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, 8, 11, 13, 15, 20-22, 25, 26, 30, 32, 35, 38 and 40-43 are pending in the instant invention. According to the Amendments to the Claims, filed January 13, 2026, claims 1, 8, 11, 13, 15, 20 and 21 were amended and claims 4-7, 9, 10, 12, 14, 16-19, 23, 24, 27-29, 31, 33, 34, 36, 37 and 39 were cancelled.
Status of Priority
This invention is a 35 U.S.C. § 371 National Stage Filing of International Application No. PCT/CN2021/123366, filed October 12, 2021, which claims priority under 35 U.S.C. § 119(a-d) to CHINA International Application No. PCT/CN2020/120911, filed October 14, 2020.
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 January 13, 2026, is acknowledged: a) Group I - claims 1-3, 8, 11, 13, 15, 20-22, 25, 26, 30, 32, 35, 38 and 40-42; and b) substituted benzo[e]pyrimido[5,4-b][1,4]diazepine - pp. 39-40, Example 1, Compound 001, shown to the right below, and hereafter referred to as 2-((4-(4-(2-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)-piperazin-1-yl)-2-oxoethoxy)piperidin-1-yl)-2-ethoxyphenyl)amino)-5,11-dimethyl-5,11-dihydro-
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6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-one, where k = 0; v = 0; R17 = -CH3; R18 = -CH3; R11 = -H; R12 = -CH2CH3; L = -a linker-, shown to the left; and A = -a chemical moiety that binds HSP90 protein, shown to the right below. Claims 1-3, 8, 11, 13, 15, 20-22, 25, 26, 30, 38, 40 and 42 read on the elected species. Affirmation of this election must be made by the inventor or
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joint inventor in replying to this Office action.
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Similarly, the inventor or joint inventor should further note that there is no search and examination burden on the Examiner if Group I and Group II were examined simultaneously. This is not found persuasive because the multiple inventions in the instant invention are independent or distinct for the reasons disclosed in the Requirement for Restriction / Election of Species, mailed on August 26, 2025.
Likewise, the inventor or joint inventor should further note that there would be a serious burden on the examiner if restriction was not required because the inventions have acquired a separate status in the art due to their divergent subject matter and would require a different field of search.
Next, the inventor or joint inventor should further note that the requirement is still deemed proper and is therefore made FINAL.
Then, 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 claim 43 was 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, 8, 11, 13, 15, 20-22, 25, 26, 30, 32, 35, 38 and 40-42 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 additionally identifying the substituted benzo[e]pyrimido[5,4-b][1,4]-diazepines of the Formula I.
The following title is suggested: SUBSTITUTED BENZO[e]PYRIMIDO[5,4-b][1,4]DIAZEPINES FOR TARGETED PROTEIN DEGRADATION.
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) and/or 35 U.S.C. § 112(b), the existing recitation should be replaced with the following recitation:
A compound of the following formula:
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or a pharmaceutically acceptable salt thereof,
wherein:
each R16 is independently halo, CN, C1-C6 alkyl, C1-C6 alkyl-C(O)NRdRd, C1-C6 alkyl-C(O)ORd, C1-C6 alkyl-NRdRd, C1-C6 alkyl-ORc, C1-C6 alkyl-OC1-C6 alkyl-NRdRd, C1-C6 alkyl-S(O)Rd, C1-C6 alkyl-S(O)NRdRd, C1-C6 alkyl-S(O)2Rd, C1-C6 alkyl-S(O)2NRdRd, C1-C6 alkyl-cycloalkyl, C1-C6 alkyl-aryl, C1-C6 alkyl-heterocylyl, C1-C6 alkyl-heteroaryl, C2-C6 alkenyl, C2-C6 haloalkeny1, C2-C6 alkynyl, C(O)Rd, C(O)NRdRd, C(O)ORd, C(O)NRd-C1-C6 alkyl-NRdRd, NRdRd, NRd-C1-C6 alkyl-NRdRd, NRd-C1-C6 alkyl-ORd, OC1-C6 alkyl, OC1-C6 haloalkyl, S(O)Rd, S(O)NRdRd, S(O)2Rd, S(O)2NRdRd, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein any cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally and independently substituted with 1, 2, or 3 independently selected Re substituents;
k is 0, 1, 2, or 3;
R17 is H, C1-C6 alkyl, or S(O)2C1-C6 alkyl;
R18 is H, C1-C6 alkyl, or S(O)2C1-C6 alkyl;
R11 is H, C1-C6 alkyl, or S(O)2C1-C6 alkyl;
R12 is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-ORc, C1-C6 alkyl-aryl, C(O)C1-C6 alkyl, S(O)2C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein any cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1, 2, or 3 independently selected Re substituents;
each R10 is independently halo, CN, C1-C6 alkyl, C1-C6 alkyl-C(O)NRdRd, C1-C6 alkyl-C(O)ORd, C1-C6 alkyl-NRdRd, C1-C6 alkyl-ORc, C1-C6 alkyl-OC1-C6 alkyl-NRdRd, C1-C6 alkyl-S(O)Rd, C1-C6 alkyl-S(O)NRdRd, C1-C6 alkyl-S(O)2Rd, C1-C6 alkyl-S(O)2NRdRd, C1-C6 alkyl-cycloalkyl, C1-C6 alkyl-aryl, C1-C6 alkyl-heterocylyl, C1-C6 alkyl-heteroaryl, C2-C6 alkenyl, C2-C6 haloalkeny1, C2-C6 alkynyl, C(O)Rd, C(O)NRdRd, C(O)ORd, C(O)NRd-C1-C6 alkyl-NRdRd, NRdRd, NRd-C1-C6 alkyl-NRdRd, NRd-C1-C6 alkyl-ORd, OC1-C6 alkyl, OC1-C6 haloalkyl, S(O)Rd, S(O)NRdRd, S(O)2Rd, S(O)2NRdRd, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein any cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally and independently substituted with 1, 2, or 3 independently selected Re substituents;
v is 0, 1, 2, or 3;
each Re is independently halo, CN, NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-C(O)NRdRd, C1-C6 alkyl-C(O)ORd, C1-C6 alkyl-NRdRd, C1-C6 alkyl-ORc, C1-C6 alkyl-SRd, C2-C6 alkenyl, C2-C6 haloalkeny1, C2-C6 alkynyl, C(O)NRdRd, C(O)ORd, C(O)NRd-C1-C6 alkyl-NRdRd, NRdRd, NRd-C1-C6 alkyl-NRdRd, NRd-C1-C6 alkyl-ORd, ORd, OC1-C6 alkyl, OC1-C6 haloalkyl, =O, S(O)Rd, S(O)NRdRd, S(O)2Rd, S(O)2NRdRd, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
L is:
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,
wherein the left side of L is the point of attachment to the phenyl ring and the right side of L or * is the point of attachment to A;
each Rc is independently H, C1-C6 alkyl, or C1-C6 haloalkyl;
each Rd is independently H, C1-C6 alkyl, or C1-C6 haloalkyl;
A is:
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,
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,
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, or
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;
Q is cycloalkylene, heterocyclylene, phenylene, or heteroarylene, wherein cycloalkylene, heterocyclylene, phenylene, or heteroarylene is optionally substituted with 1, 2, or 3 independently selected R2 substituents;
U is cycloalkylene, heterocyclylene, phenylene, or heteroarylene, wherein cycloalkylene, heterocyclylene, phenylene, or heteroarylene is optionally substituted with 1, 2, or 3 independently selected R2 substituents;
V is phenylene or 5- to 9-membered heteroarylene, wherein the phenylene or 5- to 9-membered heteroarylene is optionally substituted with 1, 2, or 3 independently selected R3 substituents;
W is 5- or 6-membered heteroarylene, wherein the 5- or 6-membered heteroarylene is optionally substituted with 1, 2, or 3 independently selected R2 substituents;
R1 is halo, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, or OC1-C4 haloalkyl;
each R2 is independently CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C6 alkyl-C(O)NRaRb, C1-C4 alkyl-NRaRb, C1-C4 alkyl-ORa, C2-C6 alkenyl, C2-C6 haloalkeny1, C2-C6 alkynyl, C2-C6 haloalkynyl, C(O)Ra, C(O)NRaRb, C(O)ORa, C(O)NRa-C1-C4 alkyl-NRaRb, C(O)NRa-C1-C4 alkyl-ORa, NRaRb, NRa-C1-C4 alkyl-NRaRb, NRa-C1-C4 alkyl-ORa, ORa, O-C1-C4 alkyl-NRaRb, O-C1-C4 alkyl-NRaC(O)-C1-C4 alkyl-NRaRb, SRa, S(O)Ra, S(O)NRaRb, S(O)2Ra, phenyl, or 5- to 7-membered heteroaryl, wherein each phenyl and 5- to 7-membered heteroaryl is optionally and independently substituted with 1, 2, or 3 independently selected R4 substituents;
each R3 is independently halo, C1-C4 alkyl, C1-C4 haloalkyl, NRaRb, OC1-C4 alkyl, or OC1-C4 haloalkyl;
each R4 is independently halo, C1-C4 alkyl, C1-C4 haloalkyl, NRaRb, OC1-C4 alkyl, or OC1-C4 haloalkyl;
each R13 is independently H, halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, or C(O)NRaRb;
R14 is H, halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, or C(O)NRaRb;
R15 is H, C1-C4 alkyl, or C1-C4 haloalkyl;
each Ra is independently H or C1-C4 alkyl, wherein each C1-C4 alkyl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo and 3- to 7-membered heterocyclyl; and
each Rb is independently H or C1-C4 alkyl, wherein each C1-C4 alkyl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo and 3- to 7-membered heterocyclyl.
Appropriate correction is required. See MPEP § 2173.02.
Claim 3 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 thereof, wherein A is:
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.
Appropriate correction is required. See MPEP § 2173.02.
Claim 8 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
R11 is H; and
R17 is C1-C6 alkyl.
Appropriate correction is required. See MPEP § 2173.02.
Claim 11 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 thereof, wherein R12 is C1-C6 alkyl.
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 thereof, wherein R18 is C1-C3 alkyl or S(O)2C1-C3 alkyl.
Appropriate correction is required. See MPEP § 2173.02.
Claim 15 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
A is:
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; and
Z is CH or N.
Appropriate correction is required. See MPEP § 2173.02.
Claim 20 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is:
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.
Appropriate correction is required. See MPEP § 2173.02.
Claim 21 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 thereof, wherein A is:
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.
Appropriate correction is required. See MPEP § 2173.02.
Claim 22 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 15, or a pharmaceutically acceptable salt thereof, wherein R1 is halo or C1-C4 alkyl.
Appropriate correction is required. See MPEP § 2173.02.
Claim 25 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 15, or a pharmaceutically acceptable salt thereof, wherein R2 is C(O)NRaRb, C(O)NRa-C1-C4 alkyl-NRaRb, ORa, or SRa.
Appropriate correction is required. See MPEP § 2173.02.
Claim 26 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein:
each Ra is independently H or C1-C4 alkyl, wherein each C1-C4 alkyl is optionally and independently substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo and 6-membered heterocyclyl; and
each Rb is independently H or C1-C4 alkyl, wherein each C1-C4 alkyl is optionally and independently substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo and 6-membered heterocyclyl.
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(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 of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is:
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.
Appropriate correction is required. See MPEP § 2173.02.
Claim 40 is objected to because of the following informalities: a) for clarity and precision, The compound of Claim 1, wherein the compound is selected from the following structural formula: should be replaced with The compound of claim 1, wherein the compound is selected from the group consisting of: ; and b) for clarity and precision, or a pharmaceutically acceptable salt of any of the foregoing should be replaced with or a pharmaceutically acceptable salt thereof. Appropriate correction is required. See MPEP § 2173.02.
Claim 41 is objected to because of the following informalities: a) for clarity and precision, The compound of Claim 1, wherein the compound is selected from the following structural formula: should be replaced with The compound of claim 1, wherein the compound is selected from the group consisting of: ; and b) for clarity and precision, or a pharmaceutically acceptable salt of any of the foregoing should be replaced with 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:
A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 1, 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.
Substituted benzo[e]pyrimido[5,4-b][1,4]diazepines of the instantly recited generic formula
Claims 1-3, 8, 11, 13, 15, 20-22, 25, 26, 30, 32, 35, 38 and 42 are rejected under 35 U.S.C. § 112(a) because the specification, while being enabling for substituted benzo[e]pyrimido[5,4-b][1,4]diazepines of the instantly recited generic formula, where L and A, respectively, are as disclosed in the section above entitled Claim Objections, does not reasonably provide enablement for substituted benzo[e]pyrimido[5,4-b][1,4]diazepines of the instantly recited generic formula, where L and A, respectively, are not as disclosed in the section above entitled Claim Objections. 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 benzo[e]pyrimido[5,4-b][1,4]diazepines of the instantly recited generic formula, where L and A, respectively, are not as disclosed in the section above entitled Claim Objections, as recited in claims 1 and 42, 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 substituted benzo[e]pyrimido[5,4-b][1,4]diazepines of the instantly recited generic formula, where L and A, respectively, are not as disclosed in the section above entitled Claim Objections.
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 benzo[e]-pyrimido[5,4-b][1,4]diazepines of the instantly recited generic formula, shown to the right;
(b) Nature of the invention - the nature of the invention is evaluation of substituted benzo[e]pyrimido[5,4-b][1,4]diazepines of the instantly recited generic formula, shown to the right above, and the pharmacokinetic behavior of these substances as chaperone-mediated protein degraders (CHAMPs);
(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 22/078470 provides a synthesis of the substituted benzo[e]-pyrimido[5,4-b][1,4]diazepines of the instantly recited generic formula {Ying, et al. WO 22/078470, 2022};
(d) Level of one of ordinary skill in the art - the artisans synthesizing the inventor’s or joint inventor’s substituted benzo[e]pyrimido[5,4-b][1,4]diazepines of the instantly recited generic formula, where L and A, respectively, are not as disclosed in the section above entitled Claim Objections, 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 Ying, et al. in WO 22/078470, whether the instantly recited substituted benzo[e]pyrimido[5,4-b][1,4]diazepines of the instantly recited generic formula, where L and A, respectively, are not as disclosed in the section above entitled Claim Objections, are enabled. Moreover, the following excerpt is taken from Dörwald, which has relevance to the synthesis of substituted benzo[e]pyrimido[5,4-b][1,4]diazepines of the instantly recited generic formula, where L and A, respectively, are not as disclosed in the section above entitled Claim Objections (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 benzo[e]pyrimido[5,4-b][1,4]diazepines of the instantly recited generic formula, where L and A, respectively, are not as disclosed in the section above entitled Claim Objections;
(g) Existence of working examples - the inventor or joint inventor has provided sufficient guidance to make and/or use substituted benzo[e]pyrimido[5,4-b][1,4]diazepines of the instantly recited generic formula, where L and A, respectively, are as disclosed in the section above entitled Claim Objections; however, the disclosure is insufficient to allow extrapolation of the limited examples to enable the instantly recited substituted benzo[e]pyrimido[5,4-b][1,4]diazepines of the instantly recited generic formula, where L and A, respectively, are not as disclosed in the section above entitled Claim Objections. The specification lacks working examples of substituted benzo[e]-pyrimido[5,4-b][1,4]diazepines of the instantly recited generic formula, where L and A, respectively, are not as disclosed in the section above entitled Claim Objections.
Within the specification, [A]t least one specific operative embodiment or example of the invention must be set forth. The example(s) and description should be of sufficient scope as to justify the scope of the claims. Markush claims must be provided with support in the disclosure for each member of the Markush group. Where the constitution and formula of a chemical compound is stated only as a probability or speculation, the disclosure is not sufficient to support claims identifying the compound by such composition or formula. See MPEP § 608.01(p) and MPEP § 2173.05.
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(h) Quantity of experimentation needed to make or use the invention based on the content of the disclosure - predicting whether a recited compound 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 substituted benzo[e]-pyrimido[5,4-b][1,4]diazepines of the instantly recited generic formula, where L and A, respectively, are not as disclosed in the section above entitled Claim Objections. Thus, it is unclear, based on the guidance provided by the specification, whether a solvate of a substituted benzo[e]pyrimido[5,4-b][1,4]diazepine of the instantly recited generic formula, such as 5-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]-pyrimido[5,4-b][1,4]diazepin-2-yl)amino)-3-ethoxyphenyl)pyrazin-2-yl (4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzoyl)cyclo-hexyl)carbamate, shown to the left above, is either synthetically feasible or possesses utility as a chaperone-mediated protein degrader (CHAMP).
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 benzo[e]-pyrimido[5,4-b][1,4]diazepines of the instantly recited generic formula, where L and A, respectively, are not as disclosed in the section above entitled Claim Objections, 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, 8, 11, 13, 15, 20-22, 25, 26 and 42 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 term, linker, in claim 1, with respect to L, is a relative phrase which renders the claim indefinite. The term, linker, 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 term, linker, with respect to L. Similarly, the meaning of a term 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 benzo[e]pyrimido[5,4-b][1,4]diazepines of the Formula I have been rendered indefinite by the use of the term, linker, with respect to L. {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.
Claims 1, 8, 11, 13, 30, 32, 35, 38 and 42 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, chemical moiety that binds HSP90, in claim 1, with respect to A, is a relative phrase which renders the claim indefinite. The phrase, chemical moiety that binds HSP90, 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, chemical moiety that binds HSP90, with respect to A. 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 benzo[e]pyrimido[5,4-b][1,4]diazepines of the Formula I have been rendered indefinite by the use of the phrase, chemical moiety that binds HSP90, with respect to A. {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.
Claim 2 is 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 2 recites the limitation, -C(O)NRa-C1-4 alkylene-OR, with respect to R2, where R is indefinite, resulting in an incomplete valence. Claims are unduly speculative where they define only a portion of a substituted benzo[e]pyrimido[5,4-b][1,4]diazepine of the Formula I. Consequently, since incomplete valences are not permitted in the structure of the substituted benzo[e]pyrimido[5,4-b][1,4]diazepines of the Formula I, an essential portion of the substituted benzo[e]pyrimido[5,4-b][1,4]diazepines 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 benzo[e]pyrimido[5,4-b][1,4]diazepines of the Formula I. {See Ex parte Pedlow and Miner, 90 USPQ 395 (Bd. Pat. App. & Int. 1951)}.
The examiner suggests amending the claim, particularly as stated in the section above entitled Claim Objections, to overcome this section of the rejection.
Similarly, the inventor or joint inventor should further 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).
Likewise, the inventor or joint inventor should further note that claim 2 recites the broad limitation, SRa, with regard to R2, and the claim also recites SH and SC1-4 alkyl, respectively, with regard to R2, which are the narrower statements of the limitation.
Next, 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 section of the 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