EA045398B1 - COMPOSITIONS AND METHODS FOR INHIBITION OF HEPATITIS B VIRUS GENE EXPRESSION - Google Patents

Description

Prerequisites for creating the invention

The present invention relates to double-stranded ribonucleic acids (dsRNAs) and their use in mediating RNA interference to inhibit the expression of genes necessary for the replication and pathogenesis of the hepatitis B virus, in particular, to inhibit viral polymerase, surface antigen, E antigen and X protein. Moreover, the use of these lncRNAs for the treatment or prevention of chronic liver diseases/disorders, inflammation, fibrotic conditions and proliferation disorders such as cancer resulting from hepatitis B virus infection is also part of the present invention.

Hepatitis B virus is a strictly hepatotropic virus containing double-stranded DNA. Although the genetic material is DNA, the replication cycle involves a reverse transcription step that copies pregenomic RNA into DNA. To perform this important step, the virus-encoded polymerase has reverse transcriptase activity. According to the classification, the hepatitis B virus belongs to the hepadnaviruses and belongs to the family Hepadnaviridae. Primary infection of adults with the hepatitis B virus causes acute hepatitis with symptoms of organ inflammation, fever, jaundice and elevated levels of liver transaminases in the blood. About 95% of cases of acute hepatitis resolve without treatment. Patients who are unable to overcome the viral infection suffer chronic progression of the disease over many years, with an increased risk of developing cirrhosis or liver cancer. Perinatal transmission to newborns from mothers infected with hepatitis B virus also leads to chronic hepatitis. Treatments for chronic hepatitis B infection are limited and only in some cases lead to complete and long-term remission. Additional clinical and therapeutic complications occur in patients with hepatitis B virus coinfected with hepatitis C virus, hepatitis D virus, or human immunodeficiency virus.

The hepatitis B virus is transmitted through blood or blood products, semen, vaginal secretions, or saliva. Drug use and sexual intercourse are risk factors and support the spread of the virus. Contact of damaged mucosal epithelium with infected body fluids may be sufficient for infection. The incubation period ranges from 40 to 200 days. The risk of infection is proportional to the number of hepatitis B virus particles received. Infants are often infected perinatally from mothers who have hepatitis B virus, which is a major health problem in endemic areas.

Approximately 2 billion people are infected with hepatitis B virus and 400 million are chronic carriers. Areas of widespread distribution are Africa and Southeast Asia with a local concentration of infected individuals of 20-80%.

Based on sequence homology, hepatitis B viruses are classified into genotypes A-H; the most important of which are genotypes A-D. Genotype A is often found in Northwestern Europe, the USA, South and Central America. Genotypes B and C predominate in China, Japan, Indonesia and other East Asian countries. Genotype D is found in Southern Europe, North Africa and South Africa. The course of the disease and response to pharmaceutical treatment differ between genotypes.

Infectious particles of the hepatitis B virus have a diameter of approximately 42 nm. The outer bilayer membrane contains large, medium and small surface proteins. The cognate receptor on hepatocytes for surface protein binding and internalization is unknown. Multiple copies of the core protein form a spherical nucleocapsid structure within the viral particle. Each nucleocapsid carries partial double-stranded DNA as genetic material along with a viral polymerase.

Once taken up by hepatocytes, the nucleocapsid is transported into the nucleus and the DNA is released. DNA strand synthesis is completed and the double-strand breaks are repaired to form a 3.2-kb covalently closed circular (ccc) supercoiled DNA. cccDNA acts as a template for the transcription of four major viral mRNAs, 3.5 each; 2.4; 2.1 and 0.7 t.n. length. All mRNAs are 5'-capped and polyadenylated at the 3' end. There is sequence overlap at the 3' end between all four mRNAs.

3.5 kb mRNA acts as a template for the formation of core protein and polymerase. Additionally, this transcript acts as a pregenomic replication intermediate and allows the viral polymerase to initiate reverse transcription of DNA. The core protein is required for the formation of the nucleocapsid. In addition, subsequent processing steps convert some core proteins into secreted E antigen. The amount of E antigen in the blood correlates with hepatitis B virus replication in the liver and is an important diagnostic marker for monitoring the course of the disease.

mRNAs of 2.4 and 2.1 kb. carry open reading frames pre-S1, pre-S2 and S2 for the expression of large, medium and small surface antigens of the virus. The S antigen is associated with full-fledged infectious particles. Additionally, the blood of an infected patient also contains non-infectious particles formed only from S antigen, free of genomic DNA or polymerase. The function of these particles is not fully understood. Complete and sustained depletion of detectable S antigen

- 1045398 in the blood is considered a reliable indicator of hepatitis B virus clearance and thus successful treatment.

0.7 kb mRNA encodes protein X. This gene product is important for efficient transcription of viral genes and also acts as a transactivator for host gene expression. The latter activity appears to be important for the transformation of hepatocytes during the development of liver cancer.

Recombinant hepatitis B virus S antigen is used for vaccination. Administration of three doses of formulated S antigen at the time points of day 1, 4 weeks, and 6 months usually produces sufficient neutralizing antibody titers. Vaccinated patients are protected for 10 years or longer. However, vaccines are not substitutes for therapy.

Patients with acute hepatitis B virus infection are not treated because of the high natural remission rate. However, patients with detectable S antigen, E antigen, or viral DNA in the blood for more than 6 months are considered chronically infected. Nucleoside analogs as inhibitors of reverse transcriptase activity are the first line of treatment for many patients. Lamivudine, tenofovir, or entecavir inhibit hepatitis B virus replication, sometimes to undetectable levels. The most important effects are improved liver function and reduced liver inflammation. However, only a few patients achieve complete and lasting remission after treatment. Moreover, the hepatitis B virus develops drug resistance with increasing duration of treatment. This is especially critical for patients coinfected with hepatitis B and human immunodeficiency viruses. Both viruses are susceptible to nucleoside analogue drugs and may jointly develop resistance to them.

The second treatment is the administration of interferon alpha. In this case, the patient receives large doses of interferon alpha for 6 months. Depending on the genotype of the virus, more than 50% of chronic infections can be treated. However, the Asian genotype B gives a very weak response rate. Coinfection with hepatitis D or human immunodeficiency virus renders interferon alpha therapy completely ineffective. Interferon alfa therapy is not recommended for patients with significant liver damage and severe fibrotic conditions.

Despite significant advances in the treatment of hepatitis B virus, there remains a need for an agent that can selectively and effectively suppress viral gene expression, block replication, and consistently reduce viral load in chronically infected patients.

Double-stranded RNA (dsRNA) molecules have been shown to block gene expression through a highly conserved regulatory mechanism known as RNA interference (RNAi). The present invention provides double-stranded ribonucleic acid (dsRNA) molecules, as well as compositions and methods for inhibiting hepatitis B virus gene expression, in particular hepatitis B virus gene expression, in a cell, tissue or mammal using such lncRNAs. The present invention also provides compositions and methods for treating or preventing pathological conditions and diseases caused by hepatitis B virus infection, such as chronic liver diseases/disorders, inflammation, fibrotic conditions and proliferation disorders such as cancer.

Brief description of the invention

The present invention provides double-stranded ribonucleic acid (dsRNA) molecules capable of selectively and effectively reducing hepatitis B virus gene expression. The use of hepatitis B virus RNAi provides a method for the therapeutic and/or prophylactic treatment of diseases/disorders associated with chronic liver diseases/disorders, inflammation, fibrotic conditions and proliferation disorders such as cancer; these methods involve introducing lncRNA targeting the hepatitis B virus into a human or animal body.

In one preferred embodiment, the disclosed lncRNA molecule is capable of inhibiting hepatitis B virus gene expression by at least 60%, preferably by at least 70%, and most preferably by at least 80%.

In one embodiment, the present invention provides double-stranded ribonucleic acid (dsRNA) molecules for inhibiting hepatitis B virus gene expression, particularly the expression of genes related to hepatitis B virus replication or pathogenesis. The lncRNA includes at least two sequences that are complementary to each other. lncRNA includes a coding strand, including a first sequence, and a non-coding strand, including a second sequence, see the sequences presented in the sequence list, as well as specific lncRNA pairs in the accompanying tables. 1 and table. 2. In one embodiment, the coding sequence includes a sequence that is at least 90% identical to at least a portion of the hepatitis B virus mRNA. The sequence is located in the region of complementarity of the coding strand to the non-coding strand, preferably within nucleotides 2-7 with 5 'the end of the non-coding chain. In one preferred embodiment, the lncRNA specifically targets a hepatitis B virus gene that encodes a core protein, viral polymerase, surface antigen, E antigen, or protein X. Moreover, it is preferred that the lncRNA specifically targets a consensus sequence that is highly conserved in sequence nucleic acid among the genomic sequences of hepatitis B virus genotypes A, B, C and D. Preferably, the consensus sequence is at least 13 contiguous nucleotides in length, more preferably at least 17 contiguous nucleotides, and most preferably at least 19 consecutive nucleotides. Preferred highly conserved nucleic acid sequences are presented in table. 5.

In one embodiment, the non-coding strand includes a nucleotide sequence substantially complementary to at least a portion of the mRNA encoding said hepatitis B virus gene, and a region of complementarity most preferably less than 30 nucleotides in length. Moreover, it is preferable that the length of the lncRNA molecules of the present invention described in the present invention (duplex length) is in the range of 16 to 30 nucleotides, in particular in the range of 18 to 28 nucleotides. Particularly useful in the context of the present invention are duplex lengths of approximately 19, 20, 21, 22, 23 or 24 nucleotides. The most preferred duplex regions are 19, 21 or 23 nucleotides in length. The lncRNA, when delivered into a hepatitis B virus-infected cell, inhibits hepatitis B virus gene expression in vitro by at least 60%, preferably at least 70%, and most preferably by at least 80%.

Brief description of the figures

Fig. 1. Table 1. Core sequences of lncRNAs targeting the hepatitis B virus gene. Capital letters indicate RNA nucleotides.

Fig. 2 Table. 2. Characterization of lncRNAs targeting hepatitis B virus: single dose activity study. Capital letters indicate RNA nucleotides, lower case letters c, g, a and u indicate 2'-O-methyl-modified nucleotides, s stands for phosphorothioate, dT stands for deoxythymidine, capital letters A, C, G, U followed by f indicate 2'-fluoro nucleotide. The lowercase p denotes 5'-phosphate. (invdT) stands for inverted deoxythymidine (3'3' linked).

Fig. 3. Table. 3. Characteristics of lncRNAs targeting hepatitis B virus: stability. t ¹ / ₂ = half-life of the chain as defined in the examples.

Fig. 4. Table. 4. Core sequences of lncRNAs targeting the hepatitis B virus gene and their modified copies. Capital letters indicate RNA nucleotides, lower case letters c, g, a and u indicate 2'-O-methyl-modified nucleotides, s indicates phosphorothioate, dT indicates deoxythymidine, capital letters A, C, G, U followed by f indicate 2'-fluoro nucleotide. The lowercase p denotes 5'-phosphate. (invdT) stands for inverted deoxythymidine (3'3' linked).

Fig. 5. Table. 5. Target site sequences of lncRNAs targeting hepatitis B virus and their degree of overlap with respect to hepatitis B virus genotypes A, B, C and D. n=number of available hepatitis B virus (HBV) sequences of each genotype.

Fig. 6. Table. 6. Account numbers in the NCBI Genbank database of genomic sequences of the hepatitis B virus.

Fig. 7. Table. 7. Comparison of the efficiency of knockdown and overlap of HBV genomes for a single lncRNA and their combinations. The study of activity for a combination of two lncRNAs was carried out at a final concentration of 10 nM and 1 nM with the highest efficiency of lncRNAs in accordance with Table. 2 and compared with the corresponding data.

Fig. 8. Table. 8. Negative control lncRNA sequences used in the psiCHECK™-2 screening assay.

Detailed Description of the Invention

Attached table 1 refers to preferred molecules used as lncRNAs in accordance with the present invention. The present invention also provides for modified lncRNA molecules, which are, in particular, disclosed in the accompanying table. 2, presenting illustrative examples of modified lncRNA molecules according to the present invention. As indicated above in the text, table. 2 contains illustrative examples of modified lncRNAs according to the present invention (thereby, the corresponding coding strand and non-coding strand are shown in this table). The relationship of the preferred unmodified molecules shown in table. 1, with modified lncRNAs from table. 2 is illustrated in table. 4. Meanwhile, exemplary modifications of these lncRNA components according to the present invention are provided in the present invention as examples of modifications.

In table 3 shows the selective biologically, clinically and pharmaceutically significant parameters of certain lncRNA molecules according to the present invention.

Some of the preferred lncRNA molecules are presented in the accompanying table. 1, wherein, among other things and preferably, the coding strand is selected from the group consisting of the nucleic acid sequences set forth in SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7 and 26. The non-coding strand is selected from the group consisting of from the nucleic acid sequences shown in SEQ ID NOs: 157, 158, 160, 161, 162, 163, 164 and 186. Accordingly, the lncRNA molecule of the present invention

- 3 045398 may, inter alia, include sequence pairs selected from the group consisting of SEQ ID

NO: 1/157, 2/158, 3/160, 4/161, 5/162, 6/163, 7/164 and 26/186. In the context of the specific lncRNA molecules provided herein, SEQ ID NO pairs refer to the corresponding coding and non-coding strand sequences (5' to 3') as shown in the tables.

In one embodiment, the lncRNA molecules include a non-coding strand with a 3' overhang that is 1-5 nucleotides in length, preferably 1-2 nucleotides in length. Preferably, the sticky end of the non-coding strand contains uracil or nucleotides that are complementary to mRNA encoding a protein that is essential for replication or pathogenesis of the hepatitis B virus, in particular core protein, viral polymerase, surface antigen, E antigen and X protein. In another preferred embodiment implementations, said lncRNA molecules include a coding strand with a 3' overhang of 1-5 nucleotides in length, preferably 1-2 nucleotides in length. Preferably, said sticky end of the coding strand contains uracil or nucleotides that are identical to the mRNA encoding a protein required for replication or pathogenesis of the hepatitis B virus.

In another preferred embodiment, lncRNA molecules include a coding strand with a 3' overhang of 1-5 nucleotides in length, preferably 1-2 nucleotides in length, and a non-coding strand with a 3' overhang of 1-5 nucleotides in length, preferably 1-2 nucleotides in length. Preferably, said sticky end of the coding strand contains uracil or nucleotides that are at least 90% identical to pregenomic RNA and/or mRNA encoding a protein required for replication or pathogenesis of the hepatitis B virus, and said sticky end of the non-coding strand contains uracil or nucleotides, that are at least 90% complementary to an mRNA encoding a protein essential for hepatitis B virus replication or pathogenesis.

The lncRNA molecules of the present invention may consist of nucleotides existing in nature, or may consist of at least one modified nucleotide, such as a 2'O-methyl-modified nucleotide, an inverted deoxythymidine, a nucleotide including a 5'phosphothioate group, and a terminal nucleotide , bound to a cholesterol derivative or bisdecylamide group of dodecanoic acid. The 2'-modified nucleotides may have the additional benefit of inhibiting certain immunostimulatory factors or cytokines when the lncRNA molecules of the present invention are administered in vivo, for example, in a medical setting. Alternatively and without limitation, the modified nucleotide may be selected from the group consisting of: 2'-deoxy-2'-fluoro-modified nucleotide, 2'-deoxy-modified nucleotide, closed nucleotide, dehydrogenated nucleotide, 2'-amino -modified nucleotide, 2'-alkyl modified nucleotide, morpholino nucleotide, phosphoramidate and nucleotide including a base not found in nature. In one preferred embodiment, the lncRNA molecules contain at least one of the following modified nucleotides: a 2'-O-methyl modified nucleotide, a nucleotide including a 5'-phosphothioate group, and deoxythymidine. Preferred lncRNA molecules that contain modified nucleotides are presented in table. 2. In another preferred embodiment, one of the deoxythymidine nucleotides at the 3' end of both strands is inverted deoxythymidine.

In a preferred embodiment, lncRNA molecules according to the present invention contain modified nucleotides, detailed in the sequences presented in table. 2. In one preferred embodiment, the lncRNA molecule of the present invention includes pairs of sequences that are selected from the group consisting of SEQ ID NO: 1/157, 2/158, 3/160, 4/161, 5/162, 6/ 163, 7/164 and 26/186, and includes sticky ends on the non-coding and/or coding strand, consisting of 1-2 deoxythymidines. In one preferred embodiment, the lncRNA molecule of the present invention includes pairs of sequences that are selected from the group consisting of SEQ ID NO: 1/157, 2/158, 3/160, 4/161, 5/162, 6/163, 7/164 and 26/186, and contains modifications described in detail in table. 2. Preferred lncRNA molecules including modified nucleotides are listed in Table. 2-4, of which the most preferred lncRNA molecules are presented in SEQ ID No: 321/485, 322/486, 324/488, 325/489, 326/490, 327/491, 328/492 and 350/514.

In another embodiment, lncRNAs according to the present invention contain modified nucleotides at positions other than those disclosed in table. 2. In one preferred embodiment, two dioxythymidine nucleotides are located at the 3' ends of both strands of the lncRNA molecule. Preferably, said deoxythymidine nucleotides form a cohesive end.

In one embodiment, lncRNA molecules of the present invention include coding and non-coding strands, both strands having a half-life that is at least 0.9 hours. In one preferred embodiment, lncRNA molecules of the present invention include coding and non-coding strands, wherein both chains have a half-life of at least 48 hours, preferably in human serum.

In another embodiment, a nucleic acid sequence is provided that encodes a coding strand and/or a non-coding strand included in a lncRNA as defined herein.

The invention also provides cells that contain at least one of the lncRNAs according to the present invention. The cells are preferably mammalian cells, such as human cells. Moreover, non-human tissues and/or organisms that include lncRNA molecules as defined herein are embodiments of the present invention, provided that said non-human organism is particularly useful for research use or as a research tool, for example in drug research.

In addition, the present invention relates to a method of inhibiting the expression of a hepatitis B virus gene, in particular a hepatitis B virus gene that encodes a core protein, viral polymerase, surface antigen, E antigen or X protein, in a cell, tissue or organism, including the following steps :

(a) introducing into a cell, tissue or organism double-stranded ribonucleic acid (dsRNA), as defined in the present invention; and (b) maintaining the cell, tissue or organism obtained in step (a) for a time sufficient to achieve degradation of the hepatitis B virus gene transcript mRNA, thereby inhibiting the expression of the hepatitis B virus gene in the cell.

The present invention also relates to pharmaceutical compositions that contain at least one type of lncRNA according to the present invention. These pharmaceutical compositions are particularly useful for inhibiting hepatitis B virus gene expression in a cell, tissue or organism.

Preferably, said at least one type of double-stranded ribonucleic acid molecule according to the present invention is targeted to a region of pregenomic RNA and/or mRNA encoding a protein required for the replication or pathogenesis of a hepatitis B virus gene. More preferably, said target region of the double-stranded ribonucleic acid molecule according to The present invention includes a consensus sequence that is highly conserved among the genomic sequences of hepatitis B virus genotypes A, B, C and D, and said consensus sequence is at least 13 contiguous nucleotides in length, preferably at least 17 contiguous nucleotides, most preferably at least 19 consecutive nucleotides. Preferred highly conserved nucleic acid sequences are listed in Table. 5. Pharmaceutical compositions can be used to treat patients infected with any genotype of hepatitis B virus or coinfected with different genotypes of hepatitis B virus.

In case the pharmaceutical composition contains at least two kinds of double-stranded ribonucleic acid molecules according to the present invention, it is preferable that the targets of said double-stranded ribonucleic acid molecules are different from each other. The pharmaceutical compositions of the present invention can be used to treat patients and to prevent the development of resistance of the hepatitis B virus to the pharmaceutical compositions. In a preferred embodiment, the pharmaceutical compositions of the present invention contain a combination of lncRNA molecules detailed in the sequences presented in table. 7. In one preferred embodiment, the pharmaceutical compositions of the present invention contain combinations of lncRNA pairs that are selected from the group consisting of SEQ ID NO: 322/486 and 333/497, 322/486 and 346/510, 322/486 and 330 /494 and 322/486 and 324/488.

The pharmaceutical compositions described above may also contain pharmaceutically acceptable carrier(s), solvent(s) and/or excipient(s).

In another embodiment, the present invention provides methods for treating, preventing or controlling chronic liver diseases/disorders, inflammation, fibrotic conditions and/or proliferative disorders, such as cancer, caused by the hepatitis B virus; said method comprising administering to a subject in need of such treatment, prevention or control a therapeutically or prophylactically effective amount of one or more lncRNAs of the present invention. Preferably, said subject is a mammal, most preferably a human patient.

In one embodiment, the present invention provides a method of treating a subject having a condition caused by hepatitis B virus infection. Such conditions include disorders associated with chronic liver diseases/disorders, inflammation, fibrotic conditions and/or proliferation disorders such as cancer, such as described above. In this embodiment, the lncRNA acts as a therapeutic agent to control the expression of a hepatitis B virus gene. The method includes administering to a patient (e.g., a human) a pharmaceutical composition according to the present invention, thereby suppressing the expression of the hepatitis B virus gene. Due to its high specificity, lncRNA according to The present invention specifically targets hepatitis B virus gene mRNA. In one preferred embodiment, the described lncRNA specifically reduces hepatitis B virus mRNA levels and does not directly affect the expression and/or mRNA levels of non-target genes in the cell.

In one preferred embodiment, the disclosed lncRNA reduces hepatitis B virus mRNA levels in the liver in vivo by at least 60%, preferably by at least 70%, most preferably by at least 80%. In another embodiment, the described lncRNAs reduce hepatitis B virus mRNA levels in vivo for at least 4 days. In another preferred embodiment, the lncRNAs of the present invention are used for the preparation of a pharmaceutical composition for the treatment of chronic liver diseases/disorders, inflammation, fibrotic conditions and/or proliferation disorders such as cancer. Diseases that can be treated with this pharmaceutical composition include, but are not limited to: chronic hepatitis (CH), liver cirrhosis (LC) and hepatocellular carcinoma (HCC).

In another embodiment, the present invention provides vectors for inhibiting the expression of a hepatitis B virus gene in a cell, in particular, a hepatitis B virus gene, that contain a regulatory sequence operably linked to a nucleotide sequence that encodes at least one strand of lncRNA molecules according to the present invention .

In another embodiment, the present invention provides a cell that contains a vector for inhibiting hepatitis B virus gene expression in the cell. Said vector contains a regulatory sequence operably linked to a nucleotide sequence that encodes at least one strand of the lncRNA molecule according to the present invention. It is preferable that said vector contains, in addition to said regulatory sequence, a sequence that encodes at least one coding strand of a lncRNA according to the present invention and at least one non-coding strand of said lncRNA. It is also provided that the claimed cell contains two or more vectors that contain, in addition to the specified regulatory sequences, a sequence defined in the present invention that encodes (or sequences that encode) at least one chain of lncRNA molecules according to the present invention.

In one embodiment, the method includes administering a composition that contains a lncRNA, wherein the lncRNA includes a nucleotide sequence that is complementary to at least a portion of the RNA transcript of a hepatitis B virus gene of a mammal being treated. As stated above, vectors and cells comprising nucleic acid molecules that encode at least one chain of lncRNA molecules defined in the present invention can also be used as pharmaceutical compositions and can therefore also be used in methods of treating a subject in need of medical intervention described in the present invention. It is also noteworthy that these embodiments relating to pharmaceutical compositions and corresponding methods of treating a human subject also relate to approaches such as gene therapy approaches.

Hepatitis B virus gene-specific lncRNA molecules provided in the present invention, or nucleic acid molecules encoding individual strands of these lncRNA molecules according to the present invention, can also be incorporated into vectors and used as gene therapy vectors for human patients. Gene therapy vectors can be delivered to a subject by, for example, intravenous injection, local administration (see US Pat. No. 5,328,470) or by stereotactic injection (see, for example, Chen et al. Proc. Natl. Acad. Sci. USA (1994) 91:3054 -3057). The gene therapy vector pharmaceutical preparation may comprise the gene therapy vector in a suitable solvent or may include a sustained release matrix into which a gene delivery vehicle is included. Alternatively, if a complete gene delivery vector can be prepared readily from recombinant cells, such as retroviral vectors, the pharmaceutical preparations may comprise one or more cells that produce the gene delivery system.

In another aspect of the present invention, hepatitis B virus-specific lncRNA molecules that modulate hepatitis B virus gene expression activity are expressed from transcription units inserted into DNA or RNA vectors (see, for example, Skillern A et al., international PCT Application No. WO 00/22113). These transgenes can be introduced as a linear construct, a circular plasmid, or a viral vector that can be inserted into the host genome and will be inherited as a transgene integrated into the host genome. The transgene can also be engineered to be inherited as an extrachromosomal plasmid (Gassmann et al., Proc. Natl. Acad. Sci. USA (1995) 92:1292).

Individual lncRNA strands can be transcribed from promoters in two separate expression vectors and cotransfected into target cells. Alternatively, each individual lncRNA strand can be transcribed from promoters, both of which are located on the same expression plasmid. In a preferred embodiment, lncRNA is expressed as an inverted repeat united by a linker polynucleotide sequence, in

- 6 045398 as a result of which lncRNA forms a stem-loop structure.

Vectors expressing recombinant lncRNA are preferably DNA plasmids or viral vectors. Viral vectors expressing lncRNAs can be constructed based on, but not limited to, adeno-associated virus (for review, see Muzyczka et al., Curr. Topics Micro. Immunol. (1992) 158:97-129); adenovirus (see, for example, Berkner et al., BioTechniques (1998) 6:616; Rosenfeld et al. Science (1991) 252:431-434; and Rosenfeld et al. Cell (1992) 68:143-155); or alphavirus, as well as others known in the art. Retroviruses have been used to introduce a variety of genes into various cell types, including epithelial cells, in vitro and/or in vivo (see, for example, Danos and Mulligan, Proc. Natl. Acad. Sci. USA (1998) 85:6460-6464) . Recombinant retroviral vectors capable of transducing and expressing genes integrated into a cell's genome can be produced by transfecting the recombinant retroviral genome into suitable packaging cell lines such as PA317 and Psi-CRIP (Comette et al., Human Gene Therapy (1991) 2:5 -10; Cone et al., Proc. Natl. Acad. Sci. USA (1984) 81:6349). Recombinant adenoviral vectors can be used to infect a wide variety of cells and tissues in susceptible hosts (eg, rat, hamster, dog and chimpanzee) (Hsu et al., J. Infectious Disease, (1992) 166:769); they have the advantage of not requiring miotically active cells for infection.

The promoter driving the expression of lncRNA in the DNA plasmid or viral vector of the present invention may be a eukaryotic RNA polymerase I (eg, ribosomal RNA promoter), RNA polymerase II (eg, CMV early promoter or actin promoter, or snRNA U1 promoter ) or preferably an RNA polymerase III promoter (for example, a U6 snRNA or 7SK RNA promoter) or a prokaryotic promoter, for example, a T7 promoter; the provided expression plasmid also encodes T7 RNA polymerase required for transcription from the T7 promoter. The promoter may also direct expression of the transgene to the pancreas (see, for example, the insulin regulatory sequence for the pancreas (Bucchini et al., Proc. Natl. Acad. Sci. USA (1986) 83:2511-2515).

Expression of a transgene can also be precisely regulated, for example, by using an inducible regulatory sequence and expression systems, such as a regulatory sequence that is sensitive to certain physiological regulators, such as circulating blood glucose levels, or hormones (Docherty et al., FASEB J. ( 1994) 8:20-24). Such inducible expression systems suitable for controlling transgene expression in cells or mammals include regulation by ecdysone, estrogen, progesterone, tetracycline, chemical dimerization inducers and isopropyl beta-D1-thiogalactopyranoside (IPTG). One skilled in the art will be able to select an appropriate regulatory/promoter sequence based on the intended use of the lncRNA transgene.

Recombinant vectors for expressing lncRNA molecules are preferably delivered as described below and maintained in target cells. Alternatively, viral vectors that provide transient expression of lncRNA molecules can be used. Such vectors can be entered repeatedly if necessary. Once expressed, lncRNA binds to target RNA and modulates its function or expression. Delivery of lncRNA expression vectors may be systemic, for example, by intravenous or intramuscular administration to target cells collected from a patient followed by reintroduction to the patient, or may be by any other route that allows administration to the desired target cell.

DNA plasmids expressing lncRNAs are typically transfected into target cells as a complex with cationic lipid carriers (eg, Oligofectamine) or non-cationic lipid-based carriers (eg, Transit-TKO™). The present invention also contemplates multiple lipid transfections for lncRNA-mediated knockdowns targeting different regions of a single hepatitis B virus gene or multiple hepatitis B virus genes over a period of a week or more. Successful introduction of vectors according to the present invention into host cells can be studied using various known methods. For example, transient transfection can be identified using a reporter such as a fluorescent marker such as green fluorescent protein (GFP). Stable transfection of cells ex vivo can be confirmed by using markers that confer resistance to specific environmental factors (e.g., antibiotics or drugs) on transfected cells, such as resistance to hygromycin B.

The following detailed description discloses processes for creating and using lncRNAs and compositions containing lncRNAs for inhibiting the expression of a target gene of the hepatitis B virus, as well as compositions and methods for treating diseases and disorders caused by infection with the specified hepatitis B virus.

Definitions.

For convenience, the meaning of certain terms and phrases used in the present invention is set forth below by way of example and the accompanying claims. If there is an apparent discrepancy between the use of a term in other parts of this application and its meaning as given in this

- 7 045398 of this section, the definition from this section must prevail.

Each of G, C, A, U and T or dT, respectively, generally means a nucleotide that contains guanine, cytosine, adenine, uracil and deoxythymidine, respectively, as a base. However, the term ribonucleotide or nucleotide can also refer to a modified nucleotide, as described in more detail below, or to a substituent substituent group. Sequences including such substituent groups are embodiments of the present invention. As described in detail below, the lncRNA molecules described herein may also include overhangs, i.e. unpaired overhanging nucleotides that are not directly involved in the double-stranded RNA structure normally formed by the pair of coding strand and non-coding strand as defined herein. Often this overhang contains a deoxythymidine nucleotide, and in most embodiments, two deoxythymidines at the 3' end. Such sticky ends will be described and illustrated below.

The term hepatitis B virus gene as used in the present invention refers to genes required for the replication and pathogenesis of hepatitis B virus, in particular genes that encode core protein, viral polymerase, surface antigen, E antigen or X protein, and genes which encode their functional fragments. The term hepatitis B virus gene/sequence refers not only to the wild-type sequence/sequences, but also to mutations and changes that may be included in the gene/sequence. Accordingly, the present invention is not limited to the specific lncRNA molecules provided in the present invention. The present invention also relates to lncRNA molecules that include a non-coding strand that is at least 85% complementary to the corresponding RNA nucleotide region of the hepatitis B virus gene transcript that contains such mutations/changes.

The term consensus sequence as used in the present invention refers to at least 13 contiguous nucleotides, preferably at least 17 contiguous nucleotides, most preferably at least 19 contiguous nucleotides, which are highly conserved among the genomic sequences of genotypes A, B, C and D hepatitis B virus.

As used herein, the term target sequence refers to the sequential portion of the nucleotide sequence of an mRNA molecule generated by transcription of a hepatitis B virus gene, including mRNA that is the result of processing of the primary RNA transcription product.

The term chain including sequence as used in the present invention refers to an oligonucleotide comprising a chain of nucleotides that are described by sequence with reference to the use of standard nucleotide nomenclature. However, as described in detail in the present invention, such chain including sequence may also include modifications, such as modified nucleotides.

The term complementary as used in the present invention, unless otherwise indicated, when used to describe a first nucleotide sequence with respect to a second nucleotide sequence, refers to the ability of an oligonucleotide or polynucleotide comprising the first nucleotide sequence to hybridize and form a duplex structure under certain conditions with the oligonucleotide or a polynucleotide comprising a first nucleotide sequence. Complementary sequences, when used in the present invention, may also include (or may be formed solely by) non-Watson-Crick base pairs formed by non-naturally occurring and modified nucleotides, provided that the above requirements regarding their ability to hybridize are met.

Sequences designated as fully complementary involve the base pairing of oligonucleotides or polynucleotides comprising a first nucleotide sequence with an oligonucleotide or polynucleotide comprising a second nucleotide sequence over the entire length of the first and second nucleotide sequences.

However, if the first sequence is referred to in the present invention as being substantially complementary to the second sequence, the two sequences may be completely complementary, or they may hybridize to form one or more, but preferably no more than 13, non-complementary base pairs. .

The terms complementary, fully complementary, and substantially complementary in the present invention may be used to refer to the base correspondence between a coding strand and a non-coding strand of a lncRNA, or between a non-coding strand of a lncRNA and a target sequence, as will be understood from the context of their use.

The term double-stranded RNA, lncRNA molecule or lncRNA as used in the present invention refers to a ribonucleic acid molecule or complex of ribonucleic acid molecules having a duplex structure comprising two antiparallel and substantially complementary nucleic acid strands. The two chains forming the duplex structure can be represented

- 8 045398 represent different parts of one larger RNA molecule or can represent individual RNA molecules. When two strands are parts of one larger molecule, resulting in them being connected by a continuous chain of nucleotides between the 3' end of one strand and the 5' end of the corresponding other strand, forming a duplex structure, the connecting strand of RNA is referred to as a hairpin loop. When two strands are linked covalently by a strand other than a continuous strand of nucleotides between the 3' end of one strand and the 5' end of the corresponding other strand, forming a duplex structure, the connecting structure is referred to as a linker. RNA strands can have the same or different numbers of nucleotides. In addition to the duplex structure, lncRNA may include one or more sticky nucleotide ends. The nucleotides at said overhangs may include from 0 to 5 nucleotides, where 0 means no additional nucleotide/nucleotides forming the overhang, and where 5 means five additional nucleotides on the individual strands of the lncRNA duplex. These additional sticky ends are located at the 3' end of the individual strands. As will be described in detail below, lncRNA molecules that include only a sticky end on one of the two strands may also be useful and even preferred in the context of the present invention. The face end preferably contains from 0 to 2 nucleotides. Most preferably, two dT (deoxythymidine) nucleotides are found at the 3' end of both lncRNA strands. Also, two U (uracil) nucleotides can be used as sticky ends at the 3' end of both lncRNA strands. Accordingly, the term sticky end nucleotides refers to the unpaired nucleotide or nucleotides that protrude from the lncRNA duplex structure when the 3' end of one lncRNA strand protrudes beyond the 5' end of the other strand, or vice versa. For example, the noncoding strand contains 23 nucleotides and the coding strand contains 21 nucleotides, forming a two nucleotide overhang at the 3' end of the noncoding strand. Preferably, the two nucleotides of the overhang are completely complementary to the target gene mRNA. A blunt or blunt end means that there are no unpaired nucleotides at the end of the lncRNA, i.e. lack of sticky end nucleotides. A blunt-ended lncRNA is a lncRNA that is double-stranded throughout its entire length, i.e. sticky end nucleotides are absent at both ends of the molecule.

The term non-coding strand refers to a lncRNA strand that includes a region that is substantially complementary to the target sequence. The term complementarity region as used in the present invention refers to a region of a non-coding strand that is substantially complementary to a sequence, eg, a target sequence. If the region of complementarity is not completely complementary to the target sequence, complementarity violations are most permissible beyond nucleotides 2-7 from the 5' end of the non-coding strand.

The term coding strand as used in the present invention refers to a lncRNA strand that includes a region that is substantially complementary to a region of the non-coding strand. Substantially complementary means that preferably at least 85% of the overlapping nucleotides in the coding and non-coding strands are complementary.

Introducing into a cell, in relation to lncRNA, means promoting uptake or absorption into a cell, as understood by those skilled in the art. Absorption or uptake of lncRNAs can occur through spontaneous diffusion or active cellular processes or through the use of auxiliary agents or devices. The meaning of this term is not limited to cells in vitro; lncRNA can also be introduced into a cell if the cell is part of a living organism. In such a case, introduction into a cell would involve delivery to the body. For example, for in vivo delivery, lncRNAs can be injected into a tissue site or administered systemically. It is envisaged that, for example, lncRNA molecules according to the present invention are administered to a subject in need of medical intervention. Such administration may include injection of a lncRNA, vector or cell according to the present invention into a site affected by a disease in a specified subject, for example, into liver tissue/cells or into cancerous tissues/cells, such as liver cancer tissue. Injection is also provided, preferably in close proximity to the tissue affected by the disease. Introduction into cells in vitro includes methods known in the art, such as electroporation and lipofection.

As used herein, the term chronic liver disease/disorder refers to functional abnormalities of the liver lasting more than six months, which may be caused by infection with a virus. An example of a chronic liver disease/disorder is chronic hepatitis (CH).

The term inflammation as used herein refers to the biological response of body tissues to injury, irritation or disease, which may be caused by a noxious stimulus, such as pathogens, damaged cells or irritants. The inflammation is usually characterized by pain and swelling. The term inflammation is intended to encompass both acute responses, in which the inflammatory process is active (eg, neutrophils and white blood cells), and chronic responses, which are characterized by a slow progression, changes in the type of cells present at the site of inflammation, and the formation of connective tissue. One example of a disease caused by inflammation is fibrosis.

The term fibrotic conditions as used in the present invention refers to a functional problem of organs that may be caused by the growth of fibrous tissue. An example of this type

- 9 045398 disease is liver cirrhosis (LC).

The term proliferative and proliferation as used in the present invention refers to cells undergoing mitosis. Throughout the present invention, the term proliferation disorder refers to any disease/disorder that is characterized by unwanted or abnormal tissue proliferation. As used herein, the term proliferation disorder also refers to conditions in which unregulated and/or abnormal cell growth can lead to the development of an undesirable condition or disease, which may be malignant or benign.

The cancer being treated includes, but is not limited to, liver cancer, wherein said liver cancer may be selected from the group consisting of hepatocellular carcinoma (HCC), hepatoblastoma, mixed liver cancer, mesenchymal tissue-derived cancer, among others. liver sarcoma or cholangiocarcinoma.

The terms suppress, inhibit expression and knockdown in relation to the hepatitis B virus gene refer in the present invention to at least partial suppression of the expression of the hepatitis B virus gene, which is manifested by a decrease in the amount of mRNA transcribed from the hepatitis B virus gene that can be isolated from the first cell of a group of cells in which the hepatitis B virus gene is transcribed and which have been/have been treated in such a way that the expression of the hepatitis B virus gene is inhibited, in comparison with a second cell of a group of cells substantially identical to the first cell of a group of cells, but which were not subjected to such treatment (control cells). The degree of inhibition is usually expressed in terms of:

(mRNA in control cells) - (mRNA in treated cells) ^χ 100% (mRNA in control cells)

Alternatively, the degree of inhibition can be thought of in the context of a decrease in a parameter operably associated with hepatitis B virus gene transcription, for example, the amount of protein encoded by the hepatitis B virus gene that is secreted by the cell, or the number of cells exhibiting a particular phenotype.

As illustrated in the accompanying Examples and accompanying Tables provided herein, the lncRNA molecules of the present invention are capable of inhibiting hepatitis B virus expression by at least 60%, preferably by at least 70%, most preferably by at least 80% in an assay in vitro, i.e. in vitro. The term in vitro as used in the present invention includes, but is not limited to, cell culture assays. One skilled in the art can readily determine the extent of such inhibition and associated effects, particularly in light of the assays presented in the present invention.

The term non-target as used in the present invention refers to all non-target mRNAs in the transcriptome that are predicted by in silico methods to hybridize to the described lncRNA based on sequence complementarity. The lncRNA of the present invention preferably specifically inhibits hepatitis B virus gene expression, i.e. does not inhibit the expression of any non-target gene.

The term half-life as used in the present invention is a measurement of the stability of a compound or molecule; it can be assessed by methods known to one skilled in the art, especially in light of the assays provided in the present invention.

The term non-immunostimulatory as used in the present invention refers to the absence of any induction of an immune response by the lncRNA molecules of the present invention. Methods for determining immune responses are well known to one skilled in the art, for example, determination by assessing the release of cytokines, as described in the examples section.

The terms treat, cure and the like mean in the context of the present invention the alleviation or reduction of a disorder associated with hepatitis B virus infection, such as chronic liver diseases/disorders, inflammation, fibrotic conditions and proliferative disorders such as cancer.

As used herein, the term pharmaceutical composition contains a pharmacologically effective amount of at least one type of lncRNA and a pharmaceutically acceptable carrier. However, such pharmaceutical composition may also include individual strands of such lncRNA molecules or vector/vectors described in the present invention, including a regulatory sequence operably linked to a nucleotide sequence that encodes at least one strand of the coding or non-coding strand included in the lncRNA according to the present invention invention. It is also contemplated that cells, tissues or isolated organs that express or include the lncRNAs defined herein can be used as pharmaceutical compositions. As used herein, the term pharmacologically effective amount, therapeutically effective amount, or simply effective amount refers to that amount of RNA that is effective to produce the intended pharmacological, therapeutic, or preventive result.

The term pharmaceutically acceptable carrier refers to a carrier for administration of a therapeutic

- 10 045398 agent. Such carriers include, but are not limited to, saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof. The term specifically excludes cell culture medium. For preparations that are administered orally, pharmaceutically acceptable carriers include, but are not limited to, pharmaceutically acceptable excipients such as inert solvents, disintegrating agents, binding agents, lubricants, sweeteners, flavoring agents, coloring agents and preservatives, as known to those skilled in the art. .

In particular, it is contemplated that a pharmaceutically acceptable carrier allows systemic administration of lncRNAs, vectors or cells according to the present invention. Since intestinal administration is also contemplated, possible routes of administration to a patient in need of medical intervention of the compounds of the present invention are parenteral administration, as well as transdermal or transmucosal administration (eg, insufflation, buccal, vaginal, anal administration), as well as inhalation of the drug. If parenteral administration is used, it may involve direct injection of the compounds of the present invention into, or at least in close proximity to, tissue affected by the disease. However, also intravenous, intraarterial, subcutaneous, intramuscular, intraperitoneal, intradermal, intrathecal and other routes of administration of the compounds according to the present invention are within the competence of a person skilled in the art, for example, a physician.

Pharmaceutical compositions for intramuscular, subcutaneous and intravenous use according to the present invention will typically be supplied in sterile aqueous solutions or suspensions buffered to a suitable pH and isotonicity. In a preferred embodiment, the carrier consists solely of an aqueous buffer. In this context, exclusively means the absence of auxiliary agents or encapsulating substances that can influence or mediate the uptake of lncRNA by cells expressing the hepatitis B virus gene. Aqueous suspensions in accordance with the present invention may include suspending agents such as cellulose derivatives, sodium alginate, polyvinyl pyrrolidone and tragacanthum, and a wetting agent such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl rhydroxybenzoate. Pharmaceutical compositions useful in accordance with the present invention also include encapsulated formulations to protect lncRNA from rapid elimination from the body, such as controlled release formulations, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid can be used. Methods for preparing such compositions will be apparent to those skilled in the art. Liposomal suspensions and bispecific antibodies can also be used as pharmaceutically acceptable carriers. They can be prepared in accordance with methods known to those skilled in the art, for example, those described in PCT publication WO91/06309 and WO2011/003780, which are incorporated by reference herein.

As used herein, the term transformed cell represents a cell into which at least one vector from which a lncRNA molecule or at least one strand of such a lncRNA molecule can be expressed has been inserted. Such a vector is preferably a vector including a regulatory sequence operably linked to a nucleotide sequence that encodes at least one coding strand or non-coding strand of a lncRNA according to the present invention.

It can be reasonably expected that shorter lncRNAs, including one of the sequences from the table. 1 and 4, minus a few nucleotides at one or both ends, may have similar efficiency compared to the lncRNA described above.

In one preferred embodiment, lncRNA molecules according to the present invention include nucleotides 1-19 of the sequences presented in table. 1.

As noted above, in most embodiments of the present invention, lncRNA molecules provided in the present invention include a duplex (without overhangs) of about 16 to about 30 nucleotides in length. Particularly useful lncRNA duplexes range from approximately 19 to approximately 25 nucleotides in length. The most preferred are duplex structures with a length of 19 nucleotides. In the lncRNA molecules of the present invention, the non-coding strand is at least partially complementary to the coding strand.

The lncRNAs of the present invention may contain one or more mismatches to the target sequence. In a preferred embodiment, the lncRNA of the present invention contains no more than 13 complementarity disorders. If the non-coding strand of a lncRNA contains mismatches to the target sequence, it is preferred that the mismatch site is not located within nucleotides 2-7 from the 5' end of the non-coding strand. In another embodiment, it is preferred that the mismatch site is not located within nucleotides 2-9 of the 5' end of the non-coding strand.

As stated above, at least one end/strand of the lncRNA may have a single-stranded overhang of 1 to 5, preferably 1 or 2 nucleotides. lncRNA having

- 11 045398 at least one sticky end, has unexpectedly superior inhibitory properties than its blunt-ended counterpart. Moreover, the present inventors have found that the presence of a sticky end of just one nucleotide enhances the interfering activity of lncRNA without affecting its overall stability. LncRNA, which has only one sticky end, has been shown to be extremely stable and efficient in vivo, as well as in a variety of cells, cell culture media, blood and serum. Preferably, the single-stranded overhang is located at the 3' end of the non-coding strand or, alternatively, at the 3' end of the coding strand. The lncRNA may also have a blunt end, preferably located at the 5' end of the non-coding strand. Preferably, the non-coding lncRNA strand has a sticky end at the 3' end and a blunt end at the 5' end. In another embodiment, one or more of the nucleotides at the sticky end is replaced with a nucleoside triphosphate.

The lncRNAs of the present invention can also be chemically modified to improve stability. The nucleic acids of the present invention can be synthesized and/or modified using methods well established in the art. Chemical modifications may include, but are not limited to, 2' modifications, introduction of bases not found in nature, covalent attachment to a ligand and replacement of phosphate bonds with thiophosphate bonds, inverted deoxythymidines. In this embodiment, the integrity of the duplex structure is enhanced by at least one, and preferably two, chemical bonds. Chemical bonds can be formed using any of a variety of well-known techniques, for example, by introducing covalent, ionic or hydrogen bonds; hydrophobic interactions, van der Waals or stacking interactions, through coordination with metal ions or through the use of purine analogues. Preferably, chemical groups that can be used to modify lncRNA include, but are not limited to, methylene blue; bifunctional groups, preferably bis-(2-chloroethyl)amine; N-acetyl-N'-(p-glyoxybenzoyl)cystamine; 4-thiouracil; and psoralen. In one preferred embodiment, the linker is a hexaethylene glycol linker. Here, lncRNA is prepared by solid phase synthesis and a hexa-ethylene glycol linker is inserted according to standard methods (eg, Williams DJ and Hall KB, Biochem. (1996) 35:14665-14670). In a particular embodiment, the 5' end of the non-coding strand and the 3' end of the coding strand are chemically linked via a hexaethylene glycol linker. In another embodiment, at least one nucleotide of the lncRNA contains phosphorothioate or phosphodithioate groups. The chemical bond at the ends of lncRNAs is preferentially formed by triple helix bonds.

In some embodiments, the chemical bond may be formed by one or more linking groups, wherein such linking groups are preferably poly(oxyphosphinicoxy-1,3-propanediol) and/or polyethylene glycol chains. In other embodiments, the chemical bond may also be formed using purine analogues introduced into the double-stranded structure in place of purines. In further embodiments, the chemical bond may be formed by azabenzene units that are introduced into the double-stranded structure. In yet other embodiments, the chemical bond may be formed by branched nucleotide analogues introduced into a double-stranded structure instead of nucleotides. In certain embodiments, the formation of a chemical bond can be induced by exposure to ultraviolet light.

In other embodiments, nucleotides on one or both of two separate chains may be modified to prevent or inhibit the activation of cellular enzymes, such as certain nucleases. Techniques for inhibiting the activation of cellular enzymes are known in the art, including, but not limited to, 2'-amino modifications, 2'-amino modifications of sugars, 2'F modifications of sugars, 2'-F modifications, 2'-alkyl -sugar modifications, uncharged backbone modifications, morpholino modifications, 2'-O-methyl modifications, and phosphoramidate (see, eg, Wagner, Nat. Med. (1995) 1:1116-8). Thus, at least one 2'hydroxyl group of the lncRNA nucleotides is replaced by a chemical group, preferably a 2'-amino or 2'-methyl group. Also, at least one nucleotide can be modified to form a closed nucleotide. This closed nucleotide contains a methylene bridge that connects the 2' oxygen of ribose to the 4' carbon of ribose. The introduction of a closed nucleotide into an oligonucleotide improves the affinity of complementary sequences and increases the melting temperature by several degrees.

Modifications of lncRNA molecules provided in the present invention can positively influence their stability in vivo as well as in vitro, as well as improve their delivery to the target site. Moreover, such structural and chemical modifications may positively influence physiological responses to lncRNA molecules during administration, e.g. release of cytokines, which is preferentially inhibited. Such chemical and structural modifications are known in the art and, among others, are covered in Nawrot Current Topics in Med Chem, (2006) 6:913-925.

Conjugating a ligand to a lncRNA can enhance the latter's cellular uptake as well as targeting to a specific tissue. In some cases, a hydrophobic ligand is conjugated to lncRNA to

- 12 045398 facilitating direct penetration through the cell membrane. Alternatively, ligand conjugated to lncRNA is a substrate for receptor-mediated endocytosis. These approaches have been used to facilitate cellular entry of antisense nucleotides. For example, cholesterol has been conjugated to various antisense nucleotides, resulting in compounds that are substantially more active than their unconjugated counterparts (see Manoharan M, Antisense & Nucleic Acid Drug Development (2002) 12:103). Other lipophilic compounds that have been conjugated to oligonucleotides include 1-pyrenebutyric acid, 1,3-bisO-(hexadecyl)glycerol, and menthol. One example of a ligand for receptor-mediated endocytosis is folic acid. Folic acid enters cells by folate receptor-mediated endocytosis. LncRNA compounds carrying folic acid will be efficiently transported into the cell through folate receptor-mediated endocytosis. Attachment of folic acid to the 3' end of the oligonucleotide results in increased efficiency of cellular uptake of the oligonucleotide (Li S, Deshmukh HM, and Huang L, Pharm. Res. (1998) 15:1540). Other ligands that have been conjugated to oligonucleotides include polyethylene glycols, carbohydrate clusters, cross-linkers, porphyrin conjugates, and delivery peptides.

In some cases, conjugation of a cationic ligand to oligonucleotides often results in improved nuclease resistance. Typical examples of cationic ligands are propylammonium and dimethylpropylammonium. Notably, antisense nucleotides have been reported to retain their high binding affinity for mRNA when the cationic ligand is dispersed throughout the length of the oligonucleotide. See Manoharan M, Antisense & Nucleic Acid Drug Development (2002) 12:103 and references therein.

The ligand-conjugated lncRNA of the present invention can be synthesized using a lncRNA that maintains reactive functional properties, such as properties derived from the attachment of a binding molecule to the lncRNA. This reactive oligonucleotide can react directly with commercially available ligands, synthesized ligands bearing any of a variety of protecting groups, or ligands bearing a linking group attached thereto. The methods of the present invention facilitate the synthesis of ligand-conjugated lncRNA using, in some preferred embodiments, nucleoside monomers that have been suitably conjugated to ligands, which can then be attached to a solid support material. Such ligand-nucleoside conjugates, optionally attached to a solid support material, are prepared in accordance with some preferred embodiments of the methods of the present invention by reacting a selected serum-binding ligand with a linking group located on the 5' portion of the nucleoside or oligonucleotide. In some cases, a lncRNA bearing an aralkyl ligand attached to the 3' end of the lncRNA is prepared by first covalently attaching a monomer binding block to a pore-controlled stele support via a long-chain aminoalkyl group. The nucleotides are then coupled via standard solid phase synthesis techniques to a monomer binding unit attached to a solid support. The monomer binding unit may be a nucleoside or other organic compound compatible with solid phase synthesis.

The lncRNA used in the conjugates of the present invention can be easily and routinely generated through a well-known solid-phase synthesis technique. It is also known to use similar techniques for the preparation of other oligonucleotides, such as phosphorothioates and alkylated derivatives.

Guidance regarding the synthesis of specific modified oligonucleotides can be found in the following US patents: US Patent No. 5,218,105, which describes polyamine-conjugated nucleotides; US Patent No. 5,541,307, which describes oligonucleotides with modified backbones; US Patent No. 5,521,302, which describes processes for the preparation of oligonucleotides having chiral phosphorus bonds; US Patent No. 5,539,082, which describes peptide nucleic acids; US Patent No. 5,554,746, which describes oligonucleotides with β-lactam backbones; US Patent No. 5,571,902, which describes methods and materials for the synthesis of oligonucleotides; US Patent No. 5,578,718, which describes nucleotides having alkylthiol groups, where such groups can be used as linkers to other groups attached to any of a variety of nucleoside positions; US Patent No. 5,587,361, which describes oligonucleotides having phosphorothioate linkages of high chiral purity; US Patent No. 5,506,351, which describes processes for the preparation of 2'-O-alkylguanosine and related compounds, including 2,6-diaminopurine compounds; US Patent No. 5,587,469, which describes oligonucleotides having N-2-substituted purines; US Patent No. 5,587,470, which describes oligonucleotides having 3-deazapurines; US Patent No. 5,608,046, which describes conjugated 4'desmethyl nucleoside analogues; US Patent No. 5,610,289, which describes backbone-modified nucleotide analogues; US Patent No. 6,262,241, which describes, among other things, methods for the synthesis of 2'fluoro-oligonucleotides.

- 13 045398

In the ligand-conjugated lncRNA and sequence-specific linked nucleosides of the present invention carrying the ligand molecules, the oligonucleotides and oligonucleosides can be combined on a suitable oligonucleotide synthesizer using standard nucleotide or nucleoside precursors or nucleotide or nucleoside conjugate precursors that already carry a binding group, precursors of ligand-nucleotide or nucleoside conjugates that already carry a ligand molecule, or binding units that carry a ligand and do not carry a nucleoside.

When using nucleotide-conjugated precursors that already carry a linking group, the synthesis of sequence-specific binding nucleosides is completed in the usual manner and the ligand molecule is then reacted with the linking group to form the ligand-conjugated nucleotide. Oligonucleotide conjugates carrying a variety of molecules such as steroids, vitamins, lipids and reporter molecules have been described previously (see Manoharan et al., PCT Application WO 93/07883). In preferred embodiments, the oligonucleotides or linked nucleosides of the present invention are synthesized using an automated synthesizer using phosphoramidites derived from ligand-nucleoside conjugates in addition to commercially available phosphoramidites.

Incorporation of 2'-O-methyl, 2'-O-ethyl, 2'-O-propyl, 2'-O-allyl, 2'-O-aminoalkyl, or 2'-deoxy-2'-fluoro groups into nucleotide nucleosides increases hybridization properties of the oligonucleotide. Also, oligonucleotides containing phosphorothioate backbones have increased stability to nucleases. Thus, the substituted linked nucleosides of the present invention may be supplemented to include one or both phosphorothioate backbones or 2'-O-methyl, 2'-O-ethyl, 2'-Opropyl, 2'-O-allyl, 2'-O -aminoalkyl or 2'-deoxy-2'-fluoro groups.

In some preferred embodiments, substituted nucleoside sequences of the present invention having an amino group at the 5' end are prepared using a DNA synthesizer and then reacted with the active ester derivative of the selected ligand. Active ester derivatives are well known to those skilled in the art. Typical active esters include N-hydrosuccinimide esters, tetrafluorophenol esters, pentafluorophenol ethers and pentachlorophenol ethers. As a result of the reaction of the amino group and the active ester, an oligonucleotide is formed in which the selected ligand is attached to the 5' position via a linker group. The amino group at the 5' end can be prepared using the 5' amino modifier C6 reagent. In preferred embodiments, ligand molecules can be conjugated to oligonucleotides at the 5' position using a ligand-nucleoside phosphoramidite, where the ligand is linked to the 5'-hydroxy group directly or indirectly through a linker. Such ligand-nucleoside phosphoramidites are typically used at the end of an automated synthesis procedure to produce a ligand-conjugated oligonucleotide bearing the ligand at the 5' end.

In one preferred embodiment of the methods of the present invention, the preparation of ligand-conjugated oligonucleotides begins with the selection of suitable precursor molecules from which the ligand molecule is designed. Typically the precursor is a suitably protected derivative of commonly used nucleosides. For example, synthetic precursors for the synthesis of ligand-conjugated oligonucleotides of the present invention include, but are not limited to, 2'-aminoalkyloxy5'-ODMT nucleosides, 2',6-aminoalkylamino-5'-ODMT nucleosides, 5',6 -aminoalkoxy-2'deoxynucleosides, 5',6-aminoalkoxy-2-protected-nucleosides, 3'-6-aminoalkoxy-5'-ODMTnucleosides and 3'-aminoalkylamino-5'-ODMT-nucleosides, which may be protected in part the nucleic base of the molecule. Methods for synthesizing such amino-linked protected nucleoside precursors are known to one of ordinary skill in the art.

In many cases, protecting groups are used during the preparation of the compounds of the present invention. As used in the present invention, the term protected means that the specified group has a protecting group attached to it. In some preferred embodiments of the present invention, the compounds contain one or more protecting groups. A wide variety of protecting groups can be used in the methods of the present invention. In general, protecting groups render chemical functional groups inert to specific reaction conditions, and can be introduced into or removed from such functional groups in a molecule without significantly damaging the rest of the molecule.

Protecting groups in general and hydroxyl protecting groups in particular are well known in the art (Greene and Wuts, Protective Groups in Organic Synthesis, Chapter 2, 2d ed., John Wiley & Sons, New York, 1991). Amino protecting groups that are stable to acid treatment can be selectively removed by base treatment; these groups are used to make reactive amino groups selectively available for substitution. Examples of such groups are Fmoc and various substituted sulfonylethyl carbamates, of which the Nsc group is an example.

Additionally, amino protecting groups include, but are not limited to, carbamate protecting groups such as 2-trimethylsilylethoxycarbonyl (Teoc), 1-methyl-1-(4-biphenylyl)

- 14 045398 ethoxycarbonyl (Bpoc), t-butoxycarbonyl (BOC), allyloxycarbonyl (Alloc), 9-fluorenylmethyloxycarbonyl (Fmoc) and benzyloxycarbonyl (Cbz); amide protecting groups such as formyl, acetyl, trihaloacetyl, benzoyl and nitrophenylacetyl; sulfonamide protecting groups such as 2nitrobenzenesulfonyl; and imino- and cyclic imide protecting groups such as phthalimide and dithiasuccinoyl. The compounds and methods of the present invention also provide equivalents of these amino protecting groups.

Many solid supports are commercially available, and one of ordinary skill in the art can easily select a solid support for use in solid phase synthesis steps. In certain embodiments, universal substrates are used. The universal support, well known in the art, allows the preparation of oligonucleotides having unusual or modified nucleotides located at the 3' end of the oligonucleotide. In addition, it has been reported that the oligonucleotide can be removed from the universal support under milder reaction conditions if the oligonucleotide is attached to the solid support via a syn1,2-acetoxyphosphate group, which is more easily susceptible to alkaline hydrolysis. See Guzaev AI, and Manoharan MJ. Am. Chem. Soc. (2003) 125:2380.

Nucleosides are linked by phosphorus-containing or phosphorus-free covalent intranucleoside bonds. For identification purposes, such conjugated nucleosides can be characterized as ligand-carrying nucleosides or ligand-nucleoside conjugates. Bound nucleosides having an aralkyl ligand conjugated to a nucleoside within their sequence will exhibit increased lncRNA activity compared to lncRNA compounds that are not conjugated.

Oligonucleotides of the present invention conjugated to an aralkyl ligand also include oligonucleotide-linked nucleoside conjugates, where the ligand is attached directly to the nucleoside or nucleotide without the mediation of a linker group. The ligand may preferably be attached via linking groups via its carboxyl, amino or oxo group. Typical linking groups may be ester, amide or carbamate groups.

Specific examples of preferred modified oligonucleotides provided for use in the ligand-conjugated nucleotides of the present invention include oligonucleotides containing modified backbones or intranucleoside linkages not found in nature. As defined herein, oligonucleotides having modified backbones or intranucleoside linkages include oligonucleotides that contain a phosphorus atom in the backbone and oligonucleotides that do not contain a phosphorus atom in the backbone. For purposes of the present invention, modified oligonucleotides that do not contain a phosphorus atom in the intrasaccharide backbone can also be considered oligonucleotides.

Specific chemical modifications of the oligonucleotides are described below. Not all provisions in a presented compound need to be uniformly modified. In contrast, more than one modification can be included in a single lncRNA compound or even a single nucleotide.

Preferred modified intranucleoside linkages or backbones include, for example, phosphothioates, chiral phosphothioates, phosphodithioates, phosphotriesters, aminoalkyl phosphotriesters, methyl and other alkylphosphonates, including 3'-alkylenephosphonates and chiral phosphonates, phosphinates, phosphoramidates, including 3'-aminophosphoramidate and aminoalkylphosphoramidates , thionophosphoramidates, thionoalkylphosphonates , thionoalkyl phosphotriesters and boranophosphates having normal 3'-5' bonds, their 2'-5' linked analogs, and analogs having inverted polarity, where adjacent pairs of nucleoside units are linked from 3'-5' to 5'-3' or from 2 '-5' to 5'-2'. Also included are various salts, mixed salts and free acid forms.

Representative United States patents related to the preparation of the phosphorus atom containing bonds described above include, but are not limited to, US Patent Nos. 4,469,863, 5,023,243, 5,264,423, 5,321,131, 5,399,676, 5,405,939, 5,453,496, 5,455,233 and 5,466,677, each of which is included herein application via link.

Preferred modified intranucleoside linkages or backbones that do not include a phosphorus atom (i.e., oligonucleosides) have backbones formed by short-chain alkyl or cycloalkyl intrasaccharide linkages, mixed heteroatom and alkyl or cycloalkyl intrasaccharide linkages, or one or more short-chain heteroatomic or heterocyclic intrasaccharide linkages. These include backbones that have morpholino linkages (formed in part by the saccharide moiety of the nucleoside); siloxane backbones; sulfide, sulfoxide and sulfone skeletons; formacetyl and thioformacetyl backbones, methyleneformacetyl and thioformacetyl backbones; alkene-containing backbones; sulfamate backbones; methyleneimino and methylenehydrazine backbones; sulfonate and sulfonamide backbones; amide backbones and others having mixed parts of the components N, O, S and CH ₂ .

Representative United States patents related to the preparation of the oligonucleotides described above include, but are not limited to, US Patent Nos. 5,034,506, 5,214,134, 5,216,141,

5,264,562, 5,466,677, 5,470,967, 5,489,677, 5,602,240 and 5,663,312, each of which is incorporated herein by reference.

In other preferred oligonucleotide mimetics, both the sugar and the intranucleoside linkage (ie, the backbone) of the nucleoside units are replaced with new groups. The nucleic base units are supported to hybridize with the corresponding target nucleic acid compound. One such nucleotide, an oligonucleotide mimetic that has been demonstrated to have excellent hybridization properties, is called a peptide nucleic acid (PNA). In PNA compounds, the sugar backbone of the oligonucleotide is replaced by an amide-containing backbone, in particular, an aminoethylglycine backbone. Nucleic bases are conserved and are associated directly or indirectly with the atoms of the amide part of the backbone. Instructions for PNA compounds can be found, for example, in US Patent No. 5,539,082.

Some preferred embodiments of the present invention employ oligonucleotides with phosphorothioate bonds and oligonucleotides with heteroatomic backbones, in particular -CH2NH-O-CH ₂ -, -CH ₂ -N(CH ₃ )-O-CH ₂ -[known as methylene (methylimino) or MMI core], -CH2-ON(CH ₃ )-CH2-, -CH ₂ -N(CH ₃ )-N(CH ₃ )-CH ₂ - and -ON(CH ₃ )-CH ₂ -CH ₂ - [where the native phosphodiester backbone is represented by -OPO-CH2-] according to the above reference to US Patent No. 5,489,677, and the amide backbones according to the above reference to US Patent No. 5,602,240. Also preferred are oligonucleotides having a backbone of morpholino structures according to the above reference to US Patent No. 5,034,506.

Oligonucleotides used in the ligand-conjugated oligonucleotides of the present invention may additionally or alternatively include modifications or substitutions of a nucleotide base (often referred to in the art simply as a base). As used herein, the term unmodified or naturally occurring nucleotide bases includes the purine bases adenine (A) and guanine (G) and the pyrimidine bases thymine (T), cytosine (C), and uracil (U). Modified nucleobases include other synthetic and naturally occurring nucleobases such as 5-methylcytosine (5-me-C), 5-hydroxymethylcytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouracil and cytosine, 5-propynyl uracil and cytosine, 6-azouracil, cytosine and thymine, 5-uracil (pseudouracil), 4- thiouracil, 8-halo, 8-amino, 8-thiol, 8thioalkyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo, especially 5-bromo, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7- methylguanine and 7-methyladenine, 8-azaguanine and 8-azaadenine, 7-deazaguanine and 7-deazaadenine and 3-deazaguanine and 3-azaadenine.

Other nucleic acid bases include those disclosed in US Pat. No. 3,687,808 or otherwise known in the art or commercially available. Some of these nucleic acid bases are particularly useful for increasing the binding affinity of the oligonucleotides of the present invention. These include 5-substituted pyrimidines, 6-azapyrimidines, and N-2, N-6, and O-6-substituted purines, including 2-aminopropyladenine, 5-propynyluracil, and 5-propynylcytosine. Substitutions to 5-methylcytosine have been shown to increase the stability of the nucleic acid duplex by 0.61.2°C and are currently the preferred base substitutions, even more preferred when combined with 2'-methoxyethyl sugar modifications.

Examples of United States patents relating to the preparation of some of the above modified nucleic acid bases, as well as other modified nucleic acid bases, include, but are not limited to, US Patent No. 3,687,808, as well as US Patent Nos. 5,134,066, 5,459,255, 5,552,540, 5,594,121 and 5,596,091 , all of which are incorporated herein by reference.

In some embodiments, the oligonucleotides used in the ligand-conjugated oligonucleotides of the present invention may additionally or alternatively include one or more substituted sugar groups. Preferred oligonucleotides include one of the following groups at the 2' position: OH; F; O-, S- or N-alkyl, O-, S- or N-alkenyl or O, S- or N-alkenyl, where alkyl, alkenyl and alkynyl may be substituted or unsubstituted with C1-C ₁₀ -alkyl or C ₂ -C ₁₀ -alkenyl and alkynyl. Particularly preferred are O[( _CH2 ) _nO ] _mCH3 , O(CH2)nOCH3, O(CH2)nNH2, O(CH2) _nCH3 , O(CH2)nONH2 and O(CH2)nON[(CH2)nCH ₃ )]2, where n and m are numbers from 1 to about 10. Other preferred oligonucleotides include one of the following groups at the 2' position: C1-C10 lower alkyl, substituted lower alkyl, alkaryl, aralkyl, O-alkaryl, or O -aralkyl, SH, SCH ₃ , OCN, Cl, Br, CN, CF ₃ , OCF ₃ , SOCH3, SO ₂ CH ₃ , ONO2, NO2, N ₃ , NH2, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl and RNA -a cleavage group, a reporter group, an intercalator, a group to improve the pharmacokinetic properties of the oligonucleotide or a group to improve the pharmacodynamic properties of the oligonucleotide and other substituents having similar properties. The preferred modification includes 2'-methoxyethoxy (2'-O-CH ₂ CH ₂ OCH ₃ , also known as 2'-O-(2-methoxyethyl) or

2'-MOE), i.e. alkoxyalkoxy group. Another preferred modification includes 2'dimethylaminooxyethoxy, i.e. the O(CH ₂ ) ₂ ON(CH ₃ ) ₂ group, also known as 2'-DMAOE, as described in US Patent No. 6,127,533.

Other preferred modifications include 2'-methoxy (2'-O-CH ₃ ), 2'-aminopropoxy (2OCH2CH2CH2NH2) and 2'-fluoro (2'-F). Similar modifications can also be made at other positions of the oligonucleotide, especially at the 3' position of a sugar on a 3' terminal nucleotide or in 2'-5' linked oligonucleotides.

As used herein, the term sugar substituent group or 2'-substituent group includes groups attached to the position of the 2'-ribofuranosyl group with or without an oxygen atom. Sugar substituents include, but are not limited to, fluorine, O-alkyl, O-alkylamino, O-alkylalkoxy, protected O-alkylamino, O-alkylaminoalkyl, O-alkylimidazole, and polyesters of the formula (O-alkyl)m, where m is the number from 1 to about 10. Preferred among these polyethers are linear and cyclic polyethylene glycols (PEG) and (PEG) containing groups such as crown ethers and, among others, those disclosed by Delgardo et al. (Critical Reviews in Therapeutic Drug Carrier Systems (1992) 9:249). Additional sugar modifications have been disclosed by Cook (Anti-fibrosis Drug Design, (1991) 6:585-607). Fluorine, O-alkyl, O-alkylamino, Oalkylimidazole, O-alkylaminoalkyl and alkylamino substituents are described in US Patent No. 6,166,197 entitled Oligomeric Compounds Having Pyrimidine Nucleotide(s) with 2' and 5' Substituents, incorporated herein application by reference in its entirety.

Additional sugar substituents of the present invention include 2'-SR and 2'-NR2 groups, where each R is independently hydrogen, a protecting group, or substituted or unsubstituted alkyl, alkenyl, or alkynyl. The 2'-SR nucleosides are disclosed in US Pat. No. 5,670,633, which is incorporated herein by reference in its entirety. Incorporation of 2'-SR monomer synthons has been disclosed by Hamm et al (J. Org. Chem., (1997) 62:3415-3420). 2'NR nucleosides disclosed by Thomson JB, J. Org. Chem., (1996) 61:6273-6281; and Polushin et al., Tetrahedron Lett., (1996) 37:3227-3230. Still other exemplary 2'-substituted groups of the present invention include those having a group according to Formula I or II:

—fO-(CH ₂ ) _ql )— (O)q ₃ E। '' q2

III where E represents C ₁ -C ₁₀ -alkyl, N(Q3)(Q4) or N=C(Q3)(Q4); each of Q3 and Q4 is, independently, H, C ₁ -C ₁₀ -alkyl, dialkylaminoalkyl, a nitrogen protecting group, a bound or unlinked conjugate group, a linker to a solid support, or Q3 and Q4 both together form a nitrogen protecting group or ring a structure further comprising at least one additional heteroatom selected from N and O;

q1 represents a number from 1 to 10;

q2 represents a number from 1 to 10;

q3 represents 0 or 1;

q4 represents 0, 1 or 2;

each of Z1, Z ₂ and Z ₃ is, independently, C ₄ -C ₇ -cycloalkyl, C ₅ -C ₁₄ -aryl or C ₃ -C ₁₅ heterocyclyl, where the heteroatom in said heterocyclyl group is selected from oxygen, nitrogen and sulfur ;

Z ₄ represents OM1, SM1 or N(M1) ₂ ; each M1 is, independently, H, _C1C8- alkyl, _C1 - _C8 -haloalkyl, C(=NH)N(H)M2, C(=O)N(H)M2 or OC(=O)N (H)M2; M2 represents H or C ₁ -C ₈ -alkyl; And

Z ₅ is C ₁ -C ₁₀ -alkyl, C ₁ -C ₁₀ -haloalkyl, C ₂ -C ₁₀ -alkenyl, C ₂ -C ₁₀ -alkynyl, C ₆ -C ₁₄ -aryl, N(Q3)(Q4) ), OQ3, halo, SQ3 or CN.

Exemplary substituent groups for 2'-O-sugars of Formula I are disclosed in US Patent No. 6,172,209 entitled Copied 2'-hydroxyethoxy oligonucleotides, which is incorporated herein by reference in its entirety. Exemplary cyclic substituent groups for 2'-O-sugars of Formula II are disclosed in US Pat. No. 6,271,358 entitled RNA-Targeting 2'-Modified Oligonucleotides That Are Conformationally Preorganized, incorporated herein by reference in its entirety.

Sugars having O-substituents on the ribosyl ring are also within the scope of the present invention. Typical substituents for the O ring include, but are not limited to, S, CH2, CHF and CF2.

Oligonucleotides may also have sugar mimetics, such as cyclobutyl groups, in place of the pentofuranose sugar. Typical United States patents relating to the production of such

- 17 045398 modified sugars, includes, but is not limited to, US Patent No. 5,359,044,

5,466,786, 5,519,134, 5,591,722, 5,597,909, 5,646,265 and 5,700,920, all of which are incorporated herein by reference.

Additional modifications can also be introduced at other positions of the oligonucleotide, especially at the 3' position of the sugar on the 3' terminal nucleotide. For example, one additional modification of the ligand-conjugated oligonucleotides of the present invention includes chemically linking to the oligonucleotide one or more additional non-ligand groups or conjugates that enhance the activity, cellular distribution or cellular uptake of the oligonucleotide. Such groups include, but are not limited to, lipid groups such as the cholesterol group (Letsinger et al., Proc. Natl. Acad. Sci. USA, (1989) 86:6553), cholic acid (Manoharan et al., Bioorg. Med. Chem. Lett., (1994) 4:1053), thioester, for example, hexyl-S-tritylthiol (Manoharan et al., Ann. N.Y. Acad. Sci., (1992) 660:306; Manoharan et al., Bioorg. Med. Chem. Let., (1993) 3:2765), thiocholesterol (Oberhauser et al., Nucl. Acids Res., (1992) 20:533), aliphatic chain, for example, dodecanediol or undecyl residues (Saison- Behmoaras et al., EMBO J., (1991) 10:111; Kabanov et al., FEBS Lett., (1990) 259:327; Svinarchuk et al., Biochimie, (1993) 75:49), phospholipid, e.g. , di-hexadecyl-rac-glycerol or triethylammonium 1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonate (Manoharan et al., Tetrahedron Lett., (1995) 36:3651; Shea et al. , Nucl. Acids Res., (1990) 18:3777), a polyamine or polyethylene glycol chain (Manoharan et al., Nucleosides & Nucleotides, (1995) 14:969) or adamantane acetic acid (Manoharan et al., Tetrahedron Lett., (1995) 36:3651), palmityl group (Mishra et al., Biochim. Biophys. Acta, (1995) 1264:229), or an octadecylamine or hexylaminocarbonyl oxycholesterol group (Crooke et al., J. Pharmacol. Exp. Ther., (1996) 277:923).

The present invention also includes compositions that use oligonucleotides that are substantially chirally pure with respect to specific positions of the oligonucleotides. Examples of substantially chirally pure oligonucleotides include, but are not limited to, oligonucleotides having phosphorothioate linkages that are at least 75% Sp or Rp (Cook et al., US Pat. No. 5,587,361), and oligonucleotides having substantially chirally pure (Sp or Rp) alkylphosphonate, phosphoramidate or phosphotriester linkages (Cook, US Patent Nos. 5,212,295 and 5,521,302).

In some cases, the oligonucleotide can be modified with a non-ligand group. The number of unliganded molecules conjugated to oligonucleotides to enhance activity, improve cellular distribution or cellular uptake of the oligonucleotide, and procedures for carrying out such conjugation are available in the scientific literature. Such unliganded groups include lipid groups such as cholesterol (Letsinger et al., Proc. Natl. Acad. Sci. USA, (1989, 86:6553), cholic acid (Manoharan et al., Bioorg. Med. Chem. Lett. , (1994) 4:1053), a thioester, for example, hexyl-S-tritylthiol (Manoharan et al., Ann. N.Y. Acad. Sci., (1992) 660:306; Manoharan et al., Bioorg. Med. Chem. Let., (1993) 3:2765), thiocholesterol (Oberhauser et al., Nucl. Acids Res., (1992) 20:533), aliphatic chain, such as dodecanediol or undecyl residues (Saison-Behmoaras et al., EMBO J., (1991) 10:111; Kabanov et al., FEBS Lett., (1990) 259:327; Svinarchuk et al., Biochimie, (1993) 75:49), phospholipid, e.g. di-hexadecyl-rac -glycerol or triethylammonium 1,2-di-O-hexadecyl-rac-glycero-3-Hphosphonate (Manoharan et al., Tetrahedron Lett., (1995) 36:3651; Shea et al., Nucl. Acids Res., ( 1990) 18:3777), polyamine or polyethylene glycol chain (Manoharan et al., Nucleosides & Nucleotides, (1995) 14:969) or adamantane acetic acid (Manoharan et al., Tetrahedron Lett., (1995) 36:3651), palmityl group (Mishra et al., Biochim. Biophys. Acta, (1995) 1264:229), or an octadecylamine or hexylaminocarbonyl oxycholesterol group (Crooke et al., J. Pharmacol. Exp. Ther., (1996) 277:923). Typical conjugation procedures involve the synthesis of oligonucleotides bearing an amino linker at one or more sequence positions. The amino group then reacts with the conjugated molecule, with the participation of an appropriate coupling or activating agent. The conjugation reaction can be carried out with an oligonucleotide that remains bound to a solid support, or after separation of the oligonucleotide in the liquid phase. Purification of the oligonucleotide conjugate by HPLC usually produces a pure conjugate.

Alternatively, the molecule to be conjugated can be converted into a structural element, such as phosphoramidite, by an alcohol group present on the molecule or by attaching a linker bearing an alcohol group that can be phosphorylated.

Importantly, each of these approaches can be used to synthesize ligand-conjugated oligonucleotides. Amino-linked oligonucleotides can be combined directly with a ligand through the use of coupling reagents or after activation of the ligand as an NHS Nhydroxysuccinimide or penfluorophenolate ester. Phosphoramidite ligands can be synthesized by attaching an aminohexanol linker to one of the carboxyl groups, followed by phosphitylation of the terminal alcohol functionality. Other linkers, such as cystamine, can also be used to conjugate to the chloroacetyl linker present on the synthesized oligonucleotide.

- 18 045398

Methods for incorporating the molecules of the present invention into cells, tissues and organisms are well known to those skilled in the art. Corresponding examples have also been provided above in the detailed description of the present invention. For example, nucleic acid molecules or vectors of the present invention encoding at least one lncRNA strand of the present invention can be incorporated into cells or tissues using methods known in the art, such as transfections and the like.

Routes and methods for introducing lncRNA molecules were also presented. For example, targeted delivery using glycosylated and folic acid-modified molecules, including the use of polymeric carriers with ligands such as galactose and lactose, or the attachment of folic acid to various macromolecules, allows the molecules to be delivered to bind to folate receptors. Targeted delivery using peptides and proteins other than antibodies is known, for example, including RGD modified nanoparticles for in vivo delivery of siRNA or multicomponent (non-viral) delivery systems including short cyclodextrins, adamantine-PEG. Targeted delivery using antibodies or antibody fragments, including (monovalent) Fab fragments of an antibody (or other fragments of such an antibody) or single chain antibodies, is also contemplated. Injection approaches for targeted delivery include, but are not limited to, hydrodynamic intravenous injection. Also, cholesterol conjugates of lncRNA can be used for targeted delivery, where conjugation with lipophilic groups increases cellular uptake and improves the pharmacokinetics and biodistribution of oligonucleotides in tissues. Cationic delivery systems are also known, in which synthetic vectors with a net positive (cationic) charge facilitate the formation of a complex with a polyanionic nucleic acid and interaction with the negatively charged cell membrane. Such cationic delivery systems also include cationic liposomal delivery systems, cationic polymer-based and peptide-based delivery systems. Other delivery systems for cellular uptake of dsRNA/siRNA are aptamer ds/siRNA. Also, gene therapy approaches can be used to deliver lncRNA molecules according to the present invention or nucleic acid molecules encoding them. Such systems include the use of non-pathogenic viruses, modified viral vectors, and delivery via nanoparticles or liposomes. Other delivery methods for cellular uptake of lncRNAs are extracorporeal, such as ex vivo treatment of cells, organs, and tissues. Some of these technologies are described and summarized in publications such as Akhtar, Journal of Clinical Investigation (2007) 117:3623-3632, Nguyen et al., Current Opinion in Molecular Therapeutics (2008) 10:158-167, Zamboni, Clin Cancer Res (2005) 11:8230–8234 or Ikeda et al., Pharmaceutical Research (2006) 23:1631–1640.

Unless otherwise defined, all technical and scientific terms used in the present invention have the meaning commonly understood by one skilled in the art to which the present invention pertains. Although methods and materials similar or equivalent to those described in the present invention can be used in the practice or testing of the invention, suitable methods and materials are described below. All publications, patent applications and patents are incorporated herein by reference in their entirety. In the event of a conflict, this description, including definitions, will control. Moreover, the materials, methods, and examples are illustrative only and are not intended to be limiting.

The above embodiments and aspects of the present invention are illustrated by the following non-limiting examples.

Examples

Identification of lncRNAs for therapeutic applications. lncRNA engineering was performed to identify lncRNAs specifically targeting hepatitis B virus genotypes A, B, C, and D for therapeutic applications.

First, known genomic sequences of the hepatitis B virus were downloaded from the NCBI Genbank database (accession numbers are given in Table 6). Information on genotypes was taken from NCBI Genbank files or determined using computer-assisted semi-automated comparison with reference genomes (accession numbers are given in Table 6).

The genomic sequences of hepatitis B virus genotypes A-D were studied using computer analysis to identify optimal target regions for RNAi agents, namely highly conserved 17-nucleotide-long regions that are at least 90% identical across all sequences.

When identifying mRNA agents, selection was limited to 17-mer sequences having at least two complementarity violations to any sequence in the human RefSeq database (version 41), which we assumed to represent the complete human transcriptome using an appropriate algorithm.

All 17-mer sequences containing four or more consecutive Gs (poly-G sequences) were excluded from synthesis.

Sequences 19 nucleotides long were determined to hide selected 17-mers at positions 2 to 18.

These 19-mer sequences yielded RNA interference (RNAi) agents cross-reactive with the genomic sequences of hepatitis B virus genotypes A-D and formed the basis for the synthesis of the RNAi agents in the accompanying Tables. 1 and 2.

lncRNA synthesis. Oligonucleotides were synthesized in accordance with phosphoramidite technology on the solid phase. Depending on the scale, an ABI 394 synthesizer (Applied Biosystems) or an AKTA oligopilot 100 (GE Healthcare, Freiburg, Germany) was used. The synthesis was carried out on a solid support made of controlled pore glass (CPG, 520A, loading 75 micromol/g, obtained from Prime Synthesis, Aston, PA, USA). All 2′-modified RNA phosphoramidites as well as auxiliary reagents were ordered from SAFC (Hamburg, Germany). The following 2'-O-methylphosphoramidites were used: (5'-O-dimethoxytrityl-N ⁶ -(benzoyl)-2'-O-methyl-adenosine-3'-O-(2cyanoethyl-N,N-diisopropylamino)phosphoramidite, 5 '-O-dimethoxytrityl-N ⁴ -(acetyl)-2'-O-methylcytidine-3'-O-(2-cyanoethyl-N,N-idiisopropylamino)phosphoramidite, (5'-O-dimethoxy-trityl-N( isobutyryl)-2'-O-methyl-guanosine-3'-O-(2-cyanoethyl-N,N-diisopropylamino)phosphoramidite and 5'-Odimethoxy-trityl-2'-O-methyluridine-3'-O-( 2-cyanoethyl-N,N-diisopropylamino)phosphoramidite The 2'deoxy-2'-fluorophosphoramidites carried the same protecting groups as the 2'-O-methyl RNA amidites.All amidites were dissolved in anhydrous acetonitrile (100 mM) and molecular sieves were added (3A) To form the 5'-phosphate, 2-[2-(4,4'-dimethoxytrityloxy)ethylsulfonyl]ethyl-(2-cyanoethyl)-(N^diisopropyl)-phosphoramidite from Glen Research (Sterling, VA, USA) was used To introduce a C-6 amino linker at the 5' end of the oligomers, 6(trifluoroacetylamino)-hexyl-(2-cyanoethyl)(K,K-diisopropyl)-phosphoramidite from Thermo Fisher Scientific (Milwaukee, WI, USA) was used. 5' modifications were introduced without any changes in the synthesis cycle. 5-ethylthiotetrazole (ETT, 500 mM in acetonitrile) was used as the activating solution. The contact time was 6 minutes. To introduce phosphorothioate bonds, a 50 mM solution of 3((dimethylamino-methylidene)amino)-3H1,2,4-dithiazole-3-thione (DDTT, obtained from AM Chemicals, Oceanside, CA, USA) in anhydrous acetonitrile/pyridine (1 :1 v/v).

Separation and removal of protective groups from the oligomer attached to the substrate. After completion of the solid-phase synthesis, the cyanoethyl protecting groups were removed by a 30-minute treatment with 20% diethylamine in acetonitrile without separating the oligonucleotides from the support. The dried solid support was then transferred to a 15 mL tube and treated with concentrated aqueous ammonia (Aldrich) for 18 h at 40°C. After centrifugation, the supernatant was transferred to a new tube and the controlled pore size slides were washed with aqueous ammonia. The combined solutions were evaporated and the solid residue was dissolved in buffer A (see below).

Purification of oligonucleotides. Crude oligomers were purified by anion exchange HPLC using a column packed with Source Q15 (GE Healthcare) and an AKTA Explorer system (GE Healthcare). Buffer A was 10 mM sodium perchlorate, 20 mM Tris, 1 mM EDTA, pH 7.4 (Fluka, Buchs, Switzerland) and contained 20% acetonitrile, buffer B was buffer B minus 500 mM sodium perchlorate. A gradient of 22% B to 42% B was applied in 32 column volumes (CV). UV absorbance was recorded at 280 nm. The appropriate fractions were pooled and precipitated with 3 M NaOAc, pH 5.2 and 70% ethanol. The precipitate was then washed with 70% ethanol. Alternatively, desalting was performed using Sephadex HiTrap columns (GE Healthcare) according to the manufacturer's instructions.

Annealing of oligonucleotides to form siRNA. Complementary strands were mixed by combining equimolar RNA solutions. The mixture was lyophilized and reconstituted with an appropriate volume of annealing buffer (100 mM NaCl, 20 mM sodium phosphate, pH 6.8) to achieve the desired concentration. The solution was placed in a water bath at 80°C, which was cooled to room temperature over 3 hours.

In vitro screening of HBV mRNA-targeted lncRNA. The psiCHECK™-2 vector (Promega) contains two reporter genes for monitoring RNAi activity: a synthetic version of the renilla luciferase gene (hRluc) and a synthetic version of the firefly luciferase gene (hluc+). Measuring firefly luciferase activity makes it possible to evaluate changes that are not associated with the RNAi activity of the lncRNA being studied. Renilla and firefly luciferase activities were measured using the Dual-Glo® Luciferase Assay System (Promega). HBV target sites of interest were inserted after cloning into the psiCHECK™-2 vector, into the multiple cloning region located 3' from the translation stop codon and polyA tail of the synthetic renilla luciferase gene. The COS-7 cell line was transfected with the vector and sequentially treated with lncRNA-Lipofectamine 2000 lipoplexes targeting HBV sequences. The RNAi effect of lncRNA on the cloned HBV target site was determined by measuring the activity of the renilla luciferase gene fusion.

Generation of psiCHECK vectors containing target sequences. In order to study the activity of lncRNA against HBV, a dual HBV luciferase reporter was constructed. Regions 84 to 805, 1075 to 1992, 2165 to 2530, and 2718 to 2940 of the hepatitis B virus c genomic sequence

- 20 045398 accession number EU554538.1 (genotype C) were combined in silico. Two mutations were deliberately introduced (128 A^T, 598 T^C. positions refer to EU554538.1). One mutation was necessary to remove the internal XhoI site. The second mutation resulted in the removal of a single lncRNA complementarity disorder. This HBV target construct was extended by adding restriction sites at both the 5' and 3' ends. The artificial DNA sequence was chemically synthesized at Geneart (Regensburg, Germany) and cloned into the XhoI/NotI site of the psiCHECK™-2 dual-luciferase vector.

Transfection and luciferase quantitation. Cos-7 cells (DSMZ, Braunschweig, Germany, catalog no. ACC-60) were seeded at a density of 2.25 x ^{10 4} cells/well in 96-well plates. Plasmid transfection was carried out at a concentration of 50 ng/well with 0.5 μl/well of Lipofectamine 2000 (Invitrogen GmbH, Karlsruhe, Germany, catalog no. 11668-019) as described by the manufacturer. 4 h after vector transfection, the medium was removed and fresh medium was added. After this, lncRNA was added to the cells at a concentration of 10 nM or 1 nM using Lipofectamine 2000 as described above. To optimize HBV genotype overlap and minimize the development of lncRNA resistance, two different lncRNAs can be used in combination simultaneously. To demonstrate the validity of this approach, pairs of two different lncRNAs were selected from the best-performing lncRNAs with an additional bias toward optimized genotype overlap.

lncRNAs were added to cells at a concentration of 5 nM or 0.5 nM for each lncRNA, resulting in a total lncRNA concentration of 10 nM or 1 nM using Lipofectamine 2000 as described above. Cells were lysed after 48 h using luciferase reagents as described by the manufacturer. The protein level of renilla luciferase was normalized to that of firefly luciferase to assess transfection efficiency. For each lncRNA, data were collected from four separate points. At least one lncRNA unrelated to all target sites was used as a negative control to determine the relative level of renilla luciferase protein in lncRNA-treated cells (Table 8). To compare the suppressive activity under conditions of complete complementarity, lncRNAs with complete complementarity to the renilla open reading frame were synthesized and studied in parallel with HBV lncRNAs.

Data regarding inhibition are presented in the accompanying table. 2.

lncRNA stability. The stability of lncRNA targeting human hepatitis B virus was determined in an in vitro assay with any one of human, cynomolgus or mouse sera by measuring the half-life of each individual strand.

Measurements were performed in triplicate for each time point using 3 μL of 50 μM lncRNA sample mixed with 30 μL of human serum (Sigma), cynomolgus serum (Sigma), or mouse serum (Sigma). The mixtures were incubated for 0 min, 30 min, 1 h, 3 h, 6 h, 24 h, or 48 h at 37°C. As a control for nonspecific degradation, lncRNA was incubated with 30 μl of 1x PBS pH 6.8 for 48 h. Reactions were stopped by adding 4 μl of proteinase K (20 mg/ml), 25 μl of Tissue and Cell Lysis Solution (Epicentre) and 38 μl of water Millipore for 30 min at 65°C. Samples were then filtered through a 0.2 μm 96-well filter plate at 1400 rpm for 8 min, washed twice with 55 μl millipore water, and filtered again.

To separate individual chains and analyze the remaining full-length product (FLP), samples were separated by ion-exchange HPLC on a Dionex Summit chromatograph under denaturing conditions, using 20 mM Na ₃ PO ₄ in 10% acetonitrile pH 11 as eluent A and 1 M NaBr in 10% acetonitrile as eluent B. eluent A.

The following gradient was applied: Time %A %IN (min.) -ι,ο 75 25 1.00 75 25 19.0 38 62 19.5 0 100 21.5 0 100 22.0 75 25 24.0 75 25

For each injection, chromatograms were integrated automatically using Dionex Chromeleon 6.60 HPLC software and manually assessed when necessary. All peak areas were corrected relative to the peak of the internal standard (IS) and normalized with respect to the incubation time t = 0 min. The peak area and the resulting PRP value were calculated for each individual strand and triplicates separately. The half-life (t1/ ₂ ) of the chain was determined by the average time point (h) for three repetitions, at which half of the PRP was degraded. The results are presented in the attached table. 3.

- 21 045398

List of sequences < 110> ARROWHEAD RESEARCH CORPORATION Chin, Daniel Deckert, Jochen Hossbach, Markus Jon, Matthias < 12 0> COMPOSITIONS AND METHODS FOR INHIBITION OF HEPATITIS B VIRUS GENE EXPRESSION < 130> 27394 WO1 < 160> 648 < 170> PatentIn version 3.5 < 210 > 1 < 211> 19 < 212> RNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 1 caagguaugu ugcccguuu 19 < 210> 2 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 2 cuguaggcau aaauuggua 19 < 210> 3 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking a 5'-phosphate group < 400> 3 ucugcggcgu uuuaucaua 19 <210> 4

- 22 045398 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 4 accucugccu aaucaucuc 19 < 210> 5 <211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 5 uuuacuagug ccauuugua 19 < 210> 6 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 6 accucugccu aaucaucua 19 < 210> 7 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 7 cuguaggcau aaauugguc 19 <210> 8 <211> 19 <212> RNA

- 23 045398 <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 8 ugucugcggc guuuuauca 19 < 210> 9 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 9 uacuagugcc auuuguuca 19 < 210> 10 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 10 caacuuuuuc accucugca 19 < 210> 11 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 11 ccauuuguuc agugguucg 19 <210> 12 <211> 19 <212> RNA <213> Artificial sequence

- 24 045398 <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 12 ccaaguguuu gcugacgca 19 < 210> 13 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 13 ccauuuguuc agugguuca 19 <210> 14 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 14 uuuacuagug ccauuuguu 19 < 210> 15 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 15 caccucugcc uaauucauca 19 <210> 16 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand

- 25 045398 <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 16 cuggcucagu uuacuagug 19 < 210> 17 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 17 caagguaugu ugcccguua 19 < 210> 18 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 18 cuggcucagu uuacuagua 19 <210> 19 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 19 gaggcuguag gcauaaauu 19 <210> 20 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

- 26 045398 <221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 20 caguuuacua gugccauuu 19 <210> 21 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 21 agguauguug cccguuugu 19 <210> 22 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 22 uauguugccc guuugucca 19 <210> 23 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 23 gaggcuguag gcauaaaua 19 <210> 24 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1

- 27 045398 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 24 gucugcggcg uuuuaucau 19 <210> 25 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 25 caacuuuuuc accucugcc 19 < 210> 26 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 26 ccgugugcac uucgcuuca 19 <210> 27 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 27 ucaagguaug uugcccgua 19 < 210> 28 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 <223> /modified base = nucleoside lacking a 5'-phosphate group

- 28 045398 <400> 28 caguuuacua gugccaauua 19 <210> 29 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 29 ugguggacuu cucucaauu 19 <210> 30 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 30 agguauguug cccguuuga 19 < 210> 31 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 31 cugcucgugu uacaggcgg 19 <210> 32 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 32 uauguugccc guuuguccu 19

- 29 045398 <210> 33 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 33 ucaagguaug uugcccguu 19 <210> 34 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 34 ucuuaucaac acuuccgga 19 < 210> 35 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 35 caccucugcc uaauucaucu 19 < 210> 36 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 36 auaagaggac ucuuggacu 19

- 30 045398 <210> 37 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 37 gucugcggcg uuuuaucaa 19 <210> 38 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 38 ggcgcugaau cccgcggac 19 < 210> 39 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 39 cgcgucgcag aagaucuca 19 < 210> 40 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking a 5'-phosphate group < 400> 40 aaugucaacg accgaccuu 19 <210> 41 <211> 19

- 31 045398 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 41 gcucaguuua cuagugcca 19 <210> 42 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 42 ugguggacuu cucucaaua 19 < 210> 43 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 43 aucgccgcgu cgcagaaga 19 <210> 44 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 44 gccauuuguu cagugguuc 19 <210> 45 <211> 19 <212> RNA <213> Artificial sequence

- 32 045398 <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 45 cgauccauac ugcggaacu 19 <210> 46 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 46 ucaccucugc cuaaucauc 19 <210> 47 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 47 guggacuucu cucaauuuu 19 <210> 48 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 48 gggucaccau auucuuggg 19 <210> 49 <211> 19 <212> RNA <213> Artificial sequence <220 >

- 33 045398 <223> Description of the artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 49 gccgcgucgc agaagaucu 19 <210> 50 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 50 ucaaucgccg cgucgcaga 19 <210> 51 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 51 uggauguguc ugcggcguu 19 <210> 52 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 52 uacuguucaa gccuccaag 19 <210> 53 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand

- 34 045398 <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 53 guuuacuagu gccauuugu 19 <210> 54 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 54 acuagugcca uuuguucag 19 < 210> 55 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 55 ccgcgucgca gaagaucuc 19 <210> 56 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 56 uaucuuauca acacuuccg 19 <210> 57 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base

- 35 045398 <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 57 ggccaaaauu cgcaguccc 19 <210> 58 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 58 uucaccucug ccuaaucau 19 < 210> 59 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 59 cucaguuuac uagugccau 19 <210> 60 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 60 uguugcccgu uuguccucu 19 < 210> 61 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking a 5'-phosphate group

- 36 045398 <400> 61 uagugccauu uguucagug 19 <210> 62 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 62 aggcuguagg cauaaauug 19 < 210> 63 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 63 augugucugc ggcguuuua 19 < 210> 64 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 64 acuucgcuuc accucugca 19 < 210> 65 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 65

- 37 045398 cgugugcacu ucgcuucac 19 <210> 66 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 66 gugguggacu ucucucaau 19 <210> 67 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 67 ugugucugcg gcguuuuau 19 < 210> 68 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 68 aagguauguu gcccguuug 19 <210> 69 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 69 ucaacgaccg accuugagg 19

- 38 045398 <210> 70 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 70 cauaagagga cucuuggac 19 <210> 71 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 71 gucaacgacc gaccuugag 19 < 210> 72 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 72 auauucuugg gaacaagag 19 <210> 73 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 73 ugcucguguu acaggcggg 19 <210> 74

- 39 045398 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 74 caaucgccgc gucgcagaa 19 < 210> 75 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 75 acuguucaag ccuccaagc 19 < 210> 76 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 76 cgccgcgucg cagaagauc 19 < 210> 77 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 77 cauuuguuca gugguucgu 19 <210> 78 <211> 19 <212> RNA

- 40 045398 <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 78 cgcugaaucc cgcggacga 19 <210> 79 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 79 ugggucacca uauucuugg 19 <210> 80 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 80 uccucugccg auccauacu 19 < 210> 81 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 81 augucaacga ccgaccuug 19 <210> 82 <211> 19 <212> RNA <213> Artificial sequence

- 41 045398 <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 82 ccucugccua aucaucuca 19 < 210> 83 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 83 accgugugca cuucgcuuc 19 <210> 84 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 84 ugccgaucca uacugcgga 19 < 210> 85 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 85 cagagucuag acucguggu 19 <210> 86 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand

- 42 045398 <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 86 cuguucaagc cuccaagcu 19 <210> 87 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 87 ggaggcugua ggcauaaau 19 < 210> 88 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 88 aggaggcugu aggcauaaa 19 <210> 89 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 89 gguggacuuc ucucaauuu 19 <210> 90 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

- 43 045398 <221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 90 gcaacuuuuu caccucugc 19 <210> 91 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 91 cugcucgugu uacaggcga 19 < 210> 92 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 92 cuagugccau uuguucagu 19 < 210> 93 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 93 cugccgaucc auacugcgg 19 < 210> 94 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1

- 44 045398 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 94 gugugcacuu cgcuucacc 19 <210> 95 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 95 gcucgugua caggcgggc 19 < 210> 96 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 96 ccuaucuuau caacacuuc 19 <210> 97 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 97 ucucaaucgc cgcgucgca 19 < 210> 98 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking a 5'-phosphate group

- 45 045398 <400> 98 gcccgucugu gccuucuca 19 <210> 99 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 99 cuaucuuauc aacacuucc 19 < 210> 100 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 100 auguugcccg uuuguccuc 19 <210> 101 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 101 guauguugcc cguuugucc 19 <210> 102 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 102 cuucgcuuca ccuugcac 19

- 46 045398 <210> 103 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 103 ugugcacuuc gcuucaccu 19 <210> 104 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 104 gccaaaauuc gcagucccg 19 <210> 105 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 105 ccugcucgug uuacaggcg 19 <210> 106 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 106 uggagugugg auucgcacu 19

- 47 045398 <210> 107 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 107 aacgaccgac cuugaggca 19 < 210> 108 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 108 acagagucua gacucgugg 19 < 210> 109 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 109 aaucgccgcg ucgcagaag 19 <210> 110 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 110 gguauguugc ccguuuguc 19 <210> 111 <211> 19

- 48 045398 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 111 gccgauccau acugcggaa 19 <210> 112 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 112 gcccuaucuu aucaacacu 19 <210> 113 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 113 aguuuacuag ugccauuug 19 <210> 114 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 114 ugucaacgac cgaccuuga 19 <210> 115 <211> 19 <212> RNA <213> Artificial sequence

- 49 045398 <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 115 acuucucuca auuuucuag 19 <210> 116 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 116 gcgcgggacg uccuuuguc 19 <210> 117 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 117 ucuagacucg ugguggacu 19 <210> 118 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 118 gauccauacu gcggaacuc 19 <210> 119 <211> 19 <212> RNA <213> Artificial sequence <220 >

- 50 045398 <223> Description of the artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 119 cucugccgau ccaauacugc 19 <210> 120 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 120 ucugccgauc cauacugcg 19 <210> 121 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 121 ccucugccga uccauacug 19 <210> 122 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 122 gcaccucucu uuacgcggu 19 <210> 123 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand

- 51 045398 <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 123 aagaacuccc ucgccucgc 19 <210> 124 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 124 gaacucccuc gccucgcag 19 <210> 125 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 125 ucucucaauu uucuagggc 19 <210> 126 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 126 gggcgcaccu cucuuuacg 19 <210> 127 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base

- 52 045398 <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 127 ccgauccaua cugcggaac 19 <210> 128 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 128 aacucccucg ccucgcaga 19 < 210> 129 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 129 cuccucugcc gauccaauac 19 <210> 130 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 130 ggagugugga uucgcacuc 19 <210> 131 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 <223> /modified base = nucleoside lacking a 5'-phosphate group

- 53 045398 <400> 131 cgggcgcacc ucucuuuac 19 <210> 132 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 132 gucucaaucg ccgcgucgc 19 <210> 133 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 133 auccauacug cggaacucc 19 <210> 134 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 134 cgcaccucuc uuuacgcgg 19 < 210> 135 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base <222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group <400> 135

- 54 045398 caacgaccga ccuugaggc 19 <210> 136 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 136 ccaauacugcg gaacuccua 19 <210> 137 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 137 ugaaucccgc ggacgaccc 19 <210> 138 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 138 agaacucccu cgccucgca 19 <210> 139 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 139 ggcgcaccuc ucuuuacgc 19

- 55 045398 <210> 140 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 140 gcgcaccucu cuuuacgcg 19 <210> 141 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 141 gcugaauccc gcggacgac 19 <210> 142 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 142 cacuucgcuu caccucugc 19 < 210> 143 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 143 cucaaucgcc gcgucgcag 19 <210> 144

- 56 045398 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 144 ucccgucggc gcugaaucc 19 <210> 145 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 145 cugaaucccg cggacgacc 19 < 210> 146 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 146 agagucuaga cucguggug 19 <210> 147 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 147 uccauacugc ggaacuccu 19 <210> 148 <211> 19 <212> RNA

- 57 045398 <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 148 gcgcugaauc ccgcggacg 19 < 210> 149 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 149 aguguggauu cgcacuccu 19 < 210> 150 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 150 cccugcucgu guuacaggc 19 <210> 151 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 151 gaaucccgcg gacgacccg 19 <210> 152 <211> 19 <212> RNA <213> Artificial sequence

- 58 045398 <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 152 aagcugugcc uuggguggc 19 <210> 153 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 153 gcccugcucg uguuacagg 19 <210> 154 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 154 gucccgucgg cgcugaauc 19 <210> 155 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 155 aucuuaucaa cacuuccgg 19 <210> 156 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand

- 59 045398 <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 156 cuuaucaaca cuuccggaa 19 < 210> 157 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 157 aaacgggcaa cauaccuug 19 <210> 158 <211> 19 <212> DNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 158 taccaauuua ugccuacag 19 <210> 159 <211> 19 <212> RNA < 213> Artificial sequence < 220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 159 uaugauaaaa cgccgcaga 19 <210> 160 <211> 19 <212> DNA <213> Artificial sequence

- 60 045398 <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 2..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 160 taugauaaaa cgccgcaga 19 <210> 161 <211> 19 < 212> RNA < 213> Artificial sequence < 220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 161 gagaugauua ggcagaggu 19 <210> 162 <211> 19 <212> DNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 162 tacaaauggc acuaguaaa 19 <210> 163 <211> 19 <212> DNA < 213> Artificial sequence < 220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking a 5'-phosphate group

- 61 045398 <220>

<221> modified base <222> 2..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 163 tagaugauua ggcagaggu 19 <210> 164 <211> 19 <212> RNA < 213> Artificial sequence < 220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 164 gaccaauuua ugccuacag 19 <210> 165 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 165 ugauaaaacg ccgcagaca 19 <210> 166 <211> 19 <212> DNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 166 tgauaaaacg ccgcagaca 19 <210> 167 <211> 19 <212> RNA <213> Artificial sequence

- 62 045398 <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 167 ugaacaaaug gcacuagua 19 <210> 168 <211> 19 <212> DNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 2..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 168 tgaacaaaug gcacuagua 19 <210> 169 <211> 19 < 212> DNA < 213> Artificial sequence < 220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 169 tgcagaggug aaaaaguug 19 <210> 170 <211> 19 <212> RNA < 213> Artificial sequence < 220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 170

- 63 045398 cgaaccacug aacaaaugg 19 <210> 171 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 171 ugcgucagca aacacuugg 19 <210> 172 <211> 19 <212> DNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 172 tgcgucagca aacacuugg 19 <210> 173 <211> 19 <212> DNA < 213> Artificial sequence < 220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 173 tgaaccacug aacaaaugg 19 <210> 174 <211> 19 <212> RNA < 213> Artificial sequence < 220>

- 64 045398 <223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 174 aacaaauggc acuaguaaa 19 <210> 175 <211> 19 <212> DNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 2..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 175 tgaugauuag gcagaggug 19 <210> 176 <211> 19 < 212> RNA < 213> Artificial sequence < 220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 176 cacuaguaaa cugagccag 19 <210> 177 <211> 19 <212> DNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 177 taacgggcaa cauaccuug 19

- 65 045398 <210> 178 <211> 19 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 2..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 178 tacuaguaaa cugagccag 19 <210> 179 <211> 19 < 212> RNA < 213> Artificial sequence < 220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 179 aauuuaugcc uacagccuc 19 <210> 180 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 180 aaauggcacu aguaaacug 19 <210> 181 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

< 221> modified base < 222> 1 <223> /modified base = nucleoside lacking a 5'-phosphate group

- 66 045398 <400> 181 acaaacgggc aacauaccu 19 <210> 182 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 182 uggacaaacg ggcaacaua 19 <210> 183 <211> 19 <212> DNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 183 tauuuaugcc uacagccuc 19 <210> 184 <211> 19 <212> RNA < 213> Artificial sequence < 220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 184 augauaaaac gccgcagac 19 <210> 185 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

- 67 045398 <221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 185 ggcagaggug aaaaaguug 19 <210> 186 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 186 ugaagcgaag ugcacacgg 19 <210> 187 <211> 19 <212> DNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 187 tgaagcgaag ugcacacgg 19 <210> 188 <211> 19 <212> DNA < 213> Artificial sequence < 220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 188 tacgggcaac auaccuuga 19 <210> 189

- 68 045398 <211> 19 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 2..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 189 taauggcacu aguaaacug 19 <210> 190 <211> 19 <212> RNA < 213> Artificial sequence < 220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 190 aauugagaga aguccacca 19 <210> 191 <211> 19 < 212> DNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 2..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 191 tcaaacgggc aacauaccu 19 <210> 192 <211> 19 < 212> RNA < 213> Artificial sequence < 220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base

- 69 045398 <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 192 ccgccuguaa cacgagcag 19 <210> 193 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 193 aggacaaacg ggcaacaua 19 < 210> 194 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 194 aacgggcaac auaccuuga 19 < 210> 195 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 195 uccggaagug uugauaaga 19 <210> 196 <211> 19 <212> DNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking a 5'-phosphate group

- 70 045398 <220>

<221> modified base <222> 2..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 196 tccggaagug uugauaaga 19 <210> 197 <211> 19 <212> RNA < 213> Artificial sequence < 220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 197 agaugauuag gcagaggug 19 <210> 198 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 198 aguccaagag uccucuuau 19 <210> 199 <211> 19 < 212> DNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 199 tugauaaaac gccgcagac 19 <210> 200 <211> 19 <212> RNA <213> Artificial sequence

- 71 045398 <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 200 guccgcggga uucagcgcc 19 <210> 201 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 201 ugagaucuuc ugcgacgcg 19 <210> 202 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 202 aaggucgguc guugacauu 19 <210> 203 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 203 uggcacuagu aaacugagc 19 <210> 204 <211> 19 <212> DNA <213> Artificial sequence <220 >

- 72 045398 <223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 2..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 204 tauugagaga aguccacca 19 <210> 205 <211> 19 <212> RNA < 213> Artificial sequence < 220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 205 ucuucugcga cgcggcgau 19 <210> 206 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 206 gaaccacuga acaaauggc 19 <210> 207 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 207 aguuccgcag uauggaucg 19 <210> 208 <211> 19 <212> RNA

- 73 045398 <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 208 gaugauuagg cagagguga 19 < 210> 209 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 209 aaaauugaga gaagucccac 19 <210> 210 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 210 cccaagaaua uggugaccc 19 <210> 211 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 211 agaucuucug cgacgcggc 19 <210> 212 <211> 19 <212> RNA <213> Artificial sequence

- 74 045398 <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 212 ucugcgacgc ggcgauuga 19 < 210> 213 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 213 aacgccgcag acacaucca 19 < 210> 214 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 214 cuuggaggcu ugaacagua 19 <210> 215 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 215 acaaauggca cuaguaaac 19 <210> 216 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand

- 75 045398 <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 216 cugaacaaau ggcacuagu 19 <210> 217 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 217 gagaucuucu gcgacgcgg 19 <210> 218 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 218 cggaaguguu gauaagaua 19 <210> 219 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group <400> 219 gggacugcga auuuuggcc 19 < 210> 220 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

- 76 045398 <221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 220 augauuaggc agaggugaa 19 <210> 221 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 221 auggcacuag uaaacugag 19 < 210> 222 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 222 agaggacaaa cgggcaaca 19 <210> 223 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group <400> 223 cacugaacaa auggcacua 19 < 210> 224 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

< 221> modified base < 222> 1

- 77 045398 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 224 caauuuaugc cuacagccu 19 <210> 225 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 225 uaaaacgccg cagacacau 19 <210> 226 <211> 19 <212> DNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 2..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 226 taaaacgccg cagacacau 19 <210> 227 <211> 19 < 212> RNA < 213> Artificial sequence < 220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 227 ugcagaggug aagcgaagu 19 <210> 228 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand

- 78 045398 <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 228 gugaagcgaa gugcacacg 19 <210> 229 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 229 auugagagaa guccaccac 19 < 210> 230 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 230 auaaaacgcc gcagacaca 19 <210> 231 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group <400> 231 caaacgggca acauaccuu 19 < 210> 232 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base

- 79 045398 <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 232 ccucaagguc ggucguuga 19 <210> 233 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 233 guccaagagu ccucuuaug 19 <210> 234 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 234 cucaaggucg gucguugac 19 <210> 235 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 235 cucuuguucc caagaauau 19 <210> 236 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

< 221> modified base < 222> 1 <223> /modified base = nucleoside lacking a 5'-phosphate group

- 80 045398 <400> 236 cccgcgua acacgagca 19 <210> 237 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 237 uucugcgacg cggcgauug 19 <210> 238 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 238 gcuuggaggc uugaacagu 19 <210> 239 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 239 gaucuucugc gacgcggcg 19 <210> 240 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 240

- 81 045398 acgaaccacu gaacaaaug 19 <210> 241 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 241 ucguccgcgg gauucagcg 19 <210> 242 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 242 ccaagaauau ggugaccca 19 <210> 243 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 243 aguauggauc ggcagagga 19 <210> 244 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 244 caaggucggu cguugacau 19

- 82 045398 <210> 245 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 245 ugagaugauu aggcagagg 19 <210> 246 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 246 gaagcgaagu gcacacggu 19 <210> 247 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 247 uccgcaguau ggaucggca 19 <210> 248 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking a 5'-phosphate group <400> 248 accacgaguc uagacucug 19 <210> 249

- 83 045398 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 249 agcuuggagg cuugaacag 19 < 210> 250 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 250 auuuaugccu acagccucc 19 <210> 251 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 251 uuuaugccua cagccuccu 19 <210> 252 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 252 aaauugagag aaguccacc 19 <210> 253 <211> 19 <212> RNA

- 84 045398 <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 253 gcagagguga aaaaguugc 19 <210> 254 <211> 19 <212> DNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 254 tcgccuguaa cacgagcag 19 <210> 255 <211> 19 <212> RNA < 213> Artificial sequence < 220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 255 acugaacaaa uggcacuag 19 <210> 256 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 256 ccgcaguaug gaucggcag 19

- 85 045398 <210> 257 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 257 ggugaagcga agugcacac 19 <210> 258 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 258 gcccgccugu aacacgagc 19 <210> 259 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 259 gaaguguuga uaagauagg 19 <210> 260 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking a 5'-phosphate group <400> 260 ugcgacgcgg cgauugaga 19 <210> 261 <211> 19

- 86 045398 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 261 ugagaaggca cagacgggc 19 <210> 262 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 262 ggaaguguug auaagauag 19 <210> 263 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 263 gaggacaaac gggcaacau 19 <210> 264 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 264 ggacaaacgg gcaacauac 19 <210> 265 <211> 19 <212> RNA <213> Artificial sequence

- 87 045398 <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 265 gugcagaggu gaagcgaag 19 <210> 266 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 266 aggugaagcg aagugcaca 19 < 210> 267 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 267 cgggacugcg aauuuuggc 19 <210> 268 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 268 cgcguaac acgagcagg 19 <210> 269 <211> 19 <212> RNA <213> Artificial sequence <220 >

- 88 045398 <223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 269 agugcgaauc cacacucca 19 <210> 270 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 270 ugccucaagg ucggucguu 19 <210> 271 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 271 ccacgagucu agacucugu 19 <210> 272 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 272 cuucugcgac gcggcgauu 19 <210> 273 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand

- 89 045398 <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 273 gacaaacggg caacauacc 19 <210> 274 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 274 uuccgcagua uggaucggc 19 <210> 275 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 275 aguguugaa agauagggc 19 <210> 276 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group <400> 276 caaauggcac uaguaaacu 19 < 210> 277 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base

- 90 045398 <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 277 ucaaggucgg ucguugaca 19 <210> 278 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 278 cuagaaaauu gagagaagu 19 <210> 279 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 279 gacaaaggac gucccgcgc 19 <210> 280 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 280 aguccaccac gagucuaga 19 <210> 281 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

< 221> modified base < 222> 1 <223> /modified base = nucleoside lacking a 5'-phosphate group

- 91 045398 <400> 281 gaguuccgca guauggauc 19 <210> 282 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 282 gcaguaugga ucggcagag 19 <210> 283 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 283 cgcaguaugg aucggcaga 19 <210> 284 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 284 caguauggau cggcagagg 19 <210> 285 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 285

- 92 045398 accgcguaaa gagaggugc 19 <210> 286 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 286 gcgaggcgag ggaguucuu 19 <210> 287 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 287 cugcgaggcg agggaguuc 19 <210> 288 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 288 gcccuagaaa auugagaga 19 <210> 289 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 289 cguaaagaga ggugcgccc 19

- 93 045398 <210> 290 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 290 guuccgcagu auggaucgg 19 <210> 291 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 291 ucugcgaggc gagggaguu 19 <210> 292 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 292 guauggaucg gcagaggag 19 <210> 293 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking a 5'-phosphate group <400> 293 gagugcgaau ccacacucc 19 <210> 294

- 94 045398 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 294 guaaagagag gugcgcccg 19 <210> 295 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 295 gcgacgcggc gauugagac 19 <210> 296 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 296 ggaguuccgc aguauggau 19 <210> 297 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 297 ccgcguaaag agaggugcg 19 <210> 298 <211> 19 <212> RNA

- 95 045398 <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 298 gccucaaggu cggucguug 19 <210> 299 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 299 uaggaguucc gcaguaugg 19 <210> 300 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 300 gggucguccg cgggauuca 19 <210> 301 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 301 ugcgaggcga gggaguucu 19 <210> 302 <211> 19 <212> RNA <213> Artificial sequence

- 96 045398 <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 302 gcguaaagag aggugcgcc 19 < 210> 303 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 303 cgcguaaaga gaggugcgc 19 < 210> 304 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 304 gucguccgcg ggauucagc 19 <210> 305 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 305 gcagagguga agcgaagug 19 <210> 306 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand

- 97 045398 <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 306 cugcgacgcg gcgauugag 19 <210> 307 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 307 ggauucagcg ccgacggga 19 <210> 308 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 308 ggucguccgc gggauucag 19 <210> 309 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 309 caccacgagu cuagacucu 19 < 210> 310 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

- 98 045398 <221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 310 aggaguuccg caguaugga 19 <210> 311 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group < 400> 311 cguccgcggg auucagcgc 19 < 210> 312 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 312 aggagugcga auccacacu 19 <210> 313 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking 5'-phosphate group <400> 313 gcguaaca cgagcaggg 19 < 210> 314 < 211> 19 < 212> RNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

< 221> modified base < 222> 1

- 99 045398 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 314 cgggucgucc gcgggauuc 19 <210> 315 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 315 gccacccaag gcacagcuu 19 <210> 316 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 316 ccuguaacac gagcagggc 19 <210> 317 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 317 gauucagcgc cgacgggac 19 <210> 318 <211> 19 <212> RNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

< 221> modified base < 222> 1 <223> /modified base = nucleoside lacking a 5'-phosphate group

- 100 045398 <400> 318 ccggaagugu ugauaagau 19 <210> 319 <211> 19 <212> RNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <400> 319 uuccggaagu guugauaag 19 <210> 320 <211> 19 <212> DNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 320 tuccggaagu guugauaag 19 <210> 321 <211> 21 <212> DNA < 213> Artificial sequence < 220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 6, 8, 10, 11, 13, 14, 15, 17, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

< 221> modified base < 222> 3, 4, 5, 7, 9, 12, 16 < 223> /modified base = corresponding 2'-hydroxy nucleoside

- 101 045398 <400> 321 caagguaugu ugcccguuut t 21 <210> 322 <211> 20 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 20 <223> /modified base = 3'-3'-linked deoxythymidine <400> 322 cuguaggcau aaauugguat 20 <210> 323 <211> 21 <212> DNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 5, 8, 10, 11, 12, 13, 15, 16, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 4, 6, 7, 9, 14, 17, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 323 ucugcggcgu uuuaucauat t 21 <210> 324

- 102 045398 <211> 20 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 20 <223> /modified base = 3'-3'-linked deoxythymidine <400> 324 ucugcggcgu uuuaucauat 20 <210> 325 <211> 21 <212> DNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 1, 2, 3, 4, 5, 6, 8, 9, 10, 13, 14, 16, 17, 18, 19 < 223> /modified base = corresponding 2'-O- methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 7, 11, 12, 15 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 325 accucugccu aaucaucuct t 21 <210> 326 <211> 20 <212> DNA <213 > Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand

- 103 045398 <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 20 <223> /modified base = 3'-3'-linked deoxythymidine <400> 326 uuuacuagug ccauuuguat 20 <210> 327 <211> 20 <212> DNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 20 <223> /modified base = 3'-3'-linked deoxythymidine <400> 327 accucugccu aaucaucuat 20 <210> 328 <211> 21 <212> DNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking a 5'-phosphate group

- 104 045398 <220>

<221> modified base <222> 1, 2, 4, 8, 10, 14, 15, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 5, 6, 7, 9, 11, 12, 13, 16, 17 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 328 cuguaggcau aaauugguct t 21 <210 > 329 <211> 21 < 212> DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 4, 5, 7, 10, 12, 13, 14, 15, 17, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220 >

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 6, 8, 9, 11, 16, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 329 ugucugcggc guuuuaucat t 21 <210> 330 <211> 20 <212 > DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

- 105 045398 <221> modified base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220 >

<221> modified base <222> 20 <223> /modified base = 3'-3'-linked deoxythymidine <400> 330 ugucugcggc guuuuaucat 20 <210> 331 <211> 21 <212> DNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 4, 7, 9, 10, 12, 13, 14, 16, 17, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220 >

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 5, 6, 8, 11, 15, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 331 uacuagugcc auuuguucat t 21 <210> 332 <211> 20 <212 > DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base

- 106 045398 <222> 20 <223> /modified base = 3'-3'-linked deoxythymidine <400> 332 uacuagugcc auuuguucat 20 <210> 333 <211> 20 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

< 221> modified base < 222> 20 < 223> /modified base = 3'-3'-linked deoxythymidine < 400> 333 caacuuuuuc accucugcat 20 < 210> 334 < 211> 21 < 212> DNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 4, 5, 6, 8, 9, 10, 13, 16, 17, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 7, 11, 12, 14, 15, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 334 ccauuuguuc agugguucgt t 21

- 107 045398 <210> 335 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 6, 8, 9, 10, 12, 13, 16, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

< 221 > modified base < 222 > 3, 4, 5, 7, 11, 14, 15, 17, 19 < 223 > /modified base = corresponding 2'-hydroxy nucleoside < 400 > 335 ccaaguguuu gcugacgcat t 21 < 210 > 336 < 211> 20 < 212> DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 20 <223> /modified base = 3'-3'-linked deoxythymidine <400> 336 ccaaguguuu gcugacgcat 20 <210> 337 <211> 20 <212> DNA <213> Artificial sequence

- 108 045398 <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 20 <223> /modified base = 3'-3'-linked deoxythymidine <400> 337 ccauuuguuc agugguucat 20 <210> 338 <211> 21 <212> DNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 5, 6, 9, 11, 12, 14, 15, 16, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220 >

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 4, 7, 8, 10, 13, 17 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 338 uuuacuagug ccauuuguut t 21 <210> 339 <211> 20 <212 > DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1

- 109 045398 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 20 <223> /modified base = 3'-3'-linked deoxythymidine <400> 339 caccucugcc uaauucaucat 20 <210> 340 <211> 21 <212> DNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 5, 6, 7, 10, 11, 12, 14, 15, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 4, 8, 9, 13, 16, 17, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 340 cuggcucagu uuacuagugt t 21 <210> 341 <211 > 20 < 212> DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside

- 110 045398 <220>

<221> modified base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 20 <223> /modified base = 3'-3'-linked deoxythymidine <400> 341 caagguaugu ugcccguuat 20 <210> 342 <211> 20 <212> DNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 20 <223> /modified base = 3'-3'-linked deoxythymidine <400> 342 cuggcucagu uuacuaguat 20 <210> 343 <211> 21 <212> DNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 5, 6, 8, 12, 14, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 <223> /modified base = thymidine 5'-phosphothioate

- 111 045398 <220>

<221> modified base <222> 3, 4, 7, 9, 10, 11, 13, 15, 16, 17 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 343 gaggcuguag gcauaaauut t 21 <210 > 344 <211> 21 < 212> DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 4, 5, 6, 8, 9, 12, 14, 15, 17, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220 >

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 7, 10, 11, 13, 16 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 344 caguuuacua gugccauuut t 21 <210> 345 <211> 21 <212 > DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 4, 6, 8, 9, 11, 12, 13, 15, 16, 17, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220 >

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 5, 7, 10, 14, 18 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 345

- 112 045398 agguauguug cccguuugut t 21 <210> 346 <211> 20 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 20 <223> /modified base = 3'-3'-linked deoxythymidine <400> 346 uauguugccc guuuguccat 20 <210> 347 <211> 20 <212> DNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 20 <223> /modified base = 3'-3'-linked deoxythymidine <400> 347 gaggcuguag gcauaaauat 20 <210> 348 <211> 21 <212> DNA

- 113 045398 <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 4, 6, 9, 11, 12, 13, 14, 16, 17, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220 >

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 5, 7, 8, 10, 15, 18 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 348 gucugcggcg uuuuaucaut t 21 <210> 349 <211> 21 <212 > DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 1, 2, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 18, 19 < 223> /modified base = corresponding 2'- O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 11, 17 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 349 caacuuuuuc accucugcct t 21 <210> 350 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

- 114 045398 <221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 4, 6, 8, 10, 11, 12, 13, 15, 16, 17, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220 >

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 5, 7, 9, 14, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 350 ccgugugcac uucgcuucat t 21 <210> 351 <211> 20 <212 > DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 20 <223> /modified base = 3'-3'-linked deoxythymidine <400> 351 ccgugugcac uucgcuucat 20 <210> 352 <211> 20 <212> DNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base

- 115 045398 <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

< 221> modified base < 222> 20 < 223> /modified base = 3'-3'-linked deoxythymidine < 400> 352 ucaagguaug uugcccguat 20 < 210> 353 < 211> 20 < 212> DNA < 213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 20 <223> /modified base = 3'-3'-linked deoxythymidine <400> 353 caguuuacua gugccauuat 20 <210> 354 <211> 21 <212> DNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 4, 8, 9, 10, 11, 12, 13, 14, 15, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220 >

<221> modified base <222> 21

- 116 045398 <223> /modified base = thymidine 5'-phosphothioate <220>

< 221 > modified base < 222 > 3, 5, 6, 7, 16, 17 < 223 > /modified base = corresponding 2'-hydroxy nucleoside < 400 > 354 ugguggacuu cucucaauut t 21 < 210 > 355 < 211 > 20 < 212 > DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 20 <223> /modified base = 3'-3'-linked deoxythymidine <400> 355 agguauguug cccguuugat 20 <210> 356 <211> 21 <212> DNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 4, 5, 6, 8, 10, 11, 13, 17 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 7, 9, 12, 14, 15, 16, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside

- 117 045398 <400> 356 cugcucgugu uacaggcggt t 21 < 210> 357 < 211> 21 < 212> DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 1, 2, 3, 5, 6, 8, 9, 10, 12, 13, 14, 16, 17, 18, 19 < 223> /modified base = corresponding 2'-O- methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

< 221 > modified base < 222 > 4, 7, 11, 15 < 223 > /modified base = corresponding 2'-hydroxy nucleoside < 400 > 357 uauguugccc guuuguccut t 21 < 210 > 358 < 211 > 21 < 212 > DNA < 213 > Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 7, 9, 11, 12, 14, 15, 16, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

< 221> modified base < 222> 3, 4, 5, 6, 8, 10, 13, 17 < 223> /modified base = corresponding 2'-hydroxy nucleoside < 400> 358 ucaagguaug uugcccguut t 21 <210> 359

- 118 045398 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 4, 6, 7, 10, 12, 13, 14, 15, 16 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 5, 8, 9, 11, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 359 ucuuaucaac acuuccggat t 21 <210> 360 <211> 20 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 20 <223> /modified base = 3'-3'-linked deoxythymidine <400> 360 ucuuaucaac acuuccggat 20 <210> 361 <211> 21 <212> DNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand

- 119 045398 <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 14, 15, 17, 18, 19 < 223> /modified base = corresponding 2'-O- methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 8, 12, 13, 16 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 361 caccucugcc uaaucaucut t 21 <210> 362 <211> 21 <212> DNA <213 > Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 10, 11, 12, 13, 14, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 4, 5, 6, 7, 8, 9, 15, 16, 17 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 362 auaagaggac ucuuggacut t 21 <210 > 363 <211> 20 < 212> DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking a 5'-phosphate group

- 120 045398 <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 20 <223> /modified base = 3'-3'-linked deoxythymidine <400> 363 gucugcggcg uuuuaucaat 20 <210> 364 <211> 21 <212> DNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 5, 6, 10, 11, 12, 13, 15, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 4, 7, 8, 9, 14, 16, 17, 18 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 364 ggcgcugau cccgcggact t 21 <210> 365 <211 > 21 < 212> DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 5, 6, 8, 15, 16, 17, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

- 121 045398 <221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 4, 7, 9, 10, 11, 12, 13, 14, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 365 cgcgucgcag aagaucucat t 21 <210> 366 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 5, 6, 9, 12, 13, 16, 17, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 4, 7, 8, 10, 11, 14, 15 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 366 aaugucaacg accgaccuut t 21 <210> 367 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 4, 7, 8, 9, 11, 12, 15, 17, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base

- 122 045398 <222> 5, 6, 10, 13, 14, 16, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 367 gcucaguuua cuagugccat t 21 <210> 368 <211> 20 <212 > DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 20 <223> /modified base = 3'-3'-linked deoxythymidine <400> 368 ugguggacuu cucucaauat 20 <210> 369 <211> 21 <212> DNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 5, 6, 8, 10, 11, 13 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 4, 7, 9, 12, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 369 aucgccgcgu cgcagaagat t 21

- 123 045398 <210> 370 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 5, 6, 7, 9, 10, 11, 14, 17, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220 >

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 4, 8, 12, 13, 15, 16 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 370 gccauuuguu cagugguuct t 21 <210> 371 <211> 21 <212 > DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 4, 5, 6, 8, 10, 11, 13, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 7, 9, 12, 14, 15, 16, 17 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 371 cgauccauac ugcggaacut t 21 <210> 372 <211 > 21 <212> DNA <213> Artificial sequence

- 124 045398 <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 4, 5, 6, 7, 8, 10, 11, 12, 15, 16, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 9, 13, 14, 17 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 372 ucaccucugc cuaaucauct t 21 <210> 373 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 6, 7, 8, 9, 10, 11, 12, 13, 16, 17, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 4, 5, 14, 15 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 373 guggacuucu cucaauuuut t 21 <210> 374 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1

- 125 045398 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 4, 5, 7, 8, 10, 12, 13, 14, 15, 16 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 6, 9, 11, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 374 gggucaccau auucuugggt t 21 <210> 375 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 5, 7, 8, 10, 17, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 4, 6, 9, 11, 12, 13, 14, 15, 16 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 375 gccgcgucgc agaagaucut t 21 <210> 376 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 5, 6, 8, 9, 11, 13, 14, 16 <223> /modified base = corresponding 2'-O-methyl nucleoside

- 126 045398 <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 4, 7, 10, 12, 15, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 376 ucaaucgccg cgucgcagat t 21 <210> 377 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 5, 7, 9, 10, 11, 13, 16, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 4, 6, 8, 12, 14, 15, 17 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 377 uggauguguc ugcggcguut t 21 <210> 378 <211 > 21 < 212> DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 4, 6, 7, 8, 12, 13, 14, 15, 16 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 < 223> /modified base = thymidine 5'-phosphothioate

- 127 045398 <220>

< 221> modified base < 222> 5, 9, 10, 11, 17, 18, 19 < 223> /modified base = corresponding 2'-hydroxy nucleoside < 400> 378 uacuguucaa gccuccaagt t 21 < 210> 379 < 211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 4, 6, 7, 10, 12, 13, 15, 16, 17, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220 >

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 5, 8, 9, 11, 14, 18 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 379 guuuacuagu gccauuugut t 21 <210> 380 <211> 21 <212 > DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 6, 8, 9, 11, 12, 13, 15, 16, 17 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 4, 5, 7, 10, 14, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 380

- 128 045398 acuagugcca uuuguucagt t 21 <210> 381 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 4, 6, 7, 9, 16, 17, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 5, 8, 10, 11, 12, 13, 14, 15 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 381 ccgcgucgca gaagaucuct t 21 <210> 382 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 8, 9, 12, 14, 15, 16, 17, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 7, 10, 11, 13, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 382 uaucuuauca acacuuccgt t 21 <210> 383 <211> 21 <212> DNA

- 129 045398 <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 4, 9, 10, 11, 13, 16, 17, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 5, 6, 7, 8, 12, 14, 15 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 383 ggccaaaauu cgcaguccct t 21 <210> 384 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 5, 6, 7, 8, 9, 11, 12, 13, 16, 17, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 4, 10, 14, 15, 18 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 384 uucaccucug ccuaaucaut t 21 <210> 385 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

- 130 045398 <221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 6, 7, 8, 10, 11, 14, 16, 17, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 4, 5, 9, 12, 13, 15, 18 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 385 cucaguuuac uagugccaut t 21 <210> 386 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 1, 2, 3, 4, 6, 7, 8, 10, 11, 12, 14, 15, 16, 17, 18, 19 < 223> /modified base = corresponding 2'- O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 5, 9, 13 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 386 uguugcccgu uuguccucut t 21 <210> 387 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base

- 131 045398 <222> 1, 2, 4, 6, 7, 9, 10, 11, 13, 14, 15, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 5, 8, 12, 16, 17, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 387 uagugccauu uguucagugt t 21 <210> 388 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 4, 5, 7, 11, 13, 17, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 6, 8, 9, 10, 12, 14, 15, 16, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 388 aggcuguagg cauaaauugt t 21 <210 > 389 <211> 21 < 212> DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 4, 6, 7, 8, 10, 13, 15, 16, 17, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21

- 132 045398 <223> /modified base = thymidine 5'-phosphothioate <220>

< 221> modified base < 222> 3, 5, 9, 11, 12, 14, 19 < 223> /modified base = corresponding 2'-hydroxy nucleoside < 400> 389 augugucugc ggcguuuuat t 21 < 210> 390 < 211> 20 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 20 <223> /modified base = 3'-3'-linked deoxythymidine <400> 390 augugucugc ggcguuuuat 20 <210> 391 <211> 21 <212> DNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 1, 2, 3, 4, 5, 7, 8, 9, 10, 12, 13, 14, 15, 16, 18 < 223> /modified base = corresponding 2'-O- methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

< 221> modified base < 222> 6, 11, 17, 19 < 223> /modified base = corresponding 2'-hydroxy nucleoside

- 133 045398 <400> 391 acuucgcuuc accucugcat t 21 <210> 392 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 5, 7, 9, 10, 11, 12, 14, 15, 16, 17, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 4, 6, 8, 13, 18 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 392 cgugugcacu ucgcuucact t 21 <210> 393 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 5, 9, 10, 11, 12, 13, 14, 15, 16, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 4, 6, 7, 8, 17, 18 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 393 gugguggacu ucucucaaut t 21 <210> 394

- 134 045398 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 5, 6, 7, 9, 12, 14, 15, 16, 17, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220 >

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 4, 8, 10, 11, 13, 18 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 394 ugugucugcg gcguuuuaut t 21 <210> 395 <211> 21 <212 > DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 5, 7, 9, 10, 12, 13, 14, 16, 17, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 4, 6, 8, 11, 15, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 395 aagguauguu gcccguuugt t 21 <210> 396 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand

- 135 045398 <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 5, 8, 9, 12, 13, 14, 15 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 4, 6, 7, 10, 11, 16, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 396 ucaacgaccg accuugaggt t 21 <210 > 397 <211> 21 < 212> DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 11, 12, 13, 14, 15, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 4, 5, 6, 7, 8, 9, 10, 16, 17, 18 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 397 cauaagagga cucuuggact t 21 <210 > 398 <211> 21 < 212> DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking a 5'-phosphate group

- 136 045398 <220>

<221> modified base <222> 1, 2, 3, 6, 9, 10, 13, 14, 15, 16 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 4, 5, 7, 8, 11, 12, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 398 gucaacgacc gaccuugagt t 21 <210> 399 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 4, 5, 6, 7, 8, 14 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 399 auauucuugg gaacaagagt t 21 <210> 400 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 4, 5, 7, 9, 10, 12, 16 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

- 137 045398 <221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 6, 8, 11, 13, 14, 15, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 400 ugcucguguu acaggcgggt t 21 <210> 401 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 4, 5, 7, 8, 10, 12, 13, 15 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 6, 9, 11, 14, 16, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 401 caaucgccgc gucgcagaat t 21 <210> 402 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 5, 6, 7, 11, 12, 13, 14, 15, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base

- 138 045398 <222> 4, 8, 9, 10, 16, 17, 18 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 402 acuguucaag ccuccaagct t 21 <210> 403 <211> 21 <212 > DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 4, 6, 8, 9, 11, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 5, 7, 10, 12, 13, 14, 15, 16, 17 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 403 cgccgcgucg cagaagauct t 21 <210> 404 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 4, 5, 7, 8, 9, 12, 15, 16, 17, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220 >

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 6, 10, 11, 13, 14, 18 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 404 cauuuguuca gugguucgut t 21

- 139 045398 <210> 405 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 4, 8, 9, 10, 11, 13, 17 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 5, 6, 7, 12, 14, 15, 16, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 405 cgcugaaucc cgcggacgat t 21 <210> 406 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 5, 6, 8, 9, 11, 13, 14, 15, 16, 17 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 4, 7, 10, 12, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 406 ugggucacca uauucuuggt t 21 <210> 407 <211> 21 <212> DNA <213> Artificial sequence

- 140 045398 <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 8, 9, 12, 13, 14, 16, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 7, 10, 11, 15, 17 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 407 uccucugccg auccauacut t 21 <210> 408 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 4, 5, 8, 11, 12, 15, 16, 17, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 6, 7, 9, 10, 13, 14, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 408 augucaacga ccgaccuugt t 21 <210> 409 <211 > 21 < 212> DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1

- 141 045398 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 4, 5, 7, 8, 9, 12, 13, 15, 16, 17, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 6, 10, 11, 14, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 409 ccucugccua aucaucucat t 21 <210> 410 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 5, 7, 9, 11, 12, 13, 14, 16, 17, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 4, 6, 8, 10, 15 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 410 accgugugca cuucgcuuct t 21 <210> 411 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 1, 2, 3, 4, 7, 8, 9, 11, 13, 14, 16 < 223> /modified base = corresponding 2'-O-methyl nucleoside

- 142 045398 <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 5, 6, 10, 12, 15, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 411 ugccgaucca uacugcggat t 21 <210> 412 <211 > 21 < 212> DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 6, 7, 8, 12, 13, 14, 16, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 4, 5, 9, 10, 11, 15, 17, 18 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 412 cagagucuag acucguggut t 21 <210> 413 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 4, 5, 6, 10, 11, 12, 13, 14, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 < 223> /modified base = thymidine 5'-phosphothioate

- 143 045398 <220>

<221> modified base <222> 3, 7, 8, 9, 15, 16, 17 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 413 cuguucaagc cuccaagcut t 21 <210> 414 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 6, 7, 9, 13, 15, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 4, 5, 8, 10, 11, 12, 14, 16, 17, 18 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 414 ggaggcugua ggcauaaaut t 21 <210> 415 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 7, 8, 10, 14, 16 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 4, 5, 6, 9, 11, 12, 13, 15, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 415

- 144 045398 aggaggcugu aggcauaaat t 21 <210> 416 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 7, 8, 9, 10, 11, 12, 13, 14, 17, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 4, 5, 6, 15, 16 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 416 gguggacuuc ucucaauuut t 21 <210> 417 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 1, 2, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16, 17, 19 < 223> /modified base = corresponding 2'-O- methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 4, 12, 18 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 417 gcaacuuuuu caccucugct t 21 <210> 418 <211> 20 <212> DNA

- 145 045398 <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 20 <223> /modified base = 3'-3'-linked deoxythymidine <400> 418 cugcucgugu uacaggcgat 20 <210> 419 <211> 21 <212> DNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 5, 7, 8, 10, 11, 12, 14, 15, 16, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 4, 6, 9, 13, 17, 18 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 419 cuagugccau uuguucagut t 21 <210> 420 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

- 146 045398 <221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 4, 5, 8, 9, 10, 12, 14, 15, 17 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 6, 7, 11, 13, 16, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 420 cugccgaucc auacugcggt t 21 <210> 421 <211 > 21 < 212> DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 4, 6, 8, 9, 10, 11, 13, 14, 15, 16, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 5, 7, 12, 17 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 421 gugugcacuu cgcuucacct t 21 <210> 422 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base

- 147 045398 <222> 1, 2, 3, 4, 6, 8, 9, 11, 15, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 5, 7, 10, 12, 13, 14, 16, 17, 18 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 422 gcucguguua caggcgggct t 21 <210> 423 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 5, 6, 7, 8, 10, 11, 14, 16, 17, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 4, 9, 12, 13, 15 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 423 ccuaucuuau caacacuuct t 21 <210> 424 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 4, 7, 8, 10, 11, 13, 15, 16, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21

- 148 045398 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 5, 6, 9, 12, 14, 17, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 424 ucucaaucgc cgcgucgcat t 21 <210> 425 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 1, 2, 3, 4, 6, 7, 8, 10, 12, 13, 14, 15, 16, 17, 18 < 223> /modified base = corresponding 2'-O- methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 5, 9, 11, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 425 gcccgucugu gccuucucat t 21 <210> 426 <211> 21 <212> DNA <213 > Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 4, 5, 6, 7, 9, 10, 13, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

< 221> modified base < 222> 3, 8, 11, 12, 14 < 223> /modified base = corresponding 2'-hydroxy nucleoside

- 149 045398 <400> 426 cuaucuuauc aacacuucct t 21 < 210> 427 < 211> 21 < 212> DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 1, 2, 4, 5, 7, 8, 9, 11, 12, 13, 15, 16, 17, 18, 19 < 223> /modified base = corresponding 2'-O- methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 6, 10, 14 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 427 auguugcccg uuuguccuct t 21 <210> 428 <211> 21 <212> DNA <213 > Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 4, 6, 7, 9, 10, 11, 13, 14, 15, 17, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 5, 8, 12, 16 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 428 guauguugcc cguuugucct t 21 <210> 429

- 150 045398 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 1, 2, 3, 4, 6, 7, 8, 9, 11, 12, 13, 14, 15, 17, 19 < 223> /modified base = corresponding 2'-O- methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 5, 10, 16, 18 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 429 cuucgcuuca ccucugcact t 21 <210> 430 <211> 21 <212> DNA <213 > Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 1, 2, 3, 5, 7, 8, 9, 10, 12, 13, 14, 15, 17, 18, 19 < 223> /modified base = corresponding 2'-O- methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 4, 6, 11, 16 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 430 ugugcacuuc gcuucaccut t 21 <210> 431 <211> 21 <212> DNA <213 > Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand

- 151 045398 <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 8, 9, 10, 12, 15, 16, 17, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 4, 5, 6, 7, 11, 13, 14, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 431 gccaaaauuc gcagucccgt t 21 <210> 432 <211 > 21 < 212> DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 5, 6, 7, 9, 11, 12, 14, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 4, 8, 10, 13, 15, 16, 17, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 432 ccugcucgug uuacaggcgt t 21 <210> 433 <211 > 21 < 212> DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking a 5'-phosphate group

- 152 045398 <220>

<221> modified base <222> 1, 2, 6, 8, 12, 13, 14, 16, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 4, 5, 7, 9, 10, 11, 15, 17 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 433 uggagugugg auucgcacut t 21 <210> 434 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 6, 7, 10, 11, 12, 13, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 4, 5, 8, 9, 14, 15, 16, 17, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 434 aacgaccgac cuugaggcat t 21 <210> 435 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 7, 8, 9, 13, 14, 15, 17 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

- 153 045398 <221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 4, 5, 6, 10, 11, 12, 16, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 435 acagagucua gacucguggt t 21 <210 > 436 <211> 21 < 212> DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 4, 6, 7, 9, 11, 12, 14 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 5, 8, 10, 13, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 436 aaucgccgcg ucgcagaagt t 21 <210> 437 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 5, 7, 8, 10, 11, 12, 14, 15, 16, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base

- 154 045398 <222> 4, 6, 9, 13, 17 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 437 gguauguugc ccguuuguct t 21 <210> 438 <211> 21 <212> DNA <213 > Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 6, 7, 8, 10, 12, 13, 15 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 4, 5, 9, 11, 14, 16, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 438 gccgauccau acugcggaat t 21 <210> 439 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 4, 5, 7, 8, 9, 10, 12, 13, 16, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 6, 11, 14, 15, 17 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 439 gcccuaucuu aucaacacut t 21

- 155 045398 <210> 440 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 4, 5, 7, 8, 11, 13, 14, 16, 17, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220 >

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

< 221 > modified base < 222 > 6, 9, 10, 12, 15, 19 < 223 > /modified base = corresponding 2'-hydroxy nucleoside < 400 > 440 aguuuacuag ugccauuugt t 21 < 210 > 441 < 211 > 21 < 212 > DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 4, 7, 10, 11, 14, 15, 16, 17 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 5, 6, 8, 9, 12, 13, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 441 ugucaacgac cgaccuugat t 21 <210> 442 <211 > 21 <212> DNA <213> Artificial sequence

- 156 045398 <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 12, 13, 14, 15, 16, 17 < 223> /modified base = corresponding 2'-O- methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 10, 11, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 442 acuucucuca auuuucuagt t 21 <210> 443 <211> 21 <212> DNA <213 > Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 4, 9, 11, 12, 13, 14, 15, 16, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 5, 6, 7, 8, 10, 17 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 443 gcgcgggacg uccuuuguct t 21 <210> 444 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1

- 157 045398 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 7, 8, 9, 11, 14, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 4, 5, 6, 10, 12, 13, 15, 16, 17 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 444 ucuagacucg ugguggacut t 21 <210> 445 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 4, 5, 7, 9, 10, 12, 17, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 6, 8, 11, 13, 14, 15, 16 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 445 gauccauacu gcggaacuct t 21 <210> 446 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 4, 6, 7, 10, 11, 12, 14, 16, 17, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside

- 158 045398 <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

< 221> modified base < 222> 5, 8, 9, 13, 15, 18 < 223> /modified base = corresponding 2'-hydroxy nucleoside < 400> 446 cucugccgau ccauacugct t 21 < 210> 447 <211> 21 < 212 > DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 5, 6, 9, 10, 11, 13, 15, 16, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 4, 7, 8, 12, 14, 17, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 447 ucugccgauc cauacugcgt t 21 <210> 448 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 4, 5, 7, 8, 11, 12, 13, 15, 17, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220 >

<221> modified base <222> 21 < 223> /modified base = thymidine 5'-phosphothioate

- 159 045398 <220>

< 221 > modified base < 222 > 6, 9, 10, 14, 16, 19 < 223 > /modified base = corresponding 2'-hydroxy nucleoside < 400 > 448 ccucugccga uccauacugt t 21 < 210 > 449 < 211 > 21 < 212 > DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 13, 15, 17, 18 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 449 gcaccucucu uuacgcggut t 21 <210> 450 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 4, 5, 13, 18 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 450

- 160 045398 aagaacuccc ucgccucgct t 21 <210> 451 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 17 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 11, 16, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 451 gaacucccuc gccucgcagt t 21 <210> 452 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 9, 10, 11, 12, 13, 14, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220 >

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 7, 8, 15, 16, 17, 18 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 452 ucucucaauu uucuagggct t 21 <210> 453 <211> 21 <212 > DNA

- 161 045398 <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 4, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 5, 7, 17, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 453 gggcgcaccu cucuuuacgt t 21 <210> 454 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 5, 6, 7, 9, 11, 12, 14, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 4, 8, 10, 13, 15, 16, 17, 18 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 454 ccgauccaua cugcggaact t 21 <210> 455 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

- 162 045398 <221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 16 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 10, 15, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 455 aacucccucg ccucgcagat t 21 <210> 456 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 7, 9, 10, 13, 14, 15, 17, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 8, 11, 12, 16, 18 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 456 cuccucugcc gauccauact t 21 <210> 457 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base

- 163 045398 <222> 1, 2, 5, 7, 11, 12, 13, 15, 17, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 4, 6, 8, 9, 10, 14, 16 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 457 ggagugugga uucgcacuct t 21 <210> 458 <211 > 21 < 212> DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 5, 7, 9, 10, 11, 12, 13, 14, 15, 16, 17, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 4, 6, 8, 18 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 458 cgggcgcacc ucucuuuact t 21 <210> 459 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 4, 5, 8, 9, 11, 12, 14, 16, 17, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220 >

<221> modified base <222> 21

- 164 045398 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 6, 7, 10, 13, 15, 18 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 459 gucucaaucg ccgcgucgct t 21 <210> 460 <211> 21 <212 > DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 4, 6, 8, 9, 11, 16, 17, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 5, 7, 10, 12, 13, 14, 15 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 460 auccauacug cggaacucct t 21 <210> 461 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 17 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 4, 14, 16, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside

- 165 045398 <400> 461 cgcaccucuc uuuacgcggt t 21 < 210> 462 < 211> 21 < 212> DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 4, 7, 8, 11, 12, 13, 14, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 5, 6, 9, 10, 15, 16, 17, 18 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 462 caacgaccga ccuugaggct t 21 <210> 463 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 4, 6, 7, 9, 14, 15, 16, 17, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 5, 8, 10, 11, 12, 13, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 463 ccaauacugcg gaacuccuat t 21 <210> 464

- 166 045398 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 5, 6, 7, 8, 10, 14, 17, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 4, 9, 11, 12, 13, 15, 16 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 464 ugaaucccgc ggacgaccct t 21 <210> 465 <211 > 21 < 212> DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 4, 12, 17, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 465 agaacucccu cgccucgcat t 21 <210> 466 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand

- 167 045398 <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 1, 2, 3, 5, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 19 < 223> /modified base = corresponding 2'-O- methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 4, 6, 16, 18 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 466 ggcgcaccuc ucuuuacgct t 21 <210> 467 <211> 21 <212> DNA <213 > Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 5, 15, 17, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 467 gcgcaccucu cuuuacgcgt t 21 <210> 468 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking a 5'-phosphate group

- 168 045398 <220>

<221> modified base <222> 1, 2, 3, 7, 8, 9, 10, 12, 16, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 4, 5, 6, 11, 13, 14, 15, 17, 18 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 468 gcugaauccc gcggacgact t 21 <210> 469 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 13, 14, 15, 16, 17, 19 < 223> /modified base = corresponding 2'- O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 7, 12, 18 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 469 cacuucgcuu caccucugct t 21 <210> 470 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 6, 7, 9, 10, 12, 14, 15, 17 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

- 169 045398 <221> modified base <222> 21 <223> /modified base =

Thymidine 5'-phosphothioate <220>

<221> modified base <222> 4, 5, 8, 11, 13, 16, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 470 cucaaucgcc gcgucgcagt t 21 <210> 471 <211 > 21 < 212> DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 4, 6, 7, 10, 12, 13, 17, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 5, 8, 9, 11, 14, 15, 16 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 471 ucccgucggc gcugaaucct t 21 <210> 472 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 6, 7, 8, 9, 11, 15, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base

- 170 045398 <222> 3, 4, 5, 10, 12, 13, 14, 16, 17 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 472 cugaaucccg cggacgacct t 21 <210> 473 <211 > 21 < 212> DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 5, 6, 7, 11, 12, 13, 15, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 4, 8, 9, 10, 14, 16, 17, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 473 agagucuaga cucguggugt t 21 <210> 474 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 5, 7, 8, 10, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 4, 6, 9, 11, 12, 13, 14 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 474 uccauacugc ggaacuccut t 21

- 171 045398 <210> 475 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 4, 5, 9, 10, 11, 12, 14, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 6, 7, 8, 13, 15, 16, 17, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 475 gcgcugaauc ccgcggacgt t 21 <210> 476 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 5, 9, 10, 11, 13, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220 >

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 4, 6, 7, 8, 12, 14 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 476 aguguggauu cgcacuccut t 21 <210> 477 <211> 21 <212 > DNA <213> Artificial sequence

- 172 045398 <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 4, 6, 7, 8, 10, 12, 13, 15, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 5, 9, 11, 14, 16, 17, 18 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 477 cccugcucgu guuacaggct t 21 <210> 478 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 4, 5, 6, 7, 9, 13, 16, 17, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 8, 10, 11, 12, 14, 15, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 478 gaaucccgcg gacgacccgt t 21 <210> 479 <211 > 21 < 212> DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

< 221> modified base < 222> 1

- 173 045398 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 4, 5, 7, 9, 10, 11, 12, 16, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 3, 6, 8, 13, 14, 15, 17, 18 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 479 aagcugugcc uuggguggct t 21 <210> 480 <211 > 21 < 212> DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 4, 5, 7, 8, 9, 11, 13, 14, 16 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 6, 10, 12, 15, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 480 gcccugcucg uguuacaggt t 21 <210> 481 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 4, 5, 7, 8, 11, 13, 14, 18, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside

- 174 045398 <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 6, 9, 10, 12, 15, 16, 17 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 481 gucccgucgg cgcugaauct t 21 <210> 482 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 4, 5, 7, 8, 11, 13, 14, 15, 16, 17 <223> /modified base = corresponding 2'-O-methyl nucleoside <220 >

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 6, 9, 10, 12, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 482 aucuuaucaa cacuuccggt t 21 <210> 483 <211> 21 <212 > DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 2, 3, 5, 6, 9, 11, 12, 13, 14, 15 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 < 223> /modified base = thymidine 5'-phosphothioate

- 175 045398 <220>

<221> modified base <222> 4, 7, 8, 10, 16, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 483 cuuaucaaca cuuccggaat t 21 <210> 484 <211 > 20 < 212> DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: dsRNA coding strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 20 <223> /modified base = 3'-3'-linked deoxythymidine <400> 484 cuuaucaaca cuuccggaat 20 <210> 485 <211> 21 <212> DNA <213> Artificial sequence <220 >

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 8, 11, 13 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 7, 9, 10, 12, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'- hydroxy nucleoside <400> 485

- 176 045398 aaacgggcaa cauaccuugt t 21 <210> 486 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <400> 486 taccaauuua ugccuacagt t 21 <210> 487 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 6, 16 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 18, 19 <223> /modified base = corresponding 2'- hydroxy nucleoside <400> 487 uaugauaaaa cgccgcagat t 21 <210> 488 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand

- 177 045398 <220>

<221> modified base <222> 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <400> 488 taugauaaaa cgccgcagat t 21 <210> 489 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 9, 13 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2 '-hydroxy nucleoside <400> 489 gagaugauua ggcagaggut t 21 <210> 490 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

- 178 045398 <221> modified base <222> 21 <223> /modified base = 5'-phosphothioate thymidine <400> 490 tacaaauggc acuaguaaat t 21 <210> 491 <211> 21 <212> DNA <213> Artificial sequence < 220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <400> 491 tagaugauua ggcagaggut t 21 <210> 492 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 4, 9, 15, 17 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 14, 16, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 492 gaccaauuua ugccuacagt t 21 <210> 493 <211> 21 <212> DNA

- 179 045398 <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 4, 14, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17, 19 <223> /modified base = corresponding 2'- hydroxy nucleoside <400> 493 ugauaaaacg ccgcagacat t 21 <210> 494 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 21 <223> /modified base = 5'-phosphothioate thymidine <400> 494 tgauaaaacg ccgcagacat t 21 <210> 495 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

- 180 045398 <221> modified base <222> 5, 12, 15, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 13, 14, 16, 17, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 495 ugaacaaaug gcacuaguat t 21 <210> 496 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 21 <223> /modified base = 5'-phosphothioate thymidine <400> 496 tgaacaaaug gcacuaguat t 21 <210> 497 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 21 <223> /modified base = 5'-phosphothioate thymidine <400> 497 tgcagaggug aaaaaguugt t 21

- 181 045398 <210> 498 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 6, 13 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2 '-hydroxy nucleoside <400> 498 cgaaccacug aacaaauggt t 21 <210> 499 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 6, 9, 13 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 7, 8, 10, 11, 12, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'- hydroxy nucleoside <400> 499 ugcgucagca aacacuuggt t 21 <210> 500 <211> 21 <212> DNA <213> Artificial sequence

- 182 045398 <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <400> 500 tgcgucagca aacacuuggt t 21 <210> 501 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <400> 501 tgaaccacug aacaaauggt t 21 <210> 502 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 3, 10, 13, 16 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base

- 183 045398 <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 4, 5, 6, 7, 8, 9, 11, 12, 14, 15, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside < 400> 502 aacaaauggc acuaguaaat t 21 < 210> 503 < 211> 21 < 212> DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <400> 503 tgaugauuag gcagaggugt t 21 <210> 504 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 4, 7, 17 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 2, 3, 5, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 504 cacuaguaaa cugagccagt t 21

- 184 045398 <210> 505 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <400> 505 taacgggcaa cauaccuugt t 21 <210> 506 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <400> 506 tacuaguaaa cugagccagt t 21 <210> 507 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base

- 185 045398 <222> 5, 11, 13 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

< 221> modified base < 222> 1, 2, 3, 4, 6, 7, 8, 9, 10, 12, 14, 15, 16, 17, 18, 19 < 223> /modified base = corresponding 2'- hydroxy nucleoside <400> 507 aauuuaugcc uacagccuct t 21 <210> 508 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 7, 10, 13 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 8, 9, 11, 12, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'- hydroxy nucleoside <400> 508 aaauggcacu aguaaacugt t 21 <210> 509 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2, 10, 13, 15 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21

- 186 045398 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 3, 4, 5, 6, 7, 8, 9, 11, 12, 14, 16, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside < 400> 509 acaaacgggc aacauaccut t 21 < 210> 510 < 211> 21 < 212> DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <400> 510 tggacaaacg ggcaacauat t 21 <210> 511 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <400> 511 tauuuaugcc uacagccuct t 21 <210> 512 <211> 21 <212> DNA <213> Artificial sequence

- 187 045398 <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 5, 15 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19 <223> /modified base = corresponding 2 '-hydroxy nucleoside <400> 512 augauaaaac gccgcagact t 21 <210> 513 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 3 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 513 ggcagaggug aaaaaguugt t 21 <210> 514 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1

- 188 045398 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 13, 15 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 17, 18, 19 <223> /modified base = corresponding 2 '-hydroxy nucleoside <400> 514 ugaagcgaag ugcacacggt t 21 <210> 515 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <400> 515 tgaagcgaag ugcacacggt t 21 <210> 516 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 21 < 223> /modified base = thymidine 5'-phosphothioate

- 189 045398 <400> 516 tacgggcaac auaccuugat t 21 <210> 517 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate < 400> 517 taauggcacu aguaaacugt t 21 < 210> 518 < 211> 21 < 212> DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 15, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

< 221> modified base < 222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 19 < 223> /modified base = corresponding 2 '-hydroxy nucleoside <400> 518 aauugagaga aguccaccat t 21 <210> 519 <211> 21 <212> DNA <213> Artificial sequence <220>

- 190 045398 <223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <400> 519 tcaaacgggc aacauaccut t 21 <210> 520 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 8, 11, 17 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 7, 9, 10, 12, 13, 14, 15, 16, 18, 19 <223> /modified base = corresponding 2'- hydroxy nucleoside <400> 520 ccgcguaa cacgagcagt t 21 <210> 521 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 5, 13, 16, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside

- 191 045398 <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 14, 15, 17, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 521 aggacaaacg ggcaacauat t 21 <210> 522 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 7, 10, 12 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 8, 9, 11, 13, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'- hydroxy nucleoside <400> 522 aacgggcaac auaccuugat t 21 <210> 523 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 15 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate

- 192 045398 <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 523 uccggaagug uugauaagat t 21 <210> 524 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <400> 524 tccggaagug uugauaagat t 21 <210> 525 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 8, 12 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

< 221> modified base < 222> 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 13, 14, 15, 16, 17, 18, 19 < 223> /modified base = corresponding 2 '-hydroxy nucleoside <400> 525 agaugauuag gcagaggugt t 21 <210> 526 <211> 21

- 193 045398 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 5, 17 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19 <223> /modified base = corresponding 2 '-hydroxy nucleoside <400> 526 aguccaagag uccucuuaut t 21 <210> 527 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 21 <223> /modified base = 5'-phosphothioate thymidine <400> 527 tugauaaaac gccgcagact t 21 <210> 528 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking a 5'-phosphate group

- 194 045398 <220>

<221> modified base <222> 13 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 528 guccgcggga uucagcgcct t 21 <210> 529 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 529 ugagaucuuc ugcgacgcgt t 21 <210> 530 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 16 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

- 195 045398 <221> modified base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 18, 19 <223> / modified base = corresponding 2'-hydroxy nucleoside <400> 530 aaggucgguc guugacauut t 21 <210> 531 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 4, 7, 10 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 5, 6, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'- hydroxy nucleoside <400> 531 uggcacuagu aaacugagct t 21 <210> 532 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 21 <223> /modified base = 5'-phosphothioate thymidine <400> 532 tauugagaga aguccaccat t 21 <210> 533 <211> 21 <212> DNA

- 196 045398 <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 533 ucuucugcga cgcggcgaut t 21 <210> 534 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 5, 12 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2 '-hydroxy nucleoside <400> 534 gaaccacuga acaaauggct t 21 <210> 535 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

- 197 045398 <221> modified base <222> 8, 11 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 7, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2 '-hydroxy nucleoside <400> 535 aguuccgcag uauggaucgt t 21 <210> 536 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 7, 11 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2 '-hydroxy nucleoside <400> 536 gaugauuagg cagaggugat t 21 <210> 537 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 17 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base

- 198 045398 <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

< 221> modified base < 222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19 < 223> /modified base = corresponding 2'-hydroxy nucleoside <400> 537 aaaauugaga gaaguccact t 21 <210> 538 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 3, 9 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2 '-hydroxy nucleoside <400> 538 cccaagaaua uggugaccct t 21 <210> 539 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 539 agaucuucug cgacgcggct t 21

- 199 045398 <210> 540 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 540 ucugcgacgc ggcgauugat t 21 <210> 541 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 8, 12, 14, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 13, 15, 16, 17, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 541 aacgccgcag acacauccat t 21 <210> 542 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base

- 200 045398 <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 15, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 19 <223> /modified base = corresponding 2 '-hydroxy nucleoside <400> 542 cuuggaggcu ugaacaguat t 21 <210> 543 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2, 9, 12, 15 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 3, 4, 5, 6, 7, 8, 10, 11, 13, 14, 16, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 543 acaaauggca cuaguaaact t 21 <210> 544 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 6, 13, 16

- 201 045398 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 14, 15, 17, 18, 19 <223> /modified base = corresponding 2'- hydroxy nucleoside <400> 544 cugaacaaau ggcacuagut t 21 <210> 545 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 545 gagaucuucu gcgacgcggt t 21 <210> 546 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 13, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

< 221> modified base < 222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 19 < 223> /modified base = corresponding 2 '-hydroxy nucleoside

- 202 045398 <400> 546 cggaaguguu gauaagauat t 21 < 210> 547 < 211> 21 < 212> DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

< 221> modified base < 222> 1..19 < 223> /modified base = corresponding 2'-hydroxy nucleoside < 400> 547 gggacugcga auuuuggcct t 21 < 210> 548 < 211> 21 < 212> DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 6, 10 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

< 221> modified base < 222> 1, 2, 3, 4, 5, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19 < 223> /modified base = corresponding 2 '-hydroxy nucleoside <400> 548 augauuaggc agaggugaat t 21 <210> 549 <211> 21 <212> DNA <213> Artificial sequence <220>

- 203 045398 <223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 5, 8, 11 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 6, 7, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'- hydroxy nucleoside <400> 549 auggcacuag uaaacugagt t 21 <210> 550 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 7, 15, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14, 16, 17, 19 <223> /modified base = corresponding 2'- hydroxy nucleoside <400> 550 agaggacaaa cgggcaacat t 21 <210> 551 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking a 5'-phosphate group

- 204 045398 <220>

<221> modified base <222> 1, 8, 15, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 16, 17, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 551 cacugaacaa auggcacuat t 21 <210> 552 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 6, 12, 14 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 2, 3, 4, 5, 7, 8, 9, 10, 11, 13, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 552 caauuuaugc cuacagccut t 21 <210> 553 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 11, 15, 17 <223> /modified base = corresponding 2'-O-methyl nucleoside

- 205 045398 <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 16, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 553 uaaaacgccg cagacacaut t 21 <210> 554 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 21 <223> /modified base = 5'-phosphothioate thymidine <400> 554 taaaacgccg cagacacaut t 21 <210> 555 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 3 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 555

- 206 045398 ugcagaggug aagcgaagut t 21 <210> 556 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 14, 16 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 17, 18, 19 <223> /modified base = corresponding 2 '-hydroxy nucleoside <400> 556 gugaagcgaa gugcacacgt t 21 <210> 557 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 14, 17 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

< 221> modified base < 222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 18, 19 < 223> /modified base = corresponding 2 '-hydroxy nucleoside <400> 557 auugagagaa guccaccact t 21 <210> 558 <211> 21 <212> DNA

- 207 045398 <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2, 12, 16, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, 17, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 558 auaaaacgcc gcagacacat t 21 <210> 559 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 9, 12, 14 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 2, 3, 4, 5, 6, 7, 8, 10, 11, 13, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 559 caaacggggca acauaccuut t 21 <210> 560 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

- 208 045398 <221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 4 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 560 ccucaagguc ggucguugat t 21 <210> 561 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 4, 16 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 18, 19 <223> /modified base = corresponding 2 '-hydroxy nucleoside <400> 561 guccaagagu ccucuuaugt t 21 <210> 562 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base

- 209 045398 <222> 3 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

< 221> modified base < 222> 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 < 223> /modified base = corresponding 2'-hydroxy nucleoside <400> 562 cucaaggucg gucguugact t 21 <210> 563 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 11, 17 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 18, 19 <223> /modified base = corresponding 2 '-hydroxy nucleoside <400> 563 cucuuguucc caagaauaut t 21 <210> 564 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 9, 12, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21

- 210 045398 <223> /modified base = thymidine 5'-phosphothioate <220>

< 221> modified base < 222> 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 13, 14, 15, 16, 17, 19 < 223> /modified base = corresponding 2'- hydroxy nucleoside <400> 564 cccgcgua acacgagcat t 21 <210> 565 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 565 uucugcgacg cggcgauugt t 21 <210> 566 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 16 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 566 gcuuggaggc uugaacagut t 21

- 211 045398 <210> 567 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 567 gaucuucugc gacgcggcgt t 21 <210> 568 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 7, 14 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2 '-hydroxy nucleoside <400> 568 acgaaccacu gaacaaaugt t 21 <210> 569 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1

- 212 045398 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 15 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 569 ucguccgcgg gauucagcgt t 21 <210> 570 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2, 8, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15, 16, 17, 19 <223> /modified base = corresponding 2'- hydroxy nucleoside <400> 570 ccaagaauau ggugacccat t 21 <210> 571 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 3, 13 < 223> /modified base = corresponding 2'-O-methyl nucleoside

- 213 045398 <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2 '-hydroxy nucleoside <400> 571 aguauggauc ggcagaggat t 21 <210> 572 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 17 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19 <223> /modified base = corresponding 2 '-hydroxy nucleoside <400> 572 caaggucggu cguugacaut t 21 <210> 573 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 10, 14 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate

- 214 045398 <220>

< 221> modified base < 222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 15, 16, 17, 18, 19 < 223> /modified base = corresponding 2 '-hydroxy nucleoside <400> 573 ugagaugauu aggcagaggt t 21 <210> 574 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 12, 14 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2 '-hydroxy nucleoside <400> 574 gaagcgaagu gcacacggut t 21 <210> 575 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 5, 8, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 6, 7, 9, 10, 11, 12, 13, 14, 15, 16, 17, 19 <223> /modified base = corresponding 2'- hydroxy nucleoside <400> 575

- 215 045398 uccgcaguau ggaucggcat t 21 <210> 576 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 3, 11 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2 '-hydroxy nucleoside <400> 576 accacgaguc uagacucugt t 21 <210> 577 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 17 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

< 221> modified base < 222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19 < 223> /modified base = corresponding 2'-hydroxy nucleoside <400> 577 agcuuggagg cuugaacagt t 21 <210> 578 <211> 21 <212> DNA

- 216 045398 <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 4, 10, 12 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 5, 6, 7, 8, 9, 11, 13, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'- hydroxy nucleoside <400> 578 auuuaugccu acagccucct t 21 <210> 579 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 3, 9, 11 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 4, 5, 6, 7, 8, 10, 12, 13, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'- hydroxy nucleoside <400> 579 uuuaugccua cagccuccut t 21 <210> 580 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

- 217 045398 <221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 16 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 580 aaauugagag aaguccacct t 21 <210> 581 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 581 gcagagguga aaaaguugct t 21 <210> 582 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base

- 218 045398 <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <400> 582 tcgccuguaa cacgagcagt t 21 <210> 583 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 7, 14, 17 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 15, 16, 18, 19 <223> /modified base = corresponding 2'- hydroxy nucleoside <400> 583 acugaacaaa uggcacuagt t 21 <210> 584 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 4, 7, 17 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 5, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19

- 219 045398 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 584 ccgcaguaug gaucggcagt t 21 <210> 585 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 15, 17 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 18, 19 <223> /modified base = corresponding 2 '-hydroxy nucleoside <400> 585 ggugaagcga agugcacact t 21 <210> 586 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 10, 13 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2 '-hydroxy nucleoside <400> 586 gcccgccugu aacacgagct t 21

- 220 045398 <210> 587 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 11, 16 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 17, 18, 19 <223> /modified base = corresponding 2 '-hydroxy nucleoside <400> 587 gaaguguuga uaagauaggt t 21 <210> 588 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 588 ugcgacgcgg cgauugagat t 21 <210> 589 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

< 221> modified base < 222> 1

- 221 045398 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 9, 11 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 13, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2 '-hydroxy nucleoside <400> 589 ugagaaggca cagacggggct t 21 <210> 590 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 12, 17 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16, 18, 19 <223> /modified base = corresponding 2 '-hydroxy nucleoside <400> 590 ggaaguguug auaagauagt t 21 <210> 591 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 6, 14, 17 < 223> /modified base = corresponding 2'-O-methyl nucleoside

- 222 045398 <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 15, 16, 18, 19 <223> /modified base = corresponding 2'- hydroxy nucleoside <400> 591 gaggacaaac gggcaacaut t 21 <210> 592 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 4, 12, 15, 17 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 13, 14, 16, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 592 ggacaaacgg gcaacauact t 21 <210> 593 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 4 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 < 223> /modified base = thymidine 5'-phosphothioate

- 223 045398 <220>

< 221> modified base < 222> 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 < 223> /modified base = corresponding 2'-hydroxy nucleoside <400> 593 gugcagaggu gaagcgaagt t 21 <210> 594 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 16, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 19 <223> /modified base = corresponding 2 '-hydroxy nucleoside <400> 594 aggugaagcg aagugcacat t 21 <210> 595 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 595 cgggacugcg aauuuuggct t 21 <210> 596 <211> 21

- 224 045398 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 7, 10, 16 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 8, 9, 11, 12, 13, 14, 15, 17, 18, 19 <223> /modified base = corresponding 2'- hydroxy nucleoside <400> 596 cgcguaac acgagcaggt t 21 <210> 597 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 11, 13, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 15, 16, 17, 19 <223> /modified base = corresponding 2'- hydroxy nucleoside <400> 597 agugcgaauc cacacuccat t 21 <210> 598 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand

- 225 045398 <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 6 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 598 ugccucaagg ucggucguut t 21 <210> 599 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2, 10 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2 '-hydroxy nucleoside <400> 599 ccacgagucu agacucugut t 21 <210> 600 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

- 226 045398 <221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 600 cuucugcgac gcggcgauut t 21 <210> 601 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 3, 11, 14, 16 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 4, 5, 6, 7, 8, 9, 10, 12, 13, 15, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 601 gacaaacggg caacauacct t 21 <210> 602 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 6, 9 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base

- 227 045398 <222> 1, 2, 3, 4, 5, 7, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'- hydroxy nucleoside <400> 602 uuccgcagua uggaucggct t 21 <210> 603 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 9, 14 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

< 221> modified base < 222> 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 15, 16, 17, 18, 19 < 223> /modified base = corresponding 2 '-hydroxy nucleoside <400> 603 aguguugaua agauagggct t 21 <210> 604 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 8, 11, 14 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 2, 3, 4, 5, 6, 7, 9, 10, 12, 13, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 604 caaauggcac uaguaaacut t 21

- 228 045398 <210> 605 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2, 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 19 <223> /modified base = corresponding 2 '-hydroxy nucleoside <400> 605 ucaaggucgg ucguugacat t 21 <210> 606 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 606 cuagaaaauu gagagaagut t 21 <210> 607 <211> 21 <212> DNA <213> Artificial sequence

- 229 045398 <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 3 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 607 gacaaaggac gucccgcgct t 21 <210> 608 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 5, 8, 16 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 6, 7, 9, 10, 11, 12, 13, 14, 15, 17, 18, 19 <223> /modified base = corresponding 2'- hydroxy nucleoside <400> 608 aguccaccac gagucuagat t 21 <210> 609 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

< 221> modified base < 222> 1

- 230 045398 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 9, 12 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 13, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2 '-hydroxy nucleoside <400> 609 gaguuccgca guauggauct t 21 <210> 610 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2, 5, 15 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19 <223> /modified base = corresponding 2'- hydroxy nucleoside <400> 610 gcaguaugga ucggcagagt t 21 <210> 611 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 3, 6, 16 < 223> /modified base = corresponding 2'-O-methyl nucleoside

- 231 045398 <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

< 221> modified base < 222> 1, 2, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 18, 19 < 223> /modified base = corresponding 2'- hydroxy nucleoside <400> 611 cgcaguaugg aucggcagat t 21 <210> 612 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 4, 14 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

< 221> modified base < 222> 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19 < 223> /modified base = corresponding 2'- hydroxy nucleoside <400> 612 caguauggau cggcagaggt t 21 <210> 613 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 7 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate

- 232 045398 <220>

< 221> modified base < 222> 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 < 223> /modified base = corresponding 2'-hydroxy nucleoside <400> 613 accgcguaaa gagaggugct t 21 <210> 614 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 614 gcgaggcgag ggaguucuut t 21 <210> 615 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 615 cugcgaggcg agggaguuct t 21 <210> 616 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand

- 233 045398 <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 5 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 616 gcccuagaaa auugagagat t 21 <210> 617 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 3 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 617 cguaaagaga ggugcgccct t 21 <210> 618 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

< 221> modified base < 222> 1 < 223> /modified base = nucleoside lacking a 5'-phosphate group

- 234 045398 <220>

<221> modified base <222> 7, 10 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2 '-hydroxy nucleoside <400> 618 guuccgcagu auggaucggt t 21 <210> 619 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 619 ucugcgaggc gagggaguut t 21 <210> 620 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2, 12 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

- 235 045398 <221> modified base <222> 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 620 guauggaucg gcagaggagt t 21 <210> 621 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 12, 14 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2 '-hydroxy nucleoside <400> 621 gagugcgaau ccacacucct t 21 <210> 622 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

< 221> modified base < 222> 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 < 223> /modified base = corresponding 2'-hydroxy nucleoside <400> 622 guaaagagag gugcgcccgt t 21

- 236 045398 <210> 623 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 623 gcgacgcggc gauugagact t 21 <210> 624 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 10, 13 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2 '-hydroxy nucleoside <400> 624 ggaguuccgc aguauggaut t 21 <210> 625 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

- 237 045398 <221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 6 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 625 ccgcguaaag agaggugcgt t 21 <210> 626 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 5 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 626 gccucaaggu cggucguugt t 21 <210> 627 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base

- 238 045398 <222> 1, 12, 15 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13, 14, 16, 17, 18, 19 <223> /modified base = corresponding 2'- hydroxy nucleoside <400> 627 uaggaguucc gcaguauggt t 21 <210> 628 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 18 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 628 gggucguccg cgggauucat t 21 <210> 629 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

< 221> modified base < 222> 1..19

- 239 045398 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 629 ugcgaggcga gggaguucut t 21 <210> 630 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 4 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

< 221> modified base < 222> 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 < 223> /modified base = corresponding 2'-hydroxy nucleoside <400> 630 gcguaaagag aggugcgcct t 21 <210> 631 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 5 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

< 221> modified base < 222> 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 < 223> /modified base = corresponding 2'-hydroxy nucleoside <400> 631 cgcguaaaga gaggugcgct t 21

- 240 045398 <210> 632 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 16 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 632 gucguccgcg ggauucagct t 21 <210> 633 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 2 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 633 gcagagguga agcgaagugt t 21 <210> 634 <211> 21 <212> DNA <213> Artificial sequence <220>

- 241 045398 <223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 634 cugcgacgcg gcgauugagt t 21 <210> 635 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 6 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 635 ggauucagcg ccgacgggat t 21 <210> 636 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 17 < 223> /modified base = corresponding 2'-O-methyl nucleoside

- 242 045398 <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 636 ggucguccgc gggauucagt t 21 <210> 637 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 1, 4, 12 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 2, 3, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'- hydroxy nucleoside <400> 637 caccacgagu cuagacucut t 21 <210> 638 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 11, 14 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 < 223> /modified base = thymidine 5'-phosphothioate

- 243 045398 <220>

< 221> modified base < 222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 15, 16, 17, 18, 19 < 223> /modified base = corresponding 2 '-hydroxy nucleoside <400> 638 aggaguuccg caguauggat t 21 <210> 639 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 14 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 639 cguccgcggg auucagcgct t 21 <210> 640 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 14, 16 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

< 221> modified base < 222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 17, 18, 19 < 223> /modified base = corresponding 2 '-hydroxy nucleoside <400> 640

- 244 045398 aggagugcga auccacacut t 21 < 210> 641 < 211> 21 < 212> DNA < 213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 6, 9, 15 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 7, 8, 10, 11, 12, 13, 14, 16, 17, 18, 19 <223> /modified base = corresponding 2'- hydroxy nucleoside <400> 641 gcguaaca cgagcagggt t 21 <210> 642 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1..19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 642 cgggucgucc gcgggauuct t 21 <210> 643 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand

- 245 045398 <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 3, 7, 12, 14 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 4, 5, 6, 8, 9, 10, 11, 13, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 643 gccacccaag gcacagcuut t 21 <210> 644 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 5, 8, 14 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 6, 7, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'- hydroxy nucleoside <400> 644 ccuguaacac gagcagggct t 21 <210> 645 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

- 246 045398 <221> modified base <222> 5 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 645 gauucagcgc cgacgggact t 21 <210> 646 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 14 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 646 ccggaagugu ugauaagaut t 21 <210> 647 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 1 <223> /modified base = nucleoside lacking 5'-phosphate group <220>

<221> modified base <222> 16 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base

- 247 045398 <222> 21 <223> /modified base = thymidine 5'-phosphothioate <220>

<221> modified base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 18, 19 <223> /modified base = corresponding 2'-hydroxy nucleoside <400> 647 uuccggaagu guugauaagt t 21 <210> 648 <211> 21 <212> DNA <213> Artificial sequence <220>

<223> Description of artificial sequence: non-coding dsRNA strand <220>

<221> modified base <222> 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /modified base = corresponding 2'-O-methyl nucleoside <220>

<221> modified base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /modified base = corresponding 2'-deoxy-2'-fluoro nucleoside <220>

< 221> modified base < 222> 21 < 223> /modified base = thymidine 5'-phosphothioate <400> 648 tuccggaagu guugauaagt t 21

Claims (37)

1. A method for producing a double-stranded ribonucleic acid molecule capable of inhibiting the expression of the hepatitis B virus gene, comprising: synthesis of a coding strand containing in order nucleotides 1-19 any of SEQ ID NO: 2, 3, 5, 6, 10, 13, 15, 17, 18, 22, 23, 26-28, 30, 37 and 42; synthesizing a non-coding strand at least partially complementary to said coding strand; and annealing said coding strand and said non-coding strand to produce a double-stranded ribonucleic acid molecule, wherein the double-stranded ribonucleic acid molecule has a duplex length of from 16 to 30 nucleotides. 2. The method according to claim 1, where the specified non-coding strand contains, in order, nucleotides 2-18 of any of SEQ ID NO: 158-160, 162, 163, 169, 173, 175, 177, 178, 182, 183, 186, 188 , 189, 191, 199 and 204. 3. A method for producing a double-stranded ribonucleic acid molecule capable of inhibiting the expression of the hepatitis B virus gene, comprising: synthesis of a non-coding strand containing, in order, nucleotides 2-18 of any of SEQ ID NO: 158160, 162, 163, 169, 173, 175, 177, 178, 182, 183, 186, 188, 189, 191, 199 and 204; synthesizing a coding strand at least partially complementary to said non-coding strand; and annealing said coding strand and said non-coding strand to produce a double-stranded ribonucleic acid molecule, wherein the double-stranded ribonucleic acid molecule has a duplex length of from 16 to 30 nucleotides. 4. A method for producing a double-stranded ribonucleic acid molecule capable of inhibiting the expression of the hepatitis B virus gene, comprising: synthesis of a coding strand containing a modified sequence according to any one of SEQ ID NO: 321-484; and synthesizing a non-coding strand at least partially complementary to said coding strand; And - 248 045398 annealing said coding strand and said non-coding strand to produce a double-stranded ribonucleic acid molecule, wherein the double-stranded ribonucleic acid molecule has a duplex length of 16 to 30 nucleotides. 5. The method according to claim 4, wherein said non-coding strand contains, in order, nucleotides 2-18 of any of SEQ ID NO: 157-320. 6. The method according to claim 4, where the specified non-coding strand contains, in order, nucleotides 2-18 of any of SEQ ID NO: 158-160, 162, 163, 169, 173, 175-178, 182, 183, 186-189, 191 , 199, 204, 205, 235, 242, 245, 254, 258, 261, 267, 270, 271, 275, 279, 285, 288, 294, 295, 314 and 316. 7. The method according to any one of claims 1 to 6, wherein said non-coding strand contains at least one modified nucleotide. 8. The method according to claim 7, wherein said at least one modified nucleotide is selected from the group consisting of a 2'-O-methyl-modified nucleotide, a nucleotide containing a 5'phosphothioate group, a terminal nucleotide linked to a cholesterol derivative, a terminal nucleotide , linked to the bisdecylamide group of dodecanoic acid, 2'-deoxy-2'-fluoro-modified nucleotide, 2'-deoxy-modified nucleotide, closed nucleotide, nucleotide devoid of a nitrogenous base, deoxythymidine, inverted deoxythymidine, 2'amino-modified nucleotide, 2' -alkyl-modified nucleotide, morpholino nucleotide, phosphoramidate and nucleotide including a base not found in nature. 9. The method of claim 7, wherein said non-coding strand comprises a 2'-O-methyl-modified nucleotide, a nucleotide containing a 5'-phosphothioate group, and deoxythymidine. 10. The method according to claim 9, wherein said non-coding strand contains a sticky end of 1-2 deoxythymidines. 11. The method of claim 4, wherein said non-coding strand comprises a modified sequence of any one of SEQ ID NO: 485-648. 12. A method for producing a double-stranded ribonucleic acid molecule capable of inhibiting the expression of the hepatitis B virus gene, comprising: synthesis of a non-coding strand containing a modified sequence of any of SEQ ID NO: 485-648; synthesizing a coding strand at least partially complementary to said non-coding strand; and annealing said coding strand and said non-coding strand to produce a double-stranded ribonucleic acid molecule, wherein the double-stranded ribonucleic acid molecule has a duplex length of from 16 to 30 nucleotides. 13. The method according to claim 12, wherein said coding strand contains at least one modified nucleotide. 14. The method according to claim 13, wherein said at least one modified nucleotide is selected from the group consisting of a 2'-O-methyl-modified nucleotide, a nucleotide containing a 5'phosphothioate group, a terminal nucleotide linked to a cholesterol derivative, a terminal nucleotide , linked to the bisdecylamide group of dodecanoic acid, 2'-deoxy-2'-fluoro-modified nucleotide, 2'-deoxy-modified nucleotide, closed nucleotide, nucleotide devoid of a nitrogenous base, deoxythymidine, inverted deoxythymidine, 2'amino-modified nucleotide, 2' -alkyl-modified nucleotide, morpholino nucleotide, phosphoramidate and nucleotide including a base not found in nature. 15. The method according to claim 13, wherein said coding strand contains a 2'-O-methyl-modified nucleotide, a nucleotide containing a 5'-phosphothioate group, and deoxythymidine. 16. The method according to claim 15, wherein said coding strand contains a sticky end of 1-2 deoxythymidines. 17. The method according to any one of claims 1 to 16, wherein said coding strand contains, in order, nucleotides 1 to 19 of any of SEQ ID NO: 2, 3 or 6. 18. The method according to any one of claims 1-17, wherein said non-coding strand contains, in order, nucleotides 2-18 of any of SEQ ID NO: 158, 159, 160 or 163. 19. The method according to any one of claims 1 to 18, wherein said double-stranded ribonucleic acid molecule contains sequence pairs selected from the group consisting of SEQ ID NOs: 2/158, 3/159, 3/160 and 6/163. 20. The method of claim 19, wherein said coding strand comprises the sequence SEQ ID NO: 2, and said non-coding strand comprises the sequence SEQ ID NO: 158. 21. The method of claim 19, wherein said coding strand comprises the sequence SEQ ID NO: 3, and said non-coding strand comprises the sequence SEQ ID NO: 159. 22. The method of claim 19, wherein said coding strand comprises the sequence SEQ ID NO: 3, and said non-coding strand comprises the sequence SEQ ID NO: 160. 23. The method of claim 19, wherein said coding strand comprises the sequence SEQ ID NO: 6, and said non-coding strand comprises the sequence SEQ ID NO: 163. - 249 045398 24. The method according to any one of claims 1 to 19, wherein said double-stranded ribonucleic acid molecule contains pairs of sequences selected from the group consisting of SEQ ID NO: 322/486, 323/487, 324/488 and 327/491. 25. The method of claim 24, wherein said coding strand comprises the sequence of SEQ ID NO: 322, and said non-coding strand comprises the sequence of SEQ ID NO: 486. 26. The method of claim 24, wherein said coding strand comprises the sequence of SEQ ID NO: 323, and said non-coding strand comprises the sequence of SEQ ID NO: 487. 27. The method of claim 24, wherein said coding strand comprises the sequence of SEQ ID NO: 324, and said non-coding strand comprises the sequence of SEQ ID NO: 488. 28. The method of claim 24, wherein said coding strand comprises the sequence of SEQ ID NO: 327, and said non-coding strand comprises the sequence of SEQ ID NO: 491. 29. The method according to any one of claims 1 to 28, wherein said coding strand or said non-coding strand is synthesized using solid phase oligonucleotide synthesis. 30. The method according to any one of claims 1 to 29, further comprising purifying said coding strand or said non-coding strand before annealing using an HPLC column. 31. The method of claim 30, wherein said HPLC column is an anion exchange column. 32. The method of claim 30 or 31, further comprising desalting said purified coding strand or purified non-coding strand. 33. The method according to any one of claims 1 to 32, wherein annealing said coding strand and non-coding strand comprises lyophilizing a mixture containing said coding strand and said non-coding strand. 34. The method according to any one of claims 1 to 33, wherein said double-stranded ribonucleic acid molecule is conjugated to a ligand. 35. The method of claim 34, wherein said ligand is selected from the group consisting of galactose, folic acid, cholesterol, polyethylene glycols, carbohydrate clusters, cross-linking agents, porphyrin conjugates and delivery peptides. 36. The method according to claim 34, wherein said ligand contains galactose. 37. The method according to claim 34, wherein said ligand comprises a carbohydrate cluster.