Precision RNA cleavage and editing using trans-cleaving ribozyme and guide rnas

Abstract

Provided are compositions for site-specific cleavage, splicing and ligation of nucleic acid molecules including RNA and DNA, and methods of use of the compositions for generating spliced or ligated nucleic acid molecules and for the treatment of diseases.

Description

Attorney Docket No.204606-0174-00WO PRECISION RNA CLEAVAGE AND EDITING USING TRANS-CLEAVING RIBOZYME AND GUIDE RNAS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No.63 / 551,572 filed on February 9, 2024, which is incorporated herein by reference in its entirety. REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

[0002] This application contains a Sequence Listing, which is submitted electronically via EFS-Web as an XML Document formatted sequence listing with a file name: “204606-0174- 00WO Sequence Listing.xml” created on February 6, 2025, and 753,223 bytes in size. The sequence listing submitted via EFS-Web is part of the specification and is herein incorporated by reference in its entirety. BACKGROUND OF THE INVENTION

[0003] RNA targeting, RNA-activated CRISPR-Cas13 systems are generally composed of a targeting CRISPR guide RNA (gRNA) and CRISPR associated protein, Cas13, which function as a programmable endoribonuclease (O’Connell, 2019, J Mol. Biol 431:66-87; Abudayyeh et al., 2018, Nature 550:280-84; Mohanraju et al., 2016, Science 343:aad5147). Cas13 proteins have two Higher Eukaryotes and Prokaryotes Nucleotide binding (HEPN) domains which allow for cleavage of single stranded RNA. In vitro and in bacteria, binding of a target RNA complementary to the guide-RNA results in constitutive activation of HEPN-RNase activity leading to target RNA degradation and non-specific RNA cleavage (collateral cleavage) (Abudayyeh et al., 2018, Nature 550:280-84; Abudayyeh et al., 2016, Science 343:aaf5573; Konermann et al., 2018, Cell 173:665-76).

[0004] There remains a need in the art for compositions and methods for useful for achieving site-specific RNA cleavage events.Attorney Docket No.204606-0174-00WO SUMMARY OF THE INVENTION

[0005] In some embodiments, the invention relates to a fusion construct comprising at least one guide RNA (gRNA), and at least one ribozyme or DNAzyme. In some embodiments, the fusion construct comprises at least two guide RNA (gRNA), and at least two ribozymes or DNAzymes.

[0006] In some embodiments, the ribozyme or DNAzyme is specific for trans-cleavage of RNA or DNA. In some embodiments, the ribozyme or DNAzyme comprises hammerhead (HH), Hepatitis delta virus (HDV), Hairpin (HP), Varkud Satellite (VS), Twister, Twister Sister, Pistol, Hatchet, HOV, GlmS, Deoxyribozyme 8–17, Deoxyribozyme 10-23, or deoxyribozyme I- R3, or a fragment or trans-cleavage variant thereof.

[0007] In some embodiments, the fusion construct comprises a trans-cleavage ribozyme. In some embodiments the trans-cleavage ribozyme comprises a nucleotide sequence as set forth in SEQ ID NO:1-53, or a fragment or variant thereof.

[0008] In some embodiments, the fusion construct further comprises at least one linker.

[0009] In some embodiments, the invention relates to a fusion construct comprising at least two ribozymes or DNAzymes. In some embodiments, each of the two ribozymes or DNAzymes are specific for RNA cleavage. In some embodiments, each of the two ribozymes or DNAzymes are specific for DNA cleavage.

[0010] In some embodiments, each of the at least two ribozymes or DNAzymes comprises hammerhead (HH), Hepatitis delta virus (HDV), Hairpin (HP), Varkud Satellite (VS), Twister, Twister Sister, Pistol, Hatchet, HOV, GlmS, Deoxyribozyme 8–17, Deoxyribozyme 10- 23, or deoxyribozyme I-R3, or a fragment or trans-cleavage variant thereof.

[0011] In some embodiments, each of the at least two ribozymes comprises a trans- cleavage ribozyme. In some embodiments, each of the at least two ribozymes comprises a nucleotide sequence as set forth in SEQ ID NO:1-53, or a fragment or variant thereof.

[0012] In some embodiments, the construct further comprises at least one linker.

[0013] In some embodiments, the invention relates to a complex comprising at least one fusion construct comprising at least one guide RNA (gRNA), and at least one ribozyme or DNAzyme or a fusion construct comprising at least two ribozymes or DNAzymes. In some embodiments, the complex further comprises a CRISPR Cas protein. In some embodiments, the Cas protein is catalytically active. In some embodiments, the Cas protein comprises a mutation inAttorney Docket No.204606-0174-00WO one or both of the HEPN domains. In some embodiments, the Cas protein is catalytically dead Cas13 (dCas13). In some embodiments, the Cas protein comprises a sequence selected from SEQ ID NOs: 54-101, or a variant thereof. In some embodiments, the Cas protein further comprises a nuclear localization signal (NLS). In some embodiments, the NLS comprises a sequence selected from SEQ ID NOs: 111 - 725, or a variant thereof.

[0014] In some embodiments, the invention relates to a composition comprising at least one fusion construct comprising at least one guide RNA (gRNA), and at least one ribozyme or DNAzyme. In some embodiments, the complex further comprises a CRISPR Cas protein.

[0015] In some embodiments, the invention relates to a composition comprising at least one fusion construct comprising at least two ribozymes or DNAzymes. In some embodiments, each of the two ribozymes or DNAzymes are specific for RNA cleavage.

[0016] In some embodiments, the invention relates to a composition comprising a complex comprising at least one fusion construct comprising at least one guide RNA (gRNA), and at least one ribozyme or DNAzyme and further comprising a CRISPR Cas protein.

[0017] In some embodiments, the invention relates to a method of decreasing the number of a target RNA transcript or cleaving a target RNA transcript, the method comprising contacting the target RNA molecule with at least one fusion construct comprising at least one guide RNA (gRNA), and at least one ribozyme or DNAzyme. In some embodiments, the method is an in vitro or in vivo method.

[0018] In some embodiments, the method comprises contacting the target RNA molecule with at least two fusion constructs, wherein each of the fusion constructs or complexes comprises a gRNA for targeting the fusion construct or complex to a target site on the RNA molecule for cleavage. In some embodiments, each of the fusion constructs or complexes comprises the same ribozyme. In some embodiments, each of the fusion constructs or complexes comprises a different ribozyme. In some embodiments, the method promotes splicing or ligation of the target RNA molecule. In some embodiments, the splicing or ligation is cis-splicing, trans-splicing, cis- RNA ligation or trans-RNA ligation.

[0019] In some embodiments, the invention relates to a method of cleaving, splicing or ligating a target DNA molecule, the method comprising contacting the target DNA molecule with at least one fusion construct comprising at least one guide RNA (gRNA), and at least one ribozyme or DNAzyme. In some embodiments, the method is an in vitro or in vivo method.Attorney Docket No.204606-0174-00WO

[0020] In some embodiments, the method comprises contacting the target DNA molecule with at least two fusion constructs, wherein each of the fusion constructs or complexes comprises a gRNA for targeting the fusion construct or complex to a target site on the DNA molecule for cleavage. In some embodiments, each of the fusion constructs or complexes comprises the same ribozyme or DNAzyme. In some embodiments, each of the fusion constructs or complexes comprises a different ribozyme or DNAzyme. In some embodiments, the method promotes splicing or ligation of the target DNA molecule. In some embodiments, the splicing or ligation is cis-splicing, trans-splicing, cis-DNA ligation or trans-DNA ligation.

[0021] In some embodiments, the invention relates to a method of treating a disease or disorder associated with nucleic acid level or expression in a subject, the method comprising administering to the subject at least one fusion construct comprising at least one guide RNA (gRNA) and at least one ribozyme or DNAzyme or a fusion construct comprising at least two ribozymes or DNAzymes. In some embodiments, the disease or disorder is associated with the presence of an aberrant DNA molecule or RNA transcript, wherein the method promotes degradation of the aberrant DNA molecule or RNA transcript.

[0022] In some embodiments, the disease or disorder is associated with the presence of a premature stop codon (PTC) in a target RNA transcript, wherein the method promotes splicing of the target RNA transcript to remove the PTC.

[0023] In some embodiments, the invention relates to a method of generating a trans- ligated RNA molecule, the method comprising contacting a first RNA molecule with a first fusion construct comprising at least one guide RNA (gRNA) and at least one ribozyme or DNAzyme and a second RNA molecule with a second fusion construct comprising at least one guide RNA (gRNA) and at least one ribozyme or DNAzyme, whereby cleavage of the first and second RNA molecule and subsequent ligation of the cleaved RNA molecules generates a trans- ligated RNA molecule. In some embodiments, the first and second trans-cleaving ribozyme are connected by a flexible linker.

[0024] In some embodiments, the invention relates to a method of generating a trans- ligated RNA molecule, the method comprising contacting a first RNA and a second RNA molecule with a fusion construct comprising at least two ribozymes or DNAzymes, whereby cleavage of the first and second RNA molecule and subsequent ligation of the cleaved RNAAttorney Docket No.204606-0174-00WO molecules generates a trans-ligated RNA molecule. In some embodiments, the first and second trans-cleaving ribozyme are connected by a flexible linker.

[0025] In some embodiments, the invention relates to a method of generating a trans- ligated RNA molecule, the method comprising contacting a first RNA molecule and a second RNA molecule with a Cas protein which cleaves the first and second RNA, thereby generating compatible RNA ends, whereby cleavage of the first and second RNA molecule and subsequent ligation of the cleaved RNA molecules generates a trans-ligated RNA molecule. In some embodiments, the Cas protein is a subtype II-A or subtype II-C class Cas protein. In some embodiments, the method further comprises contacting the first and second RNA molecules with a first and second guide RNA to target the Cas protein to a specific site for cleavage. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1A through Figure 1G depict precision RNA cleavage, and subsequent RNA ligation in cells, can occur through multiple cleavage mechanisms. Figure 1A depicts that in stitchR, encoded ribozymes, which cleave in cis, generate RNA termini which are recognized and repaired through RNA ligation either in cis or in trans. Figure 1B depicts biomolecular complexes of various ribozyme sequences, such as hammerhead ribozymes, have been described which are capable of assembly in trans to form functional ribozyme sequences. This allows for targeting of endogenous cellular RNAs through delivery and expression of small target- complementary sequences. Figure 1C and Figure 1D depict the stability, targeting efficiency and / or localization of trans-cleaving ribozymes may be enhanced through incorporation into the targeting guide RNAs of CRISPR-Cas systems on either 5’ or 3’ ends. Figure 1E through Figure 1G depict that a similar strategy can be used for HDV trans-cleaving ribozymes, as well as many others. Figure 1H depicts a diagram demonstrating that some CRISPR-Cas systems have demonstrated site-specific RNA cleavage, which when combined into multiple cleavage events, may allow for repair of sequences in cis or the combination of RNA sequences in trans, through RNA trans ligation.

[0027] Figure 2A and Figure 2B depicts diagrams of tandem fusion of trans-cleaving ribozymes using the same (Figure 2A) or different (Figure 2B) ribozymes sequences can allow for site-specific deletion and induction of RNA ligation of target sequences.Attorney Docket No.204606-0174-00WO

[0028] Figure 3 depicts sequences of the trans-cleaving hammerhead and trans-cleaving extended hammerhead with tertiary stabilizing motif (TSM). DETAILED DESCRIPTION

[0029] In one embodiment, the disclosure is based on the use of trans-cleaving ribozymes or CRISPR-Cas proteins to site-specifically cleave nucleic acid molecules. In some embodiments, the invention provides methods of site-specific cleavage and subsequent ligation of nucleic acid molecules. Therefore, in some embodiments, the invention relates to methods of trans-splicing RNA molecules, trans-splicing DNA molecules, trans-ligating RNA molecules and trans-ligating DNA molecules.

[0030] In one embodiment, the invention provides fusion constructs comprising one or more linked catalytic RNA which has a trans-cleavage activity, and cleaves a target nucleic acid molecule. In some embodiments, the fusion constructs combine the catalytic activity of a trans- cleaving ribozyme and the programmable targeting capability of guide RNA (gRNA). In some embodiment, the fusion construct comprises one or more linked catalytic RNA with trans- cleavage activity operably linked to a targeting gRNA. In one embodiment, the gRNA targets the catalytic RNA molecule to a specific sequence for site-specific trans-cleavage of the target nucleic acid molecule. In some embodiments, the catalytic RNA is a trans-cleaving ribozyme. In one embodiment, the trans-cleaving ribozyme is a trans-cleaving variant of a natural or synthetic ribozyme or deoxyribozyme. In some embodiments, the trans-cleaving ribozyme is a trans- cleaving variant of hammerhead (HH), Hepatitis delta virus (HDV), Hairpin (HP), Varkud Satellite (VS), Twister, Twister Sister, Pistol, Hatchet, HOV, or GlmS. In one embodiment, the fusion construct further comprises a tertiary stabilizing motif (TSM).

[0031] In one embodiment, the invention provides fusion constructs comprising two or more linked catalytic RNA which has a trans-cleavage activity, and cleaves a target nucleic acid molecule. In some embodiment, the fusion construct comprises two or more linked catalytic RNA with trans-cleavage activity operably linked to two or more targeting gRNA. In one embodiment, the gRNA target the catalytic RNA molecules to a specific sequence for site- specific trans-cleavage of the target nucleic acid molecule(s). Subsequent repair of the cleaved nucleic acid molecule generates a spliced or ligated nucleic acid molecule. In some embodiments, the two or more catalytic RNA are trans-cleaving ribozymes. In someAttorney Docket No.204606-0174-00WO embodiments, each of the two catalytic RNA is a trans-cleaving ribozyme. In one embodiment, each of the two trans-cleaving ribozyme is a trans-cleaving variant of a natural or synthetic ribozyme or deoxyribozyme. In some embodiments, the trans-cleaving ribozyme is a trans- cleaving variant of hammerhead (HH), Hepatitis delta virus (HDV), Hairpin (HP), Varkud Satellite (VS), Twister, Twister Sister, Pistol, Hatchet, HOV, or GlmS. In one embodiment, the fusion construct further comprises a tertiary stabilizing motif (TSM).

[0032] In one embodiment, the invention provides fusion constructs comprising two or more linked gRNA and a CRISPR-Cas protein which can cleave one or more target nucleic acid molecule leaving compatible ends for ligation or splicing of the cleaved target nucleic acid molecule(s). In some embodiment, the fusion construct comprises one or more linked gRNA. In such an embodiment, the linked gRNA fusion construct holds the cleaved ends in proximity for subsequent ligation by cellular machinery. Definitions

[0033] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0034] Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry, and nucleic acid chemistry and hybridization are those well-known and commonly employed in the art.

[0035] Standard techniques are used for nucleic acid and peptide synthesis. The techniques and procedures are generally performed according to conventional methods in the art and various general references (e.g., Sambrook and Russell, 2012, Molecular Cloning, A Laboratory Approach, Cold Spring Harbor Press, Cold Spring Harbor, NY, and Ausubel et al., 2012, Current Protocols in Molecular Biology, John Wiley & Sons, NY), which are provided throughout this document.

[0036] The nomenclature used herein, and the laboratory procedures used in analytical chemistry and organic syntheses described below, are those well-known and commonly employed in the art. Standard techniques or modifications thereof are used for chemical syntheses and chemical analyses.Attorney Docket No.204606-0174-00WO

[0037] The term “a,” “an,” “the” and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context.

[0038] “About” as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20%, or ±10%, or ±5%, or ±1%, or ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.

[0039] “Antisense” refers particularly to the nucleic acid sequence of the non-coding strand of a double stranded DNA molecule encoding a protein, or to a sequence which is substantially homologous to the non-coding strand. As defined herein, an antisense sequence is complementary to the sequence of a double stranded DNA molecule encoding a protein. It is not necessary that the antisense sequence be complementary solely to the coding portion of the coding strand of the DNA molecule. The antisense sequence may be complementary to regulatory sequences specified on the coding strand of a DNA molecule encoding a protein, which regulatory sequences control expression of the coding sequences.

[0040] A “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate.

[0041] In contrast, a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal’s state of health.

[0042] A disease or disorder is “alleviated” if the severity of a sign or symptom of the disease or disorder, the frequency with which such a sign or symptom is experienced by a patient, or both, is reduced.

[0043] “Encoding” refers to the inherent property of specific sequences of nucleotides in a polynucleotide, such as a gene, a cDNA, or an mRNA, to serve as templates for synthesis of other polymers and macromolecules in biological processes having either a defined sequence of nucleotides (i.e., rRNA, tRNA and mRNA) or a defined sequence of amino acids and the biological properties resulting therefrom. Thus, a gene encodes a protein if transcription and translation of mRNA corresponding to that gene produces the protein in a cell or other biologicalAttorney Docket No.204606-0174-00WO system. Both the coding strand, the nucleotide sequence of which is identical to the mRNA sequence and is usually provided in sequence listings, and the non-coding strand, used as the template for transcription of a gene or cDNA, can be referred to as encoding the protein or other product of that gene or cDNA.

[0044] The terms “patient,” “subject,” “individual,” and the like are used interchangeably herein, and refer to any animal or cell whether in vitro or in vivo, amenable to the methods described herein. In one embodiment, the subjects include vertebrates and invertebrates. Invertebrates include, but are not limited to, Drosophila melanogaster and Caenorhabditis elegans. Vertebrates include, but are not limited to, primates, rodents, domestic animals or game animals. Primates include, but are not limited to, chimpanzees, cynomologous monkeys, spider monkeys, and macaques (e.g., Rhesus). Rodents include, but are not limited to, mice, rats, woodchucks, ferrets, rabbits and hamsters. Domestic and game animals include, but are not limited to, cows, horses, pigs, deer, bison, buffalo, feline species (e.g., domestic cat), canine species (e.g., dog, fox, wolf), avian species (e.g., chicken, emu, ostrich), and fish (e.g., zebrafish, trout, catfish and salmon). In some embodiments, the subject is a mammal, e.g., a primate, e.g., a human. In certain non-limiting embodiments, the patient, subject or individual is a human.

[0045] By the term “specifically binds,” as used herein with respect to an antibody, is meant an antibody which recognizes a specific antigen, but does not substantially recognize or bind other molecules in a sample. For example, an antibody that specifically binds to an antigen from one species may also bind to that antigen from one or more species. But, such cross-species reactivity does not itself alter the classification of an antibody as specific. In another example, an antibody that specifically binds to an antigen may also bind to different allelic forms of the antigen. However, such cross reactivity does not itself alter the classification of an antibody as specific.

[0046] In some instances, the terms “specific binding” or “specifically binding,” can be used in reference to the interaction of an antibody, a protein, or a peptide with a second chemical species, to mean that the interaction is dependent upon the presence of a particular structure (e.g., an antigenic determinant or epitope) on the chemical species; for example, an antibody recognizes and binds to a specific protein structure rather than to proteins generally. If an antibody is specific for epitope “A”, the presence of a molecule containing epitope A (or free,Attorney Docket No.204606-0174-00WO unlabeled A), in a reaction containing labeled “A” and the antibody, will reduce the amount of labeled A bound to the antibody.

[0047] A “coding region” of a gene consists of the nucleotide residues of the coding strand of the gene and the nucleotides of the non-coding strand of the gene which are homologous with or complementary to, respectively, the coding region of an mRNA molecule which is produced by transcription of the gene.

[0048] A “coding region” of a mRNA molecule also consists of the nucleotide residues of the mRNA molecule which are matched with an anti-codon region of a transfer RNA molecule during translation of the mRNA molecule or which encode a stop codon. The coding region may thus include nucleotide residues comprising codons for amino acid residues which are not present in the mature protein encoded by the mRNA molecule (e.g., amino acid residues in a protein export signal sequence).

[0049] “Complementary” as used herein to refer to a nucleic acid, refers to the broad concept of sequence complementarity between regions of two nucleic acid strands or between two regions of the same nucleic acid strand. It is known that an adenine residue of a first nucleic acid region is capable of forming specific hydrogen bonds (“base pairing”) with a residue of a second nucleic acid region which is antiparallel to the first region if the residue is thymine or uracil. Similarly, it is known that a cytosine residue of a first nucleic acid strand is capable of base pairing with a residue of a second nucleic acid strand which is antiparallel to the first strand if the residue is guanine. A first region of a nucleic acid is complementary to a second region of the same or a different nucleic acid if, when the two regions are arranged in an antiparallel fashion, at least one nucleotide residue of the first region is capable of base pairing with a residue of the second region. In one embodiment, the first region comprises a first portion and the second region comprises a second portion, whereby, when the first and second portions are arranged in an antiparallel fashion, at least about 50%, at least about 75%, at least about 90%, or at least about 95% of the nucleotide residues of the first portion are capable of base pairing with nucleotide residues in the second portion. In one embodiment, all nucleotide residues of the first portion are capable of base pairing with nucleotide residues in the second portion.

[0050] The term “DNA” as used herein is defined as deoxyribonucleic acid.

[0051] The term “expression” as used herein is defined as the transcription and / or translation of a particular nucleotide sequence driven by its promoter.Attorney Docket No.204606-0174-00WO

[0052] The term “expression vector” as used herein refers to a vector containing a nucleic acid sequence coding for at least part of a gene product capable of being transcribed. In some cases, RNA molecules are then translated into a protein, polypeptide, or peptide. In other cases, these sequences are not translated, for example, in the production of antisense molecules, siRNA, ribozymes, and the like. Expression vectors can contain a variety of control sequences, which refer to nucleic acid sequences necessary for the transcription and possibly translation of an operatively linked coding sequence in a particular host organism. In addition to control sequences that govern transcription and translation, vectors and expression vectors may contain nucleic acid sequences that serve other functions as well.

[0053] As used herein the term “wild type” is a term of the art understood by skilled persons and means the typical form of an organism, strain, gene or characteristic as it occurs in nature as distinguished from mutant or variant forms.

[0054] The term “homology” refers to a degree of complementarity. There may be partial homology or complete homology (i.e., identity). Homology is often measured using sequence analysis software (e.g., Sequence Analysis Software Package of the Genetics Computer Group. University of Wisconsin Biotechnology Center.1710 University Avenue. Madison, Wis.53705). Such software matches similar sequences by assigning degrees of homology to various substitutions, deletions, insertions, and other modifications. Conservative substitutions typically include substitutions within the following groups: glycine, alanine; valine, isoleucine, leucine; aspartic acid, glutamic acid, asparagine, glutamine; serine, threonine; lysine, arginine; and phenylalanine, tyrosine.

[0055] By “nucleic acid” is meant any nucleic acid, whether composed of deoxyribonucleosides or ribonucleosides, and whether composed of phosphodiester linkages or modified linkages such as phosphotriester, phosphoramidate, siloxane, carbonate, carboxymethylester, acetamidate, carbamate, thioether, bridged phosphoramidate, bridged methylene phosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, bridged phosphorothioate or sulfone linkages, and combinations of such linkages. The term nucleic acid also specifically includes nucleic acids composed of bases other than the five biologically occurring bases (adenine, guanine, thymine, cytosine and uracil). The term “nucleic acid” typically refers to large polynucleotides.Attorney Docket No.204606-0174-00WO

[0056] Conventional notation is used herein to describe polynucleotide sequences: the left-hand end of a single-stranded polynucleotide sequence is the 5'-end; the left-hand direction of a double-stranded polynucleotide sequence is referred to as the 5'-direction.

[0057] The direction of 5' to 3' addition of nucleotides to nascent RNA transcripts is referred to as the transcription direction. The DNA strand having the same sequence as an mRNA is referred to as the “coding strand”; sequences on the DNA strand which are located 5' to a reference point on the DNA are referred to as “upstream sequences”; sequences on the DNA strand which are 3' to a reference point on the DNA are referred to as “downstream sequences.”

[0058] In the context of the present invention, the following abbreviations for the commonly occurring nucleic acid bases are used. “A” refers to adenosine, “C” refers to cytosine, “G” refers to guanosine, “T” refers to thymidine, and “U” refers to uridine.

[0059] As used herein, the terms “peptide,” “polypeptide,” and “protein” are used interchangeably, and refer to a compound comprised of amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and no limitation is placed on the maximum number of amino acids that can comprise a protein's or peptide's sequence. Polypeptides include any peptide or protein comprising two or more amino acids joined to each other by peptide bonds. As used herein, the term refers to both short chains, which also commonly are referred to in the art as peptides, oligopeptides and oligomers, for example, and to longer chains, which generally are referred to in the art as proteins, of which there are many types. “Polypeptides” include, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, among others. The polypeptides include natural peptides, recombinant peptides, synthetic peptides, or a combination thereof.

[0060] The term “RNA” as used herein is defined as ribonucleic acid.

[0061] “Variant” as the term is used herein, is a nucleic acid sequence or a peptide sequence that differs in sequence from a reference nucleic acid sequence or peptide sequence respectively, but retains essential biological properties of the reference molecule. Changes in the sequence of a nucleic acid variant may not alter the amino acid sequence of a peptide encoded by the reference nucleic acid, or may result in amino acid substitutions, additions, deletions, fusions and truncations. Changes in the sequence of peptide variants are typically limited or conservative, so that the sequences of the reference peptide and the variant are closely similarAttorney Docket No.204606-0174-00WO overall and, in many regions, identical. A variant and reference peptide can differ in amino acid sequence by one or more substitutions, additions, deletions in any combination. A variant of a nucleic acid or peptide can be a naturally occurring such as an allelic variant, or can be a variant that is not known to occur naturally. Non-naturally occurring variants of nucleic acids and peptides may be made by mutagenesis techniques or by direct synthesis.

[0062] A “vector” is a composition of matter which comprises an isolated nucleic acid and which can be used to deliver the isolated nucleic acid to the interior of a cell. Numerous vectors are known in the art including, but not limited to, linear polynucleotides, polynucleotides associated with ionic or amphiphilic compounds, plasmids, and viruses. Thus, the term “vector” includes an autonomously replicating plasmid or a virus. The term should also be construed to include non-plasmid and non-viral compounds which facilitate transfer of nucleic acid into cells, such as, for example, polylysine compounds, liposomes, and the like. Examples of viral vectors include, but are not limited to, adenoviral vectors, adeno-associated virus vectors, retroviral vectors, and the like.

[0063] Ranges: throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range. Fusion Constructs

[0064] In one aspect, the present disclosure is based on the development of novel fusions constructs for site specific cleavage of one or more target nucleic acid molecule. In some embodiments, site specific cleavage of one or more target nucleic acid molecule using the fusion constructs of the invention generates compatible ends which are subsequently ligated by cellular machinery. Therefore, in some embodiments, the invention provides methods for splicing, ligating or degrading nucleic acid molecules by contacting one or more target nucleic acidAttorney Docket No.204606-0174-00WO molecule with the fusion construct of the invention. In some embodiments, the fusion constructs are effectively delivered to a cell.

[0065] In one embodiment, the fusion construct combines the catalytic activity of a trans- cleaving ribozymes and the programmable nucleic acid targeting capability of gRNA for site specific cleavage of RNA molecules. In some embodiments, the fusion construct combines the catalytic activity of a trans-cleaving ribozymes or DNAzymes and the programmable nucleic acid targeting capability of gRNA for RNA-ligation, RNA-splicing, RNA degradation, or for the generation circular RNA molecules.

[0066] In one embodiment, the fusion construct combines the catalytic activity of two or more linked trans-cleaving ribozymes or DNAzymes for site specific cleavage of RNA molecules. In some embodiments, the fusion construct combines the catalytic activity of two or more linked trans-cleaving ribozymes for RNA-ligation, RNA-splicing, RNA degradation, or for the generation of circular RNA molecules.

[0067] In one embodiment, the fusion construct combines the catalytic activity of two or more linked DNA-cleaving ribozymes or DNAzymes for site specific cleavage of DNA molecules. In some embodiments, the fusion construct combines the catalytic activity of two or more linked trans-cleaving ribozymes or DNAzymes for DNA-ligation, DNA-splicing, DNA degradation, or for the generation of circular DNA molecules.

[0068] In one embodiment, the fusion construct combines the catalytic activity of DNA- cleaving ribozymes or DNAzymes and the programmable nucleic acid targeting capability of gRNA for site specific cleavage of DNA molecules. In some embodiments, the fusion construct combines the catalytic activity of a DNA-cleaving ribozymes or DNAzymes and the programmable nucleic acid targeting capability of gRNA for DNA-ligation, DNA-splicing, DNA degradation, or for the generation of circular DNA molecules.

[0069] In one embodiment, the fusion construct combines the catalytic activity of two or more linked DNA-cleaving ribozymes or DNAzymes for site specific cleavage of DNA molecules. In some embodiments, the fusion construct combines the catalytic activity of two or more linked trans-cleaving ribozymes or DNAzymes for DNA-ligation, DNA-splicing, DNA degradation, or for the generation of circular DNA molecules.

[0070] In one embodiment, the fusion construct comprises a linker. In one embodiment, the linker links a gRNA and a trans-cleaving ribozyme. In one embodiment, the linker links aAttorney Docket No.204606-0174-00WO gRNA and a DNA-cleaving ribozyme. In one embodiment, the linker links two trans-cleaving ribozymes. In one embodiment, the linker links two DNA-cleaving ribozymes. In one embodiment, the linker links two gRNAs.

[0071] In another aspect, the present invention comprises methods for site-specific deletion and subsequent ligation of target sequences using two or more fusion constructs of the invention. In some embodiments, the two or more fusion constructs comprise the same ribozyme. In some embodiments, the two or more fusion constructs comprise different ribozymes. In some embodiments, a first fusion construct comprises a ribozyme linked to a gRNA targeting a region upstream of a target nucleotide sequence to be edited or deleted and a second fusion construct comprises a ribozyme linked to a gRNA targeting a region downstream of a target nucleotide sequence to be edited or deleted. Co-administration of the two fusion constructs facilitates deletion of an intervening sequence, or splicing, of the targeted nucleic acid molecule. In some embodiments, a first fusion construct comprises a ribozyme linked to a gRNA targeting a target nucleotide sequence on a first nucleic acid molecule and a second fusion construct comprises a ribozyme linked to a gRNA targeting a target nucleotide sequence on a second nucleic acid molecule. Co-administration of the two fusion constructs facilitates site specific cleavage and subsequent ligation to generate a ligated nucleic acid molecule. Therefore, in one embodiment, the present invention relates to methods for trans-ligating RNA or DNA molecules, comprising contacting at least two different RNA or DNA molecules in a cell or in vitro with one or more fusion construct.

[0072] Exemplary nucleic acid molecules that can be ligated, degraded or spliced according to the methods of the invention include, but are not limited to, genomic DNA, extrachromosomal DNA, plasmid DNA, viral DNA, viral RNA, mRNA, lncRNA, non-coding RNA, or circular RNA molecules.

[0073] In some embodiments, cleavage of the RNA generates at least one RNA molecule with a ‘3’-phosphate or 2’,3’-cyclic phosphate termini and at least one RNA molecule with a 5’ hydroxyl RNA termini. In one embodiment, the method further comprises contacting said at least one RNA molecule with a ‘3’-phosphate or 2’,3’-cyclic phosphate termini and at least one RNA molecule with a 5’ hydroxyl RNA termini with RtcB ligase or a nucleic acid encoding RtcB ligase.Attorney Docket No.204606-0174-00WO Trans-cleaving Ribozyme

[0074] Ribozymes are autocatalytic RNAs which cleave in cis, to produce unique RNA 3’ and 5’ termini, as described herein. However, cis-cleaving ribozymes can be engineered to cleave in trans, such that target RNAs can be cleaved in a nucleotide specific manner, resulting in similar RNA termini. In some embodiments, the present invention comprises a composition comprising a single nucleic acid molecule encoding a single RNA molecule comprising a trans- cleaving engineered ribozyme. In one embodiment, said trans-cleaving engineered ribozyme is capable of trans-cleaving a separate RNA molecule. In one embodiment, said trans-cleaving engineered ribozyme recognizes a specific nucleic acid sequence in the separate RNA molecule. In some embodiments, the trans-cleaving engineered ribozyme targets a disease causing mutation for deletion. In some embodiment, the disease causing mutation is in an exon. In some embodiment, the disease causing mutation is in an intron. In some embodiments, the composition comprises two trans-cleaving engineered ribozymes, targeted upstream and downstream of the disease causing mutation. In some embodiments, trans-cleavage upstream and downstream of the disease causing mutation results in removal of the disease causing mutation. In some embodiments, the remaining portions of the gene are trans-spliced together after trans-cleavage of the disease causing mutation. In some embodiments, the trans-spliced gene is expressed as a functional protein.

[0075] In some embodiments, said one or more ribozyme of the composition is capable of spontaneously trans-cleaving one or more target RNA molecule. In some embodiments, one or more ribozyme is a 3’ ribozyme. In some embodiments, the 3’ ribozyme generates a 3’- phosphate (3’P) or 2’,3’-cyclic phosphate (2’3’ cP) end on the remaining one or more RNA molecule after spontaneous trans-cleavage. In some embodiments, one or more ribozyme is a 5’ ribozyme. In some embodiments, the 5’ ribozyme generates a 5’OH end on the remaining one or more RNA molecules after spontaneous trans-cleavage. In some embodiments, said 3’P or 2’3’ cP end and said 5’OH end can be ligated together.

[0076] In one embodiment, the fusion construct comprises one or more trans-cleaving ribozyme. In one embodiment, the trans-cleaving ribozyme is a trans-cleaving hammerhead (HH) ribozyme, or a trans-cleaving Hepatitis delta virus (HDV) ribozyme. In one embodiment, the fusion construct comprises at least two linked trans-cleaving hammerhead (HH) ribozymes. In one embodiment, the fusion construct comprises at least two linked trans-cleaving HepatitisAttorney Docket No.204606-0174-00WO delta virus (HDV) ribozymes. In one embodiment, the fusion construct comprises a trans- cleaving hammerhead (HH) ribozyme linked to a trans-cleaving Hepatitis delta virus (HDV) ribozyme.

[0077] In some embodiments, the fusion construct comprises a 3’ ribozyme. In one embodiment, the 3’ ribozyme is a trans-cleaving variant of a natural or synthetic ribozyme or deoxyribozyme. In some embodiments, said 3’ ribozyme is from one or more family selected from the group consisting of: hammerhead (HH), Hepatitis delta virus (HDV), Hairpin (HP), Varkud Satellite (VS), Twister, Twister Sister, Pistol, Hatchet, HOV, or GlmS, or a variant or fragment thereof that has trans-cleaving functionality. In some embodiments, the 3’ ribozyme comprises an overhang of one or more nucleotides. In one embodiment, the overhang comprises a nucleotide sequence that targets the ribozyme to a sequence upstream of a target cleavage site within a target RNA molecule. In some embodiments, the overhang comprises a gRNA.

[0078] In some embodiments, the fusion construct comprises a 5’ ribozyme. In one embodiment, the 5’ ribozyme is a trans-cleaving variant of a natural or synthetic ribozyme or deoxyribozyme. In some embodiments, said 3’ ribozyme is from one or more family selected from the group consisting of: hammerhead (HH), Hepatitis delta virus (HDV), Hairpin (HP), Varkud Satellite (VS), Twister, Twister Sister, Pistol, Hatchet, HOV, or GlmS, or a variant or fragment thereof that has trans-cleaving functionality. In some embodiments, the 5’ ribozyme comprises an overhang of one or more nucleotides. In one embodiment, the overhang comprises a nucleotide sequence that targets the ribozyme to a sequence downstream of a target cleavage site within a target RNA molecule. In some embodiments, the overhang comprises a gRNA.

[0079] In some embodiments, one or more ribozyme is a HH ribozyme, or a variant or fragment thereof that is capable of trans-cleavage. In one embodiment, the trans-cleaving HH ribozyme of the composition comprises SEQ ID NO:1, SEQ ID NO:2, or SEQ ID NO:3, or a variant or fragment thereof. In one embodiment, the trans-cleaving HH ribozyme comprises the nucleic acid sequence of SEQ ID NO: 1. In one embodiment, the trans-cleaving HH ribozyme comprises the nucleic acid sequence of SEQ ID NO: 2. In one embodiment, the trans-cleaving HH ribozyme comprises the nucleic acid sequence of SEQ ID NO: 3. In one embodiment, the fusion construct comprises SEQ ID NO:1, SEQ ID NO:2, or SEQ ID NO:3 operably linked to a gRNA. In one embodiment, the fusion construct comprises SEQ ID NO:1, SEQ ID NO:2, or SEQ ID NO:3 operably linked to one or more additional trans-cleaving ribozyme. In oneAttorney Docket No.204606-0174-00WO embodiment, the fusion construct comprises SEQ ID NO:1, SEQ ID NO:2, or SEQ ID NO:3 operably linked to one or more additional trans-cleaving ribozyme and one or more gRNA sequence. In one embodiment, the HH ribozyme is modified to include a tertiary stabilizing motif (TSM).

[0080] In some embodiments, one or more ribozyme is a HDV ribozyme, or a variant or fragment thereof that is capable of trans-cleavage. In one embodiment, the trans-cleaving HDV ribozyme of the composition comprises SEQ ID NO:4, or a variant or fragment thereof. In one embodiment, the fusion construct comprises SEQ ID NO:4 operably linked to a gRNA. In one embodiment, the fusion construct comprises SEQ ID NO:4 operably linked to one or more additional trans-cleaving ribozyme. In one embodiment, the fusion construct comprises SEQ ID NO:4 operably linked to one or more additional trans-cleaving ribozyme and one or more gRNA sequence. In one embodiment, the HDV ribozyme is modified to include a tertiary stabilizing motif (TSM).

[0081] In one embodiment, the fusion construct of the composition comprises a sequence of a ribozyme as set forth in any one of SEQ ID NO:1-53 or a variant or fragment thereof that is capable of trans-cleavage. In one embodiment, the fusion construct comprises at least one of SEQ ID NO: 1-53, or a variant or fragment thereof that is capable of trans-cleavage operably linked to a gRNA. In one embodiment, the fusion construct comprises at least one of SEQ ID NO: 1-53, or a variant or fragment thereof that is capable of trans-cleavage operably linked to one or more additional trans-cleaving ribozyme. In one embodiment, the fusion construct comprises at least one of SEQ ID NO: 1-53, or a variant or fragment thereof that is capable of trans-cleavage operably linked to one or more additional trans-cleaving ribozyme and one or more gRNA sequence. In one embodiment, the fusion construct comprises a trans-cleavage ribozyme that has been modified to include a tertiary stabilizing motif (TSM).

[0082] In some embodiments, the 3’P or 2’3’ cP end and the 5’OH end of nucleic acid molecules that have undergone ribozyme-mediated cleavage can be ligated together. As such, separated nucleic acid sequences on the same or on separate nucleic acid molecules can be trans- spliced or trans-ligated together. In one embodiment, the trans-spliced or trans-ligated nucleic acid molecule expresses a longer protein or fusion protein.

[0083] In one embodiment, the trans-cleaving ribozyme comprises a sequence at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at leastAttorney Docket No.204606-0174-00WO 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to one of SEQ ID NOs:1-53. In one embodiment, the trans- cleaving ribozyme comprises a sequence of SEQ ID NO:1. In one embodiment, the trans- cleaving ribozyme comprises a sequence of SEQ ID NO:2. In one embodiment, the trans- cleaving ribozyme comprises a sequence of SEQ ID NO:3. In one embodiment, the trans- cleaving ribozyme comprises a sequence of SEQ ID NO:4.

[0084] In one embodiment, the nucleic acid sequence encoding a fusion construct comprises a nucleic acid sequence comprising at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to one of SEQ ID NOs: 1-53 operably linked to second nucleic acid sequence comprising at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to one of SEQ ID NOs: 1-53.

[0085] In one embodiment, the trans-cleaving ribozyme protein is a fragment of a trans- cleaving ribozyme. In one embodiment, the fragment of the trans-cleaving ribozyme is capable of being complemented with a second fragment of the trans-cleaving ribozyme in trans providing inducible catalytic activity.

[0086] In one embodiment, the fragment of the trans-cleaving ribozyme is a fragment of a trans-cleaving hammerhead (HH) ribozyme, or trans-cleaving ribozyme Hepatitis delta virus (HDV) ribozyme. In one embodiment, the fragment of the trans-cleaving ribozyme comprises at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, atAttorney Docket No.204606-0174-00WO least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the full length of SEQ ID NO:1-4. DNAzymes that target RNA

[0087] In one embodiment, the fusion construct comprises one or more DNAzyme (also known as Deoxyribozyme, or DNA enzyme) that cleaves RNA molecules. Exemplary RNA cleaving DNAzymes that can be incorporated into the fusion construct of the invention include, but are not limited to DNAzymes described in Breaker et al., (1994, Chem Biol 1, 223-229) and Wang et al., (2019, Scientific reports 9, 8224.) In one embodiment, the DNAzyme is Deoxyribozyme 8–17 or Deoxyribozyme 10-23 or a fragment or variant thereof. DNAzymes that target DNA

[0088] In one embodiment, the fusion construct comprises one or more DNAzyme that cleaves DNA molecules. Exemplary DNA cleaving DNAzymes that can be incorporated into the fusion construct of the invention include, but are not limited to DNAzymes described in Gu et al., (2013, Journal of the American Chemical Society 135, 9121-9129.) In one embodiment, the DNAzyme is deoxyribozyme I-R3 or a fragment or variant thereof. RNA Stabilization

[0089] In some embodiments, the ribozyme (or DNAzyme) or the fusion construct may contain a modification to increase the stability of the ribozyme (or DNAzyme) or fusion construct. In some embodiments, the modification comprises inclusion of a tertiary stabilizing motif (TSM). In some embodiments, the TSM comprises an amendment to at least one stem loop of a ribozyme (or DNAzyme) that alters the stability of the stem loop. In some embodiments the TSM increases hybridization of the ribozyme or the fusion construct comprising the ribozyme to a target nucleic acid molecule.

[0090] In some embodiments, the ribozyme (or DNAzyme) or the fusion construct may contain a modification which holds two complementary RNA motifs in proximity. LinkerAttorney Docket No.204606-0174-00WO

[0091] In one embodiment, the fusion construct comprises a linker. In one embodiment, the linker links the gRNA and catalytic RNA. In one embodiment, the linker is connected to the 5’ end of the gRNA and to the 3’ end of the catalytic RNA. In one embodiment, the linker is connected to the 3’ end of the catalytic RNA and to the 5’ end of the gRNA. Linkers can be flexible linkers or more rigid linkers. Expression of Fusion Constructs

[0092] The fusion constructs of the present disclosure may be made using recombinant expression vectors or be in vitro transcribed RNA. The recombinant expression vectors of the disclosure comprise a nucleic acid of the invention in a form suitable for expression of the nucleic acid in a host cell, which means that the recombinant expression vectors include one or more regulatory sequences, selected on the basis of the host cells to be used for expression, that is operatively-linked to the nucleic acid sequence to be expressed. Within a recombinant expression vector, “operably-linked” is intended to mean that the nucleotide sequence of interest is linked to the regulatory sequences in a manner that allows for expression of the nucleotide sequence (e.g., in an in vitro transcription / translation system or in a host cell when the vector is introduced into the host cell).

[0093] The term “regulatory sequence” is intended to include promoters, enhancers and other expression control elements (e.g., polyadenylation signals). Such regulatory sequences are described, for example, in Goeddel, Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, Calif. (1990). Regulatory sequences include those that direct constitutive expression of a nucleotide sequence in many types of host cell and those that direct expression of the nucleotide sequence only in certain host cells (e.g., tissue-specific regulatory sequences). It will be appreciated by those skilled in the art that the design of the expression vector can depend on such factors as the choice of the host cell to be transformed, the level of expression of protein desired, etc. The expression vectors of the invention can be introduced into host cells to thereby produce proteins or peptides, including fusion proteins or peptides, encoded by nucleic acids.

[0094] The recombinant expression vectors of the invention can be designed for production of RNA molecules in prokaryotic or eukaryotic cells. For example, fusion constructs of the invention can be expressed in bacterial cells such as Escherichia coli, insect cells (usingAttorney Docket No.204606-0174-00WO baculovirus expression vectors) yeast cells or mammalian cells. Suitable host cells are discussed further in Goeddel, Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, Calif. (1990). Alternatively, the recombinant expression vector can be transcribed and translated in vitro, for example using T7 promoter regulatory sequences and T7 polymerase.

[0095] In one embodiment, a fusion construct of the disclosure is expressed in mammalian cells using a mammalian expression vector. Mammalian cell lines available in the art for expression of a heterologous polypeptide include Chinese hamster ovary (CHO) cells, HeLa cells, baby hamster kidney cells, NSO mouse melanoma cells, YB2 / 0 rat myeloma cells, human embryonic kidney cells, human embryonic retina cells and many others. Examples of mammalian expression vectors include pCDM8 (Seed, 1987. Nature 329: 840) and pMT2PC (Kaufman, et al., 1987. EMBO J.6: 187-195), pIRESpuro (Clontech), pUB6 (Invitrogen), pCEP4 (Invitrogen) pREP4 (Invitrogen), pcDNA3 (Invitrogen). When used in mammalian cells, the expression vector's control functions are often provided by viral regulatory elements. For example, commonly used promoters are derived from polyoma, adenovirus 2, cytomegalovirus, Rous Sarcoma Virus, and simian virus 40. For other suitable expression systems for both prokaryotic and eukaryotic cells see, e.g., Chapters 16 and 17 of Sambrook, et al., Molecular Cloning: A Laboratory Manual.2nd ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989.

[0096] In another embodiment, the recombinant mammalian expression vector is capable of directing expression of the nucleic acid preferentially in a particular cell type (e.g., tissue- specific regulatory elements are used to express the nucleic acid). Tissue-specific regulatory elements are known in the art. Non-limiting examples of suitable tissue-specific promoters include the albumin promoter (liver-specific; Pinkert, et al., 1987. Genes Dev.1: 268-277), lymphoid-specific promoters (Calame and Eaton, 1988. Adv. Immunol.43: 235-275), in particular promoters of T cell receptors (Winoto and Baltimore, 1989. EMBO J.8: 729-733) and immunoglobulins (Banerji, et al., 1983. Cell 33: 729-740; Queen and Baltimore, 1983. Cell 33: 741-748), neuron-specific promoters (e.g., the neurofilament promoter; Byrne and Ruddle, 1989. Proc. Natl. Acad. Sci. USA 86: 5473-5477), pancreas-specific promoters (Edlund, et al., 1985. Science 230: 912-916), and mammary gland-specific promoters (e.g., milk whey promoter; U.S. Pat. No.4,873,316 and European Application Publication No.264,166). Developmentally-Attorney Docket No.204606-0174-00WO regulated promoters are also encompassed, e.g., the murinehox promoters (Kessel and Gruss, 1990. Science 249: 374-379) and the alpha-fetoprotein promoter (Campes and Tilghman, 1989. Genes Dev.3: 537-546). Targeting Nucleic Acids and CRISPR guide RNAs (gRNAs)

[0097] In one aspect, the fusion constructs of the invention include targeting nucleic acids, including CRISPR guide RNAs (gRNAs) for targeting the fusion construct or a complex comprising the fusion construct to a target RNA. In one embodiment, the targeting nucleic acids is a gRNA. In one embodiment, the gRNA comprises guide sequence. In one embodiment, the gRNA comprises a direct repeat (DR) sequence. In one embodiment the gRNA comprises a direct repeat sequence and a guide sequence fused or linked to a guide sequence or spacer sequence. In one embodiment the direct repeat sequence may be located upstream (i.e., 5′) from the guide sequence or spacer sequence. In other embodiments, the direct repeat sequence may be located downstream (i.e., 3′) from the guide sequence or spacer sequence.

[0098] In some embodiments, the gRNA comprises a stem loop. In one embodiment, the gRNA comprises a single stem loop. In one embodiment, the direct repeat sequence forms a stem loop. In one embodiment, the direct repeat sequence forms a single stem loop. In one embodiment, the gRNA is complementary to a target RNA. For example, in one embodiment, the fusion construct comprises a catalytic RNA capable of cleaving ssRNA and the gRNA guide sequence comprises a sequence having sufficient complementarity to a sequence adjacent to the target sequence. In one embodiment, the RNase is capable of cleaving ssRNA and the crRNA guide sequence comprises a sequence having sufficient complementarity to the target sequence and creating a bulge ssRNA at the target site.

[0099] In one embodiment, the spacer length of the guide RNA is from 15 to 35 nt. In one embodiment, the spacer length of the guide RNA is at least 15 nucleotides. In one embodiment the spacer length is from 15 to 17 nt, e.g., 15, 16, or 17 nt, from 17 to 20 nt, e.g., 17, 18, 19, or 20 nt, from 20 to 24 nt, e.g., 20, 21, 22, 23, or 24 nt, from 23 to 25 nt, e.g., 23, 24, or 25 nt, from 24 to 27 nt, e.g., 24, 25, 26, or 27 nt, from 27-30 nt, e.g., 27, 28, 29, or 30 nt, from 30-35 nt, e.g., 30, 31, 32, 33, 34, or 35 nt, or 35 nt or longer.Attorney Docket No.204606-0174-00WO

[0100] In general, a guide sequence is any polynucleotide sequence having sufficient complementarity with a target polynucleotide sequence to hybridize with the target sequence and direct sequence-specific cleavage of the polynucleotide. In some embodiments, the degree of complementarity between a guide sequence and its corresponding target sequence, when optimally aligned using a suitable alignment algorithm, is about or more than about 50%, 60%, 75%, 80%, 85%, 90%, 95%, 97.5%, 99%, or more. Optimal alignment may be determined with the use of any suitable algorithm for aligning sequences, non-limiting example of which include the Smith-Waterman algorithm, the Needleman-Wunsch algorithm, algorithms based on the Burrows-Wheeler Transform (e.g. the Burrows Wheeler Aligner), ClustalW, Clustal X, BLAT, Novoalign (Novocraft Technologies; available at www.novocraft.com), ELAND (Illumina, San Diego, Calif.), SOAP (available at soap.genomics.org.cn), and Maq (available at maq.sourceforge.net). In some embodiments, a guide sequence is about or more than about 5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 75, or more nucleotides in length. In some embodiments, a guide sequence is less than about 75, 50, 45, 40, 35, 30, 25, 20, 15, 12, or fewer nucleotides in length. Preferably the guide sequence is 1030 nucleotides long. The ability of a guide sequence to direct sequence-specific cleavage by a fused catalytic RNA may be assessed by any suitable assay. For example, the components of a system including the guide sequence to be tested, may be provided to a host cell having the corresponding target sequence, followed by an assessment of preferential cleavage of a polynucleotide comprising the target sequence. Similarly, cleavage of a target polynucleotide sequence may be evaluated in a test tube by providing the target sequence, components of a system, including the guide sequence to be tested and a control guide sequence different from the test guide sequence, and comparing binding or rate of cleavage at the target sequence between the test and control guide sequence reactions. Other assays are possible, and will occur to those skilled in the art.

[0101] In some embodiments, the degree of complementarity between a guide sequence and its corresponding target sequence can be about or more than about 50%, 60%, 75%, 80%, 85%, 90%, 95%, 97.5%, 99%, or 100%; a guide or RNA or sgRNA can be about or more than about 5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 75, or more nucleotides in length; or guide or RNA or sgRNA can be less than about 75, 50, 45, 40, 35, 30, 25, 20, 15, 12, or fewer nucleotides in length; and advantageously tracr RNAAttorney Docket No.204606-0174-00WO is 30 or 50 nucleotides in length. However, an aspect of the invention is to reduce off-target interactions, e.g., reduce the guide interacting with a target sequence having low complementarity. Indeed, in the examples, it is shown that the invention involves mutations that result in the CRISPR-Cas system being able to distinguish between target and off-target sequences that have greater than 80% to about 95% complementarity, e.g., 83%-84% or 88-89% or 94-95% complementarity (for instance, distinguishing between a target having 18 nucleotides from an off-target of 18 nucleotides having 1, 2 or 3 mismatches). Accordingly, in the context of the present invention the degree of complementarity between a guide sequence and its corresponding target sequence is greater than 94.5% or 95% or 95.5% or 96% or 96.5% or 97% or 97.5% or 98% or 98.5% or 99% or 99.5% or 99.9%, or 100%. Off target is less than 100% or 99.9% or 99.5% or 99% or 99% or 98.5% or 98% or 97.5% or 97% or 96.5% or 96% or 95.5% or 95% or 94.5% or 94% or 93% or 92% or 91% or 90% or 89% or 88% or 87% or 86% or 85% or 84% or 83% or 82% or 81% or 80% complementarity between the sequence and the guide, with it advantageous that off target is 100% or 99.9% or 99.5% or 99% or 99% or 98.5% or 98% or 97.5% or 97% or 96.5% or 96% or 95.5% or 95% or 94.5% complementarity between the sequence and the guide. Nucleic Acids

[0102] The isolated nucleic acid sequences of the disclosure can be obtained using any of the many recombinant methods known in the art, such as, for example by screening libraries from cells expressing the gene, by deriving the gene from a vector known to include the same, or by isolating directly from cells and tissues containing the same, using standard techniques. Alternatively, the gene of interest can be produced synthetically, rather than cloned.

[0103] The isolated nucleic acid may comprise any type of nucleic acid, including, but not limited to DNA and RNA. For example, in one embodiment, the composition comprises an isolated DNA molecule, including for example, an isolated cDNA molecule, encoding a protein of the disclosure. In one embodiment, the composition comprises an isolated RNA molecule encoding a fusion of the disclosure, or a functional fragment thereof.

[0104] The nucleic acid molecules of the present invention can be modified to improve stability in serum or in growth medium for cell cultures. Modifications can be added to enhance stability, functionality, and / or specificity and to minimize immunostimulatory properties of theAttorney Docket No.204606-0174-00WO nucleic acid molecule of the invention. For example, in order to enhance the stability, the 3’- residues may be stabilized against degradation, e.g., they may be selected such that they consist of purine nucleotides, particularly adenosine or guanosine nucleotides. Alternatively, substitution of pyrimidine nucleotides by modified analogues, e.g., substitution of uridine by 2’- deoxythymidine is tolerated and does not affect function of the molecule.

[0105] In one embodiment of the present invention the nucleic acid molecule may contain at least one modified nucleotide analogue. For example, the ends may be stabilized by incorporating modified nucleotide analogues.

[0106] Non-limiting examples of nucleotide analogues include sugar- and / or backbone- modified ribonucleotides (i.e., include modifications to the phosphate-sugar backbone). For example, the phosphodiester linkages of natural RNA may be modified to include at least one of a nitrogen or sulfur heteroatom. In exemplary backbone-modified ribonucleotides the phosphoester group connecting to adjacent ribonucleotides is replaced by a modified group, e.g., of phosphothioate group. In exemplary sugar-modified ribonucleotides, the 2’ OH-group is replaced by a group selected from H, OR, R, halo, SH, SR, NH2, NHR, NR2 or ON, wherein R is C1-C6 alkyl, alkenyl or alkynyl and halo is F, Cl, Br or I.

[0107] Other examples of modifications are nucleobase-modified ribonucleotides, i.e., ribonucleotides, containing at least one non-naturally occurring nucleobase instead of a naturally occurring nucleobase. Bases may be modified to block the activity of adenosine deaminase. Exemplary modified nucleobases include, but are not limited to, uridine and / or cytidine modified at the 5-position, e.g., 5-(2-amino)propyl uridine, 5-bromo uridine; adenosine and / or guanosines modified at the 8 position, e.g., 8-bromo guanosine; deaza nucleotides, e.g., 7-deaza-adenosine; O- and N-alkylated nucleotides, e.g., N6-methyl adenosine are suitable. It should be noted that the above modifications may be combined.

[0108] In some instances, the nucleic acid molecule comprises at least one of the following chemical modifications: 2’-H, 2’-O-methyl, or 2’-OH modification of one or more nucleotides. In certain embodiments, a nucleic acid molecule of the invention can have enhanced resistance to nucleases. For increased nuclease resistance, a nucleic acid molecule, can include, for example, 2’-modified ribose units and / or phosphorothioate linkages. For example, the 2’ hydroxyl group (OH) can be modified or replaced with a number of different “oxy” or “deoxy” substituents. For increased nuclease resistance the nucleic acid molecules of the invention canAttorney Docket No.204606-0174-00WO include 2’-O-methyl, 2’-fluorine, 2’-O-methoxyethyl, 2’-O-aminopropyl, 2’-amino, and / or phosphorothioate linkages. Inclusion of locked nucleic acids (LNA), ethylene nucleic acids (ENA), e.g., 2’-4’-ethylene-bridged nucleic acids, and certain nucleobase modifications such as 2-amino-A, 2-thio (e.g., 2-thio-U), G-clamp modifications, can also increase binding affinity to a target.

[0109] In one embodiment, the nucleic acid molecule includes a 2’-modified nucleotide, e.g., a 2’-deoxy, 2’-deoxy-2’-fluoro, 2’-O-methyl, 2’-O-methoxyethyl (2’-O-MOE), 2’-O- aminopropyl (2’-O-AP), 2’-O-dimethylaminoethyl (2’-O-DMAOE), 2’-O-dimethylaminopropyl (2’-O-DMAP), 2’-O-dimethylaminoethyloxyethyl (2’-O-DMAEOE), or 2’-O-N- methylacetamido (2’-O-NMA). In one embodiment, the nucleic acid molecule includes at least one 2’-O-methyl-modified nucleotide, and in some embodiments, all of the nucleotides of the nucleic acid molecule include a 2’-O-methyl modification.

[0110] In certain embodiments, the nucleic acid molecule of the invention has one or more of the following properties:

[0111] Nucleic acid agents discussed herein include otherwise unmodified RNA and DNA as well as RNA and DNA that have been modified, e.g., to improve efficacy, and polymers of nucleoside surrogates. Unmodified RNA refers to a molecule in which the components of the nucleic acid, namely sugars, bases, and phosphate moieties, are the same or essentially the same as that which occur in nature, or as occur naturally in the human body. The art has referred to rare or unusual, but naturally occurring, RNAs as modified RNAs, see, e.g., Limbach et al. (Nucleic Acids Res., 1994, 22:2183-2196). Such rare or unusual RNAs, often termed modified RNAs, are typically the result of a post-transcriptional modification and are within the term unmodified RNA as used herein. Modified RNA, as used herein, refers to a molecule in which one or more of the components of the nucleic acid, namely sugars, bases, and phosphate moieties, are different from that which occur in nature, or different from that which occurs in the human body. While they are referred to as “modified RNAs” they will of course, because of the modification, include molecules that are not, strictly speaking, RNAs. Nucleoside surrogates are molecules in which the ribophosphate backbone is replaced with a non-ribophosphate construct that allows the bases to be presented in the correct spatial relationship such that hybridization is substantially similar to what is seen with a ribophosphate backbone, e.g., non-charged mimics of the ribophosphate backbone.Attorney Docket No.204606-0174-00WO

[0112] Modifications of the nucleic acid of the invention may be present at one or more of, a phosphate group, a sugar group, backbone, N-terminus, C-terminus, or nucleobase.

[0113] The present invention also includes a vector in which the isolated nucleic acid of the present invention is inserted. The art is replete with suitable vectors that are useful in the present invention.

[0114] In brief summary, the expression of natural or synthetic nucleic acids encoding a protein of the disclosure is typically achieved by operably linking a nucleic acid encoding the protein of the disclosure or portions thereof to a promoter, and incorporating the construct into an expression vector. The vectors to be used are suitable for replication and, optionally, integration in eukaryotic cells. Typical vectors contain transcription and translation terminators, initiation sequences, and promoters useful for regulation of the expression of the desired nucleic acid sequence.

[0115] The vectors of the present invention may also be used for nucleic acid immunization and gene therapy, using standard gene delivery protocols. Methods for gene delivery are known in the art. See, e.g., U.S. Pat. Nos.5,399,346, 5,580,859, 5,589,466, incorporated by reference herein in their entireties. In another embodiment, the invention provides a gene therapy vector.

[0116] The isolated nucleic acid of the invention can be cloned into a number of types of vectors. For example, the nucleic acid can be cloned into a vector including, but not limited to a plasmid, a phagemid, a phage derivative, an animal virus, and a cosmid. Vectors of particular interest include expression vectors, replication vectors, probe generation vectors, and sequencing vectors.

[0117] Further, the vector may be provided to a cell in the form of a viral vector. Viral vector technology is well known in the art and is described, for example, in Sambrook et al. (2012, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York), and in other virology and molecular biology manuals. Viruses, which are useful as vectors include, but are not limited to, retroviruses, adenoviruses, adeno- associated viruses, herpes viruses, and lentiviruses. In general, a suitable vector contains an origin of replication functional in at least one organism, a promoter sequence, convenient restriction endonuclease sites, and one or more selectable markers, (e.g., WO 01 / 96584; WO 01 / 29058; and U.S. Pat. No.6,326,193).Attorney Docket No.204606-0174-00WO

[0118] In one embodiment, the nucleic acid encoding one or more fusion construct of the present invention comprises a nucleic acid sequence at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:3 or SEQ ID NO:4 linked to a gRNA.

[0119] Methods of introducing and expressing polynucleotides into a cell are known in the art. In the context of an expression vector, the vector can be readily introduced into a host cell, e.g., mammalian, bacterial, yeast, or insect cell by any method in the art. For example, an expression vector can be transferred into a host cell by physical, chemical, or biological means.

[0120] Physical methods for introducing a polynucleotide into a host cell include calcium phosphate precipitation, lipofection, particle bombardment, microinjection, electroporation, and the like. Methods for producing cells comprising vectors and / or exogenous nucleic acids are well-known in the art. See, for example, Sambrook et al. (2012, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York). An exemplary method for the introduction of a polynucleotide into a host cell is calcium phosphate transfection.

[0121] Biological methods for introducing a polynucleotide of interest into a host cell include the use of DNA and RNA vectors. Viral vectors, and especially retroviral vectors, have become the most widely used method for inserting genes into mammalian, e.g., human cells. Other viral vectors can be derived from lentivirus, poxviruses, herpes simplex virus I, adenoviruses and adeno-associated viruses, and the like. See, for example, U.S. Pat. Nos. 5,350,674 and 5,585,362.

[0122] Chemical means for introducing a polynucleotide into a host cell include colloidal dispersion systems, such as macromolecule complexes, nanocapsules, microspheres, beads, and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, and liposomes. An exemplary colloidal system for use as a delivery vehicle in vitro and in vivo is a liposome (e.g., an artificial membrane vesicle).

[0123] In the case where a non-viral delivery system is utilized, an exemplary delivery vehicle is a liposome. The use of lipid formulations is contemplated for the introduction of the nucleic acids into a host cell (in vitro, ex vivo or in vivo). In another aspect, the nucleic acid mayAttorney Docket No.204606-0174-00WO be associated with a lipid. The nucleic acid associated with a lipid may be encapsulated in the aqueous interior of a liposome, interspersed within the lipid bilayer of a liposome, attached to a liposome via a linking molecule that is associated with both the liposome and the oligonucleotide, entrapped in a liposome, complexed with a liposome, dispersed in a solution containing a lipid, mixed with a lipid, combined with a lipid, contained as a suspension in a lipid, contained or complexed with a micelle, or otherwise associated with a lipid. Lipid, lipid / DNA or lipid / expression vector associated compositions are not limited to any particular structure in solution. For example, they may be present in a bilayer structure, as micelles, or with a “collapsed” structure. They may also simply be interspersed in a solution, possibly forming aggregates that are not uniform in size or shape. Lipids are fatty substances which may be naturally occurring or synthetic lipids. For example, lipids include the fatty droplets that naturally occur in the cytoplasm as well as the class of compounds which contain long-chain aliphatic hydrocarbons and their derivatives, such as fatty acids, alcohols, amines, amino alcohols, and aldehydes.

[0124] Lipids suitable for use can be obtained from commercial sources. For example, dimyristyl phosphatidylcholine (“DMPC”) can be obtained from Sigma, St. Louis, MO; dicetyl phosphate (“DCP”) can be obtained from K & K Laboratories (Plainview, NY); cholesterol (“Choi”) can be obtained from Calbiochem-Behring; dimyristyl phosphatidylglycerol (“DMPG”) and other lipids may be obtained from Avanti Polar Lipids, Inc. (Birmingham, AL). Stock solutions of lipids in chloroform or chloroform / methanol can be stored at about -20°C. Chloroform is used as the only solvent since it is more readily evaporated than methanol. “Liposome” is a generic term encompassing a variety of single and multilamellar lipid vehicles formed by the generation of enclosed lipid bilayers or aggregates. Liposomes can be characterized as having vesicular structures with a phospholipid bilayer membrane and an inner aqueous medium. Multilamellar liposomes have multiple lipid layers separated by aqueous medium. They form spontaneously when phospholipids are suspended in an excess of aqueous solution. The lipid components undergo self-rearrangement before the formation of closed structures and entrap water and dissolved solutes between the lipid bilayers (Ghosh et al., 1991 Glycobiology 5: 505-10). However, compositions that have different structures in solution than the normal vesicular structure are also encompassed. For example, the lipids may assume aAttorney Docket No.204606-0174-00WO micellar structure or merely exist as nonuniform aggregates of lipid molecules. Also contemplated are lipofectamine-nucleic acid complexes.

[0125] Regardless of the method used to introduce exogenous nucleic acids into a host cell, in order to confirm the presence of the recombinant DNA sequence in the host cell, a variety of assays may be performed. Such assays include, for example, “molecular biological” assays well known to those of skill in the art, such as Southern and Northern blotting, RT-PCR and PCR; “biochemical” assays, such as detecting the presence or absence of a particular peptide, e.g., by immunological means (ELISAs and Western blots) or by assays described herein to identify agents falling within the scope of the invention. Nanoparticles

[0126] In some embodiments, the present disclosure provides fusion constructs, nucleic acids, or a combination thereof of any of the preceding paragraphs formulated in a nanoparticle (e.g., a lipid nanoparticle).

[0127] In some embodiments, the , nucleic acids, or a combination thereof is formulated in a lipid nanoparticle. In some embodiments, the fusion constructs, nucleic acids, or a combination thereof is formulated in a lipid-polycation complex, referred to as a cationic lipid nanoparticle. As a non-limiting example, the polycation may include a cationic peptide or a polypeptide such as, but not limited to, polylysine, polyornithine and / or polyarginine. In some embodiments, the fusion constructs, nucleic acids, or a combination thereof is formulated in a lipid nanoparticle that includes a non-cationic lipid such as, but not limited to, cholesterol or dioleoyl phosphatidyl-ethanolamine (DOPE). In some embodiments, the lipid nanoparticle comprises at least one ionizable cationic lipid, at least one non-cationic lipid, at least one sterol, and / or at least one polyethylene glycol (PEG)-modified lipid.

[0128] A lipid nanoparticle formulation may be influenced by, but not limited to, the selection of the cationic lipid component, the degree of cationic lipid saturation, the nature of the PEGylation, ratio of all components and biophysical parameters such as size. In one example by Semple et al. (Nature Biotech.201028:172-176), the lipid nanoparticle formulation is composed of 57.1% cationic lipid, 7.1% dipalmitoylphosphatidylcholine, 34.3% cholesterol, and 1.4% PEG-c-DMA. As another example, changing the composition of the cationic lipid can moreAttorney Docket No.204606-0174-00WO effectively deliver siRNA to various antigen presenting cells (Basha et al. Mol Ther.2011 19:2186-2200).

[0129] In some embodiments, lipid nanoparticle formulations may comprise 35 to 45% cationic lipid, 40% to 50% cationic lipid, 50% to 60% cationic lipid and / or 55% to 65% cationic lipid. In some embodiments, the ratio of lipid to RNA (e.g., mRNA) in lipid nanoparticles may be 5:1 to 20:1, 10:1 to 25:1, 15:1 to 30:1 and / or at least 30:1.

[0130] In some embodiments, the ratio of PEG in the lipid nanoparticle formulations may be increased or decreased and / or the carbon chain length of the PEG lipid may be modified from C14 to C18 to alter the pharmacokinetics and / or biodistribution of the lipid nanoparticle formulations. As a non-limiting example, lipid nanoparticle formulations may contain 0.5% to 3.0%, 1.0% to 3.5%, 1.5% to 4.0%, 2.0% to 4.5%, 2.5% to 5.0% and / or 3.0% to 6.0% of the lipid molar ratio of PEG-c-DOMG (R-3-[(ω-methoxy-poly(ethyleneglycol)2000)carbamoyl)]-1,2- dimyristyloxypropyl-3-amine) (also referred to herein as PEG-DOMG) as compared to the cationic lipid, DSPC and cholesterol. In some embodiments, the PEG-c-DOMG may be replaced with a PEG lipid such as, but not limited to, PEG-DSG (1,2-Distearoyl-sn-glycerol, methoxypolyethylene glycol), PEG-DMG (1,2-Dimyristoyl-sn-glycerol) and / or PEG-DPG (1,2- Dipalmitoyl-sn-glycerol, methoxypolyethylene glycol). The cationic lipid may be selected from any lipid known in the art such as, but not limited to, DLin-MC3-DMA, DLin-DMA, C12-200 and DLin-KC2-DMA.

[0131] In some embodiments, the fusion constructs, nucleic acids, or a combination thereof is formulated as a nanoparticle that comprises at least one lipid selected from, but not limited to, DLin-DMA, DLin-K-DMA, 98N12-5, C12-200, DLin-MC3-DMA, DLin-KC2-DMA, DODMA, PLGA, PEG, PEG-DMG, PEGylated lipids and amino alcohol lipids. In some embodiments, the lipid may be a cationic lipid such as, but not limited to, DLin-DMA, DLin-D- DMA, DLin-MC3-DMA, DLin-KC2-DMA, DODMA and amino alcohol lipids. The amino alcohol cationic lipid may be the lipids described in and / or made by the methods described in U.S. Patent Publication No. US20130150625, herein incorporated by reference in its entirety. As a non-limiting example, the cationic lipid may be 2-amino-3-[(9Z,12Z)-octadeca-9,12-dien-1- yloxy]-2-{[(9Z,2Z)-octadeca-9,12-dien-1-yloxy]methyl}propan-1-ol (Compound 1 in US20130150625); 2-amino-3-[(9Z)-octadec-9-en-1-yloxy]-2{[(9Z)-octadec-9-en-1- yloxy]methyl}propan-1-ol (Compound 2 in US20130150625); 2-amino-3-[(9Z,12Z)-octadeca-Attorney Docket No.204606-0174-00WO 9,12-dien-1-yloxy]-2-[(octyloxy)methyl]propan-1-ol (Compound 3 in US20130150625); and 2- (dimethylamino)-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-2-{[(9Z,12Z)-octadeca-9,12-dien-1- yloxy]methyl}propan-1ol (Compound 4 in US20130150625); or any pharmaceutically acceptable salt or stereoisomer thereof.

[0132] Lipid nanoparticle formulations typically comprise a lipid, in particular, an ionizable cationic lipid, for example, 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin-KC2-DMA), dilinoleyl-methyl-4-dimethylaminobutyrate (DLin-MC3-DMA), or di((Z)- non-2-en-1-yl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (L319), and further comprise a neutral lipid, a sterol and a molecule capable of reducing particle aggregation, for example a PEG or PEG-modified lipid.

[0133] In some embodiments, a lipid nanoparticle formulation consists essentially of (i) at least one lipid selected from the group consisting of 2,2-dilinoleyl-4-dimethylaminoethyl- [1,3]-dioxolane (DLin-KC2-DMA), dilinoleyl-methyl-4-dimethylaminobutyrate (DLin-MC3- DMA), and di((Z)-non-2-en-1-yl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (L319); (ii) a neutral lipid selected from DSPC, DPPC, POPC, DOPE and SM; (iii) a sterol, e.g., cholesterol; and (iv) a PEG-lipid, e.g., PEG-DMG or PEG-cDMA, in a molar ratio of 20-60% cationic lipid:5-25% neutral lipid: 25-55% sterol; 0.5-15% PEG-lipid.

[0134] In some embodiments, a lipid nanoparticle formulation includes 25% to 75% on a molar basis of a cationic lipid selected from 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin-KC2-DMA), dilinoleyl-methyl-4-dimethylaminobutyrate (DLin-MC3-DMA), and di((Z)- non-2-en-1-yl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (L319), e.g., 35 to 65%, 45 to 65%, 60%, 57.5%, 50% or 40% on a molar basis.

[0135] In some embodiments, a lipid nanoparticle formulation includes 0.5% to 15% on a molar basis of the neutral lipid, e.g., 3 to 12%, 5 to 10% or 15%, 10%, or 7.5% on a molar basis. Examples of neutral lipids include, without limitation, DSPC, POPC, DPPC, DOPE and SM. In some embodiments, the formulation includes 5% to 50% on a molar basis of the sterol (e.g., 15 to 45%, 20 to 40%, 40%, 38.5%, 35%, or 31% on a molar basis. A non-limiting example of a sterol is cholesterol. In some embodiments, a lipid nanoparticle formulation includes 0.5% to 20% on a molar basis of the PEG or PEG-modified lipid (e.g., 0.5 to 10%, 0.5 to 5%, 1.5%, 0.5%, 1.5%, 3.5%, or 5% on a molar basis. In some embodiments, a PEG or PEG modified lipid comprises a PEG molecule of an average molecular weight of 2,000 Da. In some embodiments, aAttorney Docket No.204606-0174-00WO PEG or PEG modified lipid comprises a PEG molecule of an average molecular weight of less than 2,000, for example around 1,500 Da, around 1,000 Da, or around 500 Da. Non-limiting examples of PEG-modified lipids include PEG-distearoyl glycerol (PEG-DMG) (also referred herein as PEG-C14 or C14-PEG), PEG-cDMA (further discussed in Reyes et al. J. Controlled Release, 107, 276-287 (2005) the contents of which are herein incorporated by reference in their entirety).

[0136] In some embodiments, the molar lipid ratio is 50 / 10 / 38.5 / 1.5 (mol % cationic lipid / neutral lipid, e.g., DSPC / Chol / PEG-modified lipid, e.g., PEG-DMG, PEG-DSG or PEG- DPG), 57.2 / 7.1134.3 / 1.4 (mol % cationic lipid / neutral lipid, e.g., DPPC / Chol / PEG-modified lipid, e.g., PEG-cDMA), 40 / 15 / 40 / 5 (mol % cationic lipid / neutral lipid, e.g., DSPC / Chol / PEG- modified lipid, e.g., PEG-DMG), 50 / 10 / 35 / 4.5 / 0.5 (mol % cationic lipid / neutral lipid, e.g., DSPC / Chol / PEG-modified lipid, e.g., PEG-DSG), 50 / 10 / 35 / 5 (cationic lipid / neutral lipid, e.g., DSPC / Chol / PEG-modified lipid, e.g., PEG-DMG), 40 / 10 / 40 / 10 (mol % cationic lipid / neutral lipid, e.g., DSPC / Chol / PEG-modified lipid, e.g., PEG-DMG or PEG-cDMA), 35 / 15 / 40 / 10 (mol % cationic lipid / neutral lipid, e.g., DSPC / Chol / PEG-modified lipid, e.g., PEG-DMG or PEG-cDMA) or 52 / 13 / 30 / 5 (mol % cationic lipid / neutral lipid, e.g., DSPC / Chol / PEG-modified lipid, e.g., PEG-DMG or PEG-cDMA).

[0137] Non-limiting examples of lipid nanoparticle compositions and methods of making them are described, for example, in Semple et al. (2010) Nat. Biotechnol.28:172-176; Jayarama et al. (2012), Angew. Chem. Int. Ed., S1: 8529-8533; and Maier et al. (2013) Molecular Therapy 21, 1570-1578 (the contents of each of which are incorporated herein by reference in their entirety).

[0138] In some embodiments, lipid nanoparticle formulations may comprise a cationic lipid, a PEG lipid and a structural lipid and optionally comprise a non-cationic lipid. As a non- limiting example, a lipid nanoparticle may comprise 40-60% of cationic lipid, 5-15% of a non- cationic lipid, 1-2% of a PEG lipid and 30-50% of a structural lipid. As another non-limiting example, the lipid nanoparticle may comprise 50% cationic lipid, 10% non-cationic lipid, 1.5% PEG lipid and 38.5% structural lipid. As yet another non-limiting example, a lipid nanoparticle may comprise 55% cationic lipid, 10% non-cationic lipid, 2.5% PEG lipid and 32.5% structural lipid. In some embodiments, the cationic lipid may be any cationic lipid described herein such as, but not limited to, DLin-KC2-DMA, DLin-MC3-DMA and L319.Attorney Docket No.204606-0174-00WO

[0139] In some embodiments, the lipid nanoparticle formulations described herein may be 4 component lipid nanoparticles. The lipid nanoparticle may comprise a cationic lipid, a non- cationic lipid, a PEG lipid and a structural lipid. As a non-limiting example, the lipid nanoparticle may comprise 40-60% of cationic lipid, 5-15% of a non-cationic lipid, 1-2% of a PEG lipid and 30-50% of a structural lipid. As another non-limiting example, the lipid nanoparticle may comprise 50% cationic lipid, 10% non-cationic lipid, 1.5% PEG lipid and 38.5% structural lipid. As yet another non-limiting example, the lipid nanoparticle may comprise 55% cationic lipid, 10% non-cationic lipid, 2.5% PEG lipid and 32.5% structural lipid. In some embodiments, the cationic lipid may be any cationic lipid described herein such as, but not limited to, DLin-KC2-DMA, DLin-MC3-DMA and L319.

[0140] In some embodiments, the lipid nanoparticle formulations described herein may comprise a cationic lipid, a non-cationic lipid, a PEG lipid and a structural lipid. As a non- limiting example, the lipid nanoparticle comprise 50% of the cationic lipid DLin-KC2-DMA, 10% of the non-cationic lipid DSPC, 1.5% of the PEG lipid PEG-DOMG and 38.5% of the structural lipid cholesterol. As a non-limiting example, the lipid nanoparticle comprise 50% of the cationic lipid DLin-MC3-DMA, 10% of the non-cationic lipid DSPC, 1.5% of the PEG lipid PEG-DOMG and 38.5% of the structural lipid cholesterol. As a non-limiting example, the lipid nanoparticle comprise 50% of the cationic lipid DLin-MC3-DMA, 10% of the non-cationic lipid DSPC, 1.5% of the PEG lipid PEG-DMG and 38.5% of the structural lipid cholesterol. As yet another non-limiting example, the lipid nanoparticle comprise 55% of the cationic lipid L319, 10% of the non-cationic lipid DSPC, 2.5% of the PEG lipid PEG-DMG and 32.5% of the structural lipid cholesterol.

[0141] In some embodiments, a nanoparticle (e.g., a lipid nanoparticle) has a mean diameter of 10-500 nm, 20-400 nm, 30-300 nm, 40-200 nm. In some embodiments, a nanoparticle (e.g., a lipid nanoparticle) has a mean diameter of 50-150 nm, 50-200 nm, 80-100 nm or 80-200 nm. Cas-Mediated RNA Ligation

[0142] In one aspect, the present disclosure includes the use of one or more Cas protein which cleaves RNA to promote ligation or splicing of RNA molecules. In some embodiments, the invention relates to use of one or more Cas protein which cleaves RNA resulting inAttorney Docket No.204606-0174-00WO compatible ends for ligation of the cleaved RNA. In some embodiments, one or more Cas protein or one or more nucleic acid molecules encoding one or more Cas protein are effectively delivered to a cell in combination with two or more gRNA to provide targeted RNA cleavage and subsequent RNA ligation. In some embodiments, the invention provides for cleavage and subsequent RNA ligation of two or more RNA molecules. In some embodiments, the invention provides for cleavage and subsequent ligation of a single RNA molecule, thereby providing a method for generating a spliced RNA molecule.

[0143] Non-limiting examples of Cas proteins that can be delivered according to the methods of the invention include, but are not limited to, Cas1, Cas1B, Cas2, Cas3, Cas4, Cas5, Cas6, Cas7, Cas8, Cas9, Cas10, Csy1, Csy2, Csy3, Cse1, Cse2, Csc1, Csc2, Csa5, Csn2. Csm2, Csm3, Csm4, Csm5, Csm6, Cmr1, Cmr3, Cmr4, Cmr5, Cmr6, Csb1, Csb2, Csb3, Csx17, Csx14, Csx10, Csx16, CsaX, Csx3, Csxl, Csx15, Csf1, Csf2, Csf3, Csf4, SpCas9, StCas9, NmCas9, SaCas9, CjCas9, CjCas9, AsCpf1, LbCpf1, FnCpf1, VRER SpCas9, VQR SpCas9, xCas93.7, homologs thereof, orthologs thereof, or modified versions thereof. In some embodiments, the Cas protein has DNA or RNA cleavage activity. In some embodiments, the Cas protein directs cleavage of one or both strands of a nucleic acid molecule at the location of a target sequence, such as within the target sequence and / or within the complement of the target sequence. In some embodiments, the Cas protein directs cleavage of one or both strands within about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100, 200, 500, or more base pairs from the first or last nucleotide of a target sequence.

[0144] In one embodiment, the Cas protein has RNA binding activity. In some embodiments, the Cas protein is catalytically active. In some embodiments, the Cas protein comprises a mutation in one or both of the HEPN domains. In some embodiments, the Cas protein is catalytically dead. In some embodiments, the catalytically dead Cas protein retains its pre-cRNA processing RNAse activity, and therefore is capable of generating the necessary ends for RNA stitching.

[0145] In one embodiment, Cas protein is Cas13. In one embodiment, the Cas protein is PspCas13b, PspCas13b Truncation, AdmCas13d, AspCas13b, AspCas13c, BmaCas13a, BzoCas13b, CamCas13a, CcaCas13b, Cga2Cas13a, CgaCas13a, EbaCas13a, EreCas13a, EsCas13d, FbrCas13b, FnbCas13c, FndCas13c, FnfCas13c, FnsCas13c, FpeCas13c, FulCas13c, HheCas13a, LbfCas13a, LbmCas13a, LbnCas13a, LbuCas13a, LseCas13a, LshCas13a,Attorney Docket No.204606-0174-00WO LspCas13a, Lwa2cas13a, LwaCas13a, LweCas13a, PauCas13b, PbuCas13b, PgiCas13b, PguCas13b, Pin2Cas13b, Pin3Cas13b, PinCas13b, Pprcas13a, PsaCas13b, PsmCas13b, RaCas13d, RanCas13b, RcdCas13a, RcrCas13a, RcsCas13a, RfxCas13d, UrCas13d, dPspCas13b, PspCas13b_A133H, PspCas13b_A1058H, dPspCas13b truncation, dAdmCas13d, dAspCas13b, dAspCas13c, dBmaCas13a, dBzoCas13b, dCamCas13a, dCcaCas13b, dCga2Cas13a, dCgaCas13a, dEbaCas13a, dEreCas13a, dEsCas13d, dFbrCas13b, dFnbCas13c, dFndCas13c, dFnfCas13c, dFnsCas13c, dFpeCas13c, dFulCas13c, dHheCas13a, dLbfCas13a, dLbmCas13a, dLbnCas13a, dLbuCas13a, dLseCas13a, dLshCas13a, dLspCas13a, dLwa2cas13a, dLwaCas13a, dLweCas13a, dPauCas13b, dPbuCas13b, dPgiCas13b, dPguCas13b, dPin2Cas13b, dPin3Cas13b, dPinCas13b, dPprCas13a, dPsaCas13b, dPsmCas13b, dRaCas13d, dRanCas13b, dRcdCas13a, dRcrCas13a, dRcsCas13a, dRfxCas13d, dUrCas13d, dCas13X.1, or mini- dCas13X.1. Additional Cas proteins are known in the art (e.g., Konermann et al., Cell, 2018, 173:665-676 e14, Yan et al., Mol Cell, 2018, 7:327-339 e5; Cox, D.B.T., et al., Science, 2017, 358: 1019-1027; Abudayyeh et al., Nature, 2017, 550: 280-284, Gootenberg et al., Science, 2017, 356: 438-442; and East-Seletsky et al., Mol Cell, 2017, 66: 373-383 e3, which are herein incorporated by reference).

[0146] In some embodiments, the Cas protein is a subtype II-A or subtype II-C Cas protein. Exemplary subtype II-A or subtype II-C Cas proteins include, but are not limited to S. aureus Cas9 (SauCas9) and C. jejuni Cas9 (CjeCas9).

[0147] In one embodiment, the nucleic acid sequence encoding a Cas protein comprises a nucleic acid sequence encoding an amino acid sequence at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to one of SEQ ID NOs: 54-101. In one embodiment, the nucleic acid sequence encoding a Cas protein comprises a nucleic acid sequence encoding an amino acid sequence of a variant of one of SEQ ID NOs: 54-101, wherein the variant renders the Cas protein catalytically inactive. In some embodiments, the catalytically dead Cas protein retains its pre-cRNA processing RNAse activity, and therefore is capable of generating the necessary ends for RNA stitching.Attorney Docket No.204606-0174-00WO

[0148] In one embodiment, the nucleic acid sequence encoding a Cas protein comprises a nucleic acid sequence encoding an amino acid sequence of one of SEQ ID NOs: 54-101 having one or more insertions, deletions or substitutions, wherein the one or more insertions, deletions or substitutions renders the Cas protein catalytically inactive. In some embodiments, the catalytically dead Cas protein retains its pre-cRNA processing RNAse activity, and therefore is capable of generating the necessary ends for RNA stitching. In one embodiment, the nucleic acid sequence encoding a Cas protein comprises a nucleic acid sequence encoding an amino acid sequence of one of SEQ ID NOs: 54-101. Localization Signals

[0149] In some embodiments, the Cas protein is operably linked to a localization signal, such as a nuclear localization signal (NLS), nuclear export signal (NES) or other localization signals to localize to organelles, such as mitochondria. In one embodiment, the localization signal localizes the Cas protein to the site in which the target RNA is located.

[0150] Nuclear Localization Signal

[0151] In one embodiment, the Cas protein is operably linked to a NLS. In one embodiment, the NLS is a retrotransposon NLS. In one embodiment, the NLS is derived from Ty1, yeast GAL4, SKI3, L29 or histone H2B proteins, polyoma virus large T protein, VP1 or VP2 capsid protein, SV40 VP1 or VP2 capsid protein, Adenovirus El a or DBP protein, influenza virus NS1 protein, hepatitis vims core antigen or the mammalian lamin, c-myc, max, c- myb, p53, c-erbA, jun, Tax, steroid receptor or Mx proteins, Nucleoplasmin (NPM2), Nucleophosmin (NPM1), or simian vims 40 (“SV40”) T-antigen. In one embodiment, the NLS is a Ty1 or Ty1-derived NLS, a Ty2 or Ty2-derived NLS or a MAK11 or MAK11-derived NLS. In one embodiment, the NLS comprises a sequence at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to one of SEQ ID NOs: 111 - 725. In one embodiment, the NLS protein comprises a sequence of one of SEQ ID NOs: 111 - 725.Attorney Docket No.204606-0174-00WO Nuclear Export Signal

[0152] In one embodiment, the Cas protein is operably linked to a Nuclear Export Signal (NES). In one embodiment, the NES is attached to the N-terminal end of the Cas protein. In one embodiment, the NES localizes the Cas protein to the cytoplasm for targeting cytoplasmic RNA. Organelle Localization Signal

[0153] In one embodiment, the Cas protein is operably linked to a localization signal that localizes the Cas protein to an organelle. In one embodiment, the localization signal localizes the protein to the nucleolus, ribosome, vesicle, rough endoplasmic reticulum, Golgi apparatus , cytoskeleton, smooth endoplasmic reticulum, mitochondria, vacuole, cytosol, lysosome, or centriole. A number of localization signals are known in the art.

[0154] In one embodiment, the Cas protein is operably linked to a localization signal that localizes the Cas protein to an organelle or extracellularly. In one embodiment, the localization signal localizes the protein to the nucleolus, ribosome, vesicle, rough endoplasmic reticulum, Golgi apparatus , cytoskeleton, smooth endoplasmic reticulum, mitochondria, vacuole, cytosol, lysosome, or centriole.

[0155] A number of localization signals are known in the art. Exemplary localization signals include, but are not limited to 1x mitochondrial targeting sequence, 4x mitochondrial targeting sequence, secretory signal sequence (IL-2), myristylation, Calsequestrin leader, KDEL retention and peroxisome targeting sequence. Systems

[0156] In one aspect, the present invention provides systems for site specific cleavage of nucleic acid molecules, splicing nucleic acid molecules, ligating nucleic acid molecules, for decreasing the numbers of an RNA transcript in a subject, or any combination thereof. In one embodiment the system comprises a fusion construct comprising one or more ribozyme or DNAzyme. In one embodiment the system comprises one or more fusion construct comprising a gRNA and one or more ribozyme or DNAzyme, wherein the gRNA substantially hybridizes to a target nucleotide sequence. In one embodiment the system comprises a CRISPR-Cas system at least two gRNA and further comprises a Cas protein which cleaves RNA to generate compatible ends for ligation. In one embodiment, the CRISPR-Cas system gRNA substantially hybridizes to a target RNA sequence in an RNA transcript. In one embodiment, the nucleic acid sequenceAttorney Docket No.204606-0174-00WO encoding the Cas protein and the nucleic acid sequence encoding a gRNA are in the same vector. In one embodiment, the nucleic acid sequence encoding the Cas protein and the nucleic acid sequence encoding a gRNA are in different vectors.

[0157] In one embodiment, the nucleic acid sequence encoding a fusion construct comprises a nucleic acid sequence comprising at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to one of SEQ ID NOs: 1-4 operably linked to a gRNA.

[0158] In one embodiment the system comprises, in one or more vectors, a) a nucleic acid sequence encoding a fusion construct, wherein the fusion construct comprises a CRISPR- Cas system gRNA and a catalytic RNA, and optionally a TSM, a linker or a combination thereof and b) a nucleic acid sequence encoding a CRISPR-Cas protein optionally operably linked to a localization signal such as an NLS or NES. In one embodiment, the CRISPR-Cas system gRNA substantially hybridizes to a target RNA sequence.

[0159] In one embodiment the system comprises, in one or more vectors, a nucleic acid sequence encoding a fusion construct, wherein the fusion construct comprises at least two linked gRNA molecules and optionally a linker, a TSM or a combination thereof, a localization signal such as an NLS or NES, and b) a nucleic acid sequence encoding a CRISPR-Cas protein and optionally a linker or a combination thereof and b) a nucleic acid sequence encoding a CRISPR- Cas protein optionally operably linked to a localization signal such as an NLS or NES. In one embodiment, each of the two or more CRISPR-Cas system gRNA substantially hybridizes to a target RNA sequence. In some embodiments, the two or more target RNA sequences are on the same RNA molecule. In some embodiments, the two or more target RNA sequences are on separate RNA molecules. Compositions and Formulations

[0160] In one aspect, the present invention provides compositions for site specific cleavage of nucleic acid molecules, splicing nucleic acid molecules, ligating nucleic acid molecules, for decreasing the numbers of an RNA transcript in a subject, or any combinationAttorney Docket No.204606-0174-00WO thereof. In one embodiment, the composition comprises a fusion construct, wherein the fusion construct comprises at least one catalytic RNA, and optionally a gRNA, a tertiary stabilizing motif (TSM), a linker or any combination thereof. In one embodiment, the gRNA substantially hybridizes to a target RNA sequence in an RNA transcript. In one embodiment, the gRNA substantially hybridizes to a target DNA sequence in a DNA molecule. In one embodiment, the composition comprises a fusion construct, wherein the fusion construct comprises two linked catalytic RNA, and optionally a gRNA, a tertiary stabilizing motif (TSM), or a combination thereof.

[0161] The disclosure also encompasses the use of pharmaceutical compositions of the disclosure to practice the methods of the disclosure. Such a pharmaceutical composition may consist of at least one modulator (e.g., inhibitor or activator) composition of the invention or a salt thereof in a form suitable for administration to a subject, or the pharmaceutical composition may comprise at least one modulator (e.g., inhibitor or activator) composition of the invention or a salt thereof, and one or more pharmaceutically acceptable carriers, one or more additional ingredients, or some combination of these. The compound of the invention may be present in the pharmaceutical composition in the form of a physiologically acceptable salt, such as in combination with a physiologically acceptable cation or anion, as is well known in the art.

[0162] In an embodiment, the pharmaceutical compositions useful for practicing the methods of the invention may be administered to deliver a dose of between 1 ng / kg / day and 100 mg / kg / day. In another embodiment, the pharmaceutical compositions useful for practicing the invention may be administered to deliver a dose of between 1 ng / kg / day and 500 mg / kg / day.

[0163] The relative amounts of the active ingredient, the pharmaceutically acceptable carrier, and any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1% and 100% (w / w) active ingredient.

[0164] Pharmaceutical compositions that are useful in the methods of the invention may be suitably developed for oral, rectal, vaginal, parenteral, topical, pulmonary, intranasal, buccal, ophthalmic, or another route of administration. A composition useful within the methods of the invention may be directly administered to the skin, or any other tissue of a mammal. Other contemplated formulations include liposomal preparations, resealed erythrocytes containing theAttorney Docket No.204606-0174-00WO active ingredient, and immunologically-based formulations. The route(s) of administration will be readily apparent to the skilled artisan and will depend upon any number of factors including the type and severity of the disease being treated, the type and age of the veterinary or human subject being treated, and the like.

[0165] The formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of bringing the active ingredient into association with a carrier or one or more other accessory ingredients, and then, if necessary or desirable, shaping or packaging the product into a desired single- or multi-dose unit.

[0166] As used herein, a “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient that would be administered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage. The unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose.

[0167] In one embodiment, the compositions of the invention are formulated using one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical compositions of the invention comprise a therapeutically effective amount of a compound or conjugate of the invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers that are useful, include, but are not limited to, glycerol, water, saline, ethanol and other pharmaceutically acceptable salt solutions such as phosphates and salts of organic acids. Examples of these and other pharmaceutically acceptable carriers are described in Remington’s Pharmaceutical Sciences (1991, Mack Publication Co., New Jersey).

[0168] The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases,Attorney Docket No.204606-0174-00WO isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol are included in the composition. Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate or gelatin. In one embodiment, the pharmaceutically acceptable carrier is not DMSO alone.

[0169] Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, vaginal, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art. The pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and / or aromatic substances and the like. They may also be combined where desired with other active agents, e.g., other analgesic agents.

[0170] As used herein, “additional ingredients” include, but are not limited to, one or more of the following: excipients; surface active agents; dispersing agents; inert diluents; granulating and disintegrating agents; binding agents; lubricating agents; sweetening agents; flavoring agents; coloring agents; preservatives; physiologically degradable compositions such as gelatin; aqueous vehicles and solvents; oily vehicles and solvents; suspending agents; dispersing or wetting agents; emulsifying agents, demulcents; buffers; salts; thickening agents; fillers; emulsifying agents; antioxidants; antibiotics; antifungal agents; stabilizing agents; and pharmaceutically acceptable polymeric or hydrophobic materials. Other “additional ingredients” that may be included in the pharmaceutical compositions of the invention are known in the art and described, for example in Genaro, ed. (1985, Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, PA), which is incorporated herein by reference.

[0171] The composition of the invention may comprise a preservative from about 0.005% to 2.0% by total weight of the composition. The preservative is used to prevent spoilage in the case of exposure to contaminants in the environment. Examples of preservatives useful in accordance with the invention included but are not limited to those selected from the group consisting of benzyl alcohol, sorbic acid, parabens, imidurea and combinations thereof. An exemplary preservative is a combination of about 0.5% to 2.0% benzyl alcohol and 0.05% to 0.5% sorbic acid.Attorney Docket No.204606-0174-00WO

[0172] In one embodiment, the composition includes an anti-oxidant and a chelating agent that inhibits the degradation of the compound. Exemplary antioxidants for some compounds are BHT, BHA, alpha-tocopherol and ascorbic acid in the range of about 0.01% to 0.3% and BHT in the range of 0.03% to 0.1% by weight by total weight of the composition. In one embodiment, the chelating agent is present in an amount of from 0.01% to 0.5% by weight by total weight of the composition. Exemplary chelating agents include edetate salts (e.g. disodium edetate) and citric acid in the weight range of about 0.01% to 0.20%. In some embodiments, the chelating agent is in the range of 0.02% to 0.10% by weight by total weight of the composition. The chelating agent is useful for chelating metal ions in the composition that may be detrimental to the shelf life of the formulation. While BHT and disodium edetate are exemplary antioxidants and chelating agent respectively for some compounds, other suitable and equivalent antioxidants and chelating agents may be substituted therefore as would be known to those skilled in the art.

[0173] Liquid suspensions may be prepared using conventional methods to achieve suspension of the active ingredient in an aqueous or oily vehicle. Aqueous vehicles include, for example, water, and isotonic saline. Oily vehicles include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin. Liquid suspensions may further comprise one or more additional ingredients including, but not limited to, suspending agents, dispersing or wetting agents, emulsifying agents, demulcents, preservatives, buffers, salts, flavorings, coloring agents, and sweetening agents. Oily suspensions may further comprise a thickening agent. Known suspending agents include, but are not limited to, sorbitol syrup, hydrogenated edible fats, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, and cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose. Known dispersing or wetting agents include, but are not limited to, naturally-occurring phosphatides such as lecithin, condensation products of an alkylene oxide with a fatty acid, with a long chain aliphatic alcohol, with a partial ester derived from a fatty acid and a hexitol, or with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, and polyoxyethylene sorbitan monooleate, respectively). Known emulsifying agents include, but are not limited to, lecithin, and acacia. Known preservatives include, but are not limited to,Attorney Docket No.204606-0174-00WO methyl, ethyl, or n-propyl-para- hydroxybenzoates, ascorbic acid, and sorbic acid. Known sweetening agents include, for example, glycerol, propylene glycol, sorbitol, sucrose, and saccharin. Known thickening agents for oily suspensions include, for example, beeswax, hard paraffin, and cetyl alcohol.

[0174] Liquid solutions of the active ingredient in aqueous or oily solvents may be prepared in substantially the same manner as liquid suspensions, the primary difference being that the active ingredient is dissolved, rather than suspended in the solvent. As used herein, an “oily” liquid is one which comprises a carbon-containing liquid molecule and which exhibits a less polar character than water. Liquid solutions of the pharmaceutical composition of the invention may comprise each of the components described with regard to liquid suspensions, it being understood that suspending agents will not necessarily aid dissolution of the active ingredient in the solvent. Aqueous solvents include, for example, water, and isotonic saline. Oily solvents include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin.

[0175] Powdered and granular formulations of a pharmaceutical preparation of the invention may be prepared using known methods. Such formulations may be administered directly to a subject, used, for example, to form tablets, to fill capsules, or to prepare an aqueous or oily suspension or solution by addition of an aqueous or oily vehicle thereto. Each of these formulations may further comprise one or more of dispersing or wetting agent, a suspending agent, and a preservative. Additional excipients, such as fillers and sweetening, flavoring, or coloring agents, may also be included in these formulations.

[0176] A pharmaceutical composition of the invention may also be prepared, packaged, or sold in the form of oil-in-water emulsion or a water-in-oil emulsion. The oily phase may be a vegetable oil such as olive or arachis oil, a mineral oil such as liquid paraffin, or a combination of these. Such compositions may further comprise one or more emulsifying agents such as naturally occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soybean or lecithin phosphatide, esters or partial esters derived from combinations of fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of such partial esters with ethylene oxide such as polyoxyethyleneAttorney Docket No.204606-0174-00WO sorbitan monooleate. These emulsions may also contain additional ingredients including, for example, sweetening or flavoring agents.

[0177] Methods for impregnating or coating a material with a chemical composition are known in the art, and include, but are not limited to methods of depositing or binding a chemical composition onto a surface, methods of incorporating a chemical composition into the structure of a material during the synthesis of the material (i.e., such as with a physiologically degradable material), and methods of absorbing an aqueous or oily solution or suspension into an absorbent material, with or without subsequent drying.

[0178] The regimen of administration may affect what constitutes an effective amount. The therapeutic formulations may be administered to the subject either prior to or after a diagnosis of disease. Further, several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.

[0179] Administration of the compositions of the present invention to a subject, include a mammal, for example a human, may be carried out using known procedures, at dosages and for periods of time effective to prevent or treat disease. An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the activity of the particular compound employed; the time of administration; the rate of excretion of the compound; the duration of the treatment; other drugs, compounds or materials used in combination with the compound; the state of the disease or disorder, age, sex, weight, condition, general health and prior medical history of the subject being treated, and like factors well-known in the medical arts. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A non-limiting example of an effective dose range for a therapeutic compound of the invention is from about 1 and 5,000 mg / kg of body weight / per day. One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation.

[0180] The compound may be administered to a subject as frequently as several times daily, or it may be administered less frequently, such as once a day, once a week, once every twoAttorney Docket No.204606-0174-00WO weeks, once a month, or even less frequently, such as once every several months or even once a year or less. It is understood that the amount of compound dosed per day may be administered, in non-limiting examples, every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, with every other day administration, a 5 mg per day dose may be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, and so on. The frequency of the dose will be readily apparent to the skilled artisan and will depend upon any number of factors, such as, but not limited to, the type and severity of the disease being treated, the type and age of the animal, etc.

[0181] Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular subject, composition, and mode of administration, without being toxic to the subject.

[0182] A medical doctor, e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0183] In particular embodiments, it is especially advantageous to formulate the compound in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. The dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding / formulating such a therapeutic compound for the treatment of a disease in a subject.

[0184] In one embodiment, the compositions of the invention are administered to the subject in dosages that range from one to five times per day or more. In another embodiment, the compositions of the invention are administered to the subject in range of dosages that include,Attorney Docket No.204606-0174-00WO but are not limited to, once every day, every two, days, every three days to once a week, and once every two weeks. It will be readily apparent to one skilled in the art that the frequency of administration of the various combination compositions of the invention will vary from subject to subject depending on many factors including, but not limited to, age, disease or disorder to be treated, gender, overall health, and other factors. Thus, the invention should not be construed to be limited to any particular dosage regime and the precise dosage and composition to be administered to any subject will be determined by the attending physical taking all other factors about the subject into account.

[0185] Compounds of the invention for administration may be in the range of from about 1 mg to about 10,000 mg, about 20 mg to about 9,500 mg, about 40 mg to about 9,000 mg, about 75 mg to about 8,500 mg, about 150 mg to about 7,500 mg, about 200 mg to about 7,000 mg, about 3050 mg to about 6,000 mg, about 500 mg to about 5,000 mg, about 750 mg to about 4,000 mg, about 1 mg to about 3,000 mg, about 10 mg to about 2,500 mg, about 20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 50 mg to about 1,000 mg, about 75 mg to about 900 mg, about 100 mg to about 800 mg, about 250 mg to about 750 mg, about 300 mg to about 600 mg, about 400 mg to about 500 mg, and any and all whole or partial increments there between.

[0186] In some embodiments, the dose of a compound of the invention is from about 1 mg and about 2,500 mg. In some embodiments, a dose of a compound of the invention used in compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, a dose of a second compound (i.e., a drug used for treating the same or another disease as that treated by the compositions of the invention) as described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof.Attorney Docket No.204606-0174-00WO

[0187] In one embodiment, the present invention is directed to a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound or conjugate of the invention, alone or in combination with a second pharmaceutical agent; and instructions for using the compound or conjugate to treat, prevent, or reduce one or more symptoms of a disease in a subject.

[0188] The term “container” includes any receptacle for holding the pharmaceutical composition. For example, in one embodiment, the container is the packaging that contains the pharmaceutical composition. In other embodiments, the container is not the packaging that contains the pharmaceutical composition, i.e., the container is a receptacle, such as a box or vial that contains the packaged pharmaceutical composition or unpackaged pharmaceutical composition and the instructions for use of the pharmaceutical composition. Moreover, packaging techniques are well known in the art. It should be understood that the instructions for use of the pharmaceutical composition may be contained on the packaging containing the pharmaceutical composition, and as such the instructions form an increased functional relationship to the packaged product. However, it should be understood that the instructions may contain information pertaining to the compound’s ability to perform its intended function, e.g., treating or preventing a disease in a subject, or delivering an imaging or diagnostic agent to a subject.

[0189] Routes of administration of any of the compositions of the invention include oral, nasal, parenteral, sublingual, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, and (intra)nasal,), intravesical, intraduodenal, intragastrical, rectal, intra-peritoneal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, or administration.

[0190] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions that would be useful in the present invention are not limited to the particular formulations and compositions that are described herein.Attorney Docket No.204606-0174-00WO Methods of Use

[0191] In one aspect, the invention provides methods of site-specific cleavage of nucleic acid molecules, splicing of nucleic acid molecules, ligation of nucleic acid molecules and degradation of nucleic acid molecules. In one embodiment, the method comprises administering to a subject a fusion construct of the disclosure comprising at least one catalytic RNA molecule. In one embodiment, the method comprises administering to a subject a fusion construct of the disclosure comprising at least one gRNA molecule and at least one CRISPR-Cas protein, or nucleic acid molecule encoding at least one CRISPR-Cas protein for site-specific cleavage of one or more target nucleic acid molecule. In such embodiments, the method comprises administering to a subject or a cell at least one fusion construct of the disclosure, or a composition comprising at least one fusion construct of the disclosure.

[0192] In some embodiments, the method is used for site-specific cleavage of cytoplasmic RNA, nuclear RNA, lncRNA, mRNA, genomic DNA, extrachromosomal DNA, or plasmid DNA.

[0193] In some embodiments, the method is useful for generating a spliced nucleic acid molecule. Exemplary spliced nucleic acid molecules may be linear or circular. In some embodiments, the spliced nucleic acid molecule is a spliced RNA molecule. In some embodiments, the spliced nucleic acid molecule is a spliced DNA molecule.

[0194] In some embodiments, the method is useful for generating a ligated nucleic acid molecule. Exemplary ligated nucleic acid molecules may be linear or circular. In some embodiments, the ligated nucleic acid molecule is a ligated RNA molecule. In some embodiments, the ligated nucleic acid molecule is a ligated DNA molecule.

[0195] In one embodiment, the fusion construct is administered to a cell. In one embodiment, the cell is a prokaryotic cell or eukaryotic cell. In one embodiment, the cell is a eukaryotic cell. In one embodiment, the cell is a plants, animals, or fungi cell. In one embodiment, the cell is a plant cell. In one embodiment, the cell is an animal cell. In one embodiment, the cell is a yeast cell.

[0196] In one embodiment, the subject is a mammal. For example, in one embodiment, the subject is a human, non-human primate, dog, cat, horse, cow, goat, sheep, rabbit, pig, rat, or mouse. In one embodiment, the subject is a non-mammalian subject. For example, in one embodiment, the subject is a zebrafish, fruit fly, or roundworm.Attorney Docket No.204606-0174-00WO

[0197] In one embodiment, the amount of nuclear RNA is reduced in vitro. In one embodiment, the amount of nuclear RNA is reduced in vivo.

[0198] In one aspect, the present invention provides methods of treating a subject with a disease or disorder. In one embodiment, the method comprises administering to the subject a fusion construct of the invention comprising at least one catalytic RNA and optionally a gRNA, a TSM or any combination thereof. In some embodiments the method further comprises administering at least one CRISPR-Cas protein to the subject. In one embodiment, the CRISPR- Cas protein is operably linked to a localization sequence, such as an NLS or NES.

[0199] In one aspect, the present invention provides methods of treating a subject with a disease or disorder associated with abnormal nuclear RNA. In one embodiment, the disease or disorder associated with abnormal nuclear RNA is selected from the group consisting of Myotonic Dystrophy type 2 (DM2), Amyotrophic lateral sclerosis (ALS), Huntington’s disease- like 2 (HDL2), Spinocerebellar ataxias 8, 31 and 10 (SCA8, -31, -10) and fragile X-associated tremor ataxia syndrome (FXTAS).

[0200] In one embodiment, the abnormal nuclear RNA is toxic nuclear RNA foci. In one embodiment, the disease or disorder associated with toxic nuclear RNA foci Myotonic Dystrophy type 1. In one embodiment, the targeting nucleotide sequence comprises a sequence complementary to a CTG repeat expansion in the 3’UTR of the human dystrophia myotonica- protein kinase (DMPK) gene.

[0201] In one aspect, the present invention provides methods of treating a disease or disorder associated with increased gene expression. In one embodiment, the method comprises administering to the subject administering to the subject a fusion construct of the invention comprising at least one catalytic RNA and optionally a gRNA, a localization sequence, such as an NLS or NES, a TSM or any combination thereof. In some embodiment the guide nucleic acid molecule comprises a targeting nucleotide sequence complimentary to a target RNA sequence in the RNA transcript of the gene or a guide nucleic acid molecule comprising a targeting nucleotide sequence complimentary to a target RNA sequence in the RNA transcript of the gene. In one embodiment, the method further comprises administering at least one Cas protein.

[0202] In one aspect, the present invention provides methods of treating a disease or disorder associated with increased gene expression. In one embodiment, the method comprises administering to the subject administering to the subject a fusion construct comprising at leastAttorney Docket No.204606-0174-00WO two gRNA molecules. In some embodiment the guide nucleic acid molecule comprises a targeting nucleotide sequence complimentary to a target RNA sequence in the RNA transcript of the gene or a guide nucleic acid molecule comprising a targeting nucleotide sequence complimentary to a target RNA sequence in the RNA transcript of the gene. In one embodiment, the method further comprises administering at least one Cas protein which cleaves the RNA transcript thereby preventing translation and protein expression.

[0203] In one aspect, the present invention provides methods of treating a disease or disorder associated with RNA. For example, in one embodiment, the invention provides a method of treating an RNA virus infection. In one embodiment, the catalytic RNA cleaves the viral RNA sequence thereby preventing translation and expression of viral protein.

[0204] In one aspect, the present invention provides methods of treating a disease or disorder associated with DNA. For example, in one embodiment, the invention provides a method of treating an DNA virus infection. In one embodiment, the catalytic RNA cleaves the viral DNA sequence thereby preventing translation and expression of viral protein.

[0205] The present invention provides methods of treating, reducing the symptoms of, and / or reducing the risk of developing a disease or disorder in a subject. For example, in one embodiment, methods of the invention can be used to treat, reduce the symptoms of, and / or reduce the risk of developing a disease or disorder in a mammal. In one embodiment, the methods of the invention can be used to treat, reduce the symptoms of, and / or reduce the risk of developing a disease or disorder in a plant. In one embodiment, the methods of the invention can be used treat, reduce the symptoms of, and / or reduce the risk of developing a disease or disorder in a yeast organism.

[0206] In one embodiment, the subject is a cell. In one embodiment, the cell is a prokaryotic cell or eukaryotic cell. In one embodiment, the cell is a eukaryotic cell. In one embodiment, the cell is a plant, animal, or fungi cell. In one embodiment, the cell is a plant cell. In one embodiment, the cell is an animal cell. In one embodiment, the cell is a yeast cell.

[0207] In one embodiment, the subject is a mammal. For example, in one embodiment, the subject is a human, non-human primate, dog, cat, horse, cow, goat, sheep, rabbit, pig, rat, or mouse. In one embodiment, the subject is a non-mammalian subject. For example, in one embodiment, the subject is a zebrafish, fruit fly, or roundworm.Attorney Docket No.204606-0174-00WO

[0208] In one embodiment, the disease or disorder is caused by one or more mutations in a genomic locus. Thus, in one embodiment, the disease or disorder may be treated, reduced, or the risk can be reduced via an element that prevents or reduces mRNA transcript, or prevents or reduces translation of the protein. Thus, in one embodiment, the method comprises manipulation of an RNA transcript.

[0209] In one embodiment, the disease or disorder is caused by abnormal RNA. Thus, in one embodiment, the disease or disorder may be treated, reduced, or the risk can be reduced via an element that prevents or reduces RNA transcript. Thus, in one embodiment, the method comprises manipulation of an RNA transcript.

[0210] In one embodiment, the disease or disorder is associated with abnormal RNA or increased RNA transcription. For example, in one embodiment, the disease or disorder is an endocrine disease. For example, in one embodiment, endocrine diseases include but are not limited to, β-thalassemias, neonatal diabetes, IPEX syndrome, Mayer–Rokitanski–Küster– Hausersyndrome, Hypothalamic-pituitary-adrenal axis dysregulation, Adrenal dysfunction, Gonadal dysfunction, Ectopic Cushing syndrome, Pre-eclampsia, Diabetic nephropathy, Type I diabetes, Type II diabetes, and IGF-1 deficiency.

[0211] In one embodiment, the disease or disorder is a tumorigenic disease. For example, in one embodiment, tumorigenic diseases include but are not limited to, mantle cell lymphoma, hereditary & sporadic parathyroid tumors, Medullary thyroid carcinoma, poliverative conditions, colorectal cancer, gliblastoma, Chronic lymphocytic leukemia, and Breast cancer.

[0212] In one embodiment, the disease or disorder is a neurological disease or disorder. For example, in one embodiment, neurological diseases include but are not limited to, Parkinsons diseases, Oculopharyngeal muscular dystrophy, Huntington’s disease, Fabry disease, Fragile X syndrome, spinal muscular atrophy, Amyotrophic Lateral Sclerosis, Spinocerebellar ataxia Spinocerebellar ataxia 1, Spinocerebellar ataxia 2, Spinocerebellar ataxia 3, Spinocerebellar ataxia 6, Spinocerebellar ataxia 7, Spinocerebellar ataxia 8, Spinocerebellar ataxia 10, Spinocerebellar ataxia 17, Spinocerebellar ataxia 31, and Alzheimer’s disease, .

[0213] In one embodiment, the disease or disorder is a hematological disease or disorder. For example, in one embodiment, hematological diseases include but are not limited to, β- Thalassemia, and α-Thalassemia.Attorney Docket No.204606-0174-00WO

[0214] In one embodiment, the disease or disorder is an infection or immunological disease or disorder. For example, in one embodiment, infection or immunological diseases include but are not limited to, B-cell differentiation, T-cell activation, systemic lupus erythematosus, Wiskott-Aldrich syndrome, Osteoarthritis, scleroderma, and IPEX syndrome.

[0215] In one embodiment, the disease or disorder is a musculoskeletal disease or disorder. For example, in one embodiment, infection or immunological diseases include Myotonic dystrophy type 1, Spinal and bulbar muscular atrophy, and Dentatorubral- pallidoluysian atrophy.

[0216] Exemplary diseases or disorders and corresponding targets include, but are not limited to those listed in Table 1. Additional diseases and disorders and corresponding genes are known in the art, for example in Rehfeld et al., Alternations in Polyadenylation and its Implications for Endocrine Disease, Front. Endocrinol.4:53 (2013), Chang et al., Alternative Polyadenylation in Human Diseases, Endocrinol Metab.32:413-421 (2017), and Curinha et al., Implications of polyadenylation in health and disease, Nucleus 5:508-519 (2014), which are herein incorporated by reference in their entireties. Table 1. Diseases or disorders and target gene Condition Target Adrenal dysfunction STAR ABCA3, EIF2B3, MSTO2P, OGDHL, PARP6, SLC33A1, SUPV3L1, TAF3, WASH7P, JAK1, Alzheimer’s disease ABCA3, UBR1, ALDOC, C10ord10, GABARAPL2, KAT2A, POLR3A, SH3BGRL2, TIMM23, TMC6, UNC80, WTAP ALS (GGGGCC repeat), CCDC92, CRYAB, MAP7D2, PRPH, RTN4, SEC22B, SNAP25, Amyotrophic Lateral Sclerosis UCHL1, YWHAB, C14ord2, C6orf203, ALDOC, ARL6IP1, CSDE1, CMC2, GAP43, LDHB, MLLT11, NCL, PFN2, TMOD1, VAMP1 B-cell differentiation IGHM Breast cancer Cancer, Colorectal DMKN, PDXK, PPIE Cancer, Various TP53 Chronic lymphocytic leukaemia Intronic loci Colorectal cancer DMKN, PDXK, PPIE Dentatorubral-pallidoluysian atrophy DRPLA (CAG repeat) Diabetic nephropathy HGRG-14 Ectopic Cushing syndrome ACTH Fabry disease α-GalA Fragile X Syndrome FMR1, FXTAS (CGG repeat)Attorney Docket No.204606-0174-00WO Friedreich’s Ataxia YSH1 Glioblastoma CCND1, MECP2 Gonadal dysfunction STAR Huntington’s disease HTT, HD (CAG repeat) Huntington’s disease-like 2 HDL2 (CTG repeat) Hypothalamic-pituitary-adrenal axis dysregulation SERT IGF-1 deficiency IGF-1 IPEX syndrome FOP3 Mayer–Rokitanski–Küster–Hausersyndrome AMH Myotonic Dystrophy Type I DMPK, DM1 (CTG Repeat), DM2 (CCTG repeat) Myotonic Dystrophy Type II ZFN9 Neonatal diabetes INS Oculopharyngeal muscular dystrophy CCND1, PABPN1 Parkinson disease SNCA Pre-eclampsia SFLT-1 Proliferative conditions RBX1 Spinal Muscular Atrophy SMN Spinocerebellar Ataxia 1 ATXN1, SCA1 (CAG repeat) Spinocerebellar Ataxia 10 ATXN10, SCA10 (ATTCT repeat) Spinocerebellar Ataxia 17 TATA-box binding protein, SCA17 (CAG repeat) Spinocerebellar Ataxia 2 ATXN2, SCA2 (CAG repeat) Spinocerebellar Ataxia 3 ATXN3, SCA3 (CAG repeat) Spinocerebellar Ataxia 31 BEAN1, SCA31 (TGGA repeat) Spinocerebellar Ataxia 6 CACNA1A, SCA6 (CAG repeat) Spinocerebellar Ataxia 7 TPP1, SCA7 (CAG repeat) Spinocerebellar Ataxia 8 ATXN8OS, SCA8 (CTG / CAG repeat) Spinal and bulbar muscular atrophy SBMA (CAG repeat) Steroidogenesis STAR Systemic lupus erythematosus GIMAP5 Systemic lupus erythematosus IRF5 T-cell activation NF-ATC1 Thrombophilia F2 Type I diabetes GIMAP5 Type II diabetes TCF7L2 Wiskott-Aldrich Syndrome WAS α-Thalassemia HBA1, HBA2 β-Thalassemia HBB

[0217] In one embodiment, the disease or disorder is a viral infection. Thus, in one embodiment, the disease or disorder is may be treated, reduced, or the risk can be reduced via an element that prevents or reduces viral mRNA transcript, or prevents or reduces translation of viral protein. Thus, in one embodiment, the method comprises manipulation of a viral RNA transcript.

[0218] In one embodiment, the virus is an RNA virus. In one embodiment, the virus produces RNA during its lifecycle. In one embodiment, the virus is a human virus, a plant virusAttorney Docket No.204606-0174-00WO or an animal virus. Exemplary viruses include, but are not limited to, viruses of families Adenoviridae, Adenoviridae, Alphaflexiviridae, Anelloviridae, Arenavirus, Arteriviridae, Asfarviridae, Astroviridae, Benyviridae, Betaflexiviridae, Birnaviridae, Bornaviridae, Bromoviridae, Caliciviridae, Caulimoviridae, Circoviridae, Closteroviridae, Coronaviridae, Filoviridae, Flaviviridae, Geminiviridae, Hantaviridae, Hepadnaviridae, Hepeviridae, Herpesviridae, Kitaviridae, Luteoviridae, Nairoviridae, Nanoviridae, Nimaviridae, Orthomyxoviridae, Paramyxoviridae, Phenuiviridae, Picornaviridae, Polyomaviridae, Pospiviridae, Potyviridae, Poxviridae, Reoviridae, Retroviridae, Retrovirus, Rhabdoviridae, Secoviridae, Togaviridae, Tombusviridae, Tospoviridae, Tymoviridae, and Virgaviridae. Amino Acid and Nucleic Acid Sequences Table 2 provides a summary of CRISRP-Cas amino acid and nucleic acid sequences. Table 2. Summary of sequences SEQ ID NO Type Description 54 Amino AcidPspCas13b55 Amino AcidPspCas13b Truncation56 Amino AcidAspCas13b57 Amino AcidAspCas13c58 Amino AcidBmaCas13a59 Amino AcidBzoCas13b60 Amino AcidCamCas13a61 Amino AcidCcaCas13b62 Amino AcidCga2Cas13a63 Amino AcidCgaCas13a64 Amino AcidEbaCas13a65 Amino AcidEreCas13a66 Amino AcidEsCas13d67 Amino AcidFbrCas13b68 Amino AcidFnbCas13c69 Amino AcidFndCas13c70 Amino AcidFnfCas13c71 Amino AcidFnsCas13c72 Amino AcidFpeCas13c73 Amino AcidFulCas13c74 Amino AcidHheCas13a75 Amino AcidLbfCas13aAttorney Docket No.204606-0174-00WO 76 Amino AcidLbmCas13a77 Amino AcidLbnCas13a78 Amino AcidLbuCas13a79 Amino AcidLseCas13a80 Amino AcidLshCas13a81 Amino AcidLspCas13a82 Amino AcidLwa2cas13a83 Amino AcidLwaCas13a84 Amino AcidLweCas13a85 Amino AcidPauCas13b86 Amino AcidPbuCas13b87 Amino AcidPgiCas13b88 Amino AcidPguCas13b89 Amino AcidPin2Cas13b90 Amino AcidPin3Cas13b91 Amino AcidPinCas13b92 Amino AcidPprcas13a93 Amino AcidPsaCas13b94 Amino AcidPsmCas13b95 Amino AcidRanCas13b96 Amino AcidRcdCas13a97 Amino AcidRcrCas13a98 Amino AcidRcsCas13a99 Amino AcidUrCas13d100 Amino AciddPspCas13b101 Amino AciddPspCas13b truncation726 nucleotide PspCas13b 727 nucleotide PspCas13b Truncation 728 nucleotide dPspCas13b 729 nucleotide dPspCas13b truncation EXPERIMENTAL EXAMPLES

[0219] The invention is further described in detail by reference to the following experimental examples. These examples are provided for purposes of illustration only and are not intended to be limiting unless otherwise specified. Thus, the invention should in no way be construed as being limited to the following examples, but rather, should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.Attorney Docket No.204606-0174-00WO

[0220] Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the present invention and practice the claimed methods. The following working examples therefore, specifically point out certain embodiments of the present invention, and are not to be construed as limiting in any way the remainder of the disclosure. Example 1: Precision RNA cleavage and editing using trans-cleaving ribozyme and CRISPR-Cas systems

[0221] Previously, catalytically dead CRISPR-CAS systems fused to active RNAase domains (CRISPRase) were developed to achieve single RNA cleavage events, which could be used to inactivate functional sequences, or when generated multiple times in cis or trans, could allow for RNA ligation to bypass deleterious mutations (cis) or ligate two or more separate RNA independent RNA species (trans).

[0222] Here additional systems useful for achieving these site-specific RNA cleavage events are developed, for RNA editing applications, using either trans-cleaving ribozymes (Huang et al., 2019, Nucleic acids research 47, 2514-2522; Fauzi et al., 1997, Nucleic acids research 25, 3124-3130; Roth et al., 2014, Nat Chem Biol 10, 56-60), trans-cleaving ribozymes as fusions to CRISPR-Cas guide-RNAs, or CRISPR-Cas systems alone. For example, some Cas enzymes, such as Cas9 from both subtypes II-A and II-C, recognize and cleave single-stranded RNA (ssRNA) site-specifically, which themselves could be used to induce RNA trans-ligation when targeted to multiple sequences in cis or trans (Strutt et al., 2018, Elife 7, doi:10.7554 / eLife.32724). Sequences: SEQ ID NO  Description  Sequence 1  Trans‐cleaving 3’nnnnnnnndwaagcaggcgauggccugaguagucnnnnnnnnn5’  Hammerhead  2  Trans‐cleaving Extended 3’nnnnnnnndwaagcagcguaaagucgcugaguagucnnnnnaatnnnn5’  Hammerhead with TSM  (tertiary stabilizing motif)  and PLMV catalytic  sequence  3  Trans‐cleaving Extended 3’nnnnnnnndwaagcagcguagggucgcugaguagucnnnnnaaunnnn5’  Hammerhead with TSM Attorney Docket No.204606-0174-00WO (tertiary stabilizing motif)  and RzB catalytic sequence Trans‐cleaving HDV  3’gggccccaggguaagcgguacggcuucguacaacgggunnnnnncggucgcuccuccgacccuggnnnnnnn5’ HDV68  GGCCGGCAUGGUCCCAGCCUCCUCGCUGGCGCCGGCUGGGCAACAUGCUUCGGCAUGGCGAAUGGGAC HDV67  GGGUCGGCAUGGCAUCUCCACCUCCUCGCGGUCCGACCUGGGCUACUUCGGUAGGCUAAGGGAGAAG  HDV56  GAGGGAUAGUACAGAGCCUCCCCGUGGCUCCCUUGGAUAACCAACUGAUACUGUAC  Genomic HDV (genHDV)  GGCCGGCAUGGUCCCAGCCUCCUCGCUGGCGCCGGCUGGGCAACAUUCCGAGGGGACCGUCCCCUCGGUAAUGGCGAAUGGGACCCA  Antigenomic HDV GGGUCGGCAUGGCAUCUCCACCUCCUCGCGGUCCGACCUGGGCAUC (antiHDV)  CGAAGGAGGACGCACGUCCACUCGGAUGGCUAAGGGAGAGCCACU Twister  AGCCUUAACACUGCCAAUGCCGGUCCCAAGCCCGGAUAAAAGUGGAGGG   VS Ribozyme  GCGGUAGUAAGCAGGGAACUCACCUCCAAUUUCAGUACUGAAAUUGUCGUAGCAGUUGACUACUGUUAUGUGAUUGGUAGAGGCUAAGU GACGGUAUUGGCGUAAGUCAGUAUUGCAGCACAGCACAAGCCCGC UUGCGAGAAU  VS‐S  GAAGGGCGUCGUCGCCCCGAG   HDV68 catalytic mutant  5’‐ GGCCGGCAUGGUCCCAGCCUCCUCGCUGGCGCCGGCUGGGCAACAUGCUUCGGCAUGGUGAAUGGGAC ‐3’ cis‐cleaving HH  nnnnnnnnnctgatgagtcgctgggatgcgacgaawdnnnnnnnnnnnnnnnnnndwhnnnnnnnnnnnnnnn trans‐cleaving HH  nnnnnnnnnctgatgagtccggtagcggatgaawdnnnnnnn cis‐cleaving HDV  nnnnnnnnngnnnnnnatggtcccagcctcctcgctggcgccggctgggcaacatgcttcggcatggcgaatgggac Hammerhead (HH) for 3’  NNNNDWHACCGGAUGUGUUUUCCGGUCUGAUGAGUCCGGUAGCGGACGAAWHNNNN Twister WT with 5 nt P1 NNNNNUAACACUGCCAAUGCCGGUCCCAAGCCCGGAUAAAAGUGG stem  AGGGNNNNN Twister Mutant with 5 nt NNNNNUAACUCUUCCAAUGCCGGUCCCAAGCCCGGAUAAAAGUGG P1 stem  AGGGNNNNN Twister with 5 nt P1 stem NNNNNAAACACUGCCAAUGCCGGUCCCAAGCCCGGAUAAAAGUGGA with U1A mutation  GGGNNNNN Twister with 5 nt P1 stem NNNNNCAACACUGCCAAUGCCGGUCCCAAGCCCGGAUAAAAGUGGA with U1C mutation  GGGNNNNN Twister with 5 nt P1 stem NNNNNGAACACUGCCAAUGCCGGUCCCAAGCCCGGAUAAAAGUGG with U1G mutation  AGGGNNNNN Hammerhead 4 nt NNNNCUGAUGAGUCCGUGAGGACGAAACGAGUAAGCUCGUC  overhang for 5’ Attorney Docket No.204606-0174-00WOHammerhead 6 nt NNNNNNCUGAUGAGUCCGUGAGGACGAAACGAGUAAGCUCGUC  overhang for 5’ Hammerhead 8 nt NNNNNNNNCUGAUGAGUCCGUGAGGACGAAACGAGUAAGCUCGU overhang for 5’  C Hammerhead 10 nt NNNNNNNNNNCUGAUGAGUCCGUGAGGACGAAACGAGUAAGCUC overhang for 5’  GUC Hammerhead 12 nt NNNNNNNNNNNNCUGAUGAGUCCGUGAGGACGAAACGAGUAAGC overhang for 5’  UCGUC Hammerhead 14 nt NNNNNNNNNNNNNNCUGAUGAGUCCGUGAGGACGAAACGAGUAA overhang for 5’  GCUCGUC Hammerhead 16 nt NNNNNNNNNNNNNNNNCUGAUGAGUCCGUGAGGACGAAACGAGU overhang for 5’  AAGCUCGUC TX2 Hammerhead 4 nt NNNNCUGAUGAGUCCGGUAGCGGACGAAACGCGCUUCGGUGCGUC  overhang for 5’   TX2 Hammerhead 6 nt NNNNNNCUGAUGAGUCCGGUAGCGGACGAAACGCGCUUCGGUGCG overhang for 5’  UC TX2 Hammerhead 8 nt NNNNNNNNCUGAUGAGUCCGGUAGCGGACGAAACGCGCUUCGGU overhang for 5’  GCGUC TX2 Hammerhead 10 nt NNNNNNNNNNCUGAUGAGUCCGGUAGCGGACGAAACGCGCUUCG overhang for 5’    GUGCGUC TX2 Hammerhead 12 nt NNNNNNNNNNNNCUGAUGAGUCCGGUAGCGGACGAAACGCGCUU overhang for 5’    CGGUGCGUC TX2 Hammerhead 14 nt NNNNNNNNNNNNNNCUGAUGAGUCCGGUAGCGGACGAAACGCGC overhang for 5’    UUCGGUGCGUC TX2 Hammerhead 16 nt NNNNNNNNNNNNNNNNCUGAUGAGUCCGGUAGCGGACGAAACGC overhang for 5’    GCUUCGGUGCGUC RzB Hammerhead for 5’  NNNNNNUAANNNNNCUGAUGAGUCGCUGGGAUGCGACGAAACGCCUUCGGGCGUC RzB, with stem1 overhang UUGUAAUAAUCCUGCUGAUGAGUCGCUGGGAUGCGACGAAACGCC specific to Ct‐Luc  UUCGGGCGUC Twister (Osa)  NNNNNNAACACTGCCAATGCCGGTCCCAAGCCCGGATAAAAGTGGAGGGNNNNN Twister (Dre)  TTAGAAACTCCGCCATTGCCGGTCCCAAGCCCGGATGAAAAAGGAGGAGGGTTGA Twister (Nvi)  CTTTTAATGCGGCCTATTGTCGGTCTTAAGCCCGAAGAAAACGCATAGAGAAGG Twister (Sbi)  TGCCTAGCACTGCCAATGCCGGTCCCAAGCCCGGATAAATGTGGAGGGGGCA Twister (Env1)  ATGCTCAGCGGTCCCAAGTCCGCATCAAAGCCTGAGGGCTGCAGTAAAGGTACTGAGCTG Twister (Spu)  AGGGAGGGAGGGGTATTGGAACCAAACCTCTTAACCAACCGTCGCCCGTCCCAAGTCGGG Twister (Cpa)  GCAGATGGGCCGGAGAAATCCGGTTAATGCCGATACCGTAAGGTATGCAGTCCAAACGCTGC Attorney Docket No.204606-0174-00WO 46  Twister Sister  GCAGGGCAAGGCCCAGTCCCGTGAAAGCCGGGACCGCCCCTTCGGGGGCGCGGCGCTCATGCCTGC  47  Hammerhead (RzB)  CTGTCTTAACGACACTGATGAGTCGCTGGGATGCGACGAAACGCCTTCGGGCGTCTGTCGAGACAG  48  Pistol  ACTCGACTAAGCGAGTATAAACAGGCATTAGGCTTAGAGCGTTCTCACGTTATCTGAATGATGATGTGAGAGGTTGCA  49  Varkud Satellite (VS)  GAAGGGCGTCGTCGCCCCGAGCGGTAGTAAGCAGGGAACTCACCTCCAATTTCAGTACTGAAATTGTCGTAGCAGTTGACTACTGTTATGTGATTG GTAGAGGCTAAGTGACGGTATTGGCGTAAGTCAGTATTGCAGCACAGC ACAAGCCCGCTTGCGAGAATATT  50  Hatchet  GTTCTTACTGTGAGAATCAGTGACAAACATGTGGGGCTTATATCTAATCTTCGGATTAGTATTAGTGCAGACGTTAAAACCATGTA  51  Hairpin  AAACAGAGAAGTCAACCAGAGAAACACACGTTGTGGTATATTACCTGGTACCCCCTGACAGTCCTGTTT  52  Hovlinc  ACCTAGACTAAGCCCAGGAACATAAGACCTCAGAGCTAATGAGCCACATACCTACCCAAGGTGAAAGCTCCTTCTCTCGCAATGTGTAACTCATGAT TCTCATGACCCCTGGTTGGAGAGATCCGGACTAGGAGCCAGGGGGCC TCTGATTCTGCCAGCCACTGCTAA  53  Trans‐cleaving extended nnnnnnngtcccagcctcctcgctggcgccggctgggcaacatgcttcggcatggcgaatg HDV ribozyme  ggac  Trans cleaving extended SEQ ID NO:54 NIPALVENQKKYFGTYSVMAMLNAQTVLDHIQKVADIEGEQNENNENLWFHPVMSHLYNAKNGYDKQPEKT MFIIERLQSYFPFLKIMAENQREYSNGKYKQNRVEVNSNDIFEVLKRAFGVLKMYRDLTNHYKTYEEKLNDG CEFLTSTEQPLSGMINNYYTVALRNMNERYGYKTEDLAFIQDKRFKFVKDAYGKKKSQVNTGFFLSLQDYNG DTQKKLHLSGVGIALLICLFLDKQYINIFLSRLPIFSSYNAQSEERRIIIRSFGINSIKLPKDRIHSEKSNKSVAMDM LNEVKRCPDELFTTLSAEKQSRFRIISDDHNEVLMKRSSDRFVPLLLQYIDYGKLFDHIRFHVNMGKLRYLLKA DKTCIDGQTRVRVIEQPLNGFGRLEEAETMRKQENGTFGNSGIRIRDFENMKRDDANPANYPYIVDTYTHYILE NNKVEMFINDKEDSAPLLPVIEDDRYVVKTIPSCRMSTLEIPAMAFHMFLFGSKKTEKLIVDVHNRYKRLFQA MQKEEVTAENIASFGIAESDLPQKILDLISGNAHGKDVDAFIRLTVDDMLTDTERRIKRFKDDRKSIRSADNKM GKRGFKQISTGKLADFLAKDIVLFQPSVNDGENKITGLNYRIMQSAIAVYDSGDDYEAKQQFKLMFEKARLIG KGTTEPHPFLYKVFARSIPANAVEFYERYLIERKFYLTGLSNEIKKGNRVDVPFIRRDQNKWKTPAMKTLGRIY SEDLPVELPRQMFDNEIKSHLKSLPQMEGIDFNNANVTYLIAEYMKRVLDDDFQTFYQWNRNYRYMDMLKG EYDRKGSLQHCFTSVEEREGLWKERASRTERYRKQASNKIRSNRQMRNASSEEIETILDKRLSNSRNEYQKSE KVIRRYRVQDALLFLLAKKTLTELADFDGERFKLKEIMPDAEKGILSEIMPMSFTFEKGGKKYTITSEGMKLKN YGDFFVLASDKRIGNLLELVGSDIVSKEDIMEEFNKYDQCRPEISSIVFNLEKWAFDTYPELSARVDREEKVDF KSILKILLNNKNINKEQSDILRKIRNAFDHNNYPDKGVVEIKALPEIAMSIKKAFGEYAIMKAttorney Docket No.204606-0174-00WO SEQ ID NO:55 NIPALVENQKKYFGTYSVMAMLNAQTVLDHIQKVADIEGEQNENNENLWFHPVMSHLYNAKNGYDKQPEKT MFIIERLQSYFPFLKIMAENQREYSNGKYKQNRVEVNSNDIFEVLKRAFGVLKMYRDLTNHYKTYEEKLNDG CEFLTSTEQPLSGMINNYYTVALRNMNERYGYKTEDLAFIQDKRFKFVKDAYGKKKSQVNTGFFLSLQDYNG DTQKKLHLSGVGIALLICLFLDKQYINIFLSRLPIFSSYNAQSEERRIIIRSFGINSIKLPKDRIHSEKSNKSVAMDM LNEVKRCPDELFTTLSAEKQSRFRIISDDHNEVLMKRSSDRFVPLLLQYIDYGKLFDHIRFHVNMGKLRYLLKA DKTCIDGQTRVRVIEQPLNGFGRLEEAETMRKQENGTFGNSGIRIRDFENMKRDDANPANYPYIVDTYTHYILE NNKVEMFINDKEDSAPLLPVIEDDRYVVKTIPSCRMSTLEIPAMAFHMFLFGSKKTEKLIVDVHNRYKRLFQA MQKEEVTAENIASFGIAESDLPQKILDLISGNAHGKDVDAFIRLTVDDMLTDTERRIKRFKDDRKSIRSADNKM GKRGFKQISTGKLADFLAKDIVLFQPSVNDGENKITGLNYRIMQSAIAVYDSGDDYEAKQQFKLMFEKARLIG KGTTEPHPFLYKVFARSIPANAVEFYERYLIERKFYLTGLSNEIKKGNRVDVPFIRRDQNKWKTPAMKTLGRIY SEDLPVELPRQMFDNEIKSHLKSLPQMEGIDFNNANVTYLIAEYMKRVLDDDFQTFYQWNRNYRYMDMLKG EYDRKGSLQHCFTSVEEREGLWKERASRTERYRKQASNKIRSNRQMRNASSEEIETILDKRLSNSRNEYQKSE KVIRRYRVQDALLFLLAKKTLTELADFDGERFKLKEIMPDAEKGILSEIMPMSFTFEKGGKKYTITSEGMKLKN YGDFFVLASDKRIGNLLELVGSDIVSKED SEQ ID NO:56 MSNEIGAFREHQFAYAPGNEKQEEATFATYFNLALSNVEGMMFGEVESNPDKIEKSLDTLPPAILRQIASFIWL SKEDHPDKAYSTEEVKVIVTDLVRRLCFYRNYFSHCFYLDTQYFYSDELVDTTAIGEKLPYNFHHFITNRLFRY SLPEITLFRWNEGERKYEILRDGLIFFCCLFLKRGQAERFLNELRFFKRTDEEGRIKRTIFTKYCTRESHKHIGIEE QDFLIFQDIIGDLNRVPKVCDGVVDLSKENERYIKNRETSNESDENKARYRLLIREKDKFPYYLMRYIVDFGVL PCITFKQNDYSTKEGRGQFHYQDAAVAQEERCYNFVVRNGNVYYSYMPQAQNVVRISELQGTISVEELRNMV YASINGKDVNKSVEQYLYHLHLLYEKILTISGQTIKEGRVDVEDYRPLLDKLLLRPASNGEELRRELRKLLPKR VCDLLSNRFDCSEGVSAVEKRLKAILLRHEQLLLSQNPALHIDKIKSVIDYLYLFFSDDEKFRQQPTEKAHRGL KDEEFQMYHYLVGDYDSHPLALWKELEASGRLKPEMRKLTSATSLHGLYMLCLKGTVEWCRKQLMSIGKGT AKVEAIADRVGLKLYDKLKEYTPEQLEREVKLVVMHGYAAAATPKPKAQAAIPSKLTELRFYSFLGKREMSF AAFIRQDKKAQKLWLRNFYTVENIKTLQKRQAAADAACKKLYNLVGEVERVHTNDKVLVLVAQRYRERLL NVGSKCAVTLDNPERQQKLADVYEVQNAWLSIRFDDLDFTLTHVNLSNLRKAYNLIPRKHILAFKEYLDNRV KQKLCEECRNVRRKEDLCTCCSPRYSNLTSWLKENHSESSIEREAATMMLLDVERKLLSFLLDERRKAIIEYGK FIPFSALVKECRLADAGLCGIRNDVLHDNVISYADAIGKLSAYFPKEASEAVEYIRRTKEVREQRREELMANSS Q SEQ ID NO:57 MKSGRREKAKSNKSSIVRVIISNFDDKQVKEIKVLYTKQGGIDVIKFKSTEKDEKGRMKFNFDCAYNRLEEEEF NSFGGKGKQSFFVTTNEDLTELHVTKRHKTTGEIIKDYTIQGKYTPIKQDRTKVTVSITDNKDHFDSNDLGDKI RLSRSLTQYTNRILLDADVMKNYREIVCSDSEKVDETINIDSQEIYKINRFLSYRSNMIIYYQMINNFLLHYDGE EDKGGNDSINLINEIWKYENKKNDEKEKIIERSYKSIEKSINQYILNHNTEVESGDKEKKIDISEERIKEDLKKTFI LFSRLRHYMVHYNYKFYENLYSGKNFIIYNKDKSKSRRFSELLDLNIFKELSKIKLVKNRAVSNYLDKKTTIHV LNKNINAIKLLDIYRDICETKNGFNNFINNMMTISGEEDKEYKEMVTKHFNENMNKLSIYLENFKKHSDFKTN NKKKETYNLLKQELDEQKKLRLWFNAPYVYDIHSSKKYKELYVERKKYVDIHSKLIEAGINNDNKKKLNEIN VKLCELNTEMKEMTKLNSKYRLQYKLQLAFGFILEEFNLDIDKFVSAFDKDNNLTISKFMEKRETYLSKSLDR RDNRFKKLIKDYKFRDTEDIFCSDRENNLVKLYILMYILLPVEIRGDFLGFVKKNYYDLKHVDFIDKRNNDNK DTFFHDLRLFEKNVKRLEVTSYSLSDGFLGKKSREKFGKELEKFIYKNVSIALPTNIDIKEFNKSLVLPMMKNY QIIFKLLNDIEISALFLIAKKEGNEGSITFKKVIDKVRKEDMNGNINFSQVMKMALNEKVNCQIRNSIAHINMKQ LYIEPLNIYINNNQNKKTISEQMEEIIDICITKGLTGKELNKNIINDYYMKKEKLVFNLKLRKRNNLVSIDAQQK NMKEKSILNKYDLNYKDENLNIKEIILKVNDLNNKQKLLKETTEGESNYKNALSKDILLLNGIIRKNINFKIKEM ILGIIQQNEYRYVNINIYDKIRKEDHNIDLKINNKYIEISCYENKSNESTDERINFKIKYMDLKVKNELLVPSCYE DIYIKKKIDLEIRYIENCKVVYIDIYYKKYNINLEFDGKTLFVKFNKDVKKNNQKVNLESNYIQNIKFIVS SEQ ID NO:58 MKISKVDHVKSGIDQKLSSQRGMLYKQPQKKYEGKQLEEHVRNLSRKAKALYQVFPVSGNSKMEKELQIINS FIKNILLRLDSGKTSEEIVGYINTYSVASQISGDHIQELVDQHLKESLRKYTCVGDKRIYVPDIIVALLKSKFNSE TLQYDNSELKILIDFIREDYLKEKQIKQIVHSIENNSTPLRIAEINGQKRLIPANVDNPKKSYIFEFLKEYAQSDPK GQESLLQHMRYLILLYLYGPDKITDDYCEEIEAWNFGSIVMDNEQLFSEEASMLIQDRIYVNQQIEEGRQSKDT AKVKKNKSKYRMLGDKIEHSINESVVKHYQEACKAVEEKDIPWIKYISDHVMSVYSSKNRVDLDKLSLPYLA KNTWNTWISFIAMKYVDMGKGVYHFAMSDVDKVGKQDNLIIGQIDPKFSDGISSFDYERIKAEDDLHRSMSG YIAFAVNNFARAICSDEFRKKNRKEDVLTVGLDEIPLYDNVKRKLLQYFGGASNWDDSIIDIIDDKDLVACIKE NLYVARNVNFHFAGSEKVQKKQDDILEEIVRKETRDIGKHYRKVFYSNNVAVFYCDEDIIKLMNHLYQREKP YQAQIPSYNKVISKTYLPDLIFMLLKGKNRTKISDPSIMNMFRGTFYFLLKEIYYNDFLQASNLKEMFCEGLKN NVKNKKSEKPYQNFMRRFEELENMGMDFGEICQQIMTDYEQQNKQKKKTATAVMSEKDKKIRTLDNDTQK YKHFRTLLYIGLREAFIIYLKDEKNKEWYEFLREPVKREQPEEKEFVNKWKLNQYSDCSELILKDSLAAAWYV VAHFINQAQLNHLIGDIKNYIQFISDIDRRAKSTGNPVSESTEIQIERYRKILRVLEFAKFFCGQITNVLTDYYQD ENDFSTHVGHYVKFEKKNMEPAHALQAFSNSLYACGKEKKKAGFYYDGMNPIVNRNITLASMYGNKKLLEN AMNPVTEQDIRKYYSLMAELDSVLKNGAVCKSEDEQKNLRHFQNLKNRIELVDVLTLSELVNDLVAQLIGWV YIRERDMMYLQLGLHYIKLYFTDSVAEDSYLRTLDLEEGSIADGAVLYQIASLYSFNLPMYVKPNKSSVYCKK HVNSVATKFDIFEKEYCNGDETVIENGLRLFENINLHKDMVKFRDYLAHFKYFAKLDESILELYSKAYDFFFSY NIKLKKSVSYVLTNVLLSYFINAKLSFSTYKSSGNKTVQHRTTKISVVAQTDYFTYKLRSIVKNKNGVESIEND DRRCEVVNIAARDKEFVDEVCNVINYNSDKAttorney Docket No.204606-0174-00WO SEQ ID NO:59 MENKTSLGNNIYYNPFKPQDKSYFAGYFNAAMENTDSVFRELGKRLKGKEYTSENFFDAIFKENISLVEYERY VKLLSDYFPMARLLDKKEVPIKERKENFKKNFKGIIKAVRDLRNFYTHKEHGEVEITDEIFGVLDEMLKSTVLT VKKKKVKTDKTKEILKKSIEKQLDILCQKKLEYLRDTARKIEEKRRNQRERGEKELVAPFKYSDKRDDLIAAIY NDAFDVYIDKKKDSLKESSKAKYNTKSDPQQEEGDLKIPISKNGVVFLLSLFLTKQEIHAFKSKIAGFKATVIDE ATVSEATVSHGKNSICFMATHEIFSHLAYKKLKRKVRTAEINYGEAENAEQLSVYAKETLMMQMLDELSKVP DVVYQNLSEDVQKTFIEDWNEYLKENNGDVGTMEEEQVIHPVIRKRYEDKFNYFAIRFLDEFAQFPTLRFQVH LGNYLHDSRPKENLISDRRIKEKITVFGRLSELEHKKALFIKNTETNEDREHYWEIFPNPNYDFPKENISVNDKD FPIAGSILDREKQPVAGKIGIKVKLLNQQYVSEVDKAVKAHQLKQRKASKPSIQNIIEEIVPINESNPKEAIVFGG QPTAYLSMNDIHSILYEFFDKWEKKKEKLEKKGEKELRKEIGKELEKKIVGKIQAQIQQIIDKDTNAKILKPYQD GNSTAIDKEKLIKDLKQEQNILQKLKDEQTVREKEYNDFIAYQDKNREINKVRDRNHKQYLKDNLKRKYPEA PARKEVLYYREKGKVAVWLANDIKRFMPTDFKNEWKGEQHSLLQKSLAYYEQCKEELKNLLPEKVFQHLPF KLGGYFQQKYLYQFYTCYLDKRLEYISGLVQQAENFKSENKVFKKVENECFKFLKKQNYTHKELDARVQSIL GYPIFLERGFMDEKPTIIKGKTFKGNEALFADWFRYYKEYQNFQTFYDTENYPLVELEKKQADRKRKTKIYQQ KKNDVFTLLMAKHIFKSVFKQDSIDQFSLEDLYQSREERLGNQERARQTGERNTNYIWNKTVDLKLCDGKITV ENVKLKNVGDFIKYEYDQRVQAFLKYEENIEWQAFLIKESKEEENYPYVVEREIEQYEKVRREELLKEVHLIEE YILEKVKDKEILKKGDNQNFKYYILNGLLKQLKNEDVESYKVFNLNTEPEDVNINQLKQEATDLEQKAFVLTY IRNKFAHNQLPKKEFWDYCQEKYGKIEKEKTYAEYFAEVFKKEKEALIK SEQ ID NO:60 MKFSKVDHTRSAVGIQKATDSVHGMLYTDPKKQEVNDLDKRFDQLNVKAKRLYNVFNQSKAEEDDDEKRF GKVVKKLNRELKDLLFHREVSRYNSIGNAKYNYYGIKSNPEEIVSNLGMVESLKGERDPQKVISKLLLYYLRK GLKPGTDGLRMILEASCGLRKLSGDEKELKVFLQTLDEDFEKKTFKKNLIRSIENQNMAVQPSNEGDPIIGITQG RFNSQKNEEKSAIERMMSMYADLNEDHREDVLRKLRRLNVLYFNVDTEKTEEPTLPGEVDTNPVFEVWHDH EKGKENDRQFATFAKILTEDRETRKKEKLAVKEALNDLKSAIRDHNIMAYRCSIKVTEQDKDGLFFEDQRINR FWIHHIESAVERILASINPEKLYKLRIGYLGEKVWKDLLNYLSIKYIAVGKAVFHFAMEDLGKTGQDIELGKLS NSVSGGLTSFDYEQIRADETLQRQLSVEVAFAANNLFRAVVGQTGKKIEQSKSEENEEDFLLWKAEKIAESIKK EGEGNTLKSILQFFGGASSWDLNHFCAAYGNESSALGYETKFADDLRKAIYSLRNETFHFTTLNKGSFDWNAK LIGDMFSHEAATGIAVERTRFYSNNLPMFYRESDLKRIMDHLYNTYHPRASQVPSFNSVFVRKNFRLFLSNTLN TNTSFDTEVYQKWESGVYYLFKEIYYNSFLPSGDAHHLFFEGLRRIRKEADNLPIVGKEAKKRNAVQDFGRRC DELKNLSLSAICQMIMTEYNEQNNGNRKVKSTREDKRKPDIFQHYKMLLLRTLQEAFAIYIRREEFKFIFDLPK TLYVMKPVEEFLPNWKSGMFDSLVERVKQSPDLQRWYVLCKFLNGRLLNQLSGVIRSYIQFAGDIQRRAKAN HNRLYMDNTQRVEYYSNVLEVVDFCIKGTSRFSNVFSDYFRDEDAYADYLDNYLQFKDEKIAEVSSFAALKT FCNEEEVKAGIYMDGENPVMQRNIVMAKLFGPDEVLKNVVPKVTREEIEEYYQLEKQIAPYRQNGYCKSEED QKKLLRFQRIKNRVEFQTITEFSEIINELLGQLISWSFLRERDLLYFQLGFHYLCLHNDTEKPAEYKEISREDGTV IRNAILHQVAAMYVGGLPVYTLADKKLAAFEKGEADCKLSISKDTAGAGKKIKDFFRYSKYVLIKDRMLTDQ NQKYTIYLAGLELFENTDEHDNITDVRKYVDHFKYYATSDENAMSILDLYSEIHDRFFTYDMKYQKNVANML ENILLRHFVLIRPEFFTGSKKVGEGKKITCKARAQIEIAENGMRSEDFTYKLSDGKKNISTCMIAARDQKYLNTV ARLLYYPHEAKKSIVDTREKKNNKKTNRGDGTFNKQKGTARKEKDNGPREFNDTGFSNTPFAGFDPFRNS SEQ ID NO:61 MKNIQRLGKGNEFSPFKKEDKFYFGGFLNLANNNIEDFFKEIITRFGIVITDENKKPKETFGEKILNEIFKKDISIV DYEKWVNIFADYFPFTKYLSLYLEEMQFKNRVICFRDVMKELLKTVEALRNFYTHYDHEPIKIEDRVFYFLDK VLLDVSLTVKNKYLKTDKTKEFLNQHIGEELKELCKQRKDYLVGKGKRIDKESEIINGIYNNAFKDFICKREKQ DDKENHNSVEKILCNKEPQNKKQKSSATVWELCSKSSSKYTEKSFPNRENDKHCLEVPISQKGIVFLLSFFLNK GEIYALTSNIKGFKAKITKEEPVTYDKNSIRYMATHRMFSFLAYKGLKRKIRTSEINYNEDGQASSTYEKETLM LQMLDELNKVPDVVYQNLSEDVQKTFIEDWNEYLKENNGDVGTMEEEQVIHPVIRKRYEDKFNYFAIRFLDE FAQFPTLRFQVHLGNYLCDKRTKQICDTTTEREVKKKITVFGRLSELENKKAIFLNEREEIKGWEVFPNPSYDFP KENISVNYKDFPIVGSILDREKQPVSNKIGIRVKIADELQREIDKAIKEKKLRNPKNRKANQDEKQKERLVNEIV STNSNEQGEPVVFIGQPTAYLSMNDIHSVLYEFLINKISGEALETKIVEKIETQIKQIIGKDATTKILKPYTNANSN SINREKLLRDLEQEQQILKTLLEEQQQREKDKKDKKSKRKHELYPSEKGKVAVWLANDIKRFMPKAFKEQWR GYHHSLLQKYLAYYEQSKEELKNLLPKEVFKHFPFKLKGYFQQQYLNQFYTDYLKRRLSYVNELLLNIQNFK NDKDALKATEKECFKFFRKQNYIINPINIQIQSILVYPIFLKRGFLDEKPTMIDREKFKENKDTELADWFMHYKN YKEDNYQKFYAYPLEKVEEKEKFKRNKQINKQKKNDVYTLMMVEYIIQKIFGDKFVEENPLVLKGIFQSKAER QQNNTHAATTQERNLNGILNQPKDIKIQGKITVKGVKLKDIGNFRKYEIDQRVNTFLDYEPRKEWMAYLPND WKEKEKQGQLPPNNVIDRQISKYETVRSKILLKDVQELEKIISDEIKEEHRHDLKQGKYYNFKYYILNGLLRQL KNENVENYKVFKLNTNPEKVNITQLKQEATDLEQKAFVLTYIRNKFAHNQLPKKEFWDYCQEKYGKIEKEKT YAEYFAEVFKREKEALIKAttorney Docket No.204606-0174-00WO SEQ ID NO:62 MRMTKVKINGSPVSMNRSKLNGHLVWNGTTNTVNILTKKEQSFAASFLNKTLVKADQVKGYKVLAENIFIIFE QLEKSNSEKPSVYLNNIRRLKEAGLKRFFKSKYHEEIKYTSEKNQSVPTKLNLIPLFFNAVDRIQEDKFDEKNW SYFCKEMSPYLDYKKSYLNRKKEILANSIQQNRGFSMPTAEEPNLLSKRKQLFQQWAMKFQESPLIQQNNFAV EQFNKEFANKINELAAVYNVDELCTAITEKLMNFDKDKSNKTRNFEIKKLWKQHPHNKDKALIKLFNQEGNE ALNQFNIELGKYFEHYFPKTGKKESAESYYLNPQTIIKTVGYQLRNAFVQYLLQVGKLHQYNKGVLDSQTLQE IGMYEGFQTKFMDACVFASSSLRNIIQATTNEDILTREKFKKELEKNVELKHDLFFKTEIVEERDENPAKKIAMT PNELDLWAIRGAVQRVRNQIFHQQINKRHEPNQLKVGSFENGDLGNVSYQKTIYQKLFDAEIKDIEIYFAEKIK SSGALEQYSMKDLEKLFSNKELTLSLGGQVVAFAPSYKKLYKQGYFYQNEKTIELEQFTDYDFSNDVFKANY YLIKLIYHYVFLPQFSQANNKLFKDTVHYVIQQNKELNTTEKDKKNNKKIRKYAFEQVKLMKNESPEKYMQY LQREMQEERTIKEAKKTNEEKPNYNFEKLLIQIFIKGFDTFLRNFDLNLNPAEELVGTVKEKAEGLRKRKERIA KILNVDEQIKTGDEEIAFWIFAKLLDARHLSELRNEMIKFKQSSVKKGLIKNGDLIEQMQPILELCILSNDSESME KESFDKIEVFLEKVELAKNEPYMQEDKLTPVKFRFMKQLEKYQTRNFIENLVIENPEFKVSEKIVLNWHEEKEK IADLVDKRTKLHEEWASKAREIEEYNEKIKKNKSKKLDKPAEFAKFAEYKIICEAIENFNRLDHKVRLTYLKNL HYLMIDLMGRMVGFSVLFERDFVYMGRSYSALKKQSIYLNDYDTFANIRDWEVNENKHLFGTSSSDLTFQET AEFKNLKKPMENQLKALLGVTNHSFEIRNNIAHLHVLRNDGKGEGVSLLSCMNDLRKLMSYDRKLKNAVTK AIIKILDKHGMILKLTNNDHTKPFEIESLKPKKIIHLEKSNHSFPMDQVSQEYCDLVKKMLVFTN SEQ ID NO:63 MRITKVKIKLDNKLYQVTMQKEEKYGTLKLNEESRKSTAEILRLKKASFNKSFHSKTINSQKENKNATIKKNG DYISQIFEKLVGVDTNKNIRKPKMSLTDLKDLPKKDLALFIKRKFKNDDIVEIKNLDLISLFYNALQKVPGEHFT DESWADFCQEMMPYREYKNKFIERKIILLANSIEQNKGFSINPETFSKRKRVLHQWAIEVQERGDFSILDEKLSK LAEIYNFKKMCKRVQDELNDLEKSMKKGKNPEKEKEAYKKQKNFKIKTIWKDYPYKTHIGLIEKIKENEELNQ FNIEIGKYFEHYFPIKKERCTEDEPYYLNSETIATTVNYQLKNALISYLMQIGKYKQFGLENQVLDSKKLQEIGI YEGFQTKFMDACVFATSSLKNIIEPMRSGDILGKREFKEAIATSSFVNYHHFFPYFPFELKGMKDRESELIPFGE QTEAKQMQNIWALRGSVQQIRNEIFHSFDKNQKFNLPQLDKSNFEFDASENSTGKSQSYIETDYKFLFEAEKNQ LEQFFIERIKSSGALEYYPLKSLEKLFAKKEMKFSLGSQVVAFAPSYKKLVKKGHSYQTATEGTANYLGLSYY NRYELKEESFQAQYYLLKLIYQYVFLPNFSQGNSPAFRETVKAILRINKDEARKKMKKNKKFLRKYAFEQVRE MEFKETPDQYMSYLQSEMREEKVRKAEKNDKGFEKNITMNFEKLLMQIFVKGFDVFLTTFAGKELLLSSEEK VIKETEISLSKKINEREKTLKASIQVEHQLVATNSAISYWLFCKLLDSRHLNELRNEMIKFKQSRIKFNHTQHAE LIQNLLPIVELTILSNDYDEKNDSQNVDVSAYFEDKSLYETAPYVQTDDRTRVSFRPILKLEKYHTKSLIEALLK DNPQFRVAATDIQEWMHKREEIGELVEKRKNLHTEWAEGQQTLGAEKREEYRDYCKKIDRFNWKANKVTLT YLSQLHYLITDLLGRMVGFSALFERDLVYFSRSFSELGGETYHISDYKNLSGVLRLNAEVKPIKIKNIKVIDNEE NPYKGNEPEVKPFLDRLHAYLENVIGIKAVHGKIRNQTAHLSVLQLELSMIESMNNLRDLMAYDRKLKNAVT KSMIKILDKHGMILKLKIDENHKNFEIESLIPKEIIHLKDKAIKTNQVSEEYCQLVLALLTTNPGNQLN SEQ ID NO:64 MKISKESHKRTAVAVMEDRVGGVVYVPGGSGIDLSNNLKKRSMDTKSLYNVFNQIQAGTAPSEYEWKDYLS EAENKKREAQKMIQKANYELRRECEDYAKKANLAVSRIIFSKKPKKIFSDDDIISHMKKQRLSKFKGRMEDFV LIALRKSLVVSTYNQEVFDSRKAATVFLKNIGKKNISADDERQIKQLMALIREDYDKWNPDKDSSDKKESSGT KVIRSIEHQNMVIQPEKNKLSLSKISNVGKKTKTKQKEKAGLDAFLKEYAQIDENSRMEYLKKLRRLLDTYFA APSSYIKGAAVSLPENINFSSELNVWERHEAAKKVNINFVEIPESLLNAEQNNNKINKVEQEHSLEQLRTDIRRR NITCYHFANALAADERYHTLFFENMAMNQFWIHHMENAVERILKKCNVGTLFKLRIGYLSEKVWKDMLNLL SIKYIALGKAVYHFALDDIWKADIWKDASDKNSGKINDLTLKGISSFDYEMVKAQEDLQREMAVGVAFSTNN LARVTCKMDDLSDAESDFLLWNKEAIRRHVKYTEKGEILSAILQFFGGRSLWDESLFEKAYSDSNYELKFLDD LKRAIYAARNETFHFKTAAIDGGSWNTRLFGSLFEKEAGLCLNVEKNKFYSNNLVLFYKQEDLRVFLDKLYG KECSRAAQIPSYNTILPRKSFSDFMKQLLGLKEPVYGSAILDQWYSACYYLFKEVYYNLFLQDSSAKALFEKA VKALKGADKKQEKAVESFRKRYWEISKNASLAEICQSYITEYNQQNNKERKVRSANDGMFNEPIYQHYKMLL KEALKMAFASYIKNDKELKFVYKPTEKLFEVSQDNFLPNWNSEKYNTLISEVKNSPDLQKWYIVGKFMNARM LNLLLGSMRSYLQYVSDIQKRAAGLGENQLHLSAENVGQVKKWIQVLEVCLLLSVRISDKFTDYFKDEEEYAS YLKEYVDFEDSAMPSDYSALLAFSNEGKIDLYVDASNPKVNRNIIQAKLYAPDMVLKKVVKKISQDECKEFNE KKEQIMQFKNKGDEVSWEEQQKILEYQKLKNRVELRDLSEYGELINELLGQLINWSYLRERDLLYFQLGFHYS CLMNESKKPDAYKTIRRGTVSIENAVLYQIIAMYINGFPVYAPEKGELKPQCKTGSAGQKIRAFCQWASMVEK KKYELYNAGLELFEVVKEHDNIIDLRNKIDHFKYYQGNDSILALYGEIFDRFFTYDMKYRNNVLNHLQNILLR HNVIIKPIISKDKKEVGRGKMKDRAAFLLEEVSSDRFTYKVKEGERKIDAKNRLYLETVRDILYFPNRAVNDKG EDVIICSKKAQDLNEKKADRDKNHDKSKDTNQKKEGKNQEEKSENKEPYSDRMTWKPFAGIKLEAttorney Docket No.204606-0174-00WO SEQ ID NO:65 MLRRDKEVKKLYNVFNQIQVGTKPKKWNNDEKLSPEENERRAQQKNIKMKNYKWREACSKYVESSQRIIND VIFYSYRKAKNKLRYMRKNEDILKKMQEAEKLSKFSGGKLEDFVAYTLRKSLVVSKYDTQEFDSLAAMVVFL ECIGKNNISDHEREIVCKLLELIRKDFSKLDPNVKGSQGANIVRSVRNQNMIVQPQGDRFLFPQVYAKENETVT NKNVEKEGLNEFLLNYANLDDEKRAESLRKLRRILDVYFSAPNHYEKDMDITLSDNIEKEKFNVWEKHECGK KETGLFVDIPDVLMEAEAENIKLDAVVEKRERKVLNDRVRKQNIICYRYTRAVVEKYNSNEPLFFENNAINQY WIHHIENAVERILKNCKAGKLFKLRKGYLAEKVWKDAINLISIKYIALGKAVYNFALDDIWKDKKNKELGIVD ERIRNGITSFDYEMIKAHENLQRELAVDIAFSVNNLARAVCDMSNLGNKESDFLLWKRNDIADKLKNKDDMA SVSAVLQFFGGKSSWDINIFKDAYKGKKKYNYEVRFIDDLRKAIYCARNENFHFKTALVNDEKWNTELFGKIF ERETEFCLNVEKDRFYSNNLYMFYQVSELRNMLDHLYSRSVSRAAQVPSYNSVIVRTAFPEYITNVLGYQKPS YDADTLGKWYSACYYLLKEIYYNSFLQSDRALQLFEKSVKTLSWDDKKQQRAVDNFKDHFSDIKSACTSLAQ VCQIYMTEYNQQNNQIKKVRSSNDSIFDQPVYQHYKVLLKKAIANAFADYLKNNKDLFGFIGKPFKANEIREI DKEQFLPDWTSRKYEALCIEVSGSQELQKWYIVGKFLNARSLNLMVGSMRSYIQYVTDIKRRAASIGNELHVS VHDVEKVEKWVQVIEVCSLLASRTSNQFEDYFNDKDDYARYLKSYVDFSNVDMPSEYSALVDFSNEEQSDLY VDPKNPKVNRNIVHSKLFAADHILRDIVEPVSKDNIEEFYSQKAEIAYCKIKGKEITAEEQKAVLKYQKLKNRV ELRDIVEYGEIINELLGQLINWSFMRERDLLYFQLGFHYDCLRNDSKKPEGYKNIKVDENSIKDAILYQIIGMYV NGVTVYAPEKDGDKLKEQCVKGGVGVKVSAFHRYSKYLGLNEKTLYNAGLEIFEVVAEHEDIINLRNGIDHF KYYLGDYRSMLSIYSEVFDRFFTYDIKYQKNVLNLLQNILLRHNVIVEPILESGFKTIGEQTKPGAKLSIRSIKSD TFQYKVKGGTLITDAKDERYLETIRKILYYAENEEDNLKKSVVVTNADKYEKNKESDDQNKQKEKKNKDNK GKKNEETKSDAEKNNNERLSYNPFANLNFKLSN SEQ ID NO:66 MGKKIHARDLREQRKTDRTEKFADQNKKREAERAVPKKDAAVSVKSVSSVSSKKDNVTKSMAKAAGVKSV FAVGNTVYMTSFGRGNDAVLEQKIVDTSHEPLNIDDPAYQLNVVTMNGYSVTGHRGETVSAVTDNPLRRFNG RKKDEPEQSVPTDMLCLKPTLEKKFFGKEFDDNIHIQLIYNILDIEKILAVYSTNAIYALNNMSADENIENSDFF MKRTTDETFDDFEKKKESTNSREKADFDAFEKFIGNYRLAYFADAFYVNKKNPKGKAKNVLREDKELYSVLT LIGKLRHWCVHSEEGRAEFWLYKLDELKDDFKNVLDVVYNRPVEEINNRFIENNKVNIQILGSVYKNTDIAEL VRSYYEFLITKKYKNMGFSIKKLRESMLEGKGYADKEYDSVRNKLYQMTDFILYTGYINEDSDRADDLVNTL RSSLKEDDKTTVYCKEADYLWKKYRESIREVADALDGDNIKKLSKSNIEIQEDKLRKCFISYADSVSEFTKLIY LLTRFLSGKEINDLVTTLINKFDNIRSFLEIMDELGLDRTFTAEYSFFEGSTKYLAELVELNSFVKSCSFDINAKR TMYRDALDILGIESDKTEEDIEKMIDNILQIDANGDKKLKKNNGLRNFIASNVIDSNRFKYLVRYGNPKKIRET AKCKPAVRFVLNEIPDAQIERYYEACCPKNTALCSANKRREKLADMIAEIKFENFSDAGNYQKANVTSRTSEA EIKRKNQAIIRLYLTVMYIMLKNLVNVNARYVIAFHCVERDTKLYAESGLEVGNIEKNKTNLTMAVMGVKLE NGIIKTEFDKSFAENAANRYLRNARWYKLILDNLKKSERAVVNEFRNTVCHLNAIRNININIKEIKEVENYFAL YHYLIQKHLENRFADKKVERDTGDFISKLEEHKTYCKDFVKAYCTPFGYNLVRYKNLTIDGLFDKNYPGKDD SDEQK SEQ ID NO:67 MENLNKILDKENEICISKIFNTKGIAAPITEKALDNIKSKQKNDLNKEARLHYFSIGHSFKQIDTKKVFDYVLIEE LKDEKPLKFITLQKDFFTKEFSIKLQKLINSIRNINNHYVHNFNDINLNKIDSNVFHFLKESFELAIIEKYYKVNK KYPLDNEIVLFLKELFIKDENTALLNYFTNLSKDEAIEYILTFTITENKIWNINNEHNILNIEKGKYLTFEAMLFLI TIFLYKNEANHLLPKLYDFKNNKSKQELFTFFSKKFTSQDIDAEEGHLIKFRDMIQYLNHYPTAWNNDLKLESE NKNKIMTTKLIDSIIEFELNSNYPSFATDIQFKKEAKAFLFASNKKRNQTSFSNKSYNEEIRHNPHIKQYRDEIAS ALTPISFNVKEDKFKIFVKKHVLEEYFPNSIGYEKFLEYNDFTEKEKEDFGLKLYSNPKTNKLIERIDNHKLVKS HGRNQDRFMDFSMRFLAENNYFGKDAFFKCYKFYDTQEQDEFLQSNENNDDVKFHKGKVTTYIKYEEHLKN YSYWDCPFVEENNSMSVKISIGSEEKILKIQRNLMIYFLENALYNENVENQGYKLVNNYYRELKKDVEESIASL DLIKSNPDFKSKYKKILPKRLLHNYAPAKQDKAPENAFETLLKKADFREEQYKKLLKKAEHEKNKEDFVKRN KGKQFKLHFIRKACQMMYFKEKYNTLKEGNAAFEKKDPVIEKRKNKEHEFGHHKNLNITREEFNDYCKWMF AFNGNDSYKKYLRDLFSEKHFFDNQEYKNLFESSVNLEAFYAKTKELFKKWIETNKPTNNENRYTLENYKNLI LQKQVFINVYHFSKYLIDKNLLNSENNVIQYKSLENVEYLISDFYFQSKLSIDQYKTCGKLFNKLKSNKLEDCL LYEIAYNYIDKKNVHKIDIQKILTSKIILTINDANTPYKISVPFNKLERYTEMIAIKNQNNLKARFLIDLPLYLSKN KIKKGKDSAGYEIIIKNDLEIEDINTINNKIINDSVKFTEVLMELEKYFILKDKCILSKNYIDNSEIPSLKQFSKVWI KENENEIINYRNIACHFHLPLLETFDNLLLNVEQKFIKEELQNVSTINDLSKPQEYLILLFIKFKHNNFYLNLFNK NESKTIKNDKEVKKNRVLQKFINQVILKKKAttorney Docket No.204606-0174-00WO SEQ ID NO:68 MKVRYRKQAQLDTFIIKTEIVNNDIFIKSIIEKAREKYRYSFLFDGEEKYHFKNKSSVEIVKNDIFSQTPDNMIRN YKITLKISEKNPRVVEAEIEDLMNSTILKDGRRSARREKSMTERKLIEEKVAENYSLLANCPIEEVDSIKIYKIKR FLTYRSNMLLYFASINSFLCEGIKGKDNETEEIWHLKDNDVRKEKVKENFKNKLIQSTENYNSSLKNQIEEKEK LSSKEFKKGAFYRTIIKKLQQERIKELSEKSLTEDCEKIIKLYSELRHPLMHYDYQYFENLFENKENSELTKNLN LDIFKSLPLVRKMKLNNKVNYLEDNDTLFVLQKTKKAKTLYQIYDALCEQKNGFNKFINDFFVSDGEENTVFK QIINEKFQSEMEFLEKRISESEKKNEKLKKKLDSMKAHFRNINSEDTKEAYFWDIHSSRNYKTKYNERKNLVNE YTKLLGSSKEKKLLREEITKINRQLLKLKQEMEEITKKNSLFRLEYKMKIAFGFLFCEFDGNISKFKDEFDASNQ EKIIQYHKNGEKYLTSFLKEEEKEKFNLEKMQKIIQKTEEEDWLLPETKNNLFKFYLLTYLLLPYELKGDFLGF VKKHYYDIKNVDFMDENQNNIQVSQTVEKQEDYFYHKIRLFEKNTKKYEIVKYSIVPNEKLKQYFEDLGIDIK YLTGSVESGEKWLGENLGIDIKYLTVEQKSEVSEEKNKKVSLKNNGMFNKTILLFVFKYYQIAFKLFNDIELYS LFFLREKSEKPFEVFLEELKDKMIGKQLNFGQLLYVVYEVLVKNKDLDKILSKKIDYRKDKSFSPEIAYLRNFL SHLNYSKFLDNFMKINTNKSDENKEVLIPSIKIQKMIQFIEKCNLQNQIDFDFNFVNDFYMRKEKMFFIQLKQIF PDINSTEKQKKSEKEEILRKRYHLINKKNEQIKDEHEAQSQLYEKILSLQKIFSCDKNNFYRRLKEEKLLFLEKQ GKKKISMKEIKDKIASDISDLLGILKKEITRDIKDKLTEKFRYCEEKLLNISFYNHQDKKKEEGIRVFLIRDKNSD NFKFESILDDGSNKIFISKNGKEITIQCCDKVLETLMIEKNTLKISSNGKIISLIPHYSYSIDVKY SEQ ID NO:69 MEKFRRQNRSSIIKIIISNYDTKGIKELKVRYRKQAQLDTFIIKTEIVNNDIFIKSIIEKAREKYRYSFLFDGEEKYH FKNKSSVEIVKKDIFSQTPDNMIRNYKITLKISEKNPRVVEAEIEDLMNSTILKDGRRSARREKSMTERKLIEEK VAENYSLLANCPMEEVDSIKIYKIKRFLTYRSNMLLYFASINSFLCEGIKGKDNETEEIWHLKDNDVRKEKVKE NFKNKLIQSTENYNSSLKNQIEEKEKLLRKESKKGAFYRTIIKKLQQERIKELSEKSLTEDCEKIIKLYSELRHPL MHYDYQYFENLFENKENSELTKNLNLDIFKSLPLVRKMKLNNKVNYLEDNDTLFVLQKTKKAKTLYQIYDAL CEQKNGFNKFINDFFVSDGEENTVFKQIINEKFQSEIEFLEKRISESEKKNEKLKKKLDSMKAHFRNINSEDTKE AYFWDIHSSRNYKTKYNERKNLVNEYTELLGSSKEKKLLREEITKINRQLLKLKQEMEEITKKNSLFRLEYKM KMAFGFLFCEFDGNISRFKDEFDASNQEKIIQYHKNGEKYLTYFLKEEEKEKFNLKKLQETIQKTGEENWLLPQ NKNNLFKFYLLTYLLLPYELKGDFLGFVKKHYYDIKNVDFMDENQSSKIIESKEDDFYHKIRLFEKNTKKYEIV KYSIVPDKKLKQYFKDLGIDTKYLILDQKSEVSGEKNKKVSLKNNGMFNKTILLFVFKYYQIAFKLFNDIELYS LFFLREKSGKPFEVFLKELKDKMIGKQLNFGQLLYVVYEVLVKNKDLSEILSERIDYRKDMCFSAEIADLRNFL SHLNYSKFLDNFMKINTNKSDENKEVLIPSIKIQKMIKFIEECNLQSQIDFDFNFVNDFYMRKEKMFFIQLKQIFP DINSTEKQKMNEKEEILRNRYHLTDKKNEQIKDEHEAQSQLYEKILSLQKIYSSDKNNFYGRLKEEKLLFLEKQ EKKKLSMEEIKDKIAGDISDLLGILKKEITRDIKDKLTEKFRYCEEKLLNLSFYNHQDKKKEESIRVFLIRDKNSD NFKFESILDDGSNKIFISKNGKEITIQCCDKVLETLIIEKNTLKISSNGKIISLIPHYSYSIDVKY SEQ ID NO:70 MTEKKSIIFKNKSSVEIVKKDIFSQTPDNMIRNYKITLKISEKNPRVVEAEIEDLMNSTILKDGRRSARREKSMTE RKLIEEKVAENYSLLANCPMEEVDSIKIYKIKRFLTYRSNMLLYFASINSFLCEGIKGKDNETEEIWHLKDNDVR KEKVKENFKNKLIQSTENYNSSLKNQIEEKEKLLRKESKKGAFYRTIIKKLQQERIKELSEKSLTEDCEKIIKLYS ELRHPLMHYDYQYFENLFENKENSELTKNLNLDIFKSLPLVRKMKLNNKVNYLEDNDTLFVLQKTKKAKTLY QIYDALCEQKNGFNKFINDFFVSDGEENTVFKQIINEKFQSEMEFLEKRISESEKKNEKLKKKFDSMKAHFHNI NSEDTKEAYFWDIHSSSNYKTKYNERKNLVNEYTELLGSSKEKKLLREEITQINRKLLKLKQEMEEITKKNSLF RLEYKMKIAFGFLFCEFDGNISKFKDEFDASNQEKIIQYHKNGEKYLTYFLKEEEKEKFNLEKMQKIIQKTEEE DWLLPETKNNLFKFYLLTYLLLPYELKGDFLGFVKKHYYDIKNVDFMDENQNNIQVSQTVEKQEDYFYHKIR LFEKNTKKYEIVKYSIVPNEKLKQYFEDLGIDIKYLTGSVESGEKWLGENLGIDIKYLTVEQKSEVSEEKIKKFL SEQ ID NO:71 MEKFRRQNRNSIIKIIISNYDTKGIKELKVRYRKQAQLDTFIIKTEIVNNDIFIKSIIEKAREKYRYSFLFDGEEKYH FKNKSSVEIVKKDIFSQTPDNMIRNYKITLKISEKNPRVVEAEIEDLMNSTILKDGRRSARREKSMTERKLIEEK VAKNYSLLANCPMEEVDSIKIYKIKRFLTYRSNMLLYFASINSFLCEGIKGKDNETEEIWHLKDNDVRKEKVRE NFKNKLIQSTENYNSSLKNQIEEKEKLLRKEFKKGAFYRTIIKKLQQERIKELSEKSLTEDCEKIIKLYSKLRHSL MHYDYQYFENLFENKKNDDLMKDLNLDLFKSLPLIRKMKLNNKVNYLEDGDTLFVLQKTKKAKTLYQIYDA LCEQKNGFNKFINDFFVSDGEENTVFKQIINEKFQSEMEFLEKRISESEKKNEKLKKKLDSMKAHFRNINSEDT KEAYFWDIHSSRNYKTKYNERKNLVNEYTELLGSSKEKKLLREEITKINRQLLKLKQEMEEITKKNSLFRLEYK MKIAFGFLFCEFDGNISKFKDEFDASNQEKIIQYHKNGEKYLTSFLKEEEKEKFNLEKMQKIIQKTEEEDWLLPE TKNNLFKFYLLTYLLLPYELKGDFLGFVKKHYYDIKNVDFIDENQNNIQVSQTVEKQEDYFYHKIRLFEKNTK KYEIVKYSIVPNEKLKQYFEDLGIDIKYLTVEQKSEVSEEKNKKVSLKNNGMFNKTILLFVFKYYQIAFKLFNDI ELYSLFFLREKSGKPLEIFRKELESKMKDGYLNFGQLLYVVYEVLVKNKDLDKILSKKIDYRKDKSFSPEIAYL RNFLSHLNYSKFLDNFMKINTNKSDENKEVLIPSIKIQKMIQFIEKCNLQNQIDFDFNFVNDFYMRKEKMFFIQL KQIFPDINSTEKQKMNEKEEILRNRYHLTDKKNEQIKDEHEAQSQLYEKILSLQKIYSSDKNNFYGRLKEEKLLF LEKQGKKKLSMEEIKDKIAGDISDLLGILKKEITRDIKDKLTEKFRYCEEKLLNLSFYNHQDKKKEESIRVFLIR DKNSDNFKFESILDDGSNKIFISKNGKEITIQCCDKVLETLIIEKNTLKISSNGKIISLIPHYSYSIDVKYAttorney Docket No.204606-0174-00WO SEQ ID NO:72 MGKPNRSSIIKIIISNYDNKGIKEVKVRYNKQAQLDTFLIKSELKDGKFILYSIVDKAREKYRYSFEIDKTNINKN EILIIKKDIYSNKEDKVIRKYILSFEVSEKNDRTIVTKIKDCLETQKKEKFERENTRRLISETERKLLSEETQKTYS KIACCSPEDIDSVKIYKIKRYLAYRSNMLLFFSLINDIFVKGVVKDNGEEVGEIWRIIDSKEIDEKKTYDLLVENF KKRMSQEFINYKQSIENKIEKNTNKIKEIEQKLKKEKYKKEINRLKKQLIELNRENDLLEKDKIELSDEEIREDIE KILKIYSDLRHKLMHYNYQYFENLFENKKISKEKNEDVNLTELLDLNLFRYLPLVRQLKLENKTNYLEKEDKIT VLGVSDSAIKYYSYYNFLCEQKNGFNNFINSFFSNDGEENKSFKEKINLSLEKEIEIMEKETNEKIKEINKNELQL MKEQKELGTAYVLDIHSLNDYKISHNERNKNVKLQNDIMNGNRDKNALDKINKKLVELKIKMDKITKRNSIL RLKYKLQVAYGFLMEEYKGNIKKFKDEFDISKEKIKSYKSKGEKYLEVKSEKKYITKILNSIEDIHNITWLKNQ EENNLFKFYVLTYILLPFEFRGDFLGFVKKHYYDIKNVEFLDENNDRLTPEQLEKMKNDSFFNKIRLFEKNSKK YDILKESILTSERIGKYFSLLNTGAKYFEYGGEENRGIFNKNIIIPIFKYYQIVLKLYNDVELAMLLTLSESDEKDI NKIKELVTLKEKVSPKKIDYEKKYKFSVLLDCFNRIINLGKKDFLASEEVKEVAKTFTNLAYLRNKICHLNYSK FIDDLLTIDTNKSTTDSEGKLLINDRIRKLIKFIRENNQKMNISIDYNYINDYYMKKEKFIFGQRKQAKTIIDSGK KANKRNKAEELLKMYRVKKENINLIYELSKKLNELTKSELFLLDKKLLKDIDFTDVKIKNKSFFELKNDVKEV ANIKQALQKHSSELIGIYKKEVIMAIKRSIVSKLIYDEEKVLSIIIYDKTNKKYEDFLLEIRRERDINKFQFLIDEKK EKLGYEKIIETKEKKKVVVKIQNNSELVSEPRIIKNKDKKKAKTPEEISKLGILDLTNHYCFNLKITL SEQ ID NO:73 MENKGNNKKIDFDENYNILVAQIKEYFTKEIENYNNRIDNIIDKKELLKYSEKKEESEKNKKLEELNKLKSQKL KILTDEEIKADVIKIIKIFSDLRHSLMHYEYKYFENLFENKKNEELAELLNLNLFKNLTLLRQMKIENKTNYLEG REEFNIIGKNIKAKEVLGHYNLLAEQKNGFNNFINSFFVQDGTENLEFKKLIDEHFVNAKKRLERNIKKSKKLE KELEKMEQHYQRLNCAYVWDIHTSTTYKKLYNKRKSLIEEYNKQINEIKDKEVITAINVELLRIKKEMEEITKS NSLFRLKYKMQIAYAFLEIEFGGNIAKFKDEFDCSKMEEVQKYLKKGVKYLKYYKDKEAQKNYEFPFEEIFEN KDTHNEEWLENTSENNLFKFYILTYLLLPMEFKGDFLGVVKKHYYDIKNVDFTDESEKELSQVQLDKMIGDSF FHKIRLFEKNTKRYEIIKYSILTSDEIKRYFRLLELDVPYFEYEKGTDEIGIFNKNIILTIFKYYQIIFRLYNDLEIHG LFNISSDLDKILRDLKSYGNKNINFREFLYVIKQNNNSSTEEEYRKIWENLEAKYLRLHLLTPEKEEIKTKTKEE LEKLNEISNLRNGICHLNYKEIIEEILKTEISEKNKEATLNEKIRKVINFIKENELDKVELGFNFINDFFMKKEQFM FGQIKQVKEGNSDSITTERERKEKNNKKLKETYELNCDNLSEFYETSNNLRERANSSSLLEDSAFLKKIGLYKV KNNKVNSKVKDEEKRIENIKRKLLKDSSDIMGMYKAEVVKKLKEKLILIFKHDEEKRIYVTVYDTSKAVPENIS KEILVKRNNSKEEYFFEDNNKKYVTEYYTLEITETNELKVIPAKKLEGKEFKTEKNKENKLMLNNHYCFNVKII Y SEQ ID NO:74 MKLTRRRISGNSVDQKITAAFYRDMSQGLLYYDSEDNDCTDKVIESMDFERSWRGRILKNGEDDKNPFYMFV KGLVGSNDKIVCEPIDVDSDPDNLDILINKNLTGFGRNLKAPDSNDTLENLIRKIQAGIPEEEVLPELKKIKEMIQ KDIVNRKEQLLKSIKNNRIPFSLEGSKLVPSTKKMKWLFKLIDVPNKTFNEKMLEKYWEIYDYDKLKANITNR LDKTDKKARSISRAVSEELREYHKNLRTNYNRFVSGDRPAAGLDNGGSAKYNPDKEEFLLFLKEVEQYFKKY FPVKSKHSNKSKDKSLVDKYKNYCSYKVVKKEVNRSIINQLVAGLIQQGKLLYYFYYNDTWQEDFLNSYGLS YIQVEEAFKKSVMTSLSWGINRLTSFFIDDSNTVKFDDITTKKAKEAIESNYFNKLRTCSRMQDHFKEKLAFFY PVYVKDKKDRPDDDIENLIVLVKNAIESVSYLRNRTFHFKESSLLELLKELDDKNSGQNKIDYSVAAEFIKRDIE NLYDVFREQIRSLGIAEYYKADMISDCFKTCGLEFALYSPKNSLMPAFKNVYKRGANLNKAYIRDKGPKETGD QGQNSYKALEEYRELTWYIEVKNNDQSYNAYKNLLQLIYYHAFLPEVRENEALITDFINRTKEWNRKETEERL NTKNNKKHKNFDENDDITVNTYRYESIPDYQGESLDDYLKVLQRKQMARAKEVNEKEEGNNNYIQFIRDVVV WAFGAYLENKLKNYKNELQPPLSKENIGLNDTLKELFPEEKVKSPFNIKCRFSISTFIDNKGKSTDNTSAEAVKT DGKEDEKDKKNIKRKDLLCFYLFLRLLDENEICKLQHQFIKYRCSLKERRFPGNRTKLEKETELLAELEELMEL VRFTMPSIPEISAKAESGYDTMIKKYFKDFIEKKVFKNPKTSNLYYHSDSKTPVTRKYMALLMRSAPLHLYKDI FKGYYLITKKECLEYIKLSNIIKDYQNSLNELHEQLERIKLKSEKQNGKDSLYLDKKDFYKVKEYVENLEQVAR YKHLQHKINFESLYRIFRIHVDIAARMVGYTQDWERDMHFLFKALVYNGVLEERRFEAIFNNNDDNNDGRIV KKIQNNLNNKNRELVSMLCWNKKLNKNEFGAIIWKRNPIAHLNHFTQTEQNSKSSLESLINSLRILLAYDRKRQ NAVTKTINDLLLNDYHIRIKWEGRVDEGQIYFNIKEKEDIENEPIIHLKHLHKKDCYIYKNSYMFDKQKEWICN GIKEEVYDKSILKCIGNLFKFDYEDKNKSSANPKHT SEQ ID NO:75 MKITKMRVDGRTIVMERTSKEGQLGYEGIDGNKTTEIIFDKKKESFYKSILNKTVRKPDEKEKNRRKQAINKAI NKEITELMLAVLHQEVPSQKLHNLKSLNTESLTKLFKPKFQNMISYPPSKGAEHVQFCLTDIAVPAIRDLDEIKP DWGIFFEKLKPYTDWAESYIHYKQTTIQKSIEQNKIQSPDSPRKLVLQKYVTAFLNGEPLGLDLVAKKYKLAD LAESFKLVDLNEDKSANYKIKACLQQHQRNILDELKEDPELNQYGIEVKKYIQRYFPIKRAPNRSKHARADFLK KELIESTVEQQFKNAVYHYVLEQGKMEAYELTDPKTKDLQDIRSGEAFSFKFINACAFASNNLKMILNPECEK DILGKGNFKKNLPNSTTRSDVVKKMIPFFSDELQNVNFDEAIWAIRGSIQQIRNEVYHCKKHSWKSILKIKGFEF EPNNMKYADSDMQKLMDKDIAKIPEFIEEKLKSSGVVRFYRHDELQSIWEMKQGFSLLTTNAPFVPSFKRVYA KGHDYQTSKNRYYNLDLTTFDILEYGEEDFRARYFLTKLVYYQQFMPWFTADNNAFRDAANFVLRLNKNRQ QDAKAFINIREVEEGEMPRDYMGYVQGQIAIHEDSIEDTPNHFEKFISQVFIKGFDRHMRSANLKFIKNPRNQG LEQSEIEEMSFDIKVEPSFLKNKDDYIAFWIFCKMLDARHLSELRNEMIKYDGHLTGEQEIIGLALLGVDSREND WKQFFSSEREYEKIMKGYVVEELYQREPYRQSDGKTPILFRGVEQARKYGTETVIQRLFDANPEFKVSKCNLA EWERQKETIEETIKRRKELHNEWAKNPKKPQNNAFFKEYKECCDAIDAYNWHKNKTTLAYVNELHHLLIEIL GRYVGYVAIADRDFQCMANQYFKHSGITERVEYWGDNRLKSIKKLDTFLKKEGLFVSEKNARNHIAHLNYLS LKSECTLLYLSERLREIFKYDRKLKNAVSKSLIDILDRHGMSVVFANLKENKHRLVIKSLEPKKLRHLGGKKID GGYIETNQVSEEYCGIVKRLLEMAttorney Docket No.204606-0174-00WO SEQ ID NO:76 MQISKVNHKHVAVGQKDRERITGFIYNDPVGDEKSLEDVVAKRANDTKVLFNVFNTKDLYDSQESDKSEKDK EIISKGAKFVAKSFNSAITILKKQNKIYSTLTSQQVIKELKDKFGGARIYDDDIEEALTETLKKSFRKENVRNSIK VLIENAAGIRSSLSKDEEELIQEYFVKQLVEEYTKTKLQKNVVKSIKNQNMVIQPDSDSQVLSLSESRREKQSSA VSSDTLVNCKEKDVLKAFLTDYAVLDEDERNSLLWKLRNLVNLYFYGSESIRDYSYTKEKSVWKEHDEQKA NKTLFIDEICHITKIGKNGKEQKVLDYEENRSRCRKQNINYYRSALNYAKNNTSGIFENEDSNHFWIHLIENEVE RLYNGIENGEEFKFETGYISEKVWKAVINHLSIKYIALGKAVYNYAMKELSSPGDIEPGKIDDSYINGITSFDYEI IKAEESLQRDISMNVVFATNYLACATVDTDKDFLLFSKEDIRSCTKKDGNLCKNIMQFWGGYSTWKNFCEEY LKDDKDALELLYSLKSMLYSMRNSSFHFSTENVDNGSWDTELIGKLFEEDCNRAARIEKEKFYNNNLHMFYSS SLLEKVLERLYSSHHERASQVPSFNRVFVRKNFPSSLSEQRITPKFTDSKDEQIWQSAVYYLCKEIYYNDFLQSK EAYKLFREGVKNLDKNDINNQKAADSFKQAVVYYGKAIGNATLSQVCQAIMTEYNRQNNDGLKKKSAYAE KQNSNKYKHYPLFLKQVLQSAFWEYLDENKEIYGFISAQIHKSNVEIKAEDFIANYSSQQYKKLVDKVKKTPE LQKWYTLGRLINPRQANQFLGSIRNYVQFVKDIQRRAKENGNPIRNYYEVLESDSIIKILEMCTKLNGTTSNDIH DYFRDEDEYAEYISQFVNFGDVHSGAALNAFCNSESEGKKNGIYYDGINPIVNRNWVLCKLYGSPDLISKIISR VNENMIHDFHKQEDLIREYQIKGICSNKKEQQDLRTFQVLKNRVELRDIVEYSEIINELYGQLIKWCYLRERDL MYFQLGFHYLCLNNASSKEADYIKINVDDRNISGAILYQIAAMYINGLPVYYKKDDMYVALKSGKKASDELN SNEQTSKKINYFLKYGNNILGDKKDQLYLAGLELFENVAEHENIIIFRNEIDHFHYFYDRDRSMLDLYSEVFDR FFTYDMKLRKNVVNMLYNILLDHNIVSSFVFETGEKKVGRGDSEVIKPSAKIRLRANNGVSSDVFTYKVGSKD ELKIATLPAKNEEFLLNVARLIYYPDMEAVSENMVREGVVKVEKSNDKKGKISRGSNTRSSNQSKYNNKSKN RMNYSMGSIFEKMDLKFD SEQ ID NO:77 MKISKVREENRGAKLTVNAKTAVVSENRSQEGILYNDPSRYGKSRKNDEDRDRYIESRLKSSGKLYRIFNEDK NKRETDELQWFLSEIVKKINRRNGLVLSDMLSVDDRAFEKAFEKYAELSYTNRRNKVSGSPAFETCGVDAAT AERLKGIISETNFINRIKNNIDNKVSEDIIDRIIAKYLKKSLCRERVKRGLKKLLMNAFDLPYSDPDIDVQRDFID YVLEDFYHVRAKSQVSRSIKNMNMPVQPEGDGKFAITVSKGGTESGNKRSAEKEAFKKFLSDYASLDERVRD DMLRRMRRLVVLYFYGSDDSKLSDVNEKFDVWEDHAARRVDNREFIKLPLENKLANGKTDKDAERIRKNTV KELYRNQNIGCYRQAVKAVEEDNNGRYFDDKMLNMFFIHRIEYGVEKIYANLKQVTEFKARTGYLSEKIWKD LINYISIKYIAMGKAVYNYAMDELNASDKKEIELGKISEEYLSGISSFDYELIKAEEMLQRETAVYVAFAARHLS SQTVELDSENSDFLLLKPKGTMDKNDKNKLASNNILNFLKDKETLRDTILQYFGGHSLWTDFPFDKYLAGGK DDVDFLTDLKDVIYSMRNDSFHYATENHNNGKWNKELISAMFEHETERMTVVMKDKFYSNNLPMFYKNDD LKKLLIDLYKDNVERASQVPSFNKVFVRKNFPALVRDKDNLGIELDLKADADKGENELKFYNALYYMFKEIY YNAFLNDKNVRERFITKATKVADNYDRNKERNLKDRIKSAGSDEKKKLREQLQNYIAENDFGQRIKNIVQVN PDYTLAQICQLIMTEYNQQNNGCMQKKSAARKDINKDSYQHYKMLLLVNLRKAFLEFIKENYAFVLKPYKHD LCDKADFVPDFAKYVKPYAGLISRVAGSSELQKWYIVSRFLSPAQANHMLGFLHSYKQYVWDIYRRASETGT EINHSIAEDKIAGVDITDVDAVIDLSVKLCGTISSEISDYFKDDEVYAEYISSYLDFEYDGGNYKDSLNRFCNSD AVNDQKVALYYDGEHPKLNRNIILSKLYGERRFLEKITDRVSRSDIVEYYKLKKETSQYQTKGIFDSEDEQKNI KKFQEMKNIVEFRDLMDYSEIADELQGQLINWIYLRERDLMNFQLGYHYACLNNDSNKQATYVTLDYQGKK NRKINGAILYQICAMYINGLPLYYVDKDSSEWTVSDGKESTGAKIGEFYRYAKSFENTSDCYASGLEIFENISEH DNITELRNYIEHFRYYSSFDRSFLGIYSEVFDRFFTYDLKYRKNVPTILYNILLQHFVNVRFEFVSGKKMIGIDKK DRKIAKEKECARITIREKNGVYSEQFTYKLKNGTVYVDARDKRYLQSIIRLLFYPEKVNMDEMIEVKEKKKPS DNNTGKGYSKRDRQQDRKEYDKYKEKKKKEGNFLSGMGGNINWDEINAQLKN SEQ ID NO:78 MKVTKVGGISHKKYTSEGRLVKSESEENRTDERLSALLNMRLDMYIKNPSSTETKENQKRIGKLKKFFSNKMV YLKDNTLSLKNGKKENIDREYSETDILESDVRDKKNFAVLKKIYLNENVNSEELEVFRNDIKKKLNKINSLKYS FEKNKANYQKINENNIEKVEGKSKRNIIYDYYRESAKRDAYVSNVKEAFDKLYKEEDIAKLVLEIENLTKLEK YKIREFYHEIIGRKNDKENFAKIIYEEIQNVNNMKELIEKVPDMSELKKSQVFYKYYLDKEELNDKNIKYAFCH FVEIEMSQLLKNYVYKRLSNISNDKIKRIFEYQNLKKLIENKLLNKLDTYVRNCGKYNYYLQDGEIATSDFIAR NRQNEAFLRNIIGVSSVAYFSLRNILETENENDITGRMRGKTVKNNKGEEKYVSGEVDKIYNENKKNEVKENL KMFYSYDFNMDNKNEIEDFFANIDEAISSIRHGIVHFNLELEGKDIFAFKNIAPSEISKKMFQNEINEKKLKLKIF RQLNSANVFRYLEKYKILNYLKRTRFEFVNKNIPFVPSFTKLYSRIDDLKNSLGIYWKTPKTNDDNKTKEIIDAQ IYLLKNIYYGEFLNYFMSNNGNFFEISKEIIELNKNDKRNLKTGFYKLQKFEDIQEKIPKEYLANIQSLYMINAG NQDEEEKDTYIDFIQKIFLKGFMTYLANNGRLSLIYIGSDEETNTSLAEKKQEFDKFLKKYEQNNNIKIPYEINEF LREIKLGNILKYTERLNMFYLILKLLNHKELTNLKGSLEKYQSANKEEAFSDQLELINLLNLDNNRVTEDFELE ADEIGKFLDFNGNKVKDNKELKKFDTNKIYFDGENIIKHRAFYNIKKYGMLNLLEKIADKAGYKISIEELKKYS NKKNEIEKNHKMQENLHRKYARPRKDEKFTDEDYESYKQAIENIEEYTHLKNKVEFNELNLLQGLLLRILHRL VGYTSIWERDLRFRLKGEFPENQYIEEIFNFENKKNVKYKGGQIVEKYIKFYKELHQNDEVKINKYSSANIKVL KQEKKDLYIRNYIAHFNYIPHAEISLLEVLENLRKLLSYDRKLKNAVMKSVVDILKEYGFVATFKIGADKKIGI QTLESEKIVHLKNLKKKKLMTDRNSEELCKLVKIMFEYKMEEKKSENAttorney Docket No.204606-0174-00WO SEQ ID NO:79 MWISIKTLIHHLGVLFFCDYMYNRREKKIIEVKTMRITKVEVDRKKVLISRDKNGGKLVYENEMQDNTEQIMH HKKSSFYKSVVNKTICRPEQKQMKKLVHGLLQENSQEKIKVSDVTKLNISNFLNHRFKKSLYYFPENSPDKSEE YRIEINLSQLLEDSLKKQQGTFICWESFSKDMELYINWAENYISSKTKLIKKSIRNNRIQSTESRSGQLMDRYMK DILNKNKPFDIQSVSEKYQLEKLTSALKATFKEAKKNDKEINYKLKSTLQNHERQIIEELKENSELNQFNIEIRK HLETYFPIKKTNRKVGDIRNLEIGEIQKIVNHRLKNKIVQRILQEGKLASYEIESTVNSNSLQKIKIEEAFALKFIN ACLFASNNLRNMVYPVCKKDILMIGEFKNSFKEIKHKKFIRQWSQFFSQEITVDDIELASWGLRGAIAPIRNEIIH LKKHSWKKFFNNPTFKVKKSKIINGKTKDVTSEFLYKETLFKDYFYSELDSVPELIINKMESSKILDYYSSDQLN QVFTIPNFELSLLTSAVPFAPSFKRVYLKGFDYQNQDEAQPDYNLKLNIYNEKAFNSEAFQAQYSLFKMVYYQ VFLPQFTTNNDLFKSSVDFILTLNKERKGYAKAFQDIRKMNKDEKPSEYMSYIQSQLMLYQKKQEEKEKINHF EKFINQVFIKGFNSFIEKNRLTYICHPTKNTVPENDNIEIPFHTDMDDSNIAFWLMCKLLDAKQLSELRNEMIKF SCSLQSTEEISTFTKAREVIGLALLNGEKGCNDWKELFDDKEAWKKNMSLYVSEELLQSLPYTQEDGQTPVIN RSIDLVKKYGTETILEKLFSSSDDYKVSAKDIAKLHEYDVTEKIAQQESLHKQWIEKPGLARDSAWTKKYQNV INDISNYQWAKTKVELTQVRHLHQLTIDLLSRLAGYMSIADRDFQFSSNYILERENSEYRVTSWILLSENKNKN KYNDYELYNLKNASIKVSSKNDPQLKVDLKQLRLTLEYLELFDNRLKEKRNNISHFNYLNGQLGNSILELFDD ARDVLSYDRKLKNAVSKSLKEILSSHGMEVTFKPLYQTNHHLKIDKLQPKKIHHLGEKSTVSSNQVSNEYCQL VRTLLTMK SEQ ID NO:80 MGNLFGHKRWYEVRDKKDFKIKRKVKVKRNYDGNKYILNINENNNKEKIDNNKFIRKYINYKKNDNILKEFT RKFHAGNILFKLKGKEGIIRIENNDDFLETEEVVLYIEAYGKSEKLKALGITKKKIIDEAIRQGITKDDKKIEIKRQ ENEEEIEIDIRDEYTNKTLNDCSIILRIIENDELETKKSIYEIFKNINMSLYKIIEKIIENETEKVFENRYYEEHLREK LLKDDKIDVILTNFMEIREKIKSNLEILGFVKFYLNVGGDKKKSKNKKMLVEKILNINVDLTVEDIADFVIKELE FWNITKRIEKVKKVNNEFLEKRRNRTYIKSYVLLDKHEKFKIERENKKDKIVKFFVENIKNNSIKEKIEKILAEF KIDELIKKLEKELKKGNCDTEIFGIFKKHYKVNFDSKKFSKKSDEEKELYKIIYRYLKGRIEKILVNEQKVRLKK MEKIEIEKILNESILSEKILKRVKQYTLEHIMYLGKLRHNDIDMTTVNTDDFSRLHAKEELDLELITFFASTNMEL NKIFSRENINNDENIDFFGGDREKNYVLDKKILNSKIKIIRDLDFIDNKNNITNNFIRKFTKIGTNERNRILHAISKE RDLQGTQDDYNKVINIIQNLKISDEEVSKALNLDVVFKDKKNIITKINDIKISEENNNDIKYLPSFSKVLPEILNLY RNNPKNEPFDTIETEKIVLNALIYVNKELYKKLILEDDLEENESKNIFLQELKKTLGNIDEIDENIIENYYKNAQIS ASKGNNKAIKKYQKKVIECYIGYLRKNYEELFDFSDFKMNIQEIKKQIKDINDNKTYERITVKTSDKTIVINDDF EYIISIFALLNSNAVINKIRNRFFATSVWLNTSEYQNIIDILDEIMQLNTLRNECITENWNLNLEEFIQKMKEIEKD FDDFKIQTKKEIFNNYYEDIKNNILTEFKDDINGCDVLEKKLEKIVIFDDETKFEIDKKSNILQDEQRKLSNINKK DLKKKVDQYIKDKDQEIKSKILCRIIFNSDFLKKYKKEIDNLIEDMESENENKFQEIYYPKERKNELYIYKKNLF LNIGNPNFDKIYGLISNDIKMADAKFLFNIDGKNIRKNKISEIDAILKNLNDKLNGYSKEYKEKYIKKLKENDDF FAKNIQNKNYKSFEKDYNRVSEYKKIRDLVEFNYLNKIESYLIDINWKLAIQMARFERDMHYIVNGLRELGIIK LSGYNTGISRAYPKRNGSDGFYTTTAYYKFFDEESYKKFEKICYGFGIDLSENSEINKPENESIRNYISHFYIVRN PFADYSIAEQIDRVSNLLSYSTRYNNSTYASVFEVFKKDVNLDYDELKKKFKLIGNNDILERLMKPKKVSVLEL ESYNSDYIKNLIIELLTKIENTNDTL SEQ ID NO:81 MGNLFGHKRWYEVRDKKDFKIKRKVKVKRNYDGNKYILNINENNNKEKIDNNKFIGEFVNYKKNNNVLKEF KRKFHAGNILFKLKGKEEIIRIENNDDFLETEEVVLYIEVYGKSEKLKALEITKKKIIDEAIRQGITKDDKKIEIKR QENEEEIEIDIRDEYTNKTLNDCSIILRIIENDELETKKSIYEIFKNINMSLYKIIEKIIENETEKVFENRYYEEHLRE KLLKDNKIDVILTNFMEIREKIKSNLEIMGFVKFYLNVSGDKKKSENKKMFVEKILNTNVDLTVEDIVDFIVKE LKFWNITKRIEKVKKFNNEFLENRRNRTYIKSYVLLDKHEKFKIERENKKDKIVKFFVENIKNNSIKEKIEKILAE FKINELIKKLEKELKKGNCDTEIFGIFKKHYKVNFDSKKFSNKSDEEKELYKIIYRYLKGRIEKILVNEQKVRLK KMEKIEIEKILNESILSEKILKRVKQYTLEHIMYLGKLRHNDIVKMTVNTDDFSRLHAKEELDLELITFFASTNM ELNKIFNGKEKVTDFFGFNLNGQKITLKEKVPSFKLNILKKLNFINNENNIDEKLSHFYSFQKEGYLLRNKILHN SYGNIQETKNLKGEYENVEKLIKELKVSDEEISKSLSLDVIFEGKVDIINKINSLKIGEYKDKKYLPSFSKIVLEIT RKFREINKDKLFDIESEKIILNAVKYVNKILYEKITSNEENEFLKTLPDKLVKKSNNKKENKNLLSIEEYYKNAQ VSSSKGDKKAIKKYQNKVTNAYLEYLENTFTEIIDFSKFNLNYDEIKTKIEERKDNKSKIIIDSISTNINITNDIEYII SIFALLNSNTYINKIRNRFFATSVWLEKQNGTKEYDYENIISILDEVLLINLLRENNITDILDLKNAIIDAKIVEND ETYIKNYIFESNEEKLKKRLFCEELVDKEDIRKIFEDENFKFKSFIKKNEIGNFKINFGILSNLECNSEVEAKKIIGK NSKKLESFIQNIIDEYKSNIRTLFSSEFLEKYKEEIDNLVEDTESENKNKFEKIYYPKEHKNELYIYKKNLFLNIGN PNFDKIYGLISKDIKNVDTKILFDDDIKKNKISEIDAILKNLNDKLNGYSNDYKAKYVNKLKENDDFFAKNIQN ENYSSFGEFEKDYNKVSEYKKIRDLVEFNYLNKIESYLIDINWKLAIQMARFERDMHYIVNGLRELGIIKLSGY NTGISRAYPKRNGSDGFYTTTAYYKFFDEESYKKFEKICYGFGIDLSENSEINKPENESIRNYISHFYIVRNPFAD YSIAEQIDRVSNLLSYSTRYNNSTYASVFEVFKKDVNLDYDELKKKFRLIGNNDILERLMKPKKVSVLELESYN SDYIKNLIIELLTKIENTNDTLAttorney Docket No.204606-0174-00WO SEQ ID NO:82 MKVTKVDGISHKKYIEEGKLVKSTSEENRTSERLSELLSIRLDIYIKNPDNASEEENRIRRENLKKFFSNKVLHL KDSVLYLKNRKEKNAVQDKNYSEEDISEYDLKNKNSFSVLKKILLNEDVNSEELEIFRKDVEAKLNKINSLKYS FEENKANYQKINENNVEKVGGKSKRNIIYDYYRESAKRNDYINNVQEAFDKLYKKEDIEKLFFLIENSKKHEK YKIREYYHKIIGRKNDKENFAKIIYEEIQNVNNIKELIEKIPDMSELKKSQVFYKYYLDKEELNDKNIKYAFCHF VEIEMSQLLKNYVYKRLSNISNDKIKRIFEYQNLKKLIENKLLNKLDTYVRNCGKYNYYLQVGEIATSDFIARN RQNEAFLRNIIGVSSVAYFSLRNILETENENDITGRMRGKTVKNNKGEEKYVSGEVDKIYNENKQNEVKENLK MFYSYDFNMDNKNEIEDFFANIDEAISSIRHGIVHFNLELEGKDIFAFKNIAPSEISKKMFQNEINEKKLKLKIFK QLNSANVFNYYEKDVIIKYLKNTKFNFVNKNIPFVPSFTKLYNKIEDLRNTLKFFWSVPKDKEEKDAQIYLLKN IYYGEFLNKFVKNSKVFFKITNEVIKINKQRNQKTGHYKYQKFENIEKTVPVEYLAIIQSREMINNQDKEEKNT YIDFIQQIFLKGFIDYLNKNNLKYIESNNNNDNNDIFSKIKIKKDNKEKYDKILKNYEKHNRNKEIPHEINEFVRE IKLGKILKYTENLNMFYLILKLLNHKELTNLKGSLEKYQSANKEETFSDELELINLLNLDNNRVTEDFELEANEI GKFLDFNENKIKDRKELKKFDTNKIYFDGENIIKHRAFYNIKKYGMLNLLEKIADKAKYKISLKELKEYSNKKN EIEKNYTMQQNLHRKYARPKKDEKFNDEDYKEYEKAIGNIQKYTHLKNKVEFNELNLLQGLLLKILHRLVGY TSIWERDLRFRLKGEFPENHYIEEIFNFDNSKNVKYKSGQIVEKYINFYKELYKDNVEKRSIYSDKKVKKLKQE KKDLYIRNYIAHFNYIPHAEISLLEVLENLRKLLSYDRKLKNAIMKSIVDILKEYGFVATFKIGADKKIEIQTLES EKIVHLKNLKKKKLMTDRNSEELCELVKVMFEYKALE SEQ ID NO:83 MKVTKVDGISHKKYIEEGKLVKSTSEENRTSERLSELLSIRLDIYIKNPDNASEEENRIRRENLKKFFSNKVLHL KDSVLYLKNRKEKNAVQDKNYSEEDISEYDLKNKNSFSVLKKILLNEDVNSEELEIFRKDVEAKLNKINSLKYS FEENKANYQKINENNVEKVGGKSKRNIIYDYYRESAKRNDYINNVQEAFDKLYKKEDIEKLFFLIENSKKHEK YKIREYYHKIIGRKNDKENFAKIIYEEIQNVNNIKELIEKIPDMSELKKSQVFYKYYLDKEELNDKNIKYAFCHF VEIEMSQLLKNYVYKRLSNISNDKIKRIFEYQNLKKLIENKLLNKLDTYVRNCGKYNYYLQVGEIATSDFIARN RQNEAFLRNIIGVSSVAYFSLRNILETENENDITGRMRGKTVKNNKGEEKYVSGEVDKIYNENKQNEVKENLK MFYSYDFNMDNKNEIEDFFANIDEAISSIRHGIVHFNLELEGKDIFAFKNIAPSEISKKMFQNEINEKKLKLKIFK QLNSANVFNYYEKDVIIKYLKNTKFNFVNKNIPFVPSFTKLYNKIEDLRNTLKFFWSVPKDKEEKDAQIYLLKN IYYGEFLNKFVKNSKVFFKITNEVIKINKQRNQKTGHYKYQKFENIEKTVPVEYLAIIQSREMINNQDKEEKNT YIDFIQQIFLKGFIDYLNKNNLKYIESNNNNDNNDIFSKIKIKKDNKEKYDKILKNYEKHNRNKEIPHEINEFVRE IKLGKILKYTENLNMFYLILKLLNHKELTNLKGSLEKYQSANKEETFSDELELINLLNLDNNRVTEDFELEANEI GKFLDFNENKIKDRKELKKFDTNKIYFDGENIIKHRAFYNIKKYGMLNLLEKIADKAKYKISLKELKEYSNKKN EIEKNYTMQQNLHRKYARPKKDEKFNDEDYKEYEKAIGNIQKYTHLKNKVEFNELNLLQGLLLKILHRLVGY TSIWERDLRFRLKGEFPENHYIEEIFNFDNSKNVKYKSGQIVEKYINFYKELYKDNVEKRSIYSDKKVKKLKQE KKDLYIRNYIAHFNYIPHAEISLLEVLENLRKLLSYDRKLKNAIMKSIVDILKEYGFVATFKIGADKKIEIQTLES EKIVHLKNLKKKKLMTDRNSEELCELVKVMFEYKALE SEQ ID NO:84 MLALLHQEVPSQKLHNLKSLNTESLTKLFKPKFQNMISYPPSKGAEHVQFCLTDIAVPAIRDLDEIKPDWGIFFE KLKPYTDWAESYIHYKQTTIQKSIEQNKIQSPDSPRKLVLQKYVTAFLNGEPLGLDLVAKKYKLADLAESFKV VDLNEDKSANYKIKACLQQHQRNILDELKEDPELNQYGIEVKKYIQRYFPIKRAPNRSKHARADFLKKELIEST VEQQFKNAVYHYVLEQGKMEAYELTDPKTKDLQDIRSGEAFSFKFINACAFASNNLKMILNPECEKDILGKGD FKKNLPNSTTQSDVVKKMIPFFSDEIQNVNFDEAIWAIRGSIQQIRNEVYHCKKHSWKSILKIKGFEFEPNNMK YTDSDMQKLMDKDIAKIPDFIEEKLKSSGIIRFYSHDKLQSIWEMKQGFSLLTTNAPFVPSFKRVYAKGHDYQT SKNRYYDLGLTTFDILEYGEEDFRARYFLTKLVYYQQFMPWFTADNNAFRDAANFVLRLNKNRQQDAKAFIN IREVEEGEMPRDYMGYVQGQIAIHEDSTEDTPNHFEKFISQVFIKGFDSHMRSADLKFIKNPRNQGLEQSEIEEM SFDIKVEPSFLKNKDDYIAFWTFCKMLDARHLSELRNEMIKYDGHLTGEQEIIGLALLGVDSRENDWKQFFSSE REYEKIMKGYVGEELYQREPYRQSDGKTPILFRGVEQARKYGTETVIQRLFDASPEFKVSKCNITEWERQKETI EETIERRKELHNEWEKNPKKPQNNAFFKEYKECCDAIDAYNWHKNKTTLVYVNELHHLLIEILGRYVGYVAI ADRDFQCMANQYFKHSGITERVEYWGDNRLKSIKKLDTFLKKEGLFVSEKNARNHIAHLNYLSLKSECTLLYL SERLREIFKYDRKLKNAVSKSLIDILDRHGMSVVFANLKENKHRLVIKSLEPKKLRHLGEKKIDNGYIETNQVS EEYCGIVKRLLEI SEQ ID NO:85 MEDDKKTTGSISYELKDKHFWAAFLNLARHNVYITINHINKLLEIREIDNDEKVLDIKTLWQKGNKDLNQKAR LRELMTKHFPFLETAIYTKNKEDKKEVKQEKQAEAQSLESLKDCLFLFLDKLQEARNYYSHYKYSEFSKEPEF EEGLLEKMYNIFGNNIQLVINDYQHNKDINPDEDFKHLDRKGQFKYSFADNEGNITESGLLFFVSLFLEKKDAI WMQQKLNGFKDNLENKKKMTHEVFCRSRILMPKLRLESTQTQDWILLDMLNELIRCPKSLYERLQGDDREKF KVPFDPADEDYNAEQEPFKNTLIRHQDRFPYFVLRYFDYNEIFKNLRFQIDLGTYHFSIYKKLIGGQKEDRHLT HKLYGFERIQEFAKQNRPDEWKAIVKDLDTYETSNKRYISETTPHYHLENQKIGIRFRNGNKEIWPSLKTNDEN NEKSKYKLDKQYQAEAFLSVHELLPMMFYYLLLKKEKPNNDEINASIVEGFIKREIRNIFKLYDAFANGEINNI DDLEKYCADKGIPKRHLPKQMVAILYDEHKDMVKEAKRKQKEMVKDTKKLLATLEKQTQKEKEDDGRNVK LLKSGEIARWLVNDMMRFQPVQKDNEGKPLNNSKANSTEYQMLQRSLALYNNEEKPTRYFRQVNLIESNNPH PFLKWTKWEECNNILTFYYSYLTKKIEFLNKLKPEDWKKNQYFLKLKEPKTNRETLVQGWKNGFNLPRGIFTE PIREWFKRHQNNSKEYEKVEALDRVGLVTKVIPLFFKEEYFKDKEENFKEDTQKEINDCVQPFYNFPYNVGNI HKPKEKDFLHREERIELWDKKKDKFKGYKEKIKSKKLTEKDKEEFRSYLEFQSWNKFERELRLVRNQDIVTW LLCKELIDKLKIDELNIEELKKLRLNNIDTDTAKKEKNNILNRVMPMELPVTVYEIDDSHKIVKDKPLHTIYIKE AETKLLKQGNFKALVKDRRLNGLFSFVKTNSEAESKRNPISKLRVEYELGEYQEARIEIIQDMLALEEKLINKY KDLPTNKFSEMLNSWLEGKDEADKARFQNDVDFLIAVRNAFSHNQYPMHNKIEFANIKPFSLYTANNSEEKGL GIANQLKDKTKETTDKIKKIEKPIETKEAttorney Docket No.204606-0174-00WO SEQ ID NO:86 MQKQDKLFVDRKKNAIFAFPKYITIMENKEKPEPIYYELTDKHFWAAFLNLARHNVYTTINHINRRLEIAELKD DGYMMGIKGSWNEQAKKLDKKVRLRDLIMKHFPFLEAAAYEMTNSKSPNNKEQREKEQSEALSLNNLKNVL FIFLEKLQVLRNYYSHYKYSEESPKPIFETSLLKNMYKVFDANVRLVKRDYMHHENIDMQRDFTHLNRKKQV GRTKNIIDSPNFHYHFADKEGNMTIAGLLFFVSLFLDKKDAIWMQKKLKGFKDGRNLREQMTNEVFCRSRISL PKLKLENVQTKDWMQLDMLNELVRCPKSLYERLREKDRESFKVPFDIFSDDYNAEEEPFKNTLVRHQDRFPY FVLRYFDLNEIFEQLRFQIDLGTYHFSIYNKRIGDEDEVRHLTHHLYGFARIQDFAPQNQPEEWRKLVKDLDHF ETSQEPYISKTAPHYHLENEKIGIKFCSAHNNLFPSLQTDKTCNGRSKFNLGTQFTAEAFLSVHELLPMMFYYL LLTKDYSRKESADKVEGIIRKEISNIYAIYDAFANNEINSIADLTRRLQNTNILQGHLPKQMISILKGRQKDMGK EAERKIGEMIDDTQRRLDLLCKQTNQKIRIGKRNAGLLKSGKIADWLVNDMMRFQPVQKDQNNIPINNSKANS TEYRMLQRALALFGSENFRLKAYFNQMNLVGNDNPHPFLAETQWEHQTNILSFYRNYLEARKKYLKGLKPQ NWKQYQHFLILKVQKTNRNTLVTGWKNSFNLPRGIFTQPIREWFEKHNNSKRIYDQILSFDRVGFVAKAIPLYF AEEYKDNVQPFYDYPFNIGNRLKPKKRQFLDKKERVELWQKNKELFKNYPSEKKKTDLAYLDFLSWKKFERE LRLIKNQDIVTWLMFKELFNMATVEGLKIGEIHLRDIDTNTANEESNNILNRIMPMKLPVKTYETDNKGNILKE RPLATFYIEETETKVLKQGNFKALVKDRRLNGLFSFAETTDLNLEEHPISKLSVDLELIKYQTTRISIFEMTLGLE KKLIDKYSTLPTDSFRNMLERWLQCKANRPELKNYVNSLIAVRNAFSHNQYPMYDATLFAEVKKFTLFPSVDT KKIELNIAPQLLEIVGKAIKEIEKSENKN SEQ ID NO:87 MTEQNEKPYNGTYYTLEDKHFWAAFLNLARHNAYITLAHIDRQLAYSKADITNDEDILFFKGQWKNLDNDLE RKARLRSLILKHFSFLEGAAYGKKLFESQSSGNKSSKKKELSKKEKEELQANALSLDNLKSILFDFLQKLKDFR NYYSHYRHPESSELPLFDGNMLQRLYNVFDVSVQRVKRDHEHNDKVDPHRHFNHLVRKGKKDKYGNNDNP FFKHHFVDREGTVTEAGLLFFVSLFLEKRDAIWMQKKIRGFKGGTEAYQQMTNEVFCRSRISLPKLKLESLRT DDWMLLDMLNELVRCPKSLYDRLREEDRARFRVPVDILSDEDDTDGTEEDPFKNTLVRHQDRFPYFALRYFD LKKVFTSLRFHIDLGTYHFAIYKKNIGEQPEDRHLTRNLYGFGRIQDFAEEHRPEEWKRLVRDLDYFETGDKPY ITQTTPHYHIEKGKIGLRFVPEGQHLWPSPEVGATRTGRSKYAQDKRLTAEAFLSVHELMPMMFYYFLLREKY SEEVSAEKVQGRIKRVIEDVYAVYDAFARDEINTRDELDACLADKGIRRGHLPRQMIAILSQEHKDMEEKVRK KLQEMIADTDHRLDMLDRQTDRKIRIGRKNAGLPKSGVVADWLVRDMMRFQPVAKDTSGKPLNNSKANSTE YRMLQRALALFGGEKERLTPYFRQMNLTGGNNPHPFLHETRWESHTNILSFYRSYLEARKAFLQSIGRSDRVE NHRFLLLKEPKTDRQTLVAGWKGEFHLPRGIFTEAVRDCLIEMGYDEVGSYKEVGFMAKAVPLYFERASKDR VQPFYDYPFNVGNSLKPKKGRFLSKEKRAEEWESGKERFRLAKLKKEILEAKEHPYHDFKSWQKFERELRLV KNQDIITWMMCRDLMEENKVEGLDTGTLYLKDIRTDVQEQGSLNVLNRVKPMRLPVVVYRADSRGHVHKE QAPLATVYIEERDTKLLKQGNFKSFVKDRRLNGLFSFVDTGALAMEQYPISKLRVEYELAKYQTARVCAFEQT LELEESLLTRYPHLPDKNFRKMLESWSDPLLDKWPDLHGNVRLLIAVRNAFSHNQYPMYDETLFSSIRKYDPS SPDAIEERMGLNIAHRLSEEVKQAKEMVERIIQA SEQ ID NO:88 MTEQSERPYNGTYYTLEDKHFWAAFLNLARHNAYITLTHIDRQLAYSKADITNDQDVLSFKALWKNFDNDLE RKSRLRSLILKHFSFLEGAAYGKKLFESKSSGNKSSKNKELTKKEKEELQANALSLDNLKSILFDFLQKLKDFR NYYSHYRHSGSSELPLFDGNMLQRLYNVFDVSVQRVKIDHEHNDEVDPHYHFNHLVRKGKKDRYGHNDNPS FKHHFVDGEGMVTEAGLLFFVSLFLEKRDAIWMQKKIRGFKGGTETYQQMTNEVFCRSRISLPKLKLESLRMD DWMLLDMLNELVRCPKPLYDRLREDDRACFRVPVDILPDEDDTDGGGEDPFKNTLVRHQDRFPYFALRYFDL KKVFTSLRFHIDLGTYHFAIYKKMIGEQPEDRHLTRNLYGFGRIQDFAEEHRPEEWKRLVRDLDYFETGDKPYI SQTSPHYHIEKGKIGLRFMPEGQHLWPSPEVGTTRTGRSKYAQDKRLTAEAFLSVHELMPMMFYYFLLREKYS EEVSAERVQGRIKRVIEDVYAVYDAFARDEINTRDELDACLADKGIRRGHLPRQMIAILSQEHKDMEEKIRKK LQEMMADTDHRLDMLDRQTDRKIRIGRKNAGLPKSGVIADWLVRDMMRFQPVAKDASGKPLNNSKANSTE YRMLQRALALFGGEKERLTPYFRQMNLTGGNNPHPFLHETRWESHTNILSFYRSYLRARKAFLERIGRSDRVE NRPFLLLKEPKTDRQTLVAGWKGEFHLPRGIFTEAVRDCLIEMGHDEVASYKEVGFMAKAVPLYFERACEDR VQPFYDSPFNVGNSLKPKKGRFLSKEERAEEWERGKERFRDLEAWSYSAARRIEDAFAGIEYASPGNKKKIEQ LLRDLSLWEAFESKLKVRADRINLAKLKKEILEAQEHPYHDFKSWQKFERELRLVKNQDIITWMMCRDLMEE NKVEGLDTGTLYLKDIRPNVQEQGSLNVLNRVKPMRLPVVVYRADSRGHVHKEEAPLATVYIEERDTKLLKQ GNFKSFVKDRRLNGLFSFVDTGGLAMEQYPISKLRVEYELAKYQTARVCVFELTLRLEESLLTRYPHLPDESFR EMLESWSDPLLAKWPELHGKVRLLIAVRNAFSHNQYPMYDEAVFSSIRKYDPSSPDAIEERMGLNIAHRLSEE VKQAKETVERIIQAAttorney Docket No.204606-0174-00WO SEQ ID NO:89 MEDDKKTTDSIRYELKDKHFWAAFLNLARHNVYITVNHINKILEEDEINRDGYENTLENSWNEIKDINKKDRL SKLIIKHFPFLEATTYRQNPTDTTKQKEEKQAEAQSLESLKKSFFVFIYKLRDLRNHYSHYKHSKSLERPKFEED LQNKMYNIFDVSIQFVKEDYKHNTDINPKKDFKHLDRKRKGKFHYSFADNEGNITESGLLFFVSLFLEKKDAI WVQKKLEGFKCSNKSYQKMTNEVFCRSRMLLPKLRLESTQTQDWILLDMLNELIRCPKSLYERLQGVNRKKF YVSFDPADEDYDAEQEPFKNTLVRHQDRFPYFALRYFDYNEVFANLRFQIDLGTYHFSIYKKLIGGQKEDRHL THKLYGFERIQEFDKQNRPDEWKAIVKDSDTFKKKEEKEEEKPYISETTPHYHLENKKIGIAFKNHNIWPSTQT ELTNNKRKKYNLGTSIKAEAFLSVHELLPMMFYYLLLKTENTKNDNKVGGKKETKKQGKHKIEAIIESKIKDI YALYDAFANGEINSEDELKEYLKGKDIKIVHLPKQMIAILKNEHKDMAEKAEAKQEKMKLATENRLKTLDKQ LKGKIQNGKRYNSAPKSGEIASWLVNDMMRFQPVQKDENGESLNNSKANSTEYQLLQRTLAFFGSEHERLAP YFKQTKLIESSNPHPFLNDTEWEKCSNILSFYRSYLKARKNFLESLKPEDWEKNQYFLMLKEPKTNRETLVQG WKNGFNLPRGFFTEPIRKWFMEHWKSIKVDDLKRVGLVAKVTPLFFSEKYKDSVQPFYNYPFNVGDVNKPKE EDFLHREERIELWDKKKDKFKGYKAKKKFKEMTDKEKEEHRSYLEFQSWNKFERELRLVRNQDIVTWLLCTE LIDKLKIDELNIKELKKLRLKDINTDTAKKEKNNILNRVMPMELPVTVYKVNKGGYIIKNKPLHTIYIKEAETKL LKQGNFKALVKDRRLNGLFSFVKTPSEAESESNPISKLRVEYELGKYQNARLDIIEDMLALEKKLIDKYNSLDT DNFHNMLTGWLELKGEAKKARFQNDVKLLTAVRNAFSHNQYPMYDENLFGNIERFSLSSSNIIESKGLDIAAK LKEEVSKAAKKIQNEEDNKKEKET SEQ ID NO:90 MEDDKKTKESTNMLDNKHFWAAFLNLARHNVYITVNHINKVLELKNKKDQDIIIDNDQDILAIKTHWEKVNG DLNKTERLRELMTKHFPFLETAIYTKNKEDKEEVKQEKQAKAQSFDSLKHCLFLFLEKLQEARNYYSHYKYSE STKEPMLEKELLKKMYNIFDDNIQLVIKDYQHNKDINPDEDFKHLDRTEEEFNYYFTTNKKGNITASGLLFFVS LFLEKKDAIWMQQKLRGFKDNRESKKKMTHEVFCRSRMLLPKLRLESTQTQDWILLDMLNELIRCPKSLYER LQGEYRKKFNVPFDSADEDYDAEQEPFKNTLVRHQDRFPYFALRYFDYNEIFTNLRFQIDLGTYHFSIYKKLIG GQKEDRHLTHKLYGFERIQEFAKQNRTDEWKAIVKDFDTYETSEEPYISETAPHYHLENQKIGIRFRNDNDEIW PSLKTNGENNEKRKYKLDKQYQAEAFLSVHELLPMMFYYLLLKKEEPNNDKKNASIVEGFIKREIRDIYKLYD AFANGEINNIDDLEKYCEDKGIPKRHLPKQMVAILYDEHKDMAEEAKRKQKEMVKDTKKLLATLEKQTQGEI EDGGRNIRLLKSGEIARWLVNDMMRFQPVQKDNEGNPLNNSKANSTEYQMLQRSLALYNKEEKPTRYFRQV NLINSSNPHPFLKWTKWEECNNILSFYRSYLTKKIEFLNKLKPEDWEKNQYFLKLKEPKTNRETLVQGWKNGF NLPRGIFTEPIREWFKRHQNDSEEYEKVETLDRVGLVTKVIPLFFKKEDSKDKEEYLKKDAQKEINNCVQPFYG FPYNVGNIHKPDEKDFLPSEERKKLWGDKKYKFKGYKAKVKSKKLTDKEKEEYRSYLEFQSWNKFERELRLV RNQDIVTWLLCTELIDKLKVEGLNVEELKKLRLKDIDTDTAKQEKNNILNRVMPMQLPVTVYEIDDSHNIVKD RPLHTVYIEETKTKLLKQGNFKALVKDRRLNGLFSFVDTSSETELKSNPISKSLVEYELGEYQNARIETIKDMLL LEETLIEKYKTLPTDNFSDMLNGWLEGKDEADKARFQNDVKLLVAVRNAFSHNQYPMRNRIAFANINPFSLSS ADTSEEKKLDIANQLKDKTHKIIKRIIEIEKPIETKE SEQ ID NO:91 MEDDKKTTDSIRYELKDKHFWAAFLNLARHNVYITVNHINKILEEGEINRDGYETTLKNTWNEIKDINKKDRL SKLIIKHFPFLEAATYRLNPTDTTKQKEEKQAEAQSLESLRKSFFVFIYKLRDLRNHYSHYKHSKSLERPKFEEG LLEKMYNIFNASIRLVKEDYQYNKDINPDEDFKHLDRTEEEFNYYFTKDNEGNITESGLLFFVSLFLEKKDAIW MQQKLRGFKDNRENKKKMTNEVFCRSRMLLPKLRLQSTQTQDWILLDMLNELIRCPKSLYERLREEDREKFR VPIEIADEDYDAEQEPFKNTLVRHQDRFPYFALRYFDYNEIFTNLRFQIDLGTYHFSIYKKQIGDYKESHHLTHK LYGFERIQEFTKQNRPDEWRKFVKTFNSFETSKEPYIPETTPHYHLENQKIGIRFRNDNDKIWPSLKTNSEKNEK SKYKLDKSFQAEAFLSVHELLPMMFYYLLLKTENTDNDNEIETKKKENKNDKQEKHKIEEIIENKITEIYALYD TFANGEIKSIDELEEYCKGKDIEIGHLPKQMIAILKDEHKVMATEAERKQEEMLVDVQKSLESLDNQINEEIEN VERKNSSLKSGKIASWLVNDMMRFQPVQKDNEGKPLNNSKANSTEYQLLQRTLAFFGSEHERLAPYFKQTKL IESSNPHPFLKDTEWEKCNNILSFYRSYLEAKKNFLESLKPEDWEKNQYFLKLKEPKTKPKTLVQGWKNGFNL PRGIFTEPIRKWFMKHRENITVAELKRVGLVAKVIPLFFSEEYKDSVQPFYNYHFNVGNINKPDEKNFLNCEER RELLRKKKDEFKKMTDKEKEENPSYLEFKSWNKFERELRLVRNQDIVTWLLCMELFNKKKIKELNVEKIYLK NINTNTTKKEKNTEEKNGEEKNIKEKNNILNRIMPMRLPIKVYGRENFSKNKKKKIRRNTFFTVYIEEKGTKLL KQGNFKALERDRRLGGLFSFVKTPSKAESKSNTISKLRVEYELGEYQKARIEIIKDMLALEKTLIDKYNSLDTD NFNKMLTDWLELKGEPDKASFQNDVDLLIAVRNAFSHNQYPMRNRIAFANINPFSLSSANTSEEKGLGIANQL KDKTHKTIEKIIEIEKPIETKEAttorney Docket No.204606-0174-00WO SEQ ID NO:92 MRVSKVKVKDGGKDKMVLVHRKTTGAQLVYSGQPVSNETSNILPEKKRQSFDLSTLNKTIIKFDTAKKQKLN VDQYKIVEKIFKYPKQELPKQIKAEEILPFLNHKFQEPVKYWKNGKEESFNLTLLIVEAVQAQDKRKLQPYYD WKTWYIQTKSDLLKKSIENNRIDLTENLSKRKKALLAWETEFTASGSIDLTHYHKVYMTDVLCKMLQDVKPL TDDKGKINTNAYHRGLKKALQNHQPAIFGTREVPNEANRADNQLSIYHLEVVKYLEHYFPIKTSKRRNTADDI AHYLKAQTLKTTIEKQLVNAIRANIIQQGKTNHHELKADTTSNDLIRIKTNEAFVLNLTGTCAFAANNIRNMVD NEQTNDILGKGDFIKSLLKDNTNSQLYSFFFGEGLSTNKAEKETQLWGIRGAVQQIRNNVNHYKKDALKTVFN ISNFENPTITDPKQQTNYADTIYKARFINELEKIPEAFAQQLKTGGAVSYYTIENLKSLLTTFQFSLCRSTIPFAPG FKKVFNGGINYQNAKQDESFYELMLEQYLRKENFAEESYNARYFMLKLIYNNLFLPGFTTDRKAFADSVGFV QMQNKKQAEKVNPRKKEAYAFEAVRPMTAADSIADYMAYVQSELMQEQNKKEEKVAEETRINFEKFVLQVF IKGFDSFLRAKEFDFVQMPQPQLTATASNQQKADKLNQLEASITADCKLTPQYAKADDATHIAFYVFCKLLDA AHLSNLRNELIKFRESVNEFKFHHLLEIIEICLLSADVVPTDYRDLYSSEADCLARLRPFIEQGADITNWSDLFVQ SDKHSPVIHANIELSVKYGTTKLLEQIINKDTQFKTTEANFTAWNTAQKSIEQLIKQREDHHEQWVKAKNADD KEKQERKREKSNFAQKFIEKHGDDYLDICDYINTYNWLDNKMHFVHLNRLHGLTIELLGRMAGFVALFDRDF QFFDEQQIADEFKLHGFVNLHSIDKKLNEVPTKKIKEIYDIRNKIIQINGNKINESVRANLIQFISSKRNYYNNAFL HVSNDEIKEKQMYDIRNHIAHFNYLTKDAADFSLIDLINELRELLHYDRKLKNAVSKAFIDLFDKHGMILKLKL NADHKLKVESLEPKKIYHLGSSAKDKPEYQYCTNQVMMAYCNMCRSLLEMKK SEQ ID NO:93 MEDKPFWAAFFNLARHNVYLTVNHINKLLDLEKLYDEGKHKEIFEREDIFNISDDVMNDANSNGKKRKLDIK KIWDDLDTDLTRKYQLRELILKHFPFIQPAIIGAQTKERTTIDKDKRSTSTSNDSLKQTGEGDINDLLSLSNVKS MFFRLLQILEQLRNYYSHVKHSKSATMPNFDEDLLNWMRYIFIDSVNKVKEDYSSNSVIDPNTSFSHLIYKDEQ GKIKPCRYPFTSKDGSINAFGLLFFVSLFLEKQDSIWMQKKIPGFKKASENYMKMTNEVFCRNHILLPKIRLETV YDKDWMLLDMLNEVVRCPLSLYKRLTPAAQNKFKVPEKSSDNANRQEDDNPFSRILVRHQNRFPYFVLRFFD LNEVFTTLRFQINLGCYHFAICKKQIGDKKEVHHLIRTLYGFSRLQNFTQNTRPEEWNTLVKTTEPSSGNDGKT VQGVPLPYISYTIPHYQIENEKIGIKIFDGDTAVDTDIWPSVSTEKQLNKPDKYTLTPGFKADVFLSVHELLPMM FYYQLLLCEGMLKTDAGNAVEKVLIDTRNAIFNLYDAFVQEKINTITDLENYLQDKPILIGHLPKQMIDLLKGH QRDMLKAVEQKKAMLIKDTERRLKLLDKQLKQETDVAAKNTGTLLKNGQIADWLVNDMMRFQPVKRDKE GNPINCSKANSTEYQMLQRAFAFYATDSCRLSRYFTQLHLIHSDNSHLFLSRFEYDKQPNLIAFYAAYLKAKLE FLNELQPQNWASDNYFLLLRAPKNDRQKLAEGWKNGFNLPRGLFTEKIKTWFNEHKTIVDISDCDIFKNRVGQ VARLIPVFFDKKFKDHSQPFYRYDFNVGNVSKPTEANYLSKGKREELFKSYQNKFKNNIPAEKTKEYREYKNF SLWKKFERELRLIKNQDILIWLMCKNLFDEKIKPKKDILEPRIAVSYIKLDSLQTNTSTAGSLNALAKVVPMTLA IHIDSPKPKGKAGNNEKENKEFTVYIKEEGTKLLKWGNFKTLLADRRIKGLFSYIEHDDIDLKQHPLTKRRVDL ELDLYQTCRIDIFQQTLGLEAQLLDKYSDLNTDNFYQMLIGWRKKEGIPRNIKEDTDFLKDVRNAFSHNQYPD SKKIAFRRIRKFNPKELILEEEEGLGIATQMYKEVEKVVNRIKRIELFD SEQ ID NO:94 MSKECKKQRQEKKRRLQKANFSISLTGKHVFGAYFNMARTNFVKTINYILPIAGVRGNYSENQINKMLHALFL IQAGRNEELTTEQKQWEKKLRLNPEQQTKFQKLLFKHFPVLGPMMADVADHKAYLNKKKSTVQTEDETFAM LKGVSLADCLDIICLMADTLTECRNFYTHKDPYNKPSQLADQYLHQEMIAKKLDKVVVASRRILKDREGLSV NEVEFLTGIDHLHQEVLKDEFGNAKVKDGKVMKTFVEYDDFYFKISGKRLVNGYTVTTKDDKPVNVNTMLP ALSDFGLLYFCVLFLSKPYAKLFIDEVRLFEYSPFDDKENMIMSEMLSIYRIRTPRLHKIDSHDSKATLAMDIFG ELRRCPMELYNLLDKNAGQPFFHDEVKHPNSHTPDVSKRLRYDDRFPTLALRYIDETELFKRIRFQLQLGSFRY KFYDKENCIDGRVRVRRIQKEINGYGRMQEVADKRMDKWGDLIQKREERSVKLEHEELYINLDQFLEDTADS TPYVTDRRPAYNIHANRIGLYWEDSQNPKQYKVFDENGMYIPELVVTEDKKAPIKMPAPRCALSVYDLPAML FYEYLREQQDNEFPSAEQVIIEYEDDYRKFFKAVAEGKLKPFKRPKEFRDFLKKEYPKLRMADIPKKLQLFLCS HGLCYNNKPETVYERLDRLTLQHLEERELHIQNRLEHYQKDRDMIGNKDNQYGKKSFSDVRHGALARYLAQ SMMEWQPTKLKDKEKGHDKLTGLNYNVLTAYLATYGHPQVPEEGFTPRTLEQVLINAHLIGGSNPHPFINKV LALGNRNIEELYLHYLEEELKHIRSRIQSLSSNPSDKALSALPFIHHDRMRYHERTSEEMMALAARYTTIQLPDG LFTPYILEILQKHYTENSDLQNALSQDVPVKLNPTCNAAYLITLFYQTVLKDNAQPFYLSDKTYTRNKDGEKA ESFSFKRAYELFSVLNNNKKDTFPFEMIPLFLTSDEIQERLSAKLLDGDGNPVPEVGEKGKPATDSQGNTIWKR RIYSEVDDYAEKLTDRDMKISFKGEWEKLPRWKQDKIIKRRDETRRQMRDELLQRMPRYIRDIKDNERTLRRY KTQDMVLFLLAEKMFTNIISEQSSEFNWKQMRLSKVCNEAFLRQTLTFRVPVTVGETTIYVEQENMSLKNYGE FYRFLTDDRLMSLLNNIVETLKPNENGDLVIRHTDLMSELAAYDQYRSTIFMLIQSIENLIITNNAVLDDPDADG FWVREDLPKRNNFASLLELINQLNNVELTDDERKLLVAIRNAFSHNSYNIDFSLIKDVKHLPEVAKGILQHLQS MLGVEITKAttorney Docket No.204606-0174-00WO SEQ ID NO:95 MEKPLLPNVYTLKHKFFWGAFLNIARHNAFITICHINEQLGLKTPSNDDKIVDVVCETWNNILNNDHDLLKKS QLTELILKHFPFLTAMCYHPPKKEGKKKGHQKEQQKEKESEAQSQAEALNPSKLIEALEILVNQLHSLRNYYS HYKHKKPDAEKDIFKHLYKAFDASLRMVKEDYKAHFTVNLTRDFAHLNRKGKNKQDNPDFNRYRFEKDGFF TESGLLFFTNLFLDKRDAYWMLKKVSGFKASHKQREKMTTEVFCRSRILLPKLRLESRYDHNQMLLDMLSEL SRCPKLLYEKLSEENKKHFQVEADGFLDEIEEEQNPFKDTLIRHQDRFPYFALRYLDLNESFKSIRFQVDLGTYH YCIYDKKIGDEQEKRHLTRTLLSFGRLQDFTEINRPQEWKALTKDLDYKETSNQPFISKTTPHYHITDNKIGFRL GTSKELYPSLEIKDGANRIAKYPYNSGFVAHAFISVHELLPLMFYQHLTGKSEDLLKETVRHIQRIYKDFEEERI NTIEDLEKANQGRLPLGAFPKQMLGLLQNKQPDLSEKAKIKIEKLIAETKLLSHRLNTKLKSSPKLGKRREKLIK TGVLADWLVKDFMRFQPVAYDAQNQPIKSSKANSTEFWFIRRALALYGGEKNRLEGYFKQTNLIGNTNPHPF LNKFNWKACRNLVDFYQQYLEQREKFLEAIKNQPWEPYQYCLLLKIPKENRKNLVKGWEQGGISLPRGLFTE AIRETLSEDLMLSKPIRKEIKKHGRVGFISRAITLYFKEKYQDKHQSFYNLSYKLEAKAPLLKREEHYEYWQQN KPQSPTESQRLELHTSDRWKDYLLYKRWQHLEKKLRLYRNQDVMLWLMTLELTKNHFKELNLNYHQLKLE NLAVNVQEADAKLNPLNQTLPMVLPVKVYPATAFGEVQYHKTPIRTVYIREEHTKALKMGNFKALVKDRRL NGLFSFIKEENDTQKHPISQLRLRRELEIYQSLRVDAFKETLSLEEKLLNKHTSLSSLENEFRALLEEWKKEYAA SSMVTDEHIAFIASVRNAFCHNQYPFYKEALHAPIPLFTVAQPTTEEKDGLGIAEALLKVLREYCEIVKSQI SEQ ID NO:96 MQIGKVQGRTISEFGDPAGGLKRKISTDGKNRKELPAHLSSDPKALIGQWISGIDKIYRKPDSRKSDGKAIHSPT PSKMQFDARDDLGEAFWKLVSEAGLAQDSDYDQFKRRLHPYGDKFQPADSGAKLKFEADPPEPQAFHGRWY GAMSKRGNDAKELAAALYEHLHVDEKRIDGQPKRNPKTDKFAPGLVVARALGIESSVLPRGMARLARNWGE EEIQTYFVVDVAASVKEVAKAAVSAAQAFDPPRQVSGRSLSPKVGFALAEHLERVTGSKRCSFDPAAGPSVLA LHDEVKKTYKRLCARGKNAARAFPADKTELLALMRHTHENRVRNQMVRMGRVSEYRGQQAGDLAQSHYW TSAGQTEIKESEIFVRLWVGAFALAGRSMKAWIDPMGKIVNTEKNDRDLTAAVNIRQVISNKEMVAEAMARR GIYFGETPELDRLGAEGNEGFVFALLRYLRGCRNQTFHLGARAGFLKEIRKELEKTRWGKAKEAEHVVLTDK TVAAIRAIIDNDAKALGARLLADLSGAFVAHYASKEHFSTLYSEIVKAVKDAPEVSSGLPRLKLLLKRADGVR GYVHGLRDTRKHAFATKLPPPPAPRELDDPATKARYIALLRLYDGPFRAYASGITGTALAGPAARAKEAATAL AQSVNVTKAYSDVMEGRSSRLRPPNDGETLREYLSALTGETATEFRVQIGYESDSENARKQAEFIENYRRDML AFMFEDYIRAKGFDWILKIEPGATAMTRAPVLPEPIDTRGQYEHWQAALYLVMHFVPASDVSNLLHQLRKWE ALQGKYELVQDGDATDQADARREALDLVKRFRDVLVLFLKTGEARFEGRAAPFDLKPFRALFANPATFDRLF MATPTTARPAEDDPEGDGASEPELRVARTLRGLRQIARYNHMAVLSDLFAKHKVRDEEVARLAEIEDETQEK SQIVAAQELRTDLHDKVMKCHPKTISPEERQSYAAAIKTIEEHRFLVGRVYLGDHLRLHRLMMDVIGRLIDYA GAYERDTGTFLINASKQLGAGADWAVTIAGAANTDARTQTRKDLAHFNVLDRADGTPDLTALVNRAREMM AYDRKRKNAVPRSILDMLARLGLTLKWQMKDHLLQDATITQAAIKHLDKVRLTVGGPAAVTEARFSQDYLQ MVAAVFNGSVQNPKPRRRDDGDAWHKPPKPATAQSQPDQKPPNKAPSAGSRLPPPQVGEVYEGVVVKVIDT GSLGFLAVEGVAGNIGLHISRLRRIREDAIIVGRRYRFRVEIYVPPKSNTSKLNAADLVRID SEQ ID NO:97 MQIGKVQGRTISEFGDPAGGLKRKISTDGKNRKELPAHLSSDPKALIGQWISGIDKIYRKPDSRKSDGKAIHSPT PSKMQFDARDDLGEAFWKLVSEAGLAQDSDYDQFKRRLHPYGDKFQPADSGAKLKFEADPPEPQAFHGRWY GAMSKRGNDAKELAAALYEHLHVDEKRIDGQPKRNPKTDKFAPGLVVARALGIESSVLPRGMARLARNWGE EEIQTYFVVDVAASVKEVAKAAVSAAQAFDPPRQVSGRSLSPKVGFALAEHLERVTGSKRCSFDPAAGPSVLA LHDEVKKTYKRLCARGKNAARAFPADKTELLALMRHTHENRVRNQMVRMGRVSEYRGQQAGDLAQSHYW TSAGQTEIKESEIFVRLWVGAFALAGRSMKAWIDPMGKIVNTEKNDRDLTAAVNIRQVISNKEMVAEAMARR GIYFGETPELDRLGAEGNEGFVFALLRYLRGCRNQTFHLGARAGFLKEIRKELEKTRWGKAKEAEHVVLTDK TVAAIRAIIDNDAKALGARLLADLSGAFVAHYASKEHFSTLYSEIVKAVKDAPEVSSGLPRLKLLLKRADGVR GYVHGLRDTRKHAFATKLPPPPAPRELDDPATKARYIALLRLYDGPFRAYASGITGTALAGPAARAKEAATAL AQSVNVTKAYSDVMEGRSSRLRPPNDGETLREYLSALTGETATEFRVQIGYESDSENARKQAEFIENYRRDML AFMFEDYIRAKGFDWILKIEPGATAMTRAPVLPEPIDTRGQYEHWQAALYLVMHFVPASDVSNLLHQLRKWE ALQGKYELVQDGDATDQADARREALDLVKRFRDVLVLFLKTGEARFEGRAAPFDLKPFRALFANPATFDRLF MATPTTARPAEDDPEGDGASEPELRVARTLRGLRQIARYNHMAVLSDLFAKHKVRDEEVARLAEIEDETQEK SQIVAAQELRTDLHDKVMKCHPKTISPEERQSYAAAIKTIEEHRFLVGRVYLGDHLRLHRLMMDVIGRLIDYA GAYERDTGTFLINASKQLGAGADWAVTIAGAANTDARTQTRKDLAHFNVLDRADGTPDLTALVNRAREMM AYDRKRKNAVPRSILDMLARLGLTLKWQMKDHLLQDATITQAAIKHLDKVRLTVGGPAAVTEARFSQDYLQ MVAAVFNGSVQNPKPRRRDDGDAWHKPPKPATAQSQPDQKPPNKAPSAGSRLPPPQVGEVYEGVVVKVIDT GSLGFLAVEGVAGNIGLHISRLRRIREDAIIVGRRYRFRVEIYVPPKSNTSKLNAADLVRIDAttorney Docket No.204606-0174-00WO SEQ ID NO:98 MQIGKVQGRTISEFGDPAGGLKRKISTDGKNRKELPAHLSSDPKALIGQWISGIDKIYRKPDSRKSDGKAIHSPT PSKMQFDARDDLGEAFWKLVSEAGLAQDSDYDQFKRRLHPYGDKFQPADSGAKLKFEADPPEPQAFHGRWY GAMSKRGNDAKELAAALYEHLHVDEKRIDGQPKRNPKTDKFAPGLVVARALGIESSVLPRGMARLARNWGE EEIQTYFVVDVAASVKEVAKAAVSAAQAFDPPRQVSGRSLSPKVGFALAEHLERVTGSKRCSFDPAAGPSVLA LHDEVKKTYKRLCARGKNAARAFPADKTELLALMRHTHENRVRNQMVRMGRVSEYRGQQAGDLAQSHYW TSAGQTEIKESEIFVRLWVGAFALAGRSMKAWIDPMGKIVNTEKNDRDLTAAVNIRQVISNKEMVAEAMARR GIYFGETPELDRLGAEGNEGFVFALLRYLRGCRNQTFHLGARAGFLKEIRKELEKTRWGKAKEAEHVVLTDK TVAAIRAIIDNDAKALGARLLADLSGAFVAHYASKEHFSTLYSEIVKAVKDAPEVSSGLPRLKLLLKRADGVR GYVHGLRDTRKHAFATKLPPPPAPRELDDPATKARYIALLRLYDGPFRAYASGITGTALAGPAARAKEAATAL AQSVNVTKAYSDVMEGRTSRLRPPNDGETLREYLSALTGETATEFRVQIGYESDSENARKQAEFIENYRRDML AFMFEDYIRAKGFDWILKIEPGATAMTRAPVLPEPIDTRGQYEHWQAALYLVMHFVPASDVSNLLHQLRKWE ALQGKYELVQDGDATDQADARREALDLVKRFRDVLVLFLKTGEARFEGRAAPFDLKPFRALFANPATFDRLF MATPTTARPAEDDPEGDGASEPELRVARTLRGLRQIARYNHMAVLSDLFAKHKVRDEEVARLAEIEDETQEK SQIVAAQELRTDLHDKVMKCHPKTISPEERQSYAAAIKTIEEHRFLVGRVYLGDHLRLHRLMMDVIGRLIDYA GAYERDTGTFLINASKQLGAGADWAVTIAGAANTDARTQTRKDLAHFNVLDRADGTPDLTALVNRAREMM AYDRKRKNAVPRSILDMLARLGLTLKWQMKDHLLQDATITQAAIKHLDKVRLTVGGPAAVTEARFSQDYLQ MVAAVFNGSVQNPKPRRRDDGDAWHKPPKPATAQSQPDQKPPNKAPSAGSRLPPPQVGEVYEGVVVKVIDT GSLGFLAVEGVAGNIGLHISRLRRIREDAIIVGRRYRFRVEIYVPPKSNTSKLNAADLVRID SEQ ID NO:99 MAKKNKMKPRELREAQKKARQLKAAEINNNAAPAIAAMPAAEVIAPVAEKKKSSVKAAGMKSILVSENKMY ITSFGKGNSAVLEYEVDNNDYNKTQLSSKDNSNIELGDVNEVNITFSSKHGFGSGVEINTSNPTHRSGESSPVRG DMLGLKSELEKRFFGKTFDDNIHIQLIYNILDIEKILAVYVTNIVYALNNMLGIKDSESYDDFMGYLSARNTYE VFTHPDKSNLSDKVKGNIKKSLSKFNDLLKTKRLGYFGLEEPKTKDTRASEAYKKRVYHMLAIVGQIRQCVFH DKSGAKRFDLYSFINNIDPEYRDTLDYLVEERLKSINKDFIEGNKVNISLLIDMMKGYEADDIIRLYYDFIVLKS QKNLGFSIKKLREKMLEEYGFRFKDKQYDSVRSKMYKLMDFLLFCNYYRNDVAAGEALVRKLRFSMTDDEK EGIYADEAAKLWGKFRNDFENIADHMNGDVIKELGKADMDFDEKILDSEKKNASDLLYFSKMIYMLTYFLDG KEINDLLTTLISKFDNIKEFLKIMKSSAVDVECELTAGYKLFNDSQRITNELFIVKNIASMRKPAASAKLTMFRD ALTILGIDDNITDDRISEILKLKEKGKGIHGLRNFITNNVIESSRFVYLIKYANAQKIREVAKNEKVVMFVLGGIP DTQIERYYKSCVEFPDMNSSLEAKRSELARMIKNISFDDFKNVKQQAKGRENVAKERAKAVIGLYLTVMYLL VKNLVNVNARYVIAIHCLERDFGLYKEIIPELASKNLKNDYRILSQTLCELCDDRNESSNLFLKKNKRLRKCVE VDINNADSSMTRKYRNCIAHLTVVRELKEYIGDIRTVDSYFSIYHYVMQRCITKRGDDTKQEEKIKYEDDLLK NHGYTKDFVKALNSPFGYNIPRFKNLSIEQLFDRNEYLTEK SEQ ID NO:100 NIPALVENQKKYFGTYSVMAMLNAQTVLDHIQKVADIEGEQNENNENLWFHPVMSHLYNAKNGYDKQPEKT MFIIERLQSYFPFLKIMAENQREYSNGKYKQNRVEVNSNDIFEVLKRAFGVLKMYRDLTNAYKTYEEKLNDG CEFLTSTEQPLSGMINNYYTVALRNMNERYGYKTEDLAFIQDKRFKFVKDAYGKKKSQVNTGFFLSLQDYNG DTQKKLHLSGVGIALLICLFLDKQYINIFLSRLPIFSSYNAQSEERRIIIRSFGINSIKLPKDRIHSEKSNKSVAMDM LNEVKRCPDELFTTLSAEKQSRFRIISDDHNEVLMKRSSDRFVPLLLQYIDYGKLFDHIRFHVNMGKLRYLLKA DKTCIDGQTRVRVIEQPLNGFGRLEEAETMRKQENGTFGNSGIRIRDFENMKRDDANPANYPYIVDTYTHYILE NNKVEMFINDKEDSAPLLPVIEDDRYVVKTIPSCRMSTLEIPAMAFHMFLFGSKKTEKLIVDVHNRYKRLFQA MQKEEVTAENIASFGIAESDLPQKILDLISGNAHGKDVDAFIRLTVDDMLTDTERRIKRFKDDRKSIRSADNKM GKRGFKQISTGKLADFLAKDIVLFQPSVNDGENKITGLNYRIMQSAIAVYDSGDDYEAKQQFKLMFEKARLIG KGTTEPHPFLYKVFARSIPANAVEFYERYLIERKFYLTGLSNEIKKGNRVDVPFIRRDQNKWKTPAMKTLGRIY SEDLPVELPRQMFDNEIKSHLKSLPQMEGIDFNNANVTYLIAEYMKRVLDDDFQTFYQWNRNYRYMDMLKG EYDRKGSLQHCFTSVEEREGLWKERASRTERYRKQASNKIRSNRQMRNASSEEIETILDKRLSNSRNEYQKSE KVIRRYRVQDALLFLLAKKTLTELADFDGERFKLKEIMPDAEKGILSEIMPMSFTFEKGGKKYTITSEGMKLKN YGDFFVLASDKRIGNLLELVGSDIVSKEDIMEEFNKYDQCRPEISSIVFNLEKWAFDTYPELSARVDREEKVDF KSILKILLNNKNINKEQSDILRKIRNAFDANNYPDKGVVEIKALPEIAMSIKKAFGEYAIMK SEQ ID NO:101 NIPALVENQKKYFGTYSVMAMLNAQTVLDHIQKVADIEGEQNENNENLWFHPVMSHLYNAKNGYDKQPEKT MFIIERLQSYFPFLKIMAENQREYSNGKYKQNRVEVNSNDIFEVLKRAFGVLKMYRDLTNAYKTYEEKLNDG CEFLTSTEQPLSGMINNYYTVALRNMNERYGYKTEDLAFIQDKRFKFVKDAYGKKKSQVNTGFFLSLQDYNG DTQKKLHLSGVGIALLICLFLDKQYINIFLSRLPIFSSYNAQSEERRIIIRSFGINSIKLPKDRIHSEKSNKSVAMDM LNEVKRCPDELFTTLSAEKQSRFRIISDDHNEVLMKRSSDRFVPLLLQYIDYGKLFDHIRFHVNMGKLRYLLKA DKTCIDGQTRVRVIEQPLNGFGRLEEAETMRKQENGTFGNSGIRIRDFENMKRDDANPANYPYIVDTYTHYILE NNKVEMFINDKEDSAPLLPVIEDDRYVVKTIPSCRMSTLEIPAMAFHMFLFGSKKTEKLIVDVHNRYKRLFQA MQKEEVTAENIASFGIAESDLPQKILDLISGNAHGKDVDAFIRLTVDDMLTDTERRIKRFKDDRKSIRSADNKM GKRGFKQISTGKLADFLAKDIVLFQPSVNDGENKITGLNYRIMQSAIAVYDSGDDYEAKQQFKLMFEKARLIG KGTTEPHPFLYKVFARSIPANAVEFYERYLIERKFYLTGLSNEIKKGNRVDVPFIRRDQNKWKTPAMKTLGRIY SEDLPVELPRQMFDNEIKSHLKSLPQMEGIDFNNANVTYLIAEYMKRVLDDDFQTFYQWNRNYRYMDMLKG EYDRKGSLQHCFTSVEEREGLWKERASRTERYRKQASNKIRSNRQMRNASSEEIETILDKRLSNSRNEYQKSE KVIRRYRVQDALLFLLAKKTLTELADFDGERFKLKEIMPDAEKGILSEIMPMSFTFEKGGKKYTITSEGMKLKN YGDFFVLASDKRIGNLLELVGSDIVSKEDAttorney Docket No.204606-0174-00WO SEQ ID Description Sequence NO:102 Linker sequence 1SRGGGGSGGGGSTR103 Linker sequence 2RGGGGSGGGGSTR104 Linker sequence 3GGGGSGGGGSLEP105 Linker sequence 4GGGG106 Linker sequence 5GGGGSGGGGS107 Linker sequence 6EAAAK108 Linker sequence 7EAAAKEAAAK109 Linker sequence 8KAEEEKKAAEEK110 Linker sequence 9SGSETPGTSESATPES111 Ty1 NLSNSKKRSLEDNETEIKVSRDTWNTKNMRSLEPPRSKKRIH112 Ty2 NLSKSKKRSLEDNETEIEVSRDTWNNKNMRSLEPPRSKKRIN113 Ty1-like NLS O28090-0KKRNSNEYRLVPTKWQDYKKPGPNQKYTSDGKKR114 Ty1-like NLS O50087-0KKRLHLIIADAELETVPPEILDHPAIVNYAKRRKKR115 Ty1-like NLS O58353-0KKRIEELEIELGLRAPPKKEKKGKKSKKR116 Ty1-like NLS Q57602-0KKRALKYRLNPKLLKENNKKDVNKKR117 Ty1-like NLS Q6L1X9-0KKRNFLESIEISINLKDVDLSDPKKR118 Ty1-like NLS A0K3M1-0KKRSEKSMALRLAGELSEAAEGRGGAMKKR119 Ty1-like NLS A0LYZ1-0KKRFKLTGTGKIKRKHAFKSHILTKKSKKR120 Ty1-like NLS A1B022-0KKRNEHTMEERLAGELADAVNGRGTAVKKR121 Ty1-like NLS A1V8A7-0KKRSEKSMALRLAGELSEAAEGRGGAMKKR122 Ty1-like NLS A1VIP6-0KKRGEKSMSLRLANELMEATEGRGGAMKKR123 Ty1-like NLS A2RDW6-0KKRLATHNAGKGAKYTRYRLPVSLLYYEVFDSKEAAMSAEALFKKR124 Ty1-like NLS A2S7H2-0KKRSEKSMALRLAGELSEAAEGRGGAMKKR125 Ty1-like NLS A3MRV0-0KKRSEKSMALRLAGELSEAAEGRGGAMKKR126 Ty1-like NLS A3NEI3-0KKRSEKSMALRLAGELSEAAEGRGGAMKKR127 Ty1-like NLS A3P0B7-0KKRSEKSMALRLAGELSEAAEGRGGAMKKR128 Ty1-like NLS A4JAN6-0KKRSEKSMALRLAGELSEAAEGRGGAMKKR129 Ty1-like NLS A4SUV7-0KKRGEKSMAQRLANELLEAAEGRGGAMKKR130 Ty1-like NLS A5FP03-0KKRFKVTGSGKIKRKHAFKSHILTKKSKKR131 Ty1-like NLS A5ILZ2-0KKRKKYLKAAKGYRGALSRRYKLAKQMYVRSKWYSYVGRKLKKR132 Ty1-like NLS A6GY20-0KKRFKVTGSGKIKRKHAFKSHILTKKSKKR133 Ty1-like NLS A6LLI5-0KKRKKIMKAVKGYRGALSRRYRLAKQAYIKAKKHAYVGRKLKKR134 Ty1-like NLS A6LQX4-0KKRGYQTHGIRPRLAKKKTVMSKIARKQGKKR135 Ty1-like NLS A8F6X2-0KKRREKFLKSAKGYRGAIKRRYRLAKQHYYRAKWYAYAGRKLKKRAttorney Docket No.204606-0174-00WOTy1-like NLS A8G6B7-0KKRIGLIFGGYSNEHEVSISSAKTVFQAFNSEINKKRTy1-like NLS A9ADI9-0KKRSEKSMALRLAGELSEAAEGRGGAMKKRTy1-like NLS A9IJ08-0KKRGEKSMDLRLAGELIDASEGRGAAMKKRTy1-like NLS A9IXA1-0KKRFSFHALHLRLSPRLLKSEKAQRHTKEYTARLYRAFMRSVEKKRTy1-like NLS A9NEN2-0KKRNEKTMEERLAKEILDASQGTGAAVKKRTy1-like NLS B0S140-0KKRAMELGIDVITPKNINDEEVFDLLDKLNPDFIVVVAYGQLIKKRTy1-like NLS B1JU18-0KKRSEKSMALRLAGELSEAAEGRGGAMKKRTy1-like NLS B1LBA1-0KKRKKYLKAAKGYRGALSRRYKLAKQMYVRSKWYSYVGRKQKKRTy1-like NLS B1W354-0KKRRAILEAASGYRGQRSRLYRKAKEQVTHSLVYNYNDRKKRTy1-like NLS B1XSP7-0KKRGEKSMAQRLANELLEAAEGRGGAMKKRTy1-like NLS B1YRC6-0KKRSEKSMALRLAGELSEAAEGRGGAMKKRTy1-like NLS B2JIH0-0KKRSEKSMALRLAGELSEAAEGRGGAMKKRTy1-like NLS B2T755-0KKRSEKSMALRLAGELSEAAEGRGGAMKKRTy1-like NLS B2UEM3-0KKRSEKSMALRLAGELLEASEGRGGAMKKRTy1-like NLS B3PLU0-0KKRMKSIGTVEVPQEAFLAILKTDTSKKRTy1-like NLS B3R7T2-0KKRSEKSMALRLAGELLEAAEGRGGAMKKRTy1-like NLS B4E5B6-0KKRSEKSMALRLAGELSEAAEGRGGAMKKRTy1-like NLS B4S3C9-0KKRILNKAKGYWGSRGTILTVAKHAVDKAEQYAYRDRRVKKRTy1-like NLS B7IHT4-0KKRRKILKAVKGYHGALSRRYRLAKQAYIKAKKHAYVGRKLKKRTy1-like NLS B8E0X6-0KKRGIGVKVNNGILWLLELQPEGKKRTy1-like NLS B9K7W0-0KKRKKFLKEAKGYRGALSRRYKLAKQMYIRSKWYSYVGRKIKKRTy1-like NLS C1A494-0KKRFSVTGSGKVRRLKAYKSHILTKMSGKKKRTy1-like NLS C5CE41-0KKRKYLKAAKGYRGALSRRYRLAKQYYIRSGVYAYVGRKQKKRTy1-like NLS O88058-0KKRRAILEQASGYRGQRSRLYRKAKEQVTHSLVYNYNDRKKRTy1-like NLS P0DG92-0KKRLATHNAGKGAKYTRYRLPVSLLYYEVFDSKEAAMSAEALFKKRTy1-like NLS P0DG93-0KKRLATHNAGKGAKYTRYRLPVSLLYYEVFDSKEAAMSAEALFKKRTy1-like NLS P60554-0KKRIPNTVFIFLVPPEKKALYDRLKKRTy1-like NLS P67354-0KKRLATHNAGKGAKYTRYRLPVSLLYYEVFDSKEAAMSAEALFKKRTy1-like NLS P75311-0KKRILDTLFTRSPKNQQDFIEHTDDKKSIVNFFVGAFKKRTy1-like NLS P75471-0KKRELQELNQIRRNLEQSNASLLKKRTy1-like NLS P94372-0KKRNHMAWVWGIVGLIQAPMPLICYYFFVIRPDRKKRTy1-like NLS Q056Y0-0KKRLFEEQQEAKKIDYANSRIKAIKLIGAIIFFMKSSKKRTy1-like NLS Q057D7-0KKRKKIPGLAMIVIGNNPASLIYVNKKRTy1-like NLS Q0AYB7-0KKRPELLIAFGGCMAQLPEVRQKLKKRTy1-like NLS Q0BJ50-0KKRSEKSMALRLAGELSEAAEGRGGAMKKRTy1-like NLS Q0K610-0KKRSEKSMALRLAGELLEASEGRGGAMKKRTy1-like NLS Q0STA4-0KKRGYQKYGVRPRLAKKKTVMCKIARKQGKKRTy1-like NLS Q0STL9-0KKRSSHSKKQRGNKSRGFDQKSQRVSKGKKRTy1-like NLS Q0TQV7-0KKRGYQKYGVRPRLAKKKTVMCKIARKQGKKRTy1-like NLS Q0TR88-0KKRSSHSKKQRGNKSRGFDQKSQRSSKGKKRTy1-like NLS Q12GX5-0KKRGEKSMSLRLANELMEATEGRGGAMKKRAttorney Docket No.204606-0174-00WOTy1-like NLS Q13TG6-0KKRSEKSMALRLAGELSEAAEGRGGAMKKRTy1-like NLS Q1AWG1-0KKRRKLLKEARGYRGTKHTSYKRAKEQVWKSGVYAYVGRKQKKRTy1-like NLS Q1BRU4-0KKRSEKSMALRLAGELSEAAEGRGGAMKKRTy1-like NLS Q1J5X5-0KKRLATHNAGKGAKYTRYRLPVSLLYYEVFDSKEAAMSAEALFKKRTy1-like NLS Q1JAY8-0KKRLATHNAGKGAKYTRYRLPVSLLYYEVFDSKEAAMSAEALFKKRTy1-like NLS Q1JG57-0KKRLATHNAGKGAKYTRYRLPVSLLYYEVFDSKEAAMSAEALFKKRTy1-like NLS Q1JL34-0KKRLATHNAGKGAKYTRYRLPVSLLYYEVFDSKEAAMSAEALFKKRTy1-like NLS Q1LI28-0KKRSEKSMALRLAGELLEAAEGRGGAMKKRTy1-like NLS Q2L2H3-0KKRGEKSMDLRLAGELIDASEGRGAAMKKRTy1-like NLS Q2NIH1-0KKRMPNTVFIFLVPPKKKDLYDRLKKRTy1-like NLS Q2SU23-0KKRSEKSMALRLAGELSEAAEGRGGAMKKRTy1-like NLS Q39KH1-0KKRSEKSMALRLAGELSEAAEGRGGAMKKRTy1-like NLS Q3JMQ8-0KKRSEKSMALRLAGELSEAAEGRGGAMKKRTy1-like NLS Q3YRL8-0KKRKGMSNKKVLTGVVVATKCDKTIKVMVSRMVRHKTYKKIVKKRTy1-like NLS Q46WD9-0KKRSEKSMALRLAGELLEASEGRGGAMKKRTy1-like NLS Q48SQ4-0KKRLATHNAGKGAKYTRYRLPVSLLYYEVFDSKEAAMSAEALFKKRTy1-like NLS Q49418-0KKRILDTFFKRNNSNHKDFVEHEEKRKSLLKIAINAFKKRTy1-like NLS Q56307-0KKRDNTRLIHYEGTTRRGESYYVDVFSLMYPKMDILLEYASKKRTy1-like NLS Q5LEQ4-0KKRFALTGTGKIKRKHAFHSHILTKKSKKRTy1-like NLS Q5WEJ7-0KKRATVRIQGQTYKVVSSEEPAHVKEVASYMNKKMEELKKRTy1-like NLS Q5XBA0-0KKRLATHNAGKGAKYTRYRLPVSLLYYEVFDSKEAAMSAEALFKKRTy1-like NLS Q62GK1-0KKRSEKSMALRLAGELSEAAEGRGGAMKKRTy1-like NLS Q63Q07-0KKRSEKSMALRLAGELSEAAEGRGGAMKKRTy1-like NLS Q64VP0-0KKRFALTGTGKIKRKHAFHSHILTKKSKKRTy1-like NLS Q6G3V1-0KKREFETQGRKPHWRFLLPNFENDPLQKKRTy1-like NLS Q6G5M0-0KKRKIIALCGIDTRALTVLIREKGALNGIIAHDPNGNFDINTLKKRTy1-like NLS Q6LLQ8-0KKRSRGVGSEGPAVFREKSTTQVDVEARKSQKDKKRTy1-like NLS Q6MDC1-0KKRLFKLAKGFVGDRKNHLRLTSGAVMRAMAYNYAHRKQKKRTy1-like NLS Q6MDH4-0KKRFERKKEASPADTPPESDSTTENASVEKKAEKKRTy1-like NLS Q6ME08-0KKRLDKEGVMKSVKAHRFYSKPSIKKRTy1-like NLS Q73PH4-0KKRPEQGRIAALYSDIVILADEDPRGEDSVELLEMIAAGCPEKKRTy1-like NLS Q7MAD1-0KKRSLPNLRTVRVKLEDGTTVKLRVAASTLRTMKKRTy1-like NLS Q7UP72-0KKRFRLSAKGKAMHRQSGTSHLAKGLSKKRTy1-like NLS Q7VTD6-0KKRGEKSMDLRLAGELIDASEGRGAAMKKRTy1-like NLS Q7W2F9-0KKRGEKSMDLRLAGELIDASEGRGAAMKKRTy1-like NLS Q7WRC8-0KKRGEKSMDLRLAGELIDASEGRGAAMKKRTy1-like NLS Q828D0-0KKRRAILEAASGYRGQRSRLYRKAKEQVTHSLVYNYNDRKKRTy1-like NLS Q895M9-0KKRIQYNERLEFLGDSVLQLVITEYLFMNYKDKSEGELSKKRTy1-like NLS Q8AAP0-0KKRFTLTGTGKIKRKHAFHSHILTKKSKKRTy1-like NLS Q8D1X2-0KKRDLENCSYQASGISVVSHPKNPYVPTSHLNIRFFLAKNKKRTy1-like NLS Q8K908-0KKRRDFLKNNHVSFLISIHADSSKKRAttorney Docket No.204606-0174-00WOTy1-like NLS Q8P0C9-0KKRLATHNAGKGAKYTRYRLPVSLLYYEVFDSKEAAMSAEALFKKRTy1-like NLS Q8XKR1-0KKRGYQKYGVRPRLAKKKTVMCKIARKQGKKRTy1-like NLS Q8XL46-0KKRSSHSKKQRGNKSRGFDQKSQRGSKGKKRTy1-like NLS Q8XV09-0KKRSEKSMALRLAGELLEASEGRGGAMKKRTy1-like NLS Q93Q47-0KKREIFTSIFEDKIDLKLFSFLIILIEKKRTy1-like NLS Q9L0Q6-0KKRARRPGVPTRGDKKRAPRLGVPARGDKKRTy1-like NLS Q9L0Q6-1KKRAPRLGVPARGDKKRARRPGVPAREDKKRTy1-like NLS Q9L0Q6-2KKRARRPGVPAREDKKRAPRPGVPTRGDKKRTy1-like NLS Q9L0Q6-3KKRAPRPGVPTRGDKKRAPRLGVPARGDKKRTy1-like NLS Q9L0Q6-4KKRARRPGVPTRGDKKRAPRLGVPARGDKKRARRPGVPAREDKKRTy1-like NLS Q9L0Q6-5KKRAPRLGVPARGDKKRARRPGVPAREDKKRAPRPGVPTRGDKKRTy1-like NLS Q9L0Q6-6KKRARRPGVPAREDKKRAPRPGVPTRGDKKRAPRLGVPARGDKKRTy1-like NLS Q9X1S8-0KKRKKYLKAAKGYRGALSRRYKLAKQMYVRSKWYSYVGRKQKKRTy1-like NLS A1CNV8-0KKRTSVPDDDFVFTLSDDENDVLENGADEGDEQADEETASGSKKRTy1-like NLS A1D1R8-0KKRAAAKDDDFVLTLSDDENDVLENGVEEDTLSSSKKRTy1-like NLS A1D731-0KKRLQKQAKEEERARREAEKAAEEAAAKAEQEKKLEEQRKKRTy1-like NLS A2QAX7-0KKRANADDDFVLTLSDDENDTLNQLEEEGEGDDGALATGSKTKKRTy1-like NLS A3LQ55-0KKRAQETKIDSKESVKESPKQENSILKRLASSIKKQELPFTKKRTy1-like NLS A5DGY0-0KKRSAEEEEKDLKKIMMTNKQRKLYNKMQYGINKKETRQDELAKKRTy1-like NLS A5DKW3-0KKRKAHEERKEEKRSYKKTKSDRSAPKTKAKSKKRTy1-like NLS A5DLG8-0KKRTIDKVDDSVEDGAEKKPEAAVKNDGETAEKPEKKHKKRTy1-like NLS A5DY34-0KKRKANEERKEEGKERSYKKTKADRTKLKTKAKSSSKKRTy1-like NLS A6RBB0-0KKRAAQKKKEEEELERQKMMMSRKKRTy1-like NLS A6RMZ2-0KKRKREIERLEKMTDEEKKEEQAKEKELQDLIEQVKKRTy1-like NLS A6ZL85-0KKRGHNSIIGHEKTNALETLKKKKKRTy1-like NLS A6ZZJ1-0KKRSAKIKKATFDANKKKEVGVSDLTLLSKISDESINENLKKRTy1-like NLS A7E4K0-0KKRKAREILDKHRKEEKELVKEGKTPYYLKKAEQKKRTy1-like NLS G0S8I1-0KKRTHDELEQDGKEEEEKKEGEKPSSQNRAERDEPEKKRTy1-like NLS O13527-0KKRSLEDNETEIKVSRDTWNTKNMRSLEPPRSKKRTy1-like NLS O13535-0KKRSLEDNETEIKVSRDTWNTKNMRSLEPPRSKKRTy1-like NLS O13658-0KKRLPQAKRACAKCQKDNKKCDDARPCQRCIKAKTDCIDLPRKKRTy1-like NLS O14064-0KKRNSEEANDENDETNLKIPIPEKKRTy1-like NLS O14076-0KKRKVNELSQDVISLHSPKESNARKTKKNKNKKKKKRTy1-like NLS O42668-0KKRKSKSKQESSDSGVSEDDEIPLSDARNKTKKRTy1-like NLS O43068-0KKRKLKDTVSNCEFTEEDSESSFLLETIQPTKSTLRRSISPLKKRTy1-like NLS O74777-0KKRAEKKEQQKEKKKEKEKERMKAFIPPEESSKKRTy1-like NLS O74862-0KKRSANELAIDDQDTKESTDLAGTEDSAPKANKKRTy1-like NLS O94383-0KKRLTYSELFHKTQELNEELQSCLQKILEASADRNESKQDAKKRTy1-like NLS O94487-0KKRTKIQCSHFDLLVKLGQGGYGSVWLAKKRTy1-like NLS O94585-0KKRKSKLVEMTPKGLKKRKRVQIQEGSVSTNTKKRTy1-like NLS O94652-0KKRNVEEQNLIEQSITESQRIFSEKQRLEQERFNRELLEKKRAttorney Docket No.204606-0174-00WOTy1-like NLS P0C2I2-0KKRSLEDNETEIKVSRDTWNTKNMRSLEPPRSKKRTy1-like NLS P0C2I3-0KKRSLEDNETEIKVSRDTWNTKNMRSLEPPRSKKRTy1-like NLS P0C2I5-0KKRSLEDNETEIKVSRDTWNTKNMRSLEPPRSKKRTy1-like NLS P0C2I6-0KKRSLEDNETEIKVSRDTWNTKNMRSLEPPRSKKRTy1-like NLS P0C2I7-0KKRSLEDNETEIKVSRDTWNTKNMRSLEPPRSKKRTy1-like NLS P0C2I9-0KKRSLEDNETEIKVSRDTWNTKNMRSLEPPRSKKRTy1-like NLS P0C2J0-0KKRSLEDNETEIKVSRDTWNTKNMRSLEPPRSKKRTy1-like NLS P0C2J1-0KKRSLEDNETEIKVSRDTWNTKNMRSLEPPRSKKRTy1-like NLS P0C2J3-0KKRSLEDNETEIEVSRDTWNNKNMRSLEPPRSKKRTy1-like NLS P0C2J5-0KKRSLEDNETEIEVSRDTWNNKNMRSLEPPRSKKRTy1-like NLS P0CM98-0KKRVEKLDWMYAAPSTEGGALGGARIGERDMEEYLLGKKRTy1-like NLS P0CM99-0KKRVEKLDWMYAAPSTEGGALGGARIGERDMEEYLLGKKRTy1-like NLS P0CX63-0KKRSLEDNETEIEVSRDTWNNKNMRSLEPPRSKKRTy1-like NLS P0CX64-0KKRSLEDNETEIEVSRDTWNNKNMRSLEPPRSKKRTy1-like NLS P13902-0KKRKRRSKKINKLTDGQIRINHVSSEKKRTy1-like NLS P14746-0KKRSKLTSKHAETADSQSSAASSDHESGQSQAHTKKRTy1-like NLS P20484-0KKRDAETADIGDQSEVESDTEELKKIMFGEKKKLNKKKRTy1-like NLS P22936-0KKRAGGTKRKKATAEPSDNDILSQMTKKRTy1-like NLS P25384-0KKRSLEDNETEIEVSRDTWNNKNMRSLEPPRSKKRTy1-like NLS P32597-0KKRVYYDDGLTEEQFLEAVEDDNMSLEDAIKKRTy1-like NLS P36006-0KKRSAKIKKATFDANKKKEVGISDLTLLSKISDESINENLKKRTy1-like NLS P36080-0KKRKRLESEQEQDQDEIASDSDMEDIDSDLENNSKKRTy1-like NLS P38112-0KKRGHNSIIGHEKTNALETLKKKKKRTy1-like NLS P47098-0KKRSLEDNETEIKVSRDTWNTKNMRSLEPPRSKKRTy1-like NLS P47100-0KKRSLEDNETEIKVSRDTWNTKNMRSLEPPRSKKRTy1-like NLS P51599-0KKRAHSSGERRSSVSKPARDPSDKPEESPSKKKKRTy1-like NLS P53119-0KKRLKSSLRFRKLEILLELPFFIPFEERVDLFYMFIALDKKRTy1-like NLS P53123-0KKRMQAVFTNVHKFKPDASRDESKETYYIGLKKKRTy1-like NLS P53125-0KKRKPTEVNDSENNSSEEDKKKGQNVTSETHSKKRTy1-like NLS Q01301-0KKREAEAQWCRIHGQSCWKRDALPEAEPQWCRIHGQSCWKKRTy1-like NLS Q03434-0KKRSLEDNETEIKVSRDTWNTKNMRSLEPPRSKKRTy1-like NLS Q03494-0KKRSLEDNETEIEVSRDTWNNKNMRSLEPPRSKKRTy1-like NLS Q03612-0KKRSLEDNETEIKVSRDTWNTKNMRSLEPPRSKKRTy1-like NLS Q03619-0KKRSLEDNETEIKVSRDTWNTKNMRSLEPPRSKKRTy1-like NLS Q03707-0KKRKDPDSDDWSESNSKENKIDNKHLNLLSSDSEIEQDYQKAKKRTy1-like NLS Q03855-0KKRSLEDNETEIKVSRDTWNTKNMRSLEPPRSKKRTy1-like NLS Q04214-0KKRSLEDNETEIKVSRDTWNTKNMRSLEPPRSKKRTy1-like NLS Q04500-0KKRVIDDEDDKEVDTTLPGWGEWAGAGSKPKNKKRTy1-like NLS Q04670-0KKRSLEDNETEIKVSRDTWNTKNMRSLEPPRSKKRTy1-like NLS Q04711-0KKRSLEDNETEIKVSRDTWNTKNMRSLEPPRSKKRTy1-like NLS Q06132-0KKRRRGNGKHLSRKEKRKMERADKKRAttorney Docket No.204606-0174-00WOTy1-like NLS Q07163-0KKRSLEDNETEIKVSRDTWNTKNMRSLEPPRSKKRTy1-like NLS Q07509-0KKRNGSMHNMYYASVPFLLFSNAYSIDFSRHVNEFLEKKRTy1-like NLS Q07791-0KKRSLEDNETEIEVSRDTWNNKNMRSLEPPRSKKRTy1-like NLS Q07793-0KKRSLEDNETEIKVSRDTWNTKNMRSLEPPRSKKRTy1-like NLS Q09094-0KKRYMTTKQTRTVQNQTMPRSNTTTKKRTy1-like NLS Q09180-0KKREFEAAPAKTYADFLRAYQSWNTFVNPDRPNLKKRTy1-like NLS Q09180-1KKREFEAAPEKSYADFLRAYHSWNTFVNPDRPNLKKRTy1-like NLS Q09180-2KKREFEAAPAKTYADFLRAYQSWNTFVNPDRPNLKKRTy1-like NLS Q09863-0KKRDKKKQLKLAKEEERQRREAERLAEQAAQKALEAKRQEEARKKRTy1-like NLS Q0U8V9-0KKREALLNIEEGRDVKGNRMVGMKKRTy1-like NLS Q12088-0KKRSLEDNETEIKVSRDTWNTKNMRSLEPPRSKKRTy1-like NLS Q12112-0KKRSLEDNETEIKVSRDTWNTKNMRSLEPPRSKKRTy1-like NLS Q12113-0KKRSLEDNETEIEVSRDTWNNKNMRSLEPPRSKKRTy1-like NLS Q12141-0KKRSLEDNETEIKVSRDTWNTKNMRSLEPPRSKKRTy1-like NLS Q12193-0KKRSLEDNETEIKVSRDTWNTKNMRSLEPPRSKKRTy1-like NLS Q12269-0KKRSLEDNETEIKVSRDTWNTKNMRSLEPPRSKKRTy1-like NLS Q12273-0KKRSLEDNETEIKVSRDTWNTKNMRSLEPPRSKKRTy1-like NLS Q12316-0KKRSLEDNETEIKVSRDTWNTKNMRSLEPPRSKKRTy1-like NLS Q12337-0KKRSLEDNETEIEVSRDTWNNKNMRSLEPPRSKKRTy1-like NLS Q12339-0KKRKLGPKAPNPLSVKKKKKVNSPSDEVKDKEDTSKEKKKRTy1-like NLS Q12414-0KKRSLEDNETEIKVSRDTWNTKNMRSLEPPRSKKRTy1-like NLS Q12472-0KKRSLEDNETEIEVSRDTWNNKNMRSLEPPRSKKRTy1-like NLS Q12490-0KKRSLEDNETEIKVSRDTWNTKNMRSLEPPRSKKRTy1-like NLS Q12491-0KKRSLEDNETEIEVSRDTWNNKNMRSLEPPRSKKRTy1-like NLS Q12501-0KKRSLEDNETEIEVSRDTWNNKNMRSLEPPRSKKRTy1-like NLS Q1DNW5-0KKRKGGNGSSDEEEDSDDDMAGKDKGKRKKRTy1-like NLS Q1EA54-0KKRKRKHGGSGNAALTSANAAKSLVKTTLSSKGEASAEKQEMKKRTy1-like NLS Q2HFA6-0KKRKADRRSDKEDDKLGKKEKKSKKRTy1-like NLS Q2HFA6-1KKRDKKEKKERRDKKEKKEKRRIEKAAAESGAETGDSISEEKKRTy1-like NLS Q2UQI6-0KKRTAPKDDDFVLTLSDDENDVFSGINEDGDDHLDEETAKSTTKKRTy1-like NLS Q4HZ42-0KKRVDEAREKRVGRFRDGMGSKKELKGREDIRKARIEKEKKRTy1-like NLS Q4P6I3-0KKRIDRVDWMYATPATTGSGSAAEMEDYLLGKKRTy1-like NLS Q4WHF8-0KKRKTSDRETQNVTTKKQKIETIERKKSSLKKKRTy1-like NLS Q4WRV2-0KKRAAARDDDFVLTLSDDENDIFENGVEEDGDNAQEDTLSSSKKRTy1-like NLS Q4WXQ7-0KKRLQKQAKEEERARREAEKAAEEAAAKAEQEKKLEEQRKKRTy1-like NLS Q5A2K0-0KKRLQQLAKEEERKRKEEELKAKEEEQRLQKEKLKAEQKKRTy1-like NLS Q5A310-0KKRSEIERYSKMFWQNYQKIEGYEKYLSQIEAVEKKRTy1-like NLS Q5ACW8-0KKRVAPLLVSTSAAPKNVLQKPLEKKRTy1-like NLS Q5B6K3-0KKRAAKKRQEEEELERQKMMMSRKKRTy1-like NLS Q6BXL7-0KKRSAEDEEKDLKKIMMSNKQRKLYKKMQYGIDKKEARQDDLTKKRTy1-like NLS Q6C1L3-0KKRGSEAVEESDSDSEESESESDDDKKSRKSSKKEKKDKKSKKRAttorney Docket No.204606-0174-00WOTy1-like NLS Q6C233-0KKRAEKSRTPLTSSTAVISDRPVASVSADTTLVGSVASKKRTy1-like NLS Q6C2J1-0KKRFSGSSVTVAMTTAAAAAARLTAFKVTKPKKRTy1-like NLS Q6C7C0-0KKREVGVSDLTLLSKVSEEAINENLKKRTy1-like NLS Q6CJY0-0KKRLKRTKVPSKIWVDNLNMEYIYAKGESIKKRTy1-like NLS Q6CJY0-1KKRYKSELDRAEAIERQLIREEEHLKSLQEKGETQAKKRTy1-like NLS Q6FML5-0KKRKLEVKSDQQTPPATQSEINHTSSVRLEENIQGIKRKKRTy1-like NLS Q75F02-0KKRGQAAKEAVEVDLVDVGDYVKKATERFQHTVELHKKRTy1-like NLS Q7S2A9-0KKRQRKRRREAGSGDEEDEGVSDEVLAARAKKRTy1-like NLS Q7S9J4-0KKRVAEAKEKRIGKYKDGEGSKRELKTATDIRKARAVAEKKRTy1-like NLS Q7SFJ3-0KKRDPPPRPKYEVFTDAQLSREIASYGFKPIKKRTy1-like NLS Q875K1-0KKRGISALMAKAKEASDVATNGYFKHWDGGVSEDDEKKRTy1-like NLS Q8SUT1-0KKRQSKRLTTRKREGMLKRARANERKKRTy1-like NLS Q8SVI7-0KKRKKKTVKELNRIRRASRISKKEKKRTy1-like NLS Q8SVI7-1KKRKKKTVKELNRIRRASRISKKEKKRIFKRYIGMKKRTy1-like NLS Q92393-0KKRSLEDNETEIKVSRDTWNTKNMRSLEPPRSKKRTy1-like NLS Q99109-0KKRTGSQYSYYNGGHNVESTNENKLVDASDLLANVDILKKRTy1-like NLS Q99231-0KKRSLEDNETEIKVSRDTWNTKNMRSLEPPRSKKRTy1-like NLS Q99337-0KKRSLEDNETEIKVSRDTWNTKNMRSLEPPRSKKRTy1-like NLS Q9USK2-0KKRVWSREKRLLSEMAITNHSPLLNVDDYRKFREDLWKKRTy1-like NLS Q9UTQ5-0KKRKRRAKAAEREAQEAEELSMELGLDENLKKRTy1-like NLS A7MD48-0KKRRRSSSYSPSPVKKKKKKSSKKHKRRRSFSKKRTy1-like NLS O15446-0KKRKKPKGKETFEPEDKTVKQEQINTEPLEDTVLSPTKKRTy1-like NLS O15446-1KKRKKQSQESRMPETVPQEEMPGPPLNSESGEEAPTGRDKKRTy1-like NLS O15446-2KKRKRQKGTEGMEPEEGVTVESQPQVKVEPLEEAIPLPPTKKRTy1-like NLS O43148-0KKRKLDPEIVPEEKDCGDAEGNSKKRTy1-like NLS O60271-0KKRSSIWQFFSRLFSSSSNTTKKPEPPVNLKYNAPTSHVTPSVKKRTy1-like NLS O75128-0KKRRAPPPPGSGPPVQDKASEKVSLGSQIDLQKKKRTy1-like NLS O75400-0KKRQRSESRSASEHSSSAESERSYKKSKKHKKKSKKRTy1-like NLS O75691-0KKRKALEFVTNPDIAAKKKMKKHKNKSEAKKRTy1-like NLS O75937-0KKRFRQLSILVHPDKNQDDADRAQKAFEAVDKAYKLLLDQEQKKRTy1-like NLS O76021-0KKRQQARKTASVLSKDDVAPESGDTTVKKPESKKEQTPEHGKKKRTy1-like NLS O94964-0KKRARLEEENEELRQRLIETELAKQVLQTELERPREHSLKKRTy1-like NLS P23497-0KKRRHRSKVNGLQRGRKKDRPRKHLTLNNKVQKKRTy1-like NLS P30414-0KKRRKEKKVKHKKKGKKQKHCRRHKQTKKRTy1-like NLS P42081-0KKRPRNSYKCGTNTMEREESEQTKKRTy1-like NLS P46100-0KKRQTQSESSNYDSELEKEIKSMSKIGAARTTKKRTy1-like NLS P51608-0KKRGRKPGSVVAAAAAEAKKKAVKESSIRSVQETVLPIKKRTy1-like NLS P59797-0KKRGDGFVNESRLQKIVSVIDEEIKKRTy1-like NLS P82979-0KKRKERFGIVTSSAGTGTTEDTEAKKRTy1-like NLS Q12830-0KKRKREESVEQKRSKQNATKLSALLFKHKEQLRAEILKKRTy1-like NLS Q13409-0KKRKEEERKKKETDQKKEAVAPVQEESDLEKKRAttorney Docket No.204606-0174-00WOTy1-like NLS Q13427-0KKRHKSSSSSSSSSSDSDSSSDSQSSSDSSDSESATEEKSKKRTy1-like NLS Q15361-0KKRKKDFQHLISSPLKKSRICDETANATSTLKKRTy1-like NLS Q15361-1KKRKKDFQHLISSPLKKSRICDETANATSTLKKRKKRTy1-like NLS Q53SF7-0KKRDQTASAPATPLVNKHRPTFTRSNTISKPYISNTLPSDAPKKRTy1-like NLS Q5M9Q1-0KKRKNKSSKRKHRKYSDSDSNSESDTNSDSDDDKKRTy1-like NLS Q5T3I0-0KKRRQKEEEEATASERNDADEKHPEHAEQNIRKSKKKKRTy1-like NLS Q5T3I0-1KKRQQQEEEDLNLEDRGEETVLGGGTREAESRACSDGRSRKSKKKRTy1-like NLS Q68D10-0KKRIELKHDKKARAMAKRTKDNFHGYNGIPIEEKSKKRTy1-like NLS Q6IPR3-0KKRIERFYNCLQHALERETMTNLHPKIKEKNNSSYIHKKKRTy1-like NLS Q6PD62-0KKRRKGSGSEQEGEDEEGGERKKKKRTy1-like NLS Q6PD62-1KKRRRHPKGEEGSDDDETENGPKPKKRTy1-like NLS Q6PD62-2KKRGGGGGRRSKKGGEFDEFVNDDTDDDLPISKKKKRTy1-like NLS Q6S8J7-0KKRTALHLACANGNSEVVSLLLDRQCQLHVFDSKKRTy1-like NLS Q6ZU65-0KKRKRKEEGEKEKKPRKKVPKQLGVVALNSHKSEKKKKRTy1-like NLS Q7Z7B0-0KKRLDGIEEVEREITRGRSRKGSELTCPEDNKIKELTLEIERLKKRTy1-like NLS Q8N9E0-0KKRKKSYPDDKPLSSESSSESDYEEDVQAKKKRTy1-like NLS Q8NCU4-0KKRKALEAKKEEEEIQREMVKLRREIIERRRTVKAAWKIEKKRTy1-like NLS Q8NFU7-0KKRKRCGVCEPCQQKTNCGECTYCKNRKNSHQICKKRTy1-like NLS Q96DY2-0KKRMEAEQEMVRMVRAATLIQALWKGYLVRSLLRSKKKRTy1-like NLS Q96GD3-0KKRGRTPKTLISHPISAPSKTAEPLKFPKKRTy1-like NLS Q96P65-0KKRVGDGSVLRTIHGKEMSKIARKKKRTy1-like NLS Q96QC0-0KKRKDEGKSRTTLPERPLTEVKAETRAEEAPEKKRTy1-like NLS Q9BQG0-0KKRKSEDGTPAEDGTPAATGGSQPPSMGRKKRTy1-like NLS Q9BQG0-1KKRKKRKSEDGTPAEDGTPAATGGSQPPSMGRKKRTy1-like NLS Q9BRU9-0KKRKKISGPNPLSCLKKKKKAPDTQSSASEKKRTy1-like NLS Q9H0S4-0KKRSREDAGDNDDTEGAIGVRNKVAGGKMKKRTy1-like NLS Q9H6F5-0KKRKGSSSQAPASKKLNKEELPVIPKGKPKSGRVWKDRSKKRTy1-like NLS Q9HCK1-0KKRSKLKHRDLEVSCEPDGFEMNFQCAPPLPSDTDQPQETVKKRTy1-like NLS Q9HCK8-0KKRRKKSAGERLKEEKPKKSKTSGASKTKGKSKLNTITPVVGKKRTy1-like NLS Q9NPI1-0KKRKKGEKQIPGEEKGRKRRRVKEDKKKRTy1-like NLS Q9NSV4-0KKREAEEKEKRVRIAKELAERERLERQQKKKRTy1-like NLS Q9NUL3-0KKRAATTVLQELKKLPPLPVVEKPKLFFKKRTy1-like NLS Q9NWT1-0KKRGLTGDSKKATKESGLISTKKRKMVEMLEKKRTy1-like NLS Q9NX58-0KKRKREKKELKLENHQENSRNQKPKKRTy1-like NLS Q9UGU5-0KKRSYKDFLREEEEIAAQVRNSSKKKLKDSELYFLGTDTHKKKRTy1-like NLS Q9UNS1-0KKRQLLDSDEEQEEDEGRNRAPELGAPGIQKKKRTy1-like NLS Q9Y2X3-0KKRGKKKHIKEEPLSEEEPCTSTAIASPEKKKKKKKKRTy1-like NLS Q9Y6X0-0KKRGRPKKQPLLTVETIHEGTSTSPVSPISREFPGTKKRTy1-like NLS KKRKGKVKKTKKKKTSNKKEKTKKSKSKNKKDAKKKAKKR A0A1I8M2I8-0Ty1-like NLS A1XDC0-0KKRKFTKEDAIYGVFNDGWGDYEDEEESKMTEEEYYKMKKRAttorney Docket No.204606-0174-00WOTy1-like NLS A7S6A5-0KKRKRATTTEEPQGSRNELVALENIEGIYKKRTy1-like NLS A8XI07-0KKRGPKKKKYKPEAAEVEKKNEEGDTVKENPIAEAKKRTy1-like NLS A8XI07-1KKRINEVSTTEGAPAEKKKKVEKWLNTSSEDGEGTKKKKRTy1-like NLS C0HKU9-0KKRNFDEIDRSSMPFPYATKRFYHLSSFDKKRTy1-like NLS C6KTD2-0KKRKNIKLFLNIINSNEYINVNKIFHGKCIYELPFYVNKERIKKKRTy1-like NLS O16140-0KKRKAMVEELIKRGYAPDPIADWKKRTy1-like NLS O17828-0KKRRGRKPKKKDDPKMELKDEVKDLKDFVVEESTSASSSAPKKRTy1-like NLS O17966-0KKRLEKENRKIKEEDDEDSDDEDDEKAKKKKRTy1-like NLS O44410-0KKRKRGPKKKKFKPEVAGKAAETENDDVAAAPEEADPIAEAKKRTy1-like NLS O44410-1KKRKITDEKDAQHVPAEKREKVENWLKKSTEKPTSSQSDAEKKKKRTy1-like NLS O45244-0KKRDDNKDKEGSSMDKLREESRRQYLKKRTy1-like NLS P0DP78-0KKRVTSKSRTKRVKMFKQCQWVDADNQRDIKRKKRTy1-like NLS P0DP78-1KKRMTEKDISSSESSISESKSLNCSASNQNENEKRKKRTy1-like NLS P0DP79-0KKRVTSKSRTKRVKMFKQCQWVDADNQRDIKRKKRTy1-like NLS P0DP79-1KKRMTEKDISSSESSISESKSLNCSASNQNENEKRKKRTy1-like NLS P0DP80-0KKRVTSKSRTKRVKMFKQCQWVDADNQRDIKRKKRTy1-like NLS P0DP80-1KKRMTEKDISSSESSISESKSLNCSASNQNENEKRKKRTy1-like NLS P0DP81-0KKRVTSKSRTKRVKMFKQCQWVDADNQRDIKRKKRTy1-like NLS P0DP81-1KKRMTEKDISSSESSISESKSLNCSASNQNENEKRKKRTy1-like NLS P14196-0KKRGRPKKPKDENESDYNNTSFSDSNTDGTPKKRTy1-like NLS P22058-0KKRGRPSKASVGGKSSTAAVAAISPGIKKRTy1-like NLS P26023-0KKRANRKKANNNKKRASNNRKKANNNNNNKKRTy1-like NLS P26991-0KKRDWYIQPTCARSGDGLYQGLDWLSDYIFDKKNKKKGKKRTy1-like NLS P35978-0KKRHLEDSLDMLNEEIVKLRAAEEIRLTDQEDKKRTy1-like NLS P46758-0KKRNNVFLTITDVIGRVVVSQSAGSCKITTKKKKRTy1-like NLS P46758-1KKRYYLFFSKKRNNVFLTITDVIGRVVVSQSAGSCKITTKKKKRTy1-like NLS P46867-0KKREIEIQQQLELQEETTLEIRERNVSLEQEVELKKRTy1-like NLS P54644-0KKRWFILKGGDLSYYKTKGELVPLGVIHLNTSGHIKNSDRKKRTy1-like NLS P54812-0KKRPNRLIIDQSDNDDNSMVMLSQAKMDELGLFRGDSVILKGKKRTy1-like NLS P83212-0KKRKGKGKKRGKGRRRGSKGRKKKKGKGKKRTy1-like NLS Q04621-0KKRARSPSKKARRRSRSTKKTAAKRRKRSSSPKKRTy1-like NLS Q08696-0KKREAEKKKCAKLAKKEKEAAEKKKRTy1-like NLS Q08696-1KKRCKDLAKNKKKGHKKKGRNENRKKRTy1-like NLS Q08696-2KKRKEAAEKKKCEKAAKKRKEAAEKKKCEKSAKKRTy1-like NLS Q08696-3KKRKEEAEKKKCEKTAKKRKEAAEKKKCEKAAKKRTy1-like NLS Q08696-4KKRKEAAEKKKCEKAAKKRKEEAEKKKCEKTAKKRTy1-like NLS Q08696-5KKRKEEAEKKKCEKTAKKRKETAEKKKCEKAAKKRTy1-like NLS Q08696-6KKRKETAEKKKCEKAAKKRKQAAEKKKCEKAAKKRTy1-like NLS Q09223-0KKRGSKTSELKQNETTDAVVVNNEKVKKRTy1-like NLS Q09595-0KKRKSAIDVLKMPLFDILRSSPPKKRTy1-like NLS Q1ELU8-0KKRFNLNLEEARQAFQTFKPDWNKIRYDAMKMQTSLGQMKKRAttorney Docket No.204606-0174-00WOTy1-like NLS Q23120-0KKRSDKRARSESKSRSRSGGRRSRSNSPPNRSPSPKKRTy1-like NLS Q23272-0KKRGVVLKPSVDEETDRRRMLNRIAAVRYREKKRTy1-like NLS Q24537-0KKRFHEMAEKDKQRYEAEMQNYVPPKGAVVGRGKKRTy1-like NLS Q27450-0KKRQHSSRSNESVSSSTSTEKSHKKTKKTKMKEKKRTy1-like NLS Q29DY1-0KKREIEIQQQLELQEETTLEIRERNVSLEQEVELKKRTy1-like NLS Q4N4T9-0KKRMDDFVSQVGEDRLATYKPFTEDPSKKRTy1-like NLS Q54QQ2-0KKRSKKRNSIDSGRKDKSKKRKSKKKKRTy1-like NLS Q54QQ2-1KKRDSKNRRSHSKSDENEEGEEDDEERRKKRTy1-like NLS Q54S20-0KKRLFEDFTNLYIEDDCLLSCSFSFFIYNKSIHLHFNVDKKRTy1-like NLS Q54US6-0KKRIPNATEEEIEILEGMLCWNPKKRTy1-like NLS Q54VU4-0KKRKKDRDHNNNNNNNNNNNNNNNEQTSDSSDSSDSDSESRSKKKRTy1-like NLS Q54XP6-0KKRAAEQKIIDDEKARLKSIENSKKRTy1-like NLS Q551H0-0KKRKCNFSSPLLFSPFKYGVTSPFSPSKMKLKSPFKKRTy1-like NLS Q557G1-0KKRLKREKRLKEKQDLLLIKLEKQKEKQLEEQMKKRTy1-like NLS Q55CE0-0KKRIKFTHMVGRGQYGKVYDALYDKKRTy1-like NLS Q61R02-0KKRREKEARKMKRAGGRFKSRATGANAEEKRAKKRTy1-like NLS Q75JP5-0KKRLQKEEQDRLAAAELERKRLEKEAEEKRIAQELEKKRTy1-like NLS Q8I5P7-0KKRKITSSEYGMSLEFFKKNPKKVVQNLKKRTy1-like NLS Q8I5P7-1KKRDLIKNNKLIHNVDVNYINMITNDNHISSEKCRDIKKKRTy1-like NLS Q8IBP1-0KKRIYGYLFYTTLLKNITSLNNLFVHYILNNYFFFHSKSMYMLKKRTy1-like NLS Q8ILR9-0KKRIFIYENTVYYTPDDCVFCTQLNCTIKKRTy1-like NLS Q93591-0KKRRNEETRSARSVGIAAADARQAAIVAEKTSGPSLLEIHQKKRTy1-like NLS Q95Y36-0KKRPGTTSKKSIATVTASPEMSSKTTQMEPEQDGEGKKRTy1-like NLS Q9NBL2-0KKRLARGGHVEDPTADPLDISLPSSKKKRTy1-like NLS Q9NDE8-0KKRSDESDDDNIGLVARGSPRFFGKKRTy1-like NLS Q9NDE8-1KKRADDEDILLGERGSPRFFGKKRANDENISFSLRGSPRFFGKKRTy1-like NLS Q9NDE8-2KKRSDDNVALDLRGSPRFFGKRQSSDLDDEISVALRGSPRFFGKKRTy1-like NLS Q9V5P6-0KKRTEDGRPTLSAHPARFSPEDKYSRQRLTIKKRTy1-like NLS Q9VDS6-0KKRRVEKKKSKTKWTERKQKVEHDKEKRQKKRTy1-like NLS Q9VGW1-0KKRPRQPRKRIVMVEEVKRKIRTPIKEEEEVQERKKRTy1-like NLS Q9VH89-0KKRVQILYIESESEDEDEQDSHDKSLDSPEKKRTy1-like NLS Q9VKM6-0KKRKRGVVNTKAYKETKPAVKKETKATPALHKKRTy1-like NLS Q9VNH1-0KKRKCVITLDEKQVESKRLKKEESNVEATSRPPAQSPKKRTy1-like NLS Q9W261-0KKRKKPQTAAKSSSRSDSDSDWANNKAGAPSSKKKKRTy1-like NLS E1B7L7-0KKRKRKEEGEKEKKPRKKVPKQLGVMALNSHKSEKKKKRTy1-like NLS Q08DU1-0KKRKKVSGPNPLSCLKKKKKTQDTNSSASEKKRTy1-like NLS Q0III3-0KKRKEEERKKKETDQKKEAVAPVQEESDLEKKRTy1-like NLS Q17QH9-0KKRLEDEQEMVRMVRAATLIQALWKGYLVRSMLKSKKKKRTy1-like NLS Q29S22-0KKRSREDVGDNDDTEGAIGVRNKVAGGKMKKRTy1-like NLS Q2KIQ2-0KKREEMEEENRKIIEFAKLQQQREEDRMAKVQEKVKKKRTy1-like NLS Q2KJE1-0KKRRQYQEEEVLDGPGVNTAQKAKKKKQKKRAttorney Docket No.204606-0174-00WOTy1-like NLS Q2KJE1-1KKRKQKEEEEPTTTERSAEKYSEHTDESIRKSKKKKRTy1-like NLS Q2TBX7-0KKREGSSAQAPASKKPKEEIPVIPKGKPKSGRVWKDRSKKRTy1-like NLS Q4R7K1-0KKRKLDPEIVPEEKDCGDDEGNSKKRTy1-like NLS Q4R8Y5-0KKRMEAEQEMVRMVRAATLIQAFWKGYLVRSLLRSKKKRTy1-like NLS Q58DE2-0KKRSTSVMSFFSKVSWNLRLQKQEPLKNVFFILAETARDPSVKKRTy1-like NLS Q58DU0-0KKRHKKEKRKKEKDRGRRLDSSLAPAPIQHDSDSSTCCKKRTy1-like NLS Q5E9U4-0KKRIERFYHCLQHALEKETVSTTSQPKEKVNTSYIRKKKRTy1-like NLS Q5NVM2-0KKRKEEERKKKETDQKKEAVAPVQEESDLEKKRTy1-like NLS Q5R4V4-0KKRKERFGIVTSSAGTGTTEDTEAKKRTy1-like NLS Q5R8B0-0KKRKKGEKQIPGEEKGRKRRRVKEDKKKRTy1-like NLS Q5RB69-0KKRKGSSSLAPASKKLNKEELPVIPKGKPKSGRVWKDRSKKRTy1-like NLS Q5RCE6-0KKRQQARKTASVLSKDDVAPESGDTTVKKPESKKEQTPEHGKKKRTy1-like NLS Q5TM61-0KKRKDEGKSRTTPPERPLTEVKAETRAEEAPEKKRTy1-like NLS Q767K9-0KKRKEEGKSRTTPPERPLTEVKAETRAEEAPEKKRTy1-like NLS Q7YQM3-0KKRQTQSESSNYDSELEKEIKSMSKIGAARTTKKRTy1-like NLS Q7YQM4-0KKRQTQSESSNYDSELEKEIKSMSKIGAARTTKKRTy1-like NLS Q7YR38-0KKRKDEGKSRTTLPERPLTEVKAETRAEEAPEKKRTy1-like NLS Q95KD7-0KKRKALEAKKEEEEIQREMVKLRREIIERRRTVKEAWKIEKKRTy1-like NLS Q95LG8-0KKRGRKPGSVVAAAAAEAKKKAVKESSIRSVQETVLPIKKRTy1-like NLS Q9N1Q7-0KKRILESHNNTLVDPCEEHKKKNPDASVKFSEFLKKRTy1-like NLS A2WSD3-0KKRLRMLAVLGVELVFMLAVILGVLLGAHTHKKRTy1-like NLS A2XVF7-0KKRKRGDDDYALPGDGDLVVECEEEGEKGEKRVKKKRTy1-like NLS A2XVF7-1KKRKKRKRGDDDYALPGDGDLVVECEEEGEKGEKRVKKKRTy1-like NLS A2XVF7-2KKRKRGDDDYALPGDGDLVVECEEEGEKGEKRVKKKRRSRKKRTy1-like NLS A2XVF7-3KKRKKRKRGDDDYALPGDGDLVVECEEEGEKGEKRVKKKRRSRKKRTy1-like NLS A3AVH5-0KKRKRGDDDYALPGDGDLVVECEEEGEKGEKRVKKKRTy1-like NLS A3AVH5-1KKRKKRKRGDDDYALPGDGDLVVECEEEGEKGEKRVKKKRTy1-like NLS A3AVH5-2KKRKRGDDDYALPGDGDLVVECEEEGEKGEKRVKKKRRSRKKRTy1-like NLS A3AVH5-3KKRKKRKRGDDDYALPGDGDLVVECEEEGEKGEKRVKKKRRSRKKRTy1-like NLS A4QJZ0-0KKRNPESALLNQEKNIEENYAESTIKKRTy1-like NLS A4QK78-0KKRNPESALSNQEKNIEKNYAESKIKKRTy1-like NLS A4QKG5-0KKRDKGEKKDFCFLTVWGMETELPFGSAQKKPSFFEPISKELKKRTy1-like NLS A4QKQ3-0KKRNPESALLNQEKNIEENFAESMIKKRTy1-like NLS A6MN03-0KKRQDKKNPGSDAQNQKDVEEDSTRSDSKKRTy1-like NLS A8MS85-0KKRKKKDEGLDEDDYLLLQDNNVKFKKRTy1-like NLS A9XMT3-0KKRKSLERYGSITSAVSDDKGDTTKKRTy1-like NLS B8YIE8-0KKRHYGGESSLAGTQSSIIMRTAAEMLAVYQACGIKKKRTy1-like NLS F4HVZ5-0KKRGRNIDDAEEVENELKRVEDELYKIPDHLKVKKRTy1-like NLS F4IQK5-0KKREEEAEQARKREEEREKEEEMAKKRTy1-like NLS F4IQK5-1KKREEEEARKREEERKREEEEAKRREEERKKRTy1-like NLS O22812-0KKRRGRPRKYGPDSGEMSLGLNPGAPSFTVSQPSSGGDGGEKKRAttorney Docket No.204606-0174-00WOTy1-like NLS O49323-0KKRQDFVKDRRWIKREYDEFKVRINGLPEQIKKRTy1-like NLS O64571-0KKRKLETCDETWKREVVQAEEAKGGGEQKSESKKAKKQDKEKKRTy1-like NLS O64639-0KKRKPREWWKEEFCEELTRKKRKKKKKKKRTy1-like NLS O64639-1KKRGLSSISSIDSWFHRDDGASSVHDHNLNPTKRKKRTy1-like NLS O64639-2KKRKKKKKKKRGLSSISSIDSWFHRDDGASSVHDHNLNPTKRKKRTy1-like NLS O65743-0KKRRRATKKPYSRSIVGATLEVIQKKRTy1-like NLS O81072-0KKRVDSVVIGRSSKARRGHREPRKARSSGRLEAEKKRTy1-like NLS P09975-0KKRNKKFTISIKLFKKFYKNKLNENGEYKIESQILQNEKELNKKRTy1-like NLS P0C262-0KKRIYLISDRNPSTGETGWYDKDKGRESKKGIWQIFKKRTy1-like NLS P29345-0KKRIAKAKSEAAEYQKLLASRLKEQREKRSESLAKKRTy1-like NLS P50888-0KKRRRTTKKPYSRSIVGATLEVIQKKRTy1-like NLS P51269-0KKRRAKVFKLAKGFKGAHNSLFRTAKQQVLKALRYSYVGRKRKKRTy1-like NLS P51430-0KKRIAKANSDAADYQKLLASRLKEQRDRRSESLAKKRTy1-like NLS Q06FP6-0KKRFLDEMNKKKSCLKMVAQFFFQFKKKRTy1-like NLS Q06FP6-1KKRTNLKKGPQSKLTKKKKERKVDKTRAIINEIERVLKEKKKRTy1-like NLS Q06FP6-2KKRFLDEMNKKKSCLKMVAQFFFQFKKKRKNKKIDKAIKGINKKKRTy1-like NLS Q06R72-0KKRNKMQDLTNRANKARNEIERIRKEKKKKKRTy1-like NLS Q06R98-0KKRASVRKICQKCRLTRRRGRIRVICSNPRHKKRTy1-like NLS Q1KVQ9-0KKRRTLQEWQIQPKKYLLEKHNIKVLKKRTy1-like NLS Q1XDL7-0KKRRAKIFKLAKGFKGAHKCLFRTAKQQVLKALRYSYVGRKRKKRTy1-like NLS Q38873-0KKRLTAAQVLEHTWILNAKKAPNVSLGETVKARLKQFSVMNKLKKRTy1-like NLS Q3E8X3-0KKRLTLKHRIEIVMGIICMIVAGFQEKKRTy1-like NLS Q3ZJ77-0KKRIDNFKKEALLKANPQIQANPQLKKRTy1-like NLS Q42438-0KKRLSAAQVLEHSWIQNAKKAPNVSLGETVKARLKQFSVMNKLKKRTy1-like NLS Q4V3E0-0KKRRGRPRKYEANGAPLPSSSVPLVKKRTy1-like NLS Q66GN2-0KKRGYNGKVIALIVALSTVISIMLVLLFLFMMYKKRTy1-like NLS Q6K5K2-0KKRDASFVQPDERTAQTFSTKNKEKKRTy1-like NLS Q6YS30-0KKRKLEAEAEVVVVEAAAATSTDEATKSSKKKRTy1-like NLS Q84WK0-0KKRSRATSTDKNKRARVNKRAQKNVEMSGDNNEGEEEEGETKLKKRTy1-like NLS Q84Y18-0KKRVSDESDSDSDSGDRKRRRRSMKKRTy1-like NLS Q8H991-0KKRKRSKPLRPAPSRVLRSTSEKKNKAHNELLNDGAGVQPAEKKRTy1-like NLS Q8RWY7-0KKRKRSSKKDKHRRSKQRDKRHEKKRTy1-like NLS Q8RWY7-1KKRSMRDKRPKRKSRRSPDSLEDSNSGSEASLSDVNVEIGAKKRTy1-like NLS Q8VZ67-0KKRKSKKNKRHKKHSSRTVEETDESSTGSEDSREKRGSKKRTy1-like NLS Q8VZN4-0KKREEQLEKARLAMERKRKLHEKAAAKAVIRVKKEAEKKRTy1-like NLS Q8W0K2-0KKRLRMLAVLGVELVFMLAVILGVLLSAHTHKKRTy1-like NLS Q8W490-0KKRKGSETEGWENLPDDLSCSTASRSSNFRSHFSLEGYARLKKRTy1-like NLS Q9CAE4-0KKRVYKDKSRCYECGDEGHLSYECPKNQLGPRERPPPPKKRTy1-like NLS Q9FMZ4-0KKRMEALNLPKLSQILNSTSVKISPMKKRTy1-like NLS Q9FMZ4-1KKRSIPRTPEKKMVDVKRVHIQRRGVGKKRTy1-like NLS Q9FRI0-0KKRVKTQCVIKSSDKSDHDTLLKKKRAttorney Docket No.204606-0174-00WOTy1-like NLS Q9LKI5-0KKRVYRLVKASDVKSKEHVKNKSGKKRTy1-like NLS Q9LUJ5-0KKRPGVSPGDRSGGKGRPTSRMGNKKRTy1-like NLS Q9LUR0-0KKRNTCSVSSQTRKVSLKISKINGVGVRCTPNSKKRTy1-like NLS Q9LVU8-0KKRQDKLEMSEIKQFFDRPIMKAAKELNVGLTVLKKRTy1-like NLS Q9LVU8-1KKRNLKKKRQDKLEMSEIKQFFDRPIMKAAKELNVGLTVLKKRTy1-like NLS Q9LYK7-0KKRKLYDAMKISQSRKRSGVEIIEQRKKRTy1-like NLS Q9M020-0KKRGYNSQVLALIVALSGVTVILLALLFFFVMYKKRTy1-like NLS Q9M1L7-0KKRQPEFRMLGKDHLSDQESVEVRVPDSIKKPIDSSKKRTy1-like NLS Q9M3V8-0KKRVAKAKSEAAEYQKLLASRLKEQRDRRSESLAKKRTy1-like NLS Q9SRQ3-0KKRKEETVLLPSGVQGLGMGLPDMRSKKRTy1-like NLS Q9ZPV5-0KKRVKKLKSKKLEAEEELNNVQEIDAHDIVMEQKSDKKRTy1-like NLS B1AQJ2-0KKRKKTPNGDPQRLGIDTLLPQCLRGAPAAARRKRKKRTy1-like NLS D3ZUI5-0KKRRAPPPPSPGLLGQDKVSEKASLSSQADLQKKKRTy1-like NLS D4A666-0KKRKRKEEGEKEKKPRKKVPKQLGVVALNSHKSEKKKKRTy1-like NLS E1U8D0-0KKRMRLEEENEGLRQRLIETELAKQVLQTELDRPREHSLKKRTy1-like NLS G3V8T1-0KKRAKMGKLKDKFKTELESTSEILGFDVKTKKRTy1-like NLS O35821-0KKRKKLKSEGTTSEKKAASQQDAVTEGAMPAATGKDQPPSTGKKRTy1-like NLS O88487-0KKRKEEERKKKETDQKKEAAVSVQEESDLEKKRTy1-like NLS O88665-0KKRKKGEKQAPGEEKGRKRRRVKEDKKKRTy1-like NLS P61364-0KKRSFSGFGSPLDRLSAGSVEHRGKQRKAVDHSKKRTy1-like NLS P61365-0KKRSFSGFGSPLDRLSAGSVEHRGKQRRVVDHSKKRTy1-like NLS P83858-0KKRVGDSSALQTIHGKEMSKIARKKKRTy1-like NLS P83861-0KKRVGDSSALQTIHGKEMSKIARKKKRTy1-like NLS Q00566-0KKRGRKPGSVVAAAAAEAKKKAVKESSIRSVQETVLPIKKRTy1-like NLS Q05CL8-0KKRDKVEASSLPEARAGKRERCSAEDEDCLPPRPKAKKRTy1-like NLS Q09XV5-0KKRRKKSSGERLKEEKPKKSKTAAASKTKGKSKLNTITPVVGKKRTy1-like NLS Q3TFK5-0KKRKQKEGEEAATTEKSLGDELLGHTDRSFRDSRKKKKRTy1-like NLS Q3TFK5-1KKRQKAERQGTAIGSEEEEAAGESGPRELSTEQSDQPSRKKKKRTy1-like NLS Q3TFK5-2KKRRKQRHEEDGEMGVCDEGGRDVTSRPKAVNSGGDKDPRRSSKKRTy1-like NLS Q3TYA6-0KKRTKMGKLKDKFKTELESTSEIIGFDVKTKKRTy1-like NLS Q3UMF0-0KKREQTASAPATPLVSKHRPSFTRSNTISKPYISNTLPSDAPKKRTy1-like NLS Q498U4-0KKRKERFGIVTSSAGTGTTEDTEAKKRTy1-like NLS Q4V7C4-0KKRPKGYVQTRTGRTSLKNSSETVGQKRKKAEETKGLPPKKRTy1-like NLS Q4V8G7-0KKRQRLIDVQDELIRLEPQLKQLQTKYDDLKKRTy1-like NLS Q505I5-0KKRKMYEDKPLSSESLSESDCGEVQAKKKKSGEERERTTDKAKKRTy1-like NLS Q562C7-0KKRVKQFKNKPQGGKGPKDKFQKANKFNKKRTy1-like NLS Q566R3-0KKRQTCEEDLDTQDEEDKDDLTKKERKVRKKDKKKRTy1-like NLS Q566R3-1KKRQQYCEEVLDVSNKDDGRTWEAEDGGERSQPHPKARAKKKKRTy1-like NLS Q566R3-2KKRRRRHHEEEEEMGVCDEGGRDVTGGPKAVNSGADTDPWRSSKKRTy1-like NLS Q58A65-0KKRSSIWQFFSRLFSSSSNATKKPEPPVNLKYNAPTSHVTPSVKKRTy1-like NLS Q5NBX1-0KKRRAPPPPSPKLLGQDKVSEKASLSSQADLQKKKRAttorney Docket No.204606-0174-00WOTy1-like NLS Q5XG71-0KKRKALEFVTNPDIAAKKKLKKHKNKSEAKKRTy1-like NLS Q5XI01-0KKRDKVETGGLPESKAGKRERSSAEDEDCLPPRPKLKKRTy1-like NLS Q5XIB5-0KKRVIASPQAPASKKLKEELPVIPKGKPKSGRVWKDRSKKRTy1-like NLS Q5XIR6-0KKRVEAEREMVRMVRAATLIQAMWKGYLVRSMLRSRKKKRTy1-like NLS Q60848-0KKRSLKLTEGKSLVDGNGEKPVMKKKRTy1-like NLS Q62018-0KKRRRRPPKGEEGSEEEETENGPKPKKRTy1-like NLS Q62018-1KKRGGGGGRRSKKGGEFDEFVNDDTDDDLPVSKKKKRTy1-like NLS Q62187-0KKRRREPQTPAQETLESEWPQKAKKKKRTy1-like NLS Q62871-0KKRKEEERKKKETDQKKEAAVSVQEESDLEKKRTy1-like NLS Q63520-0KKRSAGIIEDVGGEVQNMLEKFGADINKALLAKKKRTy1-like NLS Q642C0-0KKRFRQLSILVHPDKNQDDADRAQKAFEAVDKAYKLLLDQEQKKRTy1-like NLS Q68SB1-0KKRAATTVLQELKKLPPLPVIEKPKLFFKKRTy1-like NLS Q6AYK5-0KKRKKGQEAGHEAGGEDAAEANGAPEKKRTy1-like NLS Q6NZB0-0KKRFRQLSILVHPDKNQDDADRAQKAFEAVDKAYKLLLDQEQKKRTy1-like NLS Q76KJ5-0KKRKRYFMQEEMEAKTMEPVAELPVPSATSSKKRTy1-like NLS Q76KJ5-1KKRKKSKGTETSQVEHTEPVAQTEPPEGTFLFPTKKRTy1-like NLS Q76KJ5-2KKRKRQKEADGTEEVDGIVADSQPQVIVEAQEETILLSPTKKRTy1-like NLS Q78WZ7-0KKRHQEDQDPIFQASDSSGYQSDHNKKKKKRTy1-like NLS Q78WZ7-1KKRHQEDQDPIFQASDSSGYQSDHNKKKKKRKHSEEANFESPKKRTy1-like NLS Q7TNB4-0KKRRTPLLSFLSKVSWKLRLQKRELLKNALFVLAERARDPNAKKRTy1-like NLS Q7TPV4-0KKRKKLKSEGTTPEKNAASQQDAVTEGAMPAATGKDQPPSTGKKKRTy1-like NLS Q80WC1-0KKRKRKEEGEKEKKPRKKVPKQLGVVALNSHKSEKKKKRTy1-like NLS Q80Z37-0KKRLRNKRSRSRESSSRPRARKDKKRTy1-like NLS Q811R2-0KKRREKAIGEGRVVYIRNLSGDMSSRELKKRTy1-like NLS Q8BKA3-0KKRRRSPSYSPSPVKKKKKKSSKKHKRHRSFSKKRTy1-like NLS Q8CJ67-0KKRAATTVLQELKKLPPLPVVEKPKLFFKKRTy1-like NLS Q8K214-0KKRGRTPKILIPHPTSTPSKSAEPLKFPKKRTy1-like NLS Q8K4T4-0KKRLDGIEEVEREINRGRSCKGSEFTCPEDNKIRELTLEIERLKKRTy1-like NLS Q8R5F3-0KKRFGGVQELLSQQKKSGEVAVLKRDGRYIYYLITKKRTy1-like NLS Q91X13-0KKRLRRMTPFWRGVSLRPIGASCRDDSECITRLCKKRTy1-like NLS Q9CS72-0KKRLDGIEEVEREINRGRLCKGSEFTCPEDNKIRELTLEIERLKKRTy1-like NLS Q9CVI2-0KKRKMYEDKPLSSESLSESDCGEVQAKRKKSGEERERTTDKAKKRTy1-like NLS Q9CWX9-0KKRKREDAGDDDDKEGAIGVRNKVAGGKMKKRTy1-like NLS Q9CZX5-0KKRDRAELQPGGPSEDECSDASVEAAEDCVQTPDIQDDVPKPKKRTy1-like NLS Q9D1J3-0KKRKERFGIVTSSAGTGTTEDTEAKKRTy1-like NLS Q9D3V1-0KKRVEAEREMVRMVRAATLIQAVWKGYLVRSILRSKKKKRTy1-like NLS Q9DBQ9-0KKRKLKADDTDNVYYNANRKNSKRLNVEVFIPKKRTy1-like NLS Q9JIX5-0KKRRKKSSGERLKEEKPKKSKTAAASKTKGKSKLNTITPVVGKKRTy1-like NLS Q9JJ80-0KKRKNISQDTFGTTFGRIHMQKQDLSKLQTRKMKGLKKRTy1-like NLS Q9JJ89-0KKRVIASPQAPASKKLKEKEELPVIPKGKPKSGRVWKDRSKKRTy1-like NLS Q9R1C7-0KKRQRSESHSASERSSSAESERSYKKSKKHKKKSKKRAttorney Docket No.204606-0174-00WOTy1-like NLS Q9R1X4-0KKRQLLDSDEEEDDEGRRQAVSGTPRVHRKKRTy1-like NLS Q9Z180-0KKRGRPKKQPLLTVETIHEGTSTSPVSPISREFPGTKKRTy1-like NLS Q9Z207-0KKREAAEKEKRARIAKERAEKERLERQQEKKRTy1-like NLS Q9Z2D6-0KKRGRKPGSVVAAAAAEAKKKAVKESSIRSVHETVLPIKKRTy1-like NLS KKRKRCGVCVPCLRKEPCGACYNCVNRSTSHQICKMRKCEQLKKKR A0A1L8GSA2-0Ty1-like NLS A0JP82-0KKRKRCGVCVPCLRKEPCGACYNCVNRSTSHQICKMRKCEQLKKKRTy1-like NLS A1A5I1-0KKRKRSSTRKASDETDSESETDSRESFKKKRTy1-like NLS A1L2T6-0KKRKKKHPSKKERKGTIRDYECAETKQKKKHKKRTy1-like NLS A2RUV0-0KKRRREHGQLWFPEGFIPKEPSKKKRTy1-like NLS A9JRD8-0KKRMAAELYPVSDHATLQKSGAVMLSLPEKKRTy1-like NLS E7F568-0KKRRAPAPPPAPTQTLPPTSQISLGSPSSHNLLKKRTy1-like NLS F1QFU0-0KKRKHVKNEEDETNHEKTKQHLKEEKRRKKRTy1-like NLS F1QWK4-0KKRSSLFSPRKSRKNGNAAAESGRETGKHKSLWKTVFSVYKKDKKRTy1-like NLS K9JHZ4-0KKRKRCGVCVPCLRKEPCGTCYNCVNRSTSHQICKMRKCEQLKKKRTy1-like NLS P07193-0KKRGLKPSGKRELAHPPSSEPPLPKKRTy1-like NLS P0CB65-0KKRKRHRSASRKGRHSGSSSRRKRKEDKKHKKRTy1-like NLS P12957-0KKRREERRKILEEEEQKKKQEEAERKIREEEEKKRTy1-like NLS P13505-0KKRREERRKILEEEEQKKKQEEAERKIREEEEKKRTy1-like NLS P21783-0KKRRREHGQLWFPDGFIPKEPSKKKRTy1-like NLS Q28BS0-0KKRRRRDEDSDTEGEQQTQPDGEAKKRTy1-like NLS Q28BS0-1KKRRRRDEDSDTEGEQQTQPDGEAKKRRKKRTy1-like NLS Q28G05-0KKRECAANGVDYERAKLLEISAEDAERWERKKKRTy1-like NLS Q32N87-0KKRDEERKRELEERRKKEQEEQLRRLREEEREEDEKKKRTy1-like NLS Q3KPW4-0KKRSSSRCRSGSDSPARKHSTLAKYRAEVPDRRKKERRKKRTy1-like NLS Q4QR29-0KKRRKRPQKAAGSDDDEEQTPQSKKRTy1-like NLS Q4QR29-1KKRKKGGSSSGEQGEGGDEGEGGEKKKKKRTy1-like NLS Q5BL56-0KKRSYKDLLREEEEIAEQVRKSSKKRTy1-like NLS Q5XJK9-0KKRKVEKQIPDATKKKKATVKKECFITQERSEEKPDNESNKNKKRTy1-like NLS Q5ZIJ0-0KKRHDSPDLSPQEQQTTPDLSLQRKKRTy1-like NLS Q640I9-0KKRKFEKPPDPSVRKRLKLVKEEKLLRKKRTy1-like NLS Q6DEU9-0KKRRKRPQKGGDGSDDDEDQAPQPKKRTy1-like NLS Q6DEU9-1KKRRKRPQKGGDGSDDDEDQAPQPKKRQPKKRTy1-like NLS Q6DEU9-2KKRKKGGGSSGSGGEQGEGGEEGEGGEKKKKKRTy1-like NLS Q6DK85-0KKRPEVLTIHENSRQENYETETVQVKQAKPNKKRTy1-like NLS Q6DRI7-0KKRKHKLQETKGKIKKSESVQNTDPTEEADSSVKKKKKRTy1-like NLS Q6DRL5-0KKRKNRKKPTILEGKETETPVEKTPEGASGEGKKNKNKKKNKKRTy1-like NLS Q6NV26-0KKRKKNFMMMRHSQNVRTKGKRSFREKQIALRDSLLKKRTy1-like NLS Q6NWI1-0KKRRARSRSNSRSKHRHRSRSRSKSREKKKRTy1-like NLS Q6NYJ3-0KKRRKTCKTSTTDSRSSRLEEDPVGQDIPDESNAQSSPKKKRTy1-like NLS Q6P4K1-0KKRDEERRRELEERRKKEQEEQLRRLREEEREEEERKKRAttorney Docket No.204606-0174-00WO708 Ty1-like NLS Q6WKW9-0KKRSYKDLLREEEEIAEQVRKSSKKR709 Ty1-like NLS Q7ZUF2-0KKREREQSETASTAPVEPFTLPKPVEVVVEEKKR710 Ty1-like NLS Q7ZW47-0KKRAALSILQELKKLPVLPVVEKPKVHYKKR711 Ty1-like NLS Q7ZXZ0-0KKRRRREGESDTEEEQTQPDGEGKKR712 Ty1-like NLS Q7ZXZ0-1KKRRRREGESDTEEEQTQPDGEGKKRRKKR713 Ty1-like NLS Q7ZYR8-0KKRRPRSRSRSRSKHRHRSKSRSKSREKKKR714 Ty1-like NLS Q8AVQ6-0KKRECAANGVDFERAKLLEISAEDAERWERKKKR715 Ty1-like NLS Q9DE07-0KKRKELDDVSEDVETLEMVFESRDLDWEEQTANGDQEAQSNKRKKR716 Ty1-like NLS P03086-0KKRAQRILIFLLEFLLDFCTGEDSVDGKKR717 Ty1-like NLS P09814-0KKRAPKLRATCSSSGLDNLYNAVANIAKASSLRVEVIHKKR718 Ty1-like NLS P0CK10-0KKRAPKLRATCSSSGLDNLYNAVANIAKASSLRVEVIHKKR719 Ty1-like NLS P15075-0KKRRYFMDIWMKDSSGQEFFIEIKPKKETQPPVKPAHLTTAAKKR720 Ty1-like NLS P51724-0KKREILIRSLQMIKRQAVKSAANQRNPMGGSWKKR721 Ty1-like NLS P52344-0KKRPCKVKRKLFGSENIRPNKKIPLASDVDNELEKKR722 Ty1-like NLS P52531-0KKRMDDTEKRKLQEDRRNEKQDLKKR723 Ty1-like NLS Q5UP41-0KKRYRSPSSDRSLSRDRSSSRDRSYKKR724 Ty1-like NLS Q9DUC0-0KKRRPGRGDTSATSDGGTSPKRPLRDSWNLLPQRRAAHKKR725 Ty1-like NLS Q9XJS3-0KKRVVGLESCSNVLKTRLMRFALKKRSEQ ID NO:726 aacatccccgctctggtggaaaaccagaagaagtactttggcacctacagcgtgatggccatgctgaacgctcagaccgtgctggaccacatccagaaggtggccgatattg agggcgagcagaacgagaacaacgagaatctgtggtttcaccccgtgatgagccacctgtacaacgccaagaacggctacgacaagcagcccgagaaaaccatgttcatc atcgagcggctgcagagctacttcccattcctgaagatcatggccgagaaccagagagagtacagcaacggcaagtacaagcagaaccgcgtggaagtgaacagcaacg acatcttcgaggtgctgaagcgcgccttcggcgtgctgaagatgtacagggacctgaccaaccactacaagacctacgaggaaaagctgaacgacggctgcgagttcctga ccagcacagagcaacctctgagcggcatgatcaacaactactacacagtggccctgcggaacatgaacgagagatacggctacaagacagaggacctggccttcatccag gacaagcggttcaagttcgtgaaggacgcctacggcaagaaaaagtcccaagtgaataccggattcttcctgagcctgcaggactacaacggcgacacacagaagaagctg cacctgagcggagtgggaatcgccctgctgatctgcctgttcctggacaagcagtacatcaacatctttctgagcaggctgcccatcttctccagctacaatgcccagagcgag gaacggcggatcatcatcagatccttcggcatcaacagcatcaagctgcccaaggaccggatccacagcgagaagtccaacaagagcgtggccatggatatgctcaacga agtgaagcggtgccccgacgagctgttcacaacactgtctgccgagaagcagtcccggttcagaatcatcagcgacgaccacaatgaagtgctgatgaagcggagcagcg acagattcgtgcctctgctgctgcagtatatcgattacggcaagctgttcgaccacatcaggttccacgtgaacatgggcaagctgagatacctgctgaaggccgacaagacct gcatcgacggccagaccagagtcagagtgatcgagcagcccctgaacggcttcggcagactggaagaggccgagacaatgcggaagcaagagaacggcaccttcggca acagcggcatccggatcagagacttcgagaacatgaagcgggacgacgccaatcctgccaactatccctacatcgtggacacctacacacactacatcctggaaaacaaca aggtcgagatgtttatcaacgacaaagaggacagcgccccactgctgcccgtgatcgaggatgatagatacgtggtcaagacaatccccagctgccggatgagcaccctgg aaattccagccatggccttccacatgtttctgttcggcagcaagaaaaccgagaagctgatcgtggacgtgcacaaccggtacaagagactgttccaggccatgcagaaaga agaagtgaccgccgagaatatcgccagcttcggaatcgccgagagcgacctgcctcagaagatcctggatctgatcagcggcaatgcccacggcaaggatgtggacgcctt catcagactgaccgtggacgacatgctgaccgacaccgagcggagaatcaagagattcaaggacgaccggaagtccattcggagcgccgacaacaagatgggaaagag aggcttcaagcagatctccacaggcaagctggccgacttcctggccaaggacatcgtgctgtttcagcccagcgtgaacgatggcgagaacaagatcaccggcctgaacta ccggatcatgcagagcgccattgccgtgtacgatagcggcgacgattacgaggccaagcagcagttcaagctgatgttcgagaaggcccggctgatcggcaagggcacaa cagagcctcatccatttctgtacaaggtgttcgcccgcagcatccccgccaatgccgtcgagttctacgagcgctacctgatcgagcggaagttctacctgaccggcctgtcca acgagatcaagaaaggcaacagagtggatgtgcccttcatccggcgggaccagaacaagtggaaaacacccgccatgaagaccctgggcagaatctacagcgaggatct gcccgtggaactgcccagacagatgttcgacaatgagatcaagtcccacctgaagtccctgccacagatggaaggcatcgacttcaacaatgccaacgtgacctatctgatcg ccgagtacatgaagagagtgctggacgacgacttccagaccttctaccagtggaaccgcaactaccggtacatggacatgcttaagggcgagtacgacagaaagggctccc tgcagcactgcttcaccagcgtggaagagagagaaggcctctggaaagagcgggcctccagaacagagcggtacagaaagcaggccagcaacaagatccgcagcaacc ggcagatgagaaacgccagcagcgaagagatcgagacaatcctggataagcggctgagcaacagccggaacgagtaccagaaaagcgagaaagtgatccggcgctac agagtgcaggatgccctgctgtttctgctggccaaaaagaccctgaccgaactggccgatttcgacggcgagaggttcaaactgaaagaaatcatgcccgacgccgagaag ggaatcctgagcgagatcatgcccatgagcttcaccttcgagaaaggcggcaagaagtacaccatcaccagcgagggcatgaagctgaagaactacggcgacttctttgtgc tggctagcgacaagaggatcggcaacctgctggaactcgtgggcagcgacatcgtgtccaaagaggatatcatggaagagttcaacaaatacgaccagtgcaggcccgag atcagctccatcgtgttcaacctggaaaagtgggccttcgacacataccccgagctgtctgccagagtggaccgggaagagaaggtggacttcaagagcatcctgaaaatcc tgctgaacaacaagaacatcaacaaagagcagagcgacatcctgcggaagatccggaacgccttcgatcacaacaattaccccgacaaaggcgtggtggaaatcaaggcc ctgcctgagatcgccatgagcatcaagaaggcctttggggagtacgccatcatgaag SEQ ID NO:727 aacatccccgctctggtggaaaaccagaagaagtactttggcacctacagcgtgatggccatgctgaacgctcagaccgtgctggaccacatccagaaggtggccgatattg agggcgagcagaacgagaacaacgagaatctgtggtttcaccccgtgatgagccacctgtacaacgccaagaacggctacgacaagcagcccgagaaaaccatgttcatc atcgagcggctgcagagctacttcccattcctgaagatcatggccgagaaccagagagagtacagcaacggcaagtacaagcagaaccgcgtggaagtgaacagcaacg acatcttcgaggtgctgaagcgcgccttcggcgtgctgaagatgtacagggacctgaccaaccactacaagacctacgaggaaaagctgaacgacggctgcgagttcctga ccagcacagagcaacctctgagcggcatgatcaacaactactacacagtggccctgcggaacatgaacgagagatacggctacaagacagaggacctggccttcatccagAttorney Docket No.204606-0174-00WO gacaagcggttcaagttcgtgaaggacgcctacggcaagaaaaagtcccaagtgaataccggattcttcctgagcctgcaggactacaacggcgacacacagaagaagctg cacctgagcggagtgggaatcgccctgctgatctgcctgttcctggacaagcagtacatcaacatctttctgagcaggctgcccatcttctccagctacaatgcccagagcgag gaacggcggatcatcatcagatccttcggcatcaacagcatcaagctgcccaaggaccggatccacagcgagaagtccaacaagagcgtggccatggatatgctcaacga agtgaagcggtgccccgacgagctgttcacaacactgtctgccgagaagcagtcccggttcagaatcatcagcgacgaccacaatgaagtgctgatgaagcggagcagcg acagattcgtgcctctgctgctgcagtatatcgattacggcaagctgttcgaccacatcaggttccacgtgaacatgggcaagctgagatacctgctgaaggccgacaagacct gcatcgacggccagaccagagtcagagtgatcgagcagcccctgaacggcttcggcagactggaagaggccgagacaatgcggaagcaagagaacggcaccttcggca acagcggcatccggatcagagacttcgagaacatgaagcgggacgacgccaatcctgccaactatccctacatcgtggacacctacacacactacatcctggaaaacaaca aggtcgagatgtttatcaacgacaaagaggacagcgccccactgctgcccgtgatcgaggatgatagatacgtggtcaagacaatccccagctgccggatgagcaccctgg aaattccagccatggccttccacatgtttctgttcggcagcaagaaaaccgagaagctgatcgtggacgtgcacaaccggtacaagagactgttccaggccatgcagaaaga agaagtgaccgccgagaatatcgccagcttcggaatcgccgagagcgacctgcctcagaagatcctggatctgatcagcggcaatgcccacggcaaggatgtggacgcctt catcagactgaccgtggacgacatgctgaccgacaccgagcggagaatcaagagattcaaggacgaccggaagtccattcggagcgccgacaacaagatgggaaagag aggcttcaagcagatctccacaggcaagctggccgacttcctggccaaggacatcgtgctgtttcagcccagcgtgaacgatggcgagaacaagatcaccggcctgaacta ccggatcatgcagagcgccattgccgtgtacgatagcggcgacgattacgaggccaagcagcagttcaagctgatgttcgagaaggcccggctgatcggcaagggcacaa cagagcctcatccatttctgtacaaggtgttcgcccgcagcatccccgccaatgccgtcgagttctacgagcgctacctgatcgagcggaagttctacctgaccggcctgtcca acgagatcaagaaaggcaacagagtggatgtgcccttcatccggcgggaccagaacaagtggaaaacacccgccatgaagaccctgggcagaatctacagcgaggatct gcccgtggaactgcccagacagatgttcgacaatgagatcaagtcccacctgaagtccctgccacagatggaaggcatcgacttcaacaatgccaacgtgacctatctgatcg ccgagtacatgaagagagtgctggacgacgacttccagaccttctaccagtggaaccgcaactaccggtacatggacatgcttaagggcgagtacgacagaaagggctccc tgcagcactgcttcaccagcgtggaagagagagaaggcctctggaaagagcgggcctccagaacagagcggtacagaaagcaggccagcaacaagatccgcagcaacc ggcagatgagaaacgccagcagcgaagagatcgagacaatcctggataagcggctgagcaacagccggaacgagtaccagaaaagcgagaaagtgatccggcgctac agagtgcaggatgccctgctgtttctgctggccaaaaagaccctgaccgaactggccgatttcgacggcgagaggttcaaactgaaagaaatcatgcccgacgccgagaag ggaatcctgagcgagatcatgcccatgagcttcaccttcgagaaaggcggcaagaagtacaccatcaccagcgagggcatgaagctgaagaactacggcgacttctttgtgc tggctagcgacaagaggatcggcaacctgctggaactcgtgggcagcgacatcgtgtccaaagaggat SEQ ID NO:728 aacatccccgctctggtggaaaaccagaagaagtactttggcacctacagcgtgatggccatgctgaacgctcagaccgtgctggaccacatccagaaggtggccgatattg agggcgagcagaacgagaacaacgagaatctgtggtttcaccccgtgatgagccacctgtacaacgccaagaacggctacgacaagcagcccgagaaaaccatgttcatc atcgagcggctgcagagctacttcccattcctgaagatcatggccgagaaccagagagagtacagcaacggcaagtacaagcagaaccgcgtggaagtgaacagcaacg acatcttcgaggtgctgaagcgcgccttcggcgtgctgaagatgtacagggacctgaccaacgcatacaagacctacgaggaaaagctgaacgacggctgcgagttcctga ccagcacagagcaacctctgagcggcatgatcaacaactactacacagtggccctgcggaacatgaacgagagatacggctacaagacagaggacctggccttcatccag gacaagcggttcaagttcgtgaaggacgcctacggcaagaaaaagtcccaagtgaataccggattcttcctgagcctgcaggactacaacggcgacacacagaagaagctg cacctgagcggagtgggaatcgccctgctgatctgcctgttcctggacaagcagtacatcaacatctttctgagcaggctgcccatcttctccagctacaatgcccagagcgag gaacggcggatcatcatcagatccttcggcatcaacagcatcaagctgcccaaggaccggatccacagcgagaagtccaacaagagcgtggccatggatatgctcaacga agtgaagcggtgccccgacgagctgttcacaacactgtctgccgagaagcagtcccggttcagaatcatcagcgacgaccacaatgaagtgctgatgaagcggagcagcg acagattcgtgcctctgctgctgcagtatatcgattacggcaagctgttcgaccacatcaggttccacgtgaacatgggcaagctgagatacctgctgaaggccgacaagacct gcatcgacggccagaccagagtcagagtgatcgagcagcccctgaacggcttcggcagactggaagaggccgagacaatgcggaagcaagagaacggcaccttcggca acagcggcatccggatcagagacttcgagaacatgaagcgggacgacgccaatcctgccaactatccctacatcgtggacacctacacacactacatcctggaaaacaaca aggtcgagatgtttatcaacgacaaagaggacagcgccccactgctgcccgtgatcgaggatgatagatacgtggtcaagacaatccccagctgccggatgagcaccctgg aaattccagccatggccttccacatgtttctgttcggcagcaagaaaaccgagaagctgatcgtggacgtgcacaaccggtacaagagactgttccaggccatgcagaaaga agaagtgaccgccgagaatatcgccagcttcggaatcgccgagagcgacctgcctcagaagatcctggatctgatcagcggcaatgcccacggcaaggatgtggacgcctt catcagactgaccgtggacgacatgctgaccgacaccgagcggagaatcaagagattcaaggacgaccggaagtccattcggagcgccgacaacaagatgggaaagag aggcttcaagcagatctccacaggcaagctggccgacttcctggccaaggacatcgtgctgtttcagcccagcgtgaacgatggcgagaacaagatcaccggcctgaacta ccggatcatgcagagcgccattgccgtgtacgatagcggcgacgattacgaggccaagcagcagttcaagctgatgttcgagaaggcccggctgatcggcaagggcacaa cagagcctcatccatttctgtacaaggtgttcgcccgcagcatccccgccaatgccgtcgagttctacgagcgctacctgatcgagcggaagttctacctgaccggcctgtcca acgagatcaagaaaggcaacagagtggatgtgcccttcatccggcgggaccagaacaagtggaaaacacccgccatgaagaccctgggcagaatctacagcgaggatct gcccgtggaactgcccagacagatgttcgacaatgagatcaagtcccacctgaagtccctgccacagatggaaggcatcgacttcaacaatgccaacgtgacctatctgatcg ccgagtacatgaagagagtgctggacgacgacttccagaccttctaccagtggaaccgcaactaccggtacatggacatgcttaagggcgagtacgacagaaagggctccc tgcagcactgcttcaccagcgtggaagagagagaaggcctctggaaagagcgggcctccagaacagagcggtacagaaagcaggccagcaacaagatccgcagcaacc ggcagatgagaaacgccagcagcgaagagatcgagacaatcctggataagcggctgagcaacagccggaacgagtaccagaaaagcgagaaagtgatccggcgctac agagtgcaggatgccctgctgtttctgctggccaaaaagaccctgaccgaactggccgatttcgacggcgagaggttcaaactgaaagaaatcatgcccgacgccgagaag ggaatcctgagcgagatcatgcccatgagcttcaccttcgagaaaggcggcaagaagtacaccatcaccagcgagggcatgaagctgaagaactacggcgacttctttgtgc tggctagcgacaagaggatcggcaacctgctggaactcgtgggcagcgacatcgtgtccaaagaggatatcatggaagagttcaacaaatacgaccagtgcaggcccgag atcagctccatcgtgttcaacctggaaaagtgggccttcgacacataccccgagctgtctgccagagtggaccgggaagagaaggtggacttcaagagcatcctgaaaatcc tgctgaacaacaagaacatcaacaaagagcagagcgacatcctgcggaagatccggaacgccttcgatgcaaacaattaccccgacaaaggcgtggtggaaatcaaggcc ctgcctgagatcgccatgagcatcaagaaggcctttggggagtacgccatcatgaag SEQ ID NO:729 atggactacaaagaccatgacggtgattataaagatcatgacatcgattacaaggatgacgatgacaagggcggaaactcaaagaaaaggtcactggaggacaacgaaacg gaaatcaaagtctccagagacacctggaacactaagaacatgcggtccctggaaccgccacgaagcaagaaacggatacatggaggcaacatccccgctctggtggaaaa ccagaagaagtactttggcacctacagcgtgatggccatgctgaacgctcagaccgtgctggaccacatccagaaggtggccgatattgagggcgagcagaacgagaaca acgagaatctgtggtttcaccccgtgatgagccacctgtacaacgccaagaacggctacgacaagcagcccgagaaaaccatgttcatcatcgagcggctgcagagctactt cccattcctgaagatcatggccgagaaccagagagagtacagcaacggcaagtacaagcagaaccgcgtggaagtgaacagcaacgacatcttcgaggtgctgaagcgc gccttcggcgtgctgaagatgtacagggacctgaccaacgcatacaagacctacgaggaaaagctgaacgacggctgcgagttcctgaccagcacagagcaacctctgag cggcatgatcaacaactactacacagtggccctgcggaacatgaacgagagatacggctacaagacagaggacctggccttcatccaggacaagcggttcaagttcgtgaa ggacgcctacggcaagaaaaagtcccaagtgaataccggattcttcctgagcctgcaggactacaacggcgacacacagaagaagctgcacctgagcggagtgggaatcg ccctgctgatctgcctgttcctggacaagcagtacatcaacatctttctgagcaggctgcccatcttctccagctacaatgcccagagcgaggaacggcggatcatcatcagatc cttcggcatcaacagcatcaagctgcccaaggaccggatccacagcgagaagtccaacaagagcgtggccatggatatgctcaacgaagtgaagcggtgccccgacgag ctgttcacaacactgtctgccgagaagcagtcccggttcagaatcatcagcgacgaccacaatgaagtgctgatgaagcggagcagcgacagattcgtgcctctgctgctgc agtatatcgattacggcaagctgttcgaccacatcaggttccacgtgaacatgggcaagctgagatacctgctgaaggccgacaagacctgcatcgacggccagaccagagt cagagtgatcgagcagcccctgaacggcttcggcagactggaagaggccgagacaatgcggaagcaagagaacggcaccttcggcaacagcggcatccggatcagaga cttcgagaacatgaagcgggacgacgccaatcctgccaactatccctacatcgtggacacctacacacactacatcctggaaaacaacaaggtcgagatgtttatcaacgaca aagaggacagcgccccactgctgcccgtgatcgaggatgatagatacgtggtcaagacaatccccagctgccggatgagcaccctggaaattccagccatggccttccacaAttorney Docket No.204606-0174-00WO tgtttctgttcggcagcaagaaaaccgagaagctgatcgtggacgtgcacaaccggtacaagagactgttccaggccatgcagaaagaagaagtgaccgccgagaatatcg ccagcttcggaatcgccgagagcgacctgcctcagaagatcctggatctgatcagcggcaatgcccacggcaaggatgtggacgccttcatcagactgaccgtggacgaca tgctgaccgacaccgagcggagaatcaagagattcaaggacgaccggaagtccattcggagcgccgacaacaagatgggaaagagaggcttcaagcagatctccacagg caagctggccgacttcctggccaaggacatcgtgctgtttcagcccagcgtgaacgatggcgagaacaagatcaccggcctgaactaccggatcatgcagagcgccattgc cgtgtacgatagcggcgacgattacgaggccaagcagcagttcaagctgatgttcgagaaggcccggctgatcggcaagggcacaacagagcctcatccatttctgtacaa ggtgttcgcccgcagcatccccgccaatgccgtcgagttctacgagcgctacctgatcgagcggaagttctacctgaccggcctgtccaacgagatcaagaaaggcaacag agtggatgtgcccttcatccggcgggaccagaacaagtggaaaacacccgccatgaagaccctgggcagaatctacagcgaggatctgcccgtggaactgcccagacaga tgttcgacaatgagatcaagtcccacctgaagtccctgccacagatggaaggcatcgacttcaacaatgccaacgtgacctatctgatcgccgagtacatgaagagagtgctg gacgacgacttccagaccttctaccagtggaaccgcaactaccggtacatggacatgcttaagggcgagtacgacagaaagggctccctgcagcactgcttcaccagcgtg gaagagagagaaggcctctggaaagagcgggcctccagaacagagcggtacagaaagcaggccagcaacaagatccgcagcaaccggcagatgagaaacgccagca gcgaagagatcgagacaatcctggataagcggctgagcaacagccggaacgagtaccagaaaagcgagaaagtgatccggcgctacagagtgcaggatgccctgctgttt ctgctggccaaaaagaccctgaccgaactggccgatttcgacggcgagaggttcaaactgaaagaaatcatgcccgacgccgagaagggaatcctgagcgagatcatgcc catgagcttcaccttcgagaaaggcggcaagaagtacaccatcaccagcgagggcatgaagctgaagaactacggcgacttctttgtgctggctagcgacaagaggatcgg caacctgctggaactcgtgggcagcgacatcgtgtccaaagaggatcgaggcggtggaggtagtggagggggaggatcaacgcgttctgtggtaccgcccaatcgctcgc agaccggctggccccggggggtcactcagttcggcaacaagtacatccagcagacgaagcccctcaccctggagcgcaccatcaacctgtaccctcttaccaattatactttt ggtacaaaagagcccctctacgagaaggacagctctgttgcagccagatttcagcgcatgagggaagaatttgataaaattggaatgaggaggactgtagaaggggttctgat tgtacatgagcaccggctaccccatgtgttactgctgcagctgggaacaactttcttcaaactacctggtggtgaacttaacccaggagaagatgaagttgaaggactaaaacg cttaatgacagagatactgggtcgtcaggatggagttttgcaagactgggtcattgacgattgcattggtaactggtggagaccaaattttgaacctcctcagtatccatatattcct gcacatattacaaagcctaaggaacataagaagttgtttctggttcagcttcaagaaaaagccttgtttgcagtccctaaaaattacaagctggtagctgcaccattgtttgaattgt atgacaatgcaccaggatatggacccatcatttctagtctccctcagctgttgagcaggttcaattttatttacaactagtaa SEQ ID Description Sequence NO:730 Linker sequence 1tcgcgaggcggtggaggtagtggagggggaggatcaacgcgt731 Linker sequence 2cgaggcggtggaggtagtggagggggaggatcaacgcgt732 Linker sequence 3ggcggtggaggtagtggagggggaggatcactcgagcca733 Ty1 NLSaactcaaagaaaaggtcactggaggacaacgaaacggaaatcaaagtctccagagacacctggaacactaagaacatgcggtccctggaaccgccacgaagcaagaaacggatacat 734 Nuclear Export Signal LQLPPLERLTL (NES) 1 735 Nuclear Export Signal cttcaactgcctccacttgaaagactgacactg (NES) 1736 NES 2GSLQLPPLERLTLGSS737 NES 2ggatcccttcaactgcctccacttgaaagactgacactgggtagttcc738 N-terminal 1x MSVLTPLLLRGLTGSARRLPVPRAKIHSLGDP Mitochondrial Targeting Sequence 739 N-terminal 4x MSVLTPLLLRGLTGSARRLPVPRAKIHSLGDPMSVLTPLLLRGLTGSARRLP Mitochondrial Targeting VPRAKIHSLGKLATMSVLTPLLLRGLTGSARRLPVPRAKIHSLGDPMSVLTPL LLRGLTGSARRLPVPRAKIHSLGKL Sequence 740 N-terminal Secretory MYRMQLLSCIALSLALVTNS Signal Sequence (IL-2) 741 N-terminal Myristoylation MGCCFSKTAAKGEAAAERPGEAAVASSPSKANGQENGHVKVGS (Membrane Targeting Sequence) 742 ER Localization - N- MLLPVPLLLGLLGAAA terminal Calsequestrin leader sequence 743 ER Localization - C- GITLGKDEL terminal KDEL retention signal 744 C-terminal Peroxisome SKL Targeting Sequence 745 N-terminal 1x atgagtgtgttgacgccgttgcttctgcgagggcttaccgggtctgctagaagacttccggtccccagggccaagatacat Mitochondrial Targeting agcctcggagacccg SequenceAttorney Docket No.204606-0174-00WO 746 N-terminal 4x atgagtgtgttgacgccgttgcttctgcgagggcttaccgggtctgctagaagacttccggtccccagggccaagatacat Mitochondrial Targeting agcctcggagacccgatgtctgtgctcactcctctgcttttgcgaggactgactgggtccgccagacgactcccggtgcc gagagctaaaatccatagcctgggaaaattggcaactatgtcagtcctgacgccgcttcttctccggggtcttacagggtc Sequence tgcaagaaggctgcctgtacctcgggcgaaaattcatagcttgggcgacccgatgagtgtattgacgcccctgttgctga gaggattgactgggtcagcgcgccggctccctgtcccccgagctaagattcactcccttggtaagctg 747 N-terminal Secretory atgtacaggatgcaactcctgtcttgcattgcactaagtcttgcacttgtcacgaattcc Signal Sequence (IL-2) 748 N-terminal Myristoylation atgggttgttgtttcagcaagacagcggcgaaaggtgaagcagcagcagaaagaccaggcgaggctgcggtagcatc (Membrane Targeting aagtccctccaaggctaatgggcaggaaaacggacacgtcaaagttggaagc Sequence) 749 ER Localization - N- atgctgctgcccgtccccctgctgctgggcctgctgggcgccgccgccgac terminal Calsequestrin leader sequence 750 ER Localization - C- gggatcactctcggcaaggacgagctgtaa terminal KDEL retention signal 751 C-terminal Peroxisome tccaaattataa Targeting Sequence

[0223] The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety. While this invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention. The appended claims are intended to be construed to include all such embodiments and equivalent variations.

Claims

Attorney Docket No.204606-0174-00WO CLAIMS 1. A fusion construct comprising: a) at least one guide RNA (gRNA), and b) at least one ribozyme or DNAzyme.

2. The fusion construct of claim 1, comprising: a) at least two guide RNA (gRNA), and b) at least two ribozymes or DNAzymes.

3. The fusion construct of claim 1 or 2, wherein the ribozyme or DNAzyme is specific for trans-cleavage of RNA.

4. The fusion construct of claim 1 or 2, wherein the ribozyme or DNAzyme is specific for trans-cleavage of DNA.

5. The fusion construct of claim 3, wherein the ribozyme or DNAzyme comprises hammerhead (HH), Hepatitis delta virus (HDV), Hairpin (HP), Varkud Satellite (VS), Twister, Twister Sister, Pistol, Hatchet, HOV, GlmS, Deoxyribozyme 8–17, Deoxyribozyme 10-23, or deoxyribozyme I-R3, or a fragment or trans-cleavage variant thereof.

6. The fusion construct of any one of claims 1-5, wherein the construct further comprises at least one linker.

7. A fusion construct comprising at least two ribozymes or DNAzymes.

8. The fusion construct of claim 7, wherein each of the two ribozymes or DNAzymes are specific for RNA cleavage.

9. The fusion construct of claim 7, wherein each of the two ribozymes or DNAzymes are specific for DNA cleavage.Attorney Docket No.204606-0174-00WO 10. The fusion construct of claim 8, wherein each of the two ribozymes or DNAzymes comprises hammerhead (HH), Hepatitis delta virus (HDV), Hairpin (HP), Varkud Satellite (VS), Twister, Twister Sister, Pistol, Hatchet, HOV, GlmS, Deoxyribozyme 8–17, Deoxyribozyme 10-23, or deoxyribozyme I-R3, or a fragment or trans-cleavage variant thereof.

11. The fusion construct of any one of claims 7-10, wherein the construct further comprises at least one linker.

12. A complex comprising at least one fusion construct of any one of claims 1-11.

13. The complex of claim 12, wherein the complex further comprises a CRISPR Cas protein.

14. The complex of claim 13, wherein the Cas protein is catalytically active.

15. The complex of claim 13, wherein the Cas protein comprises at least one mutation in one or both of the higher eukaryotes and prokaryotes nucleotide-binding (HEPN) domains.

16. The complex of claim 13, wherein the Cas protein is catalytically dead Cas13 (dCas13).

17. The complex of any one of claims 13 to 16, wherein the Ca13 retains its pre- cRNA processing RNAse activity.

18. The complex of claim 16, wherein the Cas protein comprises a sequence selected from SEQ ID NOs: 54-101, or a variant thereof.

19. The complex of any one of claims 13-18, wherein the Cas protein further comprises a nuclear localization signal (NLS).Attorney Docket No.204606-0174-00WO 20. The complex of claim 19, wherein the NLS comprises a sequence selected from SEQ ID NOs: 111 - 725, or a variant thereof.

21. A composition comprising the fusion construct of any of claims 1-11 or the complex of any one of claims 12-20.

22. A method of decreasing the number of a target RNA transcript or cleaving a target RNA transcript, the method comprising contacting the target RNA molecule with at least one fusion construct of any of claims 1-11, or at least one complex of any of claims 12-20, or the composition of claim 21.

23. The method of claim 22 being either an in vitro or in vivo method.

24. The method of claim 22 or 23, wherein the method comprises contacting the target RNA molecule with at least two fusion constructs of any one of claims 1-6, or at least two complexes of any one of claims 12-20, wherein each of the fusion constructs or complexes comprises a gRNA for targeting the fusion construct or complex to a target site on the RNA molecule for cleavage.

25. The method of claim 24, wherein each of the fusion constructs or complexes comprises the same ribozyme or DNAzyme.

26. The method of claim 24, wherein each of the fusion constructs or complexes comprises a different ribozyme or DNAzyme.

27. The method of any one of claims 22-26, wherein the method promotes splicing or ligation of the target RNA molecule.

28. The method of claim 27, wherein the splicing or ligation is cis-splicing, trans- splicing, cis-RNA ligation or trans-RNA ligation.Attorney Docket No.204606-0174-00WO 29. A method of treating a disease or disorder associated with nucleic acid level or expression in a subject, the method comprising administering to the subject: at least one fusion construct of any of claims 1-11, or at least one complex of any of claims 12-20, or a composition of claim 21.

30. The method of claim 29, wherein the disease or disorder is associated with the presence of an aberrant DNA molecule or RNA transcript, wherein the method promotes degradation of the aberrant DNA molecule or RNA transcript.

31. The method of claim 29, wherein the disease or disorder is associated with the presence of a premature stop codon (PTC) in a target RNA transcript, wherein the method promotes splicing of the target RNA transcript to remove the PTC.

32. A method of generating a trans-ligated RNA molecule, the method comprising contacting a first RNA molecule with a first fusion construct of any one of claims 1-6 and a second RNA molecule with a second fusion construct of any one of claims 1-6, whereby cleavage of the first and second RNA molecule and subsequent ligation of the cleaved RNA molecules generates a trans-ligated RNA molecule.

33. The method of claim 32, wherein the first and second fusion construct are connected by a flexible linker.

34. A method of generating a trans-ligated RNA molecule, the method comprising contacting a first RNA and a second RNA molecule with a fusion construct of any one of claims 7-11, whereby cleavage of the first and second RNA molecule and subsequent ligation of the cleaved RNA molecules generates a trans-ligated RNA molecule.

35. The method of claim 34, wherein the first and second trans-cleaving ribozyme or DNAzyme are connected by a flexible linker.Attorney Docket No.204606-0174-00WO 36. A method of generating a trans-ligated DNA molecule, the method comprising contacting a first DNA molecule with a first fusion construct of any one of claims 1-6 and a second DNA molecule with a second fusion construct of any one of claims 1-6, whereby cleavage of the first and second DNA molecule and subsequent ligation of the cleaved DNA molecules generates a trans-ligated DNA molecule.

37. The method of claim 36, wherein the first and second fusion construct are connected by a flexible linker.

38. A method of generating a trans-ligated DNA molecule, the method comprising contacting a first DNA and a second DNA molecule with a fusion construct of any one of claims 7-11, whereby cleavage of the first and second DNA molecule and subsequent ligation of the cleaved DNA molecules generates a trans-ligated DNA molecule.

39. The method of claim 38, wherein the first and second trans-cleaving DNAzyme are connected by a flexible linker.

40. A method of generating a trans-ligated RNA molecule, the method comprising contacting a first RNA molecule and a second RNA molecule with a Cas protein which cleaves the first and second RNA, thereby generating compatible RNA ends, whereby cleavage of the first and second RNA molecule and subsequent ligation of the cleaved RNA molecules generates a trans-ligated RNA molecule.

41. The method of claim 40, wherein the Cas protein is a subtype II-A or subtype II-C class Cas protein.

42. The method of claim 40, wherein the method further comprises contacting the first and second RNA molecules with a first and second guide RNA to target the Cas protein to a specific site for cleavage.