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 .
Claims Status
The Amendment, filed on 15Dec2023, is acknowledged in which claim(s) 1-50 are canceled by Applicant, and claim(s) 51-80 are new.
The Amendment, filed on 06Nov2025, is acknowledged in which claim(s) 61-73 are canceled by Applicant.
Claim(s) 51-80 are presented for examination on the merits.
Priority
Acknowledgement is made of applicant’s claim of benefit to Application No. PCT/US2020/058328, filed on 30Oct2020, which claims domestic benefit to Provisional Patent Application Number 62/929,674, filed on 01Nov2019.
Domestic benefit to the Provisional Application (01Nov2019) is applied for claims 51, 54-60, 74-80.
Domestic benefit to the PCT Application (30Oct2020) is applied for claims 52-53 as the PCT discloses E3 ligase arm Kd testing/results (but the Provisional does not).
Response to Amendment
The objection(s) to the specification have been withdrawn in view of the Amendment filed on 06Nov2025.
All previous rejections and/or objections of claim(s) 61-73 are moot in view of claim cancelation.
All other previously presented rejection(s) and objection(s) are maintained for reasons given in the "Response to Arguments" below. Applicant' s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Rejections Maintained in Modified Form as Necessitated by Claim Amendments
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.
Claim(s) 51-60 and 74-80 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2017/069628 A9 (published 27Apr2017, hereinafter “WO628”), in view of Shin et al. (Scientific Reports, 5:14269, 26Sep2015; hereinafter “Shin”), Clague and Ubre (Cell, 143: 682-685, 24Nov2010; hereinafter “Clague”), and Wurz et al. (Ther Adv Med Oncol 2016, Vol. 8(1) 4–31; hereinafter “Wurz”).
Regarding claims 51, 54-58, 74, and 78-79, WO628 teaches binding molecules that inhibit cancer growth [e.g., title and abstract]. WO628 further teaches embodiments wherein the binding molecule is a bispecific antibody, functional part, derivative, and/or analogue thereof [e.g., pg. 3, lines6-7; claims 2, 7], the bispecific is for the treatment of cancer [e.g., pg. 4, lines 18-19; claim 11], that the two arms of the bispecific comprise an anti-EGFR (extracellular) and a member of the WNT pathway [e.g., pg. 4, lines 21-22; claim 1], RNF43 and ZNRF3 ubiquitin E3 ligases as preferred membrane associated (extracellular) members of the canonical WNT pathway [e.g., pg. 25, lines 9-17; claim 5].
WO628 does not disclose PD-L1 as a target antigen, that binding E3 ligase(s) results in degradation, or internalization and lysosomal aggregation of the target protein(s).
Shin teaches Nanobody-targeted E3-ubituitin ligase complex degrades nuclear proteins, that targeted protein degradation is a powerful tool, and that fusing a nanobody to a protein that binds an E3 ubiquitin ligase complex resulted in rapid ubiquitination and subsequent proteasome-dependent degradation of specific nuclear proteins in mammalian cells [e.g., Title and Abstract]. One of ordinary skill in the art would understand that internalization and lysosomal aggregation are part of the process of ubiquitination-mediated degradation via the autophagy pathway, as evidenced by Clague [e.g., pg. 3, “Autophagy”].
Shin does not teach PD-L1 as a target antigen.
Wurz teaches novel cancer antigens for personalized immunotherapies, the clinical successes of monoclonal antibodies that modulate (by binding) immune checkpoint inhibitors, and that the identification of tumor associated antigens (TAAs) and negative immune checkpoint regulators have led to the development of monoclonal antibodies targeting specific tumor antigens and/or immune checkpoints [e.g., Title and Abstract]. Wurz further teaches established targets of anticancer immunotherapies including EGFR [e.g., pg. 6, “Established targets…”], and that a great deal of research in cancer immunotherapy is being concentrated on the development of immune checkpoint modulators, particularly those targeting the PD-L1 ligand [e.g., pg. 6, “Immune checkpoint blockade…”]. Wurz further teaches that the PD-1 expressed on activated T cells interacting with PD-L1 on the surface of cancer cells results in T cell immunosuppression and immune escape and are in clinical development for a variety of cancers [e.g., pg. 11, “immune checkpoints: PD-L1…”].
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the bispecific monoclonal targeting EGFR and E3 ligase (e.g., RNF43, ZNRF3) to treat cancer(s) in WO628, with the E3 ubiquitination and subsequent target degradation taught by Shin, the known mechanisms of ubiquitin pathway (e.g., autophagy) as evidence by Clague, and the multiple TAA targets for cancer immunotherapies (e.g., EGFR and PD-1) teachings of Wurz, in the context of designing monoclonal bispecific antibodies to treat cancer.
This rationale aligns with the principle of applying a known technique to a known method to yield predictable results, supporting a conclusion of obviousness (see MPEP § 2143). Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Regarding claims 52-53, which depend from claims51 (claims 52), claims 51-52 (claim 53), the teachings of WO628, Shin, Clague, and/or Wurz apply as recited above for claims 51 and 65.
WO628 further teaches the antibody has a Kd of less than or equal to (the lower the Kd, the greater binding affinity) 1x10e-6 (1000 nM), 1x10e-7 (100 nM), 1x10e-9 (1 nM), and 1x10e-10 (0.1 nM) (1 nM, 0.1 nM and 100 nM meet the limitations of the instant claims) [e.g., pg. 19, lines 29-32].
Regarding claim 59, and 75-76, which depends from claim 51 (claim 59), claim 74 (claims 75-76), the teachings of WO628, Shin, Clague, and/or Wurz apply as recited above for claims 51, 65, and 74.
WO628 further teaches the antibody is a human IgG subclass [e.g., pg. 20, lines 2-3], and that heterodimerization of heavy chains can be achieved by generating ‘knob into hole’ (knob and hole) bispecific antibodies [e.g., pg. 59, lines 13-15].
Regarding claims 60 and 77, which depends from claim 51 (claim 60) or claim 74 (claim 77), the teachings of WO628, Shin, Clague, and/or Wurz apply as recited above for claims 51 and 77.
The Examiner notes for clarity of the record, that Applicant discloses “The term "immunoconjugate" or "conjugate" as used herein refers to a compound or a derivative thereof that is linked to a binding agent, such as the bi specific binding agents or the engineered transmembrane proteins provided herein. The immunoconjugate of the present disclosure generally comprises a binding agent, such as the bispecific binding agents or the engineered transmembrane proteins provided herein and a small molecule. In some embodiments, the immunoconjugate further comprises a linker.” [e.g., paragraph 0095].
WO268 teaches a bispecific antibody (see above) and does not teach small molecules or other Applicant-defined immunoconjugates [e.g., pg. 4, lines 1-33].
Regarding claim 80, which depends from claim 51, the teachings of WO628, Shin, Clague, and/or Wurz apply as recited above for claim 51.
WO628 further teaches “preferred cancers” include breast, pancreatic, ovarian, prostate, lung, melanoma, and colorectal [e.g., pg. 31, lines12-27].
Wurz further teaches anti-PD-L1 monoclonal antibody clinical trials show promise in the treatment of bladder, NSCLC, metastatic melanoma, and triple-negative breast cancers [e.g., pg. 14, column 1, paragraph 1].
Response to Arguments
Applicant argues:
Neither WO628 nor Wurz provides guidance to select and combine an E3 ligase-binding domain with a PDL1 binding domain. Neither WO628 nor Wurz provide guidance on selecting and combining PDL1 and E3 ligase as extracellular targets for a bispecific antibody (bsAb). WO628 generally describes bsAbs binding both (i) a small subset of cell surface proteins and (ii) members of the WNT signaling pathway. As an initial matter, as conceded by the Office, PDL1 is not one of the small subset of cell surface proteins taught in WO628. Therefore, WO628 fails to teach a PDL1/E3 ligase binding bsAb. WO628 further fails to provide any suggestion as to the interchangeability of this small subset of cell surface proteins for other cell surface protein generally nor PDL1 specifically. Wurz, a review article that discloses over 45 investigational targets and numerous therapeutics for many of those targets provides no guidance as to selecting a PDL1 binding domain in combination in any bsAb format, nor specifically with an E3 ligase binding arm.
In response, while neither WO628 nor Wurz expressly disclose an anti-PDL1/anti-E3 ligase bsAb embodiment, as provided in the Office Action mailed on 05/07/2025, WO628 was relied upon to teach a bsAb that targets an extracellular TAA and E3 ligase for cancer therapy (and methods of treating comprising administration thereof) and Wurz was relied upon to teach PDL1 (and EGFR) as a well-known extracellular TAA targets for cancer therapy, and further that a great deal of research is being concentrated on the development of immune checkpoint modulators, particularly those in those targeting the PDL1 ligand. The disclosure of Wurz that there is a great concentration on PDL1 as a target specifically for cancer therapy serves as the teaching/reason to select PDL1 from among the variety of known TAA targets for cancer therapy. The Applicant’s arguments have been considered and are not found persuasive.
WO628 teaches away from the combination of Wurz and WO628. WO628 teaches away from combination with Wurz in that WO628 identifies as solving the problem of binding cell surface proteins without clinically effective blocking antibodies. In contrast to the discussion of EGFR in WO628, the PDL1 antibodies described in Wurz are clinically effective blocking antibodies with response rates of up to 53%. Specifically, WO628 suggests that EGFR was selected due to the lack of clinically effective blocking antibodies targeting EGFR in the introduction of the disclosure, stating that most cancer drug discovery has focused on agents that block essential cell function but that treatment with EGFR blocking therapies result in poor DOR (~10%). Applicants fail to see motivation to modify the antibodies of Wurz in any way, nor specifically in the way described in WO628, which solves a disparate problem for targets without clinically successful blocking antibodies. As WO628 suggests the need for novel bsAbs when blocking towards a given target are not clinically effective, and Wurz teaches that PDL1 blocking Abs are successful, WO628 teaches away from combination with Wurz.
In response, the selection of WO628 in full states “Traditionally, most cancer discovery has focused on agents that block essential cell functions and kill dividing cells…More recently the focus of cancer drug development has moved away from broadly cytotoxic chemotherapy to targeted therapy that specifically inhibits signaling pathway components has been validated clinically in leukemia. However, in a majority of carcinomas, targeted approaches are still proving ineffective. In colorectal cancer, over 80% of patients overexpress the receptor tyrosine kinase EGFR, but treatment with EGFR blocking therapies results in response rates of ~10% and, as with chemotherapy, these responses are not durable. While in some patients the poor response rate can be linked to activating mutations downstream of the blocking agent, there is accumulating scientific evidence that a special type of self-renewing cancer cell may explain the limited activity of cancer drugs in many situations...”. Briefly, the teachings of WO628 summarize difficulties of a specific target (EGFR) within a specific indication (colorectal cancer), non-exhaustive theories regarding the mechanism(s), and do not at any point expressly teach away from using targets of signaling pathways that have been ”validated clinically effective in leukemia”. Rather, when read in the full context, one having ordinary skill in the art would understand that WO628 teaches there are a variety of targets as well as potential outcomes, and that different approaches for the same TAA target may increase DOR and/or patient response (e.g., adding an E3 ligase targeting arm may increase anti-tumor efficacy). In summary, for the reasons discussed above, WO628 is not considered to teach away. The Applicant’s arguments have been considered and were not found to be persuasive.
WO628 and Shin fail to teach a method of targeting proteins on the surface of a target cell. With regard to method of claim 51, WO628 fails to teach a method comprising degradation of PDL1 on the surface of a cell wherein contacting of PDL1 and E3 with an anti-PDL1/anti-E3 bsAb leads to PDL1 protein degradation. Shin does not remedy the deficiencies of WO628 as Shin teaches target internalization and degradation, however, as recognized by the Office, Shin teaches a nanobody-targeted E3 ubiquitin ligation complex that degrades nuclear proteins. Shin fails to teach a method of targeting proteins on the surface of a target cell for internalization and degradation, as recited in the present claims. Neither Wurz, Clague, or Li capture the deficiency to teach all limitations of the claim. The combination of recited references fail, either alone in combination, to teach all the limitations of claim 51 and those dependent thereon.
In response, WO628 was relied upon to teach the base bsAb structure of anti-TAA/anti-E3 ligase, extracellular membrane associated E3 ligase, and a method of treating cancer comprising administration of an anti-TAA/anti-E3 ligase bsAb, Wurz was relied upon to teach that both EGFR and PDL1 are TAAs and that PDL1 was a target of particular focus in cancer therapy at the time of filing, and Shin was relied upon the teach that E3 ligase is associated with the ubiquitin pathway, that leads to protein degradation of tagged proteins. Specifically, Shin teaches targeted protein degradation is a powerful tool, that fusing of an antibody to a protein that binds E3 ligase complex resulted in rapid ubiquitination and subsequent proteasome-dependent degradation of targeted protein(s). In summary, WO628 taught membrane bound extracellular E3 ligase as a target (e.g., one arm of a bsAb) and Shin taught the E3 ligase mediate mechanism of autophagy (e.g., protein degradation). For the reasons provided above, the combination of references as provided in the 35 USC 103 rejection above is considered to teach all of the limitations of claim 51. The Applicant’s arguments have been considered and were not found to be persuasive.
In summary, Applicant arguments have been thoroughly reviewed but are not persuasive. The rejection(s) of claim(s) 51-60 and 74-80 are maintained.
Conclusion
No claims are currently 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 AMY M CHATTIN whose telephone number is (571)270-0646. The examiner can normally be reached T-F 0600-1600 PST.
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/AMY M. CHATTIN/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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