DETAILED ACTION
Claims 1-2, 6, 10, 13, 17, 25, 38-39, 47-58, 68-73, 77, 90, 92, 94, 96, 98 and 102, submitted 03 April 2026, are pending in the application. Claims 55, 58,
96, 98 and 102 are withdrawn. Claims 1-2, 6, 10, 13, 17, 25, 38-39, 47-54, 56-57, 68-73, 77, 90, 92 and 94 are under examination in the instant Office 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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-2, 6, 10, 13, 17, 25, 38-39, 47-58, 68-73, 77, 90, 92 and 94, and the elected species,
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, in the reply filed on 03 April 2026 is acknowledged.
Claims 55, 58, 96, 98 and 102 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03 April 2026.
The Examiner did not find prior art on the elected species, therefore, the elected
species is free of the art. As such, the scope of the search was expanded to include the
broader genus.
Claim Objections
Claim 39 is objected to because of the following informalities: Line 4 of claim 39 currently recites “(i) modulating the folding of the target protein”. The term “modulating” is in a subscript font size. Applicant could overcome this objection by correcting the font to be consistent with points (ii)-(ix). Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 6, 13, 39, 50, 69-70 and 72 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.
Regarding claim 6, the phrase "e.g." renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). The term “e.g.” is found in line 3 of the instant claim.
Regarding claim 39, the phrase "e.g." renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). The term “e.g.” is found in line 8 of the instant claim.
Regarding claim 50, the phrase "e.g." renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).The term “e.g.” is found in line 3 of the instant claim.
Regarding claim 69, the phrase "e.g." renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). The term “e.g.” is found in line 3 of the instant claim.
Regarding claim 70, the phrase "e.g." renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). The term “e.g.” is found in line 3 of the instant claim.
Regarding claim 72, the phrase "e.g." renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). The term “e.g.” is found in line 3 of the instant claim.
Additionally, claims 6, 39, 69-70, and 72 are indefinite due to the use of parentheticals that create ambiguity of whether the item in the parenthetical is a required limitation or not. The Examiner respectfully suggests deleting the parentheticals in these claims.
Claim 13 is 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. The claim recites the limitation “(iv) the deubiquitinase is selected from Table 1”. It is not clear which of the compounds of Table 1 are intended to be claimed. Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." See MPEP 2173.05(s).
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(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.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
Claim 1-2, 6, 10, 13, 17, 25, 38-39, 47-54, 56-57, 68-73 and 77 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 recites the limitation “the Target Ligand comprises a moiety capable of binding to a target protein” and the limitation “the DUB Recruiter comprises a moiety capable of binding to a deubiquitinase” for which the specification does not provide adequate written description to convey that the inventors were in possession of the full scope of the claimed invention.
Claim 47 recites “…or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof…” for which the specification does not provide adequate written description to convey that the inventors were in possession of the full scope of the claimed invention.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor has possession of the claimed invention. See MPEP 2163.
The Applicant has provided adequate written description for certain aspects of the instantly claimed invention. For example, the Applicant has provided guidance with respect to the synthesis of the bifunctional compounds of specific structures, found in Example 3 of the specification on pages 88-131, and the synthesis of DUB recruiters of specific structures, found in Example 4 on pages 131-141. Written description was also adequately provided in Example 5 in-part pertaining to bio-NMR analysis of the DUB recruiter-deubiquitinase interactions regarding the binding to the deubiquitinase, OTUB1. Finally, there was evidence provided with regards to the transepithelial conductance assay data provided through the means of preparing human bronchial epithelial cells from cystic fibrosis patients bearing the DF508-CFTR mutation in Example 7 on pages 142-143. Figure 8 provides specification evidence of a gel-based analysis of OTUB1 binding for a select number of exemplary DUB recruiters which demonstrates their structure-activity relationships.
The Applicant does not provide adequate written description with regards to the structure-activity relationship of the compounds of the invention and all claimed target deubiquitinase through experimentation in vitro or binding assays. The exemplifications drawn to the compounds of the invention do not teach the function of the compounds in binding assays, outside of the aforementioned example containing transepithelial conductance assay and the bio-NMR analysis of the DUB recruiter and OTUB1, in vitro experimental function, nor in in vivo experimental function.
The instant specification does not adequately teach the structure-activity
relationship for one skilled in the art to envisage which compounds bind to which target
proteins. With the assistance of a computer an artisan might be able to identify all the
possible compounds encompassed by the claimed genus, however, this would still be
insufficient for the ordinary skilled artisan to clearly envisage which compounds would
bind to which target. Without additional resources detailing which compound
targets which protein, one skilled in the art would not be able to decipher the instantly
claimed invention.
The instant specification also fails to adequately describe wherein the derivative of Formula (I-a) is a prodrug thereof. It’s known in the art that the design and synthesis of prodrugs is complex and presents many challenges. For example, the prior art, Rautio et al. ("The expanding role of prodrugs in contemporary drug design and development." Nature reviews drug discovery 17.8 (2018): 559-587.), teaches the challenges associated with prodrug design and development. Rautio states
“Though great progress has been made to characterize prodrugs, the limitations of the
different approaches should be carefully considered with respect to the uncertainty in
translation to humans. The development of prodrugs is, in general, much more complex
and less predictable in the clinic than that of other drugs” (pg. 578, Section “Prodrug
challenges and considerations”, Right Col., 1st paragraph).
The instant specification does not provide sufficient evidence of written description of the following:
“The target ligand comprises a moiety capable of binding to a target protein” as this encompasses all known target protein and all known and unknown target ligands.
“The DUB Recruiter comprises a moiety capable of binding to a deubiquitinase” as this encompasses all known deubiquitinase and all known and unknown DUB recruiters.
Wherein the derivative of Formula (I-a) is a prodrug thereof.
The instant claim lacks written description because the claim is claiming compounds based on the compounds function while the evidence found within the specification is drawn to very particular target ligands, linkers, and DUB recruiters. The Examiner would like to point the Applicant to MPEP 2163(II)(A)(3)(a) which recites “An applicant may also show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that inventor was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613 (quoting the Written Description Guidelines, 66 Fed. Reg. at 1106, n. 49, stating that "if the art has established a strong correlation between structure and function, one skilled in the art would be able to predict with a reasonable degree of confidence the structure of the claimed invention from a recitation of its function".). As claim 1 currently reads, the Examiner cannot conclude that the Applicant was in possession of the full scope of the claimed invention.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2, 6, 10, 13, 38-39, and 94 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Sheppard (WO 2020/169650 A1).
Sheppard discloses synthetic, multi-domain, multi-functional survival-targeting chimeric (SURTAC) molecule comprising a binding domain, a second binding domain, and a linker domain wherein: (i) the first binding domain is configured to bind to an ubiquitinylated protein; (ii) the second binding domain is configured to bind to an ubiquitin protease that cleaves ubiquitin from the ubiquitinylated protein bound to the first binding domain, and (iii) the linker domain is configured to link the first binding domain and the second binding domain (Paragraph 0032 and Claim 1). It’s also taught that the target ubiquitinylated protein can be cystic fibrosis transmembrane conductance regulator (CFTR) (Claim 15) which reads on the limitations of instant claims 2 and 6.
Regarding claim 10, Sheppard teaches wherein the SURTAC compound, having a target engagement motif which specifically binds to ubiquitinylated ΔF508 CFTR proteins and a DUB engagement motif which specifically binds to a known deubiquitinating protease of ubiquitinylated CFTR protein (Paragraph 0196).
Regarding claim 13, Sheppard discloses the cleaving of lysine-linked polyubiquitin chain by reciting “This polarised residue lowers the pKa of the cysteine, allowing it to perform a nucleophilic attack on the isopeptide bond between the ubiquitin C-terminus and the substrate lysine (paragraph 0188). This paragraph also discloses wherein the deubiquitinase is a cysteine protease. Sheppard further teaches wherein the deubiquitinase is selected from USP5, OTUD1, or OTUD5 (paragraph 0142).
With respect to claim 38, Sheppard teaches wherein the chimeric molecules perform a manipulation (e.g., decreasing) on the number of ubiquitin molecules attaches to proteins of interest, can be used to interfere, modulate or control these key aspects of cellular proteins (paragraph 0046). This also reads on instant claim 39 which recites the limitation that the modulating comprises modulating target protein interactions with other proteins.
With respect to claim 94, Sheppard teaches a pharmaceutical composition comprising the bifunctional compound in Example 3 by treating a mouse model of blood cancer (paragraph 0195).
Allowable Subject Matter
Claims 90 and 92 are objected to 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
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JUSTIN CHRISTOPHER SANCHEZ whose telephone number is (703)756-5336. The examiner can normally be reached Monday -Friday (0730-1700).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James H Alstrum-Acevedo can be reached at 571-272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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JUSTIN CHRISTOPHER SANCHEZ
Examiner
Art Unit 1622
/J.C.S./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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