(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property
`Organization
`International Bureau
`
`
`
`(43) International Publication Date
`22 December 2005 (22.12.2005)
`
`(10) International Publication Number
`WO 2005/120542 A2
`
`(51) International Patent Classification7:
`A61P 25/00
`
`A61K 38/02,
`
`(21) International Application Number:
`PCT/US2005/016340
`
`(22) International Filing Date:
`
`9 May 2005 (09.05.2005)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(74)
`
`(81)
`
`(30) Priority Data:
`60/569,292
`60/663,333
`
`7 May 2004 (07.05.2004)
`18 March 2005 (18.03.2005)
`
`US
`US
`
`(71) Applicant (for all designated States except US): PEPTIM-
`MUNE, INC. [US/US]; 64 Sidney Street, Suite 380, Cam—
`bridge, MA 02139 (US).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): RASMUSSEN,
`James [US/US]; 75 Cambridge Parkway, Unit E410,
`Cambridge, MA 02142 (US). ZHANG, Jianxin [US/US];
`2 Farley Lane, Acton, MA 01720 (US). BALDWIN, Sam
`
`[US/US]; 12 Almeria Circle, Westford, MA 01886 (US).
`ZANELLI, Eric [FR/US]; 160 Woodside Road, Sudbury,
`MA 01776 (US). YU, Bei [CN/US]; 72 Wlilowdean AV—
`enue, West Roxbury, MA 02132 (US). BONNIN, Dustan
`[US/US]; 35 Dalton Road, Belmont, MA 02478 (US).
`JOHNSON, Keith [US/US]; 35 Pleasant Street, Hudson,
`MA 01749 (US).
`
`Agents: TAKEUCHI, Erika et al.; c/o Fish & Neave IP
`Group of Ropes & Gray LLP, 1251 Avenue of the Ameri—
`cas, New York, NY 10020 (US).
`
`Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
`CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI,
`GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE,
`KG, KM, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA,
`MD, MG, MK, MN, MW, MX, MZ, NA, NG, NI, NO, NZ,
`OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL,
`SM, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC,
`VN, YU, ZA, ZM, ZW.
`
`(84)
`
`Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`
`[Continued on next page]
`
`(54) Title: METHODS OF TREATING DISEASE WITH RANDOM COPOLYMERS
`
`Antibody response against respective Copolymers
`— total 19 ELISA, day 37 —
`
`2.0‘
`
`1.5'
`
`OD
`450nm '
`
`V
`
`- El- Vehicle
`- A- {ED-14, 7.5 mg/kg daily
`"" (30-14, 7.5 mg/kg weekly
`' ‘7‘ Copaxone, 7.5 mg/kg daily
`""""" Copaxone, 7.5 mg/kg weekly
`
`
`
`5.
`
`
` . .
`10,000
`1,000,000
`100,000
`Serum dilution
`
`(57) Abstract: The invention relates to novel methods and kits for treating or preventing disease through the administration of
`random copolymers. The invention also relates to the treatment of autoimmune diseases, such as multiple sclerosis, and to the
`administration of random copolymers in treatment regimen comprising formulations that are administered at intervals greater than 24
`hours, or to sustained release formulations which administer the copolymer over a period greater than 24 hours. The invention further
`relates to methods for conducting a pharmaceutical business comprising manufacturing, licensing, or distributing kits containing or
`relating to the formulations or dosing regimens of random copolymer described herein.
`
`MYLAN INC. EXHIBIT NO. 1036 Page 1
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`2005/120542A2|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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`W0
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`|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
`
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
`FR, GB, GR, HU, IE, IS, IT, LT, LU, MC, NL, PL, PT, RO,
`SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN,
`GQ, GW, ML, MR, NE, SN, TD, TG).
`Published:
`
`— without international search report and to be republished
`upon receipt of that report
`
`For two—letter codes and other abbreviations, refer to the ”Guid—
`ance Notes on Codes and Abbreviations ” appearing at the begin—
`ning of each regular issue of the PCT Gazette.
`
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`WO 2005/120542
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`PCT/US2005/016340
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`METHODS OF TREATING DISEASE WITH RANDOM COPOLYMERS
`
`CROSS-REFERENCE TO RELATED APPLICATIONS
`
`This application claims priority to US. Provisional Application Ser. No. 60/569292
`
`filed May 7, 2004, and to US. Provisional Application Ser. No. 60/663333 filed March 18,
`
`2005.
`
`10
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`15
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`20
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`25
`
`BACKGROUND OF THE INVENTION
`
`An autoimmune disease results from an inappropriate immune response directed
`
`against a self antigen (an autoantigen), which is a deviation from the normal state of self-
`
`tolerance. Self—tolerance arises when the production of T cells and B cells capable of reacting
`
`against autoantigens has been prevented by events that occur in the early development of the
`
`immune system. The cell surface proteins that play a central role in regulation of immune
`
`responses through their ability to bind and present processed peptides to T cells are the major
`
`histocompatibility complex (MHC) molecules (Rothbard, J .B., et al., 1991, Annu. Rev. Immunol.
`
`9:527). Autoimmune diseases include rheumatoid arthritis (RA), multiple sclerosis (MS),
`
`human type I or insulin-dependent diabetes mellitus (IDDM), autoimmune uveitis, primary
`
`biliary cirrhosis (PBC) and celiac disease.
`
`One target for inhibition of an autoimmune response is the set of lymphocyte surface
`
`protein MHC molecules, particularly a protein encoded by an MHC class II gene, for example,
`
`HLA—DR, -DQ and —DP. Each of the MHC genes is found in a large number of alternative or
`
`allelic forms within a mammalian population. The genomes of subjects affected with certain
`
`autoimmune diseases, for example MS and RA, are more likely to carry one or more
`
`characteristic MHC class II alleles, to which that disease is linked.
`
`A number of therapeutic agents have been developed to treat autoimmune diseases,
`
`including general anti-inflammatory drugs such as COX-2 inhibitors, i.e., agents that can prevent
`
`formation of low molecular weight inflammatory compounds by inhibiting a cyclooxygenase;
`
`agents that can function by inhibiting a protein mediator of inflammation, for example, by
`
`sequestering the inflammatory protein tumor necrosis factor (TNF) with an anti-TNF specific
`
`monoclonal antibody or antibody fragment, or with a soluble form of the TNF receptor; and
`
`agents that target a protein on the surface of a T cell and generally prevent interaction with an
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`antigen presenting cell (APC) by inhibiting the CD4 receptor or the cell adhesion receptor
`
`ICAM-l. However, compositions having natural folded proteins as therapeutic agents can
`
`encounter problems in production, formulation, storage, and delivery. Several of these problems
`
`necessitate delivery to the patient in a hospital setting.
`
`An agent that interacts and binds relatively nonspecifically to several MHC class II
`
`molecules is Copolymer 1 (Cop 1), a synthetic amino acid heteropolymer that was shown to be
`
`capable of suppressing experimental allergic encephalomyelitis (EAE; Sela, M. et al., 1990,
`
`Bull. Inst. Pasteur (Paris)), which can be induced in the mouse and is a model for MS.
`
`Copolymer 1, which is poly(Y,E,A,K) also known as glatiramer acetate or "YEAK" using the
`
`one letter amino acid code (see infra; Y represents tyrosine, E glutamic acid, A alanine, and K
`
`lysine), has been used to treat relapsing forms of MS but does not suppress the disease entirely
`
`(Bornstein, M.B., et al., 1987, N. Engl. J Med. 3172408; Johnson, K.P. et al., 1995, Neurology
`
`45: 1268).
`
`'
`
`Although random copolymers may be effective for the treatment of autoimmune
`
`diseases (Simpson, D. et al., 2003, BioDrugs 17(3):207-10), their repeated administration may
`
`cause undesired side effects. Accordingly, there is a need for improved methods for the
`
`treatment of autoimmune diseases with random copolymers which result in fewer side effects.
`
`BRIEF SUMMARY OF THE INVENTION
`
`The invention provides methods and kits for the treatment or prevention of disease in
`
`a subject, preferably in a human. One aspect of the invention provides methods of treating or
`
`preventing a disease, the method comprising administering to said subject a dosing regimen of
`
`an effective amount of a random copolymer for the amelioration of a disease treatable with the
`
`random copolymer, said effective amount delivered to said subject at time intervals greater than
`
`24 hours, 36 hours, or more preferably greater than 48 hours. A related aspect of the invention
`
`provides a method for the treatment of a subject in need thereof, comprising administering to
`
`said subject a dosing regimen of an effective amount of a random copolymer for the
`
`amelioration of a disease treatable with the random copolymer, said effective amount delivered
`
`to the subject using a sustained-release formulation which administers the random copolymer
`
`over a period of at least 2 days, at least 4 days, or at least 6 days, wherein the effective amount is
`
`an amount that is effective if delivered daily. In some embodiments, the disease of the methods
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`10
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`15
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`20
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`25
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`30
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`2
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`of the present invention is mediated by T-cells, and in particular THl cells or cells with T H1
`
`immune posture, or is a disease which is exacerbated by an excess of inflammatory cytokines.
`
`In some embodiments, the disease is an autoimmune disease, such as multiple sclerosis. In some
`
`preferred embodiments, the random copolymer comprises tyrosine (Y), phenylalanine (F),
`
`alanine (A) and lysine (K) (YFAK copolymer). In other embodiments, the random copolymer is
`
`Copolymer l (YEAK). The invention is not limited to any particular random copolymer or
`
`mode of administration.
`
`10
`
`15
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`20
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`25
`
`The invention also provides kits for the treatment of disease. One aspect of the
`
`invention provides a kit for the treatment of an autoimmune disease comprising (i) a
`
`composition comprising a random copolymer and (ii) instructions for administering the
`
`composition to a subject at time intervals of at least 24 hours, or more preferably 36 or 48 hours
`
`or longer.
`
`In preferred embodiments, the composition is formulated for subcutaneous injection,
`
`the random copolymer is YFAK or Copolymer 1, and the disease is an autoimmune disease,
`
`such as multiple sclerosis, particularly relapsing-remitting multiple sclerosis.
`
`The invention further provides agents for the manufacture of medicaments to treat
`
`diseases. Any methods disclosed herein for treating or preventing a disease by administering a
`
`random copolymer to a subject may be applied to the use of the random copolymer in the
`
`manufacture of a medicament to treat that disease. Accordingly, one aspect of the invention
`
`provides the use of a random copolymer for the treatment of a disease in a subject, wherein the
`
`random copolymer is formulated to be administered to the subject at intervals greater than 24
`
`hours, 36 hours, and more preferably of at least 48 hours. In preferred embodiments, the random
`
`copolymer is Copolymer l (YEAK), and the disease is an autoimmune disease, such as multiple
`
`sclerosis, particularly relapsing-remitting multiple sclerosis.
`
`The invention further provides methods of conducting a pharmaceutical business.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`Figure 1 shows the effect of copolymer administration on the disease progression of
`
`EAE.
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`Figure 2. shows the survival rate of mice with EAE when administered with random
`
`copolymers.
`
`Figure 3 shows IgG antibody production against copolymers administered at daily or
`
`weekly doses.
`
`Figure 4 shows IgGl antibody production against copolymers administered at daily
`
`or weekly doses.
`
`Figure 5 shows IgG2b antibody production against copolymers administered at daily
`
`or weekly doses.
`
`Figure 6 shows the changes in antibody titer against copolymers during the time
`
`10
`
`course of a treatment.
`
`Figure 7 shows the IgGl antibody production against PLP peptide in mice
`
`administered with random copolymers.
`
`Figure 8 shows the IgG2b antibody production against PLP peptide in mice
`
`administered with random copolymers.
`
`15
`
`Figure 9 shows the ratio of IL-13 over IFN 7 in mice administered with random
`
`copolymers.
`
`Figure 10 shows the bias for induction of TH2 related cytokines compared to TH 1
`
`related cytokines in mice administered with random copolymers.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`20
`
`1. Overview
`
`The invention broadly relates to the treatment and prophylaxis of diseases by the
`
`administration of random copolymers, to the use of the random copolymers in the manufacture
`
`of medicaments to treat disease, and to kits comprising both random copolymers and
`
`instructions. The invention also relates to the treatment of autoimmune diseases and to long-
`
`25
`
`lasting random copolymer formulations for the treatment of disease.
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`One aspect of the invention provides a method for the treatment of a subject
`
`comprising administering to said subject a dosing regimen of an effective amount of a random
`
`copolymer for the amelioration of a disease treatable with the random copolymer, said effective
`
`amount delivered to said subject at time intervals greater than 36 hours. A related aspect of the
`
`invention provides a method for the treatment of a subject comprising administering to said
`
`subject a dosing regimen of an effective amount of at least one random copolymer for the
`
`amelioration of a disease treatable with the random copolymer, said effective amount of at least
`
`one copolymer being delivered to said subject at time intervals greater than 24 hours, and in
`
`particular greater than 48 hours. In one embodiment, the effective amount of the random
`
`copolymer that is administered at intervals greater than 24 hours is an amount that is effective
`
`when administered daily. In a related embodiment, the effective amount that is administered at
`
`intervals greater than 24 hours is an amount that would be effective if administered daily. In yet
`
`another related embodiment, the effective amount that is administered at intervals greater than
`
`24 hours is an amount that is known to be effective if administered daily. In an embodiment of
`
`this invention, the effective amount consists of between 10mg and 30mg, or between 15mg and
`
`25mg. In other embodiments, the effective amount is about 20mg. In another embodiment, the
`
`effective amount is less than 20mg. In specific embodiments, the effective amount is x mg,
`
`wherein “x” is any integer between 1 and 20.
`
`In one embodiment of the methods provided herein, the subject is afflicted with a
`
`disease treatable with the random copolymer. In one embodiment, the disease is mediated by T—
`
`cells, and in particular THl cells or cells with T H1 immune posture, or is a disease which is
`
`exacerbated by an excess of inflammatory cytokines.
`
`In another embodiment, the subject is
`
`afflicted with at least one autoimmune disease. In one embodiments, the subject is afflicted with
`
`at least one disease selected from the group consisting of multiple sclerosis, type—I diabetes,
`
`Hashimoto’s thyroiditis, Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus
`
`(SLE), gastritis, autoimmune hepatitis, hemolytic anemia, autoimmune hemophilia, autoimmune
`
`lymphoproliferative syndrome (ALPS), autoimmune uveoretinitis, glomerulonephritis, Guillain-
`
`Barré syndrome, psoriasis, myasthenia gravis, autoimmune encephalomyelitis, Goodpasture's
`
`syndrome, Grave's disease, paraneoplastic pemphigus, autoimmune thrombocytopenic purpura,
`
`scleroderrna with anti-collagen antibodies, mixed connective tissue disease, pernicious anemia,
`
`polymyositis, idiopathic Addison's disease, autoimmune-associated infertility,
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`10
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`30
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`glomerulonephritis, bullous pemphigoid, Sjogren's syndrome, idiopathic myxedema and colitis.
`
`In preferred embodiments, the disease is multiple sclerosis or relapsing-remitting multiple
`
`sclerosis. In additional embodiments of the methods provided herein, the disease is host-versus-
`
`graft disease (HVGD) or graft-versus-host disease (GVHD) or both. In preferred embodiments
`
`of the methods described herein, the subject is a mammal, or more preferably a human.
`
`In one embodiment of the methods described herein, the dosing regimen comprises
`
`intravenous, subcutaneous, intramuscular, intradermal, intraperitoneal, intradermal or oral
`
`administration. The random copolymer may also be administered via devices designed to
`
`deliver the random copolymer continuously, such as a transdermal patch or pump or implant.
`
`For example, a transdermal patch may be used to administer the random copolymer over a span
`
`of 12 hours every 48 hours or longer, or a pump may be used to administer the copolymer over a
`
`period of two days every four or more days. In a related aspect, the copolymer is administered in
`
`a sustained release formulation.
`
`The invention also provides a method for the treatment of a subject in need thereof
`
`comprising administering to said subject a dosing regimen of an effective amount of a random
`
`copolymer for the amelioration of a disease treatable with the random copolymer, said effective
`
`amount delivered to the subject using a sustained-release formulation which administers the
`
`random copolymer over a period of at least 2 days, at least 4 days, or at least 6 days, wherein the
`
`effective amount is an amount that is effective if delivered daily. In preferred embodiments, the
`
`sustained release formulation administers the copolymer over a period of at least 2, 3, 4, 5, 6, 7,
`
`8, 9, 10, 11, 12, 13 or 14 days. In another embodiment, the total dosage delivered daily by the
`
`sustained release formulation is less than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10% or
`
`5% of a daily dosage known to be effective in the treatment of the disease. In an specific
`
`embodiment, the sustained release formulation administers 25% or less, per day, of a dosage of a
`
`random copolymer which is known to be effective in treating the disease when administered
`
`daily. As an illustrative example, if Copolymer l (YEAK) is known to be effective in the
`
`treatment of relapsing-remitting multiple sclerosis when administered daily in dosages of 20mg,
`
`such as by one daily subcutaneous injection of 20mg, the invention provides sustained release
`
`formulations of Copolymer 1 which results in a daily administration of copolymer of less than
`
`10
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`15
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`20
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`20mg, and in particular less than about 10mg, 9mg, 8mg, 7mg, 6mg, 5mg, 4mg, 3mg, 2mg or
`
`1mg of Copolymer 1.
`
`In some embodiments of the methods described herein, the methods further comprise
`
`administering an additional therapeutically active agent to the subject, such as an anti-
`
`inflammatory agent. In preferred embodiments, the agent is useful in treating the disease. In
`
`another preferred embodiment, the agent synergizes with the random copolymer to treat the
`
`disease.
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`10
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`15
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`20
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`25
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`In some embodiments of the methods described herein, the dosing regimen comprises
`
`administering the random copolymer to the subject multiple times, with a time interval between
`
`each administration.
`
`In preferred embodiments, the time interval between each administration
`
`is at least 36, 48, 72, 96, 120, or 144 hours. In another preferred embodiment, the time interval
`
`between each administration is between 36 hours and 14 days, or at least 7 days. In a related
`
`embodiment, at least one of the time intervals between administrations is at least 36, 48, 72, 96,
`
`120, or 144 hours, at least 7 days, or between 36 hours and 14 days. In another related
`
`embodiment, at least 10%, 20%, 30%, 40% or more preferably 50% of the time intervals
`
`between administrations are at least 36, 48, 72, 96, 120, or 144 hours, at least 7 days, or between
`
`36 hours and 14 days. In yet another related embodiment, the average time interval between
`
`administrations is at least 36, 48, 72, 96, 120, or 144 hours, at least 7 days, or between 36 hours
`
`and 14 days.
`
`In some embodiments of the methods described herein, the effective amount of the
`
`random copolymer is between 0.02 mg per dose and 2000 mg per dose, or more preferably
`between 2 mg per dose and 200 mg per dose.
`
`In some embodiments of the methods described herein, the random copolymer is
`
`selected from the group consisting of Copolymer 1 (YEAK), YFAK, VYAK, VWAK, VEAK
`
`and FEAK.
`
`In a preferred embodiment, the random copolymer is Copolymer 1. In another
`
`preferred embodiment, the random copolymer is YFAK. In another embodiment, the random
`
`copolymer is a terpolymer, such as one selected from the group consisting of YAK, YEK, KEA
`
`and YEA. In yet another embodiment, the random copolymer has between one and 10 anchor
`
`residues.
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`The invention also provides kits for the treatment of disease. One aspect of the
`
`invention provides a kit for the treatment of an autoimmune disease comprising (i) a
`
`composition comprising a random copolymer and (ii) instructions for administering the
`
`composition to a subject at time intervals of at least 36 hours. In a preferred embodiment, the
`
`random copolymer in the kit is Copolymer 1. In another preferred embodiments, the random
`
`copolymer in the kit is YFAK. In some embodiments, the random copolymer in the kit is
`
`formulated for administration every about 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, 84, 90, 96, 102,
`
`108,114,120,126,132,138,144,150,156,162,168,174,180,186,192,198, 204, 210, 216,
`
`222, 228, 234, or 240 hours. In some embodiments, the instructions of the kit indicate that the
`
`random polymer is to be administered to the subject at time intervals of at least 24, 30, 36, 42,
`
`48, 54, 60,66, 72, 78, 84, 90, 96, 102, 108, 114, 120,126,132, 138, 144, 150, 156, 162, 168,
`
`174, 180, 186, 192, 198, 204, 210, 216, 222, 228, 234, or 240 hours.
`
`In some embodiments of the kits provided by the invention, the composition is
`
`formulated as a sustained release formulation. In specific embodiments, the sustained release
`
`formulation delivers a total dosage that would be effective in treating the disease if said total
`
`dosage were administered daily. In other embodiments, the total dosage is about 20mg, less than
`
`20mg, or x mg, wherein x is any integer between 1 and 20.
`
`In another embodiment of the kits provided by the invention, the kit comprises
`instructions for administering the composition to a subject in need thereof at time intervals of at
`
`least 24, 36, 48, 72, 96, 120 or 144 hours or longer, at a dosage of about 20mg per
`
`administration, while in other embodiments the dosage is less than 20mg, such as x mg, wherein
`
`x is any integer between 1 and 20. In a related embodiments, the kit comprises instructions for
`
`administering the composition to a subject in need thereof at time intervals of at least 24 hours at
`
`a dosage that is effective in treating the disease if it were to be administered daily. In another
`
`related embodiment, the kit comprises instructions for administering the composition to a subject
`
`in need thereof at time intervals of at least 24 hours at a dosage that is effective in treating the
`
`disease when administered daily.
`
`In some embodiments, the disease for which the kit is directed is mediated by T-cells,
`
`and in particular THl cells, or the disease is one which is exacerbated by an excess of
`
`inflammatory cytokines. In another embodiments, the disease is an autoimmune disease for
`
`10
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`15
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`20
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`25
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`30
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`which the kit provides treatment is selected from the group consisting of multiple sclerosis, type-
`
`I diabetes, Hashimoto‘s thyroiditis, Crohn's disease, rheumatoid arthritis, systemic lupus
`
`erythematosus (SLE), gastritis, autoimmune hepatitis, hemolytic anemia, autoimmune
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`hemophilia, autoimmune lymphoproliferative syndrome (ALPS), autoimmune uveoretinitis,
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`glomerulonephritis, Guillain-Barré syndrome, psoriasis, myasthenia gravis, autoimmune
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`encephalomyelitis, Goodpasture's syndrome, Grave's disease, paraneoplastic pemphigus,
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`autoimmune thrombocytopenic purpura, scleroderma with anti-collagen antibodies, mixed
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`connective tissue disease, pernicious anemia, polymyositis, idiopathic Addison's disease,
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`autoimmune-associated infertility, bullous pemphigoid, Sjogren's syndrome, idiopathic
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`myxedema and colitis. In specific embodiments, the disease is multiple sclerosis, diabetes or
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`arthritis. In a preferred embodiment, the disease is relapsing-remitting multiple sclerosis. The
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`kit may also comprise packaging and a means of administrating the copolymer, such as a
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`hypodermic syringe, needles, measuring devices such as a spoon or graduated container, an
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`inhaler or a pump. The instructions on the kit may also contain instructions for home use.
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`The invention further provides agents for the manufacture of medicaments to treat
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`diseases. Any methods disclosed herein for treating or preventing a disease by administering a
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`random copolymer to a subject may be applied to the use of the random copolymer in the
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`manufacture of a medicament to treat that disease. Accordingly, one aspect of the invention
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`provides the use of a random copolymer for the treatment of a disease in a subject, wherein the
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`random copolymer is formulated to be administered to the subject at intervals greater than 24
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`hours, and more preferably of at least 48 hours. In preferred embodiments, the random
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`copolymer is Copolymer 1, and the disease is an autoimmune disease, such as multiple sclerosis
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`or more particularly relapsing-remitting multiple sclerosis. In other preferred embodiments, the
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`random copolymer is YFAK.
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`Another aspects of the invention provides for certain methods of doing business. In
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`particular, the invention provides methods of conducting a pharmaceutical business wherein the
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`kits and formulations are marketed to healthcare providers or directly to subjects in need of such
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`kits. One aspect provides a method for conducting a pharmaceutical business, comprising
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`marketing to healthcare providers, or to patients in need of such kits, the benefits of using any of
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`the kits described herein in the treatment of a disease or disorder. A related aspect provides a
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`method for conducting a pharmaceutical business, comprising: (a) manufacturing any of the kits
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`described herein; and (b) marketing to healthcare providers, or to patients in need of such kits,
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`the benefits of using the kit in the treatment of a disease or disorder. In some embodiments, the
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`rights to develop and market such formulations or to conduct such manufacturing steps may be
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`licensed to a third party for consideration. In some embodiments, the disease is multiple
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`sclerosis, such as relapse-remitting multiple sclerosis. In another embodiment, the kits comprise
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`Copolymer 1 or YFAK.
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`In another embodiment, the marketing to healthcare providers or to patients
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`comprises an indication to administer 50mg, or more preferably 20mg or less of the random
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`copolymer every 5 to 7 days. In other embodiments, the marketing comprises an indication to
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`administer the random copolymer every at least 2, 3, 4, 5, 6, 7, 8, 9, 10, ll, 12, 13 or 14 days. In
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`another embodiment, the marketing to healthcare providers or to patients comprises an
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`indication to administer 50mg, or more preferably 20mg or less of the random copolymer, every
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`5 to 7 days. In yet another embodiments, the marketing comprises an indication of reduced side
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`effects in using the kits or formulations described herein compared to existing formulations of
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`the same or a different random copolymer. In a specific embodiment, the existing formulations
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`are administered more frequently to the patient, or with shorter intervals between
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`administrations, while in another embodiment the existing formulations result in a higher
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`average daily dosage than those of the kit that is marketed. The higher average daily dosage
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`may be, for example, 20, 50, 100, 200, or 500% higher than those provided by the kits.
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`11. Definitions
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`For convenience, certain terms employed in the specification, examples, and
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`appended claims, are collected here. Unless defined otherwise, all technical and scientific terms
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`used herein have the same meaning as commonly understood by one of ordinary skill in the art
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`to which this invention belongs.
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`The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at
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`least one) of the grammatical object of the article. By way of example, “an element” means one
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`element or more than one element.
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`The term “including” is used herein to mean, and is used interchangeably with, the
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`phrase “including but not limited" to.
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`The term “or” is used herein to mean, and is used interchangeably with, the term
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`“and/or,” unless context clearly indicates otherwise.
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`The term "such as" is used herein to mean, and is used interchangeably, with the
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`phrase "such as but not limited to".
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`A "patient" or "subject" to be treated by the method of the invention can mean either
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`a human or non-human animal, preferably a mammal.
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`The term "autoimmune condition" or "autoimmune disease" means a disease state
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`caused by an inappropriate immune response that is directed to a self-encoded entity which is
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`known as an autoantigen. The copolymer compounds provided herein can be used to treat
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`symptoms of an autoimmune disease, a class of disorder which includes Hashimoto's thyroiditis;
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`idiopathic myxedema, a severe hypothyroidism; multiple sclerosis, a demyelinating disease
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`marked by patches or hardened tissue in the brain or the spinal cord; myasthenia gravis which is
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`a disease having progressive weakness of muscles caused by autoimmune attack on
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`acetylcholine receptors at neuromuscular junctions; Guillain-Barre syndrome, a polyneuritis;
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`systemic lupus erythematosis; uveitis; autoimmune oophoritis; chronic immune
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`thrombocytopenic purpura; colitis; diabetes; Grave's disease, which is a form of hypothyroidism;
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`psoriasis; pemphigus vulgaris; and rheumatoid arthritis (RA).
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`The term "demyelinating condition" includes a disease state in which a portion of the
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`myelin sheath, consisting of plasma membrane wrapped around the elongated portion of the
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`nerve cell, is removed by degradation. A demyelinating condition can arise post-vaccination,
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`post-anti TNF treatment, post-viral infection, and in MS.
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`The term "derivative" of an amino acid means a chemically related form of that
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`amino acid having an additional substituent, for example, N—carboxyanhydride group, a 'y-benzyl
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`group, an e—N-trifluoroacetyl group, or a halide group attached to an atom of the amino acid.
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`The term "analog" means a chemically related form of that amino acid having a
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`different configuration, for example, an isomer, or a D-configuration rather than an L-
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`configuration, or an organic molecule with the approximate size, charge, and shape of the amino
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`acid, or an amino acid with modification to the atoms that are involved in the peptide bond, so
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`that the copolymer having the analog residue is more protease resistant than an otherwise similar
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`copolymer lacking such analog, whether the analog is interior or is located at a terminus of the
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`copolymer, compared to the copolymer without the analog.
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`The phrases "amino acid" and "amino acid copolymer" can include one or more
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`components which are amino acid derivatives and/or amino acid analogs as defined herein, the
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`derivative or analog comprising part or the entirety of the residues for any one or more of the 20
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`naturally occurring amino acids indicated b