Claims
`1. A method of treating a human patient
`suffering from a relapsing form of
`multiple sclerosis, while inducing
`reduced severity of injection site
`reactions in the human patient relative to
`administration of 20 mg of glatiramer
`acetate s.c. daily, the method consisting
`of one subcutaneous injection of 1 ml of
`a pharmaceutical composition
`comprising 40 mg of glatiramer acetate
`on only each of three days during each
`week of treatment with at least one day
`without a subcutaneous injection of the
`pharmaceutical composition between
`each day on which there is a
`subcutaneous injection, wherein the
`pharmaceutical composition is in a
`prefilled syringe, and wherein the
`pharmaceutical composition further
`comprises mannitol and has a pH in the
`range 5.5 to 7.0,
`so as to thereby treat the human
`patient with reduced severity of
`injection site reactions relative to
`administration of 20 mg of
`glatiramer acetate s.c. daily.
`
`Written Description
`Copaxone® (“Copaxone”, Full
`Prescribing Information, (February,
`2009), FDA Marketing. Label) (20 mg
`glatiramer acetate daily injection) is an
`approved therapy for patients
`
`Col. 2, ll. 18-20
`
`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-
`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.
`
`Col. 2, ll. 38-52
`
`This invention also provides a method
`of increasing the tolerability of GA
`treatment in a human patient suffering
`from relapsing-remitting multiple
`
`
`
`Page 1 of 14
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`YEDA EXHIBIT NO. 2003
`MYLAN PHARM. v YEDA
`PGR2016-00010
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`

`
`
`
`
`
`Claims
`
`Written Description
`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.
`
`Col. 2, 11. 66-col. 3, ll. 8
`
`In another embodiment, the
`therapeutically effective dose of
`glatiramer acetate is 40 mg/ml.
`
`Col. 3, ll. 9-10
`
`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 a period of seven days
`with at least one day between every
`subcutaneous injection.
`
`Col. 3, l. 63 – col. 4, l. 3
`
`As used herein, “tolerability” relates to
`the level of discomfort associated with
`GA treatment. Tolerability is associated
`with the frequency and severity of post
`injection reactions and injection site
`
`Page 2 of 14
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`YEDA EXHIBIT NO. 2003
`MYLAN PHARM. v YEDA
`PGR2016-00010
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`

`
`
`
`
`
`Claims
`
`Written Description
`reactions. Tolerability influences the
`period that a patient can follow GA
`treatment.
`
`Col. 7, ll. 38-42
`
`In an embodiment the frequency of an
`immediate post injection reaction or the
`frequency of an injection site reaction is
`reduced relative to daily subcutaneous
`administration of 20 mg glatiramer
`acetate
`
`This invention also provides a method
`of increasing the tolerability of GA
`treatment in a human patient … 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.
`
`Col. 5, ll. 19-32
`
`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 a period of seven days
`with at least one day between every
`subcutaneous injection.
`
`
`Page 3 of 14
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`YEDA EXHIBIT NO. 2003
`MYLAN PHARM. v YEDA
`PGR2016-00010
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`

`
`
`
`
`
`Claims
`
`Written Description
`Col. 7, ll. 4-11
`
`A multinational, multicenter,
`randomized, phase III parallel-group
`study performed in subjects with
`Relapsing-Remitting Multiple Sclerosis
`(RRMS) to assess the efficacy, safety
`and tolerability of Glatiramer Acetate
`(GA) injection 40 mg/ml administered
`three times weekly by subcutaneous
`injection over placebo in a double-blind
`design.
`
`Col. 8, ll. 62-67
`
`Study Objective(s):
`To assess the efficacy, safety and
`tolerability of Glatiramer Acetate (GA)
`injection 40 mg/ml administered three
`times weekly compared to placebo in a
`double-blind study design.
`
`Example, Col. 9, ll. 21-24
`
`
`Adverse Events (AEs) are monitored
`throughout the study.
`
`Example, Col. 10, ll. 10
`
`Tolerability:
`Proportion of subjects (%) who
`prematurely discontinued from the
`study, reason of discontinuation and
`the time to withdrawal.
`
`Proportion of subjects (%) who
`prematurely discontinued from the
`study due to AEs and the time to
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`Page 4 of 14
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`YEDA EXHIBIT NO. 2003
`MYLAN PHARM. v YEDA
`PGR2016-00010
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`

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`
`
`
`
`Claims
`
`Written Description
`withdrawal.
`
`Example, Col. 12, ll. 62-67
`
`A significant drawback to GA therapy is
`the requirement of daily injections,
`which can be inconvenient. Moreover,
`in all clinical trials, injection-site
`reactions were seen to be the most
`frequent adverse reactions and were
`reported by the majority of patients
`receiving GA. In controlled studies, the
`proportion of patients reporting these
`reactions, at least once, was higher
`following treatment with GA (70%)
`than placebo injections (37%). The
`most commonly reported injection-site
`reactions, which were more frequently
`reported in GA vs. placebo-treated
`patients, were erythema, pain, mass,
`puritus, edema, inflammation and
`hypersensitivity.
`
`Col. 15, ll. 51-62
`
`In an additional embodiment, the
`pharmaceutical composition is in a
`prefilled syringe for self administration
`by the patient.
`
`Col. 5, ll. 1-3
`
`In an embodiment, the pharmaceutical
`composition has a pH in the range of 5.5
`to 7 .0.
`
`Col. 5, ll. 17-18
`
`In another embodiment, the
`pharmaceutical composition further
`
`Page 5 of 14
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`YEDA EXHIBIT NO. 2003
`MYLAN PHARM. v YEDA
`PGR2016-00010
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`

`
`
`
`Claims
`
`2. The method of claim 1, which
`induces reduced frequency and severity
`of immediate post injection reactions
`and injection site reactions in the human
`patient relative to administration of 20
`mg of glatiramer acetate s.c. daily.
`
`Written Description
`comprises mannitol.
`
`Col. 5, ll. 13-14
`
`As used herein, “tolerability” relates to
`the level of discomfort associated with
`GA treatment. Tolerability is associated
`with the frequency and severity of post
`injection reactions and injection site
`reactions. Tolerability influences the
`period that a patient can follow GA
`treatment.
`
`Col. 7, ll. 38-42
`
`In an embodiment the frequency of an
`immediate post injection reaction or the
`frequency of an injection site reaction is
`reduced relative to daily subcutaneous
`administration of 20 mg glatiramer
`acetate.
`
`Col 5, ll. 19-22
`
`3. The method of claim 1, wherein the
`human patient has not received
`glatiramer acetate therapy prior to
`initiation of the treatment.
`
`In a further embodiment, the patient has
`not received glatiramer acetate therapy
`prior to initiation of the subcutaneous
`injections.
`
`Col. 5, ll. 8-10
`
`4. The method of claim 2, wherein the
`human patient has not received
`glatiramer acetate therapy prior to
`initiation of the treatment.
`
`In a further embodiment, the patient has
`not received glatiramer acetate therapy
`prior to initiation of the subcutaneous
`injections.
`
`5. A method for reducing the frequency
`of relapses by 30% or more as compared
`to placebo in a human population, for
`reducing brain atrophy, for reducing the
`
`Col. 5, ll. 8-10
`See Claim 1 above and
`
`Treatment with 40 mg s.c. GA three
`times weekly reduces the subject
`
`
`
`Page 6 of 14
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`YEDA EXHIBIT NO. 2003
`MYLAN PHARM. v YEDA
`PGR2016-00010
`
`

`
`
`
`Claims
`cumulative number of enhancing lesions
`on T1-weighted images, or for reducing
`the level of disability as measured by
`EDSS Score of a human patient
`suffering from a relapsing form of
`multiple sclerosis, while inducing
`reduced severity of injection site
`reactions in the human patient relative to
`administration of 20 mg of glatiramer
`acetate s.c. daily, which method consists
`of one subcutaneous injection of 1 ml of
`a pharmaceutical composition
`comprising 40 mg of glatiramer acetate
`on only each of three days during each
`week of treatment with at least one day
`without a subcutaneous injection of the
`pharmaceutical composition between
`each day on which there is a
`subcutaneous injection, wherein the
`pharmaceutical composition is in a
`prefilled syringe, and wherein the
`pharmaceutical composition further
`comprises mannitol and has a pH in the
`range 5.5 to 7.0,
`so as to thereby reduce the frequency
`of relapses by 30% or more as
`compared to placebo in a human
`population, reduce brain atrophy,
`reduce the cumulative number of
`enhancing lesions on T1-weighted
`images, or reduce the 15 level of
`disability as measured by EDSS
`Score of the human patient with
`reduced severity of injection site
`reactions relative to
`administration of 20 mg of
`glatiramer acetate s.c. daily.
`6. The method of claim 5, which
`reduces brain atrophy and 20 for
`
`Written Description
`population annualized relapse rate by
`30% or more when compared to the
`placebo group. Treatment with 40 mg
`s.c. GA three times weekly is at least as
`effective as 20 mg s.c. GA daily
`administration at reducing the subject
`population annualized relapse rate.
`
`Example, Col. 13, ll. 47-52
`
`Treatment with 40 mg s.c. GA three
`times weekly significantly reduces brain
`
`
`
`Page 7 of 14
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`YEDA EXHIBIT NO. 2003
`MYLAN PHARM. v YEDA
`PGR2016-00010
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`

`
`
`
`Claims
`reducing the frequency of relapses by
`30% or more as compared to placebo in
`a human population.
`
`7. The method of claim 5, which
`reduces the cumulative number of
`enhancing lesions on T1-weighted
`images.
`
`8. The method of claim 5, which
`reduces the level of disability of the
`human patient as measured by EDSS
`Score.
`
`Written Description
`atrophy as defined by the percent brain
`volume change from baseline to month
`12. Treatment with 40 mg s.c. GA three
`times weekly is at least as effective as
`20 mg s.c. GA daily administration at
`reducing brain atrophy as defined by the
`percent brain volume change from
`baseline to month 12.
`
`Example, Col. 13, ll. 66-67 – col. 14, ll.
`1-5
`
`Treatment with 40 mg s.c. GA three
`times weekly significantly reduces the
`cumulative number of enhancing lesions
`on T 1-weightedimages taken at months
`6 and 12. Treatment with 40 mg s.c.
`GA three times weekly is at least as
`effective as 20 mg s.c. GA daily
`administration at reducing the
`cumulative number of enhancing lesions
`on T 1-weighted images taken at months
`6 and 12.
`
`Example, Col. 13, ll. 59-65
`
`Treatment with 40 mg s.c. GA three
`times weekly significantly reduces the
`level of disability as measured by EDSS
`Score. Treatment with 40 mg s.c. GA
`three times weekly is at least as
`effective as 20 mg s.c. GA daily
`administration at reducing the level of
`disability as measured by EDSS Score.
`
`Example, Col. 15, ll. 5-10
`
`9. The method of claim 5, which
`induces reduced frequency and severity
`of immediate post injection reactions
`
`As used herein, “tolerability” relates to
`the level of discomfort associated with
`GA treatment. Tolerability is associated
`
`
`
`Page 8 of 14
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`YEDA EXHIBIT NO. 2003
`MYLAN PHARM. v YEDA
`PGR2016-00010
`
`

`
`
`
`Claims
`and injection site reactions in the human
`patient relative to administration of 20
`mg of glatiramer acetate s.c. daily.
`
`Written Description
`with the frequency and severity of post
`injection reactions and injection site
`reactions. Tolerability influences the
`period that a patient can follow GA
`treatment.
`
`Col. 7, ll. 38-42
`
`In an embodiment the frequency of an
`immediate post injection reaction or the
`frequency of an injection site reaction is
`reduced relative to daily subcutaneous
`administration of 20 mg glatiramer
`acetate.
`
`Col. 5, ll. 19-22
`
`10. The method of claim 5, wherein
`the human patient has not received
`glatiramer acetate therapy prior to
`initiation of the treatment.
`
`In a further embodiment, the patient has
`not received glatiramer acetate therapy
`prior to initiation of the subcutaneous
`injections.
`
`Col. 5, ll. 8-10
`
`11. The method of claim 9, wherein
`the human patient has not received
`glatiramer acetate therapy prior to
`initiation of the treatment.
`
`In a further embodiment, the patient has
`not received glatiramer acetate therapy
`prior to initiation of the subcutaneous
`injections.
`
`Col. 5, ll. 8-10
`See Claim 1 above
`
`12. A method for improving the
`tolerability of glatiramer acetate
`treatment of a human patient suffering
`from a relapsing form of multiple
`sclerosis which is as effective as
`administration of 20 mg of glatiramer
`acetate s.c. daily, which method consists
`of one subcutaneous injection of 1 ml of
`a pharmaceutical composition
`comprising 40 mg of glatiramer acetate
`
`
`
`Page 9 of 14
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`YEDA EXHIBIT NO. 2003
`MYLAN PHARM. v YEDA
`PGR2016-00010
`
`

`
`
`
`Claims
`on only each of three days during each
`week of treatment with at least one day
`without a subcutaneous injection of the
`pharmaceutical composition between
`each day on which there is a
`subcutaneous injection, wherein the
`pharmaceutical composition is in a
`prefilled syringe, and wherein the
`pharmaceutical composition further
`comprises mannitol and has a pH in the
`range 5.5 to 7.0,
`so as to thereby treat the human
`patient as effectively as by
`administration of 20 mg of
`glatiramer acetate s.c. daily, and
`with reduced severity of injection
`site reactions relative to
`administration of20 mg of
`glatiramer acetate s.c. daily.
`13. The method of claim 12, which
`treats the human patient with reduced
`frequency and severity of immediate
`post injection reactions and injection
`site reactions relative to administration
`of 20 mg of glatiramer acetate s.c. daily.
`
`Written Description
`
`As used herein, “tolerability” relates to
`the level of discomfort associated with
`GA treatment. Tolerability is associated
`with the frequency and severity of post
`injection reactions and injection site
`reactions. Tolerability influences the
`period that a patient can follow GA
`treatment.
`
`Col. 7, ll. 38-42
`
`In an embodiment the frequency of an
`immediate post injection reaction or the
`frequency of an injection site reaction is
`reduced relative to daily subcutaneous
`administration of 20 mg glatiramer
`acetate.
`
`Col. 5, ll. 19-22
`
`14. The method of claim 12, wherein
`
`In a further embodiment, the patient has
`
`
`
`Page 10 of 14
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`YEDA EXHIBIT NO. 2003
`MYLAN PHARM. v YEDA
`PGR2016-00010
`
`

`
`Written Description
`not received glatiramer acetate therapy
`prior to initiation of the subcutaneous
`injections.
`
`Col. 5, ll. 8-10
`In a further embodiment, the patient has
`not received glatiramer acetate therapy
`prior to initiation of the subcutaneous
`injections.
`
`Col. 5, ll. 8-10
`See Claim 5 above
`
`
`
`Claims
`the human patient has not received
`glatiramer acetate therapy prior to
`initiation of the treatment.
`
`15. The method of claim 14, wherein
`the human patient has not received
`glatiramer acetate therapy prior to
`initiation of the treatment.
`
`16. A method for improving the
`tolerability of glatiramer acetate therapy
`reducing the frequency of relapses,
`reducing brain atrophy, reducing the
`cumulative number of enhancing lesions
`on T1-weighted images, or reducing the
`level of disability as measured by EDSS
`Score, of a human patient suffering from
`a relapsing form of multiple sclerosis as
`effectively as administration of 20 mg
`of glatiramer acetate s.c. daily, which
`method consists of one subcutaneous
`injection of 1 ml of a pharmaceutical
`composition comprising 40 mg of
`glatiramer acetate on only each of three
`days during each week of treatment with
`at least one day without a subcutaneous
`injection of the pharmaceutical
`composition between each day on which
`there is a subcutaneous injection,
`wherein the pharmaceutical composition
`is in a prefilled syringe, and wherein the
`pharmaceutical composition further
`comprises mannitol and has a pH in the
`range 5.5 to 7.0,
`so as to thereby reduce the frequency of
`relapses, reduce brain atrophy,
`reduce the cumulative number of
`
`
`
`Page 11 of 14
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`YEDA EXHIBIT NO. 2003
`MYLAN PHARM. v YEDA
`PGR2016-00010
`
`

`
`
`
`Claims
`enhancing lesions on T1-weighted
`images, or reduce the level of
`disability as measured by EDSS
`Score, of the human patient as
`effectively as by administration of
`20 mg of glatiramer acetate s.c.
`daily, and with reduced severity
`of injection site reactions relative
`to administration of 20 mg of
`glatiramer acetate s.c. daily.
`17. The method of claim 16, which
`reduces the frequency of relapses as
`effectively as administration of 20 mg
`of glatiramer acetate s.c. daily.
`
`18. The method of claim 17, which
`reduces brain atrophy as effectively as
`administration of 20 mg of glatiramer
`acetate S.C. daily.
`
`19. The method of claim 18, which
`reduces the cumulative number of
`enhancing lesions on T1-weighted
`images as effectively as administration
`of 20 mg of glatiramer acetate S.C.
`daily.
`
`20. The method of claim 19, which
`reduces the level of 35 disability as
`measured by EDSS Score as effectively
`as administration of 20 mg of glatiramer
`acetate s.c. daily.
`
`21. The method of claim 17, which
`treats the human patient with reduced
`frequency and severity of immediate
`post injection reactions and injection
`site reactions relative to administration
`of 20 mg of glatiramer acetate s.c. daily.
`
`Written Description
`
`See Claim 5 above
`
`See Claim 6 above
`
`See Claim 7 above
`
`See Claim 8 above
`
`See Claim 9 above
`
`
`
`Page 12 of 14
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`YEDA EXHIBIT NO. 2003
`MYLAN PHARM. v YEDA
`PGR2016-00010
`
`

`
`
`
`Claims
`22. The method of claim 18, which
`treats the human patient with reduced
`frequency and severity of immediate
`post injection reactions and injection
`site reactions relative to administration
`of 20 mg of glatiramer acetate s.c. daily.
`
`23. The method of claim 19, which
`treats the human patient with reduced
`frequency and severity of immediate
`post injection reactions and injection
`site reactions relative to administration
`of 20 mg of glatiramer acetate s.c. daily.
`
`24. The method of claim 20, which
`treats the human patient with reduced
`frequency and severity of immediate
`post injection reactions and injection
`site reactions relative to administration
`of 20 mg of glatiramer acetate s.c. daily.
`
`Written Description
`See Claim 9 above
`
`See Claim 9 above
`
`See Claim 9 above
`
`25. The method of claim 17, wherein
`the human patient has not received
`glatiramer acetate therapy prior to
`initiation of the treatment.
`
`In a further embodiment, the patient has
`not received glatiramer acetate therapy
`prior to initiation of the subcutaneous
`injections.
`
`26. The method of claim 18, wherein
`the human patient has not received
`glatiramer acetate therapy prior to
`initiation of the treatment.
`
`27. The method of claim 19, wherein
`the human patient has not received
`glatiramer acetate therapy prior to
`initiation of the treatment.
`
`28. The method of claim 21, wherein
`
`Col. 5, ll. 8-10
`In a further embodiment, the patient has
`not received glatiramer acetate therapy
`prior to initiation of the subcutaneous
`injections.
`
`Col. 5, ll. 8-10
`In a further embodiment, the patient has
`not received glatiramer acetate therapy
`prior to initiation of the subcutaneous
`injections.
`
`Col. 5, ll. 8-10
`In a further embodiment, the patient has
`
`
`
`Page 13 of 14
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`YEDA EXHIBIT NO. 2003
`MYLAN PHARM. v YEDA
`PGR2016-00010
`
`

`
`
`
`Claims
`the human patient has not received
`glatiramer acetate therapy prior to
`initiation of the treatment.
`
`29. The method of claim 22, wherein
`the human patient has not received
`glatiramer acetate therapy prior to
`initiation of the treatment.
`
`30. The method of claim 23, wherein
`the human patient has not received
`glatiramer acetate therapy prior to
`initiation of the treatment.
`
`Written Description
`not received glatiramer acetate therapy
`prior to initiation of the subcutaneous
`injections.
`
`Col. 5, ll. 8-10
`In a further embodiment, the patient has
`not received glatiramer acetate therapy
`prior to initiation of the subcutaneous
`injections.
`
`Col. 5, ll. 8-10
`In a further embodiment, the patient has
`not received glatiramer acetate therapy
`prior to initiation of the subcutaneous
`injections.
`
`Col. 5, ll. 8-10
`
`
`
`
`
`Page 14 of 14
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`YEDA EXHIBIT NO. 2003
`MYLAN PHARM. v YEDA
`PGR2016-00010