Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 1-3, 6, 10, 18, 20-27, and 42-47 are pending.
Claims 1-3, 6, 10, 18, 20-27, and 42-47 are examined on the merits.
Specification
35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, requires the specification to be written in “full, clear, concise, and exact terms.” The specification is replete with terms which are not clear, concise and exact. The specification should be revised carefully in order to comply with 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112. Examples of some unclear, inexact or verbose terms used in the specification are: on page 15 in line 13 “By “fusion protein” is meant a protein that comprises” should be changed to “By “fusion protein” it is meant that a protein portion of fragment of a target protein”.
Claim Objections
Claim 22 is objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim should refer to other claims in the alternative only. See MPEP § 608.01(n). Accordingly, the claim has not been further treated on the merits.
Claim 23 is objected to because of the following informalities: a comma is missing after “The method of claim 18”, see claim 21 for an example which includes the comma. This should be corrected for syntax and consistency in the claims. Appropriate correction is requested.
Claim 22 is objected to because of the following informalities: the claim recites “delivering a fusion protein according to claim 1 comprising a target moiety that is specific for said CRISPR enzyme”. Claim 1 does not recite a “target moiety” but instead recites a “target-binding moiety”. In order to maintain consistency the term “target moiety” in claim 22 should be amended to recite “target-binding moiety”. Appropriate correction is required.
Claim 43 is objected to because of the following informalities: the claim recites “The method of claim 1, wherein the target-binding domain”. Claim 1 does not recite a “target-binding domain” but instead recites a “target-binding moiety”. In order to maintain consistency the term “target binding domain” in claim 43 should be amended to recite “target-binding moiety”. Appropriate correction is required.
Claim Rejections - 35 USC § 112 (Indefiniteness)
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.
Claims 1-3, 6, 10, 18, 20-27, and 42-47 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1-2, 6, 10-, 18, 20, 22, 24, 26 and 42-43 recite “fusion protein”. These recitations render the claims indefinite because the scope imparted upon the claim from this term is unclear.
Specifically, the normal meaning of this term in the art is “a protein that comprises portions (for example, subunits, motifs or domains) from two or more proteins” where “The two or more proteins are typically heterologous proteins”, the quotations from applicant’s specification confirm that normal meaning (Instant specification, Page 15, Lines 13-22).
However, applicant has expanded this definition, by including the following highlighted statements in their definition of “fusion protein”:
“By “fusion protein” is meant a protein that comprises portions (for example, subunits, motifs or domains) from two or more proteins; for example a fusion protein may comprise a SAP05 protein and an immunoglobulin domain. Alternatively, the fusion protein may comprises a bispecific antibody or nanobody (i.e.an antibody with two binding specificities) which can recognize both a vWA domain, or portion thereof and a target protein. The two or more proteins are typically heterologous proteins, but in some circumstances a fusion protein may comprise multiple portions from the same protein. A fusion protein may be encoded by a nucleic acid generated through the joining of two or more genes or motifs or domains from genes that originally coded for separate proteins. Fusion proteins are also known as chimeric proteins” (Instant specification, Page 15, Lines 13-22).
Applicant provides a non-limiting aspect of the invention in the paragraph spanning pages 3-4 of the specification, which appears relevant to the scope of “fusion protein”. In this paragraph Applicant makes clear that the vWA targeting moiety can also be called a vWA binding moiety. In the following paragraph on page 4, Applicant states that the vWA targeting moiety is a SAP05 peptide. Importantly, earlier in lines 13-14 and 24-28 on page 3, Applicant describes SAP05 as a vWA-binding protein and even describes the region of vWA that SAP05 binds.
Given the information presented in the disclosure it appears that “fusion protein” could be reasonably interpreted to refer to the following:
A protein that comprises portions (for example, subunits, motifs or domains) from two or more proteins where the two proteins are heterologous proteins.
A protein with two distinct binding specificities such as an antibody.
A single protein with a vWA targeting moiety and a target-binding moiety. Importantly it appears that the vWA targeting moiety and the target-binding moiety came be the same moiety as appears to be the case in SAP05 which applicant describes as possessing a vWA targeting moiety and also being a vWA binding protein.
Given that there are at least three distinct scopes of the claims imparted by the use of the term “fusion protein” claims 1-2, 6, 10-, 18, 20, 22, 24, 26 and 42-43 are rejected as indefinite. Dependent claims are included.
Claims 1 recites “a von Willebrand factory type A (vWA) targeting moiety and a target-binding moiety”. These recitations render the claims indefinite because the scope imparted upon the claim from this term is unclear.
Specifically, it is unclear whether the vWA targeting moiety and target-binding moiety are distinct regions within the protein or if instead these two elements can be found in the same moiety within a protein.
This is because applicant provides the following information in the specification:
By “vWA targeting moiety” is meant any structure capable of binding to a vWA domain”. Also, the term “vWA targeting moiety” makes clear that vWA is a target.
By “target-binding moiety” is meant any structure capable of binding to a target protein or a portion of fragment of a target protein.
Given these disclosures in the instant specification it is clear that the vWA targeting moiety also binds to the vWA domain and therefore the vWA targeting moiety is also a target binding moiety.
In contrast the claim recites a fusion protein comprising a vWA targeting moiety and a target-binding moiety and given this language the plain meaning of this recitation would indicate that these domains are distinct.
Therefore, given the indefinite language in the claim the metes and bounds of the vWA targeting moiety and the target binding moiety are not clear as there are at least two distinct scopes imparted to the claims by these recitations. One where the fusion protein comprises one moiety which targets and binds vWA and a second moiety which binds to another target and a second where the vWA targeting moiety is also the target binding moiety.
Thus, claim 1 is rejected as indefinite, dependent claims 2-3, 6, 10, 18, 21, 23-27, and 42-45 and 47 are included.
Claim 10 is rejected for reciting 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 10 recites the broad recitation "The fusion protein of claim 1, wherein the fusion protein further comprises a RPN10 protein or a vWA domain", and the claim also recites "wherein, preferably the RPN10 protein comprises an amino acid sequence as defined in SEQ ID NO: 5, 24 or 26 or a functional variant thereof, wherein said functional variant has at least 75% overall identity to SEQ ID NO: 5, 24 or 26 and wherein the vWA domain comprises an amino acid sequence as defined in SEQ ID NO: 21 or a functional variant thereof, wherein said functional variant has at least 75% overall identity to SEQ ID NO: 21" 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.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 18, 21, 24-25, and 42-44, are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more.
Independent claim 1 recites “a fusion protein comprising a von Willebrand factory type A (vWA) targeting moiety and a target-binding moiety”. As noted above, in the indefiniteness rejections when the plain language of the claims is viewed in light of the specification it appears that applicant has expanded the meaning of the term “fusion protein” to include any protein whatsoever and further that the vWA targeting moiety and the target-binding moiety can be the same structure.
Specifically, the normal meaning of this term in the art is “a protein that comprises portions (for example, subunits, motifs or domains) from two or more proteins” where “The two or more proteins are typically heterologous proteins”, the quotations from applicant’s specification confirm that normal meaning (Instant specification, Page 15, Lines 13-22).
However, applicant has expanded this definition, by including the following highlighted statements in their definition of “fusion protein”:
“By “fusion protein” is meant a protein that comprises portions (for example, subunits, motifs or domains) from two or more proteins; for example a fusion protein may comprise a SAP05 protein and an immunoglobulin domain. Alternatively, the fusion protein may comprises a bispecific antibody or nanobody (i.e.an antibody with two binding specificities) which can recognize both a vWA domain, or portion thereof and a target protein. The two or more proteins are typically heterologous proteins, but in some circumstances a fusion protein may comprise multiple portions from the same protein” (Instant Specification, Page 15, Lines 13-20).
Applicant provides a non-limiting aspect of the invention in the paragraph spanning pages 3-4 of the specification, which appears relevant to the scope of “fusion protein”. In this paragraph Applicant makes clear that the vWA targeting moiety can also be called a vWA binding moiety. In the following paragraph on page 4, Applicant states that the vWA targeting moiety is a SAP05 peptide. Importantly, earlier in lines 13-14 and 24-28 on page 3, Applicant describes SAP05 as a vWA-binding protein and even describes the region of vWA that SAP05 binds.
Given the information presented in the disclosure the term “fusion protein” appears to impart more than one distinct scope to the claims. One of these is as follows:
A single protein with a vWA targeting moiety and a target-binding moiety. Importantly it appears that the vWA targeting moiety and the target-binding moiety came be the same moiety as appears to be the case in SAP05 which applicant describes as possessing a vWA targeting moiety and also being a vWA binding protein.
Therefore, it appears that any protein which comprises at least a vWA-targeting moiety which binds to vWA is considered a fusion protein. Thus any vWA-targeting moiety containing protein is considered to be a fusion protein of the independent claim.
This claimed fusion protein is interpreted to encompass naturally occurring proteins which are products of nature and therefore are a judicial exception. Specifically, Schmidtke is drawn to the role of HLA-F adjacent transcript 10 (FAT10) in protein degradation (Schmidtke, Page 97, Abstract). Schmidtke makes clear that FAT10 comprises two distinct ubiquitin-like (UBL) domains. One of these domains, UBL2 targets and binds to the vWA domain in the 26sproteosome subunit Rpn10 (S5a). Given this function and applicants definition of a vWA targeting moiety it is clear that the UBL2 of FAT10 is a vWA targeting moiety of the claimed invention. Given that the UBL2 domain targets the vWA domain of Rpn10 and also binds to this domain, it appears that UBL2 is also a target-binding domain of the claimed invention (Schmidtke, Page 100, Figure 2 and Figure 2 Legend).
UBL2 is not FAT10’s only target-binding domain. FAT10 also contains a UBL1 domain which binds to the ubiquitin-associated (UBA) domains of NUB1L (Schmidtke, Page 100, Figure 2 and Figure 2 Legend).
Therefore, the naturally occurring FAT10 protein of Schmidtke fits applicant’s definition of fusion protein and comprises a vWA targeting moiety (UBL2, which binds to the vWA domain of RPN10) and a target-binding moiety (UBL1, which binds to the UBA domains of NUB1L).
Thus applicant’s claimed invention is identical to the naturally occurring FAT10 protein described in Schmidtke.
This judicial exception is not integrated into a practical application because it is simply a recitation of a naturally occurring protein and is not integrated into any application practical or otherwise.
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because it is simply a recitation of a naturally occurring phenomenon.
The claim does not add any further limitations or functional language that would amount to anything more than the judicial exception of a naturally occurring FAT10 protein.
Claims 42 and 43 depend on the fusion protein of claim 1 and limit the vWA targeting moiety and the target-binding moiety to a peptide, a cyclic peptide, a binding domain, a small molecule, chemical , a T-cell receptor, an antibody, a functional fragment of an antibody, a nanobody, and an aptamer, respectively. As described above, FAT10 is a naturally occurring counterpart of the fusion protein of claim 1, importantly, the vWA targeting moiety and the target-binding moiety of FAT10 are binding domains (UBL2, which binds to the vWA domain of RPN10 and UBL1, which binds to the UBA domains of NUB1L) (Schmidtke, Page 100, Figure 2 and Figure 2 Legend). Therefore, for the same reasons as claim 1, claims 42 and 43 do not include additional elements that are sufficient to amount to significantly more than the judicial exception because it is simply a recitation of a naturally occurring phenomenon.
Claim 18, 21, 24-25 and 44 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more.
Claim 18 recites “A method of targeted protein degradation, the method comprising applying the fusion protein of claim 1 to a sample, a cell or an organism”, claim 21 limits these methods to targeting a cytosolic protein or a cell surface protein, while claims 24 and 25 are methods of modulating a biochemical response or physiological response in an organism, the method comprising administering the fusion protein of claim 1 to the organism, where the physiological response is an immune response. Claim 44 limits the scope of claim 18 to methods that act in a ubiquitin independent manner.
Thus the claimed methods require the following: applying the fusion protein to a sample, a cell or an organism (Claim 18), where the target is a cytosolic protein or a cell surface protein (Claim 21).
Administering the fusion protein of claim 1 to the organism (Claim 24), where an immune response is modulated (Claim 25) and wherein the mechanism of action is ubiquitin independent (Claim 44).
Given that the claimed fusion protein of independent claim 1 appears to be a product of nature with significantly more, see above for 35 U.S.C. 101 analysis with respect to the fusion protein of claim 1, applicant’s method appears to encompass naturally occurring processes.
The only additional limitation claim 18 adds to the fusion protein of claim 1 is a step of applying the fusion protein to a sample. In determining the broadest reasonable scope of this claim the specification notes that “Applying or administering (such terms may be used interchangeably) may comprise simply adding the fusion protein or expression vector to the sample” (Specification, Page 23, Lines 23-25), while “The sample can be any form of sample that contains the target protein” (Specification, page 23, Line 19).
Therefore any circumstance where the fusion protein of claim 1 is added to any sample comprising the target protein falls within the scope of the claimed invention. This has naturally occurring counterparts such as any time that a FAT10 protein is translated from mRNA into a protein and is therefore added into a solution with its target, the cytosolic protein Rpn10, see above for analysis on FAT10 as a naturally occurring counterpart to the fusion protein of claim 1.
Claim 24 does not appear to add any additional steps compared to claim 18, while claim 25 only adds the limitation that an immune response is modulated. Schmidtke makes clear that FAT10 has a function in the immune system and that FAT10 knockout mice under specific conditions have a mutant phenotype. While, claim 44, does add an additional limitation to claim 18, Schmidtke makes clear that FAT10 acts in a ubiquitin independent manner (Schmidtke, Page 97, Abstract)
This judicial exception is not integrated into a practical application because they are simply recitations of natural phenomena. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because they are simply recitations of naturally occurring phenomena.
The claims do not add any further limitations or functional language that would amount to anything more than the judicial exception of naturally occurring phenomena.
Claim Rejections - 35 USC § 112 (Written Description)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3, 6, 10, 18, 20-27, and 42-47 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Applicant claims a fusion protein comprising a von Willebrand factory type A (vWA) targeting moiety and a target-binding moiety.
This claim is interpreted to mean any protein (see indefiniteness rejections above) comprising anything whatsoever which can target a von Willebrand factor type A (vWA) domain in any target by binding to that domain and which further comprises a second moiety, which can be any structure whatsoever which is capable of binding to a target.
Given the disclosure, it appears that applicants described fusion protein should have a structure such that a target protein could be bound by the target-binding moiety and then this complex recruited to the proteosome complex through binding of the vWA targeting moiety of the fusion protein binding to vWA domains in the proteosome degradation complex including those on Rpn10 (See, figure 2 on page 100 of Schmidtke).
The dependent claims add further limitations on the structure of this fusion protein and provide methods for its use, these are described below. Two dependent claims in particular are of note because the additional limitations that they provide make clear the extremely broad nature of the independent claim.
Claim 42, is drawn to the fusion protein of the independent claim, where the vWA targeting moiety is a peptide, a cyclic peptide, a binding domain, a small molecule, a chemical, a T-cell receptor, an antibody, a functional fragment of an antibody, a nanobody and an aptamer.
This claim makes clear that the scope of the independent claim is even more broad than it appears at first glance. Given the recitation of a fusion protein in the independent claim at first glance it appears that each of the moieties is a domain with a certain requisite function, however claim 42 states that the vWA targeting moiety could be any chemical which can bind to vWA. The specification states with respect to chemical responses that examples of chemicals include toxins or volatile compounds (Specification, Page 29, Lines 14-15), however the specification is silent on how to include these chemicals in the fusion protein.
Claim 43, is identical to claim 42, except that it further limits the target-binding domain of claim 1. Given that claim 1 recites a moiety not a domain and that volatile chemicals may not be protein domains this limitation is interpreted to refer to the target-binding moiety of claim 1 further selected from the recited group. This claim adds breadth for the same reasons as claim 42.
The scope of the dependent claims is as follows:
Claim 2 is drawn to the fusion protein, wherein the vWA targeting moiety binds at least the HS residue at position 38 or the GA residue at position 39 of SEQ ID NO: 2, 21, 24 or 26 or corresponding positions in a homologous sequence of a vWA domain.
Claim 3 is drawn to the fusion protein, wherein the vWA targeting moiety is SAP05 or functional variant thereof having at least 75% sequence identity to the sequence of SEQ ID NO: 1.
Claim 6 is drawn to the fusion protein, wherein the fusion protein comprises a bispecific antibody or nanobody.
Claim 10 is drawn to the fusion protein, wherein the fusion protein further comprises a RPM10 protein or a vWA domain.
Claim 18 is drawn to a method of targeted protein degradation comprising applying the fusion protein of claim 1, to a sample, cell or an organism.
Claim 20 depends on claim 18 and is drawn to the method comprising a step of applying a fluorescently tagged antibody to label a protein of interest prior to applying the fusion protein, which targets the fluorescent tag with its target-binding moiety.
Claim 21 depends on claim 18 and is drawn to the method wherein the target protein is a cytosolic protein or a cell surface protein.
Claim 22 depends on claim 18 and is drawn to the method comprising introducing a CRISPR-Cas system to the sample, cell or organism, allowing the CRISPR-Cas system to edit a gene, delivering the fusion protein comprising a target moiety that is specific for said CRISPR enzyme and allowing the fusion protein to degrade the CRISPR enzyme.
Claim 23 depends on claim 18 and further limits the scope of the claim to those wherein the target protein can cause pathology in a target organism or wherein the target protein is a drug target.
Claim 24 is drawn to a method of modulating a biochemical response or physiological response in an organism, the method comprising administering the fusion protein to the organism.
Claim 25 depends on claim 24 and further limits the claim scope to the following group of physiological responses; stress, immune, hormone or light.
Claim 26 is drawn to a method of treating a condition in a patient in need thereof, the method comprising administering the fusion protein to the patient in need thereof.
Claim 27 depends on claim 26 and further limits the claim to conditions characterized by increased expression or activity of a target protein and the target-binding moiety is specific for said target protein.
Claim 42 is drawn to the fusion protein where the vWA targeting moiety is selected from the group consisting of a peptide, cyclic peptide, binding domain, small molecule, chemical, t-cell receptor, antibody, functional fragment of an antibody, nanobody and an aptamer.
Claim 43 is drawn to the fusion protein, wherein the target-binding moiety is selected from the group consisting of a peptide, cyclic peptide, binding domain, small molecule, chemical, t-cell receptor, antibody, functional fragment of an antibody, nanobody and an aptamer.
Claim 44 depends on claim and further limits the targeted protein degradation to ubiquitin-independent degradation.
Claim 45 depends on claim 24 and further limits the method to those where the organism is a plant, the method increases yield in a plant, the target-binding moiety is specific for a target protein and the expression or activity of said target protein is negatively correlated with yield.
Claim 46 depends on claim 24 and further limits the method to those where the organism is a plant, the method reduces or removes glutens in the plant and wherein the target-binding moiety is specific for gliadin or glutenin.
Claim 47 depends on claim 26 and further limits the method to those where the condition is cancer, an infection, a neurodegenerative disorder or a proteopathy.
These claims include several areas which add breadth. First, as noted above the independent claim is drawn to any fusion protein which includes any element even chemicals that can target and bind to any von Willebrand factory type A (vWA) domain in any target protein whatsoever. targeting moiety and a target-binding moiety. This is because the specification notes that a fusion protein is a protein that comprises portions from two or more proteins but alternatively the fusion protein may comprise a bispecific antibody or nanobody and that while the proteins which make up a fusion protein are normally heterologous proteins in some circumstances a fusion protein may comprise multiple portions from the same protein. Since this disclosure indicates that fusion proteins may comprise multiple portions from the same protein it is not clear what separates fusion proteins from other naturally occurring proteins (Specification, Page 15 Lines 13-22).
Additionally claims 42 and 43 make clear that these moieties are not only polypeptides but can be nearly any structure including any chemical. Therefore, the meaning of the term fusion protein appears to be expanded from the ordinary meaning and this large and diverse genus includes any structure whatsoever that can bind to a vWA domain.
Similarly, the instant disclosure notes that a target-binding moiety is any structure capable of binding to a target protein and that a vWA targeting moiety is any structure capable of binding to a vWA domain. Given the name “vWA targeting moiety” it is clear that vWA is a target and that the vWA targeting moiety binds to this target. Thus it appears that the vWA targeting moiety can also be a target-binding moiety.
Therefore, it appears that any protein comprising a vWA targeting moiety is included within the broadest reasonable interpretation of the claims.
As noted above, given that vWA targeting moiety refers to any structure capable of binding to a vWA domain this genus of claimed fusion proteins appears exceedingly broad and diverse. Particularly because applicant does not describe the structure function relationship between any structure whatsoever and the function of being capable of binding to a vWA domain. Therefore, even though the vWA domain is well known in the art the broad genus of any vWA targeting moiety is not clear and further the structures conferring this function are not clear such that the ordinary artisan would recognize if they are in possession of such a moiety.
In contrast to this broad scope, Applicant describes experiments investigating the role of SAP05 in protein degradation, although it is not clear which organism this exact protein was isolated from.
Specifically, applicant describes SAP05 interactions with proteins in Arabidopsis thaliana, with a focus on zinc-finger transcription factors, specifically GATAs and SPLs which were found to interact with the SAP05 protein in a yeast-two hybrid screen (Specification, Page 38, Lines 9-21). Experiments in protoplasts confirmed that SAP05 lead to lower levels of GATA proteins, other evidence included proteosome inhibitor mediated inhibition of SAP05 mediated GATA degradation. Further, applicant demonstrated that the role of SAP05 in protein degradation in Arabidopsis protoplasts requires RPN10 (Specification, Pages 38-39, Paragraph spanning pages). In combination theses data indicate that SAP05 directly targets proteins it interacts with for degradation without the requirement of lysine ubiquitination (Specification, Pages 38-39, paragraph spanning pages).
Further, Applicant describes SAP05 binding to zinc-finger transcription factors and notes that SAP05 binding to RPN10 requires the GA residues of the vWA domain. Finally, applicant notes that SAP05 can also mediate the degradation of proteins through the human 26s proteasome.
Applicant does provide one example of a fusion protein. SAP05 was fused to a GFP-nanobody (a single-chain antibody that specifically recognizes GFP), this fusion protein degraded GFP in Arabidopsis protoplasts (Specification, Page 40, Lines 2-8).
Thus, applicant describes a single protein capable of binding to vWA domains and which appears to have a role in targeting proteins for degradation. Importantly, the origin of this protein is unclear and while it appears that the GA residues of the vWA domain in the RPN10 protein are important for this binding the specific structure required for vWA-targeting is unclear.
Applicant does not describe a representative number of species across the claimed genus of fusion proteins. Applicant’s single example of a vWA targeting protein is insufficient to build a structure-function relationship such that the ordinary artisan would be able to determine if a given sequence would have the requisite function of targeting and binding any vWA domain in any protein in any cell in any organism at any developmental time.
Instead, applicants have investigated the role of a single SAP05 protein of unknown origin in the degradation of zinc-finger transcription factors in Arabidopsis thaliana protoplasts and plants. Therefore, applicant has described a single vWA targeting moiety which targets a specific vWA moiety in a single closely related family of target proteins in one organism.
Given the breadth of the genera encompassed by the claims which includes fusion proteins wherein both of the required moieties can be any chemical, the described species are not sufficiently representative. The Applicant has not set forth the structure-function relationship for the claimed genus such that one of ordinary skill in the art would be able to recognize which members of the vast and structurally diverse genus of any fusion protein comprising a vWA targeting moiety would have the function of vWA targeting and binding.
Given the breadth of the dependent claims, the additional limitations do not overcome the lack of description for the scope of the claimed invention. Even in those dependent claims (Claims 2-3, 6, 20, 22 and 42-43), where applicant has limited the vWA targeting moiety and the target-binding moiety the claims remain broad. Specifically, the vWA targeting moiety is limited to sequences that bind the HS or GS residues at positions 38 and 39 of SEQ ID NOs: 2, 21, 24, 26 or corresponding positions in a homologous sequence of a vWA which can be interpreted to be any HS or GA residue in a vWA domain (Claim 2), a SAP05 peptide or a functional variant having at least 75% sequence identity to SEQ ID NO: 1 (Claim 3), an antibody (Claim 6), a peptide, a cyclic peptide, a binding domain, a small molecule, a chemical, a T-cell receptor, an antibody, a functional fragment of an antibody, a nanobody, or an aptamer (Claim 42). These limitations still read on a large and diverse genus of fusion proteins and fail to limit the scope of the vWA targeting moiety to a genus of sequences where the relationship between the sequence and the function of binding to a vWA target is clear. Therefore, even in these claims there is no structure/function relationship between the a sequence and the requisite function of vWA binding and therefore even in these more limited claims applicant has not demonstrated possession of the claimed invention.
The prior art does not provide resolution for the lack of description provided by Applicant. Specifically, there is insufficient teaching in the art for the ordinary artisan to be able to determine if the broad genus of any sequence comprised a vWA moiety and if so if this moiety was capable of binding to a vWA domain. Therefore, the specification fails to sufficiently describe the claimed invention in such full, clear, concise, and exact terms that a skilled artisan would recognize that Applicant was in possession of the invention as broadly claimed at the time of filing.
Claim Rejections - 35 USC § 112 (Enablement)
Claims 1-3, 6, 10, 18, 20-27, and 42-47 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Applicant claims a fusion protein comprising a von Willebrand factory type A (vWA) targeting moiety and a target-binding moiety.
This claim is interpreted to mean any protein (see indefiniteness rejections above) comprising anything whatsoever which can target a von Willebrand factor type A (vWA) domain in any target by binding to that domain and which further comprises a second moiety, which can be any structure whatsoever which is capable of binding to a target.
Given the disclosure, it appears that applicants described fusion protein should have a structure such that a target protein could be bound by the target-binding moiety and then this complex recruited to the proteosome complex through binding of the vWA targeting moiety of the fusion protein binding to vWA domains in the proteosome degradation complex including those on Rpn10 (See, figure 2 on page 100 of Schmidtke).
The dependent claims add further limitations on the structure of this fusion protein and provide methods for its use, these are described below. Two dependent claims in particular are of note because the additional limitations that they provide make clear the extremely broad nature of the independent claim.
Claim 42, is drawn to the fusion protein of the independent claim, where the vWA targeting moiety is a peptide, a cyclic peptide, a binding domain, a small molecule, a chemical, a T-cell receptor, an antibody, a functional fragment of an antibody, a nanobody and an aptamer.
This claim makes clear that the scope of the independent claim is even more broad than it appears at first glance. Given the recitation of a fusion protein in the independent claim at first glance it appears that each of the moieties is a domain with a certain requisite function, however claim 42 states that the vWA targeting moiety could be any chemical which can bind to vWA. The specification states with respect to chemical responses that examples of chemicals include toxins or volatile compounds (Specification, Page 29, Lines 14-15), however the specification is silent on how to include these chemicals in the fusion protein.
Claim 43, is identical to claim 42, except that it further limits the target-binding domain of claim 1. Given that claim 1 recites a moiety not a domain and that volatile chemicals may not be protein domains this limitation is interpreted to refer to the target-binding moiety of claim 1 further selected from the recited group. This claim adds breadth for the same reasons as claim 42.
The scope of the dependent claims is as follows:
Claim 2 is drawn to the fusion protein, wherein the vWA targeting moiety binds at least the HS residue at position 38 or the GA residue at position 39 of SEQ ID NO: 2, 21, 24 or 26 or corresponding positions in a homologous sequence of a vWA domain.
Claim 3 is drawn to the fusion protein, wherein the vWA targeting moiety is SAP05 or functional variant thereof having at least 75% sequence identity to the sequence of SEQ ID NO: 1.
Claim 6 is drawn to the fusion protein, wherein the fusion protein comprises a bispecific antibody or nanobody.
Claim 10 is drawn to the fusion protein, wherein the fusion protein further comprises a RPM10 protein or a vWA domain.
Claim 18 is drawn to a method of targeted protein degradation comprising applying the fusion protein of claim 1, to a sample, cell or an organism.
Claim 20 depends on claim 18 and is drawn to the method comprising a step of applying a fluorescently tagged antibody to label a protein of interest prior to applying the fusion protein, which targets the fluorescent tag with its target-binding moiety.
Claim 21 depends on claim 18 and is drawn to the method wherein the target protein is a cytosolic protein or a cell surface protein.
Claim 22 depends on claim 18 and is drawn to the method comprising introducing a CRISPR-Cas system to the sample, cell or organism, allowing the CRISPR-Cas system to edit a gene, delivering the fusion protein comprising a target moiety that is specific for said CRISPR enzyme and allowing the fusion protein to degrade the CRISPR enzyme.
Claim 23 depends on claim 18 and further limits the scope of the claim to those wherein the target protein can cause pathology in a target organism or wherein the target protein is a drug target.
Claim 24 is drawn to a method of modulating a biochemical response or physiological response in an organism, the method comprising administering the fusion protein to the organism.
Claim 25 depends on claim 24 and further limits the claim scope to the following group of physiological responses; stress, immune, hormone or light.
Claim 26 is drawn to a method of treating a condition in a patient in need thereof, the method comprising administering the fusion protein to the patient in need thereof.
Claim 27 depends on claim 26 and further limits the claim to conditions characterized by increased expression or activity of a target protein and the target-binding moiety is specific for said target protein.
Claim 42 is drawn to the fusion protein where the vWA targeting moiety is selected from the group consisting of a peptide, cyclic peptide, binding domain, small molecule, chemical, t-cell receptor, antibody, functional fragment of an antibody, nanobody and an aptamer.
Claim 43 is drawn to the fusion protein, wherein the target-binding moiety is selected from the group consisting of a peptide, cyclic peptide, binding domain, small molecule, chemical, t-cell receptor, antibody, functional fragment of an antibody, nanobody and an aptamer.
Claim 44 depends on claim and further limits the targeted protein degradation to ubiquitin-independent degradation.
Claim 45 depends on claim 24 and further limits the method to those where the organism is a plant, the method increases yield in a plant, the target-binding moiety is specific for a target protein and the expression or activity of said target protein is negatively correlated with yield.
Claim 46 depends on claim 24 and further limits the method to those where the organism is a plant, the method reduces or removes glutens in the plant and wherein the target-binding moiety is specific for gliadin or glutenin.
Claim 47 depends on claim 26 and further limits the method to those where the condition is cancer, an infection, a neurodegenerative disorder or a proteopathy.
These claims include several areas which add breadth. First, as noted above the independent claim is drawn to any fusion protein which includes any element even chemicals that can target and bind to any von Willebrand factory type A (vWA) domain in any target protein whatsoever. targeting moiety and a target-binding moiety. This is because the specification notes that a fusion protein is a protein that comprises portions from two or more proteins but alternatively the fusion protein may comprise a bispecific antibody or nanobody and that while the proteins which make up a fusion protein are normally heterologous proteins in some circumstances a fusion protein may comprise multiple portions from the same protein. Since this disclosure indicates that fusion proteins may comprise multiple portions from the same protein it is not clear what separates fusion proteins from other naturally occurring proteins (Specification, Page 15 Lines 13-22).
Additionally claims 42 and 43 make clear that these moieties are not only polypeptides but can be nearly any structure including any chemical. Therefore, the meaning of the term fusion protein appears to be expanded from the ordinary meaning and this large and diverse genus includes any structure whatsoever that can bind to a vWA domain.
Similarly, the instant disclosure notes that a target-binding moiety is any structure capable of binding to a target protein and that a vWA targeting moiety is any structure capable of binding to a vWA domain. Given the name “vWA targeting moiety” it is clear that vWA is a target and that the vWA targeting moiety binds to this target. Thus it appears that the vWA targeting moiety can also be a target-binding moiety.
Therefore, it appears that any protein comprising a vWA targeting moiety is included within the broadest reasonable interpretation of the claims.
As noted above, given that vWA targeting moiety refers to any structure capable of binding to a vWA domain this genus of claimed fusion proteins appears exceedingly broad and diverse. Particularly because applicant does not describe the structure function relationship between any structure whatsoever and the function of being capable of binding to a vWA domain. Therefore, even though the vWA domain is well known in the art the broad genus of any vWA targeting moiety is not clear and further the structures conferring this function are not clear such that the ordinary artisan would recognize if they are in possession of such a moiety.
In contrast to this broad scope, Applicant provides enabling guidance on one example of a fusion protein. SAP05 was fused to a GFP-nanobody (a single-chain antibody that specifically recognizes GFP), this fusion protein degraded GFP in Arabidopsis protoplasts (Specification, Page 40, Lines 2-8).
Thus applicant, provides enabled guidance on a single fusion protein which can target a single vWA domain in a single target species. Importantly, the origin of this protein is unclear and while it appears that the GA residues of the vWA domain in the RPN10 protein are important for this binding the specific structure required for vWA-targeting is unclear.
The breadth of the claim includes any fusion protein which comprises a vWA targeting/binding moiety and a target-binding moiety. These moieties appear to be defined by their function and therefore the scope of the claim is drawn to a protein which comprises any moiety capable of targeting/binding any vWA domain in any target protein, in any cell, in any organism, at any developmental time and under any conditions and where the protein also comprises a target binding domain that is capable of binding to any target whatsoever.
Applicant does not describe a representative number of species across the claimed genus of fusion proteins nor does the Applicant describe a structure-function relationship reduced to practice other than the single example of SAP05 in Arabidopsis thaliana. Given the limited guidance provided by Applicant, the single example reduced to practice is insufficient to allow for the development of a structure function relationship between an amino acid sequence and the function of binding to any vWA domain, in any conditions at all.
Therefore, applicant has not provided sufficient enabled guidance for the ordinary artisan to make and use the broadly claimed invention without undue experimentation.
Given the breadth of the dependent claims, the additional limitations do not overcome the lack of guidance for the scope of the claimed invention. Even in those dependent claims (Claims 2-3, 6, 20, 22 and 42-43), where applicant has limited the vWA targeting moiety and the target-binding moiety, the claims remain broad.
Specifically, the vWA targeting moiety is limited to sequences that bind the HS or GS residues at positions 38 and 39 of SEQ ID NOs: 2, 21, 24, 26 or corresponding positions in a homologous sequence of a vWA which can be interpreted to be any HS or GA residue in a vWA domain (Claim 2), a SAP05 peptide or a functional variant having at least 75% sequence identity to SEQ ID NO: 1 (Claim 3), an antibody (Claim 6), a peptide, a cyclic peptide, a binding domain, a small molecule, a chemical, a T-cell receptor, an antibody, a functional fragment of an antibody, a nanobody, or an aptamer (Claim 42).
These limitations still read on a large and diverse genus of fusion proteins and fail to limit the scope of the vWA targeting moiety to a genus of sequences where the relationship between the sequence and the function of binding to a vWA target is clear. Therefore, even in these claims there is no structure/function relationship between the a sequence and the requisite function of vWA binding and therefore even in these more limited claims applicant has provided insufficient guidance for the ordinary artisan to make and use the claimed invention without undue experimentation.
Therefore, one of ordinary skill in the art would be unable to make and use or predictably practice the methods of the claimed invention without undue experimentation, i.e., it would be necessary to identify vWA domain containing proteins from all organisms. Then screen through every single protein there is in order to identify any domain that can bind to any vWA domain. Alternatively, the ordinary artisan could identify known vWA domains and use this information to identify a broad group of putative vWA domains and collect a similarly broad group of any protein and then test the ability of this second group to bind to the vWA domains thus identifying structures capable of binding to vWA domains. With this information the ordinary artisan would then be able to make a fusion protein comprising a vWA targeting domain.
In looking at the experimentation required to make and use the invention as it is currently claimed it is clear that applicants guidance is simply a single example of a protein capable of binding to a single vWA domain in a single organism (Arabidopsis under two sets of conditions, protoplast and in planta assays) and an invitation to investigate vWA domains and the proteins that bind them in any organism and then to develop a fusion protein containing a vWA targeting moiety. As such it is clear that the required experimentation is undue.
The prior art does not provide resolution for the lack of guidance provided by Applicant. Specifically, there is insufficient teaching in the art for the ordinary artisan to be able to determine if the broad genus of any sequence comprised a vWA moiety and if so if this moiety was capable of binding to a vWA domain. Therefore, the specification fails to provide sufficient enabled guidance such that a skilled artisan would be able to make and use the full scope of the claimed invention at the time of filing. The lack of predictability in the art and the lack of guidance provided by Applicant would not have enabled one of ordinary skill in the art to predictably make and use the full scope of the claimed invention without undue experimentation.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as