DETAILED ACTION
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 .
Application Status
The amendment filed on 1/28/2026 in response to the Notice of Non-Compliant Amendment of 1/28/2026 is acknowledged and has been entered.
Claims 1-10 and 15-20 are currently pending.
Applicant’s election without traverse of the following species represented by formula (I) in claim 1:
-alpha-synuclein targeting ligand TL-3,
-Degron D1-a, and
-the linker present in Compound 7 having the structure:
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, wherein the Degron is attached to the left side of the linker and the TL is attached to the right side of the linker in the reply filed on 9/02/2025 is acknowledged. Applicants assert that Claims 1, 6 and 13-20 are readable thereon. A search of the prior art renders the selected species to be obvious. In addition to the elected species, the examiner has expanded the search to include,
-Alpha-synuclein targeting ligand TL-1, wherein X is the phenol and R1 is Nitro, and TL-2; and
-Degron also includes D1-b.
-Linker includes the alkyl linker, as well as, variations in linker length.
Note: In both the alkyl and PEG linkers, the -R’C(O)N(R’)R’- is towards the Degron as set forth above. .
Accordingly, claims 1-2, 4-6 and 15-20 read on the species and expanded species search. Claims 3 and 7-10 are withdrawn from consideration as being drawn to non-elected species.
Rejections Withdrawn:
The rejection of Claims 1-2, 4-6 and 11-20 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in view of Applicants amendments.
Rejections Maintained:
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-2, 4-6 and 15-20 remain rejected under 35 U.S.C. 103 as being unpatentable over Arvinas Operations (WO2020/041331A1, 2020-02-27, IDS) in view of Dana-Farber Cancer Institute (WO2019/014429A1, 2019-01-17) referred to herein as Dana.
Arvinas Operations teaches a bifunctional compound having an alpha-synuclein protein targeting moiety at one end, a linker and an E3 ubiquitin ligase binding molecule at the other end (Abstract). Arvinas Operations further provides numerous examples of the bifunctional compounds having the formula Targeting Moeity-Linker-E3 ubiquitin ligase binding molecule including, but not limited to,
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,
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,
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, and
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(page 404, Table 1, compounds 2, 3, 59 and 63). Moreover, Arvinas Operations teaches pharmaceutical compositions comprising at least one bifunctional compound and a pharmaceutically acceptable carrier (paragraph 00328). Lastly, Arvinas Operations teaches that the composition are useful in methods of treating a disease condition associated with accumulation or aggregation of alpha synuclein such as Parkinson Disease or dementia (paragraph 0007).
Arvinas Operations differs from the instant claims in that the linker does not terminate at the E3 ubiquitin ligase binding molecule in a -R’C(O)N(R’)R’- or that the E3 ubiquitin ligase binding molecule is
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. Moreover, Arvinas Operations does not teach that the linker is an alkyl liker terminating at the E3 ubiquitin ligase binding molecule in a -R’C(O)N(R’)R’-
Dana teaches compounds of Formula I: T-L-E, wherein T is a tau protein binding moiety, E is an E3 ubiquitin binding moiety and L is a substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted arylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted heteroalkylene, a bond or a variety of substituted heteroatoms (paragraph 00121). With regards to the E, Dana et al. teach that E includes, but is not limited to,
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,
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,
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, wherein q is 1-4 (claims 46-53 of Dana). For example, Dana teaches a compound having the formula
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(page 128, 1st compound).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the linking group or substitute the E3 ubiquitin binding moiety as taught by Arvinas Operations so that the linking group is either a PEG or alkyl which terminates with a -R’C(O)N(R’)R’- or that the E3 ubiquitin ligase binding molecule is
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in view of the teachings of Dana.
One of ordinary skill in the art would have been motivated to make such a modification or substitution, with a reasonable expectation of success, because:
-Dana teaches that both PEG and alkyl linkers ending in -R’C(O)N(R’)R’- can be linked to E3 ubiquitin ligase binding moieties and further, E3 ubiquitin ligase binding molecule
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is an alternative E3 ubiquitin ligase binding molecule to choose from.
It should be noted that the specification (example 13) teaches an in vitro experiment showing that the compounds can permeate the cell and engage the E3-ligase CRBN. However, the specification does not appear to show a criticality of the linker or the E3 ubiquitin ligase binding moiety.
In response to this rejection, Applicants contend that Tau protein and a-synuclein are structurally disparate proteins that differ in sequence, aggregation behavior, conformation (e.g. before and after binding to the targeting ligand), and location within the cell. As such, Applicants contend that a person having ordinary skill in the art would understand, e.g., that the accessibility and spatial orientation required for tau or a-synuclein to form a ternary complex with the bispecific compound and E3-ubiquitan are different. For example, Applicants assert that the orientation required for the linker to orient the E3 ligase to ubiquitinate tau is different from that required for the linker to orient the E3 ligase to ubiquitinate a-synuclein. Therefore, Applicants contend that a linker suitable for ubiquitination of tau may be too short or long, or too rigid or too flexible to ubiquitinate a-synuclein. Lastly, Applicants contend that None of the specific compounds disclosed in Dana-Farber include the claimed linkers:
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.
These arguments have been carefully considered, but are not found persuasive.
In response to Applicants arguments, it appears that Applicants are arguing each of the references individually instead of arguing the reference in combination. In response to applicant's argument that Tau protein and a-synuclein are structurally disparate proteins, applicants are reminded that the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In the instant case, both the prior art references are directed to bifunctional compounds having protein targeting moiety at one end, a linker and an E3 ubiquitin ligase binding molecule at the other end. While Arvinas Operations teaches a variety of linkers and E3 ubiquitin ligase binding molecules, Arvinas Operations differs from the instant claims in that the linker does not terminate at the E3 ubiquitin ligase binding molecule in a -R’C(O)N(R’)R’- or that the E3 ubiquitin ligase binding molecule is
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. However, Dana et al. teach a variety of linkers conjugated to the E3 ubiquitin ligase binding molecule including, but not limited to,
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or
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which read on the currently claimed linkers and E3 ubiquitin ligase binding molecule. As such, it would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the linking group or substitute the E3 ubiquitin binding moiety as taught by Arvinas Operations in view of the teachings of Dana et al. as set forth above. It is important to note that Obviousness does not require absolute predictability, but at least some degree of predictability is required. Evidence showing there was no reasonable expectation of success may support a conclusion of nonobviousness. In re Rinehart, 531 F.2d 1048, 189 USPQ 143 (CCPA 1976) (See MPEP 2143.02). In the instant case, Applicants have not provided any factual evidenced showing that there is not reasonable expectation of success or that the instantly claimed linker provide any unexpected results. As noted above, the specification (example 13) teaches an in vitro experiment showing that the compounds can permeate the cell and engage the E3-ligase CRBN. However, the specification does not appear to show a criticality of the linker or the E3 ubiquitin ligase binding moiety.
Conclusion
Therefore, No claim is allowed.
THIS ACTION IS MADE FINAL. 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 BRANDON J FETTEROLF whose telephone number is (571)272-2919. The examiner can normally be reached M-F 6AM-4PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S Lundgren can be reached at 571-272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/BRANDON J FETTEROLF/ Primary Examiner, Art Unit 1626
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