TREATMENT AND/OR PREVENTION OF MULTIPLE SCLEROSIS

Cross-Reference to Related Applications This application claims the benefit under 35 U.S.C. §119(e)(l) of U.S.

Provisional Application Nos. 61/209,045, filed March 3, 2009; 61/192,529, filed September 18, 2008; and 61/123,787, filed April 11, 2008, which applications are incorporated herein by reference in their entireties.

Field

[0001] Described herein are combinations including a therapeutically effective amount of an antiviral agent or a pharmaceutically acceptable salt, hydrate or solvate thereof and a therapeutically effective amount of a multiple sclerosis drug or a pharmaceutically acceptable salt, hydrate or solvate thereof and pharmaceutical compositions thereof. Also described herein are methods for the treatment and/or prevention of various diseases and disorders including multiple sclerosis (MS) and viral infections with a therapeutically effective amount of an antiviral agent or a pharmaceutically acceptable salt, hydrate or solvate thereof or a pharmaceutical composition thereof or the combinations above or pharmaceutical compositions thereof and methods for the manufacture of these pharmaceutical compositions.

Background

[0002] Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease that affects the central nervous system. MS can cause a variety of symptoms, including changes in sensation, visual problems, muscle weakness, depression, difficulties with coordination and speech, severe fatigue, cognitive impairment, problems with balance, overheating and pain. MS also causes impaired mobility and disability in more severe cases. [0003] MS may result from attacks by the immune system on the nervous system and is therefore usually categorized as an autoimmune disease. There is a minority view that MS is not an autoimmune disease, but rather a metabolically dependent neurodegenerative disease. Although much is known about how MS causes damage, its exact cause remains unknown. MS cannot be cured at the current

3850-0001.40 PATENT time, although several treatments are available that may slow the appearance of new symptoms.

[0004] Common viral infections may trigger MS relapses as MS disease activity is associated with systemic immune activation, reflected by the increased production of pro-inflammatory cytokines and elevated serum levels of neopterin and soluble human leukocyte antigens (HLAs). The mechanisms by which infections may precipitate disease exacerbation have been studied and MS has been considered a T- cell mediated autoimmune disease. Myelin proteins appear to be the most likely autoantigens. Various viral or bacterial peptides can activate encephalitogenic autoreactive T-cells efficiently in the peripheral immune system (Wandinger et al, Neurology 2000, 182).

[0005] One potential infectious agent that may be associated with MS is

Epstein-Barr virus (EBV). When compared with individuals never infected by EBV, MS risk is about 10 times greater among individuals who experienced an undiagnosed EBV infection in childhood and at least 20-fold greater among individuals who developed mononucleosis. The presence of other infectious or noninfectious factors can modify the host's response to EBV or otherwise contribute to a determination of MS risk (Alberto et al, Annals of Neurology Vol. 61 No. 4. 2007). However, the exact role EBV plays in MS is unknown. [0006] One role of EBV infection in the pathogenesis of MS may be the expansion and activation of self-reactive T-cells in peripheral lymphoid organs during the course of periodic viral reactivation. EBV DNA polymerase, which is expressed during the lytic cycle of the virus, may be effective in activating myelin basic protein- specific T-cell clones. Of additional significance is the generation of antibodies that cross-react with neuralgia antigens during an immune response against EBV, because immune-mediated myelin destruction in active MS lesions is believed to be an antibody-dependent process (Wandinger et al, Neurology 2000, 183). [0007] There may also be a correlation between MS and other herpes viruses such as human herpes virus 6 (HHV6). Evidence for involvement of HHV6 in MS includes: pathological data showing the presence of the virus in MS lesions postmortem, the neurotropic nature of HHV6, immunological and molecular studies showing an increase in viral DNA or other markers of HHV6 infections in blood cells, serum, or cerebrospinal fluid of MS patients, and evidence of greater frequency of reactivation in MS patients as compared with healthy control subjects. The

3850-0001.40 PATENT correlation between MS and HHV6 is discussed in Alvarez-Lafuente et al., Brain Pathol. 2006, 16:20-27; Derfuss et al., J. Neurol 2005, 252:968-971; Knox et al, Clin. Infect. Dis. 2000, 31 :894-903; and Soldan et al., Nat. Med. 1997, 3: 1394-1397. [0008] Currently, MS does not have a cure and available treatments only slow the appearance of new symptoms. Accordingly, there is a need for new and more effective treatments of MS.

Summary

[0009] The present invention meets such needs by providing, in a first aspect, a combination including a therapeutically effective amount of an antiviral agent or a pharmaceutically acceptable salt, hydrate or solvate thereof or a pharmaceutical composition thereof and a therapeutically effective amount of a MS drug or pharmaceutically acceptable salt, hydrate or solvate thereof or a pharmaceutical composition thereof. In some embodiments, the antiviral agent is effective in treating or preventing infection by EBV, HHV6, or another herpes virus.

[0010] In a second aspect, methods for treating and preventing MS in a subject are provided. In some embodiments, a subject in need of such treatment or prevention is administered a therapeutically effective amount of one or more antiviral agents or pharmaceutically acceptable salts, hydrates or solvates thereof or pharmaceutical compositions thereof. In other embodiments, a subject in need of such treatment or prevention is administered a therapeutically effective amount of one or more antiviral agents or pharmaceutically acceptable salts, hydrates or solvates thereof or pharmaceutical compositions thereof and a therapeutically effective amount of one or more MS drugs or pharmaceutically acceptable salts, hydrates or solvates thereof or pharmaceutical compositions thereof.

[0011] In a third aspect, pharmaceutical compositions for treating subjects suffering from MS are provided. In some embodiments, the pharmaceutical compositions include a therapeutically effective amount of one or more antiviral agents or pharmaceutically acceptable salts, hydrates or solvates thereof and a pharmaceutically acceptable vehicle. In other embodiments, the pharmaceutical compositions include a therapeutically effective amount of one or more antiviral agents or pharmaceutically acceptable salts, hydrates or solvates thereof and a therapeutically effective amount of one or more MS drugs or pharmaceutically

3850-0001.40 PATENT acceptable salts, hydrates or solvates thereof and a pharmaceutically acceptable vehicle.

[0012] In a fourth aspect, pharmaceutical compositions for preventing MS in a subject at a risk of developing MS are provided. In some embodiments, the pharmaceutical compositions include a therapeutically effective amount of one or more antiviral agents or pharmaceutically acceptable salts, hydrates or solvates thereof, and a pharmaceutically acceptable vehicle. In other embodiments, the pharmaceutical compositions include a therapeutically effective amount of one or more antiviral agents or pharmaceutically acceptable salts, hydrates or solvates thereof, and a therapeutically effective amount of one or more MS drugs or pharmaceutically acceptable salts, hydrates or solvates thereof and a pharmaceutically acceptable vehicle.

Detailed Description

Section I: Definitions

[0013] "MS drug" refers to medications used to modulate the course of the disease. MS drugs include, without limitation, Type I interferons and/or monoclonal antibodies used alone or together with other MS drugs.

[0014] "Pharmaceutically acceptable salt" refers to a salt of an antiviral agent or MS drug, which possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-di sulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid,

3850-0001.40 PATENT muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like.

[0015] "Pharmaceutically acceptable vehicle" refers to a diluent, adjuvant, excipient or carrier with which an antiviral agent or combination of antiviral agent and MS agent is administered.

[0016] The terms "subject", "individual" or "patient" are used interchangeably herein and refer to a vertebrate, preferably a mammal. Mammals include, but are not limited to, murines, rodents, simians, humans, farm animals, sport animals and pets.

[0017] "Preventing" or "prevention" refers to a reduction in risk of acquiring a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease).

[0018] "Prodrug" refers to a derivative of a drug molecule that requires a transformation within the body to release the active drug. Prodrugs are frequently, although not necessarily, pharmacologically inactive until converted to the parent drug. A hydroxyl containing drug may be converted to, for example, to a sulfonate, ester or carbonate prodrug, which may be hydrolyzed in vivo to provide the hydroxyl compound. An amino containing drug may be converted, for example, to a carbamate, amide, enamine, imine, N-phosphonyl, N-phosphoryl or N-sulfenyl prodrug, which may be hydrolyzed in vivo to provide the amino compound. A carboxylic acid drug may be converted to an ester (including silyl esters and thioesters), amide or hydrazide prodrug, which be hydrolyzed in vivo to provide the carboxylic acid compound. Prodrugs for drugs which have functional groups different than those listed above are well known to the skilled artisan.

[0019] "Promoiety" refers to a form of protecting group that when used to mask a functional group within a drug molecule converts the drug into a prodrug. Typically, the promoiety will be attached to the drug via bond(s) that are cleaved by enzymatic or non-enzymatic means in vivo.

3850-0001.40 PATENT

[0020] "Treating" or "treatment" of any disease or disorder refers, in some embodiments, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In other embodiments "treating" or "treatment" refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet other embodiments, "treating" or "treatment" refers to inhibiting the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter) or both. In yet other embodiments, "treating" or "treatment" refers to delaying the onset of the disease or disorder. Treating MS also refers to the ability of an agent, such as the antiviral/MS agent combination described herein, to prevent or inhibit the number and/or frequency of relapses in a subject with existing MS.

[0021] "Therapeutically effective amount" means the amount of an antiviral agent or combination of antiviral agent and MS agent that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the antiviral agent or combination of antiviral agent and MS agent, the disease and its severity and the age, weight, etc., of the subject to be treated.

[0022] Reference will now be made in detail to certain embodiments of the invention. While the invention will be described in conjunction with these embodiments, it will be understood that it is not intended to limit the invention to those embodiments. To the contrary, it is intended to cover alternatives, modifications, and equivalents as may be included within the spirit and scope of the invention as defined by the appended claims.

Section H: Antiviral Agents and MS Drugs [0023] Some suitable antiviral agents include compounds of the formula below

3850-0001.40 PATENT

wherein:

R ¹ is hydrogen, hydroxy, mercapto or amino; R ² is hydrogen, hydroxy, fluoro, chloro or amino; R ³ and R ⁴ are independently selected from

[0024] amino, hydroxy or an ether or ester residue thereof, or R ³ together with R ⁴ is

P — O —

OM wherein:

[0025] M is hydrogen or a pharmaceutically acceptable salt, hydrate or solvate thereof; and n is 1 or 2; and pharmaceutically acceptable salts. [0026] The compounds of the formula above contain one asymmetric center when CH ₂ CH ₂ R ₃ and (CH ₂ ) _n R ₄ are different

[0027] Exemplary anti-viral compounds are those wherein R ¹ and R ² are independently hydrogen, hydroxy or amino and wherein R ³ is O P(OM) ₂

[0028] hydroxy or an ester derivative thereof, and R ⁴ is OH or an ester derivative thereof or wherein R ³ and R ⁴ together are

3850-0001.40 PATENT

-P — O- OM

[0029] In some embodiments, R ³ and R ⁴ are both hydroxy. [0030] In some embodiments, compounds of the formula below include the following:

wherein: R ¹ = OH, R ² = NH ₂ , R ³ = OH, R ⁴ = OH R ¹ = H, R ² = NH ₂ , R ³ = OH, R ⁴ = OH R ¹ = NH ₂ , R ² = H, R ³ = OH, R ⁴ = OH

O

-P — O—

R , i' ₌ = OH, R^ = NH ₂ , R ³ and R ⁴ = OM

-P — O —

R » 1 ¹ - = H, R >2^ _ = NH ₂ , R ³ and R ⁴ = OM O

P — O —

R ¹ = OH, R ² = N, R ³ and R ⁴ = OM R ¹ = OH, R ² = NH ₂ , R ³ = OCOCi _-3 , R ⁴ = OCOC _1-3 , R ¹ = H, R ² = NH ₂ , R ³ = OCOC _1-3 , R ⁴ = OCOC _1-3 , R ¹ = NH ₂ , R ² = H, R ³ = OCOC _1-3 , R ⁴ = OCOC _1-3 , R ¹ = OH, R ² = NH ₂ , R ³ = OCONH-phenyl,R ⁴ = OCONH- phenyl,

3850-0001.40 PATENT

R ¹ = H, R ² = NH ₂ , R ³ = OCONH-phenyl, R ⁴ = OCONH- phenyl,

R ¹ = NH ₂ , R ² = H, R ³ = OCONH-phenyl, R ⁴ = OCONH- phenyl,

[0031] Esters and ethers of the above compounds are also useful antiviral agents. Examples of esters are phosphate esters, carboxylic esters, carbonate esters, carbamate esters or sulphonic esters. The acid part of the esters may have alkyl, aryl or arylalkyl chains, where the aryl functionalities are optionally substituted for example by alkoxy, amino, nitrile, alkyl or sulphonamido groups or by one or more halogen atoms.

[0032] Other types of derivatives of the above compounds which may be useful as antiviral agents include alkyl or arylalkyl derivatives of the primary hydroxyl group(s). The arylalkyl ether derivatives may be for example benzyl or triphenyl methyl and the aryl moiety may be optionally substituted.

[0033] In compounds of the formula I R ³ and R ⁴ as an ether residue can be defined as OR ⁵ , wherein R ⁵ is Ci^ alkyl, arylalkyl optionally substituted with one or more alkoxy, amino, nitrile or sulphamido groups or one or more halogen atoms. [0034] R ³ and R ⁴ as an ester residue can be derived from a carboxylic acid R ⁶ COOH, a carbonic acid R ⁷ OCOOH, a double ester of a carbonic acid R ⁷ CO ₂

CH(R ⁸ )OCO ₂ H, a sulphonic acid R ⁷ SO ₂ OH, a carbamic acid R ⁷ NHCOOH or a phosphoric acid, wherein R ⁶ is hydrogen, Ci _-I7 alkyl, alkoxyalkyl, arylalkyl or aryl, R ⁷ is Ci _-I7 alkyl, arylalkyl or aryl, R ⁸ is hydrogen or C _M3 alkyl and said aryl and arylalkyl groups optionally can be substituted with one or more alkyl, alkoxy, amino, nitrile, sulphonamide groups or one or more halogen atoms.

[0035] Other useful antiviral agents include those of the formula below

wherein:

3850-0001.40 PATENT

R ¹ is hydrogen, hydroxy, mercapto or amino; R ² is hydrogen, hydroxy, fluoro, chloro or amino; R ³ and R ⁴ are independently selected from

[0036] amino, hydroxy or an ether or ester residue thereof, or R ³ together with

R ⁴ is

P — O —

OM wherein [0037] M is hydrogen or a pharmaceutically acceptable salt, solvate or hydrate thereof; and n is 1 or 2; with the proviso that, when R ² is amino and R ³ and R ⁴ are hydroxy, R ¹ is not hydroxy and in addition, when n=l, R ² is not hydrogen, and pharmaceutically acceptable salts thereof.

[0038] It should be understood that any of the above antiviral agents or pharmaceutically acceptable salts, hydrates and solvates or pharmaceutical compositions thereof or combinations thereof may be used either alone or combination with another antiviral agent to treat or prevent MS, or in combination with any of the MS drugs or pharmaceutically acceptable salts, hydrates and solvates or pharmaceutical compositions thereof or combinations thereof provided below to treat or prevent MS. [0039] Other suitable antiviral agents include, but are not limited to, valomaciclovir (EPB-348), valganciclovir (Valcyte), cidofovir (Vistide), octadecyloxyethyl-cidofovir (ODE-CDV, CMX-001), and hexadecyloxypropyl- cidofovir (HDP-CDV), abacavir, acyclovir, acyclovir (Zovirax),, adefovir, amantadine, amprenavir, arbidol, atzanavir, atripla, brivudine, combivir, darunavir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, entry inhibitors, famciclovir (Famvir), antiretroviral, fomivirsen, fosamprenavir, foscarnet, fosfonet (Foscavir), fusion inhibitors, ganciclovir, gardasil, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, integrase inhibitor, interferon type III, interferon type II, interferon type I, interferon, lamivudine,

3850-0001.40 PATENT lopinavir, lopinavir, loviride, MK-0518, maraviroc, moroxydine, nelfinavir, nevirapine, nexavir, nucleoside analogues, oseltamivir, omaciclovir (H2G), penciclovir, peramivir, pleconaril, podophyllotoxin, protease inhibitors, reverse transcriptase inhibitors, ribavirin, rimantadine, ritonavir, saquinavir, stavudine, synergistic enhancer, tenofovir, tenofovir disproxil, tipranavir, trifluridine, trizivir, tromantadine, truvada, valavivlovir, valacyclovir (Valtrex), vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, zidovudine, S2242 (2-amino-7-[(l,3-dihydroxy-2- propoxy)methyl]purine]), A-5021 ([1 'S, 2'R)-9[[l '2'-bis(hydroxymethyl)cycloprop- 1 '-yl]-methyl]guanine]), cyclopropavir (CPV, ZSM-I-62), 2,4-diamino-6-R-[3- hydroxy-2(phosphonomethoxy)propoxy]-pyrimidine (HPMPO-DaPy), HPMPA, 3- Deaza-HPMPA, cyclopropavir (CPV, ZSM-I-62), N-(4-Chlorobenzyl)-l-methyl-6-(4- moφholinylmethyl)-4-oxo-l,4-dihydro-3-quinolinecarboxamind (PNU-183792), 2- Bromo-5,6-dichloro-l-(beta-D-ribofuranosyl)benzimidazole (BDCRB), l-(beta-L- ribofuranosy l)-2-isopropy lamino-5 ,6-dichlorobenzimidazole (Maribavir, 1263 W94), 3-Hydroxy-2,2-dimethyl-N-[4-{[(5-dimethylamino)-l-naphthyl]- sulfonyl}- amino)phenyl}propamide (BAY 38-4766), 4-(2-amino-4-thiazolyl)phenyl derivative (BILS 179BS), N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-{ 4-(2- pyridinyl)phenyl}acetamide (BAY 57-1293), 2H-3-(4-chlorophenyl)-3,4-dihydro-l,4- benzo-thiazine-2-carbonitrile 1,1 -dioxide, and 2-chloro-3-pyridin-3-yl-5,6,7,8- tetrahydronindolizine-1-carboxamide (CMV423).

[0040] In some embodiments, the antiviral agent is as valomaciclovir, valganciclovir, and cidofovir.

[0041] In other embodiments, the antiviral agent is foscarnet (Foscavir), acyclovir (Zovirax), valacyclovir (Valtrex), penciclovir, famciclovir (Famvir), omaciclovir (H2G), valomaciclovir (EPB-348), ganciclovir, valganciclovir (Valcyte), cidofovir (Vistide), octadecyloxyethyl-cidofovir (ODE-CDV, CMX-001), and hexadecyloxypropyl-cidofovir (HDP-CDV).

[0042] In still other embodiments, the antiviral agent is maribavir (Camvia), foscarnet (Foscavir), ganciclovir, valganciclovir (Valcyte), cidofovir (Vistide), octadecyloxyethyl-cidofovir (ODE-CDV, CMX-001), hexadecyloxypropyl-cidofovir (HDP-CDV), S2242 (2-amino-7-[(l,3-dihydroxy-2-propoxy)methyl]purine]), A-5021 ([I 'S, 2'R)-9[[1 '2'-bis(hydroxymethyl)cycloprop-r-yl]-methyl]guanine]), cyclopropavir (CPV, ZSM-I-62), 2,4-diamino-6-R-[3-hydroxy- 2(phosphonomethoxy)propoxy]-pyrimidine (HPMPO-DaPy), HPMPA, 3-Deaza-

3850-0001.40 PATENT

HPMPA, cyclopropavir (CPV, ZSM-I-62), N-(4-Chlorobenzyl)-l-methyl-6-(4- moφholinylmethyl)-4-oxo-l,4-dihydro-3-quinolinecarboxamind (PNU-183792), 2- Bromo-5,6-dichloro-l-(beta-D-ribofuranosyl)benzimidazole (BDCRB), l-(beta-L- ribofuranosyl)-2-isopropylamino-5,6-dichlorobenzimidazole (Maribavir, 1263W94), 3-Hydroxy-2,2-dimethyl-N-[4-{[(5-dimethylamino)-l-naphthyl]- sulfonyl}- amino)phenyl}propamide (BAY 38-4766), 4-(2-amino-4-thiazolyl)phenyl derivative (BILS 179BS), N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-{ 4-(2- pyridinyl)phenyl}acetamide (BAY 57-1293), 2H-3-(4-chlorophenyl)-3,4-dihydro-l,4- benzo-thiazine-2-carbonitrile 1,1 -dioxide, and 2-chloro-3-pyridin-3-yl-5,6,7,8- tetrahydronindolizine-1-carboxamide (CMV423).

[0043] In some embodiments, the combination of antiviral agents comprises two or more of valomaciclovir (EPB-348), valganciclovir (Valcyte), cidofovir (Vistide), octadecyloxyethyl-cidofovir (ODE-CDV, CMX-001), and hexadecyloxypropyl-cidofovir (HDP-CDV), abacavir, acyclovir, acyclovir (Zovirax), adefovir, amantadine, amprenavir, arbidol, atzanavir, atripla, brivudine, combivir, darunavir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, entry inhibitors, famciclovir (Famvir), antiretroviral, fomivirsen, fosamprenavir, foscarnet, fosfonet (Foscavir), fusion inhibitors, ganciclovir, gardasil, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, integrase inhibitor, interferon type III, interferon type II, interferon type I, interferon, lamivudine, lobucavir, lopinavir, lopinavir, loviride, MK-0518, maraviroc, moroxydine, nelfmavir, nevirapine, nexavir, nucleoside analogues, oseltamivir, omaciclovir (H2G), penciclovir, peramivir, pleconaril, podophyllotoxin, protease inhibitors, reverse transcriptase inhibitors, ribavirin, rimantadine, ritonavir, saquinavir, stavudine, synergistic enhancer, tenofovir, tenofovir disproxil, tipranavir, trifluridine, trizivir, tromantadine, truvada, valavivlovir, valacyclovir (Valtrex), vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, zidovudine, S2242 (2- amino-7-[(l,3-dihydroxy-2-propoxy)rnethyl]purine]), A-5021 ([1 'S, 2'R)-9[[1 '2'- bis(hydroxymethyl)cycloprop-l '-yl]-methyl]guanine]), cyclopropavir (CPV, ZSM-I- 62), 2,4-diamino-6-®-[3-hydroxy-2(phosphonomethoxy)propoxy]-pyri midine

(HPMPO-DaPy), HPMPA, 3-Deaza-HPMPA, cyclopropavir (CPV, ZSM-I-62), N-(4- Chlorobenzyl)-l-methyl-6-(4-moφholinylmethyl)-4-oxo-l,4-dih ydro-3- quinolinecarboxamind (PNU-183792), 2-Bromo-5,6-dichloro-l-(beta-D- ribofuranosyl)benzimidazole (BDCRB), 1 -(beta-L-ribofuranosyl)-2-isopropylamino-

3850-0001.40 PATENT

5,6-dichlorobenzimidazole (Maribavir, 1263W94), 3-Hydroxy-2,2-dimethyl-N-[4- {[(5-dimethylamino)-l-naphthyl]-sulfonyl}-amino)phenyl}propa mide (BAY 38- 4766), 4-(2-amino-4-thiazolyl)phenyl derivative (BILS 179BS), N-[5- (aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-{4-(2- pyridinyl)phenyl}acetamide (BAY 57-1293), 2H-3-(4-chlorophenyl)-3,4-dihydro-l,4- benzo-thiazine-2-carbonitrile 1,1 -dioxide, and 2-chloro-3-pyridin-3-yl-5,6,7,8- tetrahydronindolizine-1-carboxamide (CMV423).

[0044] In other embodiments, the combination of antiviral agents comprises two or more of valomaciclovir, valganciclovir, and cidofovir. [0045] In still other embodiments, the combination of antiviral agents comprises two or more of foscarnet (Foscavir), acyclovir (Zovirax), valacyclovir (Valtrex), penciclovir, famciclovir (Famvir), omaciclovir (H2G), valomaciclovir (EPB-348), ganciclovir, valganciclovir (Valcyte), cidofovir (Vistide), octadecyloxyethyl-cidofovir (ODE-CDV, CMX-001), and hexadecyloxypropyl- cidofovir (HDP-CDV).

[0046] In still other embodiments, the combination of antiviral agents comprises two or more of maribavir (Camvia), foscarnet (Foscavir), ganciclovir, valganciclovir (Valcyte), cidofovir (Vistide), octadecyloxyethyl-cidofovir (ODE- CDV, CMX-001), hexadecyloxypropyl-cidofovir (HDP-CDV), S2242 (2-amino-7- [(l,3-dihydroxy-2-propoxy)methyl]purine]), A-5021 ([1'S, 2'R)-9[[1 '2'- bis(hydroxymethyl)cycloprop-r-yl]-methyl]guanine]), cyclopropavir (CPV, ZSM-I- 62), 2,4-diamino-6-R-[3-hydroxy-2(phosphonomethoxy)propoxy]-pyrim idine (HPMPO-DaPy), HPMPA, 3-Deaza-HPMPA, cyclopropavir (CPV, ZSM-I-62), N-(4- Chlorobenzyl)- 1 -methyl-6-(4-morpholinylmethyl)-4-oxo- 1 ,4-dihydro-3- quinolinecarboxamind (PNU-183792), 2-Bromo-5,6-dichloro-l-(beta-D- ribofuranosyl)benzimidazole (BDCRB), 1 -(beta-L-ribofuranosyl)-2-isopropylamino- 5,6-dichlorobenzimidazole (Maribavir, 1263W94), 3-Hydroxy-2,2-dimethyl-N-[4- {[(5-dimethylamino)-l-naphthyl]-sulfonyl}-amino)phenyl}propa mide (BAY 38- 4766), 4-(2-amino-4-thiazolyl)phenyl derivative (BILS 179BS), N-[5- (aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-{4-(2- pyridinyl)phenyl}acetamide (BAY 57-1293), 2H-3-(4-chlorophenyl)-3,4-dihydro-l,4- benzo-thiazine-2-carbonitrile 1,1 -dioxide, and 2-chloro-3-pyridin-3-yl-5,6,7,8- tetrahydronindolizine-1 -carboxamide (CMV423).

3850-0001.40 PATENT

[0047] Suitable MS drugs include, but are not limited to, interferon, a monoclonal antibody, interferon beta Ia, interferon beta Ib, natalizumab (Tysabri), rixtuximab (Rituxan, MabThera), glatiramer acetate, mitoxantrone, azathioprine, cyclophosphamide, cyclosporine, dimethyl fumarate, methotrexate, cladribine, methylprednisolone, prednisone, prednisolone, dexamethasone, adreno-corticotrophic hormone, corticotrophin, carbamazepine, gabapentin, tropirmate, zonisamide, phenytoin, desipramine, amitriptyline, imipramine, doexepin, protriptyline, pentoxifylline, 4-aminopyridine, 3,4 diaminopyridine, eliprodil, pregabalin and ziconotide, ofatumumab, ocrelizumab, alemtuzumab (Campath), daclizumab (Zenapax), belimumab (Lympho-Stat-B), glatiramer acetate (Copaxone), mitoxantrone (Novantrone), azathioprine, cyclosporine, methotrexate, cyclophosphamide, intravenous immunoglobulin, prednisone, methylprednisone, prednisolone, methylprednisolone, dexamethasone, adreno-corticotrophic hormone (ACTH), corticotropin, 2-chlorodexyadenosine (2-CDA, cladribine), inosine, Interleukin-2 antibody (Zenapax, daclizumab), leucovorin, teriflunomide, estroprogestins, desogestrel, etinilestradiol, BHT- 3009, ABT-874, Bacille Calmette- Guerin (BCG) Vaccine, T cell vaccination, CNTO 1275, Rituximab, Tysabri (natalizumab), N-acetylcysteine, minocycline, RO0506997, or a statin. [0048] In some embodiments, the MS drug is an anti-CD-20 monoclonal antibody, such as rixtuximab (Rituxan, MabThera), ofatumumab or ocrelizumab. Other non-limiting examples of suitable monoclonal antibodies include natalizumab (Tysabri), alemtuzumab (Campath), daclizumab (Zenapax) and belimumab (Lympho- Stat-B). [0049] In other embodiments, the MS drug is interferon, and the interferon is Type 1 interferon, in either pure formulation or modified for prolonged exposure, such as, for example, pegylated beta-interferon, beta-interferon, interferon beta Ia, interferon beta Ib, pegylated alpha-interferon, omega-interferon, pegylated omega- interferon, interferon (IFN) - βlb (Betaseron or Betaferon), IFN — βla (Avonex, Rebif), or any other related Type 1 interferon. [0050] In still other embodiments, the MS drug is glatiramer acetate

(Copaxone), mitoxantrone (Novantrone), azathioprine, cyclosporine, methotrexate, cyclophosphamide, intravenous immunoglobulin, prednisone, methylprednisone, prednisolone, methylprednisolone, dexamethasone, adreno-corticotrophic hormone (ACTH), corticotropin, 2-chlorodexyadenosine (2-CDA, cladribine), inosine,

3850-0001.40 PATENT

Interleukin-2 antibody (Zenapax, daclizumab), leucovorin, teriflunomide, estroprogestins, desogestrel, etinilestradiol, BHT- 3009, ABT-874, Bacille Calmette- Guerin (BCG) Vaccine, T cell vaccination, CNTO 1275, Rituximab, Tysabri (natalizumab), N-acetylcysteine, minocycline, RO0506997, or a statin. [0051] In some embodiments the antiviral agent is selected from the group comprising valomaciclovir, valganciclovir, and cidofovir, and the MS drugs is selected from the group comprising an anti-CD-20 monoclonal antibody, such as, rituximab (Rituxan, MabThera), ofatumumab or ocrelizumab. [0052] In other embodiments the antiviral agent is selected from the group comprising foscarnet (Foscavir), acyclovir (Zovirax), valacyclovir (Valtrex), penciclovir, famciclovir (Famvir), omaciclovir (H2G), valomaciclovir (EPB-348), ganciclovir, valganciclovir (Valcyte), cidofovir (Vistide), octadecyloxyethyl-cidofovir (ODE-CDV, CMX-OOl), and hexadecyloxypropyl-cidofovir (HDP-CDV), and the MS drugs is selected from the group comprising an interferon, and the interferon is Type 1 interferon, in either pure formulation or modified for prolonged exposure, such as, for example, pegylated beta-interferon, beta-interferon, interferon beta Ia, interferon beta Ib, pegylated alpha-interferon, omega-interferon, pegylated omega-interferon, interferon (IFN) - βlb (Betaseron or Betaferon), IFN — βla (Avonex, Rebif), or any other related Type 1 interferon. [0053] In still other embodiments the antiviral agent is selected from the group comprising maribavir (Camvia), foscarnet (Foscavir), ganciclovir, valganciclovir (Valcyte), cidofovir (Vistide), octadecyloxyethyl-cidofovir (ODE-CDV, CMX-001), hexadecyloxypropyl-cidofovir (HDP-CDV), S2242 (2-amino-7-[(l,3-dihydroxy-2- propoxy)methyl]purine]), A-5021 ([1 'S, 2'R)-9[[l'2'-bis(hydroxymethyl)cycloprop- 1 '-yl]-methyl]guanine]), cyclopropavir (CPV, ZSM-I-62), 2,4-diamino-6-R-[3- hydroxy-2(phosphonomethoxy)propoxy]-pyrimidine (HPMPO-DaPy), HPMPA, 3- Deaza-HPMPA, cyclopropavir (CPV, ZSM-I-62), N-(4-Chlorobenzyl)-l-methyl-6-(4- morpholinylmethyl)-4-oxo-l ,4-dihydro-3-quinolinecarboxamind (PNU-183792), 2- Bromo-5,6-dichloro- 1 -(beta-D-ribofuranosyl)benzimidazole (BDCRB), 1 -(beta-L- ribofuranosyl)-2-isopropylamino-5,6-dichlorobenzimidazole (Maribavir, 1263W94), 3-Hydroxy-2,2-dimethyl-N-[4-{[(5-dimethylamino)-l-naphthyl]- sulfonyl}- amino)phenyl}propamide (BAY 38-4766), 4-(2-amino-4-thiazolyl)phenyl derivative (BILS l 79BS), N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-{ 4-(2- pyridinyl)phenyl}acetamide (BAY 57-1293), 2H-3-(4-chlorophenyl)-3,4-dihydro-l,4-

3850-0001.40 PATENT benzo-thiazine-2-carbonitrile 1,1 -dioxide, and 2-chloro-3-pyridin-3-yl-5,6,7,8- tetrahydronindolizine-1-carboxamide (CMV423) , and the MS drugs is selected from the group comprising glatiramer acetate (Copaxone), mitoxantrone (Novantrone), azathioprine, cyclosporine, methotrexate, cyclophosphamide, intravenous immunoglobulin, prednisone, methyl prednisone, prednisolone, methylprednisolone, dexamethasone, adreno-corticotrophic hormone (ACTH), corticotropin, 2- chlorodexyadenosine (2 -CDA, cladribine), inosine, Interleukin-2 antibody (Zenapax, daclizumab), leucovorin, teriflunomide, estroprogestins, desogestrel, etinilestradiol, BHT- 3009, ABT-874, Bacille Calmette-Guerin (BCG) Vaccine, T cell vaccination, CNTO 1275, Rituximab, Tysabri (natal izumab), N-acetylcysteine, minocycline, RO0506997, or a statin

[0054] Some exemplary antiviral agents and combinations of antiviral agents and MS drugs are listed in Table 1 below.

[0055] Table 1

Valomaciclovir

Valganciclovir

Cidofovir

Valomaciclovir; Valganciclovir

Valomaciclovir; Cidofovir

Valganciclovir; Cidofovir

Valomaciclovir; Interferons

Valganciclovir; Interferons

Cidofovir; Interferons

Valomaciclovir ; Valganciclovir; Interferons

Valomaciclovir; Cidofovir; Interferons

Valganciclovir; Cidofovir; Interferons

Valomaciclovir; Monoclonal Antibody Rituximab

Valganciclovir; Monoclonal Antibody Rituximab

Cidofovir; Monoclonal Antibody Rituximab

Valomaciclovir; Valganciclovir; Monoclonal Antibody Rituximab

Valomaciclovir; Cidofovir; Monoclonal Antibody Rituximab

Valganciclovir; Cidofovir; Monoclonal Antibody Rituximab

Valomaciclovir; Monoclonal Antibody Natalizumab

Valganciclovir; Monoclonal Antibody Natalizumab

Cidofovir; Monoclonal Antibody Natalizumab

3850-0001.40 PATENT

Valomaciclovir; Valganciclovir; Monoclonal Antibody Natal izumab

Valomaciclovir; Cidofovir; Monoclonal Antibody Natalizumab

Valganciclovir; Cidofovir; Monoclonal Antibody Natalizumab

Valomaciclovir; Anti-CD-20 monoclonal antibody

Valganciclovir; Anti-CD-20 monoclonal antibody

Cidofovir; Anti-CD-20 monoclonal antibody

[0055] In any of the above embodiments, Valomaciclovir may be present as a particular polymorphic form. In some embodiments, the Valomaciclovir polymorph has 2-theta angles of 22.9° +/- 0.2° and 18.6° +/- 0.2°. In other embodiments, the Valomaciclovir polymorph has 2-theta angles of 22.9° +/- 0.2°, 18.6° +/- 0.2°, 19.5° +/- 0.2°, and 24.3° +/- 0.2°. In still other embodiments, the Valomaciclovir polymorph has 2-theta angles of 22.9° +/- 0.2°, 18.6° +/- 0.2°, 19.5° +/- 0.2°, 24.3° +12 0.2°, 20.8° +/- 0.2°, 21.8° +/- 0.2°, and 27.0° +/- 0.2°. In still other embodiments, the Valomaciclovir polymorph has 2-theta angles of 22.9° +/- 0.2°, 18.6° +/- 0.2°, 19.5° +/- 0.2°, 24.3° +/- 0.2°, 20.8 +/- 0.2°, 21.8° +/- 0.2°, 27.0° +/- 0.2°, 14.7° +/- 0.2°, and 15.5° +/- 0.2°. In still other embodiments, the Valomaciclovir polymorph has 2-theta angles of 22.9° +/- 0.2°, 18.6° +/- 0.2°, 19.5° +/- 0.2°, 24.3° +/- 0.2°, 20.8° +/- 0.2°, 21.8 +/- 0.2°, 27.0 +/- 0.2°, 14.7° +/- 0.2°, 15.5° +/- 0.2°, 25.5° +/- 0.2°, and 29.9° +/- 0.2°. [0056] In some embodiments, the Valomaciclovir polymorph has the characteristic DSC features of an endotherm from about 105 ⁰ C to about 125°C and centered near 1 15 ⁰ C (typically 20-30 J/g) and a melting endotherm from about 170 ⁰ C to about 18O ⁰ C, and centered near 171 ⁰ C (typically around 20-30 J/g).

[0057] In some embodiments, the Valomaciclovir polymorph has Carr index value range from about 35 to about 50, particle size range from about 10 to about 300 microns, a residue on ignition of not more than 0.2%, moisture content of not more than 1.0%, residual solvents not more than as defined above, or purity of not less than 97%.

[0058] The antiviral agents and MS drugs described herein may be identified either by their chemical structure and/or chemical name. The antiviral agents and MS drugs described herein may contain one or more chiral centers and/or double bonds

3850-0001.40 PATENT and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers or diastereomers. Accordingly, when stereochemistry at chiral centers is not specified, the chemical structures depicted herein encompass all possible configurations at those chiral centers including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan. The antiviral agents and MS drugs described herein may also exist in several tautomeric forms including the enol form, the keto form and mixtures thereof. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated antiviral agents and MS drugs described herein. The antiviral agents and MS drugs described herein also include isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass conventionally found in nature. Examples of isotopes that may be incorporated into the antiviral agents and MS drugs described herein include, but are not limited to, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, and ¹⁸ O. The antiviral agents and MS drugs described herein may exist in unsolvated forms as well as solvated forms, including hydrated forms and as N-oxides. In general, the hydrated, solvated and N-oxide forms are within the scope of the present disclosure. Certain antiviral agents and MS drugs described herein may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present disclosure.

[0059] The antiviral agents and MS drugs described herein are commercially available or may be synthesized by methods described in the art. Accordingly, obtention of antiviral agents and MS drugs described herein is well within the ambit of those skilled in the art

Section IH: Therapeutic Methods of Use [0060] In some embodiments, a therapeutically effective amount of an antiviral agent or a pharmaceutically acceptable salt, hydrate or solvate thereof or a pharmaceutical composition thereof is administered to a subject suffering from MS. In other embodiments, a therapeutically effective amount of an antiviral agent or a

3850-0001.40 PATENT pharmaceutically acceptable salt, hydrate or solvate thereof or a pharmaceutical composition thereof and a therapeutically effective amount of a MS drug or a pharmaceutically acceptable salt, hydrate or solvate thereof or a pharmaceutical composition thereof are administered to a subject suffering from MS. [0061] In some embodiments, a therapeutically effective amount of an antiviral agent or a pharmaceutically acceptable salt, hydrate or solvate thereof or a pharmaceutical composition thereof is administered to a subject as a preventive measure against developing MS. In other embodiments, a therapeutically effective amount of an antiviral agent or a pharmaceutically acceptable salt, hydrate or solvate thereof or a pharmaceutical composition thereof and a therapeutically effective amount of a MS drug or a pharmaceutically acceptable salt, hydrate or solvate thereof or a pharmaceutical composition thereof are administered to a subject as a preventive measure against developing MS. [0062] In some embodiments, a therapeutically effective amount of an antiviral agent or a pharmaceutically acceptable salt, hydrate or solvate thereof or a pharmaceutical composition thereof and a therapeutically effective amount of a MS drug or a pharmaceutically acceptable salt, hydrate or solvate thereof or a pharmaceutical composition thereof are administered to a subject suffering from a viral infection. [0063] In some embodiments, a therapeutically effective amount of an antiviral agent or a pharmaceutically acceptable salt, hydrate or solvate thereof or a pharmaceutical composition thereof and a therapeutically effective amount of a MS drug or a pharmaceutically acceptable salt, hydrate or solvate thereof or a pharmaceutical composition thereof are administered to a subject as a preventive measure against developing a viral infection.

[0064] In some embodiments, a therapeutically effective amount of an antiviral agent or a pharmaceutically acceptable salt, hydrate or solvate thereof or a pharmaceutical composition thereof and a therapeutically effective amount of a MS drug or a pharmaceutically acceptable salt, hydrate or solvate thereof or a pharmaceutical composition thereof, are administered separately. In other embodiments, a therapeutically effective amount of an antiviral agent or a pharmaceutically acceptable salt, hydrate or solvate thereof or a pharmaceutical composition thereof and a therapeutically effective amount of a MS drug or a pharmaceutically acceptable salt, hydrate or solvate thereof or a pharmaceutical

3850-0001.40 PATENT composition thereof are admixed prior to administration to the subject. In still other embodiments, a therapeutically effective amount of an antiviral agent or a pharmaceutically acceptable salt, hydrate or solvate thereof or a pharmaceutical composition thereof is administered immediately before, concurrently or immediately after the administration of one daily dose of a therapeutically effective amount of a MS drug or a pharmaceutically acceptable salt, hydrate or solvate thereof or a pharmaceutical composition thereof and the remaining daily doses of the therapeutically effective amount of a MS drug or a pharmaceutically acceptable salt, hydrate or solvate thereof or a pharmaceutical composition thereof are administered alone, i.e., without the antiviral agent or a pharmaceutically acceptable salt, hydrate or solvate thereof or a pharmaceutical composition thereof.

3850-0001.40 PATENT

Section IV: Pharmaceutical Compositions

[0065] Pharmaceutical compositions comprising antiviral agents or combinations of antiviral agents and MS drugs described herein may be manufactured by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. Pharmaceutical compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries, which facilitate processing of antiviral agents or combinations of antiviral agents and MS drugs described herein into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.

[0066] The present pharmaceutical compositions can take the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use. In some embodiments, the pharmaceutically acceptable vehicle is a capsule (see e.g., Grosswald et al, United States Patent No. 5,698,155). Other examples of suitable pharmaceutical vehicles have been described in the art (see Remington: The Science and Practice of Pharmacy, Philadelphia College of Pharmacy and Science, 20 ^th Edition, 2000). [0067] For topical administration antiviral agents or combinations of antiviral agents and MS drugs described herein may be formulated as solutions, gels, ointments, creams, suspensions, etc. as is well-known in the art. [0068] Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral or pulmonary administration. Systemic formulations may be made in combination with a further active agent that improves mucociliary clearance of airway mucus or reduces mucous viscosity. These active agents include, but are not limited to, sodium channel blockers, antibiotics, N-acetyl cysteine, homocysteine and phospholipids. [0069] In some embodiments, antiviral agents or combinations of antiviral agents and MS drugs described herein are formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings. Typically, antiviral agents or combinations of antiviral agents and MS drugs for intravenous administration are solutions in sterile isotonic aqueous buffer. For injection, an antiviral agent or a combination of antiviral agents and MS drug

3850-0001.40 PATENT described herein may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer. The solution may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. When necessary, the pharmaceutical compositions may also include a solubilizing agent.

[0070] Pharmaceutical compositions for intravenous administration may optionally include a local anesthetic such as lignocaine to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent. When the pharmaceutical composition is administered by infusion, it can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline. When the pharmaceutical composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.

[0071] For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. [0072] Pharmaceutical compositions for oral delivery may be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, for example. Orally administered pharmaceutical compositions may contain one or more optional agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry coloring agents and preserving agents, to provide a pharmaceutically palatable preparation.

[0073] Moreover, when in tablet or pill form, the pharmaceutical compositions may be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over an extended period of time. Selectively permeable membranes surrounding an osmotically active driving compound are also suitable for orally administered pharmaceutical compositions. In these later platforms, fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells to displace the agent or agent composition through an aperture. These delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations. A time

3850-0001.40 PATENT delay material such as glycerol monostearate or glycerol stearate may also be used. Oral compositions can include standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. [0074] For oral liquid preparations such as, for example, suspensions, elixirs and solutions, suitable carriers, excipients or diluents include water, saline, alkyleneglycols (e.g., propylene glycol), polyalkylene glycols (e.g., polyethylene glycol) oils, alcohols, slightly acidic buffers between pH 4 and pH 6 (e.g., acetate, citrate, ascorbate at between about 5.0 mM to about 50.0 mM) etc. Additionally, flavoring agents, preservatives, coloring agents, bile salts, acylcarnitines and the like may be added.

[0075] For buccal administration, the pharmaceutical compositions may take the form of tablets, lozenges, etc. formulated in conventional manner. [0076] Liquid drug formulations suitable for use with nebulizers and liquid spray devices and EHD aerosol devices will typically include an antiviral agent or combination of antiviral agents and MS drug described herein with a pharmaceutically acceptable vehicle. In some embodiments, the pharmaceutically acceptable vehicle is a liquid such as alcohol, water, polyethylene glycol or a perfluorocarbon. Optionally, another material may be added to alter the aerosol properties of the solution or suspension of combinations of antiviral agents and MS drugs described herein. In some embodiments, this material is liquid such as an alcohol, glycol, polyglycol or a fatty acid. Other methods of formulating liquid drug solutions or suspension suitable for use in aerosol devices are known to those of skill in the art (see, e.g., Biesalski, United States Patent No. 5,112,598; Biesalski, United States Patent No. 5,556,611). [0077] An antiviral agent or combination of antiviral agents and MS drug described herein may also be formulated in rectal or vaginal pharmaceutical compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides. [0078] In addition to the formulations described previously, an antiviral agent thereof or combination of antiviral agents and MS drug or thereof described herein may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, an antiviral agent or combination of antiviral agents and MS drug described herein may be formulated with suitable

3850-0001.40 PATENT polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

3850-0001.40 PATENT

Section V: Methods of Administration and Dosages

[0079] When used to treat and/or prevent diseases or disorders, the antiviral agents and/or pharmaceutical compositions thereof or the combinations of antiviral agents and MS drugs described herein and/or pharmaceutical compositions may be administered or applied singly, or in combination with other agents. The antiviral agents and/or pharmaceutical compositions thereof or combinations of antiviral agents and MS drugs and/or pharmaceutical compositions thereof may also be administered or applied singly, in combination with other active agents. [0080] Methods of treatment and prophylaxis by administration to a subject of a therapeutically effective amount of an antiviral agent and/or pharmaceutical compositions thereof or a therapeutically effective amount of a combination of antiviral agents and MS drug described herein and/or pharmaceutical composition thereof are provided herein. [0081] In some embodiments, the antiviral agents and/or pharmaceutical compositions thereof or the combinations of antiviral agents and MS drugs described herein and/or pharmaceutical compositions thereof, are administered orally. The antiviral agents and/or pharmaceutical compositions thereof or combinations of antiviral agents and MS drugs described herein and/or pharmaceutical compositions thereof may also be administered by any other convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.). Administration can be systemic or local. Various delivery systems are known, (e.g., encapsulation in liposomes, microparticles, microcapsules, capsules, etc.) that can be used to administer a antiviral agent and/or pharmaceutical composition thereof or a combination of antiviral agents and MS drug described herein and/or pharmaceutical composition thereof. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, intravaginal, transdermal, rectally, by inhalation, or topically, particularly to the ears, nose, eyes, or skin. The mode of administration is left to the discretion of the practitioner and will depend in-part upon the site of the medical condition. In most instances, administration will result in the release of the antiviral agents and/or pharmaceutical compositions thereof or the combinations of antiviral agents and MS drugs and/or pharmaceutical compositions thereof into the bloodstream.

3850-0001.40 PATENT

[0082] In other embodiments, it may be desirable to administer one or more antiviral agents and/or pharmaceutical compositions thereof or one or more combinations of antiviral agents and MS drugs described herein and/or pharmaceutical compositions thereof locally to the area in need of treatment. This may be achieved, for example, and not by way of limitation, by local infusion during surgery, topical application, e.g., in conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers. In some embodiments, administration can be by direct injection at the site (or former site) of the condition. [0083] In still other embodiments, it may be desirable to introduce one or more antiviral agents and/or pharmaceutical compositions thereof or one or more combinations of antiviral agents and MS drugs described herein and/or pharmaceutical compositions thereof into the central nervous system by any suitable route, including intraventricular, intrathecal and epidural injection. Intraventricular injection may be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir.

[0084] An antiviral agent and/or pharmaceutical composition thereof or a combination of antiviral agents and MS drug described herein and/or pharmaceutical composition thereof may also be administered directly to the lung by inhalation. For administration by inhalation, an antiviral agent and/or pharmaceutical composition thereof or a combination of antiviral agents and MS drug described herein and/or pharmaceutical composition thereof may be conveniently delivered to the lung by a number of different devices. For example, a Metered Dose Inhaler ("MDI"), which utilizes canisters that contain a suitable low boiling propellant, (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or any other suitable gas) may be used to deliver antiviral agents and/or pharmaceutical compositions thereof or combinations of antiviral agents and MS drugs described herein and/or pharmaceutical compositions thereof directly to the lung.

[0085] Alternatively, a Dry Powder Inhaler ("DPI") device may be used to administer an antiviral agent and/or pharmaceutical composition thereof or a combination of antiviral agents and MS drug described herein and/or pharmaceutical composition thereof to the lung. DPI devices typically use a mechanism such as a

3850-0001.40 PATENT burst of gas to create a cloud of dry powder inside a container, which may then be inhaled by the subject. DPI devices are also well known in the art. A popular variation is the multiple dose DPI ("MDDPI") system, which allows for the delivery of more than one therapeutic dose. For example, capsules and cartridges of gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of an antiviral agent and/or pharmaceutical composition thereof or a combination of antiviral agents and MS drug or pharmaceutical composition thereof herein and a suitable powder base such as lactose or starch for these systems. [0086] Another type of device that may be used to deliver an antiviral agent and/or pharmaceutical composition thereof or combination of antiviral agents and MS drug described herein and/or pharmaceutical composition thereof to the lung is a liquid spray device supplied, for example, by Aradigm Corporation, Hayward, CA. Liquid spray systems use extremely small nozzle holes to aerosolize liquid drug formulations that may then be directly inhaled into the lung. [0087] In still other embodiments, a nebulizer is used to deliver an antiviral agent and/or pharmaceutical composition thereof or a combination of antiviral agents and MS drug described herein and/or pharmaceutical composition thereof to the lung. Nebulizers create aerosols from liquid drug formulations by using, for example, ultrasonic energy to form fine particles that may be readily inhaled (see e.g., Verschoyle et al, British J. Cancer, 1999, 80, Suppl. 2, 96). Examples of nebulizers include devices supplied by Sheffield Pharmaceuticals, Inc (See, Armer et al, United States Patent No. 5,954,047; van der Linden et al., United States Patent No. 5,950,619; van der Linden et al, United States Patent No. 5,970,974), and Batelle Pulmonary Therapeutics, Columbus, OH. [0088] In still other embodiments, an electrohydrodynamic ("EHD") aerosol device is used to deliver an antiviral agent and/or pharmaceutical composition thereof or a combination of antiviral agents and MS drug described herein and/or pharmaceutical composition thereof to the lung. EHD aerosol devices use electrical energy to aerosolize liquid drug solutions or suspensions (see e.g., Noakes et al, United States Patent No. 4,765,539). The electrochemical properties of the formulation may be important parameters to optimize when delivering an antiviral agent and/or pharmaceutical composition thereof or a combination of antiviral agents and MS drug described herein and/or pharmaceutical composition thereof to the lung with an EHD aerosol device and such optimization is routinely performed by one of

3850-0001.40 PATENT skill in the art. EHD aerosol devices may more efficiently deliver antiviral agents or combinations of antiviral agents and MS drugs to the lung than other pulmonary delivery technologies.

[0089] In still other embodiments, the antiviral agents and/or pharmaceutical composition thereof or the combinations of antiviral agents and MS drugs described herein and/or pharmaceutical compositions thereof can be delivered in a vesicle, in particular a liposome (Langer, 1990, Science 249:1527-1533; Treat et al, in "Liposomes in the Therapy of Infectious Disease and Cancer," Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); see generally "Liposomes in the Therapy of Infectious Disease and Cancer," Lopez-Berestein and Fidler (eds.), Liss, New York, pp.353-365 (1989)).

[0090] In still other embodiments, the antiviral agents and/or pharmaceutical composition thereof or the combinations of antiviral agents and MS drugs described herein and/or pharmaceutical compositions thereof can be delivered via sustained release systems, preferably oral sustained release systems. In some embodiments, a pump may be used (See, Langer, supra, Sefton, 1987, CRC Crit. Ref. Biomed Eng. 14:201; Saudek ef α/., 1989, N. Engl. J Med. 321:574).

[0091] In still other embodiments, polymeric materials can be used (see

"Medical Applications of Controlled Release," Langer and Wise (eds.), CRC Pres., Boca Raton, Florida (1974); "Controlled Drug Bioavailability," Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Langer et al, 1983, J Macromol. ScL Rev. Macromol Chem. 23:61 ; see also Levy et al., 1985, Science 228: 190; During et al, 1989, Ann. Neurol 25:351; Howard et al, 1989, J. Neurosurg. 71: 105). [0092] In still other embodiments, polymeric materials are used for oral sustained release delivery. Exemplary polymers include sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and hydroxyethylcellulose. Other cellulose ethers have been described (Alderman, Int. J. Pharm. Tech. & Prod. Mfr., 1984, 5(3) 1-9). Factors affecting drug release are well known to the skilled artisan and have been described in the art (Bamba et al, Int. J. Pharm., 1979, 2, 307).

[0093] In still other embodiments, enteric-coated preparations can be used for oral sustained release administration. Exemplary coating materials include polymers with a pH-dependent solubility (i.e., pH-controlled release), polymers with a slow or

3850-0001.40 PATENT pH-dependent rate of swelling, dissolution or erosion (i.e., time-controlled release), polymers that are degraded by enzymes (i.e., enzyme-controlled release) and polymers that form firm layers that are destroyed by an increase in pressure (i.e., pressure-controlled release). [0094] In still other embodiments, osmotic delivery systems are used for oral sustained release administration (Verma et al, Drug Dev. Ind. Pharm., 2000, 26:695-708). In yet other embodiments, OROS™ osmotic devices are used for oral sustained release delivery devices (Theeuwes et al, United States Patent No. 3,845,770; Theeuwes et al, United States Patent No. 3,916,899). [0095] In still other embodiments, a controlled-re lease system can be placed in proximity of the target of the antiviral agents and/or pharmaceutical composition thereof or combinations of antiviral agents and MS drugs and/or pharmaceutical composition of the invention, thus requiring only a fraction of the systemic dose (See, e.g., Goodson, in "Medical Applications of Controlled Release," supra, vol. 2, pp. 1 15-138 (1984). Other controlled-release systems discussed in Langer, 1990, Science 249: 1527-1533 may also be used.

[0096] An antiviral agent and/or pharmaceutical composition thereof or a combination of antiviral agents and MS drug described herein, and/or pharmaceutical composition thereof, will generally be used in an amount effective to achieve the intended purpose. For use to treat or prevent diseases or disorders the antiviral agents and/or pharmaceutical compositions thereof or combinations of antiviral agents and MS drugs described herein and/or pharmaceutical compositions thereof, are administered or applied in a therapeutically effective amount. [0097] The amount of an antiviral agent and/or pharmaceutical composition thereof or a combination of antiviral agents and MS drug described herein and/or pharmaceutical composition thereof, which will be effective in the treatment of a particular disorder or condition disclosed herein, will depend on the nature of the disorder or condition and can be determined by standard clinical techniques known in the art. In addition, in vitro or in vivo assays may optionally be employed to help identify optimal dosage ranges. The amount of an antiviral agent and/or pharmaceutical composition thereof or a composition described herein and/or pharmaceutical composition thereof administered, will, of course, be dependent on, among other factors, the subject being treated, the weight of the subject, the severity

3850-0001.40 PATENT of the affliction, the manner of administration and the judgment of the prescribing physician.

[0098] For example, the dosage may be delivered in a pharmaceutical composition by a single administration, by multiple applications or controlled release. Dosing may be repeated intermittently, may be provided alone or in combination with other drugs and may continue as long as required for effective treatment of the disease state or disorder.

[0099] Suitable dosage ranges for oral administration depend on potency, but are generally between about 0.001 mg to about 200 mg of an antiviral agent or combination of antiviral agents and MS drug described herein per kilogram body weight. Dosage ranges may be readily determined by methods known to the artisan of ordinary skill the art.

[00100] Suitable dosage ranges for intravenous (i.v.) administration are about

0.01 mg to about 100 mg per kilogram body weight. Suitable dosage ranges for intranasal administration are generally about 0.01 mg/kg body weight to about 1 mg/kg body weight. Suppositories generally contain about 0.01 milligram to about 50 milligrams of an antiviral agent or combination of antiviral agents and MS drug described herein per kilogram body weight and comprise active ingredient in the range of about 0.5% to about 10% by weight. Recommended dosages for intradermal, intramuscular, intraperitoneal, subcutaneous, epidural, sublingual or intracerebral administration are in the range of about 0.001 mg to about 200 mg per kilogram of body weight. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems. Such animal models and systems are well-known in the art. [00101] A therapeutically effective dose of an antiviral agent and/or pharmaceutical composition thereof or a combination of antiviral agents and MS drugs described herein will provide therapeutic benefit without causing substantial toxicity. Toxicity of antiviral agents or combinations of antiviral agents and MS drugs described herein may be determined using standard pharmaceutical procedures and may be readily ascertained by the skilled artisan. The dose ratio between toxic and therapeutic effect is the therapeutic index. An antiviral agent or combination of antiviral agents and MS drug described herein will preferably exhibit particularly high therapeutic indices in treating disease and disorders. The dosage of an antiviral agent

3850-0001.40 PATENT or described herein described herein will preferably be within a range of circulating concentrations that include an effective dose with little or no toxicity. [00102] In some embodiments, the daily dose of an antiviral agent, for example valomaciclovir, administered to the subject may range from about 0.1 gram to about 8 grams per day, given in one daily dose or 2-5 divided doses. In other embodiments, the daily dose of an antiviral agent will comprise a mixture of antiviral agents, for example valomaciclovir and valganciclovir, administered to the subject and may range from about 0.1 gram to about 8 grams per day, given in one daily dose or 2-5 divided doses. In some embodiments, valomaciclovir and valganciclovir are co- administered. In other embodiments, valomaciclovir and valganciclovir are administered on separate dosing schedules.

[00103] In some embodiments, the daily dose of the MS drug, for example, interferon administered to the subject may range from about 0.1 milligrams to about 0.75 milligrams, given in one daily dose or 2-5 divided doses. In other embodiments, the daily dose of the MS drug will comprise a mixture of MS drugs, for example, interferon and natalizumab administered to the subject and may range from about 0.1 milligrams to about 0.75 milligrams of interferon and about 100 milligrams to about 400 milligrams of natalizumab, in one daily dose or 2-5 divided doses. In some embodiments, interferon and natalizumab are co-administered. In other embodiments, interferon and natalizumab are administered on separate dosing schedules.

[00104] In some embodiments, the daily dose will comprise a mixture of at least one antiviral agent and at least one MS agent, for example, valomaciclovir and interferon, administered to the subject and may range from about 0.1 gram to about 8 grams of valomaciclovir and about 0.1 milligrams to about 0.75 milligrams of interferon, in one daily dose or 2-5 divided doses. In some embodiments, valomaciclovir and interferon are co-administered. In other embodiments, valomaciclovir and interferon are administered on separate dosing schedules. [00105] In some embodiments, a patient diagnosed with MS is treated with use of an antiviral directed against EBV, such as for example, valomaciclovir dosed 2 g BID orally for 4 weeks prior to the introduction of an immunomodulatory agent, including but not limited to, a monoclonal antibody, type I or type II interferon, laquinimod and/or an integrin antagonist affecting white blood cell chemotaxis. Subsequently, the patient is maintained on a chronic dose of an antiviral such as, for example, valomaciclovir 2 g BID for 6 months or longer in accordance with the

3850-0001.40 PATENT methods described herein or the patient is switched to a maintenance dose after the initial four-week loading dose.

Section VI. Kits: [00106] Therapeutic kits comprising therapeutically effective amounts of antiviral agents or pharmaceutically acceptable salts, hydrates or solvates thereof or pharmaceutical compositions thereof and MS drugs or pharmaceutically acceptable salts, hydrates or solvates thereof or pharmaceutical compositions thereof are also provided herein. The therapeutic kits may also contain other compounds or pharmaceutical compositions of these other compounds.

[00107] Therapeutic kits may have a single container which contains the antiviral agents or pharmaceutically acceptable salts, hydrates or solvates thereof or pharmaceutical compositions thereof and MS drugs or pharmaceutically acceptable salts, hydrates or solvates thereof or pharmaceutical compositions thereof with or without other components (e.g., other compounds or pharmaceutical compositions of these other compounds) or may have distinct container for each component. [00108] The components of the kit may be provided in one or more liquid solutions, e.g., an aqueous solution, e.g., a sterile aqueous solution. The components of the kit may also be provided as solids, which may be converted into liquids by addition of suitable solvents, which may be provided in another distinct container. [00109] The container of a therapeutic kit may be a vial, test tube, flask, bottle, syringe, or any other means of enclosing a solid or liquid. Usually, when there is more than one component, the kit will contain a second vial or other container, which allows for separate dosing. The kit may also contain another container for a pharmaceutically acceptable liquid.

[00110] In some embodiments, the therapeutic kit will contain apparatus (e.g., one or more needles, syringes, eye droppers, pipette, etc.), which enables administration of the components of the kit and written instructions for using and administering the components of the kit. [00111] In some embodiments, the antiviral agent or pharmaceutically acceptable salts, hydrates or solvates thereof or pharmaceutical compositions thereof is orally administered while the MS agent or pharmaceutically acceptable salts, hydrates or solvates thereof or pharmaceutical compositions thereof is delivered intravenously. In other embodiments, the antiviral agent or pharmaceutically

3850-0001.40 PATENT acceptable salts, hydrates or solvates thereof or pharmaceutical compositions thereof is delivered intravenously while the MS agent or pharmaceutically acceptable salts, hydrates or solvates thereof or pharmaceutical compositions thereof is orally administered. [00112] The ability of particular combinations of antiviral agents and MS drugs to treat and/or prevent MS can be tested in animal models, well known in the art. For example, experimental autoimmune encephalomyelitis (EAE) mice and rats are scientifically recognized models for studying MS and can be used to determine the efficiacy of the combinations described herein.

Section VII. Examples:

[00113] The invention will now be described in greater detail by reference to the following non-limiting examples.

3850-0001.40 PATENT

[00114]

[00115] Treatment Example 1. An adult human diagnosed with MS is treated with valomaciclovir dosed 2g BID orally for 6 months or longer in accordance with the methods described herein.

[00116] Treatment Example 2. An adult human diagnosed with MS is treated with valomaciclovir dosed 2g BID orally for 6 months or longer in accordance with the methods of the invention. Concurrently, the subject is treated with valganciclovir dosed 900 mg QD orally for 6 months or longer in accordance with the methods described herein.

[00117] Treatment Example 3. An adult human diagnosed with MS is treated with rituximab (Rituxan) dosed 375 mg/m ² given as an IV infusion once weekly for four doses (days 1, 8, 15, and 22). Following rituximab treatment, the subject is treated with valomaciclovir dosed 2g BID orally for 6 months or longer in accordance with the methods described herein.

[00118] Treatment Example 4. An adult human diagnosed with MS is treated with rituximab (Rituxan) dosed 375 mg/m ² given as an IV infusion once weekly for four doses (days 1, 8, 15, and 22). Concurrently, the subject is treated with valomaciclovir dosed 2g BID orally for 6 months or longer in accordance with the methods described herein.

[00119] Treatment Example 5. An adult human diagnosed with MS is treated with a single dose of rituximab (Rituxan) dosed at 375 mg/m ² given as an IV infusion.

3850-0001.40 PATENT

Concurrently, the subject is treated with an induction dose of valomaciclovir at 2g BID orally for 1 month, followed by a suppression dose of valomaciclovir at Ig QD orally for 6 months or longer in accordance with the methods described herein. [00120] Treatment Example 6. An adult human diagnosed with MS is treated with a single dose of rituximab (Rituxan) dosed at 375 mg/m ² given as an IV infusion. Following rituximab treatment, the subject is treated with valomaciclovir dosed 2g BID orally for 6 months or longer in accordance with the methods described herein. [00121] Treatment Example 7. An adult human diagnosed with MS is treated with a single dose of rituximab (Rituxan) dosed at 375 mg/m ² given as an IV infusion. Concurrently, the subject is treated with valomaciclovir dosed 2g BID orally for 6 months or longer in accordance with the methods described herein. [00122] Treatment Example 8. An adult human diagnosed with MS is treated with a single dose of rituximab (Rituxan) dosed at 375 mg/m ² given as an IV infusion. Concurrently, the subject is treated with an induction dose of valomaciclovir at 2g BID orally for 1 month, followed by a suppression dose of valomaciclovir at Ig QD orally for 6 months or longer in accordance with the methods described herein. [00123] Treatment Example 9. An adult human diagnosed with MS is pretreated with valomaciclovir 2g BID orally daily for over 4 weeks prior to the initiation of rituximab dosing. Upon completion of the pretreatment period with valomaciclovir, the subject is treated with rituximab (Rituxan) dosed 375 mg/m ² given as an IV infusion once weekly for four doses (days 1, 8, 15, and 22). Concurrently, the subject is treated with valomaciclovir dosed 2g BED orally for 6 months or longer in accordance with the methods described herein. [00124] Treatment Example 10. An adult human diagnosed with MS is treated with 30 meg of Interferon beta-la (Avonex) by IM injection once weekly for 2 years. Concurrently, the subject is treated with valomaciclovir dosed 2g BID orally for 2 years or longer in accordance with the methods described herein. [00125] Treatment Example 11. An adult human diagnosed with relapsing MS is treated with 300 mg IV infusion of natalizumab (Tysabri) every 4 weeks for 28 months. Concurrently, the subject is treated with valomaciclovir dosed 2g BID orally for 28 months or longer in accordance with the methods described herein. [00126] Treatment Example 12. An adult human diagnosed with MS is treated with rituximab (Rituxan) dosed 375 mg/m ² given as an IV infusion once weekly for four doses (days 1, 8, 15, and 22). Simultaneously the subject is treated with both

3850-0001.40 PATENT valomaciclovir dosed 2g BID and valganciclovir dosed 900 mg QD orally for 6 months or longer in accordance with the methods described herein. [00125] Treatment Example 13. An adult human diagnosed with MS is treated with rituximab (Rituxan) dosed 375 mg/m ² given as an IV infusion once weekly for four doses (days 1, 8, 15, and 22). Simultaneously the subject is treated with both valomaciclovir dosed 2g BID for 2 years or longer in accordance with the methods of the invention. Concurrently, the subject is also treated with 30 meg of Interferon beta- la (Avonex) by IM injection once weekly for 2 years. [00126] Recrystallization process for Valomaciclovir polymorph Example 14. The production of valomaciclovir and valomaciclovir polymorphs is described in detail in U.S. Provisional Application 60/994,719, filed September 21, 2007 and PCT Application entitled "Valomaciclovir Polymorphs" filed on even date herewith, which applications are incorporated herein by reference in their entireties. To a 2L round bottom flask, equipped with mechanical stirring, oil bath controlled by a model 210 T J KEM temperature controller/thermocouple, internal thermocouple attached to a Yokagowa temperature recorder and a drying tube was added 110 g of valomaciclovir, 1.1 L of a premixed solution consisting of 55 mL of 2 propanol (Fisher, lot 050564) and 1045 mL of 200 proof ethanol (Aaper, lot 06128WA) (The equivalent of SDA 3C Denatured anhydrous alcohol). The resulting stirred mixture was heated to an internal temperature of 72 ⁰ C, which achieved almost complete dissolution of the solids. The heating process occurred over about one half hour. The bulk of the solids went into solution readily; the last bits required stirring at about 72 ⁰ C internal temperature for 30 minutes to achieve complete dissolution. The internal temperature was allowed to reach as high as 74 ⁰ C* The solution was then cooled at a rate of 10 ⁰ C per hour**, with stirring throughout the cooling cycle. The solids by and large crystallized out of solution when the internal temperature reached between 55 and 61 ⁰ C. There was a 2 ⁰ C exotherm as a result of the crystallization. Stirring was continued for one hour after coming to room temperature (approximately 25 ⁰ C), the resulting mixture was filtered and the resulting solid was air dried and then vacuum oven dried overnight (50 ⁰ C, approximately half an atmosphere of vacuum, slow nitrogen sweep), to afford 106 g of a white solid (52772-10-6).

* HPLC evidence (Column: Phenomenex Inersil ODS-2, 250 x 4.6 mm, 5microm particle size; Mobile Phase: 0.2% perchloric acid in 62:38

3850-0001.40 PATENT

Acetonitrile:water/ Acetonitrile; Gradient: 0 to 95% over 25 minutes; Flow Rate: 1.5 mL/min; Detection: 254 nm) suggests that by extending the timing of the crystallization (to include an overnight stir of the suspension after crystallization), an impurity (guanine stearate alcohol) builds to about 0.9 area%, from an original starting level of about 0.3 area%. By following the times and temperatures quoted, the build of the impurity is limited to 0.6 area%, which is currently considered acceptable.

** Cooling rates ranging from 5 ⁰ C per hour about 12 ⁰ C per hour have been explored, and found to afford product of comparable chemical purity and polymorphic form.

[00127] Although the foregoing invention has been described in some detail by way of illustration for purposes of clarity and understanding, it will be apparent to those of ordinary skill in the art in light of the teachings above that certain changes and modifications may be made thereto without departing from the spirit or scope of the claims.