DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 06/15/2026 has been entered.
The claim listing filed June 15, 2026 is pending.
Claims 2, 3, 5, 7, 12-20, and 26-28 are canceled.
Claim 29 is new.
Claims 1, 4, 6, 8-11, 21-25, and 29 are pending.
Claims 1 and 21 are independent claims.
Claims 8-10 and 21-24 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions.
Claims 1, 4, 6, 11, 25, and 29 are currently under consideration.
In view of the applicant’s amendment filed on June 15, 2026, the following rejections are set forth.
Claim Rejections - 35 USC § 112
Written Description
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.
Claims 1, 4, 6, 11, 25, and 29 stand 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 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 for the reasons of record.
In view of the Applicant’s election filed 09/01/2025, the instant claims are drawn to a heterobifunctional molecule comprising a first and a second binding domain, wherein
i) the first binding domain is capable of specific binding to an extracellular portion of a transmembrane E3 ubiquitin ligase; and
ii) the second binding domain is capable of specific binding to an extracellular portion of a transmembrane protein,
wherein the first binding domain and the second binding domain each comprise a VHH domain of a heavy chain only antibody
wherein simultaneous binding of the heterobifunctional molecule to the transmembrane E3 ubiquitin ligase and the transmembrane protein results in lysosomal degradation by ubiquitination and internalization of the transmembrane protein,
wherein the heterobifunctional molecule is a bi-specific antibody, and
wherein the transmembrane E3 ubiquitin ligase is RNF149, and
wherein the transmembrane protein is a receptor.
It is noted that as the claim is currently written, the heterobifunctional molecule of the instant invention may or may not comprise a linker between the first and second binding domains.
The Applicant has disclosed a single species heterobifunctional molecule, bi-VHH (VHH Alpha - (G4S)3 - VHH E6) (e.g. see page 66, line 2). This bi-VHH comprises two VHH-based antigen binding domains that bind to epitope tags fused to the extracellular domains of both the targets (E6 tag) and E3 ligases (Alpha tag), respectively (e.g. see page 66, lines 14-30).
The Applicant has also disclosed that a preferred anti-E6 VHH comprises a CDR3 sequence that has at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 99 and a preferred anti-alpha VHH comprises a sequence that has at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 98 (e.g. see page 56, lines 24-29). The amino acid sequences of the anti-E6 VHH and the anti-alpha VHH are based on the teachings of Ling et al. (2019, Molecular Immunology, 114(July), 513-523) and Gotzke et al (2019, Nature Communications, 10(1), 1-12), respectively (e.g. see page 56, lines 15-23).
It is noted, though, that the disclosed species of heterobifunctional molecule is not encompassed by the instantly claimed genus of heterobifunctional molecules. This is because the instantly claimed genus of heterobifunctional molecules encompass heterobifunctional molecules that specifically bind to RNF149 and a transmembrane receptor protein but the genus does not encompass heterobifunctional molecules that specifically bind to tags fused to RNF149 and a transmembrane receptor protein.
Therefore, the Applicant has not disclosed a single heterobifunctional molecule with sufficient structure that binds specifically to: (a) RNF149 and a transmembrane receptor protein or even (b) an alpha tag fused to RNF149 and a E6 tag fused to a transmembrane receptor protein. Thus, the Applicant has not disclosed a single species of heterobifunctional molecule of the instant invention.
Regarding how to first and second binding domains of the heterobifunctional molecule are meant to be joined together, the Applicant has disclosed that the two binding domain can be coupled directly together, or there can be a linker present between the two binding domains, preferably a linker as specified herein (e.g. see page 44, lines 10-40). The Applicant has disclosed that the preferred linker is a peptide linker, specifically, (GGGGS)n, wherein n is preferably 1, 2, 3, 4, 5, 6, or 7, preferably wherein n is 3 or 5 (e.g. see page 6, lines 35-38).
The Applicant has also disclosed that linker may be any suitable linker known in the art (e.g. see page 45, lines 1-10). Preferably, the linker is a Gly-Ser sequence. The skilled person knows how to select the linker, dependent on the first binding domain and the second binding domain. The linker may be e.g. a very flexible linker in the form (GGGGS)n, (GGS)n, and (G)n to more rigid linkers of the form (EAAAK)n, (SPKKKRKVEAS)n (SEQ ID NO: 81), or (SGSETPGTSESATPES)n (SEQ ID NO: 82), or (KSGSETPGTSESATPES)n, (SEQ ID NO: 83), or any variant thereof, wherein n preferably is between 1 and 7, i.e. 1, 2, 3, 4, 5, 6, or 7. The linker preferably has a length between 2 and 30 amino acids, or between 3 and 23 amino acids, or between 3 and 18 amino acids (e.g. see page 45, lines 1-10).
The Applicant has only described the application of one example of a heterobifunctional molecule comprising a first and second binding domain (bi-VHH (VHH Alpha - (G4S)3 - VHH E6) (e.g. see page 66, line 2)). This molecule comprises a (G4S)3 which permits binding of the two targets.
When given the broadest reasonable interpretation in light of specification, the heterobifunctional molecules of the instant invention are defined broadly to be any heterobifunctional molecule that is a bi-specific antibody comprising: i) any first VHH-based binding domain that is capable of specific binding to an extracellular portion of RNF149; and ii) any second VHH-based binding domain that is capable of specific binding to an extracellular portion of a transmembrane receptor protein, wherein simultaneous binding of the heterobifunctional molecule to RNF149 and the transmembrane receptor protein results in in lysosomal degradation by ubiquitination and internalization of the transmembrane receptor protein.
It is noted that no claim indicates any specific structure for the genus of heterobifunctional molecules as currently claimed.
It is also noted that as the claim is currently written, the heterobifunctional molecule of the instant invention may or may not comprise a linker between the first and second binding domains.
Claim 6 limits the transmembrane receptor protein is LRP6.
Claim 11 limits the heterobifunctional molecule to that which comprises a linker between the first binding domain and the second binding domain.
Claim 25 limits the transmembrane receptor protein to one that is involved in cancer.
Claim 29 limits the VHH domain of a heavy chain only antibody to that which is derived from the camelidae family.
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus (Federal Register, Vol. 66, No. 4, pages 1099-1111, January 5, 2001, see especially page 1106 column 3). In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted:
“A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.”). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”
Artisans are well aware that knowledge of a given antigen (for instance RNF149 and a transmembrane domain) provides no information concerning the sequence/structure of antibodies that bind the given antigen. For example, Edwards et al. (J. Mol. Biol., 2003, 334:103-118, a reference of record) teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences spanning almost the entire heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines, and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well, see entire document).
As such, it does not seem possible to predict the sequence/structure of an antibody that binds a given antigen, as there does not appear to be any common or core structure present within all antibodies that gives rise to the function of antigen binding. Further, given data, such as that of Edwards et al., indicating the diversity of sequences in a population of antibodies that bind to a given antigen, no number of species appears to reasonably representative of the breadth of the genus of antibodies that bind the given antigen.
It should be pointed out that it is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (Janeway Jr et al., Immunology, 3rd Edition, 1997 Garland Publishing Inc., pages 3:1-3:11.see entire selection, a reference of record).
It is noted that examples of antigen binding domains comprising a heavy chain only antibody (i.e. less than six CDRs) certainly do exist in the literature, but those antibodies generally comprise unique structures such as the VHH domains of camelids. De Genst et al. 2006 (Dev Comp Immunol; 30:187-98, a reference of record) teach that the antigen binding domains found in camelids share some similarities to human heavy chain variable regions (VH) of the VHIII family, but there are notable differences in framework 2 and the CDRs. In particular, CDRs 1 and 3 are generally extended in length (De Genst, p. 188, 2nd column). In addition, CDR1 and CDR3 are frequently tethered by a disulfide bond. Also, there are residues in the framework that are important for avoiding pairing with VL (De Genst, p. 188, paragraph bridging 1st and 2nd columns). De Genst ultimately teaches that “[a]s a consequence, the canonical loop structures found in the first and second variable hypervariable region of human and mouse VH are rather exceptional for the corresponding loops in VHHs . . ." (De Genst, p. 188, 2nd column and Fig. 3).
Thus, based upon the prior art, skilled artisans would reasonably understand that it is the structure of the CDRs within an antibody, including a VHH-based antibody, which gives rise to the functional property of antigen binding, whether that be a full set of six CDRs in the case an antibody comprising a VH and a VL or a set of three CDRs in the case of a heavy chain only antibody (VHH). The epitope to which said CDRs bind is an inherent property which appears to necessarily be present due to conservation of critical structural elements, namely the CDR sequences themselves.
This applies to the instant invention which is drawn to a genus heterobifunctional molecules that are bi-specific VHH-based antibodies that bind to RNF149 and a transmembrane receptor.
Regarding the subgenera of heterobifunctional molecules that comprise a linker between the first and second antigen binding domains, BenchChem Technical Support Team 2026 (BenchChem. Validation & Comparative. “A Head-to-Head Comparison of LYTAC Linker Chemistries: A Guide for Researchers”) teach the strategic design of Lysosome-Targeting Chimeras (LYTACs) is paramount for achieving potent and selective degradation of extracellular and membrane-bound proteins (e.g. see page 1, first paragraph). BenchChem Technical Support Team also teach that a critical component of this design is the chemical linker that connects the target-binding moiety to the lysosome-targeting ligand (e.g. see page 1, first paragraph).
LYTACs are heterobifunctional molecules that hijack the endosomal-lysosomal pathway to degrade proteins of interest (POIs) (e.g. see page 1, second paragraph). They consist of a ligand that binds to a POI and another ligand that engages a lysosome-shuttling receptor. The linker connecting these
two components is not merely a spacer but plays a crucial role in the efficacy, selectivity, and physicochemical properties of the LYTAC. The composition, length, and flexibility of the linker
can significantly impact the formation of a productive ternary complex between the POI, the
LYTAC, and the lysosome-shuttling receptor, ultimately influencing the efficiency of protein
Degradation (e.g. see page 1, second paragraph).
The design of the linker is a multifaceted challenge that is paramount to the success of a
LYTAC therapeutic (e.g. see page 7, first paragraph under “Conclusion and Future Directions”). As the compiled data suggests, linker chemistry and length can have a dramatic impact on degradation efficacy. The DNA aptamer-based LYTACs demonstrate that linker length is a critical parameter, with a 5-bp extension enhancing HER2 degradation, while longer extensions were detrimental. M6Pn-polypeptide linkers showed robust EGFR degradation irrespective of being "short" or "long," suggesting that for this type of linker, achieving a certain threshold of multivalency might be more critical than the precise length (e.g. see page 7, first paragraph under “Conclusion and Future Directions”). The continued exploration of novel linker chemistries, including variations in rigidity, hydrophilicity, and metabolic stability, will be crucial for optimizing LYTAC performance (e.g. see page 7, second paragraph under “Conclusion and Future Directions”).
Thus, the art teaches that selecting a proper linker for connecting the first and second binding domains of a LYTAC or the heterobifunctional molecule of the instant invention is unpredictable and does not guarantee target binding or lysosomal degradation by ubiquitination and internalization of the target transmembrane receptor protein.
As noted above, the Applicant has not disclosed a single species of heterobifunctional molecule of the instant invention. The Applicant has only disclosed a single species heterobifunctional molecule, bi-VHH (VHH Alpha - (G4S)3 - VHH E6) which binds to epitope tags fused to the extracellular domains of both the targets (E6 tag) and E3 ligases (Alpha tag), respectively, and comprises a (G4S)3 linker between the first and second binding domain.
Such a disclosure does not serve to provide sufficient written description of the claimed genus of heterobifunctional molecules that are bi-specific antibodies comprising: i) a first VHH-based binding domain that is capable of specific binding to an extracellular portion of RNF149; and ii) a second VHH-based binding domain that is capable of specific binding to an extracellular portion of a transmembrane receptor protein, wherein simultaneous binding of the heterobifunctional molecule to RNF149 and the transmembrane receptor protein results in in lysosomal degradation by ubiquitination and internalization of the transmembrane receptor protein. The disclosure also does not serve to provide sufficient written description of the claimed subgenera which may or may not comprise a linker between the first and second binding domains.
It is noted that the disclosed species of heterobifunctional molecule is not encompassed by the instantly claimed genus of heterobifunctional molecules. This is because the instantly claimed genus of heterobifunctional molecules encompass heterobifunctional molecules that specifically bind to RNF149 and a transmembrane protein but the genus does not encompass heterobifunctional molecules that specifically bind to tags fused to RNF149 and a transmembrane protein.
The disclosure does not identify any specific structural features or combination of features which give rise to the function of simultaneous binding to RNF149 and a transmembrane protein which causes lysosomal degradation by ubiquitination and internalization of the transmembrane receptor protein. Additionally, there does not appear to be any reasonable shared structure present in the genus or subgenera of recited heterobifunctional molecules which gives rise to their functional activity. Ultimately, identifying a heterobifunctional molecule simply on the basis of being a bi-specific VHH-based antibody that permits simultaneous binding to RNF149 and a transmembrane receptor protein which causes lysosomal degradation by ubiquitination and internalization of the transmembrane receptor protein, rather than by identifying the sequence/structure, namely the CDRs and the linker, for the bi-specific VHH-based antibody of the heterobifunctional molecule in question is generally insufficient to provide written description.
The claims are drawn to a broad genus (and subgenera which may or may not comprise a linker) of heterobifunctional molecules that are bi-specific VHH-based antibodies which are functionally defined by their ability to simultaneously and specifically bind to an extracellular portion of RNF149 and an extracellular portion of a transmembrane receptor protein, wherein simultaneous binding of the heterobifunctional molecule to RNF149 and the transmembrane receptor protein results in in lysosomal degradation by ubiquitination and internalization of the transmembrane receptor protein. However, the claims fail to recite any corresponding structure (CDRs and linker) expected to correlate with this ability as supported by Applicant’s disclosure.
Thus, there is insufficient written description for the breadth of heterobifunctional molecules that are bi-specific antibodies comprising: i) a first VHH-based binding domain that is capable of specific binding to an extracellular portion of RNF149; and ii) a second VHH-based binding domain that is capable of specific binding to an extracellular portion of a transmembrane receptor protein, wherein simultaneous binding of the heterobifunctional molecule to RNF149 and the transmembrane receptor protein results in lysosomal degradation by ubiquitination and internalization of the transmembrane receptor protein as currently claimed, which are distinct and diverse and do not share a common structure that contributes to a common ability to bind RNF149 and a transmembrane domain and cause lysosomal degradation by ubiquitination and internalization of the transmembrane receptor protein.
Therefore, in view of the breadth of the claims and the limited disclosure, artisans would reasonably conclude that applicant was not in possession of the full breadth of heterobifunctional molecules encompassed by the claims at the time the instant application was filed.
Applicant's arguments filed June 16, 2026 have been fully considered but they are not persuasive.
The Applicant argues that, in view of the amendment to claim 1 to recite “a heterobifunctional molecule wherein the first binding domain and the second binding domain each comprise a VHH domain of a heavy chain only antibody," and wherein simultaneous binding "results in lysosomal degradation of the transmembrane protein," claim 1 is now directed to a bi-specific nanobody, a mechanism-based heterobifunctional molecule that harnesses transmembrane E3 ubiquitin ligases for targeted lysosomal degradation of transmembrane proteins. The Applicant further argues that the inventive contribution lies in this mechanism of action, not in any particular CDR sequence.
The Applicant argues that the Examiner’s analysis that the claims lack written description because no CDR sequences are recited and because the disclosed bi-VHH species binds epitope tags rather than native targets applies only to a traditional antibody written description framework, requiring disclosure of CDR sequences, which is inappropriate for the present claims. The Applicant asserts that amended claim 1 is not directed to antibodies per se defined by their binding specificity to a particular epitope, but rather, it is directed to a mechanism-based molecule: a bi-specific nanobody (two VHH domains) that simultaneously binds a transmembrane E3 ubiquitin ligase and a transmembrane protein to cause lysosomal degradation.
The Applicant argues that the specification amply demonstrates that this mechanism works broadly. The Applicant asserts that Examples 2 and 3 demonstrate that the bi-VHH (VHH Alpha - (G4S)3 - VHH E6) successfully induces cell surface removal across multiple E3 ligases (RNF43, RNF167, RNF128, RNF130) and multiple transmembrane protein targets (T3RII, EGFR, CTLA-4, FLT-3, PD-1, PD-L1). The Applicant asserts that, specifically, Example 2 shows that "both RNF43 and RNF167 induced removal of T
β
RII as well as EGFR from the plasma membrane" and that "internalized proteins co-clustered in the perinuclear area in bafilomycin-treated cells, which inhibits lysosomal turnover, indicating accumulation of E3 ligases and their targets in late endosomal/lysosomal structures." The Applicant asserts that Example 3 further demonstrates that "the following E3-target combinations lead to target removal of the surface: CTLA-4 and RNF167; FLT-3 and RNF43, RNF128 or RNF167, PD-1 and RNF128, RNF130 or RNF167 and PD-L1 and RNF43, RNF128 or RNF130." The Applicant argues that this breadth of demonstrated combinations shows that the mechanism is not dependent on any particular binding specificity but works generally when a transmembrane E3 ligase is brought into proximity with a transmembrane target.
The Applicant also argues that, moreover, VHH/nanobody generation against known extracellular targets is routine in the art. The Applicant asserts that the specification references Pardon et al., Nature Protocols (2014) for the generation of VHH/nanobodies against native epitopes. The Applicant asserts that the art recognizes that generating nanobodies against known extracellular protein targets is a well-established, routine procedure. The Applicant argues that the skilled person would have no difficulty generating VHH domains against any of the recited transmembrane E3 ligases or transmembrane proteins using standard immunization and selection techniques.
The Applicant further argues that the Examiner's concern that the tag-based bi-VHH is "outside the claimed genus" is addressed by amended claim 1 and by the specification's explicit disclosure. The Applicant asserts that the tag-based system is a screening tool used to validate the mechanism across many E3 ligase/target combinations. The Applicant asserts that the specification explicitly contemplates that "following the selection of an effective combination of a transmembrane E3 ubiquitin ligase and a membrane-bound protein, a heterobifunctional molecule may be constructed comprising a first binding domain capable of specific binding to the extracellular portion of a (native) transmembrane E3 ubiquitin ligase and a second binding domain capable of specific binding to the extracellular portion of a (native) membrane-bound protein.” The Applicant argues that the amended claims relating to a bi- specific nanobody (two VHH domains) causing lysosomal degradation are well-supported by this disclosure.
This is not found persuasive for the following reasons:
Contrary to the Applicant’s argument the amended claims relating to a bi-specific nanobody (two VHH domains) causing lysosomal degradation are well-supported by this disclosure because (i) amended claim 1 is not directed to antibodies per se defined by their binding specificity to a particular epitope, but rather, it is directed to a mechanism-based molecule: a bi-specific nanobody (two VHH domains) that simultaneously binds a transmembrane E3 ubiquitin ligase and a transmembrane protein to cause lysosomal degradation; and (ii) the inventive contribution lies in this mechanism of action, not in any particular CDR sequence; note that the description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.
The Applicant’s argument that the instant invention lies in a “mechanism of action” is not persuasive because the claims are drawn to a product, not a “mechanism of action.” The claims are drawn to a heterobifunctional molecule that comprises two VHH-based binding domain wherein the heterobifunctional molecule is functionally defined by its ability to simultaneously bind a transmembrane E3 ubiquitin ligase and a transmembrane receptor protein and cause lysosomal degradation by ubiquitination and internalization of the transmembrane receptor protein. Accordingly and as noted above, a definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.”). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.
Regarding the Applicant’s arguments that (i) the amendment to claim 1 to limit the binding domains to VHH-based binding domains satisfies the written description requirement and (ii) the Examiner’s analysis that the claims lack written description because no CDR sequences are recited applies only to a traditional antibody written description framework, requiring disclosure of CDR sequences, and is therefore inappropriate for the present claims; note that, based upon the prior art, skilled artisans would reasonably understand that it is the structure of the CDRs within an antibody, including a VHH-based antibody, which gives rise to the functional property of antigen binding, whether that be a full set of six CDRs in the case an antibody comprising a VH and a VL or a set of three CDRs in the case of a heavy chain only antibody (VHH). The epitope to which said CDRs bind is an inherent property which appears to necessarily be present due to conservation of critical structural elements, namely the CDR sequences themselves.
Regarding the Applicant’s arguments that (i) the specification amply demonstrates that this mechanism works broadly and (ii) the mechanism is not dependent on any particular binding specificity but works generally when a transmembrane E3 ligase is brought into proximity with a transmembrane target; note that claims are drawn to a product not a “mechanism of action.” The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.
Regarding the Applicant’s arguments that (i) VHH/nanobody generation against known extracellular targets is routine in the art and (ii) the skilled person would have no difficulty generating VHH domains against any of the recited transmembrane E3 ligases or transmembrane proteins using standard immunization and selection techniques; the Examiner agrees that the generation of VHH-based antibodies against a particular target is routine in the art, however, the written description rejection is not based on how one is meant to make and/or use the claimed invention it is instead based on what the invention actually is. Given that the Applicant’s has claimed the instant invention by what it does and not by what it is, the instant claims failed to satisfy the written description requirement for the reasons outlined above.
Regarding the Applicant’s arguments that (i) the Examiner's concern that the tag-based bi-VHH is "outside the claimed genus" is addressed by amended claim 1 and by the specification's explicit disclosure and (ii) the tag-based system is a screening tool used to validate the mechanism across many E3 ligase/target combinations; note that the instant invention is drawn to a product that simultaneously binds a transmembrane E3 ubiquitin ligase and a transmembrane receptor protein, not a “screening tool” or “mechanism.” Therefore, the disclosed “screening tool” and “mechanism” fails to satisfy the written description requirement because they are not what is actually being claimed. Simply identifying that certain E3 ligase/target combinations can be used to downregulate a given target, does not demonstrate to a skilled artisan that the Applicant was in possession of a product that is able to directly bind said E3 ligase and target.
The species of “screening tool” is not in scope with the instantly claimed genus of heterobifunctional molecules. The instantly claimed genus of heterobifunctional molecules encompass heterobifunctional molecules that specifically bind to RNF149 and a transmembrane protein but the genus does not encompass heterobifunctional molecules that specifically bind to tags fused to RNF149 and a transmembrane protein. Therefore, the Applicant has not disclosed a single species of heterobifunctional molecule of the instant invention.
As such, the applicant’s argument has not been found persuasive.
Amending claim 1 to recite that the first binding domain is capable of specific binding to an alpha tag fused to an extracellular portion of a transmembrane E3 ubiquitin ligase, the second binding domain is capable of specific binding to an E6 tag fused to an extracellular portion of a transmembrane protein, wherein the first antigen binding domain comprises the amino acid sequence of SEQ ID NO: 98, and wherein the second antigen binding domain comprises the amino acid sequence of SEQ ID NO: 99 (CDR3) and the amino acid sequences for CDRs 1 and 2 of the anti-E6 VHH disclosed by Ling et al. (2019, Molecular Immunology, 114(July), 513-523) and to also include that the binding domains are joined by the (G4S)3 linker would obviate this part of the rejection.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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, 4, 6, 11, 25, and 29 stand rejected under 35 U.S.C. 103 as being unpatentable over Throsby et al. 2017 (WO2017069628, an IDS reference filed 09/05/2022) in view of Riching et al. 2018 (ACS Chem. Biol. 13, 2758−2770) and Hong et al. 2012 (J. Biol. Chem., 287(28); 24017-24025, a reference of record).
In view of the Applicant’s election filed 09/01/2025, instant claim 1 is drawn to a heterobifunctional molecule comprising a first and a second binding domain, wherein i) the first binding domain is capable of specific binding to an extracellular portion of a transmembrane E3 ubiquitin ligase; and ii) the second binding domain is capable of specific binding to an extracellular portion of a transmembrane protein, wherein the first binding domain and the second binding domain each comprise a VHH domain of a heavy chain only antibody, wherein simultaneous binding of the heterobifunctional molecule to the transmembrane E3 ubiquitin ligase and the transmembrane protein results in lysosomal degradation by ubiquitination and internalization of the transmembrane protein, wherein the heterobifunctional molecule is a bi-specific antibody, and wherein the transmembrane E3 ubiquitin ligase is RNF149, and wherein the transmembrane protein is a receptor.
Dependent claim 4 is drawn to the heterobifunctional molecule wherein the transmembrane E3 ubiquitin ligase ubiquitinates the transmembrane protein with monoubiquitin, multiubiquitin, Lys48-linked or Lys63-linked polyubiquitin chains.
Dependent claim 11 limits the heterobifunctional molecule to that wherein the molecule comprises a linker between the first binding domain and the second binding domain.
Dependent claim 25 limits the transmembrane receptor protein to that which is involved in cancer.
Dependent claim 29 limits the VHH domain of a heavy chain only antibody to that which is derived from the camelidae family.
Regarding claim 1, Throsby et al. teach bispecific antibodies (heterobifunctional molecules) that bind a transmembrane E3 ubiquitin ligase (RNF43 or ZNRF3) and a transmembrane receptor protein (EGFR or HER3) (e.g. see table 6 on page 162, lines 1-7; page 130, lines 5-20; page 140, lines 6-9; and page 140, lines 16-22). Throsby et al. also teach that these binding molecules specifically bind to an extracellular part of a the transmembrane E3 ubiquitin ligase (member of a WNT signaling pathway) and the transmembrane receptor protein (e.g. see Abstract).
Regarding claim 11, Throsby et al. teach that the binding domains can be covalently joined, optionally by a linking region (or linker) (e.g. see page 11, lines 31 and 32).
Regarding claim 25, Throsby et al. teach that in a majority of carcinomas, targeted approaches are still proving ineffective (e.g. see page 2, lines 2-5). EGFR is implicated in several human epithelial malignancies, notably cancers of the breast, bladder, non-small cell lung cancer lung, colon, ovarian head and neck and brain (e.g. see page 25, lines 28-33). Activating mutations in the gene have been found, as well as over-expression of the receptor and of its ligands, giving rise to autocrine activation loops. EGFR has therefore been extensively used as target for cancer therapy (e.g. see page 25, lines 28-33). For example, 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 (e.g. see page 2, lines 2-5).
Regarding claim 29, Throsby et al. teach that single-domain antibody fragments are mostly engineered from heavy-chain antibodies found in camelids; these are called VHH fragments (Nanobodies®) (e.g. see page 23, lines 17-19).
Throsby et al. do not teach only bispecific antibodies that bind a transmembrane E3 ubiquitin ligase and a transmembrane protein or that the E3 ubiquitin ligase is RNF149 (claim 1).
Riching et al. teach that targeting key drivers of disease for degradation has been a desirable outcome for numerous therapeutic treatments (e.g. see page 2758, paragraph spanning left and right columns). The first examples of compounds affecting degradation used small molecules or peptides to bridge interactions between a target protein with components of ubiquitination machinery. More recently, the approach has been refined for efficacy and efficiency, comprising a heterobifunctional compound termed proteolysis targeting chimera (PROTAC). Chemically, these compounds consist of a target binder on one side fused to an E3 ligase recruiter compound on the other side. PROTACs induce degradation by simultaneously binding the target protein and the E3 ligase complex proteins, bringing the target protein into proximity for ubiquitination and targeting it for degradation (e.g. see page 2758, paragraph spanning left and right columns).
Riching et al. also teach that active research efforts are underway to identify other efficacious E3 ligase components to serve as recruiters (e.g. see paragraph spanning pages 2764 and 2765). This will result in an expansion of options in the future, directly translating to increased chemical development and furthering the need for robust and relevant technologies to efficiently profile and triage PROTAC cellular activity (e.g. see paragraph spanning pages 2764 and 2765).
Hong et al. teach that RNF149 (RING finger protein 149) is an E3 ubiquitin ligase (e.g. see page 24023, right column, third paragraph). Hong et al. teach that RNF149 physically interacts with wild-type BRAF to induce its ubiquitination and promote its subsequent proteasomal degradation (e.g. see page 24023, right column, third paragraph). Hong et al. also teach that their results do not rule out the possibility that RNF149 has additional substrates that might be involved in tumorigenesis (e.g. see paragraph spanning pages 24023 and 24024).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Throsby et al. to incorporate the teachings of Riching et al. and Hong et al. to specifically select bispecific antibodies that bind a transmembrane E3 ubiquitin ligase and a transmembrane protein wherein the E3 ubiquitin ligase is specifically RNF149. This is because the heterobifunctional compounds termed PROTACs, which comprise a E3 ubiquitin ligase binding domain fused to a target binding domain, induce target degradation by simultaneously binding the target and the E3 ubiquitin ligase, bringing the target protein into proximity for ubiquitination and targeting it for degradation (Riching et al.).
EGFR is implicated in several human epithelial malignancies and has been extensively used as target for cancer therapy (Throsby et al.). However, in a majority of carcinomas, targeted approaches are still proving ineffective (Throsby et al.). For example, in colorectal cancer, treatment with EGFR blocking therapies results in low response rates (Throsby et al.).
As an alternative to treatment with targeting blocking therapies with low response rates, targeting key drivers of disease for degradation is desirable (Riching et al.). As such, heterobifunctional compounds termed PROTACs, which comprise a E3 ubiquitin ligase binding domain fused to a target binding domain, were designed to induce target degradation by simultaneously binding the target and the E3 ubiquitin ligase, bringing the target protein into proximity with the E3 ubiquitin ligase for ubiquitination and leading to target protein degradation (Riching et al.).
Given that EGFR is implicated in several cancers, EGFR is a good target for cancer therapy, current EGFR blocking therapies can result in low response rates, degradation of key drivers of disease is desirable alternative treatment to blocking therapies, and PROTACs, which comprise a E3 ubiquitin ligase binding domain fused to a target binding domain, are designed to induce target degradation; it would have been obvious to a skilled artisan to specifically select bispecific antibodies that bind a transmembrane E3 ubiquitin ligase and EGFR, a transmembrane protein, with a reasonable expectation of success. Given their structure, these bispecific antibodies are essentially PROTACs. Thus, a skilled artisan would have reasonably expected the heterobifunctional bispecific antibodies that simultaneously bind a transmembrane E3 ubiquitin ligase and a transmembrane protein, such as EGFR, to bring the target transmembrane protein into proximity with the transmembrane E3 ubiquitin ligase for ubiquitination of the target transmembrane protein and, in turn, its degradation.
Regarding the limitation of claim 1 wherein the transmembrane E3 ubiquitin ligase is RNF149, given that RNF149 can induce ubiquitination of BRAF to promote its subsequent proteasomal degradation and the possibility of RNF149 having additional substrates that might be involved in tumorigenesis; it would have been obvious to a skilled artisan to modify the bispecific antibodies taught by Throsby et al., which bind the transmembrane E3 ubiquitin ligases RNF43 or ZNRF3 and a transmembrane protein, to instead bind RNF149 with a reasonable expectation of success. There is a known desire to expand the repertoire of targeted E3 ubiquitin ligases in designing PROTACs (Riching et al.) and there is a possibility of RNF149 having additional substrates that might be involved in tumorigenesis (Hong et al.), which may include the transmembrane proteins EGFR and HER3 (Throsby et al.). Therefore, a skilled artisan would be motivated to experiment with substituting the RNF43/ZNRF3 binding domains of the indicated bispecific antibodies taught by Throsby et al. with a RNF149 binding domain.
Regarding the properties recited in claims 1 and 4, namely, “results in lysosomal degradation by ubiquitination and internalization of the transmembrane protein” and “ubiquitinates the transmembrane protein with monoubiquitin, multiubiquitin, Lys48-linked or Lys63-linked polyubiquitin chains,” respectively, the properties recited in these claims flow naturally from the teachings of the prior art. (citing Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985 (“The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.”), and Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347 (Fed. Cir. 1999) (“[T]he discovery of... a scientific explanation for the prior art's functioning, does not render the old composition patentably new to the discoverer.”)).
An obvious formulation cannot become nonobvious simply by measuring and claiming an activity of the formulation in a particular context, “because ‘[t]o hold otherwise would allow any formulation—no matter how obvious—to become patentable merely by testing and claiming an inherent property.’” Persion Pharm., slip op. at 13 (Fed. Cir. Dec. 27, 2019) (citing Santarus, Inc. v. Par Pharm., Inc., 694 F.3d 1344, 1354 (Fed. Cir. 2012)); see also Gen. Elec. Co. v. Jewel Incandescent Lamp Co., 326 U.S. 242, 249 (1945) (“It is not invention to perceive that the product which others had discovered had qualities they failed to detect.”).
Therefore, the bispecific antibody taught by Throsby et al. in view of Riching et al. and Hong et al. would necessarily have the properties recited in claims 1 and 4, especially in the absence of evidence to the contrary.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Applicant's arguments filed June 16, 2026 have been fully considered but they are not persuasive.
The Applicant argues that claim 1, as amended, represents a fundamentally distinct mode of action compared to the teachings of the cited references. The Applicant asserts that the purpose of Throsby et al.’s molecules is to modulate signaling pathways, in particular to block or alter receptor- mediated signaling, not to induce degradation. The Applicant asserts that Throsby et al. describes a binding arm that "specifically blocks a growth receptor pathway," while the other arm targets a stem cell marker. The Applicant argues that this teaching is entirely consistent with the disclosure of Throsby et al. itself, which focuses on inhibition of signaling and cancer growth, rather than removal of the receptor from the cell surface. The Applicant asserts that Throsby et al. does not disclose recruitment of an E3 ubiquitin ligase for degradation purposes, ubiquitination of a target receptor, internalization triggered by induced proximity, or lysosomal degradation of a transmembrane protein. The Applicant asserts that instead, Throsby et al. relates to antagonistic or blocking antibody mechanisms, i.e., a targeting blocking therapy. The Applicant argues that claim 1, by contrast, requires that simultaneous binding results in lysosomal degradation by ubiquitination and internalization. The Applicant asserts that accordingly, Throsby et al. does not disclose or suggest the claimed mechanism and cannot serve as a proper starting point for an obviousness analysis.
The Applicant also argues that Riching et al and Hong et al do not remedy these deficiencies. The Applicant asserts that since Throsby et al. and Riching et al. concern alternative therapeutic strategies, a skilled artisan would not be motivated to combine these two references. The Applicant argues that, moreover, three key distinctions separate Riching et al. from the present claims, namely, first PROTACs are small molecules, not antibodies. The Applicant asserts that there is no teaching or suggestion in Riching et al. to use bi-specific antibodies, let alone bi-specific nanobodies comprising VHH domains, to achieve degradation. The Applicant asserts that, second, PROTACs function intracellularly, recruiting cytosolic E3 ligases such as VHL or CRBN to intracellular targets. The Applicant asserts that in contrast, claim 1 as amended operates extracellularly at the cell surface, using a transmembrane E3 ubiquitin ligase and a transmembrane target protein, with both binding events occurring outside the cell. The applicant further asserts that, third, PROTACs primarily exploit proteasomal degradation, whereas claim 1 requires ubiquitination-triggered internalization and lysosomal degradation of membrane proteins. The Applicant argues that, thus, Riching et al. teaches a completely different molecular format, biological context, and degradation mechanism. The Applicant further argues that a skilled artisan would not derive from Riching et al. any motivation to modify the extracellular bispecific antibodies of Throsby et al. into constructs capable of inducing ubiquitination-mediated lysosomal degradation at the cell surface.
The Applicant also argues that Hong et al. does not disclose heterobifunctional molecules, induced proximity strategies, extracellular targeting, or antibody- mediated recruitment of E3 ligases. The Applicant asserts that, thus, Hong et al. merely confirms that RNF149 is an E3 ligase-it does not suggest that RNF149 could be recruited via a bispecific antibody to degrade unrelated transmembrane proteins at the cell surface.
The Applicant ultimately argues that, in view of the foregoing, none of the cited references, alone or in combination, teaches or suggests a bi-specific nanobody comprising two VHH domains that simultaneously binds an extracellular portion of a transmembrane E3 ubiquitin ligase and an extracellular portion of a transmembrane receptor to cause lysosomal degradation by ubiquitination and internalization. The Applicant argues that the present claims introduce a new platform for selective degradation of transmembrane proteins by exploiting transmembrane E3 ligases extracellularly, a mechanism that enables removal of cell surface receptors that were previously difficult or impossible to target effectively.
This is not found persuasive for the following reasons:
Contrary to the Applicant’s argument that Throsby et al. cannot serve as a proper starting point for an obviousness analysis because Throsby et al. do not disclose or suggest the claimed mechanism, namely, recruitment of an E3 ubiquitin ligase for degradation purposes, ubiquitination of a target receptor, internalization triggered by induced proximity, or lysosomal degradation of a transmembrane protein, and instead Throsby et al. teach antagonistic or blocking antibody mechanisms; note that the properties recited in these claims flow naturally from the teachings of the prior art. (citing Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985 (“The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.”), and Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347 (Fed. Cir. 1999) (“[T]he discovery of... a scientific explanation for the prior art's functioning, does not render the old composition patentably new to the discoverer.”)).
An obvious formulation cannot become nonobvious simply by measuring and claiming an activity of the formulation in a particular context, “because ‘[t]o hold otherwise would allow any formulation—no matter how obvious—to become patentable merely by testing and claiming an inherent property.’” Persion Pharm., slip op. at 13 (Fed. Cir. Dec. 27, 2019) (citing Santarus, Inc. v. Par Pharm., Inc., 694 F.3d 1344, 1354 (Fed. Cir. 2012)); see also Gen. Elec. Co. v. Jewel Incandescent Lamp Co., 326 U.S. 242, 249 (1945) (“It is not invention to perceive that the product which others had discovered had qualities they failed to detect.”).
E3 ubiquitin ligases, such as RNF43 and RNF149, inherently possess the function of directing ubiquitination-dependent target protein degradation (Riching et al.). Therefore, a skilled artisan would reasonably expect that molecule that possesses the ability to simultaneously bind a E3 ubiquitin ligase and a target, such as a transmembrane receptor protein, would permit proximity-based ubiquitination and degradation of the target.
Therefore, the bispecific antibody taught by Throsby et al. in view of Riching et al. and Hong et al. would necessarily have the properties recited in claims 1 and 4, especially in the absence of evidence to the contrary.
Regarding the Applicant’s arguments that (i) Throsby et al. and Riching et al. concern alternative therapeutic strategies and a skilled artisan would not be motivated to combine these two references and (ii) a skilled artisan would not derive from Riching et al. any motivation to modify the extracellular bispecific antibodies of Throsby et al. into constructs capable of inducing ubiquitination-mediated lysosomal degradation at the cell surface; note that Riching et al. is used as a secondary reference to demonstrate utility of proximity-based E3 ligase ubiquitination and degradation of a target protein. The PROTACs taught by Riching et al. simply illustrate a mechanism in which the Throsby et al.’s heterobifunctional molecule might work given that it is designed to also bring two molecules, one being a E3 ubiquitin ligase and the other a transmembrane receptor protein associated with cancer, into close proximity. Given that Riching et al. teach that PROTACs have a similar design, a skilled artisan would reasonably expect Throsby et al.’s heterobifunctional molecule to have a similar function.
Given that degradation of key drivers of disease is a desirable alternative treatment to blocking therapies, and PROTACs, which comprise a E3 ubiquitin ligase binding domain fused to a target binding domain, are designed to induce target degradation (Riching et al.); it would have been obvious to a skilled artisan to specifically select Throsby et al.’s bispecific antibodies that bind a transmembrane E3 ubiquitin ligase and EGFR, a transmembrane protein, with a reasonable expectation of success. Given their structure, Throsby et al.’s bispecific antibodies are essentially PROTACs. Thus, a skilled artisan would have reasonably expected the heterobifunctional bispecific antibodies that simultaneously bind a transmembrane E3 ubiquitin ligase and a transmembrane protein, such as EGFR, to bring the target transmembrane protein into proximity with the transmembrane E3 ubiquitin ligase for ubiquitination of the target transmembrane protein and, in turn, its degradation.
Regarding the Applicant’s arguments that (i) claim 1 as amended operates extracellularly at the cell surface, using a transmembrane E3 ubiquitin ligase and a transmembrane target protein, with both binding events occurring outside the cell; (ii) PROTACs primarily exploit proteasomal degradation, whereas claim 1 requires ubiquitination-triggered internalization and lysosomal degradation of membrane proteins and therefore, Riching et al. teaches a completely different molecular format, biological context, and degradation mechanism; and (iii) the present claims introduce a new platform for selective degradation of transmembrane proteins by exploiting transmembrane E3 ligases extracellularly, a mechanism that enables removal of cell surface receptors that were previously difficult or impossible to target effectively; note that Riching et al. is simply used to illustrate the effect of proximity-based E3 ligase ubiquitination and degradation of a target protein. While the Examiner agrees that PROTACs primarily operate intracellularly and the intended use of the instant heterobifunctional molecule is for it to work extracellularly through an alternative degradation pathway, the purpose of using Riching et al. as a secondary reference is not to say that the instant invention is a PROTAC but to simply demonstrate that by using a molecule that is able to bring an E3 ubiquitin ligase into close proximity with a target protein one may be able to include ubiquitination-dependent target protein degradation, regardless of where it is happening in or on the cell.
Regarding the Applicant’s argument that Hong et al. does not disclose heterobifunctional molecules, induced proximity strategies, extracellular targeting, or antibody- mediated recruitment of E3 ligases and, thus, Hong et al. merely confirms that RNF149 is an E3 ligase-it does not suggest that RNF149 could be recruited via a bispecific antibody to degrade unrelated transmembrane proteins at the cell surface; it is noted that Hong et al. is used to merely demonstrate that RNF149 is an E3 ubiquitin ligase that shows promiscuous ubiquitination capabilities.
Given that RNF149 can induce ubiquitination of BRAF to promote its subsequent proteasomal degradation and the possibility of RNF149 having additional substrates that might be involved in tumorigenesis (Hong et al.); it would have been obvious to a skilled artisan, in view of the teachings of Throsby et al. in view of Riching et al., to modify the bispecific antibodies taught by Throsby et al., which bind the transmembrane E3 ubiquitin ligases RNF43 or ZNRF3 and a transmembrane protein, to instead bind RNF149 with a reasonable expectation of success. There is a known desire to expand the repertoire of targeted E3 ubiquitin ligases in designing PROTACs (Riching et al.) and there is a possibility of RNF149 having additional substrates that might be involved in tumorigenesis (Hong et al.), which may include the transmembrane proteins EGFR and HER3 (Throsby et al.). Therefore, a skilled artisan would be motivated to experiment with substituting the RNF43/ZNRF3 binding domains of the indicated bispecific antibodies taught by Throsby et al. with a RNF149 binding domain.
Regarding the Applicant’s argument that none of the cited references, alone or in combination, teaches or suggests a bi-specific nanobody comprising two VHH domains that simultaneously binds an extracellular portion of a transmembrane E3 ubiquitin ligase and an extracellular portion of a transmembrane receptor to cause lysosomal degradation by ubiquitination and internalization; note the above responses to the Applicant’s arguments.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Throsby et al. to incorporate the teachings of Riching et al. and Hong et al. to specifically select bispecific antibodies that bind a transmembrane E3 ubiquitin ligase and a transmembrane protein wherein the E3 ubiquitin ligase is specifically RNF149. This is because the heterobifunctional compounds termed PROTACs, which comprise a E3 ubiquitin ligase binding domain fused to a target binding domain, induce target degradation by simultaneously binding the target and the E3 ubiquitin ligase, bringing the target protein into proximity for ubiquitination and targeting it for degradation (Riching et al.).
Given that degradation of key drivers of disease is a desirable alternative treatment to blocking therapies, and PROTACs, which comprise a E3 ubiquitin ligase binding domain fused to a target binding domain, are designed to induce target degradation (Riching et al.); it would have been obvious to a skilled artisan to specifically select Throsby et al.’s bispecific antibodies that bind a transmembrane E3 ubiquitin ligase and EGFR, a transmembrane protein, with a reasonable expectation of success. Given their structure, Throsby et al.’s bispecific antibodies are essentially PROTACs. Thus, a skilled artisan would have reasonably expected the heterobifunctional bispecific antibodies that simultaneously bind a transmembrane E3 ubiquitin ligase and a transmembrane protein, such as EGFR, to bring the target transmembrane protein into proximity with the transmembrane E3 ubiquitin ligase for ubiquitination of the target transmembrane protein and, in turn, its degradation.
Furthermore, given that RNF149 can induce ubiquitination of BRAF to promote its subsequent proteasomal degradation and the possibility of RNF149 having additional substrates that might be involved in tumorigenesis (Hong et al.); it would have been obvious to a skilled artisan, in view of the teachings of Throsby et al. in view of Riching et al., to modify the bispecific antibodies taught by Throsby et al., which bind the transmembrane E3 ubiquitin ligases RNF43 or ZNRF3 and a transmembrane protein, to instead bind RNF149 with a reasonable expectation of success. There is a known desire to expand the repertoire of targeted E3 ubiquitin ligases in designing PROTACs (Riching et al.) and there is a possibility of RNF149 having additional substrates that might be involved in tumorigenesis (Hong et al.), which may include the transmembrane proteins EGFR and HER3 (Throsby et al.). Therefore, a skilled artisan would be motivated to experiment with substituting the RNF43/ZNRF3 binding domains of the indicated bispecific antibodies taught by Throsby et al. with a RNF149 binding domain.
As such, the applicant’s arguments have not been found persuasive.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 1 and 6 stand rejected under 35 U.S.C. 103 as being unpatentable over Throsby et al. 2017 (WO2017069628, an IDS reference filed 09/05/2022) in view of Riching et al. 2018 (ACS Chem. Biol. 13, 2758−2770) and Hong et al. 2012 (J. Biol. Chem., 287(28); 24017-24025, a reference of record), as applied to claim 1, and further in view of Liu et al. 2010 (Proc. Natl. Acad. Sci. U.S.A., 107(11); 5136-5141, a reference of record).
Dependent claim 6 limits the transmembrane receptor protein is LRP6.
The combined teachings of Throsby et al. in view of Riching et al. and Hong et al. pertaining to claim 1, and the rationale for combining them are outlined in the 103 rejection above.
The combined reference teachings do not teach that the transmembrane receptor protein is LRP6.
Liu et al. teach that the Wnt/β-catenin signaling pathway is involved in various differentiation events during embryonic development and can lead to tumor formation when aberrantly activated (e.g. see page 5136, paragraph spanning left and right columns). Liu et al. also teach that LRP6 is up-regulated in a subpopulation of human breast cancers (e.g. see Abstract). LRP6 silencing in breast cancer cells reduces Wnt signaling, cell proliferation, and in vivo tumor growth. In vivo administration of an LRP6 antagonist, Mesd (mesoderm development), markedly suppressed growth of MMTV-Wnt1 tumors without causing undesirable side effects. Liu et al.’s results demonstrate that Wnt activation at the cell surface contributes to breast cancer tumorigenesis and highlights LRP6 as a potential therapeutic target in breast cancer (e.g. see Abstract).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the combined teachings of Throsby et al. in view of Riching et al. and Hong et al. as applied to claim 1, and incorporate the teachings of Liu et al. to include that that that the transmembrane protein is LRP6. This is because LRP6 is a potential therapeutic target in breast cancer.
Given that LRP6 is up-regulated in a subpopulation of human breast cancers, LRP6 silencing and antagonism in breast cancer cells reduces cell proliferation and in vivo tumor growth, degradation of key drivers of disease is desirable alternative treatment to blocking therapies, and PROTACs, which comprise a E3 ubiquitin ligase binding domain fused to a target binding domain, are designed to induce target degradation; it would have been obvious to a skilled artisan to modify the bispecific antibody targeting an extracellular portion of RNF149 and an extracellular portion of a transmembrane protein taught by Throsby et al. in view of Riching et al. and Hong et al. to specifically bind the transmembrane protein LRG6 with a reasonable expectation of success. A skilled artisan would have reasonably expected that a heterobifunctional bispecific antibody which simultaneously binds RNF149 and LRP6 would bring LRP6 into proximity with the RNF149 for ubiquitination of the LRP6 and, in turn, its degradation. This bispecific antibody would essentially silence LRP6 by degradation and a skilled artisan would reasonably expect this silencing to have the same effect on tumor cell growth and proliferation as described by Liu et al.
Combining prior art elements according to known methods to yield predictable results is obvious to one of ordinary skill in the art (see MPEP § 2143(A)). From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Applicant's arguments filed June 16, 2026 have been fully considered but they are not persuasive.
The Applicant argues that, as explained above, Throsby et al. is directed to bispecific antibodies that modulate or block signaling pathways, not to molecules that induce degradation. The Applicant asserts that Throsby et al. does not disclose or suggest ubiquitination, internalization, or degradation of a transmembrane protein, but instead relies on antagonistic (blocking) mechanisms. The applicant argues that Liu et al. does not remedy this deficiency and that Liu et al. investigates LRP6 as a therapeutic target and teaches that inhibition of LRP6 - e.g., by antagonists such as Mesd or by gene silencing- reduces Wnt signaling and tumor growth. The Applicant asserts that, however, Liu et al. is limited to blocking receptor function, and contains no teaching or suggestion of inducing ubiquitination or degradation via recruitment of an E3 ubiquitin ligase. The Applicant argues that. thus, Liu et al. reinforces the conventional alternative approach of inhibition rather than degradation.
The Applicant argues that Hong et al. merely identifies RNF149 as an E3 ubiquitin ligase acting on intracellular substrates and does not disclose heterobifunctional molecules, extracellular targeting, or antibody-mediated recruitment of ligases.
The Applicant argues that, accordingly, the cited combination fails to provide any teaching or motivation to modify the signaling-blocking antibodies of Throsby et al., in view of Liu et al. and Hong et al., into heterobifunctional molecules that simultaneously bind a transmembrane E3 ligase and a transmembrane protein to induce ubiquitination, internalization, and degradation. The Applicant asserts that such a modification would require a fundamental conceptual shift from inhibition to induced degradation, which is not suggested in the prior art.
This is not found persuasive for the following reasons:
Contrary to the Applicant’s arguments that (i) Throsby et al. is directed to bispecific antibodies that modulate or block signaling pathways, not to molecules that induce degradation; (ii) Throsby et al. does not disclose or suggest ubiquitination, internalization, or degradation of a transmembrane protein, but instead relies on antagonistic (blocking) mechanisms; (iii) Liu et al. reinforces the conventional alternative approach of inhibition rather than degradation; and (iv) Hong et al. merely identifies RNF149 as an E3 ubiquitin ligase acting on intracellular substrates and does not disclose heterobifunctional molecules, extracellular targeting, or antibody-mediated recruitment of ligases; note that the properties recited in these claims flow naturally from the teachings of the prior art. (citing Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985 (“The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.”), and Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347 (Fed. Cir. 1999) (“[T]he discovery of... a scientific explanation for the prior art's functioning, does not render the old composition patentably new to the discoverer.”)).
An obvious formulation cannot become nonobvious simply by measuring and claiming an activity of the formulation in a particular context, “because ‘[t]o hold otherwise would allow any formulation—no matter how obvious—to become patentable merely by testing and claiming an inherent property.’” Persion Pharm., slip op. at 13 (Fed. Cir. Dec. 27, 2019) (citing Santarus, Inc. v. Par Pharm., Inc., 694 F.3d 1344, 1354 (Fed. Cir. 2012)); see also Gen. Elec. Co. v. Jewel Incandescent Lamp Co., 326 U.S. 242, 249 (1945) (“It is not invention to perceive that the product which others had discovered had qualities they failed to detect.”).
E3 ubiquitin ligases, such as RNF43 and RNF149, inherently possess the function of directing ubiquitination-dependent target protein degradation (Riching et al.). Therefore, a skilled artisan would reasonably expect that molecule that possesses the ability to simultaneously bind a E3 ubiquitin ligase and a target, such as a transmembrane receptor protein, would permit proximity-based ubiquitination and degradation of the target.
Therefore, the bispecific antibody taught by Throsby et al. in view of Riching et al. and Hong et al. would necessarily have the properties recited in claims 1 and 4, especially in the absence of evidence to the contrary.
Furthermore, Riching et al. is used as a secondary reference to demonstrate utility of proximity-based E3 ligase ubiquitination and degradation of a target protein. The PROTACs taught by Riching et al. simply illustrate a mechanism in which the Throsby et al.’s heterobifunctional molecule might work given that it is designed to also bring two molecules, one being a E3 ubiquitin ligase and the other a transmembrane receptor protein associated with cancer, into close proximity. Given that Riching et al. teach that PROTACs have a similar design, a skilled artisan would reasonably expect Throsby et al.’s heterobifunctional molecule to have a similar function.
Given that degradation of key drivers of disease is a desirable alternative treatment to blocking therapies, and PROTACs, which comprise a E3 ubiquitin ligase binding domain fused to a target binding domain, are designed to induce target degradation (Riching et al.); it would have been obvious to a skilled artisan to specifically select Throsby et al.’s bispecific antibodies that bind a transmembrane E3 ubiquitin ligase and EGFR, a transmembrane protein, with a reasonable expectation of success. Given their structure, Throsby et al.’s bispecific antibodies are essentially PROTACs. Thus, a skilled artisan would have reasonably expected the heterobifunctional bispecific antibodies that simultaneously bind a transmembrane E3 ubiquitin ligase and a transmembrane protein, such as EGFR, to bring the target transmembrane protein into proximity with the transmembrane E3 ubiquitin ligase for ubiquitination of the target transmembrane protein and, in turn, its degradation.
Additionally, Hong et al. is used to merely demonstrate that RNF149 is an E3 ubiquitin ligase that shows promiscuous ubiquitination capabilities. Given that RNF149 can induce ubiquitination of BRAF to promote its subsequent proteasomal degradation and the possibility of RNF149 having additional substrates that might be involved in tumorigenesis (Hong et al.); it would have been obvious to a skilled artisan, in view of the teachings of Throsby et al. in view of Riching et al., to modify the bispecific antibodies taught by Throsby et al., which bind the transmembrane E3 ubiquitin ligases RNF43 or ZNRF3 and a transmembrane protein, to instead bind RNF149 with a reasonable expectation of success. There is a known desire to expand the repertoire of targeted E3 ubiquitin ligases in designing PROTACs (Riching et al.) and there is a possibility of RNF149 having additional substrates that might be involved in tumorigenesis (Hong et al.), which may include the transmembrane proteins EGFR and HER3 (Throsby et al.). Therefore, a skilled artisan would be motivated to experiment with substituting the RNF43/ZNRF3 binding domains of the indicated bispecific antibodies taught by Throsby et al. with a RNF149 binding domain.
Regarding the Applicant’s argument that Liu et al. does not remedy this deficiencies of Throsby et al.; note that Liu et al. is simply used to demonstrate that LRP6 is a good therapeutic target for treating cancer. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the combined teachings of Throsby et al. in view of Riching et al. and Hong et al. as applied to claim 1, and incorporate the teachings of Liu et al. to include that that that the transmembrane protein is LRP6. This is because LRP6 is a potential therapeutic target in breast cancer.
Given that LRP6 is up-regulated in a subpopulation of human breast cancers, LRP6 silencing and antagonism in breast cancer cells reduces cell proliferation and in vivo tumor growth, degradation of key drivers of disease is desirable alternative treatment to blocking therapies, and PROTACs, which comprise a E3 ubiquitin ligase binding domain fused to a target binding domain, are designed to induce target degradation; it would have been obvious to a skilled artisan to modify the bispecific antibody targeting an extracellular portion of RNF149 and an extracellular portion of a transmembrane protein taught by Throsby et al. in view of Riching et al. and Hong et al. to specifically bind the transmembrane protein LRG6 with a reasonable expectation of success. A skilled artisan would have reasonably expected that a heterobifunctional bispecific antibody which simultaneously binds RNF149 and LRP6 would bring LRP6 into proximity with the RNF149 for ubiquitination of the LRP6 and, in turn, its degradation. This bispecific antibody would essentially silence LRP6 by degradation and a skilled artisan would reasonably expect this silencing to have the same effect on tumor cell growth and proliferation as described by Liu et al.
As such, the applicant’s arguments have not been found persuasive.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 4, 11, 25, and 29 stand rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Application No. 17/926,668 (the ‘668 Application) in view of Throsby et al. 2017 (WO2017069628, an IDS reference filed 09/05/2022), Riching et al. 2018 (ACS Chem. Biol. 13, 2758−2770), and Hong et al. 2012 (J. Biol. Chem., 287(28); 24017-24025, a reference of record) for the reasons of record.
Claims 1 and 6 stand rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Application No. 17/926,668 (the ‘668 Application) in view of Throsby et al. 2017 (WO2017069628, an IDS reference filed 09/05/2022), Riching et al. 2018 (ACS Chem. Biol. 13, 2758−2770), and Hong et al. 2012 (J. Biol. Chem., 287(28); 24017-24025, a reference of record), as applied to claim 1, and further in view of Liu et al. 2010 (Proc. Natl. Acad. Sci. U.S.A., 107(11); 5136-5141, a reference of record) for the reasons of record.
Applicant's arguments filed June 16, 2026 have been fully considered but they are not persuasive.
The Applicant argues that the claims of the instant application are not obvious over the co-pending application. The further argues that, moreover, the instant application has an earlier effective filing date (March 5, 2021) than the co-pending application (June 18, 2021) and, hence, in line with M.P.E.P. § 1490 (VI)(D)(2)(a), now that all other remaining rejections have been properly addressed, this rejection should be withdrawn, and the present application should be permitted to issue as a patent.
This is not found persuasive for the following reasons:
Regarding the Applicant’s argument that the claims of the instant application are not obvious over the co-pending application; see NSDP rejections of record in previous Office Action and the rejections under 35 U.S.C. 103 and the Examiner’s responses to the Applicant’s arguments above. Furthermore, this argument amounts to no more than a general allegation that the claims define a patentable invention without specifically pointing out how the language of the claims patentably distinguishes them from the references.
Regarding the Applicant’s argument that the instant application has an earlier effective filing date (March 5, 2021) than the co-pending application (June 18, 2021) and, hence, in line with M.P.E.P. § 1490 (VI)(D)(2)(a), now that all other remaining rejections have been properly addressed, this rejection should be withdrawn, and the present application should be permitted to issue as a patent; to the remaining rejections under 35 U.S.C. 112(a) and 103 above.
As such, the applicant’s arguments have not been found persuasive.
Conclusion
No claim is allowed
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/GRACE H LUNDE/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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