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 31-49 are pending in the instant invention. According to the Amendments to the Claims, filed September 22, 2023, claims 1-30 were cancelled and claims 31-49 were amended.
Status of Priority
This invention is a Divisional (DIV) of US ApplicationNo. 17/683,549, filed March 1, 2022 and now US 11,634,432, which is a Continuation (CON) of International Application No. PCT/US2021/024536, filed March 26, 2021, which claims priority under 35 U.S.C. § 119(e) to US Provisional Application Nos.: a) 63/054,762, filed July 21, 2020; b) 63/054,763, filed July 21, 2020; c) 63/054,768, filed July 21, 2020; d) 63/019,176, filed May 1, 2020; e) 63/001,187, filed March 27, 2020; and f) 63/001,177, filed March 27, 2020.
Restrictions / Election of Species
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The forthcoming first Office action and prosecution on the merits includes claims 31-49, drawn to a method of treating a subject with a chronic disease, wherein the subject would benefit from inhibition of the activity of mTORC1, comprising administering to the subject a macrocyclic substituted piperidine represented by the Formula I, shown to the right.
Thus, a first Office action and prosecution on the merits of claims 31-49 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 macrocyclic substituted piperidines represented by the Formula I.
The following title is suggested: MACROCYCLIC SUBSTITUTED PIPERIDINES AS MTORC1 MODULATORS.
Appropriate correction is required.
Claim Objections
Claim 31 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 method for inhibiting mammalian target of rapamycin complex 1 (mTORC1) signaling activity in a subject, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of a compound represented by Formula I:
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I
or a pharmaceutically acceptable salt thereof,
wherein:
R1 is OR22:
R22 is C1-6 alkyl, P(O)R24R24, C3-10 carbocyclyl, or 3- to 10-membered heterocyclyl;
wherein the C1-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C(O)R30, C(O)NR30R30, C(O)OR30, NR30R30, NR30C(O)R30, =NR30, P(O)(OR30)2, OR30, (OCH2(CH2)p)nW, OC(O)R30, OP(O)(OR30)2, SR30, S(O)R30, S(O)2R30, C3-10 carbocyclyl, and 3- to 10-membered heterocyclyl;
wherein the C3-10 carbocyclyl or 3- to 10-membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C(O)R30, C(O)NR30R30, C(O)OR30, NR30R30, NR30C(O)R30, =NR30, P(O)(OR30)2, OR30, (OCH2(CH2)p)nW, OC(O)R30, OP(O)(OR30)2, =O, SR30, S(O)R30, S(O)2R30, and =S;
wherein each C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl substituent is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C(O)R30, C(O)NR30R30, C(O)OR30, NR30R30, NR30C(O)R30, =NR30, P(O)(OR30)2, OR30, OC(O)R30, OP(O)(OR30)2, SR30, S(O)R30, S(O)2R30, C3-10 carbocyclyl, and 3- to 10-membered heterocyclyl; and
wherein each C3-10 carbocyclyl and 3- to 10-membered heterocyclyl substituent is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C1-6 alkyl, C1-6 alkylene-R30, C2-10 alkenyl, C2-10 alkynyl, C(O)R30, C(O)NR30R30, C(O)OR30, NR30R30, NR30C(O)R30, =NR30, P(O)(OR30)2, OR30, OC(O)R30, OP(O)(OR30)2, =O, SR30, S(O)R30, S(O)2R30, and =S;
each R24 is independently C1-6 alkyl;
wherein each C1-6 alkyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C(O)R30, C(O)NR30R30, C(O)OR30, NR30R30, NR30C(O)R30, =NR30, P(O)(OR30)2, OR30, (OCH2(CH2)p)nW, OC(O)R30, OP(O)(OR30)2, SR30, S(O)R30, S(O)2R30, C3-10 carbocyclyl, and 3- to 10-membered heterocyclyl; and
wherein each C3-10 carbocyclyl and 3- to 10-membered heterocyclyl substituent is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C1-6 alkyl, C1-6 alkylene-R30, C2-10 alkenyl, C2-10 alkynyl, C(O)R30, C(O)NR30R30, C(O)OR30, NR30R30, NR30C(O)R30, =NR30, P(O)(OR30)2, OR30, OC(O)R30, OP(O)(OR30)2, =O, SR30, S(O)R30, S(O)2R30, and =S;
R2 is H or OC1-6 alkyl;
wherein the OC1-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, OH, OC1-6 alkyl, C3-10 carbocyclyl, and 3- to 10-membered heterocyclyl; and
wherein each C3-10 carbocyclyl and 3- to 10- membered heterocyclyl substituent is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, OH, and OC1-6 alkyl;
R6 and R7, taken together with the carbon atom to which they are attached, form -C(O)-.
R3 is H or OC1-6 alkyl;
wherein the OC1-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, OH, OC1-6 alkyl, C3-10 carbocyclyl, and 3- to 10-membered heterocyclyl; and
wherein each C3-10 carbocyclyl and 3- to 10- membered heterocyclyl substituent is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, OH, and OC1-6 alkyl;
R5 is H, OH, or OC1-6 alkyl;
wherein the OC1-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, OH, OC1-6 alkyl, C3-10 carbocyclyl, and 3- to 10-membered heterocyclyl; and
wherein each C3-10 carbocyclyl and 3- to 10- membered heterocyclyl substituent is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, OH, and OC1-6 alkyl;
R4’ is NR100R110’;
R100 is H, (CH2CH2G)yV, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl;
wherein the C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C(O)R31, C(O)NR31R31, C(O)OR31, NR31R31, NR31C(O)R31, OR31, OC(O)R31, OP(O)(OR31)2, P(O)(OR31)2, SR31, S(O)R31, S(O)2R31, C3-20 carbocyclyl, and 3- to 20-membered heterocyclyl; and
wherein each C3-20 carbocyclyl and 3- to 20-membered heterocyclyl substituent is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C1-6 alkyl, C1-6 alkylene-R31, C2-6 alkenyl, C2-6 alkynyl, C(O)R31, C(O)NR31R31, C(O)OR31, NR31R31, NR31C(O)R31, =NR31, OR31, OC(O)R31, =O, OP(O)(OR31)2, P(O)(OR31)2, SR31, S(O)R31, S(O)2R31, and =S;
each R31 is independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, or 3- to 10-membered heterocyclyl;
wherein each C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, NH2, OH, OC1-10 alkyl, C3-10 carbocyclyl, and 3- to 10- membered heterocyclyl;
wherein each C3-10 carbocyclyl and 3- to 10-membered heterocyclyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C1-10 alkyl, C1-10 haloalkyl, C2-10 alkenyl, C2-10 alkynyl, NH2, OH, OC1-10 alkyl, =O, =S, C3-10 carbocyclyl, and 3- to 10- membered heterocyclyl;
each G is independently -NR32-, -O-, -S-, or -S(O)2-;
y is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, or 20;
V is H or C1-6 alkyl;
wherein each C1-6 alkyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C(O)R30, C(O)NR30R30, C(O)OR30, NR30R30, NR30C(O)R30, =NR30, P(O)(OR30)2, OR30, (OCH2(CH2)p)nW, OC(O)R30, OP(O)(OR30)2, SR30, S(O)R30, S(O)2R30, C3-10 carbocyclyl, and 3- to 10-membered heterocyclyl; and
wherein each C3-10 carbocyclyl and 3- to 10-membered heterocyclyl substituent is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C1-6 alkyl, C1-6 alkylene-R30, C2-10 alkenyl, C2-10 alkynyl, C(O)R30, C(O)NR30R30, C(O)OR30, NR30R30, NR30C(O)R30, =NR30, P(O)(OR30)2, OR30, OC(O)R30, OP(O)(OR30)2, =O, SR30, S(O)R30, S(O)2R30, and =S;
R110’ is S(O)R51’ or S(O)2R51’;
R51’ is C1-4 alkyl, C5-30 alkyl, ((CH2)qCH2D)zT, C3-8 carbocyclyl, or 3- to 10-membered heterocyclyl;
wherein the C1-4 alkyl is substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C(O)R30, C(O)NR30R30, C(O)OR30, NR30R30, NR30C(O)R30, =NR30, P(O)(OR30)2, OR30, (OCH2(CH2)p)nW, OC(O)R30, OP(O)(OR30)2, SR30, S(O)R30, S(O)2R30, C3-10 carbocyclyl, and 3- to 10-membered heterocyclyl;
wherein the C5-30 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C(O)R30, C(O)NR30R30, C(O)OR30, NR30R30, NR30C(O)R30, =NR30, P(O)(OR30)2, OR30, (OCH2(CH2)p)nW, OC(O)R30, OP(O)(OR30)2, SR30, S(O)R30, S(O)2R30, C3-10 carbocyclyl, and 3- to 10-membered heterocyclyl;
wherein the C3-8 carbocyclyl or 3- to 10-membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C(O)R30, C(O)NR30R30, C(O)OR30, NR30R30, NR30C(O)R30, =NR30, P(O)(OR30)2, OR30, (OCH2(CH2)p)nW, OC(O)R30, OP(O)(OR30)2, =O, SR30, S(O)R30, S(O)2R30, and =S;
wherein each C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl substituent is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C(O)R30, C(O)NR30R30, C(O)OR30, NR30R30, NR30C(O)R30, =NR30, P(O)(OR30)2, OR30, OC(O)R30, OP(O)(OR30)2, SR30, S(O)R30, S(O)2R30, C3-10 carbocyclyl, and 3- to 10-membered heterocyclyl; and
wherein each C3-10 carbocyclyl and 3- to 10-membered heterocyclyl substituent is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C1-6 alkyl, C1-6 alkylene-R30, C2-10 alkenyl, C2-10 alkynyl, C(O)R30, C(O)NR30R30, C(O)OR30, NR30R30, NR30C(O)R30, =NR30, P(O)(OR30)2, OR30, OC(O)R30, OP(O)(OR30)2, =O, SR30, S(O)R30, S(O)2R30, and =S;
each q is independently 1, 2, 3, 4, 5, or 6;
each D is independently -NR32-, -O-, -S-, or -S(O)2-;
each R32 is independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, or 3- to 10-membered heterocyclyl;
wherein each C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, NH2, OH, OC1-10 alkyl, C3-10 carbocyclyl, and 3- to 10- membered heterocyclyl;
wherein each C3-10 carbocyclyl and 3- to 10-membered heterocyclyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C1-10 alkyl, C1-10 haloalkyl, C2-10 alkenyl, C2-10 alkynyl, NH2, OH, OC1-10 alkyl, =O, =S, C3-10 carbocyclyl, and 3- to 10- membered heterocyclyl;
z is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20;
T is H or C1-6 alkyl;
wherein the C1-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C(O)R30, C(O)NR30R30, C(O)OR30, NR30R30, NR30C(O)R30, =NR30, P(O)(OR30)2, OR30, (OCH2(CH2)p)nW, OC(O)R30, OP(O)(OR30)2, SR30, S(O)R30, S(O)2R30, C3-10 carbocyclyl, and 3- to 10-membered heterocyclyl; and
wherein each C3-10 carbocyclyl and 3- to 10-membered heterocyclyl substituent is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C1-6 alkyl, C1-6 alkylene-R30, C2-10 alkenyl, C2-10 alkynyl, C(O)R30, C(O)NR30R30, C(O)OR30, NR30R30, NR30C(O)R30, =NR30, P(O)(OR30)2, OR30, OC(O)R30, OP(O)(OR30)2, =O, SR30, S(O)R30, S(O)2R30, and =S;
each R30 is independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, or 3-10 membered heterocyclyl;
wherein each C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, NH2, OH, OC1-10 alkyl, C3-10 carbocyclyl, and 3- to 10- membered heterocyclyl; and
wherein each C3-10 carbocyclyl and 3- to 10-membered heterocyclyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C1-10 alkyl, C1-10 haloalkyl, C2-10 alkenyl, C2-10 alkynyl, NH2, OH, OC1-10 alkyl, =O, =S, C3-10 carbocyclyl, and 3- to 10- membered heterocyclyl;
each n is independently 3, 4, 5, 6, or 7;
each p is independently 1 or 2; and
each W is independently H, C1-4 alkyl, OH, or OC1-4 alkyl.
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(s):
32. The method of claim 31, wherein the subject has a chronic disease or disorder selected from the group consisting of an age-related disease that benefits from inhibition of the activity of mTORC1, an age-related disease that results in hyperactivation of mTORC1, an autism spectrum disorder, an autoimmune disease, a cardiovascular disease, a cognitive disorder, cancer, a disease of impaired autophagy, epilepsy, an eye disorder, an infectious disease, an inflammatory disease, a kidney disease, a metabolic disease, an mTORopathy, muscular atrophy, a neurocutaneous disease, a neurodegenerative disease, a neurodevelopmental disorder, a pulmonary disease, a tauopathy,
50. The method of claim 32, wherein the age-related disease that benefits from inhibition of the activity of mTORC1 is reduced immune activity in the elderly.
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 of claim 32, wherein the mTORopathy is selected from the group consisting of focal cortical dysplasia, a phosphatase and tensin homolog (PTEN) disease, and tuberous sclerosis.
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 of claim 32, wherein the kidney disease or pulmonary disease is lymphangioleiomyomatosis or polycystic kidney disease.
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 of claim 32, wherein the kidney disease is polycystic kidney disease.
Appropriate correction is required. See MPEP § 2173.02.
Claim 36 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The method of claim 35, wherein the polycystic kidney disease is autosomal dominant polycystic kidney disease (ADPKD) or autosomal recessive polycystic kidney disease (ARPKD).
Appropriate correction is required. See MPEP § 2173.02.
Claim 37 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The method of claim 31, wherein R1 is OCH2CH2OH, OCH2CH2CH2OH, OCH2CH2CH2S(O)2CH3, or OCH2C(O)OCH2CH3.
Appropriate correction is required. See MPEP § 2173.02.
Claim 38 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 of claim 31, wherein R4’ is NHS(O)2CH2CH2OCH3, NHS(O)2CH2CH2OCH2CH2OCH3, NHS(O)2CH2cyclopropyl, NHS(O)2CH2cyclobutyl, or NHS(O)2cyclopropyl.
Appropriate correction is required. See MPEP § 2173.02.
Claim 39 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The method of claim 31, wherein the compound is selected from the group consisting of:
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and
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or a pharmaceutically acceptable salt thereof.
Appropriate correction is required. See MPEP § 2173.02.
Claim 40 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The method of claim 31, wherein the compound is:
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,
or a pharmaceutically acceptable salt thereof.
Appropriate correction is required. See MPEP § 2173.02.
Claim 41 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The method of claim 31, wherein the compound is:
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,
or a pharmaceutically acceptable salt thereof.
Appropriate correction is required. See MPEP § 2173.02.
Claim 42 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The method of claim 31, wherein the compound is:
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or a pharmaceutically acceptable salt thereof.
Appropriate correction is required. See MPEP § 2173.02.
Claim 43 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The method of claim 31, wherein the compound is:
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or a pharmaceutically acceptable salt thereof.
Appropriate correction is required. See MPEP § 2173.02.
Claim 44 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The method of claim 31, wherein the compound is:
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or a pharmaceutically acceptable salt thereof.
Appropriate correction is required. See MPEP § 2173.02.
Claim 45 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The method of claim 31, wherein the compound is:
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or a pharmaceutically acceptable salt thereof.
Appropriate correction is required. See MPEP § 2173.02.
Claim 46 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The method of claim 31, wherein the compound is
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or a pharmaceutically acceptable salt thereof.
Appropriate correction is required. See MPEP § 2173.02.
Claim 47 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The method of claim 31, wherein the compound is:
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or a pharmaceutically acceptable salt thereof.
Appropriate correction is required. See MPEP § 2173.02.
Claim 48 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The method of claim 31, wherein the compound is:
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or a pharmaceutically acceptable salt thereof.
Appropriate correction is required. See MPEP § 2173.02.
Claim 49 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):
49. A method for inhibiting mammalian target of rapamycin complex 1 (mTORC1) signaling activity in a subject, wherein the method comprises administering to the subject in need thereof a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound represented by Formula I:
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I
or a pharmaceutically acceptable salt thereof,
wherein:
R1 is OR22:
R22 is C1-6 alkyl, P(O)R24R24, C3-10 carbocyclyl, or 3- to 10-membered heterocyclyl;
wherein the C1-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C(O)R30, C(O)NR30R30, C(O)OR30, NR30R30, NR30C(O)R30, =NR30, P(O)(OR30)2, OR30, (OCH2(CH2)p)nW, OC(O)R30, OP(O)(OR30)2, SR30, S(O)R30, S(O)2R30, C3-10 carbocyclyl, and 3- to 10-membered heterocyclyl;
wherein the C3-10 carbocyclyl or 3- to 10-membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C(O)R30, C(O)NR30R30, C(O)OR30, NR30R30, NR30C(O)R30, =NR30, P(O)(OR30)2, OR30, (OCH2(CH2)p)nW, OC(O)R30, OP(O)(OR30)2, =O, SR30, S(O)R30, S(O)2R30, and =S;
wherein each C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl substituent is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C(O)R30, C(O)NR30R30, C(O)OR30, NR30R30, NR30C(O)R30, =NR30, P(O)(OR30)2, OR30, OC(O)R30, OP(O)(OR30)2, SR30, S(O)R30, S(O)2R30, C3-10 carbocyclyl, and 3- to 10-membered heterocyclyl; and
wherein each C3-10 carbocyclyl and 3- to 10-membered heterocyclyl substituent is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C1-6 alkyl, C1-6 alkylene-R30, C2-10 alkenyl, C2-10 alkynyl, C(O)R30, C(O)NR30R30, C(O)OR30, NR30R30, NR30C(O)R30, =NR30, P(O)(OR30)2, OR30, OC(O)R30, OP(O)(OR30)2, =O, SR30, S(O)R30, S(O)2R30, and =S;
each R24 is independently C1-6 alkyl;
wherein each C1-6 alkyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C(O)R30, C(O)NR30R30, C(O)OR30, NR30R30, NR30C(O)R30, =NR30, P(O)(OR30)2, OR30, (OCH2(CH2)p)nW, OC(O)R30, OP(O)(OR30)2, SR30, S(O)R30, S(O)2R30, C3-10 carbocyclyl, and 3- to 10-membered heterocyclyl; and
wherein each C3-10 carbocyclyl and 3- to 10-membered heterocyclyl substituent is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C1-6 alkyl, C1-6 alkylene-R30, C2-10 alkenyl, C2-10 alkynyl, C(O)R30, C(O)NR30R30, C(O)OR30, NR30R30, NR30C(O)R30, =NR30, P(O)(OR30)2, OR30, OC(O)R30, OP(O)(OR30)2, =O, SR30, S(O)R30, S(O)2R30, and =S;
R2 is H or OC1-6 alkyl;
wherein the OC1-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, OH, OC1-6 alkyl, C3-10 carbocyclyl, and 3- to 10-membered heterocyclyl; and
wherein each C3-10 carbocyclyl and 3- to 10- membered heterocyclyl substituent is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, OH, and OC1-6 alkyl;
R6 and R7, taken together with the carbon atom to which they are attached, form -C(O)-.
R3 is H or OC1-6 alkyl;
wherein the OC1-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, OH, OC1-6 alkyl, C3-10 carbocyclyl, and 3- to 10-membered heterocyclyl; and
wherein each C3-10 carbocyclyl and 3- to 10- membered heterocyclyl substituent is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, OH, and OC1-6 alkyl;
R5 is H, OH, or OC1-6 alkyl;
wherein the OC1-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, OH, OC1-6 alkyl, C3-10 carbocyclyl, and 3- to 10-membered heterocyclyl; and
wherein each C3-10 carbocyclyl and 3- to 10- membered heterocyclyl substituent is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, OH, and OC1-6 alkyl;
R4’ is NR100R110’;
R100 is H, (CH2CH2G)yV, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl;
wherein the C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C(O)R31, C(O)NR31R31, C(O)OR31, NR31R31, NR31C(O)R31, OR31, OC(O)R31, OP(O)(OR31)2, P(O)(OR31)2, SR31, S(O)R31, S(O)2R31, C3-20 carbocyclyl, and 3- to 20-membered heterocyclyl; and
wherein each C3-20 carbocyclyl and 3- to 20-membered heterocyclyl substituent is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C1-6 alkyl, C1-6 alkylene-R31, C2-6 alkenyl, C2-6 alkynyl, C(O)R31, C(O)NR31R31, C(O)OR31, NR31R31, NR31C(O)R31, =NR31, OR31, OC(O)R31, =O, OP(O)(OR31)2, P(O)(OR31)2, SR31, S(O)R31, S(O)2R31, and =S;
each R31 is independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, or 3- to 10-membered heterocyclyl;
wherein each C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, NH2, OH, OC1-10 alkyl, C3-10 carbocyclyl, and 3- to 10- membered heterocyclyl;
wherein each C3-10 carbocyclyl and 3- to 10-membered heterocyclyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C1-10 alkyl, C1-10 haloalkyl, C2-10 alkenyl, C2-10 alkynyl, NH2, OH, OC1-10 alkyl, =O, =S, C3-10 carbocyclyl, and 3- to 10- membered heterocyclyl;
each G is independently -NR32-, -O-, -S-, or -S(O)2-;
y is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, or 20;
V is H or C1-6 alkyl;
wherein each C1-6 alkyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C(O)R30, C(O)NR30R30, C(O)OR30, NR30R30, NR30C(O)R30, =NR30, P(O)(OR30)2, OR30, (OCH2(CH2)p)nW, OC(O)R30, OP(O)(OR30)2, SR30, S(O)R30, S(O)2R30, C3-10 carbocyclyl, and 3- to 10-membered heterocyclyl; and
wherein each C3-10 carbocyclyl and 3- to 10-membered heterocyclyl substituent is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C1-6 alkyl, C1-6 alkylene-R30, C2-10 alkenyl, C2-10 alkynyl, C(O)R30, C(O)NR30R30, C(O)OR30, NR30R30, NR30C(O)R30, =NR30, P(O)(OR30)2, OR30, OC(O)R30, OP(O)(OR30)2, =O, SR30, S(O)R30, S(O)2R30, and =S;
R110’ is S(O)R51’ or S(O)2R51’;
R51’ is C1-4 alkyl, C5-30 alkyl, ((CH2)qCH2D)zT, C3-8 carbocyclyl, or 3- to 10-membered heterocyclyl;
wherein the C1-4 alkyl is substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C(O)R30, C(O)NR30R30, C(O)OR30, NR30R30, NR30C(O)R30, =NR30, P(O)(OR30)2, OR30, (OCH2(CH2)p)nW, OC(O)R30, OP(O)(OR30)2, SR30, S(O)R30, S(O)2R30, C3-10 carbocyclyl, and 3- to 10-membered heterocyclyl;
wherein the C5-30 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C(O)R30, C(O)NR30R30, C(O)OR30, NR30R30, NR30C(O)R30, =NR30, P(O)(OR30)2, OR30, (OCH2(CH2)p)nW, OC(O)R30, OP(O)(OR30)2, SR30, S(O)R30, S(O)2R30, C3-10 carbocyclyl, and 3- to 10-membered heterocyclyl;
wherein the C3-8 carbocyclyl or 3- to 10-membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C(O)R30, C(O)NR30R30, C(O)OR30, NR30R30, NR30C(O)R30, =NR30, P(O)(OR30)2, OR30, (OCH2(CH2)p)nW, OC(O)R30, OP(O)(OR30)2, =O, SR30, S(O)R30, S(O)2R30, and =S;
wherein each C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl substituent is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C(O)R30, C(O)NR30R30, C(O)OR30, NR30R30, NR30C(O)R30, =NR30, P(O)(OR30)2, OR30, OC(O)R30, OP(O)(OR30)2, SR30, S(O)R30, S(O)2R30, C3-10 carbocyclyl, and 3- to 10-membered heterocyclyl; and
wherein each C3-10 carbocyclyl and 3- to 10-membered heterocyclyl substituent is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C1-6 alkyl, C1-6 alkylene-R30, C2-10 alkenyl, C2-10 alkynyl, C(O)R30, C(O)NR30R30, C(O)OR30, NR30R30, NR30C(O)R30, =NR30, P(O)(OR30)2, OR30, OC(O)R30, OP(O)(OR30)2, =O, SR30, S(O)R30, S(O)2R30, and =S;
each q is independently 1, 2, 3, 4, 5, or 6;
each D is independently -NR32-, -O-, -S-, or -S(O)2-;
each R32 is independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, or 3- to 10-membered heterocyclyl;
wherein each C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, NH2, OH, OC1-10 alkyl, C3-10 carbocyclyl, and 3- to 10- membered heterocyclyl;
wherein each C3-10 carbocyclyl and 3- to 10-membered heterocyclyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C1-10 alkyl, C1-10 haloalkyl, C2-10 alkenyl, C2-10 alkynyl, NH2, OH, OC1-10 alkyl, =O, =S, C3-10 carbocyclyl, and 3- to 10- membered heterocyclyl;
z is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20;
T is H or C1-6 alkyl;
wherein the C1-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C(O)R30, C(O)NR30R30, C(O)OR30, NR30R30, NR30C(O)R30, =NR30, P(O)(OR30)2, OR30, (OCH2(CH2)p)nW, OC(O)R30, OP(O)(OR30)2, SR30, S(O)R30, S(O)2R30, C3-10 carbocyclyl, and 3- to 10-membered heterocyclyl; and
wherein each C3-10 carbocyclyl and 3- to 10-membered heterocyclyl substituent is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C1-6 alkyl, C1-6 alkylene-R30, C2-10 alkenyl, C2-10 alkynyl, C(O)R30, C(O)NR30R30, C(O)OR30, NR30R30, NR30C(O)R30, =NR30, P(O)(OR30)2, OR30, OC(O)R30, OP(O)(OR30)2, =O, SR30, S(O)R30, S(O)2R30, and =S;
each R30 is independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, or 3-10 membered heterocyclyl;
wherein each C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, NH2, OH, OC1-10 alkyl, C3-10 carbocyclyl, and 3- to 10- membered heterocyclyl; and
wherein each C3-10 carbocyclyl and 3- to 10-membered heterocyclyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C1-10 alkyl, C1-10 haloalkyl, C2-10 alkenyl, C2-10 alkynyl, NH2, OH, OC1-10 alkyl, =O, =S, C3-10 carbocyclyl, and 3- to 10- membered heterocyclyl;
each n is independently 3, 4, 5, 6, or 7;
each p is independently 1 or 2; and
each W is independently H, C1-4 alkyl, OH, or OC1-4 alkyl.
51. The method of claim 49, wherein the compound is selected from the group consisting of:
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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.
Method of treating a subject with a chronic disease, wherein the subject would benefit from inhibition of the activity of mTORC1, comprising administering to the subject a macrocyclic substituted piperidine represented by the Formula I
Claims 31-49 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 of treating a subject with a chronic disease, wherein the subject would benefit from inhibition of the activity of mTORC1, comprising administering to the subject a macrocyclic substituted piperidine represented by the Formula 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:
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(a) Breadth of the claims - the breadth of the claims includes a method of treating a subject with a chronic disease, wherein the subject would benefit from inhibition of the activity of mTORC1, comprising administering to the subject a macrocyclic substituted piperidine represented by the Formula I, shown to the right;
(b) Nature of the invention - the nature of the invention is performance of a method of treating a subject with a chronic disease, wherein the subject would benefit from inhibition of the activity of mTORC1, comprising administering to the subject a macrocyclic substituted piperidine represented by the Formula 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 chronic diseases benefiting from the inhibition of the activity of mTORC1 in a subject, including, but not limited to, an age-related disease that benefits from inhibition of the activity of mTORC1, an age-related disease that results in hyperactivation of mTORC1, an autism spectrum disorder, an autoimmune disease, a cardiovascular disease, a cognitive disorder, cancer, a disease of impaired autophagy, epilepsy, an eye disorder, an infectious disease, an inflammatory disease, a kidney disease, a metabolic disease, an mTORopathy, muscular atrophy, a neurocutaneous disease, a neurodegenerative disease, a neurodevelopmental disorder, a pulmonary disease, and/or a tauopathy {See In re Hokum, 226 USPQ 353 (ComrPats 1985)}. Moreover, WO 21/195599, as provided in the file and cited on the IDS, illustrates the synthesis of macrocyclic substituted piperidines of the Formula I, and/or methods of use thereof {J. Kincaid. WO 21/195599, 2021};
(d) Level of one of ordinary skill in the art - the artisans performing the inventor’s or joint inventor’s method of treating a subject with a chronic disease, wherein the subject would benefit from inhibition of the activity of mTORC1, comprising administering to the subject a macrocyclic substituted piperidine represented by the Formula 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 of treating a subject with a chronic disease, wherein the subject would benefit from inhibition of the activity of mTORC1, comprising administering to the subject a macrocyclic substituted piperidine represented by the Formula I;
(g) Existence of working examples - the disclosure is insufficient to allow extrapolation of the limited examples to enable performing the instantly recited method of treating a subject with a chronic disease, wherein the subject would benefit from inhibition of the activity of mTORC1, comprising administering to the subject a macrocyclic substituted piperidine represented by the Formula I.
Similarly, according to the specification, macrocyclic substituted piperidines of the Formula I are capable of treating a variety of chronic diseases benefiting from the inhibition of the activity of mTORC1 in a subject, including, but not limited to, an age-related disease that benefits from inhibition of the activity of mTORC1, an age-related disease that results in hyperactivation of mTORC1, an autism spectrum disorder, an autoimmune disease, a cardiovascular disease, a cognitive disorder, cancer, a disease of impaired autophagy, epilepsy, an eye disorder, an infectious disease, an inflammatory disease, a kidney disease, a metabolic disease, an mTORopathy, muscular atrophy, a neurocutaneous disease, a neurodegenerative disease, a neurodevelopmental disorder, a pulmonary disease, and/or a tauopathy; however, the specification fails to set forth any convincing in vitro and/or in vivo assays corroborating the alleged activity in association with any chronic diseases benefiting from the inhibition of the activity of mTORC1 in a subject, including, but not limited to, an age-related disease that benefits from inhibition of the activity of mTORC1, an age-related disease that results in hyperactivation of mTORC1, an autism spectrum disorder, an autoimmune disease, a cardiovascular disease, a cognitive disorder, cancer, a disease of impaired autophagy, epilepsy, an eye disorder, an infectious disease, an inflammatory disease, a kidney disease, a metabolic disease, an mTORopathy, muscular atrophy, a neurocutaneous disease, a neurodegenerative disease, a neurodevelopmental disorder, a pulmonary disease, and/or a tauopathy. There is insufficient disclosure to reasonably conclude that the method of treating a subject with a chronic disease, wherein the subject would benefit from inhibition of the activity of mTORC1, comprising administering to the subject a macrocyclic substituted piperidine represented by the Formula I, as recited, would contribute to treatment of any chronic diseases benefiting from the inhibition of the activity of mTORC1 in a subject, including, but not limited to, an age-related disease that benefits from inhibition of the activity of mTORC1, an age-related disease that results in hyperactivation of mTORC1, an autism spectrum disorder, an autoimmune disease, a cardiovascular disease, a cognitive disorder, cancer, a disease of impaired autophagy, epilepsy, an eye disorder, an infectious disease, an inflammatory disease, a kidney disease, a metabolic disease, an mTORopathy, muscular atrophy, a neurocutaneous disease, a neurodegenerative disease, a neurodevelopmental disorder, a pulmonary disease, and/or a tauopathy. Furthermore, the combination of the instant specification and J. Kincaid. in WO 21/195599, as provided in the file and cited on the IDS, lacks adequate credible evidence to support the assertion that a method of treating a subject with a chronic disease, wherein the subject would benefit from inhibition of the activity of mTORC1, comprising administering to the subject a macrocyclic substituted piperidine represented by the Formula I, as recited, would contribute to the prophylaxis of any chronic diseases benefiting from the inhibition of the activity of mTORC1 in a subject, including, but not limited to, an age-related disease that benefits from inhibition of the activity of mTORC1, an age-related disease that results in hyperactivation of mTORC1, an autism spectrum disorder, an autoimmune disease, a cardiovascular disease, a cognitive disorder, cancer, a disease of impaired autophagy, epilepsy, an eye disorder, an infectious disease, an inflammatory disease, a kidney disease, a metabolic disease, an mTORopathy, muscular atrophy, a neurocutaneous disease, a neurodegenerative disease, a neurodevelopmental disorder, a pulmonary disease, and/or a tauopathy, since the inventor or joint inventor has neither provided convincing data for any subject 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 macrocyclic substituted piperidine of the Formula I, such as N-((3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,-27R,34aS)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-(3-hydroxypropoxy)-3-methoxycyclohexyl)propan-2-yl)-10-methoxy-6,8,12,14,20,26-hexamethyl-1,5,11,28,29-pentaoxo-1,4,5,6,9,10,11,12,13,14,21,22,23,24,25,26,27,-28,29,31,32,33,34,34a-tetracosahydro-3H-23,27-epoxypyrido[2,1-c][1]oxa[4]-azacyclohentriacontin-21-yl)-2-(2-methoxyethoxy)ethane-1-sulfonamide, shown to the left above, possesses utility as a therapeutic agent, useful in a method of treating a subject with a chronic disease, wherein the subject would benefit from inhibition of the activity of mTORC1, comprising administering to the subject a macrocyclic substituted piperidine represented by the Formula 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 of treating a subject with a chronic disease, wherein the subject would benefit from inhibition of the activity of mTORC1, comprising administering to the subject a macrocyclic substituted piperidine represented by the Formula I, wherein the chronic disease benefiting from the inhibition of the activity of mTORC1 in a subject, includes, but is not limited to, an age-related disease that benefits from inhibition of the activity of mTORC1, an age-related disease that results in hyperactivation of mTORC1, an autism spectrum disorder, an autoimmune disease, a cardiovascular disease, a cognitive disorder, cancer, a disease of impaired autophagy, epilepsy, an eye disorder, an infectious disease, an inflammatory disease, a kidney disease, a metabolic disease, an mTORopathy, muscular atrophy, a neurocutaneous disease, a neurodegenerative disease, a neurodevelopmental disorder, a pulmonary disease, and/or a tauopathy, to any subject 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 of treating a subject with a chronic disease, wherein the subject would benefit from inhibition of the activity of mTORC1, comprising administering to the subject a macrocyclic substituted piperidine represented by 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 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 32 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 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 32 recites the broad limitation, age-related disease that benefits from inhibition of the activity of mTORC1, and the claim also recites reduced immune activity in the elderly, 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.
Moreover, 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).
The examiner suggests amending the claim, particularly as stated in the section above entitled Claim Objections, to overcome this rejection.
Claim 38 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 38 recites the limitation, The method of claim 31, wherein R4 is…, in line 1 of the claim. There is insufficient antecedent basis, in claim 31, for this limitation, with respect to the macrocyclic substituted piperidines of the Formula I administered within the method of treating a subject with a chronic disease. According to claim 31, R4’, not R4, is recited, with respect to the macrocyclic substituted piperidines of the Formula I administered within the method of treating a subject with a chronic disease.
The examiner suggests amending the claim, 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 49 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 49 recites the limitation, The method of claim 31, wherein a pharmaceutical composition comprising a compound or salt of Formula I and a pharmaceutically acceptable excipient… is administered to the subject. According to claim 31, a compound represented by Formula I, or a pharmaceutically acceptable salt thereof, is administered to the subject in need thereof, with respect to the method of treating a subject with a chronic disease, wherein the subject would benefit from inhibition of the activity of mTORC1. Consequently, since The method of claim 31, wherein a pharmaceutical composition comprising a compound or salt of Formula I and a pharmaceutically acceptable excipient… is administered to the subject, fails to specify a further limitation to the method of treating a subject with a chronic disease, wherein the subject would benefit from inhibition of the activity of mTORC1, comprising administering to the subject a macrocyclic substituted piperidine represented by the Formula I, as recited in claim 31, and/or fails to include all the limitations of the method of treating a subject with a chronic disease, wherein the subject would benefit from inhibition of the activity of mTORC1, comprising administering to the subject a macrocyclic substituted piperidine represented by the Formula I, as recited in claim 31, 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, (3) rewrite the dependent claim in independent form, particularly as stated in the section above entitled Claim Objections, or (4) present a sufficient showing that the dependent claim complies with the statutory requirements, to overcome this rejection.
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