IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Docket No. 2609/80798—A/JPW/GJG/ML
`
`U.S. PTO
`1 2/806684
`08/1 9/201 0
`
`G E
`
`S—A
`<9
`
`.C
`.‘D
`
`I:
`_O
`
`COMMISSIONER FOR PATENTS
`P.O. Box 1450
`Alexandria, VA 22313—1450
`
`Sir:
`
`Date: August 19, 2010
`
`Transmitted herewith for filing is the utility patent application of:
`
`Ety Klinger
`
`Inventor(s)
`
`
`
`for
`
`LOW FREQUENCY GLATIRAMER ACETATE THERAPY
`Title of Invention
`
`including the following:
`
`
`44
`X Application (
`including
`pages in total),
`1
`of specification;
`5
`page(s) of claims;
`
`abstract;
`0
`page(s) of sequence listing; and
`of drawings
`
`37
`
`pages
`page(s) of
`O
`sheet(s)
`
`X
`
`
`Oath or Declaration of Applicant(s)
`
`(
`
`X
`
`signed
`
`
`
`unsigned)
`
`X
`
`
`Power of Attorney (
`
`X
`
`signed
`
`unsigned)
`
`
`X
`
`Preliminary Amendment
`
`(
`
`including claim to benefit of earlier U.S.
`Provisional Application(s))
`
`The following are also enclosed:
`
` X
`
`Assignment to
`
`Teva Pharmaceutical Industries, Ltd.
`
`Verified Statement to establish small entity status under 37 C.F.R. §l.9 and
`§1.27
`
`Information Disclosure Statement,
`including Form PTO-1449
`; No
`)
`(Copies of citations are included: Yes
`
`Non—Publication Request
`
`(Form PTO/SB/135 must be attached)
`
`Computer Readable Form (CRF)
`of Sequence Listing and Statement Verifying
`Identity of CRF and Sequence Listing
`
`Certified copy of previously filed foreign application(s)
`
`as follows:
`
`Country
`
`Application No.
`
`Filing Date
`
`Applicant(s) hereby claim(s)
`priority based upon the aforementioned foreign
`under 35 U.S.C. §119
`application(s)
`
`JPW Rev. 10-2-08
`
`MYLAN INC. EXHIBIT NO. 1002 Page 1
`
`Ill/l
`
`Iilwlmilill‘fiI/bfiifin)
`
`MYLAN INC. EXHIBIT NO. 1002 Page 1
`
`

`

`2609f80798-AgJPWgGJGZML
`Docket NO.
`Inventor(s)EtZ Klinger
`Patent Application Transmittal Letter
`Page 2/2
`
`X
`
`X
`
`Two copies of this Patent Application Transmittal Letter
`
`- Return Receipt Postcard
`
`Express Mail Certificate of Mailing Label No.
`dated
`August 19, 2010
`
`EM 520849611 US
`
`Other (identify):
`
`The filing fee is calculated as follows:
`
`NUMBER OF CLAIMS AS
`PRELIMINARY AMENDMENT
`
`FILED, MINUS ALL CLAIMS CANCELED BY ANY ACCOMPANYING
`
`
`
`
`Total
`Claims
`
`Claims
`Pages in
`Excess of
`100
`
`
`
`
`
`—3 =
`X
`$110
`
`
`$ 220-
`
` * If less than zero, enter“0”
`
`$ 270-
`$ 540-
`T Round upwards to integer, e.g. 1.1 = 2,
`
`
`and
`insert
`$ 110-
`
`
`
`X
`
`A check in the amount of $11402.00
`
`is enclosed.
`
`Please charge Deposit Account No.
`
`in the amount of $
`
`fees
`is hereby authorized to charge any additional
`The Commissioner
`required or credit any overpayment
`to Deposit Account No.
`03—3125 as
`follows:
`
`Filing fees under 37 C.F.R. §1.16
`Patent application processing fees under 37 C.F.R. §1.17
`
`Respectfully submitte
`
`
`
`Registrat on No. 28,678
`Gary J. Gershik
`Registration No. 39,992
`Attorneys for Applicant(s)
`Cooper & Dunham LLP (Customer #23432)
`30 Rockefeller Plaza
`20’:h Floor
`New York, New York 10112
`(212) 278-0400
`
`JPW Rev. 10-2-08
`
`MYLAN INC. EXHIBIT NO. 1002 Page 2
`
`MYLAN INC. EXHIBIT NO. 1002 Page 2
`
`

`

`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Docket NO. 2609/80798-A/JPW/GJG/ML
`
`Applicant:
`
`Ety Klinger
`
`Serial No.:
`
`Not Yet Known
`
`Filed:
`
`For:
`
`'Herewith
`
`LOW FREQUENCY GLATIRAMER ACETATE THERAPY
`
`30 Rockefeller Plaza
`
`New York, New York 10112
`August 19, 2010
`
`Commissioner for Patents
`P.O. Box 1450
`
`Alexandria, VA 22313—1450
`
`SIR:
`
`EXPRESS MAIL CERTIFICATE OF MAILING
`FOR ABOVE-IDENTIFIED APPLICATION
`
`“Express Mail” mailing label number:
`
`EM 520 849 611 US
`
`Date of Deposit:
`
`Au ust 19, 2010
`
`I hereby certify that this paper or fee is being deposited to the
`United States Postal Service
`“Express Mail Post Office
`to
`Addressee” service under 37 C.F.R. §1.1O on the date indicated
`above and is addressed to the Commissioner for Patents, P.O. Box
`1450,
`'
`
`VA 22 13—1450
`
`ted Name:
`
`
`
`Respectfully submitted,
`
`
`
`Registrat on No.
`Gary J. Gershik
`Registration No. 39,992
`Attorneys for Applicant
`Cooper & Dunham LLP
`30 Rockefeller Plaza
`
`New York, New York 10112
`Tel. No.
`(212) 278-0400
`
`MYLAN INC. EXHIBIT NO. 1002 Page 3
`
`MYLAN INC. EXHIBIT NO. 1002 Page 3
`
`

`

`€811):
`
`Docket Number: §QIZ9§-fl,lPW/§JGML
`
`DECLARA TION AND POWER OF A TTORNEY
`
`As a below-named inventor, I hereby declare that:
`
`My residence, post office address. and citizenship are as stated below next to my name.
`
`I believe I am the original, first and sole inventor (ifonly one name is listed below) or an original. first
`andjoint inventor (ifplural names are listed below) ofthe subject matter which is claimed andfor which a
`patent is sought on the invention entitled:
`
`LOW FREQUENCY GLATIRAMER ACETATE THERAPY
`
`the specification of which:
`(check one)
`
`X
`
`is attached hereto.
`
`wasfiled on
`
`
`
`as
`
`Application Serial No.
`
`and was amended
`
`(ifapplicable)
`
`I hereby state that I have reviewed and understand the contents of the above-identified specification,
`including the claims, as amended by any amendment referred to above.
`
`I acknowledge the duty to disclose to the U. S. Patent and Trademark Oflice all information known to me
`to be material to patentability as defined in Title 37. Code ofFederal Regulations. Section 1.56.
`
`'
`
`I hereby claimforeign priority benefits under Title 35. United States Code, Section I 19(o)-(d) or Section
`365(b) of anyforeign applications) for patent or inventor's certificate, or Section 365(0) of any PCT
`International Application which designated at least one country other than the United States, listed
`below. I have also identified below anyforeign application for patent or inventor’s certificate, or PCT
`International Application having a filing date before that ofthe earliest application from which prim-it);
`is claimed:
`
`Prior Foreign Application (5)
`
`Priority Claimed
`
`Number
`NlA
`
`Cguntgg
`
`F[ling Date
`
`Xe;
`
`M
`
`JPWRev. 8/13/08
`
`ZMYLANINC.EXHHHTNO.HM2 Page 4
`
`MYLAN INC. EXHIBIT NO. 1002 Page 4
`
`

`

`581104.
`
`Docket Number: 80798-A/JPW/GJGIML
`
`Declaration and Power ofAttorney
`
`Page .2
`
`I hereby claim the benefit under Title 35, United States Code. Section [19(e) of any United States
`provisional application(s) listed below:
`
`Provisional Application No.
`
`Filing Date
`
`Status
`
`g 1/2 Z4,§§Z
`
`gygzmz
`
`Au
`
`t 2
`
`Febm 1 1.2010
`
`Eggding
`
`pending
`
`'
`
`
`
`I hereby claim the benefit under Title 35, United States Code, Section 120 of any United States
`ApplicationCv). or Section 365(c) ofany PCT International Application(s) designating the United States
`listed below. Insofar as this application discloses and claims subject matter in addition to that disclosed
`in any such prior Application in the manner provided by lhefirst paragraph of Title 3-5, United States
`Code, Section 112. I acknowledge the duty to disclose to the United States Patent and Trademark Ofl'ice
`all information known to me to be material to patentability as defined in Title 37. Code of Federal
`Regulations, Section 1.56, which became available between thefiling date(s) ofsuch prior Application(s)
`and the national or PCT internationalfiling date of this application:
`
`Application Serial No,
`
`filing Dgte
`
`Status
`
`N/A
`
`And I hereby appoint
`
`John P. White (Reg No. 28 678); Chn'stopherC. Dunham (Reg. No. 22031), Norman?! Zivin (Reg. No.
`25.;385) William E. Pclton (Reg. No. 25 .7;02) RobeflD. Katz (Reg. No. 30,141); Paul Teng (Reg. No.
`40.837); and Gary J. Gcrshflc (Reg. No. 39.992).
`
`and each ofthem. all do Cooper & Dunham LLP. 30 Rockefeller Plaza. 20” Floor, New York. New York
`10112, my attomeys, each. withfullpower ofsubstitution and revocation. to prosecute this application. to
`make alterations and amendments therein, to receive the patent, to transact all business in the Patent and
`Trademark Oflice connected therewith and tofile any International Applications which are based thereon
`under the provisions ofthe Patent Cooperation Treaty.
`
`JP W Rev. 8/! 3/08
`
`:MYLANINC.EXHHHTNO.HM2 Page 5
`
`MYLAN INC. EXHIBIT NO. 1002 Page 5
`
`

`

`Declaration and Power ofAuomay
`
`908‘ 3
`
`sear-LA
`
`Dada! Miter:W
`
`Flame addms allmm and dim all telephone calls: reganflng dub application to:
`
`W Hawk—2L...—
`Cooper & Bauhaus. LLP (amour Number 23432)
`30 WellerHm
`20" Hoar
`New York, New York 10112
`Tel. (312) 278-0400
`
`[hembydaahmtkuaflmkm McMillan-yam Memorandum: allmm
`madccnnfirmtiunandbeflgfmbeflewdmbcMaudfinbcrdmnhuexmnmnndewM
`MWMyMWWMWMfiemImMMW¢byfimehMor
`both.mm 1001 qffldz 18 qflha WMMMMM’I wiWfivbemmnamay
`Mike validity 0]!th ammmm
`
`mam
`
`‘
`
`quu vam x' 20/:
`
`Citizenship
`Refine:
`
`_
`1mg
`”M'mmm‘ man
`
`.
`
`
`
`Full name daddin'aul
`joint imam!!- (Um)
`
`Inventor's signature
`thip
`Rm
`
`Pm: Wine Addrm
`
`
`
`
`Date 1W
`
`—__'_'————————_—_
`
`M name ofadflfloml
`1‘01!" MW (raw _________ .
`
`banana/.9 31mm
`CW
`
`001'4W“
`
`Rm
`PM Ofi‘we Adding
`
`11’7ch mm
`
`MYLAN INC. EXHIBIT NO. 1002 Page 6
`
`MYLAN INC. EXHIBIT NO. 1002 Page 6
`
`

`

`Docket No. 80798-A/JPW/GJG/ML
`
`Application
`for
`United States Letters Patent
`
`To all whom it may concern:
`
`Be it known that
`
`Ety Klinger
`
`have invented certain new and useful improvements in
`
`LOW FREQUENCY GLATIRAMER ACETATE THERAPY
`
`of which the following is a full, clear and exact description.
`
`MYLAN INC. EXHIBIT NO. 1002 Page 7
`
`MYLAN INC. EXHIBIT NO. 1002 Page 7
`
`

`

`Docket 2609/80798—A/JPW/GJG/ML
`
`LOW FREQUENCY GLATIRAMER ACETATE THERAPY
`
`This
`
`application claims
`
`the benefit
`
`of U.S.
`
`Provisional
`
`Application Nos.
`
`61/274,687,
`
`filed August
`
`20,
`
`2009
`
`and
`
`61/337,612, filed February 11, 2010. The contents of which are
`
`hereby incorporated by reference in their entirety.
`
`Throughout
`
`this
`
`application
`
`various
`
`publications
`
`are
`
`referenced by their full citations. 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
`
`10
`
`15
`
`Multiple Sclerosis
`
`(MS)
`
`is a chronic, debilitating disease of
`
`the central nervous system (CNS). MS has also been classified
`
`as an autoimmune disease. MS disease activity can be monitored
`by magnetic resonance imaging (MRI) of the brain, accumulation
`
`20
`
`of disability, as well as rate and severity of relapses.
`
`There are five main forms of multiple sclerosis:
`
`25
`
`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 after the initial onset. Benign multiple sclerosis may,
`
`3O
`
`however, progress into other forms of multiple sclerosis.
`
`2) Relapsing—Remitting Multiple Sclerosis (RRMS):
`
`Patients suffering from RRMS experience sporadic exacerbations
`
`or
`
`relapses,
`
`as well
`
`as periods of
`
`remission. Lesions
`
`and
`
`MYLAN INC. EXHIBIT NO. 1002 Page 8
`
`MYLAN INC. EXHIBIT NO. 1002 Page 8
`
`

`

`evidence of axonal
`
`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 afflicted with SPMS have
`
`relapses,
`
`a diminishing degree of
`
`recovery during remissions,
`
`less
`
`frequent
`
`remissions
`
`and more
`
`pronounced neurological
`
`deficits than RRMS patients. Enlarged ventricles, which are
`
`markers for atrophy of the corpus callosum, midline center and
`
`spinal cord, are visible on MRI of patients with SPMS.
`
`4) Primary Progressive Multiple Sclerosis (PPMS);
`
`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.
`
`5) Progressive—Relapsing Multiple Sclerosis (PRMS):
`
`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
`
`(Multiple sclerosis:
`
`its diagnosis,
`
`symptoms,
`
`types
`
`and
`
`stages,
`
`2003,
`
`albany.net/.about
`
`.tjc/multiple-
`
`sclerosis.html; What are the Types of Multiple Sclerosis?,
`
`10
`
`15
`
`20
`
`25
`
`2005,
`
`mode=1>).
`
`<imaginis.com/multiple—sclerosis/types—of-ms.asp?
`
`Chronic progressive multiple
`
`sclerosis
`
`is
`
`a
`
`term used to
`
`collectively refer to SPMS,
`
`PPMS, and PRMS
`
`(Types of Multiple
`
`30
`
`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.
`
`MYLAN INC. EXHIBIT NO. 1002 Page 9
`
`MYLAN INC. EXHIBIT NO. 1002 Page 9
`
`

`

`Glatiramer acetate (GA),
`
`a ndxture of polypeptides which do
`
`not all have the same amino acid sequence,
`
`is marketed under
`
`the tradename CopaxoneCL 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
`
`CopaxoneC> is between 5,000 and 9,000 daltons.
`
`("Copaxone",
`
`'Physician's Desk Reference,
`
`(2005), Medical Economics Co.,
`
`Inc.,
`
`(Montvale, N.J.), 3115.) Chemically, glatiramer acetate
`
`10
`
`is designated L—glutamic
`
`acid polymer‘ with L—alanine,
`
`L—
`
`lysine, L—tyrosine, acetate (salt).
`
`Its structural formula is:
`
`15
`
`(Glu,Ala,Lys,Tyr)x.X CH3COOH
`
`(C5H9NO4 'C3H7N02'C6H14N202‘C9H11NO3) X'X CHO
`
`CAS-l47245-92-9
`
`20
`
`25
`
`30
`
`CopaxoneC)
`
`("Copaxone",
`
`Full
`
`Prescribing
`
`Information,
`
`(February,
`
`2009),
`
`FDA Marketing. Label)
`
`(20mg
`
`glatiramer
`
`acetate daily injection)
`
`is an approved therapy for patients
`
`with relapsing remitting multiple sclerosis (RRMS),
`
`including
`
`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 of other
`
`autoimmune diseases
`
`(U.S. Patent Publication No. 2002/0055466
`
`A1
`
`(R. Aharoni et al.),
`
`inflammatory non—autoimmune 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 a1.))
`
`and other diseases
`
`(U.S. Patent Publication Nos. 2003/0004099 A1 and 2002/0037848
`
`A1
`
`(Eisenbach—Schwartz, et al.); U.S. Pat. No. 6,514,938 81,
`
`issued
`
`Feb.
`
`4,
`
`2003
`
`(Gad
`
`et
`
`al.);
`
`PCT
`
`International
`
`MYLAN INC. EXHIBIT NO. 1002 Page 10
`
`MYLAN INC. EXHIBIT NO. 1002 Page 10
`
`

`

`Publication No. WO 01/60392, published Aug. 23, 2001
`
`(Gilbert
`
`et al.);
`
`PCT
`
`International Publication No.
`
`WO
`
`00/27417,
`
`published May 19, 2000 (Aharoni et al.); and PCT International
`
`Publication No. WO 01/97846, published Dec. 27, 2001 (Moses et
`
`al.).
`
`The 20mg/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—Controlled
`
`Study
`
`of
`
`the Effects
`
`of Glatiramer Acetere
`
`on Magnetic
`
`Resonance
`
`Imaging-Measured Disease Activity and Burden
`
`in
`
`Patients with Relapsing Multiple Sclerosis, Ann. Neurol.
`
`49:290-297 (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
`
`administration to patients suffering from a relapsing form of
`
`multiple sclerosis,
`
`including patients who have experienced a
`
`first clinical episode and have MRI
`
`features consistent with
`
`multiple sclerosis.
`
`10
`
`15
`
`20
`
`25
`
`MYLAN INC. EXHIBIT NO. 1002 Page 11
`
`MYLAN INC. EXHIBIT NO. 1002 Page 11
`
`

`

`SUMMARY OF THE INVENTION
`
`This invention provides a method of alleviating 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
`
`therapeutically effective dose of glatiramer acetate over
`
`a
`
`a
`
`period of
`
`seven days with at
`
`least one day between every
`
`subcutaneous injection so as to thereby alleviate the symptom
`
`of the patient.
`
`This
`
`invention also provides
`
`a method of
`
`increasing the
`
`tolerability of GA 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
`comprising a
`
`injections
`of
`a
`pharmaceutical
`composition
`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 40mg/ml.
`
`This
`
`invention also provides a use of glatiramer acetate in
`
`the preparation of
`
`a medicament
`
`for
`
`treating 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 wherein the administration pattern of the medicament
`
`10
`
`15
`
`20
`
`25
`
`30
`
`MYLAN INC. EXHIBIT NO. 1002 Page 12
`
`MYLAN INC. EXHIBIT NO. 1002 Page 12
`
`

`

`is
`
`three
`
`subcutaneous
`
`injections
`
`of
`
`a
`
`therapeutically
`
`effective dose of glatiramer acetate over
`
`a period of
`
`seven
`
`days with
`
`at
`
`least
`
`one
`
`day
`
`between
`
`every
`
`subcutaneous
`
`injection.
`
`This
`
`invention additionally provides
`
`a
`
`use
`
`of glatiramer
`
`acetate
`
`in the preparation of
`
`a medicament
`
`for
`
`treating
`
`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 wherein the medicament is prepared
`for an administration pattern of three subcutaneous injections
`
`of a therapeutically effective dose of glatiramer acetate over
`
`a period of
`
`seven days with at
`
`least one day between every
`
`subcutaneous injection.
`
`This invention yet also provides a use of glatiramer acetate
`
`in
`
`the preparation of
`
`a medicament
`
`for
`
`increasing
`
`the
`
`tolerability of GA 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 wherein the administration pattern of the medicament
`
`is
`
`three
`
`subcutaneous
`
`injections
`
`of
`
`a
`
`therapeutically
`
`effective dose of glatiramer acetate over
`days with
`at.
`least
`one
`day between
`
`a period of
`seven
`every
`subcutaneous
`
`injection.
`
`This invention further provides a use of glatiramer acetate in
`
`the
`
`preparation
`
`of
`
`a medicament
`
`for
`
`increasing
`
`the
`
`tolerability of GA 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
`
`10
`
`15
`
`20
`
`25
`
`3O
`
`35
`
`MYLAN INC. EXHIBIT NO. 1002 Page 13
`
`MYLAN INC. EXHIBIT NO. 1002 Page 13
`
`

`

`sclerosis wherein
`
`the medicament
`
`is
`
`prepared
`
`for
`
`an
`
`administration pattern of
`
`three subcutaneous
`
`injections of
`
`therapeutically effective doSe of glatiramer acetate over
`
`a
`
`a
`
`period of
`
`seven days with at
`
`least one day between every
`
`subcutaneous injection.
`
`This invention provides glatiramer acetate for use in treating
`
`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
`
`51 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 of GA 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 by three subcutaneous
`
`injections
`
`over
`
`51 period of
`
`seven days with at
`
`least one day between
`
`every subcutaneous injection.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`MYLAN INC. EXHIBIT NO. 1002 Page 14
`
`MYLAN INC. EXHIBIT NO. 1002 Page 14
`
`

`

`DETAILED DESCRIPTION OF THE INVENTION
`
`This invention provides a method of alleviating 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
`
`therapeUtically' effective dose of glatiramer acetate over
`
`a
`
`a
`
`period of
`
`seven days with at
`
`least one day between every
`
`subcutaneous injection 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
`
`schedules include Day 1, Day %, 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 comprises
`
`reducing the mean cumulative number of Gd—enhancing 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.
`
`10
`
`15
`
`20
`
`25
`
`3O
`
`MYLAN INC. EXHIBIT NO. 1002 Page 15
`
`MYLAN INC. EXHIBIT NO. 1002 Page 15
`
`

`

`In
`
`a
`
`further
`
`embodiment,
`
`alleviating a
`
`symptom comprises
`
`reducing the cumulative number of enhancing lesions
`
`on
`
`T1—
`
`weighted images in the patient.
`
`In
`
`another
`
`embodiment,
`
`alleviating Va
`
`‘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
`
`of
`
`confirmed
`
`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 lesionsin the patient.
`
`\
`
`In
`
`another
`
`embodiment,
`
`alleviating
`
`a
`
`symptom comprises
`
`reducing the number of new hypointense lesions on enhanced T1
`
`scans in the patient.
`
`In
`
`another
`
`embodiment,
`
`alleviating
`
`a
`
`symptom comprises
`
`reducing the total volume of hypointense lesions on enhanced T1
`
`scans in the patient.
`
`In
`
`another
`
`embodiment,
`
`alleviating
`
`a
`
`symptom comprises
`
`reducing the level of disability as measured.by EDSS Score in
`
`the patient.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`MYLAN INC. EXHIBIT 'NO. 1002 Page 16
`
`MYLAN INC. EXHIBIT NO. 1002 Page 16
`
`

`

`-10—
`
`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 composition is
`
`in a prefilled syringe for self administration by the patient.
`
`In yet another embodiment,
`
`the therapeutically effective dose
`
`of glatiramer acetate is 40mg/ml.
`
`In a further embodiment,
`
`the
`
`therapeutically
`
`effective
`
`dose
`
`of
`
`glatiramer
`
`acetate
`
`is
`
`40mg/0.75ml.
`
`In
`
`a
`
`further
`
`embodiment,
`
`the patient
`
`has
`
`not
`
`received
`
`glatiramer
`
`acetate
`
`therapy
`
`prior
`
`to
`
`initiation of
`
`the
`
`subcutaneous injections.
`
`In an embodiment,
`
`the pharmaceutical composition is in the
`
`form of a sterile solution.
`
`In another embodiment,
`
`the pharmaceutical composition further
`
`comprises mannitol.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`MYLAN INC. EXHIBIT NO. 1002 Page 17
`
`MYLAN INC. EXHIBIT NO. 1002 Page 17
`
`

`

`In yet another embodiment,
`
`the pharmaceutical composition has
`
`a pH in the range of 5.5 to 8.5.
`
`In an embodiment,
`
`the pharmaceutical composition has a pH in
`
`the range of 5.5 to 7.0.
`
`In an embodimentthe frequency of an immediate post
`
`injection
`
`reaction or
`
`the frequency of
`
`an injection 'site reaction is
`
`reduced relative to daily subcutaneous administration of 20mg
`
`glatiramer acetate.
`
`This
`
`invention also provides
`
`a method of
`
`increasing the
`
`tolerability of GA 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
`subcutaneous,
`injections
`of
`
`reducing
`the
`frequency
`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‘
`
`10
`
`15
`
`20
`
`25
`
`30
`
`'MYLAN INC. EXHIBIT NO. 1002 Page 18
`
`MYLAN INC. EXHIBIT NO. 1002 Page 18
`
`

`

`_12_
`
`site induration,
`
`injection site inflammation,
`
`injection site
`
`mass,
`
`injection site pain,
`
`injection site pruritus,
`
`injection
`
`site urticaria,
`
`injection site welt, neck pain, pain, migrane,
`
`syncope,
`
`tachycardia,
`
`vasodilatation,
`
`anorexia,
`
`diarrhea,
`
`gastroenteritis, gastrointestinal disorder, nausea, vomiting,
`
`ecchymosis, peripheral edema, arthralgia, agitation, anxiety,
`
`confusion,
`
`foot
`
`drop,
`
`hypertonia,
`
`nervousness,
`
`nystagmus,
`
`speech
`
`disorder,
`
`tremor,
`
`vertigo,
`
`bronchitis,
`
`dyspnea,
`
`laryngismus,
`
`rhinitis,
`
`erythema,
`
`herpes
`
`simplex, pruritus,
`
`rash,
`
`skin
`
`nodule,
`
`sweating,
`
`urticaria,
`
`ear
`
`pain,
`
`eye
`
`disorder,
`
`dysmenorrheal,
`
`urinary
`
`urgency,
`
`or
`
`vaginal
`
`moniliasis.
`
`In an additional 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
`
`injection site reaction.
`
`a
`
`further
`
`embodiment,
`
`the
`
`injection site reaction is
`
`10
`
`15
`
`20
`
`25
`
`30
`
`In
`
`erythema,
`
`hemorrhage,
`
`induration,
`
`inflammation, mass, pain,
`
`pruritus, urticaria, or welt
`
`that occurs
`
`immediately around
`
`the site of injection.
`
`In an embodiment,
`
`a 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,
`
`clumsiness
`
`of
`
`a
`
`limb,
`
`lack of
`
`coordination, weakness of
`
`one or more
`
`extremity,
`
`altered
`
`muscle tone, muscle stiffness,
`
`spasms,
`
`tingling, paraesthesia,
`
`burning
`
`sensations, muscle pains,
`
`facial pain,
`
`trigeminal
`
`neuralgia,
`
`stabbing
`
`sharp
`
`pains,
`
`burning
`
`tingling pain,
`
`slowing of
`
`speech,
`
`slurring of words,
`
`changes
`
`in rhythm of
`
`speech,
`
`dysphagia,
`
`fatigue,
`
`bladder
`
`problems
`
`(including
`
`urgency,
`
`frequency,
`
`incomplete
`
`emptying
`
`and
`
`incontinence),
`
`MYLAN INC. EXHIBIT NO. 1002 Page 19
`
`MYLAN INC. EXHIBIT NO. 1002 Page 19
`
`

`

`-13—
`
`bowel
`
`problems
`
`(including constipation and
`
`loss
`
`of
`
`bowel
`
`control),
`
`impotence,
`
`diminished
`
`sexual
`
`arousal,
`
`loss
`
`of
`
`sensation,
`
`sensitivity to heat,
`
`loss of
`
`short
`
`term memory,
`
`loss of concentration, or loss of judgment or reasoning.
`
`In another embodiment, prior to administration the patient has
`
`at
`
`least
`
`1 cerebral
`
`lesion detectable by
`
`an MRI
`
`scan and
`
`suggestive of multiple sclerosis.
`
`In yet another embodiment,
`
`the lesion is associated with brain
`
`tissue inflammation, myelin sheath damage or axonal damage.
`
`In an additional
`
`embodiment,
`
`the lesion is a demyelinating
`
`white matter lesion visible on brain MRI.
`
`10
`
`15
`
`In a further embodiment,
`
`the white matter lesions are at least
`
`3 mm in diameter.
`
`This
`
`invention also provides a use of glatiramer acetate in
`
`the preparation of
`
`a medicament
`
`for
`
`treating 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 wherein the administration pattern of the medicament
`
`is
`
`three
`
`subcutaneous
`
`injections
`
`of
`
`a
`
`therapeutically
`
`effective dose of glatiramer acetate over
`
`a period of
`
`seven
`
`days with
`
`at
`
`least
`
`one
`
`day
`
`between
`
`every
`
`subcutaneous
`
`injection.
`
`This
`
`invention additionally provides
`
`a
`
`use
`
`of glatiramer
`
`acetate
`
`in the preparation of
`
`a medicament
`
`for
`
`treating
`
`relapsing—remitting multiple
`
`sclerosis
`
`in a
`
`human patient
`
`suffering from relapsing—remitting multiple
`
`sclerosis or
`
`a
`
`MYLAN INC. EXHIBIT NO. 1002 Page 20
`
`MYLAN INC. EXHIBIT NO. 1002 Page 20
`
`

`

`_l4_
`
`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 effective dose of glatiramer acetate over
`
`a period of
`
`seven days with at
`
`least one day between every
`
`subcutaneous injection.
`
`This invention yet also provides a use of glatiramer acetate
`
`in
`
`the preparation
`
`of ‘a medicament
`
`for
`
`increasing
`
`the
`
`tolerability of GA 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 wherein the administration pattern of the medicament
`
`is
`
`three
`
`subcutaneous
`
`injections
`
`of
`
`a _therapeutically
`
`effective dose of glatiramer acetate over
`
`a period of
`
`seven
`
`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
`
`tolerability of GA treatment
`
`in a human patient suffering from
`
`relapsing—remitting Hmltiple 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
`
`therapeutically effective dose of glatiramer acetate over
`
`a
`
`a
`
`period of
`
`seven days with at
`
`least
`
`one day between every
`
`subcutaneous injection.
`
`This invention provides glatiramer acetate for use in treating
`
`relapsing—remitting multiple
`
`sclerosis
`
`in a
`
`human patient
`
`suffering from relapsing—remitting multiple
`
`sclerosis or
`
`a
`
`MYLAN INC. EXHIBIT NO. 1002 Page 21
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`MYLAN INC. EXHIBIT NO. 1002 Page 21
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`_15_
`
`patient who has experienced a first clinical episode and is
`
`determined
`
`to be
`
`at
`
`high
`
`risk of
`
`developing clinically
`
`definite nmltiple sclerosis by three subcutanedus
`
`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 of GA 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 by three subcutaneou