(12) Umted States Patent
`Klinger
`
`(10) Patent No.:
`
`(45) Date of Patent:
`
`US 8,399,413 B2
`*Mar. 19, 2013
`
`US008399413B2
`
`(54) LOW FREQUENCY GLATIRAMER ACETATE
`THERAPY
`
`(75)
`
`Inventor: Ety Klinger, Tel Aviv (IL)
`
`(73) Assignee: Yeda Research & Development Co.,
`Ltd., Rehovot (IL)
`
`( " ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. l54(b) by 18 days.
`
`This patent is subject to a terminal dis-
`claimer.
`
`(21) Appl. No.: 12/806,684
`
`(22) Filed:
`
`Aug. 19. 2010
`
`(65)
`
`Prior Publication Data
`
`US 2011/0046065 Al
`
`Feb. 24, 2011
`
`Related U.S. Application Data
`
`(60) Provisional application No. 61/274,687, filed on Aug.
`20, 2009, provisional application No. 61/337,612,
`filed on Feb. 11, 2010.
`
`(51)
`
`Int. Cl.
`A6IK 36/00
`514/17.9; 514/1.1
`(52) U.S. Cl.
`(58) Field of Classification Search ...................... .. None
`See application file for complete search history.
`
`(2006.01)
`
`(56)
`
`References Cited
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`
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`
`(Continued)
`
`Primary Examiner — John Ulm
`(74) Attorngz, Agent, or Firm — John P. White; Gary J.
`Gershik; Cooper & Dunham LLP
`
`(57)
`
`ABSTRACT
`
`A method of alleviating a symptom of relapsing-remitting
`multiple sclerosis in a human patient suffering from relaps-
`ing-remitting multiple sclerosis or a patient who has experi-
`enced a first clinical episode and is determined to be at high
`risk of developing clinically definite multiple sclerosis com-
`prising administering to the human patient three subcutane-
`ous injections ofa therapeutically efi°ective dose ofglatiramer
`acetate over a period of seven days with at least one day
`between every subcutaneous injection so as to thereby alle-
`viate the symptom of the patient.
`
`20 Claims, No Drawings
`
`AMNEAL
`
`EXHIBIT NO. 1001 Page 1
`
` AMNEAL
`
`

`
`US 8,399,413 B2
`Page 2
`
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`Feb. 14, 2012 Ofiice Action Issued in Connection With U.S. Appl.
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`Nov. 25, 201 1 Examiner's Report Iwued in connection with Austra-
`lian Application No. 2010284666, filed Aug. 19, 2012 (Klinger).
`Feb. 29, 2012 Ofiicial Action Issued in connection with Canadian
`Application No. 2,760,802, filed Aug. 19, 2012 (Klinger).
`Response to the Feb. 29, 2012 outstanding Examiner‘s Report filed
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`AMNEAL
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`EXHIBIT NO. 1001 Page 2
`
` AMNEAL
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`

`
`US 8,399,413 B2
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`
`" cited by examiner
`
`AMNEAL
`
`EXHIBIT NO. 1001 Page 3
`
` AMNEAL
`
`

`
`US 8,399,413 B2
`
`1
`LOW FREQUENCY GLATIRAMER ACETATE
`THERAPY
`
`This application claims the benefit of U.S. Provisional
`Application Nos. 61/274,687, filedAug. 20, 2009 and 61/337,
`612, filed Feb. 11, 2010. The contents of which are hereby
`incorporated by reference in their entirety.
`Throughout this application various publications are refer-
`enced by their full citations. The disclosures of these publi-
`cations in their entireties are hereby incorporated by refer-
`ence into this application in order to more fully describe the
`state of the art to which this invention pertains.
`
`BACKGROUND OF THE INVENTION
`
`Multiple Sclerosis (MS) is a chronic, debilitating disease of
`the central nervous system (CNS). MS has also been classi-
`fied as an autoimmune disease. MS disease activity can be
`monitored by magnetic resonance imaging (MRI) of the
`brain, accumulation of disability, as well as rate and severity
`of relapses.
`There are five main forms of multiple sclerosis:
`1) Benign Multiple Sclerosis:
`Benign multiple sclerosis is a retrospective diagnosis
`which is characterized by 1-2 exacerbations with complete
`recovery, no lasting disability and no disease progression for
`10-15 years afier the initial onset. Benign multiple sclerosis
`may, however, progress into other forms ofmultiple sclerosis.
`2) Relapsing-Remitting Multiple Sclerosis (RRMS):
`Patients suffering from RRMS experience sporadic exac-
`erbations or relapses, as well as periods ofremission. Lesions
`and evidence ofaxonal loss may or may not be visible on MRI
`for patients with RRMS.
`3) Secondary Progressive Multiple Sclerosis (SPMS):
`SPMS may evolve from RRMS. Patients afllicted with
`SPMS have relapses, a diminishing degree ofrecovery during
`remissions, less frequent remissions and more pronounced
`neurological deficits than RRMS patients. Enlarged ven-
`tricles, which are markers for atrophy ofthe corpus callosum,
`midline center and spinal cord, are visible on MRI ofpatients
`with SPMS.
`4) Primary Progressive Multiple Sclerosis (PPMS);
`PPMS is characterized by a steady progression of increas-
`ing neurological deficits without distinct attacks or remis-
`sions. Cerebral lesions, diffuse spinal cord damage and evi-
`dence of axonal loss are evident on the MRI ofpatients with
`PPMS.
`
`5) Progressive-Relapsing Multiple Sclerosis (PRMS):
`PRMS has periods of acute exacerbations while proceed-
`ing along a course of increasing neurological deficits without
`remissions. Lesions are evident on MRI of patients suffering
`from PRMS (Multiple sclerosis: its diagnosis, symptoms,
`types and stages, 2003, albany.net/.about.tjc/multiple-sclero-
`sishtml; What are the Types of Multiple Sclerosis?, 2005,
`<imaginis.com/multiple-sclerosis/types-of-ms.asp-
`?modFl>).
`Chronic progressive multiple sclerosis is a term used to
`collectively refer to SPMS, PPMS, and PRMS (Types of
`Multiple Sclerosis (MS), 2005, <themcfox.com/multiple-
`sclerosis/types-of-ms/types-of-multi-ple-sclerosis.htm>).
`The relapsing forms of multiple sclerosis are SPMS with
`superimposed relapses, RRMS and PRMS.
`Glatiramer acetate (GA), a mixture of polypeptides which
`do not all have the same amino acid sequence, is marketed
`under the tradename 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,
`
`10
`
`20
`
`30
`
`35
`
`45
`
`50
`
`60
`
`65
`
`2
`
`0.427, 0.095 and 0.338, respectively. The average molecular
`weight of Copaxone® is between 5,000 and 9.(X)0 daltons.
`(“Copaxone”, Physician's Desk Reference, (2005), Medical
`Economics Co., Inc., (Montvale, N.J.), 3115.) Chemically,
`glatiramer acetate is designated L-glutamic acid polymer
`with L-alanine, L-lysine, L-tyrosine, acetate (salt).
`Its structural fonnula is:
`
`(Glu.Ala,Lys.Tyr)x.X CI-l,COOH
`(c_.-,H,No,.C,H7No,.c,c,,,N,o,.c9H. ,NO3)t.x
`CHO CAS-147245-92-9
`
`Copaxone® (“Copaxone", Full Prescribing Information,
`(February, 2009), FDA Marketing. Label) (20 mg glatiramer
`acetate daily injection) is an approved therapy for patients
`with relapsing remitting multiple sclerosis (RRMS), includ-
`ing patients who have experienced a first clinical episode and
`have MRI features consistent with multiple sclerosis.
`GA has also been disclosed for use in the treatment ofother
`
`autoimmune diseases (U.S. Patent Publication No. 2002/
`0055466 AI (R. Aharoni et al.), inflammatory non-autoim-
`mune diseases (U.S. Patent Publication No. 2005/0014694
`A1 (V. Wee Yong et al.); and U.S. Patent Application No.
`2002/0077278 A1, published Jun. 20, 2002 (Young et al.))
`and other diseases (U.S. Patent Publication Nos. 2003/
`0004099 Al and 2002/0037848 A1 (Eisenbach-Schwartz, et
`al.); U.S. Pat. No. 6,514,938 B1, issued Feb. 4, 2003 (Gad et
`al.); PCT International Publication No. WO 01/60392, pub-
`lished Aug. 23, 2001 (Gilbert et al.); PCT International Pub-
`lication No. W0 00/27417, published May 1 9, 2000 (Aharoni
`et al.); and PCT lntemational Publication No. WO 01/97846,
`published Dec. 27, 2001 (Moses et al.).
`The 20 mg/day subcutaneous (s.c.) dose has been shown to
`reduce the total number of enhancing lesions in MS patients
`as measured by MRI (G. Comi et al., European/Canadian
`Multicenter, Double-Blind, Randomized, Placebo-Con-
`trolled Study of the Effects of Glatiramer Acetere on Mag-
`netic Resonance Imaging-Measured Disease Activity and
`Burden in Patients with Relapsing Multiple Sclerosis, Ann.
`Neurol. 492290-297 (2001)).
`Safety data accumulated for GA in clinical trials shows that
`the drug product is safe and well tolerated.
`Disclosed is an effective low frequency dosage regimen of
`GA administrationto patients suffering from a relapsing form
`of multiple sclerosis, including patients who have experi-
`enced a first clinical episode and have MRI features consis-
`tent with multiple sclerosis.
`
`SUMMARY OF THE INVENTION
`
`This invention provides a method ofalleviating a symptom
`of relapsing-remitting multiple sclerosis in a human patient
`suffering from relapsing-remitting multiple sclerosis or a
`patient who has experienced a first clinical episode and is
`determined to be at high risk of developing clinically definite
`multiple sclerosis comprising administering to the human
`patient three subcutaneous injections of a therapeutically
`etfective dose of glatiramer acetate over a period of seven
`days with at least one day between every subcutaneous injec-
`tion so as to thereby alleviate the symptom of the patient.
`This invention also provides a method of increasing the
`tolerability ofGA treatment in a human patient sufl'en'ng from
`relapsing-remitting multiple sclerosis or a patient who has
`experienced a first clinical episode and is determined to be at
`high risk of developing clinically definite multiple sclerosis
`which comprises reducing the frequency of subcutaneous
`injections of a pharmaceutical composition comprising a
`
`AMNEAL
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`US 8,399,413 B2
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`therapeutically effective dose of glatiramer acetate to three
`times over a period of seven days with at least one day
`between every injection.
`In another embodiment, the therapeutically effective dose
`of glatiramer acetate is 40 mg/ml.
`This invention also provides a use of glatiramer acetate in
`the preparation ofa medicament for treating relapsing-remit-
`ting multiple sclerosis in a human patient suffering from
`relapsing-remitting multiple sclerosis or a patient who has
`experienced a first clinical episode and is determined to be at
`high risk of developing clinically definite multiple sclerosis
`wherein the administration pattern ofthe medicament is three
`subcutaneous injections ofa therapeutically effective dose of
`glatiramer acetate over a period ofseven days with at least one
`day between every subcutaneous injection.
`This invention additionally provides a use of glatiramer
`acetate in the preparation ofa medicament for treating relaps-
`ing-remitting multiple sclerosis in a human patient suffering
`from relapsing-remitting multiple sclerosis or a patient who
`has experienced a first clinical episode and is detennined to be
`at high risk ofdeveloping clinically definite multiple sclerosis
`wherein the medicament is prepared for an administration
`pattern of three subcutaneous injections of a therapeutically
`elfective dose of glatiramer acetate over a period of seven
`days with at least one day between every subcutaneous injec-
`tion.
`
`This invention yet also provides a use ofglatiramer acetate
`in the preparation of a medicament for increasing the toler-
`ability of GA treatment in a human patient sufl'ering from
`relapsing-remitting multiple sclerosis or a patient who has
`experienced a first clinical episode and is determined to be at
`high risk of developing clinically definite multiple sclerosis
`wherein the administration pattern ofthe medicament is three
`subcutaneous injections ofa therapeutically elfective dose of
`glatiramer acetate overa period ofseven days with at least one
`day between every subcutaneous injection.
`This invention further provides a use of glatiramer acetate
`in the preparation of a medicament for increasing the toler-
`ability of GA treatment in a human patient suflering trom
`relapsing-remitting multiple sclerosis or a patient who has
`experienced a first clinical episode and is determined to be at
`high risk of developing clinically definite multiple sclerosis
`wherein the medicament is prepared for an administration
`pattern of three subcutaneous injections of a therapeutically
`etfective dose of glatiramer acetate over a period of seven
`days with at least one day between every subcutaneous injec-
`tion.
`
`This invention provides glatiramer acetate for use in treat-
`ing relapsing-remitting multiple sclerosis in a human patient
`suffering from relapsing-remitting multiple sclerosis or a
`patient who has experienced a first clinical episode and is
`determined to be at high risk of developing clinically definite
`multiple sclerosis by three subcutaneous injections over a
`period of seven days with at least one day between every
`subcutaneous injection.
`This invention also provides glatiramer acetate for use in
`increasing the tolerability ofGA treatment in a human patient
`sutfering from relapsing-remitting multiple sclerosis or a
`patient who has experienced a first clinical episode and is
`determined to be at high risk of developing clinically definite
`multiple sclerosis by three subcutaneous injections over a
`period of seven days with at least one day between every
`subcutaneous injection.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`This invention provides a method ofalleviating a symptom
`of relapsing-remitting multiple sclerosis in a human patient
`
`10
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`20
`
`30
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`35
`
`45
`
`50
`
`55
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`60
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`4
`
`suffering from relapsing-remitting multiple sclerosis or a
`patient who has experienced a first clinical episode and is
`determined to be at high risk ofdeveloping clinically definite
`multiple sclerosis comprising administering to the human
`patient three subcutaneous injections of a therapeutically
`eifective dose of glatiramer acetate over a period of seven
`days with at least one day between every subcutaneous injec-
`tion so as to thereby alleviate the symptom of the patient.
`In another embodiment, there are three injections for every
`seven days and there must be at least one day between each
`injection. In a further embodiment, possible injection sched-
`ules include Day 1, Day 3, Day 5; Day 1, Day 3, Day 6; Day
`1, Day 3, Day 7; Day 1, Day 4, Day 6; Day 1, Day 4, Day 7;
`Day 1, Day 5, Day 7; Day 2, Day 4, Day 6; Day 2, Day 4, Day
`7; Day 2, Day 5, Day 7; or Day 3, Day 5, Day 7.
`In an embodiment, alleviating a symptom comprises
`reducing the frequency of relapses.
`In yet another embodiment, alleviating a symptom com-
`prises reducing the mean cumulative number of Gd-enhanc-
`ing lesions in the brain of the patient.
`In another embodiment, alleviating a symptom comprises
`reducing the mean number of new T2 lesions in the brain of
`the patient.
`In a further embodiment, alleviating a symptom comprises
`reducing the cumulative number of enhancing lesions on
`T,-weighted images in the patient.
`In another embodiment, alleviating symptom comprises
`reducing brain atrophy in the patient.
`In another embodiment, alleviating a symptom comprises
`increasing the time to a confirmed relapse in the patient
`In another embodiment, alleviating a symptom comprises
`reducing the total number ofconfirmed relapses in the patient.
`In another embodiment, alleviating a symptom comprises
`reducing the progression of MRI-monitored disease activity
`in the patient.
`In another embodiment, alleviating a symptom comprises
`reducing total volume of T2 lesions in the patient.
`In another embodiment, alleviating a symptom comprises
`reducing the number ofnew hypointense lesions on enhanced
`T, scans in the patient.
`In another embodiment, alleviating a symptom comprises
`reducing the total volume ofhypointense lesions on enhanced
`T, scans in the patient.
`In another embodiment, alleviating a symptom comprises
`reducing the level ofdisability as measured by EDSS Score in
`the patient.
`In another embodiment, alleviating a symptom comprises
`reducing the change in EDSS Score in the patient.
`In another embodiment, alleviating a symptom comprises
`reducing the change in Ambulation Index in the patient.
`In another embodiment, alleviating a symptom comprises
`reducing the level of disability as measured by EuroQoL
`(EQSD) questionnaire in the patient.
`In another embodiment, alleviating a symptom comprises
`reducing the level of disability as measured by the work
`productivity and activities impairment—General Health
`(WPAI-GH) questionnaire in the patient.
`In an additional embodiment, the pharmaceutical compo-
`sition is in a prefilled syringe for self administration by the
`patient.
`In yet another embodiment, the therapeutically efiective
`dose of glatiramer acetate is 40 myml. In a further embodi-
`ment, the therapeutically effective dose of glatiramer acetate
`is 40 mg/0.75 ml.
`In a further embodiment, the patient has not received glati-
`ramer acetate therapy prior to initiation of the subcutaneous
`injections.
`
`AMNEAL
`
`EXHIBIT NO. 1001 Page 5
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`US 8,399,413 B2
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`5
`In an embodiment, the pharmaceutical composition is in
`the form of a sterile solution.
`
`In another embodiment, the pharmaceutical composition
`further comprises mannitol.
`In yet another embodiment, the pharmaceutical composi-
`tion has a pH in the range of5.5 to 8.5.
`In an embodiment, the pharmaceutical composition has a
`pH in the range of5.5 to 7,0.
`In an embodiment the frequency of an immediate post
`injection reaction or the frequency ofan injection site reaction
`is reduced relative to daily subcutaneous administration of20
`mg glatiramer acetate.
`This invention also provides a method of increasing the
`tolerability ofGA treatment in a human patient suffering from
`relapsing-remitting multiple sclerosis or a patient who has
`experienced a first clinical episode and is determined to be at
`high risk of developing clinically definite multiple sclerosis
`which comprises reducing the frequency of subcutaneous
`injections of a pharmaceutical composition comprising a
`therapeutically effective dose of glatiramer acetate to three
`times over a period of seven days with at least one day
`between every injection.
`In another embodiment, increasing the tolerability of GA
`treatment in the human patient suffering from a relapsing
`form of multiple sclerosis comprises reducing the frequency
`of an immediate post injection reaction.
`In yet another embodiment, the immediate post injection
`reaction is palpitations, feeling hot, flushing, hot flushes,
`tachycardia, dyspnoea, chest discomfort, chest pain, non-
`cardiac chest, asthenia, back pain, bacterial infection, chills,
`cyst, face edema, fever, flu syndrome, infection, injection site
`erythema, injection site hemorrhage, injection site indura-
`tion, injection site inflammation, injection site mass, inject