Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Status of 17/775,265
Claims 1-66 and 70-113 are currently pending.
Priority
Instant application 17/775,265, filed 5/6/2022, claims priority as follows:
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The PCT application provides support for the instant claims, and thus claims 1-66 and 70-113 are therefore granted the priority date of 11/8/2019.
Information Disclosure Statement
All references from the IDS’s submitted 9/9/2022, 5/10/2023, 7/29/2025, and 12/5/2025 have been considered unless marked with a strikethrough. The Examiner notes that the reference struck through in the IDS of 12/5/2025 did not have a translated abstract.
Response to Applicant’s Arguments/Amendments
The amendment filed 12/5/2025 has been entered. Claims 1, 7, 8, 19, 44, and 107 have been amended. No claims have been added or cancelled.
In the Non-Final dated 10/10/2025, the abstract was objected to for a minor informality. Specifically, it states the word “disease” in the last line, but should read “diseases”. Applicant did not address the objection in the most recent reply and thus, the objection is maintained.
Claims 1-2, 6, 9-10, 13, 28-30, 33-41, 47-48, 51, and 108 were rejected in the Non-Final dated 10/10/2025 on the basis that they contain an improper Markush grouping of alternatives. Applicant argues that the Markush group options of Formula (I), depicted in Applicant Arguments/Remarks of 12/5/2025, are structurally similar because the structures are structurally the same, and that they differ by the position of nitrogen atoms on the left ring (bound to ring A), and in the addition of 1 or 2 nitrogen atoms on the right ring. Applicant’s arguments have been considered, but are not considered persuasive because they are structurally different in view of the heteroatoms of the core. They do not share a single structural similarity. Additionally, Applicant argues that the Markush grouping is proper because the originally filed disclosure describes the common use of the collection of claimed alternatives in Example 7 of the disclosure. However, this argument is also not considered persuasive because compounds 1-58 tested in Example 7 all contain the same variations of A4, A5, and D; they are A4 as N, A5 as C-R15, where R15 is H, and D as CH. There can be no structure/function correlation when only one set of core variables was tested, and thus no common use can be established. Thus, the rejection is not overcome and is maintained. The claims rejected have been updated to reflect Applicants amendments.
In the Non-Final dated 10/10/2025, claims 1-2, 6, 9-10, 13, 28-30, 33-41, 47-48, 51, and 108 were rejected under 35 U.S.C. 102(a)(1) and 102(a)(2). In response, Applicant has amended the claims to recite that A4 is solely N, which overcomes the rejection. Thus, the rejection is withdrawn.
Election/Restriction
Applicant’s election of Group I, claims 1-108, drawn to compounds and compositions of Formula I, without traverse, in the reply filed 3/7/2025, is acknowledged. Applicant’s election of compound 25:
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without traverse in the reply filed 3/7/2025, is also acknowledged.
Examination will begin with the elected species. In accordance with MPEP § 803.02, if upon examination of the elected species, no prior art is found that would anticipate or render obvious the instant invention based on the elected species, the search of the Markush-type claim will be extended. If prior art is then found that anticipates or renders obvious the non- elected species, the Markush-type claim will be rejected. It should be noted that the prior art search will not be extended unnecessarily to cover all non-elected species. Should Applicant overcome the rejection by amending the claim, the amended claim will be examined again. The prior art search will be extended to the extent necessary to determine patentability of the Markush-type claim. In the event prior art is found during further examination that renders obvious or anticipates the amended Markush-type claim, the claim will be rejected and the action made final.
The elected species was searched and no prior art was identified. The search was expanded to Formula (III-A):
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In the Non-Final dated 4/1/2025, and the prior art rejection was withdrawn. See the “Response to Arguments/Amendments” section above. Subsequent examination is based on the species expansion to Formula I-A:
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where A4 and A5 are C-R15, where R15 is H, D is CH, and R3 is C1 alkyl, and prior art was identified. In response, Applicant has amended the claims to recite that A4 is solely N, which overcomes the rejection. Thus, the Examiner expanded the search to the full scope of Formula (I), and no prior art was identified. However, there are remaining rejections in Group I (claims 1-66 and 70-108) upon expansion to the claims of Group I. Further, the Examiner acknowledges that method claims 109-113 of Group II are not in condition for allowance, as they contain 112(a) issues. Claims 1-66 and 70-108 are the subject of this Office Action. Claims 109-113 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected species and/or group, there being no allowable generic or linking claim.
MAINTAINED OBJECTIONS AND REJECTIONS
Objection to the Abstract
The abstract is objected to because it states the word “disease” in the last line, but should read “diseases”. Appropriate correction is required.
Claim Rejections – Improper Markush
Claims 1-10, 12-15, 23-51 and 108 are rejected on the basis that they contain an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
With respect to the Markush groupings of A5 and D in Formula (I), and sub formulas thereof, are improper because the alternatives defined by the Markush groupings do not share both a single structural similarity and a common use. Primarily, instant Formula (I) does not contain a common core or single structural singularity because the contains variables A5, which can be N or CR15, where R15 can be H or C1-6 alkyl, and D that can selected from N or CH. From these definitions, the variables A5 and D generate the above formulas that share no common core. A skilled artisan would recognize the variation in this number of variables, resulting in changes in core can lead to variations in biological and chemical properties such as bond angles and binding pose of the substrate in the target. They do not belong to the same recognized physical or chemical class or to the same art-recognized class.
The instant specification discloses compounds 1-58 of Table 1 that have the property of BTK degradation, but said compounds solely contain the combination of A4 as N, A5 as C-R15, where R15 is H, and D as CH. No other data supporting atom and substituent variation of the common core is disclosed, in contrast with the instant claims. Therefore, no structure-function relationship between the variables is corroborated. In this case, the claims are so expansive that a common utility cannot be expected. Dependent claims 2-10, 12-15, 23-51 and 108 do not resolve the issue and are therefore also rejected.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
NEW OBJECTIONS AND REJECTIONS NECESSITATED BY AMENDMENT
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 3, 70-73, 81-83, 86-94, and 96-106 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 3 recites the limitation
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as the variable Z. Claim 1, from which claim 3 depends, does not recite this limitation and even recites the variable E as a ring, not as a variable within a ring. Thus, there is insufficient antecedent basis for this limitation in the claim. Appropriate correction is required.
Claim 70 recites the limitation, “bivalent heterocycle”, in reference to a variable of L. Claims 52 and 1, from which 70 ultimately depends, do not recite an instance of bivalent heterocycle. Thus, there is insufficient antecedent basis for this limitation in the claim. Appropriate correction is required.
Claim 71 recites the limitation, “bivalent heterocycloalkyl”. Claims 52 and 1, from which 71 ultimately depends, do not recite an instance of bivalent heterocycloalkyl. Thus, there is insufficient antecedent basis for this limitation in the claim. Appropriate correction is required.
Claims 72 and 73 recite the limitation, “bivalent cycloalkyl”. Claims 52 and 1, from which 72 and 73 ultimately depend, do not recite an instance of bivalent cycloalkyl. Thus, there is insufficient antecedent basis for this limitation in the claim. Appropriate correction is required.
Claim 81 recites a listing of specific groups in reference to the variable L. However claims 40, 30, and 1, from which 81 ultimately depends, require L to be Y1-Y2-Y3-Y4-Y5-Y6. Thus, there is insufficient antecedent basis for this limitation in the claim. Appropriate correction is required.
Claim 82 recites the variable R4 as a variable on Formula (III). Claim 82 does not define this variable, nor does claim 1, the claim from which 82 depends. Thus, the limitation is unclear and there is insufficient antecedent basis for this limitation in the claim. Dependent claims 83, 86-94, and 96-106 do not resolve this issue by defining R4 and are therefore also rejected. Appropriate correction is required.
Claim 94 recites -C(O)-(CH2-CH2-O)-(CH2)3- or-C(O)-(CH2-CH2-O)-(CH2-CH2-N(R))- in reference to the variable L. Claims 82 and 1, from which 94 depends, require L to be Y1-Y2-Y3-Y4-Y5-Y6. Thus, there is insufficient antecedent basis for this limitation in the claim. Appropriate correction is required.
Claim 105 recites a listing of specific groups in reference to the variable L. However claims 82 and 1, from which 105 ultimately depends, require L to be Y1-Y2-Y3-Y4-Y5-Y6. Thus, there is insufficient antecedent basis for this limitation in the claim. Appropriate correction is required.
Claim Objections
Claim 7 is objected to for a minor informality. Claim 7 recites, “A4 and A5 is N”, but should read, “A4 and A5 are N”. Appropriate correction is required.
Claims 11, 16-22, 52-66, 74-80, 84-85, 95, and 107 are objected to as they are dependent on a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Close Prior Art Not Cited under 35 U.S.C. 102 or 103
Close art identified during the search is Dana-Farber Cancer Institute, Inc. (WO 2019/148150 A1, herein after “Dana-Farber”), which is drawn to bifunctional compounds capable of degrading Bruton’s tyrosine kinase (BTK) of the modular genus Formula (X) (abstract and page 193, claim 1):
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Where the targeting ligand is capable of binding to BTK, the linker group covalently binds to the targeting ligand and the degron, and the degron is capable of binding to the ubiquitin ligase. Dana Farber teaches compounds with the targeting ligand genera of Formula TL-I and TL-II (page 192, claim 1):
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And further teaches specific compounds such as the following (page 125, entry 3):
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Which overlaps with a compound of Formula I-A:
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When ring A is
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, C is a 6-membered fully unsaturated carbocycle substituted with R1 and R2, where R1 is 3-membered cycloaliphatic and R2 is a fluoro, XB is C, ---- is a bond, X1 is -CH=, r is 1, A5 is C-R15, where R15 is H, D is CH, R3 is C1 alkyl, Xy is
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, ring B is 6 membered monocyclic heteroaryl having 1 nitrogen atom, ring D is a 6-membered heterocycle having two nitrogen atoms, L is Y1-Y2-Y3-Y4-Y5-Y6, where Y1-Y4 are C1-4 alkyl, Y5 is -N(R)-, R is H, Y6 is a bond, Z is Z-1
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, A1-A3 are -C(RB)=, RB is H, W is -C(O)-, and RA is H. However, the compounds of Dana Farber differ from compounds of the instant claims because they contain a phenylmethanol core, whereas the instant claims contain a pyridinyl-methanol core because A4 is required to be N.
Additional prior art identified during the search is Crawford (Crawford, J. J. J. Med. Chem. 2018, 61, 2227-2245), which teaches the known oral BTK inhibitor GDC-0853 (page 2240, scheme 2, compound 29):
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Which partially maps to the instant expanded species of Formula (III-A):
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where R4 is C1 alkyl.
However, the compound CDC-0853 of Crawford contains an additional oxetane moiety on the terminal end of the piperazine not present in the instant disclosure and fails to teach the linker and degron attached to the BTK inhibitor, depicted as L and Z of the instant claims. Further, Crawford discloses additional compounds with substituents other than oxetane on the terminal end of the piperazine, which did not improve biological activity (page 2231). One of ordinary skill would therefore not be motivated to remove the oxetane due to the reduction in biological activity, much less replace it with the L and Z variables of the instant claims.
Conclusion
Claims 1-10, 12-15, 23-51, 70-73, 81-83, 86-94, 96-106, and 108 are rejected. Claims 7, 11, 16-22, 52-66, 74-80, 84-85, 95, and 107 are objected to. Claims 109-113 are withdrawn.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kendall Heitmeier whose telephone number is (703)756-1555. The examiner can normally be reached Monday-Friday 8:30AM-5:00PM ET.
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/K.N.H./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621