "compound of formula (I) is administered in non-salt (i.e., free base) form). Murtie 2020 teaches that the non-salt form which was “formulated at a concentration of 5 mg/mL in a vehicle of 0.5% methylcellulose, 0.2% Tween 80, and water” (page 26, column 23, line 20) and several “combination of Compound A and radiation therapy shows no antagonism in vivo in an orthotopic mutant IDH1 glioma brain tumor model” (page 16, column 24, line 65). It would have been obvious to the person of ordinary skill in the art to include the non-salt form of vorasidenib as taught by Murtie 2020 and expect similar inhibitory activity in combination with other therapeutic agents.
Regarding instant claims 19, 25, and 26, Lane 2022 claim 29 recites the cocrystal is administered in an amount of about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, or about 300 mg per day, based on the amount of the compound of formula (I). Further, Lane 2022 claim 30 recites the cocrystal, is administered in an amount of about 10 mg or about 50 mg, twice per day, based on the amount of the compound of formula (I).
Regarding instant claims 1, 35, 38, 41, 42, 43, 45, 46, 48, and 50, Lane 2022 claim 27 recites comprising co-administering an additional therapy to the patient. However, Lane 2022 does not recite pembrolizumab as the second therapeutic agent useful in the treatment of cancer. As described above, Murtie 2020 (cited previously) recites the checkpoint inhibitors pembrolizumab as recited in instant claim 1 (page 11, column 13, line 50-53). Murtie 2020 further discloses that the checkpoint inhibitor “would prevent immune system attacks on cancer cells, thereby allowing the immune system to attack the cancer cells” (page 11, column 13, line 50). It would have been obvious to the person of ordinary skill in the art to use pembrolizumab to enhance the immune system to attack brain cancer cells.
Lane 2022 does not recite dosing regimen for pembrolizumab as recited in instant claims 35, 38, 41, 43, 45, and 46. As described above Cloughesy et al., 2019 teaches the method of treating recurrent glioblastoma, wherein pembrolizumab is administered 200 mg every three weeks (Q3W) (page 10, Methods, Study design and patients). Cloughesy et al., 2019 discloses that the dosing regimen resulted in a statistical improvement in overall survival and progression-free survival in patients with recurrent glioblastoma (page 7, discussion).
Further, as described above, the FDA drug label for Keytruda® (pembrolizumab) 2020 discloses approved dosing regimen for a number of different cancers and one of them is administered at 400mg every 6 weeks (Q6W) as recited in instant claim 42 but they do not teach that the pembrolizumab is administered at a dose about 400 mg Q3W as recited in instant claim 48 (page 7, Table 1: recommended dosage, “200 mg every 3 weeks or 400 mg every 6 weeks”). Keytruda® FDA drug label 2020 further teaches that there are no differences in efficacy and safety between the dosing regimen (page 46, 12.2 pharmacokinetics) and teaches dose modifications for adverse reactions (page 8, Table 2).
The dosing regimen of pembrolizumab is clearly a result effective parameter that a person having ordinary skill in the art would routinely optimize to reduce adverse reactions due to the therapeutic agent. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient, i.e., the dosage and dosing regimen, needed to achieve the desired results. The principle of law states from MPEP §§ 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages," (see In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382). Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation," (See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)).
Therefore, it would have been obvious to the person of ordinary skill in the art to optimize the dosing regimen of pembrolizumab as taught by Cloughesy et al., 2019 and the FDA drug safety label for Keytruda ® 2020 and expect reasonable success in improving overall survival and progression-free survival in patients with glioma receiving combination therapy with vorasidenib.
Regarding instant claim 49, Lane 2022 does not recite the vorasidenib and pembrolizumab is administered sequentially . Murtie 2020 teaches vorasidenib and pembrolizumab are administered sequentially or concurrently (page 6, column 4, line 48-50, "additional therapeutic agents may be administered concurrently with or sequentially with (prior to or following) the administration of the compound of formula (I)"). As described above, it would have been obvious to the person of ordinary skill in the art to optimize the dosing regimen of the vorasidenib and pembrolizumab to improve survival in patient with glioma receiving vorasidenib and pembrolizumab.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Lam Thuy Vi Tran Ho whose telephone number is (571)272-9135. The examiner can normally be reached Monday-Friday 7:30-4.
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/LAM THUY VI TRAN HO/Examiner, Art Unit 1647 /L.T./Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647