DETAILED ACTION
Notice of 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
The amendments filed 8/11/2025 have been entered.
Priority
The earliest effective filing date afforded to pending claims 22-25 wherein CLM is a cereblon E3 Ubiquitin Ligase binding moiety of chemical structure (a) or (d) is 4/14/2014, based on PRO 61/979,351.
Specifically, PRO 61/979,351 provides support for compounds having the structure PTM-L-CLM wherein:
CLM is a cereblon E3 Ubiquitin Ligase binding moiety of chemical structure (a) or (d) as recited by claim 22 (Paragraphs 0061, 0075 and 00115);
L is a linker group (Paragraph 0014); and
PTM is a compound targeting human BET Bromodomain-containing proteins selected from compounds 1, 2, 4 and 4 (Paragraphs 00293-00306).
PRO 61/979,351 does not provide support for CLM wherein CLM is cereblon E3 Ubiquitin Ligase binding moiety of chemical structure (e) as recited by claim 22.
The earliest effective filing date for CLM wherein CLM is cereblon E3 Ubiquitin Ligase binding moiety of chemical structure (e) is 6/04/2015 based on PRO 62/171,090 (Paragraph 0060).
Additionally, PRO 61/979,351 does not provide support for PTM wherein PTM is defined in claim 30 as:
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The earliest effective filing date for PTM wherein PTM is one of said four structures is 7/06/2015 based on US 14/792,414 (Paragraph 00208);
Lastly, although PRO 61/979,351 generically discloses that the linker L can be -Aq- (Paragraph 00119) wherein A can be each of:
NH (i.e., A can be (CH2)i-NR wherein i is 0 (see Paragraphs 00120 and 00124; see also Paragraph 00125 “[i]n preferred embodiments, A1 to Aq are, each independently… NRx”));
aryl (Paragraph 00125); and
OCH2CH2 (i.e., A can be (CH2)i-O wherein i is 2 (see Paragraphs 00120 and 00124)),
PRO 61/979,351 is not considered to provide support for Applicant’s instantly elected linker wherein L is -Aq- wherein q is 15 and wherein each A, in order, is be NRL3, aryl, O, CRL1RL2, CRL1RL2, O, CRL1RL2, CRL1RL2, O, CRL1RL2, CRL1RL2, O, CRL1RL2, CRL1RL2, and NRL3 wherein RL1, RL2 and RL3 are all H.
The earliest effective filing date for said linker is 7/06/2015 based on US 14/792,414 (Paragraph 00101).
And, based on the foregoing, the earliest effective filing date for Applicant’s elected species is 7/06/2015.
Response to Arguments
Applicant’s elected species:
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reads upon claims 22-25 and 30-31.
As discussed in the previous Action mailed on 2/12/2025, the elected species has been searched and is deemed to be free of the prior art and non-obvious.
Accordingly, in the action mailed on 2/12/2025, the search was expanded as called for under current Office Markush practice – a compound-by-compound search – to include a single additional species (M.P.E.P. § 803.02). That species was:
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,
which reads on claims 22-25 and 30. Those claims were rejected under 35 U.S.C. 103(a) as being unpatentable over Crews et al (WO 2013/106643 – published 7/18/2013; of record) in view of Gandhi et al (Br J Haematol 164:811-821, published online 12/13/2013; of record).
Applicant traverses. As argued by Applicant, “Crews does not synthesize or test a single compound having a BRD4 targeting moiety” and “there is no data or other information to support BRD4 degradation of the disclosed compounds. The utility of the disclosed compounds as BRD4 degraders is, at best, prophetic” (Applicant Arguments, Page 15). And, as further argued by Applicant, “Gandhi fails to teach bifunctional compounds in any capacity” and only teaches lenalidomide as “useful in facilitating the degradation of two transcription factors Ikaros and Aiolos… there is no data or information in Gandhi to support BRD4 degradation… [and] no indication that modifying the ULM of a bifunctional compound with a CLM targeting moiety such as lenalidomide would maintain the lenalidomide… activity and lead to degradation activity” (Applicant Arguments, Page 15). As such, Applicant argues that “one of skill in the art would not be motivated by the teachings of Crews in view of Gandhi to arrive at the instantly claimed compounds, nor would there be any reasonable expectation that doing so would lead to compounds with BRD4 degradation activity” (Applicant Arguments, Page 16).
Applicant’s arguments have been considered but are not found persuasive. Although it is acknowledged that Crews et al does not provide specific embodiments of bifunctional compounds comprising a BRD4 targeting moiety as the PTM (protein/polypeptide targeting moiety) group, as taught by Crews et al, the “PTM groups according to the present invention include… any moiety which binds to a protein specifically” (Page 50) and “places/presents that protein… in proximity to an ubiquitin ligase such that degradation of the protein… by ubiquitin ligase may occur” (Page 55). Considering that Crews et al specifically identify a BRD4 targeting moiety as a useable PTM in the bifunctional compound (Page 378), and further considering that Gandhi et al teach “binding of lenalidomide… can promote the E3 ligase activity towards specific substrates” (Page 819, Column 1), it is maintained that a person of ordinary skill in the art would have found it prima facie obvious to formulate bifunctional compounds of Crews et al comprising a BRD4 targeting moiety as the PTM and lenalidomide as the ULM with the reasonable expectation that said BRD4 targeting moiety would bind BRD4 such that degradation of the protein by the lenalidomide-bound ubiquitin ligase may occur. Obviousness does not require absolute predictability, only a reasonable expectation of success of obtaining similar properties. In re O'Farrell, 853 F.2d 894 (Fed. Cir. 1988).
Applicant, however, further argues that “when dealing with technology surrounding the chemical arts, as is the case here, there is a heightened burden on the Office to justify whether a claimed invention would have been predictable” (Applicant Arguments, Page 16).
It is believed that the burden has been met in the instant case. This is not a case of altering atoms in a prior art parent compound in the hopes of developing a structurally related compound having related activity. Rather, the modification of Crews et al to arrive at the instantly claimed bifunctional compound merely involves the linking of a known PTM group with a known ULM group such that binding of the PTM to its target protein will place a ULM-bound ligase in proximity of the target protein for degradation to occur.
For all the foregoing reasons, Applicant’s arguments are not found persuasive. The rejection is MAINTAINED.
The objection to claim 1 (which should have been directed to claim 22) is WITHDRAWN in view of Applicant’s amendments to the claims.
The non-statutory double patenting rejection of claims based on ALLOWED Application No. 17/571,018 is WITHDRAWN in view of Applicant’s filing of a Terminal Disclaimer.
Claim Rejections - 35 USC § 103
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.
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.
Claims 22-25 and 30 are MAINTAINED rejected under 35 U.S.C. 103(a) as being unpatentable over Crews et al (WO 2013/106643 – published 7/18/2013; of record) in view of Gandhi et al (Br J Haematol 164:811-821, published online 12/13/2013; of record).
Claims 22-23 and 30 are drawn to a compound (and compositions thereof (claim 24) further comprising a pharmaceutically acceptable carrier, additive, and/or excipient (claim 25)) having the chemical structure PTM-L-CLM which embraces the following structure:
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wherein,
PTM is
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,
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, or
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(as recited by claim 30);
L is -Aq- wherein q is 12 or 13 and each A, in order is [O]0-1, CRL1RL2, CRL1RL2, O, CRL1RL2, CRL1RL2, O, CRL1RL2, CRL1RL2, O, CRL1RL2, CRL1RL2, and NRL3 wherein RL1, RL2 and RL3 are each H (as recited by claim 23); and
CLM is
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i.e., lenalidomide (as recited by claim 22).
Crews et al teach “bifunctional compounds, which find utility as modulators of targeted ubiquitination” comprising “on one end a VHL ligand, which binds to the VHL E3 ubiquitin ligase (defined as a ubiquitin ligand binding moiety or ULM group) and on the other end a moiety, which binds a target protein (defined as a protein/polypeptide targeting moiety or PTM group)” (Page 1), “such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein” (Abstract), and compositions thereof further comprising an excipient (Page 386, claim 103).
More specifically, Crews et al disclose bifunctional compounds having the chemical structure PTM-L-ULM wherein:
“PTM is a chemical moiety (protein targeting moiety), which binds to a target protein or polypeptide, which is ubiquinated by an ubiquitin ligase”;
“L is a linker moiety… which chemically (covalently) links ULM to PTM”; and
“ULM is an ubiquitin ligase binding moiety… which binds ubiquitin ligase, preferably an E3 ubiquitin ligase” (Page 9).
In particular, Crews et al teach bifunctional compounds wherein:
PTM is “[a] compound targeting human BET Bromodomain-containing protein Brd2, Brd3, Brd 4” such as
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or
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(Page 378); and
L is “preferably a polyethylene glycol group ranging in size from about 1 to about 12 ethylene glycol units” (Page 47).
And, as taught by Gandhi et al, “binding of lenalidomide… can promote the E3 ligase activity towards specific substrates” (Page 819, Column 1).
Accordingly, based further on Gandhi et al, it would have been obvious to modify the bifunctional compounds of Crews et al so as to comprise lenalidomide as the CLM. It would have been obvious to do so considering that Gandhi et al teach that lenalidomide is an ubiquitin ligase binding moiety which binds to E3 ubiquitin ligase. The simple substitution for one known equivalent for another is prima facie obvious.
Accordingly, claims 22-25 and 30 are rejected as prima facie obvious.
Claim Objections
New claim 31 is objected for the following reason:
New claim 31 is drawn to a compound including the following Compound 40 which appears to be missing a bond as indicated by arrow:
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As such, the claim is objected to. However, claim 31 – which is directed to Applicant’s elected compound species but which does not comprise the additionally searched compound species rejected above – has not been further examined.
Conclusion
No new ground(s) of rejection are 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CRAIG D RICCI whose telephone number is (571) 270-5864. The examiner can normally be reached on Monday through Thursday, and every other Friday, 7:30 am - 5:00 pm ET.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bethany Barham can be reached on (571) 272-6175. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CRAIG D RICCI/Primary Examiner, Art Unit 1611