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 1-59 and 68-71 are pending in the instant invention. According to the Amendments to the Claims, filed November 18, 2022, claims 58, 59, 68 and 69 were amended and claims 60-67 were cancelled.
Status of Priority
This invention is a 35 U.S.C. § 371 National Stage Filing of International Application No. PCT/CN2021/095191, filed May 21, 2021, which claims priority under 35 U.S.C. § 119(a-d) to: a) CN 202110529033.5, filed May 14, 2021; and b) CN 202010433988.6, filed May 21, 2020.
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 September 5, 2025, is acknowledged: a) Group I - claims 1-15 and 57-59; and b) substituted 3-azabicyclo[3.1.0]-hexane of Formula (I) - p. 46, Example 1, Compound 1a, shown to the right below, and hereafter referred to as (1R,5S,6r)-N-(2-(8-(methylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-aza-bicyclo[3.1.0]hexane-6-carboxamide, where R1 = -H; R4 = -H; R5 = -H; R8 = -H; L1 = -NH-; R2 = -CH3; R3 = -CH3; L2 = -a single bond-; and ring A = -imidazo[1,5-a]-pyridin-3-yl, substituted at C-8 with R10, wherein R10 = -SR11, where R11 = -CH3. Claims 1-8,
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11-15, 57 and 59 read on the elected species. Affirmation 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 above, 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Moreover, the inventor or joint inventor should further note that claims 16-56 and 68-71 were withdrawn from further consideration, pursuant to 37 CFR 1.142(b), as being drawn to a nonelected or cancelled invention, there being no allowable generic or linking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 1-15 and 57-59 is contained within.
Specification Objection - Disclosure
The following guidelines illustrate the preferred layout for the specification of a utility application. These guidelines are suggested for the inventor’s or joint inventor’s use.
Arrangement of the Specification
As provided in 37 CFR 1.77(b), the specification of a utility invention should include the following sections in order. Each of the lettered items should appear in upper case, without underlining or bold type, as a section heading. If no text follows the section heading, the phrase Not Applicable should follow the section heading:
(a) TITLE OF THE INVENTION.
(b) CROSS-REFERENCE TO RELATED APPLICATIONS.
(c) STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR
DEVELOPMENT.
(d) THE NAMES OF THE PARTIES TO A JOINT RESEARCH AGREEMENT.
(e) INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ON A
COMPACT DISC.
(f) BACKGROUND OF THE INVENTION.
(1) Field of the Invention.
(2) Description of Related Art (including information disclosed under 37 CFR 1.97
and 1.98).
(g) BRIEF SUMMARY OF THE INVENTION.
(h) BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S).
(i) DETAILED DESCRIPTION OF THE INVENTION.
(j) CLAIM OR CLAIMS (commencing on a separate sheet).
(k) ABSTRACT OF THE DISCLOSURE (commencing on a separate sheet).
(l) SEQUENCE LISTING (See MPEP § 2424 and 37 CFR 1.821-1.825).
The inventor or joint inventor is advised to format the specification according to 37 CFR 1.77(b) above and 37 CFR 1.77(c). Revisions should particularly include and/or address: a) section headings (b-i), where applicable; and b) 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 identifying: a) the substituted 3-azabicyclo[3.1.0]hexanes of the Formula (I); and b) a particular utility for the substituted 3-azabicyclo[3.1.0]hexanes of the Formula (I).
The following title is suggested: SUBSTITUTED 3-AZABICYCLO[3.1.0]HEXANES AS SSTR4 AGONISTS.
Appropriate correction is required.
Claim Objections
Claim 1 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(a), 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:
R1 is H or C1-6 alkyl;
R4 is H, C1-6 alkyl, C1-6 alkylene-OC1-6 alkyl, OC1-6 alkyl, (CH2)m-OC3-10 carbocyclyl, (CH2)m-O(3- to 10-membered heterocyclyl), (CH2)m-C3-10 carbocyclyl, (CH2)m-3- to 10-membered heterocyclyl, OC3-10 carbocyclyl, O(3- to 10-membered heterocyclyl), C3-10 carbocyclyl, 3- to 10-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl;
wherein any 3- to 10-membered heterocyclyl or 5- or 6-membered heteroaryl contains 1, 2, 3, or 4 heteroatoms or heteroatomic groups independently selected from the group consisting of N, NH, O, and S;
wherein the C1-6 alkyl, C1-6 alkylene-OC1-6 alkyl, or OC1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of F, Cl, Br, I, CN, NH2, OH, OC1-6 alkyl, and SH; and
wherein the OC3-10 carbocyclyl, O(3- to 10-membered heterocyclyl), C3-10 carbocyclyl, 3- to 10-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of F, Cl, Br, I, CN, C1-4 alkyl, NH2, OH, OC1-6 alkyl, and SH;
R5 is H, C1-6 alkyl, C1-6 alkylene-OC1-6 alkyl, OC1-6 alkyl, (CH2)m-OC3-10 carbocyclyl, (CH2)m-O(3- to 10-membered heterocyclyl), (CH2)m-C3-10 carbocyclyl, (CH2)m-3- to 10-membered heterocyclyl, OC3-10 carbocyclyl, O(3- to 10-membered heterocyclyl), C3-10 carbocyclyl, 3- to 10-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl;
wherein any 3- to 10-membered heterocyclyl or 5- or 6-membered heteroaryl contains 1, 2, 3, or 4 heteroatoms or heteroatomic groups independently selected from the group consisting of N, NH, O, and S;
wherein the C1-6 alkyl, C1-6 alkylene-OC1-6 alkyl, or OC1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of F, Cl, Br, I, CN, NH2, OH, OC1-6 alkyl, and SH; and
wherein the OC3-10 carbocyclyl, O(3- to 10-membered heterocyclyl), C3-10 carbocyclyl, 3- to 10-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of F, Cl, Br, I, CN, C1-4 alkyl, NH2, OH, OC1-6 alkyl, and SH;
R6 is H, C1-6 alkyl, C1-6 alkylene-OC1-6 alkyl, OC1-6 alkyl, (CH2)m-OC3-10 carbocyclyl, (CH2)m-O(3- to 10-membered heterocyclyl), (CH2)m-C3-10 carbocyclyl, (CH2)m-3- to 10-membered heterocyclyl, OC3-10 carbocyclyl, O(3- to 10-membered heterocyclyl), C3-10 carbocyclyl, 3- to 10-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl;
wherein any 3- to 10-membered heterocyclyl or 5- or 6-membered heteroaryl contains 1, 2, 3, or 4 heteroatoms or heteroatomic groups independently selected from the group consisting of N, NH, O, and S;
wherein the C1-6 alkyl, C1-6 alkylene-OC1-6 alkyl, or OC1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of F, Cl, Br, I, CN, NH2, OH, OC1-6 alkyl, and SH; and
wherein the OC3-10 carbocyclyl, O(3- to 10-membered heterocyclyl), C3-10 carbocyclyl, 3- to 10-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of F, Cl, Br, I, CN, C1-4 alkyl, NH2, OH, OC1-6 alkyl, and SH;
R7 is H, C1-6 alkyl, C1-6 alkylene-OC1-6 alkyl, OC1-6 alkyl, (CH2)m-OC3-10 carbocyclyl, (CH2)m-O(3- to 10-membered heterocyclyl), (CH2)m-C3-10 carbocyclyl, (CH2)m-3- to 10-membered heterocyclyl, OC3-10 carbocyclyl, O(3- to 10-membered heterocyclyl), C3-10 carbocyclyl, 3- to 10-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl;
wherein any 3- to 10-membered heterocyclyl or 5- or 6-membered heteroaryl contains 1, 2, 3, or 4 heteroatoms or heteroatomic groups independently selected from the group consisting of N, NH, O, and S;
wherein the C1-6 alkyl, C1-6 alkylene-OC1-6 alkyl, or OC1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of F, Cl, Br, I, CN, NH2, OH, OC1-6 alkyl, and SH; and
wherein the OC3-10 carbocyclyl, O(3- to 10-membered heterocyclyl), C3-10 carbocyclyl, 3- to 10-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of F, Cl, Br, I, CN, C1-4 alkyl, NH2, OH, OC1-6 alkyl, and SH;
R8 is H, C1-6 alkyl, C1-6 alkylene-OC1-6 alkyl, OC1-6 alkyl, (CH2)m-OC3-10 carbocyclyl, (CH2)m-O(3- to 10-membered heterocyclyl), (CH2)m-C3-10 carbocyclyl, (CH2)m-3- to 10-membered heterocyclyl, OC3-10 carbocyclyl, O(3- to 10-membered heterocyclyl), C3-10 carbocyclyl, 3- to 10-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl;
wherein any 3- to 10-membered heterocyclyl or 5- or 6-membered heteroaryl contains 1, 2, 3, or 4 heteroatoms or heteroatomic groups independently selected from the group consisting of N, NH, O, and S;
wherein the C1-6 alkyl, C1-6 alkylene-OC1-6 alkyl, or OC1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of F, Cl, Br, I, CN, NH2, OH, OC1-6 alkyl, and SH; and
wherein the OC3-10 carbocyclyl, O(3- to 10-membered heterocyclyl), C3-10 carbocyclyl, 3- to 10-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of F, Cl, Br, I, CN, C1-4 alkyl, NH2, OH, OC1-6 alkyl, and SH;
each m is independently 1, 2, or 3;
L1 is -NH- or -O-;
R2 is H, C1-6 alkyl, or C3-6 cycloalkyl;
R3 is H, C1-6 alkyl, or C3-6 cycloalkyl; or
R2 and R3, together with the carbon atom to which they are attached, form a saturated 3- to 6-membered cyclyl, wherein the 3- to 6-membered cyclyl optionally comprises one additional heteroatom or heteroatomic group selected from the group consisting of -NR9-, -O-, -S(O)-, and -S(O)2-;
R9 is H, halogen, CN, C1-6 alkyl, C1-6 alkylene-OC1-4 alkyl, OH, or C3-6 cycloalkyl;
(i) L2 is a single bond, -(CRaRb)n-, -(CRaRb)nO-, or -O-; and
each R10 is independently H, F, Cl, Br, I, CN, C1-6 alkyl, C1-6 alkylene-OC1-4 alkyl, NH2, OH, SR11, or C3-6 cycloalkyl;
with the proviso that at least one R10 is SR11; or
(ii) L2 is -(CRaRb)nS- or -S-; and
each R10 is independently H, F, Cl, Br, I, CN, C1-6 alkyl, C1-6 alkylene-OC1-4 alkyl, (CH2)n-C3-10 carbocyclyl, (CH2)n-(3- to 10-membered heterocyclyl), C2-6 alkenyl, (CH2)n-C2-6 alkenyl, C2-6 alkynyl, (CH2)n-C2-6 alkynyl, NH2, OH, OC1-4 alkyl, O(CH2)n-C3-10 carbocyclyl, O(CH2)n-(3- to 10-membered heterocyclyl), OC3-10 carbocyclyl, O-(3- to 10-membered heterocyclyl), SR11, C3-10 carbocyclyl, or 3- to 10-membered heterocyclyl;
Ra is H or C1-6 alkyl;
Rb is H or C1-6 alkyl;
each R11 is independently H, C1-6 alkyl, C1-6 alkylene-OC1-4 alkyl, (CH2)n-C3-10 carbocyclyl, (CH2)n-(3- to 10-membered heterocyclyl), C2-6 alkenyl, (CH2)n-C2-6 alkenyl, C2-6 alkynyl, (CH2)n-C2-6 alkynyl, C3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C6-10 aryl, or 5- or 6- membered heteroaryl;
wherein any 3- to 10-membered heterocyclyl and any 5- or 6- membered heteroaryl independently contain 1, 2, 3, or 4 heteroatoms or heteroatomic groups independently selected from the group consisting of N, NH, O, and S;
wherein any C1-6 alkyl and C1-6 alkylene-OC1-4 alkyl is optionally and independently substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, OH, and OC1-4 alkyl; and
wherein any C3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C6-10 aryl, and 5- or 6- membered heteroaryl is optionally and independently substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C1-4 alkyl, OH, and OC1-4 alkyl;
each n is independently 1, 2, or 3; and
ring A is C5-14 cycloalkyl, 5- to 14-membered heterocyclyl, C6-14 aryl, or 5- to 14-membered heteroaryl;
wherein the 5- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl contains 1, 2, 3, or 4 heteroatoms or heteroatomic groups independently selected from the group consisting of N, NH, O, and S; and
wherein the C5-14 cycloalkyl, 5- to 14-membered heterocyclyl, C6-14 aryl, or 5- to 14-membered heteroaryl is optionally substituted with 1, 2, 3, or 4 independently selected R10 substituents;
with the proviso that R2 and R3 are not both H.
Appropriate correction is required. See MPEP § 2173.02.
Claim 2 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 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R1 is H; and
L1 is -NH-.
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), 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 compound according to claim 1, wherein the compound is of Formula (VI):
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(VI)
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
L2 is a single bond, -(CRaRb)n-, -(CRaRb)nO-, or -O-.
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), 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 compound according to claim 1, wherein the compound is of Formula (II):
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(II)
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
L2 is a single bond, -(CRaRb)n-, -(CRaRb)nO-, or -O-.
Appropriate correction is required. See MPEP § 2173.02.
Claim 5 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 4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R1 is H;
L1 is -NH-; and
L2 is a single bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2O-, or -CH2CH2O-.
Appropriate correction is required. See MPEP § 2173.02.
Claim 6 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 4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R2 is C1-6 alkyl or C3-6 cycloalkyl;
R3 is C1-6 alkyl or C3-6 cycloalkyl; or
R2 and R3, together with the carbon atom to which they are attached, form a saturated 3- to 6-membered cyclyl, wherein the 3- to 6-membered cyclyl optionally comprises one additional heteroatom or heteroatomic group selected from the group consisting of -O-, -S(O)-, and -S(O)2-.
Appropriate correction is required. See MPEP § 2173.02.
Claim 7 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(a), 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
The compound according to claim 4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R11 is H, C1-4 alkyl, C1-4 alkyl-OC1-4 alkyl, (CH2)n-C3-6 carbocyclyl, (CH2)n-(3- to 6-membered heterocyclyl), C2-4 alkenyl, (CH2)n-C2-4 alkenyl, C2-4 alkynyl, (CH2)n-C2-4 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6-10 aryl, or 5- or 6- membered heteroaryl;
wherein any 3- to 6-membered heterocyclyl or 5- or 6- membered heteroaryl contains 1, 2, 3, or 4 heteroatoms or heteroatomic groups independently selected from the group consisting of N, NH, O, and S;
wherein any C1-4 alkyl or C1-4 alkyl-OC1-4 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, OH, and OC1-4 alkyl; and
wherein any C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6-10 aryl, or 5- or 6- membered heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C1-4 alkyl, OH, and OC1-4 alkyl.
Appropriate correction is required. See MPEP § 2173.02.
Claim 8 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 7, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R11 is CH3, CH2CH3, CH(CH3)2, CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, or pyridinyl.
Appropriate correction is required. See MPEP § 2173.02.
Claim 9 is objected to because of the following informalities: for brevity, clarity, precision and to avoid issues under 35 U.S.C. § 112(a), 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
The compound according to claim 1, wherein the compound is of Formula (III):
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(III)
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
R10 is H, F, Cl, Br, I, CN, C1-4 alkyl, C1-6 alkyl-OC1-4 alkyl, (CH2)n-C3-10 carbocyclyl, (CH2)n-(3- to 10-membered heterocyclyl), C2-4 alkenyl, (CH2)n-C2-4 alkenyl, C2-4 alkynyl, (CH2)n-C2-4 alkynyl, NH2, OH, OC1-4 alkyl, O(CH2)n-C3-10 carbocyclyl, O(CH2)n-(3- to 10-membered heterocyclyl), OC3-10 carbocyclyl, O-(3- to 10-membered heterocyclyl), SR11, C3-10 carbocyclyl, or 3- to 10-membered heterocyclyl.
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), 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 compound according to claim 9, wherein the compound is of Formula (III):
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(III)
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
Ra is H, CH3, CH2CH3, or CH(CH3)2;
Rb is H, CH3, CH2CH3, or CH(CH3)2;
R10 is H, F, Cl, Br, I, CN, CH3, CH2CH3, CH(CH3)2, NH2, OH, Ocyclobutyl, SR11, cyclopropyl, cyclobutyl, cyclopentyl, or tetrahydrofuranyl; and
R11 is CH3, CH2CH3, CH(CH3)2, CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, or pyridinyl.
Appropriate correction is required. See MPEP § 2173.02.
Claim 11 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(a), 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
The compound according to claim 1, wherein the compound is of Formula (IV):
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(IV)
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
R4 is C1-6 alkyl, C1-6 alkylene-OC1-6 alkyl, OC1-6 alkyl, (CH2)m-OC3-10 carbocyclyl, (CH2)m-O(3- to 10-membered heterocyclyl), (CH2)m-C3-10 carbocyclyl, (CH2)m-3- to 10-membered heterocyclyl, OC3-10 carbocyclyl, O(3- to 10-membered heterocyclyl), C3-10 carbocyclyl, 3- to 10-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl;
wherein any 3- to 10-membered heterocyclyl or 5- or 6-membered heteroaryl contains 1, 2, 3, or 4 heteroatoms or heteroatomic groups independently selected from the group consisting of N, NH, O, and S;
wherein the C1-6 alkyl, C1-6 alkylene-OC1-6 alkyl, or OC1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of F, Cl, Br, I, CN, NH2, OH, OC1-6 alkyl, and SH; and
wherein the OC3-10 carbocyclyl, O(3- to 10-membered heterocyclyl), C3-10 carbocyclyl, 3- to 10-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of F, Cl, Br, I, CN, C1-4 alkyl, NH2, OH, OC1-6 alkyl, and SH.
Appropriate correction is required. See MPEP § 2173.02.
Claim 12 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(a), 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
The compound according to claim 1, wherein the compound is of Formula (V):
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(V)
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
R4 is H, C1-6 alkyl, C1-6 alkylene-OC1-6 alkyl, or OC1-6 alkyl, wherein the C1-6 alkyl, C1-6 alkylene-OC1-6 alkyl, or OC1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of F, Cl, Br, I, CN, NH2, OH, OC1-4 alkyl, and SH;
R5 is H, C1-6 alkyl, C1-6 alkylene-OC1-6 alkyl, or OC1-6 alkyl, wherein the C1-6 alkyl, C1-6 alkylene-OC1-6 alkyl, or OC1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of F, Cl, Br, I, CN, NH2, OH, OC1-4 alkyl, and SH;
R6 is H, C1-6 alkyl, C1-6 alkylene-OC1-6 alkyl, or OC1-6 alkyl, wherein the C1-6 alkyl, C1-6 alkylene-OC1-6 alkyl, or OC1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of F, Cl, Br, I, CN, NH2, OH, OC1-4 alkyl, and SH;
R7 is H, C1-6 alkyl, C1-6 alkylene-OC1-6 alkyl, or OC1-6 alkyl, wherein the C1-6 alkyl, C1-6 alkylene-OC1-6 alkyl, or OC1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of F, Cl, Br, I, CN, NH2, OH, OC1-4 alkyl, and SH;
R2 is C1-6 alkyl or C3-6 cycloalkyl;
R3 is C1-6 alkyl or C3-6 cycloalkyl; or
R2 and R3, together with the carbon atom to which they are attached, form a saturated 3- to 6-membered cycloalkyl;
(i) L2 is a single bond; and
each R10 is independently H, F, Cl, Br, I, CN, C1-6 alkyl, C1-6 alkylene-OC1-4 alkyl, NH2, OH, SR11, or C3-6 cycloalkyl;
with the proviso that at least one R10 is SR11; or
(ii) L2 is -(CRaRb)nS- or -S-; and
each R10 is independently H, F, Cl, Br, I, CN, C1-4 alkyl, C1-6 alkylene-OC1-4 alkyl, NH2, OH, or OC1-4 alkyl;
each R11 is independently H, C1-6 alkyl, C1-6 alkylene-OC1-4 alkyl, (CH2)n-C3-10 carbocyclyl, (CH2)n-(3- to 10-membered heterocyclyl), C3-10 carbocyclyl, 3- to 10-membered heterocyclyl, or 5- or 6- membered heteroaryl;
wherein any 3- to 10-membered heterocyclyl and any 5- or 6- membered heteroaryl independently contain 1, 2, 3, or 4 heteroatoms or heteroatomic groups independently selected from the group consisting of N, NH, O, and S; and
wherein any C1-6 alkyl and C1-6 alkylene-OC1-4 alkyl is optionally and independently substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, OH, and OC1-4 alkyl; and
wherein any C3-10 carbocyclyl, 3- to 10-membered heterocyclyl, and 5- or 6- membered heteroaryl is optionally and independently substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C1-4 alkyl, OH, and OC1-4 alkyl; and
ring A is C5-14 cycloalkyl, 5- to 14-membered heterocyclyl, C6-14 aryl, or 5- to 14-membered heteroaryl;
wherein the 5- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl contains 1, 2, 3, or 4 N heteroatoms or NH heteroatomic groups; and
wherein the C5-14 cycloalkyl, 5- to 14-membered heterocyclyl, C6-14 aryl, or 5- to 14-membered heteroaryl is optionally substituted with 1, 2, 3, or 4 independently selected R10 substituents.
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), 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 compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring A is 1,3a,5,6,7,7a-hexahydropyrano[2,3-d]imidazolyl, 3a,6,7,7a-tetrahydro-5H-pyrano[2,3-d]oxazolyl, 6,7-dihydro-5H-pyrano[2,3-d]pyrimidinyl, 7,8-dihydro-6H-pyrano[3,2-d]pyrimidinyl, 7,8-dihydro-6H-pyrano[2,3-b]pyrazinyl, phenyl, pyridinyl, indolizinyl, indazolyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, 1H-imidazo[4,5-b]pyridinyl, benzo[d]isoxazolyl, benzo[d]isothiazolyl, 1H-pyrazolo[3,4-c]pyridinyl, imidazo[1,2-a]pyrazinyl, isoxazolo[5,4-c]pyridinyl, isothiazolo[5,4-c]pyridinyl, quinolinyl, isoquinolinyl, phthalazinyl, or quinazolinyl.
Appropriate correction is required. See MPEP § 2173.02.
Claim 14 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(a), 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring A is 1,3a,5,6,7,7a-hexahydropyrano[2,3-d]imidazolyl, 3a,6,7,7a-tetrahydro-5H-pyrano[2,3-d]oxazolyl, 6,7-dihydro-5H-pyrano[2,3-d]pyrimidinyl, 7,8-dihydro-6H-pyrano[3,2-d]pyrimidinyl, 7,8-dihydro-6H-pyrano[2,3-b]pyrazinyl, phenyl, indolizinyl, indazolyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, 1H-imidazo[4,5-b]pyridinyl, benzo[d]isoxazolyl, benzo[d]isothiazolyl, 1H-pyrazolo[3,4-c]pyridinyl, imidazo[1,2-a]pyrazinyl, isoxazolo[5,4-c]pyridinyl, isothiazolo[5,4-c]pyridinyl, quinolinyl, isoquinolinyl, phthalazinyl, or quinazolinyl.
Appropriate correction is required. See MPEP § 2173.02.
Claim 15 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(a), 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring A is phenyl, indazolyl, or imidazo[1,5-a]pyridinyl.
Appropriate correction is required. See MPEP § 2173.02.
Claim 57 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(a), 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation(s):
57. The compound according to claim 1, or a stereoisomer thereof, wherein the compound, or stereoisomer thereof, is selected from the group consisting of:
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or a pharmaceutically acceptable salt thereof.
72. A compound:
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or a pharmaceutically acceptable salt thereof.
Appropriate correction is required. See MPEP § 2173.02.
Claim 58 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(a), 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the pharmaceutically acceptable salt is selected from the group consisting of an acetate salt, an aspartate salt, a benzenesulfonate salt, a benzoate salt, a cinnamate salt, a citrate salt, an ethanesulfonate salt, a fumarate salt, a galacturonate salt, a glucoronate salt, a glutamate salt, a glycolate salt, a hydrobromide salt, a hydrochloride salt, a 2-hydroxypropionate salt, a malate salt, a maleate salt, a malonate salt, a mandelate salt, a mesylate salt, a nitrate salt, an oxalate salt, a phosphate salt, a salicylate salt, a succinate salt, a sulfate salt, a tartrate salt, a p-toluenesulfonate salt, and a trifluormethanesulfonate salt, or a combination thereof.
Appropriate correction is required. See MPEP § 2173.02.
Claim 59 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(a), 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective dose of the compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer 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.
N-oxides, hydrates, solvates, metabolites, polymorphs, and/or prodrugs of substituted 3-azabicyclo[3.1.0]hexanes of the Formula (I)
Claims 1-15 and 57-59 are rejected under 35 U.S.C. § 112(a) because the specification, while being enabling for substituted 3-azabicyclo[3.1.0]hexanes of the Formula (I), does not reasonably provide enablement for N-oxides, hydrates, solvates, metabolites, polymorphs, and/or prodrugs of substituted 3-azabicyclo[3.1.0]hexanes 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. N-oxides, hydrates, solvates, metabolites, polymorphs, and/or prodrugs of substituted 3-azabicyclo[3.1.0]hexanes of the Formula (I), as recited in claims 1-15 and 57-59, 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 N-oxides, hydrates, solvates, metabolites, polymorphs, and/or prodrugs of substituted 3-azabicyclo[3.1.0]hexanes 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 3-azabicyclo-[3.1.0]hexanes of the Formula (I), shown to the right, as well as the myriad of potential N-oxides, hydrates, solvates, metabolites, polymorphs, and/or prodrugs formulated from these substituted 3-azabicyclo[3.1.0]hexanes of the Formula (I), shown to the right, respectively;
(b) Nature of the invention - the nature of the invention is evaluation of substituted 3-azabicyclo[3.1.0]hexanes of the Formula (I), shown to the right above, and/or N-oxides, hydrates, solvates, metabolites, polymorphs, and/or prodrugs thereof, and the pharmacokinetic behavior of these substances as somatostatin receptor subtype 4 (SSTR4) agonists;
(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). Moreover, US 2019/0269650, as cited on the IDS, provides a synthesis of substituted 3-azabicyclo[3.1.0]hexanes {Giovannini, et al. US 2019/0269650, 2019};
(d) Level of one of ordinary skill in the art - the artisans synthesizing the inventor’s or joint inventor’s substituted 3-azabicyclo[3.1.0]hexanes of the Formula (I), and/or N-oxides, hydrates, solvates, metabolites, polymorphs, and/or prodrugs 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 Examples 1-17, on pages 43-108 of the instant specification, and Giovannini, et al. in US 2019/0269650, as cited on the IDS, whether the instantly recited N-oxides, hydrates, solvates, metabolites, polymorphs, and/or prodrugs of substituted 3-azabicyclo[3.1.0]hexanes of the Formula (I), are enabled. Likewise, the following excerpt is taken from Dörwald, which has relevance to the synthesis of N-oxides and/or metabolites of substituted 3-azabicyclo[3.1.0]hexanes of the Formula (I) {Dörwald, F. Zaragoza. Side Reactions in Organic Synthesis: A Guide to Successful Synthesis Design, Weinheim: WILEY-VCH Verlag GmbH & Co. KGaA, 2005, Preface}:
Most non-chemists would probably be horrified if they were to learn how many attempted syntheses fail, and how inefficient research chemists are. The ratio of successful to unsuccessful chemical experiments in a normal research laboratory is far below unity, and synthetic research chemists, in the same way as most scientists, spend most of their time working out what went wrong, and why.
Despite the many pitfalls lurking in organic synthesis, most organic chemistry textbooks and research articles do give the impression that organic reactions just proceed smoothly and that the total synthesis of complex natural products, for instance, is maybe a labor-intensive but otherwise undemanding task. In fact, most syntheses of structurally complex natural products are the result of several years of hard work by a team of chemists, with almost every step requiring careful optimization. The final synthesis usually looks quite different from that originally planned, because of unexpected difficulties encountered in the initially chosen synthetic sequence. Only the seasoned practitioner who has experienced for himself the many failures and frustrations which the development (sometimes even the repetition) of a synthesis usually implies will be able to appraise such work.
Chemists tend not to publish negative results, because these are, as opposed to positive results, never definite (and far too copious).
Next, the following excerpt is taken from Vippagunta, et al., with respect to the synthesis of hydrates and/or solvates of substituted 3-azabicyclo[3.1.0]hexanes 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.
Then, the following excerpt is further taken from Vippagunta, et al., with respect to the synthesis of polymorphs of substituted 3-azabicyclo[3.1.0]hexanes of the Formula (I) {Vippagunta, et al. Advanced Drug Delivery Reviews, 48, 2001, 18}:
There are many limitations in using computational methods for predicting polymorphs theoretically. The first limitation is that the ab initio screening is useful only for nonionic rigid molecules. For more complex systems, the method is very useful for generating plausible crystal structures, but it is not accurate enough to determine which of these possible structures can actually be crystallized.
Another issue of concern is that the existing methods only predict the lattice energies, which relate to internal energies or enthalpies of the crystals. However, the relative thermodynamic stability of polymorphs is determined by the Gibbs free energy, which is a linear function of both enthalpy and entropy. Predictions of the relative stability of polymorphs will be more accurate when the entropies, as well as lattice energies, are considered. Hence, no general method is currently available for the prediction or interpretation of the properties of complicated polymorphic or pseudopolymorphic systems.
Moreover, the following excerpt is taken from Burger’s, with respect to the synthesis of prodrugs of 3-azabicyclo[3.1.0]hexanes of the Formula (I) {Wolff, Manfred E., Ed. Burger’s Medicinal Chemistry and Drug Discovery - Fifth Edition, Volume 1: Principles and Practice, New York: John Wiley & Sons, 1994, 975-977}:
The design of prodrugs in a rational manner requires that the underlying causes which necessitate or stimulate the use of the prodrug approach be defined and clearly understood. It may then be possible to identify the means by which the difficulties can be overcome. The rational design of the prodrug can thus be divided into three basic steps: (1) identification of the drug delivery problem; (2) identification of the physiochemical properties required for optimal delivery; and (3) selection of a prodrug derivative that has the proper physiochemical properties and that will be cleaved in the desired biological compartment.
The difficulty of extrapolating data from animal to humans encountered during toxicokinetic and toxicologic studies with drugs is amplified with prodrugs, since not only metabolism of the active moiety might differ, but also its availability from the prodrug. As a matter of fact, there is presently no published rational for the conduct of animal and human pharmacokinetic programs during prodrug research and development.
(f) Amount of direction provided by the inventor - the invention lacks direction with respect to making and/or using N-oxides, hydrates, solvates, metabolites, polymorphs, and/or prodrugs of substituted 3-azabicyclo[3.1.0]hexanes of the Formula (I);
(g) Existence of working examples - the inventor or joint inventor has provided sufficient guidance to make and/or use substituted 3-azabicyclo[3.1.0]hexanes of the Formula (I); however, the disclosure is insufficient to allow extrapolation of the limited examples to enable the instantly recited N-oxides, hydrates, solvates, metabolites, polymorphs, and/or prodrugs of substituted 3-azabicyclo[3.1.0]hexanes of the Formula (I). The specification lacks working examples of N-oxides, hydrates, solvates, metabolites, polymorphs, and/or prodrugs of substituted 3-azabicyclo-[3.1.0]hexanes 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.
(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(n) N-oxide, hydrate, solvate, metabolite, polymorph, and/or prodrug 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 N-oxides, hydrates,
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solvates, metabolites, polymorphs, and/or prodrugs of substituted 3-azabicyclo[3.1.0]hexanes of the Formula (I). Thus, it is unclear, based on the guidance provided by the specification, whether a hydrate of a substituted 3-azabicyclo[3.1.0]hexane of the Formula (I), such as (1R,5S,6r)-N-(2-(8-(methylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-aza-bicyclo[3.1.0]hexane-6-carboxamide dihydrate, shown to the left above, is either synthetically feasible or possesses utility as a somatostatin receptor subtype 4 (SSTR4) agonist.
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 N-oxides, hydrates, solvates, metabolites, polymorphs, and/or prodrugs of substituted 3-azabicyclo[3.1.0]hexanes 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 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 9 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 9 recites the limitation, The compound… according to claim 1, wherein… R10 is… (CH2)n-alkenyl or (CH2)n-alkynyl, in lines 1-7 of the claim. There is insufficient antecedent basis, in claim 1, for this limitation, with respect to the substituted 3-azabicyclo[3.1.0]hexanes of the Formula (I). According to claim 1, R10 is neither recited as (CH2)n-alkenyl, nor (CH2)n-alkynyl, respectively, with regard to the substituted 3-azabicyclo[3.1.0]hexanes of the Formula (I).
The examiner suggests amending the claims, particularly as stated in the section above entitled Claim Objections, to overcome this rejection.
Claim 10 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 10 recites the limitation, The compound… according to claim 9, wherein… R10 is… trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, or tetrahydrofuran