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 .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The present application is drawn from PCT/US2022/014938, filed 2/2/2022; and claims benefit under 35 U.S.C. 119(e) to U.S. Provisional applications 63/274288, filed 11/1/2021, 63/217470, filed 7/1/2021 and 63/145336, filed 2/3/2021.
Election/Restrictions
Applicant’s election without traverse of Group I, encompassing claims 1-2, 6, 11, 16, 22, 24-26, 29-30, 36, 44, 62 and 64-65, in the reply filed on 5/11/2026 is acknowledged. Claims 39-41, 54, 56 and 63 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Groups II-IV, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 5/11/2026. Applicant’s species election in the reply filed on 5/11/2026 is acknowledged. Specifically, applicants elected the species “ZNRF3-55” wherein the antibody is “bispecific” and further binds “EGFR”. Claim 30 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 5/11/2026.
Status of Claims
Claims 1-2, 6, 11, 16, 22, 24-26, 29-30, 36, 39-41, 44, 54, 56 and 62-65 are pending; claims 30, 39-41, 54, 56 and 63 are withdrawn, claims 1-2, 6, 11, 16, 22, 24-26, 29, 36, 44, 62 and 64-65 are being examined on the merits.
Claim Objections
Claim 22 is objected to because of the following informalities: Claim 22 recites a VL comprising (a) a light chain complementarity determining region…”. As the claim previous recited (a) for a VH and (b) for a VL, it is believed that the extra “(a)” is a typo. Appropriate correction is required.
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.
Claims 6, 16, and 56 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 6, 16, and 56, the phrase "optionally" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claims 22 and 24-25 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.
Specifically, claim 22 recites a multispecific binding protein which comprises a VH comprising HCDRs 1-3 and a VL comprising LCDRs 1-3 of any one of the listed antibodies, though the claim does not explicitly define the residues of the larger VH or VL sequences that correspond to the CDRs. It is known in the art that various numbering schemes define the CDRs of an antigen binding domain differently. The specifications describe this scenario (specs., pg. 23, lines 17-34). For example, the Kabat numbering scheme identifies the CDR residues (e.g., VH CDR1) differently than the Chothia system. It is also known in the art that alternative systems exist, such as IMGT and others, whereby the resides of the CDRs are differentially defined. As numerous numbering systems exist, and more schemes may be introduced (or modified) in the future, whereby each scheme defines the CDR residues differently, it is indefinite to describe the CDRs by “any definition known in the art” (see pg. 23, line 34); as the types of numbering schemes known in the art is open-ended and subject to change. Claim 22 does not claim the antibody, or multispecific binding protein, by the full VH and VL sequences. If this were the case, the necessary residues of the CDRs are present regardless of which number scheme is applied. Instead, claim 22 attempts to claim a multispecific antibody solely by the CDRs of the full VH and VL sequences, whereby the framework regions are undefined and variable; therefore the CDR residues must be explicitly defined. The skilled artisan, attempting to determine the limitations of the claim, must know what residues of the full VH or VL constitute the necessary CDRs that meet the limitations of the claim. As different numbering schemes are known in the art, and the different numbering schemes, applied to the various species of antibodies listed, would result in different amino acid sequences for the claimed CDRs, it is unclear what the metes and bounds of the necessary structural limitations of the antibodies of the claim are. Thus claim 22 is rejected for indefiniteness.
Whereas claim 26, which depends from claim 22, overcomes the issue of indefiniteness by requiring the full VH/VL sequences, with no substitution residues, claims 24-25 also depend from claim 22, yet fail to rectify the issue of indefiniteness. Claims 24-25 allow up to 15% divergence from the referenced VH or VL amino acid sequences, and which may include alternative residues in the CDRs. Thus, the CDR residues are not explicitly defined and it is unclear what the metes and bounds of the claimed CDR sequences of the antibodies are. Thus, claims 24-25 are also rejected.
Claim 26 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.
Claim 26 recites a binding molecule comprising a VH or VL domain “comprising an amino acid sequence” of any of the listed antibodies. Use of the terminology “an amino acid sequence” reads on as little as 2-3 amino acids of any of the claimed sequences. That is, the claims do not require the full length sequence identifiers, and it is not close-ended and defined by the recited sequences; rather, that any 2-3 consecutive amino acid residues constitute “an amino acid sequence of”. Thus, in claim 26, where the claim recites a VH comprising an amino acid sequence of, for example, RNF43-104, it is unclear which amino acid residues of RNF43-104 are required, as all that is claimed is an amino acid sequence of RNF43-104. This is repeated for the VL domains, such that it is unclear what amino acid residues are required from the VL domains of the recited antibody species. As the structure of the binding molecule of claim 26 is limited by the VH/VL of the recited antibodies, and the claim language is unclear with regard to how the antibody VH/VL sequences are defined, the metes and bounds of the claims are unclear, and claim 26 is rendered indefinite. It is suggested that applicants use definitive language such as “comprising the amino acid sequence of SEQ ID NO”, when referencing the required amino acid sequences that encode the required domains of the claimed product.
Claims 22 and 24-26 are rejected on the basis that it contains an improper Markush grouping of alternatives.
See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of alternative anti-RNF43 and/or anti-ZNRF3 antibodies is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
It is known in the art that the amino acid residues that define the structure of the complementarity determining regions (CDR) of an antibody, or antigen-binding molecule, are critical to the functional specificity and affinity of the antibody for the target antigen, such that the 3 CDRs of the heavy and light chains form the antigen-binding domain of the antibody paratope, where critical contacts with the antigen epitope occur during binding (for review see MacCallum et al., 1996). Further, it is known that the heavy chain CDR2 and CDR3 regions contain most of the residues that have a major contribution to the binding free energy of the antigen binding domain (Dondelinger et al., 2018; pg. 8, col. 1, para. 2 – col. 2, para. 1).
Regarding the “single structural similarity” of a proper Markush grouping, the
alternatives must share a substantial structural feature from which the common use flows. In the case of the instant antibodies, the common functionality of binding RNF43 or ZNRF3 would flow from the CDRs. Applicants present 100+ alternative embodiments of antibodies, wherein there are numerous embodiments with distinct CDR sequences. For example, applicant’s elected species, ZNRF3-55, has a VH of SEQ ID NO: 391 and a VL of SEQ ID NO: 392 (specs., pg. 125). Comparing the VH/VL sequences of ZNRF3-55 to the first embodiment listed, RNF43-104 (VH-SEQ ID NO: 35; VL-SEQ ID NO: 36), reveals that the VH of ZNRF3-55 shares < 50% amino acid sequence identity to RNF43-104 and the VL of ZNRF3-55 shares < 60% sequence identity to the VL of RNF43-104. This includes sharing 0/5 HCDR1 residues, 4/17 HCDR2 resides and 0/12 HCDR3 residues. Thus, there is no shared similarity in the VHs of ZNRF3-55 and RNF43-104, as the HCDRs 1-3 of the two antibodies are entirely distinct. Alternatively, when comparing the elected species, ZNRF3-55, to an alternate species with the “ZNRF3” moniker, such as ZNRF3-101 (VH-SEQ ID NO: 239; VL-SEQ ID NO: 240); there is < 50% shared amino acid sequence identity in the corresponding VHs and < 70% shared sequence identity in the VLs. This includes sharing 0/5 HCDR1 residues, 6/17 HCDR2 resides and 2/12 HCDR3 residues. Thus, there is no shared similarity in the VHs of ZNRF3-55 and ZNRF3-101, as the HCDRs 1-3 of the two antibodies are entirely distinct. Thus it is clear that the alternative antibody embodiments are not, for example, humanizing a common set of CDRs, or affinity maturation of a single antibody species, (i.e. proper Markush groupings of antibody species); rather, the alternative embodiments appear to be structurally distinct antibodies. Indeed, Example 1 of the specifications (pg. 61, line 15) discloses the antibodies were individually derived from rats and rabbits, including isolating various B-cell clones from immunized animals, whereby it is known that variant antibodies with quite disparate structural sequences may be obtained, and would not be a proper Markush grouping; each B-cell clone, and the antibody it produces, is a distinct invention.
Section 803.04 of the MPEP states that “sequences that encode different proteins are structurally distinct and are deemed to constitute distinct and independent inventions.” The 100+ variant anti-RNF43 and/or anti-ZNRF3 antibodies described are not all members of the same recognized physical or chemical class or the same art-recognized class, as the disclosed antibodies are novel. Also, the 100+ variant antibodies described do not share a single structural similarity from which the common functionality of binding RNF43 and/or ZNRF3 naturally flows, rather the critical HCDR regions are structurally distinct from each other in amino acid sequence. Therefore, the 100+ distinct species of antibodies do not comprise a “proper” Markush grouping. The elected species, comprising the VH of SEQ ID NO: 391 and the VL of SEQ ID NO: 392, has been searched. However, as the alternative species of claims 22 and 24-26 are not a proper Markush grouping, the examiner has not extended the search beyond the elected species, as per MPEP section 803.03(III)(C)(2).
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use. However, it is also noted that the present application is restricted to a single invention of Group I, and new claims to structurally distinct products will not read on the elected invention, or species election, of the requirement for restriction of 2/11/2026.
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.
Claims 22 and 24-26 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.
Claims 24-26 recite an anti-RFN43 or an anti-ZNRF3 antibody comprising a heavy chain variable region (VH) having an amino acid sequence with 85% or greater sequence identity to any of the listed antibody species, and a light chain variable region (VL) having an amino acid sequence with 85% or greater sequence identity to any of the listed antibody species. Claims 24-26 depend from claim 22, which recites an anti-RFN43 or an anti-ZNRF3 antibody comprising the HCDRs 1-3 or LCDRs 1-3 of any of the antibody species listed in the claim. As described above, claim 22 does not explicitly define what residues of the VH or VL constitute the CDR residues for any species of antibody listed as numerous CDR numbering schemes exist, which would differentially define the residues that constitute the CDRs. Thus, the CDRs of claim 22 are undefined. The elected species, ZNRF3-55, has a VH of instant SEQ ID NO: 391 and a VL of instant SEQ ID NO: 392 (specs., pg. 125). The VH of SEQ ID NO: 391 is 121 amino acid residues; the VL of SEQ ID NO: 392 is 106 residues. Thus, the claims allow for up to 18 amino acid differences within the 121 amino acid VH regions, and whereby the substitutions may occur within the undefined CDR regions. There are 20 alternative amino acids that may be substituted at up to 18 residues, in any combination, at any location in the VH; thus the 360 alternative amino acid substitutions may be made in any combination of residues throughout the 121 amino acid VH domain. Thus, it is clear that the claim encompasses a vast number of alternative embodiments. For example, substituting any one of 20 amino acids, across 10 consecutive residues, in any order, allows for 184,756 different combinations. In this case there are 121 residues from which any 18 non-consecutive residues may be selected to apply the various combinations; thus there are millions of combinations of amino acids substitutions encompassed by limitation of “an amino acid sequence at least 85% identical to SEQ ID NO: 391.” Further, allowing 18 mutations encompasses mutating within a CDR, or mutating an entire CDR region, of any one of HCDRs 1-3, depending on how the CDRs are defined (this is why an explicit definition of the CDR residues of any antibody sequence is necessary). Similarly, the VL region of SEQ ID NO: 392 comprises a minimum of 106 amino acids residues; thus, the VL regions may have up to 15 amino acid differences within the VL sequence, and whereby the substitutions may occur within the LCDRs, as its unclear what residues constitute the LCDRs. The broadest reasonable interpretation of claims 22 and 24-26 is to a sub-genus of an anti-ZNRF3-55 variant antibodies comprising HCDRs 1-3 and LCDRs 1-3 which have unidentified mutated residues. Claim 26 also allows for matching a selected VH or VL with a corresponding variable domain wherein the entire framework regions may be different. Claim 26 also relies on the CDRs of the corresponding variable domain being those of claim 22, whereby the specific residues of the CDRs are not delineated, and are thus open to interpretation. Thus, the claims are interpreted to encompass a vast number of variant peptides, comprising a sub-genus of any one of the variable domains of instant SEQ ID NOs: 391 and/or 392, with no guidance as to which residues may be substituted, or with which amino acids, and wherein the substitutions may occur anywhere within any of the CDRs of each variable domain, such that the sub-genus of variant embodiments comprise unidentified CDR sequences. Further, the scope of the sub-genus of peptides extends to each one of the VH or VL domains of the 100+ distinct antibodies recited in the claims. That is, each distinct antibody species encompasses its own sub-genus of variant antibodies, as claimed.
In support of the claimed genus of variants of the elected species, the specification disclose only ZNRF-55. The specifications describe the process of affinity maturation (pg. 47, lines 20-34); however examples of affinity matured ZNRF-55 are not reduced to practice, and it is not made clear which CDR residues may be substituted, and with which amino acids. As described above, the differences in sequence identity between different species of antibodies listed in the claims is significant. For example, the VH of ZNRF-55 has only 46% sequence identity to the VH of RNF43-104 (56/121 matching residues). Thus, the different species of antibodies listed in claims 22 and 24-26 are not examples of variants of each other; rather they constitute distinct alternative species of antibodies, whereby each species may be mutated within 85% sequence identity of its clone sequence. Thus, no guidance is provided as to which residues in any one of the recited antibodies may be substituted, or with which alternative amino acids. Further, no CDRs are described within the variable domains, and no guidance is provided as to which of the CDR residues may be mutated with alternative amino acid residues. When determining the representative examples and the art, it is important to consider whether there is evidence of a singular shared structural feature which imparts the defining property of the claimed genus, and which would necessarily be present in every species of the claimed genus. In this case, only 100+ distinct antibodies are disclosed, which do not share structural identity, and no variants of any one of them, which are “at least 85%” identical in sequence to the original clone, are disclosed. Further there is no teaching of where the substitutions may be made in variant embodiments, or what the defining structural feature of all claimed species are required to have, in order to impart the required properties of functionally binding a transmembrane E3 ubiquitin ligase.
Regarding the state of the art; it is known in the art that the antigen binding domain of an antibody requires the 6 CDRs of the heavy and light chains, whereby the 3 CDRs of the heavy chain and the 3 CDRs of the light chain are structurally inter-dependent in forming the unique binding pocket of the antibody paratope region; and thus the CDRs constitute critical aspects of the antibody paratope and ultimately impart the paratope-epitope binding functionality with regard to specificity and affinity (for review see MacCallum et al., 1996). However, the structure-to-function correlation continues to be highly unpredictable. For example, Chen et al., (1992) teaches that a single amino acid substitution in the VH CDR2 of PC-specific T15 antibody could increase, decrease or ablate binding the target antigen (abstract, Fig. 3), and this occurred in an unpredictable manner based on which residue was mutated. Similarly, a single point mutation in the heavy chain CDR3 region of the high affinity anti-VEGF antibody G6.31, could in some cases enhance, or otherwise completely ablate binding to the target antigen, and this also occurred in an unpredictable manner (Koenig et al., PNAS, 2017). That is, only screening each mutation individually provided insight as to the resulting changes in functionality. In some cases this extends even beyond the CDRs. Within the framework regions, Koenig et al. (PNAS, 2017) teaches that various amino acid point mutations can increase or decrease binding or neutralization capacity. Some amino acid residues are more tolerant to substitution, while other “conserved” residues are less tolerant, such that a single amino acid substitution may defunctionalize the antibody (pg. E487, Fig. 1). Thus, while antibodies share certain characteristics such as Fc regions or hinge regions, these regions are not correlated with the binding function of the antibody. Conversely, the hyper-variable regions, comprising the complementary set of 6 CDRs, are well established in the art as the portion of the binding regions which impart the specificity of the antibody; and yet, there is no way to look at an amino acid sequence and envision, a priori, whether the combination of six CDRs will bind a particular epitope, even when the CDRs are highly related, without teachings of the basic shared amino acid residues that are sufficient to impart functional binding across all variants. Further, even when provided with several related antibodies that bind the desired target, this does not represent the astronomical and potentially unknowable breadth of all possible amino acid sequences which will result in the desired binding properties. This is exemplified by the Court decision in Abbvie (Abbvie v Janssen 759 F.3d 1285 (Fed. Cir. 2014)), where Abbvie developed over 200 antibodies that shared 99.5% identity in the variable regions (pg. 7) and which bound the target, but in no way allowed one to envisage the unique structure of Centocor’s antibodies which bound the same target but shared only 50% sequence similarity (see table on pg. 11). Thus, when claiming a genus of antibodies based on their binding to a common target, the representative examples must cover the full scope of structural variabilities which encompass all species variants that would bind the target.
Section 2163(II)(A)(3)(a)(ii) of the MPEP states that the written description for a claimed genus may be satisfied through either a) a representative number of species, or b) disclosed correlation between function and structure. Here the applicants do not provide any variants of the (100+) claimed embodiments, in which alternative mutations were made, which were reduced to practice; nor do they identify the shared structural properties of the variants, such as the CDR residues, that would define the genus beyond the desired functionality. Currently the essential property of binding RNF43 or ZNRF3 is imparted by the specific variable domain combinations embodied in the Table IV (pg. 87), with un-delineated CDR sequences, that have been reduced to practice; and that accounts for only a small fraction of the millions of potential embodiments, as claimed. Specifically, the physical features (or amino acid residues encoding said features) which impart the property of binding the same epitope of ZNRF3, as does the elected species ZNRF3-55, should be disclosed; and the said shared structural feature should be disclosed for each of the 100+ distinct antibody species of claims 22 and 24-26. Further, a description of the type and number of amino acid residue substitutions that may be made at such identified positions within the sequence, that result in “at least 85%, at least 90%, or at least 99%” sequence identity to a selected clone sequence, would be essential in determining the degree of variability that may be allotted in total sequence identity. This lack of definition complicates the determination of the boundaries of the claimed genus with regard to which, as of yet unidentified, species variants (variable domains with 85%, 90% or 99% identical sequences) would be anticipated, a priori, by one skilled in the art, to fall within the scope of the claims. Without the identification of the necessary shared structural properties of all species variants that fall within the scope of the genus, it may be that an embodiment species comprising the VH and VL of, for example, the ZNRF3-101 antibody, with < 60 % sequence identity in either the VH or VL to ZNRF3-55 would still bind to ZNRF3; or conversely, that antibodies with > 99% sequence identity, but comprising a deleterious mutation in a CDR region would lose functional binding to ZNRF3.
In view of this uncertainty and the lack of a representative number of examples of the claimed genus, claims 22 and 24-26 are rejected for lack of adequate written description support.
Claim Rejections - 35 USC § 102
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, 11, 16, 36, 44 and 62 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Luca et al., (from IDS; WO 2020139950; published 7/2/2020).
Luca teaches bispecific antibodies for membrane clearance of target receptors (title). Specifically, Luca teaches ubiquibodies that are able to target cell surface receptors on a target cell, wherein the ubiquibodies comprise 1) variable domains of antibodies that specifically bind a target cell surface receptor, and 2) variable domains of antibodies that specifically bind a transmembrane E3 ubiquitin ligase (TMUL; abstract). Luca teaches the ubiquitination proteosome pathway mediates protein degradation through the actions of E1 and E2 enzymes and E3 ligases (para. 0105). Luca teaches, in this example, biologics are developed that hijack the outside-in ubiquitination function of TMULs to destroy their targets outright, resulting in knock down therapeutic receptor targets (Example 2, pg. 24, para. 0120). Further, “bispecific ligands that cross-link TMULs to the ECDs of receptors identified above are engineered in order to mark the receptors for ubiquitin-mediated proteolysis; this approach enables targeting virtually any receptor in its native context and circumvents the need to cross the membrane, which will overcome nearly all of the obstacles that previously impeded the development of proteolysis targeting drugs,” (pg. 25, para. 0122; see also Fig. 1). Regarding the TUML, the targeted ligand may be ZNRF3 or RNF43 (pg. 28, claim 5). Regarding the cell surface target protein, Luca teaches PD-L1, EGFR or HER2 as suitable targets (pg. 3, para. 0015). Further, Luca reduces to practice an embodiment of a bispecific molecule targeting ZNRF3 and Frizzled (i.e. FZD).
Regarding claims 1-2, 6, 11, 16 and 36; the anti-ZNRF3/anti-FZD bispecific antibody of Luca anticipates the multispecific binding protein of instant claim 1, and wherein the multispecific binding protein reduces the level of the cell surface protein of instant claim 2. The antibody of Luca is a bispecific antibody and thus anticipates instant claim 6. The bispecific antibody targets ZNRF3 and FZD and thus anticipates instant claims 11, 16 and 36.
Regarding claims 44 and 62; Luca claims a nucleic acid encoding the bispecific antibody (pg. 28, claim 6), a host cell (pg. 28, claim 18), a pharmaceutical composition (pg. 29, claim 14), as well as a kit (pg. 29, claim 16). Thus, Luca anticipates instant claims 44 and 62.
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.
Claims 1-2, 6, 11, 16, 29, 36, 44, 62 and 64-65 are rejected under 35 U.S.C. 103 as being unpatentable over Luca et al., (from IDS; WO 2020139950; published 7/2/2020) and Boontanrart et al., (WO 2015/164392; published 10/29/2015).
The reasons why claims 1-2, 6, 11, 16, 36, 44 and 62 are anticipated by the bispecific construct of Luca are described above. However, Luca does not teach wherein the anti-ZMRF3 or anti-RNF43 antibodies have a binding affinity of less than 1 nM.
Boontanrart et al. teaches novel anti-RNF43 antibodies (abstract). Boontanrart teaches anti-RNF43 antibodies were generated by inoculating a mouse with rhRNF43-Fc protein, isolating a single cell suspension of B cells (pgs. 101-102, Example 6). Boontanrart teaches the affinity of select antibodies for hRNF43 protein was determined using surface plasmon resonance, and the selected antibodies exhibited affinities for hRNF43 in the nanomolar range (pg. 103, lines 8-23). Figure 5 displays the results of the assessment of binding affinity of the antibodies for hRNF43. Figure 5A demonstrates examples of select antibodies including, for example, clone SC37.28, which has a Kd of 0.3 nM. Thus, Boontanrart teaches anti-RNF43 antibodies which bind to RNF43 with a binding affinity of less than 1 nM. Boontanrart teaches the antibodies may be used in multivalent constructs, including bispecific or trispecific antibodies (pg. 37, lines 11-12). Boontanrart teaches the antibodies may be polyclonal, whereby they are generated from mouse, rat or rabbit by immunizing and obtaining antibodies from the serum (pg. 26, lines 4-6).
It would have been obvious to one of skill in the art at the time of the invention to substitute the RNF43 antibody of the bispecific ubiquibodies of Luca to instead comprise the anti-RNF43 antibody clone SC37.28, of Boontanrart. One would have been motivated to do so in order to generate ubiquibodies which have higher affinity for the target protein RNF43, such that the degradation of the cross-linked cell surface protein is improved. There would have been a reasonable expectation for success given that the TMUL component of the ubiquibodies are antibody variable domains (i.e. scFv) that target E3 ubiquitin ligase, and include ZNRF3 or RNF43, as taught by Luca, and that the SC37.28 clone is an anti-RNF43 antibody for use in bispecific or multi-specific constructs, as taught by Boontanrart. Thus, the invention as a whole was prima facie obvious to one of skill in the art at the time the invention was made.
Regarding claim 29, Boontanrart teaches the antibodies are derived from B cells clones isolated from an immunized mouse; however, that polyclonal antibodies may be obtained by inoculating a rat or rabbit with the human RNF43 antigen, thus resulting an B cell clones expressing rat anti-human FNF43 antibodies. Thus, the combination bispecific antibodies of Luca and Boontanrart make obvious instant claim 29.
Regarding claims 64-65; the combination anti-RNF43/anti-FZD bispecific antibody of Luca and Boontanrart comprises the anti-RNF43 antibody, or scFv, of clone SC37.28, which has a binding affinity for RNF43 of 0.3 nM (Fig. 5). Thus, the combination bispecific of Luca and Boontanrart make obvious instant claims 64-65.
Conclusion
No claims are allowed.
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/JAMES RYLAND MELCHIOR/Examiner, Art Unit 1644
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642
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