DETAILED CORRESPONDENCE
Status of the Application
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-18, 22-24, 27-29, and 31-32 are pending.
Election
Applicant’s election without traverse of
Group I, claims 1-18 and 31-32, drawn to the technical feature of a proteasomal degradation protein complex comprising an E3 ubiquitin ligase component tethered to an alpha-synuclein-specific peptide binder, wherein the proteasomal degradation protein complex is capable of targeting alpha-synuclein for proteasomal degradation; one or more nucleic acid constructs encoding the proteasomal degradation protein complex; an expression construct comprising the nucleic acid construct; a vector comprising the expression construct; a pharmaceutical composition comprising the proteasomal degradation protein complex, one or more nucleic acid constructs encoding the proteasomal degradation protein complex, an expression construct comprising the one or more nucleic acid constructs, or a vector comprising the expression construct and a pharmaceutically acceptable carrier or diluent; and a kit comprising the proteasomal degradation protein complex, one or more nucleic acid constructs encoding the proteasomal degradation protein complex, an expression construct comprising the one or more nucleic acid constructs, or a vector comprising the expression construct and a pharmaceutically acceptable carrier or diluent, and
the species of the A53T point mutation of the alpha-synuclein of SEQ ID NO: 11,
in the reply filed 06/25/2026 is acknowledged.
Claims 22-24 and 27-29 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/25/2026.
Claims 1-18 and 31-32 are being examined on the merits only to the extent they read on the elected subject matter.
Priority
The instant application is a national stage filing under 35 U.S.C. 371 of international application PCT/GB2022/053257 filed 12/15/2022, which claims foreign priority to United Kingdom Application No. 2118272.0 filed 12/16/2021.
Information Disclosure Statement
The Information Disclosure Statement (IDS) submitted on 06/14/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS has been considered by the examiner.
The listing of references in the specification beginning on page 59 is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Objections to Specification
The disclosure is objected to because of the following informalities.
The use of the terms POLYBRENE, STARBRIGHT, CHEMIDOC, ALEXA FLUOR, ADOBE, XBRIDGE, ORBITRAP, DIONEX, NANOVIPER, PROTAC
which are trade names or marks used in commerce, have been noted in this application on pages 34-37, and 39. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM, or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on page 34. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Appropriate correction is required.
Objections to Drawings
The drawings are objected to under 37 CFR 1.83(a) because they fail to show any red line in Figure 4D as described in the specification on page 43, and they fail to show any red or blue markings in Figure 8C as described in the specification on page 23. Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d).
The drawings are objected to because Figure 2A comprises two panels without distinction in the description, Figure 2B comprises seven panels without distinction in the description and Figure 2C comprises four panels without distinction in the description.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action.
The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 6 is objected to for the typo in the phrase “CUL3 orCUL4”. In the interest of improving claim form, Applicant should consider an amendment to recite “CUL3 or CUL4”.
Claim 7 is objected to for the phrase “comprises a sequence that is at least 60% identical to wild type VHL … at least 70, 80% … or 99% identical to wild type VHL”. In the interest of improving claim form, Applicant should consider an amendment to recite “comprises a sequence sharing at least 60% identity with wild type VHL … at least 70%, 80% … or 99% identity with wild type VHL”.
Claim 12 is objected to for the phrase “comprising … a sequence that is at least 60, 70% … identical thereto”. In the interest of improving claim form, Applicant should consider an amendment to recite “comprising … a sequence sharing at least 60% 70% … identity with SEQ ID NO: 3”.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 3-4, 7-8, 11 and 15 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 3 is indefinite for the phrase “wherein the α-synuclein-specific polypeptide binder binds to a target epitope in the C-terminal region of the α-synuclein protein”. As there are no specific bounds of the α-synuclein to define the recited C-terminal region, one of ordinary skill in the art would be unable to determine whether the binding location of an α-synuclein-specific polypeptide binder falls within the scope of the claims.
Claim 4 is indefinite for the phrase “wherein the α-synuclein-specific polypeptide binder is NbSYN87 or a functional variant thereof which comprises a sequence that is at least 70% … identical to NbSYN87”. As there is no nucleic acid or amino acid sequence recited in the claim, one of skill in the art would be unable to determine whether an α-synuclein falls within the scope of the claim.
Additionally, claim 4 is indefinite for the phrase “wherein the α-synuclein-specific polypeptide binder targets the same epitope on α-synuclein as NbSYN87”. As there is no limitation for the epitope bound by NbSYN87, it is unclear what epitope is intended to be bound by the claimed α-synuclein-polypeptide binder.
Additionally claim 4 is indefinite for the phrase “wherein the α-synuclein-specific polypeptide binder with a similar affinity as NbSYN87”. It is entirely unclear what is intended to be limited by the recitation of this phrase.
Claim 7 is indefinite for the phrases “suitably wherein the functional variant comprises a sequence that is at least 60% identical to wild type VHL” and “preferably at least 70% … identical to wild type VHL”, as MPEP 2173.05(c) states claims that recite the use of narrow numerical range that falls within a broader range in the same claim may render the claim indefinite, as it is unclear whether the narrower or broader range is being limited by the claim.
Additionally, claim 7 is indefinite for the recitation of the terms “suitably” and preferably”, as these terms are considered exemplary claim language according to MPEP 2173.05(d), wherein examples and preferences may lead to confusion over the intended scope of the claim. In the instant claim, it is not clear whether the narrower ranges that are “suitable” or “preferable” are limitations.
Claim 8 is indefinite for the phrase “wherein the α-synuclein protein is targeted for degradation by ubiquitin-mediated proteasomal degradation. As claim 8 depends from claim 1 which recites “wherein the proteasomal degradation complex is capable of targeting α-synuclein for proteasomal degradation”, it is unclear how the limitation in claim 8 differs from that of claim 1.
Claim 11 is indefinite for the term “functional variant” in the phrase “wherein the E3 ligase component is VHL or a functional variant thereof and the α-synuclein-specific peptide binder is NbSYN87 or a functional variant thereof” because it is unclear as to the intended function of the “functional variant thereof.” It is suggested that applicant clarify the meaning of the recited phrase.
Claim 15 is indefinite for the phrase “a gene therapy vector, suitably a viral vector, suitably an AAV vector, an adenoviral vector, a retroviral vector or a lentiviral vector”, as the claim recites multiple instances of broad limitations with narrow limitations. For example, “a gene therapy vector” is a broad limitation whereas “a viral vector” is a narrower limitation of “a gene therapy vector”. Additionally, “a viral vector” can be considered a broad limitation whereas “an AAV vector, an adenoviral vector, a retroviral vector or a lentiviral vector” are considered narrower limitations of “a viral vector”. As written, it is unclear which limitation is intended to be limiting according to MPEP 2173.05(c).
Additionally, claim 15 is indefinite for the recitation of the terms “suitably” and preferably”, as these terms are considered exemplary claim language according to MPEP 2173.05(d), wherein examples and preferences may lead to confusion over the intended scope of the claim. In the instant claim, it is not clear whether the narrower ranges that are “suitable” or “preferable” are limitations.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-2, 8, 16-18 and 31 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Du et al. (ACS Central Sci, 2020, 11:2362; cited on the IDS filed 06/14/2024; herein Du).
Claim 1 is drawn to a proteasomal degradation protein complex comprising an E3 ubiquitin ligase component tethered to an α-synuclein (AS)-specific polypeptide binder, wherein the proteasomal degradation protein complex is capable of targeting AS for proteasomal degradation.
Claim 2 is drawn to the complex of claim 1, wherein the AS-specific polypeptide is an antibody, an antibody fragment, a monobody and/or a nanobody.
Claim 8 is drawn to the complex of claim 1, wherein the AS protein is target for degradation by ubiquitin-mediated proteasomal degradation system.
Claim 16 is drawn to a pharmaceutical composition comprising the complex of claim 1, one or more nucleic acid constructs encoding the proteasomal degradation protein complex, an expression construct comprising the one or more nucleic acid constructs operably linked to one or more expression control sequences, or a vector comprising the expression construct and a pharmaceutically acceptable carrier or diluent.
Claim 17 is drawn to the proteasomal degradation protein complex of claim 1, one or more nucleic acid constructs encoding the proteasomal degradation protein complex, an expression construct comprising the one or more nucleic acid constructs operably linked to one or more expression control sequences, a vector comprising the expression construct, or a pharmaceutical composition comprising the proteasomal degradation protein complex, the one or more nucleic acid constructs, the expression construct, the vector and a pharmaceutically acceptable carrier or diluent for use in the treatment of a subject with a neurodegenerative disorder.
Claim 18 is drawn to the use in accordance with claim 17, wherein the neurodegenerative disorder is a synucleinopathy; or wherein the neurodegenerative disorder is Parkinson's disease, dementia and/or multiple system atrophy; or wherein the proteasomal degradation protein complex targets a-synuclein for proteasomal degradation; or wherein the subject has a SNCA duplication, SNCA triplication or an A53T, A30P, H50Q, E46K, G51D and/or A53E point mutation of SEQ ID NO: 11.
Claim 31 is drawn to the proteasomal degradation protein complex of claim 1, one or more nucleic acid constructs encoding the proteasomal degradation protein complex, an expression construct comprising the one or more nucleic acid constructs operably linked to one or more expression control sequences, a vector comprising the expression construct, or a pharmaceutical composition comprising the proteasomal degradation protein complex, the one or more nucleic acid constructs, the expression construct, the vector and a pharmaceutically acceptable carrier or diluent for use as a research tool to target.
Du relates to bioadaptors for cytosolic delivery of native antibodies [title].
Regarding claims 1-2, Du discloses a cell-permeant bioadaptor derived from TRIM21 with an antibody which mediates endogenous protein degradation via TRIM21 [abstract], wherein the protein being target is AS via an anti-AS antibody [Figure 6].
Regarding claim 8, the limitation “wherein the AS protein is target for degradation by ubiquitin-mediated proteasomal degradation system” is considered an intended use of the claimed proteasomal degradation complex according to MPEP 2111.02, and does not limit the structure of the claimed complex. As the disclosure of Du satisfies the structural limitations of the complex of claim 1, it is considered to satisfy the structural limitations recited in claim 8.
Regarding claim 16, the limitations of the claim are presented as linked by the conjunction “or” and are therefore considered to be alternatives, wherein “a vector comprising the expression construct and a pharmaceutically acceptable carrier or diluent” are considered to be required together in view of their connection with the conjunction “and”. As the complex of Du is delivered to cell culture and resulted in the reduction of detectable AS [Figure 6], the complex of Du is considered to be encompassed by the limitation of a pharmaceutical composition comprising the proteasomal complex of claim 1.
Regarding claim 17, the limitations in lines 1-10 are considered to be alternatives in view of the conjunction “or” to link them, and therefore claim is only required to have one of:
the proteasomal degradation complex of claim 1,
one or more nucleic acid constructs encoding the proteasomal degradation complex,
an expression construct comprising the one or more nucleic acid constructs operably linked to one or more expression control sequences,
a vector comprising the expression construct, or
a pharmaceutical composition comprising:
the proteasomal degradation complex,
the one or more nucleic acid constructs,
the expression construct,
the vector and a pharmaceutically acceptable carrier or diluent.
The final limitation in claim 17 of “for use in the treatment of a subject with a neurodegenerative disorder” is considered an intended use of the claimed proteasomal degradation complex according to MPEP 2111.02, and does not limit the structure of the claimed complex. As the complex of Du satisfies the structural limitations of the proteasomal complex of claim 1, it is considered to satisfy the limitations of claim 17.
Regarding claim 18, the limitations of the claims are drawn to the intended use of the proteasomal complex of claim 1 as discussed in the rejection of claim 17 above, and as such the limitations of the neurodegenerative disorder is considered to further limit the intended use according to MPEP 2111.02, and as such does not limit the structure of the proteasomal complex of claim 1. As the complex of Du satisfies the structural limitations of the proteasomal complex of claim 1, it is considered to satisfy the limitations of claim 18.
Regarding claim 31, the limitations in lines 1-10 are considered to be alternatives in view of the conjunction “or” to link them, and therefore claim is only required to have one of:
the proteasomal degradation complex of claim 1,
one or more nucleic acid constructs encoding the proteasomal degradation complex,
an expression construct comprising the one or more nucleic acid constructs operably linked to one or more expression control sequences,
a vector comprising the expression construct, or
a pharmaceutical composition comprising:
the proteasomal degradation complex,
the one or more nucleic acid constructs,
the expression construct,
the vector and a pharmaceutically acceptable carrier or diluent.
The final limitation in claim 31 of “for use as a research tool to target” is considered an intended use of the claimed proteasomal degradation complex according to MPEP 2111.02, and does not limit the structure of the claimed complex. As the complex of Du satisfies the structural limitations of the proteasomal complex of claim 1, it is considered to satisfy the limitations of claim 31.
For these reasons, Du anticipates claims 1-2, 8, 16-18 and 31.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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 3-4, 10 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Du in view of WO 2011/147890 A1 (cited on the attached Form PTO-892; herein VZW).
Claim 3 is drawn to the proteasomal degradation protein complex of claim 1, wherein the AS-specific polypeptide binder binds to a target epitope in the C-terminal region of the AS protein, that is capable of degrading AS.
Claim 4 is drawn to the proteasomal degradation protein complex of claim 1, wherein the a-synuclein-specific polypeptide binder is NbSYN87 or a functional variant thereof which comprises a sequence that is at least 70, 80%, 90%, 95% or 99% identical to NbSYN87; or wherein the AS-specific polypeptide binder targets the same epitope on a-synuclein as NbSYN87; or wherein the AS-specific polypeptide binder with a similar or higher affinity as NbSYN87.
Claim 10 is drawn to one or more nucleic acid constructs encoding the proteasomal degradation protein complex of claim 1.
Claim 32 is drawn to the a kit comprising the proteasomal degradation protein complex of claim 1, one or more nucleic acid constructs encoding the proteasomal degradation protein complex, an expression construct comprising the one or more nucleic acid constructs operably linked to one or more expression control sequences, a vector comprising the expression construct, or a pharmaceutical composition comprising the proteasomal degradation protein complex, the one or more nucleic acid constructs, the expression construct, the vector and a pharmaceutically acceptable carrier or diluent, and instructions for use.
The teachings of Du as applied to claims 1-2, 8, 16-18 and 31 are discussed above. Du does not teach the binding of an AS-specific polypeptide binder to a target epitope in the C-terminus of AS.
VZW relates to epitope tags for affinity-based applications [title], and discusses fusion proteins, methods for preparing fusion proteins, nucleic acid molecules encoding fusion proteins, nanobodies specifically recognizing epitope tags and uses thereof in affinity-based applications [abstract].
Regarding claims 3-4, VZW teaches the nanobody Nb87 which binds the C-terminal end of AS [p 28, lines 30-34], wherein the Nb87 nanobody shares 100% sequence identity with NbSyn87 recited in the claims [see Appendix A], as NbSyn87 is disclosed by the instant specification on [page 3] to be the nanobody according to SEQ ID NO: 12.
In view of VZW, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to modify the complex of Du by using Nb87 of VZW, since the simple substitution of one known element for another results in a predictable result. One of ordinary skill in the art would have recognized that the anti-AS antibody of Du and Nb87 of VZW are both antibodies that bind AS, and as such both are capable of being incorporated into such complexes as described Du. Thus it would have been obvious to one of ordinary skill in the art to replace the anti-AS antibody of Du with the Nb87 of VZW, as one of ordinary skill in the art would have been able to carry out such a substitution with a reasonable expectation of success because both the VZW and Du relate to the use of antibodies that bind AS.
Regarding claim 10, VZW teaches fusion constructs of GFP hybrids and their expression in E. coli using standard DNA cloning techniques to determine the binding site of the Nb87 antibody [p 28, lines 32-33 and p 29, lines 1-9], which is considered to correspond to generation of nucleic acid constructs encoding proteins. It would have been obvious to one of ordinary skill in the art before the effective filing date to similarly express the components of the combined complex of Du and VZW in one or more nucleic acid constructs encoding these components.
Regarding claim 32, the limitations in lines 1-12 are considered to be alternatives in view of the conjunction “or” to link them, and therefore the kit of claim 32 is only required to contain instructions for use, and one of:
the proteasomal degradation complex of claim 1,
one or more nucleic acid constructs encoding the proteasomal degradation complex,
an expression construct comprising the one or more nucleic acid constructs operably linked to one or more expression control sequences,
a vector comprising the expression construct, or
a pharmaceutical composition comprising:
the proteasomal degradation complex,
the one or more nucleic acid constructs,
the expression construct,
the vector and a pharmaceutically acceptable carrier or diluent.
As Du teaches the components of the proteasomal complex of claim 1, and the use of said components for the reduction of AS abundance in cell culture as described in the rejection of claim 1, it would have been obvious for one of ordinary skill in the rt to combine the components of the complex of Du in a reagent kit, as it is routine in the art to optimize methods for reproducibility of results that would include the incorporation of necessary reagents into a kit.
Regarding the instructions for use recited by claim 32, as the instructions do not pertain to the structure of the product (i.e., a kit), and are broadly interpreted to pertain to the method for using the kit, no functional relationship is determined to exist, and therefore the limitation of “instructions for use” is given no patentable weight in accordance with MPEP 2111.05.
Therefore, the invention of claims 3-4, 10 and 32 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claims 5-7 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Du in view of Gettemans et al. (Am J Physiol Cell Physiol, 2021, 320:C195; cited on the attached Form PTO-892; herein Gettemans).
Claim 5 is drawn to the proteasomal degradation protein complex of claim 1, wherein the E3 ubiquitin ligase component is a Cullin ring E3 ligase complex substrate receptor.
Claim 6 is drawn to the proteasomal degradation protein complex of claim 1, wherein the E3 ubiquitin ligase component is capable of recruiting a-synuclein to any of CUL2-CRL, CUL3 or CUL4.
Claim 7 is drawn to the proteasomal degradation protein complex of claim 1, wherein the E3 ubiquitin ligase component is the von-Hippel Lindau tumor suppressor (VHL) or a functional variant thereof, suitably wherein the functional variant comprises a sequence that is at least 60% identical to wild type VHL, preferably at least 70, 80%, 90%, 95% or 99% identical to wild type VHL.
Claim 9 is drawn to the proteasomal degradation protein complex of claim 1 which is an affinity-directed protein missile (AdPROM).
The teachings of Du as applied to claims 1-2, 8, 16-18 and 31 are discussed above. Du does not teach the E3 ubiquitin ligase component is a Cullin ring E3 ligase complex substrate receptor.
Gettemans relates to transforming nanobodies into high-precision tools for protein function analysis [title] and discusses the use of single domain antibodies and nanobodies and the ability to alter their primary structure while retaining specificity and biological activity for use in intracellular delivery, capturing devices, reversible binding of targets, and as protein-slicing devices in cells [abstract].
Regarding claims 5-7 and 9, Gettemans teaches the use of nanobodies in protein silencing comprising VHL [Figure 2C], which is considered to correspond to a Cullen ring E3 Ligase complex substrate receptor (corresponding to claims 5 and 7) that is capable of recruiting a protein of interest to CUL2-CRL (corresponding to claim 6) as Gettemans describes that nanobodies are coupled to the substrate recognition domain of the E3 cullin-RING ubiquitin ligase (CRL) complexes [p C206, col 2, para 3]. The complex of Gettemans additionally is considered an AdPROM [Figure 2C] corresponding to claim 9.
In view of Gettemans, it would have been prima facie obvious for one of ordinary skill in the art to modify the complex of Du by using the VHL protein of Gettemans, since the simple substitution of one known element for another results in a predictable result. One of ordinary skill in the art would have recognized that the TRIM21 of Du and VHL of Gettemans are both E3 ubiquitin ligase components, and as such both are capable of being incorporated into such complexes as described Du. Thus it would have been obvious to one of ordinary skill in the art to replace the TRIM21 of Du with the VHL of Gettemans, as one of ordinary skill in the art would have been able to carry out such a substitution with a reasonable expectation of success because Gettemans and Du relate to the use of E3 ubiquitin ligase complexes to target proteins of interest for degradation.
Therefore, the invention of claims 5-7 and 9 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claims 11 and 13-15 are rejected under 35 U.S.C. 103 as being unpatentable over Du and VZW as applied to claims 3-4, 10, and 32 above, and further in view of Gettemans.
Claim 11 is drawn to the one or more nucleic acid constructs of claim 10, wherein the E3 ligase component is VHL or a functional variant thereof and the AS-specific polypeptide binder is NbSYN87 or a functional variant thereof.
Claim 13 is drawn to an expression construct comprising the nucleic acid construct of claim 10 operably linked to one or more expression control sequences.
Claim 14 is drawn to a vector comprising the expression construct of claim 13.
Claim 15 is drawn to the vector of claim 14, which is a gene therapy vector, suitably a viral vector, suitably an AAV vector, an adenoviral vector, a retroviral vector or a lentiviral vector.
The teachings of Du and VZW as applied to claims 1-4, 8, 10, 16-18 and 31-32 are discussed above, and include a complex comprising an E3 ligase component with the AS-specific antibody Nb87 of VZW, as well as one or more nucleic acids encoding the components of the complex. These references do not teach the E3 ligase component is VHL or a functional fragment thereof.
Gettemans relates to transforming nanobodies into high-precision tools for protein function analysis [title] and discusses the use of single domain antibodies and nanobodies and the ability to alter their primary structure while retaining specificity and biological activity for use in intracellular delivery, capturing devices, reversible binding of targets, and as protein-slicing devices in cells [abstract].
Regarding claim 11, Gettemans teaches the use of nanobodies in protein silencing comprising complexing with CUL2 proteins and VHL [Figure 2C] which is considered to correspond to the von-Hippel Lindau tumor suppressor.
In view of Gettemans, it would have been prima facie obvious for one of ordinary skill in the art to modify the combined complex of Du and VZW by using the VHL protein of Gettemans, since the simple substitution of one known element for another results in a predictable result. One of ordinary skill in the art would have recognized that the TRIM21 of Du and VHL of Gettemans are both E3 ubiquitin ligase components, and as such both are capable of being incorporated into such complexes as described Du. Thus it would have been obvious to one of ordinary skill in the art to replace the TRIM21 of Du with the VHL of Gettemans, as one of ordinary skill in the art would have been able to carry out such a substitution with a reasonable expectation of success because Gettemans and Du relate to the use of E3 ubiquitin ligase complexes to target proteins of interest for degradation.
Regarding claim 13, VZW teaches fusion constructs of GFP hybrids and their expression in E. coli using standard DNA cloning techniques to determine the binding site of the Nb87 antibody [p 28, lines 32-33 and p 29, lines 1-9], which is considered to correspond to an expression construct comprising a nucleic acid construct operably linked to one or more expression control sequences.
Regarding claim 14, VZW teaches the incorporation of nucleic acid constructs into a vector [p 29, line 7].
Regarding claim 15, VZW teaches the use of a phage display vector [p 31, lines 3-4], which is considered to correspond to a viral vector.
Therefore, the invention of claims 11 and 13-15 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Du, VZW and Gettemans as applied to claims 3-4, 10-11, 13-15, and 32above, and further in view of WO 2013/070984 A1 (cited on the attached Form PTO-892; herein Bayer).
Claim 12 is drawn to the one or more nucleic acid constructs of claim 10, comprising the nucleotide sequence of SEQ ID NO: 3 or a sequence that is at least 60, 70%, 80%, 90%, 95% or 99% identical thereto.
The teachings of Du, VZW and Gettemans as applied to claims 1-4, 8, 10-11, 13-18 and 31-32 are discussed above. These references do not teach one or more nucleic acid constructs comprising the nucleotide sequence of SEQ ID NO: 3 or a sequence that is at least 60, 70%, 80%, 90%, 95% or 99% identical thereto.
Bayer relates to systems and methods for gene expression analysis in multiple sclerosis [title] and discusses gene expression analysis [para 00009] and biomarker detection [para 000010].
Regarding claim 12, Bayer teaches a gene expression profile through the analysis of gene signatures using probes to detect specific genes [para 000038] including the gene encoding VHL [p 33, Table 5] which is a nucleic acid comprising a sequence that shares at least 99% sequence identity with SEQ ID NO: 3 [see Appendix B]. As the combined complex of Du, VZW and Gettemans comprises one or more nucleic acids encoding the components of the complex, it would have been obvious for one of ordinary skill in the art to use the sequence of Bayer for the E3 ubiquitin ligase component.
In view of Bayer, it would have been prima facie obvious for one of ordinary skill in the art to modify the combined complex of Du, VZW and Gettemans by using the nucleotide sequence of Bayer, since the simple substitution of one known element for another results in a predictable result. One of ordinary skill in the art would have recognized that the nucleotide sequence encoding the VHL of Gettemans and the nucleotide sequence of Bayer encoding VHL both correspond to functional E3 ubiquitin ligase components, and as such both are capable of being incorporated into such complexes as described Du. Thus it would have been obvious to one of ordinary skill in the art to replace the nucleotide sequence encoding the VHL of Gettemans with the nucleotide sequence encoding VHL of Bayer, as one of ordinary skill in the art would have been able to carry out such a substitution with a reasonable expectation of success because Gettemans and Bayer relate to VHL.
Therefore, the invention of claim 12 would have been obvious to one of ordinary skill in the art before the effective filing date.
Conclusion
Status of the Application:
Claims 1-18, 22-24, 27-29, and 31-32 are pending.
Claims 22-24 and 27-29 are withdrawn.
Claims 1-18 and 31-32 are rejected.
No claim is in condition for allowance.
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/JOSEPH R SPANGLER/
Examiner
Art Unit 1656
/David Steadman/Primary Examiner, Art Unit 1656
APPENDIX A
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324
644
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Sequence alignment of SEQ ID NO: 12, defined in the instant specification as the sequence of NbSYN87, with SED ID NO: 26 of WO 2011/147890 A1 (reference VZW).
APPENDIX B
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329
630
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Sequence alignment of SEQ ID NO: 3 with SEQ ID NO: 135 of WO 2013/070984 A1 (reference Bayer)
Prosecution Insights