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, 3, 4, 11, 13-16, 31, 34, 44, 56, 57, 64, 68, 98, 99 and 103 are pending in the instant invention. According to the Amendments to the Claims, filed June 26, 2026, claims 13, 31, 44, 56, 57, 98, 99 and 103 were amended and claims 2, 5-10, 12, 17-30, 32, 33, 35-43, 45-55, 58-63, 65-67, 69-97, 100-102 and 104-115 were cancelled.
Status of Priority
This invention is a 35 U.S.C. § 371 National Stage Filing of International Application No. PCT/CN2022/131290, filed November 11, 2022, which claims priority under 35 U.S.C. § 119(a-d) to: a) International Application No. PCT/CN2022/123821, filed October 8, 2022; and b) International Application No. PCT/CN2021/130284, filed November 12, 2021.
Restrictions / Election of Species
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The inventor’s or joint inventor’s provisional election of the following, with traverse, in the reply filed on June 26, 2026, is acknowledged: a) Group I - claims 1, 3, 4, 13, 31, 34, 44, 56, 57, 98 and 99; and b) substituted heteroaryl of Formula (I) - p. 126, compound 2, shown to the right below, and hereafter referred to as 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-3-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)-benzyl)imidazo[1,5-a]pyrazine, where m = 2; n = 2; p = 1; ring A = -pyrimidin-5-yl, substituted at C-4, with RA, wherein RA = -cyclopropyl and at C-6, with RA, wherein RA = -OR11, where R11 = -CH3; X1
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= CR1, wherein R1 = -H; X3
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= CR3, wherein R3 = -H; X7
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= CR7, wherein R7 = -H; R8 = -H; R9 = -H; ring B = -phenyl, substituted at C-4 with RB1, wherein RB1 = -pyrazol-1-yl, substituted at C-3, with RB, where RB = -CF3 and at C-5, with RB, where RB = -CH3. Claims 1, 3, 4, 13, 31, 34, 44, 56, 57, 98 and 99 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 since supposed errors in the restriction requirement were not distinctly and specifically pointed out, the election has been treated as an election, without traverse. See MPEP § 818.03(a).
Likewise, the inventor or joint inventor should further note that the requirement is still deemed proper and is therefore made FINAL.
Next, 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.
Moreover, the inventor or joint inventor should further note that claims 11, 14-16, 64, 68 and 103 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, 3, 4, 13, 31, 34, 44, 56, 57, 98 and 99 is contained within.
Specification Objection - Disclosure
The inventor or joint inventor is advised to format the specification according to 37 CFR 1.77(c). Revisions should particularly address bold-type, underline, and/or upper case formatting. Appropriate correction may be required.
Specification Objection - Title
The inventor or joint inventor is reminded of the proper content of the title of the invention.
The title of the invention should be brief, but technically accurate and descriptive and should contain fewer than 500 characters. See 37 CFR 1.72(a) and MPEP § 606.
The title of the invention is not technically accurate and descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed. In the revised title, the examiner suggests additionally identifying the substituted heteroaryls of the Formula (I).
The following title is suggested: SUBSTITUTED IMIDAZO[1,5-a]PYRAZINES, 1,2,4-TRIAZOLO[4,3-a]PYRAZINES, AND IMIDAZO[5,1-f][1,2,4]TRIAZINES AS INHIBITORS OF UBIQUITIN SPECIFIC PROTEASE 1 (USP1).
Appropriate correction is required.
Specification Objection - Abstract
The inventor or joint inventor is reminded of the proper content of an abstract of the disclosure.
With regard particularly to chemical patents, for compounds or compositions, the general nature of the compound or composition should be given as well as the use thereof, e.g., The compounds are of the class of alkyl benzene sulfonyl ureas, useful as oral anti-diabetics. Exemplification of a species could be illustrative of members of the class. For processes, the reactions, reagents and process conditions should be stated, generally illustrated by a single example, unless variations are necessary. See MPEP § 608.01(b), Section B.
The abstract of the disclosure is objected to because it fails to exemplify any members or formulae illustrative of its class. Correction is required. See MPEP § 608.01(b).
The examiner suggests incorporating the structure of Formula (I) into the abstract, to overcome this objection.
Claim Objections
Claim 1 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(a) and/or 35 U.S.C. § 112(b), the existing recitation should be replaced with the following recitation:
A compound of Formula (I):
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Formula (I)
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
ring A is phenyl, naphthyl, or heteroaryl;
each RA is halogen, CN, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)R12, C(O)NR11R12, C(O)OR12, NR11R12, NR12C(O)R12, NR12C(O)NR11R12, NR12C(O)OR12, NR12S(O)2R12, NO2, OR11, OC(O)R12, OC(O)NR11R12, SR11, S(O)R12, S(O)2R12, S(O)2NR11R12, C3-8 cycloalkyl, or C2-7 heterocycloalkyl, wherein each C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, and C2-7 heterocycloalkyl is optionally and independently substituted;
m is 1, 2, 3, or 4;
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is:
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,
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, or
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;
R1 is H, halogen, CN, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, NR12R12, OR11, or SR11, wherein the C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted;
R3 is H, halogen, CN, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, NR12R12, OR11, or SR11, wherein the C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted;
R7 is H, halogen, CN, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, NR12R12, OR11, or SR11, wherein the C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted;
R8 is H, halogen, CN, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, or C2-6 alkynyl, wherein the C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted;
R9 is H, halogen, CN, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, or C2-6 alkynyl, wherein the C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted; or
R8 and R9, taken together with the carbon atom to which they are attached, form -C(O)-; or
R8 and R9, taken together with the carbon atom to which they are attached, form a C3-6 cycloalkyl or heterocycloalkyl, wherein the C3-6 cycloalkyl or heterocycloalkyl is optionally substituted;
p is 0 or 1;
ring B is phenyl or a 6-membered heteroaryl;
RB1 is C3-8 cycloalkyl, C2-9 heterocycloalkyl, phenyl, naphthyl, or heteroaryl, wherein the C3-8 cycloalkyl, C2-9 heterocycloalkyl, phenyl, naphthyl, or heteroaryl is optionally substituted;
each RB is independently halogen, CN, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)R12, C(O)NR11R12, C(O)OR12, NR11R12, NR12C(O)R12, NR12C(O)NR11R12, NR12C(O)OR12, NR12S(O)2R12, NO2, OR11, OC(O)R12, OC(O)NR11R12, SR11, S(O)R12, S(O)2R12, S(O)2NR11R12, C3-8 cycloalkyl, C2-9 heterocycloalkyl, phenyl, naphthyl, or heteroaryl, wherein each C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C2-9 heterocycloalkyl, phenyl, naphthyl, and heteroaryl is optionally and independently substituted; or
two geminal RB, taken together with the atom to which they are attached, form a C3-8 cycloalkyl or C2-9 heterocycloalkyl, wherein the C3-8 cycloalkyl or C2-9 heterocycloalkyl is optionally substituted;
n is 0, 1, 2, 3, or 4;
each R11 is independently H, C1-6 alkyl, C1-6 heteroalkyl, C1-4 alkylene-C3-8 cycloalkyl, C1-4 alkylene-C2-7 heterocycloalkyl, C1-4 alkylene-phenyl, C1-4 alkylene-heteroaryl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C2-7 heterocycloalkyl, phenyl, or heteroaryl, wherein each C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 alkylene-C3-8 cycloalkyl, C1-4 alkylene-C2-7 heterocycloalkyl, C1-4 alkylene-phenyl, C1-4 alkylene-heteroaryl, C3-8 cycloalkyl, C2-7 heterocycloalkyl, phenyl, and heteroaryl is optionally and independently substituted; and
each R12 is independently H, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, NO2, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein each C3-6 carbocyclyl and 3- to 6-membered heterocyclyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-6 alkyl, C1-6 haloalkyl, amino, NO2, OH, OC1-6 alkyl, and =O;
wherein each C1-6 alkyl, C1-4 alkylene, C1-6 heteroalkyl, C2-6 alkenyl, and C2-6 alkynyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of D, halogen, CN, amino, NO2, OH, O(alkyl), cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
wherein each cycloalkyl and heterocycloalkyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, amino, NO2, OH, O(alkyl), =O, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
wherein each phenyl, naphthyl, and aryl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, alkyl, deuteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, heteroalkyl, alkenyl, alkynyl, amino, alkylamino, NO2, OH, O(alkyl), S(O)2NHC1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and
wherein each heteroaryl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, amino, NO2, OH, O(alkyl), cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.
Appropriate correction is required. See MPEP § 2173.02.
Claim 3 is objected to because of the following informalities: for brevity, clarity and precision, the existing recitation should be replaced with the following recitation:
The compound of claim 1, wherein the compound is of Formula (Ia):
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Formula (Ia)
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
Y1 is CRY1 or N;
RY1 is H, halogen, CN, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, NR12R12, OR11, or SR11, wherein the C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted;
Y2 is CRY2 or N;
RY2 is H, halogen, CN, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, NR12R12, OR11, or SR11, wherein the C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted;
Y3 is CRY3 or N;
RY3 is H, halogen, CN, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, NR12R12, OR11, or SR11, wherein the C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted;
Y4 is CRY4 or N; and
RY4 is H, halogen, CN, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, NR12R12, OR11, or SR11, wherein the C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted.
Appropriate correction is required. See MPEP § 2173.02.
Claim 4 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The compound of claim 1, wherein the compound is of Formula (Ib):
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Formula (Ib)
or a pharmaceutically acceptable salt or stereoisomer thereof.
Appropriate correction is required. See MPEP § 2173.02.
Claim 13 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
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is
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;
Y1 is CRY1 or N;
RY1 is H, halogen, CN, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, NR12R12, OR11, or SR11, wherein the C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted;
Y2 is CRY2 or N;
RY2 is H, halogen, CN, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, NR12R12, OR11, or SR11, wherein the C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted;
Y3 is CRY3 or N;
RY3 is H, halogen, CN, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, NR12R12, OR11, or SR11, wherein the C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted;
Y4 is CRY4 or N; and
RY4 is H, halogen, CN, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, NR12R12, OR11, or SR11, wherein the C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted.
Appropriate correction is required. See MPEP § 2173.02.
Claim 34 is objected to because of the following informalities: for clarity, precision and to avoid duplication of the disubstituted pyridazine ring, the existing recitation should be replaced with the following recitation:
The compound of claim 31, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein
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is:
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,
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,
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,
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87
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,
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,
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87
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,
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,
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90
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,
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89
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, or
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.
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 compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R8 is H; and
R9 is H.
Appropriate correction is required. See MPEP § 2173.02.
Claim 56 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 compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein RB1 is C3-8 cycloalkyl, C2-9 heterocycloalkyl, phenyl, naphthyl, or heteroaryl;
wherein the C3-8 cycloalkyl or C2-9 heterocycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-6 alkyl, C1-6 deuteroalkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, NO2, =O, C3-8 cycloalkyl, and C2-7 heterocycloalkyl;
wherein the phenyl or naphthyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-6 alkyl, C1-6 deuteroalkyl, C1-6 haloalkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, NO2, C3-8 cycloalkyl, and C2-7 heterocycloalkyl; and
wherein the heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-6 alkyl, C1-6 deuteroalkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, NO2, C3-8 cycloalkyl, and C2-7 heterocycloalkyl.
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(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein RB1 is:
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,
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, or
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.
Appropriate correction is required. See MPEP § 2173.02.
Claim 98 is objected to because of the following informalities: for clarity, precision and to comply with the Requirement for Restriction/Election of Species, mailed on April 28, 2026, the existing recitation should be replaced with the following recitation:
The compound of claim 1, 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 99 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of 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.
Substituted heteroaryls of the Formula (I)
Claims 1, 3, 4, 13, 31, 34, 44, 56, 57, 98 and 99 are rejected under 35 U.S.C. § 112(a) because the specification, while being enabling for substituted heteroaryls of the Formula (I), where (1) X1 = CR1, X3 = CR3, and X7 = CR7; (2) X1 = CR1, X3 = CR3, and X7 = N; and (3) X1 = CR1, X3 = N, and X7 = CR7, respectively, does not reasonably provide enablement for substituted heteroaryls of the Formula (I), where (1) X1 ≠ CR1, X3 ≠ CR3, and X7 ≠ CR7; (2) X1 ≠ CR1, X3 ≠ CR3, and X7 ≠ N; and (3) X1 ≠ CR1, X3 ≠ N, and X7 ≠ CR7, respectively. 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. Substituted heteroaryls of the Formula (I), where (1) X1 ≠ CR1, X3 ≠ CR3, and X7 ≠ CR7; (2) X1 ≠ CR1, X3 ≠ CR3, and X7 ≠ N; and (3) X1 ≠ CR1, X3 ≠ N, and X7 ≠ CR7, respectively, as recited in claim 1, 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 substituted heteroaryls of the Formula (I), where (1) X1 ≠ CR1, X3 ≠ CR3, and X7 ≠ CR7; (2) X1 ≠ CR1, X3 ≠ CR3, and X7 ≠ N; and (3) X1 ≠ CR1, X3 ≠ N, and X7 ≠ CR7, respectively.
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 heteroaryls of the Formula (I), shown to the right;
(b) Nature of the invention - the nature of the invention is evaluation of substituted heteroaryls of the Formula (I), shown to the right above, and the pharmacokinetic behavior of these substances as ubiquitin specific protease 1 (USP1) inhibitors;
(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, WO 22/253188 provides a synthesis of the instantly recited substituted heteroaryls of the Formula (I) {Cai, et al. WO 22/253188, 2022};
(d) Level of one of ordinary skill in the art - the artisans synthesizing the inventor’s or joint inventor’s substituted heteroaryls of the Formula (I), where (1) X1 ≠ CR1, X3 ≠ CR3, and X7 ≠ CR7; (2) X1 ≠ CR1, X3 ≠ CR3, and X7 ≠ N; and (3) X1 ≠ CR1, X3 ≠ N, and X7 ≠ CR7, respectively, would be a collaborative team of synthetic chemists and/or health practitioners, possessing commensurate degree level and/or skill in the art, as well as several years of professional experience;
(e) Level of predictability in the art - Synthetic organic chemistry is quite unpredictable (See In re Marzocchi and Horton 169 USPQ at 367 ¶3). Similarly, it is unclear based on the combination of the instant specification, and Cai, et al. in WO 22/253188, whether the instantly recited substituted heteroaryls of the Formula (I), where (1) X1 ≠ CR1, X3 ≠ CR3, and X7 ≠ CR7; (2) X1 ≠ CR1, X3 ≠ CR3, and X7 ≠ N; and (3) X1 ≠ CR1, X3 ≠ N, and X7 ≠ CR7, respectively, are enabled. Moreover, the following excerpt is taken from Dörwald, which has relevance to the synthesis of substituted heteroaryls of the Formula (I), where (1) X1 ≠ CR1, X3 ≠ CR3, and X7 ≠ CR7; (2) X1 ≠ CR1, X3 ≠ CR3, and X7 ≠ N; and (3) X1 ≠ CR1, X3 ≠ N, and X7 ≠ CR7, respectively (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).
(f) Amount of direction provided by the inventor - the invention lacks direction with respect to making and/or using substituted heteroaryls of the Formula (I), where (1) X1 ≠ CR1, X3 ≠ CR3, and X7 ≠ CR7; (2) X1 ≠ CR1, X3 ≠ CR3, and X7 ≠ N; and (3) X1 ≠ CR1, X3 ≠ N, and X7 ≠ CR7, respectively;
(g) Existence of working examples - the inventor or joint inventor has provided sufficient guidance to make and/or use substituted heteroaryls of the Formula (I), where (1) X1 = CR1, X3 = CR3, and X7 = CR7; (2) X1 = CR1, X3 = CR3, and X7 = N; and (3) X1 = CR1, X3 = N, and X7 = CR7, respectively; however, the disclosure is insufficient to allow extrapolation of the limited examples to enable the instantly recited substituted heteroaryls of the Formula (I), where (1) X1 ≠ CR1, X3 ≠ CR3, and X7 ≠ CR7; (2) X1 ≠ CR1, X3 ≠ CR3, and X7 ≠ N; and (3) X1 ≠ CR1, X3 ≠ N, and X7 ≠ CR7, respectively. The specification lacks working examples of substituted heteroaryls of the Formula (I), where (1) X1 ≠ CR1, X3 ≠ CR3, and X7 ≠ CR7; (2) X1 ≠ CR1, X3 ≠ CR3, and X7 ≠ N; and (3) X1 ≠ CR1, X3 ≠ N, and X7 ≠ CR7, respectively.
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 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
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required by 35 U.S.C. § 112(a) to enable the instantly recited substituted heteroaryls of the Formula (I), where (1) X1 ≠ CR1, X3 ≠ CR3, and X7 ≠ CR7; (2) X1 ≠ CR1, X3 ≠ CR3, and X7 ≠ N; and (3) X1 ≠ CR1, X3 ≠ N, and X7 ≠ CR7, respectively. Thus, it is unclear, based on the guidance provided by the specification, whether a substituted heteroaryl of the Formula (I), such as that shown to the left above, is either synthetically feasible or possesses utility as an ubiquitin specific protease 1 (USP1) inhibitor.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the invention was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. {See In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)}.
The determination that undue experimentation would have been needed to make and use the claimed invention is not a single, simple factual determination. Rather, it is a conclusion reached by weighing all the above noted factual considerations. (See In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404). These factual considerations are discussed comprehensively in MPEP § 2164.08 (scope or breadth of the claims), § 2164.05(a) (nature of the invention and state of the prior art), § 2164.05(b) (level of one of ordinary skill), § 2164.03 (level of predictability in the art and amount of direction provided by the inventor or joint inventor), § 2164.02 (the existence of working examples) and § 2164.06 (quantity of experimentation needed to make or use the invention based on the content of the disclosure).
Based on a preponderance of the evidence presented herein, the conclusion that the inventor or joint inventor is insufficiently enabled for making and/or using substituted heteroaryls of the Formula (I), where (1) X1 ≠ CR1, X3 ≠ CR3, and X7 ≠ CR7; (2) X1 ≠ CR1, X3 ≠ CR3, and X7 ≠ N; and (3) X1 ≠ CR1, X3 ≠ N, and X7 ≠ CR7, respectively, 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.
Claims 1, 3, 4, 13, 31, 34, 44, 56, 57 and 99 are rejected under 35 U.S.C. § 112(b) as being indefinite for failing to set forth the subject matter which the inventor or joint inventor regards as the invention.
The inventor or joint inventor should note that the phrase, optionally substituted, in claim 1, with regard to RA, RB, RB and RB, RB1, R1, R3, R7, R8, R9, R8 and R9, and/or R11, respectively, is a relative phrase which renders the claim indefinite. The phrase, optionally substituted, is not defined by the claim, the specification does not provide an adequate standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the metes and bounds of the invention. The specification, on page 28, uses open language, such as include and for example, to define the term, substituent, as halogen, etc., and further discloses that the substituents themselves may be further substituted; however, neither the specification, nor the claim, explicitly limits the invention to any specifically disclosed or recited embodiments. Consequently, the substituted heteroaryls of the Formula (I) have been rendered indefinite by the use of the phrase, optionally substituted, with regard to RA, RB, RB and RB, RB1, R1, R3, R7, R8, R9, R8 and R9, and/or R11, respectively.
Moreover, the inventor or joint inventor should further note that [C]laims which depend from indefinite claims are also indefinite. {See Ex parte Cordova, 10 USPQ 2d 1949, 1952 (PTO Bd. App. 1989)}.
The examiner suggests amending the claims, particularly as stated in the section above entitled Claim Objections, to overcome this rejection.
Claims 1, 3, 4, 13, 31, 34, 44, 56, 57 and 99 are further 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 1 recites the limitations, oxo and N(R12)2S(O)2R12, with respect to RA, where the limitations are implausible, resulting in an incomplete valence. Claims are unduly speculative where they define only a portion of a substituted heteroaryl of the Formula (I). Consequently, since incomplete valences are not permitted in the structure of the substituted heteroaryls of the Formula (I), an essential portion of the substituted heteroaryls of the Formula (I) is indefinite and one of ordinary skill in the art would not be reasonably apprised of the metes and bounds of the substituted heteroaryls of the Formula (I). {See Ex parte Pedlow and Miner, 90 USPQ 395 (Bd. Pat. App. & Int. 1951)}.
Moreover, the inventor or joint inventor should further note that [C]laims which depend from indefinite claims are also indefinite. {See Ex parte Cordova, 10 USPQ 2d 1949, 1952 (PTO Bd. App. 1989)}.
The examiner suggests amending the claims, particularly as stated in the section above entitled Claim Objections, to overcome this rejection.
Claims 1, 31, 34, 44, 56, 57 and 99 are further 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 the phrase, phenyl isostere, in claim 1, is a relative phrase which renders the claim indefinite. The phrase, phenyl isostere, is not defined by the claim, the specification does not provide an adequate standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the metes and bounds of the invention. The specification fails to adequately define the phrase, phenyl isostere. Similarly, the meaning of a phrase cannot depend on the unrestrained, subjective opinion of the inventor or joint inventor practicing the invention. Moreover, neither the specification, nor the claim, explicitly limits the invention to any specifically disclosed or recited embodiments. Consequently, the substituted heteroaryls of the Formula (I) have been rendered indefinite by the use of the phrase, phenyl isostere. {See Datamize LLC v. Plumtree Software, Inc., 417 F.3d 1342, 1347-48, 75 USPQ2d 1801, 1807 (Fed. Cir. 2005); and MPEP § 2173.05(b)}.
Moreover, the inventor or joint inventor should further note that [C]laims which depend from indefinite claims are also indefinite. {See Ex parte Cordova, 10 USPQ 2d 1949, 1952 (PTO Bd. App. 1989)}.
The examiner suggests amending the claims, particularly as stated in the section above entitled Claim Objections, to overcome this rejection.
Allowable Subject Matter
No claims are allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DOUGLAS M. WILLIS, whose telephone number is 571-270-5757. The examiner may normally be reached on Monday thru Thursday from 8:00-6:00 EST. The examiner is also available on alternate Fridays.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Mr. Jeffrey Murray, may be reached on 571-272-9023. The fax phone number for the organization where this invention or proceeding is assigned is 571-273-8300.
Information regarding the status of an invention may be obtained from Patent Center. For more information about Patent Center, see https://www.uspto.gov/patents/apply/patent-center. Should you have questions on access to Patent Center, contact the Patent Electronic Business Center (PEBC) at 866-217-9197 (toll-free) or ebc@uspto.gov.
/DOUGLAS M WILLIS/
Primary Examiner, Art Unit 1624
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