PRODUCTS AND COMPOSITIONS

Abstract

Products, compositions, and their uses are provided. In particular, nucleic acid products that modulate, in particular interfere with or inhibit, Factor XI (FXI) gene expression are provided. The products can be oligomeric compounds that comprise at least a first region of linked nucleosides having at least a first nucleobase sequence that is at least partially complementary to at least a portion of RNA transcribed from an FXI gene, wherein said first nucleobase sequence is selected from the following sequences, or a portion thereof: SEQ ID NOs 1 to 250.

Description

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on May 27, 2022, is named 4690_0046C_SL.txt and is 650.004 bytes in size.

FIELD

Nucleic acid products are provided that modulate, interfere with, or inhibit, Factor XI (FXI) gene expression. Methods, compounds, and compositions are provided for reducing expression of FXI mRNA and protein in an animal. Such methods, compounds, and compositions are useful to treat, prevent, or ameliorate thromboembolic diseases, such as deep vein thrombosis, venous or arterial thrombosis, pulmonary embolism, myocardial infarction, stroke, thrombosis associated with chronic kidney disease or end-stage renal disease (ESRD), including thrombosis associated with dialysis, or other procoagulant condition.

BACKGROUND

The circulatory system requires mechanisms that prevent blood loss, as well as those that counteract inappropriate intravascular obstructions. Generally, coagulation comprises a cascade of reactions culminating in the conversion of soluble fibrinogen to an insoluble fibrin gel. The steps of the cascade involve the conversion of an inactive zymogen to an activated enzyme. The active enzyme then catalyzes the next step in the cascade.

Coagulation Cascade

The coagulation cascade may be initiated through two branches, the tissue factor pathway (also “extrinsic pathway”), which is the primary pathway, and the contact activation pathway (also “intrinsic pathway”).

The tissue factor pathway is initiated by the cell surface receptor tissue factor (TF, also referred to as Factor III), which is expressed constitutively by extravascular cells (pericytes, cardiomyocytes, smooth muscle cells, and keratinocytes) and expressed by vascular monocytes and endothelial cells upon induction by inflammatory cytokines or endotoxin. (Drake et al., Am J Pathol 1989, 134: 1087-1097). TF is the high affinity cellular receptor for coagulation Factor Vila, a serine protease. In the absence of TF, Vila has very low catalytic activity, and binding to TF is necessary to render Vila functional through an allosteric mechanism (Drake et al., Am J Pathol 1989, 134: 1087-1097). The TF-VIIa complex activates Factor X to Xa. Xa in turn associates with its co-factor Factor Va into a prothrombinase complex which in turn activates prothrombin, (also known as Factor II or Factor 2) to thrombin (also known as Factor IIa, or Factor 2a).

Thrombin activates platelets, converts fibrinogen to fibrin and promotes fibrin cross-linking by activating Factor XIII, thus forming a stable plug at sites where TF is exposed on extravascular cells. In addition, thrombin reinforces the coagulation cascade response by activating Factors V and VIII.

The contact activation pathway is triggered by activation of Factor XII to XIIa. Factor XIIa converts XI to XIa, and XIa converts IX to IXa. IXa associates with its cofactor Villa to convert X to Xa. The two pathways converge at this point as Factor Xa associates with Factor Va to activate prothrombin (Factor II) to thrombin (Factor IIa). Factor XI enhances both the formation and stability of clots in vitro, but is not thought to be involved in the initiation of clotting. Rather, Factor XI is important in the propagation phase of clot growth (von de Borne, et al., Blood Coagulation and Fibrinolysis, 2006, 17:251-257). Additionally, Factor XI-dependent amplification of thrombin formation leads to activation of TAFI (thrombin activatable fibrinolysis inhibitor), which renders clots less sensitive to fibrinolysis (Bouma et al, J Thromb Haemost 1999; 82: 1703-1708).

Inhibition of Coagulation

At least three mechanisms keep the coagulation cascade in check, namely the action of activated protein C, antithrombin, and tissue factor pathway inhibitor. Activated protein C is a serine protease that degrades cofactors Va and Villa. Protein C is activated by thrombin with thrombomodulin, and requires coenzyme Protein S to function. Antithrombin is a serine protease inhibitor (serpin) that inhibits serine proteases: thrombin, Xa, XIIa, XIa and IXa. Tissue factor pathway inhibitor inhibits the action of Xa and the TF-VIIa complex. (Schwartz A L et al., Trends Cardiovasc Med. 1997; 7:234-239.)

Disease

Thrombosis is the pathological development of blood clots, and an embolism occurs when a blood clot migrates to another part of the body and interferes with organ function. Thromboembolism may cause conditions such as deep vein thrombosis, pulmonary embolism, myocardial infarction, and stroke. While most cases of thrombosis are due to acquired extrinsic problems, for example, surgery, cancer, immobility, some cases are due to a genetic predisposition, for example, antiphospholipid syndrome and the autosomal dominant condition, Factor V Leiden. (Bertina R M et al. Nature 1994; 369:64-67.)

Treatment

The most commonly used anticoagulants, warfarin, heparin, low molecular weight heparin (LMWH), and newer direct oral anticoagulants (DOAC), all possess significant drawbacks. Warfarin is typically used to treat patients suffering from atrial fibrillation. The drug interacts with vitamin K-dependent coagulation factors which include Factors II, VII, IX and X. Anticoagulant proteins C and S are also inhibited by warfarin. Drug therapy using warfarin is further complicated by the fact that warfarin interacts with other medications, including drugs used to treat atrial fibrillation, such as amiodarone.

Because therapy with warfarin is difficult to predict, patients must be carefully monitored in order to detect any signs of anomalous bleeding.

Heparin functions by activating antithrombin which inhibits both thrombin and Factor X (Bjork I, Lindahl U. Mol Cell Biochem. 1982 48: 161-182). Treatment with heparin may cause an immunological reaction that makes platelets aggregate within blood vessels that can lead to thrombosis. This side effect is known as heparin-induced thrombocytopenia (HIT) resulting in increased bleeding and requires patient monitoring. Prolonged treatment with heparin may also lead to osteoporosis. LMWH can also inhibit Factor II, but to a lesser degree than unfractioned heparin (UFH). LMWH has been implicated in the development of HIT.

Several direct oral anticoagulants have been FDA-approved for the treatment of thrombotic disease, including four Factor Xa inhibitors Betrixaban, Apixaban, Rivaroxaban and Edoxaban and one direct thrombin inhibitor Dabigatran. (Smith, M., Surg Clin N Am 2018 98:219-238). Rivaroxaban, Dabigatran and Edoxaban all exhibit increased bleeding, especially increased GI bleeding risk compared to warfarin.

There therefore remains a need for therapies to treat thromboembolic diseases without risk of increased bleeding. We, therefore, aim to provide compounds, methods, and pharmaceutical compositions for the treatment of such diseases.

Double-stranded RNA (dsRNA) able to complementarily bind expressed mRNA has been shown to be able to block gene expression (Fire et a.l, 1998, Nature. 1998 Feb. 19; 391 (6669):806-1 1 and Elbashir et at., 2001, Nature. 2001 May 24; 41 1 (6836):494-8) by a mechanism that has been termed RNA interference (RNAi). Short dsRNAs direct gene-specific, post-transcriptional silencing in many organisms, including vertebrates, and have become a useful tool for studying gene function. RNAi is mediated by the RNA-induced silencing complex (RISC), a sequence-specific, multi-component nuclease that destroys messenger RNAs homologous to the silencing trigger loaded into the RISC complex. Interfering RNA (iRNA) such as siRNAs, antisense RNA, and micro-RNA are oligonucleotides that prevent the formation of proteins by gene-silencing i.e. inhibiting gene translation of the protein through degradation of mRNA molecules. Gene-silencing agents are becoming increasingly important for therapeutic applications in medicine.

According to Watts and Corey in the Journal of Pathology (2012; Vol 226, p 365-379) there are algorithms that can be used to design nucleic acid silencing triggers, but all of these have severe limitations. It may take various experimental methods to identify potent siRNAs, as algorithms do not take into account factors such as tertiary structure of the target mRNA or the involvement of RNA binding proteins. Therefore the discovery of a potent nucleic acid silencing trigger with minimal off-target effects is a complex process. For the pharmaceutical development of these highly charged molecules it is necessary that they can be synthesised economically, distributed to target tissues, enter cells and function within acceptable limits of toxicity. An aim is to, therefore, provide compounds, methods, and pharmaceutical compositions for the treatment of thromboembolic diseases as described herein, which comprise oligomeric compounds that modulate and inhibit, gene expression by RNAi.

SUMMARY

Nucleic acid products are provided that modulate, interfere with, or inhibit, Factor XI (FXI) gene expression, and associated therapeutic uses. Specific oligomeric compounds and sequences are described herein. This summary is not intended to identify key features or essential features of the subject matter as described herein, nor is it intended to be used to determine the scope of that subject matter.

DETAILED DESCRIPTION AND EMBODIMENTS

The embodiments described below are exemplary but the skilled artisan will recognize that additional embodiments may be achieved.

It will be understood that the benefits and advantages described herein may relate to one embodiment or may relate to several embodiments. The embodiments are not limited to those that solve any or all of the stated problems or those that have any or all of the stated benefits and advantages.

Features of different aspects and embodiments may be combined as appropriate, as would be apparent to a skilled person, and may be combined with any of the aspects as described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

The embodiments described below are by way of example only and with reference to the following non-limiting drawings, in which:

FIGS. 1a-1zvi illustrate the stability of 250 duplexes: Table 1a displays the nucleobase sequences of 250 antisense sequences (SEQ ID NOs: 1 to 250) and of 250 corresponding sense sequences (SEQ ID NOs: 251 to 500). Table 1b displays the corresponding modified constructs (constructs 501 to 750 being the modified counterparts of SEQ ID NOs: 1 to 250; and constructs 751 to 1000 being the modified counterparts of SEQ ID NOs: 251 to 500). Owing to complementarity, construct 501 base pairs with construct 751, construct 502 base pairs with construct 752 and so forth, giving rise to duplexes (double-stranded molecules). These duplexes are numbered according to the SEQ ID NO of the antisense nucleobase sequence they comprise, e.g. the duplex formed from constructs 501 and 751 is referred to as duplex 1, the duplex formed from constructs 502 and 752 is referred to duplex 2, and so forth. Based on this numbering scheme, the parts of FIG. 1 illustrate the following:

FIG. 1a illustrates the stability of duplexes 1 to 8.

FIG. 1b illustrates the stability of duplexes 9 to 16.

FIG. 1c illustrates the stability of duplexes 17 to 24.

FIG. 1d illustrates the stability of duplexes 25 to 32.

FIG. 1e illustrates the stability of duplexes 33 to 40.

FIG. 1f illustrates the stability of duplexes 41 to 48.

FIG. 1g illustrates the stability of duplexes 49 to 56.

FIG. 1h illustrates the stability of duplexes 57 to 64.

FIG. 1i illustrates the stability of duplexes 65 70 72.

FIG. 1j illustrates the stability of duplexes 73 to 80.

FIG. 1k illustrates the stability of duplexes 81 to 88.

FIG. 1l illustrates the stability of duplexes 89 to 96.

FIG. 1m illustrates the stability of duplexes 97 to 104.

FIG. 1n illustrates the stability of duplexes 105 to 112.

FIG. 1o illustrates the stability of duplexes 113 to 120.

FIG. 1p illustrates the stability of duplexes 121 to 128.

FIG. 1q illustrates the stability of duplexes 129 to 136.

FIG. 1r illustrates the stability of duplexes 137 to 144.

FIG. 1s illustrates the stability of duplexes 145 to 152.

FIG. 1t illustrates the stability of duplexes 153 to 160.

FIG. 1u illustrates the stability of duplexes 161 to 168.

FIG. 1v illustrates the stability of duplexes 169 to 176.

FIG. 1w illustrates the stability of duplexes 177 to 184.

FIG. 1x illustrates the stability of duplexes 185 to 192.

FIG. 1y illustrates the stability of duplexes 193 to 200.

FIG. 1z illustrates the stability of duplexes 201 to 208.

FIG. 1 zi illustrates the stability of duplexes 209 to 216.

FIG. 1 zii illustrates the stability of duplexes 217 to 224.

FIG. 1 ziii illustrates the stability of duplexes 225 to 232.

FIG. 1 ziv illustrates the stability of duplexes 233 to 241.

FIG. 1 zv illustrates the stability of duplexes 242 to 248.

FIG. 1 zvi illustrates the stability of duplexes 249 and 250.

FIG. 2 illustrates the linear dose response of the two independent F11 qPCR assays as described in Example 2.

FIGS. 3 to 12 show the screening results for FXI gene expression as a percentage of gene expression in non-treated cells for oligomeric compounds including oligonucleotides of Table 1a/1b of Example 1.

FIG. 13 provides dose response curves for the 26 FXI lead compounds as identified in Example 2.

FIG. 14 provides dose response curves for the 5 FXI lead compounds as identified further to the results of FIG. 13.

FIGS. 15 to 17 show the overall sequences for oligomeric compounds F11-91, F11-46, F11-152.

FIGS. 18a-18p illustrate compounds selected for medicinal chemistry:

FIG. 18a illustrates a generic duplex.

FIG. 18b illustrates a duplex containing 5′ vinyl phosphonate.

FIG. 18c illustrates a duplex containing an iR loop stabilizer.

FIG. 18d illustrates a duplex containing an iR end stabilizer and seed de-stabilizer.

FIG. 18e illustrates a duplex containing an iR seed de-stabilizer.

FIG. 18f illustrates a duplex containing a minimum 2′-F.

FIG. 18g illustrates a duplex containing internal GalNAc.

FIG. 18h illustrates a duplex containing internal GalNAc and iR 3′-end stabilizer.

FIG. 18i illustrates a duplex containing 5′ bi-methyl vinyl-phosphonate.

FIG. 18j illustrates a duplex containing iR 5′-end stabilizer.

FIG. 18k illustrates a duplex containing 3×TEG-linker GalNAc.

FIG. 18l illustrates a generic duplex with matching 5′ nucleotide.

FIG. 18m illustrates a duplex containing iR 5′-end stabilizer.

FIG. 18n illustrates a duplex containing iR 3′-end stabilizer.

FIG. 18o illustrates a duplex containing iR 3′-end stabilizer.

FIG. 18p illustrates a duplex with canonical control.

FIGS. 19a-19c illustrate the performance of compounds shown in FIGS. 18a-18p:

FIG. 19a is a table showing percent k/d at the highest concentration and IC₅₀ values for 91A to 910 and 91 Control constructs of FIGS. 18a-18p.

FIG. 19b illustrates gene expression as a percent of NT for a variety of constructs (91A-91F, 91I).

FIG. 19c illustrates gene expression as a percent of NT for a variety of constructs (91J-91O).

FIGS. 20a-20h depict several constructs.

FIG. 20a illustrates a duplex containing an iR loop stabilizer.

FIG. 20b illustrates a duplex containing 5′ bi-methyl vinyl-phosphonate.

FIG. 20c illustrates a conventional duplex (34mer).

FIG. 20d illustrates a duplex containing an iR 3′-end stabilizer.

FIG. 20e illustrates a duplex containing vinyl-phosphonate.

FIG. 20f illustrates a conventional duplex (31 mer).

FIG. 20g illustrates a conventional duplex (33mer).

FIG. 20h provides the sequences of seven constructs.

FIG. 21 shows data for the compounds displayed in FIG. 20.

FIG. 22 shows the structure of compounds tested in humanized mice.

FIG. 23 shows the data obtained from testing in humanized mice.

FIG. 24 shows the design of an in vivo study with compound 91-Conv-31.

FIG. 25 shows performance of a compound in an in vivo study in terms of Factor XI activity knock-down.

FIG. 26 shows the molecular mechanism underlying the tests for targeting specificity as performed in the course of an in vivo study.

FIGS. 27a-27b provides the read-out of the results of the tests performed in FIG. 26:

FIG. 27a shows the time (sec) for activated partial thromboplastin (APTT) based on concentrations between 1 and 10 mg/kg.

FIG. 27b shows the time (sec) for prothrombin (PT) based on concentrations between 1 and 10 mg/kg.

FIG. 28 presents data demonstrating a lack of side effects.

DEFINITIONS

Unless specific definitions are provided, the nomenclature used in connection with, and the procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well known and commonly used in the art. Standard techniques may be used for chemical synthesis, and chemical analysis. Certain such techniques and procedures may be found for example in “Carbohydrate Modifications in Antisense Research” Edited by Sangvi and Cook, American Chemical Society, Washington D.C., 1994; “Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, Pa., 21^st edition, 2005; and “Antisense Drug Technology, Principles, Strategies, and Applications” Edited by Stanley T. Crooke, CRC Press, Boca Raton, Fla.; and Sambrook et al., “Molecular Cloning, A laboratory Manual,” 2^nd Edition, Cold Spring Harbor Laboratory Press, 1989, which are hereby incorporated by reference for any purpose. Where permitted, all patents, applications, published applications and other publications and other data referred to throughout in the disclosure are incorporated by reference herein in their entirety.

Unless otherwise indicated, the following terms have the following meanings:

As used herein, “excipient” means any compound or mixture of compounds that is added to a composition as provided herein that is suitable for delivery of an oligomeric compound.

As used herein, “nucleoside” means a compound comprising a nucleobase moiety and a sugar moiety. Nucleosides include, but are not limited to, naturally occurring nucleosides (as found in DNA and RNA) and modified nucleosides. Nucleosides may be linked to a phosphate moiety, phosphate-linked nucleosides also being referred to as “nucleotides”.

As used herein, “chemical modification” or “chemically modified” means a chemical difference in a compound when compared to a naturally occurring counterpart. Chemical modifications of oligonucleotides include nucleoside modifications (including sugar moiety modifications and nucleobase modifications) and internucleoside linkage modifications. In reference to an oligonucleotide, chemical modification does not include differences only in nucleobase sequence.

As used herein, “furanosyl” means a structure comprising a 5-membered ring comprising four carbon atoms and one oxygen atom.

As used herein, “naturally occurring sugar moiety” means a ribofuranosyl as found in naturally occurring RNA or a deoxyribofuranosyl as found in naturally occurring DNA. A “naturally occurring sugar moiety” as referred to herein is also termed as an “unmodified sugar moiety”. In particular, such a “naturally occurring sugar moiety” or an “unmodified sugar moiety” as referred to herein has a —H (DNA sugar moiety) or —OH (RNA sugar moiety) at the 2′-position of the sugar moiety, especially a —H (DNA sugar moiety) at the 2′-position of the sugar moiety.

As used herein, “sugar moiety” means a naturally occurring sugar moiety or a modified sugar moiety of a nucleoside. As used herein, “modified sugar moiety” means a substituted sugar moiety or a sugar surrogate.

As used herein, “substituted sugar moiety” means a furanosyl that has been substituted. Substituted sugar moieties include, but are not limited to furanosyls comprising substituents at the 2′-position, the 3′-position, the 5′-position and/or the 4′-position. Certain substituted sugar moieties are bicyclic sugar moieties.

As used herein, “2′-substituted sugar moiety” means a furanosyl comprising a substituent at the 2′-position other than H or OH. Unless otherwise indicated, a 2′-substituted sugar moiety is not a bicyclic sugar moiety (i.e., the 2′-substituent of a 2′-substituted sugar moiety does not form a bridge to another atom of the furanosyl ring).

As used herein, “MOE” means —OCH₂CH₂OCH₃.

As used herein, “2′-F nucleoside” refers to a nucleoside comprising a sugar comprising fluorine at the 2′ position. Unless otherwise indicated, the fluorine in a 2′-F nucleoside is in the ribo position (replacing the OH of a natural ribose). Duplexes of uniformly modified 2′-fluorinated (ribo) oligonucleotides hybridized to RNA strands are not RNase H substrates while the ara analogs retain RNase H activity.

As used herein the term “sugar surrogate” means a structure that does not comprise a furanosyl and that is capable of replacing the naturally occurring sugar moiety of a nucleoside, such that the resulting nucleoside sub-units are capable of linking together and/or linking to other nucleosides to form an oligomeric compound which is capable of hybridizing to a complementary oligomeric compound. Such structures include rings comprising a different number of atoms than furanosyl (e.g., 4, 6, or 7-membered rings); replacement of the oxygen of a furanosyl with a non-oxygen atom (e.g., carbon, sulfur, or nitrogen); or both a change in the number of atoms and a replacement of the oxygen. Such structures may also comprise substitutions corresponding to those described for substituted sugar moieties (e.g., 6-membered carbocyclic bicyclic sugar surrogates optionally comprising additional substituents). Sugar surrogates also include more complex sugar replacements (e.g., the non-ring systems of peptide nucleic acid). Sugar surrogates include without limitation morpholinos, cyclohexenyls and cyclohexitols.

As used herein, “bicyclic sugar moiety” means a modified sugar moiety comprising a 4 to 7 membered ring (including but not limited to a furanosyl) comprising a bridge connecting two atoms of the 4 to 7 membered ring to form a second ring, resulting in a bicyclic structure. In certain embodiments, the 4 to 7 membered ring is a sugar ring. In certain embodiments the 4 to 7 membered ring is a furanosyl. In certain such embodiments, the bridge connects the 2 ‘-carbon and the 4’-carbon of the furanosyl.

As used herein, “nucleotide” means a nucleoside further comprising a phosphate linking group. As used herein, “linked nucleosides” may or may not be linked by phosphate linkages and thus includes, but is not limited to “linked nucleotides.” As used herein, “linked nucleosides” are nucleosides that are connected in a continuous sequence (i.e. no additional nucleosides are present between those that are linked).

As used herein, “nucleobase” means a group of atoms that can be linked to a sugar moiety to create a nucleoside that is capable of incorporation into an oligonucleotide, and wherein the group of atoms is capable of bonding with a complementary naturally occurring nucleobase of another oligonucleotide or nucleic acid. Nucleobases may be naturally occurring or may be modified.

As used herein the terms, “unmodified nucleobase” or “naturally occurring nucleobase” means the naturally occurring heterocyclic nucleobases of RNA or DNA: the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C) (including 5-methyl C), and uracil (U).

As used herein, “modified nucleobase” means any nucleobase that is not a naturally occurring nucleobase.

As used herein, “modified nucleoside” means a nucleoside comprising at least one chemical modification compared to naturally occurring RNA or DNA nucleosides. Modified nucleosides can comprise a modified sugar moiety and/or a modified nucleobase.

As used herein, “bicyclic nucleoside” or “BNA” means a nucleoside comprising a bicyclic sugar moiety.

As used herein, “locked nucleic acid nucleoside” or “LNA” means a nucleoside comprising a bicyclic sugar moiety comprising a 4′-CH₂—O-2′ bridge.

As used herein, “2′-substituted nucleoside” means a nucleoside comprising a substituent at the 2′-position of the sugar moiety other than H or OH. Unless otherwise indicated, a 2′-substituted nucleoside is not a bicyclic nucleoside.

As used herein, “deoxynucleoside” means a nucleoside comprising 2′-H furanosyl sugar moiety, as found in naturally occurring deoxyribonucleosides (DNA). In certain embodiments, a 2′-deoxynucleoside may comprise a modified nucleobase or may comprise an RNA nucleobase (e.g., uracil).

As used herein, “oligonucleotide” means a compound comprising a plurality of linked nucleosides. In certain embodiments, an oligonucleotide comprises one or more unmodified ribonucleosides (RNA) and/or unmodified deoxyribonucleosides (DNA) and/or one or more modified nucleosides.

As used herein, “modified oligonucleotide” means an oligonucleotide comprising at least one modified nucleoside and/or at least one modified internucleoside linkage.

As used herein, “linkage” or “linking group” means a group of atoms that link together two or more other groups of atoms.

As used herein “internucleoside linkage” means a covalent linkage between adjacent nucleosides in an oligonucleotide.

As used herein “naturally occurring internucleoside linkage” means a 3′ to 5′ phosphodiester linkage.

As used herein, “modified internucleoside linkage” means any internucleoside linkage other than a naturally occurring internucleoside linkage. In particular, a “modified internucleoside linkage” as referred to herein can include a modified phosphorous linking group such as a phosphorothioate or phosphorodithioate internucleoside linkage.

As used herein, “terminal internucleoside linkage” means the linkage between the last two nucleosides of an oligonucleotide or defined region thereof.

As used herein, “phosphorus linking group” means a linking group comprising a phosphorus atom and can include naturally occurring phosphorous linking groups as present in naturally occurring RNA or DNA, such as phosphodiester linking groups, or modified phosphorous linking groups that are not generally present in naturally occurring RNA or DNA, such as phosphorothioate or phosphorodithioate linking groups. Phosphorus linking groups can therefore include without limitation, phosphodiester, phosphorothioate, phosphorodithioate, phosphonate, methylphosphonate, phosphoramidate, phosphorothioamidate, thionoalkylphosphonate, phosphotriesters, thionoalkylphosphotriester and boranophosphate.

As used herein, “internucleoside phosphorus linking group” means a phosphorus linking group that directly links two nucleosides.

As used herein, “oligomeric compound” means a polymeric structure comprising two or more substructures. In certain embodiments, an oligomeric compound comprises an oligonucleotide, such as a modified oligonucleotide. In certain embodiments, an oligomeric compound further comprises one or more conjugate groups and/or terminal groups and/or ligands. In certain embodiments, an oligomeric compound consists of an oligonucleotide. In certain embodiments, an oligomeric compound comprises a backbone of one or more linked monomeric sugar moieties, where each linked monomeric sugar moiety is directly or indirectly attached to a heterocyclic base moiety. In certain embodiments, oligomeric compounds may also include monomeric sugar moieties that are not linked to a heterocyclic base moiety, thereby providing abasic sites. Oligomeric compounds may be defined in terms of a nucleobase sequence only, i.e., by specifying the sequence of A, G, C, U (or T). In such a case, the structure of the sugar-phosphate backbone is not particularly limited and may or may not comprise modified sugars and/or modified phosphates. On the other hand, oligomeric compounds may be more comprehensively defined, i.e, by specifying not only the nucleobase sequence, but also the structure of the backbone, in particular the modification status of the sugars (unmodified, 2′-OMe modified, 2′-F modified etc.) and/or of the phosphates.

As used herein, “terminal group” means one or more atom attached to either, or both, the 3′ end or the 5′ end of an oligonucleotide. In certain embodiments, a terminal group comprises one or more terminal group nucleosides.

As used herein, “conjugate” or “conjugate group” means an atom or group of atoms bound to an oligonucleotide or oligomeric compound. In certain embodiments, a conjugate group links a ligand to a modified oligonucleotide or oligomeric compound. In general, conjugate groups can modify one or more properties of the compound to which they are attached, including, but not limited to pharmacodynamic, pharmacokinetic, binding, absorption, cellular distribution, cellular uptake, charge and/or clearance properties.

As used herein, “conjugate linker” or “linker” in the context of a conjugate group means a portion of a conjugate group comprising any atom or group of atoms and which covalently link an oligonucleotide to another portion of the conjugate group. In certain embodiments, the point of attachment on the oligomeric compound is the 3 ‘-oxygen atom of the 3’-hydroxyl group of the 3′ terminal nucleoside of the oligonucleotide. In certain embodiments the point of attachment on the oligomeric compound is the 5′-oxygen atom of the 5′-hydroxyl group of the 5′ terminal nucleoside of the oligonucleotide. In certain embodiments, the bond for forming attachment to the oligomeric compound is a cleavable bond. In certain such embodiments, such cleavable bond constitutes all or part of a cleavable moiety.

In certain embodiments, conjugate groups comprise a cleavable moiety (e.g., a cleavable bond or cleavable nucleoside) and ligand portion that can comprise one or more ligands, such as a carbohydrate cluster portion, such as an N-Acetyl-Galactosamine, also referred to as “GalNAc”, cluster portion. In certain embodiments, the carbohydrate cluster portion is identified by the number and identity of the ligand. For example, in certain embodiments, the carbohydrate cluster portion comprises 2 GalNAc groups. For example, in certain embodiments, the carbohydrate cluster portion comprises 3 GalNAc groups and this is particularly preferred. In certain embodiments, the carbohydrate cluster portion comprises 4 GalNAc groups. Such ligand portions are attached to an oligomeric compound via a cleavable moiety, such as a cleavable bond or cleavable nucleoside. The ligands can be arranged in a linear or branched configuration, such as a biantennary or triantennary configurations.

As used herein, “cleavable moiety” means a bond or group that is capable of being cleaved under physiological conditions. In certain embodiments, a cleavable moiety is cleaved inside a cell or sub-cellular compartments, such as an endosome or lysosome. In certain embodiments, a cleavable moiety is cleaved by endogenous enzymes, such as nucleases. In certain embodiments, a cleavable moiety comprises a group of atoms having one, two, three, four, or more than four cleavable bonds.

In certain embodiments, a cleavable moiety is a phosphodiester linkage.

As used herein, “cleavable bond” means any chemical bond capable of being broken.

As used herein, “carbohydrate cluster” means a compound having one or more carbohydrate residues attached to a linker group.

As used herein, “modified carbohydrate” means any carbohydrate having one or more chemical modifications relative to naturally occurring carbohydrates.

As used herein, “carbohydrate derivative” means any compound which may be synthesized using a carbohydrate as a starting material or intermediate.

As used herein, “carbohydrate” means a naturally occurring carbohydrate, a modified carbohydrate, or a carbohydrate derivative. A carbohydrate is a biomolecule including carbon (C), hydrogen (H) and oxygen (O) atoms. Carbohydrates can include monosaccharide, disaccharides, trisaccharides, tetrasaccharides, oligosaccharides or polysaccharides, such as one or more galactose moieties, one or more lactose moieties, one or more N-Acetyl-Galactosamine moieties, and/or one or more mannose moieties. A particularly preferred carbohydrate is N-Acetyl-Galactosamine moieties.

As used herein, “strand” means an oligomeric compound comprising linked nucleosides. The linker is not particularly limited, but includes phosphodiesters and variants thereof as disclosed herein. A strand may also be viewed as a plurality of linked nucleotides in which case the linker would be a covalent bond.

The term “construct” means a region of linked nucleosides which is defined in terms of nucleobase sequence and sugar modifications. A construct may coincide with a strand or compound, but may also be part thereof.

As used herein, “single strand” or “single-stranded” means an oligomeric compound comprising linked nucleosides that are connected in a continuous sequence without a break therebetween. Such single strands may include regions of sufficient self-complementarity so as to be capable of forming a stable self-duplex in a hairpin structure.

As used herein, “hairpin” means a single stranded oligomeric compound that includes a duplex formed by base pairing between sequences in the strand that are self-complementary and opposite in directionality.

As used herein, “hairpin loop” means an unpaired loop of linked nucleosides in a hairpin that is created as a result of hybridization of the self-complementary sequences. The resulting structure looks like a loop or a U-shape.

In particular, short hairpin RNA, also denoted as shRNA, comprises a duplex region and a loop connecting the regions forming the duplex. The end of the duplex region which does not carry the loop may be blunt-ended or carry (a) 3′ and/or (a) 5′ overhang(s). Advantageously, the construct is blunt-ended. Such molecules are also referred to as “mxRNAs”. As used herein, the term “mxRNA” is in particular understood as defined in WO 2020/044186 A2 which is incorporated by reference herein in its entirety. Particularly preferred hairpin RNAs in accordance with the invention are those shown in Tables 6 and 7 and FIGS. 15 to 18, 20 and 22.

As used herein, “directionality” means the end-to-end chemical orientation of an oligonucleotide based on the chemical convention of numbering of carbon atoms in the sugar moiety meaning that there will be a 5′-end defined by the 5′ carbon of the sugar moiety, and a 3′-end defined by the 3′ carbon of the sugar moiety. In a duplex or double stranded oligonucleotide, the respective strands run in opposite 5′ to 3′ directions to permit base pairing between them.

As used herein, “duplex”, also abbreviated as “dup”, means two or more complementary strand regions, or strands, of an oligonucleotide or oligonucleotides, hybridized together by way of non-covalent, sequence-specific interaction therebetween. Most commonly, the hybridization in the duplex will be between nucleobases adenine (A) and thymine (T), and/or (A) adenine and uracil (U), and/or guanine (G) and cytosine (C). The duplex may be part of a single stranded structure, wherein self-complementarity leads to hybridization, or as a result of hybridization between respective strands in a double stranded molecule.

As used herein, “double strand” or “double stranded” means a pair of oligomeric compounds that are hybridized to one another. In certain embodiments, a double-stranded oligomeric compound comprises a first and a second oligomeric compound.

As used herein, “expression” means the process by which a gene ultimately results in a protein.

Expression includes, but is not limited to, transcription, post-transcriptional modification (e.g., splicing, polyadenlyation, addition of 5′-cap), and translation.

As used herein, “transcription” or “transcribed” refers to the first of several steps of DNA based gene expression in which a target sequence of DNA is copied into RNA (especially mRNA) by the enzyme RNA polymerase. During transcription, a DNA sequence is read by an RNA polymerase, which produces a complementary, antiparallel RNA sequence called a primary transcript.

As used herein, “target sequence” means a sequence to which an oligomeric compound is intended to hybridize to result in a desired activity with respect to Factor XI expression. Oligonucleotides have sufficient complementarity to their target sequences to allow hybridization under physiological conditions.

As used herein, “nucleobase complementarity” or “complementarity” when in reference to nucleobases means a nucleobase that is capable of base pairing with another nucleobase. For example, in DNA, adenine (A) is complementary to thymine (T). For example, in RNA, adenine (A) is complementary to uracil (U). In both DNA and RNA, guanine (G) is complementary to cytosine (C). In certain embodiments, complementary nucleobase means a nucleobase of an oligomeric compound that is capable of base pairing with a nucleobase of its target sequence. For example, if a nucleobase at a certain position of an oligomeric compound is capable of hydrogen bonding with a nucleobase at a certain position of a target sequence, then the position of hydrogen bonding between the oligomeric compound and the target sequence is considered to be complementary at that nucleobase pair. Nucleobases comprising certain modifications may maintain the ability to pair with a counterpart nucleobase and thus, are still capable of nucleobase complementarity.

As used herein, “non-complementary” in reference to nucleobases means a pair of nucleobases that do not form hydrogen bonds with one another.

As used herein, “complementary” in reference to oligomeric compounds (e.g., linked nucleosides, oligonucleotides) means the capacity of such oligomeric compounds or regions thereof to hybridize to a target sequence, or to a region of the oligomeric compound itself, through nucleobase complementarity.

Complementary oligomeric compounds need not have nucleobase complementarity at each nucleoside. Rather, some mismatches are tolerated. In certain embodiments, complementary oligomeric compounds or regions are complementary at 70% of the nucleobases (70% complementary). In certain embodiments, complementary oligomeric compounds or regions are 80%> complementary. In certain embodiments, complementary oligomeric compounds or regions are 90%> complementary. In certain embodiments, complementary oligomeric compounds or regions are 95% complementary. In certain embodiments, complementary oligomeric compounds or regions are 100% complementary.

As used herein, “self-complementarity” in reference to oligomeric compounds means a compound that may fold back on itself, creating a duplex as a result of nucleobase hybridization of internal complementary strand regions. Depending on how close together and/or how long the strand regions are, then the compound may form hairpin loops, junctions, bulges or internal loops.

As used herein, “mismatch” means a nucleobase of an oligomeric compound that is not capable of pairing with a nucleobase at a corresponding position of a target sequence, or at a corresponding position of the oligomeric compound itself when the oligomeric compound hybridizes as a result of self-complementarity, when the oligomeric compound and the target sequence and/or self-complementary regions of the oligomeric compound, are aligned.

As used herein, “hybridization” means the pairing of complementary oligomeric compounds (e.g., an oligomeric compound and its target sequence). While not limited to a particular mechanism, the most common mechanism of pairing involves hydrogen bonding, which may be Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, between complementary nucleobases.

As used herein, “specifically hybridizes” means the ability of an oligomeric compound to hybridize to one nucleic acid site with greater affinity than it hybridizes to another nucleic acid site.

As used herein, “fully complementary” in reference to an oligomeric compound or region thereof means that each nucleobase of the oligomeric compound or region thereof is capable of pairing with a nucleobase of a complementary nucleic acid target sequence or a self-complementary region of the oligomeric compound. Thus, a fully complementary oligomeric compound or region thereof comprises no mismatches or unhybridized nucleobases with respect to its target sequence or a self-complementary region of the oligomeric compound.

As used herein, “percent complementarity” means the percentage of nucleobases of an oligomeric compound that are complementary to an equal-length portion of a target nucleic acid. Percent complementarity is calculated by dividing the number of nucleobases of the oligomeric compound that are complementary to nucleobases at corresponding positions in the target nucleic acid by the total length of the oligomeric compound.

As used herein, “percent identity” means the number of nucleobases in a first nucleic acid that are the same type (independent of chemical modification) as nucleobases at corresponding positions in a second nucleic acid, divided by the total number of nucleobases in the first nucleic acid.

As used herein, “modulation” means a change of amount or quality of a molecule, function, or activity when compared to the amount or quality of a molecule, function, or activity prior to modulation. For example, modulation includes the change, either an increase (stimulation or induction) or a decrease (inhibition or reduction) in gene expression.

As used herein, “type of modification” in reference to a nucleoside or a nucleoside of a “type” means the chemical modification of a nucleoside and includes modified and unmodified nucleosides.

Accordingly, unless otherwise indicated, a “nucleoside having a modification of a first type” may be an unmodified nucleoside.

As used herein, “differently modified” mean chemical modifications or chemical substituents that are different from one another, including absence of modifications. Thus, for example, a MOE nucleoside and an unmodified naturally occurring RNA nucleoside are “differently modified,” even though the naturally occurring nucleoside is unmodified. Likewise, DNA and RNA oligonucleotides are “differently modified,” even though both are naturally-occurring unmodified nucleosides. Nucleosides that are the same but for comprising different nucleobases are not differently modified. For example, a nucleoside comprising a 2′-OMe modified sugar moiety and an unmodified adenine nucleobase and a nucleoside comprising a 2′-OMe modified sugar moiety and an unmodified thymine nucleobase are not differently modified.

As used herein, “the same type of modifications” refers to modifications that are the same as one another, including absence of modifications. Thus, for example, two unmodified RNA nucleosides have “the same type of modification,” even though the RNA nucleosides are unmodified. Such nucleosides having the same type modification may comprise different nucleobases.

As used herein, “region” or “regions”, or “portion” or “portions”, mean a plurality of linked nucleosides that have a function or character as defined herein, in particular with reference to the subject-matter and definitions described herein. Typically such regions or portions comprise at least 10, at least 11, at least 12 or at least 13 linked nucleosides. For example, such regions can comprise 13 to 20 linked nucleosides, such as 13 to 16 or 18 to 20 linked nucleosides. Typically a first region as defined herein consists essentially of 18 to 20 nucleosides and a second region as defined herein consists essentially of 13 to 16 linked nucleosides.

As used herein, “pharmaceutically acceptable carrier or diluent” means any substance suitable for use in administering to an animal. In certain embodiments, a pharmaceutically acceptable carrier or diluent is sterile saline. In certain embodiments, such sterile saline is pharmaceutical grade saline.

As used herein, “substituent” and “substituent group,” means an atom or group that replaces the atom or group of a named parent compound. For example a substituent of a modified nucleoside is any atom or group that differs from the atom or group found in a naturally occurring nucleoside (e.g., a modified 2′-substituent is any atom or group at the 2′-position of a nucleoside other than H or OH). Substituent groups can be protected or unprotected. In certain embodiments, compounds of the present disclosure have substituents at one or at more than one position of the parent compound. Substituents may also be further substituted with other substituent groups and may be attached directly or via a linking group such as oxygen or an alkyl or hydrocarbyl group to a parent compound.

Such substituents can be present as the modification on the sugar moiety, in particular a substituent present at the 2′-position of the sugar moiety. Unless otherwise indicated, groups amenable for use as substituents include without limitation, one or more of halo, hydroxyl, alkyl, alkenyl, alkynyl, acyl, carboxyl, alkoxy, alkoxyalkylene and amino substituents. Certain substituents as described herein can represent modifications directly attached to a ring of a sugar moiety (such as a halo, such as fluoro, directly attached to a sugar ring), or a modification indirectly linked to a ring of a sugar moiety by way of an oxygen linking atom that itself is directly linked to the sugar moiety (such as an alkoxyalkylene, such as methoxyethylene, linked to an oxygen atom, overall providing an MOE substituent as described herein attached to the 2′-position of the sugar moiety).

As used herein, “alkyl,” as used herein, means a saturated straight or branched monovalent C_1-6 hydrocarbon radical, with methyl being a most preferred alkyl as a substituent at the 2′-position of the sugar moiety. The alkyl group typically attaches to an oxygen linking atom at the 2′ position of the sugar, therefore, overall providing an —O-alkyl substituent, such as an —OCH₃ substituent, on a sugar moiety of an oligomeric compound as described herein. This will be well understood be a person skilled in the art.

As used herein, “alkylene” means a saturated straight or branched divalent hydrocarbon radical of the general formula —C_nH_2n— where n is 1-6. Methylene or ethylene are preferred alkylenes.

As used herein, “alkenyl” means a straight or branched unsaturated monovalent C_2-6 hydrocarbon radical, with ethenyl or propenyl being most preferred alkenyls as a substituent at the 2′-position of the sugar moiety. As will be well understood in the art, the degree of unsaturation that is present in an alkenyl radical is the presence of at least one carbon to carbon double bond. The alkenyl group typically attaches to an oxygen linking atom at the 2′-position of the sugar, therefore, overall providing a —Oalkenyl substituent, such as an —OCH₂CH═CH₂ substituent, on a sugar moiety of an oligomeric compound as described herein. This will be well understood be a person skilled in the art.

As used herein, “alkynyl” means a straight or branched unsaturated C_2-6 hydrocarbon radical, with ethynyl being a most preferred alkynyl as a substituent at the 2′-position of the sugar moiety. As will be well understood in the art, the degree of unsaturation that is present in an alkynyl radical is the presence of at least one carbon to carbon triple bond. The alkynyl group typically attaches to an oxygen linking atom at the 2′-position of the sugar, therefore, overall providing a —Oalkynyl substituent on a sugar moiety of an oligomeric compound as described herein. This will be well understood be a person skilled in the art.

As used herein, “carboxyl” is a radical having a general formula —CO₂H.

As used herein, “acyl” means a radical formed by removal of a hydroxyl group from a carboxyl radical as defined herein and has the general Formula —C(O)—X where X is typically C_1-6 alkyl.

As used herein, “alkoxy” means a radical formed between an alkyl group, such as a C_1-6 alkyl group, and an oxygen atom wherein the oxygen atom is used to attach the alkoxy group either to a parent molecule (such as at the 2′-position of a sugar moiety), or to another group such as an alkylene group as defined herein. Examples of alkoxy groups include without limitation, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy and tert-butoxy. Alkoxy groups as used herein may optionally include further substituent groups.

As used herein, alkoxyalkylene means an alkoxy group as defined herein that is attached to an alkylene group also as defined herein, and wherein the oxygen atom of the alkoxy group attaches to the alkylene group and the alkylene attaches to a parent molecule. The alkylene group typically attaches to an oxygen linking atom at the 2′-position of the sugar, therefore, overall providing a —Oalkylenealkoxy substituent, such as an —OCH₂CH₂OCH₃ substituent, on a sugar moiety of an oligomeric compound as described herein. This will be well understood by a person skilled in the art and is generally referred to as an MOE substituent as defined herein and as known in the art.

As used herein, “amino” includes primary, secondary and tertiary amino groups.

As used herein, “halo” and “halogen,” mean an atom selected from fluorine, chlorine, bromine and iodine.

It will also be understood that oligomeric compounds as described herein may have one or more non-hybridizing nucleosides at one or both ends of one or both strands (overhangs) and/or one or more internal non-hybridizing nucleosides (mismatches) provided there is sufficient complementarity to maintain hybridization under physiologically relevant conditions. Alternatively, oligomeric compounds as described herein may be blunt ended at at least one end.

The term “comprising” is used herein to mean including the method steps or elements identified, but that such steps or elements do not comprise an exclusive list and as such there may be present additional steps or elements.

Further, to the extent that the term “includes” is used in either the detailed description or the claims, such term is intended to be inclusive in a manner similar to the term “comprising” as “comprising” is interpreted when employed as a transitional word in a claim.

Each of the constructs of the invention may or may not have a phosphate modification at the 5′ end group. Furthermore, and independently, each of the above constructs may or may not have a “3× GalNAc” coupled to the 3′ end group. Advantageously, a construct bears a 3× GalNAc ligand, such as a “toothbrush” moiety as disclosed herein. Particularly preferred are constructs which in addition have a 5′ phosphate, even though this is not a strict requirement, given that in the absence thereof, mammalian cells will add such phosphate in case it is absent from the molecule as administered.

The following are aspects of the present embodiments.

Aspect 1. An oligomeric compound capable of modulating, preferably inhibiting, expression of FXI, wherein the compound comprises at least a first region of linked nucleosides having at least a first nucleobase sequence that is at least partially complementary to at least a portion of RNA transcribed from an FXI gene, wherein the first nucleobase sequence is selected from the following sequences, or a portion thereof: SEQ ID NOs 1 to 250, or SEQ ID NOs 1251 to 1500.

Aspect 2. An oligomeric compound according to aspect 1, which further comprises at least a second region of linked nucleosides having at least a second nucleobase sequence that is at least partially complementary to the first nucleobase sequence and is selected from the following sequences, or a portion thereof: SEQ ID NOs 251 to 500, or SEQ ID NOs 1501 to 1750.

Aspect 3. An oligomeric compound according to aspect 1 or 2, wherein the first nucleobase sequence is selected from the following sequences, or a portion thereof: SEQ ID NOs 8, 13, 27, 39, 46, 91, 98, 103, 105, 109, 120, 140, 146, 151, 152, 163, 182, 183, 199, 207, 210, 218, 220, 223, 224, 238, or SEQ ID NOs 1258, 1263, 1277, 1289, 1296, 1341, 1348, 1353, 1355, 1359, 1370, 1390, 1396, 1401, 1402, 1413, 1432, 1433, 1449, 1457, 1460, 1468, 1470, 1473, 1474, 1488.

Aspect 4. An oligomeric compound according to aspect 3, wherein the second nucleobase sequence is selected from the following sequences, or a portion thereof: SEQ ID NOs 258, 263, 277, 289, 296, 341, 348, 353, 355, 359, 370, 390, 396, 401, 402, 413, 432, 433, 449, 457, 460, 468, 470, 473, 474, 488, or SEQ ID NOs 1508, 1513, 1527, 1539, 1546, 1591, 1598, 1603, 1605, 1609, 1620, 1640, 1646, 1651, 1652, 1663, 1682, 1683, 1699, 1707, 1710, 1718, 1720, 1723, 1724, 1738.

Aspect 5. An oligomeric compound according to any of aspects 1 to 4, wherein the first nucleobase sequence is selected from the following sequences, or a portion thereof: SEQ ID NOs 8, 46, 91, 146, 152, 207, or SEQ ID NOs 1258, 1296, 1341, 1396, 1402, 1457.

Aspect 6. An oligomeric compound according to aspect 5, wherein the second nucleobase sequence is selected from the following sequences, or a portion thereof: SEQ ID NOs 258, 296, 341, 396, 402, 457, or SEQ ID NOs 1508, 1546, 1591, 1646, 1652, 1707.

Aspect 7. An oligomeric compound according to any of aspects 1 to 6, wherein the first nucleobase sequence is selected from the following sequences, or a portion thereof: SEQ ID NOs 46, 91, 152, or SEQ ID NOs 1296, 1341, 1402.

Aspect 8. An oligomeric compound according to aspect 7, wherein the second nucleobase sequence is selected from the following sequences, or a portion thereof: SEQ ID NOs 296, 341, 402, or SEQ ID NOs 1546, 1591, 1652.

Aspect 9. An oligomeric compound according to any of aspects 1 to 8, wherein the first nucleobase sequence is at least partially complementary to any of the following sequences, or a portion thereof: SEQ ID NOs 1001 to 1250.

Aspect 10. An oligomeric compound according to aspect 3 and/or 4, wherein the first nucleobase sequence is at least partially complementary to any of the following sequences, or a portion thereof: SEQ ID NOs 1008, 1013, 1027, 1039, 1046, 1091, 1098, 1103, 1105, 1109, 1120, 1140, 1146, 1151, 1152, 1163, 1182, 1183, 1199, 1207, 1210, 1218, 1220, 1223, 1224, 1238.

Aspect 11. An oligomeric compound according to aspect 5 and/or 6, wherein the first nucleobase sequence is at least partially complementary to any of the following sequences, or a portion thereof: SEQ ID NOs 1008, 1046, 1091, 1146, 1152, 1207.

Aspect 12. An oligomeric compound according to aspect 7 and/or 8, wherein the first nucleobase sequence is at least partially complementary to any of the following sequences, or a portion thereof: SEQ ID NOs 1046, 1091, 1152.

Aspect 13. An oligomeric compound capable of modulating, preferably inhibiting, expression of FXI, which compound comprises at least a first region of linked nucleosides having at least a first nucleobase sequence that is at least partially complementary to at least a portion of RNA transcribed from an FXI gene, wherein the RNA is selected from the following sequences, or a portion thereof: SEQ ID NOs 1001 to 1250.

Aspect 14. An oligomeric compound according to aspect 13, wherein the RNA is selected from the following sequences, or a portion thereof: SEQ ID NOs 1008, 1013, 1027, 1039, 1046, 1091, 1098, 1103, 1105, 1109, 1120, 1140, 1146, 1151, 1152, 1163, 1182, 1183, 1199, 1207, 1210, 1218, 1220, 1223, 1224, 1238.

Aspect 15. An oligomeric compound according to aspect 13 or 14, wherein the RNA is selected from the following sequences, or a portion thereof: SEQ ID NOs 1008, 1046, 1091, 1146, 1152, 1207.

Aspect 16. An oligomeric compound according to any of aspects 13 to 15, wherein the RNA is selected from the following sequences, or a portion thereof: SEQ ID NOs 1046, 1091, 1152.

Aspect 17. An oligomeric compound according to any of aspects 1 to 16, wherein the first region of linked nucleosides consists essentially of 18 to 20 linked nucleosides.

Aspect 18. An oligomeric compound according to any of aspects 2 to 17, wherein the second region of linked nucleosides consists essentially of 11 to 16, advantageously 12 to 15 or 13 to 16 linked nucleosides.

Aspect 19. An oligomeric compound according to any of aspects 2 to 18, which comprises at least one complementary duplex region that comprises at least a portion of the first nucleoside region directly or indirectly linked to at least a portion of the second nucleoside region.

Aspect 20. An oligomeric compound according to aspect 19, wherein each of the first and second nucleoside regions has a 5′ to 3′ directionality thereby defining 5′ and 3′ regions respectively thereof.

Aspect 21. An oligomeric compound according to aspect 20, wherein the 5′ region of the first nucleoside region is directly or indirectly linked to the 3′ region of the second nucleoside region, for example by complementary base pairing, and/or wherein the 3′ region of the first nucleoside region is directly or indirectly linked to the 5′ region of the second nucleoside region.

Aspect 22. An oligomeric compound according to any of aspects 1 to 21, which further comprises one or more ligands.

Aspect 23. An oligomeric compound according to aspect 21, wherein the one or more ligands are conjugated to the second nucleoside region.

Aspect 24. An oligomeric compound according to aspect 23, as dependent on aspect 20, wherein the one or more ligands are conjugated at the 3′ region of the second nucleoside region.

Aspect 25. An oligomeric compound according to any of aspects 22 to 24, wherein the one or more ligands are any cell directing moiety, such as lipids, carbohydrates, aptamers, vitamins and/or peptides that bind cellular membrane or a specific target on cellular surface.

Aspect 26. An oligomeric compound according to aspect 25, wherein the one or more ligands comprise one or more carbohydrates.

Aspect 27. An oligomeric compound according to aspect 26, wherein the one or more carbohydrates can be a monosaccharide, disaccharide, trisaccharide, tetrasaccharide, oligosaccharide or polysaccharide.

Aspect 28. An oligomeric compound according to aspect 27, wherein the one or more carbohydrates comprise one or more galactose moieties, one or more lactose moieties, one or more N-Acetyl-Galactosamine moieties, and/or one or more mannose moieties.

Aspect 29. An oligomeric compound according to aspect 28, wherein the one or more carbohydrates comprise one or more N-Acetyl-Galactosamine moieties.

Aspect 30. An oligomeric compound according to aspect 29, which comprises two or three N-Acetyl-Galactosamine moieties, preferably three.

Aspect 31. An oligomeric compound according to any of aspects 22 to 30, wherein the one or more ligands are attached to the oligomeric compound, preferably to the second nucleoside region thereof, in a linear configuration, or in a branched configuration.

Preferred is that the ligand has the following structure, also referred to as “toothbrush” herein:

A particularly preferred embodiment of “GalNAc” (as used herein) is the above structure.

Aspect 32. An oligomeric compound according to aspect 31, wherein the one or more ligands are attached to the oligomeric compound as a biantennary or triantennary configuration.

Aspect 33. An oligomeric compound according to aspect 19, wherein the oligomeric compound comprises a single strand comprising the first and second nucleoside regions, wherein the single strand dimerises whereby at least a portion of the first nucleoside region is directly or indirectly linked to at least a portion of the second nucleoside region so as to form the at least partially complementary duplex region.

Aspect 34. An oligomeric compound according to aspect 33, wherein the first nucleoside region has a greater number of linked nucleosides compared to the second nucleoside region, whereby the additional number of linked nucleosides of the first nucleoside region form a hairpin loop linking the first and second nucleoside regions.

Aspect 35. An oligomeric compound according to aspect 34, as dependent on aspect 20, whereby the hairpin loop is present at the 3′ region of the first nucleoside region.

Aspect 36. An oligomeric compound according to aspect 34 or 35, wherein the hairpin loop comprises 4 or 5 linked nucleosides.

Aspect 37. An oligomeric compound according to any of aspects 1 to 36, which comprises internucleoside linkages and wherein at least one internucleoside linkage is a modified internucleoside linkage.

Aspect 38. An oligomeric compound according to aspect 37, wherein the modified internucleoside linkage is a phosphorothioate or phosphorodithioate internucleoside linkage.

Aspect 39. An oligomeric compound according to aspect 38, which comprises 1 to 15 phosphorothioate or phosphorodithioate internucleoside linkages.

Aspect 40. An oligomeric compound according to aspect 39, which comprises 7, 8, 9 or 10 phosphorothioate or phosphorodithioate internucleoside linkages.

Aspect 41. An oligomeric compound according to any of aspects 38 to 40, as dependent on aspect 20, which comprises one or more phosphorothioate or phosphorodithioate internucleoside linkages at the 5′ region of the first nucleoside region.

Aspect 42. An oligomeric compound according to any of aspects 38 to 41, as dependent on aspect 20, which comprises one or more phosphorothioate or phosphorodithioate internucleoside linkages at the 5′ region of the second nucleoside region.

Aspect 43. An oligomeric compound according to any of aspects 38 to 42, as dependent on aspect 34, which comprises phosphorothioate or phosphorodithioate internucleoside linkages between at least two, preferably at least three, preferably at least four, preferably at least five, adjacent nucleosides of the hairpin loop, dependent on the number of nucleotides present in the hairpin loop.

Aspect 44. An oligomeric compound according to aspect 43, which comprises a phosphorothioate or phosphorodithioate internucleoside linkage between each adjacent nucleoside that is present in the hairpin loop.

Aspect 45. An oligomeric compound according to any of aspects 1 to 44, wherein at least one nucleoside comprises a modified sugar.

Aspect 46. An oligomeric compound according to aspect 45, wherein the modified sugar is selected from 2′ modified sugars; conformationally restricted nucleotides (CRN) sugar such as locked nucleic acid (LNA), (S)-constrained ethyl bicyclic nucleic acid, and constrained ethyl (cEt), tricyclo-DNA; morpholino, unlocked nucleic acid (UNA), glycol nucleic acid (GNA), D-hexitol nucleic acid (HNA), and cyclohexene nucleic acid (CeNA), and preferably is a 2′-O-methyl modified sugar.

Further 2′ modified sugars include 2′-O-alkyl modified sugar, 2′-O-methoxyethyl modified sugar, 2′-O-allyl modified sugar, 2′-C-allyl modified sugar, 2′-deoxy modified sugar such as 2′-deoxy ribose, 2′-F modified sugar, 2′-arabino-fluoro modified sugar, 2′-O-benzyl modified sugar, 2′-amino modified sugar, and 2′-O-methyl-4-pyridine modified sugar.

Aspect 47. An oligomeric compound according to aspect 45 or 46, wherein the modified sugar is a 2′-F modified sugar.

Aspect 48. An oligomeric compound according to any of aspects 45 to 47, as dependent on aspect 20, wherein sugars of the nucleosides at any of positions 2 and 14 downstream from the first nucleoside of the 5′ region of the first nucleoside region, do not contain 2′-O-methyl modifications.

Aspect 49. An oligomeric compound according to any of aspects 45 to 48, as dependent on aspect 20, wherein sugars of the nucleosides of the second nucleoside region, that correspond in position to any of the nucleosides of the first nucleoside region at any of positions 9 to 11 downstream from the first nucleotide of the 5′ region of the first nucleoside region, do not contain 2′-O-methyl modifications.

Aspect 50. An oligomeric compound according to aspect 48 or 49, wherein sugars of the nucleosides at any of positions 2 and 14 downstream from the first nucleoside of the 5′ region of the first nucleoside region, contain 2′-F modifications.

Aspect 51. An oligomeric compound according to any of aspects 48 to 50, wherein sugars of the nucleosides of the second nucleoside region, that correspond in position to any of the nucleosides of the first nucleoside region at any of positions 9 to 11 downstream from the first nucleoside of the 5′ region of the first nucleoside region, contain 2′-F modifications.

Aspect 52. An oligomeric compound according to any of aspects 45 to 51, as dependent on aspect 20, wherein one or more of the odd numbered nucleosides starting from the 5′ region of the first nucleoside region are modified, and/or wherein one or more of the even numbered nucleotides starting from the 5′ region of the first nucleoside region are modified, wherein typically the modification of the even numbered nucleotides is a second modification that is different from the modification of odd numbered nucleotides.

Aspect 53. An oligomeric compound according to aspect 52, wherein one or more of the odd numbered nucleosides starting from the 3′ region of the second nucleoside region are modified by a modification that is different from the modification of odd numbered nucleosides of the first nucleoside region.

Aspect 54. An oligomeric compound according to aspect 52 or 53, wherein one or more of the even numbered nucleosides starting from the 3′ region of the second nucleoside region are modified by a modification that is different from the modification of even numbered nucleosides of the first nucleoside region according to aspect 53.

Aspect 55. An oligomeric compound according to any of aspects 52 to 54, wherein at least one or more of the modified even numbered nucleosides of the first nucleoside region is adjacent to at least one or more of the differently modified odd numbered nucleosides of the first nucleoside region.

Aspect 56. An oligomeric compound according to any of aspects 52 to 55, wherein at least one or more of the modified even numbered nucleosides of the second nucleoside region is adjacent to at least one or more of the differently modified odd numbered nucleosides of the second nucleoside region.

Aspect 57. An oligomeric compound according to any of aspects 52 to 56, wherein sugars of one or more of the odd numbered nucleosides starting from the 5′ region of the first nucleoside region are 2′-O-methyl modified sugars.

Aspect 58. An oligomeric compound according to any of aspects 52 to 57, wherein one or more of the even numbered nucleosides starting from the 5′ region of the first nucleoside region are 2′-F modified sugars.

Aspect 59. An oligomeric compound according to any of aspects 52 to 58, wherein sugars of one or more of the odd numbered nucleosides starting from the 3′ region of the second nucleoside region are 2′-F modified sugars.

Aspect 60. An oligomeric compound according to any of aspects 52 to 59, wherein one or more of the even numbered nucleosides starting from the 3′ region of the second nucleoside region are 2′-O-methyl modified sugars.

Aspect 61. An oligomeric compound according to any of aspects 45 to 60, wherein sugars of a plurality of adjacent nucleosides of the first nucleoside region are modified by a common modification.

Aspect 62. An oligomeric compound according to any of aspects 45 to 61, wherein sugars of a plurality of adjacent nucleosides of the second nucleoside region are modified by a common modification.

Aspect 63. An oligomeric compound according to any of aspects 52 to 62, as dependent on aspect 34, wherein sugars of a plurality of adjacent nucleosides of the hairpin loop are modified by a common modification.

Aspect 64. An oligomeric compound according to any of aspects 61 to 63, wherein the common modification is a 2′-F modified sugar.

Aspect 65. An oligomeric compound according to any of aspects 61 to 63, wherein the common modification is a 2′-O-methyl modified sugar.

Aspect 66. An oligomeric compound according to aspect 65, wherein the plurality of adjacent 2′-O-methyl modified sugars are present in at least eight adjacent nucleosides of the first and/or second nucleoside regions.

Aspect 67. An oligomeric compound according to aspect 65, wherein the plurality of adjacent 2′-O-methyl modified sugars are present in three or four adjacent nucleosides of the hairpin loop.

Aspect 68. An oligomeric compound according to aspect 45, as dependent on aspect 34, wherein the hairpin loop comprises at least one nucleoside having a modified sugar.

Aspect 69. An oligomeric compound according to aspect 68, wherein the at least one nucleoside is adjacent a nucleoside with a differently modified sugar.

Aspect 70. An oligomeric compound according to aspect 69, wherein the modified sugar is a 2′-O-methyl modified sugar, and the differently modifies sugar is a 2′-F modified sugar.

Aspect 71. An oligomeric compound according to any of aspects 1 to 70, which comprises one or more nucleosides having an un-modified sugar moiety.

Aspect 72. An oligomeric compound according to aspect 71, wherein the unmodified sugar is present in the 5′ region of the second nucleoside region.

Aspect 73. An oligomeric compound according to aspect 71 or 72, as dependent on aspect 34, wherein the unmodified sugar is present in the hairpin loop.

Aspect 74. An oligomeric compound according to any of aspects 1 to 73, wherein one or more nucleosides of the first nucleoside region and/or the second nucleoside region is an inverted nucleoside and is attached to an adjacent nucleoside via the 3′ carbon of its sugar and the 3′ carbon of the sugar of the adjacent nucleoside, and/or one or more nucleosides of the first nucleoside region and/or the second nucleoside region is an inverted nucleoside and is attached to an adjacent nucleoside via the 5′ carbon of its sugar and the 5′ carbon of the sugar of the adjacent nucleoside.

Aspect 75. An oligomeric compound according to any of aspects 1 to 74, which is blunt ended.

Aspect 76. An oligomeric compound according to any of aspects 1 to 74, wherein either the first or second nucleoside region has an overhang.

Aspect 77. An oligomeric compound capable of modulating, preferably inhibiting, expression of FXI, wherein the compound comprises at least a first region of linked nucleosides having at least a first nucleobase sequence that is at least partially complementary to at least a portion of RNA transcribed from an FXI gene, wherein the first nucleobase sequence is a modified sequence and is selected from the following sequences, or a portion thereof: construct NOs 501 to 750, or construct NOs 1751 to 2000.

Aspect 78. An oligomeric compound according to aspect 77, which further comprises at least a second region of linked nucleosides having at least a second nucleobase sequence that is at least partially complementary to the first nucleobase sequence, wherein the second nucleobase sequence is a modified sequence and is selected from the following sequences, or a portion thereof: construct NOs 751 to 1000, or construct NOs 2001 to 2250.

Aspect 79. An oligomeric compound according to aspect 77 or 78, wherein the first nucleobase sequence is selected from the following sequences, or a portion thereof: construct NOs 508, 513, 527, 539, 546, 591, 598, 603, 605, 609, 620, 640, 646, 651, 652, 663, 682, 683, 699, 707, 710, 718, 720, 723, 724, 738, or construct NOs 1758, 1763, 1777, 1789, 1796, 1841, 1848, 1853, 1855, 1859, 1870, 1890, 1896, 1901, 1902, 1913, 1932, 1933, 1949, 1957, 1960, 1968, 1970, 1973, 1974, 1988.

Aspect 80. An oligomeric compound according to aspect 79, wherein the second nucleobase sequence is selected from the following sequences, or a portion thereof: construct NOs 758, 763, 777, 789, 796, 841, 848, 853, 855, 859, 870, 890, 896, 901, 902, 913, 932, 933, 949, 957, 960, 968, 970, 973, 974, 988, or construct NOs 2008, 2013, 2027, 2039, 2046, 2091, 2098, 2103, 2105, 2109, 2120, 2140, 2146, 2151, 2152, 2163, 2182, 2183, 2199, 2207, 2210, 2218, 2220, 2223, 2224, 2238.

Aspect 81. An oligomeric compound according to any of aspects 77 to 80, wherein the first nucleobase sequence is selected from the following sequences, or a portion thereof: construct NOs 508, 546, 591, 646, 652, 707, or construct NOs 1758, 1796, 1841, 1896, 1902, 1957.

Aspect 82. An oligomeric compound according to aspect 81, wherein the second nucleobase sequence is selected from the following sequences, or a portion thereof: construct NOs 758, 796, 841, 896, 902, 957, or construct NOs 2008, 2046, 2091, 2146, 2152, 2207.

Aspect 83. An oligomeric compound according to any of aspects 77 to 82, wherein the first nucleobase sequence is selected from the following sequences, or a portion thereof: construct NOs 546, 591, 652, or construct NOs 1796, 1841, 1902.

Aspect 84. An oligomeric compound according to aspect 83, wherein the second nucleobase sequence is selected from the following sequences, or a portion thereof: construct NOs 796, 841, 902, or construct NOs 2046, 2091, 2152.

Aspect 85. An oligomeric compound according to any of aspects 77 to 84, which is further characterised according to any of aspects 17 to 44, or 74 to 76.

Aspect 86. An oligomeric compound capable of modulating, preferably inhibiting, expression of FXI, which is selected from the following sequences: SEQ ID NOs 2251 to 2253, or SEQ ID NOs 2284 to 2288, preferably SEQ ID NO: 2287.

Aspect 87. An oligomeric compound capable of modulating, preferably inhibiting, expression of FXI, which is selected from the following sequences: construct NOs 2254 to 2283.

Aspect 88. An oligomeric compound according to aspect 86 or 87, which further comprises one or more ligands.

Aspect 89. An oligomeric compound according to aspect 88, wherein the one or more ligands are conjugated at the 3 ‘ region of the sequences, preferably at the 3’ terminal nucleoside.

Aspect 90. An oligomeric compound according to aspect 88, wherein the one or more ligands are conjugated at non-terminal positions.

Aspect 91. An oligomeric compound according to any of aspects 88 to 90, wherein the one or more ligands are any cell directing moiety, such as lipids, carbohydrates, aptamers, vitamins and/or peptides that bind cellular membrane or a specific target on cellular surface.

Aspect 92. An oligomeric compound according to aspect 91, wherein the one or more ligands comprise one or more carbohydrates.

Aspect 93. An oligomeric compound according to aspect 92, wherein the one or more carbohydrates can be a monosaccharide, disaccharide, trisaccharide, tetrasaccharide, oligosaccharide or polysaccharide.

A preferred monosaccharide is hexose.

Aspect 94. An oligomeric compound according to aspect 93, wherein the one or more carbohydrates comprise one or more galactose moieties, one or more lactose moieties, one or more N-Acetyl-Galactosamine moieties, and/or one or more mannose moieties.

Aspect 95. An oligomeric compound according to aspect 94, wherein the one or more carbohydrates comprise one or more N-Acetyl-Galactosamine moieties.

Aspect 96. An oligomeric compound according to aspect 95, which comprises two or three N-Acetyl-Galactosamine moieties, preferably three.

Aspect 97. An oligomeric compound according to any of aspects 88 to 96, wherein the one or more ligands are attached to the oligomeric compound in a linear configuration, or in a branched configuration.

Aspect 98. An oligomeric compound according to aspect 97, wherein the one or more ligands are attached to the oligomeric compound as a biantennary or triantennary configuration.

Aspect 99. An oligomeric compound according to any of aspects 86 to aspect 98, wherein the sequences self dimerise so as to form an at least partially complementary duplex region.

Aspect 100. An oligomeric compound according to aspect 99, having a nucleobase sequence and structure as shown in any of FIGS. 15 to 17 or 18 to 20, construct NOs: 2290 to 2292 being preferred, construct NO: 2290 being particularly preferred.

Aspect 101. A composition comprising an oligomeric compound according to any of aspects 1 to 100, and a physiologically acceptable excipient.

Aspect 102. An oligomeric compound according to any of aspects 1 to 100, for use in therapy.

Aspect 103. An oligomeric compound according to any of aspects 1 to 100, for use in the treatment of a disease or disorder.

Aspect 104. A method of treating a disease or disorder comprising administration of an oligomeric compound according to any of aspects 1 to 100, to an individual in need of treatment.

Aspect 105. A method according to aspect 104, wherein the oligomeric compound is administered subcutaneously or intravenously to the individual.

Aspect 106. Use of an oligomeric compound according to any of aspects 1 to 100, for use in research as a gene function analysis tool.

Aspect 107. Use according to aspect 103, or a method according to aspect 104, wherein the disease or disorder is a thromboembolic disease.

Aspect 108. Use or method according to aspect 107, wherein the thromboembolic disease is selected from the group consisting of deep vein thrombosis, venous or arterial thrombosis, pulmonary embolism, myocardial infarction, stroke, thrombosis associated with chronic kidney disease or end-stage renal disease (ESRD), including thrombosis associated with dialysis, or other procoagulant condition.

Aspect 109. Use or method according to aspect 108, wherein the thromboembolic disease is deep vein thrombosis, pulmonary embolism, or a combination thereof.

Aspect 110. Use of an oligomeric compound according to any of items 1 to 100 in the manufacture of a medicament for a treatment of a disease or disorder. The diseases and disorders are advantageously the same as set forth herein above.

The molecules disclosed herein, including, but not limited to, the hairpin RNAs as shown in Tables 6 and 7 and FIGS. 15 to 18, 20 and 22 are characterized by surprisingly outstanding performance, including in an in vivo setting; see, for example, the evidence shown in FIGS. 24 and 25. These data show a long-lasting down-regulation of Factor XI in response to administration of constructs as described herein. Further evidence of surprising performance of a plurality of constructs can be seen in the in vitro data provided in the Examples, including the data shown in FIG. 19.

The Figures as provided herein illustrate exemplary methods and data. While the methods are shown and described as being a series of acts that are performed in a particular sequence, it is to be understood and appreciated that the methods are not limited by the order of the sequence. For example, some acts can occur in a different order than what is described herein. In addition, an act can occur concurrently with another act. Further, in some instances, not all acts may be required to implement a method described herein.

The order of the steps of the methods described herein is exemplary, but the steps may be carried out in any suitable order, or simultaneously where appropriate. Additionally, steps may be added or substituted in, or individual steps may be deleted from any of the methods without departing from the scope of the subject matter described herein. Aspects of any of the Examples described above may be combined with aspects of any of the other Examples described to form further Examples.

It will be understood that the above description of a preferred embodiment is given by way of example only and that various modifications may be made by those skilled in the art. What has been described above includes Examples of one or more embodiments. It is, of course, not possible to describe every conceivable modification and alteration of the above compounds, compositions or methods for purposes of describing the aforementioned aspects, but one of ordinary skill in the art can recognize that many further modifications and permutations of various aspects are possible. Accordingly, the described aspects are intended to embrace all such alterations, modifications, and variations that fall within the scope of the appended claims.

EXAMPLES

The following Examples illustrate certain embodiments of the present disclosure and are not limiting. Moreover, where specific embodiments are provided, the inventors have contemplated generic application of those specific embodiments. For example, disclosure of an oligonucleotide having a particular motif or modification patterns provides reasonable support for additional oligonucleotides having the same or similar motif or modification patterns.

The syntheses of the RNAi constructs disclosed herein may be carried out using synthesis methods known to the person skilled in the art, such as synthesis methods disclosed in https://en.wikipedia.org/wiki/Oligonucleotide_synthesis {retrieved on 16 Feb. 2022}, wherein the methods disclosed on this website are incorporated by reference herein in their entirety. The only difference to the synthesis method disclosed in this reference is that GalNAc phosphoramidite immobilized on a support is used in the synthesis method during the first synthesis step.

The terms “construct number” and “SEQ ID NO” are used equivalently herein, especially with respect to 67 nucleobase sequences. Nucleobase sequences generally do not carry information about modifications of the sugar-phosphate backbone.

Example 1

Oligomeric compounds were synthesized using the oligonucleotides as set out in Tables 1a and 1 b below.

TABLE 1a
Summary sequence table for active nucleobase sequences:
	Seq		Seq
Oligo	ID	Antisense (Guide) Strand	ID	Sense (Passenger) Strand
Name	No	Sequence (5′ to 3′)	No	Sequence (5′ to 3′)
F11-	1	UCAAAAUCUUAGGUGACUC	251	CACCUAAGAUUUUGA
01
F11-	2	UAUUGAUUUAAAAUGCCAC	252	CAUUUUAAAUCAAUA
02
F11-	3	UAGAAAUCGCUGCUGUCCU	253	CAGCAGCGAUUUCUA
03
F11-	4	UAUAAGAAAAUCAUCCUGA	254	GAUGAUUUUCUUAUA
04
F11-	5	UAAACACCGUAUUAGGGAA	255	CUAAUACGGUGUUUA
05
F11-	6	UAAAUCAGUGUCAUGGUAA	256	CAUGACACUGAUUUA
06
F11-	7	UAUACCCGCUUUCUGCCAU	257	CAGAAAGCGGGUAUA
07
F11-	8	UAGAUGUUUUAAGGAGACA	258	UCCUUAAAACAUCUA
08
F11-	9	UGGUAUCUUGGCUUUCUGG	259	AAAGCCAAGAUACCA
09
F11-	10	UCUCUGUAUCUCUUCUGGC	260	GAAGAGAUACAGAGA
10
F11-	11	UAUGGAUUAUUAUUUCUUG	261	AAAUAAUAAUCCAUA
11
F11-	12	UAGCCAGAUUAGAAAGUGC	262	UUUCUAAUCUGGCUA
12
F11-	13	UAGCGGACGGCAUUGGUGC	263	CAAUGCCGUCCGCUA
13
F11-	14	UAUUUCAGAUUGAUUUAAA	264	AAUCAAUCUGAAAUA
14
F11-	15	UUUGUCUCUUAGUUUUCUG	265	AAACUAAGAGACAAA
15
F11-	16	UAGAACACUGGGAUGCUGU	266	CAUCCCAGUGUUCUA
16
F11-	17	UCCACUUGAUAUAAGAAAA	267	CUUAUAUCAAGUGGA
17
F11-	18	UCAUUUUCUUACAAACACC	268	UUUGUAAGAAAAUGA
18
F11-	19	UUAAUGCGUGUACUGGGCA	269	CAGUACACGCAUUAA
19
F11-	20	UAGGACAGAGGGCCUCCCG	270	AGGCCCUCUGUCCUA
20
F11-	21	UCAACCGGGAUGAUGAGUG	271	CAUCAUCCCGGUUGA
21
F11-	22	UGACAAAGAUUUCUUUGAG	272	AAGAAAUCUUUGUCA
22
F11-	23	UGAGGAAGCAUGCUGGCAC	273	CAGCAUGCUUCCUCA
23
F11-	24	UGGAAAAUGUCCCUAAUAC	274	UAGGGACAUUUUCCA
24
F11-	25	UUUAAGUAACACUUGCCCU	275	CAAGUGUUACUUAAA
25
F11-	26	UCAAUAUCAUACCCGCUUU	276	CGGGUAUGAUAUUGA
26
F11-	27	UAAAUGUACCACUUGAUAU	277	CAAGUGGUACAUUUA
27
F11-	28	UAGAAAAUCAUCCUGAAAA	278	CAGGAUGAUUUUCUA
28
F11-	29	UUAACACUUGCCCUUCCCU	279	AAGGGCAAGUGUUAA
29
F11-	30	UAGCAUUUUCUUACAAACA	280	UGUAAGAAAAUGCUA
30
F11-	31	UCAAACACCGUAUUAGGGA	281	UAAUACGGUGUUUGA
31
F11-	32	UAGCGGCUGUUAAUAUCCA	282	UAUUAACAGCCGCUA
32
F11-	33	UGAGCGGCUGUUAAUAUCC	283	AUUAACAGCCGCUCA
33
F11-	34	UGAGACAAAGAUUUCUUUG	284	GAAAUCUUUGUCUCA
34
F11-	35	UUGGGUUAUUUUAUGUCCU	285	CAUAAAAUAACCCAA
35
F11-	36	UGAGCCAUGACACUGUCGA	286	CAGUGUCAUGGCUCA
36
F11-	37	UCAGAUUAGAAAGUGCACA	287	CACUUUCUAAUCUGA
37
F11-	38	UAGAAUACCCAGAAAUCGC	288	UUUCUGGGUAUUCUA
38
F11-	39	UCAGAUGUUUUAAGGAGAC	289	CCUUAAAACAUCUGA
39
F11-	40	UUGUAUCCAGAGAUGCCUC	290	CAUCUCUGGAUACAA
40
F11-	41	UGAGUCACACAUUCACCAG	291	UGAAUGUGUGACUCA
41
F11-	42	UCAAAGAAAGAUGUGUCCU	292	CACAUCUUUCUUUGA
42
F11-	43	UACCACUUGAUAUAAGAAA	293	UUAUAUCAAGUGGUA
43
F11-	44	UAAGAAAGCUUUAAGUAAC	294	CUUAAAGCUUUCUUA
44
F11-	45	UUUAUUUCAGAUUGAUUUA	295	UCAAUCUGAAAUAAA
45
F11-	46	UUGGUGUGAGCAUUGCUUG	296	CAAUGCUCACACCAA
46
F11-	47	UAUCAUCCUGAAAAGACCU	297	CUUUUCAGGAUGAUA
47
F11-	48	UGUGAGCAUUGCUUGAAAG	298	CAAGCAAUGCUCACA
48
F11-	49	UCUGUAUCUCUUCUGGCAC	299	CAGAAGAGAUACAGA
49
F11-	50	UACCUUAAUGUGUAUCCAG	300	AUACACAUUAAGGUA
50
F11-	51	UAUCAUGGAUUAUUAUUUC	301	UAAUAAUCCAUGAUA
51
F11-	52	UCAAAGAUUUCUUUGAGAU	302	CAAAGAAAUCUUUGA
52
F11-	53	UGAAGUAUUUUAGUUGGAG	303	AACUAAAAUACUUCA
53
F11-	54	UAGAUUGAUUUAAAAUGCC	304	UUUUAAAUCAAUCUA
54
F11-	55	UGGGUAUCUUGGCUUUCUG	305	AAGCCAAGAUACCCA
55
F11-	56	UAGGAGACAAAGAUUUCUU	306	AAUCUUUGUCUCCUA
56
F11-	57	UGUCAUGGUAAAAUGAAGA	307	CAUUUUACCAUGACA
57
F11-	58	UAUAUCCAGUUCUUCUCCC	308	GAAGAACUGGAUAUA
58
F11-	59	UAAUAUCCAGUUCUUCUCC	309	AAGAACUGGAUAUUA
59
F11-	60	UCUGUGGUUUCCAGUUUCA	310	ACUGGAAACCACAGA
60
F11-	61	UAGAUUAGAAAGUGCACAG	311	GCACUUUCUAAUCUA
61
F11-	62	UAGAAAUCAGUGUCAUGGU	312	UGACACUGAUUUCUA
62
F11-	63	UUGGAUUAUUAUUUCUUGA	313	GAAAUAAUAAUCCAA
63
F11-	64	UCCAGAUUAGAAAGUGCAC	314	ACUUUCUAAUCUGGA
64
F11-	65	UCUCAUUAUCCAUUUUACA	315	AAAUGGAUAAUGAGA
65
F11-	66	UUUGGGCCAUUCCUGGGAA	316	CAGGAAUGGCCCAAA
66
F11-	67	UUGGGCUUGAUUUUGGUGG	317	CAAAAUCAAGCCCAA
67
F11-	68	UCAGAUUGAUUUAAAAUGC	318	UUUAAAUCAAUCUGA
68
F11-	69	UAAGCAACCGGGAUGAUGA	319	CAUCCCGGUUGCUUA
69
F11-	70	UCUUAAUGUGUAUCCAGAG	320	GGAUACACAUUAAGA
70
F11-	71	UGUAAUUCACUGUGGUUUC	321	CCACAGUGAAUUACA
71
F11-	72	UACAUUUCUAUCUCCUUUG	322	GGAGAUAGAAAUGUA
72
F11-	73	UCACUGGUUUCCAAUGAUG	323	AUUGGAAACCAGUGA
73
F11-	74	UGAAUCUGUGUAAUUCACU	324	AAUUACACAGAUUCA
74
F11-	75	UGUCCUAUUCACUCUUGGC	325	AGAGUGAAUAGGACA
75
F11-	76	UAGCAUUGCUUGAAAGAAU	326	UUUCAAGCAAUGCUA
76
F11-	77	UAAUACCCAGAAAUCGCUG	327	GAUUUCUGGGUAUUA
77
F11-	78	UAUUAUUAUUUCUUGAACC	328	CAAGAAAUAAUAAUA
78
F11-	79	UAAGUAUUUUAGUUGGAGA	329	CAACUAAAAUACUUA
79
F11-	80	UGAAUCCAGUCCACGUACU	330	CGUGGACUGGAUUCA
80
F11-	81	UAGACAAAGAUUUCUUUGA	331	AGAAAUCUUUGUCUA
81
F11-	82	UACAGGAUUUCAGUGAAAA	332	CACUGAAAUCCUGUA
82
F11-	83	UAACAAGGCAAUAUCAUAC	333	GAUAUUGCCUUGUUA
83
F11-	84	UAAGGCAAUAUCAUACCCG	334	UAUGAUAUUGCCUUA
84
F11-	85	UAUACCCAGAAAUCGCUGC	335	CGAUUUCUGGGUAUA
85
F11-	86	UGAUUGAUUUAAAAUGCCA	336	AUUUUAAAUCAAUCA
86
F11-	87	UCCUAUUCACUCUUGGCAG	337	CAAGAGUGAAUAGGA
87
F11-	88	UGUAGACACGCAAAAUCUU	338	UUUUGCGUGUCUACA
88
F11-	89	UUGAGUUUUCUCCAGAAUC	339	CUGGAGAAAACUCAA
89
F11-	90	UAUUUCUUUGAGAUUCUUU	340	AAUCUCAAAGAAAUA
90
F11-	91	UUAUAAGAAAAUCAUCCUG	341	AUGAUUUUCUUAUAA
91
F11-	92	UAAAAUCUUAGGUGACUCU	342	UCACCUAAGAUUUUA
92
F11-	93	UACACUGGGAUGCUGUGCC	343	CAGCAUCCCAGUGUA
93
F11-	94	UUGCACAGGAUUUCAGUGA	344	UGAAAUCCUGUGCAA
94
F11-	95	UAUACAAGCCAGAUUAGAA	345	AAUCUGGCUUGUAUA
95
F11-	96	UUGUGGUUUCCAGUUUCAA	346	AACUGGAAACCACAA
96
F11-	97	UUGCCCUUCCCUUCGUUGC	347	CGAAGGGAAGGGCAA
97
F11-	98	UAAAAUCAUCCUGAAAAGA	348	UUCAGGAUGAUUUUA
98
F11-	99	UCCAAGAAAUCAGUGUCAU	349	CACUGAUUUCUUGGA
99
F11-	100	UGGCAUAUGGGUCGUUGAG	350	ACGACCCAUAUGCCA
100
F11-	101	UAGAAUCUGUGUAAUUCAC	351	AUUACACAGAUUCUA
101
F11-	102	UAUCCAGUCCACGUACUCG	352	UACGUGGACUGGAUA
102
F11-	103	UCCUCUGUAUCUCUUCUGG	353	AAGAGAUACAGAGGA
103
F11-	104	UGCACAGGAUUUCAGUGAA	354	CUGAAAUCCUGUGCA
104
F11-	105	UGUAAAAUGAAGAAUGGCA	355	AUUCUUCAUUUUACA
105
F11-	106	UGUCGUUGAGAAUCUGUGU	356	AGAUUCUCAACGACA
106
F11-	107	UGCAACAAUAUCCAGUUCU	357	CUGGAUAUUGUUGCA
107
F11-	108	UCAGCGGACGGCAUUGGUG	358	AAUGCCGUCCGCUGA
108
F11-	109	UGAAAGCUUUAAGUAACAC	359	UACUUAAAGCUUUCA
109
F11-	110	UGCAGUGUUUCUGUAACAC	360	UACAGAAACACUGCA
110
F11-	111	UGAGAAUCUGUGUAAUUCA	361	UUACACAGAUUCUCA
111
F11-	112	UUCCAGUCCACGUACUCGA	362	GUACGUGGACUGGAA
112
F11-	113	UUGUGAGCAUUGCUUGAAA	363	AAGCAAUGCUCACAA
113
F11-	114	UCCGGGAUGAUGAGUGCAG	364	ACUCAUCAUCCCGGA
114
F11-	115	UCCACUUUAUCGAGCUUCG	365	GCUCGAUAAAGUGGA
115
F11-	116	UCAUUAUCCAUUUUACACA	366	UAAAAUGGAUAAUGA
116
F11-	117	UAACCGGGAUGAUGAGUGC	367	UCAUCAUCCCGGUUA
117
F11-	118	UUUCUUUGGGCCAUUCCUG	368	AAUGGCCCAAAGAAA
118
F11-	119	UCUAAGGGUAUCUUGGCUU	369	CAAGAUACCCUUAGA
119
F11-	120	UUUGGUGUGAGCAUUGCUU	370	AAUGCUCACACCAAA
120
F11-	121	UCAUAUGGGUCGUUGAGAA	371	CAACGACCCAUAUGA
121
F11-	122	UUUAAUGUGUAUCCAGAGA	372	UGGAUACACAUUAAA
122
F11-	123	UUCAGAUGUUUUAAGGAGA	373	CUUAAAACAUCUGAA
123
F11-	124	UUUCCAAUGAUGGAGCCUC	374	CUCCAUCAUUGGAAA
124
F11-	125	UAGAAUCCAGUCCACGUAC	375	GUGGACUGGAUUCUA
125
F11-	126	UUUUGAGAUUCUUUGGGCC	376	CAAAGAAUCUCAAAA
126
F11-	127	UAAUCAUCCUGAAAAGACC	377	UUUUCAGGAUGAUUA
127
F11-	128	UAGACACGCAAAAUCUUAG	378	GAUUUUGCGUGUCUA
128
F11-	129	UCGUACUCGACCACGUUGG	379	CGUGGUCGAGUACGA
129
F11-	130	UCAUCCAGUCACCCAGCAA	380	UGGGUGACUGGAUGA
130
F11-	131	UAACACUGGGAUGCUGUGC	381	AGCAUCCCAGUGUUA
131
F11-	132	UCAGAAAGAGCUUUGCUCU	382	CAAAGCUCUUUCUGA
132
F11-	133	UUUCUUUGAGAUUCUUUGG	383	AGAAUCUCAAAGAAA
133
F11-	134	UAGCAACAAUAUCCAGUUC	384	UGGAUAUUGUUGCUA
134
F11-	135	UACCACUUUAUCGAGCUUC	385	CUCGAUAAAGUGGUA
135
F11-	136	UCCCUUCCCUUCGUUGCAG	386	AACGAAGGGAAGGGA
136
F11-	137	UCGCAAAAUCUUAGGUGAC	387	CCUAAGAUUUUGCGA
137
F11-	138	UAGCGUGUUACUGUGGAGG	388	CACAGUAACACGCUA
138
F11-	139	UCUCCUUCCCUGUAGCCGG	389	CUACAGGGAAGGAGA
139
F11-	140	UGUCCUCUGUAUCUCUUCU	390	GAGAUACAGAGGACA
140
F11-	141	UGUAUCUUGGCUUUCUGGA	391	GAAAGCCAAGAUACA
141
F11-	142	UCUCUUGGCAGUGUUUCUG	392	AACACUGCCAAGAGA
142
F11-	143	UGAAAUCAGUGUCAUGGUA	393	AUGACACUGAUUUCA
143
F11-	144	UCUUCCCUGUAGCCGGCAC	394	CGGCUACAGGGAAGA
144
F11-	145	UCUGGCCGCUCCCUUUGAG	395	AAGGGAGCGGCCAGA
145
F11-	146	UCACGCAAAAUCUUAGGUG	396	UAAGAUUUUGCGUGA
146
F11-	147	UGAAACCAGAAAGAGCUUU	397	CUCUUUCUGGUUUCA
147
F11-	148	UAAAGCUUUAAGUAACACU	398	UUACUUAAAGCUUUA
148
F11-	149	UACAAGCCAGAUUAGAAAG	399	CUAAUCUGGCUUGUA
149
F11-	150	UACUCAUUAUCCAUUUUAC	400	AAUGGAUAAUGAGUA
150
F11-	151	UCCUGAAAAGACCUUGUUG	401	AAGGUCUUUUCAGGA
151
F11-	152	UGGUUUCCAAUGAUGGAGC	402	CAUCAUUGGAAACCA
152
F11-	153	UCAGUUUCUGGCAGGCCUC	403	CCUGCCAGAAACUGA
153
F11-	154	UAUGGCAGAACACUGGGAU	404	CAGUGUUCUGCCAUA
154
F11-	155	UAGAUUUCUUUGAGAUUCU	405	UCUCAAAGAAAUCUA
155
F11-	156	UGUUUCCAGUUUCAACAAG	406	UUGAAACUGGAAACA
156
F11-	157	UUCCUCUGUAUCUCUUCUG	407	AGAGAUACAGAGGAA
157
F11-	158	UCAUCCUGAAAAGACCUUG	408	GUCUUUUCAGGAUGA
158
F11-	159	UUUGAGUUUUCUCCAGAAU	409	UGGAGAAAACUCAAA
159
F11-	160	UAAUUCACUGUGGUUUCCA	410	AACCACAGUGAAUUA
160
F11-	161	UAAGAUUUCUUUGAGAUUC	411	CUCAAAGAAAUCUUA
161
F11-	162	UGGAGACAAAGAUUUCUUU	412	AAAUCUUUGUCUCCA
162
F11-	163	UGAAAAUCAUCCUGAAAAG	413	UCAGGAUGAUUUUCA
163
F11-	164	UCUUUCUGCCAUUUUAUAC	414	AAAAUGGCAGAAAGA
164
F11-	165	UAGUCCACGUACUCGACCA	415	CGAGUACGUGGACUA
165
F11-	166	UUUAAUGCGUGUACUGGGC	416	AGUACACGCAUUAAA
166
F11-	167	UUAAUGUGUAUCCAGAGAU	417	CUGGAUACACAUUAA
167
F11-	168	UGAUUCUUUGGGCCAUUCC	418	UGGCCCAAAGAAUCA
168
F11-	169	UUGAAACCAGAAAGAGCUU	419	UCUUUCUGGUUUCAA
169
F11-	170	UCACACAUUCACCAGAAAC	420	CUGGUGAAUGUGUGA
170
F11-	171	UACAAAGAUUUCUUUGAGA	421	AAAGAAAUCUUUGUA
171
F11-	172	UCAUUUCUAUCUCCUUUGG	422	AGGAGAUAGAAAUGA
172
F11-	173	UUUUCUGUAACACUGUCUU	423	CAGUGUUACAGAAAA
173
F11-	174	UGGAUUUCAGUGAAAAUCC	424	UUUCACUGAAAUCCA
174
F11-	175	UCGCUCCCUUUGAGCACAG	425	GCUCAAAGGGAGCGA
175
F11-	176	UCAGUCCACGUACUCGACC	426	GAGUACGUGGACUGA
176
F11-	177	UAGGCAUAUGGGUCGUUGA	427	CGACCCAUAUGCCUA
177
F11-	178	UAUGUCCUCUGUAUCUCUU	428	GAUACAGAGGACAUA
178
F11-	179	UGCUUGAUUUUGGUGGUAC	429	CACCAAAAUCAAGCA
179
F11-	180	UAUGAUGGAGCCUCCACAC	430	GGAGGCUCCAUCAUA
180
F11-	181	UUCGUUGAGAAUCUGUGUA	431	CAGAUUCUCAACGAA
181
F11-	182	UUUAUCCAUUUUACACAAC	432	UGUAAAAUGGAUAAA
182
F11-	183	UUGUCCUAUUCACUCUUGG	433	GAGUGAAUAGGACAA
183
F11-	184	UCAAUAUCCAGUUCUUCUC	434	AGAACUGGAUAUUGA
184
F11-	185	UCUUUGAGAUUCUUUGGGC	435	AAAGAAUCUCAAAGA
185
F11-	186	UCACUCUUGGCAGUGUUUC	436	CACUGCCAAGAGUGA
186
F11-	187	UCUUGAAAGAAUACCCAGA	437	GGUAUUCUUUCAAGA
187
F11-	188	UAGGCAAUAUCAUACCCGC	438	GUAUGAUAUUGCCUA
188
F11-	189	UCUGUGUAAUUCACUGUGG	439	AGUGAAUUACACAGA
189
F11-	190	UAAUAUCCACUGGUUUCCA	440	AACCAGUGGAUAUUA
190
F11-	191	UUGAAAGAAUACCCAGAAA	441	UGGGUAUUCUUUCAA
191
F11-	192	UGUUAAUAUCCACUGGUUU	442	CAGUGGAUAUUAACA
192
F11-	193	UUGUCAUGGUAAAAUGAAG	443	AUUUUACCAUGACAA
193
F11-	194	UAUUCUUUGGGCCAUUCCU	444	AUGGCCCAAAGAAUA
194
F11-	195	UCAGUUCCUCCAACGAUCC	445	CGUUGGAGGAACUGA
195
F11-	196	UGGGUGUGCUUCAGUAGAC	446	ACUGAAGCACACCCA
196
F11-	197	UGAAGAAAGCUUUAAGUAA	447	UUAAAGCUUUCUUCA
197
F11-	198	UAUCCUGAAAAGACCUUGU	448	GGUCUUUUCAGGAUA
198
F11-	199	UAGAAAGCUUUAAGUAACA	449	ACUUAAAGCUUUCUA
199
F11-	200	UCAGUGUUUCUGUAACACU	450	UUACAGAAACACUGA
200
F11-	201	UGACACGCAAAAUCUUAGG	451	AGAUUUUGCGUGUCA
201
F11-	202	UGUGUGAGCAUUGCUUGAA	452	AGCAAUGCUCACACA
202
F11-	203	UACCAGAAAGAGCUUUGCU	453	AAGCUCUUUCUGGUA
203
F11-	204	UAGAAAGUGCACAGGAUUU	454	CCUGUGCACUUUCUA
204
F11-	205	UUUUAUUUCAGAUUGAUUU	455	CAAUCUGAAAUAAAA
205
F11-	206	UUAUCCAGUUCUUCUCCCA	456	AGAAGAACUGGAUAA
206
F11-	207	UCCGUGAAAGUGAAGAGUA	457	CUUCACUUUCACGGA
207
F11-	208	UGGUGUGCUUCAGUAGACA	458	UACUGAAGCACACCA
208
F11-	209	UGGACAGAGGGCCUCCCGA	459	GAGGCCCUCUGUCCA
209
F11-	210	UAAGAAAAUCAUCCUGAAA	460	AGGAUGAUUUUCUUA
210
F11-	211	UUGAGAUUCUUUGGGCCAU	461	CCCAAAGAAUCUCAA
211
F11-	212	UAUGUUUUAAGGAGACAAA	462	UCUCCUUAAAACAUA
212
F11-	213	UCACAGUUUCUGGCAGGCC	463	UGCCAGAAACUGUGA
213
F11-	214	UACAAUAUCCAGUUCUUCU	464	GAACUGGAUAUUGUA
214
F11-	215	UACAUUCACCAGAAACUGA	465	UUUCUGGUGAAUGUA
215
F11-	216	UCAAGGCAAUAUCAUACCC	466	AUGAUAUUGCCUUGA
216
F11-	217	UCUCCAACGAUCCUGGGCU	467	CAGGAUCGUUGGAGA
217
F11-	218	UCUGAAACCAGAAAGAGCU	468	CUUUCUGGUUUCAGA
218
F11-	219	UAAUCUCCCUUGCAAGCGU	469	UUGCAAGGGAGAUUA
219
F11-	220	UUGUGUAAUUCACUGUGGU	470	CAGUGAAUUACACAA
220
F11-	221	UUUUCAGUGAAAAUCCAGA	471	GAUUUUCACUGAAAA
221
F11-	222	UAAAUCAUCCUGAAAAGAC	472	UUUCAGGAUGAUUUA
222
F11-	223	UUACACUCAUUAUCCAUUU	473	GGAUAAUGAGUGUAA
223
F11-	224	UUUGGCAGUGUUUCUGUAA	474	AGAAACACUGCCAAA
224
F11-	225	UGGUACACUCAUUAUCCAU	475	AUAAUGAGUGUACCA
225
F11-	226	UAGGCAGGCAUAUGGGUCG	476	CCAUAUGCCUGCCUA
226
F11-	227	UCCAGUUUCAACAAGGCAA	477	CUUGUUGAAACUGGA
227
F11-	228	UUGGCCGCUCCCUUUGAGC	478	AAAGGGAGCGGCCAA
228
F11-	229	UACUGUGGUUUCCAGUUUC	479	CUGGAAACCACAGUA
229
F11-	230	UCUUUGGGCCAUUCCUGGG	480	GGAAUGGCCCAAAGA
230
F11-	231	UUAAGAAAAUCAUCCUGAA	481	GGAUGAUUUUCUUAA
231
F11-	232	UCUCUUUUAUUUCAGAUUG	482	CUGAAAUAAAAGAGA
232
F11-	233	UUCUUUGAGAUUCUUUGGG	483	AAGAAUCUCAAAGAA
233
F11-	234	UAAUGAUGGAGCCUCCACA	484	GAGGCUCCAUCAUUA
234
F11-	235	UGAAGAAUGGCAGAACACU	485	UUCUGCCAUUCUUCA
235
F11-	236	UCAAUGAUGGAGCCUCCAC	486	AGGCUCCAUCAUUGA
236
F11-	237	UAUGGAGCCUCCACACAGG	487	UGUGGAGGCUCCAUA
237
F11-	238	UCCCAAGAAAUCAGUGUCA	488	ACUGAUUUCUUGGGA
238
F11-	239	UGAGCCUCCACACAGGUGU	489	CUGUGUGGAGGCUCA
239
F11-	240	UCUCCCAAGAAAUCAGUGU	490	UGAUUUCUUGGGAGA
240
F11-	241	UCCUCCACACAGGUGUCUC	491	CACCUGUGUGGAGGA
241
F11-	242	UCCAAUGAUGGAGCCUCCA	492	GGCUCCAUCAUUGGA
242
F11-	243	UUUUCCAAUGAUGGAGCCU	493	UCCAUCAUUGGAAAA
243
F11-	244	UUCCCAAGAAAUCAGUGUC	494	CUGAUUUCUUGGGAA
244
F11-	245	UAGCCUCCACACAGGUGUC	495	CCUGUGUGGAGGCUA
245
F11-	246	UUCUUCUCCCAAGAAAUCA	496	UUCUUGGGAGAAGAA
246
F11-	247	UGUUUCCAAUGAUGGAGCC	497	CCAUCAUUGGAAACA
247
F11-	248	UUCCAAUGAUGGAGCCUCC	498	GCUCCAUCAUUGGAA
248
F11-	249	UUGGAGCCUCCACACAGGU	499	GUGUGGAGGCUCCAA
249
F11-	250	UGCCUCCACACAGGUGUCU	500	ACCUGUGUGGAGGCA
250

In above Table 1a:

A represents adenine;

U represents uracil;

C represents cytosine;

G represents guanine.

TABLE 1b
Summary sequence table for active nucleobase sequences with chemical modifications:
Oligo	construct	Antisense (Guide) Strand	construct	Sense (Passenger) Strand
Name	No	Sequence (5′ to 3′)	No	Sequence (5′ to 3′)
F11-	501	PmU.fC.mA.fA.mA.fA.mU.fC.mU.fU.m	751	fC.mA.fC.mC.fU.mA.fA.mG.fA.mU
01M		A.fG.mG.fU.mG.fA.mC.fU.mC		.fU.mU.fU.mG.fA
F11-	502	PmU.fA.mU.fU.mG.fA.mU.fU.mU.fA.m	752	fC.mA.fU.mU.fU.mU.fA.mA.fA.mU
02M		A.fA.mA.fU.mG.fC.mC.fA.mC		.fC.mA.fA.mU.fA
F11-	503	PmU.fA.mG.fA.mA.fA.mU.fC.mG.fC.m	753	fC.mA.fG.mC.fA.mG.fC.mG.fA.m
03M		U.fG.mC.fU.mG.fU.mC.fC.mU		U.fU.mU.fC.mU.fA
F11-	504	PmU.fA.mU.fA.mA.fG.mA.fA.mA.fA.m	754	fG.mA.fU.mG.fA.mU.fU.mU.fU.m
04M		U.fC.mA.fU.mC.fC.mU.fG.mA		C.fU.mU.fA.mU.fA
F11-	505	PmU.fA.mA.fA.mC.fA.mC.fC.mG.fU.m	755	fC.mU.fA.mA.fU.mA.fC.mG.fG.m
05M		A.fU.mU.fA.mG.fG.mG.fA.mA		U.fG.mU.fU.mU.fA
F11-	506	PmU.fA.mA.fA.mU.fC.mA.fG.mU.fG.m	756	fC.mA.fU.mG.fA.mC.fA.mC.fU.m
06M		U.fC.mA.fU.mG.fG.mU.fA.mA		G.fA.mU.fU.mU.fA
F11-	507	PmU.fA.mU.fA.mC.fC.mC.fG.mC.fU.m	757	fC.mA.fG.mA.fA.mA.fG.mC.fG.m
07M		U.fU.mC.fU.mG.fC.mC.fA.mU		G.fG.mU.fA.mU.fA
F11-	508	PmU.fA.mG.fA.mU.fG.mU.fU.mU.fU.m	758	fU.mC.fC.mU.fU.mA.fA.mA.fA.mC
08M		A.fA.mG.fG.mA.fG.mA.fC.mA		.fA.mU.fC.mU.fA
F11-	509	PmU.fG.mG.fU.mA.fU.mC.fU.mU.fG.m	759	fA.mA.fA.mG.fC.mC.fA.mA.fG.mA
09M		G.fC.mU.fU.mU.fC.mU.fG.mG		.fll.mA.fC.mC.fA
F11-	510	PmU.fC.mU.fC.mU.fG.mU.fA.mU.fC.m	760	fG.mA.fA.mG.fA.mG.fA.mU.fA.m
10M		U.fC.mU.fU.mC.fU.mG.fG.mC		C.fA.mG.fA.mG.fA
F11-	511	PmU.fA.mU.fG.mG.fA.mU.fU.mA.fU.m	761	fA.mA.fA.mU.fA.rnA.fU.mA.fA.mU
11M		U.fA.mU.fU.mU.fC.mU.fU.mG		.fC.mC.fA.mU.fA
F11-	512	PmU.fA.mG.fC.mC.fA.mG.fA.mU.fU.m	762	fU.mU.fU.mC.fU.mA.fA.mU.fC.m
12M		A.fG.mA.fA.mA.fG.mU.fG.mC		U.fG.mG.fC.mU.fA
F11-	513	PmU.fA.mG.fC.mG.fG.mA.fC.mG.fG.	763	fC.mA.fA.mU.fG.mC.fC.mG.fU.m
13M		mC.fA.mU.fU.mG.fG.mU.fG.mC		C.fC.mG.fC.mU.fA
F11-	514	PmU.fA.mU.fU.mU.fC.mA.fG.mA.fU.m	764	fA.mA.fU.mC.fA.mA.fU.mC.fU.mG
14M		U.fG.mA.fU.mU.fU.mA.fA.mA		.fA.mA.fA.mU.fA
F11-	515	PmU.fU.mU.fG.mU.fC.mU.fC.mU.fU.m	765	fA.mA.fA.mC.fU.mA.fA.mG.fA.mG
15M		A.fG.mU.fU.mU.fU.mC.fU.mG		.fA.mC.fA.mA.fA
F11-	516	PmU.fA.mG.fA.mA.fC.mA.fC.mU.fG.m	766	fC.mA.fU.mC.fC.mC.fA.mG.fU.m
16M		G.fG.mA.fU.mG.fC.mU.fG.mU		G.fU.mU.fC.mU.fA
F11-	517	PmU.fC.mC.fA.mC.fU.mU.fG.mA.fU.m	767	fC.mU.fU.mA.fU.mA.fU.mC.fA.mA
17M		A.fU.mA.fA.mG.fA.mA.fA.mA		.fG.mU.fG.mG.fA
F11-	518	PmU.fC.mA.fU.mU.fU.mU.fC.mU.fU.m	768	fU.mU.fU.mG.fU.mA.fA.mG.fA.m
18M		A.fC.mA.fA.mA.fC.mA.fC.mC		A.fA.mA.fU.mG.fA
F11-	519	PmU.fU.mA.fA.mU.fG.mC.fG.mU.fG.m	769	fC.mA.fG.mU.fA.mC.fA.mC.fG.m
19M		U.fA.mC.fU.mG.fG.mG.fC.mA		C.fA.mU.fU.mA.fA
F11-	520	PmU.fA.mG.fG.mA.fC.mA.fG.mA.fG.m	770	fA.mG.fG.mC.fC.mC.fU.mC.fU.m
20M		G.fG.mC.fC.mU.fC.mC.fC.mG		G.fU.mC.fC.mU.fA
F11-	521	PmU.fC.mA.fA.mC.fC.mG.fG.mG.fA.m	771	fC.mA.fU.mC.fA.mU.fC.mC.fC.m
21M		U.fG.mA.fU.mG.fA.mG.fU.mG		G.fG.mU.fU.mG.fA
F11-	522	PmU.fG.mA.fC.mA.fA.mA.fG.mA.fU.m	772	fA.mA.fG.mA.fA.mA.fU.mC.fU.mU
22M		U.fU.mC.fU.mU.fU.mG.fA.mG		.fU.mG.fU.mC.fA
F11-	523	PmU.fG.mA.fG.mG.fA.mA.fG.mC.fA.m	773	fC.mA.fG.mC.fA.mU.fG.mC.fU.m
23M		U.fG.mC.fU.mG.fG.mC.fA.mC		U.fC.mC.fU.mC.fA
F11-	524	PmU.fG.mG.fA.mA.fA.mA.fU.mG.fU.m	774	fU.mA.fG.mG.fG.mA.fC.mA.fU.m
24M		C.fC.mC.fU.mA.fA.mU.fA.mC		U.fU.mU.fC.mC.fA
F11-	525	PmU.fU.mU.fA.mA.fG.mU.fA.mA.fC.m	775	fC.mA.fA.mG.fU.mG.fU.mU.fA.m
25M		A.fC.mU.fU.mG.fC.mC.fC.mU		C.fU.mU.fA.mA.fA
F11-	526	PmU.fC.mA.fA.mU.fA.mU.fC.mA.fU.m	776	fC.mG.fG.mG.fU.mA.fU.mG.fA.m
26M		A.fC.mC.fC.mG.fC.mU.fU.mU		U.fA.mU.fU.mG.fA
F11-	527	PmU.fA.mA.fA.mU.fG.mU.fA.mC.fC.m	777	fC.mA.fA.mG.fU.mG.fG.mU.fA.m
27M		A.fC.mU.fU.mG.fA.mU.fA.mU		C.fA.mU.fU.mU.fA
F11-	528	PmU.fA.mG.fA.mA.fA.mA.fU.mC.fA.m	778	fC.mA.fG.mG.fA.mU.fG.mA.fU.m
28M		U.fC.mC.fU.mG.fA.mA.fA.mA		U.fU.mU.fC.mU.fA
F11-	529	PmU.fU.mA.fA.mC.fA.mC.fU.mU.fG.m	779	fA.mA.fG.mG.fG.mC.fA.mA.fG.m
29M		C.fC.mC.fU.mU.fC.mC.fC.mU		U.fG.mU.fU.mA.fA
F11-	530	PmU.fA.mG.fC.mA.fU.mU.fU.mU.fC.m	780	fU.mG.fU.mA.fA.mG.fA.mA.fA.mA
30M		U.fU.mA.fC.mA.fA.mA.fC.mA		.fU.mG.fC.mU.fA
F11-	531	PmU.fC.mA.fA.mA.fC.mA.fC.mC.fG.m	781	fU.mA.fA.mU.fA.mC.fG.mG.fU.m
31M		U.fA.mU.fU.mA.fG.mG.fG.mA		G.fU.mU.fU.mG.fA
F11-	532	PmU.fA.mG.fC.mG.fG.mC.fU.mG.fU.	782	fU.mA.fU.mU.fA.mA.fC.mA.fG.mC
32M		mU.fA.mA.fU.mA.fU.mC.fC.mA		.fC.mG.fC.mU.fA
F11-	533	PmU.fG.mA.fG.mC.fG.mG.fC.mU.fG.	783	fA.mU.fU.mA.fA.mC.fA.mG.fC.mC
33M		mU.fU.mA.fA.mU.fA.mU.fC.mC		.fG.mC.fU.mC.fA
F11-	534	PmU.fG.mA.fG.mA.fC.mA.fA.mA.fG.m	784	fG.mA.fA.mA.fU. mC.fU. mU.fU.m
34M		A.fU .mU .fU .mC.fU .mU .fU .mG		G.fU.mC.fU.mC.fA
F11-	535	PmU.fU.mG.fG.mG.fU.mU.fA.mU.fU.m	785	fC.mA.fU.mA.fA.mA.fA.mU.fA.mA
35M		U.fU.mA.fU.mG.fU.mC.fC.mU		.fC.mC.fC.mA.fA
F11-	536	PmU.fG.mA.fG.mC.fC.mA.fU.mG.fA.m	786	fC.mA.fG.mU.fG.mU.fC.mA.fU.m
36M		C.fA.mC.fU.mG.fU.mC.fG.mA		G.fG.mC.fU.mC.fA
F11-	537	PmU.fC.mA.fG.mA.fU.mU.fA.mG.fA.m	787	fC.mA.fC.mU.fU.mU.fC.mU.fA.mA
37M		A.fA.mG.fU.mG.fC.mA.fC.mA		.fU.mC.fU.mG.fA
F11-	538	PmU.fA.mG.fA.mA.fU.mA.fC.mC.fC.m	788	fU.mU.fU.mC.fU.mG.fG.mG.fU.m
38M		A.fG.mA.fA.mA.fU.mC.fG.mC		A.fU.mU.fC.mU.fA
F11-	539	PmU.fC.mA.fG.mA.fU.mG.fU.mU.fU.m	789	fC.mC.fU.mU.fA.mA.fA.mA.fC.mA
39M		U.fA.mA.fG.mG.fA.mG.fA.mC		.fU.mC.fU.mG.fA
F11-	540	PmU.fU.mG.fU.mA.fU.mC.f.mA.fG.m	790	fC.mA.fU.mC.fU.mC.fU.mG.fG.m
40M		A.fG.mA.fU.mG.fC.mC.fU.mC		A.fU.mA.fC.mA.fA
F11-	541	PmU.fG.mA.fG.mU.fC.mA.fC.mA.fC.m	791	fU.mG.fA.mA.fU.mG.fU.mG.fU.m
41M		A.fU.mU.fC.mA.fC.mC.fA.mG		G.fA.mC.fU.mC.fA
F11-	542	PmU.fC.mA.fA.mA.fG.mA.fA.mA.fG.m	792	fC.mA.fC.mA.fU. mC.fU. mU.fU.m
42M		A.fU.mG.fU.mG.fU.mC.fC.mU		C.fU.mU.fU.mG.fA
F11-	543	PmU.fA.mC.fC.mA.fC.mU.fU.mG.fA.m	793	fU.mU.fA.mU.fA.mU.fC.mA.fA.mG
43M		U.fA.mU.fA.mA.fG.mA.fA.mA		.fU.mG.fG.mU.fA
F11-	544	PmU.fA.mA.fG.mA.fA.mA.fG.mC.fU.m	794	fC.mU.fU.mA.fA.mA.fG. mC.fU. m
44M		U.fU.mA.fA.mG.fU.mA.fA.mC		U.fU.mC.fU.mU.fA
F11-	545	PmU.fU.mU.fA.mU.fU.mU.fC.mA.fG.m	795	fU.mC.fA.mA.fU.mC.fU.mG.fA.mA
45M		A.fU.mU.fG.mA.fU.mU.fU.mA		.fA.mU.fA.mA.fA
F11-	546	PmU.fU.mG.fG.mU.fG.mU.fG.mA.fG.	796	fC.mA.fA.mU.fG.mC.fU.mC.fA.m
46M		mC.fA.mU.fU.mG.fC.mU.fU.mG		C.fA.mC.fC.mA.fA
F11-	547	PmU.fA.mU.fC.mA.fU.mC.fC.mU.fG.m	797	fC.mU.fU.mU.fU.mC.fA.mG.fG.m
47M		A.fA.mA.fA.mG.fA.mC.fC.mU		A.fU.mG.fA.mU.fA
F11-	548	PmU.fG.mU.fG.mA.fG.mC.fA.mU.fU.m	798	fC.mA.fA.mG.fC.mA.fA.mU.fG.m
48M		G.fC.mU.fU.mG.fA.mA.fA.mG		C.fU.mC.fA.mC.fA
F11-	549	PmU.fC.mU.fG.mU.fA.mU.fC.mU.fC.m	799	fC.mA.fG.mA.fA.mG.fA.mG.fA.m
49M		U.fU.mC.fU.mG.fG.mC.fA.mC		U.fA.mC.fA.mG.fA
F11-	550	PmU.fA.mC.fC.mU.fU.mA.fA.mU.fG.m	800	fA.mU.fA.mC.fA.mC.fA.mU.fU.mA
50M		U.fG.mU.fA.mU.fC.mC.fA.mG		.fA.mG.fG.mU.fA
F11-	551	PmU.fA.mU.fC.mA.fU.mG.fG.mA.fU.m	801	fU.mA.fA.mU.fA.mA.fU.mC.fC.mA
51M		U.fA.mU.fU.mA.fU.mU.fU.mC		.fU.mG.fA.mU.fA
F11-	552	PmU.fC.mA.fA.mA.fG.mA.fU.mU.fU.m	802	fC.mA.fA.mA.fG.mA.fA.mA.fU.mC
52M		C.fU.mU.fU.mG.fA.mG.fA.mU		.fU.mU.fU.mG.fA
F11-	553	PmU.fG.mA.fA.mG.fU.mA.fU.mU.fU.m	803	fA.mA.fC.mU.fA.mA.fA.mA.fU.mA
53M		U.fA.mG.fU.mU.fG.mG.fA.mG		.fC.mU.fU.mC.fA
F11-	554	PmU.fA.mG.fA.mU.fU.mG.fA.mU.fU.m	804	fU.mU.fU.mU.fA.mA.fA.mU.fC.mA
54M		U.fA.mA.fA.mA.fU.mG.fC.mC		.fA.mU.fC.mU.fA
F11-	555	PmU.fG.mG.fG.mU.fA.mU.fC.mU.fU.m	805	fA.mA.fG.mC.fC.mA.fA.mG.fA.mU
55M		G.fG.mC.fU.mU.fU.mC.fU.mG		.fA.mC.fC.mC.fA
F11-	556	PmU.fA.mG.fG.mA.fG.mA.fC.mA.fA.m	806	fA.mA.fU.mC.fU.mU.fU.mG.fU.m
56M		A.fG.mA.fU.mU.fU.mC.fU.mU		C.fU.mC.fC.mU.fA
F11-	557	PmU.fG.mU.fC.mA.fU.mG.fG.mU.fA.m	807	fC.mA.fU.mU.fU.mU.fA.mC.fC.mA
57M		A.fA.mA.fU.mG.fA.mA.fG.mA		.fU.mG.fA.mC.fA
F11-	558	PmU.fA.mU.fA.mU.fC.mC.fA.mG.fU.m	808	fG.mA.fA.mG.fA.mA.fC.mU.fG.m
58M		U .fC. mU .fU .mC .fU. mC .fC .mC		G.fA.mU.fA.mU.fA
F11-	559	PmU.fA.mA.fU.mA.fU.mC.fC.mA.fG.m	809	fA.mA.fG.mA.fA.mC.fU.mG.fG.m
59M		U.fU.mC.fU.mU.fC.mU.fC.mC		A.fU.mA.fU.mU.fA
F11-	560	PmU.fC.mU.fG.mU.fG.mG.fU.mU.fU.	810	fA.mC.fU.mG.fG.mA.fA.mA.fC.m
60M		mC.fC.mA.fG.mU.fU.mU.fC.mA		C.fA.mC.fA.mG.fA
F11-	561	PmU.fA.mG.fA.mU.fU.mA.fG.mA.fA.m	811	fG.mC.fA.mC.fU.mU.fU.mC.fU.m
61M		A.fG.mU.fG.mC.fA.mC.fA.mG		A.fA.mU.fC.mU.fA
F11-	562	PmU.fA.mG.fA.mA.fA.mU.fC.mA.fG.m	812	fU.mG.fA.mC.fA.mC.fU.mG.fA.m
62M		U.fG.mU.fC.mA.fU.mG.fG.mU		U.fU.mU.fC.mU.fA
F11-	563	PmU.fU.mG.fG.mA.fU.mU.fA.mU.fU.m	813	fG.mA.fA.mA.fU.mA.fA.mU.fA.mA
63M		A.fU.mU.fU.mC.fU.mU.fG.mA		.fU.mC.fC.mA.fA
F11-	564	PmU.fC.mC.fA.mG.fA.mU.fU.mA.fG.m	814	fA.mC.fU.mU.fU.mC.fU.mA.fA.mU
64M		A.fA.mA.fG.mU.fG.mC.fA.mC		.fC.mU.fG.mG.fA
F11-	565	PmU.fC.mU.fC.mA.fU.mU.fA.mU.fC.m	815	fA.mA.fA.mU.fG.mG.fA.mU.fA.mA
65M		C.fA.mU.fU.mU.fU.mA.fC.mA		.fU.mG.fA.mG.fA
F11-	566	PmU.fU.mU.fG.mG.fG.mC.fC.mA.fU.m	816	fC.mA.fG.mG.fA.mA.fU.mG.fG.m
66M		U.fC.mC.fU.mG.fG.mG.fA.mA		C.fC.mC.fA.mA.fA
F11-	567	PmU.fU.mG.fG.mG.fC.mU.fU.mG.fA.	817	fC.mA.fA.mA.fA.mU.fC.mA.fA.mG
67M		mU.fU.mU.fU.mG.fG.mU.fG.mG		.fC.mC.fC.mA.fA
F11-	568	PmU.fC.mA.fG.mA.fU.mU.fG.mA.fU.m	818	fU.mU.fU.mA.fA.mA.fU.mC.fA.mA
68M		U.fU.mA.fA.mA.fA.mU.fG.mC		.fU.mC.fU.mG.fA
F11-	569	PmU.fA.mA.fG.mC.fA.mA.fC.mC.fG.m	819	fC.mA.fU.mC.fC.mC.fG.mG.fU.m
69M		G.fG.mA.fU.mG.fA.mU.fG.mA		U.fG.mC.fU.mU.fA
F11-	570	PmU.fC.mU.fU.mA.fA.mU.fG.mU.fG.m	820	fG.mG.fA.mU.fA.mC.fA.mC.fA.m
70M		U.fA.mU.fC.mC.fA.mG.fA.mG		U.fU.mA.fA.mG.fA
F11-	571	PmU.fG.mU.fA.mA.fU.mU.fC.mA.fC.m	821	fC.mC.fA.mC.fA.mG.fU.mG.fA.m
71M		U.fG.mU.fG.mG.fU.mU.fU.mC		A.fU.mU.fA.mC.fA
F11-	572	PmU.fA.mC.fA.mU.fU.mU.fC.mU.fA.m	822	fG.mG.fA.mG.fA.mU.fA.mG.fA.m
72M		U.fC.mU.fC.mC.fU.mU.fU.mG		A.fA.mU.fG.mU.fA
F11-	573	PmU.fC.mA.fC.mU.fG.mG.fU.mU.fU.m	823	fA.mU.fU.mG.fG.mA.fA.mA.fC.m
73M		C.fC.mA.fA.mU.fG.mA.fU.mG		C.fA.mG.fU.mG.fA
F11-	574	PmU.fG.mA.fA.mU.fC.mU.fG.mU.fG.m	824	fA.mA.fU.mU.fA.mC.fA.mC.fA.mG
74M		U.fA.mA.fU.mU.fC.mA.fC.mU		.fA.mU.fU.mC.fA
F11-	575	PmU.fG.mU.fC.mC.fU.mA.fU.mU.fC.m	825	fA.mG.fA.mG.fU.mG.fA.mA.fU.m
75M		A.fC.mU.fC.mU.fU.mG.fG.mC		A.fG.mG.fA.mC.fA
F11-	576	PmU.fA.mG.fC.mA.fU.mU.fG.mC.fU.m	826	fU.mU.fU.mC.fA.mA.fG.mC.fA.mA
76M		U.fG.mA.fA.mA.fG.mA.fA.mil		.fU.mG.fC.mU.fA
F11-	577	PmU.fA.mA.fU.mA.fC.mC.fC.mA.fG.m	827	fG.mA.fU.mU.fU.mC.fU.mG.fG.m
77M		A.fA.mA.fU.mC.fG.mC.fU.mG		G.fU.mA.fU.mU.fA
F11-	578	PmU.fA.mU.fU.mA.fU.mU.fA.mU.fU.m	828	fC.mA.fA.mG.fA.mA.fA.mil .fA.mA
78M		U.fC.mll.fll.mG.fA.mA.fC.mC		.fU.mA.fA.mU.fA
F11-	579	PmU.fA.mA.fG.mU.fA.mU.fU.mU.fU.m	829	fC.mA.fA.mC.fU.mA.fA.mA.fA.mU
79M		A.fG.mU.fU.mG.fG.mA.fG.mA		.fA.mC.fU.mU.fA
F11-	580	PmU.fG.mA.fA.mU.fC.mC.fA.mG.fU.m	830	fC. mG .fU. mG .fG. mA.fC. mU .fG. m
80M		C.fC.mA.fC.mG.fU.mA.fC.mU		G.fA.mU.fU.mC.fA
F11-	581	PmU.fA.mG.fA.mC.fA.mA.fA.mG.fA.m	831	fA.mG.fA.mA.fA.mU.fC.mU.fU.mU
81M		U .fU .mil .fC .mil .fU .mil .fG .mA		.fG.mU.fC.mU.fA
F11-	582	PmU.fA.mC.fA.mG.fG.mA.fU.mU.fU.m	832	fC. mA.fC. mU.fG.mA.fA.mA.fU.mC
82M		C.fA.mG.fU.mG.fA.mA.fA.mA		.fC.mU.fG.mU.fA
F11-	583	PmU.fA.mA.fC.mA.fA.mG.fG.mC.fA.m	833	fG.mA.fU.mA.fU.mU.fG.mC.fC.m
83M		A.fU.mA.fU.mC.fA.mU.fA.mC		U.fU.mG.fU.mU.fA
F11-	584	PmU.fA.mA.fG.mG.fC.mA.fA.mU.fA.m	834	fU.mA.fU.mG.fA.mU.fA.mU.fU.m
84M		U.fC.mA.fU.mA.fC.mC.f.mG		G.fC.mC.fU.mU.fA
F11-	585	PmU.fA.mU.fA.mC.fC.mC.fA.mG.fA.m	835	fC.mG.fA.mU.fU.mU.fC.mU.fG.m
85M		A.fA.mU.fC.mG.fC.mU.fG.mC		G.fG.mU.fA.mU.fA
F11-	586	PmU.fG.mA.fU.mU.fG.mA.fU.mU.fU.m	836	fA.mU.fU.mU.fU.mA.fA.mA.fU.mC
86M		A.fA.mA.fA.mU.fG.mC.fC.mA		.fA.mA.fU.mC.fA
F11-	587	PmU.fC.mC.fU.mA.fU.mU.fC.mA.fC.m	837	fC.mA.fA.mG.fA.mG.fU.mG.fA.m
87M		U.fC.mU.fU.mG.fG.mC.fA.mG		A.fU.mA.fG.mG.fA
F11-	588	PmU.fG.mU.fA.mG.fA.mC.fA.mC.fG.m	838	fU.mU.fU.mU.fG.mC.fG.mU.fG.m
88M		C.fA.mA.fA.mA.fU.mC.fU.mU		U.fC.mU.fA.mC.fA
F11-	589	PmU.fU.mG.fA.mG.fU.mU.fU.mU.fC.m	839	fC.mU.fG.mG.fA.mG.fA.mA.fA.m
89M		U.fC.mC.fA.mG.fA.mA.fU.mC		A.fC.mU.fC.mA.fA
F11-	590	PmU.fA.mU.fU.mU.fC.mU.fU.mU.fG.m	840	fA.mA.fU.mC.fU.mC.fA.mA.fA.mG
90M		A.fG.mA.fU.mU.fC.mU.fU.mU		.fA.mA.fA.mU.fA
F11-	591	PmU.fU.mA.fU.mA.fA.mG.fA.mA.fA.m	841	fA.mU.fG.mA.fU.mU.fU.mU.fC.m
91M		A.fU.mC.fA.mU.fC.mC.fU.mG		U.fU.mA.fU.mA.fA
F11-	592	PmU.fA.mA.fA.mA.fU.mC.fU.mU.fA.m	842	fU.mC.fA.mC.fC.mU.fA.mA.fG.mA
92M		G.fG.mU.fG.mA.fC.mU.fC.mU		.fU.mU.fU.mU.fA
F11-	593	PmU.fA.mC.fA.mC.fU.mG.fG.mG.fA.m	843	fC.mA.fG.mC.fA.mU.fC.mC.fC.m
93M		U.fG.mC.fU.mG.fU.mG.fC.mC		A.fG.mU.fG.mU.fA
F11-	594	PmU.fU.mG.fC.mA.fC.mA.fG.mG.fA.m	844	fU.mG.fA.mA.fA.mU.fC.mC.fU.m
94M		U.fU.mU.fC.mA.fG.mU.fG.mA		G.fU.mG.fC.mA.fA
F11-	595	PmU.fA.mU.fA.mC.fA.mA.fG.mC.fC.m	845	fA.mA.fU.mC.fU.mG.fG.mC.fU.m
95M		A.fG.mA.fU.mU.fA.mG.fA.mA		U.fG.mU.fA.mU.fA
F11-	596	PmU.fU.mG.fU.mG.fG.mU.fU.mU.fC.	846	fA.mA.fC.mU.fG.mG.fA.mA.fA.mC
96M		mC.fA.mG.fU.mU.fU.mC.fA.mA		.fC.mA.fC.mA.fA
F11-	597	PmU.fU.mG.fC.mC.fC.mU.fU.mC.fC.m	847	fC.mG.fA.mA.fG.mG.fG.mA.fA.m
97M		C.fU.mU.fC.mG.fU.mU.fG.mC		G.fG.mG.fC.mA.fA
F11-	598	PmU.fA.mA.fA.mA.fU.mC.fA.mU.fC.m	848	fU.mU.fC.mA.fG.mG.fA.mU.fG.m
98M		C.fU.mG.fA.mA.fA.mA.fG.mA		A.fU.mU.fU.mU.fA
F11-	599	PmU.fC.mC.fA.mA.fG.mA.fA.mA.fU.m	849	fC.mA.fC.mU.fG.mA.fU.mU.fU.m
99M		C.fA.mG.fU.mG.fU.mC.fA.mU		C.fU.mU.fG.mG.fA
F11-	600	PmU.fG.mG.fC.mA.fU.mA.fU.mG.fG.m	850	fA.mC.fG.mA.fC.mC.fC.mA.fU.mA
100M		G.fU.mC.fG.mU.fU.mG.fA.mG		.fU.mG.fC.mC.fA
F11-	601	PmU.fA.mG.fA.mA.fU.mC.fU.mG.fU.m	851	fA.mU.fU.mA.fC.mA.fC.mA.fG.mA
101M		G.fU.mA.fA.mU.fU.mC.fA.mC		.fU.mU.fC.mU.fA
F11-	602	PmU.fA.mU.fC.mC.fA.mG.fU.mC.fC.m	852	fU.mA.fC.mG.fU.mG.fG.mA.fC.m
102M		A.fC.mG.fU.mA.fC.mU.fC.mG		U.fG.mG.fA.mU.fA
F11-	603	PmU.fC.mC.fU.mC.fU.mG.fU.mA.fU.m	853	fA.mA.fG.mA.fG.mA.fU.mA.fC.mA
103M		C.fU.mC.fU.mU.fC.mU.fG.mG		.fG.mA.fG.mG.fA
F11-	604	PmU.fG.mC.fA.mC.fA.mG.fG.mA.fU.m	854	fC.mU.fG.mA.fA.mA.fU.mC.fC.m
104M		U.fU.mC.fA.mG.fU.mG.fA.mA		U.fG.mU.fG.mC.fA
F11-	605	PmU.fG.mU.fA.mA.fA.mA.fU.mG.fA.m	855	fA.mU.fU.mC.fU.mU.fC.mA.fU.m
105M		A.fG.mA.fA.mU.fG.mG.fC.mA		U.fU.mU.fA.mC.fA
F11-	606	PmU.fG.mU.fC.mG.fU.mU.fG.mA.fG.	856	fA.mG.fA.mU.fU.mC.fU.mC.fA.mA
106M		mA.fA.mU.fC.mU.fG.mU.fG.mU		.fC.mG.fA.mC.fA
F11-	607	PmU.fG.mC.fA.mA.fC.mA.fA.mU.fA.m	857	fC.mU.fG.mG.fA.mU.fA.mU.fU.m
107M		U.fC.mC.fA.mG.fU.mU.fC.mU		G.fU.mU.fG.mC.fA
F11-	608	PmU.fC.mA.fG.mC.fG.mG.fA.mC.fG.m	858	fA.mA.fU.mG.fC.mC.fG.mU.fC.m
108M		G.fC.mA.fU.mU.fG.mG.fU.mG		C.fG.mC.fU.mG.fA
F11-	609	PmU.fG.mA.fA.mA.fG.mC.fU.mU.fU.m	859	fU.mA.fC.mU.fU.mA.fA.mA.fG.mC
109M		A.fA.mG.fU.mA.fA.mC.fA.mC		.fU.mU.fU.mC.fA
F11-	610	PmU.fG.mC.fA.mG.fU.mG.fU.mU.fU.m	860	fU.mA.fC.mA.fG.mA.fA.mA.fC.mA
110M		C.fU.mG.fU.mA.fA.mC.fA.mC		.fC.mU.fG.mC.fA
F11-	611	PmU.fG.mA.fG.mA.fA.mU.fC.mU.fG.m	861	fU.mU.fA.mC.fA.mC.fA.mG.fA.mU
111M		U.fG.mU.fA.mA.fU.mU.fC.mA		.fU.mC.fU.mC.fA
F11-	612	PmU.fU.mC.fC.mA.fG.mU.fC.mC.fA.m	862	fG.mU.fA.mC.fG.mU.fG.mG.fA.m
112M		C.fG.mU.fA.mC.fU.mC.fG.mA		C.fU.mG.fG.mA.fA
F11-	613	PmU.fU.mG.fU.mG.fA.mG.fC.mA.fU.m	863	fA.mA.fG.mC.fA.mA.fU.mG.fC.m
113M		U.fG.mC.fU.mU.fG.mA.fA.mA		U.fC.mA.fC.mA.fA
F11-	614	PmU.fC.mC.fG.mG.fG.mA.fU.mG.fA.m	864	fA.mC.fU.mC.fA.mU.fC.mA.fU.mC
114M		U.fG.mA.fG.mU.fG.mC.fA.mG		.fC.mC.fG.mG.fA
F11-	615	PmU.fC.mC.fA.mC.fU.mU.fU.mA.fU.m	865	fG.mC.fU.mC.fG.mA.fU.mA.fA.m
115M		C.fG.mA.fG.mC.fU.mU.fC.mG		A.fG.mU.fG.mG.fA
F11-	616	PmU.fC.mA.fU.mU.fA.mU.fC.mC.fA.m	866	fU.mA.fA.mA.fA.mU.fG.mG.fA.mil
116M		U.fU.mU.fU.mA.fC.mA.fC.mA		.fA.mA.fU.mG.fA
F11-	617	PmU.fA.mA.fC.mC.fG.mG.fG.mA.fU.m	867	fU.mC.fA.mU.fC.mA.fU.mC.fC.m
117M		G.fA.mU.fG.mA.fG.mU.fG.mC		C.fG.mG.fU.mU.fA
F11-	618	PmU.fU.mU.fC.mU.fU.mU.fG.mG.fG.	868	fA.mA.fU.mG.fG.mC.fC.mC.fA.m
118M		mC.fC.mA.fU.mU.fC.mC.fU.mG		A.fA.mG.fA.mA.fA
F11-	619	PmU.fC.mU.fA.mA.fG.mG.fG.mU.fA.m	869	fC.mA.fA.mG.fA.mU.fA.mC.fC.mC
119M		U.fC.mU.fU.mG.fG.mC.fU.mU		.fU.mU.fA.mG.fA
F11-	620	PmU.fU.mU.fG.mG.fU.mG.fU.mG.fA.	870	fA.mA.fU.mG.fC.mU.fC.mA.fC.mA
120M		mG.fC.mA.fU.mU.fG.mC.fU.mU		.fC.mC.fA.mA.fA
F11-	621	PmU.fC.mA.fU.mA.fU.mG.fG.mG.fU.m	871	fC.mA.fA.mC.fG.mA.fC.mC.fC.mA
121M		C.fG.mU.fU.mG.fA.mG.fA.mA		.fU.mA.fU.mG.fA
F11-	622	PmU.fU.mU.fA.mA.fU.mG.fU.mG.fU.m	872	fU.mG.fG.mA.fU.mA.fC.mA.fC.m
122M		A.fU.mC.fC.mA.fG.mA.fG.mA		A.fU.mU.fA.mA.fA
F11-	623	PmU.fU.mC.fA.mG.fA.mU.fG.mU.fU.m	873	fC.mU.fU.mA.fA.mA.fA.mC.fA.mU
123M		U.fU.mA.fA.mG.fG.mA.fG.mA		.fC.mU.fG.mA.fA
F11-	624	PmU.fU.mU.fC.mC.fA.mA.fU.mG.fA.m	874	fC.mU.fC.mC.fA.mU.fC.mA.fU.m
124M		U.fG.mG.fA.mG.fC.mC.fU.mC		U.fG.mG.fA.mA.fA
F11-	625	PmU.fA.mG.fA.mA.fU.mC.fC.mA.fG.m	875	fG.mU.fG.mG.fA.mC.fU.mG.fG.m
125M		U.fC.mC.fA.mC.fG.mU.fA.mC		A.fU.mU.fC.mU.fA
F11-	626	PmU.fU.mU.fU.mG.fA.mG.fA.mU.fU.m	876	fC.mA.fA.mA.fG.mA.fA.mU.fC.mU
126M		C.fU.mU.fU.mG.fG.mG.fC.mC		.fC.mA.fA.mA.fA
F11-	627	PmU.fA.mA.fU.mC.fA.mU.fC.mC.fU.m	877	fU.mU.fU.mU.fC.mA.fG.mG.fA.m
127M		G.fA.mA.fA.mA.fG.mA.fC.mC		U.fG.mA.fU.mU.fA
F11-	628	PmU.fA.mG.fA.mC.fA.mC.fG.mC.fA.m	878	fG.mA.fU.mU.fU.mU.fG.mC.fG.m
128M		A.fA.mA.fU.mC.fU.mU.fA.mG		U.fG.mU.fC.mU.fA
F11-	629	PmU.fC.mG.fU.mA.fC.mU.fC.mG.fA.m	879	fC.mG.fU.mG.fG.mU.fC.mG.fA.m
129M		C.fC.mA.fC.mG.fU.mU.fG.mG		G.fU.mA.fC.mG.fA
F11-	630	PmU.fC.mA.fU.mC.fC.mA.fG.mU.fC.m	880	fU.mG.fG.mG.fU.mG.fA.mC.fU.m
130M		A.fC.mC.fC.mA.fG.mC.fA.mA		G.fG.mA.fU.mG.fA
F11-	631	PmU.fA.mA.fC.mA.fC.mU.fG.mG.fG.m	881	fA.mG.fC.mA.fU.mC.fC.mC.fA.m
131M		A.fU.mG.fC.mU.fG.mU.fG.mC		G.fU.mG.fU.mU.fA
F11-	632	PmU.fC.mA.fG.mA.fA.mA.fG.mA.fG.m	882	fC.mA.fA.mA.fG.mC.fU.mC.fU.m
132M		C.fU.mU.fU.mG.fC.mU.fC.mU		U.fU.mC.fU.mG.fA
F11-	633	PmU.fU.mU.fC.mU.fU.mU.fG.mA.fG.m	883	fA.mG.fA.mA.fU.mC.fU.mC.fA.mA
133M		A.fU.mU.fC.mU.fU.mU.fG.mG		.fA.mG.fA.mA.fA
F11-	634	PmU.fA.mG.fC.mA.fA.mC.fA.mA.fU.m	884	fU.mG.fG.mA.fU.mA.fU.mU.fG.m
134M		A.fU.mC.fC.mA.fG.mU.fU.mC		U.fU.mG.fC.mU.fA
F11-	635	PmU.fA.mC.fC.mA.fC.mU.fU.mU.fA.m	885	fC.mU.fC.mG.fA.mU.fA.mA.fA.m
135M		U.fC.mG.fA.mG.fC.mU.fU.mC		G.fU.mG.fG.mU.fA
F11-	636	PmU.fC.mC.fC.mU.fU.mC.fC.mC.fU.m	886	fA.mA.fC.mG.fA.mA.fG.mG.fG.m
136M		U.fC.mG.fU.mU.fG.mC.fA.mG		A.fA.mG.fG.mG.fA
F11-	637	PmU.fC.mG.fC.mA.fA.mA.fA.mU.fC.m	887	fC.mC.fU.mA.fA.mG.fA.mU.fU.m
137M		U.fU.mA.fG.mG.fU.mG.fA.mC		U.fU.mG.fC.mG.fA
F11-	638	PmU.fA.mG.fC.mG.fU.mG.fU.mU.fA.m	888	fC.mA.fC.mA.fG.mU.fA.mA.fC.mA
138M		C.fU.mG.fU.mG.fG.mA.fG.mG		.fC.mG.fC.mU.fA
F11-	639	PmU.fC.mU.fC.mC.fU.mU.fC.mC.fC.m	889	fC.mU.fA.mC.fA.mG.fG.mG.fA.m
139M		U.fG.mU.fA.mG.fC.mC.fG.mG		A.fG.mG.fA.mG.fA
F11-	640	PmU.fG.mU.fC.mC.fU.mC.fU.mG.fU.m	890	fG.mA.fG.mA.fU.mA.fC.mA.fG.m
140M		A.fU.mC.fU.mC.fU.mU.fC.mU		A.fG.mG.fA.mG.fA
F11-	641	PmU.fG.mU.fA.mU.fC.mU.fU.mG.fG.m	891	fG.mA.fA.mA.fG.mC.fC.mA.fA.m
141M		C .fU. mU .fU .mC .fU. mG .fG .mA		G.fA.mU.fA.mC.fA
F11-	642	PmU.fC.mU.fC.mU.fU.mG.fG.mC.fA.m	892	fA.mA.fC.mA.fC.mU.fG.mC.fC.mA
142M		G.fU.mG.fU.mU.fU.mC.fU.mG		.fA.mG.fA.mG.fA
F11-	643	PmU.fG.mA.fA.mA.fU.mC.fA.mG.fU.m	893	fA.mU.fG.mA.fC.mA.fC.mU.fG.m
143M		G.fU.mC.fA.mU.fG.mG.fU.mA		A.fU.mU.fU.mC.fA
F11-	644	PmU.fC.mU.fU.mC.fC.mC.fU.mG.fU.m	894	fC.mG.fG.mC.fU.mA.fC.mA.fG.m
144M		A.fG.mC.fC.mG.fG.mC.fA.mC		G.fG.mA.fA.mG.fA
F11-	645	PmU.fC.mU.fG.mG.fC.mC.fG.mC.fU.	895	fA.mA.fG.mG.fG.mA.fG.mC.fG.m
145M		mC.fC.mC.fU.mU.fU.mG.fA.mG		G.fC.mC.fA.mG.fA
F11-	646	PmU.fC.mA.fC.mG.fC.mA.fA.mA.fA.m	896	fU.mA.fA.mG.fA.mU.fU.mU.fU.m
146M		U.fC.mU.fU.mA.fG.mG.fU.mG		G.fC.mG.fU.mG.fA
F11-	647	PmU.fG.mA.fA.mA.fC.mC.fA.mG.fA.m	897	fC.mU.fC.mU.fU.mU.fC.mU.fG.m
147M		A.fA.mG.fA.mG.fC.mU.fU.mU		G.fU.mU.fU.mC.fA
F11-	648	PmU.fA.mA.fA.mG.fC.mU.fU.mU.fA.m	898	fU.mU.fA.mC.fU.mU.fA.mA.fA.mG
148M		A.fG.mU.fA.mA.fC.mA.fC.mU		.fC.mU.fU.mU.fA
F11-	649	PmU.fA.mC.fA.mA.fG.mC.fC.mA.fG.m	899	fC.mU.fA.mA.fU.mC.fU.mG.fG.m
149M		A.fU.mU.fA.mG.fA.mA.fA.mG		C.fU.mU.fG.mU.fA
F11-	650	PmU.fA.mC.fU.mC.fA.mU.fU.mA.fU.m	900	fA.mA.fU.mG.fG. mA.fU. mA.fA.mU
150M		C.fC.mA.fU.mU.fU.mU.fA.mC		.fG.mA.fG.mU.fA
F11-	651	PmU.fC.mC.fU.mG.fA.mA.fA.mA.fG.m	901	fA.mA.fG.mG.fU.mC.fU.mU.fU.m
151M		A.fC.mC.fU.mU.fG.mU.fU.mG		U.fC.mA.fG.mG.fA
F11-	652	PmU.fG.mG.fU.mU.fU.mC.fC.mA.fA.m	902	fC. mA.fU. mC.fA.mU.fU.mG.fG.m
152M		u .fG. mA.fU. mG .fG. mA .fG. mC		A.fA.mA.fC.mC.fA
F11-	653	PmU.fC.mA.fG.mU.fU.mU.fC.mU.fG.m	903	fC.mC.fU.mG.fC.mC.fA.mG.fA.m
153M		G.fC.mA.fG.mG.fC.mC.fU.mC		A.fA.mC.fU.mG.fA
F11-	654	PmU.fA.mU.fG.mG.fC.mA.fG.mA.fA.m	904	fC.mA.fG.mU.fG.mU.fU.mC.fU.m
154M		C.fA.mC.fU.mG.fG.mG.fA.mU		G.fC.mC.fA.mU.fA
F11-	655	PmU.fA.mG.fA.mU.fU.mU.fC.mU.fU.m	905	fU.mC.fU.mC.fA.mA.fA.mG.fA.mA
155M		U.fG.mA.fG.mA.fU.mU.fC.mU		.fA.mU.fC.mU.fA
F11-	656	PmU.fG.mU.fU.mU.fC.mC.fA.mG.fU.m	906	fU.mU.fG.mA.fA.mA.fC.mU.fG.m
156M		U.fU.mC.fA.mA.fC.mA.fA.mG		G.fA.mA.fA.mC.fA
F11-	657	PmU.fU.mC.fC.mU.fC.mU.fG.mU.fA.m	907	fA.mG.fA.mG.fA.mU.fA.mC.fA.m
157M		U.fC.mU.fC.mU.fU.mC.fU.mG		G.fA.mG.fG.mA.fA
F11-	658	PmU.fC. mA.fU. mC.fC.mU.fG.mA.fA.m	908	fG.mU.fC.mU.fU.mU.fU.mC.fA.m
158M		A.fA.mG.fA.mC.fC.mU.fU.mG		G.fG.mA.fU.mG.fA
F11-	659	PmU.fU.mU.fG.mA.fG.mU.fU.mU.fU.m	909	fU.mG.fG.mA.fG.mA.fA.mA.fA.m
159M		C.fU.mC.fC.mA.fG.mA.fA.mU		C.fU.mC.fA.mA.fA
F11-	660	PmU.fA.mA.fU.mU.fC.mA.fC.mU.fG.m	910	fA.mA.fC.mC.fA.mC.fA.mG.fU.m
160M		U.fG.mG.fU.mU.fU.mC.fC.mA		G.fA.mA.fU.mU.fA
F11-	661	PmU.fA.mA.fG.mA.fU.mU.fU.mC.fU.m	911	fC.mU.fC.mA.fA.mA.fG.mA.fA.mA
161M		U.fU.mG.fA.mG.fA.mU.fU.mC		.fU.mC.fU.mU.fA
F11-	662	PmU.fG.mG.fA.mG.fA.mC.fA.mA.fA.m	912	fA.mA.fA.mU.fC.mU.fU.mU.fG.m
162M		G.fA.mU.fU.mU.fC.mU.fU.mU		U.fC.mU.fC.mC.fA
F11-	663	PmU.fG.mA.fA.mA.fA.mU.fC.mA.fU.m	913	fU.mC.fA.mG.fG.mA.fU.mG.fA.m
163M		C.fC.mU.fG.mA.fA.mA.fA.mG		U.fU.mU.fU.mC.fA
F11-	664	PmU.fC.mU.fU.mU.fC.mU.fG.mC.fC.m	914	fA.mA.fA.mA.fU.mG.fG.mC.fA.m
164M		A.fU.mU.fU.mU.fA.mU.fA.mC		G.fA.mA.fA.mG.fA
F11-	665	PmU.fA.mG.fU.mC.fC.mA.fC.mG.fU.m	915	fC.mG.fA.mG.fU.mA.fC.mG.fU.m
165M		A.fC.mU.fC.mG.fA.mC.fC.mA		G.fG.mA.fC.mU.fA
F11-	666	PmU.fU.mU.fA.mA.fU.mG.fC.mG.fU.m	916	fA.mG.fU.mA.fC.mA.fC.mG.fC.m
166M		G.fU.mA.fC.mU.fG.mG.fG.mC		A.fU.mU.fA.mA.fA
F11-	667	PmU.fU.mA.fA.mU.fG.mU.fG.mU.fA.m	917	fC.mU.fG.mG.fA.mU.fA.mC.fA.m
167M		U.fC.mC.fA.mG.fA.mG.fA.mU		C.fA.mU.fU.mA.fA
F11-	668	PmU.fG.mA.fU.mU.fC.mU.fU.mU.fG.m	918	fU.mG.fG.mC.fC.mC.fA.mA.fA.m
168M		G.fG.mC.fC.mA.fU.mU.fC.mC		G.fA.mA.fU.mC.fA
F11-	669	PmU.fU.mG.fA.mA.fA.mC.fC.mA.fG.m	919	fU.mC.fU.mU.fU.mC.fU.mG.fG.m
169M		A.fA.mA.fG.mA.fG.mC.fU.mU		U.fU.mU.fC.mA.fA
F11-	670	PmU.fC.mA.fC.mA.fC.mA.fU.mU.fC.m	920	fC.mU.fG.mG.fU.mG.fA.mA.fU.m
170M		A.fC.mC.fA.mG.fA.mA.fA.mC		G.fU.mG.fU.mG.fA
F11-	671	PmU.fA.mC.fA.mA.fA.mG.fA.mU.fU.m	921	fA.mA.fA.mG.fA.mA.fA.mU.fC.mil
171M		U.fC.mU.fU.mU.fG.mA.fG.mA		.fU.mU.fG.mU.fA
F11-	672	PmU.fC.mA.fU.mU.fU.mC.fU.mA.fU.m	922	fA.mG.fG.mA.fG.mA.fU.mA.fG.m
172M		C.fU.mC.fC.mU.fU.mU.fG.mG		A.fA.mA.fU.mG.fA
F11-	673	PmU.fU.mU.fU.mC.fU.mG.fU.mA.fA.m	923	fC.mA.fG.mU.fG.mU.fU.mA.fC.m
173M		C.fA.mC.fU.mG.fU.mC.fU.mU		A.fG.mA.fA.mA.fA
F11-	674	PmU.fG.mG.fA.mU.fU.mU.fC.mA.fG.m	924	fU.mU.fU.mC.fA.mC.fU.mG.fA.m
174M		U.fG.mA.fA.mA.fA.mU.fC.mC		A.fA.mU.fC.mC.fA
F11-	675	PmU.fC.mG.fC.mU.fC.mC.fC.mU.fU.m	925	fG.mC.fU.mC.fA.mA.fA.mG.fG.m
175M		U.fG.mA.fG.mC.fA.mC.fA.mG		G.fA.mG.fC.mG.fA
F11-	676	PmU.fC.mA.fG.mU.fC.mC.fA.mC.fG.m	926	fG.mA.fG.mU.fA.mC.fG.mU.fG.m
176M		U.fA.mC.fU.mC.fG.mA.fC.mC		G.fA.mC.fU.mG.fA
F11-	677	PmU.fA.mG.fG.mC.fA.mU.fA.mU.fG.m	927	fC.mG.fA.mC.fC.mC.fA.mU.fA.m
177M		G.fG.mU.fC.mG.fU.mU.fG.mA		U.fG.mC.fC.mU.fA
F11-	678	PmU.fA.mU.fG.mU.fC.mC.fU.mC.fU.m	928	fG.mA.fU.mA.fC.mA.fG.mA.fG.m
178M		G.fU.mA.fU.mC.fU.mC.fU.mU		G.fA.mC.fA.mU.fA
F11-	679	PmU.fG.mC.fU.mU.fG.mA.fU.mU.fU.m	929	fC.mA.fC.mC.fA.mA.fA.mA.fU.mC
179M		U.fG.mG.fU.mG.fG.mU.fA.mC		.fA.mA.fG.mC.fA
F11-	680	PmU.fA.mU.fG.mA.fU.mG.fG.mA.fG.m	930	fG.mG.fA.mG.fG.mC.fU.mC.fC.m
180M		C.fC.mU.fC.mC.fA.mC.fA.mC		A.fU.mC.fA.mU.fA
F11-	681	PmU.fU.mC.fG.mU.fU.mG.fA.mG.fA.m	931	fC.mA.fG.mA.fU.mU.fC.mU.fC.m
181M		A.fU .mC .fU .mG.fU .mG .fU .mA		A.fA.mC.fG.mA.fA
F11-	682	PmU.fU.mU.fA.mU.fC.mC.fA.mU.fU.m	932	fU. mG.fU. mA.fA.mA.fA.mU.fG.m
182M		U.fU.mA.fC.mA.fC.mA.fA.mC		G.fA.mU.fA.mA.fA
F11-	683	PmU.fU.mG.fU.mC.fC.mU.fA.mU.fU.m	933	fG.mA.fG.mU.fG.mA.fA.mU.fA.m
183M		C.fA.mC.fU.mC.fU.mU.fG.mG		G.fG.mA.fC.mA.fA
F11-	684	PmU.fC.mA.fA.mU.fA.mU.fC.mC.fA.m	934	fA.mG.fA.mA.fC.mU.fG.mG.fA.m
184M		G.fU.mU.fC.mU.fU.mC.fU.mC		U.fA.mU.fU.mG.fA
F11-	685	PmU.fC.mU.fU.mU.fG.mA.fG.mA.fU.m	935	fA.mA.fA.mG.fA.mA.fU.mC.fU.mC
185M		U.fC.mU.fU.mU.fG.mG.fG.mC		.fA.mA.fA.mG.fA
F11-	686	PmU.fC.mA.fC.mU.fC.mU.fU.mG.fG.m	936	fC.mA.fC.mU.fG.mC.fC.mA.fA.m
186M		C.fA.mG.fU. mG.fU. mU.fU.mC		G.fA.mG.fU.mG.fA
F11-	687	PmU.fC.mU.fU.mG.fA.mA.fA.mG.fA.m	937	fG. mG.fU. mA.fU.mU.fC.mU.fU.m
187M		A.fU.mA.fC.mC.fC.mA.fG.mA		U.fC.mA.fA.mG.fA
F11-	688	PmU.fA.mG.fG.mC.fA.mA.fU.mA.fU.m	938	fG.mU.fA.mU.fG.mA.fU.mA.fU.m
188M		C.fA.mU.fA.mC.fC.mC.fG.mC		U.fG.mC.fC.mU.fA
F11-	689	PmU.fC.mU.fG.mU.fG.mU.fA.mA.fU.m	939	fA.mG.fU.mG.fA.mA.fU.mU.fA.m
189M		U.fC.mA.fC.mU.fG.mU.fG.mG		C.fA.mC.fA.mG.fA
F11-	690	PmU.fA.mA.fU.mA.fU.mC.fC.mA.fC.m	940	fA.mA.fG.mC.fA. mG.fU. mG.fG.m
190M		U.fG.mG.fU.mU.fU.mC.fC.mA		A.fU.mA.fU.mU.fA
F11-	691	PmU.fU.mG.fA.mA.fA.mG.fA.mA.fU.m	941	fU.mG.fG.mG.fU.mA.fU.mU.fC.m
191M		A.fC.mC.fC.mA.fG.mA.fA.mA		U.fU.mU.fC.mA.fA
F11-	692	PmU.fG.mU.fU.mA.fA.mU.fA.mU.fC.m	942	fC.mA.fG.mU.fG.mG.fA.mU.fA.m
192M		C.fA.mC.fU.mG.fG.mU.fU.mU		U.fU.mA.fA.mC.fA
F11-	693	PmU.fU. mG.fU. mC.fA.mU.fG. mG.fU. m	943	fA.mU.fU.mU.fU.mA.fC.mC.fA.mU
193M		A.fA.mA.fA.mU.fG.mA.fA.mG		.fG.mA.fC.mA.fA
F11-	694	PmU.fA.mU.fU.mC.fU.mU.fU.mG.fG.m	944	fA.mU.fG.mG.fC.mC.fC.mA.fA.m
194M		G.fC.mC.fA.mU.fU.mC.fC.mU		A.fG.mA.fA.mU.fA
F11-	695	PmU.fC.mA.fG.mU.fU.mC.fC.mU.fC.m	945	fC.mG.fU.mU.fG.mG.fA. mG.fG.m
195M		C.fA.mA.fC.mG.fA.mU.fC.mC		A.fA.mC.fU.mG.fA
F11-	696	PmU.fG.mG.fG.mU.fG.mU.fG.mC.fU.	946	fA.mC.fU.mG.fA.mA.fG.mC.fA.m
196M		mU.fC.mA.fG.mU.fA.mG.fA.mC		C.fA.mC.fC.mC.fA
F11-	697	PmU.fG.mA.fA.mG.fA.mA.fA.mG.fC.m	947	fU.mU.fA.mA.fA.mG.fC.mU.fU.m
197M		U.fU.mU.fA.mA.fG.mU.fA.mA		U.fC.mU.fU.mC.fA
F11-	698	PmU.fA.mU.fC.mC.fU.mG.fA.mA.fA.m	948	fG.mG.fU.mC.fU.mU.fU.mU.fC.m
198M		A.fG.mA.fC.mC.fU.mU.fG.mU		A.fG.mG.fA.mU.fA
F11-	699	PmU.fA.mG.fA.mA.fA.mG.fC.mU.fU.m	949	fA.mC.fU.mU.fA.mA.fA.mG.fC.mU
199M		U.fA.mA.fG.mU.fA.mA.fC.mA		.fU.mU.fC.mU.fA
F11-	700	PmU.fC.mA.fG.mU.fG.mU.fU.mU.fC.m	950	fU.mU.fA.mC.fA.mG.fA.mA.fA.mC
200M		U.fG.mU.fA.mA.fC.mA.fC.mU		.fA.mC.fU.mG.fA
F11-	701	PmU.fG.mA.fC.mA.fC.mG.fC.mA.fA.m	951	fA.mG.fA.mU.fU.mU.fU.mG.fC.m
201M		A.fA.mU.fC.mU.fU.mA.fG.mG		G.fU.mG.fU.mC.fA
F11-	702	PmU.fG.mU.fG.mU.fG.mA.fG.mC.fA.m	952	fA.mG.fC.mA.fA.mU.fG.mC.fU.m
202M		U.fU.mG.fC.mU.fU.mG.fA.mA		C.fA.mC.fA.mC.fA
F11-	703	PmU.fA.mC.fC.mA.fG.mA.fA.mA.fG.m	953	fA.mA.fG.mC.fU.mC.fU.mU.fU.m
203M		A.fG.mC.fU.mU.fU.mG.fC.mU		C.fU.mG.fG.mU.fA
F11-	704	PmU.fA.mG.fA.mA.fA.mG.fU.mG.fC.m	954	fC.mC.fU.mG.fU.mG.fC.mA.fC.m
204M		A.fC.mA.fG.mG.fA.mU.fU.mU		U.fU.mU.fC.mU.fA
F11-	705	PmU.fU.mU.fU.mA.fU.mU.fU.mC.fA.m	955	fC.mA.fA.mU.fC.mU.fG.mA.fA.mA
205M		G.fA.mU.fU.mG.fA.mU.fU.mU		.fU.mA.fA.mA.fA
F11-	706	PmU.fU.mA.fU.mC.fC.mA.fG.mU.fU.m	956	fA.mG.fA.mA.fG.mA.fA.mC.fU.m
206M		C.fU.mU.fC.mU.fC.mC.fC.mA		G.fG.mA.fU.mA.fA
F11-	707	PmU.fC.mC.fG.mU.fG.mA.fA.mA.fG.m	957	f.mU.fU.mC.fA.mC.fU.mU.fU.m
207M		U.fG.mA.fA.mG.fA.mG.fU.mA		C.fA.mC.fG.mG.fA
F11-	708	PmU.fG.mG.fU.mG.fU.mG.fC.mU.fU.	958	fU.mA.fC.mU.fG.mA.fA.mG.fC.m
208M		mC.fA.mG.fU.mA.fG.mA.fC.mA		A.fC.mA.fC.mC.fA
F11-	709	PmU.fG.mG.fA.mC.fA.mG.fA.mG.fG.m	959	fG.mA.fG.mG.fC.mC.fC.mU.fC.m
209M		G .fC .mC .fU .mC .fC .mC .fG .mA		U.fG.mU.fC.mC.fA
F11-	710	PmU.fA.mA.fG.mA.fA.mA.fA.mU.fC.m	960	fA.mG.fG.mA.fU.mG.fA.mU.fU.m
210M		A.fU.mC.fC.mU.fG.mA.fA.mA		U .fU.mC.fU.mil .fA
F11-	711	PmU.fU.mG.fA.mG.fA.mU.fU.mC.fU.m	961	fC.mC.fC.mA.fA.mA.fG.mA.fA.mU
211M		U.fU.mG.fG.mG.fC.mC.fA.mU		.fC.mU.fC.mA.fA
F11-	712	PmU.fA.mU.fG.mU.fU.mU.fU.mA.fA.m	962	fU.mC.fU.mC.fC.mU.fU.mA.fA.mA
212M		G.fG.mA.fG.mA.fC.mA.fA.mA		.fA.mC.fA.mU.fA
F11-	713	PmU.fC.mA.fC.mA.fG.mU.fU.mU.fC.m	963	fU.mG.fC.mC.fA.mG.fA.mA.fA.m
213M		U.fG.mG.fC.mA.fG.mG.fC.mC		C.fU.mG.fU.mG.fA
F11-	714	PmU.fA.mC.fA.mA.fU.mA.fU.mC.fC.m	964	fG.mA.fA.mC.fU.mG.fG.mA.fU.m
214M		A.fG.mU.fU.mC.fU.mU.fC.mU		A.fU.mU.fG.mU.fA
F11-	715	PmU.fA.mC.fA.mU.fU.mC.fA.mC.fC.m	965	fU.mU.fU.mC.fU.mG.fG.mU.fG.m
215M		A.fG.mA.fA.mA.fC.mU.fG.mA		A.fA.mU.fG.mU.fA
F11-	716	PmU.fC.mA.fA.mG.fG.mC.fA.mA.fU.m	966	fA.mU.fG.mA.fU.mA.fU.mU.fG.m
216M		A.fU.mC.fA.mU.fA.mC.fC.mC		C.fC.mU.fU.mG.fA
F11-	717	PmU.fC.mU.fC.mC.fA.mA.fC.mG.fA.m	967	fC.mA.fG.mG.fA.mU.fC.mG.fU.m
217M		U.fC.mC.fU.mG.fG.mG.fC.mU		U.fG.mG.fA.mG.fA
F11-	718	PmU.fC.mU.fG.mA.fA.mA.fC.mC.fA.m	968	fC.mU.fU.mU.fC.mU.fG.mG.fU.m
218M		G.fA.mA.fA.mG.fA.mG.fC.mU		U.fU.mC.fA.mG.fA
F11-	719	PmU.fA.mA.fU.mC.fU.mC.fC.mC.fU.m	969	fU.mU.fG.mC.fA.mA.fG.mG.fG.m
219M		U.fG.mC.fA.mA.fG.mC.fG.mU		A.fG.mA.fU.mU.fA
F11-	720	PmU.fU.mG.fU.mG.fU.mA.fA.mU.fU.m	970	fC.mA.fG.mU.fG.mA.fA.mU.fU.m
220M		C.fA.mC.fU.mG.fU.mG.fG.mU		A.fC.mA.fC.mA.fA
F11-	721	PmU.fU.mU.fU.mC.fA.mG.fU.mG.fA.m	971	fG.mA.fU.mU.fU.mU.fC.mA.fC.m
221M		A.fA.mA.fU.mC.fC.mA.fG.mA		U.fG.mA.fA.mA.fA
F11-	722	PmU.fA.mA.fA.mU.fC.mA.fU.mC.fC.m	972	fU.mU.fU.mC.fA.mG.fG.mA.fU.m
222M		U.fG.mA.fA.mA.fA.mG.fA.mC		G.fA.mU.fU.mU.fA
F11-	723	PmU.fU.mA.fC.mA.fC.mU.fC.mA.fU.m	973	fG.mG.fA.mU.fA.mA.fU.mG.fA.m
223M		U.fA.mU.fC.mC.fA.mU.fU.mU		G.fU.mG.fU.mA.fA
F11-	724	PmU.fU.mU.fG.mG.fC.mA.fG.mU.fG.	974	fA.mG.fA.mA.fA.mC.fA.mC.fU.mG
224M		mU.fU.mU.fC.mU.fG.mU.fA.mA		.fC.mC.fA.mA.fA
F11-	725	PmU.fG.mG.fU.mA.fC.mA.fC.mU.fC.m	975	fA.mU.fA.mA.fU.mG.fA.mG.fU.m
225M		A.fU.mU.fA.mU.fC.mC.fA.mU		G.fU.mA.fC.mC.fA
F11-	726	PmU.fA.mG.fG.mC.fA.mG.fG.mC.fA.m	976	fC.mC.fA.mU.fA.mU.fG.mC.fC.m
226M		U.fA.mU.fG.mG.fG.mU.fC.mG		U.fG.mC.fC.mU.fA
F11-	727	PmU.fC.mC.fA.mG.fU.mU.fU.mC.fA.m	977	fC.mU.fU.mG.fU.mU.fG.mA.fA.m
227M		A.fC.mA.fA.mG.fG.mC.fA.mA		A.fC.mU.fG.mG.fA
F11-	728	PmU.fU.mG.fG.mC.fC.mG.fC.mU.fC.	978	fA.mA.fA.mG.fG.mG.fA.mG.fC.m
228M		mC.fC.mU.fU.mU.fG.mA.fG.mC		G.fG.mC.fC.mA.fA
F11-	729	PmU.fA.mC.fU.mG.fU.mG.fG.mU.fU.m	979	fC.mU.fG.mG.fA.mA.fA.mC.fC.m
229M		U.fC.mC.fA.mG.fU.mU.fU.mC		A.fC.mA.fG.mU.fA
F11-	730	PmU.fC.mU.fU.mU.fG.mG.fG.mC.fC.	980	fG.mG.fA.mA.fU.mG.fG.mC.fC.m
230M		mA.fU.mU.fC.mC.fU.mG.fG.mG		C.fA.mA.fA.mG.fA
F11-	731	PmU.fU.mA.fA.mG.fA.mA.fA.mA.fU.m	981	fG.mG.fA.mU.fG.mA.fU.mU.fU.m
231M		C.fA.mU.fC.mC.fU.mG.fA.mA		U.fC.mU.fU.mA.fA
F11-	732	PmU.fC.mU.fC.mU.fU.mU.fU.mA.fU.m	982	fC.mU.fG.mA.fA.mA.fU.mA.fA.mA
232M		U.fU.mC.fA.mG.fA.mU.fU.mG		.fA.mG.fA.mG.fA
F11-	733	PmU.fU.mC.fU.mU.fU.mG.fA.mG.fA.m	983	fA.mA.fG.mA.fA.mU.fC.mU.fC.mA
233M		U.fU.mC.fU.mU.fU.mG.fG.mG		.fA.mA.fG.mA.fA
F11-	734	PmU.fA.mA.fU.mG.fA.mU.fG.mG.fA.m	984	fG.mA.fG.mG.fC.mU.fC.mC.fA.m
234M		G.fC.mC.fU.mC.fC.mA.fC.mA		U.fC.mA.fU.mU.fA
F11-	735	PmU.fG.mA.fA.mG.fA.mA.fU.mG.fG.m	985	fU.mU.fC.mU.fG.mC.fC.mA.fU.m
235M		C.fA.mG.fA.mA.fC.mA.fC.mU		U.fC.mU.fU.mC.fA
F11-	736	PmU.fC.mA.fA.mU.fG.mA.fU.mG.fG.m	986	fA.mG.fG.mC.fU.mC.fC.mA.fU.m
236M		A.fG.mC.fC.mU.fC.mC.fA.mC		C.fA.mU.fU.mG.fA
F11-	737	PmU.fA.mU.fG.mG.fA.mG.fC.mC.fU.m	987	fU.mG.fU.mG.fG.mA.fG.mG.fC.m
237M		C.fC.mA.fC.mA.fC.mA.fG.mG		U.fC.mC.fA.mU.fA
F11-	738	PmU.fC.mC.fC.mA.fA.mG.fA.mA.fA.m	988	fA.mC.fU.mG.fA.mU.fU.mU.fC.m
238M		U.fC.mA.fG.mU.fG.mU.fC.mA		U.fU.mG.fG.mG.fA
F11-	739	PmU.fG.mA.fG.mC.fC.mU.fC.mC.fA.m	989	fC.mU.fG.mU.fG.mU.fG.mG.fA.m
239M		C.fA.mC.fA.mG.fG.mU.fG.mU		G.fG.mC.fU.mC.fA
F11-	740	PmU.fC.mU.fC.mC.fC.mA.fA.mG.fA.m	990	fU.mG.fA.mU.fU.mU.fC.mU.fU.m
240M		A.fA.mU.fC.mA.fG.mU.fG.mU		G.fG.mG.fA.mG.fA
F11-	741	PmU.fC.mC.fU.mC.fC.mA.fC.mA.fC.m	991	fC.mA.fC.mC.fU.mG.fU.mG.fU.m
241M		A.fG.mG.fU.mG.fU.mC.fU.mC		G.fG.mA.fG.mG.fA
F11-	742	PmU.fC.mC.fA.mA.fU.mG.fA.mU.fG.m	992	fG.mG.fC.mU.fC.mC.fA.mU.fC.m
242M		G fA. mG .fC. mC .fU. mC .fC. m A		A.fU.mU.fG.mG.fA
F11-	743	PmU.fU.mU.fU.mC.fC.mA.fA.mU.fG.m	993	fU.mC.fC.mA.fU.mC.fA.mU.fU.m
243M		A.fU.mG.fG.mA.fG.mC.fC.mU		G.fG.mA.fA.mA.fA
F11-	744	PmU.fU.mC.fC.mC.fA.mA.fG.mA.fA.m	994	fC.mU.fG.mA.fU.mU.fU.mC.fU.m
244M		A.fU.mC.fA.mG.fU.mG.fU.mC		U.fG.mG.fG.mA.fA
F11-	745	PmU.fA.mG.fC.mC.fU.mC.fC.mA.fC.m	995	fC.mC.fU.mG.fU.mG.fU.mG.fG.m
245M		A.fC.mA.fG.mG.fU.mG.fU.mC		A.fG.mG.fC.mU.fA
F11-	746	PmU.fU.mC.fU.mU.fC.mU.fC.mC.fC.m	996	fU.mU.fC.mU.fU.mG.fG.mG.fA.m
246M		A.fA.mG.fA.mA.fA.mU.fC.mA		G.fA.mA.fG.mA.fA
F11-	747	PmU.fG.mU.fU.mU.fC.mC.fA.mA.fU.m	997	fC.mC.fA.mU.fC.mA.fU.mU.fG.m
247M		G.fA.mU.fG.mG.fA.mG.fC.mC		G.fA.mA.fA.mC.fA
F11-	748	PmU.fU.mC.fC.mA.fA.mU.fG.mA.fU.m	998	fG.mC.fU.mC.fC.mA.fU.mC.fA.m
248M		G.fG.mA.fG.mC.fC.mU.fC.mC		U.fU.mG.fG.mA.fA
F11-	749	PmU.fU.mG.fG.mA.fG.mC.fC.mU.fC.m	999	fG.mU.fG.mU.fG.mG.fA.mG.fG.m
249M		C.fA.mC.fA.mC.fA.mG.fG.mU		C.fU.mC.fC.mA.fA
F11-	750	PmU.fG.mC.fC.mU.fC.mC.fA.mC.fA.m	1000	fA.mC.fC.mU.fG.mU.fG.mU.fG.m
250M		C.fA.mG.fG.mU.fG.mU.fC.mU		G.fA.mG.fG.mC.fA

In above Table 1 b:

A represents adenine;

U represents uracil;

C represents cytosine;

G represents guanine;

P represents a terminal phosphate group;

m represents a methyl modification at the 2′ position of the sugar of the underlying nucleoside;

f represents a fluoro modification at the 2′ position of the sugar of the underlying nucleoside.

The target sequences in the Factor XI gene, with which the antisense (guide) sequences of Tables 1a/1b interact are set out in Table 1c below.

TABLE 1c
Summary sequence table for the nucleobases of
the target gene:
	Seq ID	Target sequence
Oligo Name	No	(5′ to 3′)
F11-01T	1001	GAGUCACCUAAGAUUUUGC
F11-02T	1002	GUGGCAUUUUAAAUCAAUC
F11-03T	1003	AGGACAGCAGCGAUUUCUG
F11-04T	1004	UCAGGAUGAUUUUCUUAUA
F11-05T	1005	UUCCCUAAUACGGUGUUUG
F11-06T	1006	UUACCAUGACACUGAUUUC
F11-07T	1007	AUGGCAGAAAGCGGGUAUG
F11-08T	1008	UGUCUCCUUAAAACAUCUG
F11-09T	1009	CCAGAAAGCCAAGAUACCC
F11-10T	1010	GCCAGAAGAGAUACAGAGG
F11-11T	1011	CAAGAAAUAAUAAUCCAUG
F11-12T	1012	GCACUUUCUAAUCUGGCUU
F11-13T	1013	GCACCAAUGCCGUCCGCUG
F11-14T	1014	UUUAAAUCAAUCUGAAAUA
F11-15T	1015	CAGAAAACUAAGAGACAAA
F11-16T	1016	ACAGCAUCCCAGUGUUCUG
F11-17T	1017	UUUUCUUAUAUCAAGUGGU
F11-18T	1018	GGUGUUUGUAAGAAAAUGC
F11-19T	1019	UGCCCAGUACACGCAUUAA
F11-20T	1020	CGGGAGGCCCUCUGUCCUG
F11-21T	1021	CACUCAUCAUCCCGGUUGC
F11-22T	1022	CUCAAAGAAAUCUUUGUCU
F11-23T	1023	GUGCCAGCAUGCUUCCUCC
F11-24T	1024	GUAUUAGGGACAUUUUCCC
F11-25T	1025	AGGGCAAGUGUUACUUAAA
F11-26T	1026	AAAGCGGGUAUGAUAUUGC
F11-27T	1027	AUAUCAAGUGGUACAUUUC
F11-28T	1028	UUUUCAGGAUGAUUUUCUU
F11-29T	1029	AGGGAAGGGCAAGUGUUAC
F11-30T	1030	UGUUUGUAAGAAAAUGCUA
F11-31T	1031	UCCCUAAUACGGUGUUUGC
F11-32T	1032	UGGAUAUUAACAGCCGCUC
F11-33T	1033	GGAUAUUAACAGCCGCUCA
F11-34T	1034	CAAAGAAAUCUUUGUCUCC
F11-35T	1035	AGGACAUAAAAUAACCCAU
F11-36T	1036	UCGACAGUGUCAUGGCUCC
F11-37T	1037	UGUGCACUUUCUAAUCUGG
F11-38T	1038	GCGAUUUCUGGGUAUUCUU
F11-39T	1039	GUCUCCUUAAAACAUCUGA
F11-40T	1040	GAGGCAUCUCUGGAUACAC
F11-41T	1041	CUGGUGAAUGUGUGACUCA
F11-42T	1042	AGGACACAUCUUUCUUUGG
F11-43T	1043	UUUCUUAUAUCAAGUGGUA
F11-44T	1044	GUUACUUAAAGCUUUCUUC
F11-45T	1045	UAAAUCAAUCUGAAAUAAA
F11-46T	1046	CAAGCAAUGCUCACACCAA
F11-47T	1047	AGGUCUUUUCAGGAUGAUU
F11-48T	1048	CUUUCAAGCAAUGCUCACA
F11-49T	1048	GUGCCAGAAGAGAUACAGA
F11-50T	1050	CUGGAUACACAUUAAGGUU
F11-51T	1051	GAAAUAAUAAUCCAUGAUC
F11-52T	1052	AUCUCAAAGAAAUCUUUGU
F11-53T	1053	CUCCAACUAAAAUACUUCA
F11-54T	1054	GGCAUUUUAAAUCAAUCUG
F11-55T	1055	CAGAAAGCCAAGAUACCCU
F11-56T	1056	AAGAAAUCUUUGUCUCCUU
F11-57T	1057	UCUUCAUUUUACCAUGACA
F11-58T	1058	GGGAGAAGAACUGGAUAUU
F11-59T	1059	GGAGAAGAACUGGAUAUUG
F11-60T	1060	UGAAACUGGAAACCACAGU
F11-61T	1061	CUGUGCACUUUCUAAUCUG
F11-62T	1062	ACCAUGACACUGAUUUCUU
F11-63T	1063	UCAAGAAAUAAUAAUCCAU
F11-64T	1064	GUGCACUUUCUAAUCUGGC
F11-65T	1065	UGUAAAAUGGAUAAUGAGU
F11-66T	1066	UUCCCAGGAAUGGCCCAAA
F11-67T	1067	CCACCAAAAUCAAGCCCAG
F11-68T	1068	GCAUUUUAAAUCAAUCUGA
F11-69T	1069	UCAUCAUCCCGGUUGCUUG
F11-70T	1070	CUCUGGAUACACAUUAAGG
F11-71T	1071	GAAACCACAGUGAAUUACA
F11-72T	1072	CAAAGGAGAUAGAAAUGUA
F11-73T	1073	CAUCAUUGGAAACCAGUGG
F11-74T	1074	AGUGAAUUACACAGAUUCU
F11-75T	1075	GCCAAGAGUGAAUAGGACA
F11-76T	1076	AUUCUUUCAAGCAAUGCUC
F11-77T	1077	CAGCGAUUUCUGGGUAUUC
F11-78T	1078	GGUUCAAGAAAUAAUAAUC
F11-79T	1079	UCUCCAACUAAAAUACUUC
F11-80T	1080	AGUACGUGGACUGGAUUCU
F11-81T	1081	UCAAAGAAAUCUUUGUCUC
F11-82T	1082	UUUUCACUGAAAUCCUGUG
F11-83T	1083	GUAUGAUAUUGCCUUGUUG
F11-84T	1084	CGGGUAUGAUAUUGCCUUG
F11-85T	1085	GCAGCGAUUUCUGGGUAUU
F11-86T	1086	UGGCAUUUUAAAUCAAUCU
F11-87T	1087	CUGCCAAGAGUGAAUAGGA
F11-88T	1088	AAGAUUUUGCGUGUCUACA
F11-89T	1089	GAUUCUGGAGAAAACUCAA
F11-90T	1090	AAAGAAUCUCAAAGAAAUC
F11-91T	1091	CAGGAUGAUUUUCUUAUAU
F11-92T	1092	AGAGUCACCUAAGAUUUUG
F11-93T	1093	GGCACAGCAUCCCAGUGUU
F11-94T	1094	UCACUGAAAUCCUGUGCAC
F11-95T	1095	UUCUAAUCUGGCUUGUAUU
F11-96T	1096	UUGAAACUGGAAACCACAG
F11-97T	1097	GCAACGAAGGGAAGGGCAA
F11-98T	1098	UCUUUUCAGGAUGAUUUUC
F11-99T	1099	AUGACACUGAUUUCUUGGG
F11-100T	1100	CUCAACGACCCAUAUGCCU
F11-101T	1101	GUGAAUUACACAGAUUCUC
F11-102T	1102	CGAGUACGUGGACUGGAUU
F11-103T	1103	CCAGAAGAGAUACAGAGGA
F11-104T	1104	UUCACUGAAAUCCUGUGCA
F11-105T	1105	UGCCAUUCUUCAUUUUACC
F11-106T	1106	ACACAGAUUCUCAACGACC
F11-107T	1107	AGAACUGGAUAUUGUUGCU
F11-108T	1108	CACCAAUGCCGUCCGCUGC
F11-109T	1109	GUGUUACUUAAAGCUUUCU
F11-110T	1110	GUGUUACAGAAACACUGCC
F11-111T	1111	UGAAUUACACAGAUUCUCA
F11-112T	1112	UCGAGUACGUGGACUGGAU
F11-113T	1113	UUUCAAGCAAUGCUCACAC
F11-114T	1114	CUGCACUCAUCAUCCCGGU
F11-115T	1115	CGAAGCUCGAUAAAGUGGU
F11-116T	1116	UGUGUAAAAUGGAUAAUGA
F11-117T	1117	GCACUCAUCAUCCCGGUUG
F11-118T	1118	CAGGAAUGGCCCAAAGAAU
F11-119T	1119	AAGCCAAGAUACCCUUAGU
F11-120T	1120	AAGCAAUGCUCACACCAAA
F11-121T	1121	UUCUCAACGACCCAUAUGC
F11-122T	1122	UCUCUGGAUACACAUUAAG
F11-123T	1123	UCUCCUUAAAACAUCUGAG
F11-124T	1124	GAGGCUCCAUCAUUGGAAA
F11-125T	1125	GUACGUGGACUGGAUUCUG
F11-126T	1126	GGCCCAAAGAAUCUCAAAG
F11-127T	1127	GGUCUUUUCAGGAUGAUUU
F11-128T	1128	CUAAGAUUUUGCGUGUCUA
F11-129T	1129	CCAACGUGGUCGAGUACGU
F11-130T	1130	UUGCUGGGUGACUGGAUGG
F11-131T	1131	GCACAGCAUCCCAGUGUUC
F11-132T	1132	AGAGCAAAGCUCUUUCUGG
F11-133T	1133	CCAAAGAAUCUCAAAGAAA
F11-134T	1134	GAACUGGAUAUUGUUGCUG
F11-135T	1135	GAAGCUCGAUAAAGUGGUG
F11-136T	1136	CUGCAACGAAGGGAAGGGC
F11-137T	1137	GUCACCUAAGAUUUUGCGU
F11-138T	1138	CCUCCACAGUAACACGCUG
F11-139T	1139	CCGGCUACAGGGAAGGAGG
F11-140T	1140	AGAAGAGAUACAGAGGACA
F11-141T	1141	UCCAGAAAGCCAAGAUACC
F11-142T	1142	CAGAAACACUGCCAAGAGU
F11-143T	1143	UACCAUGACACUGAUUUCU
F11-144T	1144	GUGCCGGCUACAGGGAAGG
F11-145T	1145	CUCAAAGGGAGCGGCCAGG
F11-146T	1146	CACCUAAGAUUUUGCGUGU
F11-147T	1147	AAAGCUCUUUCUGGUUUCA
F11-148T	1148	AGUGUUACUUAAAGCUUUC
F11-149T	1149	CUUUCUAAUCUGGCUUGUA
F11-150T	1150	GUAAAAUGGAUAAUGAGUG
F11-151T	1151	CAACAAGGUCUUUUCAGGA
F11-152T	1152	GCUCCAUCAUUGGAAACCA
F11-153T	1153	GAGGCCUGCCAGAAACUGU
F11-154T	1154	AUCCCAGUGUUCUGCCAUU
F11-155T	1155	AGAAUCUCAAAGAAAUCUU
F11-156T	1156	CUUGUUGAAACUGGAAACC
F11-157T	1157	CAGAAGAGAUACAGAGGAC
F11-158T	1158	CAAGGUCUUUUCAGGAUGA
F11-159T	1159	AUUCUGGAGAAAACUCAAG
F11-160T	1160	UGGAAACCACAGUGAAUUA
F11-161T	1161	GAAUCUCAAAGAAAUCUUU
F11-162T	1162	AAAGAAAUCUUUGUCUCCU
F11-163T	1163	CUUUUCAGGAUGAUUUUCU
F11-164T	1164	GUAUAAAAUGGCAGAAAGC
F11-165T	1165	UGGUCGAGUACGUGGACUG
F11-166T	1166	GCCCAGUACACGCAUUAAA
F11-167T	1167	AUCUCUGGAUACACAUUAA
F11-168T	1168	GGAAUGGCCCAAAGAAUCU
F11-169T	1169	AAGCUCUUUCUGGUUUCAG
F11-170T	1170	GUUUCUGGUGAAUGUGUGA
F11-171T	1171	UCUCAAAGAAAUCUUUGUC
F11-172T	1172	CCAAAGGAGAUAGAAAUGU
F11-173T	1173	AAGACAGUGUUACAGAAAC
F11-174T	1174	GGAUUUUCACUGAAAUCCU
F11-175T	1175	CUGUGCUCAAAGGGAGCGG
F11-176T	1176	GGUCGAGUACGUGGACUGG
F11-177T	1177	UCAACGACCCAUAUGCCUG
F11-178T	1178	AAGAGAUACAGAGGACAUA
F11-179T	1179	GUACCACCAAAAUCAAGCC
F11-180T	1180	GUGUGGAGGCUCCAUCAUU
F11-181T	1181	UACACAGAUUCUCAACGAC
F11-182T	1182	GUUGUGUAAAAUGGAUAAU
F11-183T	1183	CCAAGAGUGAAUAGGACAG
F11-184T	1184	GAGAAGAACUGGAUAUUGU
F11-185T	1185	GCCCAAAGAAUCUCAAAGA
F11-186T	1186	GAAACACUGCCAAGAGUGA
F11-187T	1187	UCUGGGUAUUCUUUCAAGC
F11-188T	1188	GCGGGUAUGAUAUUGCCUU
F11-189T	1189	CCACAGUGAAUUACACAGA
F11-190T	1190	UGGAAACCAGUGGAUAUUA
F11-191T	1191	UUUCUGGGUAUUCUUUCAA
F11-192T	1192	AAACCAGUGGAUAUUAACA
F11-193T	1193	CUUCAUUUUACCAUGACAC
F11-194T	1194	AGGAAUGGCCCAAAGAAUC
F11-195T	1195	GGAUCGUUGGAGGAACUGC
F11-196T	1196	GUCUACUGAAGCACACCCA
F11-197T	1197	UUACUUAAAGCUUUCUUCA
F11-198T	1198	ACAAGGUCUUUUCAGGAUG
F11-199T	1199	UGUUACUUAAAGCUUUCUU
F11-200T	1200	AGUGUUACAGAAACACUGC
F11-201T	1201	CCUAAGAUUUUGCGUGUCU
F11-202T	1202	UUCAAGCAAUGCUCACACC
F11-203T	1203	AGCAAAGCUCUUUCUGGUU
F11-204T	1204	AAAUCCUGUGCACUUUCUA
F11-205T	1205	AAAUCAAUCUGAAAUAAAA
F11-206T	1206	UGGGAGAAGAACUGGAUAU
F11-207T	1207	UACUCUUCACUUUCACGGC
F11-208T	1208	UGUCUACUGAAGCACACCC
F11-209T	1209	UCGGGAGGCCCUCUGUCCU
F11-210T	1210	UUUCAGGAUGAUUUUCUUA
F11-211T	1211	AUGGCCCAAAGAAUCUCAA
F11-212T	1212	UUUGUCUCCUUAAAACAUC
F11-213T	1213	GGCCUGCCAGAAACUGUGC
F11-214T	1214	AGAAGAACUGGAUAUUGUU
F11-215T	1215	UCAGUUUCUGGUGAAUGUG
F11-216T	1216	GGGUAUGAUAUUGCCUUGU
F11-217T	1217	AGCCCAGGAUCGUUGGAGG
F11-218T	1218	AGCUCUUUCUGGUUUCAGU
F11-219T	1219	ACGCUUGCAAGGGAGAUUC
F11-220T	1220	ACCACAGUGAAUUACACAG
F11-221T	1221	UCUGGAUUUUCACUGAAAU
F11-222T	1222	GUCUUUUCAGGAUGAUUUU
F11-223T	1223	AAAUGGAUAAUGAGUGUAC
F11-224T	1224	UUACAGAAACACUGCCAAG
F11-225T	1225	AUGGAUAAUGAGUGUACCA
F11-226T	1226	CGACCCAUAUGCCUGCCUU
F11-227T	1227	UUGCCUUGUUGAAACUGGA
F11-228T	1228	GCUCAAAGGGAGCGGCCAG
F11-229T	1229	GAAACUGGAAACCACAGUG
F11-230T	1230	CCCAGGAAUGGCCCAAAGA
F11-231T	1231	UUCAGGAUGAUUUUCUUAU
F11-232T	1232	CAAUCUGAAAUAAAAGAGG
F11-233T	1233	CCCAAAGAAUCUCAAAGAA
F11-234T	1234	UGUGGAGGCUCCAUCAUUG
F11-235T	1235	AGUGUUCUGCCAUUCUUCA
F11-236T	1236	GUGGAGGCUCCAUCAUUGG
F11-237T	1237	CCUGUGUGGAGGCUCCAUC
F11-238T	1238	UGACACUGAUUUCUUGGGA
F11-239T	1239	ACACCUGUGUGGAGGCUCC
F11-240T	1240	ACACUGAUUUCUUGGGAGA
F11-241T	1241	GAGACACCUGUGUGGAGGC
F11-242T	1242	UGGAGGCUCCAUCAUUGGA
F11-243T	1243	AGGCUCCAUCAUUGGAAAC
F11-244T	1244	GACACUGAUUUCUUGGGAG
F11-245T	1245	GACACCUGUGUGGAGGCUC
F11-246T	1246	UGAUUUCUUGGGAGAAGAA
F11-247T	1247	GGCUCCAUCAUUGGAAACC
F11-248T	1248	GGAGGCUCCAUCAUUGGAA
F11-249T	1249	ACCUGUGUGGAGGCUCCAU
F11-250T	1250	AGACACCUGUGUGGAGGCU

In above Table 1c:

A represents adenine;

U represents uracil;

C represents cytosine;

G represents guanine.

It should also be noted that the scope of the present embodiments extends to sequences that correspond to those in Table 1a or Table 1 b, and wherein the 5′ nucleoside of the antisense (guide) strand (first region as defined herein) can include any nucleobase that can be present in an RNA molecule, in other words can be any of adenine (A), uracil (U), guanine or cytosine (C). Additionally, the scope of the present embodiments extends to sequences that correspond to those in Table 1a or Table 1b, and wherein the 3′ nucleoside of the sense (passenger) strand (second region as defined herein) can include any nucleobase that can be present in an RNA molecule, in other words can be any of adenine (A), uracil (U), guanine or cytosine (C), preferably however a nucleobase that is complementary to the 5′ nucleobase of the antisense (guide) strand (first region as defined herein). These further sequences are shown in Tables 1d (unmodified) and 1e (chemically modified), where N and N′ respectively represent any RNA nucleobase that can be present in the 5′ terminal position of the antisense (guide) strand (first region as defined herein) and in the 3′ terminal position of the sense (passenger) strand (second region as defined herein).

TABLE 1d
Summary sequence table for active nucleobase sequences:
Oligo	Seq	Antisense (Guide) Strand	Seq ID	Sense (Passenger) Strand
Name	ID No	Sequence (5′ to 3′)	No	Sequence (5′ to 3′)
F11-	1251	NCAAAAUCUUAGGUGACUC	1501	CACCUAAGAUUUUGN′
01N
F11-	1252	NAUUGAUUUAAAAUGCCAC	1502	CAUUUUAAAUCAAUN′
02N
F11-	1253	NAGAAAUCGCUGCUGUCCU	1503	CAGCAGCGAUUUCUN′
03N
F11-	1254	NAUAAGAAAAUCAUCCUGA	1504	GAUGAUUUUCUUAUN′
04N
F11-	1255	NAAACACCGUAUUAGGGAA	1505	CUAAUACGGUGUUUN′
05N
F11-	1256	NAAAUCAGUGUCAUGGUAA	1506	CAUGACACUGAUUUN′
06N
F11-	1257	NAUACCCGCUUUCUGCCAU	1507	CAGAAAGCGGGUAUN′
07N
F11-	1258	NAGAUGUUUUAAGGAGACA	1508	UCCUUAAAACAUCUN′
08N
F11-	1259	NGGUAUCUUGGCUUUCUGG	1059	AAAGCCAAGAUACCN′
09N
F11-	1260	NCUCUGUAUCUCUUCUGGC	1510	GAAGAGAUACAGAGN′
10N
F11-	1261	NAUGGAUUAUUAUUUCUUG	1511	AAAUAAUAAUCCAUN′
11N
F11-	1262	NAGCCAGAUUAGAAAGUGC	1512	UUUCUAAUCUGGCUN′
12N
F11-	1263	NAGCGGACGGCAUUGGUGC	1513	CAAUGCCGUCCGCUN′
13N
F11-	1264	NAUUUCAGAUUGAUUUAAA	1514	AAUCAAUCUGAAAUN′
14N
F11-	1265	NUUGUCUCUUAGUUUUCUG	1515	AAACUAAGAGACAAN′
15N
F11-	1266	NAGAACACUGGGAUGCUGU	1516	CAUCCCAGUGUUCUN′
16N
F11-	1267	NCCACUUGAUAUAAGAAAA	1517	CUUAUAUCAAGUGGN′
17N
F11-	1268	NCAUUUUCUUACAAACACC	1518	UUUGUAAGAAAAUGN′
18N
F11-	1269	NUAAUGCGUGUACUGGGCA	1519	CAGUACACGCAUUAN′
19N
F11-	1270	NAGGACAGAGGGCCUCCCG	1520	AGGCCCUCUGUCCUN′
20N
F11-	1271	NCAACCGGGAUGAUGAGUG	1521	CAUCAUCCCGGUUGN′
21N
F11-	1272	NGACAAAGAUUUCUUUGAG	1522	AAGAAAUCUUUGUCN′
22N
F11-	1273	NGAGGAAGCAUGCUGGCAC	1523	CAGCAUGCUUCCUCN′
23N
F11-	1274	NGGAAAAUGUCCCUAAUAC	1524	UAGGGACAUUUUCCN′
24N
F11-	1275	NUUAAGUAACACUUGCCCU	1525	CAAGUGUUACUUAAN′
25N
F11-	1276	NCAAUAUCAUACCCGCUUU	1526	CGGGUAUGAUAUUGN′
26N
F11-	1277	NAAAUGUACCACUUGAUAU	1527	CAAGUGGUACAUUUN′
27N
F11-	1278	NAGAAAAUCAUCCUGAAAA	1528	CAGGAUGAUUUUCUN′
28N
F11-	1279	NUAACACUUGCCCUUCCCU	1529	AAGGGCAAGUGUUAN′
29N
F11-	1280	NAGCAUUUUCUUACAAACA	1530	UGUAAGAAAAUGCUN′
30N
F11-	1281	NCAAACACCGUAUUAGGGA	1531	UAAUACGGUGUUUGN′
31N
F12-	1282	NAGCGGCUGUUAAUAUCCA	1532	UAUUAACAGCCGCUN′
32N
F11-	1283	NGAGCGGCUGUUAAUAUCC	1533	AUUAACAGCCGCUCN′
33N
F11-	1284	NGAGACAAAGAUUUCUUUG	1534	GAAAUCUUUGUCUCN′
34N
F11-	1285	NUGGGUUAUUUUAUGUCCU	1535	CAUAAAAUAACCCAN′
35N
F11-	1286	NGAGCCAUGACACUGUCGA	1536	CAGUGUCAUGGCUCN′
36N
F11-	1287	NCAGAUUAGAAAGUGCACA	1537	CACUUUCUAAUCUGN′
37N
F11-	1288	NAGAAUACCCAGAAAUCGC	1538	UUUCUGGGUAUUCUN′
38N
F11-	1289	NCAGAUGUUUUAAGGAGAC	1539	CCUUAAAACAUCUGN′
39N
F11-	1290	NUGUAUCCAGAGAUGCCUC	1540	CAUCUCUGGAUACAN′
40N
F11-	1291	NGAGUCACACAUUCACCAG	1541	UGAAUGUGUGACUCN′
41N
F11-	1292	NCAAAGAAAGAUGUGUCCU	1542	CACAUCUUUCUUUGN′
42N
F11-	1293	NACCACUUGAUAUAAGAAA	1543	UUAUAUCAAGUGGUN′
43N
F11-	1294	UAAGAAAGCUUUAAGUAAC	1544	CUUAAAGCUUUCUUN′
44N
F11-	1295	NUUAUUUCAGAUUGAUUUA	1545	UCAAUCUGAAAUAAN′
45N
F11-	1296	NUGGUGUGAGCAUUGCUUG	1546	CAAUGCUCACACCAN′
46N
F11-	1297	NAUCAUCCUGAAAAGACCU	1547	CUUUUCAGGAUGAUN′
47N
F11-	1298	NGUGAGCAUUGCUUGAAAG	1548	CAAGCAAUGCUCACN′
48N
F11-	1299	NCUGUAUCUCUUCUGGCAC	1549	CAGAAGAGAUACAGN′
49N
F11-	1300	NACCUUAAUGUGUAUCCAG	1550	AUACACAUUAAGGUN′
50N
F11-	1301	NAUCAUGGAUUAUUAUUUC	1551	UAAUAAUCCAUGAUN′
51N
F11-	1302	NCAAAGAUUUCUUUGAGAU	1552	CAAAGAAAUCUUUGN′
52N
F11-	1303	NGAAGUAUUUUAGUUGGAG	1553	AACUAAAAUACUUCN′
53N
F11-	1304	NAGAUUGAUUUAAAAUGCC	1554	UUUUAAAUCAAUCUN′
54N
F11-	1305	NGGGUAUCUUGGCUUUCUG	1555	AAGCCAAGAUACCCN′
55N
F11-	1306	NAGGAGACAAAGAUUUCUU	1556	AAUCUUUGUCUCCUN′
56N
F11-	1307	NGUCAUGGUAAAAUGAAGA	1557	CAUUUUACCAUGACN′
57N
F11-	1308	NAUAUCCAGUUCUUCUCCC	1558	GAAGAACUGGAUAUN′
58N
F11-	1309	NAAUAUCCAGUUCUUCUCC	1559	AAGAACUGGAUAUUN′
59N
F11-	1310	NCUGUGGUUUCCAGUUUCA	1560	ACUGGAAACCACAGN′
60N
F11-	1311	NAGAUUAGAAAGUGCACAG	1561	GCACUUUCUAAUCUN′
61N
F11-	1312	NAGAAAUCAGUGUCAUGGU	1562	UGACACUGAUUUCUN′
62N
F11-	1313	NUGGAUUAUUAUUUCUUGA	1563	GAAAUAAUAAUCCAN′
63N
F11-	1314	NCCAGAUUAGAAAGUGCAC	1564	ACUUUCUAAUCUGGN′
64N
F11-	1315	NCUCAUUAUCCAUUUUACA	1565	AAAUGGAUAAUGAGN′
65N
F11-	1316	NUUGGGCCAUUCCUGGGAA	1566	CAGGAAUGGCCCAAN′
66N
F11-	1317	NUGGGCUUGAUUUUGGUGG	1567	CAAAAUCAAGCCCAN′
67N
F11-	1318	NCAGAUUGAUUUAAAAUGC	1568	UUUAAAUCAAUCUGN′
68N
F11-	1319	NAAGCAACCGGGAUGAUGA	1569	CAUCCCGGUUGCUUN′
69N
F11-	1320	NCUUAAUGUGUAUCCAGAG	1570	GGAUACACAUUAAGN′
70N
F11-	1321	NGUAAUUCACUGUGGUUUC	1571	CCACAGUGAAUUACN′
71N
F11-	1322	NACAUUUCUAUCUCCUUUG	1572	GGAGAUAGAAAUGUN′
72N
F11-	1323	NCACUGGUUUCCAAUGAUG	1573	AUUGGAAACCAGUGN′
73N
F11-	1324	NGAAUCUGUGUAAUUCACU	1574	AAUUACACAGAUUCN′
74N
F11-	1325	NGUCCUAUUCACUCUUGGC	1575	AGAGUGAAUAGGACN′
75N
F11-	1326	NAGCAUUGCUUGAAAGAAU	1576	UUUCAAGCAAUGCUN′
76N
F11-	1327	NAAUACCCAGAAAUCGCUG	1577	GAUUUCUGGGUAUUN′
77N
F11-	1328	NAUUAUUAUUUCUUGAACC	1578	CAAGAAAUAAUAAUN′
78N
F11-	1329	NAAGUAUUUUAGUUGGAGA	1579	CAACUAAAAUACUUN′
79N
F11-	1330	NGAAUCCAGUCCACGUACU	1580	CGUGGACUGGAUUCN′
80N
F11-	1331	NAGACAAAGAUUUCUUUGA	1581	AGAAAUCUUUGUCUN′
81N
F11-	1332	NACAGGAUUUCAGUGAAAA	1582	CACUGAAAUCCUGUN′
82N
F11-	1333	NAACAAGGCAAUAUCAUAC	1583	GAUAUUGCCUUGUUN′
83N
F11-	1334	NAAGGCAAUAUCAUACCCG	1584	UAUGAUAUUGCCUUN′
84N
F11-	1335	NAUACCCAGAAAUCGCUGC	1585	CGAUUUCUGGGUAUN′
85N
F11-	1336	NGAUUGAUUUAAAAUGCCA	1586	AUUUUAAAUCAAUCN′
86N
F11-	1337	NCCUAUUCACUCUUGGCAG	1587	CAAGAGUGAAUAGGN′
87N
F11-	1338	NGUAGACACGCAAAAUCUU	1588	UUUUGCGUGUCUACN′
88N
F11-	1339	NUGAGUUUUCUCCAGAAUC	1589	CUGGAGAAAACUCAN′
89N
F11-	1340	NAUUUCUUUGAGAUUCUUU	1590	AAUCUCAAAGAAAUN′
90N
F11-	1341	NUAUAAGAAAAUCAUCCUG	1591	AUGAUUUUCUUAUAN′
91N
F11-	1342	NAAAAUCUUAGGUGACUCU	1592	UCACCUAAGAUUUUN′
92N
F11-	1343	NACACUGGGAUGCUGUGCC	1593	CAGCAUCCCAGUGUN′
93N
F11-	1344	NUGCACAGGAUUUCAGUGA	1594	UGAAAUCCUGUGCAN′
94N
F11-	1345	NAUACAAGCCAGAUUAGAA	1595	AAUCUGGCUUGUAUN′
95N
F11-	1346	NUGUGGUUUCCAGUUUCAA	1596	AACUGGAAACCACAN′
96N
F11-	1347	NUGCCCUUCCCUUCGUUGC	1597	CGAAGGGAAGGGCAN′
97N
F11-	1348	NAAAAUCAUCCUGAAAAGA	1598	UUCAGGAUGAUUUUN′
98N
F11-	1349	NCCAAGAAAUCAGUGUCAU	1599	CACUGAUUUCUUGGN′
99N
F11-	1350	NGGCAUAUGGGUCGUUGAG	1600	ACGACCCAUAUGCCN′
100N
F11-	1351	NAGAAUCUGUGUAAUUCAC	1601	AUUACACAGAUUCUN′
101N
F11-	1352	NAUCCAGUCCACGUACUCG	1602	UACGUGGACUGGAUN′
102N
F11-	1353	NCCUCUGUAUCUCUUCUGG	1603	AAGAGAUACAGAGGN′
103N
F11-	1354	NGCACAGGAUUUCAGUGAA	1604	CUGAAAUCCUGUGCN′
104N
F11-	1355	NGUAAAAUGAAGAAUGGCA	1605	AUUCUUCAUUUUACN′
105N
F11-	1356	NGUCGUUGAGAAUCUGUGU	1606	AGAUUCUCAACGACN′
106N
F11-	1357	NGCAACAAUAUCCAGUUCU	1607	CUGGAUAUUGUUGCN′
107N
F11-	1358	NCAGCGGACGGCAUUGGUG	1608	AAUGCCGUCCGCUGN′
108N
F11-	1359	NGAAAGCUUUAAGUAACAC	1609	UACUUAAAGCUUUCN′
109N
F11-	1360	NGCAGUGUUUCUGUAACAC	1610	UACAGAAACACUGCN′
110N
F11-	1361	NGAGAAUCUGUGUAAUUCA	1611	UUACACAGAUUCUCN′
111N
F11-	1362	NUCCAGUCCACGUACUCGA	1612	GUACGUGGACUGGAN′
112N
F11-	1363	NUGUGAGCAUUGCUUGAAA	1613	AAGCAAUGCUCACAN′
113N
F11-	1364	NCCGGGAUGAUGAGUGCAG	1614	ACUCAUCAUCCCGGN′
114N
F11-	1365	NCCACUUUAUCGAGCUUCG	1615	GCUCGAUAAAGUGGN′
115N
F11-	1366	NCAUUAUCCAUUUUACACA	1616	UAAAAUGGAUAAUGN′
116N
F11-	1367	NAACCGGGAUGAUGAGUGC	1617	UCAUCAUCCCGGUUN′
117N
F11-	1368	NUUCUUUGGGCCAUUCCUG	1618	AAUGGCCCAAAGAAN′
118N
F11-	1369	NCUAAGGGUAUCUUGGCUU	1619	CAAGAUACCCUUAGN′
119N
F11-	1370	NUUGGUGUGAGCAUUGCUU	1620	AAUGCUCACACCAAN′
120N
F11-	1371	NCAUAUGGGUCGUUGAGAA	1621	CAACGACCCAUAUGN′
121N
F11-	1372	NUUAAUGUGUAUCCAGAGA	1622	UGGAUACACAUUAAN′
122N
F11-	1373	NUCAGAUGUUUUAAGGAGA	1623	CUUAAAACAUCUGAN′
123N
F11-	1374	NUUCCAAUGAUGGAGCCUC	1624	CUCCAUCAUUGGAAN′
124N
F11-	1375	NAGAAUCCAGUCCACGUAC	1625	GUGGACUGGAUUCUN′
125N
F11-	1376	NUUUGAGAUUCUUUGGGCC	1626	CAAAGAAUCUCAAAN′
126N
F11-	1377	NAAUCAUCCUGAAAAGACC	1627	UUUUCAGGAUGAUUN′
127N
F11-	1378	NAGACACGCAAAAUCUUAG	1628	GAUUUUGCGUGUCUN′
128N
F11-	1379	NCGUACUCGACCACGUUGG	1629	CGUGGUCGAGUACGN′
129N
F11-	1380	NCAUCCAGUCACCCAGCAA	1630	UGGGUGACUGGAUGN′
130N
F11-	1381	NAACACUGGGAUGCUGUGC	1631	AGCAUCCCAGUGUUN′
131N
F11-	1382	NCAGAAAGAGCUUUGCUCU	1632	CAAAGCUCUUUCUGN′
132N
F11-	1383	NUUCUUUGAGAUUCUUUGG	1633	AGAAUCUCAAAGAAN′
133N
F11-	1384	NAGCAACAAUAUCCAGUUC	1634	UGGAUAUUGUUGCUN′
134N
F11-	1385	NACCACUUUAUCGAGCUUC	1635	CUCGAUAAAGUGGUN′
135N
F11-	1386	NCCCUUCCCUUCGUUGCAG	1636	AACGAAGGGAAGGGN′
136N
F11-	1387	NCGCAAAAUCUUAGGUGAC	1637	CCUAAGAUUUUGCGN′
137N
F11-	1388	NAGCGUGUUACUGUGGAGG	1638	CACAGUAACACGCUN′
138N
F11-	1389	NCUCCUUCCCUGUAGCCGG	1639	CUACAGGGAAGGAGN′
139N
F11-	1390	NGUCCUCUGUAUCUCUUCU	1640	GAGAUACAGAGGACN′
140N
F11-	1391	NGUAUCUUGGCUUUCUGGA	1641	GAAAGCCAAGAUACN′
141N
F11-	1392	NCUCUUGGCAGUGUUUCUG	1642	AACACUGCCAAGAGN′
142N
F11-	1393	NGAAAUCAGUGUCAUGGUA	1643	AUGACACUGAUUUCN′
143N
F11-	1394	NCUUCCCUGUAGCCGGCAC	1644	CGGCUACAGGGAAGN′
144N
F11-	1395	NCUGGCCGCUCCCUUUGAG	1645	AAGGGAGCGGCCAGN′
145N
F11-	1396	NCACGCAAAAUCUUAGGUG	1646	UAAGAUUUUGCGUGN′
146N
F11-	1397	NGAAACCAGAAAGAGCUUU	1647	CUCUUUCUGGUUUCN′
147N
F11-	1398	NAAAGCUUUAAGUAACACU	1648	UUACUUAAAGCUUUN′
148N
F11-	1399	NACAAGCCAGAUUAGAAAG	1649	CUAAUCUGGCUUGUN′
149N
F11-	1400	NACUCAUUAUCCAUUUUAC	1650	AAUGGAUAAUGAGUN′
150N
F11-	1401	NCCUGAAAAGACCUUGUUG	1651	AAGGUCUUUUCAGGN′
151N
F11-	1402	NGGUUUCCAAUGAUGGAGC	1652	CAUCAUUGGAAACCN′
152N
F11-	1403	NCAGUUUCUGGCAGGCCUC	1653	CCUGCCAGAAACUGN′
153N
F11-	1404	NAUGGCAGAACACUGGGAU	1654	CAGUGUUCUGCCAUN′
154N
F11-	1405	NAGAUUUCUUUGAGAUUCU	1655	UCUCAAAGAAAUCUN′
155N
F11-	1406	NGUUUCCAGUUUCAACAAG	1656	UUGAAACUGGAAACN′
156N
F11-	1407	NUCCUCUGUAUCUCUUCUG	1657	AGAGAUACAGAGGAN′
157N
F11-	1408	NCAUCCUGAAAAGACCUUG	1658	GUCUUUUCAGGAUGN′
158N
F11-	1409	NUUGAGUUUUCUCCAGAAU	1659	UGGAGAAAACUCAAN′
159N
F11-	1410	NAAUUCACUGUGGUUUCCA	1660	AACCACAGUGAAUUN′
160N
F11-	1411	NAAGAUUUCUUUGAGAUUC	1661	CUCAAAGAAAUCUUN′
161N
F11-	1412	NGGAGACAAAGAUUUCUUU	1662	AAAUCUUUGUCUCCN′
162N
F11-	1413	NGAAAAUCAUCCUGAAAAG	1663	UCAGGAUGAUUUUCN′
163N
F11-	1414	NCUUUCUGCCAUUUUAUAC	1664	AAAAUGGCAGAAAGN′
164N
F11-	1415	NAGUCCACGUACUCGACCA	1665	CGAGUACGUGGACUN′
165N
F11-	1416	NUUAAUGCGUGUACUGGGC	1666	AGUACACGCAUUAAN′
166N
F11-	1417	NUAAUGUGUAUCCAGAGAU	1667	CUGGAUACACAUUAN′
167N
F11-	1418	NGAUUCUUUGGGCCAUUCC	1668	UGGCCCAAAGAAUCN′
168N
F11-	1419	NUGAAACCAGAAAGAGCUU	1669	UCUUUCUGGUUUCAN′
169N
F11-	1420	NCACACAUUCACCAGAAAC	1670	CUGGUGAAUGUGUGN′
170N
F11-	1421	NACAAAGAUUUCUUUGAGA	1671	AAAGAAAUCUUUGUN′
171N
F11-	1422	NCAUUUCUAUCUCCUUUGG	1672	AGGAGAUAGAAAUGN′
172N
F11-	1423	NUUUCUGUAACACUGUCUU	1673	CAGUGUUACAGAAAN′
173N
F11-	1424	NGGAUUUCAGUGAAAAUCC	1674	UUUCACUGAAAUCCN′
174N
F11-	1425	NCGCUCCCUUUGAGCACAG	1675	GCUCAAAGGGAGCGN′
175N
F11-	1426	NCAGUCCACGUACUCGACC	1676	GAGUACGUGGACUGN′
176N
F11-	1427	NAGGCAUAUGGGUCGUUGA	1677	CGACCCAUAUGCCUN′
177N
F11-	1428	NAUGUCCUCUGUAUCUCUU	1678	GAUACAGAGGACAU N′
178N
F11-	1429	NGCUUGAUUUUGGUGGUAC	1679	CACCAAAAUCAAGCN′
179N
F11-	1430	NAUGAUGGAGCCUCCACAC	1680	GGAGGCUCCAUCAUN′
180N
F11-	1431	NUCGUUGAGAAUCUGUGUA	1681	CAGAUUCUCAACGAN′
181N
F11-	1432	NUUAUCCAUUUUACACAAC	1682	UGUAAAAUGGAUAAN′
182N
F11-	1433	NUGUCCUAUUCACUCUUGG	1683	GAGUGAAUAGGACAN′
183N
F11-	1434	NCAAUAUCCAGUUCUUCUC	1684	AGAACUGGAUAUUGN′
184N
F11-	1435	NCUUUGAGAUUCUUUGGGC	1685	AAAGAAUCUCAAAGN′
185N
F11-	1436	NCACUCUUGGCAGUGUUUC	1686	CACUGCCAAGAGUGN′
186N
F11-	1437	NCUUGAAAGAAUACCCAGA	1687	GGUAUUCUUUCAAGN′
187N
F11-	1438	NAGGCAAUAUCAUACCCGC	1688	GUAUGAUAUUGCCUN′
188N
F11-	1439	NCUGUGUAAUUCACUGUGG	1689	AGUGAAUUACACAGN′
189N
F11-	1440	NAAUAUCCACUGGUUUCCA	1690	AACCAGUGGAUAUUN′
190N
F11-	1441	NUGAAAGAAUACCCAGAAA	1691	UGGGUAUUCUUUCAN′
191N
F11-	1442	NGUUAAUAUCCACUGGUUU	1692	CAGUGGAUAUUAACN′
192N
F11-	1443	NUGUCAUGGUAAAAUGAAG	1693	AUUUUACCAUGACAN′
193N
F11-	1444	NAUUCUUUGGGCCAUUCCU	1694	AUGGCCCAAAGAAUN′
194N
F11-	1445	NCAGUUCCUCCAACGAUCC	1695	CGUUGGAGGAACUGN′
195N
F11-	1446	NGGGUGUGCUUCAGUAGAC	1696	ACUGAAGCACACCCN′
196N
F11-	1447	NGAAGAAAGCUUUAAGUAA	1697	UUAAAGCUUUCUUCN′
197N
F11-	1448	NAUCCUGAAAAGACCUUGU	1698	GGUCUUUUCAGGAUN′
198N
F11-	1449	NAGAAAGCUUUAAGUAACA	1699	ACUUAAAGCUUUCUN′
199N
F11-	1450	NCAGUGUUUCUGUAACACU	1700	UUACAGAAACACUGN′
200N
F11-	1451	NGACACGCAAAAUCUUAGG	1701	AGAUUUUGCGUGUCN′
201N
F11-	1452	NGUGUGAGCAUUGCUUGAA	1702	AGCAAUGCUCACACN′
202N
F11-	1453	NACCAGAAAGAGCUUUGCU	1703	AAGCUCUUUCUGGUN′
203N
F11-	1454	NAGAAAGUGCACAGGAUUU	1704	CCUGUGCACUUUCUN′
204N
F11-	1455	NUUUAUUUCAGAUUGAUUU	1705	CAAUCUGAAAUAAAN′
205N
F11-	1456	NUAUCCAGUUCUUCUCCCA	1706	AGAAGAACUGGAUAN′
206N
F11-	1457	NCCGUGAAAGUGAAGAGUA	1707	CUUCACUUUCACGGN′
207N
F11-	1458	NGGUGUGCUUCAGUAGACA	1708	UACUGAAGCACACCN′
208N
F11-	1459	NGGACAGAGGGCCUCCCGA	1709	GAGGCCCUCUGUCCN′
209N
F11-	1460	NAAGAAAAUCAUCCUGAAA	1710	AGGAUGAUUUUCUUN′
210N
F11-	1461	NUGAGAUUCUUUGGGCCAU	1711	CCCAAAGAAUCUCAN′
211N
F11-	1462	NAUGUUUUAAGGAGACAAA	1712	UCUCCUUAAAACAUN′
212N
F11-	1463	NCACAGUUUCUGGCAGGCC	1713	UGCCAGAAACUGUGN′
213N
F11-	1464	NACAAUAUCCAGUUCUUCU	1714	GAACUGGAUAUUGUN′
214N
F11-	1465	NACAUUCACCAGAAACUGA	1715	UUUCUGGUGAAUGUN′
215N
F11-	1466	NCAAGGCAAUAUCAUACCC	1716	AUGAUAUUGCCUUGN′
216N
F11-	1467	NCUCCAACGAUCCUGGGCU	1717	CAGGAUCGUUGGAGN′
217N
F11-	1468	NCUGAAACCAGAAAGAGCU	1718	CUUUCUGGUUUCAGN′
218N
F11-	1469	NAAUCUCCCUUGCAAGCGU	1719	UUGCAAGGGAGAUUN′
219N
F11-	1470	NUGUGUAAUUCACUGUGGU	1720	CAGUGAAUUACACAN′
220N
F11-	1471	NUUUCAGUGAAAAUCCAGA	1721	GAUUUUCACUGAAAN′
221N
F11-	1472	NAAAUCAUCCUGAAAAGAC	1722	UUUCAGGAUGAUUUN′
222N
F11-	1473	NUACACUCAUUAUCCAUUU	1723	GGAUAAUGAGUGUAN′
223N
F11-	1474	NUUGGCAGUGUUUCUGUAA	1724	AGAAACACUGCCAAN′
224N
F11-	1475	NGGUACACUCAUUAUCCAU	1725	AUAAUGAGUGUACCN′
225N
F11-	1476	NAGGCAGGCAUAUGGGUCG	1726	CCAUAUGCCUGCCUN′
226N
F11-	1477	NCCAGUUUCAACAAGGCAA	1727	CUUGUUGAAACUGGN′
227N
F11-	1478	NUGGCCGCUCCCUUUGAGC	1728	AAAGGGAGCGGCCAN′
228N
F11-	1479	NACUGUGGUUUCCAGUUUC	1729	CUGGAAACCACAGUN′
229N
F11-	1480	NCUUUGGGCCAUUCCUGGG	1730	GGAAUGGCCCAAAGN′
230N
F11-	1481	NUAAGAAAAUCAUCCUGAA	1731	GGAUGAUUUUCUUAN′
231N
F11-	1482	NCUCUUUUAUUUCAGAUUG	1732	CUGAAAUAAAAGAGN′
232N
F11-	1483	NUCUUUGAGAUUCUUUGGG	1733	AAGAAUCUCAAAGAN′
233N
F11-	1484	NAAUGAUGGAGCCUCCACA	1734	GAGGCUCCAUCAUUN′
234N
F11-	1485	NGAAGAAUGGCAGAACACU	1735	UUCUGCCAUUCUUCN′
235N
F11-	1486	NCAAUGAUGGAGCCUCCAC	1736	AGGCUCCAUCAUUGN′
236N
F11-	1487	NAUGGAGCCUCCACACAGG	1737	UGUGGAGGCUCCAUN′
237N
F11-	1488	NCCCAAGAAAUCAGUGUCA	1738	ACUGAUUUCUUGGGN′
238N
F11-	1489	NGAGCCUCCACACAGGUGU	1739	CUGUGUGGAGGCUCN′
239N
F11-	1490	NCUCCCAAGAAAUCAGUGU	1740	UGAUUUCUUGGGAGN′
240N
F11-	1491	NCCUCCACACAGGUGUCUC	1741	CACCUGUGUGGAGGN′
241N
F11-	1492	NCCAAUGAUGGAGCCUCCA	1742	GGCUCCAUCAUUGGN′
242N
F11-	1493	NUUUCCAAUGAUGGAGCCU	1743	UCCAUCAUUGGAAAN′
243N
F11-	1494	NUCCCAAGAAAUCAGUGUC	1744	CUGAUUUCUUGGGAN′
244N
F11-	1495	NAGCCUCCACACAGGUGUC	1745	CCUGUGUGGAGGCUN′
245N
F11-	1496	NUCUUCUCCCAAGAAAUCA	1746	UUCUUGGGAGAAGAN′
246N
F11-	1497	NGUUUCCAAUGAUGGAGCC	1747	CCAUCAUUGGAAACN′
247N
F11-	1498	NUCCAAUGAUGGAGCCUCC	1748	GCUCCAUCAUUGGAN′
248N
F11-	1499	NUGGAGCCUCCACACAGGU	1749	GUGUGGAGGCUCCAN′
249N
F11-	1500	NGCCUCCACACAGGUGUCU	1750	ACCUGUGUGGAGGCN′
250N

In above Table 1d:

A represents adenine;

U represents uracil;

C represents cytosine;

G represents guanine;

N represents any RNA nucleobase;

N′ represents any RNA nucleobase and is preferably complementary to N.

TABLE 1e
Summary sequence table for active nucleobase sequences with chemical modifications:
Oligo	construct	Antisense (Guide) Strand	construct	Sense (Passenger) Strand
Name	No	Sequence (5′ to 3′)	No	Sequence (5′ to 3′)
F11-	1751	PmN.fC.mA.fA.mA.fA.mU.fC.mU.fU.	2001	fC.mA.fC.mC.fU.mA.fA.mG.fA.mU.
01NM		mA.fG.mG.fU.mG.fA.mC.fU.mC		fU.mU.fU.mG.fN′
F11-	1752	PmN.fA.mU.fU.mG.fA.mU.fU.mU.fA.	2002	fC.mA.fU.mU.fU.mU.fA.mA.fA.mU.
02NM		mA.fA.mA.fU.mG.fC.mC.fA.mC		fC.mA.fA.mU.fN′
F11-	1753	PmN.fA.mG.fA.mA.fA.mU.fC.mG.fC.	2003	fC.mA.fG.mC.fA.mG.fC.mG.fA.mU.
03NM		mU.fG.mC.fU.mG.fU.mC.fC.mU		fU.mU.fC.mU.fN′
F11-	1754	PmN.fA.mU.fA.mA.fG.mA.fA.mA.fA.	2004	fG.mA.fU.mG.fA.mU.fU.mU.fU.mC.
04NM		mU.fC.mA.fU.mC.fC.mU.fG.mA		fU.mU.fA.mU.fN′
F11-	1755	PmN.fA.mA.fA.mC.fA.mC.fC.mG.fU.	2005	fC.mU.fA.mA.fU.mA.fC.mG.fG.mU.
05NM		mA.fU.mU.fA.mG.fG.mG.fA.mA		fG.mU.fU.mU.fN′
F11-	1756	PmN.fA.mA.fA.mU.fC.mA.fG.mU.fG.	2006	fC.mA.fU.mG.fA.mC.fA.mC.fU.mG.
06NM		mU.fC.mA.fU.mG.fG.mU.fA.mA		fA.mU.fU.mU.fN′
F11-	1757	PmN.fA.mU.fA.mC.fC.mC.fG.mC.fU.	2007	fC.mA.fG.mA.fA.mA.fG.mC.fG.mG.
07NM		mU.fU.mC.fU.mG.fC.mC.fA.mU		fG.mU.fA.mU.fN′
F11-	1758	PmN.fA.mG.fA.mU.fG.mU.fU.mU.fU.	2008	fU.mC.fC.mU.fU.mA.fA.mA.fA.mC.
08NM		mA.fA.mG.fG.mA.fG.mA.fC.mA		fA.mU.fC.mU.fN′
F11-	1759	PmN.fG.mG.fU.mA.fU.mC.fU.mU.	2009	fA.mA.fA.mG.fC.mC.fA.mA.fG.mA.
09NM		fG.mG.fC.mU.fU.mU.fC.mU.fG.mG		fU.mA.fC.mC.fN′
F11-	1760	PmN.fC.mU.fC.mU.fG.mU.fA.mU.fC.	2010	fG.mA.fA.mG.fA.mG.fA.mU.fA.mC.
10NM		mU.fC.mU.fU.mC.fU.mG.fG.mC		fA.mG.fA.mG.fN′
F11-	1761	PmN.fA.mU.fG.mG.fA.mU.fU.mA.fU.	2011	fA.mA.fA.mU.fA.mA.fU.mA.fA.mU.
11NM		mU.fA.mU.fU.mU.fC.mU.fU.mG		fC.mC.fA.mU.fN′
F11-	1762	PmN.fA.mG.fC.mC.fA.mG.fA.mU.fU.	2012	fU.mU.fU.mC.fU.mA.fA.mU.fC.mU.
12NM		mA.fG.mA.fA.mA.fG.mU.fG.mC		fG.mG.fC.mU.fN′
F11-	1763	PmN.fA.mG.fC.mG.fG.mA.fC.mG.fG.	2013	fC.mA.fA.mU.fG.mC.fC.mG.fU.mC.
13NM		mC.fA.mU.fU.mG.fG.mU.fG.mC		fG.mG.fC.mU.fN′
F11-	1764	PmN.fA.mU.fU.mU.fC.mA.fG.mA.fU.	2014	fA.mA.fU.mC.fA.mA.fU.mC.fU.mG.
14NM		mU.fG.mA.fU.mU.fU.mA.fA.mA		fA.mA.fA.mU.fA
F11-	1765	PmN.fU.mU.fG.mU.fC.mU.fC.mU.fU.	2015	fA.mA.fA.mC.fU.mA.fA.mG.fA.mG.
15NM		mA.fG.mU.fU.mUc.fU.mC.fU.mG		fA.mC.fA.mA.fN′
F11-	1766	PmN.fA.mG.fA.mA.fC.mA.fC.mU.fG.	2016	fC.mA.fU.mC.fC.mC.fA.mG.fU.mG.
16NM		mG.fG.mA.fU.mG.fC.mU.fG.mU		fU.mU.fC.mU.fN′
F11-	1767	PmN.fC.mC.fA.mC.fU.mU.fG.mA.fU.	2017	fC.mU.fU.mA.fU.mA.fU.mC.fA.mA.
17NM		mA.fU.mA.fA.mG.fA.mA.fA.mA		fG.mU.fG.mG.fN′
F11-	1768	PmN.fC.mA.fU.mU.fU.mU.fC.mU.fU.	2018	fU.mU.fU.mG.fU.mA.fA.mG.fA.mA.
18NM		mA.fC.mA.fA.mA.fC.mA.fC.mC		fA.mA.fU.mG.fN′
F11-	1769	PmN.fU.mA.fA.mU.fG.mC.fG.mU.fG.	2019	fC.mA.fG.mU.fA.mC.fA.mC.fG.mC.
19NM		mU.fA.mC.fU.mG.fG.mG.fC.mA		fA.mU.fU.mA.fN′
F11-	1770	PmN.fA.mG.fG.mA.fC.mA.fG.mA.fG.	2020	fA.mG.fG.mC.fC.mC.fU.mC.fU.mG.
20NM		mG.fG.mC.fC.mU.fC.mC.fC.mG		fU.mC.fC.mU.fN′
F11-	1771	PmN.fC.mA.fA.mC.fC.mG.fG.mG.fA.	2021	fC.mA.fU.mC.fA.mU.fC.mC.fC.mG.
21NM		mU.fG.mA.fU.mG.fA.mG.fU.mG		fG.mU.fU.mG.fN′
F11-	1772	PmN.fG.mA.fC.mA.fA.mA.fG.mA.fU.	2022	fA.mA.fG.mA.fA.mA.fU.mC.fU.mU.
22NM		mU.fU.mC.fU.mU.fU.mG.fA.mG		fU.mG.fU.mC.fN′
F11-	1773	PmN.fG.mA.fG.mG.fA.mA.fG.mC.fA.	2023	fC.mA.fG.mC.fA.mU.fG.mC.fU.mU.
23NM		mU.fG.mC.fU.mG.fG.mC.fA.mC		fC.mC.fU.mC.fN′
F11-	1774	PmN.fG.mG.fA.mA.fA.mA.fU.mG.fU.	2024	fU.mA.fG.mG.fG.mA.fC.mA.fU.mU.
24NM		mC.fC.mC.fU.mA.fA.mU.fA.mC		fU.mU.fC.mC.fN′
F11-	1775	PmN.fU.mU.fA.mA.fG.mU.fA.mA.fC.	2025	fC.mA.fA.mG.fU.mG.fU.mU.fA.mC.
25NM		mA.fC.mU.fU.mG.fC.mC.fC.mU		fU.mU.fA.mA.fN′
F11-	1776	PmN.fC.mA.fA.mU.fA.mU.fC.mA.fU.	2026	fC.mG.fG.mG.fU.mA.fU.mG.fA.mU.
26NM		mA.fC.mC.fC.mG.fC.mU.fU.mU		fA.mU.fU.mG.fN′
F11-	1777	PmN.fA.mA.fA.mU.fG.mU.fA.mC.fC.	2027	fC.mA.fA.mG.fU.mG.fG.mU.fA.mC.
27NM		mA.fC.mU.fU.mG.fA.mU.fA.mU		fA.mU.fU.mU.fN′
F11-	1778	PmN.fA.mG.fA.mA.fA.mA.fU.mC.fA.	2028	fC.mA.fG.mG.fA.mU.fG.mA.fU.mU.
28NM		mU.fC.mC.fU.mG.fA.mA.fA.mA		fU.mU.fC.mU.fN′
F11-	1779	PmN.fU.mA.fA.mC.fA.mC.fU.mU.fG.	2029	fA.mA.fG.mG.fG.mC.fA.mA.fG.mU.
29NM		mC.fC.mC.fU.mU.fC.mC.fC.mU		fG.mU.fU.mA.fN′
F11-	1780	PmN.fA.mG.fC.mA.fU.mU.fU.mU.fC.	2030	fU.mG.fU.mA.fA.mG.fA.mA.fA.mA.
30NM		mU.fU.mA.fC.mA.fA.mA.fC.mA		fU.mG.fC.mU.fN′
F11-	1781	PmN.fC.mA.fA.mA.fC.mA.fC.mC.fG.	2031	fU.mA.fA.mU.fA.mC.fG.mG.fU.mG.
31NM		mU.fA.mU.fU.mA.fG.mG.fG.mA		fU.mU.fU.mG.fN′
F11-	1782	PmN.fA.mG.fC.mG.fG.mC.fU.mG.fU.	2032	fU.mA.fU.mU.fA.mA.fC.mA.fG.mC.
32NM		mU.fA.mA.fU.mA.fU.mC.fC.mA		fC.mG.fC.mU.fN′
F11-	1783	PmN.fG.mA.fG.mC.fG.mG.fC.mU.fG.	2033	fA.mU.fU.mA.fA.mC.fA.mG.fC.mC.
33NM		mU.fU.mA.fA.mU.fA.mU.fC.mC		fG.mC.fU.mC.fN′
F11-	1784	PmN.fG.mA.fG.mA.fC.mA.fA.mA.fG.	2034	fG.mA.fA.mA.fU.mC.fU.mU.fU.mG.
34NM		mA.fU.mU.fU.mC.fU.mU.fU.mG		fU.mC.fU.mC.fN′
F11-	1785	PmN.fU.mG.fG.mG.fU.mU.fA.mU.fU.	2035	fC.mA.fU.mA.fA.mA.fA.mU.fA.mA.
35NM		mU.fU.mA.fU.mG.fU.mC.fC.mU		fC.mC.fC.mA.fN′
F11-	1786	PmN.fG.mA.fG.mC.fC.mA.fU.mG.fA.	2036	fC.mA.fG.mU.fG.mU.fC.mA.fU.mG.
36NM		mC.fA.mC.fU.mG.fU.mC.fG.mA		fG.mC.fU.mC.fN′
F11-	1787	PmN.fC.mA.fG.mA.fU.mU.fA.mG.fA.	2037	fC.mA.fC.mU.fU.mU.fC.mU.fA.mA.
37NM		mA.fA.mG.fU.mG.fC.mA.fC.mA		fU.mC.fU.mG.fN′
F11-	1788	PmN.fA.mG.fA.mA.fU.mA.fC.mC.fC.	2038	fU.mU.fU.mC.fU.mG.fG.mG.fU.mA.
38NM		mA.fG.mA.fA.mA.fU.mC.fG.mC		fU.mU.fC.mU.fN′
F11-	1789	PmN.fC.mA.fG.mA.fU.mG.fU.mU.fU.	2039	fC.mC.fU.mU.fA.mA.fA.mA.fC.mA.
39NM		mU.fA.mA.fG.mG.fA.mG.fA.mC		fU.mC.fU.mG.fN′
F11-	1790	PmN.fU.mG.fU.mA.fU.mC.fC.mA.fG.	2040	fC.mA.fU.mC.fU.mC.fU.mG.fG.mA.
40NM		mA.fG.mA.fU.mG.fC.mC.fU.mC		fU.mA.fC.mA.fN′
F11-	1791	PmN.fG.mA.fG.mU.fC.mA.fC.mA.fC.	2041	fU.mG.fA.mA.fU.mG.fU.mG.fU.mG.
41NM		mA.fU.mU.fC.mA.fC.mC.fA.mG		fA.mC.fU.mC.fN′
F11-	1792	PmN.fC.mA.fA.mA.fG.mA.fA.mA.fG.	2042	fC.mA.fC.mA.fU.mC.fU.mU.fU.mC.
42NM		mA.fU.mG.fU.mG.fU.mC.fC.mU		fU.mU.fU.mG.fN′
F11-	1793	PmN.fA.mC.fC.mA.fC.mU.fU.mG.fA.	2043	fU.mU.fA.mU.fA.mU.fC.mA.fA.mG.
43NM		mU.fA.mU.fA.mA.fG.mA.fA.mA		fU.mG.fG.mU.fN′
F11-	1794	PmN.fA.mA.fG.mA.fA.mA.fG.mC.fU.	2044	fC.mU.fU.mA.fA.mA.fG.mC.fU.mU.
44NM		mU.fU.mA.fA.mG.fU.mA.fA.mC		fU.mC.fU.mU.fN′
F11-	1795	PmN.fU.mU.fA.mU.fU.mU.fC.mA.fG.	2045	fU.mC.fA.mA.fU.mC.fU.mG.fA.mA.
45NM		mA.fU.mU.fG.mA.fU.mU.fU.mA		fA.mU.fA.mA.fN′
F11-	1796	PmN.fU.mG.fG.mU.fG.mU.fG.mA.fG.	2046	fC.mA.fA.mU.fG.mC.fU.mC.fA.mC.
46NM		mC.fA.mU.fU.mG.fC.mU.fU.mG		fA.mC.fC.mA.fN′
F11-	1797	PmN.fA.mU.fC.mA.fU.mC.fC.mU.fG.	2047	fC.mU.fU.mU.fU.mC.fA.mG.fG.mA.
47NM		mA.fA.mA.fA.mG.fA.mC.fC.mU		fU.mG.fA.mU.fN′
F11-	1798	PmN.fG.mU.fG.mA.fG.mC.fA.mU.fU.	2048	fC.mA.fA.mG.fC.mA.fA.mU.fG.mC.
48NM		mG.fC.mU.fU.mG.fA.mA.fA.mG		fU.mC.fA.mC.fN′
F11-	1799	PmN.fC.mU.fG.mU.fA.mU.fC.mU.fC.	2049	TC.mA.fG.mA.fA.mG.fA.mG.fA.mU.
49NM		mU.fU.mC.fU.mG.fG.mC.fA.mC		fA.mC.fA.mG.fN′
F11-	1800	PmN.fA.mC.fC.mU.fU.mA.fA.mU.fG.	2050	fA.mU.fA.mC.fA.mC.fA.mU.fU.mA.
50NM		mU.fG.mU.fA.mU.fC.mC.fA.mG		fA.mG.fG.mU.fN′
F11-	1801	PmN.fA.mU.fC.mA.fU.mG.fG.mA.fU.	2051	fU.mA.fA.mU.fA.mA.fU.mC.fC.mA.
51NM		mU.fA.mU.fU.mA.fU.mU.fU.mC		fU.mG.fA.mU.fN′
F11-	1802	PmN.fC.mA.fA.mA.fG.mA.fU.mU.fU.	2052	fC.mA.fA.mA.fG.mA.fA.mA.fU.mC.
52NM		mC.fU.mU.fU.mG.fA.mG.fA.mU		fU.mU.fU.mG.fN′
F11-	1803	PmN.fG.mA.fA.mG.fU.mA.fU.mU.fU.	2053	fA.mA.fC.mU.fA.mA.fA.mA.fU.mA.
53NM		mU.fA.mG.fU.mU.fG.mG.fA.mG		fC.mU.fU.mC.fN′
F11-	1804	PmN.fA.mG.fA.mU.fU.mG.fA.mU.fU.	2054	fU.mU.fU.mU.fA.mA.fA.mU.fC.mA.
54NM		mU.fA.mA.fA.mA.fU.mG.fC.mC		fA.mU.fC.mU.fN′
F11-	1805	PmN.fG.mG.fG.mU.fA.mU.fC.mU.fU.	2055	fA.mA.fG.mC.fC.mA.fA.mG.fA.mU.
55NM		mG.fG.mC.fU.mU.fU.mC.fU.mG		fA.mC.fC.mC.fN′
F11-	1806	PmN.fA.mG.fG.mA.fG.mA.fC.mA.fA.	2056	fA.mA.fU.mC.fU.mU.fU.mG.fU.mC.
56NM		mA.fG.mA.fU.mU.fU.mC.fU.mU		fU.mC.fC.mU.fN′
F11-	1807	PmN.fG.mU.fC.mA.fU.mG.fG.mU.fA.	2057	fC.mA.fU.mU.fU.mU.fA.mC.fC.mA.
57NM		mA.fA.mA.fU.mG.fA.mA.fG.mA		fU.mG.fA.mC.fN′
F11-	1808	PmN.fA.mU.fA.mU.fC.mC.fA.mG.fU.	2058	fG.mA.fA.mG.fA.mA.fC.mU.fG.mG.
58NM		mU.fC.mU.fU.mC.fU.mC.fC.mC		fA.mU.fA.mU.fN′
F11-	1809	PmN.fA.mA.fU.mA.fU.mC.fC.mA.fG.	2059	fA.mA.fG.mA.fA.mC.fU.mG.fG.mA.
59NM		mU.fU.mC.fU.mU.fC.mU.fC.mC		fU.mA.fU.mU.fN′
F11-	1810	PmN.fC.mU.fG.mU.fG.mG.fU.mU.fU.	2060	fA.mC.fU.mG.fG.mA.fA.mA.fC.mC.
60NM		mC.fC.mA.fG.mU.fU.mU.fC.mA		fA.mC.fA.mG.fN′
F11-	1811	PmN.fA.mG.fA.mU.fU.mA.fG.mA.fA.	2061	fG.mC.fA.mC.fU.mU.fU.mC.fU.mA.
61NM		mA.fG.mU.fG.mC.fA.mC.fA.mG		fA.mU.fC.mU.fN′
F11-	1812	PmN.fA.mG.fA.mA.fA.mU.fC.mA.fG.	2062	fU.mG.fA.mC.fA.mC.fU.mG.fA.mU.
62NM		mU.fG.mU.fC.mA.fU.mG.fG.mU		fU.mU.fC.mU.fN′
F11-	1813	PmN.fU.mG.fG.mA.fU.mU.fA.mU.fU.	2063	fG.mA.fA.mA.fU.mA.fA.mU.fA.mA.
63NM		mA.fU.mU.fU.mC.fU.mU.fG.mA		fU.mC.fC.mA.fN′
F11-	1814	PmN.fC.mC.fA.mG.fA.mU.fU.mA.fG.	2064	fA.mC.fU.mU.fU.mC.fU.mA.fA.mU.
64NM		mA.fA.mA.fG.mU.fG.mC.fA.mC		fC.mU.fG.mG.fN′
F11-	1815	PmN.fC.mU.fC.mA.fU.mU.fA.mU.fC.	2065	fA.mA.fA.mU.fG.mG.fA.mU.fA.mA.
65NM		mC.fA.mU.fU.mU.fU.mA.fC.mA		fU.mG.fA.mG.fN′
F11-	1816	PmN.fU.mU.fG.mG.fG.mC.fC.mA.fU.	2066	fC.mA.fG.mG.fA.mA.fU.mG.fG.mC.
66NM		mU.fC.mC.fU.mG.fG.mG.fA.mA		fC.mC.fA.mA.fN′
F11-	1817	PmN.fU.mG.fG.mG.f.mU.fU.mG.fA.	2067	fC.mA.fA.mA.fA.mU.fC.mA.fA.mG.
67NM		mU.fU.mU.fU.mG.fG.mU.fG.mG		fC.mC.fC.mA.fN′
F11-	1818	PmN.fC.mA.fG.mA.fU.mU.fG.mA.fU.	2068	fU.mU.fU.mA.fA.mA.fU.mC.fA.mA.
68NM		mU.fU.mA.fA.mA.fA.mU.fG.mC		fU.mC.fU.mG.fN′
F11-	1819	PmN.fA.mA.fG.mC.fA.mA.fC.mC.fG.	2069	fC.mA.fU.mC.fC.mC.fG.mG.fU.mU.
69NM		mG.fG.mA.fU.mG.fA.mU.fG.mA		fG.mC.fU.mU.fN′
F11-	1820	PmN.fC.mU.fU.mA.fA.mU.fG.mU.fG.	2070	fG.mG.fA.mU.fA.mC.fA.mC.fA.mU.
70NM		mU.fA.mU.fC.mC.fA.mG.fA.mG		fU.mA.fA.mG.fN′
F11-	1821	PmN.fG.mU.fA.mA.fU.mU.fC.mA.fC.	2071	fC.mC.fA.mC.fA.mG.fU.mG.fA.mA.
71NM		mU.fG.mU.fG.mG.fU.mU.fU.mC		fU.mU.fA.mC.fN′
F11-	1822	PmN.fA.mC.fA.mU.fU.mU.fC.mU.fA.	2072	fG.mG.fA.mG.fA.mU.fA.mG.fA.mA.
72NM		mU.fC.mU.fC.mC.fU.mU.fU.mG		fA.mU.fG.mU.fN′
F11-	1823	PmN.fC.mA.fC.mU.fG.mG.fU.mU.fU.	2073	fA.mU.fU.mG.fG.mA.fA.mA.fC.mC.
73NM		mC.fC.mA.fA.mU.fG.mA.fU.mG		fA.mG.fU.mG.fN′
F11-	1824	PmN.fG.mA.fA.mU.fC.mU.fG.mU.fG.	2074	fA.mA.fU.mU.fA.mC.fA.mC.fA.mG.
74NM		mU.fA.mA.fU.mU.fC.mA.fC.mU		fA.mU.fU.mC.fN′
F11-	1825	PmN.fG.mU.fC.mC.fU.mA.fU.mU.fC.	2075	fA.mG.fA.mG.fU.mG.fA.mA.fU.mA.
75NM		mA.fC.mU.fC.mU.fU.mG.fG.mC		fG.mG.fA.mC.fN′
F11-	1826	PmN.fA.mG.fC.mA.fU.mU.fG.mC.fU.	2076	fU.mU.fU.mC.fA.mA.fG.mC.fA.mA.
76NM		mU.fG.mA.fA.mA.fG.mA.fA.mU		fU.mG.fC.mU.fN′
F11-	1827	PmN.fA.mA.fU.mA.fC.mC.fC.mA.fG.	2077	fG.mA.fU.mU.fU.mC.fU.mG.fG.mG.
77NM		mA.fA.mA.fU.mC.fG.mC.fU.mG		fU.mA.fU.mU.fN′
F11-	1828	PmN.fA.mU.fU.mA.fU.mU.fA.mU.fU.	2078	fC.mA.fA.mG.fA.mA.fA.mU.fA.mA.
78NM		mU.fC.mU.fU.mG.fA.mA.fC.mC		fU.mA.fA.mU.fN′
F11-	1829	PmN.fA.mA.fG.mU.fA.mU.fU.mU.fU.	2079	fC.mA.fA.mC.fU.mA.fA.mA.fA.mU.
79NM		mA.fG.mU.fU.mG.fG.mA.fG.mA		fA.mC.fU.mU.fN′
F11-	1830	PmN.fG.mA.fA.mU.fC.mC.fA.mG.fU.	2080	fC.mG.fU.mG.fG.mA.fC.mU.fG.mG.
80NM		mC.fC.mA.fC.mG.fU.mA.fC.mU		fA.mU.fU.mC.fN′
F11-	1831	PmN.fA.mG.fA.mC.fA.mA.fA.mG.fA.	2081	fA.mG.fA.mA.fA.mU.fC.mU.fU.mU.
81NM		mU.fU.mU.fC.mU.fU.mU.fG.mA		fG.mU.fC.mU.fN′
F11-	1832	PmN.fA.mC.fA.mG.fG.mA.fU.mU.fU.	2082	fC.mA.fC.mU.fG.mA.fA.mA.fU.mC.
82NM		mC.fA.mG.fU.mG.fA.mA.fA.mA		fC.mU.fG.mU.fN′
F11-	1833	PmN.fA.mA.fC.mA.fA.mG.fG.mC.fA.	2083	fG.mA.fU.mA.fU.mU.fG.mC.fC.mU.
83NM		mA.fU.mA.fU.mC.fA.mU.fA.mC		fU.mG.fU.mU.fN′
F11-	1834	PmN.fA.mA.fG.mG.fC.mA.fA.mU.fA.	2084	fU.mA.fU.mG.fA.mU.fA.mU.fU.mG.
84NM		mU.fC.mA.fU.mA.fC.mC.fC.mG		fC.mC.fU.mU.fN′
F11-	1835	PmN.fA.mU.fA.mC.fC.mC.fA.mG.fA.	2085	fC.mG.fA.mU.fU.mU.fC.mU.fG.mG.
85NM		mA.fA.mU.fC.mG.fC.mU.fG.mC		fG.mU.fA.mU.fN′
F11-	1836	PmN.fG.mA.fU.mU.fG.mA.fU.mU.fU.	2086	fA.mU.fU.mU.fU.mA.fA.mA.fU.mC.
86NM		mA.fA.mA.fA.mU.fG.mC.fC.mA		fA.mA.fU.mC.fN′
F11-	1837	PmN.fC.mC.fU.mA.fU.mU.fC.mA.fC.	2087	fC.mA.fA.mG.fA.mG.fU.mG.fA.mA.
87NM		mU.fC.mU.fU.mG.fG.mC.fA.mG		fU.mA.fG.mG.fN′
F11-	1838	PmN.fG.mU.fA.mG.fA.mC.fA.mC.fG.	2088	fU.mU.fU.mU.fG.mC.fG.mU.fG.mU.
88NM		mC.fA.mA.fA.mA.fU.mC.fU.mU		fC.mU.fA.mC.fN′
F11-	1839	PmN.fU.mG.fA.mG.fU.mU.fU.mU.fC.	2089	fC.mU.fG.mG.fA.mG.fA.mA.fA.mA.
89NM		mU.fC.mC.fA.mG.fA.mA.fU.mC		fC.mU.fC.mA.fN′
F11-	1840	PmN.fA.mU.fU.mU.fC.mU.fU.mU.fG.	2090	fA.mA.fU.mC.fU.mC.fA.mA.fA.mG.
90NM		mA.fG.mA.fU.mU.fC.mU.fU.mU		fA.mA.fA.mU.fN′
F11-	1841	PmN.fU.mA.fU.mA.fA.mG.fA.mA.fA.	2091	fA.mU.fG.mA.fU.mU.fU.mU.fC.mU.
91NM		mA.fU.mC.fA.mU.fC.mC.fU.mG		fU.mA.fU.mA.fN′
F11-	1842	PmN.fA.mA.fA.mA.fU.mC.fU.mU.fA.	2092	fU.mC.fA.mC.fC.mU.fA.mA.fG.mA.
92NM		mG.fG.mU.fG.mA.fC.mU.fC.mU		fU.mU.fU.mU.fN′
F11-	1843	PmN.fA.mC.fA.mC.fU.mG.fG.mG.fA.	2093	fC.mA.fG.mC.fA.mU.fC.mC.fC.mA.
93NM		mU.fG.mC.fU.mG.fU.mG.fC.mC		fG.mU.fG.mU.fN′
F11-	1844	PmN.fU.mG.fC.mA.fC.mA.fG.mG.fA.	2094	fU.mG.fA.mA.fA.mU.fC.mC.fU.mG.
94NM		mUfU.mU.fC.mA.fG.mU.fG.mA		fU.mG.fC.mA.fN′
F11-	1845	PmN.fA.mU.fA.mC.fA.mA.fG.mC.fC.	2095	fA.mA.fU.mC.fU.mG.fG.mC.fU.mU.
95NM		mA.fG.mA.fU.mU.fA.mG.fA.mA		fG.mU.fA.mU.fN′
F11-	1846	PmN.fU.mG.fU.mG.fG.mU.fU.mU.fC.	2096	fA.mA.fC.mU.fG.mG.fA.mA.fA.mC.
96NM		mC.fA.mG.fU.mU.fU.mC.fA.mA		fC.mA.fC.mA.fN′
F11-	1847	PmN.fU.mG.fC.mC.fC.mU.fU.mC.fC.	8207	fC.mG.fA.mA.fG.mG.fG.mA.fA.mG.
97NM		mC.fU.mU.fC.mG.fU.mU.fG.mC		fG.mG.fC.mA.fN′
F11-	1848	PmN.fA.mA.fA.mA.fU.mC.fA.mU.fC.	2098	fU.mU.fC.mA.fG.mG.fA.mU.fG.mA.
98NM		mC.fU.mG.fA.mA.fA.mA.fG.mA		fU.mU.fU.mU.fN′
F11-	1849	PmN.fC.mC.fA.mA.fG.mA.fA.mA.fU.	2099	fC.mA.fC.mU.fG.mA.fU.mU.fU.mC.
99NM		mC.fA.mG.fU.mG.fU.mC.fA.mU		fU.mU.fG.mG.fN′
F11-	1850	PmN.fG.mG.fC.mA.fU.mA.fU.mG.fG.	2100	fA.mC.fG.mA.fC.mC.fC.mA.fU.mA.
100NM		mG.fU.mC.fG.mU.fU.mG.fA.mG		fU.mG.fC.mC.fN′
F11-	1851	PmN.fA.mG.fA.mA.fU.mC.fU.mG.fU.	2101	fA.mU.fU.mA.fC.mA.fC.mA.fG.mA.
101NM		mG.fU.mA.fA.mU.fU.mC.fA.mC		fU.mU.fC.mU.fN′
F11-	1852	PmN.fA.mU.fC.mC.fA.mG.fU.mC.fC.	2102	fU.mA.fC.mG.fU.mG.fG.mA.fC.mU.
102NM		mA.fC.mG.fU.mA.fC.mU.fC.mG		fG.mG.fA.mU.fN′
F11-	1853	PmN.fC.mC.fU.mC.fU.mG.fU.mA.fU.	2103	fA.mA.fG.mA.fG.mA.fU.mA.fC.mA.
103NM		mC.fU.mC.fU.mU.fC.mU.fG.mG		fG.mA.fG.mG.fN′
F11-	1854	PmN.fG.mC.fA.mC.fA.mG.fG.mA.fU.	2104	fC.mU.fG.mA.fA.mA.fU.mC.fC.mU.
104NM		mU.fU.mC.fA.mG.fU.mG.fA.mA		fG.mU.fG.mC.fN′
F11-	1855	PmN.fG.mU.fA.mA.fA.mA.fU.mG.fA	2105	fA.mU.fU.mC.fU.mU.fC.mA.fU.mU.
105NM		mA.fG.mA.fA.mU.fG.mG.fC.mA		fU.mU.fA.mC.fN′
F11-	1856	PmN.fG.mU.fC.mG.fU.mU.fG.mA.fG.	2106	fA.mG.fA.mU.fU.mC.fU.mC.fA.mA.
106NM		mA.fA.mU.fC.mU.fG.mU.fG.mU		fC.mG.fA.mC.fN′
F11-	1857	PmN.fG.mC.fA.mA.fC.mA.fA.mU.fA.	2107	fC.mU.fG.mG.fA.mU.fA.mU.fU.mG.
107NM		mU.fC.mC.fA.mG.fU.mU.fC.mU		fU.mU.fG.mC.fN′
F11-	1858	PmN.fC.mA.fG.mC.fG.mG.fA.mC.fG.	2108	fA.mA.fU.mG.fC.mC.fG.mU.fC.mC.
108NM		mG.fC.mA.fU.mU.fG.mG.fU.mG		fG.mC.fU.mG.fN′
F11-	1859	PmN.fG.mA.fA.mA.fG.mC.fU.mU.fU.	2109	fU.mA.fC.mU.fU.mA.fA.mA.fG.mC.
109NM		mA.fA.mG.fU.mA.fA.mC.fA.mC		fU.mU.fU.mC.fN′
F11-	1860	PmN.fG.mC.fA.mG.fU.mG.fU.mU.fU.	2110	fU.mA.fC.mA.fG.mA.fA.mA.fC.mA.
110NM		mC.fU.mG.fU.mA.fA.mC.fA.mC		fC.mU.fG.mC.fN′
F11-	1861	PmN.fG.mA.fG.mA.fA.mU.fC.mU.fG.	2111	fU.mU.fA.mC.fA.mC.fA.mG.fA.mU.
111NM		mU.fG.mU.fA.mA.fU.mU.fC.mA		fU.mC.fU.mC.fN′
F11-	1862	PmN.fU.mC.fC.mA.fG.mU.fC.mC.fA.	2112	fG.mU.fA.mC.fG.mU.fG.mG.fA.mC.
112NM		mC.fG.mU.fA.mC.fU.mC.fG.mA		fU.mG.fG.mA.fN′
F11-	1863	PmN.fU.mG.fU.mG.fA.mG.fC.mA.fU.	2113	fA.mA.fG.mC.fA.mA.fU.mG.fC.mU.
113NM		mU.fG.mC.fU.mU.fG.mA.fA.mA		fC.mA.fC.mA.fN′
F11-	1864	PmN.fC.mC.fG.mG.fG.mA.fU.mG.fA.	2114	fA.mC.fU.mC.fA.mU.fC.mA.fU.mC.
114NM		mU.fG.mA.fG.mU.fG.mC.fA.mG		fC.mC.fG.mG.fN′
F11-	1865	PmN.fC.mC.fA.mC.fU.mU.fU.mA.fU.	2115	fG.mC.fU.mC.fG.mA.fU.mA.fA.mA.
115NM		mC.fG.mA.fG.mC.fU.mU.fC.mG		fG.mU.fG.mG.fN′
F11-	1866	PmN.fC.mA.fU.mU.fA.mU.fC.mC.fA.	2116	fU.mA.fA.mA.fA.mU.fG.mG.fA.mU.
116NM		mU.fU.mU.fU.mA.fC.mA.fC.mA		fA.mA.fU.mG.fN′
F11-	1867	PmN.fA.mA.fC.mC.fG.mG.fG.mA.fU.	2117	fU.mC.fA.mU.fC.mA.fU.mC.fC.mC.
117NM		mG.fA.mU.fG.mA.fG.mU.fG.mC		fG.mG.fU.mU.fN′
F11-	1868	PmN.fU.mU.fC.mU.fU.mU.fG.mG.fG.	2118	fA.mA.fU.mG.fG.mC.fC.mC.fA.mA.
118NM		mC.fC.mA.fU.mU.fC.mC.fU.mG		fA.mG.fA.mA.fN′
F11-	1869	PmN.fC.mU.fA.mA.fG.mG.fG.mU.fA.	2119	fC.mA.fA.mG.fA.mU.fA.mC.fC.mC.
119NM		mU.fC.mU.fU.mG.fG.mC.fU.mU		fU.mU.fA.mG.fN′
F11-	1870	PmN.fU.mU.fG.mG.fU.mG.fU.mG.fA.	2120	fA.mA.fU.mG.fC.mU.fC.mA.fC.mA.
120NM		mG.fC.mA.fU.mU.fG.mC.fU.mU		fC.mC.fA.mA.fN′
F11-	1871	PmN.fC.mA.fU.mA.fU.mG.fG.mG.fU.	2121	fC.mA.fA.mC.fG.mA.fC.mC.fC.mA.
121NM		mC.fG.mU.fU.mG.fA.mG.fA.mA		fU.mA.fU.mG.fN′
F11-	1872	PmN.fU.mU.fA.mA.fU.mG.fU.mG.fU.	2122	fU.mG.fG.mA.fU.mA.fC.mA.fC.mA.
122NM		mA.fU.mC.fC.mA.fG.mA.fG.mA		fU.mU.fA.mA.fN′
F11-	1873	PmN.fU.mC.fA.mG.fA.mU.fG.mU.fU.	2123	fC.mU.fU.mA.fA.mA.fA.mC.fA.mU.
123NM		mU.fU.mA.fA.mG.fG.mA.fG.mA		fC.mU.fG.mA.fN′
F11-	1874	PmN.fU.mU.fC.mC.fA.mA.fU.mG.fA.	2124	fC.mU.fC.mC.fA.mU.fC.mA.fU.mU.
124NM		mU.fG.mG.fA.mG.fC.mC.fU.mC		fG.mG.fA.mA.fN′
F11-	1875	PmN.fA.mG.fA.mA.fU.mC.fC.mA.fG.	2125	fG.mU.fG.mG.fA.mC.fU.mG.fG.mA.
125NM		mU.fC.mC.fA.mC.fG.mU.fA.mC		fU.mU.fC.mU.fN′
F11-	1876	PmN.fU.mU.fU.mG.fA.mG.fA.mU.fU.	2126	fC.mA.fA.mA.fG.mA.fA.mU.fC.mU.
126NM		mC.fU.mU.fU.mG.fG.mG.fC.mC		fC.mA.fA.mA.fN′
F11-	1877	PmN.fA.mA.fU.mC.fA.mU.fC.mC.fU.	2127	fU.mU.fU.mU.fC.mA.fG.mG.fA.mU.
127NM		mG.fA.mA.fA.mA.fG.mA.fC.mC		fG.mA.fU.mU.fN′
F11-	1878	PmN.fA.mG.fA.mC.fA.mC.fG.mC.fA.	2128	fG.mA.fU.mU.fU.mU.fG.mC.fG.mU.
128NM		mA.fA.mA.fU.mC.fU.mU.fA.mG		fG.mU.fC.mU.fN′
F11-	1879	PmN.fC.mG.fU.mA.fC.mU.fC.mG.fA.	2129	fC.mG.fU.mG.fG.mU.fC.mG.fA.mG.
129NM		mC.fC.mA.fC.mG.fU.mU.fG.mG		fU.mA.fC.mG.fN′
F11-	1880	PmN.fC.mA.fU.mC.fC.mA.fG.mU.fC.	2130	fU.mG.fG.mG.fU.mG.fA.mC.fU.mG.
130NM		mA.fC.mC.fC.mA.fG.mC.fA.mA		fG.mA.fU.mG.fN′
F11-	1881	PmN.fA.mA.fC.mA.fC.mU.fG.mG.fG.	2131	fA.mG.fC.mA.fU.mC.fC.mC.fA.mG.
131NM		mA.fU.mG.fC.mU.fG.mU.fG.mC		fU.mG.fU.mU.fN′
F11-	1882	PmN.fC.mA.fG.mA.fA.mA.fG.mA.fG.	2132	fC.mA.fA.mA.fG.mC.fU.mC.fU.mU.
132NM		mC.fU.mU.fU.mG.fC.mU.fC.mU		fU.mC.fU.mG.fN′
F11-	1883	PmN.fU.mU.fC.mU.fU.mU.fG.mA.fG.	2133	fA.mG.fA.mA.fU.mC.fU.mC.fA.mA.
133NM		mA.fU.mU.fC.mU.fU.mU.fG.mG		fA.mG.fA.mA.fN′
F11-	1884	PmN.fA.mG.fC.mA.fA.mC.fA.mA.fU.	2134	fU.mG.fG.mA.fU.mA.fU.mU.fG.mU.
134NM		mA.fU.mC.fC.mA.fG.mU.fU.mC		fU.mG.fC.mU.fN′
F11-	1885	PmN.fA.mC.fC.mA.fC.mU.fU.mU.fA.	2135	fC.mU.fC.mG.fA.mU.fA.mA.fA.mG.
135NM		mU.fC.mG.fA.mG.fC.mU.fU.mC		fU.mG.fG.mU.fN′
F11-	1886	PmN.fC.mC.fC.mU.fU.mC.fC.mC.fU.	2136	fA.mA.fC.mG.fA.mA.fG.mG.fG.mA.
136NM		mU.fC.mG.fU.mU.fG.mC.fA.mG		fA.mG.fG.mG.fN′
F11-	1887	PmN.fC.mG.fC.mA.fA.mA.fA.mU.fC.	2137	fC.mC.fU.mA.fA.mG.fA.mU.fU.mU.
137NM		mU.fU.mA.fG.mG.fU.mG.fA.mC		fU.mG.fC.mG.fN′
F11-	1888	PmN.fA.mG.fC.mG.fU.mG.fU.mU.fA.	2138	fC.mA.fC.mA.fG.mU.fA.mA.fC.mA.
138NM		mC.fU.mG.fU.mG.fG.mA.fG.mG		fC.mG.fC.mU.fN′
F11-	1889	PmN.fC.mU.fC.mC.fU.mU.fC.mC.fC.	2139	fC.mU.fA.mC.fA.mG.fG.mG.fA.mA.
139NM		mU.fG.mU.fA.mG.fC.mC.fG.mG		fG.mG.fA.mG.fN′
F11-	1890	PmN.fG.mU.fC.mC.fU.mC.fU.mG.fU.	2140	fG.mA.fG.mA.fU.mA.fC.mA.fG.mA.
140NM		mA.fU.mC.fU.mC.fU.mU.fC.mU		fG.mG.fA.mC.fN′
F11-	1891	PmN.fG.mU.fA.mU.fC.mU.fU.mG.fG.	2141	fG.mA.fA.mA.fG.mC.fC.mA.fA.mG.
141NM		mC.fU.mU.fU.mC.fU.mG.fG.mA		fA.mU.fA.mC.fN′
F11-	1892	PmN.fC.mU.fC.mU.fU.mG.fG.mC.fA.	2142	fA.mA.fC.mA.fC.mU.fG.mC.fC.mA.
142NM		mG.fU.mG.fU.mU.fU.mC.fU.mG		fA.mG.fA.mG.fN′
F11-	1893	PmN.fG.mA.fA.mA.fU.mC.fA.mG.fU.	2143	fA.mU.fG.mA.fC.mA.fC.mU.fG.mA.
143NM		mG.fU.mC.fA.mU.fG.mG.fU.mA		fU.mU.fU.mC.fN′
F11-	1894	PmN.fC.mU.fU.mC.fC.mC.fU.mG.fU.	2144	fC.mG.fG.mC.fU.mA.fC.mA.fG.mG.
144NM		mA.fG.mC.fC.mG.fG.mC.fA.mC		fG.mA.fA.mG.fN′
F11-	1895	PmN.fC.mU.fG.mG.fC.mC.fG.mC.fU.	2145	fA.mA.fG.mG.fG.mA.fG.mC.fG.mG.
145NM		mC.fC.mC.fU.mU.fU.mG.fA.mG		fC.mC.fA.mG.fN′
F11-	1896	PmN.fC.mA.fC.mG.fC.mA.fA.mA.fA.	2146	fU.mA.fA.mG.fA.mU.fU.mU.fU.mG.
146NM		mU.fC.mU.fU.mA.fG.mG.fU.mG		fC.mG.fU.mG.fN′
F11-	1897	PmN.fG.mA.fA.mA.fC.mC.fA.mG.fA.	2147	fC.mU.fC.mU.fU.mU.fC.mU.fG.mG.
147NM		mA.fA.mG.fA.mG.fC.mU.fU.mU		fU.mU.fU.mC.fN′
F11-	1898	PmN.fA.mA.fA.mG.fC.mU.fU.mU.fA.	2148	fU.mU.fA.mC.fU.mU.fA.mA.fA.mG.
148NM		mA.fG.mU.fA.mA.fC.mA.fC.mU		fC.mU.fU.mU.fN′
F11-	1899	PmN.fA.mC.fA.mA.fG.mC.fC.mA.fG.	2149	fC.mU.fA.mA.fU.mC.fU.mG.fG.mC.
149NM		mA.fU.mU.fA.mG.fA.mA.fA.mG		fU.mU.fG.mU.fN′
F11-	1900	PmN.fA.mC.fU.mC.fA.mU.fU.mA.fU.	2150	fA.mA.fU.mG.fG.mA.fU.mA.fA.mU.
150NM		mC.fC.mA.fU.mU.fU.mU.fA.mC		fG.mA.fG.mU.fN′
F11-	1901	PmN.fC.mC.fU.mG.fA.mA.fA.mA.fG.	2151	fA.mA.fG.mG.fU.mC.fU.mU.fU.mU.
151NM		mA.fC.mC.fU.mU.fG.mU.fU.mG		fC.mA.fG.mG.fN′
F11-	1902	PmN.fG.mG.fU.mU.fU.mC.fC.mA.fA.	2152	fC.mA.fU.mC.fA.mU.fU.mG.fG.mA.
152NM		mU.fG.mA.fU.mG.fG.mA.fG.mC		fA.mA.fC.mC.fN′
F11-	1903	PmN.fC.mA.fG.mU.fU.mU.fC.mU.fG.	2153	fC.mC.fU.mG.fC.mC.fA.mG.fA.mA.
153NM		mG.fC.mA.fG.mG.fC.mC.fU.mC		fA.mC.fU.mG.fN′
F11-	1904	PmN.fA.mU.fG.mG.fC.mA.fG.mA.fA.	2154	fC.mA.fG.mU.fG.mU.fU.mC.fU.mG.
154NM		mC.fA.mC.fU.mG.fG.mG.fA.mU		fC.mC.fA.mU.fN′
F11-	1905	PmN.fA.mG.fA.mU.fU.mU.fC.mU.fU.	2155	fU.mC.fU.mC.fA.mA.fA.mG.fA.mA.
155NM		mU.fG.mA.fG.mA.fU.mU.fC.mU		fA.mU.fC.mU.fN′
F11-	1906	PmN.fG.mU.fU.mU.fC.mC.fA.mG.fU.	2156	fU.mU.fG.mA.fA.mA.fC.mU.fG.mG.
156NM		mU.fU.mC.fA.mA.fC.mA.fA.mG		fA.mA.fA.mC.fN′
F11-	1907	PmN.fU.mC.fC.mU.fC.mU.fG.mU.fA.	2157	fA.mG.fA.mG.fA.mU.fA.mC.fA.mG.
157NM		mU.fC.mU.fC.mU.fU.mC.fU.mG		fA.mG.fG.mA.fN′
F11-	1908	PmN.fC.mA.fU.mC.fC.mU.fG.mA.fA.	2158	fG.mU.fC.mU.fU.mU.fU.mC.fA.mG.
158NM		mA.fA.mG.fA.mC.fC.mU.fU.mG		fG.mA.fU.mG.fN′
F11-	1909	PmN.fU.mU.fG.mA.fG.mU.fU.mU.fU.	2159	fU.mG.fG.mA.fG.mA.fA.mA.fA.mC.
159NM		mC.fU.mC.fC.mA.fG.mA.fA.mU		fU.mC.fA.mA.fN′
F11-	1910	PmN.fA.mA.fU.mU.fC.mA.fC.mU.fG.	2160	fA.mA.fC.mC.fA.mC.fA.mG.fU.mG.
160NM		mU.fG.mG.fU.mU.fU.mC.fC.mA		fA.mA.fU.mU.fN′
F11-	1911	PmN.fA.mA.fG.mA.fU.mU.fU.mC.fU.	2161	fC.mU.fC.mA.fA.mA.fG.mA.fA.mA.
161NM		mU.fU.mG.fA.mG.fA.mU.fU.mC		fU.mC.fU.mU.fN′
F11-	1912	PmN.fG.mG.fA.mG.fA.mC.fA.mA.fA.	2162	fA.mA.fA.mU.fC.mU.fU.mU.fG.mU.
162NM		mG.fA.mU.fU.mU.fC.mU.fU.mU		fC.mU.fC.mC.fN′
F11-	1913	PmN.fG.mA.fA.mA.fA.mU.fC.mA.fU.	2163	fU.mC.fA.mG.fG.mA.fU.mG.fA.mU.
163NM		mC.fC.mU.fG.mA.fA.mA.fA.mG		fU.mU.fU.mC.fN′
F11-	1914	PmN.fC.mU.fU.mU.fC.mU.fG.mC.fC.	2164	fA.mA.fA.mA.fU.mG.fG.mC.fA.mG.
164NM		mA.fU.mU.fU.mU.fA.mU.fA.mC		fA.mA.fA.mG.fN′
F11-	1915	PmN.fA.mG.fU.mC.fC.mA.fC.mG.fU.	2165	fC.mG.fA.mG.fU.mA.fC.mG.fU.mG.
165NM		mA.fC.mU.fC.mG.fA.mC.fC.mA		fG.mA.fC.mU.fN′
F11-	1916	PmN.fU.mU.fA.mA.fU.mG.fC.mG.fU.	2166	fA.mG.fU.mA.fC.mA.fC.mG.fC.mA.
166NM		mG.fU.mA.fC.mU.fG.mG.fG.mC		fU.mU.fA.mA.fN′
F11-	1917	PmN.fU.mA.fA.mU.fG.mU.fG.mU.fA.	2167	fC.mU.fG.mG.fA.mU.fA.mC.fA.mC.
167NM		mU.fC.mC.fA.mG.fA.mG.fA.mU		fA.mU.fU.mA.fN′
F11-	1918	PmN.fG.mA.fU.mU.fC.mU.fU.mU.fG.	2168	fU.mG.fG.mC.fC.mC.fA.mA.fA.mG.
168NM		mG.fG.mC.fC.mA.fU.mU.fC.mC		fA.mA.fU.mC.fN′
F11-	1919	PmN.fU.mG.fA.mA.fA.mC.fC.mA.fG.	2169	fU.mC.fU.mU.fU.mC.fU.mG.fG.mU.
169NM		mA.fA.mA.fG.mA.fG.mC.fU.mU		fU.mU.fC.mA.fN′
F11-	1920	PmN.fC.mA.fC.mA.fC.mA.fU.mU.fC.	2170	fC.mU.fG.mG.fU.mG.fA.mA.fU.mG.
170NM		mA.fC.mC.fA.mG.fA.mA.fA.mC		fU.mG.fU.mG.fN′
F11-	1921	PmN.fA.mC.fA.mA.fA.mG.fA.mU.fU.	2171	fA.mA.fA.mG.fA.mA.fA.mU.fC.mU.
171NM		mU.fC.mU.fU.mU.fG.mA.fG.mA		fU.mU.fG.mU.fN′
F11-	1922	PmN.fC.mA.fU.mU.fU.mC.fU.mA.fU.	2172	fA.mG.fG.mA.fG.mA.fU.mA.fG.mA.
172NM		mC.fU.mC.fC.mU.fU.mU.fG.mG		fA.mA.fU.mG.fN′
F11-	1923	PmN.fU.mU.fU.mC.fU.mG.fU.mA.fA.	2173	fC.mA.fG.mU.fG.mU.fU.mA.fC.mA.
173NM		mC.fA.mC.fU.mG.fU.mC.fU.mU		fG.mA.fA.mA.fN′
F11-	1924	PmN.fG.mG.fA.mU.fU.mU.fC.mA.fG.	2174	fU.mU.fU.mC.fA.mC.fU.mG.fA.mA.
174NM		mU.fG.mA.fA.mA.fA.mU.fC.mC		fA.mU.fC.mC.fN′
F11-	1925	PmN.fC.mG.fC.mU.fC.mC.fC.mU.fU.	2175	fG.mC.fU.mC.fA.mA.fA.mG.fG.mG.
175NM		mU.fG.mA.fG.mC.fA.mC.fA.Mg		fA.mG.fC.mG.fN′
F11-	1926	PmN.fC.mA.fG.mU.fC.mC.fA.mC.fG.	2176	fG.mA.fG.mU.fA.mC.fG.mU.fG.mG.
176NM		mU.fA.mC.fUn.mC.fG.mA.fC.mC		fA.mC.fU.mG.fN′
F11-	1927	PmN.fA.mG.fG.mC.fA.mU.fA.mU.fG.	2177	fC.mG.fA.mC.fC.mC.fA.mU.fA.mU.
177NM		mG.fG.mU.fC.mG.fU.mU.fG.mA		fG.mC.fC.mU.fN′
F11-	1928	PmN.fA.mU.fG.mU.fC.mC.fU.mC.fU.	2178	fG.mA.fU.mA.fC.mA.fG.mA.fG.mG.
178NM		mG.fU.mA.fU.mC.fU.mC.fU.mU		fA.mC.fA.mU.fN′
F11-	1929	PmN.fG.mC.fU.mU.fG.mA.fU.mU.fU.	2179	fC.mA.fC.mC.fA.mA.fA.mA.fU.mC.
179NM		mU.fG.mG.fU.mG.fG.mU.fA.mC		fA.mA.fG.mC.fN′
F11-	1930	PmN.fA.mU.fG.mA.fU.mG.fG.mA.fG.	2180	fG.mG.fA.mG.fG.mC.fU.mC.fC.mA.
180NM		mC.fC.mU.fC.mC.fA.mC.fA.mC		fU.mC.fA.mU.fN′
F11-	1931	PmN.fU.mC.fG.mU.fU.mG.fA.mG.fA.	2181	fC.mA.fG.mA.fU.mU.fC.mU.fC.mA.
181NM		mA.FU.mC.fU.mG.fU.mG.fU.mA		fA.mC.fG.mA.fN′
F11-	1932	PmN.fU.mU.fA.mU.fC.mC.fA.mU.fU.	2182	fU.mG.fU.mA.fA.mA.fA.mU.fG.mG.
182NM		mU.fU.mA.fC.mA.fC.mA.fA.mC		fA.mU.fA.mA.fN′
F11-	1933	PmN.fU.mG.fU.mC.fC.mU.fA.mU.fU.	2183	fG.mA.fG.mU.fG.mA.fA.mU.fA.mG.
183NM		mC.fA.mC.fU.mC.fU.mU.fG.mG		fG.mA.fC.mA.fN′
F11-	1934	PmN.fC.mA.fA.mU.fA.mU.fC.mC.fA.	2184	fA.mG.fA.mA.fC.mU.fG.mG.fA.mU.
184NM		mG.fU.mU.fC.mU.fU.mC.fU.mC		fA.mU.fU.mG.fN′
F11-	1935	PmN.fC.mU.fU.mU.fG.mA.fG.mA.fU.	2185	fA.mA.fA.mG.fA.mA.fU.mC.fU.mC.
185NM		mU.fC.mU.fU.mU.fG.mG.fG.mC		fA.mA.fA.mG.fN′
F11-	1936	PmN.fC.mA.fC.mU.fC.mU.fU.mG.fG.	2186	fC.mA.fC.mU.fG.mC.fC.mA.fA.mG.
186NM		mC.fA.mG.fU.mG.fU.mU.fU.mC		fA.mG.fU.mG.fN′
F11-	1937	PmN.fC.mU.fU.mG.fA.mA.fA.mG.fA.	2187	fG.mG.fU.mA.fU.mU.fC.mU.fU.mU.
187NM		mA.fU.mA.fC.mC.fC.mA.fG.mA		fC.mA.fA.mG.fN′
F11-	1938	PmN.fA.mG.fG.mC.fA.mA.fU.mA.fU.	2188	fG.mU.fA.mU.fG.mA.fU.mA.fU.mU.
188NM		mC.fA.mU.fA.mC.fC.mC.fG.mC		fG.mC.fC.mU.fN′
F11-	1939	PmN.fC.mU.fG.mU.fG.mU.fA.mA.fU.	2189	fA.mG.fU.mG.fA.mA.fU.mU.fA.mC.
189NM		mU.fC.mA.fC.mU.fG.mU.fG.mG		fA.mC.fA.mG.fN′
F11-	1940	PmN.fA.mA.fU.mA.fU.mC.fC.mA.fC.	92190	fA.mA.fC.mC.fA.mG.fU.mG.fG.mA.
190NM		mU.fG.mG.fU.mU.fU.mC.fC.mA		fU.mA.fU.mU.fN′
F11-	1941	PmN.fU.mG.fA.mA.fA.mG.fA.mA.fU.	2191	fU.mG.fG.mG.fU.mA.fU.mU.fC.mU.
191NM		mA.fC.mC.fC.mA.fG.mA.fA.mA		fU.mU.fC.mA.fN′
F11-	1942	PmN.fG.mU.fU.mA.fA.mU.fA.mU.fC.	2192	fC.mA.fG.mU.fG.mG.fA.mU.fA.mU.
192NM		mC.fA.mC.fU.mG.fG.mU.fU.mU		fU.mA.fA.mC.fN′
F11-	1943	PmN.fU.mG.fU.mC.fA.mU.fG.mG.fU.	2193	fA.mU.fU.mU.fU.mA.fC.mC.fA.mU.
193NM		mA.fA.mA.fA.mU.fG.mA.fA.mG		fG.mA.fC.mA.fN′
F11-	1944	PmN.fA.mU.fU.mC.fU.mU.fU.mG.fG.	2194	fA.mU.fG.mG.fC.mC.fC.mA.fA.mA.
194NM		mG.fC.mC.fA.mU.fU.mC.fC.mU		fG.mA.fA.mU.fN′
F11-	1945	PmN.fC.mA.fG.mU.fU.mC.fC.mU.fC.	2195	fC.mG.fU.mU.fG.mG.fA.mG.fG.mA.
195NM		mC.fA.mA.fC.mG.fA.mU.fC.mC		fA.mG.fU.mG.fN′
F11-	1946	PmN.fG.mG.fG.mU.fG.mU.fG.mC.	2196	fA.mC.fU.mG.fA.mA.fG.mC.fA.mC.
196NM		fU.mU.fC.mA.fG.mU.fA.mG.fA.mC		fA.mC.fC.mC.fN′
F11-	1947	PmN.fG.mA.fA.mG.fA.mA.fA.mG.fC.	2197	fU.mU.fA.mA.fA.mG.fC.mU.fU.mU.
197NM		mU.fU.mU.fA.mA.fG.mU.fA.mA		fC.mU.fU.mC.fN′
F11-	1948	PmN.fA.mU.fC.mC.fU.mG.fA.mA.fA.	2198	fG.mG.fU.mC.fU.mU.fU.mU.fC.mA.
198NM		mA.fG.mA.fC.mC.fU.mU.fG.mU		fG.mG.fA.mU.fN′
F11-	1949	PmN.fA.mG.fA.mA.fA.mG.fC.mU.fU.	2199	fA.mC.fU.mU.fA.mA.fA.mG.fC.mU.
199NM		mU.fA.mA.fG.mU.fA.mA.fC.mA		fU.mU.fC.mU.fN′
F11-	1950	PmN.fC.mA.fG.mU.fG.mU.fU.mU.fC.	2200	fU.mU.fA.mC.fA.mG.fA.mA.fA.mC.
200NM		mU.fG.mU.fA.mA.fC.mA.fC.mU		fA.mC.fU.mG.fN′
F11-	1951	PmN.fG.mA.fC.mA.fC.mG.fC.mA.fA.	2201	fA.mG.fA.mU.fU.mU.fU.mG.fC.mG.
201NM		mA.fA.mU.fC.mU.fU.mA.fG.mG		fU.mG.fU.mC.fN′
F11-	1952	PmN.fG.mU.fG.mU.fG.mA.fG.mC.fA.	2202	fA.mG.fC.mA.fA.mU.fG.mC.fU.mC.
202NM		mU.fU.mG.fC.mU.fU.mG.fA.mA		fA.mC.fA.mC.fN′
F11-	1953	PmN.fA.mC.fC.mA.fG.mA.fA.mA.fG.	2203	fA.mA.fG.mC.fU.mC.fU.mU.fU.mC.
203NM		mA.fG.mC.fU.mU.fU.mG.fC.mU		fU.mG.fG.mU.fN′
F11-	1954	PmN.fA.mG.fA.mA.fA.mG.fU.mG.fC.	2204	fC.mC.fU.mG.fU.mG.fC.mA.fC.mU.
204NM		mA.fC.mA.fG.mG.fA.mU.fU.mU		fU.mU.fC.mU.fN′
F11-	1955	PmN.fU.mU.fU.mA.fU.mU.fU.mC.fA.	2205	fC.mA.fA.mU.fC.mU.fG.mA.fA.mA.
205NM		mG.fA.mU.fU.mG.fA.mU.fU.mU		fU.mA.fA.mA.fN′
F11-	1956	PmN.fU.mA.fU.mC.fC.mA.fG.mU.fU.	2206	fA.mG.fA.mA.fG.mA.fA.mC.fU.mG.
206NM		mC.fU.mU.fC.mU.fC.mC.fC.mA		fG.mA.fU.mA.fN′
F11-	1957	PmN.fC.mC.fG.mU.fG.mA.fA.mA.fG.	2207	fC.mU.fU.mC.fA.mC.fU.mU.fU.mC.
207NM		mU.fG.mA.fA.mG.fA.mG.fU.mA		fA.mC.fG.mG.fN′
F11-	1958	PmN.fG.mG.fU.mG.fU.mG.fC.mU.fU.	2208	fU.mA.fC.mU.fG.mA.fA.mG.fC.mA.
208NM		mC.fA.mG.fU.mA.fG.mA.fC.mA		fC.mA.fC.mC.fN′
F11-	1959	PmN.fG.mG.fA.mC.fA.mG.fA.mG.fG.	2209	fG.mA.fG.mG.fC.mC.fC.mU.fC.mU.
209NM		mG.fC.mC.fU.mC.fC.mC.fG.mA		fG.mU.fC.mC.fN′
F11-	1960	PmN.fA.mA.fG.mA.fA.mA.fA.mU.fC.	2210	fA.mG.fG.mA.fU.mG.fA.mU.fU.mU.
210NM		mA.fU.mC.fC.mU.fG.mA.fA.mA		fU.mC.fU.mU.fN′
F11-	1961	PmN.fU.mG.fA.mG.fA.mU.fU.mC.fU.	2211	fC.mC.fC.mA.fA.mA.fG.mA.fA.mU.
211NM		mU.fU.mG.fG.mG.fC.mC.fA.mU		fC.mU.fC.mA.fA.fN′
F11-	1962	PmN.fA.mU.fG.mU.fU.mU.fU.mA.fA.	2212	fU.mC.fU.mC.fC.mU.fU.mA.fA.mA.
212NM		mG.fG.mA.fG.mA.fC.mA.fA.mA		fA.mC.fA.mU.fN′
F11-	1963	PmN.fC.mA.fC.mA.fG.mU.fU.mU.fC.	2213	fU.mG.fC.mC.fA.mG.fA.mA.fA.mC.
213NM		mU.fG.mG.fC.mA.fG.mG.fC.mC		fU.mG.fU.mG.fN′
F11-	1964	PmN.fA.mC.fA.mA.fU.mA.fU.mC.fC.	2214	fG.mA.fA.mC.fU.mG.fG.mA.fU.mA.
214NM		mA.fG.mU.fU.mC.fU.mU.fC.mU		fU.mU.fG.mU.fN′
F11-	1965	PmN.fA.mC.fA.mU.fU.mC.fA.mC.fC.	2215	fU.mU.fU.mC.fU.mG.fG.mU.fG.mA.
215NM		mA.G.mA.fA.mA.fC.mU.fG.mA		fA.mU.fG.mU.fN′
F11-	1966	PmN.fC.mA.fA.mG.fG.mC.fA.mA.fU.	2216	fA.mU.fG.mA.fU.mA.fU.mU.fG.mC.
216NM		mA.fU.mC.fA.mU.fA.mC.fC.mC		fC.mU.fU.mG.fN′
F11-	1967	PmN.fC.mU.fC.mC.fA.mA.fC.mG.fA.	2217	fC.mA.fG.mG.fA.mU.fC.mG.fU.mU.
217NM		mU.fC.mC.fU.mG.fG.mG.fC.mU		fG.mG.fA.mG.fN′
F11-	1968	PmN.fC.mU.fG.mA.fA.mA.fC.mC.fA.	2218	fC.mU.fU.mU.fC.mU.fG.mG.fU.mU.
218NM		mG.fA.mA.fA.mG.fA.mG.fC.mU		fU.mC.fA.mG.fN′
F11-	1969	PmN.fA.mA.fU.mC.fU.mC.fC.mC.fU.	2219	fU.mU.fG.mC.fA.mA.fG.mG.fG.mA.
219NM		mU.fG.mC.fA.mA.fG.mC.fG.mU		fG.mA.fU.mU.fN′
F11-	1970	PmN.fU.mG.fU.mG.fU.mA.fA.mU.fU.	2220	fC.mA.fG.mU.fG.mA.fA.mU.fU.mA.
220NM		mC.fA.mC.fU.mG.fU.mG.fG.mU		fC.mA.fC.mA.fN′
F11-	1971	PmN.fU.mU.fU.mC.fA.mG.fU.mG.fA.	2221	fG.mA.fU.mU.fU.mU.fC.mA.fC.mU.
221NM		mA.fA.mA.fU.mC.fC.mA.fG.mA		fG.mA.fA.mA.fN′
F11-	1972	PmN.fA.mA.fA.mU.fC.mA.fU.mC.fC.	2222	fU.mU.fU.mC.fA.mG.fG.mA.fU.mG.
222NM		mU.fG.mA.fA.mA.fA.mG.fA.mC		fA.mU.fU.mU.fN′
F11-	1973	PmN.fU.mA.fC.mA.fC.mU.fC.mA.fU.	2223	fG.mG.fA.mU.fA.mA.fU.mG.fA.mG.
223NM		mU.fA.mU.fC.mC.fA.mU.fU.mU		fU.mG.fU.mA.fN′
F11-	1974	PmN.fU.mU.fG.mG.fC.mA.fG.mU.fG.	2224	fA.mG.fA.mA.fA.mC.fA.mC.fU.mG.
224NM		mU.fU.mU.fC.mU.fG.mU.fA.mA		fC.mC.fA.mA.fN′
F11-	1975	PmN.fG.mG.fU.mA.fC.mA.fC.mU.fC.	2225	fA.mU.fA.mA.fU.mG.fA.mG.fU.mG.
225NM		mA.fU.mU.fA.mU.fC.mC.fA.mU		fU.mA.fC.mC.fN′
F11-	1976	PmN.fA.mG.fG.mC.fA.mG.fG.mC.fA.	2226	fC.mC.fA.mU.fA.mU.fG.mC.fC.mU.
226NM		mU.fA.mU.fG.mG.fG.mU.fC.mG		fG.mC.fC.mU.fN′
F11-	1977	PmN.fC.mC.fA.mG.fU.mU.fU.mC.fA.	2227	fC.mU.fU.mG.fU.mU.fG.mA.fA.mA.
227NM		mA.fC.mA.fA.mG.fG.mC.fA.mA		fC.mU.fG.mG.fN′
F11-	1978	PmN.fU.mG.fG.mC.fC.mG.fC.mU.fC.	2228	fA.mA.fA.mG.fG.mG.fA.mG.fC.mG.
228NM		mC.fC.mU.fU.mU.fG.mA.fG.mC		fG.mC.fC.mA.fN′
F11-	1979	PmN.fA.mC.fU.mG.fU.mG.fG.mU.fU.	2229	fC.mU.fG.mG.fA.mA.fA.mC.fC.mA.
229NM		mU.fC.mC.fA.mG.fU.mU.fU.mC		fC.mA.fG.mU.fN′
F11-	1980	PmN.fC.mU.fU.mU.fG.mG.fG.mC.fC.	2230	fG.mG.fA.mA.fU.mG.fG.mC.fC.mC.
230NM		mA.fU.mU.fC.mC.fU.mG.fG.mG		fA.mA.fA.mG.fN′
F11-	1981	PmN.fU.mA.fA.mG.fA.mA.fA.mA.fU.	2231	fG.mG.fA.mU.fG.mA.fU.mU.fU.mU.
231NM		mC.fA.mU.fC.mC.fU.mG.fA.mA		fC.mU.fU.mA.fN′
F11-	1982	PmN.fC.mU.fC.mU.fU.mU.fU.mA.fU.	2232	fC.mU.fG.mA.fA.mA.fU.mA.fA.mA.
232NM		mU.fU.mC.fA.mG.fA.mU.fU.mG		fA.mG.fA.mG.fN′
F11-	1983	PmN.fU.mC.fU.mU.fU.mG.fA.mG.fA.	2233	fA.mA.fG.mA.fA.mU.fC.mU.fC.mA.
233NM		mU.fU.mC.fU.mU.fU.mG.fG.mG		fA.mA.fG.mA.fN′
F11-	1984	PmN.fA.mA.fU.mG.fA.mU.fG.mG.fA.	2234	fG.mA.fG.mG.fC.mU.fC.mC.fA.mU.
234NM		mG.fC.mC.fU.mC.fC.mA.fC.mA		fC.mA.fU.mU.fN′
F11-	1985	PmN.fG.mA.fA.mG.fA.mA.fU.mG.fG.	2235	fU.mU.fC.mU.fG.mC.fC.mA.fU.mU.
235NM		mC.fA.mG.fA.mA.fC.mA.fC.mU		fC.mU.fU.mC.fN′
F11-	1986	PmN.fC.mA.fA.mU.fG.mA.fU.mG.fG.	2236	fA.mG.fG.mC.fU.mC.fC.mA.fU.mC.
236NM		mA.fG.mC.fC.mU.fC.mC.fA.mC		fA.mU.fU.mG.fN′
F11-	1987	PmN.fA.mU.fG.mG.fA.mG.fC.mC.fU.	2237	fU.mG.fU.mG.fG.mA.fG.mG.fC.mU.
237NM		mC.fC.mA.fC.mA.fC.mA.fG.mG		fC.mC.fA.mU.fN′
F11-	1988	PmN.fC.mC.fC.mA.fA.mG.fA.mA.fA.	2238	fA.mC.fU.mG.fA.mU.fU.mU.fC.mU.
238NM		mU.fC.mA.fG.mU.fG.mU.fC.mA		fU.mG.fG.mG.fN′
F11-	1989	PmN.fG.mA.fG.mC.fC.mU.fC.mC.fA.	2239	fC.mU.fG.mU.fG.mU.fG.mG.fA.mG.
239NM		mC.fA.mC.fA.mG.fG.mU.fG.mU		fG.mC.fU.mC.fN′
F11-	1990	PmN.fC.mU.fC.mC.fC.mA.fA.mG.fA.	2240	fU.mG.fA.mU.fU.mU.fC.mU.fU.mG.
240NM		mA.fA.mU.fC.mA.fG.mU.fG.mU		fG.mG.fA.mG.fN′
F11-	1991	PmN.fC.mC.fU.mC.fC.mA.fC.mA.fC.	2241	fC.mA.fC.mC.fU.mG.fU.mG.fU.mG.
241NM		mA.fG.mG.fU.mG.fU.mC.fU.mC		fG.mA.fG.mG.fN′
F11-	1992	PmN.fC.mC.fA.mA.fU.mG.fA.mU.fG.	2242	fG.mG.fC.mU.fC.mC.fA.mU.fC.mA.
242NM		mG.fA.mG.fC.mC.fU.mC.fC.mA		fU.mU.fG.mG.fN′
F11-	1993	PmN.fU.mU.fU.mC.fC.mA.fA.mU.fG.	2243	fU.mC.fC.mA.fU.mC.fA.mU.fU.mG.
243NM		mA.fU.mG.fG.mA.fG.mC.fC.mU		fG.mA.fA.mA.fN′
F11-	1994	PmN.fU.mC.fC.mC.fA.mA.fG.mA.fA.	2244	fC.mU.fG.mA.fU.mU.fU.mC.fU.mU.
244NM		mA.fU.mC.fA.mG.fU.mG.fU.mC		fG.mG.fG.mA.fN′
F11-	1995	PmN.fA.mG.fC.mC.fU.mC.fC.mA.fC.	2245	fC.mC.fU.mG.fU.mG.fU.mG.fG.mA.
245NM		mA.fC.mA.fG.mG.fU.mG.fU.mC		fG.mG.fC.mU.fN′
F11-	1996	PmN.fU.mC.fU.mU.fC.mU.fC.mC.fC.	2246	fU.mU.fC.mU.fU.mG.fG.mG.fA.mG.
246NM		mA.fA.mG.fA.mA.fA.mU.fC.mA		ffA.mA.fG.mA.fN′
F11-	1997	PmN.fG.mU.fU.mU.fC.mC.fA.mA.fU.	2247	fC.mC.fA.mU.fC.mA.fU.mU.fG.mG.
247NM		mG.fA.mU.fG.mG.fA.mG.fC.mC		A.mA.fA.mC.fN′
F11-	1998	PmN.fU.mC.fC.mA.fA.mU.fG.mA.fU.	2248	fG.mC.fU.mC.fC.mA.fU.mC.fA.mU.
248NM		mG.fG.mA.fG.mC.fC.mU.fC.mC		fU.mG.fG.mA.fN′
F11-	1999	PmN.fU.mG.fG.mA.fG.mC.fC.mU.fC.	2249	fG.mU.fG.mU.fG.mG.fA.mG.fG.mC.
249NM		mC.fA.mC.fA.mC.fA.mG.fG.mU		fU.mC.fC.mA.fN′
F11-	2000	PmN.fG.mC.fC.mU.fC.mC.fA.mC.fA.	2250	fA.mC.fC.mU.fG.mU.fG.mU.fG.mG.
250NM		mC.fA.mG.fG.mU.fG.mU.fC.mil		fA.mG.fG.mC.fN′

In above Table 1e:

A represents adenine;

U represents uracil;

C represents cytosine;

G represents guanine;

P represents a terminal phosphate group;

m represents a methyl modification at the 2′ position of the sugar of the underlying nucleoside;

f represents a fluoro modification at the 2′ position of the sugar of the underlying nucleoside

N represents any RNA nucleobase;

N′ represents any RNA nucleobase and is preferably complementary to N.

Example 2

Oligonucleotides as set out in Tables 1a/1 b above that target FXI mRNA in human hepatoma cells were screened as follows.

Native gel electrophoresis for random FXI oligomeric compounds: Oligomeric compounds including oligonucleotides as set out in Table 1a/1 b above were dissolved in sterile Rnase-, Dnase free water to the final concentration 100 μM. 10 random oligomeric compounds were selected for validation based on following Table 2.

TABLE 2
No.	Lot No.	ID
1	32407	F11-07
2	32443	F11-43
3	32467	F11-67
4	32482	F11-82
5	32521	F11-121
6	32530	F11-130
7	32555	F11-155
8	32596	F11-196
9	32615	F11-215
10	33642	F11-242

20% TBE gel electrophoresis was carried out for the above oligomeric compounds of Table 2, 10 μm oligonucleotide/lane, staining: SybrGold. FIG. 1 illustrates the stability of the resulting duplexes. Based on this QC data we used all oligomeric compounds in the following screening.

Two independent F11 qPCR assays and were validated for the screening. Both assays produced linear dose response as illustrated in FIG. 2 with high sensitivity and efficiency. Due to known qPCR artifacts caused by siRNAs overlapping with qPCR probe regions, two probes from different target gene regions were used.

Screening F11 oligomeric compounds in hepatoma cell line: Protocol details:

Cell seeding: 10,000 HepG2 cells/well.

Lipofectamine RNAiMax mediated transfection.

Transfection: 20 nM compounds, antibiotic-free EMEM medium 10% FBS, 72 h incubation.

Gene expression was measured by qPCR (Taqman chemistry), adjusted to the standard curve and normalized to the reference gene GAPDH.

Data is expressed as the percentage of gene expression in non-treated cells (NT).

Results of the screening are shown in FIGS. 3 to 12.

26 oligomeric compounds with 80% knockdown cut off were selected for the dose response curves. Basis for this selection is as follows in Table 3.

TABLE 3
	Probe 0011	Probe 0011	Probe 0014	Probe 0014
	(% of NT)	(StDev)	(% of NT)	(StDev)
F11-183	16.38125499	2.013845618	7.390709343	0.566515346
F11-140	9.879406487	3.562127243	14.22784171	3.594956374
F11-27	12.75921626	0.196272116	11.67948753	0.736184873
F11-91	13.02726487	1.209635635	11.9438287	1.262506376
F11-163	11.85412492	0.429451274	14.23620915	0.292814079
F11-207	14.0604508	0.474611347	12.58144382	0.838626235
F11-46	15.99580158	0.887618916	10.81760361	0.429607546
F11-199	12.09311021	0.561879319	16.177289	0.804157804
F11-220	10.19545315	2.801932011	18.89268438	4.374803266
F11-238	13.40181876	0.052184671	17.3012001	1.131315389
F11-98	15.77153606	1.342306305	15.82298746	1.641051662
F11-105	14.09977643	0.481691161	18.58881771	1.10194639
F11-146	13.12223851	1.009310781	19.79764347	0.70176306
F11-152	10.7295455	0.718550243	22.44897671	1.853140055
F11-109	14.71437898	0.483729553	18.58436211	0.097538284
F11-120	15.82404014	0.296398359	17.48975387	2.035559291
F11-218	14.31316962	0.304685608	19.64927627	1.469210086
F11-13	15.75002936	0.544846368	18.21711753	0.233023069
F11-39	19.6320507	2.268987147	14.61318275	1.740915389
F11-210	16.1566738	0.521574928	19.46520418	0.491427909
F11-08	17.52268129	0.100107723	18.84244532	0.566323481
F11-224	16.03733736	0.892648857	20.79529032	0.619058244
F11-182	19.06641913	0.47270836	19.16890424	1.516153913
F11-103	14.8052026	1.32389517	25.00603503	2.748462021
F11-151	17.9105237	0.303879045	21.95923162	0.360854952
F11-223	16.88767639	1.818246469	24.88274643	1.656451297

Example 3

Dose response curves for the 26 FXI lead compounds as identified in Example 2 are shown in FIG. 13.

Dose response curves for the 5 FXI lead compounds are shown in FIG. 14.

Example 4

IC50 values are shown for the 26 FXI lead compounds as identified in Example 2 in following Table 4.

TABLE 4
siRNA (nM)	50	25	12.5	5	2	0.8	0.32
F11-140	10.84824	27.26815	52.49094	74.79465	86.01931	92.5617	108.1231
F11-91	11.21362	17.5123	30.79378	52.89924	71.85335	76.62539	86.24001
F11-46	11.31357	19.1463	34.94334	58.3431	72.36898	79.03502	87.90456
F11-27	12.00189	19.71206	36.34996	58.61257	73.49525	80.52213	95.02346
F11-08	12.88477	23.17136	38.502	60.95352	75.64406	85.64319	94.30091
F11-207	13.33847	28.59863	48.07128	70.58417	80.28337	83.17787	97.52694
F11-146	13.38071	23.04423	40.71772	67.32095	87.86172	94.18917	112.7978
F11-152	14.24965	24.9051	51.57466	70.85458	81.53343	88.18263	105.3212
F11-13	16.1023	30.30924	48.19031	63.18166	75.90383	80.13827	91.06444
F11-220	16.95432	25.76435	52.68453	80.69079	87.87234	98.52989	105.8545
F11-218	17.20341	31.58884	61.17974	77.06415	101.7601	105.0303	109.3946
F11-109	17.57553	29.90478	47.49863	67.90813	83.63117	99.25234	104.6814
F11-105	17.62636	27.2131	48.11403	75.61487	91.99868	99.3779	113.5676
F11-103	19.05623	31.3836	53.66986	70.21575	87.15926	94.18358	109.3758
F11-98	19.08747	25.21664	40.70468	62.53904	90.33434	92.00181	109.9554
F11-39	20.76369	36.33147	56.83281	71.87339	85.66001	88.7146	89.9771
F11-183	22.96668	40.72956	62.72405	82.71394	91.62041	102.8007	117.0328
F11-163	23.72934	27.92605	45.96363	70.65669	90.44246	95.26864	111.0215
F11-223	25.55254	50.53311	79.41138	88.2778	102.639	100.4705	109.0358
F11-151	25.79851	29.31085	43.72433	64.81009	83.78671	85.73753	101.2187
F11-120	26.54193	37.32053	44.77477	68.73705	81.41065	91.22496	92.68608
F11-199	28.11948	37.72515	63.274	74.59009	89.97225	96.10097	97.29022
F11-224	28.19833	42.50665	62.41726	82.4676	85.58443	92.77884	100.0632
F11-210	29.66767	37.73558	58.54817	67.94156	78.98299	88.30405	103.0938
F11-182	32.95932	52.5532	72.82952	81.79542	88.47215	101.748	104.4618
F11-238	73.20162	93.24065	91.91126	90.37185	88.5052	87.39394	99.47702

Example 5

Species cross-reactivity of the 26 FXI lead compounds as identified in Example 2 are shown in following Table 5.

	TABLE 5
	Selected	Macaca	Mus	Rattus
	oligos	fascicularis	musculus	norvegicus
	F11-183	MF	0	0
	F11-140	MF	0	0
	F11-27	0	0	0
	F11-91	MF	0	0
	F11-163	MF	0	0
	F11-207	MF	0	0
	F11-46	MF	0	0
	F11-199	MF	0	0
	F11-220	MF	0	0
	F11-238	MF	MUS	RN
	F11-98	MF	0	0
	F11-105	MF	0	0
	F11-146	MF	0	0
	F11-152	MF	MUS	RN
	F11-109	MF	0	0
	F11-120	MF	0	0
	F11-218	MF	0	0
	F11-13	MF	0	0
	F11-39	MF	0	RN
	F11-210	MF	0	0
	F11-08	MF	0	0
	F11-224	MF	0	0
	F11-182	MF	0	0
	F11-103	MF	0	0
	F11-151	MF	0	0
	F11-223	MF	0	0

Example 6

Further to the data as provided in Examples 3 to 5, oligonucleotides F11-46/SEQ ID NO: 46, F11-91/SEQ ID NO: 91 and F11-152/SEQ ID NO: 152 have been identified as particularly preferred antisense oligonucleotide sequences to be used in oligomeric compounds as described herein. On this basis, these sequences have been incorporated into overall oligomeric compounds as described herein of the following sequences SEQ ID NOs 2251 to 2253 as set out in following Table 6. Furthermore, selected modifications have been applied to SEQ ID NOs 2251 to 2253 as shown in SEQ ID NOs 2254 to 2286 in following Table 6. All sequences as provided below in Table 6 are set out in the 5′ to 3′ directionality.

TABLE 6
	SEQ ID1
	or
	construct2
Oligo Name	No	Sequence
F11-46C	2251	UUGGUGUGAGCAUUGCUUGCAAUGCUCACACCAA (includes
(Oligomeric		antisense SEQ ID NO 46, and sense SEQ ID NO 296)
compound
F11-46
complete
sequence)
F11-91C	2252	UUAUAAGAAAAUCAUCCUGAUGAUUUUCUUAUAA (includes
(Oligomeric		antisense SEQ ID NO 91, and sense SEQ ID NO 341)
compound
F11-91
complete
sequence)
F11-152 C	2253	UGGUUUCCAAUGAUGGAGCCAUCAUUGGAAACCA (includes
(Oligomeric		antisense SEQ ID NO 152, and sense SEQ ID NO 402)
compound
F11-152
complete
sequence)
F11-46CPS	2254	mU(ps)fU(ps)mGfGmUfGmUfGmAfGmCfAmUfUmG(ps)fC(ps)
(Oligomeric		mU(ps)fU(ps)mG(ps)fCmAfAmUfGmCfUmCfAmCfAmCfCmAfA
compound		(includes antisense SEQ ID NO 46, and sense SEQ ID NO 296)
F11-46
complete
sequence/
(ps) modified)
F11-91CPS	2255	mU(ps)fU(ps)mAfUmAfAmGfAmAfAmAfUmCfAmU(ps)fC(ps)mC
(Oligomeric		(ps)fU(ps)mG(ps)fAmUfGmAfUmUfUmUfCmUfUmAfUmAfA
compound		(includes antisense SEQ ID NO 91, and sense SEQ ID NO 341)
F11-91
complete
sequence/
(ps) modified)
F11-152CPS	2256	mU(ps)fG(ps)mGfUmUfUmCfCmAfAmUfGmAfUmG(ps)fG(ps)mA
(Oligomeric		(ps)fG(ps)mC(ps)fCmAfUmCfAmUfUmGfGmAfAmAfCmCfA
compound		(includes antisense SEQ ID NO 152, and sense SEQ ID NO 402)
F11-152
complete / (ps)
modified)
F11-46VP	2257	(VP)mU(ps)fU(ps)mGfGmUfGmUfGmAfGmCfAmUfUmG(ps)fC(ps)
(Oligomeric		mU(ps)fU(ps)mG(ps)fCmAfAmUfGmCfUmCfAmCfAmCfCmAfA
compound		(includes antisense SEQ ID NO 46, and sense SEQ ID NO 296)
F11-46
complete
sequence / ps
and vinyl
phosphonate
modification)
F11-91VP	2258	(VP)mU(ps)fU(ps)mAfUmAfAmGfAmAfAmAfUmCfAmU(ps)fC(ps)
(Oligomeric		mC(ps)fU(ps)mG(ps)fAmUfGmAfUmUfUmUfCmUfUmAfUmAfA
compound		(includes antisense SEQ ID NO 91, and sense SEQ ID NO 341)
F11-91
complete
sequence / ps
and vinyl
phosphonate
modification)
F11-152VP	2259	(VP)mU(ps)fG(ps)mGfUmUfUmCfCmAfAmUfGmAfUmG(ps)fG(ps)
(Oligomeric		mA(ps)fG(ps)mC(ps)fCmAfUmCfAmUfUmGfGmAfAmAfCmCfA
compound		(includes antisense SEQ ID NO 152, and sense SEQ ID NO 402)
F11-152
complete
sequence / ps
and vinyl
phosphonate
modification)
F11-46IL	2260	mU(ps)fU(ps)mGfGmUfGmUfGmAfGmCfAmUfUmG(ps)fC(ps)mU
(Oligomeric		(ps)fUiGfCmAfAmUfGmCfUmCfAmCfAmCfCmAfA (includes
compound		antisense SEQ ID NO 46, and sense SEQ ID NO 296)
F11-46
complete
sequence / ps
and inverted
nucleotide
loop)
F11-91IL	2261	mU(ps)fU(ps)mAfUmAfAmGfAmAfAmAfUmCfAmU(ps)fC(ps)mC
(Oligomeric		(ps)fUiGfAmUfGmAfUmUfUmUfCmUfUmAfUmAfA (includes
compound		antisense SEQ ID NO 91, and sense SEQ ID NO 341)
F11-91
complete
sequence / ps
and inverted
nucleotide
loop)
F11-152IL	2262	mU(ps)fG(ps)mGfUmUfUmCfCmAfAmUfGmAfUmG(ps)fG(ps)mA
(Oligomeric		(ps)fGiCfCmAfUmCfAmUfUmGfGmAfAmAfCmCfA (includes
compound		antisense SEQ ID NO 152, and sense SEQ ID NO 402)
F11-152
complete
sequence / ps
and inverted
nucleotide
loop)
F11-46IE	2263	mUiUmGfGmUfGmUfGmAfGmCfAmUfUmG(ps)fC(ps)mU(ps)fU
(Oligomeric		(ps)mG(ps)fCmAfAmUfGmCfUmCfAmCfAmCfCiAfA (includes
compound		antisense SEQ ID NO 46, and sense SEQ ID NO 296)
F11-46
complete
sequence / ps
and end
inverted
nucleotide)
F11-91IE	2264	mUiUmAfUmAfAmGfAmAfAmAfUmCfAmU(ps)fC(ps)mC(ps)fU(ps)
(Oligomeric		mG(ps)fAmUfGmAfUmUfUmUfCmUfUmAfUiAfA (includes
compound		antisense SEQ ID NO 91, and sense SEQ ID NO 341)
F11-91
complete
sequence / ps
and end
inverted
nucleotide)
F11-152IE	2265	mUiGmGfUmUfUmCfCmAfAmUfGmAfUmG(ps)fG(ps)mA(ps)fG
(Oligomeric		(ps)mC(ps)fCmAfUmCfAmUfUmGfGmAfAmAfCiCfA (includes
compound		antisense SEQ ID NO 152, and sense SEQ ID NO 402)
F11-152
complete
sequence / ps
and end
inverted
nucleotide)
F11-46II	2266	mU(ps)fU(ps)mGfGmUfGiUfGmAfGmCfAmUfUmG(ps)fC(ps)mU
(Oligomeric		(ps)fU(ps)mG(ps)fmCfAmAfUmGfCfUmCiAmCfAmCfCmAfA
compound		(includes antisense SEQ ID NO 46, and sense SEQ ID NO 296)
F11-46
complete
sequence / ps
and internal
inverted
nucleotide)
F11-91II	2267	mU(ps)fU(ps)mAfUmAfAiGfAmAfAmAfUmCfAmU(ps)fC(ps)mC
(Oligomeric		(ps)fU(ps)mG(ps)fAmUfGmAfUmUfUmUiCmUfUmAfUmAfA
compound		(includes antisense SEQ ID NO 91, and sense SEQ ID NO 341)
F11-91
complete
sequence / ps
and internal
inverted
nucleotide)
F11-152II	2268	mU(ps)fG(ps)mGfUmUfUiCfCmAfAmUfGmAfUmG(ps)fG(ps)mA
(Oligomeric		(ps)fG(ps)mC(ps)fCmAfUmCfAmUfUmGiGmAfAmAfCmCfA
compound		(includes antisense SEQ ID NO 152, and sense SEQ ID NO 402)
F11-152
complete
sequence / ps
and internal
inverted
nucleotide)
F11-46MF	2269	mU(ps)fU(ps)mGmGmUmGmUmGmAmGmCmAmUfUmG(ps)mC
(Oligomeric		(ps)mU(ps)mU(ps)mG(ps)mCmAfAfUfGmCmUmCmAmCmAm
compound		CmCmAmA (includes antisense SEQ ID NO 46, and sense SEQ
F11-46		ID NO 296)
complete
sequence / ps
and minimum
2F)
F11-91MF	2270	mU(ps)fU(ps)mAmUmAmAmGmAmAmAmAmUmCfAmU(ps)mC
(Oligomeric		(ps)mC(ps)mU(ps)mG(ps)mAmUfGfAfUmUmUmUmCmUmUmA
compound		mUmAmA (includes antisense SEQ ID NO 91, and sense SEQ
F11-91		ID NO 341)
complete
sequence / ps
and minimum
2F)
F11-152MF	2271	mU(ps)fG(ps)mGmUmUmUmCmCmAmAmUmGmAfUmG(ps)mG
(Oligomeric		(ps)mA(ps)mG(ps)mC(ps)mCmAfUfCfAmUmUmGmGmAmAm
compound		AmCmCmA (includes antisense SEQ ID NO 152, and sense
F11-152		SEQ ID NO 402)
complete
sequence / ps
and minimum
2F)
F11-46ILG	2272	mU(ps)fU(ps)mGfGmUfGmUfGmAfGmCfAmUfUmG(ps)fC(ps)mU
(Oligomeric		(ps)fU(ps)mG(ps)fCmAfAmUfGmCfUCfACfAmCC(ps)mA(ps)fA
compound		(includes antisense SEQ ID NO 46, and sense SEQ ID NO 296)
F11-46
complete
sequence / ps
and internal
ligand
arrangement)
F11-91ILG	2273	mU(ps)fU(ps)mAfUmAfAmGfAmAfAmAfUmCfAmU(ps)fC(ps)mC
(Oligomeric		(ps)fU(ps)mG(ps)fAmUfGmAfUmUfUUfCmUUmAU(ps)mA(ps)fA
compound		(includes antisense SEQ ID NO 91, and sense SEQ ID NO 341)
F11-91
complete
sequence / ps
and internal
ligand
arrangement)
F11-152ILG	2274	mU(ps)fG(ps)mGfUmUfUmCfCmAfAmUfGmAfUmG(ps)fG(ps)mA
(Oligomeric		(ps)fG(ps)mC(ps)fCmAUmCfAUUmGfGmAfAmAC(ps)mC(ps)fA
compound		(includes antisense SEQ ID NO 152, and sense SEQ ID NO 402)
F11-152
complete
sequence / ps
and internal
ligand
arrangement)
F11-46ILGIE	2275	mU(ps)fU(ps)mGfGmUfGmUfGmAfGmCfAmUfUmG(ps)fC(ps)mU
(Oligomeric		(ps)fU(ps)mG(ps)fCmAfAmUfGmCfUCfACfAmCCmAiN″mN′″
compound		(includes antisense SEQ ID NO 46, and sense SEQ ID NO 296)
F11-46
complete
sequence / ps,
internal ligand
arrangement
and inverted
nucleotide end
stabilization)
F11-91ILGIE	2276	mU(ps)fU(ps)mAfUmAfAmGfAmAfAmAfUmCfAmU(ps)fC(ps)mC
(Oligomeric		(ps)fU(ps)mG(ps)fAmUfGmAfUmUfUUfCmUUmAUmAiN″mN′″
compound		(includes antisense SEQ ID NO 91, and sense SEQ ID NO 341)
F11-91
complete
sequence / ps,
internal ligand
arrangement
and inverted
nucleotide end
stabilization)
F11-152ILGIE	2277	mU(ps)fG(ps)mGfUmUfUmCfCmAfAmUfGmAfUmG(ps)fG(ps)mA
(Oligomeric		(ps)fG(ps)mC(ps)fCmAUmCfAUUmGfGmAfAmACmCiN″mN′″
compound		(includes antisense SEQ ID NO 152, and sense SEQ ID NO 402)
F11-152
complete
sequence / ps,
internal ligand
arrangement
and inverted
nucleotide end
stabilization)
F11-46MVP	2278	(mVP)mU(ps)fU(ps)mGfGmUfGmUfGmAfGmCfAmUfUmG(ps)fC
(Oligomeric		(ps)mU(ps)fU(ps)mG(ps)fCmAfAmUfGmCfUmCfAmCfAmCfCmA
compound		fA (includes antisense SEQ ID NO 46, and sense SEQ ID NO
F11-46		296)
complete
sequence / ps
and methyl
vinyl
phosphonate
modification)
F11-91MVP	2279	(mVP)mU(ps)fU(ps)mAfU mAfAmGfAmAfAmAfU mCfAmU(ps)fC(ps)
(Oligomeric		mC(ps)fU(ps)mG(ps)fAmUfGmAfUmUfUmUfCmUfUmAfUmAfA
compound		(includes antisense SEQ ID NO 91, and sense SEQ ID NO 341)
F11-91
complete
sequence / ps
and methyl
vinyl
phosphonate
modification)
F11-152MVP	2280	(mVP)mU(ps)fG(ps)mGfUmUfUmCfCmAfAmUfGmAfUmG(ps)fG
(Oligomeric		(ps)mA(ps)fG(ps)mC(ps)fCmAfUmCfAmUfUmGfGmAfAmAfCmCfA
compound		(includes antisense SEQ ID NO 152, and sense SEQ ID NO
F11-152		402)
complete
sequence / ps
and methyl
vinyl
phosphonate
modification)
F11-46IT	2281	iUfUmGfGmUfGmUfGmAfGmCfAmUfUmG(ps)fC(ps)mU(ps)fU(ps)
(Oligomeric		mG(ps)fCmAfAmUfGmCfUmCfAmCfAmCfCmAiA (includes
compound		antisense SEQ ID NO 46, and sense SEQ ID NO 296)
F11-46
complete
sequence / PS
and inverted
nucleotide
terminal
stabilization)
F11-91IT	2282	iUfUmAfUmAfAmGfAmAfAmAfUmCfAmU(ps)fC(ps)mC(ps)fU(ps)
(Oligomeric		mG(ps)fAmUfGmAfUmUfUmUfCmUfUmAfUmAiA (includes
compound		antisense SEQ ID NO 91, and sense SEQ ID NO 341)
F11-91
complete
sequence / PS
and inverted
nucleotide
terminal
stabilization)
F11-152IT	2283	iUfGmGfUmUfUmCfCmAfAmUfGmAfUmG(ps)fG(ps)mA(ps)fG
(Oligomeric		(ps)mC(ps)fCmAfUmCfAmUfUmGfGmAfAmAfCmCiA (includes
compound		antisense SEQ ID NO 152, and sense SEQ ID NO 402)
F11-152
complete
sequence / PS
and inverted
nucleotide
terminal
stabilization)
F11-46CM	2284	NUUGGUGUGAGCAUUGCUUGCAAUGCUCACACCAN′
(Oligomeric		(includes antisense SEQ ID NO 46, and sense SEQ ID NO 296)
compound
F11-46
complete
sequence)
F11-91CM	2285	NUAUAAGAAAAUCAUCCUGAUGAUUUUCUUAUAN′ (includes
(Oligomeric		antisense SEQ ID NO 91, and sense SEQ ID NO 341)
compound
F11-91
complete
sequence)
F11-152CM	2286	NGGUUUCCAAUGAUGGAGCCAUCAUUGGAAACCN′
(Oligomeric		(includes antisense SEQ ID NO 152, and sense SEQ ID NO 402)
compound
F11-152
complete
sequence)
1In case of nucleobase sequences
2In case of nucleobase and sugar modifications being given

In above Table 6:

A represents adenine;

U represents uracil;

C represents cytosine;

G represents guanine;

m represents a methyl modification at the 2′ position of the sugar of the underlying nucleoside;

f represents a fluoro modification at the 2′ position of the sugar of the underlying nucleoside

N/N″/N′″ represents any RNA nucleobase;

N′ represents any RNA nucleobase and is preferably complementary to N;

(ps) represents a phosphorothioate inter-nucleoside linkage;

i represents an inverted inter-nucleoside linkage, which can be either 3′-3′, or 5′-5′;

vp represents vinyl phosphonate;

mvp represents methyl vinyl phosphonate.

For each of the above constructs of Table 6, a ligand, such as a galnac ligand, is preferably attached at the 3′ end of the sequence. Specifically for SEQ ID NOs 2251, 2252, 2253, this can be respectively illustrated as follows, where Galnac can represent any arrangement of Galnac attachment, preferably however a triantennary galnac attachment:

UUGGUGUGAGCAUUGCUUGCAAUGCUCACACCAA - Galnac
UUAUAAGAAAAUCAUCCUGAUGAUUUUCUUAUAA - Galnac
UGGUUUCCAAUGAUGGAGCCAUCAUUGGAAACCA - Galnac.

Alternatively for SEQ ID NOs 2272 to 2273 as shown in above Table 6, the ligand, preferably Galnac, attachment can be to an internal non-terminal nucleoside, such as attachment to the nucleosides in the above sequences where the nucleobase is not shown as modified.

Example 7

This Example describes a structure-function relationship study of constructs comprising the nucleobase sequence of SEQ ID NO: 91.

FIG. 18 shows the constructs comprising the nucleobase sequence of SEQ ID NO: 91 which have been tested.

Tests have been performed in primary hepatocytes.

Human plateable 5 donor hepatocytes (Sekisui XenoTech, HPCH05+) are thawed in 45 mL of Human OptiThaw Hepatocyte media (Sekisui Xenotech, K8000), spun down at 200 g for 5 minutes, and resuspended in 2×WEM complete (5% FBS, 2 uM Dexamethasone, Pen/Strep, 8 ug/mL human insulin, 4 mM GlutaMAX, 30 mM HEPES pH 7.4). 2×WEM complete consists of WEM (Gibco, A1217601) and 2× the Hepatocyte Plating Supplement Pack (Gibco, CM3000) with only 1×FBS. The hepatocytes are then plated on 6 well Collagen 1 coated plates (Gibco, A1142803) at 25,000 cell/well at 50 uL per well and allowed to recover and adhere for 4 hours at 37 C.

After 4 hours, GalNac conjugated complexes are diluted to 2 uM in basal WEM and used to make a 2×, 7 step, 5 fold dilution series. 50 uL of each dilution is added to corresponding wells of the plated hepatocytes to make a final dilution series of 1-0.000064 uM in 1×WEM complete.

The cells are allowed to culture for 72 hours at 37 degrees without disruption before harvest and RNA isolation using the PureLink Pro 96 total RNA Purification Kit (Invitrogen, 12173011A) according to the manufacturers protocol.

Results are shown in FIG. 19.

Based on these results, 7 molecules have been designed which are to be subjected to further analysis (see following Examples). These molecules are shown in FIG. 20. Performance data in primary hepatocytes are shown in FIG. 21.

Based on these data, three molecules have been tested in humanized mice; see Example 8 below.

Example 8

This Examples describes testing of the three molecules identified in Example 7 in humanized mice.

Table 7 below shows nucleobase sequences (SEQ ID NOs) and full modification information (construct NOs) of these three molecules.

Designation
as used
herein	Nucleobase sequence	Structure of the construct
91-conv-31	UUAUAAGAAAAUCAUCCUGAU	/phos/mU*fU*mAfUmAfAmGfAmAfAmAfUmC*
	UUUCUUAUAA	fA*mU*fC*mC*mU*fGmAfUmUfUmUfCmUfUm
	(SEQ ID NO: 2287)	AfU*mA*fA*/3galnac/
		(construct NO: 2290)
91-vp	UUAUAAGAAAAUCAUCCUGAU	/vp/mU/*fU*mAfUmAfAmGfAmAfAmAfUmCfA
	GAUUUUCUUAUAA	mU*fC*mC*fU*mG*fAmUfGmAfUmUfUmUfC
	(SEQ ID NO: 2288)	mUfUmAfU*mA*fA*/3galnac/
		(construct NO: 2291)
91-conv-34	(SEQ ID NO: 2288)	/phos/mU*fU*mAfUmAfAmGfAmAfAmAfUmCf
		AmU*fC*mC*fU*mG*fAmUfGmAfUmUfUmUfC
		mUfUmAfU*mA*fA*/3galnac/
		(construct NO: 2292)

In above Table 7

A represents adenine;

U represents uracil;

C represents cytosine;

G represents guanine;

m represents a methyl modification at the 2′ position of the sugar of the underlying nucleoside;

f represents a fluoro modification at the 2′ position of the sugar of the underlying nucleoside;

* represents a phosphorothioate inter-nucleoside linkage;

vp represents vinyl phosphonate;

phos represents phosphonate; and

3galnac represents the toothbrush ligand defined herein above.

FIG. 22 also shows the structures of these molecules. FIG. 23 shows performance of these molecules 5 days after administration.

Based on these results, the construct designated “91-Conv-31” (structure displayed in FIG. 22) has been selected for testing in non-human primates; see Example 9 below. Of note, this molecule is particularly short and comprises only a total of 31 nucleotides.

Example 9

This Example describes a Pharmacodynamics Study of construct designated “91-Conv-31” (structure displayed in FIG. 22) Following Single/Repeat Subcutaneous Injection to Cynomolgus Monkeys.

Material and Methods

For an overview of the study protocol, see FIG. 24. A more detailed account is given below.

Study Protocol

TABLE 8
Study Design
			Target Dose	TOTAL	Target Dose
			Level	Target Dose	Concentration	Dose
Group/Phase	# of Males	Test Article	(mg/animal)	Volume (mL)	(mg/mL)	Route
G1P1	3 naïve1	saline	—	3.5 mL	—	SC
	non-naïve
G2P1	3 naïve 1	STP122G	3.5 (Target	3.5 mL	1	SC
	non-naïve		as 1 mg/kg)
G3P1	3 naïve 1	STP122G	10.5 (Target	3.5 mL	3	SC
	non-naïve		as 3 mg/kg)
G4P1	3 naïve 1	STP122G	35 (Target	3.5 mL	10	SC
	non-naïve		as 10 mg/kg)
G5P1	3 naïve 1	STP122G	10.5 (Target	3.5 mL	3	SC
	non-naïve		as 3 mg/kg)
G6P1	3 naïve 1	STP122G	10.5 (Target	3.5 mL	3	SC
	non-naïve		as 3 mg/kg)
Note:
1. Test article storage: Desiccated at room temperature, protected from light.
2. For SC group, animals will be fed on daily diet.
3. For all groups, saline will be used for vehicles
4. ″STP122G″ is an alternative designation for the preferred construct referred to as ″91-Conv-31″ herein

TABLE 9

Dose and Sample Collections

Day

Day

Wk

Wk

Wk

Wk

Wk

Wk

Wk

Wk

Wk

Wk

Wk

Wk

Wk

−14

0

1

2

3

4

5

6

7

8

9

10

11

12

13

Dose

G1

QD

G2

QD

G3

QD

G4

QD

G5

QD

QD

G6

QD

QD

QD

1 mL Whole

Group1-6

Bl

Bl

Bl

Bl

Bl

Bl

Bl

Blood Sampling

for Hematology

0.6 mL Serum

Group1-6

Se

Se

Se

Se

Se

Se

Se

Sampling for

Clinical

Chemistry

1.7 mL Whole

Group1-6

Bl

Bl

Bl

Bl

Bl

Bl

Bl

Bl

Bl

Bl

Bl

Bl

Bl

Bl

Bl

Blood Sampling

for Coagulation

2.5 mL Plasma

Group1-6

P, Se

P, Se

P, Se

P, Se

P, Se

P, Se

P, Se

P, Se

P, Se

P, Se

P, Se

P, Se

P, Se

P, Se

P, Se

and 0.3 mL

Serum Sampling

for PD

1.Wk1 point should be 7 days after Day 0; Wk2 point should be 14 days after Day 0.

2.Single dose with single compound, subcutaneous injection. For Day 0, Wk1 and Wk2, animals will be dosed after all samples collection.

3.(K2) EDTA as the anticoagulant for Hematology blood and sodium citrate as the anticoagulant for Coagulation blood and plasma.

4.Bl is short for blood; P is short for plasma; Se is short for Serum

5.Clinical Pathology Examination

Hematology

Erythrocyte count (RBC), Red cell distribution width (RDW), Hematocrit (HCT), Platelet count (PLT), Hemoglobin (HGB), Mean platelet volume (MPV), Mean corpuscular volume (MCV), Leukocyte counts (WBC), and Differential (absolute and percent), Mean corpuscular hemoglobin (MCH), Blood smear for possible cytology, Mean corpuscular hemoglobin concentration (MCHC), Absolute reticulocyte count (Retic).

Coagulation

Prothrombin time (PT), Activated partial thromboplastin time (APTT), Fibrinogen (FIB).

Clinical Chemistry

Alkaline Phosphatase (ALP), Total Protein (TP), Alanine Aminotransferase (ALT), Albumin (ALB), Aspartate Aminotransferase (AST), g-glutamyltransferase (GGT), Bilirubin, total (TBIL), Globulin (GLB), Phosphorus (P), Albumin/Globulin Ratio Creatinine (CRE), Sodium (Na), Glucose (GLU), Chloride (Cl), Calcium (Ca), Triglycerides (TG), Total Cholesterol (TCHO), Urea (UREA), Potassium (K), Creatine Kinase (CK), Lactate Dehydrogenase (LDH), Glutamate dehydrogenase (GLDH).

• 1 Study Information
  • 1.1 Study Objective
    • The objective of this study is to determine the pharmacodynamics (PD) of the compound selected for this study, following a single/repeat subcutaneous (SC) administration in male cynomolgus monkeys.
  • 1.2 Regulatory Compliance
    • This study is conducted in accordance with the Institutional Animal Care and Use Committee (IACUC) standard animal procedures along with the IACUC guidelines that are in compliance with the Animal Welfare Act and the Guide for the Care and Use of Laboratory Animals.
    • This study will be conducted in accordance with this protocol and protocol amendments (if applicable) and the associated study-specific procedures, and with applicable Standard Operating Procedures (SOPs) and generally recognized good laboratory practices. This study will not be considered within the scope of the Good Laboratory Practice regulations.
• 2 Test Article and Vehicle Information
  • 2.1 Test Article
    • Compounds as specified further above.

Storage Conditions: Desiccate at room temperature,
                    protected from light
Handling            Standard laboratory precautions
Instructions:       as defined in WuXi SOPs
Dose Preparation:   Doses will be prepared according to
                    instructions provided by the sponsor.
                    A copy of the instructions, as well as
                    details of preparation, will be
                    maintained in the study records.
Dose Solution
Analysis Samples:
Disposition of      Remaining formulations will be
Remaining           stored at 4°C.
Test Article
Formulations:
Disposition of      Remaining test article will be
Remaining           shipped back to sponsor or discarded
Test Article (dry   6 months after the final report
powder or solid):   is signed or at approval of Sponsor.

• 3 Test System Identification
  • 3.1 Animal Specifications

Species             Cynomolgus monkeys (Macacafascicularis)
Justification for   This is an acceptable species to support PK studies
Species             for compounds intended to use in humans.
Selection
History of Dosing   18 naïve animals and 6 non-naïve animals
Body Weight         2-7 kg
Range
Age                 ≥2.0 years old
Sex                 Male
Source              Hainan Jingang Laboratory Animal Co. Ltd and
                    other permitted vendor
Address of Supplier Nayangxintan Fucheng Town, Qiongshan District,
                    Haikou Hainan Province, P.R. China
Method of           Unique skin tattoo on chest
Identification
Justification for   The number of animals in each group is the
number of Animals   minimum number of animals necessary for
                    assessment of interanimal variability.
Selection of        24 males will be selected. Animals will have
Animals             undergone a physical examination for general health
                    by a staff veterinarian. 24 males confirmed as being
                    healthy, will be assigned to study.
Acclimation Period  Selected animals will be acclimated prior to the
                    study.

• • 3.2 Animal Care
    • 3.2.1 Environmental Conditions
      • The room(s) will be controlled and monitored for relative humidity (targeted mean range 40% to 70%, and any excursion from this range for more than 3 hours will be documented as a deviation) and temperature (targeted mean range 18° C. to 26° C., and any excursion from this range will be documented as a deviation) with 10 to 20 air changes/hour. The room will be on a 12-hour light/dark cycle except when interruptions are necessitated by study activities.
    • 3.2.2 Housing
      • Animals will be pair-housed in cages that are in accordance with applicable animal welfare laws and regulations during acclimation period. The monkeys will be housed individually in cages during experiment.
      • Diet and Feeding
      • Animals will be fed twice daily. Stock monkeys will be fed approximately 120 grams of Certified Monkey Diet daily. These amounts can be adjusted as necessary based on food consumption of the group or body weight changes of an individual and/or changes in the certified diet.
      • Animals will be fasted overnight prior to blood collections for serum chemistry.
      • Drinking Water
      • Reverse osmosis (RO) water will be available to all animals, ad libitum.
    • 3.2.3 Feed and Water Analyses
      • RO water is analyzed every three months and every batch of feed will be analyzed before use. Feed and water analyses will be maintained in the facility records.
    • 3.2.4 Environmental Enrichment
      • Enrichment toys will be provided.
• 4 Administration of Dose Formulation

Administration    Subcutaneous injection via the dorsal area of the
Route:            animals' thoracic regions.
Justification for Dose levels chosen to characterize the
the Dose Level:   pharmacodynamics of test article in monkeys over the
                  desired dose range and dosing frequencies.
Justification     This administration route is consistent with the
for the           proposed initial route of human administration.
Administration
Route:
Dose              The dose formulations will be administered per facility
Administration:   SOPs.
                  SC ADMINISTRATION: SC injection site will be
                  along the dorsal area of the animals' thoracic
                  regions. For multiple or large doses, different sites
                  will be used. When the injection site is altered,
                  the location must be documented in the record.

• • 4.1 Observations and Examinations
    • 4.1.1 Clinical Observations
      • Twice daily (approximately 9:30 a.m. and 4:00 p.m.), cage-side observations for general health and appearance will be conducted. Animals will be given physical examinations prior to study initiation to confirm animals' health. On dosing days, the animals will be observed at 2, 4 and 6-hours post-dosing. General condition, injection site, behavior, activity, excretion, respiration or other unusual observations noted throughout the study will be recorded in the raw data. When necessary, additional clinical observations will be performed and recorded. A staff veterinarian or veterinary technician will evaluate each animal if clinical observations demonstrate declining animal condition and the Study Director will be notified. The Study Director, or designee, will notify the Sponsor if warranted by the evaluation.
    • 4.1.2 Body Weight
      • All animals will be weighted weekly. On dosing days, animals will be weighed on prior to dosing to determine the dose volume to be administered.
    • 4.1.3 Blood Collection for Clinical Pathology
      • All blood samples will be collected from a peripheral vessel from restrained, non-sedated animals.

TABLE 10
Clinical Pathology Schedule
					Sample
					Volume
		Sampling		Tube Type/Size	approximately
Groups	Sample	Schedulea	Evaluations	Information	(minimum)
1-6	Blood	Once during	Hematology	K2EDTA	2 mL	2.0 mL (1.0 mL)
		pre-study;	Serum	Plain with	3.5 mL	1.2 mL (1.1 mL)
		Weeks 2, 3, 4,	Chemistry	separating
		5, 6, and 13.		gel
		Once during	Coagulation	Sodium	2 mL	1.7 mL (1.3 mL)
		pre-study;		Citrate
		Weekly.
aBlood sample may be collected from animals subjected to unscheduled euthanasia. Animals may not be fasted under that circumstance.

• • • • (1) Blood Collection for Hematology: Whole blood (at least 1.0 mL) will be collected from the animals into commercially available tubes with Potassium (K2) EDTA at room temperature (RT). The blood samples will be sent to clinical pathology lab in RT and tested for hematology parameters listed in the Table 9. A blood smear will be prepared from each hematology sample. Blood smears will be labeled, stained, and stored. Blood smears may be read to investigate results of the hematology analyses. If additional examination of blood smears is deemed necessary, the smears may be subsequently evaluated and this evaluation will be described in a study plan amendment.
      • (2) Blood Collection for Coagulation Test: Approximately 1.7 mL blood will be collected into sodium citrate anticoagulation tubes at RT and sent to clinical pathology lab. The parameters listed in Table 9 will be performed to test coagulation function.
      • (3) Blood Collection for Clinical Chemistry: Whole blood samples (approximately 1.2 mL) without anticoagulant will be collected and held at RT and up-right for at least 30 minutes and sent to clinical pathology lab. The samples will be processed to serum, which will be examined for the parameters listed in Table 9.
    • 4.1.4 Blood Collection for Pharmacodynamics (PD)

Blood:         All blood samples will be collected from a peripheral
               vessel from restrained, non-sedated animals.
Animals:       All available, all groups
Post-Dose
Blood volume:  Approximately 5.6 mL
Anticoagulant: Sodium citrate
Frequency:     Refer to Table 9. Actual sample collection times will be
               recorded in the study records. For samples collected
               within the first hour of dosing, a ± 1 minute is acceptable.
               For the remaining time points, samples that are taken
               within 5% of the scheduled time are acceptable and will
               not be considered as protocol deviation.
Sample         For FXI ELISA: 2 mL Blood will be collected into a tube
Processing:    (Purchased from sponsor’s required company) containing
               sodium citrate on wet ice. Then all the blood will be
               mixed upside down 4 times. Samples will be
               centrifuged (1000 g for 20 minutes at 4° C.) and
               approximately 1 mL plasma will be transferred
               into two tubes quickly (approximately
               0.50 mL per tube). One tube (labeled frozen plasma)
               should be frozen instantly in liquid nitrogen, then stored
               at −80° C.
               For FXI Activity Assays: 3 mL Blood will be collected
               into a tube (Purchased from sponsor’s required company)
               containing sodium citrate on wet ice. Then all the blood
               will be mixed upside down 4 times. Samples will be
               centrifuged (1660 g for 10 minutes at 4° C.) and
               approximately 1.5 mL plasma will be transferred into two
               labeled polypropylene micro-centrifuge tubes quickly
               (approximately 0.70 mL per tube). One tube (labeled
               frozen plasma) should be frozen instantly in liquid
               nitrogen, then stored at −80° C.. Another tube should be
               in a cool set to maintain 2-6° C. and shipped within
               2-4 hours in 4° C. for analysis of Factor XI protein
               for Activity Assays.
               For Serum: Whole blood samples (approximately 0.6 mL)
               without anticoagulant will be collected and held at RT
               and up-right for at least 30 minutes and then samples
               will be centrifuged (3200 g for 10 minutes at 4° C.) and
               approximately 0.3 mL serum will be transferred into tubes
               quickly. The tube should be frozen instantly in liquid
               nitrogen, then stored at −80° C. until analysis.

• 5 Protocol Amendments and Deviations
  • Changes to the approved protocol will be in the form of amendments approved by the Study Director and the Sponsor. Amendments will describe the protocol changes clearly and will include the effective date of the change and the justification for the change. The Study Director and Study Representative may authorize protocol changes by telephone or electronic means if he/she is not physically present at the time urgent or critical changes are required. Any authorization for such changes made as above must be documented appropriately and followed by a properly prepared written protocol amendment. The amendment must be signed and dated by the Study Director within 45 days of the effective date(s).
  • All deviations from the protocol and SOPs and the reasons of the deviations will be documented and acknowledged by the Study Director. The Sponsors Representative will be informed promptly of the occurrence of any deviations that might affect the results of the study, and any corrective actions taken. Protocol and SOP deviations that could impact data interpretation will be included in the final report.
• 6 Archiving of Materials
  • Test article preparation, test article tracking, in-life data, protocol, protocol amendments (if applicable), and the original final report generated as a result of this study will be archived.
• 7 STATISTICAL ANALYSIS
  • The following section does not apply to data recorded on unscheduled occasions. Such data will be reported on an individual basis.
  • All numerical data will be subjected to calculation of group means and standard deviations by using Microsoft Excel software, unless otherwise stated hereafter. These descriptive statistics will be presented for each dataset of interest, as determined by the variable to be analyzed and the dataset classification variables (for example: sex, measurement occasion, and any other relevant variable that can be used to specify on which subdivision the descriptive statistics have to be reported).
  • If a dataset has less than three non-missing values in each group, then the following inferential data analysis will not be conducted. No inferential data analysis will be conducted on toxicokinetic parameters and semi-quantitative data such as: urine protein, urine pH, urine bilirubin, urine occult blood, urine glucose, and urine ketones.
  • Whenever there are more than two groups, the homogeneity of the group variances will be evaluated using Levene's test at the 0.05 significance level. If differences between group variances are not found to be significant (p>0.05), then a parametric one-way analysis of variance (ANOVA) will be performed. When significant differences among the means are indicated by ANOVA test (p≤0.05), Dunnett's test will be used to perform the group mean comparisons between the control group and each treated group.
  • If Levene's test indicates heterogeneous group variances (p≤0.05) and the data set contains just positive values, log transformation will be performed. If transformed data still fail the test for homogeneity of variance (p≤0.05) or where the data contain zero and/or negative values, then the non-parametric Kruskal-Wallis test will be used to compare all considered groups.

When Kruskal-Wallis test is significant (p≤0.05), Dunnett's test on ranks will be used to perform the pairwise group comparisons of interest.

• • Whenever there are only two groups to compare, Levene's test will be performed as described above but a two-sample t-test will replace the one-way ANOVA, a Wilcoxon rank-sum test will be performed instead of the Kruskal-Wallis and, no Dunnett's tests or Dunnett's tests on ranks will be performed.
  • Each pairwise group comparisons of interest will be conducted via a two-sided test at the 5% significance level. Significant results will be reported as either p≤0.001, p≤0.01, or p≤0.05, where p represents the observed probability.

Results

The results of the study are depicted in FIGS. 25, 27 and 28.

FIG. 25 shows performance of construct designated “91-Conv-31” (structure displayed in FIG. 22) in an in vivo study in terms of Factor XI activity knock-down. The effect of different dosages (expressed in mg/kg) and of single or multiple dosing at the beginning are shown and compared to a negative control (saline).

Efficient and unexpectedly long-lasting knock-down is apparent.

FIG. 26 shows the molecular mechanism underlying the tests for targeting specificity as performed in the course of an in vivo study.

APTT stands for activated partial thromboplastin time. It measures the activity of intrinsic pathway of clotting that is impacted by factors like FXI. PT stands for prothrombin time which evaluates the integrity of extrinsic pathway of clotting that looks at the presence of factors like VII, V, X, prothrombin and fibrinogen.

FIG. 27 shows the read-out of the tests illustrated in FIG. 26.

The % FXI plasma activity (FIG. 25), together with APTT and PT data (FIG. 27) demonstrate that the molecule specifically targets FXI and does not have any off-target effect on the extrinsic clotting pathway.

FIG. 28 presents data demonstrating a lack of side effects. A panel liver function and hematology parameters have been assessed. In particular, no elevated levels of liver enzymes and no changes in hematology parameters could be found.

Claims

1. An oligomeric compound that inhibits expression of FXI, comprising a first nucleobase sequence that is at least partially complementary to at least a portion of RNA transcribed from an FXI gene, wherein said first nucleobase sequence is selected from the sequences selected from the group consisting of SEQ ID NOs 1 to 250, and SEQ ID NOs 1251 to 1500.

2. An oligomeric compound according to claim 1, further comprising a second nucleobase sequence that is at least partially complementary to said first nucleobase sequence and is selected from the group consisting of: SEQ ID NOs 251 to 500, and SEQ ID NOs 1501 to 1750.

3-12. (canceled)

13. An oligomeric compound that inhibits expression of FXI, comprising at least a first region of linked nucleosides that is at least partially complementary to at least a portion of an RNA transcribed from an FXI gene, wherein said RNA is selected from the sequences selected from the group consisting of SEQ ID NOs 1001 to 1250.

14. An oligomeric compound according to claim 13, wherein said RNA is selected from the following sequences, or a portion thereof: SEQ ID NOs 1008, 1013, 1027, 1039, 1046, 1091, 1098, 1103, 1105, 1109, 1120, 1140, 1146, 1151, 1152, 1163, 1182, 1183, 1199, 1207, 1210, 1218, 1220, 1223, 1224, 1238.

15. An oligomeric compound according to claim 13, wherein said RNA is selected from the following sequences, or a portion thereof: SEQ ID NOs 1008, 1046, 1091, 1146, 1152, 1207.

16. An oligomeric compound according to claim 13, wherein said RNA is selected from the following sequences, or a portion thereof: SEQ ID NOs 1046, 1091, 1152.

17. An oligomeric compound according to claim 1, wherein said first region of linked nucleosides consists essentially of 18 to 20 linked nucleosides.

18. An oligomeric compound according to claim 2, wherein said second region of linked nucleosides consists essentially of 11 to 16, 12 to 15, or 13 to 16 linked nucleosides.

19. An oligomeric compound according to claim 2, comprising at least one complementary duplex region that comprises at least a portion of said first nucleoside region directly or indirectly linked to at least a portion of said second nucleoside region.

20. An oligomeric compound according to claim 19, wherein each of said first and second nucleoside regions has a 5′ to 3′ directionality thereby defining 5′ and 3′ regions respectively thereof.

21. An oligomeric compound according to claim 20, wherein the 5′ region of said first nucleoside region is directly or indirectly linked to the 3′ region of said second nucleoside region, for example by complementary base pairing, and/or wherein the 3′ region of said first nucleoside region is directly or indirectly linked to the 5′ region of said second nucleoside region.

22. An oligomeric compound according to claim 1, further comprising one or more ligands.

23. An oligomeric compound according to claim 21, wherein said one or more ligands are conjugated to said second nucleoside region.

24-28. (canceled)

29. An oligomeric compound according to claim 28, wherein said one or more carbohydrates comprise one or more N-Acetyl-Galactosamine moieties.

30-32. (canceled)

33. An oligomeric compound according to claim 19, wherein said oligomeric compound comprises a single strand comprising said first and second nucleoside regions, wherein said single strand dimerises whereby at least a portion of said first nucleoside region is directly or indirectly linked to at least a portion of said second nucleoside region so as to form said at least partially complementary duplex region.

34-35. (canceled)

36. An oligomeric compound according to claim 34, wherein said hairpin loop comprises 4 or 5 linked nucleosides.

37-73. (canceled)

74. An oligomeric compound according to claim 1, wherein one or more nucleosides of the first nucleoside region and/or the second nucleoside region is an inverted nucleoside and is attached to an adjacent nucleoside via the 3′ carbon of its sugar and the 3′ carbon of the sugar of the adjacent nucleoside, and/or one or more nucleosides of the first nucleoside region and/or the second nucleoside region is an inverted nucleoside and is attached to an adjacent nucleoside via the 5′ carbon of its sugar and the 5′ carbon of the sugar of the adjacent nucleoside.

75-76. (canceled)

77. An oligomeric compound that inhibits expression of FXI, comprising at least a first region of linked nucleosides having at least a first nucleobase sequence selected from the group consisting of: constructs SEQ NOs 501 to 750, and constructs SEQ NOs 1751 to 2000.

78. An oligomeric compound according to claim 77, further comprising at least a second region of linked nucleosides having at least a second nucleobase sequence that is at least partially complementary to said first nucleobase sequence, wherein said second nucleobase sequence is a modified sequence and is selected from the group consisting of construct NOs 751 to 1000, and constructs NOs 2001 to 2250.

79-87. (canceled)

88. An oligomeric compound according to claim 86 or 87, further comprising one or more ligands.

89-94. (canceled)

95. An oligomeric compound according to claim 88 wherein said one or more carbohydrates comprise one or more N-Acetyl-Galactosamine moieties.

96-100. (canceled)

101. A composition comprising an oligomeric compound according to claim 1, and a physiologically acceptable excipient.

102-103. (canceled)

104. A method of treating a disease or disorder comprising administering an oligomeric compound according to claim 1 to an individual in need of treatment.

105-109. (canceled)