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 .
The claim listing filed January 14, 2026 is pending.
Claims 2, 7, and 12-20 are canceled.
Claims 26-28 are new.
Claims 1, 3-6, 8-11, and 21-28 are pending.
Claims 1 and 21 are independent claims.
Election/Restriction
Applicant’s election without traverse of Group I (claims 1-16 and 18, drawn to a heterobifunctional molecule comprising a first and a second binding domain); and the species of RNF149 as the E3 ubiquitin ligase and LRP6 as the transmembrane protein in the reply filed on September 1, 2025 is acknowledged.
Claims 8-10 and 21-24 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions.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, 3-6, 11, and 24-28 are currently under consideration.
In view of Applicant’s amendment filed on January 14, 2026, the rejections under U.S.C. 112(b), 102, and 103 as set forth in the Office Action mailed on October 17, 2025 are withdrawn and the following objection and rejections are set forth.
It is noted that Applicant’s arguments with respect to under U.S.C. 103 and Nonstatutory Double Patenting have been considered but are moot because the new grounds of rejection do not rely on the teachings of Sun et al. as applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Nucleotide and/or Amino Acid Sequence Disclosures
It is noted that the Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. The Incorporation by Reference paragraph recites the incorrect file name and date of creation. The paragraph should recite “The contents of the electronic sequence listing (Name: P6082646PCT-US_Sequence_Listing.txt; Size: 409,898 bytes; and Date of Creation: September 1, 2022) is herein incorporated by reference in its entirety.” The applicant is required to explicitly reference:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
Applicant is reminded that in order to amend the specification, applicant must provide a substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Objections
Claims 26 and 27 are objected to because of the following informalities:
Claim 26 recites “wherein the first domain and the second domain is a domain of a heavy chain only antibody” where it should recite “wherein the first domain and the second domain are a domain of a heavy chain only antibody” in lines 1 and 2.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
Indefinite Language
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
This is a New Ground of Rejection necessitated by applicant's amendment. Claim 27 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 27 recites “wherein the first domain and the second domain comprise or consist of a VHH domain of a heavy chain only antibody” in lines 1 and 2. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
In the present instance, claim 7 recites the broad recitation “wherein the first domain and the second domain comprise a VHH domain of a heavy chain only antibody”, and the claim also recites “wherein the first domain and the second domain consist of a VHH domain of a heavy chain only antibody” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Amending claim 27 to recite “wherein the first domain and the second domain comprise a VHH domain of a heavy chain only antibody” or to recite “wherein the first domain and the second domain consist of a VHH domain of a heavy chain only antibody” in lines 1 and 2 would obviate this part of the rejection.
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, 3-6, 11, and 24-28 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.
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 simultaneous binding of the heterobifunctional molecule to the transmembrane E3 ubiquitin ligase and the transmembrane protein results in degradation of the transmembrane protein, wherein the heterobifunctional molecule is a bi-specific antibody, and wherein the transmembrane E3 ubiquitin ligase is RNF149.
The Applicant has disclosed a single species heterobifunctional molecule, bi-VHH (VHH Alpha - (G4S)3 - VHH E6) (e.g. see page 65, line 26). 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 65, line 40 – page 66, line 1).
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 12-15). 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 1-9).
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.
Nonetheless, the Applicant has not disclosed a single heterobifunctional molecule with sufficient structure that binds specifically to: (a) RNF149 and a transmembrane domain or even (b) an alpha tag fused to RNF149 and a E6 tag fused to a transmembrane domain. Therefore, the Applicant has not disclosed a single species of heterobifunctional molecule of the instant invention.
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 binding domain that is capable of specific binding to an extracellular portion of RNF149; and ii) any second binding domain that is capable of specific binding to an extracellular portion of a transmembrane protein, wherein simultaneous binding of the heterobifunctional molecule to RNF149 and the transmembrane protein results in degradation of the transmembrane protein.
It is noted that no claim indicates any specific structure for the genus of heterobifunctional molecules that are a bi-specific antibody that bind to RNF149 and a transmembrane domain.
Claims 5 and 25 limit the transmembrane protein is a receptor. Claim 25 further limits the receptor to a receptor involved in cancer.
Claim 6 limits the transmembrane protein is LRP6.
Claims 26 and 27 limit the heterobifunctional molecules to that wherein the first domain and the second domain are a domain of a heavy chain only antibody. Claim 27 limit the heavy chain antibody to a VHH domain.
Claim 28 limits the heterobifunctional molecule to an Fc region-comprising bi-specific antibody.
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).
Regarding claims 26 and 27, is also 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) 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 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. 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 antibodies that bind to RNF149 and a transmembrane protein and the subgenera which are drawn to heavy chain only antibodies and VHH.
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. Such a disclosure does not serve to provide sufficient written description of the claimed genus of heterobifunctional molecules that are bi-specific antibodies that simultaneously bind to RNF149 and a transmembrane protein and cause degradation of the transmembrane protein. The disclosure also does not serve to provide sufficient written description of the claimed subgenera of heterobifunctional molecules which are drawn to heavy chain only antibodies and VHH.
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 degradation of the transmembrane 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 antibody that permits simultaneous binding to RNF149 and a transmembrane protein which causes degradation of the transmembrane protein, rather than by identifying the sequence/structure, namely the CDRs, for the bi-specific antibody of the heterobifunctional molecule in question is generally insufficient to provide written description.
The claims are drawn to a broad genus of heterobifunctional molecules that are bi-specific antibodies which are functionally defined by their ability to simultaneously bind to RNF149 and a transmembrane protein and cause degradation of the transmembrane protein without reciting any corresponding structure 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 binding domain that is capable of specific binding to an extracellular portion of RNF149; and ii) a second binding domain that is capable of specific binding to an extracellular portion of a transmembrane protein, wherein simultaneous binding of the heterobifunctional molecule to RNF149 and the transmembrane protein results in degradation of the transmembrane 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.
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 that are bi-specific antibodies that simultaneously bind to RNF149 and a transmembrane protein and cause degradation of the transmembrane protein encompassed by the claims at the time the instant application was filed.
Applicant's arguments filed January 14, 2026 have been fully considered but they are not persuasive.
The Applicant argues that given that claim 1 has been amended by specifying that the first binding domain and the second binding domain bind an extracellular portion of the transmembrane protein the amended claims recite that the heterobifunctional molecule is a bi-specific antibody, thereby limiting the heterobifunctional molecule to a defined structure; the claimed heterobifunctional molecule is now characterized both structurally and functionally.
The Applicant further argues that the skilled person understands that the function of the heterobifunctional molecule as claimed is not limited to any distinctive bispecific antibody. The Applicant asserts that the specification describes bispecific antibodies that can induce proximity of a transmembrane E3 ubiquitin ligase and a targeted transmembrane protein, which induced proximity results in the degradation of the transmembrane protein (see e.g. Fig. 1 of the specification). The Applicant asserts that the claims are supported by e.g. examples 2 and 3 of the specification, showing for different transmembrane E3 ubiquitin ligases (RNF43, RNF167, RNF130, RNF167) and a wide variety of transmembrane proteins (TGFII, EGFR, CTLA4, FLT3, PD1, PD-L1) that a bispecific antibody brings the targeted proteins into close proximity, which results in degradation of the transmembrane protein. The Applicant further asserts that the specification further shows the targeted epitope as such is thus of minor significance, except that it should be located on the extracellular portion of the targeted proteins.
The Applicant also argues that one of ordinary skill in the art would recognize that a description of a representative number of species heterobifunctional molecule encompassed by the pending claims has, in fact, been provided by the present specification. The Applicant asserts, as such, based on the Applicants' disclosure, one of ordinary skill in the art could have reasonably concluded that the inventor had possession of the claimed invention at the effective date of the instant application. The Applicant finally asserts that the skilled person would be able to practice the invention and therefore, the rejection does not hold for the set of the amended claims.
This is not found persuasive for the following reasons:
Contrary to the Applicant’s argument that, based on the Applicants' disclosure, one of ordinary skill in the art could have reasonably concluded that the inventor had possession of the claimed invention at the effective date of the instant application; note that 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. This species of heterobifunctional molecule is not in scope with claimed genus of heterobifunctional molecules (see above).
Such a disclosure does not serve to provide sufficient written description of the claimed genus of heterobifunctional molecules that are bi-specific antibodies that simultaneously bind to RNF149 and a transmembrane protein and cause degradation of the 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 degradation of the transmembrane 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 antibody that permits simultaneous binding to RNF149 and a transmembrane protein which causes degradation of the transmembrane protein, rather than by identifying the sequence/structure, namely the CDRs, for the bi-specific antibody of the heterobifunctional molecule in question is generally insufficient to provide written description.
The claims are drawn to a broad genus of heterobifunctional molecules that are bi-specific antibodies which are functionally defined by their ability to simultaneously bind to RNF149 and a transmembrane protein and cause degradation of the transmembrane protein without reciting any corresponding structure 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 binding domain that is capable of specific binding to an extracellular portion of RNF149; and ii) a second binding domain that is capable of specific binding to an extracellular portion of a transmembrane protein, wherein simultaneous binding of the heterobifunctional molecule to RNF149 and the transmembrane protein results in degradation of the transmembrane 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.
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 that are bi-specific antibodies that simultaneously bind to RNF149 and a transmembrane protein and cause degradation of the transmembrane protein encompassed by the claims at the time the instant application was filed.
Regarding the Applicant’s argument that the claimed heterobifunctional molecule is now characterized both structurally and functionally because claim 1 has been amended to specific that the first binding domain and the second binding domain bind an extracellular portion of the transmembrane protein and because the amended claims recite that the heterobifunctional molecule is a bi-specific antibody, thereby limiting the heterobifunctional molecule to a defined structure; it is noted 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.
This applies to the instant case where the Applicant has not recited any specific structure in the claims for the claimed genus of heterobifunctional molecules that are bi-specific antibodies that correlates with their function of simultaneously bind to RNF149 and a transmembrane protein and cause degradation of the transmembrane protein. Based upon the prior art, skilled artisans would reasonably understand that it is the structure of the CDRs within an 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. 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. 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.
Ultimately, identifying a heterobifunctional molecule simply on the basis of being a bi-specific antibody that permits simultaneous binding to RNF149 and a transmembrane protein which causes degradation of the transmembrane protein, rather than by identifying the sequence/structure, namely the CDRs, for the bi-specific antibody of the heterobifunctional molecule in question is generally insufficient to provide written description.
The above response also applies to the Applicant’s arguments that (a) the skilled person understands that the function of the heterobifunctional molecule as claimed is not limited to any distinctive bispecific antibody, (b) the specification shows the targeted epitope is of minor significance, except that it should be located on the extracellular portion of the targeted proteins, and (c) that one of ordinary skill in the art would recognize that a description of a representative number of species heterobifunctional molecule encompassed by the pending claims has, in fact, been provided by the present specification. As noted above, 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).
The Applicant’s disclosure does not serve to provide sufficient written description of the claimed genus of heterobifunctional molecules that are bi-specific antibodies that simultaneously bind to RNF149 and a transmembrane protein and cause degradation of the transmembrane protein. The claims are drawn to a broad genus of heterobifunctional molecules that are bi-specific antibodies which are functionally defined by their ability to simultaneously bind to RNF149 and a transmembrane protein and cause degradation of the transmembrane protein without reciting any corresponding structure (i.e. CDRs) expected to correlate with this ability as supported by Applicant’s disclosure.
Regarding the Applicant’s argument that the claims are supported by examples 2 and 3 of the specification which show for different transmembrane E3 ubiquitin ligases (RNF43, RNF167, RNF130, RNF167) and a wide variety of transmembrane proteins (TGFII, EGFR, CTLA4, FLT3, PD1, PD-L1) that a bispecific antibody brings the targeted proteins into close proximity, which results in degradation of the transmembrane protein; that the disclosed bispecific antibody used in examples 2 and 3 of the specification is 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.
However, this species of heterobifunctional molecule 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) 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.
This is a New Ground of Rejection necessitated by applicant's amendment. Claims 1, 3-5, 11, and 24-28 are 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).
Independent 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 simultaneous binding of the heterobifunctional molecule to the transmembrane E3 ubiquitin ligase and the transmembrane protein results in degradation of the transmembrane protein, wherein the heterobifunctional molecule is a bi-specific antibody, and wherein the transmembrane E3 ubiquitin ligase is RNF149.
Dependent claim 3 is drawn to the heterobifunctional molecule wherein simultaneous binding of the molecule to the transmembrane E3 ubiquitin ligase and the transmembrane protein results in lysosomal degradation of the transmembrane protein.
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 claims 5 and 25 limit the transmembrane protein is a receptor. Claim 25 further limits the receptor to a receptor involved in cancer.
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.
Claims 26 and 27 limit the heterobifunctional molecules to that wherein the first domain and the second domain are a domain of a heavy chain only antibody. Claim 27 limit the heavy chain antibody to a VHH domain.
Claim 28 limits the heterobifunctional molecule to an Fc region-comprising bi-specific antibody.
Regarding claims 1, 5, 11, and 25, Throsby et al. teach bispecific antibodies (heterobifunctional molecules) that bind a transmembrane E3 ubiquitin ligase (RNF43 or ZNRF3) and a transmembrane 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 protein (e.g. see Abstract).
Regarding claim 25, Throsby et al. also 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 claims 26 and 27, Throsby et al. also teach that the heterobifunctional protein of their invention may compromise an antibody or a part of an antibody (e.g. see page 13, lines 14-16). A part can also be a so-called single domain antibody fragment (e.g. see page 23, lines 7 and 8). Single-domain antibody fragments are mostly engineered from heavy-chain antibodies found in camelids; these are called VHH fragments (or nanobodies) (e.g. see page 23, lines 17-19). Regarding claim 28, Throsby et al. also teach that the bispecific antibodies can comprise the constant domains (Fc part) of a natural antibody (e.g. see page 18, line 32 – page 19, line 1). Full length antibodies, meaning those that comprise an Fc region, are preferred because of their favorable half-life (e.g. see page 20, line 18).
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 claims 3 and 4 which recite the limitations “wherein simultaneous binding of the molecule to the transmembrane E3 ubiquitin ligase and the transmembrane protein results in lysosomal degradation of the transmembrane protein” and “wherein the transmembrane E3 ubiquitin ligase ubiquitinates the transmembrane protein with monoubiquitin, multiubiquitin, Lys48-linked or Lys63-linked polyubiquitin chains,” respectively, Throsby et al., Riching et al., and Hong et al. are silent on these properties. However, silence about a particular property does not necessarily constitute its absence.
The office does not have the facilities and resources to provide the factual evidence needed in order to establish that there is a difference between the materials, i.e., that the claims are directed to new materials and that such a difference would have been considered unexpected by one of ordinary skill in the art, that is, the claimed subject matter, if new, is unobvious. In the absence of evidence to the contrary, the burden is on the Applicant to prove that the claimed materials are different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
Although Throsby et al., Riching et al., and Hong et al. are silent with regard to the lysosomal degradation and monoubiquitin-, multiubiquitin-, Lys48-linked or Lys63-linked polyubiquitination of the transmembrane protein as recited in claims 3 and 4; it is noted that a compound and all of its properties are inseparable; they are one and the same thing (see In re Papesch, CCPA 137 USPQ 43; In re Swinehart and Sfiligoj, 169) USPQ 226 (CCPA 1971)). Therefore, in the absence of evidence to the contrary, 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. would necessarily have the claimed properties recited in claims 3 and 4.
When a claim recites using an old composition or structure (e.g., bispecific antibody targeting an extracellular portion of RNF149 and an extracellular portion of a transmembrane protein) and the use is directed to a result or property of that composition or structure (properties recited in claims 3 and 4) then the claim is anticipated. See MPEP 2112.02. Also, see Bristol-Myers Squibb Co. v. Ben Venue Laboratories, Inc. 58 USPQ2d 1508 (CA FC 2001); Ex parte Novitski 26 USPQ 1389 (BPAI 1993); Mehl/Biophile International Corp. V. Milgraum, 52 USPQ2d 1303 (Fed. Cir. 1999); Atlas Powder Co. V. IRECO, 51 USPQ2d 1943 (Fed. Cir. 1999).
The Courts have held that there is no requirement that those of ordinary skill in the art know of the inherent property. See MPEP 2131.01(d) and MPEP 2112 - 2113.
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.
This is a New Ground of Rejection necessitated by applicant's amendment. Claims 1 and 6 are 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 de 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 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 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.
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.
This is a New Ground of Rejection necessitated by applicant's amendment. Claims 1, 3-5, 11, and 24-28 are 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).
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 simultaneous binding of the heterobifunctional molecule to the transmembrane E3 ubiquitin ligase and the transmembrane protein results in degradation of the transmembrane protein, wherein the heterobifunctional molecule is a bi-specific antibody, and wherein the transmembrane E3 ubiquitin ligase is RNF149.
Claims 1-21 of the ‘668 Application are drawn to a method for identifying an effective combination of a transmembrane E3 ubiquitin ligase and a membrane-bound protein, wherein the combination is effective when the transmembrane E3 ubiquitin ligase is capable of decreasing the surface level of the membrane- bound protein upon simultaneous binding to a heterobifunctional molecule, and wherein the method comprises the steps of a) Providing a cell, wherein the cell expresses the transmembrane E3 ubiquitin ligase and the membrane-bound protein at its cell surface; b) Exposing the cell to the heterobifunctional molecule, wherein the heterobifunctional molecule comprises: i) a first binding domain capable of specific binding to an extracellular portion of the transmembrane E3 ubiquitin ligase; and ii) a second binding domain capable of specific binding to an extracellular portion of the membrane-bound protein; and c) determining the surface level of the membrane-bound protein of the cell, wherein a decrease in the surface level of the membrane-bound protein indicates that the combination is an effective combination.
It is noted that ‘668 Application uses a generic version of the instant product in its method. It is noted that the ‘668 Application’s method of using the product would anticipate the instantly claimed product because one cannot practice the method without the product.
The claims of the ‘668 Application differ from the instant invention by not reciting that the heterobifunctional molecule is a bispecific antibody or that the E3 ubiquitin ligase is RNF149.
The teachings of Throsby et al., Riching et al., and Hong et al. are outlined in the 103 rejection above.
It would be obvious to one of ordinary skill in the art to have modify the claims in ‘668 Application to incorporate the teachings of Throsby et al., Riching et al., and Hong et al. to include that the heterobifunctional molecule is a bispecific antibody or that the E3 ubiquitin ligase is 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.).
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 PROTACs, which comprise a E3 ubiquitin ligase binding domain fused to a target binding domain, are designed to induce target degradation, Throsby et al. teach bispecific antibodies that are essentially a PROTACs, RNF149, a E3 ubiquitin ligase, 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 be obvious to a skilled artisan to modify the heterobifunctional molecules taught by the ‘668 Application to specifically be bispecific antibodies that target RNF149 with a reasonable expectation of success. A skilled artisan would reasonably expect the heterobifunctional bispecific antibodies that simultaneously bind RNF149 and a transmembrane protein to bring the target transmembrane protein into proximity with RNF149 for ubiquitination of the target transmembrane protein and, in turn, its degradation.
Regarding claims 3 and 4 which recite the limitations “wherein simultaneous binding of the molecule to the transmembrane E3 ubiquitin ligase and the transmembrane protein results in lysosomal degradation of the transmembrane protein” and “wherein the transmembrane E3 ubiquitin ligase ubiquitinates the transmembrane protein with monoubiquitin, multiubiquitin, Lys48-linked or Lys63-linked polyubiquitin chains,” respectively, the ‘668 Application, Throsby et al., Riching et al., and Hong et al. are silent on these properties. However, silence about a particular property does not necessarily constitute its absence.
The office does not have the facilities and resources to provide the factual evidence needed in order to establish that there is a difference between the materials, i.e., that the claims are directed to new materials and that such a difference would have been considered unexpected by one of ordinary skill in the art, that is, the claimed subject matter, if new, is unobvious. In the absence of evidence to the contrary, the burden is on the Applicant to prove that the claimed materials are different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
Although the ‘668 Application, Throsby et al., Riching et al., and Hong et al. are silent with regard to the lysosomal degradation and monoubiquitin-, multiubiquitin-, Lys48-linked or Lys63-linked polyubiquitination of the transmembrane protein as recited in claims 3 and 4; it is noted that a compound and all of its properties are inseparable; they are one and the same thing (see In re Papesch, CCPA 137 USPQ 43; In re Swinehart and Sfiligoj, 169) USPQ 226 (CCPA 1971)). Therefore, in the absence of evidence to the contrary, the bispecific antibody targeting an extracellular portion of RNF149 and an extracellular portion of a transmembrane protein taught by the ‘668 Application in view of Throsby et al., Riching et al., and Hong et al. would necessarily have the claimed properties recited in claims 3 and 4.
When a claim recites using an old composition or structure (e.g., bispecific antibody targeting an extracellular portion of RNF149 and an extracellular portion of a transmembrane protein) and the use is directed to a result or property of that composition or structure (properties recited in claims 3 and 4) then the claim is anticipated. See MPEP 2112.02. Also, see Bristol-Myers Squibb Co. v. Ben Venue Laboratories, Inc. 58 USPQ2d 1508 (CA FC 2001); Ex parte Novitski 26 USPQ 1389 (BPAI 1993); Mehl/Biophile International Corp. V. Milgraum, 52 USPQ2d 1303 (Fed. Cir. 1999); Atlas Powder Co. V. IRECO, 51 USPQ2d 1943 (Fed. Cir. 1999).
The Courts have held that there is no requirement that those of ordinary skill in the art know of the inherent property. See MPEP 2131.01(d) and MPEP 2112 - 2113.
Therefore, the claims in the ‘668 Application would render the instant claim obvious.
This is a provisional nonstatutory double patenting rejection because the claims have not in fact been patented.
This is a New Ground of Rejection necessitated by applicant's amendment. Claims 1 and 6 are 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).
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 simultaneous binding of the heterobifunctional molecule to the transmembrane E3 ubiquitin ligase and the transmembrane protein results in degradation of the transmembrane protein, wherein the heterobifunctional molecule is a bi-specific antibody, and wherein the transmembrane E3 ubiquitin ligase is RNF149.
Claims 1-21 of the ‘668 Application are drawn to a method for identifying an effective combination of a transmembrane E3 ubiquitin ligase and a membrane-bound protein, wherein the combination is effective when the transmembrane E3 ubiquitin ligase is capable of decreasing the surface level of the membrane- bound protein upon simultaneous binding to a heterobifunctional molecule, and wherein the method comprises the steps of a) Providing a cell, wherein the cell expresses the transmembrane E3 ubiquitin ligase and the membrane-bound protein at its cell surface; b) Exposing the cell to the heterobifunctional molecule, wherein the heterobifunctional molecule comprises: i) a first binding domain capable of specific binding to an extracellular portion of the transmembrane E3 ubiquitin ligase; and ii) a second binding domain capable of specific binding to an extracellular portion of the membrane-bound protein; and c) determining the surface level of the membrane-bound protein of the cell, wherein a decrease in the surface level of the membrane-bound protein indicates that the combination is an effective combination.
It is noted that ‘668 Application uses a generic version of the instant product in its method. It is noted that the ‘668 Application’s method of using the product would anticipate the instantly claimed product because one cannot practice the method without the product.
The combined teachings of the ‘668 Application in view of Throsby et al., Riching et al., and Hong et al. pertaining to claim 1, and the rationale for combining them are outlined in the NSDP rejection above.
The combined teachings do not teach that the transmembrane protein is LRP6.
The teachings of Liu et al. are outline in the 103 rejection above.
It would be to one of ordinary skill in the art to modify the combined teachings of the ‘668 Application in view of Throsby et al., 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 be 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 the ‘668 Application in view of Throsby et al., Riching et al., and Hong et al. to specifically bind the transmembrane protein LRG6 with a reasonable expectation of success. A skilled artisan would reasonably expect 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 claims in the ‘668 Application would render the instant claim obvious.
This is a provisional nonstatutory double patenting rejection because the claims have not in fact been patented.
Conclusion
No claim is allowed
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Grace H. Lunde whose telephone number is (703)756-1851. The examiner can normally be reached Monday - Thursday 6:00 a.m. - 3:00 p.m. (EST).
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/GRACE H LUNDE/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641