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 .
Status of the Claims
Claims 1-4, 8-10, 13-15, 17, 20-24 and 26-34 are pending in the instant invention. According to the Amendments to the Claims, filed June 21, 2024, claims 1-4, 8-10, 13-15, 17 and 20-24 were amended, claims 5-7, 11, 12, 16, 18, 19 and 25 were cancelled and claims 26-34 were added.
Status of Priority
This invention is a 35 U.S.C. § 371 National Stage Filing of International Application No. PCT/EP2022/087613, filed December 22, 2022, which claims priority under 35 U.S.C. § 119(a-d) to: a) EP 21217182.1, filed December 22, 2021; and b) EP 21217181.3, filed December 22, 2021.
Restrictions / Election of Species
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The inventor’s or joint inventor’s provisional election of the following, without traverse, in the reply filed on August 19, 2026, is acknowledged: a) Group I - claims 2-4, 8-10, 13, 22, 24 and 26-31; and b) substituted thioether of formula (I) - pp. 135-136, Example 1, shown to the right below, and hereafter referred to as N-((5-(2-((2-isopropylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)pivalamide, where Y1 is formula (Sc1), shown to the left below, wherein G1 = N, R2 = -CH(CH3)2, A1 = CR7, where R7 = -H, A2 = CR7, where R7 = -H, A3 = CR7, where R7 = -H, and A4 = CR7, where R7 = -H; Y2 is
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shown to the right below, wherein R12 = -H and R13
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= -H; L = -(CR10R11)n-, wherein n = 1, R10 = -H and R11 = -H; R1 = -H; and Z1 = -C(O)R9, wherein R9 = -C(CH3)3. Claims 2-4, 8-10, 13, 22, 24 and 26-29 read on the elected species. Affirmation
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of this election must be made by the inventor or joint inventor in replying to this Office action.
Similarly, the inventor or joint inventor should further note that the requirement is still deemed proper and is therefore made FINAL.
Likewise, the inventor or joint inventor should further note that the elected species, shown to the right, was found to be free of the prior art. Thus, the examiner has expanded the forthcoming prosecution to include all claims relevant to the genus of Group I, for a first Office action and prosecution on the merits.
Moreover, the inventor or joint inventor should further note that claims 1, 14, 15, 17, 20, 21, 23 and 32-34 were withdrawn from further consideration, pursuant to 37 CFR 1.142(b), as being drawn to a nonelected or cancelled invention, there being no allowable generic or linking claim.
Thus, a first Office action and prosecution on the merits of claims 2-4, 8-10, 13, 22, 24 and 26-31 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 - Title
The inventor or joint inventor is reminded of the proper content of the title of the invention.
The title of the invention should be brief, but technically accurate and descriptive and should contain fewer than 500 characters. See 37 CFR 1.72(a) and MPEP § 606.
The title of the invention is not technically accurate and descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed. In the revised title, the examiner suggests additionally identifying the substituted thioethers of the formula (I).
The following title is suggested: SUBSTITUTED THIOETHERS AS HDAC6 INHIBITORS.
Appropriate correction is required.
Claim Objections
Claim 2 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:
A compound of formula (I):
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(I)
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
Y1 is:
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,
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,
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171
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,
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172
135
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,
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141
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,
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138
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,
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,
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138
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,
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172
135
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,
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,
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,
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, or
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;
R2 is H, halogen, CN, C1-C6 alkyl, C1-C6 alkylene-C(O)NR17R18, C1-C6 alkylene-C(O)OR15, C1-C6 alkylene-NR17R18, C1-C6 alkylene-NR16-C(O)R15, C1-C6 alkylene-NR16-S(O)2R15, C1-C6 alkylene-OR15, C1-C6 alkylene-S(O)2-NR17R18, C1-C6 alkylene-C3-C7 cycloalkyl, C1-C6 alkylene-C3-C7 heterocycloalkyl, C(O)R15, C(O)NR17R18, C(O)OR15, NR17R18, NR16-C1-C6 alkylene-C(O)NR17R18, NR16-C1-C6 alkylene-C(O)OR15, NR16-C2-C6 alkylene-NR17R18, NR16-C2-C6 alkylene-NR16-C(O)R15, NR16-C2-C6 alkylene-NR17-S(O)2R15, NR16-C2-C6 alkylene-OR15, NR16C(O)R15, NR16-S(O)2R15, OR15, O-C1-C6 alkylene-C(O)NR17R18, O-C1-C6 alkylene-C(O)OR15, O-C2-C6 alkylene-NR17R18, O-C2-C6 alkylene-NR16-C(O)R15, O-C2-C6 alkylene-NR16-S(O)2R15, O-C2-C6 alkylene-OR15, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, aryl, or heteroaryl;
G1 is CR3 or N;
R3 is halogen, CN, C1-C6 alkyl, C1-C6 alkylene-C(O)NR17R18, C1-C6 alkylene-C(O)OR15, C1-C6 alkylene-NR17R18, C1-C6 alkylene-NR16-C(O)R15, C1-C6 alkylene-NR16-S(O)2R15, C1-C6 alkylene-OR15, C1-C6 alkylene-S(O)2-NR17R18, C1-C6 alkylene-C3-C7 cycloalkyl, C1-C6 alkylene-C3-C7 heterocycloalkyl, C(O)R15, C(O)NR17R18, C(O)OR15, NR17R18, NR16-C1-C6 alkylene-C(O)NR17R18, NR16-C1-C6 alkylene-C(O)OR15, NR16-C2-C6 alkylene-NR17R18, NR16-C2-C6 alkylene-NR16-C(O)R15, NR16-C2-C6 alkylene-NR17-S(O)2R15, NR16-C2-C6 alkylene-OR15, NR16C(O)R15, NR16-S(O)2R15, OR15, O-C1-C6 alkylene-C(O)NR17R18, O-C1-C6 alkylene-C(O)OR15, O-C2-C6 alkylene-NR17R18, O-C2-C6 alkylene-NR16-C(O)R15, O-C2-C6 alkylene-NR16-S(O)2R15, O-C2-C6 alkylene-OR15, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, aryl, or heteroaryl;
G2 is -NR4- or -O-;
R4 is H, C1-C6 alkyl, C1-C6 alkylene-C(O)NR17R18, C1-C6 alkylene-C(O)OR15, C1-C6 alkylene-NR17R18, C1-C6 alkylene-NR16-C(O)R15, C1-C6 alkylene-OR15, C1-C6 alkylene-O-C(O)R15, C1-C6 alkylene-C3-C7 cycloalkyl, C1-C6 alkylene-C3-C7 heterocycloalkyl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, or C3-C7 cycloalkyl;
B is -NR5-, -O-, or -S-;
R5 is H, C1-C6 alkyl, C1-C6 alkylene-C(O)NR17R18, C1-C6 alkylene-C(O)OR15, C1-C6 alkylene-NR17R18, C1-C6 alkylene-NR16-C(O)R15, C1-C6 alkylene-OR15, C1-C6 alkylene-O-C(O)R15, C1-C6 alkylene-C3-C7 cycloalkyl, C1-C6 alkylene-C3-C7 heterocycloalkyl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, aryl, or heteroaryl;
A1 is CR7 or N;
A2 is CR7 or N;
A3 is CR7 or N;
A4 is CR7 or N;
A5 is CR7 or N;
A6 is CR7 or N;
A7 is CR7 or N;
A8 is CR7 or N;
A9 is CR7 or N;
A10 is CR7 or N;
A11 is CR7 or N;
each R7 is independently H, halogen, C1-C6 alkyl, C1-C6 alkylene-C(O)NR17R18, C1-C6 alkylene-C(O)OR15, C1-C6 alkylene-NR17R18, C1-C6 alkylene-NR16-C(O)R15, C1-C6 alkylene-NR16-S(O)2R15, C1-C6 alkylene-OR15, C1-C6 alkylene-O-C(O)R15, C1-C6 alkylene-S(O)2-NR17R18, C1-C6 alkylene-C3-C7 cycloalkyl, C1-C6 alkylene-C3-C7 heterocycloalkyl, C(O)R15, C(O)NR17R18, C(O)OR15, NR17R18, NR16-C1-C6 alkylene-C(O)NR17R18, NR16-C1-C6 alkylene-C(O)OR15, NR16-C2-C6 alkylene-NR17R18, NR16-C2-C6 alkylene-NR17-C(O)R15, NR16-C2-C6 alkylene-NR17-S(O)2R15, NR16-C2-C6 alkylene-OR15, NR16-C2-C6 alkylene-O-C(O)R15, NR16C(O)R15, NR16-C(O)OR15, NR16-S(O)2R15, OR15, O-C1-C6 alkylene-C(O)NR17R18, O-C1-C6 alkylene-C(O)OR15, O-C2-C6 alkylene-NR17R18, O-C2-C6 alkylene-O-C(O)R15, O-C2-C6 alkylene-NR16-S(O)2R15, O-C2-C6 alkylene-OR15, OC(O)R15, S(O)R15, S(O)2R15, S(O)2NR17R18, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, aryl, or heteroaryl;
Y2 is:
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,
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108
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,
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,
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, or
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;
R12 is H, halogen, CN, C1-C6 alkyl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, OH, or OC1-C6 alkyl;
R13 is H, halogen, CN, C1-C6 alkyl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, OH, or OC1-C6 alkyl;
R14 is H, halogen, CN, C1-C6 alkyl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, OH, or OC1-C6 alkyl;
L is -(CR10R11)n-, C4-C7 cycloalkylene, or C4-C7 heterocycloalkylene;
R10 is H, halogen, C1-C3 alkyl, C1-C2 haloalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, NH2, NHC1-C3 alkyl, N(C1-C3 alkyl)2, OH, or OC1-C4 alkyl;
R11 is H, halogen, C1-C3 alkyl, C1-C2 haloalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, NH2, NHC1-C3 alkyl, N(C1-C3 alkyl)2, OH, or OC1-C4 alkyl;
n is 1 or 2;
each R15 is independently H, C1-C6 alkyl, C1-C6 alkylene-C3-C7 cycloalkyl, C1-C6 alkylene-C3-C7 heterocycloalkyl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, aryl, or heteroaryl;
each R16 is independently H, C1-C6 alkyl, C1-C6 alkylene-C3-C7 cycloalkyl, C1-C6 alkylene-C3-C7 heterocycloalkyl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, aryl, or heteroaryl;
each R17 is independently H, C1-C6 alkyl, C1-C6 alkylene-C3-C7 cycloalkyl, C1-C6 alkylene-C3-C7 heterocycloalkyl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, aryl, or heteroaryl;
each R18 is independently H, C1-C6 alkyl, C1-C6 alkylene-C3-C7 cycloalkyl, C1-C6 alkylene-C3-C7 heterocycloalkyl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, aryl, or heteroaryl; or
any R15 and R16, taken together with the atoms to which they are attached, form a C3-C7 heterocycloalkyl; or
any R16 and R17, taken together with the atoms to which they are attached, form a C3-C7 heterocycloalkyl; or
any R17 and R18, taken together with the nitrogen atom to which they are attached, form a C3-C7 heterocycloalkyl;
R1 is H, C1-C6 alkyl, C1-C6 alkylene-NR19R20, C1-C6 alkylene-OR19, C1-C6 alkylene-C3-C7 cycloalkyl, C1-C6 alkylene-C3-C7 heterocycloalkyl, C3-C7 cycloalkyl, or C3-C7 heterocycloalkyl; or
R1 and one of R10 or R11, taken together with the atoms to which they are attached, form a C3-C7 heterocycloalkyl, wherein the C3-C7 heterocycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl, CH2NHC1-C6 alkyl, CH2N(C1-C6 alkyl)2, CH2OC1-C6 alkyl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, OH, OC1-C6 alkyl, and =O;
R19 is H, C1-C6 alkyl, or C3-C7 cycloalkyl;
R20 is H, C1-C6 alkyl, or C3-C7 cycloalkyl; or
R19 and R20, taken together with the nitrogen atom to which they are attached, form a C3-C7 heterocycloalkyl;
Z1 is C(O)R9 or S(O)2R9;
R9 is C1-C6 alkyl, C1-C6 alkylene-C(O)NR23R24, C1-C6 alkylene-C(O)OR21, C1-C6 alkylene-NR23R24, C1-C6 alkylene-NR22-C(O)R21, C1-C6 alkylene-OR21, C1-C6 alkylene-S(O)2-NR23R24, C1-C6 alkylene-C3-C7 cycloalkyl, C1-C6 alkylene-C3-C7 heterocycloalkyl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, NR23R24, NR22-C1-C6 alkylene-C(O)OR21, NR22-C2-C6 alkylene-NR23R24, NR22-C2-C6 alkylene-OR21, OR21, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, aryl, or heteroaryl; or
R1 and R9, taken together with the atoms to which they are attached, form a C3-C7 heterocycloalkyl, wherein the C3-C7 heterocycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl, CH2NHC1-C6 alkyl, CH2N(C1-C6 alkyl)2, CH2OC1-C6 alkyl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, OH, OC1-C6 alkyl, and =O;
R21 is H, C1-C6 alkyl, C1-C6 alkylene-C3-C7 cycloalkyl, C1-C6 alkylene-C3-C7 heterocycloalkyl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, aryl, or heteroaryl;
R22 is H, C1-C6 alkyl, C1-C6 alkylene-C3-C7 cycloalkyl, C1-C6 alkylene-C3-C7 heterocycloalkyl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, aryl, or heteroaryl;
R23 is H, C1-C6 alkyl, C1-C6 alkylene-C3-C7 cycloalkyl, C1-C6 alkylene-C3-C7 heterocycloalkyl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, aryl, or heteroaryl; and
R24 is H, C1-C6 alkyl, C1-C6 alkylene-C3-C7 cycloalkyl, C1-C6 alkylene-C3-C7 heterocycloalkyl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, aryl, or heteroaryl; or
R21 and R22, taken together with the atoms to which they are attached, form a C3-C7 heterocycloalkyl; or
R22 and R23, taken together with the atoms to which they are attached, form a C3-C7 heterocycloalkyl; or
R23 and R24, taken together with the nitrogen atom to which they are attached, form a C3-C7 heterocycloalkyl;
wherein any C1-C6 alkyl or C1-C6 alkylene of R2, R3, R4, R5, R7, R15, R16, R17, R18, R21, R22, R23, and R24 is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, OH, and OC1-C6 alkyl;
wherein any C1-C6 alkyl or C1-C6 alkylene of R1 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, and =O;
wherein any C1-C6 alkyl or C1-C6 alkylene of R9 is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, OH, OC1-C6 alkyl, and =O;
wherein any C1-C6 alkyl of R12, R13, R14, R19, and R20 is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, OH, OC1-C6 alkyl, and =O;
wherein any C3-C7 cycloalkyl or C3-C7 heterocycloalkyl of L, R1, R2, R3, R4, R5, R7, R9, R15, R16, R17, R18, R19, R20, R21, R22, R23, and R24 is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl, CH2NHC1-C6 alkyl, CH2N(C1-C6 alkyl)2, CH2OC1-C6 alkyl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, OH, OC1-C6 alkyl, and =O; and
wherein any aryl or heteroaryl of R2, R3, R4, R5, R7, R9, R15, R16, R17, R18, R21, R22, R23, and R24 is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl, CH2NHC1-C6 alkyl, CH2N(C1-C6 alkyl)2, CH2OC1-C6 alkyl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, OH, and OC1-C6 alkyl;
with the provisos that:
(1) at least one of A8, A9, A10, or A11 is N;
(2) if Y1 is quinazolinyl and R1 is H, then Z1 is not C(O)CH3 or S(O)2CH3;
(3) if Y1 is 1H-pyrazolo[3,4-d]pyrimidinyl and R1 is H, then Z1 is not C(O)CH3, C(O)C(CH3)3, or S(O)2CH3; and
(4) the compound of formula (I) is not N-(2-(5-(2-((5-methyloxazolo[4,5-b]pyridin-2-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide of the following structure:
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.
Appropriate correction is required. See MPEP § 2173.02.
Claim 3 is objected to because of the following informalities: for brevity, clarity, precision and to avoid issues under 35 U.S.C. § 112(a), the existing recitation should be replaced with the following recitation:
The compound according to claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Y1 is:
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,
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171
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, or
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.
Appropriate correction is required. See MPEP § 2173.02.
Claim 4 is objected to because of the following informalities: for brevity, clarity, precision and to avoid issues under 35 U.S.C. § 112(a), the existing recitation should be replaced with the following recitation:
The compound according to claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Y1 is:
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209
129
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,
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192
125
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,
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197
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,
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191
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,
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189
123
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,
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194
119
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,
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,
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,
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, or
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119
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.
Appropriate correction is required. See MPEP § 2173.02.
Claim 8 is objected to because of the following informalities: for brevity, clarity, precision and to avoid issues under 35 U.S.C. § 112(a), the existing recitation should be replaced with the following recitation:
The compound according to claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Y2 is:
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118
139
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or
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108
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.
Appropriate correction is required. See MPEP § 2173.02.
Claim 9 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(a), the existing recitation should be replaced with the following recitation:
The compound according to claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R10 is H or C1-C3 alkyl; and
R11 is H or C1-C3 alkyl.
Appropriate correction is required. See MPEP § 2173.02.
Claim 10 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(a), the existing recitation should be replaced with the following recitation:
The compound according to claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1 is H or C1-C3 alkyl.
Appropriate correction is required. See MPEP § 2173.02.
Claim 13 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(a), the existing recitation should be replaced with the following recitation:
The compound according to claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R9 is CH3, CH2CF2CF3, (S)-CH2CH(OH)CF3, C(CH3)3, CH2NH2, CH2NHCH3, CH2OH, CH2OCH3, CH(OH)CH3, CH3C(OH)CH3, CH2-phenyl, CH2-pyridin-2-yl, CH2-pyridin-3-yl, CH2-pyridin-4-yl, OC(CH3)3, cyclopropyl, 2,2-difluorocyclopropyl, 1-hydroxycylopropyl, methylazetidinyl, pyrrolidinyl, or phenyl.
Appropriate correction is required. See MPEP § 2173.02.
Claim 22 is objected to because of the following informalities: a) for clarity, precision and to avoid issues under 35 U.S.C. § 112(a), The compound or a pharmaceutically acceptable salt and/or solvate thereof according to claim 2, wherein said compound is selected from should be replaced with The compound according to claim 2, or a stereoisomer thereof, wherein the compound, or stereoisomer thereof, is selected from the group consisting of: ; b) for clarity and precision, and should be inserted prior to the last species; and c) for clarity, precision and to avoid issues under 35 U.S.C. § 112(a), and pharmaceutically acceptable salts and/or solvates thereof. should be replaced with , or a pharmaceutically acceptable salt thereof. . Appropriate correction is required. See MPEP § 2173.02.
Claim 24 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a compound according to claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof.
Appropriate correction is required. See MPEP § 2173.02.
Claim 26 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(a), the existing recitation should be replaced with the following recitation:
The compound according to claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R12 is H; and
R13 is H.
Appropriate correction is required. See MPEP § 2173.02.
Claim 27 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(a), the existing recitation should be replaced with the following recitation:
The compound according to claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R10 is H; and
R11 is H.
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(a), the existing recitation should be replaced with the following recitation:
The compound according to claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein n is 1.
Appropriate correction is required. See MPEP § 2173.02.
Claim 29 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(a), the existing recitation should be replaced with the following recitation:
The compound according to claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1 is H.
Appropriate correction is required. See MPEP § 2173.02.
Claim 30 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(a), the existing recitation should be replaced with the following recitation:
The compound according to claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R9 is CH2CF2CF3, (S)-CH2CH(OH)CF3, CH2OH, CH3C(OH)CH3, cyclopropyl, 2,2-difluorocyclopropyl, or 1-hydroxycylopropyl.
Appropriate correction is required. See MPEP § 2173.02.
Claim 31 is objected to because of the following informalities: a) for clarity, precision and to avoid issues under 35 U.S.C. § 112(a), The compound or a pharmaceutically acceptable salt and/or solvate thereof according to claim 2, wherein said compound is selected from should be replaced with The compound according to claim 2, or a stereoisomer thereof, wherein the compound, or stereoisomer thereof, is selected from the group consisting of: ; b) for clarity and precision, and should be inserted prior to the last species; and c) for clarity, precision and to avoid issues under 35 U.S.C. § 112(a), and pharmaceutically acceptable salts and/or solvates thereof. should be replaced with , or a pharmaceutically acceptable salt 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.
Written Description - Substituted thioethers of the formula (I)
Claim 2 is rejected under 35 U.S.C. § 112(a) as failing to comply with the written description requirement. The claim contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or joint inventor, at the time the invention was filed, had possession of the claimed invention. Specifically, the proviso with respect to the substituted thioethers of the formula (I), wherein when A5, A6, and A7 are CR7, then B is not -S-, lacks adequate support within the original specification, as filed. The specification discloses generic substituted thioethers of the formula (I), which fail to expressly exclude substituted thioethers, wherein when A5, A6, and A7 are CR7, then B is not -S-. Consequently, one of ordinary skill in the art, at the time this invention was filed, may neither be reasonably apprised of the scope of the instantly recited substituted thioethers of the formula (I), nor recognize that the inventor or joint inventor was in possession of the instantly recited substituted thioethers of the formula (I), in view of the original specification of the invention.
The inventor or joint inventor should note that under 35 U.S.C. § 132 and 35 U.S.C. § 251, the proscription against the introduction of new matter in a patent invention serves to prevent an inventor or joint inventor from adding information that goes beyond the subject matter originally filed. {See In re Rasmussen, 650 F.2d 1212, 1214, 211 USPQ 323, 326 (CCPA 1981); and MPEP § 2163.06-2183.07}.
Similarly, the inventor or joint inventor should further note that in order to comply with the written description requirement of 35 U.S.C. § 112(a), each claim limitation must be expressly, implicitly, or inherently supported in the originally filed specification. [W]hen an explicit limitation in a claim is not present in the written description whose benefit is sought, it must be shown that a person of ordinary skill would have understood, at the time the patent invention was filed, that the description requires that limitation. {See Hyatt v. Boone, 146 F.3d 1348, 1353, 47 USPQ2d 1128, 1131 (Fed. Cir. 1998); and In re Wright, 866 F.2d 422, 425, 9 USPQ2d 1649, 1651 (Fed. Cir. 1989)}.
Likewise, the inventor or joint inventor should further note that any negative limitation or exclusionary proviso must also have basis in the original specification. See MPEP § 2173.05(i).
Next, the inventor or joint inventor should further note that [N]ew or amended claims, which introduce elements or limitations which are not supported by the as-filed disclosure, violate the written description requirement. {See In re Lukach, 442 F.2d 967, 169 USPQ 795 (CCPA 1971); and In re Smith, 458 F.2d 1389, 1395, 173 USPQ 679, 683 (CCPA 1972)}.
Moreover, the inventor or joint inventor should further note that when filing an amendment, support should be shown in the original specification for new or amended claims. See MPEP § 714.02 and § 2163.06.
The examiner suggests amending the claim, particularly as stated in the section above entitled Claim Objections, to overcome this section of the rejection.
Scope of Enablement - Solvates of substituted thioethers of the formula (I)
Claims 2-4, 8-10, 13, 22 and 26-31 are rejected under 35 U.S.C. § 112(a) because the specification, while being enabling for substituted thioethers of the formula (I), does not reasonably provide enablement for solvates of substituted thioethers of the formula (I). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims. Solvates of substituted thioethers of the formula (I), as recited in claims 2-4, 8-10, 13, 22 and 26-31, respectively, have not been adequately enabled in the specification to allow any person having ordinary skill in the art, at the time this invention was made, to make and/or use solvates of substituted thioethers of the formula (I).
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 instant invention, are summarized as follows:
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(a) Breadth of the claims - the breadth of the claims includes substituted thioethers of the formula (I), shown to the right below, as well as the myriad of potential solvates formulated from these substituted thioethers of the formula (I), shown to the right below, respectively;
(b) Nature of the invention - the nature of the invention is evaluation of substituted thioethers of the formula (I), shown to the right above, and/or solvates thereof, and the pharmacokinetic behavior of these substances as histone deacetylase 6 (HDAC6) inhibitors;
(c) State of the prior art - Nature Reviews: Drug Discovery, as provided in the file and cited on the IDS, 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). Moreover, WO 23/118507 provides a synthesis of the instantly recited substituted thioethers of the formula (I) {Celanire, et al. WO 23/118507, 2023};
(d) Level of one of ordinary skill in the art - the artisans synthesizing the inventor’s or joint inventor’s substituted thioethers of the formula (I), and/or solvates thereof, 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 unclear based on the combination of the instant specification, and Celanire, et al. in WO 23/118507, whether the instantly recited solvates of substituted thioethers of the formula (I) are enabled. Moreover, the following excerpt is taken from Vippagunta, et al., as provided in the file and cited on the IDS, with respect to the synthesis of solvates of substituted thioethers of the formula (I) {Vippagunta, et al. Advanced Drug Delivery Reviews, 48, 2001, 18}:
Predicting the formation of solvates or hydrates of a compound and the number of molecules of water or solvent incorporated into the crystal lattice of a compound is complex and difficult. Each solid compound responds uniquely to the possible formation of solvates or hydrates and hence generalizations cannot be made for a series of related compounds. Certain molecular shapes and features favor the formation of crystals without solvent; these compounds tend to be stabilized by efficient packing of molecules in the crystal lattice, whereas other crystal forms are more stable in the presence of water and/or solvents. There may be too many possibilities so that no computer programs are currently available for predicting the crystal structures of hydrates and solvates.
(f) Amount of direction provided by the inventor - the invention lacks direction with respect to making and/or using solvates of substituted thioethers of the formula (I);
(g) Existence of working examples - the inventor or joint inventor has provided sufficient guidance to make and/or use substituted thioethers of the formula (I); however, the disclosure is insufficient to allow extrapolation of the limited examples to enable the instantly recited solvates of substituted thioethers of the formula (I). The specification lacks working examples of solvates of substituted thioethers of the formula (I).
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 or use the invention based on the content of the disclosure - predicting whether a recited compound, and/or a solvate thereof, 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). Similarly, the specification, as originally filed, including any references incorporated therein, fails to provide the necessary support required by 35 U.S.C. § 112(a) to enable the instantly recited solvates of substituted thioethers of the formula (I). Thus, it is unclear, based on the guidance provided by the specification, whether a solvate of a substituted thioether of the formula (I), such as N-((5-(2-((2-isopropylquinazolin-4-yl)thio)-acetyl)thiophen-2-yl)methyl)pivalamide dihydrate, shown to the left above, is either synthetically feasible or possesses utility as a histone deacetylase 6 (HDAC6) inhibitor.
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 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 solvates of substituted thioethers of the formula (I) is clearly justified.
The examiner suggests amending the claims, particularly as stated in the section above entitled Claim Objections, to overcome this section of the 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.
Claims 2-4, 8-10, 13, 24 and 26-30 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 1 recites the broad limitations, (1) NR17R18, with regard to R2, R3, and R7; (2) OR15, with regard to R2, R3, and R7; (3) NR23R24, with regard to R9; (4) OR21, with regard to R9; (5) optionally substituted C1-C6 alkyl, with regard to R12, R13, and R14; (6) optionally substituted C1-C6 alkyl, with regard to R15, R16, R17, and R18; (7) optionally substituted C1-C6 alkyl, with regard to R1; and (8) optionally substituted C1-C6 alkylene-C3-C7 cycloalkyl, with regard to R21, R22, R23, and R24, respectively, and the claim also recites (1) NH2, with regard to R2, R3, and R7; (2) OH, with regard to R2, R3, and R7; (3) NH2, with regard to R9; (4) OH, with regard to R9, (5) CH2NHC1-C6 alkyl, CH2N(C1-C6 alkyl)2, CH2OC1-C6 alkyl, with regard to R12, R13, and R14; (6) C1-C6 haloalkyl, with regard to R15, R16, R17, and R18; (7) C1-C6 alkylene-NR19R20 and C1-C6 alkylene-OR19, with regard to R1; and (8) C1-C6 alkylene-C3-C7 halocycloalkyl, with regard to R21, R22, R23, and R24, respectively, which are the narrower statements of the limitations.
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 - 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)}.
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Consequently, claims 2-4, 8-10, 13, 22, 24 and 26-31 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over at least claims 1, 2, 7, 12, 13 and 18 of copending US Application No. 19/016,827. Although the conflicting claims are not identical, they are not patentably distinct from each other because claim 1 in the copending invention recites 2-hydroxy-N-((5-(2-((6-methoxy-2-methylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide, shown to the left above, which provides overlapping subject matter with respect to the instantly recited substituted thioethers of the formula (I), where Y1 is formula (Sc1), shown to the left, wherein G1 = N, R2 = -C1-C6 alkyl, A1 = CR7, where R7 = -H, A2 = CR7, where R7 = -H, A3 = CR7, where R7 = -OR15, wherein R15 = -C1-C6 alkyl, and A4 = CR7, where R7 = -H; Y2 is shown to the right, wherein R12 = -H and R13 = -H; L = -(CR10R11)n-, wherein n = 1, R10 = -H and R11 = -H; R1 = -H; and Z1 = -C(O)R9, wherein R9 = -C1-C6 alkylen-OR21, where R21 = -H, respectively.
The inventor or joint inventor should note that this is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
Similarly, 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.
Likewise, the inventor or joint inventor should further 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.
Moreover, 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
Prosecution Insights