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 .
Response to Amendment
Applicant’s remarks and amendments filed 01/22/2026 have been acknowledged. Claim 1 has been amended.
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 1, 5-8, 14 and 15 are rejected under 35 U.S.C. 103 as being obvious over Pillow et al, (WO 2017/201449 Al, of record), hereinafter Pillow in view of Lu et al (Lu, Jing, et al. "Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4." Chemistry & biology 22.6 (2015): 755-763, of record), hereinafter Lu, as evidenced by Jain et al (Jain, Nareshkumar et al. “Current ADC Linker Chemistry.” Pharmaceutical research vol. 32,11 (2015): 3526-40. doi:10.1007/s11095-015-1657-7), hereinafter Jain.
Pillow teaches an antibody-PROTAC conjugate having the structural formula Ab—(L1—D)p, where D is a PROTAC having the structure E3LB—L2 —PB; E3LB is an E3 ubiquitin ligase binding group covalently bound to L2; L2 is a linker covalently bound to E3LB and PB; PB is a protein binding group covalently bound to L2; Ab is an antibody covalently bound to L1, L1 is a linker, covalently bound to Ab and to D; and p has a value from about 1 to about 8 (see Abstract, Summary of Invention, and Claims). In this case, L1 bound to antibody corresponds to L2 of the instant claims; L2 bound to E3LB and PB correspond to L1 of the instant claims; E3LB corresponds to B of the instant claims; and PB corresponds to A of the instantly claimed invention.
The antibody is a monoclonal antibody or variant thereof (Page 5, Ln. 4 – 8). The E3LB group is a peptide or small molecule that binds the E3 ligase cereblon such as pomalidomide (Page 104, Ln.4-9; Page 122, Ln. 19-26 to Page 123, Ln. 1-8 and Claims 3, 4, and 5); PB is a peptide or small molecule that targets bromodomain protein 4 (BRD4) (Page 124, Ln. 12 – 33 and Page 125, Ln. 1- 14); and the antibody is specifically trastuzumab (see Anti-HER2 Antibodies section, Page 72, in particular Ln. 1-11). Pomalidomide represents structure B recited in the instant claims (see also Para. 0039 of the instant specification: pomalidomide is (3) in the figure on Page 16 of the instant specification) Pillow also teaches pharmaceutical compositions comprising the antibody-PROTAC conjugates (Page 2, Ln. 26 – 27 and Formulations section, Pages 159 - 162). Pillow further teaches that L1 bound to the antibody (corresponding to L2 of the instant claims) can be covalently linked at any available point of attachment in the PROTAC (Page 3, Ln. 22-28), which comprise three general components: the E3LB group, linker, and PB group (see Definitions on Page 4). Given that there are three available points for attachment in the PROTAC— E3LB, L2, and PB—Pillow encompasses antibody-PROTAC conjugates wherein L1 (corresponding to L2 of the instant claims) can be attached to L2, E3LB, or PB in the PROTAC (D) and thus encompasses the structure of the instant claims. Indeed, Pillow further explains that “L1 may be connected to the PROTAC through any of the E3LB, L2, or PB groups” (Page 15, Ln. 11-12). The linker can be valine-citrulline (a cleavable dipeptide linker), 4-(N-maleimidomethyl) cyclohexane-1 carboxylate (MCC, a type of lysine linker as evidenced by Jain et al, see “Lysin Linkers” section on page 3534), or a substituted or unsubstituted polyethylene glycol (PEG) group (Page 98, Ln. 4-14: Page 102, Ln. 19-24; and Page. 128, Ln. 1-8).
Pillow does not specifically teach that the compound that targets BRD4 in the antibody-PROTAC- conjugate is OTX015. OTX015 represents structure A recited in the instant claims (see also Para. 0038 of the instant specification: OTX015 is (1) in the Figure on Page 15 of the instant specification).
However, Lu teaches that the BRD4 PROTAC ARV-825 made by connecting a small molecule BRD4 binding moiety (OTX015) to an E3 ligase cereblon binding moiety (pomalidomide) achieved rapid and potent degradation of BRD4 as well as suppressed proliferation and induced apoptosis in cancer cells (see entire document, in particular, Summary, Highlights and Introduction).
It would have been obvious to one of ordinary skill in the art to modify the antibody-PROTAC conjugate disclosed by Pillow such that the compound that targets BRD4 in the antibody-PROTAC conjugate is OTX015. One of ordinary skill in the art would have been motivated to do so since ARV-825 (a PROTAC comprising OTX015 conjugated to pomalidomide) effectively suppresses c-MYC levels and downstream signaling resulting in effective cell proliferation inhibition and apoptosis induction in Burkitt’s lymphoma as taught by Lu. Therefore, one of ordinary skill in the art would expect that an antibody-PROTAC conjugate disclosed by Pillow comprising OTX015 as the BRD4 binding moiety and pomalidomide as the cereblon binding moiety would be able to effectively treat cancer in a subject.
Response to Arguments
Applicant's arguments filed 01/22/2026 have been fully considered but they are not persuasive.
With respect to rejections made under 35 U.S.C. 103, Applicant argues that the claimed invention is based at least in part upon Applicant’s discovery that an antibody-PROTAC conjugate (APC) having a branched structure of Formula (1), wherein A is a target protein binder OTX015 which targets BRD4 and B is the ubiquitin ligase/ligand binder pomalidomide,
exhibits a specific BRD4 protein degradation activity, and
the claimed APC having the branched structure is significantly more effective in causing BRD4 degradation as compared to the corresponding linear APC per the Declaration of Wei-Ting Sun.
In regards to alleged unexpected results, the Examiner reiterates that the results of the data provided in Figure 4 on the Affidavit/Declaration---in which the branched antibody PROTAC conjugate of Example 1 of the Specification (trastuzumab-BRD4-PROTAC 1 comprising the anti-HER2 antibody trastuzumab, the BRD4 binding moiety OTX015, and the E3 ubiquitin ligase pomalidomide) was more effective in inducing degradation of BRD4 in HER2 positive cell line BT-474 compared to the linear format (Example A of the Declaration)---cannot be extrapolated to the broad genus antibody-PROTAC conjugates recited in the instant claims with the expectation that the results observed in Figure 4 on the Affidavit/Declaration will still be applicable.
In particular, it is noted that the antibody-PROTAC conjugate as amended in claim 1 is only limited by the identities of the target protein ligand/binder and ubiquitin ligase ligand/binder but not by, for example, the specific linkers (L1 and L2) present: the L1 and L2 linkers can individually be any cleavable dipeptide linker, any lysine linker, or any PEG linker. Troup et al teaches that the length and composition of the linker is very important for productive ternary complex formation (i.e. when PROTAC binds to E3 ligase and protein of interest), degradation activity, and target selectivity of the PROTAC. Thus, the linker composition, and particularly its length and attachment point to the anchor/warhead (E3 ligase binder/POI binder), must be optimized for each ligand pair, especially since the structural complexity and dynamics of the ternary complex make it a formidable challenge to predict which combination of anchor/linker/warhead will lead to optimal degradation. Troup concludes that there is currently no generally applicable strategy for linker design; and bioactivity optimization through synthetic alteration of the linker is usually achieved via iterative trial and error (Troup et al, see entire document, in particular, “PROTAC linkers” section on pages 278-279) (Troup, Robert I et al. “Current strategies for the design of PROTAC linkers: a critical review.” Exploration of targeted anti-tumor therapy vol. 1,5 (2020): 273-312. doi:10.37349/etat.2020.00018, of record). Given this level of unpredictability, it is unclear if any member in the broad genera of linkers recited (cleavable dipeptide linkers, lysine linkers, and/or PEG linkers) can be used in the claimed immunoconjugate to yield the alleged unexpected results.
Applicant has further argued that artisans would not have had even a reasonable expectation that a combination of Pillow and Lu would result in an immunoconjugate with the recited activity. Pillow states that "L1 bound to the antibody can be covalently attached at any available point of attachment in the PROTAC", and the Examiner contends that L1 can be attached to any one of L2, E3LB or PB in the PROTAC. However, the fact that L1 can be so attached does not mean that an immunoconjugate formed with the recited target-protein ligand/binder (OTX015) and ubiquitin ligase/ligand/binder (pomalidomide) in a branched structure would have the activity required by the claims as amended. To the contrary, Pillow encompasses a vast number of conjugate structures but does not provide a teaching that any conjugate with a branch structure would have the recited activity.
Similarly, Applicant argues that Lu discloses a "BRD4 binding moiety" and a "Cereblon recruiting moiety" in FIG. 2, which allegedly correspond to "A" and "B" as defined in claim 1 as amended, but the structure of the PROTAC in Lu is linear. A linear-type APC requires linking the linker with the target- protein ligand/binder (A) or the ubiquitin ligase ligand/binder (B) in the PROTAC. Thus, Applicant asserts that neither Pillow nor Lu nor any other prior art reference of record shows or suggests that the formation of a branched structure as required by claim 1 with L1 attached to L2 would have the activity required by the amended claims with a reasonable expectation of success.
In response to Applicant's arguments, the Examiner notes that the reasonable expectation of success requirement refers to “the likelihood of success” in combining or modifying prior art disclosures to meet the limitations of the claimed invention. See Elekta Ltd. v. ZAP Surgical Sys., Inc., 81 F.4th 1368, 1375, 2023 USPQ2d 1100 (Fed. Cir. 2023) and Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1367, 119 USPQ2d 1171, 1176 (Fed. Cir. 2016) Conclusive proof of efficacy is not required to show a reasonable expectation of success (see MPEP 2143.02). The antibody-PROTAC conjugates disclosed by Pillow encompass both linear and branched formats since “L1 may be connected to the PROTAC through any of the E3LB, L2, or PB groups” (Page 15, Ln. 11-12), wherein the E3LB is pomalidomide (corresponding to ‘B’ of the instant claims), PB is a bromodomain protein 4 (BRD4) binding moiety, and the L1 or L2 linkers can independently be a cleavable dipeptide linker (e.g. valine-citrulline), a lysine linker (e.g. MCC), or a PEG moiety. Lu further shows that targeting BRD4 with OTX015 in a PROTAC format provides therapeutic benefit in the treatment of cancers. As such, a person of ordinary skill in the art would have been motivated to use OTX015 as the BRD4-bidning moiety in the PROTACs disclosed by Pillow to achieve similar therapeutic benefit. PROTACs comprise a protein-binding (PB) domain and an E3 ligase-binding domain connected by a linker, and are designed to facilitate degradation of a target protein via the proteasome. The PB domain binds the target protein to be degraded while the E3 ligase-binding domain recruits E3 ubiquitin ligase to tag the target protein with ubiquitin (see Background of Pillow). Thus, a person of ordinary skill in the art would expect the substituting OTX015 disclosed by Lu as the BRD4-binding moiety in the branched antibody-PROTAC conjugates encompassed by Pillow would result in degradation of BRD4 as claimed, with a reasonable expectation of success. Therefore, the 35 USC 103 rejection is maintained.
Conclusion
No claims are allowable.
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.
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/LIA E TAYLOR/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641