DETAILED ACTION
The Final rejection mailed on September 24, 2025 is vacated and is being replaced with this corrected Final rejection.
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 .
Status of the Claims
Claims 1, 4-6, 12-20 and 41-47 are pending. Claims 12-13 are withdrawn. Claims 46-47 are objected to. Claims 1, 4-6, 14-20 and 41-45 are rejected.
Response to Amendment/Arguments
Applicant’s detailed remarks submitted on June 12, 2025 are appreciated and have been fully considered. The thorough explanation of each claim amendment and corresponding support is noted with appreciation. The examiner agrees that the amendment does not introduce new matter. The amendment filed June 12, 2025 is compliant with the requirements of 37 CFR 1.121(c) and has been entered.
Priority
The non-final Office action dated March 12, 2025 indicated that claims 1, 3-6, 14-20, 41 and 43-45 have an effective filing date of November 1, 2017 and that claim 42 has an effective filing date of November 1, 2016. Applicant’s amendment to claim 1 removes subject matter that was not supported by the provisional application 62/415,830. As a result, claims 1, 4-5, 15-20, 42, 44, 46 and 47 have an effective filing date of November 1, 2016, while claims 6, 14, 41, 43 and 45 have an effective filing date of November 1, 2017. (Claim 3 is now cancelled and claims 46-47 are newly added but do not have full support in the provisional application. See, e.g., paragraphs 93-101 of ‘830 for partial support for claim 46 and pages 59-72 of ‘830 for species listing that does not include the species of claim 47.)
Claim Objections
The objection of claims 14 and 41 for informalities has been overcome amendment. The objection has been withdrawn.
35 USC § 112(b) Rejections
The rejection of claims 1, 14-20, 41-42 and 44 under 35 USC 112(b) has been overcome by amendment. The rejection has been withdrawn.
The rejection of claim 6 under 35 USC 112(b) has not been overcome by Applicant’s remarks. Applicant respectfully posited that “[c]laim 6b does not restrict only a specific phenyl ring to be substituted and as such allows any of the phenyl rings to be optionally substituted.” Remarks 58. This is not persuasive because claim 6 recites “the phenyl ring” as opposed to “each phenyl ring”, where the latter encompassing all phenyl rings while the former makes reference to a particular phenyl ring via “the” without making it clear which of the phenyl rings is being referenced. See, e.g., MPEP 2173.05(e) discussing In re Packard, 751 F.3d 1307, 1314, 110 USPQ2d 1785, 1789 (Fed. Cir. 2014) (“if two different levers are recited earlier in the claim, the recitation of "said lever" in the same or subsequent claim would be unclear where it is uncertain which of the two levers was intended”). Therefore, the rejection of claim 6 is maintained.
35 USC § 112(b) Rejections
The rejection of claims 3-5 and 44 under 35 USC 112(d) has been overcome by
amendment. The rejection has been withdrawn.
35 USC § 103 Rejection
(1 of 3) The rejection of claims 1, 3-6, 14-17 and 44 under 35 USC 103 for being obvious over Crews in view of Kroth and Chu has been overcome by deleting the rejected PTM moieties. The rejection has been withdrawn.
(2 of 3) The rejection of claims 18-20 under 35 USC 103 for being obvious over Crews, Kroth and Chu, as applied to claims 1 and 16-17, has been overcome by deleting the rejected PTM moieties. The rejection has been withdrawn.
(3 of 3) The rejection of claims 1, 3-6, 14-17 and 44 under 35 USC 103 for being obvious over Gray in view of ‘036 has not been overcome by amendment or Applicant’s remarks that the rejected PTM moieties were deleted, because all but one of the rejected PTM moieties were deleted. The rejection is withdrawn for the deleted PTMs and maintained for the remaining claimed PTM,
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, with respect to the claims having the later effective filing date: claims 6, 14 and 44. Claim 41, previously indefinite, is being included in the rejection as necessitated by amendment. The rejection is withdrawn for claims 1, 3-5, 15-17, which have been amended to have support by the instant provisional application, which accords these claims a filing date that predates Gray. See the discussion above under the Priority section.
Election/Restrictions
New claims 46-47 are drawn to the invention of Group I, which is distinct from Groups II-IV for the reasons of record. See restriction requirement mailed on September 25, 2024. Claims 1, 4-6, 14-20 and 41-47 read on the elected species 1,
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, and species 2 (bioactive agent), amiodarone
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, wherein:
ULM is
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,
X1 and X2 are C=O,
Rp is OH,
W3 ,
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, is substituted -T-N(R1aR1b), T is -(CH2)n- (n is 1 and the CH2 is
substituted with a t-butyl), R1a is H, R1b is RY3C=O, RY3 is C1-alkyl attached to L,
W4 ,
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, is
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, R14a and R14b are H or methyl, respectively,
W5 is phenyl,
R15 is substituted heteroaryl (methyl-thiazole);
PTM is
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, R1, R7, R8 and R9 are H, wherein R9 is replaced with an
attachment to L; and
L,
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, is
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, q is 17, and AL is
independently O or CRL1RL2, and RL1 and RL2 are H,
Examination of the elected invention was conducted in accordance with the MPEP 803.02. The elected species is allowable in view of the prior art; therefore, examination of the Markush-type claim has been extended. Since art was found on a nonelected species, subject matter not embraced by the elected embodiment or the rejected species is therefore withdrawn from further consideration. See the rejected species under 35 USC 103.
Claims 12-13 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant elected Group I (current claims 1, 4-6, 12-20 and 41-47) without traverse in the reply filed on November 25, 2024.
Applicant is reminded that upon the cancellation of claims to a non-elected invention, the inventorship must be amended in compliance with 37 CFR 1.48(b) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. Any amendment of inventorship must be accompanied by a request under 37 CFR 1.48(b) and by the fee required under 37 CFR 1.17(i).
Claim Objections
Claims 1, 5, 44 and 47 are objected to for the following informalities:
Claim 1 (line 1 of page 4) recites “heterocyclic” instead of “heterocyclyl.”
Claim 1 (R15 on page 4) recites “N R14aR14b” and “NR14a SO2R14b”, which contain extra spaces within the recited groups.
Claim 5 (bottom of page 9) recites “; and” which is grammatically incorrect.
Claim 44 (R11) recites “isooxazolyl” which is a misspelling of “isoxazolyl”.
Claim 47 contains blurred chemical structures on page 49.
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.
Claims 1, 4-6, 14-20, 41-42, 44 and 45 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 1 states “R15 is selected from the group of H, […][] optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, aryl, heteroaryl, cycloalkyl, or cycloheteroalkyl.” It is unclear whether the aryl, heteroaryl, cycloalkyl, or cycloheteroalkyl are optionally substituted or unsubstituted. The specification recites this R15 limitation as “optionally substituted haloalkoxy; aryl, heteroaryl, cycloalkyl, or cycloheteroalkyl (each independently optionally substituted)” (p. 37). Since claim 1 removed the semicolon between “haloalkoxy” and “aryl”, a PHOSITA might interpret the claim as encompassing optionally substituted the aryl, heteroaryl, cycloalkyl, and cycloheteroalkyl if there was a conjunction preceding “optionally substituted haloalkoxy”. Since the claim does not include a conjunction before “optionally substituted haloalkoxy,” the grammar does not support the interpretation that the aryl, heteroaryl, cycloalkyl, and cycloheteroalkyl are optionally substituted. However, in light of the specification, a PHOSITA would be confused about whether or not the aryl, heteroaryl, cycloalkyl, and cycloheteroalkyl are optionally substituted, especially given that several several dependent claims have embodiments drawn to substituted heteroaryl groups for R15. Due to the ambiguity, claim 1 is indefinite. Dependent claims 4, 14-20 and 41-42 do not resolve the indefiniteness and are likewise rejected. In fact claim 4, explicitly recites “optionally substituted haloalkoxy, cycloalkyl, or heterocyclyl”, which does not clearly convey whether the cycloalkyl and heterocyclyl groups are optionally substituted or unsubstituted as R15.
This rejection may be overcome by clarifying whether the aryl, heteroaryl, cycloalkyl, and cycloheteroalkyl are each optionally substituted or unsubstituted.
For the purposes of facilitating examination and applying prior art, claims 1, 4, 14-20 and 41-42 are construed as encompassing the optionally substituted R15 groups.
Claim 1 requires a compound of the chemical structure ULM-L-PTM and, at the bottom of page 4, also requires that “the dashed line [of ULM] indicates the site of attachment of at least one PTM, another ULM (ULM') or a chemical linker moiety coupling at least one PTM or a ULM' or both to ULM,” which conflicts with ULM-L-PTM structure required. When a ULM is attached to another ULM, the compound cannot have the structure ULM-L-PTM, but instead has the structure ULM-ULM-L-PTM. This contradiction renders the scope of the claimed structures unclear. Since dependent claims 4-6, 14-20, 41-42, 44 and 45 do not clarify the ambiguity, these claims are also indefinite.
This rejection may be overcome by deleting the embodiment allowing ULM to be connected to another ULM (ULM’).
Claim 6 depicts ULM groups selected from ULM-b1 and -b3 through -b11, all of which have two phenyl groups. ULM-b1 is representative:
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. The “wherein” clause at the end of the claim states “the phenyl ring in [] ULM-b1 through ULM-b12 [] is optionally substituted with fluorine, C1-3 alkyl, or alkoxy.” Since ULM-b1 and -b3 through -b11 each contain two phenyl groups, it is unclear which phenyl group is optionally substituted. Therefore, a PHOSITA would not be apprised of the precise scope of compounds claimed.
This rejection may be overcome by replacing “the phenyl ring” with “each phenyl ring”.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 4, 6, 41 and 43 are rejected under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 4 encompasses ULM groups selected from
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(p. 8), which groups encompass stereoisomers outside the scope of claim 1. Claim 1 is limited to a particular ULM stereoisomer:
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. Similarly, claim 6 also encompasses stereoisomers outside the scope of claim 1, since claim 6 does not limit the stereochemistry of any of the ULM groups. Lastly, claim 43 recites two compound species with the opposite stereochemistry as the ULM group of claim 1:
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and
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(p. 47). Therefore, claims 4, 6, 41 and 43 fail to further limit claim 1.
This rejection may be overcome by amending the ULM structure of claim 1 to encompass all stereoisomers.
Claim 41 encompass the PTM group
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, which was deleted from claim 1. Therefore, claim 41 fails to further limit the compounds of claim 1 when PTM is the group shown above.
Claim Rejections - 35 USC § 103
Claims 6, 14, 41 and 44 (with an effective filing date of Nov. 1, 2017) are rejected under 35 U.S.C. 103 as being unpatentable over Gray et al. WO2019/014429 A1 (claiming benefit of provisional appl. no. 62/531,773, filed on July 12, 2017) in view of WO 2017/185036 A1 (claiming benefit of provisional appl. no. 62/326,574, filed on April 22, 2016).
‘429 teaches treating Alzheimer’s disease via tau degradation using bifunctional compounds of Formula I (T-L-E), comprising a tau-binding moiety (T) linked to an E3 ubiquitin ligase binding moiety (E), and pharmaceutical compositions thereof comprising a carrier and an additional anti-neurodegenerative agent. See, e.g., ‘429 ¶¶ 6-7, 377 and 417. “In certain embodiments, T is of the formula:
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” (¶ 172). The following preferred “T” groups are also disclosed:
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’429 ¶ 187.
Linker preferences are discussed on p. 69-71. See ¶ 196, for example.
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Compared to the claimed invention, the T-L-E compounds of ‘429 publication share the same PTM-L- moieties as claimed (equivalent to the T-L- portion), but have a different ULM structure (E moiety). Although ‘429 discloses some ULM structures as instantly claimed, these structures are not supported by the provisional application 62/531,773 and, therefore, do not qualify as prior art.
‘036 teaches bifunctional compounds of Formula X,
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, for targeted degradation of proteins, wherein the targeting ligand “is capable of binding to a targeted protein” and the degron is a E3 ubiquitin ligase binding moiety. See, e.g., ‘036 4:7-19. “In one embodiment, the Degron is of Formula D2:
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” or Formula D3,
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, wherein R17 is C1-3 alkyl, q’ is 0-4, R18 is H or C1-3 alkyl, and R19 is H or C1-3 alkyl such as
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,
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,
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, or
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. ‘036 59-60. See, e.g., compounds I-23 through I-26 and I-34 (pages 75-76 and 78):
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.
Since (a) ‘429 teaches Alzheimer’s disease can be treated via tau degradation using bifunctional compounds (T-L-E) comprising a tau-binding moiety linked to a E3-ubiquitin ligase-binding moiety, (b) ‘036 teaches the ubiquitin ligase moiety is preferably
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,
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,
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or
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, a PHOSTIA would have desired to link the tau-binders of ‘429 to the ligase binders of ‘036 to compounds to obtain new T-L-E compounds for treating Alzheimer’s disease via tau-targeted ubiquitination and degradation. Thus, it would have been obvious to modify ‘036’s preferred compounds of the structure
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by replacing the EGFR-targeting ligand,
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, in compounds I-23 through I-26 and I-34, with the preferred tau-targeting ligands of ‘429:
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”
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By replacing one targeting ligand with another designed to treat Alzheimer’s, a PHOSITA would have successfully arrived at the claimed anti-Alzheimer’s compounds. For example, replacing the ‘036 EGFR ligand
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in compound I-23 or I-24 with the ‘429 tau ligand
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would have given rise to the following obvious compounds:
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and
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. These representative compounds and their pharmaceutical compositions anticipate the embodiments of claims 6, 14, 41 and 44 outlined below:
ULM is
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,
W3,
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,
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, wherein R9 is H, R10 is t-butyl (C4-alkyl), R11 is
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, R12 is H, R13 is alkylcarbonyl, R14a is methyl, R14b is H,
W5 is phenyl, R15 is substituted heteroaryl (methyl-thiazole);
PTM is
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, R1, R7, R8 and R9 are H, R9 is attached to L;
L,
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or
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, is
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, q is 7 or 10, AL is
independently CRL1RL2, O or NRL3, and RL1, RL2 and RL3 are H.
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Furthermore, replacing the EGFR-targeting ligand,
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, in compounds I-23 through I-26 and I-34, with the other preferred tau-targeting ligands of ‘429 renders obvious the claimed compounds outlined above wherein PTM is
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Allowable Subject Matter
Claims 46-47 are objected to for informalities or as being dependent upon 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.
Conclusion
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 extension fee 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 date of this final action.
Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA L AGUIRRE whose telephone number is (571)272-5592. The examiner can normally be reached 10 am-6 pm EDT.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JOSEPH K McKANE can be reached on 571-272-0699. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/AMANDA L. AGUIRRE/ Primary Examiner, Art Unit 1626