US 20090149541A1
`
`(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2009/0149541 A1
`Stark et al.
`(43) Pub. Date: Jun. 11, 2009
`
`
`(54)
`
`METHOD OF DELAYING THE ONSET OF
`CLINICALLY DEFINITE MULTIPLE
`SCLEROSIS
`
`Inventors:
`
`(76)
`
`Yafit Stark, GiV’at Shmu’el (IL);
`David Ladakani, Jerusalem (IL)
`
`Correspondence Address:
`COOPER & DUNHAM, LLP
`30 Rockefeller Plaza, 20th Floor
`NEW YORK, NY 10112 (US)
`
`(21)
`
`Appl. No.:
`
`12/315,009
`
`(22)
`
`Filed:
`
`Nov. 26, 2008
`
`Related US. Application Data
`
`(60)
`
`Provisional application No. 61/004,710, filed on Nov.
`28, 2007, provisional application No. 61/005,271,
`filed on Dec. 3, 2007, provisional application No.
`
`61/007,141, filed on Dec. 11, 2007, provisional appli-
`cation No. 61/192,455, filed on Sep. 17, 2008.
`
`Publication Classification
`
`(51)
`
`Int. Cl.
`(2006.01)
`A61K 31/195
`(2006.01)
`A61P 43/00
`(52) U.S.Cl. ........................................................ 514/566
`
`(57)
`
`ABSTRACT
`
`A method for delaying the onset of clinically definite multiple
`sclerosis in a patient at risk of developing clinically definite
`multiple sclerosis and retard long-term progression of mul-
`tiple sclerosis and its symptoms, the method comprising peri-
`odically administering a pharmaceutical composition com-
`prising a therapeutically effective amount of glatiramer
`acetate to the patient, thereby delaying onset of clinically
`definite multiple sclerosis in the patient and retarding long-
`term progression of multiple sclerosis and its symptoms.
`
`MYLAN INC. EXHIBIT NO. 1056 Page 1
`
`MYLAN INC. EXHIBIT NO. 1056 Page 1
`
`

`

`Patent Application Publication
`
`Jun. 11, 2009 Sheet 1 0f 9
`
`US 2009/0149541 A1
`
`Risk Reduction of 45%
`Hazard Ratio: 0.55
`
`p=o.ooos
`
`+386da s:+115$
`.
`
`[95% CI] 0.40-0.77 w
`
`EDOSg3m g
`
`3w B 3
`
`5‘
`
`Day 0
`GA Ring 11- 243
`Place» n= 238
`
`Day 180
`197
`197
`
`Day 3&3
`179
`165
`
`Day 500
`133
`1:5
`
`Day 720
`I4
`98
`
`Day 900
`78
`fi
`
`Day 1080
`22
`5
`
`Figure 1
`
`GA Reduces the Risk to CDMS
`
`MYLAN INC. EXHIBIT NO. 1056 Page 2
`
`MYLAN INC. EXHIBIT NO. 1056 Page 2
`
`

`

`Patent Application Publication
`
`Jun. 11, 2009 Sheet 2 0f 9
`
`US 2009/0149541 A1
`
`Kaplan-Meier Survival Curves and Log Rank* Test
`
`Product-Limit Survival Function
`
`Logrank p=0.0001
`
`mu
`
`a»
`
`am
`
`No. of
`Subjects
`
`Event
`
`ensore-
`
`Median
`Survival
`(951
`CI)
`
`
`
`GA 20 mg
`
`25% 60)
`
`75% 183
`
`NA (NA NA
`
`Time to Conversion
`
`“Alternate Analysis to the Cox Model In Case that the Proportional Hazards
`Assumption is violated
`
`Figure 2
`
`MYLAN INC. EXHIBIT NO. 1056 Page 3
`
`MYLAN INC. EXHIBIT NO. 1056 Page 3
`
`

`

`Patent Application Publication
`
`Jun. 11, 2009 Sheet 3 of 9
`
`US 2009/0149541 Al
`
`I
`
`P 01
`
`N
`
`TotalNumberofNewT2Lesions D
`.° m
`
`_\
`
`01
`
`—l
`
`
`
`GA20 mg
`
`Placebo
`
`Figure 3
`
`Total Number of New T2 lesions (LOV)
`
`MYLAN INC. EXHIBIT NO. 1056 Page 4
`
`MYLAN INC. EXHIBIT NO. 1056 Page 4
`
`

`

`Patent Application Publication
`
`Jun. 11, 2009 Sheet 4 of 9
`
`US 2009/0149541 A1
`
`2
`
`I GA 20 mg
`D Placebo
`
`NumberofNewT2Lesions
`
`Month 12
`
`Month 24
`
`Values taken during the
`placebo-controlled phase
`
`
`
`Figure 4
`
`Total Number of New T2 Lesions: Annual Comparison
`
`MYLAN INC. EXHIBIT NO. 1056 Page 5
`
`MYLAN INC. EXHIBIT NO. 1056 Page 5
`
`

`

`Patent Application Publication
`
`Jun. 11, 2009 Sheet 5 0f 9
`
`US 2009/0149541 Al
`
`N U1
`
`I GA 20 mg
`El Placebo
`
`N
`
`_L '01
`
`
`
`
`
`.—L
`
`.0 U1
`
`TotalNumberofNewT2Lesions(ITT) 0
`
`Month 12
`
`Month 24
`
`
`
`
`
`
`
`
`
`
`
`
`
`Figure 5
`
`Total Number of New T2 Lesions: Annual Comparison (ITT
`
`Cohort)
`
`MYLAN INC. EXHIBIT NO. 1056 Page 6
`
`MYLAN INC. EXHIBIT NO. 1056 Page 6
`
`

`

`Patent Application Publication
`
`Jun. 11, 2009 Sheet 6 0f 9
`
`US 2009/0149541 A1
`
`
`
` NumberofNewT1EnhancingLesions
`
`GA 20 mg
`
`Placebo
`
`Figure 6
`
`Total Number of New T1 Gd—Enhancing Lesions (LOV)
`
`MYLAN INC. EXHIBIT NO. 1056 Page 7
`
`MYLAN INC. EXHIBIT NO. 1056 Page 7
`
`

`

`Patent Application Publication
`
`Jun. 11, 2009 Sheet 7 of 9
`
`US 2009/0149541 A1
`
`1.5
`
`l GA 20 mg
`C] Placebo
`
`
`
` NumberofNewT1EnhancingLesions
`
`Month 12
`
`Month 24
`
`Values taken during the placebo-
`controlled phase
`
`
`
`
`Figure 7
`
`
`
`
`
`Total Number of New T1 Gd-Enhancing Lesions: Annual
`
`Comparison
`
`MYLAN INC. EXHIBIT NO. 1056 Page 8
`
`MYLAN INC. EXHIBIT NO. 1056 Page 8
`
`

`

`Patent Application Publication
`
`Jun. 11, 2009 Sheet 8 0f 9
`
`US 2009/0149541 A1
`
`—L ix:
`
`I GA 20 mg
`C] Placebo
`
`Oto.3
`
`O 0)
`
`.O4;
`
`
`
` .0l\> TotalNumberofNewT1Enhancing
`
`
`
`Lesions(ITT)
`
`O
`
`Month 12
`
`Month 24
`
`
`-GA20 mg
`
`
`
`
`Placebo
`
`
`Figure 8
`
`Total Number of New T1 Gd-Enhancing Lesions: Annual
`
`Comparison (ITT Cohort)
`
`MYLAN INC. EXHIBIT NO. 1056 Page 9
`
`MYLAN INC. EXHIBIT NO. 1056 Page 9
`
`

`

`Patent Application Publication
`
`Jun. 11, 2009 Sheet 9 0f 9
`
`US 2009/0149541 A1
`
`0.4
`
`0.3
`
`.° N
`
`Po_\
`
`IIIIII999999030143de
`
`Baseline'
`
`
`
`
`
`NAAICrLevels-Changefrom
`
`
`
`
`I GA 20 mg
`
`CI Placebo
`p=0.15
`
`
`
`
`
`
`
`
`——_
`——_
`
`
`
`
`
`
`Figure 9
`
`NAA/Cr: Difference Between Groups in the Change from
`Baseline
`
`MYLAN INC. EXHIBIT NO. 1056 Page 10
`
`MYLAN INC. EXHIBIT NO. 1056 Page 10
`
`

`

`US 2009/0149541 A1
`
`Jun. 11, 2009
`
`METHOD OF DELAYING THE ONSET OF
`CLINICALLY DEFINITE MULTIPLE
`SCLEROSIS
`
`[0001] This application claims the benefits of US. Provi-
`sional Patent Application Ser. Nos. 61/004,710, filed NOV. 28,
`2007, 61/005,271, filed Dec. 3, 2007, 61/007,141, filed Dec.
`11,2007 and 61/192,455, filed Sep. 17, 2008. The contents of
`which are hereby incorporated by reference in its entirety.
`[0002] Throughout this application various publications
`are referenced by Arabic numeral in parentheses. The full
`citation of the corresponding reference appears at the end of
`the specifications before the claims. The disclosures of these
`publications in their entireties are hereby incorporated by
`reference into this application in order to more fully describe
`the state of the art to which this invention pertains.
`
`BACKGROUND OF THE INVENTION
`
`[0003] With over 2 million afilicted people worldwide,
`multiple sclerosis (“MS”) is one ofthe more common chronic
`neurological diseases in human adults. MS is a chronic,
`inflammatory central nervous system (CNS) disease charac-
`terized pathologically by demyelination. MS has also been
`classified as an autoimmune disease.
`
`[0004] MS disease activity can be monitored by cranial
`scans, including magnetic resonance imaging (MRI) of the
`brain, accumulation of disability, as well as rate and severity
`of relapses. The diagnosis of clinically definite MS as deter-
`mined by the Poser criteria (1) requires at least two neuro-
`logical events suggesting demyelination in the CNS sepa-
`rated in time and in location. A clinically isolated syndrome
`(CIS) is a single monosymptomatic attack suggestive of MS,
`such as optic neuritis, brain stem symptoms, and partial
`myelitis. Patients with CIS that experience a second clinical
`attack are generally considered to have clinically definite
`multiple sclerosis (CDMS). Over 80 percent of patients with
`a CIS and MRI lesions go on to develop MS, while approxi-
`mately 20 percent have a self-limited process (2, 3).
`[0005] There are five distinct disease stages and/or types of
`MS:
`
`1) benign multiple sclerosis;
`2) relapsing-remitting multiple sclerosis (RRMS);
`3) secondary progressive multiple sclerosis (SPMS);
`4) progressive relapsing multiple sclerosis (PRMS; and
`5) primary progressive multiple sclerosis (PPMS)
`[0006] Benign multiple sclerosis is a retrospective diagno-
`sis which is characterized by 1-2 exacerbations with complete
`recovery, no lasting disability and no disease progression for
`10-15 years after the initial onset. Benign multiple sclerosis
`may, however, progress into other forms ofmultiple sclerosis.
`[0007]
`Patients suffering from RRMS experience sporadic
`exacerbations or relapses, as well as periods of remission.
`Lesions and evidence ofaxonal loss may or may not be visible
`on MRI for patients with RRMS.
`[0008]
`SPMS may evolve from RRMS. Patients afflicted
`with SPMS have relapses, a diminishing degree of recovery
`during remissions, less frequent remissions and more pro-
`nounced neurological deficits than RRMS patients. Enlarged
`ventricles, which are markers for atrophy of the corpus cal-
`losum, midline center and spinal cord, are visible on MRI of
`patients with SPMS.
`[0009]
`PPMS is characterized by a steady progression of
`increasing neurological deficits without distinct attacks or
`
`remissions. Cerebral lesions, diffuse spinal cord damage and
`evidence of axonal loss are evident on the MRI of patients
`with PPMS. PRMS has periods of acute exacerbations while
`proceeding along a course of increasing neurological deficits
`without remissions. Lesions are evident on MRI of patients
`suffering from PRMS (5).
`[0010] Glatiramer acetate (GA), a mixture of polypeptides
`which do not all have the same amino acid sequence,
`is
`marketed under the trade name Copaxone®. GA comprises
`the acetate salts of polypeptides containing L-glutamic acid,
`L-alanine, L-tyrosine and L-lysine at average molar fractions
`of 0.141, 0.427, 0.095 and 0.338, respectively. The average
`molecular weight of Copaxone® is between 5,000 and 9,000
`daltons(6). Chemically, glatiramer acetate is designated
`L-glutamic acid polymer with L-alanine, L-lysine, L-ty-
`rosine, acetate (salt). Its structural formula is:
`(Glu,Ala,Lys,Tyr)x.xCH3COOH
`(C5H9NO4.C3H7N02.C6H14N202.C9Hl 1NO3)X.xCHO
`
`CAS-147245-92-9
`
`[0011] Copaxone® (20 mg glatiramer acetate injection) is
`an approved therapy for patients with RRMS. The synthesis
`of Copaxone® has been disclosed, for example, in US. Pat.
`Nos. 3,849,550, 6,939,539, 5,800,808 and 7,199,098. The
`formulation of 40 mg Copaxone® has been disclosed in US
`Patent Publication No. US2007/0161566. The entire contents
`
`of these publications are hereby incorporated by reference.
`[0012] The efficacy of Copaxone® in reducing the fre-
`quency of relapses in patients with RRMS is well established
`(7,8). The 20 and 40 mg/day subcutaneous dose has been
`shown to reduce the total number of enhancing lesions in MS
`patients as measured by MRI (8,9). However, it is an open
`question whether Copaxone® therapy would be effective in
`subjects suffering from earlier stages of MS. Moreover, a
`debate exists in the medical and scientific communities as to
`
`the benefit of commencing MS therapy at an early stage.
`Specifically, questions exist regarding whether the benefits of
`early treatment outweigh the inconvenience, cost, potential
`adverse effects of treatment, and the risk of submitting
`patients that independently of treatment would not experi-
`ence further events to unnecessary long-term therapy (10, 11
`and 12).
`
`SUMMARY OF THE INVENTION
`
`[0013] This invention provides a method for delaying the
`onset of clinically definite multiple sclerosis in a patient at
`risk of developing clinically definite multiple sclerosis, the
`method comprising periodically administering a pharmaceu-
`tical composition comprising a therapeutically effective
`amount of glatiramer acetate to the patient, thereby delaying
`onset of clinically definite multiple sclerosis in the patient.
`[0014] This invention further provides a method for reduc-
`ing progression ofmagnetic resonance imaging (MRI)-moni-
`tored disease activity in a patient at risk for developing clini-
`cally definite multiple sclerosis,
`the method comprising
`periodically administering a pharmaceutical composition
`comprising a therapeutically effective amount of glatiramer
`acetate to the patient thereby reducing progression of MRI-
`monitored disease activity in the patient.
`[0015] This invention also provides a method for reducing
`the progression of symptoms of Multiple Sclerosis in a
`patient, the method comprising periodically administering a
`pharmaceutical composition comprising a therapeutically
`
`MYLAN INC. EXHIBIT NO. 1056 Page 11
`
`MYLAN INC. EXHIBIT NO. 1056 Page 11
`
`

`

`US 2009/0149541 A1
`
`Jun. 11, 2009
`
`effective amount of glatiramer acetate to the patient prior to
`development of clinically definite multiple sclerosis in the
`patient, thereby reducing the progression of symptoms of MS
`in the patient.
`[0016] This invention yet further provides a method for
`reducing the frequency of relapse in a patient who experi-
`enced a single clinical attack consistent with multiple sclero-
`sis and who has at least one lesion consistent with multiple
`sclerosis comprising periodically administering to the patient
`a pharmaceutical composition comprising an amount ofglati-
`ramer acetate therapeutically effective to increase the time to
`relapse in the patient.
`[0017] This invention provides a method for delaying pro-
`gression to clinically definite multiple sclerosis in a patient
`presenting a first clinical event suggestive of multiple sclero-
`sis and at least one lesion of multiple sclerosis comprising
`periodically administering to the patient a pharmaceutical
`composition comprising an amount of glatiramer acetate
`therapeutically effective to delay progression to clinically
`definite multiple sclerosis.
`[0018] This invention also provides use of glatiramer
`acetate in the manufacture of a medicament for delaying the
`onset of clinically definite multiple sclerosis, for reducing
`progression of magnetic resonance imaging (MRI)-moni-
`tored disease activity, or reducing progression of symptoms
`of multiple sclerosis in a patient at risk for developing clini-
`cally definite multiple sclerosis.
`[0019] This invention additionally provides use of glati-
`ramer acetate in the manufacture of a medicament for the
`
`treatment of a patient who experienced a single demyelinat-
`ing event and an active inflammatory process, which are
`indicative of the patient being at high risk of developing
`clinically definite multiple sclerosis.
`[0020] This invention further provides glatiramer acetate
`for use in treating of a patient who experienced a first clinical
`event suggestive of multiple sclerosis and is at risk of devel-
`oping clinically definitive multiple sclerosis.
`[0021] This invention yet further provides use of glatiramer
`acetate in the manufacture of a medicament for the treatment
`
`of a patient who experienced a first clinical event suggestive
`of multiple sclerosis and is at risk of developing clinically
`definite multiple sclerosis.
`
`BRIEF DESCRIPTION OF FIGURES
`
`FIG. 1 shows the time to conversion to CDMS,
`[0022]
`based on Kaplen-Meier analysis. Considering the 25th per-
`centile, glatiramer acetate prolonged the time to conversion to
`CDMS from 336 days on placebo to 722 days, reflecting more
`than twofold prolongation in slowing the onset of CDMS.
`[0023]
`FIG. 2 shows the Kaplan—Meier survival curves and
`log rank test by an alternative analysis to the Cox Model in
`case that the proportional hazards assumption is violated.
`[0024]
`FIG. 3 shows the total number of new T2 lesions
`when examined at the last observed value (LOV).
`[0025]
`FIG. 4 shows the total number of new T2 lesions
`when compared annually.
`[0026]
`FIG. 5 shows the total number of new T2 lesions in
`the ITT cohort when compared annually.
`[0027]
`FIG. 6 shows the total number of new Tl Gd-en-
`hancing lesions when examined at the last observed value
`(LOV).
`FIG. 7 shows the total number of new Tl Gd-en-
`[0028]
`hancing lesions when compared annually.
`
`FIG. 8 shows the total number of new Tl Gd-en-
`[0029]
`hancing lesions in the ITT cohort when compared annually.
`[0030]
`FIG. 9 shows quantification ofthe NAA/CR ratio, as
`measured by MRS, from baseline over 2 years.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`[0031] This invention provides a method for delaying the
`onset of clinically definite multiple sclerosis in a patient at
`risk of developing clinically definite multiple sclerosis, the
`method comprising periodically administering a pharmaceu-
`tical composition comprising a therapeutically effective
`amount of glatiramer acetate to the patient, thereby delaying
`onset of clinically definite multiple sclerosis in the patient.
`[0032] This invention also provides a method for reducing
`progression of magnetic resonance imaging (MRI)-moni-
`tored disease activity in a patient at risk for developing clini-
`cally definite multiple sclerosis, the method comprising peri-
`odically
`administering a pharmaceutical
`composition
`comprising a therapeutically effective amount of glatiramer
`acetate to the patient thereby reducing progression of MRI-
`monitored disease activity in the patient.
`[0033] This invention further provides a method for reduc-
`ing the progression of symptoms of Multiple Sclerosis in a
`patient, the method comprising periodically administering a
`pharmaceutical composition comprising a therapeutically
`effective amount of glatiramer acetate to the patient prior to
`development of clinically definite multiple sclerosis in the
`patient, thereby reducing the progression of symptoms of MS
`in the patient.
`[0034]
`In an embodiment of the methods onset is delayed
`by 50% to 115%, or by 60% to 115%, or by 70% to 115%, or
`by 80% to 115%, orby 90%to115%,orby100%t0115%,or
`l 15%.
`
`In another embodiment of the methods, prior to
`[0035]
`administration,
`the patient has not experienced a single
`monofocal or multifocal neurological clinical episode com-
`patible with multiple sclerosis.
`[0036]
`In an embodiment of the methods disclosed, prior to
`administration, the patient has experienced a single clinical
`attack suggestive of multiple sclerosis.
`[0037] This invention additionally provides a method for
`reducing the frequency of relapse in a patient who experi-
`enced a single clinical attack suggestive of multiple sclerosis
`and who has at least one lesion suggestive of multiple scle-
`rosis comprising periodically administering to the patient a
`pharmaceutical composition comprising an amount of glati-
`ramer acetate therapeutically effective to increase the time to
`relapse in the patient.
`[0038]
`In an embodiment ofthe methods the time to relapse
`is increased by 50% to 115%, or by 60% to 115%, or by 70%
`to 115%, orby 80% to 115%, orby 90% to 115%, orby 100%
`to 115%, or 115%.
`[0039]
`In another embodiment of the methods the single
`clinical attack includes a clinical episode of optic neuritis,
`blurring of vision, diplopia, involuntary rapid eye movement,
`blindness, loss of balance, tremors, ataxia, vertigo, clumsi-
`ness of a limb, lack ofco-ordination, weakness of one or more
`extremity, altered muscle tone, muscle stiffness, spasms, tin-
`gling, paraesthesia, burning sensations, muscle pains, facial
`pain, trigeminal neuralgia, stabbing sharp pains, burning tin-
`gling pain, slowing of speech, slurring of words, changes in
`rhythm of speech, dysphagia, fatigue, bladder problems (in-
`cluding urgency, frequency, incomplete emptying and incon-
`tinence), bowel problems (including constipation and loss of
`
`MYLAN INC. EXHIBIT NO. 1056 Page 12
`
`MYLAN INC. EXHIBIT NO. 1056 Page 12
`
`

`

`US 2009/0149541 A1
`
`Jun. 11, 2009
`
`bowel control), impotence, diminished sexual arousal, loss of
`sensation, sensitivity to heat, loss of short term memory, loss
`of concentration, or loss ofjudgment or reasoning.
`[0040] This invention also provides a method for delaying
`progression to clinically definite multiple sclerosis in a
`patient presenting a first clinical event suggestive of multiple
`sclerosis and at least one lesion ofmultiple sclerosis compris-
`ing periodically administering to the patient a pharmaceutical
`composition comprising an amount of glatiramer acetate
`therapeutically effective to delay progression to clinically
`definite multiple sclerosis.
`[0041]
`In another embodiment of the methods, prior to
`administration,
`the patient has at
`least
`1 cerebral
`lesion
`detectable by an MRI scan and suggestive of multiple scle-
`ros1s.
`
`In another embodiment of the methods the lesion is
`[0042]
`associated with brain tissue inflammation, myelin sheath
`damage or axonal damage.
`[0043]
`In another embodiment of the methods the lesion is
`a demyelinating white matter lesion visible on brain MRI.
`[0044]
`In another embodiment of the methods the white
`matter lesions are at least 3 mm in diameter.
`
`In another embodiment of the methods, prior to
`[0045]
`administration, the patient has no cerebral lesion detectable
`by a MRI scan.
`[0046]
`In another embodiment of the methods the periodic
`administration is once-a-day.
`[0047]
`In another embodiment of the methods the admin-
`istration is subcutaneous.
`
`In another embodiment ofthe methods the therapeu-
`[0048]
`tically effective amount of glatiramer acetate is 20 mg.
`[0049]
`In another embodiment ofthe methods the therapeu-
`tically effective amount of glatiramer acetate is 40 mg.
`[0050]
`In another embodiment, the methods further com-
`prise administration of a corticosteroid.
`[0051]
`In another embodiment, the methods further com-
`prise administration of a corticosteroid intravenously.
`[0052]
`In another embodiment of the methods, progression
`of symptoms is assessed by multiple sclerosis related disabil-
`ity in the patient as measured by Kurtzke Expanded Disability
`Status Scale (EDSS) Score, is assessed by relapse rate in the
`patient, or is assessed by the progression of MRI-monitored
`disease activity in the patient.
`[0053]
`In another embodiment of the methods the MRI-
`monitored disease activity is the mean cumulative number of
`T1 Gd-enhancing lesions in the brain of the patient.
`[0054]
`In another embodiment of the methods MRI-moni-
`tored disease activity is the mean volume ofT1 Gd-enhancing
`lesions in the brain of the patient.
`[0055]
`In another embodiment of the methods the MRI-
`monitored disease activity is the mean cumulative number of
`T1 hypointense lesions in the brain of the patient.
`[0056]
`In another embodiment of the methods MRI-moni-
`tored disease activity is the mean volume of hypointense
`lesions in enhanced T1 weighted images.
`[0057]
`In another embodiment of the methods the MRI-
`monitored disease activity is the mean number of new T2
`lesions in the brain of the patient.
`[0058]
`In another embodiment of the methods the MRI-
`monitored disease activity is the mean T2 lesion volume in the
`brain of the patient.
`[0059]
`In another embodiment of the methods the MRI-
`monitored disease activity is the rate of brain atrophy mea-
`sured according to the SIENA technique in the patient.
`
`In another embodiment of the methods the glati-
`[0060]
`ramer acetate is administered as monotherapy.
`[0061]
`In another embodiment of the methods axonal
`injury is reduced in the subject.
`[0062]
`In another embodiment of the methods the ratio of
`NAA/CR, as measured in the subject by MRS, increases over
`time.
`
`In another embodiment of the methods the ratio of
`[0063]
`NAA/CR, as measured in the subject by MRS, increases to
`0.13 with respect to a baseline ratio measured in said subject.
`[0064]
`In another embodiment of the methods the fre-
`quency of confirmed relapses is reduced over a period of 2-3
`years.
`
`In another embodiment of the methods the progres-
`[0065]
`sion of disease disability is reduced over a period of 2-3 years.
`[0066]
`In another embodiment of the methods the rate of
`accumulating new T2-weighted lesions is reduced by at least
`50%, as compared to a subject not treated with glatiramer
`acetate. In an additional embodiment the rate of accumulating
`new T2-weighted lesions is reduced by 50-90%, as compared
`to a subject not treated with glatiramer acetate. In a further
`embodiment
`the rate of accumulating new T2-weighted
`lesions is reduced by 50-60%, as compared to a subject not
`treated with glatiramer acetate. In yet another embodiment
`the rate of accumulating new T2-weighted lesions is reduced
`by 58%, as compared to a subject not treated with glatiramer
`acetate.
`
`In another embodiment of the methods the number
`[0067]
`ofnew T2 lesions occurring annually is reduced, as compared
`to a subject not treated with glatiramer acetate.
`[0068]
`In another embodiment of the methods the number
`ofnew Tl Gd-enhancing lesions is reduced by at least 50%, as
`compared to a subject not treated with glatiramer acetate. In
`an additional embodiment the number ofnew Tl Gd-enhanc-
`
`ing lesions is reduced by 50-90%, as compared to a subject
`not treated with glatiramer acetate. In a further embodiment
`the number of new Tl Gd-enhancing lesions is reduced by
`50-65%, as compared to a subject not treated with glatiramer
`acetate. In yet another embodiment the number of new Tl
`Gd-enhancing lesions is reduced by 61%, as compared to a
`subject not treated with glatiramer acetate.
`[0069]
`In another embodiment ofthe methods the subject is
`female and the risk to conversion to CDMS is reduced by at
`least 40%, as compared to a subject not treated with glati-
`ramer acetate. In an additional embodiment the subject is
`female and the risk to conversion to CDMS is reduced by
`40-60%, as compared to a subject not treated with glatiramer
`acetate. In a further embodiment the subject is female and the
`risk to conversion to CDMS is reduced by 45-55%, as com-
`pared to a subject not treated with glatiramer acetate. In yet
`another embodiment the subject is female and the risk to
`conversion to CDMS is reduced by 48%, as compared to a
`subject not treated with glatiramer acetate.
`[0070]
`In another embodiment ofthe methods the subject is
`male and the risk to conversion to CDMS is reduced by at
`least 35%, as compared to a subject not treated with glati-
`ramer acetate. In an additional embodiment the subject is
`male and the risk to conversion to CDMS is reduced by
`35-60%, as compared to a subject not treated with glatiramer
`acetate. In a further embodiment the subject is male and the
`risk to conversion to CDMS is reduced by 40-50%, as com-
`pared to a subject not treated with glatiramer acetate. In yet
`another embodiment the subject is male and the risk to con-
`
`MYLAN INC. EXHIBIT NO. 1056 Page 13
`
`MYLAN INC. EXHIBIT NO. 1056 Page 13
`
`

`

`US 2009/0149541 A1
`
`Jun. 11, 2009
`
`version to CDMS is reduced by 43%, as compared to a subject
`not treated with glatiramer acetate.
`[0071]
`In another embodiment ofthe methods the subject is
`less than 30 years old and the risk to conversion to CDMS is
`reduced by at least 40%, as compared to a subject not treated
`with glatiramer acetate. In an additional embodiment the
`subject is less than 30 years old and the risk to conversion to
`CDMS is reduced by 40-60%, as compared to a subject not
`treated with glatiramer acetate. In a further embodiment the
`subject is less than 30 years old and the risk to conversion to
`CDMS is reduced by 50-60%, as compared to a subject not
`treated with glatiramer acetate. In yet another embodiment
`the subject is less than 30 years old and the risk to conversion
`to CDMS is reduced by 53%, as compared to a subject not
`treated with glatiramer acetate.
`[0072]
`In another embodiment ofthe methods the subject is
`greater than 30 years old and the risk to conversion to CDMS
`is reduced by at least 25%, as compared to a subject not
`treated with glatiramer acetate. In an additional embodiment
`the subject is greater than 30 years old and the risk to conver-
`sion to CDMS is reduced by 25-45%, as compared to a
`subject not
`treated with glatiramer acetate. In a further
`embodiment the subject is greater than 30 years old and the
`risk to conversion to CDMS is reduced by 30-45%, as com-
`pared to a subject not treated with glatiramer acetate. In yet
`another embodiment the subject is greater than 30 years old
`and the risk to conversion to CDMS is reduced by 37%, as
`compared to a subject not treated with glatiramer acetate.
`[0073]
`In another embodiment of the methods the subject
`was treated with corticosteroid for the initial attack and the
`
`risk of conversion to CDMS is reduced by at least 30%, as
`compared to a subject not treated with glatiramer acetate. In
`an additional embodiment the subject was treated with corti-
`costeroid for the initial attack and the risk of conversion to
`
`CDMS is reduced by 30-50%, as compared to a subject not
`treated with glatiramer acetate. In a further embodiment the
`subject was treated with corticosteroid for the initial attack
`and the risk of conversion to CDMS is reduced by 35-50%, as
`compared to a subject not treated with glatiramer acetate. In
`yet another embodiment the subject was treated with corti-
`costeroid for the initial attack and the risk of conversion to
`
`CDMS is reduced by 39%, as compared to a subject not
`treated with glatiramer acetate.
`[0074]
`In another embodiment of the methods the subject
`was not treated with corticosteroid for the initial attack and
`
`the risk of conversion to CDMS is reduced by at least 45%, as
`compared to a subject not treated with glatiramer acetate. In
`an additional embodiment the subject was not treated with
`corticosteroid for the initial attack and the risk of conversion
`
`to CDMS is reduced by 45-85%, as compared to a subject not
`treated with glatiramer acetate. In a further embodiment the
`subject was not treated with corticosteroid for the initial
`attack and the risk of conversion to CDMS is reduced by
`50-60%, as compared to a subject not treated with glatiramer
`acetate. In yet another embodiment the subject was not
`treated with corticosteroid for the initial attack and the risk of
`
`conversion to CDMS is reduced by 54%, as compared to a
`subject not treated with glatiramer acetate.
`[0075]
`In another embodiment of the methods the subject
`presents with unifocal optic manifestation and the risk of
`conversion to CDMS is reduced by at least 55%, as compared
`to a subject not treated with glatiramer acetate. In an addi-
`tional embodiment the subject presents with unifocal optic
`manifestation and the risk of conversion to CDMS is reduced
`
`by 55-85%, as compared to a subject not treated with glati-
`ramer acetate. In a further embodiment the subject presents
`with unifocal optic manifestation and the risk ofconversion to
`CDMS is reduced by 55-75%, as compared to a subject not
`treated with glatiramer acetate. In yet another embodiment
`the subject presents with unifocal optic manifestation and the
`risk of conversion to CDMS is reduced by 66%, as compared
`to a subject not treated with glatiramer acetate.
`[0076]
`In another embodiment of the methods the subject
`presents with T1 Gd-enhanced lesions and the risk of conver-
`sion to CDMS is reduced by at least 60%, as compared to a
`subject not treated with glatiramer acetate. In an additional
`embodiment
`the subject presents with T1 Gd-enhanced
`lesions and the risk of conversion to CDMS is reduced by
`60-90%, as compared to a subject not treated with glatiramer
`acetate. In a further embodiment the subject presents with T1
`Gd-enhanced lesions and the risk of conversion to CDMS is
`
`reduced by 65-80%, as compared to a subject not treated with
`glatiramer acetate. In yet another embodiment the subject
`presents with T1 Gd-enhanced lesions and the risk of conver-
`sion to CDMS is reduced by 71%, as compared to a subject
`not treated with glatiramer acetate.
`[0077]
`In another embodiment of the methods the subject
`presents with 9 or more T2 lesions and the risk of conversion
`to CDMS is reduced by at least 50%, as compared to a subject
`not treated with glatiramer acetate. In an additional embodi-
`ment the subject presents with 9 or more T2 lesions and the
`risk of conversion to CDMS is reduced by 50-90%, as com-
`pared to a subject not treated with glatiramer acetate. In a
`further embodiment the subject presents with 9 or more T2
`lesions and the risk of conversion to CDMS is reduced by
`50-60%, as compared to a subject not treated with glatiramer
`acetate. In yet another embodiment the subject presents with
`9 or more T2 lesions and the risk of conversion to CDMS is
`
`reduced by 58%, as compared to a subject not treated with
`glatiramer acetate.
`[0078]
`In another embodiment of the methods the subject
`does not present with T1 Gd-enhanced lesions and the risk of
`conversion to CDMS is reduced by at least 35%, as compared
`to a subject not treated with glatiramer acetate. In an addi-
`tional embodiment the subject does not present with T1 Gd-
`enhanced lesions and the risk of conversion to CDMS is
`
`reduced by 35-65%, as compared to a subject not treated with
`glatiramer acetate. In a further embodiment the subject does
`not present with T1 Gd-enhanced lesions and the risk of
`conversion to CDMS is reduced by 40-50%, as compared to a
`subject not treated with glatiramer acetate. In yet another
`embodiment the subject does not present with T1 Gd-en-
`hanced lesions and the risk ofconversion to CDMS is reduced
`
`by 44%, as compared to a subject not treated with glatiramer
`acetate.
`
`In another embodiment of the methods the subject
`[0079]
`presents with less than 9 T2 lesions and the risk of conversion
`to CDMS is reduced by at least 55%, as compared to a subject
`not treated with glatiramer acetate. In an additional embodi-
`ment the subject presents with less than 9 T2 lesions and the
`risk of conversion to CDMS is reduced by 55-85%, as com-
`pared to a subject not treated with glatiramer acetate. In a
`further embodiment the subject presents with less than 9 T2
`lesions and the risk of conversio