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
Claim(s) 1-80 are pending.
The Amendment, filed on 15Dec2023, is acknowledged in which:
Claim(s) 1-50 are canceled by Applicant.
Claim(s) 51-80 are new.
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, 54-61, 63, 65, 68-80.
Domestic benefit to the PCT Application (30Oct2020) is applied for claims 52-53, 62, 64, and 66-67 as the PCT discloses E3 ligase arm Kd testing/results and SEQ ID NOs: 120-305 (but the Provisional does not).
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 24May2023 is/are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement(s) is/are being considered by the Examiner.
Specification
The disclosure is objected to because of the following informalities:
Table 3 in specification recites “Exemplary LC-CDR1, HC-CDR1…” but the table header column 3 recites “LC-CDR3”.
Table 6 is missing the title.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
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(s) 61-64 is/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.
Regarding claim(s) 61-64, are drawn to a bispecific antibody or antigen-binding fragment (‘derivative’) thereof that specifically binds either PD-L1 and E3 ligase.
Further the invention as disclosed in claim(s) 61-64 recite(s) “…the first binding domain binds to the same extracellular epitope as SEQ ID NO: (respective numbers)”. One of ordinary skill in the art would understand that the 6 CDRs of an antibody are responsible for antigen binding characteristics, including antigen bound and the epitope(s) on the antigen that are specifically bound. The claim does not disclose the structure associated with the claimed function. The instant disclosure does not provide a structure-function correlation that would allow for a person of ordinary skill in the art to envision light and heavy chain sequences, particularly in the CDR regions, such that the obtained structure would result in the claimed functions.
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Table 2: E3 ligase CDR combinations (note- only A5 is shown below, however Applicant discloses constructs A1-A43 in the instant specification full Table 2)
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Table 6: Kinetic parameter for anti-RNF43 A5 (E3 ligase arm) mutants
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The antibodies or antigen binding fragments thereof in Applicant disclosure Tables 1 and 5 (see above) with 100% sequence identity in the CDR regions of the heavy and light chain variable regions represents the antibodies and antigen binding fragments thereof that the applicant was in possession of at the time of filing. Further, the kinetics measurements in Applicant disclosure Table 7 (see above) for the “anti-RNF43 A5” construct E3 ligase arm (see Table 2 above) represents the Kd testing in the instant disclosure. It is noted that there would be support for 100% identity of the full complement of the six CDRs together with some percentages of identity in the framework region that would have been predictable.
Sela-Culang, Kunik, and Ofran (Fron. Immuno., Vol. 4, Article 302, Oct. 2013), hereinafter “Sela-Culang”, reviews the structural basis of antibody-antigen recognition in the state of the art. Naturally occurring antibodies typically consists of four polypeptide chains with two identical heavy (H) and two identical light (L) chains, with H and L chains liked to form a Y-shaped structure known as a Fab [e.g., pg. 4, Figure 2A-B]. The Fab has two variable (V) domains (VH and VL) that dimerize to form the Fv fragment which comprises the antigen-binding site of the antibody via six hypervariable loops (3 Heavy, 3 light) [e.g., pg. 3, “The Role of CDRs and their Definition”]. The six hypervariable loops are commonly termed complementary determining regions (CDRs) and are widely assumed to be responsible for antigen recognition [e.g., pg. 1, abstract] and the three-dimensional configuration of these CDRs form the antigen-recognition complex termed a paratope [e.g., pg. 3, “The Role of CDRs and their Definition”]. Despite the integrated effect of CDRs, antibodies can also be considered a modular system, composed of different elements (e.g., Fab, VH, VL) which may bind to an antigen on their own with the smaller fragments retaining affinity and specificity, which is of great potential for drug design [e.g., pg. 6, paragraph 2]. A person of ordinary skill in the art would understand that although the above basics of antibody-antigen binding are known, that the specifics of antibody structure (e.g., within the CDRs) that underlie the antigen recognition are not well characterized [e.g., pg. 1, “The Motivations for…”].
Further, Herold et al. (Nature Scientific Reports, 7:12276, 25 Sep 2017), hereinafter “Herold”, teaches that it should be emphasized that there is no correlation between experimentally determined change in antibody binding affinity and a given mutation and additionally that no such correlation is expected because antigen binding is “affected by each CDR loop differently” and changes thereto “can in principle affect antigen binding affinity in an unpredictable way” [e.g., pg. 14, paragraph 2]. Further, Herold asserts that multiple determinants regulate antigen affinity and the interactions with CDRs are complex [e.g., pg. 14, paragraph 3]. Herold further teaches that variable heavy chain (VH) mutations led to a decrease in binding affinity, with as much as 20-fold higher KD in the mutant versus wild type [e.g., pg. 4, paragraph 3], and summarizes the antigen binding KD differences based on point mutations in the VH or VL of an IgG antibody [e.g., pg. 6, table 1].
As further evidence, see Koenig et al. (PNAS, E486-E4995, January 5, 2017), which provides a large mutation analysis study where every amino acid in both variable regions are substituted with every other amino acid. In review of figure 1, the bottom half of each section (labeled VEGF) relates to the ability of the mutant to bind the original target, with blue meaning a reduced affinity and black meaning complete loss of binding ability. In VL-CDR1, for example, mutating any given residue to cysteine, which is encompassed by the instant claims (undefined sequence variability up to 3 amino acids or 5% sequence identity, depending on the claim language), resulted in reduced binding at 7 residues and a complete loss of binding (no longer binds same target) at 4 residues. That is, at 100% of positions, mutation to cysteine reduced or ablated the antibody’s ability to bind the target, even in the case of conservative mutations.
Thus, making changes to the CDR sequence of an antibody sequence is a highly unpredictable process and one skilled in the art could not a priori make any predications regarding such mutations with any reasonable expectation of success nor envisage the breadth of structurally unrelated CDR combinations that would still possess the required function(s).
As indicated by the art, a full complement of 6 CDRs are required for antigen binding and one cannot predict which CDR residues may be changed and still result in an antibody that binds PD-L1 and E3 ligase at the claimed epitope(s). Written description can be met if the claims recite the minimal structure that is needed to perform the function recited in the claims. Above, the art indicates that the 6 CDRs in an antibody are the minimal structure that binds to a target antigen. Specifically, Applicant claim(s) 61-64 would minimally need to recite the VH CDR1-3 and VL CDR1-3 sequence pair(s) (e.g., totaling 6 CDRs) that bind specific epitope(s) (e.g., which 6 CDR pair SEQ IDs bind which specific epitope), and provide evidence of epitope binding testing for claimed antibody/epitope pairs.
Claim Rejections - 35 USC § 112(b)
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.
Claim(s) 61-64 is/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 claims 61-64, the phrases “…wherein the first binding domain binds to the same extracellular epitope as SEQ ID NO: (respective number ranges)” (claims 61-62), and “wherein the second binding domain binds to the same extracellular epitope as SEQ ID NO: (respective number ranges), and SEQ ID NO: (respective number)” (claims 63-64), render the claim indefinite. Based on the language of claims 61-62, it is unclear if the limitation requires all recited SEQ ID NOs, a specific sub combination of SEQ ID NOs, or a single SEQ ID NO. Further still, for claims 63-64, the indefiniteness recited for claims 61-62 above apply, with the addition of being unclear if the “...and SEQ ID NO” portion requires the limitations of the range and the single SEQ ID NO recited, or if simply meeting the limitation of the single SEQ ID NO listed and not the range would be sufficient to meet the limitation. For the purposes of compact prosecution, the Examiner is considering a 100% sequence identity match to any SEQ ID NO recited in the claim, which binds E3 ligase (claims 61-62) or PD-L1 (claims 63-64), to meet the limitations thereof. The rejection may be overcome by amending to (1) specifically and clearly disclose the SEQ ID NO (e.g., scFv, Fab) or the SEQ ID NO set (e.g., 6 CDRS, or 1 VH and 1 VL) that the Applicant claims as the instant invention, or (2) cancel the claim(s).
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, 63, and 65-80 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”), Wurz et al. (Ther Adv Med Oncol 2016, Vol. 8(1) 4–31; hereinafter “Wurz”), and Li (CN107827990-A, published 23Mar2018).
Regarding claims 51, 54-58, 65, 68-72, 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 and 66-67, which depend from claims51 (claims 52), claims 51-52 (claim 53), claim 65 (claim 66), or claims 65-66 (claim 67), 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 of 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, 73, and 75-76, which depends from claim 51 (claim 59), claim 65 (claim 73), or 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 63, which depend from claim 51, the teachings of WO628, Shin, Clague, and/or Wurz apply as recited above for claim 51.
WO628, Shin, Clague, and Wurz do not teach the claim SEQ ID NO(s).
A sequence search of Applicant designated anti-PD-L1 construct B1 (SEQ ID NOs: 106 (VL) and 107(VH)) returned a 100% sequence identity match [If , Anti-PD-L1 monoclonal scFv antibody with linker, SEQ ID 7]:
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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 teachings of a 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 multiple TAA targets for cancer immunotherapies (e.g., EGFR and PD-1) teachings of Wurz, and the PD-L1 arm VL and VH sequences taught by Li, in the context of designing a monoclonal bispecific (e.g., anti-PD-L1/E3) antibody 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 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].
Conclusion
No claims are currently allowed.
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/AMY M. CHATTIN/Examiner, Art Unit 1647
/ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1600