Source: http://www.google.com/patents/US8168776?dq=5,581,513
Timestamp: 2014-07-31 09:49:35
Document Index: 118056745

Matched Legal Cases: ['art 1', 'Application No. 2009', 'Application No. 2009', 'Application No. 2009', 'Application No. 2009', 'Application No. 10066344', 'Application No. 2007', 'Application No. 2007', 'Application No. 2007', 'Application No. 32713', 'Application No. 2005201044', 'art 1', 'Application No. 60', 'Application No. 60']

Patent US8168776 - Comprises double-stranded RNA; extracted from HeLa cells - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign in<nobr>Advanced Patent Search</nobr>PatentsThe present invention provides methods and compositions for inhibiting gene expression using double stranded RNA molecules that are between 15 and 21 nucleotides in length and are complementary to a target gene sequence....http://www.google.com/patents/US8168776?utm_source=gb-gplus-sharePatent US8168776 - Comprises double-stranded RNA; extracted from HeLa cellsAdvanced Patent SearchPublication numberUS8168776 B2Publication typeGrantApplication numberUS 10/382,768Publication dateMay 1, 2012Filing dateMar 6, 2003Priority dateJan 30, 1999Also published asCA2359180A1, CA2359180C, DE10066235B4, DE10080167B4, DE10080167D2, DE19956568A1, DE20023125U1, DE20023125U8, DE50000414D1, DE50010528D1, DE50015501D1, EP1144623A1, EP1144623B1, EP1144623B9, EP1214945A2, EP1214945A3, EP1214945B1, EP1550719A1, EP1550719B1, EP1798285A1, EP2363479A1, US8101584, US8101742, US8114851, US8114981, US8119608, US8183362, US8202980, US8729037, US20040053875, US20040072779, US20040102408, US20050100907, US20080166800, US20080171861, US20080171862, US20080182981, US20080233651, US20080261303, US20130164366, US20130164843, US20130177631, US20140051166, WO2000044895A1Publication number10382768, 382768, US 8168776 B2, US 8168776B2, US-B2-8168776, US8168776 B2, US8168776B2InventorsRoland Kreutzer, Stefan LimmerOriginal AssigneeAlnylam Pharmaceuticals, Inc.Export CitationBiBTeX, EndNote, RefManPatent Citations (101), Non-Patent Citations (627), Referenced by (1), Classifications (26), Legal Events (2) External Links: USPTO, USPTO Assignment, EspacenetComprises double-stranded RNA; extracted from HeLa cellsUS 8168776 B2Abstract The present invention provides methods and compositions for inhibiting gene expression using double stranded RNA molecules that are between 15 and 21 nucleotides in length and are complementary to a target gene sequence.
196 31 919 C2 describes an antisense RNA with specific secondary structures, the antisense RNA being present in the form of a vector encoding it. The antisense RNA takes the form of an RNA molecule which is complementary to regions of the mRNA. Inhibition of the gene expression is caused by binding to these regions. This inhibition can be employed in particular for the diagnosis and/or therapy of diseases, for example tumor diseases or viral infections. �The disadvantage is that the antisense RNA must be introduced into the cell in an amount which is at least as high as the amount of the mRNA. The known antisense methods are not particularly effective.
BRIEF DESCRIPTION OF THE FIGURES FIG. 1 shows the schema& representation of a plasmid for the in vitro transcription with T7- and SP6- polymerase.
It has proved expedient to use at least one of the following groups for generating the chemical linkage: methylene blue; bifunctional groups, preferably bis(2-chloroethyl)amine; N-acetyl-N′�(p-glyoxyl-benzoyl)cystamine; 4-thiouracil; psoralene. The chemical linkage can furthermore be formed by thiophosphoryl groups provided at the ends of the double-stranded region. The chemical linkage at the ends of the double-stranded region is preferably formed by triple-helix bonds.
The nucleotides of the dsRNA can be modified. This counteracts the activation, in the cell, of a double-stranded-RNA-dependent protein kinase, PKR. Advantageously, at least one 2′-hydroxyl group of the nucleotides of the dsRNA in the complementary region II is replaced by a chemical group, preferably a 2′-amino or a 2′-methyl group. At least one nucleotide in at least one strand of the complementary region II can also be a locked nucleotide with a sugar ring which is chemically modified, preferably by a 2′�O, 4′�C methylene bridge. Advantageously, several nucleotides are locked nucleotides.
PCMV5 plasmid DNA was linearized with EcoRI or BamHI. It was used as DNA template for an in-vitro transcription of the complementary RNA single strands with SP6 and T7 RNA polymerase, respectively. The �Riboprobe in vitro Transcription� system by Promega, Madison, USA, was employed for this purpose. Following the manufacturer's instructions, 2 μg of linearized plasmid DNA were incubated in 100 μl of transcription buffer and 40 U T7 or SP6 RNA polymerase for 5-6 hours at 37� C. The DNA template was subsequently degraded by addition of 2.5 μl of RNase-free DNase RQ1 and incubation for minutes at 37� C. The transcription reaction was made up to 300 μl with H2O and purified by phenol extraction. The RNA was precipitated by addition of 150 μl of 7 M ammonium acatate [sic] and 1 125 μl of ethanol and stored at −65� C. until used for the hybridization.
Using the HeLaScribe� Nuclear Extract in vitro transcription kit by Promega, Madison, USA, the transcription efficiency of the abovementioned DNA fragment which is present in plasmid pCMV 1200 and homologous to the �positive control DNA� was determined in the presence of the dsRNA (dsRNA-CMV5) with sequence homology. Also, the effect of the dsRNA without sequence homology, which corresponds to the yellow fluorescent protein (YFP) gene (dsRNA-YRP), was studied. This dsRNA had been generated analogously to the dsRNA with sequence homology. The sequence of a strand of this dsRNA can be found in sequence listing No. 5. Plasmid pCMV1200 was used as template for the run-off transcription. It carries the �immediate early� cytomegalovirus promoter which is recognized by the eukaryotic RNA polymerase II, and a transcribable DNA fragment. Transcription was carried out by means of the HeLa nuclear extract, which contains all the proteins which are necessary for transcription. By addition of [�32P]rGTP to the transcription reaction, radiolabeled transcript was obtained. The [.�32P]rGTP used had a specific activity of 400 Ci/mmol, 10 mCi/ml. 3 mM MgCl2, in each case 400 μM rATP, rCTP, rUTP, 16 μM rGTP, 0.4 μM [.�32P]rGTP and depending on the experiment 1 fmol of linearized plasmid DNA and various amounts of dsRNA in transcription buffer were employed per reaction. Each batch was made up to a volume of 8.5 μl with H2O. The reactions were mixed carefully. To start the transcription, 4 U HeLa nuclear extract in a volume of 4 μl were added and incubated for 60 minutes at 30� C. The reaction was stopped by addition of 87.5 μl of quench mix which had been warmed to 30� C. To remove the proteins, the reactions were treated with 100 μl of phenol/chloroform/isoamyl alcohol (25:24:1 v/v/v) saturated with TE buffer, pH 5.0, and the reactions were mixed vigorously for 1 minute. For phase separation, the reactions were spun for approximately 1 minute at 1 2000 rpm and the top phase was transferred into a fresh reaction vessel. Each reaction was treated with 250 μl of ethanol. The reactions were mixed thoroughly and incubated for at least 15 minutes on dry ice/methanol. To precipitate the RNA, the reactions were spun for 20 minutes at 1 2000 rpm and 40� C. The supernatant was discarded. The pellet was dried in vacuo for 15 minutes and resuspended in 10 μl of H2O. Each reaction was treated with 10 μl of denaturing loading buffer. The free GTP was separated from the transcript formed by means of denaturing polyacrylamide gel electrophoresis on an 8% gel with 7 M urea. The RNA transcripts formed upon transcription with HeLa nuclear extract, in denaturing loading buffer, were heated for 10 minutes at 90� C. and 10 μl aliquots were applied immediately to the freshly washed pockets. The electrophoresis was run at 40 mA. The amount of the radioactive ssRNA formed upon transcription was analyzed after electrophoresis with the aid of an Instant Imager.
Wengel, J. (1999). Synthesis of 3′-C� and 4′-C-branched oligodeoxynucleotides and the development of locked nucleic acid (LNA). Acc. Chem. Res. 32, 301-310.
Patent CitationsCited PatentFiling datePublication dateApplicantTitleUS4868116Jul 9, 1986Sep 19, 1989Whitehead Institute For Biomedical ResearchIntroduction and expression of foreign genetic material in epithelial cellsUS4980286Jan 3, 1989Dec 25, 1990Whitehead Institute For Biomedical ResearchIn vivo introduction and expression of foreign genetic material in epithelial cellsUS4987071Dec 3, 1986Jan 22, 1991University Patents, Inc.RNA ribozyme polymerases, dephosphorylases, restriction endoribonucleases and methodsUS5107065Aug 30, 1988Apr 21, 1992Calgene, Inc.Genetic engineeringUS5112734May 26, 1989May 12, 1992Gene-Trak SystemsTarget-dependent synthesis of an artificial gene for the synthesis of a replicatable rnaUS5190931Nov 15, 1989Mar 2, 1993The Research Foundation Of State University Of New YorkRegulation of gene expression by employing translational inhibition of MRNA utilizing interfering complementary MRNAUS5208149Apr 10, 1992May 4, 1993The Research Foundation Of State University Of New YorkRegulating gene expressionUS5212295Oct 15, 1991May 18, 1993Isis PharmaceuticalsMonomers for preparation of oligonucleotides having chiral phosphorus linkagesUS5225347Mar 19, 1990Jul 6, 1993Innovir Laboratories, Inc.Therapeutic ribozyme compositions and expression vectorsUS5246921Aug 5, 1992Sep 21, 1993The Wistar Institute Of Anatomy And BiologyMethod for treating leukemiasUS5254678Aug 5, 1992Oct 19, 1993Gene Shears Pty. LimitedRibozymesUS5328470Jul 26, 1991Jul 12, 1994The Regents Of The University Of MichiganCatheterUS5496698Dec 7, 1992Mar 5, 1996Ribozyme Pharmaceuticals, Inc.Method of isolating ribozyme targetsUS5521302May 5, 1993May 28, 1996Isis Pharmaceuticals, Inc.Nucleophilic reaction of phosphate groupsUS5525468Aug 1, 1994Jun 11, 1996Ribozyme Pharmaceuticals, Inc.Assay for Ribozyme target siteUS5574142Dec 15, 1992Nov 12, 1996Microprobe CorporationDrug delivery to target cells, antisense oligodeoxynucleotidesUS5587361Jun 6, 1995Dec 24, 1996Isis Pharmaceuticals, Inc.Oligonucleotides having phosphorothioate linkages of high chiral purityUS5616459Aug 18, 1992Apr 1, 1997The Public Health Research Institute Of The City Of New York, Inc.Screening a gene expressed ribozymes for destroy human aids proteinsUS5624803Oct 13, 1994Apr 29, 1997The Regents Of The University Of CaliforniaIn vivo oligonucleotide generator, and methods of testing the binding affinity of triplex forming oligonucleotides derived therefromUS5635385Sep 15, 1993Jun 3, 1997Temple University-Of The Commonwealth System Of Higher EducationMulti-unit ribozyme inhibition of oncogene gene expressionUS5639655Apr 25, 1994Jun 17, 1997Ribozyme Pharmaceuticals, Inc.PML-RARA targeted ribozymesUS5674683Mar 21, 1995Oct 7, 1997Research Corporation Technologies, Inc.Binding domains capable of detectably binding to a nucleic acid target by watson-crick base pairing and by hoogsteen base pairingUS5703054Jul 9, 1993Dec 30, 1997Isis Pharmaceuticals, Inc.Oligonucleotide modulation of protein kinase CUS5712257May 23, 1995Jan 27, 1998Hem Research, Inc.Topically active compositions of mismatched dsRNAsUS5719271Aug 30, 1994Feb 17, 1998Isis Pharmaceuticals, Inc.Hybrids; genetic engineeringUS5731181Jun 17, 1996Mar 24, 1998Thomas Jefferson UniversityChimeric mutational vectors having non-natural nucleotidesUS5739271Jun 7, 1995Apr 14, 1998Gen-Probe IncorporatedDrug delivery of oligonucleotides, nucleic acids, peptides, images, and proteinsUS5789230Oct 7, 1994Aug 4, 1998Boehringer Ingelheim International GmbhEndosomolytically active particlesUS5801154Apr 8, 1997Sep 1, 1998Isis Pharmaceuticals, Inc.Antisense oligonucleotide modulation of multidrug resistance-associated proteinUS5811275Jun 5, 1995Sep 22, 1998The Regents Of The University Of CaliforniaHIV-specific ribozymesUS5811300Sep 23, 1994Sep 22, 1998Ribozyme Pharmaceuticals, Inc.TNF-α ribozymesUS5814500Oct 31, 1996Sep 29, 1998The Johns Hopkins University School Of MedicineDelivery construct for antisense nucleic acids and methods of useUS5824519Nov 8, 1995Oct 20, 1998Medical University Of South CarolinaA dna sequence comprising a specific binding promoter encoding a ribozyme as antitumor agents, viricides, antiproliferative agents; drug deliveryUS5837510Jun 6, 1995Nov 17, 1998Goldsmith; Mark A.Methods and polynucleotide constructs for treating host cells for infection or hyperproliferative disordersUS5854067Jan 19, 1996Dec 29, 1998Board Of Regents, The University Of Texas SystemHexokinase inhibitorsUS5864028Jun 5, 1995Jan 26, 1999Gene Shears Pty. LimitedDegradation resistant mRNA derivatives linked to TNF-α ribozymesUS5866701Jun 17, 1993Feb 2, 1999The Board Of Regents For Northern Illinois University Of DekalbHIV targeted hairpin ribozymesUS5891717Jan 19, 1996Apr 6, 1999Betagene, Inc.Methods and compositions for inhibiting hexokinaseUS5898031Jun 6, 1996Apr 27, 1999Isis Pharmaceuticals, Inc.Oligoribonucleotides for cleaving RNAUS5908779Dec 1, 1993Jun 1, 1999University Of ConnecticutA mammalian cell containing a dna construct with a promoter, an antisense sequence and a cis-ribozyme; regulating gene expression and accumulating antisense rna in the nucleus; therapy and viricidesUS5939262Jun 24, 1997Aug 17, 1999Ambion, Inc.Ribonuclease resistant RNA preparation and utilizationUS5968737Nov 12, 1996Oct 19, 1999The University Of MississippiMethod of identifying inhibitors of glutathione S-transferase (GST) gene expressionUS5985620Nov 3, 1993Nov 16, 1999Gene Shears Pty. LimitedPolynucleotideUS5998203Apr 16, 1996Dec 7, 1999Ribozyme Pharmaceuticals, Inc.Enzymatic nucleic acids containing 5'-and/or 3'-cap structuresUS6025167Jun 5, 1996Feb 15, 2000Competitive Technologies, Inc.RNA ribozyme polymerases, dephosphorylases, restriction endoribonucleases and methodsUS6054299Jun 17, 1997Apr 25, 2000Conrad; Charles A.Nucleotide sequences comprising replicon, inverted duplication, and restricion enzyme cleavage siteUS6057156Dec 4, 1997May 2, 2000Robozyme Pharmaceuticals, Inc.Enzymatic nucleic acid treatment of diseases or conditions related to levels of epidermal growth factor receptorsUS6071890Oct 19, 1995Jun 6, 2000Genzyme CorporationOrgan-specific targeting of cationic amphiphile/DNA complexes for gene therapyUS6077705May 14, 1997Jun 20, 2000Thomas Jefferson UniversityAn expression vector for the treatment of the alpha antitrypsin mutation; for gene therapyUS6080851Nov 16, 1993Jun 27, 2000American Home Products CorporationRibozymes with linked anchor sequencesUS6087164Oct 1, 1998Jul 11, 2000Yissum Research Development Company Of The Hebrew University Of JerusalemIntroducing polynucleotide comprising a regulatory sequence, derived from a genomically imprinted gene specifically expressed in tumor cell, linked to a heterologous sequence encoding cytotoxic product; antitumor agents; gene therapyUS6087172Oct 31, 1997Jul 11, 2000Hisamitsu Pharmaceutical Co., Inc.For treatment of rheumatoid arthritis by suppression of interleukin-15 productionUS6099823Jul 30, 1998Aug 8, 2000Millennium Pharmaceuticals, Inc.Compositions and methods for the treatment and diagnosis of cardiovascular diseaseUS6100087Mar 11, 1998Aug 8, 2000City Of HopeRibozymes targeted to human CCR5 mRNAUS6100444Feb 11, 1997Aug 8, 2000University Of Rochester Medical CenterNucleotide sequences coding prostate gland protein; for the treatment of prostate cancerUS6107094Jun 6, 1997Aug 22, 2000Isis Pharmaceuticals, Inc.In vitro modification of target rna by contacting solution of target and ribonuclease preferential for double-stranded rna with oligonucleotide complementary to target and including nucleotides modified to improve affinity/specificityUS6127533Jan 30, 1998Oct 3, 2000Isis Pharmaceuticals, Inc.2'-O-aminooxy-modified oligonucleotidesUS6166197Mar 6, 1995Dec 26, 2000Isis Pharmaceuticals, Inc.Oligomeric compounds having pyrimidine nucleotide (S) with 2'and 5 substitutionsUS6183959Jul 8, 1998Feb 6, 2001Ribozyme Pharmaceuticals, Inc.Identifying nucleic acid catalyst which modifies a biological system by introducing random library of catalysts into system then determining sequence of portion of substrate binding domain from system which has been modifiedUS6225291Apr 21, 1998May 1, 2001University Of FloridaRod opsin mRNA-specific ribozyme compositions and methods for the treatment of retinal diseasesUS6245560May 18, 1994Jun 12, 2001The United States Of America As Represented By The Department Of Health And Human ServicesVector with multiple target response elements affecting gene expressionUS6245748Sep 25, 1998Jun 12, 2001Georgetown UniversityInhibition of an FGF-binding protein using ribozymesUS6255071Mar 19, 1997Jul 3, 2001Cold Spring Harbor LaboratoryMammalian viral vectors and their usesUS6271358Jul 27, 1998Aug 7, 2001Isis Pharmaceuticals, Inc.For inhibiting specific gene expression; having enhanced hybrid binding affinity and/or increased nuclease resistanceUS6346398Jan 11, 1996Feb 12, 2002Ribozyme Pharmaceuticals, Inc.Ribozyme or antisense nucleic acid which inhibits synthesis, gene expression and/or stability of messenger rna encoding the flt-1 receptor of human or mouse receptor; treatment of diabetic retinopathy; angiogenesis inhibitorsUS6355415Sep 29, 1997Mar 12, 2002Ohio UniversityCompositions and methods for the use of ribozymes to determine gene functionUS6423489May 30, 1995Jul 23, 2002Isis Pharmaceuticals, Inc.Oligonucleotides for use in the treatment of viral diseasesUS6482803Sep 1, 1995Nov 19, 2002Board Of Regents, The University Of Texas SystemModification of mutated P53 gene in tumors by retroviral delivery of ribozyme AUS6486299Sep 28, 1998Nov 26, 2002Curagen CorporationGenes and proteins predictive and therapeutic for stroke, hypertension, diabetes and obesityUS6506559Dec 18, 1998Jan 14, 2003Carnegie Institute Of WashingtonMolecular hybridization of complementary strandsUS6573046Oct 28, 1999Jun 3, 2003Valigen (Us), IncTo transform a target DNA sequence using nuclease resistant oligonucleotideUS20020086356Mar 30, 2001Jul 4, 2002Whitehead Institute For Biomedical ResearchPreferential nucleotide sequences for controlling preferential ribonucleic acids; for use in therapeutic genomics; for gene therapyUS20020114784Jan 4, 2002Aug 22, 2002Medical College Of Georgia Research Institute, Inc.Composition and method for in vivo and in vitro attenuation of gene expression using double stranded RNAUS20020123034Oct 12, 2001Sep 5, 2002Dan CanaaniDetecting preferential genetic disorders; obtain cells, transform with vector, recover clones, monitor clone for preferential gene expression, propagate clone expressing preferential genes, monitor killing genesUS20020132346Mar 8, 2002Sep 19, 2002Jose CibelliUse of RNA interference for the creation of lineage specific ES and other undifferentiated cells and production of differentiated cells in vitro by co-cultureUS20020162126May 24, 2001Oct 31, 2002David BeachMethods and compositions for RNA interferenceUS20020173478Nov 14, 2001Nov 21, 2002The Trustees Of The University Of PennsylvaniaControlling, prevention gene expressionUS20030027783May 17, 2002Feb 6, 2003Magdalena Zernicka-GoetzIntroducing into the cell an RNA comprising a double stranded structure having nucleotide sequence which is substantially identical to part of target gene and which is derived from an endogenous template; verifying inhibition of expressionUS20030108923Sep 26, 2002Jun 12, 2003Whitehead Institute For Biomedical ResearchRNA sequence-specific mediators of RNA interferenceUS20030125281May 28, 2002Jul 3, 2003David LewisCompositions and processes using siRNA, amphipathic compounds and polycationsUS20030134808Nov 5, 2001Jul 17, 2003Jesper WengelOligonucleotide analoguesUS20030143732Aug 20, 2002Jul 31, 2003Kathy FosnaughRNA interference mediated inhibition of adenosine A1 receptor (ADORA1) gene expression using short interfering RNAUS20030148341Nov 5, 2002Aug 7, 2003Sin Wun CheyGene amplification and overexpression in cancerUS20030157030Nov 4, 2002Aug 21, 2003Insert Therapeutics, Inc.Methods and compositions for therapeutic use of rna interferenceUS20030176671Feb 7, 2002Sep 18, 2003The Burnham InstituteControlling cell differentiation, cell proliferation; transgenic plant, animalUS20030180756Nov 21, 2002Sep 25, 2003Yang ShiNucleic acids encoding RNAs targeting specific genes (in eukaryotic cells) and thereby inhibiting expression of these genes and expression of abnormal mutated proteinUS20030190635Jul 25, 2002Oct 9, 2003Mcswiggen James A.RNA interference mediated treatment of Alzheimer's disease using short interfering RNAUS20030198627Aug 23, 2002Oct 23, 2003Gert-Jan ArtssiRNA knockout assay method and constructsUS20040001811Mar 7, 2003Jan 1, 2004Ribopharma AgCompositions and methods for inhibiting expression of anti-apoptotic genesUS20040053875 *Mar 6, 2003Mar 18, 2004Ribopharma AgMethod and medicament for inhibiting the expression of a given geneUS20040072779Mar 6, 2003Apr 15, 2004Ribopharma AgMethod and medicament for inhibiting the expression of a given geneUS20060258608Apr 26, 2006Nov 16, 2006Rachel MeyersRNAi modulation of RSV and therapeutic uses thereofUS20080166800Oct 31, 2007Jul 10, 2008Roland KreutzerDouble stranded RNA sequence for use in suppression of genic expression; antisense agents; RNA interferenceUS20080171862Oct 31, 2007Jul 17, 2008Roland KreutzerMethod and medicament for inhibiting the expression of a given geneUS20080182981Oct 31, 2007Jul 31, 2008Roland KreutzerDouble stranded RNA packaged in liposome for use therapeutic tool in treatment of cell proliferative and viral disorders; Antisense oligonucleotide for use in prevention and treatment of viral and tumor disorders; gene expression inhibition; RNA interferenceUS20080233651Oct 31, 2007Sep 25, 2008Roland KreutzerMethod and medicament for inhibiting the expression of a given geneUS20080261303Oct 31, 2007Oct 23, 2008Roland KreutzerMethod and medicament for inhibiting the expression of a given geneAU717543B2 Title not availableAU778474B2 Title not availableAU2005201044B2 Title not availableWO2002044321A2 *Nov 29, 2001Jun 6, 2002Max Planck GesellschaftRna interference mediating small rna molecules* Cited by examinerNon-Patent CitationsReference1"InBase, The Intein Database: The Intein Registry�Inteins Sorted by Species," http://tools.neb.com/inbase/list.php (database updated on May 22, 2006).2Agami, "RNAi and related mechanisms and their potential use for therapy" Current Opin. Chem. Biol. 6:829-834 (2002).3Agami, "RNAi and related mechanisms and their potential use for therapy" Current Opin. Chem.Biol. 6:829-834 (2002).4Agrawal et al., "Self-Stabilized Oligonucleotides as Novel Antisense Agents," Delivery Strategies for Antisense Oligonucleotide Therapeutics, Edited by Saghir Akhtar, CRC Press, pp. 105-121 (1995).5Agrawal et al., "Antisense therapeutics: is it as simple as complementary base recognition?" Molecule Medicine 6:72-81 (2000).6Agrawal et al., "Self-Stabilized Oligonucleotides as Novel Antisense Agents," Delivery Strategies for Antisense Oligonucleotide Therapeutics, Edited by Saghir Akhtar, CRC Press, pp. 105-121. (1995).7Agrawal, S., "Antisense oligonucleotides: towards clinical trials," Tibtech (1996), 14: 376-387.8Agrawal, S., et al., "Oligodeoxynucleoside phosphoramidates and phosphorothioates as inhibitors of human immunodeficiency virus," Proc. Natl. Acad. Sci. USA (1988), 85:7079-7083.9Agrawal, S., et al., "Protocols for Oligonucleotides and Analogs," Chapters 5 and 6, 1993, pp. 81-140, Humana Press, Totowa, NH.10Alfonzo et al., "The mechanism of U insertion/deletion RNA editing in kinetoplastid mitochondria" Nucleic Acid Res. 25:3751-3759 (1997).11Alfonzo et al., "The mechanism of U insertion/deletion RNA editing in kinetoplastid mitochondria" Nucleic Acid Res.25:3751-3759 (1997).12Ambros, V., (2001), "Dicing Up RNAs", Science, 293:811-813.13Anderson, "Human gene therapy" Nature 392:25-30 (1998).14Armentano et al., "Expression of human factor IX in rabbit hepatocytes by retrovirus-mediated gene transfer: Potential for gene therapy of hemophilia B" Proc. Natl. Acad. Sci USA 87:614-645, 1990.15Asanuma et al., "Photoregulation der bildung and Dissoziation eines DNA-Duplex durch cis-trans-Isomerisierung einer Azobenzoleinheit" Agnew. Chem. 111:2547-2549 (1999).16Asanuma et al., "Photoregulation der bildung und Dissoziation eines DNA-Duplex durch cis-trans-Isomerisierung einer Azobenzoleinheit" Agnew. Chem.111:2547-2549 (1999).17Ausubel et al., "Cationic Lipid-Mediated Transfection of Suspension Cells with DNA", Protocols in Molecular Biology, Supplement 48, 9.4.7-9.4.8, 1999.18Auszug aus der online-Rolle des EPA, Excerpt from the European Patent Register for EP 1147204, Database last updated on Jun. 18, 2008, 4 Pages.19Auszug aus der online-Rolle des EPA.20Azhayeva et al., "Inhibitory properties of double helix forming circular oligonucleoties" Nucl. Acids Res. 25:4954-4961 (1997).21Azhayeva et al., "Inhibitory properties of double helix forming circular oligonucleoties" Nucl. Acids Res.25:4954-4961 (1997).22Bahramian et al., "Transcriptional and posttranscriptional silencing of rodent alpha 1(I) collagen by a homologous transcriptionally self-silenced transgene" Mol. Cell. Biol. 19:274-283 (1993).23Bahramian et al., "Transcriptional and posttranscriptional silencing of rodent alpha1(I) collagen by a homologous transcriptionally self-silenced transgene" Mol. Cell. Biol.19:274-283 (1993).24Barber et al., "Mutants of the RNA-Dependent Protein Kinase (PKR) Lacking Double-Stranded RNA Binding Domain I Can Act as Transdominant Inhibitors and Induce Malignant Transformation," Mol. Cell. Biol., 15(6):3138-3146 (1995).25Barlow et al., "Interferon synthesis in the early post-implantation mouse embryo", Differentiation (1984), 27:229-235.26Barwkar et al., "Synthesis, biophysical properties, and nuclease resistance properties of mixed backbone oligodeoxynucleotides containing cationic internucleoside guanidinium linkages: deoxynucleic guanidine/DNA chimeras" PNAS USA 95:11047-11052 (1998).27Basbaum et al., "Focalized proteolysis: spatial and temporal regulation of extra cellular matrix degradation at the cell surface"Curr. Opin. Cell Biol. 8:731-738, 1996.28Bass, B.L., (2000), "Double-Stranded RNA as a Template for Gene Silencing", Cell, 101:235-238.29Baulcombe, D.C., et al., "Mechanisms of Pathogen-Derived Resistance to Viruses in Transgenic Plants," The Plant Cell (1996), 8: 1833-1844.30Baxevanis, A., "The Molecular Biology Database Collection: 2003 udpate," Nucleic Acids Research, 2003, pp. 1-12, vol. 31, No. 1.31Beck, "Unknotting the Complexities of Multidrug Resistance: The Involvement of DNA Topoisomerases in Drug Action and Resistance" J. Natl. Cancer Inst. 81:1683-1685, 1989.32Berkner et al., "Development of Adenovirus Vectors for the Expression of Heterologous Genes" BioTechniues 6 (7):616-629, 1998.33Bernstein, E., et al., "Role for a bidentate ribonuclease in the initation step of RNA interference," Nature, Jan. 18, 2001, pp. 363-366, vol. 409.34Bhan et al., "2',5'-linked oligo-3'-deoxyribonucleoside phosphorothioate chimeras: thermal stability and antisense inhibition of gene expression" 25:3310-3317 (1997).35Bhan et al., "2′,5′-linked oligo-3′-deoxyribonucleoside phosphorothioate chimeras: thermal stability and antisense inhibition of gene expression" 25:3310-3317 (1997).36Billy et al., "Specific interference with gene expression induced by long, double-stranded RNA in mouse embryonal teratocarcinoma cell lines" PNAS USA 98(25):14428-14433 (2001).37Biotechnology Applied Biochemistry vol. 29, Part 1, Feb. 1999, which shows Braun, H., et al., "Oligonucleotide and plasmid DNA packaging into polyoma VPI virus-like particles expressed in Escherichia coli," as first published on the internet Dec. 22, 1998.38Birkedal-Hansen et al., "Matrix Metalloproteinases: A Review" Crit. Rev.Oral Biol. Med. 4:197-250, 1993.39Boese et al., "Mechanistic Insights Aid Computational Short Interfering RNA Design" Methods in Enzymology 392:73-95, 2005.40Borecky et al., "Therapeutic Use of Double-Stranded RNAs in Man", Texas Reports on Biology and Medicine, vol. 41, 1981-1982, pp. 575-581.41Boyd, "Invasion and metastasis" Cancer Metastass Rev. 15:77-89, 1996.42Braasch et al., "Locked nucleic acid (LNA): fine-tuning the recognition of DNA and RNA" Chem. Biol. 8:1-7, 2001.43Braich et al., "Regiospecific Solid-Phase Synthesis of Branched Oligonucleotides. Effect of Vicinal 2',5'- (or 2',3'-) and 3',5'-Phosphodiester Linkages on the Formation of Hairpin DNA," Bioconjug. Chem., 8:370-377 (1997).44Braich et al., "Regiospecific Solid-Phase Synthesis of Branched Oligonucleotides. Effects of Vicinal 2',5'-(or 2'3'-) and 3'5'-Phosphodiester Linkages on the Formation of Hairpin DNA" Bioconjugate Chemistry, 8:370-377, 1997.45Braich et al., "Regiospecific Solid-Phase Synthesis of Branched Oligonucleotides. Effect of Vicinal 2′,5′- (or 2′,3′-) and 3′,5′-Phosphodiester Linkages on the Formation of Hairpin DNA," Bioconjug. Chem., 8:370-377 (1997).46Braich et al., "Regiospecific Solid-Phase Synthesis of Branched Oligonucleotides. Effects of Vicinal 2',5'- (or 2'3'-) and 3'S'-Phosphodiester Linkages on the Formation of Hairpin DNA" Bioconjugate Chemistry, 8:370-377, 1997.47Braich et al., "Regiospecific Solid-Phase Synthesis of Branched Oligonucleotides. Effects of Vicinal 2′,5′-(or 2′3′-) and 3′5′-Phosphodiester Linkages on the Formation of Hairpin DNA" Bioconjugate Chemistry, 8:370-377, 1997.48Branch, "A good antisense molecule is hard to find" TIBS 23:45-50(1998).49Braun, H., et al., "Oligonucleotide and plasmid DNA packaging into polyoma VPI virus-like particles expressed in Escherichia coli," Biotechnol. Appl. Biochem, 1999, pp. 31-43.50Brennicke et al., "RNA editing," FEMS Microbiology Reviews, 23:297-316 (1999).51Brinckerhoff et al., "Matrix metalloproteinases: a tail of a frog that became a prince" Nature Reviews 3:207-214, 2002.52Bruening, "Plant Gene Silencing Regularized" Proc. Natl Acad Science 95:13349-13351, 1998.53Bucchini et al., "Pancreatic Expression of Human Insulin Gene in Transgenic Mice" PNAS USA 83:2511-1515,1986.54Bumcrot, D., et al., "RNAi therapeutics: a potential new class of pharmaceutical drugs," Nature Chemical Biology (2006), 2(12): 711-719.55Burke et al., "Appearance of Interferon Inducibility and Sensitivity during Differentiation of Murine Teratocarcinoma Cells in Vitro", Cell, vol. 13, 243-248, Feb. 1978.56Byrom et al., "Inducing RNAi with siRNA Cocktails Generated by RNase III," TechNotes 10(1), Ambion, http://www.ambion.com/techlib/tn/101/4.html (2004).57Cameron et al., "Inhibition of Gene Expression by a Short Sense Fragment" Nucleic Acids Research, 19:469-475, 1991.58Caplen et al., "dsRNA-Mediated Gene Silencing in Cultured Drosophila Cells: a Tissue Culture Model for the Analysis of RNA Interference" Gene 252:95-105, 2000.59Caplen, "RNAi as a gene therapy approach" Expert Opin. Biol. Ther. 3:575-586 (2003).60Caplen, "RNAi as a gene therapy approach" Expert Opin. Biol. Ther.3:575-586 (2003).61Caplen, N.J. et al., (2001), "Specific inhibition of gene expression by small double-stranded RNAs in invertebrate and vertebrate systems", Proc. Natl. Acad. Sci. USA, 98(17):9742-9747.62Caplen, N.J., (2002), "A new approach to the inhibition of gene expression", TRENDS in Biotechnology, 20(2):49-51.63Castelli et al., "The 2-5A system in viral infection and apoptosis" Biomed. Pharmacother. 52:386-390 (1998).64Castelli et al., "The 2-5A system in viral infection and apoptosis" Biomed. Pharmacother.52:386-390 (1998).65Chao et al., "BCL-2 Family: Regulators of Cell Death" Annu. Rev. Immunol. 16:395-419, 1998.66Check "RNAi to the Rescue?" Nature 425:10-12 (2003).67Chen et al., "Gene therapy for brain tumors: regression of experimental gliomas by adenovirus-mediated gene transfer in vivo" Proc. Natl Acad Sci. USA 91:3054-3057, 1994.68Chen, M., et al., "A universal plasmid library encoding all permutations of small interfering RNA," PNAS, Feb. 15, 2005, pp. 2356-2361, vol. 102, No. 7.69Chien et al., "Novel cationic cardiolipin analogue-based liposome for efficient DNA and small interfering RNA delivery in vitro and in vivo," Cancer Gene Therapy, pp. 1-8 (2004).70Childs et al., the MDR Superfamily of Genes and Its Biological Implciations Imp. Adv. Oncol. 21-36, 1994.71Chowdhury et al., "Long-Term Improvement of Hypercholesteromlemia AfierEx Vivo Gene Therapy in LDLR-Deficient Rabbits" Science 254:1802-1805, 1991.72Chowdhury et al., "Long-Term Improvement of Hypercholesteromlemia AfterEx Vivo Gene Therapy in LDLR-Deficient Rabbits" Science 254:1802-1805, 1991.73Chu, C-Y., et al., "Potent RNAi by short RNA triggers," RNA, Report, 2008, pp. 1714-1719, vol. 14.74Cioca et al., "RNA interference is a functional pathway with therapeutic potential in human myeloid leukemia cell lines" Cancer Gene Therapy 10:125-133, 2003.75Clemens MJ: PKR�a protein kinase regulated by double-stranded RNA. Int J Biochem Cell Biol 1997, 29(7):945-949.76Cobaleda, C. et al., (2000), "In vivo inhibition by a site-specific catalytic RNA subunit of Rnase P designed against the BCR-ABL oncogenic products: a novel approach for cancer treatment", Blood, 95(3):731-737.77Coburn et al., "siRNAs: a new wave of RNA-based therapeutics" J. Antimicrobial Chemotherapy 51:753-756 (2003).78Cole et al., "Overexpression of a Transporter Gene in a Multidrug-Resistant Human Lung Cancer Cell Line" Science258: 1650-1654, 1992.79Communication of Technical Board of Appeal in opposition to European Patent No. 1 144 623 (Sep. 22, 2008). (translation attached).80Cone et al., "High-efficiency gene transfer into mammalian cells: Generation of helper-free recombinant retrovirus with broad mammalian host range" Proc. Natl Acad Sci. USA 81:6349-6353, 1984.81Cook, "Medicinal chemistry of antisense oligonucleotides�future opportunities" Anti-Cancer Drug Design 6:585-607, 1991.82Corey, D.R., "Chemical modification: the key to clinical application of RNA interference?" The Journal of Clinical Investigation (2007), 117(12): 3615-3622.83Cornetta et al., "Safety Issues Related to Retroviral-Mediated Gene Transfer in Humans" Human Gene Threapy2(1):5-14, 1991.84Cotten et al., "Ribozyme Mediated Destruction of RNA in vivo" EMBO J. 8:3861-3866, 1989.85Couture et al., "Anti-gene therapy: the use of ribozymes to inhibit gene function: Trends in Genetics." 12:510-515, 1996.86Couzin, "Small RNAs Make Big Splash," Science, 298:2296-2297 (2002).87Crooke et al., "Pharmacokinetic Properties of Several Novel Oligonucleotdies Analogs in Mice" J. Pharmacol. Exp. Ther. 277:923-937, 1996.88Crooke, "Basic Principles of Antisense Therapeutics" Antisense Res. and Application Chapter 1, Springer-Verlag, New York (1988).89Crooke, S., et al., "Antisense Research and Applications," Chapters 16 and 18, 1993, CRC Press, Boca Raton, 21 pages.90Current version of Curriculum Vitae of David M. Stalker, 2010, 13 pages.91Czauderna et al., "Structural variations and stabilizing modifications of synthetic siRNAs in mammalian cells," Nucleic Acids Res., 31(11):2705-2716 (2003).92Dai et al., "Gene therapy via primary myoblasts: Long-term expression of factor IX protein following transplantation in vivo" Proc. Natl Acad. Sci. USA 89:10892-10895, 1992.93Damha, M., et al., "Chapter 5: Oligoribdonucleotides synthesis: the silyl-phosphoramidite method," Methods in Molecular Biology 20, Humana Press NJ: 81-114 (1993).94Danos et al., "Safe and efficient generation of recombinant retroviruses with amphotropic and ecotropic host ranges" Proc. Natl. Acad. Sci. USA 85:6460-6464, 1998.95D'Ari, "Cycle-regulated genes and cell cycle regulation" Bioassays 23: 563-565, 2001.96Datenbank MEDLINE bei STN:AN 1999091059 MEDLINE; DN99091059 zu: Use of dsRNA-mediated genetic interference to demonstrate that frizzled and frizzled 2 act in the wingless pathway. Kennerdell J.R.; Carthew R.W.; Cell 95(7):1017-1026 (1998).97de Fougerolles et al., "RNA interference in vivo: toward synthetic small inhibitory RNA-based therapeutics" Methods in Enzym. 392:278-296 (2005).98de Fougerolles et al., "RNA interference in vivo: toward synthetic small inhibitory RNA-based therapeutics" Methods in Enzym.392:278-296 (2005).99Dean, N. M., et al., "Identification and Characterization of Second-Generation Antisense Oligonucleotides," Antisense & Nucleic Acid Drug Development (1997), 7: 229-233.100Decision and Minutes in opposition proceedings for European Patent No. 12 14 945 (Mar. 31, 2009). (translation attached).101Decision by German Patent Office in opposition proceedings for DE 100 80 167.6 (Feb. 17, 2009).102Decision in opposition proceedings for European Patent No. 11 44 623 (Mar. 30, 2009). (translation attached).103Decision of Rejection for Japan Patent Application No. 2009-002824, Mar. 9, 2010, 4 Pages.104Decision of Rejection for Japan Patent Application No. 2009-002826, Mar. 9, 2010, 4 Pages.105Decision of the Board of Appeal of May 19, 2010 in Opposition to European Patent No. EP 1214945, Jul. 20, 2010, 28 pages.106Decision of the Technical Board of Appeals for European Patent No. 1144623, Dec. 9, 2008, 50 Pages.107Decision to revoke European Patent EP 10080167 of Alnylam Europe AG, Mar. 18, 2009, 26 Pages.108Decision to revoke European Patent EP 1144623 of Alnylam Europe AG, Dec. 19, 2008, 50 pages.109Decision to revoke European Patent EP 1214945 of Alnylam Europe AG, Jan. 20, 2009, 56 Pages.110Declaration of David Keith Myers filed in opposition proceedings for Australian Patent 778474 (Nov. 7, 2008).111Declaration of David M. Stalker filed in opposition proceedings for Australian Patent 778474 (Nov. 4, 2008) (17 pages).112Declaration of David M. Stalker filed in opposition proceedings for Australian Patent 778474 (Nov. 4, 2008) (45 pages).113Delgado et al., "The Uses and Properties of PEG-Linked Proteins" Crit. Rev. Therap. Drug Carrier Sys. 9:249-304, 1992.114Dellweg et al., ed., R�mpp Lexikon Biotechnologie, p. 354 and p. 673 (1992) (in German).115Diagramm zur Illustrierung der Offenbarung von D13.116Diagramm zur Illustrierung der Offenbarung von D5.117Diagramm zur Illustrierung des Gegenstands des angegriffenen Patents.118Docherty et al., "Nutrient regulation of insulin gene expression" FASEB J. 8:20-27, 1994.119Doench, J.G. et al., (2003), "siRNAs can function as miRNAs", Genes & Development, 17:438-442.120Dolinnaya et al., "Oligonucleotide circulization by temlate-directed chemical ligation" Nucl. Acids Res. 21:5403-5407 (1993).121Dolinnaya et al., "Oligonucleotide circulization by temlate-directed chemical ligation" Nucl. Acids Res.21:5403-5407 (1993).122Donz�, O. et al., (2002), "RNA interference in mammalian cells using siRNAs synthesized with T7 RNA Polymerase", Nucleic Acids Research, 30(10):e46(4pages).123Downward, J. et al., (1990), "Identification of a nucleotide exchange-promoting activity for p21ras", Proc. Natl. Acad. Sci. USA, 87:5998-6002.124Eder et al., "Monitoring of BCR-ABL expression using real-time RT-PCR in CML after bone marrow or peripheral blood stem cell transplantation" Leukemia 13:1383-1389, 1999.125Eglitis et al., "Gene Expression in Mice After High Efficiency Retroviral-Mediated Gene Transfer" Science 230:1395-1398, 1985.126Elbashir et al., "Analysis of gene function in somatic mammalian cells using small interfering RNAs," Methods, 26:199-213 (2002).127 *Elbashir et al., Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells, 2001, Nature, vol. 411, pp. 494-498.128 *Elbashir et al., Functional anatomy of siRNAs for mediating efficient RNAi in Drosophila melanogaster embryo lysate, 2001, The EMBO Journal, vol. 20, No. 23, pp. 6877-6888.129 *Elbashir et al., RNA Interference is mediated by 21- and 22- nucleotide RNAs, 2001, Genes & Development, vol. 15, pp. 188-200.130Elbashir, et al. (2001) Nature 411:494-498.131Elbashir, S.M. et al., (2001), "Functional anatomy of siRNAs for mediating efficient RNAi in Drosophila melanogaster embryo lysate", The EMBO Journal, 20(23):6877-6888.132Elbashir, S.M. et al., (2001), "RNA interference is mediated by 21- and 22-nucleotide RNAs", Genes & Development, 15:188-200.133Eriksson et al., "Establishment and characterization of mouse stain (TLL) that spontaneously develops T-cell lymphomas/leukemia" Exp. Hematol. 27:682:688, 1999.134Examination Report for German Divisional Patent Application No. DE 10066382.6, Apr. 8, 2011, 13 pages.135Exhibit 1 of David Keith Myers Declaration filed in opposition proceedings for Australian Patent 778474 (Nov. 7, 2008).136Exhibit 2 of David Keith Myers Declaration filed in opposition proceedings for Australian Patent 778474 (Nov. 7, 2008).137Expert-Bezancon et al., "Precise localization of several covalent RNA-RNA cross-link in Escherichia coli16S RNA" Eur. J. Biochem. 136:267-274 (1983).138Expert-Bezancon et al., "Precise localization of several covalent RNA-RNA cross-link in Escherichia coli 16S RNA" European Journal of Biochemistry, 136:267-274, 1983.139Expert-Bezancon et al., "Precise localization of several covalent RNA-RNA cross-link in Escherichia coli16S RNA" Eur. J. Biochem.136:267-274 (1983).140Extended European Search Report and Written Opinion, mailed Aug. 8, 2011 for European Patent Application No. EP 10011217.6, 21 Pages.141Fallert-Mueller, ed., Encyclopedia of Biochemistry, vol. J-Z, pp. 448-449 (2000) (in German).142Fan et al., "Reversal of Multidrug Resistance in Cancer", ed. Kellen, CRC, Boca Raton, FL, pp. 93-125.143Fan et al., "Reversal of Multidrug Resistance in Cancer", ed. Kellen, CRC, Boca Raton, FL, pp. 93-125. (1994).144Ferry et al., "Retroviral-mediated gene transfer into hepatocytes in vivo" Proc. Natl. Acad Sci. USA 88:8377-8381, 1991.145Fire et al., "Specific interference by ingested dsRNA" Nature 395:854.146Fire et al., "Production of Antisense RNA leads to effective and specific inhibition of gene expression in C. elegans muscle" Development 113:503-514 (1991).147Fire et al., "RNA Interferences�gene silencing by double-stranded RNA" The Nobel Prize in Physiology or Medicine, press release, 2006.148Fire et al., "Specific interference by ingested dsRNA" Nature 395:854 (Oct. 29, 1998).149Fire, 9/99, RNA-triggered gene silencing, Trends Genet, 15: 358-363.150Fire, A. et al., (1998), "Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans", Nature, 391:806-811.151Fire, A., "Gene Silencing by Double Stranded RNA," Nobel Lecture, Dec. 8, 2006, pp. 198-233.152Forstova, J. et al., "Polyoma Virus Pseudocapsids as Efficient Carriers of Heterologous DNA into Mammalian Cells," Human Gene Therapy (1995), 6: 297-306.153Fotedar et al., "Apoptosis and the cell cycle" Prog. Cell Cycle Res. 2:147-163,1996.154Gait, M., "Chapter 16: Oligoribdonucleotides," Antisense Research and Applications, CRC Press 289-302, 1993.155Gamier, L. et al., "Incorporation of Pseudorabies Virus gD into Human Immunodeficiency Virus Type 1 Gag Particles Produced in Baculovirus-Infected Cells," Journal of Virology (1995) 69(7): 4060-4068.156Gao et al., "Circulaization of oligonucleotides by disulfide bridge formation" Nucl. Acids Res. 23:2025-2029 (1995).157Gao et al., "Circulaization of oligonucleotides by disulfide bridge formation" Nucl. Acids Res.23:2025-2029 (1995).158Gao, H., et al., "Stabilization of double-stranded oligonucleotides using backbone-linked disulfide bridges," Nucleic Acids Research, 1995, pp. 285-292, vol. 23, No. 2.159Gassmann et al., "Maintenance of an extrachromosomal plasmid vector in mouse embryonic stem cells" PNAS USA 92:1292-1296, 1995.160Gautschi, O. et al., (2001), "Activity of a Novel bcl-2/bcl-xL-Bispecific Antisense Oligonucleotide Against Tumors of Diverse Histologic Origins", Journal of the National Cancer Institute, 93(6):463-471.161German Opposition, filed by Pfizer Inc. on Jun. 19, 2008, in opposition to German Patent DE 10066235.8 (Lederer & Keller), 34 pages.162Gewirtz, A., et al., "Nucleic Acid Therapeutics: State of the Art and Future Prospects," Blood, Aug. 1, 1998, pp. 712-736, vol. 92, No. 3.163Gibbs, J.B. et al., (1988), "Purification of ras GTPase activating protein from bovine brain", Proc. Natl. Acad. Sci. USA, 85:5026-5030.164Gillock, E. T. et al., "Polyomavirus Major Capsid Protein VP1 is Capable of Packaging Cellular DNA When Expressed in the Baculovius System," Journal of Virology (1997),71(4): 2857-2865.165Graessman et al., "Inhibition of SV40 Gene Expression by Microinjected Small Antisense RNA and DNA Molecules" Nucleic Acids Research 19:53-59, 1991.166Graham, "Mapping Transgene Activity in Plants Using Visible Phenotypes" Australian Society for Biochemistry and Molecular Biology Incorporated and Australian Society of Plant Physiologists Incorporated, vol. 28, Abstract SYM-18-06 (1996).167Grasby et al., "Purine functional groups in essential residues of the hairpin ribozyme required for catalytic cleavage of RNA" Biochem. 34(12):4068-4076 (1995).168Grasby et al., "Purine functional groups in essential residues of the hairpin ribozyme required for catalytic cleavage of RNA" Biochem.34(12):4068-4076 (1995).169Green et al., "Antisense Oligonucleotides: An evolving technology for the modulation of gene expression in human disease" J. Am. Coll. Surg. 191:93-105 American Colllage of Surgeons (2000).170Green et al., "Antisense Oligonucleotides: An evolving technology for the modulation of gene expression in human disease" J. Am. Coll. Surg.191:93-105 American Colllage of Surgeons (2000).171Grierson et al., "Does Co-Suppression of Sense Genes in Transgenic Plants Involve Antisense RNA?" Trends in Biotechnology 9:122-123, 1991.172Griffey et al., "2'-O-aminopropyl ribonucleotides: a zwitterionic modification that enhances the exonuclease resistance and biological activity of antisense oligonucleotides" J. Med. Chem. 39(26):5100-5109 (1996).173Griffey et al., "2′-O-aminopropyl ribonucleotides: a zwitterionic modification that enhances the exonuclease resistance and biological activity of antisense oligonucleotides" J. Med. Chem. 39(26):5100-5109 (1996).174Griffey et al., "2'-O-aminopropyl ribonucleotides: a zwitterionic modification that enhances the exonuclease resistance and biological activity of antisense oligonucleotides" J. Med. Chem.39(26):5100-5109 (1996).175Griffey, R., et al., "2′-O-Aminopropyl Ribonucleotides: A Zwitterionic Modification That Enhances the Exonuclease Resistance and Biological Activity of Antisense Oligonucleotides," J. Med. Chem., 1996, pp. 5100-5109, vol. 39.176Grounds of Appeal filed by Alnylam Europe AG for European Patent EP 1214945, filed Aug. 5, 2009, 21 pages.177Grounds of Appeal filed by Appellant Sanofi-Aventis Deutschland GmbH, on Oct. 26, 2010, against German Patent No. DE 10066235.8, 21 pages.178Grounds of Appeal filed by Appellant Silence Therapeutics AG, on Nov. 23, 2010, against German Patent No. DE 10066235.8, 48 pages.179Gryaznov et al., "Template controlled coupling and recombination of oligonucleotide blocks containing thiophosphoryl groups," Nucleic Acids Res., 21(6):1403-1408 (1993).180Guang et al., "An Argonaute Transports siRNAs from the Cytoplasm to the Nucleus" Science 321:537-541, 2008.181Guo et al., "Par-1 a Gene Required for Establishing Polarity in C. elegans Embryos, Encodes a Putative Ser/Thr Kinase That is Asymmetrically Distributed" Cell 81:611-620, 1995.182Ha et al., "A bulged lin-4/1in-14 RNA duplex is sufficient for Caenorhabditis elegans lin-14 temporal gradient formation" Genes Dev. 10(23):3041-3050 (1996).183Ha et al., "A bulged lin-4/lin-14 RNA duplex is sufficient for Caenorhabditis elegans lin-14 temporal gradient formation" Genes Dev.10(23):3041-3050 (1996).184Hamada M. et al., "Effects of RNA Interference in Gene Expression (RNAi) in Cultured Mammalian Cells of Mismatches and the Introduction of Chemical Modifications at the 3'-Ends of siRNAs," Antisense and Nucleic Acid Drug Development, 2002, vol. 12, pp. 301-309.185Hamilton et al., "A species of small antisense RNA in posttranscriptional gene silencing in plants" Science 286:950-951 (1999).186Hamm et al., "Incorportation of 2'-Deoxy-2'mercaptocytidine into Oligonucleotides via Phosphoramidite Chemistry" J. Org. Chem. 62:3415-3420, 1997.187Hamm et al., "Incorportation of 2′-Deoxy-2′mercaptocytidine into Oligonucleotides via Phosphoramidite Chemistry" J. Org. Chem. 62:3415-3420, 1997.188Hammond, S.M. et al., (2000), "An RNA-directed nuclease mediates post-transcriptional gene silencing in Drosophila cells", Nature, 404:293-296.189Hanahan et al., "The Hallmarks of Cancer" Cell 100:57-70, 2000.190Harada ct al., "Absence of the Type I IFN System in EC Cells: Transcriptional Activator (IRF-1) and Repressor (1RF-2) Genes Are Developmentally Regulated", Cell, vol. 83, 303-312, Oct. 19, 1990.191Harada et al., "Absence of the Type I IFN System in EC Cells: Transcriptional Activator (IRF-1) and Repressor (IRF-2) Genes Are Developmentally Regulated", Cell, vol. 83, 303-312, Oct. 19, 1990.192Harborth, J. et al., (2001), "Identification of essential genes in cultured mammalian cells using small interfering RNAs", Journal of Cell Science, 114(24):4557-4565.193Harfe et al., "Analysis of a Caenorhabditis elegans twist homolog identifies conserved and divergent aspects of mesodermal patterning, Genes and Development", 12:2623-2635 (1998).194Harfe et al., "Analysis of a Caenorhabditis elegans twist homolog identifies conserved and divergent aspects of mesodermal patterning", Genes and Development, 12:2623-2635 (1998).195Harris et al., "The Eu-myc Transgenic Mouse A Model for High-incidence Spontaneous Lymphoma and Leukemia of Early B Cells" J. Exp. Med. 167(2)353-371, 1988.196Hedges, "The Origin and Evolution of Model Organisms," Nature Reviews, 3:838-849 (2002).197Hoke et al., "Effects of phosphorothioate capping on antisense oligonucleotide stability, hybridization and antiviral efficacy versus herpes simplex virus infection" Nucl. Acids Res. 19(20):5743-5748 (1991).198Hoke et al., "Effects of phosphorothioate capping on antisense oligonucleotide stability, hybridization and antiviral efficacy versus herpes simplex virus infection" Nucl. Acids Res.19(20):5743-5748 (1991).199Holen, T. et al., (2002), "Positional effects of short interfering RNAs targeting the human coagulation trigger Tissue Factor", Nucleic Acids Research, 30(8):1757-1766.200Horn et al., "Chemical synthesis and characterization of branched oligodeoxyribonucleotides (bDNA) for use as signal amplifiers in nucleic acid quantification assays", Nucleic Acids Research, 1997, vol. 25, No. 23, pp. 4842-4849.201Hornung et al., "Sequence-specific potent induction of IFN-alpha by short interfering RNA in plasmacytoid dendritic cells through TLR7," Nature Medicine, 11(3):263-270 (2005).202Hornung et al., "Sequence-specific potent induction of IFN-α by short interfering RNA in plasmacytoid dendritic cells through TLR7," Nature Medicine, 11(3):263-270 (2005).203Hornung et al., "Sequence-specific potent induction of IFN-αby short interfering RNA in plasmacytoid dendritic cells through TLR7," Nature Medicine, 11(3):263-270 (2005).204Hsu et al., "Immunogencity of Recombinant Adenovirus-Respiratory Syncytial Virus Vaccines with Adenovirus Types 4, 5, and 7Vectors in Dogs and a Chimpanzee" J. Infectious Disease 166:769-775, 1992.205Huber et al., "Retroviral-mediated gene therapy for the treatment of hepatocellular carcinoma. An innovative approach for cancer therapy" Proc. Natl Acad. Sci USA 88:8039-8043, 1991.206Hu-Lieskovan et al., "Sequence-Specific Knockdown of EWS-FLI1 by Targeted, Nonviral Delivery of Small Interfering RNA Inhibits Tumor Growth in a Murine Model of Metastatic Ewing's Sarcoma" Cancer Res., 65(19):8984-8992 (2005).207Hung, C., et al., "A novel siRNA validation system for functional screening and identification of effective RNAi probes in mammalian cells," Biochemical and Biophysical Reseach Communications, 2006, pp. 707-720, vol. 346.208Hunter et al., "The characteristics of inhibition of protein synthesis by double stranded ribonucleic acid in reticulocyte lysates," J. Biol. Chem., 250(2):409-417 (1975).209Hunter, "A touch of elegance with RNAi" Curr. Biolo. 9:R440-R442 (1999).210Hunter, "A touch of elegance with RNAi" Curr. Biolo.9:R440-R442 (1999).211Hunter, C., "Genetics: A touch of elegance with RNAi," Current Biology, 1999, pp. R440-R442.212Hwu et al., "Functional and Molecular Characterization of Tumor-Infiltrating Lymphocytes Transduced with Tumor Necrosis Factor-alpha cDNA for the Gene Therapy of Cancer in Humans" J. Immunol. 150:4104-4115, 1993.213Interlocutory Decision and Druckexemplar in opposition proceedings for European Patent No. 11 44 623 (Sep. 25, 2006).214International Search Report of International Application No. PCT/EP02/00151.215International Search Report PCT/DE 00/00244.216Iwase et al., "Gene regulation by decoy approach (I): synthesis and properties of photo-crosslinked oligonucleotides", Nucleic Acids Symposium Series, No. 37, 1997, pp. 203-204.217Iwase et al., "Gene regulation by decoy approach (I): synthesis and properties of photo-crosslinked oligonucleotides", Nucleic Acids Symposium Series, No. 37, 1997, pps. 203-204.218Izant et al., "Constitutive and Conditional Suppression of Exogenous and Endogenous Genes by Anti-Sense RNA" Science 229:345-352, 1985.219Jackson et al., "Widespread siRNA �off-target� transcript silencing mediated by seed region sequence complementarity," RNA Journal 12:1179-1187 (2007).220Jackson, A. L. et al., "Widespread siRNA "off-target" transcript silencing mediated by seed region sequence complementarity," RNA Journal, 12(7): 1179-1187 (2007).221Jacobs et al. "When two stands are better than one: The mediators and modulators of the cellular responses to double-stranded RNA" Virology 219:339-349 (1996).222James et al., "The Therapeutic Potential of Ribozymes" Blood 91:371-382, 1998.223Jaschke et al., Nucleosides & Nucleotides 15:1519-1529 (1996).224Jen et al., "Suppression of Gene Expression by Targeted Disruption of Messenger RNA: Available Options and Current Strategies" Stem Cells 18:307-319 (2000) AlphaMed Press.225Jen et al., "Suppression of Gene Expression by Targeted Disruption of Messenger RNA: Available Options and Current Strategies" Stem Cells18:307-319 (2000) AlphaMed Press.226Jennings et al., "Inhibition of SV40 Replicon Function by Engineered Antisense RNA Transcribed by RNA Polymerase III" EMBO Journal 6:3043-3047, 1987.227Jiang, A., et al., "In vivo cell type-specific gene delivery with retroviral vectors that display single chain antibodies," Gene Therapy, 1999, pp. 1982-1987, vol. 6.228Jorgensen et al., "Silencing of Plant Genes by Homologous Transgenes" AgBiotech News and Information 4:265-273, 1992.229Judge A.D., et al., "Design of Noninflammatory Synthetic siRNA Mediating Potent Gene Silencing in Vivo," Molecular Therapy (2006), 13(3): 494-505.230Judge et al., "Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA," Nat. Biotechnol., pp. 1-6 (2005) (8 pages of supplementary content included).231Kabanov et al., "A new class of antivirals: antisense oligonucleotides combined with a hydrophobic substituent effectively inhibit influenze virus reproduction and synthesis of virus-specific proteins in MDCK cells" FEBS Lett. 259 (2):327-330,1990.232Kamio et al., "Nucleotide Sequence of an Incompatibility Region of Mini-Rts1 That Contains Five Direct Repeats" Journal of Bacteriology 155:1185-1191, 1983.233Kaufman, "Double-stranded RNA-activated protein kinase-mediates virus-induced apoptosis: A new role for an old actor" PNAS USA 96:11693-11695 (1999).234Kay et al , "Hepatic Gene Therapy: Persistent Expression of Human alpha1-Antitrypsin in Mice after Direct Gene Delivery In Vivo" Human Gene Therapy 3:641-647, 1992.235Kay et al., "Hepatic Gene Therapy: Persistent Expression of Human alphal-Antitrypsin in Mice after Direct Gene Delivery In Vivo" Human Gene Therapy 3:641-647, 1992.236Kelly, J. "Superagonist Trial Hit by Cytokine Storm," Muscoskeletal Report, Aug. 17, 2006, 3 Pages.237Kennerdell et al., "Use of dsRNA-Mediated Genetic Interference to Demonstrate that frizzled and frizzled 2 Act in the Wingless Pathway" Cell 95:1017-1026 (1998).238Kennerdell, J., et al., "Use of dsRNA-Mediated Genetic Interference to Demonstrate that frizzled and frizzled 2 Act in the Wingless Pathway," Cell, Dec. 23, 1998, pp. 1017-1026.239Kim et al., "Stable Reduction of Thymidine Kinase Activity in Cells Expressing High Levels of Anti-Sense RNA" Cell 42:129-138, 1985.240Kitabwalla et al., "RNA-Interference�A New Weapon Against HIV and Beyond," N. Engl. J. Med., 347(17):1364-1367(2002).241Klemens et al., "The 2 A Structure of helix 6 of the human signal recognition particle RNA" Structure 7(11):1345-1352 (1999).242Koshkin et al., "LNA (Locked Nucleic Acids) Synthesis of the Adenine, Cytosine, Guanine, 5-Methylcytosine, Thymine and Uracil Biclonucleoside Monomors, Oligomerisation and Unprecendented Nucleic Acid Recognition," Tetrahedron 54:3507-3630, 1998.243Kovalchuk et al., "Burkitt Lymphoma in the Mouse" J. Exp. Med. 192:1183-1190, 2000.244Krepela, "Cysteine proteinases in tumor cell growth and apoptosis" Neoplasma 48:332-349, 2001.245Kreutzer et al., "Specific inhibition of viral gene expression by double-stranded RNA in vitro", Gesellschaft fur Biochemie and Molekularbiologie, Fall Meeting S169.246Kreutzer et al., "Specific inhibition of viral gene expression by double-stranded RNA in vitro, Gesellschaft fur Biochemie and Molekularbiologie", Fall Meeting S169. (1999).247Krieger et al., "The Flavr Saw Tomato, an Early Example of RNAi Technology" HortScience 43:962-964, 2008.248Lamond, A., et al., "Antisense oligonucleotides made of 2'-0-alky1RNA: their properties and applications in RNA biochemistry," FEBS Letters (1993), 325(1-2): 123-127.249Lee et al., "The C. elegans Herochronic Gene lin-4 Encodes Small RNAs with Antisense Complementary to lin-14" Cell 75:843-854 (1993).250Lee et al., "The C. elegans Heterochronic Gene lin-4 Encodes Small RNAs with Antisense Complementary to lin-14," Cell, 75:843-854 (1993).251Lee et al., "The Cold Shock Domain Protein LIN-28 Controls Developmental Timing in C. elegans and Is Regulated by the lin-4 RNA" Cell 88:637-646 (1997).252Lee, E., et al., "The Cold Shock Domain Protein LIN-28 Controls Developmental Timing in C. elegans and Is Regulated by the lin-4 RNA," Cell, Mar. 7, 1997, pp. 637-646, vol. 88.253Letsinger et al., "Cholesteryl-conjugated oligonucleotides: Synthesis, properties, and activity as inhibitors of replication of human immunodeficiency virus in cell culture" PNAS USA 86:6553-6556, 1989.254Letter to the International Examining Authority from Gassner & Partner in the prosecution of PCT/DE00/00244 (WO 00/44895) 5 pages (Mar. 28, 2001) (in German).255Letter to the International Examining Authority from Gassner & Partner in the prosecution of PCT/DE00/00244 (WO 00/44895), 5 pages (Mar. 28, 2001) (in German).256Lewis, D.L. et al., (2002), "Efficient delivery of siRNA for inhibition of gene expression in postnatal mice", Nature Genetics, 32:107-108.257Li et al., "Folate-Mediated Targeting of Antisense Oligodeoxynucleotides to Ovarian Cancer Cells" Pharm. Res. 15(10):1540-1545, 1998.258Li et al., "Double-Stranded RNA Injection Produces Null Phenotypes in Zebrafish", Developmental Biology Program, 210:238, abstract 346 (1999).259Li et al., "Folate-Mediated Targeting of Antisense Oligodeoxynucleotides to Ovarian Cancer Cells"Pharm. Res. 15(10):1540-1545, 1998.260Lin et al., "Policing rogue genes" Nature 402:128-129 (1999).261Lipardi, C. et al., (2001), "RNAi as Random Degradative PCR: siRNA Primers Convert mRNA into dsRNAs that Are Degraded to Generate New siRNAs", Cell, 107:297-307.262Lipinski et al., "Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings", Advanced Drug Delivery Review, 23 (1997), 3-25.263Lipson et al., "Psoralen cross-linking of ribosomal RNA" Methods in Enzymology 164:330-341 (1988).264List of Documents in Oppositions to German Application No. DE 100 66 235, filed by Silence Therapeutics AG, Sanofi Aventis Deutschland GmbH, and Pfizer Inc.265Liu et al., "Detection of a novel ATP-dependent cross-linked protein at the 5' splice site-U1 small nuclear RNA duplex by methylene blue-mediated photo-cross-linking" Mol. Cell Biol. 18:6910-6920 (1998).266Liu et al., "Detection of a novel ATP-dependent cross-linked protein at the 5' splice site-U1 small nuclear RNA duplex by methylene blue-mediated photo-cross-linking" Mol. Cell Biol.18:6910-6920 (1998).267Liu et al., "Detection of a novel ATP-dependent cross-linked protein at the 5′ splice site-U1 small nuclear RNA duplex by methylene blue-mediated photo-cross-linking" Mol. Cell Biol. 18:6910-6920 (1998).268 *Livache et al., Detection of HIV1 DNA in Biological Samples by an Homogenous Assay: Fluorescence Measurement of Double-Stranded Stranded RNA Synthesized from Amplified DNA, 1994, Analytical Biochemistry, vol. 217, No. 2, pp. 248-254.269Lopez-Fraga, M., et al., "RNA Interference-Based Therapeutics: New Strategies to Fight Infectious Disease," Infectious Disorders Drug Targets (2008), 8:262-273.270Lowy, D.R. et al., (1993), "Function and Regulation of RAS", Annu. Rev. Biochem., 62:851-891.271Lubberts, E., et al., "Adenoviral Vector-Mediated Overexpression of IL-4 in the Knee Joint of Mice with Collagen-Induced Arthritis Prevents Cartilage Destruction," The Journal of Immunology, 1999, pp. 4546-4556.272Luo et al., "The Gene-Silencing Efficiency of SiRNA is Strongly Dependent on the Local Structure of mRNA at the Targeted Region" Biochemical and Biophysical Research Communications, vol. 318(1):303-10, 2004.273M13994: "Human B-cell leukemia/lymphoma 2 (bc102) proto-oncogene mRNA encoding bcl-2 beta protein," GenBank Record dated Oct. 31, 1994 (GenBank [online] Bethesda, MD, USA: United States National Library of Medicine [retrieved on Aug. 9, 2006]. Retrieved from internet using , GenBank Accession No. M13994).274M13994: "Human B-cell leukemia/lymphoma 2 (bc102) proto-oncogene mRNA encoding bcl-2 beta protein," GenBank Record dated Oct. 31, 1994 (GenBank [online] Bethesda, MD, USA: United States National Library of Medicine [retrieved on Aug. 9, 2006]. Retrieved from internet using <URL:http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=nucleotide& val=179366>, GenBank Accession No. M13994).275M13994: "Human B-cell leukemia/lymphoma 2 (bc102) proto-oncogene mRNA encoding bcl-2 beta protein," GenBank Record dated Oct. 31, 1994 (GenBank[online] Bethesda, MD, USA: United States National Library of Medicine [retrieved on Aug. 9, 2006]. Retrieved from internet using <URL:http://www.ncbi.nlm.nih.gov/entrez.fcgi?db=nucleotide&val=179366>, GenBank Accession No. M13994).276M13995: "Human B-cell leukemia/lymphoma 2 (bc102) proto-oncogene mRNA encoding bcl-2 beta protein," GenBank Record dated Oct. 31, 1994 (GenBank [online] Bethesda, MD, USA: United States National Library of Medicine [retrieved on Aug. 9, 2006]. Retrieved from internet using <URL:http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=nucleotide&val=179368>, GenBank Accession No. M13995).277Ma et al., "Design and Synthesis of RNA Miniduplexes via a Synthetic Linker Approach" Biochemistry 32:1751-1758 1993.278Madhur Kumar et al. "Antisense RNA: Function and Fate of Duplex RNA in Cells of Higher Eukaryotes" Microbiology and Molecular Biology Reviews, vol. 62, Dec. 1998, pp. 1415-1434.279Maitra et al., "HIV-1 TAR RNA Has an Intrinsic Ability to Activate Interferon-Inducible Enzymes" Virology 204:823-827, 1994.280Majumdar et al., "Targeted gene knockout mediated by triple helix forming oligonucleotides", Nature Genetics, vol. 20, Oct. 1998, pp. 212-214.281Majumdar et al., "Targeted gene knockout mediated by triple helix forming oligonucleotides", Nature Genetics, vol. 20, Oct. 1998, pps. 212-214.282Malone, R.W. et al., "Cationic liposome-mediated RNA transfection," Proc. Natl. Acad. Sci. USA (1989), 86: 6077-6081.283Manche et al., "Interactions Between Double-Stranded RNA Regulators and the Protein Kinase DA1", Molecular and Cellular Biology 1992, vol. 12, pp. 5238-5248.284Manche et al., "Interactions Between Double-Stranded RNA Regulators and the Protein Kinase DAI", Molecular and Cellular Biology 1992, vol. 12, pp. 5238-5248.285Manche, L. et al., (1992), "Interactions between Double-Stranded RNA Regulators and the Protein Kinase DAI", Molecular and Cellular Biology, 12(11):5238-5248.286Manoharan et al., "Chemical Modifications to Improve Uptake and Bioavailability of Antisense Oligonucleotides" Ann. NY Acad. Sci. 660-306-309, 1992.287Manoharan et al., "Cholic Acid-Oligonucleotide Conjugates for Antisense Applications" Bioorg. Med. Chem. Lett. 4(8):1053-1060, 1994.288Manoharan et al., "Introduction of a Lipophilic Thioether Tether in the Minor Groove of Nucleic Acids for Antisense Applications" Bioorg. Med. Chem. Lett. 3(12):2765-2770, 1993.289Manoharan et al., "Lipidic Nucleic Acids" Tetrahedron 36:3651-3654, 1995.290Manoharan et al., "Oligonucleotide Conjugates Alteration of the Pharmacokinetic Properties of Antisense Agents" Nucleosides & Nucleotides 14:969-973, 1995.291Manoharan, M., "RNA interference and chemically modified small interfering RNAs," Current Opinion in Chemical Biology (2004), 8: 570-579.292Manoharan, Oligonucleotide Conjugates as Potential Antisense Drugs with Improved Uptake, Biodistribution, Targeted Delivery and Mechanism of Action: Antisense and Nucleic Acid Drug Development 12:103-128, 2002.293Marques et al., "Activation of the mammalian immune system by siRNAs," Nat. Biotechnol., 23(11):1399-1405(2005).294Marques et al., "A Structural Basis for Discriminating Between Self and Non-Self Double-Stranded RNAs in Mammalian Cells" Nature Biotechnology 24:559-65, 2006.295Marques et al., "Activation of the mammalian immune system by siRNAs," Nat. Biotechnol., 23(11):1399-1405 (2005).296Martinez et al., "Single stranded antisense siRNAs guide target RNA cleavage in RNAi," Cell, 110:563-574 (2002).297Martinez et al., "Single-Stranded Antisense siRNAs Guide Target RNA Cleavage in RNAi," Cell, 110:563-574 (2002).298Maru, "Molecular Biology of Chronic Myeloid Leukemia" Int. J. Hematol. 73:308-322, 2001.299Matrisian, "Cancer biology: Extracellular proteinases in malignancy" Curr. Biol. 9(20)R77-6778, 1999.300Matrisian, "Cancer biology: Extracellular proteinases in malignancy" Curr. Biol. 9(20)R776-778, 1999.301McCaffrey, A.P. et al., (2002), "RNA interference in adult mice", Nature, 418:38-39.302McManus et al., "Gene Silencing in Mammals by Small Interfering RNAs," Nat. Rev. Genet., 3:737-747 (2002).303McManus et al., "Gene Silencing in Mammals by Small Interfering RNAs," Nat. Rev. Genet., 3:737- 747 (2002).304Meister, "RNA Interference in the Nucleus" Science 321:496-497, 2008.305Mendelsohn et al., "The EGF receptor family as target for cancer therapy" Oncogene 19(56):6550-6565, 2000.306Micura et al., "Cyclic oligoribonucleotides (RNA) by soli-phase synthesis" Chem. Eur. J. 5:2077-2082 (1999).307Micura et al., "Cyclic oligoribonucleotides (RNA) by soli-phase synthesis" Chem. Eur. J.5:2077- 2082 (1999).308Mignatti et al., "Biology and Biochemistry of proteinases in Tumor Invasion" Physiol. Rev. 73:161-195,1993.309Milhaud et al., "Free and Liposome-Encapsulated Double-Stranded RNAs as Inducers of Interferon, Interleukin-6, and Cellular Toxicity", Journal of Interferon Research, 11:261-265 (1991).310 *Milligan et al., Synthesis of Small RNAs Using T7 RNA Polymerase, 1989, Methods in Enzymology, vol. 180, pp. 51-62.311Minks et al., Structural Requirements of Double-stranded RNA for the Activation of 2',5'-Oligo(A) Polymerase and Protein Kinase of Interferon-treated HeLa Cells*, Journal of Biological Chemistry 1979, vol. 254, pp. 10180-10183.312Minks et al., Structural Requirements of Double-stranded RNA for the Activation of 2′,5′Oligo(A) Polymerase and Protein Kinase of Interferon-treated HeLa Cells, Journal of Biological Chemistry 1979, vol. 254, pp. 10180-10183.313Minutes of oral proceedings for European Patent EP 1214945, May 19, 2010, 13 pages.314Minutes of oral proceedings regarding opposition against German Patent DE 10066235.8, Feb. 5, 2010, 14 Pages.315Minutes of the Oral Proceedings held on Jan. 14, 2010 in Opposition to German Patent DE 10066235.8, issued by the German Patent and Trademark Office, 55 Pages.316Minutes of the Oral Proceedings in opposition proceedings for European Patent No. 11 44 623 (Jun. 22, 2006).317Mishra et al., "Improved leishmanicidal effect of phosphorotioate antisense oligonucleotides by LDL-mediated delivery" Biochem. Biophys. Acta. 264:229-237, 1995.318Misquitta et al., "Targeted disruption of gene function in Drosophila by RNA interference (RNA-): A role for nautilus in embryonic somatic muscle formation" Proc. Natl. Acad. Sci. 96:1451-1456 (1999).319Misquitta et al., "Targeted disruption of gene function in Drosophila by RNA interference (RNA-): A role for nautilus in embryonic somatic muscle formation" Proc. Nat. Acad. Sci.96:1451-1456 (1999).320Misquitta et al., "Targeted disruption of gene function in Drosophila by RNA interference (RNA-i): A role for nautilus in embryonic somatic muscle formation," PNAS USA, 96:1451-1456 (1999).321Mizuno et al., "Regulation of Gene Expression by a Small RNA Transcript (micRNA) in Escherichia coli K-12)" Proc. Japan Acad. 59:335-338, 1983.322Monia, B.P. et al., "Evaluation of 2'-Modified Oligonucleotides Containing 2'-Deoxy Gaps as Antisense Inhibitors of Gene Expression," The Journal of Biological Chemistry (1993), 268(19): 14514-14522.323Montgomery et al.,"RNA as a target of double-stranded RNA-mediated genetic interference in Caenorhabditis elegan" Proc. Natl. Acad. Sci. 95:15502-15507 (1998).324Montgomery et al.,"RNA as a target of double-stranded RNA-mediated genetic interference in Caenorhabditis elegan " Proc. Natl. Acad. Sci.95:15502-15507 (1998).325Montgomery, et al., Jul. 1998, Double-stranded RNA as a mediator in sequence-specific genetic silencing and co-suppression, TIG, vol. 14, No. pp. 255-258.326Morita et al., "RNAi Provides a New Tool for Functional Analyses of Mammalian Genes", Proteins, Nucleic Acids and Enzymes, vol. 47, No. 14, 2002, pp. 1939-1945, with English Abstract.327Moss et al., "The Cold Shock Domain Protein LIN-28 Controls Developmental Timing in C. elegans and Is Regulated by the lin-4 RNA," Cell, 88:637-646 (1997).328Mullauer et al., "Mutations in apoptosis genes: a pathogenetic factor for human disease" Mutat. Res.488:211-231, 2001.329Muzyczka, "Use of Adeno-Associated Virus as a General Transduction Vector for Mammalian Cells" Curr. Topics Micro. Immunol. 158:97-129, 1992.330Nakamura et al., "How does RNAseH recognize a DNA-RNA Hybrid?" Proc. Natl. Acad. Sci. 88:11535-11539, 1991.331Napoli et al., "Introduction of a chimeric Chalcone Synthase Gene into Petunia Results in Reversible Co-Suppression of Homologous Genes in trans" The Plant Cell 2:279-289, 1990.332Ngo et al., "Double-stranded RNA induces mRNA degradation in Trypanosoma brucei" Proc. Natl. Acad. Sci. 95:14687-14692 (1998).333Ngo et al., "Double-stranded RNA induces mRNA degradation in Trypanosoma brucei" Proc. Natl. Acad. Sci.95:14687-14692 (1998).334Nielsen et al., "A novel class of conformationally restricted oligonucleotide analogues: synthesis of 2',3'-bridged monomers and RNA-selective hybridisation" Chem. Comm.825-826 (1997).335Nielsen et al., "A novel class of conformationally restricted oligonucleotide analogues: synthesis of 2′,3′-bridged monomers and RNA-selective hybridisation" Chem. Comm. 825-826 (1997).336Nikiforov et al., "Oligodeoxynucleotides containing 4-thiothymidine and 6-thiodeoxyguanosine as affinity labels for the Eco RV restriction endonuclease and modification methylase" Nucl. Acid Res. 20(6):1209-1214 (1992).337Nikiforov et al., "Oligodeoxynucleotides containing 4-thiothymidine and 6-thiodeoxyguanosine as affinity labels for the Eco RV restriction endonuclease and modification methylase" Nucl. Acid Res.20(6):1209-1214 (1992).338Nishi, T., et al., "High-Efficiency in Vivo Gene Transfer Using Intraarterial Plasmid DNA Injection following in Vivo Electroporation'," Cancer Research, Mar. 1, 1996, pp. 1050-1055, vol. 56.339Niu, G., et al., "Gene Therapy with Dominant-negative Stat3 Suppresses Growth of the Murine Melanoma B16 Tumor in Vivo1," Cancer Research, Oct. 15, 1999, pp. 5059-5063, vol. 59.340Normanno et al., "The role of EGF-Related Peptides in Tumor Growth" Front. Biosci. 6:D685-707, 2001.341Notice of Acceptance for Australian patent application No. AU 2008202208, Oct. 19, 2009, 3 pages.342Notice of opposition by Abbott Laboratories against European Patent No. 1 214 945 (Mar. 8, 2006).343Notice of Opposition by Alexandra Oppl against DE 100 80 167.6 (Jun. 20, 2008).344Notice of Opposition by AstraZeneca against European Patent No. 11 44 623 (May 28, 2003).345Notice of Opposition by Atugen AG against European Patent No. 11 44 623 (May 28, 2003).346Notice of Opposition by Atugen AG against European Patent No. 11 44 671 (May 28, 2001).347Notice of opposition by Atugen against European Patent No. 1 214 945 (Mar. 8, 2006).348Notice of Opposition by Aventis against European Patent No. 11 44 623 (May 28, 2003).349Notice of Opposition by Dr. Martin Grund against European Patent No. 11 44 623 (May 28, 2003).350Notice of Opposition by Isis Pharmaceuticals against European Patent No. 11 44 623 (May 28, 2003).351Notice of Opposition by Janssen Pharmaceuticals against European Patent No. 11 44 623 (May 28, 2003).352Notice of Opposition by Novartis against European Patent No. 11 44 623 (May 28, 2003).353Notice of Opposition by Pfizer against DE 100 80 167.6 (Jun. 19, 2008).354Notice of opposition by Quark Biotech against European Patent No. 1 214 945 (Mar. 7, 2006).355Notice of Opposition by Sanofi Aventis against DE 100 80 167.6 (Jun. 16, 2008).356Notice of Opposition by Silence Therapeutics against DE 100 80 167.6 (Jun. 20, 2008).357Notice of Opposition by Sirna against DE 100 80 167.6 (Jun. 20, 2008).358Notice of opposition by Sirna Therapeutics against European Patent No. 1 214 945 (Mar. 7, 2006).359Notice of Opposition by Sirna Therapeutics against European Patent No. 11 44 623 (May 19, 2003).360Notice of Opposition to Australian patent application No. AU 2008202208 filed by Sirna Therapeutics, Inc., filed on Jan. 29, 2010, 1 page.361Notice of Opposition to European Patent Application No. EP 05002454.6, filed by SIRNA Therapeutics, filed Sep. 21, 2009, 42 pages.362Notice of Opposition to European Patent EP 1550719 filed by Pfizer Limited, filed Sep. 23, 2009, 21 pages.363Notice of Opposition to European Patent EP 1550719 filed by Sanofi-Aventis Deutschland GmbH, filed Sep. 23, 2009, 46 pages.364Notice of Opposition to European Patent EP 1550719 filed by Sarah Elizabeth Rogues, filed Sep. 23, 2009, 24 pages.365Notice of Opposition to European Patent EP 1550719 filed by Silence Therapeutics AG, filed Sep. 24, 2009, 35 pages.366Notice of Opposition to German Application No. DE 100 66 235, filed by Pfizer Inc. On Jul. 9, 2008.367Notice of Opposition to German Application No. DE 100 66 235, filed by Sanofi Aventis Deutschland GmbH on Jul. 10, 2008.368Notice of Opposition to German Application No. DE 100 66 235, filed by Silence Therapeutics AG on Jul. 10, 2008.369Notice of Opposition to German Application No. DE 10066235, filed by Silence Therapeutics, AG on Jul. 10, 2008, 34 pages.370Notice of Opposition to German Application No. DE 10066235.8 filed by Sanofi Aventis Deutschland GmbH on Jul. 10, 2008, 42 pages.371Notice of Reasons for Rejection for Japan Patent Application No. 2009-002824, Jun. 16, 2009, 15 Pages.372Notice of Reasons for Rejection for Japan Patent Application No. 2009-002826, Jun. 16, 2009, 15 Pages.373Notice of Reasons for Rejection, mailed on Nov. 1, 2011, Japanese Patent Application No. JP 2009-002825, 9 Pages.374Novina et al., "The RNAi revolution" Nature Publishing Group 430:161-164 (2004).375Novina et al., "The RNAi revolution" Nature Publishing Group430:161-164 (2004).376Oates et al., "Too Much Interference: Injection of Double-Stranded RNA Has Non-Specific Effects in the Zebrafish Embryo" Developmental Biology 24:20-28, 2000.377Oberhauser et al., "Effective incorporation of 2′-O-methyl-oligoribonucleotides into liposomes and enhanced cell association through modification with thiocholesterol" Nucl. Acids Res. 20:533-538, 1992.378Oberhauser et al., "Effective incorporation of 2'-O-methyl-oligoribonucleotides into liposomes and enhanced cell association through modification with thiocholesterol" Nucl. Acids Res. 20:533-538, 1992.379Obika et al., "Stability and structural features of the duplexes containing nucleoside analogues with a fixed N-type conformation, 2′-O, 4′-C-mehtyleneribonucleosides" Tetrahedron 39:5401-5404, 1998.380Obika et al., "Stability and structural features of the duplexes containing nucleoside analogues with a fixed N-type conformation, 2'-O, 4'-C-mehtyleneribonucleosides" Tetrahedron 39:5401-5404, 1998.381Office Action Communication by the German Patent and Trademark Office dated Apr. 11, 2011 for German Divisional Patent Application No. 10066344.3-41, 7 pages.382Office Action Communication pursuant to Article 94(3) EPC dated Jul. 8, 2011, for European Patent Application No. EP 06025389.5, 8 pages.383Office Action dated Aug. 26, 2011, for U.S. Appl. No. 10/383,099, 5 pages.384Office Action dated Jun. 17, 2011, for U.S. Appl. No. 10/612,179, 11 pages.385Office Action for U.S. Appl. No. 10/382,395, filed Oct. 5, 2009, 9 Pages.386Office Action for U.S. Appl. No. 10/383,099, filed Dec. 17, 2009, 9 Pages.387Office Action for U.S. Appl. No. 10/383,099, filed Mar. 30, 2011, 10 pages.388Office Action for U.S. Appl. No. 10/383,099, filed Oct. 15, 2010, 19 pages.389Office Action for U.S. Appl. No. 10/612,179, filed Dec. 17, 2009, 9 Pages.390Office Action for U.S. Appl. No. 10/612,179, filed Oct. 20, 2010, 24 pages.391Office Action for U.S. Appl. No. 11/982,305, Feb. 11, 2011, 13 pages.392Office Action for U.S. Appl. No. 11/982,305, filed Sep. 3, 2010, 10 pages.393Office Action for U.S. Appl. No. 11/982,325, filed Mar. 18, 2011, 12 pages.394Office Action for U.S. Appl. No. 11/982,325, filed Oct. 6, 2010, 11 pages.395Office Action for U.S. Appl. No. 11/982,345, filed Mar. 18, 2011, 14 pages.396Office Action for U.S. Appl. No. 11/982,345, filed Oct. 6, 2010, 11 pages.397Office Action for U.S. Appl. No. 11/982,411, filed Oct. 6, 2010, 12 pages.398Office Action for U.S. Appl. No. 11/982,425, Feb. 11, 2011, 13 pages.399Office Action for U.S. Appl. No. 11/982,425, filed Sep. 2, 2010, 10 pages.400Office Action for U.S. Appl. No. 11/982,434, filed Mar. 18, 2011, 12 pages.401Office Action for U.S. Appl. No. 11/982,434, filed Oct. 6, 2010, 11 pages.402Office Action for U.S. Appl. No. 11/982,441, filed Mar. 18, 2011, 12 pages.403Official Inquiry dated May 17, 2011, for Japanese Patent Application No. 2007-186339 (Appeal No. 2009-11870), 11 pages.404Official Inquiry dated May 17, 2011, for Japanese Patent Application No. 2007-186340 (Appeal No. 2009-11715), 11 pages.405Official Inquiry dated May 17, 2011, for Japanese Patent Application No. 2007-186341 (Appeal No. 2009-11871), 6 pages.406Opalinska et al., "Nucleic acid therapeutics: basic principles and recent applications" Nature Review 11:503-514 (2002).407Ouchi et al., "Synthesis and Antitumor Activity of Poly(Ethylene Glycol)s Linked to 5-Flurouracil via Urethane or Urea Bond" Drug Design and Discovery 9:93-105, 1992.408Overview, http://arthritis-research.com/content/figures/ar1168-1.jpg, Jan. 12, 2010.409Oxford Advanced Learner's Dictionary of Current English, p. 253.410Oxford Advanced Learner's Dictionary of Current English, p. 253. (Printed Nov. 24, 2008).411Paddison, P.J. et al., (2002), "Short hairpin RNAs (shRNAs) induce sequence-specific silencing in mammalian cells", Genes & Development, 16:948-958.412Pandolfi, "In vivo analysis of the molecular genetics of acute promyelocytic leukemia"Oncogene 20:5726-5735, 2001.413Paroo et al., "Challenges for RNAi in vivo" Trends in Biotech. 22(8):390-394 (2004) Elsevier.414Paroo et al., "Challenges for RNAi in vivo" Trends in Biotech.22(8):390-394 (2004) Elsevier.415 *Parrish et al., Functional Anatomy of a dsRNA Trigger: Differential Requirement for the Two Trigger Strands in RNA Interference, 2000, Molecular Cell, vol. 6, pp. 1077-1087.416Paul et al., "Effective expression of small interfering RNA in human cells" Nature Biotech. 29:505-508 (2002).417Paul et al., "Effective expression of small interfering RNA in human cells" Nature Biotech.29:505- 508 (2002).418Pegram et al., "Phase II Study of Receptor-Enhanced Chemosensitivity Using Recombinant Humanized Anti-p185HER2/neu Monoclonal Antibody Plus Cisplatin in Patients With HER2/neu-Overexpressing Metastatic Breast Cancer Refractory to Chemotherapy Treatment" J. Clin. Oncol. 16(8):2659-2671 (1998).419Pei et al., "On the Art of Identifying Effective and Specific siRNAs" Nature Methods 3: 670-676, 2006.420Perler, "InBase: the Intein Database," Nucleic Acids Res., 30(1):383-384 (2002).421Petition by Pfizer Inc. in opposition proceedings for German Patent No. 10066235.8 (May 25, 2009), 19 pages.422Petition by Sanofi-Aventis et al. in opposition proceedings for German Patent No. 10066235.8 (May 22, 2009).423Petition by Silence Therapeutics in opposition proceedings for German Patent No. 10066235.8 (May 25, 2009).424Petition regarding German Patent No. DE 10080167 filed by Silence Therapeutics AG, Mar. 17, 2009, 20 pages.425Petition submitted by Alnylam Europe AG against DE 100 80 167.6, including claims as filed and list of documents cited (Dec. 18, 2008).426Phillips et al., "The NZB Mouse as a Model for Chronic Lymphocyte Leukemia" Cancer Res. 52:437-443, 2000.427Phillips, M., "Antisense Inhibition and Adeno-Associated Viral Vector Delivery for Reducing Hypertension," Hypertension, Journal of the American Heart Association, 1997, pp. 177-187, vol. 29.428Pils et al., "Flexible non-nucleotide linkers as loop replacements in short double helical RNAs," Nucleic Acides Research 28:1869-963 (2000).429Pils, W. et al., "Flexible non-nucleotide linkers as loop replacements in short double helical RNAs," Nucleic Acids Research, 28(9): 1869-1963 (2000).430Pollock et al., "Mouse models of acute promyelocytic leukemia" Curr. Opin. Hematol. 8:206-211, 2001.431Polushin et al., "Synthesis of Oligonucleotides Containing 2′-Azido-′and 2′-Amnio-2′-deoxyuridine Using Phosphtriester Chemistry" Tetrahedron 37: 3227-3230, 1996.432Polushin et al., "Synthesis of Oligonucleotides Containing 2'-Azido- and 2'-Amnio-2'deoxyuridine Using Phosphtriester Chemistry" Tetrahedron 37: 3227-3230, 1996.433Prakash et al., "Positional effect of chemical modifications on short interference RNA activity in mammalian cells" J. Med. Chem. 4247-4253 (2005).434Prakash et al., "Positional effect of chemical modifications on short interference RNA activity in mammalian cells" J. Med. Chem.4247-4253 (2005).435Pschyrembel Klinisches Worterbuch, 259, neu bearbeitete Auflage, 2002.436Pschyrembel Klinisches Worterbuch, 259., neu bearbeitete Auflage, Pschyrembel Clinical Dictionary 259th, Revised Edition, 2002, 1 page, with English summary.437Pusch et al., "Nucleotide Sequence Homology Requirements of HIV-1 Specific Short Hairpin RNa" Nucleic Acids Research 31:6444-6449, 2003.438Randall, G. et al., (2003), "Clearance of replicating hepatitis C virus replicon RNAs in cell culture by small interfering RNAs", PNAS, 100(1):235-240.439Ravasio, "Selective Hydrogenations Promoted by Copper Catalysts. 1. Chemoselectivity, Regioselectivity, and Stereoselectivity in the Hydrogenation of 3-Substituted Steroids" J. Org. Chem. 56:4329-4333, 1991.440Record for the Oral proceedings before the Opposition Division from European Patent Office, in opposition of European Patent No. 1214945, Mar. 21, 2009, 92 Pages.441Reed, "Mechanisms of Apoptosis" Am. J. Pathol. 157:1415-1430, 2000.442Regalado, "Turning Off Genes Sheds New Light on How They Work," The Wall Street Journal, 4 pages (Aug. 6, 2002).443Rego et al., "Analysis of the Molecular Genetics of Acute Promyelocytic Leukemia in Mouse Models" Semin. In Hemat. 38:54-70, 2001.444Reply to notice of opposition by Alnylam Europe in the opposition proceedings of European Patent No. 1 214 945 (Dec. 28, 2006).445Reply to notice of opposition by Alnylam Europe in the opposition proceedings of European Patent No. 1214945 (Dec. 28, 2006), 81 Pages.446Reply to Office Action per article 94 (3) EPC of Jul. 8, 2011, filed on Nov. 17, 2011, European Patent Application No. EP 06025389.5, 5 pages.447Request that patent be revoked in its entirety, in Opposition against European Patent 1214945, filed with European Patent Office Opposition Division, filed by Opponent 1, SIRNA Therapeutics on Aug. 16, 2011, 49 Pages.448Response to Notice of Opposition filed against German Patent Number DE 01985833, filed by Max-Plank�Gesellschaft zur Forderung der Wissenschaften e.V., Mar. 26, 2009, 4 pages.449Response to Notice of Opposition to European Patent EP 1550719 filed by Alnylam Europe AG, filed Mar. 15, 2010, 40 pages.450Response to Official Action filed for Australian Application No. 32713/00 (Oct. 19, 2004).451Response to patentee's Grounds of Appeal filed by Quark Biotech, Inc. for European Patent EP 1214945, filed Dec. 28, 2009, 12 pages.452Response to patentee's Grounds of Appeal filed by Sirna Therapeutics AG for European Patent EP 1214945, filed Dec. 23, 2009.453Response to Preliminary Opinion of the Board of Appeal for European Patent EP 1214945, filed by Sirna Therapeutics, Inc., filed on Apr. 16, 2010.454Response to Summons for oral proceedings in Opposition against EP 1214945 filed by Silence Therapeutics AG, filed on Apr. 19, 2010, 5 pages.455Response to Summons to Attend Oral proceedings issued by the German Patent and Trademark office on Dec. 9, 2009 regarding oppositon against German Patent DE 10066235.8, filed by Alnylam Europe AG and Jan. 4, 2010, 36 Pages.456Response to the Submission of Opponent 1, filed by Alnylam Europe AG on Nov. 17, 2011, Opposition against European Patent EP 1550719, 17 Pages.457Response to three Notices of Opposition submitted by Alnylam Europe AG in German Patent No. 100 66 235.8-41 (Feb. 4, 2009), including list of documents cited (translation enclosed).458Reynolds et al., "Rational siRNA design for Rna interference" Nature Biotechnology 22:326-330, 2004.459Robbins et al., "Sensing the danger in RNA," Nat. Med., 11(3):250-251 (2005).460Rosenfeld et al., "Adenovirus-Mediated Transfer of a Recombinant a-Antitrypsin Gene to the Lung Epithelium in Vivo" Science 252:431-434, 1991.461Rosenfeld et al., "In Vivo Transfer to the Human Cystic Fibrosis Transmembrane Conductance Regulator Gene to the Airway Epithelium" Cell 68:143-155, 1992.462Rumney, S., et al., "Structural Optimization of Non-Nucleotide Loop Replacements for Duplex and Triplex DNAs," J. Am. Chem. Soc., 1995, pp. 5635-5646, vol. 117.463Saison-Behmoaras et al., "Short modified antisense oligonucleotdies directed again st Ha-ras point mutation induce selective cleavage of the mRNA and inhibit T24 cells proliferation" EMBO J. 10:111-118, 1991.464Saison-Behmoaras et al., "Short modified antisense oligonucleotdies directed again"st Ha-ras point mutation induce selective cleavage of the mRNA and inhibit T24 cells proliferation Embo J. 10:111-118, 1991.465Scheffer et al., "The drug resistance-related protein LRP is the human major vault protein" Nat. Med. 1:578-582, 1995.466Scherr et al., "Quantitative Determination of Lentiviral Vector Particle Numbers By Real-time PCR" BioTechniques 31: 520-526, 2001.467Schlingensiepen et al., Antisense�From Technology to Therapy. Blackwell Science Ltd., 1997, vol. 6.468Schlingensiepen et al., Antisense�From Technology to Therapy. Blackwell Science Ltd.,1997, vol. 6.469Schwarz et al., "Asymmetry in the assembly of the RNAi complex" Cell 115:199-208, 2003.470Schwarz et al., "Evidence that siRNAs Function as Guides, Not Primers, in the Drosophila and Human RNAi Pathways," Mol. Cell, 10:537-548 (2002).471Secrist et al., Abstract 21, Program & Abstracts, Tenth International Roundtable, Nucleotides, Nucleotides and their Biological Applications, Park City, Utah, Sep. 16-20, 1992.472Sedlik, C. et al., "Recombinant parvovirus-like particles as an antigen carrier: A novel nonreplicative exogenous antigen to elicit protective antiviral cytotoxic T cells," Proc. Natl. Acad. Sci. USA (1997) 94: 7503-7508.473Sen, G., et al., "A Brief History of RNAi: The Silence of the Genes," FASEB J., vol. 20, pp. 1293-1299, 2006.474Seow, Y., et al., "Biological Gene Delivery Vehicles: Beyond Viral Vectors," Molecular Therapy (2009), 17(5): 767-777.475Seydoux et al., "Repression of gene expression in the embryonic germ lineage of C. elegans" Nature 382:713-716 (1996).476Shannon et al., "Modelling myeloid leukemia tumors suppressor gene inactivation in the mouse" Semin. Cancer Biol. 1:191-199, 2001.477Sharp, "RNAi and double-stranded RNA" Gene and Development 13:139-141 (1999).478Sharp, P.A., (2001), "RNA interference-2001", Genes & Development, 15:485-490.479Sharp, P.A., (2001), "RNA interference�2001", Genes & Development, 15:485-490.480Shea et al., "Synthesis, hybridization properties and antiviral activity of lipid-oligodeoxynucleotide conjugates" Nucl. Acids Res. 18:3777-3783, 1990.481Shi et al., "A CBP/p300 homolog specifics multiple differentiation pathways in Caenorhabditis elegans" Genes & Development 12(7):943-955 (1998).482Shi et al., "A CBP/p300 homolog specifies multiple differentiation pathways in Caenorhabditis elegans," Genes Dev., 12:943-955 (1998).483Shi et al., "A CBP/p300 homolog specifies multiple differentiation pathways in Caenorhabditis elegans" Genes and Development 12(7):943-955 (1998).484Shiota et al., "I want to Know the RNAi Protocol of that Animal!�Effective RNAi in Mammal Cells", Cell Engineering, vol. 22, No. 3, 2003, pp. 310-315, with English summary.485Sijen, T. et al., (2001), "On the Role of RNA Amplification in dsRNA-Triggered Gene Silencing", Cell, 107:465-476.486Simons et al., "Translational Control of IS10 Transposition" Cell 34:683-691, 1983.487Simons et al., "Translational Control of ISI0 Transposition" Cell 34:683-691, 1983.488Sinha, "Large-scale Synthesis. Approaches to Large-scale Synthesis of Oligodeoxynucleotides and their Analogs," Antisense-From Technology to Therapy, vol. 6, Edited by Reimar Schlingensiepen et al., pp. 29-58 (1997).489Sinha, "Large-scale Synthesis. Approaches to Large-scale Synthesis of Oligodeoxynucleotides and their Analogs," Antisense - From Technology to Therapy, vol. 6, Edited by Reimar Schlingensiepen et al., pp. 29-58 (1997).490Sinha, "Large-scale Synthesis. Approaches to Large-scale Synthesis of Oligodeoxynucleotides and their Analogs," Antisense�From Technology to Therapy, vol. 6, Edited by Reimar Schlingensiepen et al., pp. 29-58 (1997).491Skorski et al., "Suppression of Philadelphia Leukemia cell growth in mice by BCR-ABL antisense oligodeoxynucleotide" Proc. Natl. Acad. Sci. USA 91:4504-4508, 1994.492Skripkin et al., "Psoralen crosslinking between human immunodeficiency virus type 1 RNA and primer tRNA3Lys," Nucleic Acids Res., 24(3):509-514 (1996).493Sledz et al., "Activation of the interferon system by short-interfering RNAs," Nat. Cell Biol., 5(9):834-839 (2003).494Sledz et al., "RNA Interference and Double-Stranded RNA Activated Pathways" Biochemical Society Transactions 32:956-956, 2004.495Soeda, E., et al., "Enhancement by polylysine of transient, but not stable, expression of genes carried into cells by polyoma VP1 pseudocapsids," Gene Therapy (1998), 5: 1410-1419.496Soutschek et al., "Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs," Nature, 432:173-178 (2004).497Sporlein, B., et al., "Lipofectin: direct gene transfer to higher plants using cationic liposomes," Theoretical and Applied Genetics (1991), 83: 1-5.498Sproat, B., "Chapter 18: 2-O-Alkyloligoribonucleotides," Antisense Research and Applications, CRC Press, 351-362, 1993.499Sproat, B., "Chapter 6: Synthesis of 2′-O-Alkyloligoribonucleotides," Methods in Molecular Biology 20, Humana Press, NJ: 115-142, 1993.500Statement of Grounds & Particulars of Opposition filed by Sirna Therapeutics, Inc., on Aug. 23, 2011, for Australian Patent Application No. AU 778474, 9 pages.501Statement of Grounds & Particulars of Opposition to Australian patent application No. AU 2008202208 filed by Sirna Therapeutics, Inc., filed on Apr. 29, 2010, 28 pages.502Statement of Grounds and Particulars filed in opposition for AU 2005201044 (Dec. 1, 2008).503Statement of Grounds and Particulars of Opposition to Australian Patent No. 778474, filed by SIENA Therapeutics, Inc. (Jun. 9, 2005).504Statement of Grounds and Particulars of Opposition to Australian Patent No. 778474, filed by SIRNA Therapeutics, Inc. (Jun. 9, 2005).505Statement of Grounds and Particulars of Opposition to Australian Patent No. 778474, filed by SIRNA Therapeutics, Inc. on Aug. 29, 2008.506Statutory Declaration by David Keith Myers dated Aug. 2, 2010, filed by Sirna Therapeutics, Inc., in opposition to Australia Patent No. AU 778474, 3 pages.507Statutory Declaration by David Keith Myers dated Nov. 7, 2008, filed by Sirna Therapeutics, Inc., in opposition to Australia Patent No. AU 778474, 16 pages, list of journals published before the end of 1999 which cite a journal article authored by Andrew Fire and co-workers, and published in the journal Nature on Feb. 19, 1998.508Statutory Declaration by David Keith Myers dated Nov. 7, 2008, filed by Sirna Therapeutics, Inc., in opposition to Australia Patent No. AU 778474, 3 pages, list of patent publications having an earliest claimed priority date of Nov. 24, 1999 or earlier, which cite Fire, A., et al., (1998), Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans, Nature 391: 806-811.509Statutory Declaration by Martin Edward O'Brien of Spruson and Ferguson in the matter of Opposition to Australian Patent No. 778474, filed by SIRNA Therapeutics, Inc. on Aug. 29, 2008.510Statutory Declaration by Martin Edward O'Brien of Spruson and Ferguson in the matter of Opposition to Australian Patent No. 778474, filed by SIRNA Therapeutics, Inc. on Sep. 9, 2005, 3 pages.511Statutory Declaration dated Aug. 17 , 2010 by David M. Stalker with Exhibits DMS-A to DMS-C and Exhibits DMS-41 to DMS-74 thereto in respect of opposition to accepted Australian Patent Application No. 2005201044, 30 pages.512Stetler-Stevenson et al., "Tumor Cell Interactions with the Extracellular Matrix During Invasion and Metastasis" Annu. Rev. Cell Biol. 9:541-573, 1993.513Strasser et al., "Apoptosis Signaling" Annu. Rev. Biochem. 69:217-245, 2000.514Strauss, "Candidate �Gene Silencers� Found" Science 286:886 (1999).515Stryer, L., Biochemistry, Part 1 Molecular Design of Life, Chapter 4 DNA and RNA: Molecules of Heredity, 1988, pp. 80-82.516Submission by Abbott Laboratories in the opposition proceedings of European Patent No. 1 214 945 (Nov. 20, 2008).517Submission by Abbott Laboratories in the opposition proceedings of European Patent No. 1 214 945 (Oct. 30, 2007).518Submission by Alexandra Oppl against DE 100 80 167.6 on Mar. 4, 2009.519Submission by Alexandra Oppl in opposition to DE 100 80 167.6 (Jun. 20, 2008).520Submission by Alnylam Europe AG in opposition to DE 100 80 167.6 on Mar. 4, 2009.521Submission by Alnylam Europe in opposition proceedings for European Patent No. 11 44 623 (Apr. 21, 2006).522Submission by Alnylam Europe in opposition proceedings for European Patent No. 11 44 623 (Dec. 7, 2004).523Submission by Alnylam Europe in opposition proceedings for European Patent No. 11 44 623 (Jun. 25, 2007).524Submission by Alnylam Europe in opposition proceedings for European Patent No. 11 44 623 (Jun. 7, 2006).525Submission by Alnylam Europe in opposition proceedings for European Patent No. 1144623 (Apr. 21, 2006), 63 pages.526Submission by Alnylam Europe in opposition proceedings for European Patent No. 1144623 (Dec. 7, 2004), 140 pages.527Submission by Alnylam Pharmaceuticals in the opposition proceedings of European Patent No. 1 144 623 (Nov. 7, 2008). (translation attached).528Submission by Alnylam Pharmaceuticals in the opposition proceedings of European Patent No. 1 214 945 (Nov. 20, 2008).529Submission by Atugen AG in opposition to European Patent No. 1 144 623 (Nov. 7, 2008).530Submission by Atugen in opposition proceedings for European Patent No. 11 44 623 (Apr. 21, 2006).531Submission by Pfizer against DE 100 80 167.6 on Feb. 27, 2009.532Submission by Silence Therapeutics against DE 100 80 167.6 on Feb. 20, 2009.533Submission by Silence Therapeutics in the opposition proceedings of European Patent No. 1 214 945 (Nov. 20, 2008).534Submission by SIRNA Therapeutics against DE 100 80 167.6 on Mar. 4, 2009.535Submission by Sirna Therapeutics in opposition proceedings for European Patent No. 11 44 623 (Apr. 20, 2006�Isenbruck, Bosl, Horshchler, Wichmann, Huhn).536Submission by Sirna Therapeutics in opposition proceedings for European Patent No. 11 44 623 (Apr. 20, 2006�Uexkull & Stolberg).537Submission by SIRNA Therapeutics in opposition to DE 100 80 167.6 (Jun. 20, 2008).538Submission by Sirna Therapeutics in opposition to European Patent No. 1 144 623 (Jun. 12, 2008).539Submission by Sirna Therapeutics in opposition to European Patent No. 1 144 623 (Nov. 6, 2008).540Submission by Sirna Therapeutics in the opposition proceedings of European Patent No. 1 214 945 (Jan. 4, 2008).541Submission by Sirna Therapeutics in the opposition proceedings of European Patent No. 1 214 945 (Nov. 20, 2008).542Sui, G., et al., "A DNA vector-based RNAI technology to suppress gene expression in mammalian cells," Proc. Natl. Acad. Sci. USA, Apr. 16, 2002, pp. 5515-5520, vol. 99, No. 8.543Summons to Attend Oral Hearing regarding opposition against European Patent EP 1214945, Feb. 26, 2010, 15 pages.544Summons to attend oral proceedings in the opposition proceedings of European Patent No. 1 214 945 (May 6, 2008).545Summons to attend oral proceedings pursuant to Rule 115(1) EPC issued by the European Patent Office on Nov. 25, 2011, for Opposition against European Patent No. EP 1550719, 50 Pages.546Suntharalingam, G., et al., "Cytokine Storm in a Phase 1 Trial of the Anti-CD28 Monoclonal Antibody TGN1412," New England Journal of Medicine (2006), 355(10): 1018-1028.547Svinarchuk et al., "Inhibition of HIV proliferation in MT-4 cells by antisense oligonucleotie conjugated to lipophilic groups" Biochimie 75:49-54, 1993.548Takayama et al., "Antisense RNA" Critical Reviews in Biochemistry and Molecular Biology 25:155-184, 1991.549Thompson, "Shortcuts from gene sequence to function" Nature Biotechnology 17:1158-1159 (1999).550Thomson et al., "activity of hammerhead ribozymes containing non-nucleotide linkers" Nucl. Acids Res. 21:5600-5603 (1993) Oxford Uni. Press.551Thomson et al., "activity of hammerhead ribozymes containing non-nucleotide linkers" Nucl. Acids Res.21:5600-5603 (1993) Oxford Uni. Press.552Thomson et al., "Synthesis and Properties of Diuridine Phosphate Analogues Containing Thio and Amino Modifications" J. Org.Chem. 61:6273-6281, 1996.553Tijsterman, M. et al., (2002), "The Genetics of RNA Silencing", Annu. Rev. Genet., 36:489-519.554Timmons et al., "Specific Interference by Ingested dsRNA" Nature 395:6705-6854 (1998).555Tolun et al., "Direct Repeats of the F Plasmid incC Region Express F Incompatibility" Cell 24: 687-694 (1981).556Touze, A., et al., "In vitro gene transfer using human papillomavirus-like particles," Nucleic Acids Res. (1998) 26(5): 1317-1323.557Tsutsui et al., "Role of Nine Repeating Sequences of the Mini-F Genome for Expression of F-Specific Incompatibility Phenotype and Copy Number Control" Journal of Bacteriology 155:337-344, 1983.558Tuschl et al. (Dec. 1999) Genes and Dev. 13:3191-7.559Tuschl et al., "Targeted mRNA degradation by double-stranded RNA in vitro" Genes & Development 13:3191-3197 (1999).560U.S. Appl. No. 60/117,635, Li et al. (filed Jan. 28, 1999).561U.S. Appl. No. 60/130,377, Pachuk et al. (filed Apr. 21, 1999).562U.S. Appl. No. 60/175,440, filed Jan. 11, 2000.563U.S. Provisional Application 60/175440, filed Jan. 11, 2000.564U.S. Provisional Patent Application No. 60/117,635, Li et al. (filed Jan. 28, 1999).565U.S. Provisional Patent Application No. 60/130,377, Pachuk et al. (filed Apr. 21, 1999).566U55763: "Cloning vector pEGFP-CA, complete sequence, enhanced green fluorescent protein (egfp) and neomycin phosphotransferase genes," GenBank Record dated Jun. 15, 1996 (GenBank [online] Bethesda, MD, USA: United States National Library of Medicine [retrieved on Aug. 9, 2006]. Retrieved from internet using , GenBank Accession No. U55763).567U55763: "Cloning vector pEGFP-CA, complete sequence, enhanced green fluorescent protein (egfp) and neomycin phosphotransferase genes," GenBank Record dated Jun. 15, 1996 (GenBank [online] Bethesda, MD, USA: United States National Library of Medicine [retrieved on Aug. 9, 2006]. Retrieved from interne using <URL:http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=nucleotide&val=1377914>, GenBank Accession No. U55763).568U55763: "Cloning vector pEGFP-CA, complete sequence, enhanced green fluorescent protein (egfp) and neomycin phosphotransferase genes," GenBank Record dated Jun. 15, 1996 (GenBank [online] Bethesda, MD, USA: United States National Library of Medicine [retrieved on Aug. 9, 2006]. Retrieved from internet using <URL:http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=nucleotide&val=1377914>, GenBank Accession No. U55763).569Uhlenbeck, "A Small Catalytic Oligoribonucleotide" Nature 325:596-600, 1987.570Uhlmann, E. et al. "Antisense Nucleotides: A New Therapeutic Principal" Chemical Reviews, American Chemical Society, Easton, US vol. 90, No. 4, Jun. 1, 1990, pp. 543-584, ISSN:0009-2665.571Van Beusechem et al., "Long-term expression of human adenosine deaminase in rhesus monkeys transplanted with retrovirus-infected bone-marrow cells" Proc. Natl. Acad. Sci. USA 89:7640-7644, 1992.572Van Etten, "Pathogenesis and treatment of Ph leukemia: recent insights from mouse models" Curr. Opin. Hematol. 8:224-230, 2001.573Various, "Nature Insight: RNA Interference" Nature, 431:337-378, 2004 (Table of Contents).574Verma et al., "Human gene therapy" Nature 389:239-242 (1997).575Vickers et al., "Efficient Reduction of Target RNAs by Small Interfering RNA and RNase H-dependent Antisense Agents. A Compartive Analysis" J. Biol. Chem. 278:7108-7118, 2003.576Voinnet et al., "Systemic signalling in gene silencing" Nature 389:553 (1997).577Wacheck et al., "Small Interfering RNA Targeting Bcl-2 Sensitizers Malignant Melanoma" Oligonucleotides, vol. 13 (5):393-400, 2003.578Wacheck et al., "Small Interfering RNA Targeting Bcl-2 Sensitizers Malignant Melanoma" Oligonucleotides, vol. 13 (5):393-400,2003.579Wagner et al., "Double-stranded RNA poses puzzle" Nature 391:744-745 (1998).580Wagner, "The state of the art in antisense research" Nat. Med. 1:1116-1118, 1995.581Wang et al., "Circular RNA oligonucleotides. Synthesis, nucleic acid binding properties, and a comparison with circular DNAs" Nucl. Acids Res. 22:2326-2333 (1994).582Wang et al., "RNA conformation in the Tat-TAR complex determined by site-specific photo-cross-linking" Biochem 35:6491-6499 (1996).583Wang et al., "Circular RNA oligonucleotides. Synthesis, nucleic acid binding properties, and a comparison with circular DNAs"Nucl. Acids Res.22:2326-2333 (1994).584Wang et al., "RNA conformation in the Tat-TAR complex determined by site-specific photo-cross-linking," Biochem 35:6491:6499 (1996).585Wang et al., "RNA conformation in the Tat-TAR complex determined by site-specific photo-crosslinking" Biochem 35:6491-6499 (1996).586Wang, S., et al., "Delivery of antisense oligodeoxyribonucleotides against the human epidermal growth factor receptor into cultured KB cells with liposomes conjugated to folate via polyethylene glycol," Proc. Nat. Acad. Sci., Biochemistry, Apr. 1995, pp. 3318-3322.587Wargelius et al., "Double-stranded RNA induces specific developmental defects in zebrafsh embryos" Biochem. Biophys. Res. Corn. 263:156-161 (1999).588Wargelius et al., "Double-stranded RNA induces specific developmental defects in zebrafsh embryos" Biochem. Biophys. Res. Corn.263:156-161 (1999).589Waterhouse et al., "Virus resistance and gene silencing in plants can be induced by simultaneous expression of sense and antisense RNA" PNAS 95:13959-13964 (1998).590Watkins et al., "In vivo UV cross-linking of U snRNAs that participate in trypanosome trans-splicing" Genes & Development 5:1859-1869 (1991).591Wengel, "Synthesis of 3'-C- and 4'-C-branched oligodeoxynucleotides and the development of locked nucleic acid (LNA)" Acc. Chem. Res. 32:301-310 (1999).592Wengel, "Synthesis of 3′-C- and 4′-C-branched oligodeoxynucleotides and the development of locked nucleic acid (LNA)" Acc. Chem. Res. 32:301-310 (1999).593Wengel, "Synthesis of 3'-C- and 4'-C-branched oligodeoxynucleotides and the development of locked nucleic acid (LNA)" Acc. Chem. Res.32:301-310 (1999).594Wess et al., "Early days for RNAi," BioCentury, 11(12):A1-A8 (2003).595Wess et al., "Early days for RNAi," BioCentury, 11(12):Al-A8 (2003).596Wianny, et al. (2000) Nature Cell Biology 2:70-75.597Wild, K. et al., (1999), "The 2 � structure of helix 6 of the human signal recognition particle RNA", Structure, 7(11):1345-1352.598Wild, K. et al., (1999), "The 2 Å structure of helix 6 of the human signal recognition particle RNA", Structure, 7(11):1345-1352.599Williams et al., "Thermodynamic Comparison of the Salt Dependence of Natural RNA Hairpins and RNA Hairpins with Non-Nucleotide Spacers" Biochemistry 35:14665-14670, 1996.600Wilson et al., "Retrovirus-mediated transduction of adult hepatocytes" Proc. Natl. Acad. Sci. USA 85:3014-3018, 1998.601Wink, M., "Gene Therapy: Strategies and Vectors" Molekulare Biotechnologie, 2004, pp. 557-577, Wiley-VCH, with English summary.602Wink, Molekulare Biotechnologie, Wiley-VCH, 2004, 557-577.603Wong et al., "Modeling Philadelphia chromosome positive leukemias" Oncogene 20:5644-5659, 2001.604Written Reply filed on Oct. 17, 2011, Japanese Patent Application No. JP 2007-186339, 77 pages.605Written Reply filed on Oct. 17, 2011, Japanese Patent Application No. JP 2007-186340, 76 pages.606Written Reply filed on Oct. 17, 2011, Japanese Patent Application No. Jp 2007-186341, 70 pages.607Xie, Y., et al., "Efficacy of Adenovirus-mediated CD/5-FC and HSV-I Thymidine Kinase/Ganciclovir Suicide Gene Therapies Concomitant with p53 Gene Therapy1," Clinical Cancer Research, Dec. 1999, pp. 4224-4232, vol. 5.608Yang, D. et al., (2000), "Evidence that processed small dsRNAs may mediate sequence-specific mRNA degradation during RNAi in Drosophila embryos", Current Biology, 10:1191-1200.609Yokota, "Tumor progression and metastasis" Carcinogenesis 21:497-503, 2000.610 *Yu et al., RNA interference by expression of short-interfering RNAs and hairpin RNAs in mammalian cells, 2002, PNAS, vol. 99, No. 9, pp. 6047-6052.611Yu, J. et al., (2002), "RNA interference by expression of short-interfering RNAs and hairpin RNAs in mammalian cells", PNAS, 99(9):6047-6052.612Zamecnik, P.C., et al., "Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide," Proc. Natl. Acad. Sci. USA (1978), 75(1): 280-284.613Zamore et al., "Evidence that siRNAs function as guides not primers in the drosophila and human RNAi pathways," Mol. Cell, 10:537-48 (2002).614Zamore, et al. (2000) Cell 101:25-33.615Zelphati, O., et al., "Antisense oligonucleotides in solution of encapsulated in immunoliposomes inhibit replication of HIV-1 by several different mechanisms," Nucleic Acids Research, 1994, pp. 4307-4314, vol. 22, No. 20.616Zeng et al., "RNA interference in human cells is restricted to the cytoplasm," RNA, 8:855-860 (2002).617Zeng et al., "RNA Interference in human cells is restricted to the cytoplasm", RNA (2002), 8:855-860.618Zeng et al., "The Fetal Origin of B-Precursor Leukemia in the Eu-ret Mouse" Blood 92:3529-3536, 1998.619Zhang et al., "Targeted Gene Silencing by Small Interfering RNA-based Knock-Down Technology" Current Pharma. Biotech. 5:1-7 (2004).620Zhang et al., "Single processing center models for human dicer and bacterial RNase III" Cell 118:57-68 (2004).621Zhang et al., Current Pharma. Biotech. 5:1-7 (2004).622Zhang et al., Current Pharma. Biotech.5:1-7 (2004).623Zhao et al., "Double-Stranded RNA Injection Produces Nonspecific Defects in Zebrafish," Dev. Biol., 229:215-223 (2001).624Zheng et al., "Activation of the protein kinase PKR by short double-stranded RNAs with single-stranded tails," RNA, 10:1934-1945 (2004).625Zheng, L., et al., "An approach to genomewide screens of expressed small interfering RNAs in mammalian cells," Proc. Natl. Acad. Sci. USA, Jan. 6, 2004, pp. 135-140, vol. 101, No. 1.626Zwieb et al., "Evidence for RNA-RNA cross-link formation in Escherichia coli ribosomes" Nucl. Acids Res. 5:2705-2720 (1978).627Zwieb et al., "Evidence for RNA-RNA cross-link formation in Escherichia coli ribosomes" Nucl. Acids Res.5:2705-2720 (1978).* Cited by examinerReferenced byCiting PatentFiling datePublication dateApplicantTitleUS8729037Oct 31, 2007May 20, 2014Alnylam Pharmaceuticals, Inc.Method and medicament for inhibiting the expression of a given geneClassifications U.S. Classification536/25.3, 536/24.5International ClassificationC12N15/09, A61K47/48, A61K48/00, C07H21/00, C12N15/11, A61K35/76, A61K9/127, C07H21/04, A61P31/12, A61K31/713, A61P25/28, A61K38/00, A61P35/00, A61K31/70Cooperative ClassificationC12N15/113, C12N2310/14, C12N2310/53, A61K31/713, C12N2310/111, C12N2330/30, C12N15/111, A61K38/00European ClassificationC12N15/11M, A61K31/713Legal EventsDateCodeEventDescriptionAug 7, 2009ASAssignmentOwner name: ALNYLAM PHARMACEUTICALS, INC., MASSACHUSETTSFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:ALNYLAM EUROPE AG;REEL/FRAME:023070/0300Effective date: 20090805Owner name: ALNYLAM PHARMACEUTICALS, INC.,MASSACHUSETTSFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:ALNYLAM EUROPE AG;REEL/FRAME:23070/300Dec 4, 2003ASAssignmentOwner name: RIBOPHARMA AG, GERMANYFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:KREUTZER, ROLAND;LIMMER, STEFAN;REEL/FRAME:014753/0318Effective date: 20031006RotateOriginal ImageGoogle Home - Sitemap - USPTO Bulk Downloads - Privacy Policy - Terms of Service - About Google Patents - Send FeedbackData provided by IFI CLAIMS Patent Services©2012 Google