Details for Patent: 9,585,906
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Title: | Nucleoside phosphoramidate prodrugs |
Abstract: | Disclosed herein are phosphoramidate prodrugs of nucleoside derivatives for the treatment of viral infections in mammals, which is a compound, its stereoisomer, salt (acid or basic addition salt), hydrate, solvate, or crystalline form thereof, represented by the following structure: ##STR00001## Also disclosed are methods of treatment, uses, and processes for preparing each of which utilize the compound represented by formula I. |
Inventor(s): | Du; Jinfa (Redwood City, CA), Nagarathnam; Dhanapalan (Bethany, CT), Sofia; Michael J. (Doylestown, PA), Wang; Peiyuan (San Mateo, CA) |
Assignee: | Gilead Pharmasset LLC (Foster City, CA) |
Filing Date: | Mar 12, 2015 |
Application Number: | 14/656,546 |
Claims: | 1. cited by applicant . Hrebabecky, et al. , 1-(3,5-0-alkyliDE-ne-2-DE-oxy-4-C-hydroxymethyl-alpha-L-threo-pentofurano- syl) Uracils, Collect. Czhech. Chem. Commun., vol. 62, pp. 957-970, (1997). cited by applicant . Hrebabecky, et al., "Synthesis of 1-(3-azido-2,3-diDE-oxy-4-C-hydroxymethyl-alpha-L-threo-pentofuranosyl)th- ymine, 1-(2, 3-d id eoxy-4-C-hyd roxy-methyl-alpha-L-glycero-pentofuranosyl)thymine and 1-(2,3-diDE-oxy-4-C-hydroxymethyl-alpha-L-glycero-pent-2-enofuranosyl)thy- mine," Collect Czech. Chem. Commun., vol. 58, pp. 409-420, (1992). cited by applicant . Hrebabecky, et al., "Synthesis of 1-(3-azido-2,3-diDE-oxy-.beta.-D-allofuranosyl)thymine, 1-(2,3-diDE-oxy-.beta.-D-allofuranosyl)thymine, and 1-(2,3-diDE-oxy-.about.-D-erythro-hex-2-enofuranosyl)thymine," Carbohydrate Research, vol. 216, pp. 179-186, (1991). cited by applicant . Hrebabecky, et al., "Synthesis of 1-(3-azido-2,3-diDE-oxy-.beta.-d-ribo-hexofuranosyl)-, 1-(2,3-did eoxy-.beta.-d-erythro-hexofu ranosyl )- and 1-(2,3-d iDE-oxy-.beta.-d-erythro-hex-2-enofuranosyl)pyrimidine nucleosiDE-s," Collect. Czhech. Chem. Commun., vol. 59, pp. 412-420, (1993). cited by applicant . Written Opinion of PCT/US2010/035641 mailed Sep. 28, 2010. cited by applicant . Written Opinion of PCT/EP2006/069060 mailed Jan. 30, 2007. cited by applicant . Written Opinion of PCT/US2005/025916 mailed Jun. 15, 2006. cited by applicant . Written Opinion of PCT/US2005/032406 mailed May 8, 2008. cited by applicant . International Search Report issued in International PCT application No. PCT/US2008/058183 mailed Mar. 31, 2010 (7 pages). cited by applicant . Lin, et al., "A stereospecific synthesis of 2',3'-diDE-oxy-.beta.-L-cytidine (.beta.-L-ddC), a potent inhibitor against human hepatitis B virus (HBV) and human immunoDE-ficiency virus (HIV)," Tetrahedron Letters, vol. 35, No. 21, pp. 3477-3480, (1994). cited by applicant . McGuigan et al., "Synthesis, anti-human immunoDE-ficiency virus activity and esterase lability of some novel carboxylic ester-modified phosphoramidate DE-rivatives of stavudine (d4T)," Antiviral Chemistry & Chemotherapy, vol. 9, pp. 473-479 (1998). cited by applicant . Mourier, et al., "Enantioselective synthesis and biological evaluation of 5-o-carboranyl-pyrimidine-nucleosides," Bioorganic & Medicinal Chemistry, vol. 7, pp. 2759-2766, (1999). cited by applicant . Response filed Oct. 25, 2010 at the EPO for European patent application No. EP08732818.3. cited by applicant . Response to non-final Office Action dated Oct. 1, 2009 for U.S. Appl. No. 12/142,554. cited by applicant . Robins, et al., "Nucleic acid related compounds. 91. Biomimetic reactions are in harmony with loss of 2'-substituents as free radicals (not anions) during mechanism-based inactivation of ribonucleotiDE-reductases. differential interactions of aziDE-, halogen, and alkylthio groups with tributylstannane and triphenylsilane," Journal of the American Chemical Society, vol. 118, No. 46, pp. 11341-11348, (1996). cited by applicant . Saneyoshi, "Facile synthesis of 2'-0-cyanoethyluridine by ring-opening reaction of 2,2'-anhydrouridine with cyanoethyl trimethylsilyl ether in the presence of BF3 Et2O," Tetrahedron Letters, vol. 48, pp. 8554-8557, (2007). cited by applicant . Selected Prosecution documents from U.S. Appl. No. 10/828,753 (1) Feb. 26, 2007 Amendment; (2) Mar. 30, 2007 Office Action; (3) Jun. 9, 2007 Interview Summary; (4) Sep. 12, 2007 Amendment; (5) Sep. 12, 2007 Declaration; (6) Sep. 24, 2007 Declaration; (7) Nov. 28, 2007 Amendment; (8) Feb. 26, 2008 Office Action; (9) Mar. 11, 2008 Amendment; and (10) May 29, 2008 Notice of Allowance). cited by applicant . Selected Proscution Documents from U.S. Appl. No. 11/854,218: (1) Sep. 12, 2007 Amendment; (2) Oct. 1, 2008 Office Action; (3) Mar. 31, 2010 Response; (4) Mar. 31, 2011 Declaration; (5) Jul. 22, 2010 Office Action; (6) Oct. 11, 2010 Amendment; (7) Oct. 11, 2010 Declaration; (8) Dec. 23, 2010 Office Action; (9) Jun. 28, 2011 Amendment. cited by applicant . U.S. Appl. No. 12/142,554, Pending claims filed on Dec. 17, 2009. cited by applicant . U.S. Appl. No. 13/956,195, filed Jul. 31, 2013. cited by applicant . Van Rompaey, et al., "Mycobacteriumtuberculosis thymidine monophosphate kinase inhibitors; biological evaluation and conformational analysis of 2'-and 3'-modified thymidine analogues," Eur. J. Org. Chem., pp. 2911-2918, (2003). cited by applicant . Vanheusde-N, et al., "Discovery of bicyclic thymidine analogues as selective and high-affinity inhibitors of mycobacterium tuberculosis thymidine monophosphate kinase," J. Med. Chem., vol. 47, pp. 6187-6194, (2004). cited by applicant . Vanheusde-N, et al., "Synthesis and evaluation of thymidine-5'-O-monophosphate analogues as inhibitors of mycobacterium tuberculosis thymidylate kinase," Bioorganic & Medicinal Chemistry Letters, vol. 12, pp. 2695-2698, (2002). cited by applicant . Wu et al., "Targeting NS5B RNA-DE-penDE-nt RNA Polymerase for Anti-HCV Chemotherapy," Current Drug Targets--Infectious DisorDE-rs, vol. 3, No. 3, pp. 207-219 {2003). cited by applicant . U.S. Appl. No. 11/225,724 pending claims filed Oct. 2, 2009. cited by applicant . Selected Prosecution documents from U.S. Appl. No. 12/053,015: (1) Jun. 15, 2010 Resitriction Requirements; (2) Oct. 28, 2010 Amendment ; (3) Jan. 5, 2011 Notice of Alloance; and (4) Apr. 1, 2011 Amendment. cited by applicant . U.S. Appl. No. 12/783,680, filed May 20, 210--Originally filed claims. cited by applicant . U.S. Appl. No. 13/076,552, filed Mar. 31, 2011--Originally filed claims. cited by applicant . U.S. Appl. No. 12/645,710, filed Dec. 23, 2009--Originally filed claims. cited by applicant . U.S. Appl. No. 12/878,262--Pending Claims as of Sep. 1, 2011. cited by applicant . Selected Proscution Documents for U.S. Appl. No. 12/878,262: (1) Sep. 9, 2010 Amendment; (2) Jun. 8, 2011 Office Action; and (3) Sep. 1, 2011 Amendment. cited by applicant . Office Action dated Apr. 8, 2014 for Australian Application No. 2012241173. cited by applicant . Office Action dated Jun. 25, 2014 for Colombian Application No. 09-120.744A. cited by applicant . Extended Search Report dated Sep. 18, 2014 for European Application No. 14151876.1. cited by applicant . Communication pursuant to Rules 70(2) and 70a(2) EPC and reference to Rule 39(1) EPC for European Application No. 14179593.0 dated Jan. 19, 2015. cited by applicant . English Translation of Office Action for Korean Application No. 10-2009-7022652 dated Dec. 19, 2013. cited by applicant . Office Action dated Oct. 29, 2014 for Korean Application No. 10-2012-7004146. cited by applicant . Office Action dated Jan. 4, 2015 for Israeli Application No. 222810. cited by applicant . Office Action dated Jan. 22, 2015 for Mexican Application No. MX/A/2012/000289. cited by applicant . Office Action dated Oct. 30, 201 for Mexican Application No. MX/A/2012/000289. cited by applicant . Office Action dated Oct. 31, 2014 for Chinese Application No. 200880018024.2. cited by applicant . Office Action dated Jan. 13, 2015 for Japanese Application No. 2014-093905. cited by applicant . Subsequent Substantive Examination Report for Phillipines Application No. 1/2009/501847 dated Nov. 10, 2014. cited by applicant . Opposition by the Initiative for Medicines, Access & Knowledge (I-Mak) to Indian Application No. 3658/KOLNP/2009 N. cited by applicant . Opposition by NATCO Pharma Limited to Indian Application No. 3658/KOLNP/2009 dated Mar. 3, 2014. cited by applicant . Opposition by SANKLAP Rehabilitation Trust to Indian Application No. 3658/KOLNP/2009 dated Sep. 10, 2014. cited by applicant . Opposition by Indian Pharmaceutical Alliance to Indian Application No. 3658/KOLNP/2009 dated Feb. 17, 2015. cited by applicant . Opposition by Actavis Group PTC ehf to European Application No. 08732818.3 dated Feb. 23, 2015. cited by applicant . Opposition by Teva Pharmaceutical Industries to European Application No. 08732818.3 dated Feb. 10, 2015. cited by applicant . Opposition by Medecins Du Monde to European Application No. 08732818.3 dated Feb. 10, 2015. cited by applicant . Opposition by Ellis IP Ltd. to European Application No. 08732818.3 dated Feb. 10, 2015. cited by applicant . Opposition by Mr. Holm Herbert Fleisher to European Application No. 08732818.3 dated Feb. 19, 2015. cited by applicant . Opposition by Generics [UK] Ltd (trading as Mylan) to European Application No. 08732818.3 dated Feb. 19, 2015. cited by applicant . Opposition by IPS to European Application No. 08732818.3 dated Feb. 23, 2015. cited by applicant . Opposition by Pharmaceutical Works Polpharma S.A. to European Application No. 08732818.3 dated Feb. 19, 2015. cited by applicant . Opposition by Stada Arzneimittel AG to European Application No. 08732818.3 dated Feb. 19, 2015. cited by applicant . Opposition by ZBM Patents= Zea, Barlocci & Markvardsen to European Application No. 08732818.3 dated Feb. 23, 2015. cited by applicant . Furman et al., "The Anti-Hepatitis B Virus Activities, Cytoxicities, and Anabolic Profiles of the (-) and (+) Enantiomers of cis-5-Fluoro-1-[2-(Hydroxymenthyl)-1,3-Ozathiolan-5-yl]Cytosine," Antimicrobial Agents and Chemotherapy, (1992), 36(2):2686-2692. cited by applicant . Chang et al., "Deoxyctidine-resistant Stereoisomer Is the Active Form of (.+-.)-2',3'-Dideoxy-3'-thiacytidine in the Inhibition of Hepatitis B Virsu Replication," J. Bio. Chem, (1992), 267(20):13938-13942. cited by applicant . Trousdale. et al.,"Activity of 1-(2'-Fluoro-2'-Deoxy-.beta.-D-Arabinofuranosyl)Thymine Against Herpes Simplex Virsu in Cell Cultires and Rabbit Eyes," Antimicrobial Agents and Chemotherapy, (1983), 23(6):808-813. cited by applicant . Klumpp, et al., "The Novel Nucleoside Analog R1479(4'-Azidocytidine) Is a Potent Inhibitorof NS5B-dependent RCA Synthesis and Hepatitis C Virus Replication in Cell Culture," J. Bio. Chem., (2006), 281:3793-3799. cited by applicant . Landowski et al, "Targeted delivery to PEPT1-overexpressing cells: Acidic, basic, and secondary floxurdine amino acid ester prodrugs," MCT, (2005), 4(4):659-667. cited by applicant . McGuigan, "Phosphoramidate derivatives of stavudine as inhibitors of HIV: unnatural amino acids may substitute for alanine," Antiviral Chemistry & Chemotherapy, (2000), 11:111-116. cited by applicant . Perrone, Thesis entitled "Design Synthesis an dBiological Evaluation of Novel Nucleotide Prodrugs as Potential Anti-Hepatitis C Virus Agents," (2007). cited by applicant . Zemlicka, Lipophilic phosporamidates as antiviral pornucleotides, Biochem Biophys Acta, (2002), 276-286. cited by applicant . Sofia, "Discovery of a beta-D-2'-Deoxy-2'-alpha-fluoro-2'-beta-C-methyluridine Nucleotide Prodrug (PSI-7977) for the Treament of Hepatitis C Virus," J. Med. Chem., (2010), 53. cited by applicant . Abstract, 100, presented at the 19th International Conference of Antiviral Research, May 7-11, 2006. cited by applicant . Guinic, et al., "Cyclic monophosphate prodrugs of base=modified 2'-C-methyl ribonucleosides as potent inhibitors of hepatitis C virus RNA replicaion," Bioorg Med Chem Lett., (2007), 17(9):2456-2458. cited by applicant . Abraham et al., "Synthesis and Biological Activity of Aromatic Amino Acid Phosphoramidates of 5-fluoro-2'deoxyuridine and 1-beta-Arabinofuranosylcytosine: Evidence of Phosphoramidase Activity," J. Med. Chem., vol. 39, No. 23, pp. 4569-4575, (1996). cited by applicant . Abraham et al., "Synthesis, Biological Activity and Decomposition Studies of Amino Acid Phosphomonoester Amidates of Acyclovir," Nucleosides, Nucleotides and Nucleic Acids, vol. 16, No. 10, pp. 2079-2092 (1997). cited by applicant . Aquaro et al., "Activities of Masked 2',3'-Dideoxynucleoside Monophosphate Derivaties Against Human Immunodeficiency Virus in Resting Macrophages," Antimicrobial Agents and Chemotherapy, vol. 44, No. 1, pp. 173-177 (2000). cited by applicant . Asif et al., "Pharmacokinetics of the Antiviral Agent B-D-2'-Deoxy-2'-Fluoro-2'-C-Methylcytidine in Rhesus Monkeys," Antimicrobial Agents and Chemotherapy, vol. 51, No. 8, pp. 2877-2882 (2007). cited by applicant . Balzarini et al., "Mechanism of anti-HIV action of masked alaninyl d4t-MP derivatives," Proc. Natl. Acad. Sci., vol. 93, pp. 7295-7299 (1996). cited by applicant . Banker et al., "Prodrugs," Modern Pharmaceutics, Third Edition, Revised and Expanded, pp. 451 and 596 (1996). cited by applicant . Bartenschlager et al., "Kinetic and Structural Analyses of Hepatitis C Virus Polyprotein Processing," J. Virol., vol. 68, No. 8, pp. 5045-5055 (1994). cited by applicant . Bartenschlager et al., "Nonstructural Protein 3 of the Hepatitis C Virus Encodes a Serine-Type Proteinase Required for Cleavage at the NS3/4 and NS4/5 Junctions," J. Virol., vol. 67, No. 7, pp. 3835-3844 (1993). cited by applicant . Baschang et al., "Neue Derivate von Thymidin-3',5'-cyclophosphat," Angew. Chem., vol. 85, No. 1, pp. 44-45 (1973). cited by applicant . Battaglia et al., "Combination Therapy with Interferon and Ribavirin in the Treatment of Chronic Hepatitis C Infection," The Annals of Pharmacotherapy, vol. 34, No. 4, pp. 487-494 (2000). cited by applicant . Bazan et al., "Detection of a Trypsin-like Serine Protease Domain in Flaviviruses and Pestiviruses," Virology, vol. 171, pp. 637-639 (1989). cited by applicant . Beaulieu et al., "Inhibitors of the HCV NS5B polymerase: New hope for the treatment of hepatitis C infections," Current Opinion in Investigational Drugs, vol. 5, No. 8, pp. 838-850 (2004). cited by applicant . Behrens et al., "Identification and properties of the RNA-dependent RNA polymerase of hepatitis C virus," The EMBO Journal, vol. 15, No. 1, pp. 12-22 (1996). cited by applicant . Berenguer, M., "Hepatitis C virus in the transplant setting," Antiviral Therapy, vol. 3, Supplement 3, pp. 125-136 (1998). cited by applicant . Bhat et al., "Synthesis and Pharmacokinetic Properties of Nucleoside Analogues as Possible Inhibitors of HCV RNA Replication," (Oral Session V: Hepatitis C Virus, Flaviviruses), 16th International Conference on Antiviral Research, Abstract No. 120, p. A75 (Apr. 27-May 1, 2003). cited by applicant . Broeders et al., "A 400-and 600-Mhz 'H NMR Confromational Study on Nucleoside Cyclic 3', 5' PV-TBP Systems. Conformational Transmission Induces Diequatorial Orientation of the 3', 5'-Dioxaphosphorinane Ring in a Nonchair Confirmation," J. Am. Chem. Soc., vol. 112, No. 21, pp. 7475-7482 (1990). cited by applicant . Cahard, Dominique, et al., Aryloxy Phosphoramidate Triesters as Pro-Tides, Mini-Reviews in Medicinal Chemistry (2004), 4, 371-381. cited by applicant . Calisher et al., "Antigenic Relationships between Flaviviruses as Determined by Cross-neutralization Tests with Polyclonal Antisera," J. Gen. Virol., vol. 70, pp. 37-43 (1989). cited by applicant . Carroll et al., "Nucleoside Analog Inhibitors of Hepatitis C Virus Replication," Infectious Disorders--Drug Targets, vol. 6, No. 1, pp. 17-29 (2006). cited by applicant . Chang et al., "Amino Acid Phosphoramidate Monoesters of 3'-Azido-3'-deoxythymidine: Relationship between Antiviral Potency and Intracellular Metabolism," J. Med. Chem., vol. 44, No. 2, pp. 223-231 (2001). cited by applicant . Chapman et al., "Practical Synthesis, Separation, and Stereochemical Assignment of the PMPA Pro-Drug GS-7340," Nucleosides, Nucleotides & Nucleic Acids, vol. 20, No. 4-7, pp. 621-628 (2001). cited by applicant . Chapman et al., "Purification of PMPA Amidate Prodrugs by SMB Chromatography and X-Ray Crystallography of the Diastereomerically Pure GS-7340," Nucleosides, Nucleotides & Nucleic Acids, vol. 20, No. 4-7, pp. 1085-1090 (2001). cited by applicant . Chen et al., "In Vivo Pharmacokinetics and Metabolism of Anti-Human Immunodeficiency Virus Agent D4t-5'-[P-Bromophenyl Methoxyalaninyl Phosphate] (Sampidine) in Mice," Drug Metabolism and Disposition, vol. 29, No. 7, pp. 1035-1041 (2001). cited by applicant . Chen et al., "Metabolism of Stavudine-5'-[P-Bromophenyl Methoxyalaninyl Phosphate], Stampidine, in Mice, Dogs, and Cats," Drug Metabolism and Disposition, vol. 30, No. 12, pp. 1523-1531 (2002). cited by applicant . Chou et al., "Evidence that Human Histidine Triad Nucleotide Binding Protein 3 (Hint3) is a Distinct Branch of the Histidine Triad (HIT) Superfamily," J. Mol. Biol., vol. 373, pp. 978-989 (2007). cited by applicant . Chou et al., "Phosphoramidate Pronucleotides: A Comparison of the Phosphoramidase Substrate Specificity of Human and Escherichia coli Histidine Triad Nucleotide Binding Proteins," Molecular Pharmaceutics, vol. 4, No. 2, pp. 208-217 (2006). cited by applicant . Chu et al., "Isolation and Structure of SCH 351633: A Novel Hepatitis C Virus (HCV) NS3 Protease Inhibitor from the Fungus Penicillium griseofulvum," Bioorg. & Med. Chem. Lett., vol. 9, pp. 1949-1952 (1999). cited by applicant . Chu et al., "Structure of Sch 68631: A New Hepatitis C Virue Proteinase Inhibitor from Streptomyces sp." Tet. Lett., vol. 37, No. 40, pp. 7229-7232 (1996). cited by applicant . Cihlar et al. "Design and Profiling of GS-9148, a Novel Nucleotide Analog Active against Nucleoside-Resistant Variants of Human Immunodeficiency Virus Type 1, and Its Orally Bioavailable Phosphonoamidate Prodrug, GS-9131," Antimicrobial Agents and Chemotherapy, vol. 52, No. 2, pp. 655-665 (2008). cited by applicant . Clark et al., "Design, Synthesis, and Antiviral Activity of 2'-Deoxy-2'-fluoro-2'-C-methylcytidine, a Potent Inhibitor of Hepatitis C Virus Replication," J. Med. Chem., vol. 48, No. 17, pp. 5504-5508 (2005). cited by applicant . Congiatu et al. "Molecular Modeling Studies on the Binding of Some Protides to the Putative Human Phosphoramidase Hint1," Nucleosides, Nucleotides and Nucleic Acids, vol. 26, pp. 1121-1124 (2007). cited by applicant . Congiatu et al., "Naphthyl Phosphoramidate Derivatives of BVdU as Potential Anticancer Agents: Design, Synthesis and Biological Evaluation," Nucleosides, Nucleotides, and Nucleic Acids, vol. 24, No. 5-7, pp. 485-489 (2005). cited by applicant . Curley et al., "Synthesis and anti-HIV evaluation of some phosphoramidate derivatives of AZT: studies on the effect of chain elongation on biological activity," Antiviral Research, vol. 14, pp. 345-356 (1990). cited by applicant . Davis, G. L., "Current Therapy for Chronic Hepatitis C," Gastroenterology, vol. 118, No. 2, pp. S104-S114 (2000). cited by applicant . D'Cruz et al., "Stampidine: a selective oculo-genital microbicide," Journal of Antimicrobial Chemotherapy, vol. 56, pp. 10-19 (2005). cited by applicant . De Lombaert et al., "N-Phosphonomethyl Dipeptides and Their Phosphonate Prodrugs, a New Generation of Neutral Endopeptidase (NEP, EC 3.4.24.11) Inhibitors," J. Med. Chem., vol. 37, No. 4, pp. 498-511 (1994). cited by applicant . Drontle et al., "Designing a Pronucleotide Stratagem: Lessons from Amino Acid Phosphoramidates of Anticancer and Antiviral Pyrimidines," MiniReviews in Medicinal Chemistry, vol. 4, No. 4, pp. 409-419 (2004). cited by applicant . Dumez, Darin, et al., "Large-Scale Synthesis and Formulation of GMP-Grade Stampidine, a New Anti-HIV Agent," Arzneim.-Forsch./Drug Res. (2006) 56(2a):136-151. cited by applicant . Eckart et al., "The Hepatitis C Virus Encodes a Serine Protease Involved in Processing of the Putative Nonstructural Proteins from the Viral Polyprotein Precursor," Biochemical and Biophysical Research Communications, vol. 192, No. 2, pp. 399-406 (1993). cited by applicant . Edmundson et al., "Cyclic Organophosphorus Compounds. Part 23. Configurational Assignments in the 4-Phenyl-1,3,2-dioxaphosphorinane Series. X-Ray Molecular Structure of cis2-Benzylamino-4-phenyl-1,3,2-dioxaphosphorinane 2-oxide," J. Chem. Research (S), pp. 122-123 (1989). cited by applicant . Egron et al., "S-Acyl-2-thioethyl Phosphoramidate Diester Derivatives as Mononucleotide Prodrugs" J. Med. Chem., vol. 46, No. 21, pp. 4564-4571 (2003). cited by applicant . Eisenberg et al., "Metabolism of GS-7340, a Novel Phenyl Monophosphoramidate Intracellular Prodrug of PMPA, in Blood," Nucleosides, Nucleotides & Nucleic Acids, vol. 20, No. 4-7, pp. 1091-1098 (2001). cited by applicant . Eldrup et al., "Oral Session V: Hepatitis C Virus, Flaviviruses," Program and Abstracts, The Sixteenth International Conference on Antiviral Research, p. A75, Abstract 119 (Apr. 27 to May 1, 2003). cited by applicant . Eldrup et al., "Structure-Activity Relationship of Purine Ribonucleosides for Inhibition of Hepatitis C Virus RNA-Dependent RNA Polymerase," J. Med. Chem., vol. 47, No. 9, pp. 2283-2295 (2004). cited by applicant . Engels et al., "Ctclophosphate, III. Synthese and Eignschaften von Uridin-3',5'-cyclophosphat-estern," Chemische Berichte, vol. 110, No. 6, pp. 2019-2027 (1977). cited by applicant . Failla et al., "Both NS3 and NS4A are Required for Proteolytic Processing of Hepatitis C Virus Nonstructural Proteins," J. Virol., vol. 68, No. 6, pp. 3753-3760 (1994). cited by applicant . Farquhar et al., "Synthesis and Biological Evaluation of Neutral Derivatives of 5-Fluoro-2'-deoxyuridine 5'-Phosphate," J. Med. Chem., vol. 26, No. 8, pp. 1153-1158 (1983). cited by applicant . Farquhar et al., "Synthesis of Biological Evaluation of 9[5'-(2-Oxo-1,3,2-oxazaphosphorinan-2-yl)-beta-D-arabinosyl] adenine and 9[5'-(2-Oxo-1,3,2-dioxaphosphorinan-2-yl)-beta-D-arabinosyl]adenine: Potential Neutral Precursors of 9-[beta-D-Arabinofuranosyl]adenine 5'-Monophosphate," J. Med. Chem., vol. 28, No. 9, pp. 1358-1361 (1985). cited by applicant . Freed et al., "Evidence for acyloxymethyl esters of pyrimidine 5'-deoxyribonucleotides as extracellular sources of active 5'-deoxyribonucleotides in cultured cells," Biochemical Pharmacology, vol. 38, No. 19, pp. 3193-3198 (1989). cited by applicant . Gillespie, S., et al., "Stereoselective Inhibition of Cholesterol Esterase by Enantiomeric Phosphonates," Phosphorous, Sulfur and Silicon, 1997, 122: 205-208. cited by applicant . Goekjian et al., "Synthesis of Fluorinated Marcocyclic Bis(indolyl)maleimides as Potential 19F NMR Probes for Protein Kinase C," J. Org. Chem. vol. 64., No. 12, pp. 4238-4246 (1999). cited by applicant . Gorbalenya et al., "A conserved NTP-motif in putative helicases," Nature, vol. 333, p. 22 (1988). cited by applicant . Gorbalenya et al., "N-terminal domains of putative helicases of flavi-and pestiviruses may be serine proteases," Nucleic Acids Research, vol. 17, No. 10, pp. 3889-3897 (1989). cited by applicant . Grakoui et al., "A second hepatitis C virus-encoded proteinase," Proc. Natl. Acad. Sci., vol. 90, pp. 10583-10587 (1993). cited by applicant . Grakoui et al., "Characterization of the Hepatitis C Virus-Encoded Serine Proteinase: Determination of Proteinase-Dependent Polyprotein Clevage Sites," J. Virol., vol. 67, No. 5, pp. 2832-2843 (1993). cited by applicant . Griffith et al., "HCV Anti-viral Agents," Annual Reports in Medicinal Chemistry, vol. 39, pp. 223-237 (2004). cited by applicant . Gromova et al., "Optical Rotatory Dispersion and Circular Dichroism of Mono- and Oligonucleotide-Amino Acids (Amidates),"Biochim. Biophys. Acta., vol. 240, No. 1, pp. 1-11 (1971). cited by applicant . Gudmundsson, Kristjan S., et al., "Phosphoramidate Protides of 2',3'-Dideoxy-3'-fluoroadenosine and Related Nucleosides with Potent Activity Against HIV and HBV," Nucleosides, Nucleotides & Nucleic Acids (2003) 22 (10):1953-1961. cited by applicant . Gudmundsson, Kristjan S., et al., "Phosphoramidate Protides of Carbocyclic 2',3'-Dideoxy-2',3'-Didehydro-7-Deazaadenosine with Potent Activity Against HIV and HBV," Nucleosides, Nucleotides & Nucleic Acids (2004) 23(12): 1929-1937. cited by applicant . Gunic et al., "6-Hydrazinopurine 2'-methyl ribonucleosides and their 5'-monophosphate prodrugs as potent hepatitis C virus inhibitors," Bioorg. & Med. Chem. Lett., vol. 17, pp. 2456-2458 (2007). cited by applicant . Halstead, S. B., "Pathogenesis of Dengue: Challenges to Molecular Biology," Science, vol. 239, pp. 476-481 (1988). cited by applicant . Halstead, S. B., "Selective Primary Health Care: Strategies for Control of Disease in the Developing World. XI. Dengue," Review of Infectious Diseases, vol. 6, No. 2, pp. 251-263 (1984). cited by applicant . Harris et al., "Synthesis and antiviral evaluation of phosphoramidate derivatives of (E)-5-(2-bromovinyl)-2'-deoxyuridine," Antiviral Chemistry & Chemotherapy, vol. 12, No. 5, pp. 293-300 (2001). cited by applicant . Hernandez et al., "Synthesis of Highly Functionalized Chiral Nitriles by Radical Fragmentation of beta-Hydroxy Azides. Convenient Transformation of Aldononitriles into 1,4- and 1,5- Iminoalditols," J. Org. Chem., vol. 69. No. 24, pp. 8437-8444 (2004). cited by applicant . Hertel et al., "Synthesis of 2-Deoxy-2,2-difluoro-D-ribose and 2-Deoxy-2,2-difluoro-D-ribofuranosyl Nucleosides," J. Org. Chem., vol. 53, No. 11, pp. 2406-2409 (1988). cited by applicant . Hijikata et al., "Two Distinct Proteinase Activities required for the Processing of a Putative Nonstructural Precursor Protein of Hepatitis C Virus," J. Virol., vol. 67, No. 8, pp. 4665-4675 (1993). cited by applicant . Hostetler et al., "Greatly Enhanced Inhibition of Human Immunodeficiency Virus Type 1 Replication in CEM and HT4-6C Cells by 3'-Deoxythymidine Diphosphate Dimyristoylglycerol, a Lipid Prodrug of 3'-Deoxythymidine," Antimicrobial Agents and Chemotherapy, vol. 36, No. 9, pp. 2025-2029 (1992). cited by applicant . Hostetler et al., "Synthesis and Antiretroviral Activity of Phospholipid Analogs of Azidothymidine and Other Antiviral Nucleosides," J. Biol. Chem., vol. 265, No. 11, pp. 6112-6117 (1990). cited by applicant . Howes et al., "The Regiospecific One-Pot Phosphorylation of Either the 5'-or 2'-Hydroxyl in 3'-Deoxycytidines Without Protection: Critical Role of the Base," Nucleosides, Nucleotides, and Nucleic Acids, vol. 22, No. 5-8, pp. 687-689 (2003). cited by applicant . Hunston et al., "Synthesis and Biological Properties of Some Cyclic Phosphotriesters Derived from 2'-Deoxy-5-fluorouridine," J. Med. Chem., vol. 27, No. 4, pp. 440-444 (1984). cited by applicant . International Preliminary Examination Report along with Written Opinion of the International Searching Authority issued in International PCT application No. PCT/US2008/058183 issued Apr. 7, 2010 (17 pages). cited by applicant . International Preliminary Report on Patentability and Written Opinion of the International Searching Authority issued in International Application No. PCT/EP2006/069060 (13 pages). cited by applicant . International Preliminary Report on Patentability and Written Opinion of the International Searching Authority issued in International Application No. PCT/EP2006/069060 (7 pages) (Nov. 5, 2008). cited by applicant . International Preliminary Report on Patentability and Written Opinion of the International Searching Authority issued in International Application No. PCT/US2004/012472 (8 pages) (Dec. 1, 2005). cited by applicant . International Preliminary Report on Patentability and Written Opinion of the International Searching Authority issued in International Application No. PCT/US2005/025916 (4 pages). cited by applicant . International Preliminary Report on Patentability and Written Opinion of the International Searching Authority issued in International Application No. PCT/US2005/025916 (5 pages) (Jan. 23, 2007). cited by applicant . International Preliminary Report on Patentability and Written Opinion of the International Searching Authority issued in International Application No. PCT/US2005/032406 (4 pages) (Mar. 10, 2009). cited by applicant . International Search Report and Written Opinion of the International Searching Authority issued in International Application No. PCT/US2009/069475 (21 pages). cited by applicant . International Search Report and Written Opinion of the International Searching Authority issued in International Application No. PCT/US2009/069475 (21 pages) (May 10, 2010). cited by applicant . International Search Report and Written Opinion of the International Searching Authority issued in PCT/US2010/035641 (23 pages). cited by applicant . International Search Report and Written Opinion of the International Searching Authority issued in PCT/US2010/035641 (23 pages) (Nov. 20, 2011). cited by applicant . International Search Report issued in International Application No. PCT/EP2006/069060 mailed Jan. 30, 2007 (4 pages). cited by applicant . International Search Report issued in International Application No. PCT/US2004/012472 mailed Dec. 30, 2004 (4 pages). cited by applicant . International Search Report issued in International Application No. PCT/US2005/025916 mailed Jun. 15, 2006 (2 pages). cited by applicant . International Search Report issued in International Application No. PCT/US2005/025916 mailed Jun. 15, 2006. cited by applicant . International Search Report issued in International Application No. PCT/US2005/032406 mailed May 8, 2008 (3 pages). cited by applicant . International Search Report issued in International Application No. PCT/US2009/046619 (4 pages). cited by applicant . International Search Report issued in International Application No. PCT/US2009/046619 (4 pages) (Sep. 23, 2010). cited by applicant . Invitation to Pay Additional Fees & Partial International Search Report issued in International Application No. PCT/US2010/035641 (10 pages). cited by applicant . Invitation to Pay Additional Fees & Partial International Search Report issued in International Application No. PCT/US2010/035641 (10 pages) (Jul. 23, 2010). cited by applicant . Iyer et al., "Synthesis, in Vitro Anti-Breast Cancer Activity, and Intracellular Decomposition of Amino Acid Methyl Ester and Alkyl Amide Phosphoramidate Monoesters of 3'-Azido-3'-deoxythymidine (AZT)," J. Med. Chem., vol. 43, No. 11, pp. 2266-2274 (2000). cited by applicant . Jin et al., "Expression, Isolation, and characterization of the Hepatitis C Virus ATPase/RNA Helicase," Archives of Biochemistry and Biophysics, vol. 323, No. 1, pp. 47-53 (1995). cited by applicant . Jones et al., "Minireview: Nucleotide Prodrugs," Antiviral Research, vol. 27, No. 1-2pp. 1-17 (1995). cited by applicant . Judoka et al., "Oligonucleotides and Nucleotide-Peptides. XXXIV. Synthesis and Some Properties of Complex Nucleotidyl (Oligonucleotidyl)-P-N)-Amino Acids (Peptides) and Their Ethyl Esters," J. Carbohydrates Nucleosides Nucleotides, vol. 6, No. 4, pp. 333-357 (1979). cited by applicant . Juodka et al., "Oligonucleotides and Nucleotide-Peptides. XXXV. Some Properties of Nucleotidyl-(5'-N)-Amino Acid Esters Differing in Amino Acid and Nucleotide Components," J. Carbohydrates Nucleosides Nucleotides, vol. 8, No. 1, pp. 19-39 (1981). cited by applicant . Juodka et al., "Oligonucleotides and Nucleotide-Peptides. XXXVII. On the Mechanism of Hydrolysis of Uridylyl-(5'-N)-Amino Acids. IntramolecuLar Catalysis by the alpha-Carboxyl Group of Amino Acids," J. Carbohydrates Nucleosides Nucleotides, vol. 8, No. 6, pp. 519-535 (1981). cited by applicant . Khamnei et al., "Neighboring Group Catalysis in the Design of Nucleotide Prodrugs," J. Med. Chem., vol. 39, No. 20, pp. 4109-4115 (1996). cited by applicant . Kim et al., "C-Terminal Domain of the Hepatitis C Virus NS3 Protein Contains an RNA Helicase Activity," Biochemical and Biophysical Research Communications, vol. 215, No. 1, pp. 160-166 (1995). cited by applicant . Kim et al., "Monitoring the Intracellular Metabolism of Nucleoside Phosphoramidate Pronucleotides by 31P NMR," Nucleosides, Nucleotides and Nucleic Acid, vol. 23, No. 1 & 2, pp. 483-493 (2004). cited by applicant . Koonin et al., "Evolution and Taxonomy of Positive-Strand RNA Viruses: Implications of Comparatives Analysis of Amino Acid Sequences," Critical Reviews in Biochemistry and Molecular Biology, vol. 28, No. 5, pp. 375-430 (1993). cited by applicant . Kotra et al., "Structure-Activity Relationships of 2'-Deoxy-2',2'-difluoro-L-erythro-pentofuranosyl Nucleosides," J. Med. Chem., vol. 40, No. 22, pp. 3635-3644 (1997). cited by applicant . Kryuchkov et al., "Influence of Solvent on the Strength of Cyclic Oxygen-Containing Phosphorus Acids," Bulletin of the Academy of Sciences of the USSR. Division of Chemical Science, vol. 36, No. 6, Part 1, pp. 1145-1148 (1987) Translated from Russian. cited by applicant . Kucera et al., "Novel Membrane-Interactive Ether Lipid Analogs That Inhibit Infectious HIV-1 Production and Induce Defective Virus Formation," Aids Research and Human Retroviruses, vol. 6, No. 4, pp. 491-501 (1990). cited by applicant . Lackey et al., "Enzyme-catalyzed therapeutic agent (ECTA) design: activation of the antitumor ECTA compound NB1011 by thymidylate synthase," Biochemical Pharmacology, vol. 61, No. 2, pp. 179-189 (2001). cited by applicant . Lee et al., "Selective Intracellular Activation of a Novel Prodrug of the Human Immunodeficiency Virus reverse Transcriptase Inhibitor Tenofovir Leads to Preferential Distribution and Accumulation in Lymphatic Tissue," Antimicrobial Agents and Chemotherapy, vol. 49, No. 5, pp. 1898-1906 (2005). cited by applicant . Lehsten et al., "An Improved Procedure for the Synthesis of Nucleoside Phosphoramidates," Organic Process Research and Development, vol. 6, pp. 819-822 (2002). cited by applicant . Li et al., "Synthesis of the Phosphoramidite Derivative of 2'-Deoxy-2'-C-beta-methylcytidine", J. Org. Chem., vol. 68, No. 17, pp. 6799-6802 (2003). cited by applicant . Lohmann et al., "Biochemical Properties of Hepatitis C Virus NS5B RNA-Dependent RNA Polymerase and Identification of Amino Acid Sequence Motifs Essential for Enzymatic Activity," J. Virol., vol. 71, No. 11, pp. 8416-8428 (1997). cited by applicant . Lopez Aparicio et al., "Synthesis of Saccharinic Acid Derivatives," Carbohydrate Research, vol. 129, pp. 99-109 (1984). cited by applicant . Ma et al., "Characterization of the Metabolic Activation of Hepatitis C Virus Nucleoside Inhibitor B-D-2'-Deoxy-2-Fluoro-2'-C-Methylcytidine (PSI-6130) and Identification of a Novel Active 5'-Triphosphate Species," J. Biol. Chem., vol. 282, No. 41, pp. 29812-29820 (Oct. 12, 2007). cited by applicant . McGuigan et al., "Application of Phosphoramidate Pronucleotides Technology to Abacavir Leads to a Significant Enhancement of Antiviral Potency," J. Med. Chem., vol. 48, No. 10, pp. 3504-3515 (2005). cited by applicant . McGuigan et al., "Application of Phosphoramidate ProTide Technology Significantly Improves Antiviral Potency of Carbocyclic Adenosine Derivatives," J. Med. Chem., vol. 49, No. 24, pp. 7215-7226 (2006). cited by applicant . McGuigan et al., "Aryl phosphate derivatives of AZT retain activity against HIV1 in cell lines which are resistant to the action of AZT," Antiviral Research, vol. 17, pp. 311-321 (1992). cited by applicant . McGuigan et al., "Aryl Phosphoramidate Derivatives of d4T Have Improved Anti-HIV Efficacy in Tissue Culture and May Act by the Generation of a Novel Intracellular Metabolite," J. Med. Chem., vol. 39, No. 8, pp. 1748-1753 (1996). cited by applicant . McGuigan et al., "Synthesis and anti-HIV activity of some novel chain-extended phosphoramidate derivatives of d4T (stavudine): esterase hydrolysis as a rapid predictive test for antiviral potency," Antiviral Chemistry and Chemotherapy, vol. 9, pp. 109-115 (1998). cited by applicant . McGuigan et al., "Synthesis and evaluation of some novel phosphoramidate derivatives of 3'-azido-3'-deoxythymidine (AZT) as anti-HIV compounds," Antiviral Chemistry and Chemotherapy, vol. 1, No. 2, pp. 107-113 (1990). cited by applicant . McGuigan et al., "Synthesis, anti-human immunodeficiency virus activity and esterase lability of some novel carboxylic ester-modified phosphoramidate derivatives of stavudine (d4T)," Antiviral Chemistry & Chemotherapy, vol. 9, pp. 473-479 (1998). cited by applicant . McGuigan, Christopher, et al., Certain Phosphoramidate Derivatives of Dideoxy Uridine (ddU) Are Active Against HIV and Successfully By-pass Thymidine Kinase, FEBS Letters (1994), 351, 11-14. cited by applicant . McIntee et al., "Amino Acid Phosphoramidate Nucleosides: Potential ADEPT/GDEPT Substrates," Bioorganic & Medicinal Chemistry Letters, vol. 11, No. 21, pp. 2803-2805 (2001). cited by applicant . McIntee et al., "Probing the Mechanism of Action and Decomposition of Amino Acid Phosphomonoester Amidates of Antiviral Nucleoside Prodrugs," J. Med. Chem., vol. 40, No. 21, pp. 3323-3331 (1997). cited by applicant . Meier et al., "Cyclic Saligenyl Phosphotriesters of 2',3'-Dideoxy-2',3'-didehydrothymidine (d4T)--A New Pro-Nucleotide Approach," Bioorg. & Med. Chem. Lett., vol. 7, No. 2, pp. 99-104, (1997). cited by applicant . Meyers et al., "Molecular Characterization of Pestiviruses," Advance in Virus Research, vol. 47, pp. 53-119 (1996). cited by applicant . Mitchell et al., "Bioreversible Protection for the Phospho Group: Bioactivation of the Di(4-acyloxybenzyl) and Mono(4-acyloxybenzyl) Phosphoesters of Methylphosphonate and Phosphonoacetate," J. Chem. Soc. Perkin. Trans. 1, pp. 2345-2353 (1992). cited by applicant . Moennig et al., "The Pestiviruses," Advances in Virus Research, vol. 41, pp. 53-99 (1992). cited by applicant . Monath, T. P., M.D., "Japanese Encephalitis--A Plague of the Orient," N. Engl. J. Med., vol. 319, No. 10, pp. 641-643 (Sep. 8, 1988). cited by applicant . Murakami et al., "Mechanism of Activation of beta-D-2'-Deoxy-2'-Fluoro-2'-C-Methylcytidine and Inhibition of hepatitis C Virus NS5B RNA Polymerase," Antimicrobial Agents and Chemotherapy, vol. 51, No. 2, pp. 503-509 (Feb. 2007). cited by applicant . Murakami et al., "The Mechanism of Action of beta-D-2'-Deoxy-2'-Fluoro-2'-C-Methylcytidine Involves a Second Metabolic Pathway Leading to beta-D-2'-Deoxy-2'-Fluoro-2'-C-Methyluridine 5'-Triphosphate, a Potent Inhibitor of the Hepatitis C Virus RNA-Dependent RNA Polymerase," Antimicrobial Agents and Chemotherapy, vol. 52, No. 2, pp. 458-464 (2008). cited by applicant . Murakami, E., et al., "The Mechanism of Action of beta-D-2'-Deoxy-2'-fluoro-2'-C-methylcytidine Involves a Second Metabolic Pathway Leading to beta-D-2'-Deoxy-2'-fluoro-2'-C-methyluridine 5'-Triphosphate, a Potent Inhibitor of the HCV RNA-Dependent RNA Polymerase," 14th International Symposium on Hepatitis C Virus and Related Viruses, Glasgow, Scotland (Sep. 2007). cited by applicant . Nakayama, Kensaku, et al., "A Highly Enantioselective Synthesis of Phosphate Triesters," J. Am. Chem. Soc. (1990) 112:6936-6942. cited by applicant . Neidlein et al., "Mild Preparation of 1-Benzyloxyiminoalkylphosphonic Dichlorides: Application to the Synthesis of Cyclic Phosphonic Diesters and Cyclic Monoester Amides," Heterocycles, vol. 35, No. 2, pp. 1185-1203 (1993). cited by applicant . Nelson et al., "The Question of Chair-twist Equilibria for the Phosphate Rings of Nucleoside Cyclic 3',5'Monophosphates. 1H NMR and X-ray Crystallographic Study of Diastereomers of Thymidine Phenyl Cyclic 3',5'-Monophosphate," J. Am. Chem. Soc., vol. 109, No. 13, pp. 4058-4064 (1987). cited by applicant . Ni et al., "Progress and development of small molecule HCV antivirals," Current Opinion in Drug Discovery & Development, vol. 7, No. 4, pp. 446-459 (2004). cited by applicant . Nifantyev et al., "Synthesis and Structure of Some Stable Phospholane-Phospholanes," Phosphorus, Sulfur, and Silicon, vol. 113, pp. 1-13 (1996). cited by applicant . Novak, J. J. K., "Chiroptical Properties of 2-Methyl-1,4-Lactones; Revised Absolute Configuration of 2-Deoxy-2-C-Methyl-erythro-D-Pentono-1,4-Lactones," Collection Czechoslov. Chem. Commun., vol. 39, pp. 869-882 (1974). cited by applicant . Novak, J. J. K., "Nucleic Acid Components and Their Analogues CXLIII. Nucleosides Derived from 2-Deoxy-2(R)-C-Methyl-erythro-D-Pentose," Collection Czechoslov. Chem. Commun., vol. 36, pp. 3670-3677 (1971). cited by applicant . Oishi et al., "Asymmetric Dihydroxylation of Chiral Olefins. High Control of Diastereofacial Selection," Tet. Lett., vol. 34, No. 22, pp. 3573-3576 (1993). cited by applicant . Olsen et al., "2'-Modified Nucleoside Analogs as Inhibitors of Hepatitis C RNA Replication," Program and Abstracts, 16th International Conference on Antiviral Research, Abstract No. 121, p. A76 (Apr. 27-May 1, 2003). cited by applicant . Otto, M., "Evaluation of Nucleoside Analogs in the Hepatitis C Virus Replicon System," Framing the Knowledge of Therapeutics for Viral Hepatitis, IHL Press, First Edition, pp. 247-261 (2006). cited by applicant . Partial International Search Report issued in International Application No. PCT/US2009/069475 (7 pages). cited by applicant . Partial International Search Report issued in International Application No. PCT/US2009/069475 (7 pages) (Jul. 23, 2010). cited by applicant . Perrone et al. "Application of the Phosphoramidate ProTide Approach to 4'-Azidouridine Confers Sub-micromolar Potency versus Hepatitis C Virus on an Inactive Nucleoside," J. Med. Chem., vol. 50, No. 8, 1840-1849 (2007). cited by applicant . Perrone et al., "First Example of Phosphoramidate Approach Applied to a 4'-Substituted Purine Nucleoside (4'-Azidoadenosine): Conversion of an Inactive Nucleoside to a Submicromolar Compound versus Hepatitis C Virus," J. Med. Chem., vol. 50, No. 22, pp. 5463-5470 (2007). cited by applicant . Piantadosi et al., "Synthesis and Evaluation of Novel Ether Lipid Nucleoside Conjugates for Anti-HIV-1 Activity," J. Med. Chem., vol. 34, No. 4, pp. 1408-1414 (1991). cited by applicant . Pierra et al., "Synthesis and Pharmacokinetics of Valopicitabine (NM283), an Efficient Prodrug of the Potent Anti-HCV Agent 2'-C-Methylcytidine," J. Med. Chem., vol. 49, No. 22, pp. 6614-6620 (2006). cited by applicant . Pogam et al., "No Evidence of R7128 Drug Resistance After Up to 4 Weeks Treatment of GT1, 2 and 3 Hepatitis C Virus Infected Individuals", 44th Annual Meeting of European Association for the Study of the Liver (EASL), Copenhagen, Denmark (Apr. 22-26, 2009). cited by applicant . Ray et al., "Intracellular Metabolism of the Nucleotide Prodrugs GS-9131, a Potent Anti-Human Immunodeficiency Virus Agent," Antimicrobial Agents and Chemotherapy, vol. 52, No. 2, pp. 648-654 (2008). cited by applicant . Remy et al., "Studies on Flourinated Pyrimidines. XIV. The Synthesis of Derivatives of 5-Fluoro-2'-deoxyuridine 5'-Phosphate and Related Compounds," J. Org. Chem., vol. 27, No. 7, pp. 2491-2500 (1962). cited by applicant . Rice, C. M., "Flaviviridae: The Viruses and Their Replication," Fields Virology, 3rd Edition, vol. 1, pp. 931-959 (1996). cited by applicant . Saboulard et al., "Characterization of the Activation Pathway of Phosphoramidate Triester Prodrugs of Stavudine and Zidovudine," Mol. Pharmacol., vol. 56, pp. 693-704 (1999). cited by applicant . Schultz, C., "Prodrugs of Biologically Active Phosphate Esters" Bioorg. and Med. Chem., vol. 11, pp. 885-898 (2003). cited by applicant . Shih et al., "Preparation and Structures of 2-Dimethylamino-4-phenyl-1,3,2-dioxaphosphorinane-2-oxides," Bull. Inst. Chem., Acad. Sin., vol. 41, pp. 9-16, (Mar. 1994). cited by applicant . Siccardi et al., "Stereoselective and Concentration-Dependent Polarized Epithelial Permeability of a Series of Phosphoramidate Triester Prodrugs of d4T: An in Vitro Study in Caco-2 and Madin-Darby Canine Kidney Cell Monolayers," J. Pharmacol. and Exp. Ther., vol. 307, No. 3, pp. 1112-1119 (2003). cited by applicant . Siccardi et al., "Stereospecific chemical and enzymatic stability of phosphoramidate triester prodrugs of d4T in vitro," European Journal of Pharmaceutical Sciences, vol. 22, pp. 25-31 (2004). cited by applicant . Siddiqui et al., "Design and Synthesis of Lipophilic Phosphoramidate d4T-MP Prodrugs Expressing High Potency Against HIV in Cell Culture: Structural Determinants for in Vitro Activity and QSAR," J. Med. Chem., vol. 42, No. 20, pp. 4122-4128 (1999). cited by applicant . Siddiqui et al., "Enhancing the Aqueous Solubility of d4T-based Phosphoramidate Prodrugs," Bioorg. and Med. Chem. Lett., vol. 10, pp. 381-384 (2000). cited by applicant . Siddiqui, Adam Q., et al., "The Presence of Substituents on the Aryl Moiety of the Aryl Phosphoramidate Derivatives of d4T Enhances Anti-HIV Efficacy in Cell Culture: A Structure-Activity Relationship," J. Med. Chem. (1999) 42:393-399. cited by applicant . Smirrnov et al., "A Fluorescent Study of Tryptophan Derivatives of Oligonucleotides and Their Helical Complexes with Polyuridylic," FEBS Letters, vol. 51. No. 1, pp. 211-214 (1975). cited by applicant . Sofia et al., "beta-D-2'-Deoxy-2'-C-methyluridine Phosphoramidates: Potent and Selective Inhibitors of HCV RNA Replication", Poster #P-259, 14th International Symposium on Hepatitis C Virus and Related Viruses, Glasgow, Scotland, UK (Sep. 9 to 13, 2007). cited by applicant . Sofia et al., "beta-D-2'-Deoxy-2'-fluoro-2'-C-methyluridine Phosphoramidates: Potent and Selective Inhibitors of HCV RNA Replication", 2nd International Workshop on HCV, Poster #7 (Oct. 31, 2007). cited by applicant . Sofia, M.J., "beta-D-2'-Deoxy-2'-fluoro-2'-C-methyluridine Phosphoramidates: Potent and Selective Inhibitors of HCV RNA Replication", 2nd International Workshop on HCV-Resistance and New Compounds (Oct. 31, 2007). cited by applicant . Sofia, M.J., "R7128, A Potent and Selective Nucleoside Inhibitor of HCV NS5B Polymerase: An Overview of Clinical Efficacy and Progress Toward Second Generation Inhibitors", HCV Drug Discovery 2008, Chicago, IL (Apr. 28, 2008). cited by applicant . Song et al., "Pharmacokinetics of Amino Acid Phosphoramidate Monoesters of Zidovudine in Rats," Antimicrobial Agents and Chemotherapy, vol. 46, No. 5, pp. 1357-1363 (2002). cited by applicant . Starrett, Jr. et al., "Synthesis, Oral Bioavailability Determination, and in Vitro Evaluation of Prodrugs of the Antiviral Agent 9-[2-(Phosphonomethoxy)ethyl]adenine (PMEA)," J. Med. Chem., vol. 37, No. 12, pp. 1857-1864 (1994). cited by applicant . Stella, V. J., "Prodrugs as Therapeutics," Expert opinion on therapeutic patents, vol. 14, No. 3, pp. 277-280 (Mar. 2004). cited by applicant . Stuyver et al., "Dynamics of Subgenomic Hepatitis C Virus Replicon RNA Levels in Huh-7 Cells after Exposure to Nucleoside Antimetabolites," J. Virol., vol. 77, No. 19, pp. 10689-10694 (2003). cited by applicant . Stuyver et al., "Inhibition of hepatitis C replicon RNA synthesis by B-D-2'-deoxy-2'-fluoro-2'-C-methlcytidine: a specific inhibitor of hepatitis C virus replication," Antiviral Chemistry & Chemotherapy, vol. 17, No. 2, pp. 79-87 (2006). cited by applicant . Stuyver et al., "Inhibition of the Subgenomic Hepatitis C Virus Replicon in Huh-7 Cells by 2'-Deoxy-2'-Fluorocytidine," Antimicrobial Agents and Chemotherapy, vol. 48, No. 2, pp. 651-654 (2004). cited by applicant . Stuyver et al., "Ribonucleoside Analogue that Blocks Replication of Bovine Viral Diarrhea and Hepatitis C Viruses in Culture," Antimicrobial Agents and Chemotherapy, vol. 47, No. 1, pp. 244-254 (2003). cited by applicant . Tan et al., "Hepatitis C Therapeutics: current Status and Emerging Strategies," Nature Reviews, vol. 1, pp. 867-881 (2002). cited by applicant . Tomei et al., "NS3 Is a Serine Protease Required for Processing of Hepatitis C Virus Polyprotein," J. Virol., vol. 67, No. 7, pp. 4017-4026 (1993). cited by applicant . U.S. Appl. No. 10/828,753, Final Office Action Rejection, mailed Feb. 26, 2008. cited by applicant . U.S. Appl. No. 11/225,425, Final Office Action Rejection, mailed Feb. 18, 2010. cited by applicant . U.S. Appl. No. 11/225,425, Non-Final Office Action Rejection, mailed Jul. 7, 2009. cited by applicant . U.S. Appl. No. 11/225,425, Non-Final Office Action Rejection, mailed Nov. 13, 2008. cited by applicant . U.S. Appl. No. 11/353,597, Final Office Action Rejection, mailed Dec. 2, 2008. cited by applicant . U.S. Appl. No. 11/353,597, Non-Final Office Action Rejection, mailed Oct. 2, 2007. cited by applicant . U.S. Appl. No. 11/635,898, Non-Final Office Action Rejection, mailed Jul. 28, 2009. cited by applicant . U.S. Appl. No. 11/854,218, Non-Final Office Action Rejection, mailed Oct. 1, 2009. cited by applicant . U.S. Appl. No. 12/142,536, Non-Final Office Action Rejection, mailed Oct. 2, 2009. cited by applicant . U.S. Appl. No. 12/142,554, Non-Final Office Action Rejection, mailed Oct. 1, 2009. cited by applicant . U.S. Appl. No. 12/240,342, Non-Final Office Action Rejection, mailed Oct. 1, 2009. cited by applicant . U.S. Appl. No. 12/553,483, Non-Final Office Action Rejection, mailed Dec. 17, 2009. cited by applicant . U.S. Appl. No. 11/854,218, Pending claims filed Sep. 12, 2007. cited by applicant . U.S. Appl. No. 12/142,536, Pending claims filed on Jun. 19, 2008. cited by applicant . U.S. Appl. No. 12/479,075, filed Jun. 5, 2009. cited by applicant . U.S. Appl. No. 12/645,765, filed Dec. 23, 2009. cited by applicant . U.S. Appl. No. 12/645,821, filed Dec. 23, 2009. cited by applicant . U.S. Appl. No. 13/936,448, filed Jul. 8, 2013. cited by applicant . U.S. Appl. No. 14/057,675, filed Oct. 18, 2013. cited by applicant . U.S. Appl. No. 14/152,243, filed Jan. 10, 2014. cited by applicant . U.S. Appl. No. 60/392,350, filed Jun. 28, 2002. cited by applicant . U.S. Appl. No. 60/392,351, filed Jun. 28, 2002. cited by applicant . Uchiyama, Mamoru, et al., "O-Selective Phosphorylation of Nucleosides without N-Protection," J. Org. Chem. (1993) 58:373-379. cited by applicant . Uckun et al., "In Vivo Pharmacokinetics and Toxicity Profile of the Anti-HIV Agent Stampidine in Dogs and Feline Immunodeficiency Virus-infected Cats," Arzneim.-Forsch./Drug Res., vol. 56, No. 2a, pp. 176-192 (2006). cited by applicant . Valette et al., "Decomposition Pathways and in Vitro HIV Inhibitory Effects of IsoddA Pronucleotides: Toward a Rational Approach for Intracellular Delivery of Nucleoside 5?-Monophosphates," J. Med. Chem., vol. 39, No. 10, pp. 1981-1990 (1996). cited by applicant . Venkatachalam et al., "Rational Drug Design of Multifunctional Phosphoramidate Substituted Nucleoside Analogs," Current Pharmaceutical Design, vol. 10, No. 15, pp. 1713-1726 (2004). cited by applicant . Venkatachalam et al., "Synthesis and metabolism of naphthyl substituted phosphoramidate derivatives of stavudine," Bioorg. and Med. Chem., vol. 14, pp. 5161-5177 (2006). cited by applicant . Valette et al., "Decomposition Pathways and in Vitro HIV Inhibitory Effects of IsoddA Pronucleotides: Toward a Rational Approach for Intracellular Delivery of Nucleoside 5'-Monophosphates," J. Med. Chem., vol. 39, No. 10, pp. 1981-1990 (1996). cited by applicant . Wagner et al., "Antiviral Nucleoside Drug Delivery via Amino Acid Phosphoramidates," Nucleosides, Nucleotides and Nucleic Acids, vol. 18, No. 4 & 5, pp. 913-919 (1999). cited by applicant . Walker et al., "Promising candidates for the treatment of chronic hepatitis C," Expert Opin. Investig. Drugs, vol. 12, No. 8, pp. 1269-1280 (2003). cited by applicant . Warrener et al., "Pestivirus NS3 (p80) Protein Possesses RNA Helicase Activity," J. Virol., vol. 69, No. 3, pp. 1720-1726 (1995). cited by applicant . Wu et al., "Synthesis and Biological Activity of a Gemcitabine Phosphoramidate Prodrug," J. Med. Chem., vol. 50, No. 15, pp. 3743-3746 (2007). cited by applicant . Wolff, M.E., "Burger's Medicinal Chemistry and Drug Discovery," Fifth Edition, vol. 1, pp. 975-977 (1995). cited by applicant . Wozniak, Lucyna A., et al., "The stereospecific synthesis of P-chiral biophosphates and their analogues by the Stec reaction," Chem. Soc. Rev. (2003) 32:158-169. cited by applicant . Xiao-Ling et al., "The Synthesis of (2S,3R)-Sphingosine from D-Mannitol", Acta Chimica Sinica, vol. 54, pp. 826-832 (1996). cited by applicant . Xu et al., "Bovine Viral Diarrhea Virus NS3 Serine Proteinase: Polyprotein Cleavage Sites, Cofactor Requirements, and Molecular Model of an Enzyme Essential for Pestivirus Replication," J. Virol., vol. 71, No. 7, pp. 5312-5322 (1997). cited by applicant . Yuan et al., "Expression, Purification, and Partial Characterization of HCV RNA Polymerase," Biochemical and Biophysical Research Communications, vol. 232, No. 1, pp. 231-235 (1997). cited by applicant . Wu et al., "Targeting NS5B RNA-Dependent RNA Polymerase for Anti-HCV Chemotherapy," Current Drug Targets--Infectious Disorders, vol. 3, No. 3, pp. 207-219 (2003). cited by applicant . Xiao-Ling et al., "Study on the Chirality of Sulfur in Ethyl (2S, 3R,4R)-4,5-O-Isopropylidene-2,3-sulfinyl;-2,3,4,5-tetrahydroxy-pentanoate- ", Acta Chimica Sinica, vol. 55, pp. 600-604 (1997). cited by applicant . Abraham et al. J. Med. Chem. (1996), vol. 39, pp. 4569-4575. cited by applicant . Aquaro, et al. Antimicrobial Agents and Chemotherapy, 2000, 1, 173-177. cited by applicant . Bartenschlager, J. Viral., 1993, 67, 3835-3844. cited by applicant . Bartenschlager, J. Viral., 1994, 68, 5045-5055. cited by applicant . Baschang et al., Angewandte Chemie, 85:1,44-45, 1973. cited by applicant . Bazan and Fletterick ,Virology, 1989, 171, 637-639. cited by applicant . Beaulieu, P. L., Current Opinion in Investigational Drugs, 2004, 5, 838-850. cited by applicant . Behrens, EMBO, 1996, 15, 12-22. cited by applicant . Bhat B., "Synthesis and Pharmacokinetic Properties of Nucleoside Analogues as Possible Inhibitors of HCV RNA Replication," (Oral Session V: Hepatitis C Virus, Flaviviruses), 16th International Conference on Antiviral Research, Abstract No. 120, p. A75 (Apr. 27-May 1, 2003, Savannah, GA). cited by applicant . Broeders et al., J. Am. Chem. Soc., 112:21,7475-7482, 1990. cited by applicant . Calisher, J. Gen. Viral, 1989, 70, 37-43. cited by applicant . Carrol, S., Infectious Disorders--Drug Targets, 2006, 6, 17-29. cited by applicant . Chapman, et al. Nucleotides, Nucleosides and Nucleic Acids, 2001, 20 (4-7), 1085-1090. cited by applicant . Chapman, et al. Nuecleotides, Nucleosides and Nucleic Acids, 2001, 20 (4-7), 621-628. cited by applicant . Chu, M., Bioorganic & Medicinal Chemistry Letters, vol. 9, 1949-1952, 1999. cited by applicant . Chu, M., Tetrahedron Letters, vol. 37, No. 40,7229-7232, 1996. cited by applicant . De Lombaert, S., J. Med. Chem., vol. 37, No. 4, 498-511, 1994. cited by applicant . Eckart, Biochem. Biophys. Res. Comm. 1993, 192, 399-406. cited by applicant . Edmundson, J. Chem. Res. Synop., 1989,5:122-123. cited by applicant . Eisenberg, et al. Nucleosides, Nucleotides & Nucleic Acids, 2001, 20(4-7), 1091-1098. cited by applicant . Eldrup, A., "Structure Activity Relationship of 2' Modified Nucleosides for Inhibition of Hepatitis C Virus," (Oral Session V: Hepatitis C Virus, Flavaviruses), 16th International Conference on Antiviral Research, Abstract No. 119, p. A75 (Apr. 27-May l, 2003, Savannah, GA). cited by applicant . Engels et al., Chem. Ber., 110:6, 2019-2027, 1977. cited by applicant . Failla, J. Viral., 1994, 68, 3753-3760. cited by applicant . Fields Virology, Editors: Fields, B. N., Knipe, D. M., and Howley, P.M., Lippincott-Raven Publishers, Philadelphia, PA, 1996, Chapter 31,931-959. cited by applicant . Final International Report and Written Opinion ofPCT/US2009/069475 mailed May 10, 2010. cited by applicant . Goekjian, Journal of Organic Chemistry, 1999, 64 (12) 4238-4246. cited by applicant . Gorbalenya, Nature, 1988, 333, 22. cited by applicant . Gorbalenya, Nucleic Acid Res.,1989, 17, 3889-3897. cited by applicant . Grakoui, J. Viral. 1993, 67, 2832-2843. cited by applicant . Grakoui, Proc. Natl. Acad Sci. USA 1993, 90, 10583-10587. cited by applicant . Griffith, R.C., Annual Reports in Medicinal Chemistry, 2004, 39,223-237. cited by applicant . Gromova et al., Biochem. Biophys. Acta, 1971,240, 1-11. cited by applicant . Halstead, S. B., Rev. Infect. Dis., 1984,6,251-264. cited by applicant . Halstead, S. B., Science, 1988, 239, 476-481. cited by applicant . Harris et al., Antiviral Chemistry & Chemotherapy, 2002, 12, 293-300. cited by applicant . Hernandez, Journal of Organic Chemistry, 2004, 69 (24), 8437-8444. cited by applicant . Hijikata, J. Viral. 1993, 67, 4665-4675. cited by applicant . Hostetler, K., Antimicrob. Agents Chemother., vol. 36, No. 9, 2025-2029, 1992. cited by applicant . International Preliminary Examination Report of International PCT application No. PCT/US2008/058183 issued Apr. 7, 2010. cited by applicant . International Preliminary Examination Report of PCT/EP2006/069060 mailed Nov. 5, 2008. cited by applicant . International Preliminary Examination Report of PCT/US2004/012472 issued Dec. 1, 2005. cited by applicant . International Preliminary Examination Report of PCT/US2005/025916 issued Jan. 23, 2007. cited by applicant . International Preliminary Examination Report of PCT/US2005/032406 issued Mar. 10, 2009. cited by applicant . International Search Report for International Application No. PCT/EP2006/069060 (WO2007/065829) mailed Jan. 30, 2007. cited by applicant . International Search Report for International Application No. PCT/US2004/0124 72 (WO2005/003147) mailed Dec. 30, 2004. cited by applicant . International Search Report for International Application No. PCT/US2005/025916 (WO2006/012440) mailed Jun. 15, 2006. cited by applicant . International Search Report for International Application No. PCT/US2005/032406 (WO2006/031725) mailed May 8, 2008. cited by applicant . International Search Report of International Application No. PCT/US05/25916 mailed Jun. 15, 2006. cited by applicant . International Search Report of International PCT application No. PCT/US2008/058183 mailed Mar. 31, 2010. cited by applicant . International Search Report of PCT/US2009/046619 (W0/2009/152095) mailed Sep. 23, 2010. cited by applicant . International Search Report of PCT/US2010/035641 mailed Sep. 28, 2010. cited by applicant . Invitation to Pay Additional Fees & Partial International Search Report of PCT/US2010/035641 mailed Jul. 23, 2010. cited by applicant . Jin and Peterson, Arch. Biochem. Biophys., 1995, 323, 47-53. cited by applicant . Juodka et al., J. Carbohydrates, Nucleosides, Nucleotides, 1979, 6( 4), 333-357. cited by applicant . Juodka et al., J. Carbohydrates, Nucleosides, Nucleotides, 1981, 8(1), 19-39. cited by applicant . Juodka et al., J. Carbohydrates, Nucleosides, Nucleotides, 1981, 8(6), 519-535. cited by applicant . Kim et al., Biochem. Biophys. Res. Comm., 1995, 215, 160-166. cited by applicant . Koonin, E.V. and Dolja, V.V., Crir. Rev. Biochem. Malec. Biol. 1993, 28, 375-430. cited by applicant . Kryuchkov et al., "Influence of Solvent on the Strength of Cyclic Oxygen-Containing Phosphorus Acids," Bulletin of the Academy of Sciences of the USSR. Division of Chemical Science, vol. 36, No. 6, Part 1, pp. 1145-1148 (1987). cited by applicant . Kucera, L., AIDS Research and Human Retroviruses, vol. 6, No. 4, 491-501, 1990. cited by applicant . Lackey et al., Biochemical Pharmacology, 2001, 61, 179-189. cited by applicant . Lee, et al Antimicrobial Agents and Chemotherapy, 2005, 49(5), 1898-1906. cited by applicant . Lochmann, J. Viral., 1997, 71, 8416-8428. cited by applicant . Lopez Aparicio et al., "Branched-Chain Sugars, Part VII, Synthesis of Saccharinic Acid Derivatives" Carbohydrate Research, 129, 99-109, 1984. cited by applicant . McGuigan, et al. Antiviral Chemistry and Chemotherapy 1998, 9, 473-479. cited by applicant . McIntee et al., Biorg. & Med. Chem. Lett., 2001, 11, 2803-2805. cited by applicant . Meier, C., Bioorganic & Medicinal Chemistry Letters, vol. 7, No. 2, 99-104, 1997. cited by applicant . Meyers, G. and Thiel, H.J., Advances in Virus Research, 1996, 47, 53-118. cited by applicant . Moening V., Adv. Vir. Res. 1992,41, 53-98. cited by applicant . Monath, T. P., New Eng. J. Med, 1988, 319, 641-643. cited by applicant . Murakami et al. Antimicrobial Agents and Chemotherapy (Feb. 2008), 52 (2), 458-464. cited by applicant . Murakami, et al. Antiviral Chemistry & Chemotherapy, 2007, 51(2), 503-509. cited by applicant . Neidlein, R., Heterocycles, vol. 35, No. 2, 1185-1203, 1993. cited by applicant . Nelson et al., J. Am. Chem. Soc., 109:13, 4058-4064, 1987. cited by applicant . Ni, Z-J., Current Opinion in Drug Discovery and Development, 2004, 7, 446-459. cited by applicant . Nifantyev, E., Phosphorus, Sulfur, and Silicon and the Related Elements, vol. 113, 1-13, 1996. cited by applicant . Novak J.J.K., Collection of Czechoslovak Chemical Communications, vol. 36, 3670-3677, 1971. cited by applicant . Novak, J.J .K., Collection of Czechoslovak Chemical Communications, vol. 39, 869-882, 197 4. cited by applicant . Oishi, Tetrahedron Letters, 1993, 34 (22), 3573-3576. cited by applicant . Olsen et al., "2'-Modified Nucleoside Analogs as Inhibitors of Hepatitis C RNA Replication," Program and Abstracts, 16th International Conference on Antiviral Research, Abstract No. 121, p. A76 (Apr. 27-May 1, 2003, Savannah, GA)). cited by applicant . Partial International Search Report ofPCT/US2009/069475 (W0/2010/075554) mailed Mar. 5, 2010. cited by applicant . Ray, et al. Antimicrobial Agents and Chemotherapy, 2008, 52(2), 648-654. cited by applicant . Remy et al., J. Org. Chem., 1962, 27, 2491-2500. cited by applicant . Shih, Y., Bull. Inst. Chern., Academia Sinica, 41:9-16, 1994. cited by applicant . Smimov et al., FEBS Letters, 1975, 51(1), 211-214. cited by applicant . Sofia et al., ".beta.-D-2'-Deoxy-2'-C-methyluridine Phosphoramidates: Potent and Selective Inhibitors of HCV RNA Replication", Poster #P-259, 14th International Symposium on Hepatitis C Virus and Related Viruses, Glasgow, Scotland, UK (Sep. 9 to 13, 2007). cited by applicant . Sofia et al., ".beta.-D-2'-Deoxy-2'-fluoro-2'-C-methyluridine Phosphoramidates: Potent and Selective Inhibitors of HCV RNA Replication", 2nd International Workshop on HCV, Poster #7 (Oct. 31, 2007). cited by applicant . Sofia, M.J., ".beta.-D-2'-Deoxy-2'-fluoro-2'-C-methyluridine Phosphoramidates: Potent and Selective Inhibitors of HCV RNA Replication", 2nd International Workshop on HCV-Resistance and New Compounds (Oct. 31, 2007). cited by applicant . Stella, "Prodrugs as Therapeutics", Expert Opinion Ther. Patents, 2004, 14:3,277-280. cited by applicant . Stuyver, L.J. et al. Antiviral Chemistry & Chemotherapy, 2004, 48(2), 651-654. cited by applicant . Sun Xiao-Ling and and Wu Yu-Lin, "Study on the Chirality of Sulfur in Ethyl (2S, 3R,4R)-4,5-O-Isopropylidene-2,3-sulfiny1;-2,3,4,5-tetrahydroxy-pentanoate- ", Acta Chimica Sinica, vol. 55, pp. 600-604. cited by applicant . Sun Xiao-Ling and and Wu Yu-Lin., "The Synthesis of (2S,3R)-Sphingosine from D-Mannitol", Acta Chimica Sinica, vol. 54, pp. 826-832. cited by applicant . Supplemental European Search Report of European patent appln No. EP 05775359.2 dated Sep. 15, 2010. cited by applicant . Tan, S.-L., Nature Rev. Drug Discov., 2002, 1, 867-881. cited by applicant . Tome, J. Viral., 1993, 67, 4017-4026. cited by applicant . U.S. Appl. No. 10/828,753 Final Rejection mailed Feb. 26, 2008. cited by applicant . U.S. Appl. No. 10/828,753 Non-Final Rejection mailed Mar. 30, 2007. cited by applicant . U.S. Appl. No. 11/225,425 Final Rejection mailed Feb. 18, 2010. cited by applicant . U.S. Appl. No. 11/225,425 Non-Final Rejection mailed Jul. 7, 2009. cited by applicant . U.S. Appl. No. 11/225,425 Non-Final Rejection mailed Nov. 13, 2008. cited by applicant . U.S. Appl. No. 11/225,425 pending claims filed Oct. 2, 2009. cited by applicant . U.S. Appl. No. 11/353,597 Final Rejection mailed Dec. 2, 2008. cited by applicant . U.S. Appl. No. 11/353,597 Non-Final Rejection mailed Jul. 17, 2008. cited by applicant . U.S. Appl. No. 11/353,597 Non-Final Rejection mailed Oct. 2, 2007. cited by applicant . U.S. Appl. No. 11/635,898 Non-Final Rejection mailed Jul. 28, 2009. cited by applicant . U.S. Appl. No. 11/635,898 pending claims filed Dec. 24, 2009. cited by applicant . U.S. Appl. No. 11/854,218 Non-Final Rejection mailed Oct. 1, 2009. cited by applicant . U.S. Appl. No. 11/854,218 pending claims filed Sep. 12, 2007. cited by applicant . U.S. Appl. No. 12/142,536 Non-Final Rejection mailed Oct. 2, 2009. cited by applicant . U.S. Appl. No. 12/142,536 pending claims filed Jun. 19, 2008. cited by applicant . U.S. Appl. No. 12/142,554 Non-Final Rejection mailed Oct. 1, 2009. cited by applicant . U.S. Appl. No. 12/142,554 pending claims filed Dec. 17, 2009. cited by applicant . U.S |