DETAILED ACTION
Notice of Pre-AIA or AIA Status
The inventor or joint inventor should note that the instant invention, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2, 3,
Status of the Claims
Claims 1, 4, 5, 7-10, 12, 13, 15-17, 19, 20, 22, 23, 26-28, 31-37 and 40-43 are pending in the instant invention. According to the Amendments to the Claims, filed April 3, 2024, claims 1, 4, 5, 7-10, 12, 13, 15-17, 19, 20, 22, 23, 26-28, 31-37, 40 and 43 were amended and claims 2, 3, 6, 11, 14, 18, 21, 24, 25, 29, 30, 38, 39 and 44-50 were cancelled.
Status of Priority
This invention is a Continuation (CON) of US Application No. 18/148,311, filed December 29, 2022 and now US 11,945,785, which is a Continuation (CON) of International Application No. PCT/US2022/040953, filed October 19, 2022, which claims priority under 35 U.S.C. § 119(e) to US Provisional Application Nos.: a) 63/386,772, filed December 9, 2022; b) 63/364,860, filed May 17, 2022; c) 63/316,939, filed March 4, 2022; and d) 63/295,494, filed December 30, 2021.
Restrictions / Election of Species
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The forthcoming first Office action and prosecution on the merits includes claims 1, 4, 5, 7-10, 12, 13, 15-17, 19, 20, 22, 23, 26-28, 31-37 and 40-43, drawn to a method for treating a proliferative disease or condition, comprising administering… a substituted pyrazine of the Formula (P6-I), shown to the right above, and/or a pharmaceutical composition thereof.
Thus, a first Office action and prosecution on the merits of claims 1, 4, 5, 7-10, 12, 13, 15-17, 19, 20, 22, 23, 26-28, 31-37 and 40-43 is contained within.
Specification Objection - Disclosure
The inventor or joint inventor is advised to format the specification according to 37 CFR 1.77(c). Revisions should particularly address bold-type, underline, and/or upper case formatting. Appropriate correction may be required.
Specification Objection - Abstract
The inventor or joint inventor is reminded of the proper content of an abstract of the disclosure.
With regard particularly to chemical patents, for compounds or compositions, the general nature of the compound or composition should be given as well as the use thereof, e.g., The compounds are of the class of alkyl benzene sulfonyl ureas, useful as oral anti-diabetics. Exemplification of a species could be illustrative of members of the class. For processes, the reactions, reagents and process conditions should be stated, generally illustrated by a single example, unless variations are necessary. See MPEP § 608.01(b), Section B.
The abstract of the disclosure is objected to because it fails to exemplify any members or formulae illustrative of its class. Correction is required. See MPEP § 608.01(b).
The examiner suggests incorporating the structure of Formula (P6-I) into the abstract, to overcome this objection.
Claim Objections
Claim 1 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(a) and/or 35 U.S.C. § 112(b), the existing recitation should be replaced with the following recitation(s):
1. A method for inhibiting the activity of FMS-like tyrosine kinase 3 (FLT3) in a patient, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of a compound of Formula (P6-I):
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(P6-I)
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
R2b is H or C1-4 alkyl;
R4 is C(O)CR6a=CR6bR6c, S(O)CR6a=CR6bR6c, or S(O)2CR6a=CR6bR6c;
R6a is H, halo, CN, or C1-6 alkyl;
R6b is H, halo, CN, or C1-6 alkyl; or
R6a and R6b are joined together to form a single bond;
R6c is H, halo, CN, or C1-6 alkyl;
wherein the C1-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of NH2, OH, OC1-6 alkyl, and heterocycloalkyl;
wherein each heterocycloalkyl substituent independently contains 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S; and
wherein each NH2, OC1-6 alkyl, and heterocycloalkyl substituent is optionally and independently substituted with one or more substituents independently selected from the group consisting of halo, CN, C1-4 alkyl, OH, and OC1-4 alkyl;
L3 is C1-4 alkylene, wherein the C1-4 alkylene is optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, OH, and OC1-4 alkyl;
L1 is C1-4 alkylene, wherein the C1-4 alkylene is optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, OH, and OC1-4 alkyl;
A1 is CR7 or N;
A2 is CR7 or N;
A3 is CR7 or N;
A4 is CR7 or N;
each R7 is independently H, halo, CN, C1-6 alkyl, O(alkyl), or heterocycloalkyl;
wherein each heterocycloalkyl independently contains 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S;
wherein each C1-6 alkyl and O(alkyl) is optionally and independently substituted with one or more substituents independently selected from the group consisting of halo, CN, OH, and OC1-4 alkyl; and
wherein each heterocycloalkyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halo, CN, C1-4 alkyl, OH, and OC1-4 alkyl;
R5 is H, halo, CN, C1-6 alkyl, NHC1-6 alkyl, OC1-6 alkyl, or Cy;
wherein the C1-6 alkyl, C1-6 alkyl of NHC1-6 alkyl, or OC1-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, NH2, NH(alkyl), N(alkyl)2, OH, OC1-4 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
wherein the NH of NHC1-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, C1-4 alkyl, OH, and OC1-4 alkyl;
wherein the Cy is optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, C1-4 alkyl, NH2, NH(alkyl), N(alkyl)2, OH, OC1-4 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
wherein each heterocycloalkyl substituent independently contains 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S; and
wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl substituent is optionally and independently substituted with one or more substituents independently selected from the group consisting of halo, CN, C1-4 alkyl, OH, and OC1-4 alkyl;
Cy is cycloalkyl or heterocycloalkyl; and
R1 is H, halo, CN, C1-6 alkyl, alkenyl, alkynyl, O(alkyl), cycloalkyl, or heterocycloalkyl;
wherein the heterocycloalkyl contains 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S;
wherein the C1-6 alkyl, alkenyl, alkynyl, or O(alkyl) is optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, OH, and OC1-4 alkyl; and
wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, C1-4 alkyl, OH, and OC1-4 alkyl;
with the proviso that no more than two of A1, A2, A3, and A4 are N.
Appropriate correction is required. See MPEP § 2173.02.
Claim 4 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The method according to claim 1, wherein the compound is according to Formula (P6-IIa) or Formula (P6-IIb):
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(P6-IIa) or
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(P6-IIb),
or a pharmaceutically acceptable salt or stereoisomer thereof.
Appropriate correction is required. See MPEP § 2173.02.
Claim 5 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The method according to claim 1, wherein L1 is -CH2CH2-, CH(CH3)CH2-, or CH2CH(CH3)-.
Appropriate correction is required. See MPEP § 2173.02.
Claim 7 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The method according to claim 1, wherein the compound is according to Formula (P6-IIIa), Formula (P6-IIIb), Formula (P6-IIIc), or Formula (P6-IIId):
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(P6-IIIa),
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(P6-IIIb),
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(P6-IIIc), or
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(P6-IIId),
or a pharmaceutically acceptable salt or stereoisomer thereof.
Appropriate correction is required. See MPEP § 2173.02.
Claim 8 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The method according to claim 1, wherein R1 is H, CH3, or CH2CH3.
Appropriate correction is required. See MPEP § 2173.02.
Claim 9 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The method according to claim 1, wherein the compound is according to Formula (P6-IVa), Formula (P6-IVb), Formula (P6-IVc), or Formula (P6-IVd):
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(P6-IVa),
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(P6-IVb),
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(P6-IVc), or
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(P6-IVd),
or a pharmaceutically acceptable salt or stereoisomer thereof.
Appropriate correction is required. See MPEP § 2173.02.
Claim 10 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The method according to claim 1, wherein L3 is -CH2- or -CH(CH3)-.
Appropriate correction is required. See MPEP § 2173.02.
Claim 12 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The method according to claim 1, wherein R2b is H or CH3.
Appropriate correction is required. See MPEP § 2173.02.
Claim 13 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The method according to claim 1, wherein each R7 is independently H, F, Cl, CH3, CH2CH3, CF3, or OCH3.
Appropriate correction is required. See MPEP § 2173.02.
Claim 15 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
The method according to claim 1, wherein R5 is C1-6 alkyl, NHC1-6 alkyl, or OC1-6 alkyl;
wherein the C1-6 alkyl, C1-6 alkyl of NHC1-6 alkyl, or OC1-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, NH2, NH(alkyl), N(alkyl)2, OH, OC1-4 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
wherein the NH of NHC1-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, C1-4 alkyl, OH, and OC1-4 alkyl;
wherein each heterocycloalkyl substituent independently contains 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S; and
wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl substituent is optionally and independently substituted with one or more substituents independently selected from the group consisting of halo, CN, C1-4 alkyl, OH, and OC1-4 alkyl.
Appropriate correction is required. See MPEP § 2173.02.
Claim 16 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
The method according to claim 1, wherein R5 is F, Cl, CN, C1-4 alkyl, CF3, NHCH3, NHCH2CH3, NHCH(CH3)2, NHCH2CH2CH3, N(CH3)2, N(CH3)(CH2CH3), N(CH3)(CH(CH3)2), N(CH2CH3)2, N(CH2CH3)(CH(CH3)2), N[CH(CH3)2]2, OCH3, OCH2CH3, OCH(CH3)2, OCF3, C3-6 cycloalkyl, azetidin-1-yl, pyrrolidin-1-yl, piperdin-1-yl, or morpholin-4-yl;
wherein the C3-6 cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, C1-4 alkyl, OH, and OC1-4 alkyl; and
wherein the azetidin-1-yl, pyrrolidin-1-yl, piperdin-1-yl, or morpholin-4-yl is optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, C1-4 alkyl, NH2, NH(alkyl), N(alkyl)2, OH, OC1-4 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.
Appropriate correction is required. See MPEP § 2173.02.
Claim 17 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
The method according to claim 1, wherein R5 is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH(CH3)2, NHCH(CH3)2, N(CH3)2, N(CH3)(CH2CH3), N(CH3)(CH(CH3)2), OCH3, OCH2CH3, OCH(CH3)2, or cyclopropyl.
Appropriate correction is required. See MPEP § 2173.02.
Claim 19 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The method according to claim 1, wherein:
R6a is H;
R6b is H; and
R6c is H.
Appropriate correction is required. See MPEP § 2173.02.
Claim 20 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
The method according to claim 1, wherein:
R6a is H;
R6b is H; and
R6c is C1-6 alkyl, wherein the C1-6 alkyl is substituted with one or more substituents independently selected from the group consisting of NH2, NH(C1-4 alkyl), and N(C1-4 alkyl)2.
Appropriate correction is required. See MPEP § 2173.02.
Claim 22 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(a) and/or 35 U.S.C. § 112(b), the existing recitation should be replaced with the following recitation:
The method according to claim 1, wherein:
R6a and R6b are joined together to form a single bond; and
R6c is CH3.
Appropriate correction is required. See MPEP § 2173.02.
Claim 23 is objected to because of the following informalities: for brevity, clarity and precision, the existing recitation should be replaced with the following recitation:
The method according to claim 1, wherein:
R6a is H;
R6b is H; and
R6c is CH2-heterocycloalkyl.
Appropriate correction is required. See MPEP § 2173.02.
Claim 26 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The method according to claim 1, wherein R4 is C(O)CH=CH2, C(O)CH=CHCH2NHCH3, C(O)CH=CHCH2N(CH3)2, C(O)CH=CHCH2-azetidin-1-yl, C(O)CH=CHCH2-(3-fluoroazetidin-1-yl), C(O)CH=CHCH2-(3,3-difluoroazetidin-1-yl), C(O)C≡CH, C(O)C≡CCH3, or C(O)C≡CCH2N(CH3)2.
Appropriate correction is required. See MPEP § 2173.02.
Claim 27 is objected to because of the following informalities: a) for clarity and precision, The method according to claim 1, wherein the compound is selected from any one of the compounds listed in Table 2A, should be replaced with The method according to claim 1, wherein the compound is selected from the group consisting of any one of the compounds listed in Table 2A: ; b) for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), or a pharmaceutically acceptable stereoisomer or salt thereof should be replaced with or a pharmaceutically acceptable salt thereof and relocated to the end of the claim; and c) for clarity and precision, each claim must end with a period {see MPEP § 608.01(m)}. Appropriate correction is required. See MPEP § 2173.02.
Claim 28 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
The method according to claim 27, wherein the compound is selected from the group consisting of Compound ID 204, Compound ID 252, Compound ID 308, Compound ID 310, Compound ID 315, Compound ID 506, Compound ID 507, Compound ID 508, Compound ID 509, Compound ID 511, Compound ID 512, Compound ID 513, Compound ID 516, Compound ID 516A, Compound ID 517, and Compound ID 520, or a pharmaceutically acceptable salt thereof.
Appropriate correction is required. See MPEP § 2173.02.
Claim 31 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
The method according to claim 27, wherein the compound is Compound ID 204, or a pharmaceutically acceptable salt thereof.
Appropriate correction is required. See MPEP § 2173.02.
Claim 32 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
The method according to claim 27, wherein the compound is Compound ID 516A, or a pharmaceutically acceptable salt thereof.
Appropriate correction is required. See MPEP § 2173.02.
Claim 33 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
The method according to claim 27, wherein the compound is Compound ID 252, or a pharmaceutically acceptable salt thereof.
Appropriate correction is required. See MPEP § 2173.02.
Claim 34 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
The method according to claim 27, wherein the compound is Compound ID 506, or a pharmaceutically acceptable salt thereof.
Appropriate correction is required. See MPEP § 2173.02.
Claim 35 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
The method according to claim 27, wherein the compound is Compound ID 511, or a pharmaceutically acceptable salt thereof.
Appropriate correction is required. See MPEP § 2173.02.
Claim 36 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(a), 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation(s):
36. A method for inhibiting the activity of FMS-like tyrosine kinase 3 (FLT3) in a patient, wherein the method comprises administering to the patient in need thereof a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of Formula (P6-I):
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(P6-I)
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
R2b is H or C1-4 alkyl;
R4 is C(O)CR6a=CR6bR6c, S(O)CR6a=CR6bR6c, or S(O)2CR6a=CR6bR6c;
R6a is H, halo, CN, or C1-6 alkyl;
R6b is H, halo, CN, or C1-6 alkyl; or
R6a and R6b are joined together to form a single bond;
R6c is H, halo, CN, or C1-6 alkyl;
wherein the C1-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of NH2, OH, OC1-6 alkyl, and heterocycloalkyl;
wherein each heterocycloalkyl substituent independently contains 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S; and
wherein each NH2, OC1-6 alkyl, and heterocycloalkyl substituent is optionally and independently substituted with one or more substituents independently selected from the group consisting of halo, CN, C1-4 alkyl, OH, and OC1-4 alkyl;
L3 is C1-4 alkylene, wherein the C1-4 alkylene is optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, OH, and OC1-4 alkyl;
L1 is C1-4 alkylene, wherein the C1-4 alkylene is optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, OH, and OC1-4 alkyl;
A1 is CR7 or N;
A2 is CR7 or N;
A3 is CR7 or N;
A4 is CR7 or N;
each R7 is independently H, halo, CN, C1-6 alkyl, O(alkyl), or heterocycloalkyl;
wherein each heterocycloalkyl independently contains 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S;
wherein each C1-6 alkyl and O(alkyl) is optionally and independently substituted with one or more substituents independently selected from the group consisting of halo, CN, OH, and OC1-4 alkyl; and
wherein each heterocycloalkyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halo, CN, C1-4 alkyl, OH, and OC1-4 alkyl;
R5 is H, halo, CN, C1-6 alkyl, NHC1-6 alkyl, OC1-6 alkyl, or Cy;
wherein the C1-6 alkyl, C1-6 alkyl of NHC1-6 alkyl, or OC1-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, NH2, NH(alkyl), N(alkyl)2, OH, OC1-4 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
wherein the NH of NHC1-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, C1-4 alkyl, OH, and OC1-4 alkyl;
wherein the Cy is optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, C1-4 alkyl, NH2, NH(alkyl), N(alkyl)2, OH, OC1-4 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
wherein each heterocycloalkyl substituent independently contains 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S; and
wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl substituent is optionally and independently substituted with one or more substituents independently selected from the group consisting of halo, CN, C1-4 alkyl, OH, and OC1-4 alkyl;
Cy is cycloalkyl or heterocycloalkyl; and
R1 is H, halo, CN, C1-6 alkyl, alkenyl, alkynyl, O(alkyl), cycloalkyl, or heterocycloalkyl;
wherein the heterocycloalkyl contains 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S;
wherein the C1-6 alkyl, alkenyl, alkynyl, or O(alkyl) is optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, OH, and OC1-4 alkyl; and
wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, C1-4 alkyl, OH, and OC1-4 alkyl;
with the proviso that no more than two of A1, A2, A3, and A4 are N.
Appropriate correction is required. See MPEP § 2173.02.
Claim 37 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
The method according to claim 36, wherein the pharmaceutical composition is formulated for a route of administration selected from the group consisting of buccal administration, nasal administration, oral administration, parenteral administration, rectal administration, and topical administration.
Appropriate correction is required. See MPEP § 2173.02.
Claim 40 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation(s):
40. The method according to claim 1, wherein the patient has a cancer.
51. The method according to claim 36, wherein the patient has a cancer.
Appropriate correction is required. See MPEP § 2173.02.
Claim 41 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation(s):
41. The method according to claim 40, wherein the cancer is a hematological malignancy.
52. The method according to claim 51, wherein the cancer is a hematological malignancy.
Appropriate correction is required. See MPEP § 2173.02.
Claim 42 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation(s):
42. The method according to claim 40, wherein the hematological malignancy is selected from the group consisting of acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), hairy cell leukemia (HCL), large granular lymphocytic leukemia (LGLL), mast-cell leukemia (MCL), myelodysplastic syndrome (MDS), and prolymphocytic leukemia (PLL).
53. The method according to claim 52, wherein the hematological malignancy is selected from the group consisting of acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), hairy cell leukemia (HCL), large granular lymphocytic leukemia (LGLL), mast-cell leukemia (MCL), myelodysplastic syndrome (MDS), and prolymphocytic leukemia (PLL).
Appropriate correction is required. See MPEP § 2173.02.
Claim 43 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation(s):
43. The method according to claim 1, wherein the patient has an FMS-like tyrosine kinase 3 (FLT3) mutation selected from the group consisting of D835H, D835V, D835Y, F691L, N676K, and Y842C, or a combination thereof.
54. The method according to claim 36, wherein the patient has an FMS-like tyrosine kinase 3 (FLT3) mutation selected from the group consisting of D835H, D835V, D835Y, F691L, N676K, and Y842C, or a combination thereof.
Appropriate correction is required. See MPEP § 2173.02.
Claim Rejections - 35 U.S.C. § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. § 112:
(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.
Method for treating a proliferative disease or condition, comprising administering… a substituted pyrazine of the Formula (P6-I)
Claims 1, 4, 5, 7-10, 12, 13, 15-17, 19, 20, 22, 23, 26-28, 31-37 and 40-43 are rejected under 35 U.S.C. § 112(a) as failing to comply with the enablement requirement because the claims contain subject matter, particularly a method for treating a proliferative disease or condition, comprising administering… a substituted pyrazine of the Formula (P6-I), which was not described in the specification in such a way as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use (perform) the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is undue. These factors include, but are not limited to: (a) breadth of the claims; (b) nature of the invention; (c) state of the prior art; (d) level of one of ordinary skill in the art; (e) level of predictability in the art; (f) amount of direction provided by the inventor or joint inventor; (g) existence of working examples; and (h) quantity of experimentation needed to make or use the invention based on the content of the disclosure. {See Ex parte Forman 230 USPQ 546 (Bd. Pat. App. & Inter. 1986); and In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988)}.
The above factors, regarding the present invention, are summarized as follows:
(a) Breadth of the claims - the breadth of the claims includes a method for treating a
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proliferative disease or condition, comprising administering… a substituted pyrazine of the Formula (P6-I), shown to the right;
(b) Nature of the invention - the nature of the invention is performance of a method for treating a proliferative disease or condition, comprising administering… a substituted pyrazine of the Formula (P6-I), shown to the right above;
(c) State of the prior art - Nature Reviews: Drug Discovery offers a snapshot of the state of the drug development art. Herein, drug development is stated to follow the widely accepted Ehrlich model which includes: (1) development of a broad synthetic organic chemistry program; (2) subsequent testing of compounds in an appropriate laboratory model for the disease to be treated; and (3) screening of compounds with low toxicity in prospective clinical trials (Jordan, V. C. Nature Reviews: Drug Discovery, 2, 2003, 205). Similarly, no single drug has been discovered that is effective in treating the myriad of proliferative diseases or conditions in a patient, including, but not limited to, a hematological malignancy {See In re Hokum, 226 USPQ 353 (ComrPats 1985)}. Moreover, WO 23/027966, as provided in the file and cited on the IDS, illustrates the synthesis of substituted pyrazines of the Formula (P6-I), and/or methods of use thereof {Butler, et al. WO 09/137797, 2023};
(d) Level of one of ordinary skill in the art - the artisans performing the inventor’s or joint inventor’s method for treating a proliferative disease or condition, comprising administering… a substituted pyrazine of the Formula (P6-I), would be a collaborative team of synthetic chemists and/or health practitioners, possessing commensurate degree level and/or skill in the art, as well as several years of professional experience;
(e) Level of predictability in the art - Synthetic organic chemistry is quite unpredictable (See In re Marzocchi and Horton 169 USPQ at 367 ¶3). Similarly, it is well established that [T]he scope of enablement varies inversely with the degree of unpredictability of the factors involved, and physiological activity is generally considered to be an unpredictable factor {See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970)}.
Moreover, the following excerpt is taken from Hackam, et al., with respect to the poor replication of animal research in human clinical trials {Hackam, et al. JAMA, 296(14), 2006, 1731-1732}:
Only about a third of highly cited animal research translated at the level of human randomized trials. This rate of translation is lower than the recently estimated 44% replication rate for highly cited human studies. Nevertheless, we believe these findings have important implications. First, patients and physicians should remain cautious about extrapolating the findings of prominent animal research to the care of human disease. Second, major opportunities for improving study design and methodological quality are available for preclinical research. Finally, poor replication of even high-quality animal studies should be expected by those who conduct clinical research.
(f) Amount of direction provided by the inventor - the invention lacks direction with respect to making and/or using (performing) a method for treating a proliferative disease or condition, comprising administering… a substituted pyrazine of the Formula (P6-I);
(g) Existence of working examples - the disclosure is insufficient to allow extrapolation of the limited examples to enable performing the instantly recited method for treating a proliferative disease or condition, comprising administering… a substituted pyrazine of the Formula (P6-I).
Similarly, according to the specification, substituted pyrazines of the Formula (P6-I) are capable of treating a variety of proliferative diseases or conditions in a patient, including, but not limited to, a hematological malignancy; however, the specification fails to set forth any convincing in vitro and/or in vivo assays corroborating the alleged activity in association with any proliferative diseases or conditions in a patient, including, but not limited to, a hematological malignancy. There is insufficient disclosure to reasonably conclude that the method for treating a proliferative disease or condition, comprising administering… a substituted pyrazine of the Formula (P6-I), as recited, would contribute to treatment of any proliferative diseases or conditions in a patient, including, but not limited to, a hematological malignancy. Furthermore, the combination of the instant specification and Butler, et al. in WO 09/137797, as provided in the file and cited on the IDS, lacks adequate credible evidence to support the assertion that a method for treating a proliferative disease or condition, comprising administering… a substituted pyrazine of the Formula (P6-I), as recited, would contribute to the prophylaxis of any proliferative diseases or conditions in a patient, including, but not limited to, a hematological malignancy, since the inventor or joint inventor has neither provided convincing data for any patient population, nor indicated any art recognized correlation between the disclosed data and the breadth of the claims.
Within the specification, [A]t least one specific operative embodiment or example of the invention must be set forth. The example(s) and description should be of sufficient scope as to justify the scope of the claims. Markush claims must be provided with support in the disclosure for each member of the Markush group. Where the constitution and formula of a chemical compound is stated only as a probability or speculation, the disclosure is not sufficient to support claims identifying the compound by such composition or formula. See MPEP § 608.01(p) and MPEP § 2173.05.
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(h) Quantity of experimentation needed to make and/or use (perform) the invention based on the content of the disclosure - predicting whether a recited compound is in fact one that produces a desired physiological effect at a therapeutic concentration and with useful kinetics, is filled with experimental uncertainty, and without proper guidance, would involve a substantial amount of experimentation (Jordan, V. C. Nature Reviews: Drug Discovery, 2, 2003, 205-213). Furthermore, it is unclear, based on the guidance provided by the specification, whether a substituted pyrazine of the Formula (P6-I), such as (S,E)-5-(dimethylamino)-3-((3-(2-(2-(4-(dimethylamino)-N-methyl-but-2-enamido)propanamido)ethyl)phenyl)amino)-6-ethylpyrazine-2-carboxamide, shown to the left above, possesses utility as a therapeutic agent, useful in a method for treating a proliferative disease or condition, comprising administering… a substituted pyrazine of the Formula (P6-I). Thus, one of ordinary skill in the art, at the time this invention was made, would have an unreasonable expectation of success and undue experimentation in transferring the in vitro and/or in vivo method for treating a proliferative disease or condition, comprising administering… a substituted pyrazine of the Formula (P6-I), wherein the proliferative disease or condition in a patient, includes, but is not limited to, a hematological malignancy, to any patient population.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the invention was filed, would not have taught one skilled in the art how to make and/or use (perform) the full scope of the claimed invention without undue experimentation. {See In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)}.
The determination that undue experimentation would have been needed to make and use the claimed invention is not a single, simple factual determination. Rather, it is a conclusion reached by weighing all the above noted factual considerations. (See In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404). These factual considerations are discussed comprehensively in MPEP § 2164.08 (scope or breadth of the claims), § 2164.05(a) (nature of the invention and state of the prior art), § 2164.05(b) (level of one of ordinary skill), § 2164.03 (level of predictability in the art and amount of direction provided by the inventor or joint inventor), § 2164.02 (the existence of working examples) and § 2164.06 (quantity of experimentation needed to make or use the invention based on the content of the disclosure).
Based on a preponderance of the evidence presented herein, the conclusion that the inventor or joint inventor is insufficiently enabled for making and/or using (performing) a method for treating a proliferative disease or condition, comprising administering… a substituted pyrazine of the Formula (P6-I), is clearly justified.
The examiner suggests amending the claims, particularly as stated in the section above entitled Claim Objections, to overcome this rejection.
Claim Rejections - 35 U.S.C. § 112(b)
The following is a quotation of the second paragraph of 35 U.S.C. § 112:
(b) CONCLUSION. The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or joint inventor regards as the invention.
Claim 16 is rejected under 35 U.S.C. § 112(b) as being indefinite for failing to set forth the subject matter which the inventor or joint inventor regards as the invention.
The inventor or joint inventor should note that claim 16 recites the limitation, 1-morpholinyl, with respect to R5, where the limitation is implausible, resulting in an incomplete valence. Claims are unduly speculative where they define only a portion of a substituted pyrazine of the Formula (P6-I). Consequently, since incomplete valences are not permitted in the structure of the substituted pyrazines of the Formula (P6-I), an essential portion of the substituted pyrazines of the Formula (P6-I) is indefinite and one of ordinary skill in the art would not be reasonably apprised of the metes and bounds of the substituted pyrazines of the Formula (P6-I). {See Ex parte Pedlow and Miner, 90 USPQ 395 (Bd. Pat. App. & Int. 1951)}.
The examiner suggests amending the claim, particularly as stated in the section above entitled Claim Objections, to overcome this rejection.
Claims 27, 28 and 31-35 are rejected under 35 U.S.C. § 112(b) as being indefinite for failing to set forth the subject matter which the inventor or joint inventor regards as the invention.
The inventor or joint inventor should note that a broad limitation together with a narrow limitation that falls within the broad limitation (in the same claim) is considered indefinite, since the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c), MPEP § 2173.05(h), and/or Eli Lilly & Co. v. Teva Parenteral Meds., 845 F.3d 1357, 1371, 121 USPQ2d 1277, 1287 (Fed. Cir. 2017).
Similarly, the inventor or joint inventor should further note that claim 27 recites the broad limitation, or a stereoisomer thereof, and the claim also recites abs, which is the narrower statement of the limitation.
Likewise, the inventor or joint inventor should further note the explanation given by the Board of Patent Appeals and Interferences in Ex parte Wu, 10 USPQ2d 2031, 2033 (Bd. Pat. App. & Inter. 1989), pertaining to where broad language is followed by such as and then narrow language. The Board stated that this can render a claim indefinite by raising a question or doubt as to whether the feature introduced by such language is (a) merely exemplary of the remainder of the claim, and consequently, not required, or (b) a required feature of the claim.
Next, the inventor or joint inventor should further note the explanation given by the Board of Patent Appeals and Interferences in the decisions of Ex parte Steigewald, 131 USPQ 74 (Bd. App. 1961); Ex parte Hall, 83 USPQ 38 (Bd. App. 1948); and Ex parte Hasche, 86 USPQ 481 (Bd. App. 1949).
Moreover, the inventor or joint inventor should further note that [C]laims which depend from indefinite claims are also indefinite. {See Ex parte Cordova, 10 USPQ 2d 1949, 1952 (PTO Bd. App. 1989)}.
The examiner suggests amending the claims, particularly as stated in the section above entitled Claim Objections, to overcome this rejection.
Claim Rejections - 35 U.S.C. § 112(d)
The following is a quotation of the fourth paragraph of 35 U.S.C. § 112:
(d) REFERENCE IN DEPENDENT FORMS. Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 20 is rejected under 35 U.S.C. § 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
The inventor or joint inventor should note that claim 20 recites the limitation, The method according to claim 1, wherein… R6c is C1-6 alkyl substituted with amino, alkylamino or dialkylamino, in lines 1-2 of the claim. According to claim 1, R6c is C1-6 alkyl… substituted with amino… and the substituents on each amino… are selected from… C1-4 alkyl, with respect to the substituted pyrazines of the Formula (P6-I). Consequently, since The method according to claim 1, wherein… R6c is C1-6 alkyl substituted with amino, alkylamino or dialkylamino, fails to specify a further limitation to the substituted pyrazines of the Formula (P6-I), as recited in claim 1, and/or fails to include all the limitations of the substituted pyrazines of the Formula (P6-I), as recited in claim 1, the instant dependent claim is rendered improperly dependent under 35 U.S.C. § 112(d).
Similarly, the inventor or joint inventor should further note that the U.S. Court of Appeals for the Federal Circuit indicated that although the requirements of 35 U.S.C. § 112(d) are related to matters of form, non-compliance with 35 U.S.C. § 112(d) renders the claim unpatentable just as non-compliance with other subsections of 35 U.S.C. § 112 would. {See Pfizer, Inc. v. Ranbaxy Labs., Ltd., 457 F.3d 1284, 1291-92 (Fed. Cir. 2006)}.
Moreover, the inventor or joint inventor should further note that if a dependent claim does not comply with the requirements of 35 U.S.C. § 112(d) the dependent claim should be rejected under 35 U.S.C. § 112(d) as unpatentable rather than objecting to the claim. {See also MPEP § 608.01(n), Section III, Infringement Test for dependent claims}.
The examiner suggests the inventor or joint inventor (1) cancel the dependent claim, (2) amend the dependent claim to place the dependent claim in proper dependent form, particularly as stated in the section above entitled Claim Objections, (3) rewrite the dependent claim in independent form, or (4) present a sufficient showing that the dependent claim complies with the statutory requirements, to overcome this rejection.
Claim Rejections - Obviousness-type 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 obviousness-type double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined invention claim is not patentably distinct from the reference claims because the examined invention claim is either anticipated by, or would have been obvious over, the reference claims. {See 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); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969)}.
Consequently, claims 1, 4, 5, 7-10, 12, 13, 15-17, 19, 20, 22, 23, 26-28, 31-37 and 40-43 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-28 of US Patent No. 11,945,785. Although the conflicting claims are not identical, they are not patentably distinct from each other because claim 1 in US 11,945,785 recites substituted pyrazines of the Formula (P6-I), where R2b = -C1-4 alkyl; R4 = -C(O)CR6a=CR6bR6c, wherein R6a = -H, R6b= -H, and R6c = -C1-6 alkyl-N(C1-4 alkyl)2; L3 = -C1-4 alkylene-; L1 = -C1-4 alkylene-; A1 = CR7, wherein R7 = -H; A2 = CR7, wherein R7 = -H; A3 = CR7, wherein R7 = -H; A4 = CR7, wherein R7 = -H; R5 = -N(C1-6 alkyl)2; and R1 = -C1-6 alkyl, respectively, which are administered within the instantly recited method for treating a proliferative disease or condition, comprising administering… a substituted pyrazine of the Formula (P6-I), where R2b = -C1-4 alkyl; R4 = -C(O)CR6a=CR6bR6c, wherein R6a = -H, R6b= -H, and R6c = -C1-6 alkyl-N(C1-4 alkyl)2; L3 = -C1-4 alkylene-; L1 = -C1-4 alkylene-; A1 = CR7, wherein R7 = -H; A2 = CR7, wherein R7 = -H; A3 = CR7, wherein R7 = -H; A4 = CR7, wherein R7 = -H; R5 = -N(C1-6 alkyl)2; and R1 = -C1-6 alkyl, respectively.
The inventor or joint inventor should note that [T]he discovery of a previously unappreciated property of a prior art compound, or of a scientific explanation for the prior art’s functioning, does not render the old compound patentably new to the discoverer. {See Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999)}.
Similarly, the inventor or joint inventor should further note that [T]he claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. {See In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977); and In re Crish, 393 F.3d 1253, 1258, 73 USPQ2d 1364, 1368 (Fed. Cir. 2004)}.
Likewise, the inventor or joint inventor should note that [W]hen the claim recites using an old compound and the use is directed to a result or property of that compound, then the claim is anticipated. {See In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978); and In re Tomlinson, 363 F.2d 928, 150 USPQ 623 (CCPA 1966)}.
Next, the inventor or joint inventor should further note that [P]roducts of identical chemical composition may not have mutually exclusive properties. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties the inventor or joint inventor discloses and/or claims are necessarily present. {See In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990)}.
Then, the inventor or joint inventor should further note that [A] claim to a method of using a composition is not patentably distinct from an earlier claim to the identical composition in a patent disclosing the identical use. {See Sun Pharmaceuticals Industries Ltd. v. Eli Lilly and Co., 611 F.3d 1381, 95 USPQ2d 1797 (Fed. Cir. 2010); Pfizer, Inc. v. Teva Pharmaceuticals USA, Inc., 518 F.3d 1353, 1363, 86 USPQ2d 1001 (Fed. Cir. 2008); and Geneva
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Pharmaceuticals, Inc. v. GlaxoSmithKline PLC,
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349 F.3d 1373, 68 USPQ2d 1865, (Fed. Cir. 2003)}.
Moreover, the inventor or joint inventor should further note that a timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 37 CFR 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground, provided the conflicting invention or patent either is shown to be commonly owned with this invention, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement.
Furthermore, the inventor or joint inventor should also note that the USPTO internet Web site contains terminal disclaimer forms which may be used, and the inventor or joint inventor is encouraged to visit http://www.uspto.gov/forms/, where (i) the filing date of the invention will determine what form should be used, and (ii) a web-based eTerminal Disclaimer may be filled out completely online using web-screens, respectively.
Also, the inventor or joint inventor should further note that an eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission.
Finally, for more information about eTerminal Disclaimers, the inventor or joint inventor should refer to http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Allowable Subject Matter
No claims are allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DOUGLAS M. WILLIS, whose telephone number is 571-270-5757. The examiner may normally be reached on Monday thru Thursday from 8:00-6:00 EST. The examiner is also available on alternate Fridays.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Mr. Jeffrey Murray, may be reached on 571-272-9023. The fax phone number for the organization where this invention or proceeding is assigned is 571-273-8300.
Information regarding the status of an invention may be obtained from Patent Center. For more information about Patent Center, see https://www.uspto.gov/patents/apply/patent-center. Should you have questions on access to Patent Center, contact the Patent Electronic Business Center (PEBC) at 866-217-9197 (toll-free) or ebc@uspto.gov.
/DOUGLAS M WILLIS/
Primary Examiner, Art Unit 1624
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