WO2012016042A2 - Glatiramer acetate molecular weight markers - Google Patents
Glatiramer acetate molecular weight markers Download PDFInfo
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- WO2012016042A2 WO2012016042A2 PCT/US2011/045724 US2011045724W WO2012016042A2 WO 2012016042 A2 WO2012016042 A2 WO 2012016042A2 US 2011045724 W US2011045724 W US 2011045724W WO 2012016042 A2 WO2012016042 A2 WO 2012016042A2
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- WO
- WIPO (PCT)
- Prior art keywords
- molecular weight
- daltons
- glatiramer acetate
- markers
- kda
- Prior art date
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Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
- B01D15/08—Selective adsorption, e.g. chromatography
- B01D15/26—Selective adsorption, e.g. chromatography characterised by the separation mechanism
- B01D15/34—Size selective separation, e.g. size exclusion chromatography, gel filtration, permeation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2/00—Peptides of undefined number of amino acids; Derivatives thereof
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/62—Detectors specially adapted therefor
- G01N30/72—Mass spectrometers
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/15—Medicinal preparations ; Physical properties thereof, e.g. dissolubility
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/10—Composition for standardization, calibration, simulation, stabilization, preparation or preservation; processes of use in preparation for chemical testing
- Y10T436/105831—Protein or peptide standard or control [e.g., hemoglobin, etc.]
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/25—Chemistry: analytical and immunological testing including sample preparation
- Y10T436/25375—Liberation or purification of sample or separation of material from a sample [e.g., filtering, centrifuging, etc.]
- Y10T436/255—Liberation or purification of sample or separation of material from a sample [e.g., filtering, centrifuging, etc.] including use of a solid sorbent, semipermeable membrane, or liquid extraction
Definitions
- aspects of the present application relate to polypeptides having no predetermined amino acid sequence for use as molecular weight markers of glatiramer acetate and for the accurate determination of the average molecular weight of glatiramer acetate.
- Glatiramer acetate (formerly known as copolymer-1 ) is chemically designated L-glutamic acid polymer with L-alanine, L-lysine, and L-tyrosine, acetate salt. It has the structural formula of Formula (I).
- Glatiramer acetate is the acetate salt of a synthetic mixture of polypeptides, each of which consists essentially of the four naturally occurring amino acids: L- glutamic acid, L-alanine, L-tyrosine, and L-lysine with an average molar fraction of 0.141 , 0.427, 0.095, and 0.338, respectively.
- the average molecular weight of glatiramer acetate is 5,000-9,000 Daltons.
- Glatiramer acetate is sold in USA as Copaxone®, a registered trademark of Teva Pharmaceutical Industries Ltd.
- Glatiramer acetate is indicated for reduction of the frequency of relapses in patients with Relapsing-Remitting Multiple Sclerosis (RRMS).
- U.S. Patent No. 6,514,938 discloses seven polypeptides having an amino acid sequences which are identified in the patent.
- U.S. Patent No. 7,074,580 discloses a process for obtaining a pharmaceutical product containing a mixture of polypeptides.
- Each of the polypeptides consists essentially of alanine, glutamic acid, tyrosine, and lysine.
- the mixture has an average molecular weight from 4000 to 13,000 Daltons and in the mixture the molar fraction of alanine is 0.427, of glutamic acid is 0.141 , of lysine is 0.337, and of tyrosine is 0.093.
- the patent teaches determining the molecular weight distribution of a batch of an aqueous mixture of polypeptides, each of which consists essentially of alanine, glutamic acid, tyrosine, and lysine.
- the molecular weight distribution determination uses a gel permeation chromatography column to determine whether the mixture has an average molecular weight from 4000 to 13,000 Daltons for inclusion in a pharmaceutical product.
- the determination method comprises calibrating the molecular weight obtained using the gel permeation chromatography column by subjecting a plurality of molecular weight markers, each of which is a polypeptide consisting essentially of alanine, glutamic acid, tyrosine and lysine and having a predetermined amino acid sequence, to chromatography on the column to establish a relationship between retention time on the column and molecular weight.
- molecular weight markers each of which is a polypeptide consisting essentially of alanine, glutamic acid, tyrosine and lysine and having a predetermined amino acid sequence
- U.S. Patent No. 7,163,802 discloses in a process for obtaining a pharmaceutical product containing a mixture of polypeptides, each of which consists essentially of alanine, glutamic acid, tyrosine, and lysine.
- the mixture of polypeptides has an average molecular weight between 2000 and 40,000 Daltons and in the mixture the molar fraction of alanine is 0.38 to 0.5, of glutamic acid is 0.13 to 0.15, of tyrosine is 0.08 to 0.10 and of lysine is 0.3 to 0.4.
- a batch of a mixture of polypeptides each of which consists essentially of alanine, glutamic acid, tyrosine, and lysine, is tested using a gel permeation chromatography column to determine whether the mixture has an average molecular weight between 2000 and 40,000 Daltons for inclusion in the pharmaceutical product.
- the testing method comprises calibrating the gel permeation chromatography column by subjecting a plurality of molecular weight markers, each of which is a polypeptide consisting essentially of alanine, glutamic acid, tyrosine and lysine and having a predetermined amino acid sequence, to chromatography on the column to establish a relationship between retention time on the column and molecular weight said relationship being used to determine average molecular weight of the mixture of polypeptides.
- molecular weight markers each of which is a polypeptide consisting essentially of alanine, glutamic acid, tyrosine and lysine and having a predetermined amino acid sequence
- the present application provides polypeptides having no predetermined amino acid sequence for use as molecular weight markers of glatiramer acetate , which are useful as standards for determining the peak average molecular weight of glatiramer acetate a polypeptide.
- Fig. 1 is a plot of the retention time (RT) of the present molecular weight markers versus the log molecular weight of those markers, using the RT-based algorithm.
- Fig.2 is an illustration of MALDI spectrum of molecular weight marker 1 prepared according to Example 1.
- Fig.3 is an illustration of MALDI spectrum of molecular weight marker 2 prepared according to Example 1.
- Fig.4 is an illustration of MALDI spectrum of molecular weight marker 3 prepared according to Example 1.
- Fig.5 is an illustration of MALDI spectrum of molecular weight marker 4 prepared according to Example 1.
- Fig.6 is an illustration of circular dichroism spectrum of Copaxone®.
- Fig. 7 is an illustration of circular dichroism spectrum of molecular weight marker 2 prepared according to Example .
- Fig. 8 is an illustration of circular dichroism spectrum of molecular weight marker 3 prepared according to Example 1.
- Fig. 9 is an illustration of circular dichroism spectrum of molecular weight marker 4 prepared according to Example 1.
- the present application provides polypeptides having no predetermined amino acid sequence for use as molecular weight markers of glatiramer acetate , which are useful as standards for determining the peak average molecular weight of glatiramer acetate a polypeptide.
- the present application provides polypeptides for use as molecular weight markers of glatiramer acetate for determining the peak average molecular weight of glatiramer acetate a polypeptide.
- the present application provides polypeptides having an amino acid composition corresponding to glatiramer acetate polypeptide and an identified molecular weight which is between about 2,000 Daltons and about 40,000 Daltons or between about 2,000 Daltons and about 20,000 Daltons or between about 2,000 Daltons and about 15,000 Daltons or between about 2,000 Daltons and about 10,000 Daltons; for use as molecular weight markers for determining the average molecular weight of a polypeptide.
- the present application provides polypeptides having an amino acid composition corresponding to glatiramer acetate and an identified molecular weight which is between about 2,000 Daltons and about 40,000 Daltons or between about 2,000 Daltons and about 20,000 Daltons or between about 2,000 Daltons and about 15,000 Daltons or between about 2,000 Daltons and about 10,000 Daltons; for use as molecular weight markers for determining the average molecular weight of glatiramer acetate.
- the present application provides polypeptides consisting essentially of amino acids alanine, glutamic acid, tyrosine, and lysine in molar fractions of from about 0.38 to about 0.50 alanine, from about 0.13 to about 0.155 glutamic acid, from about 0.08 to about 0.12 tyrosine, and from about 0.28 to about 0.4 lysine, for use as molecular weight markers for determining the average molecular weight of a polypeptide.
- the present application provides polypeptides consisting essentially of amino acids alanine, glutamic acid, tyrosine, and lysine in molar fractions of from about 0.38 alanine to about 0.50 alanine, from about 0.13 glutamic acid to about 0.155 glutamic acid, from about 0.08 tyrosine to about 0.12 tyrosine, and from about 0.28 lysine to about 0.4 lysine, for use as molecular weight markers for determining the average molecular weight of glatiramer acetate.
- the present application provides processes for preparing molecular weight markers of the present application, which includes one or more of the following steps, individually or in the sequence recited:
- step (b) passing the fractions collected in step (a) through molecular weight cut-off membranes;
- step (c) isolating the molecular weight markers by lyophilizing the fractions collected from step (b).
- the present application provides processes for preparing molecular weight markers of the present application, which includes one or more of the following steps, individually or in the sequence recited:
- step (b) passing the fractions collected in step (a) through molecular weight cut-off membranes;
- step (c) isolating the molecular weight markers by lyophilizing the fractions collected from step (b).
- Step (a) involves fractionating a sample of glatiramer acetate in a gel permeation chromatography (GPC) column.
- Suitable chromatography media for gel filtration that may be used in step (a) include, but are not limited to, SuperdexTM, SephacrylTM, SuperoseTM and SephadexTM , and the like.
- SuperdexTM is a composite medium based on highly cross-linked porous agarose particles to which dextran have been covalently bonded.
- SuperdexTM is a trademark of GE Healthcare companies.
- SephacrylTM is an allyl dextran cross- linked with N, N'-methylene bisacrylamide. SephacrylTM is a trademark of GE Healthcare.
- SuperoseTM is a medium with high physical and chemical stability based on highly cross-linked porous agarose particles. SuperoseTM is a trademark of GE Healthcare Ltd, a General Electric Company. SephadexTM is dextran cross-linked with epichlorohydrin. SephadexTM is a trademark of GE Healthcare companies.
- a sample of glatiramer acetate may be prepared by dissolving in a suitable solvent and then the resultant solution is filtered to remove any unwanted particulate matter through syringe filters.
- Suitable solvent that may be used for the preparation of a sample of glatiramer acetate include, but are not limited to, Milli Q® water, and the like. Milli-Q® is a registered trademark of the Millipore Corporation, Billerica, MA
- Suitable buffers that may be used in step (a) include, but are not limited to, acetate buffers, phosphate buffers, citrate buffers, and sodium chloride, or mixtures thereof.
- Step (b) involves passing of the fractions collected in step (a) through molecular cut-off membranes for obtaining the markers with a narrow molecular weight distribution.
- Suitable molecular cut-off membranes may range from 1 KDa to 10 KDa, or 1 KDa to 20 KDa, or 1 KDa to 30 KDa.
- Step (b) may be preceded by an optional lyophilization of the individual fractions collected in step (a), dissolving the lyophilizates in a solvent, and then passing through molecular cut-off membranes.
- Step (c) involves isolation of molecular weight markers by lyophilizing the fractions collected from step (b).
- the molecular weights of the markers of the present application may be determined by any method including the methods described in the art.
- molecular weight of markers of present application may be determined by Matrix-Assisted Laser Desorption/lonization (MALDI) or Low Angle Laser Light Scattering Detection (LALLS) or Multi Angle Light Scattering Detection (MALLS).
- MALDI Matrix-Assisted Laser Desorption/lonization
- LALLS Low Angle Laser Light Scattering Detection
- MALLS Multi Angle Light Scattering Detection
- Glatiramer acetate that is used as the input for the process of the present application may be obtained by any process including the processes described in the art.
- glatiramer acetate may be prepared by the processes described in International Application No. PCT/US1 1/34102.
- the present application provides a method for determining the peak average molecular weight of a polypeptide or a pharmaceutically acceptable salt thereof, which comprises subjecting the polypeptide or a pharmaceutically acceptable salt thereof to chromatography on a chromatographic column so as to determine the average molecular weight of the polypeptide or a pharmaceutically acceptable salt thereof, wherein the chromatographic column is calibrated by using a plurality of molecular weight markers of the present application, wherein each of the molecular weight marker is a polypeptide having no predetermined amino acid sequence.
- the present application provides a method for determining the peak average molecular weight of glatiramer acetate or a pharmaceutically acceptable salt thereof, which comprises subjecting the glatiramer acetate or a pharmaceutically acceptable salt thereof to chromatography on a chromatographic column so as to determine the peak average molecular weight of the glatiramer acetate or a pharmaceutically acceptable salt thereof, wherein the chromatographic column is calibrated by using a plurality of molecular weight markers of the present application, wherein each of the molecular weight markers is a polypeptide having no predetermined amino acid sequence.
- the present application provides a process of calibration of gel permeation chromatography column by using molecular weight markers of the present application.
- the present application provides a plurality of molecular weight markers for determining the average molecular weight of a polypeptide on a molecular weight fractionation column.
- the present application provides a plurality of molecular weight markers for determining the average molecular weight of glatiramer acetate on a molecular weight fractionation column.
- the present application provides a linear relationship between the log molecular weight of the glatiramer acetate molecular weight markers of the present application and the retention time of the molecular weight markers on a molecular weight fractionation column.
- polypeptide e.g., copolymer 1 glatiramer acetate preparation for use in a pharmaceutical product
- Molecular weight markers that have chemical and physical characteristics similar to polypeptide provide an accurate and robust calibration set for determination of molecular weights of production batches.
- the present application provides derivatives of polypeptide e.g., glatiramer acetate useful as molecular weight markers for determining the average molecular weight of polypeptide e.g., glatiramer acetate preparations.
- Molecular weight markers of the present application include polypeptides having an amino acid composition approximately corresponding to polypeptide e.g., glatiramer acetate , and an identified molecular weight which is between about 2,000 Daltons and about 40,000 Daltons, between about 2,000 Daltons and about 20,000 Daltons, between about 2,000 Daltons and about 15,000 Daltons, or between about 2,000 Daltons and about 10,000 Daltons; and are useful for accurately determining the average molecular weight of polypeptide e.g., glatiramer acetate. It follows from the requirement for an identified molecular weight that a molecular weight marker should not be highly polydispersed and should have a narrow molecular weight distribution. The molecular weight markers of the present application are not fixed sequence markers.
- the present application provides molecular weight markers consisting essentially of amino acids alanine, glutamic acid, tyrosine, and lysine in defined molar ratios.
- the molar ratio of amino acids of molecular weight markers of present application is same as that found in a polypeptide e.g., glatiramer acetate.
- Such a correspondence in molar ratios provides the best molecular weight markers because those markers will have a charge and a molecular shape which is similar to that of a polypeptide e.g., glatiramer acetate.
- the markers may migrate or elute somewhat differently from polypeptide e.g., glatiramer acetate copolymer preparations, though these preparations have the same molecular weight as that of markers.
- the plurality of molecular weight markers are polypeptides.
- the plurality of markers can be two to about ten or more.
- Each of these polypeptides has an identified peak average molecular weight which is between about 2,000 Daltons and about 40,000 Daltons, between about 2,000 Daltons and about 20,000 Daltons, between about 2,000 Daltons and about 15,000 Daltons, or between about 2,000 Daltons and about 10,000 Daltons; and an amino acid composition which corresponds approximately to that of polypeptide e.g., glatiramer acetate.
- the molecular weight markers of the present application may have therapeutic activity which is similar to glatiramer acetate polypeptide. These markers may be used in any molecular size discrimination system using any available molecular weight determination procedure or apparatus. For example, the present markers may be used for calibration of any chromatographic procedure or apparatus which is used for molecular weight determinations of polypeptides.
- a chromatographic apparatus may be a molecular weight sizing column which separates polypeptides on the basis of their molecular size. Examples of molecular weight sizing columns include TSK-GEL® columns, SephadexTM columns, Sepharose® columns, SephacrylTM columns, and SuperoseTM columns.
- Sephacryl® is a covalently cross linked dextran/bisacrylamide copolymer gel formed into beads. It is used in gel filtration columns for separating molecules in the size range 5 kD to 1.5 million Dalton. Sephacryl® S-100 has a 1 kD - lOOkD molecular weight range and has a particle size of 25-75 ⁇ . Sephacryl® is a registered trademark of GE Healthcare. SuperoseTM 12 is a cross-linked, agarose-based medium optimized for high performance gel filtration of biomolecules.
- EXAMPLE 1 Preparation of molecular weight markers of glatiramer acetate.
- glatiramer acetate 350 mg is dissolved in Milli-Q® water (10 mL) and filtered through 0.45 ⁇ syringe filter.
- the column is stabilized with the above prepared mobile phase.
- the flow rate of the mobile phase is kept constant and stabilization is continued until base line reaches constant value.
- Sample is loaded on to the column at the same flow rate through pump B assembly.
- the set mark option is used to indicate injection marking.
- Absorbencies are recorded at dual wavelengths such as 215 nm & 280 nm. At nearly 111 mL of elution volume, the peak at 280 nm starts rising up.
- the fraction collector is activated to deliver 9 mL of each fraction. At 180 mL of elution volume the peak reaches its maximum value. Mobile phase flow still continues. At around 300 mL of elution volume, the peak almost reaches its baseline.
- the four selected fractions, at about RT 23.0 minutes, at about RT 26 minutes, at about RT 29 minutes and at about RT 30 minutes are then concentrated through a 10 KDa molecular weight cutoff membrane, a 3 KDa molecular weight cutoff membrane, a 3 KDa molecular weight cutoff membrane and a 3 KDa molecular weight cut off membrane respectively.
- the concentrated solutions are lyophilized individually to afford 15 mg, 30 mg, 35 mg, and 12 mg of the title compound.
- EXAMPLE 2 Preparation of glatiramer acetate molecular weight markers.
- glatiramer acetate (1500 mg) is dissolved in Milli-Q® water (10 mL) and filtered through 0.45 ⁇ syringe filter.
- the column is stabilized with the above prepared mobile phase.
- the flow rate of the mobile phase is kept constant and stabilization is continued until base line at absorbance @ 215 nm reaches constant value.
- Sample is loaded on to the column at the same flow rate through pump B assembly.
- the set mark option is used to indicate injection loading.
- Absorbencies are recorded at dual wavelengths such as 2 5 nm & 280 nm.
- the peak at 215 nm starts rising up.
- the fraction collector is activated to deliver 10 mL of each fraction.
- At nearly 640 mL of elution volume the peak reaches its maximum value.
- Mobile phase flow still continues.
- the peak almost reaches its baseline.
- fractionation is stopped. Two consecutive fractions from the fraction collector are mixed together to get the required fraction volume of 20 mL each. After fractionation, the column is stabilized with mobile phase for the next cycle. The same procedure was repeated for numerous batches. Pooled fractions from the each batch were chromatographed on SuperoseTM 12 column and the peak retention time for each of the fractions recorded. Each of these fractions elutes at a distinct retention time as given in tables 1 , 2, & 3 respectively. Fractions with similar retention time from different batches are pooled together for further processing.
- Molecular weight markers that are prepared according to the procedure given in Example 1 above and a glatiramer acetate preparation are expected to demonstrate a similar correlation between retention time (RT) and log molecular weight.
- the molecular weight markers of the present application are chromatographed on SuperoseTM 12 column. The peak retention time for each of the markers is recorded.
- the linear correlation between Log Molecular Weight (MW) and the Retention Time (RT) is calculated as follows:
- MW is the molecular weight
- RT is the retention time
- a and B are the intercept and the slope of the calculated regression function.
- molecular weight markers that are prepared according to the procedure given in Example 2 above and a glatiramer acetate preparation are expected to demonstrate a similar correlation between retention time (RT) and log molecular weight.
- the molecular weight markers of the present application are chromatographed on SuperoseTM 12 column. The peak retention time for each of the markers is recorded.
- the linear correlation between Log Molecular Weight (MW) and the Retention Time (RT) is calculated as follows:
- MW is the molecular weight
- RT is the retention time
- a and B are the intercept and the slope of the calculated regression function.
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Priority Applications (12)
Application Number | Priority Date | Filing Date | Title |
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AU2011282635A AU2011282635B2 (en) | 2010-07-29 | 2011-07-28 | Glatiramer acetate molecular weight markers |
NZ606723A NZ606723A (en) | 2010-07-29 | 2011-07-28 | Glatiramer acetate molecular weight markers |
MX2013001150A MX2013001150A (en) | 2010-07-29 | 2011-07-28 | Glatiramer acetate molecular weight markers. |
US13/812,684 US9109006B2 (en) | 2010-07-29 | 2011-07-28 | Glatiramer acetate molecular weight markers |
CN201180041836.0A CN103080747B (en) | 2010-07-29 | 2011-07-28 | glatiramer acetate molecular weight marker |
CA2806997A CA2806997A1 (en) | 2010-07-29 | 2011-07-28 | Glatiramer acetate molecular weight markers |
EP11813184.6A EP2598889A4 (en) | 2010-07-29 | 2011-07-28 | Glatiramer acetate molecular weight markers |
RU2013108828/15A RU2013108828A (en) | 2010-07-29 | 2011-07-28 | MARKERS OF MOLECULAR MASS OF GLATIAMETER ACETATE |
KR1020137003967A KR20130043196A (en) | 2010-07-29 | 2011-07-28 | Glatiramer acetate moleuclar weight markers |
BR112013002230A BR112013002230A2 (en) | 2010-07-29 | 2011-07-28 | glatiramer acetate molecular weight markers |
JP2013521976A JP2013535474A (en) | 2010-07-29 | 2011-07-28 | Molecular weight marker for glatiramer acetate |
ZA2013/00980A ZA201300980B (en) | 2010-07-29 | 2013-02-06 | Glatiramer acetate molecular weight markers |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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IN2146CH2010 | 2010-07-29 | ||
IN2146/CHE/2010 | 2010-07-29 | ||
US38936010P | 2010-10-04 | 2010-10-04 | |
US61/389,360 | 2010-10-04 |
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WO2012016042A2 true WO2012016042A2 (en) | 2012-02-02 |
WO2012016042A3 WO2012016042A3 (en) | 2012-05-31 |
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PCT/US2011/045724 WO2012016042A2 (en) | 2010-07-29 | 2011-07-28 | Glatiramer acetate molecular weight markers |
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US (1) | US9109006B2 (en) |
EP (1) | EP2598889A4 (en) |
JP (1) | JP2013535474A (en) |
KR (1) | KR20130043196A (en) |
CN (1) | CN103080747B (en) |
AU (1) | AU2011282635B2 (en) |
BR (1) | BR112013002230A2 (en) |
CA (1) | CA2806997A1 (en) |
MX (1) | MX2013001150A (en) |
NZ (1) | NZ606723A (en) |
RU (1) | RU2013108828A (en) |
WO (1) | WO2012016042A2 (en) |
ZA (1) | ZA201300980B (en) |
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---|---|---|---|---|
CN104098655A (en) * | 2013-04-09 | 2014-10-15 | 深圳翰宇药业股份有限公司 | Polypeptides of mass spectrography internal standard used for synthesis of glatiramer acetate |
US9029507B2 (en) | 2011-02-14 | 2015-05-12 | Usv Limited | Copolymer-1, process for preparation and analytical methods thereof |
EP3147667A1 (en) * | 2015-09-24 | 2017-03-29 | CHEMI S.p.A. | Analysis of the molecular weight distribution of complex polypeptide mixtures |
Families Citing this family (4)
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EP3290432B1 (en) * | 2015-04-28 | 2022-03-30 | Hybio Pharmaceutical Co., Ltd. | High performance liquid chromatography method for polypeptide mixtures |
CA3050086A1 (en) | 2017-03-26 | 2018-10-04 | Mapi Pharma Ltd. | Glatiramer depot systems for treating progressive forms of multiple sclerosis |
KR102438261B1 (en) * | 2017-12-14 | 2022-08-30 | 엘지디스플레이 주식회사 | Display Device |
JP7273996B2 (en) * | 2019-12-20 | 2023-05-15 | 株式会社日立ハイテク | Molecular weight marker for electrophoresis, nucleic acid fractionation method, and nucleic acid size analysis method |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
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IL113812A (en) | 1994-05-24 | 2000-06-29 | Yeda Res & Dev | Copolymer-1 pharmaceutical compositions containing it and its use |
US6800287B2 (en) * | 1998-09-25 | 2004-10-05 | Yeda Research And Development Co., Ltd. | Copolymer 1 related polypeptides for use as molecular weight markers and for therapeutic use |
US6514938B1 (en) * | 1998-09-25 | 2003-02-04 | Yeda Research And Development Co. Ltd. At The Weizmann Institute Of Science | Copolymer 1 related polypeptides for use as molecular weight markers and for therapeutic use |
US20030157720A1 (en) | 2002-02-06 | 2003-08-21 | Expression Technologies Inc. | Protein standard for estimating size and mass |
SI1797109T1 (en) * | 2004-09-09 | 2016-07-29 | Yeda Research And Development Co., Ltd. | Mixtures of polypeptides, compositions containing and processes for preparing same, and uses thereof |
WO2006050122A1 (en) * | 2004-10-29 | 2006-05-11 | Sandoz Ag | Processes for preparing glatiramer |
AU2006211510B8 (en) * | 2005-02-02 | 2011-04-21 | Teva Pharmaceutical Industries, Ltd. | Process for producing polypeptide mixtures using hydrogenolysis |
WO2007030573A2 (en) * | 2005-09-09 | 2007-03-15 | Yeda Research And Development Co. Ltd. | Polypeptides useful for molecular weight determinations |
US20090111133A1 (en) | 2007-10-31 | 2009-04-30 | Abbott Laboratories | Gel Filtration Standard |
EP2215460A4 (en) * | 2007-11-26 | 2010-12-29 | Waters Technologies Corp | Internal standards and methods for use in quantitatively measuring analytes in a sample |
BR112012027753A2 (en) * | 2010-04-27 | 2017-01-10 | Reddys Lab Inc Dr | preparation of polypeptides and salts thereof |
ES2654291T3 (en) * | 2011-02-14 | 2018-02-13 | Usv Private Limited | Copolymer-1, preparation process and its methods of analysis |
-
2011
- 2011-07-28 KR KR1020137003967A patent/KR20130043196A/en not_active Application Discontinuation
- 2011-07-28 NZ NZ606723A patent/NZ606723A/en not_active IP Right Cessation
- 2011-07-28 MX MX2013001150A patent/MX2013001150A/en not_active Application Discontinuation
- 2011-07-28 JP JP2013521976A patent/JP2013535474A/en not_active Withdrawn
- 2011-07-28 WO PCT/US2011/045724 patent/WO2012016042A2/en active Application Filing
- 2011-07-28 CA CA2806997A patent/CA2806997A1/en not_active Abandoned
- 2011-07-28 EP EP11813184.6A patent/EP2598889A4/en not_active Withdrawn
- 2011-07-28 CN CN201180041836.0A patent/CN103080747B/en not_active Expired - Fee Related
- 2011-07-28 US US13/812,684 patent/US9109006B2/en not_active Expired - Fee Related
- 2011-07-28 AU AU2011282635A patent/AU2011282635B2/en not_active Ceased
- 2011-07-28 RU RU2013108828/15A patent/RU2013108828A/en unknown
- 2011-07-28 BR BR112013002230A patent/BR112013002230A2/en not_active IP Right Cessation
-
2013
- 2013-02-06 ZA ZA2013/00980A patent/ZA201300980B/en unknown
Non-Patent Citations (1)
Title |
---|
See references of EP2598889A4 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9029507B2 (en) | 2011-02-14 | 2015-05-12 | Usv Limited | Copolymer-1, process for preparation and analytical methods thereof |
CN104098655A (en) * | 2013-04-09 | 2014-10-15 | 深圳翰宇药业股份有限公司 | Polypeptides of mass spectrography internal standard used for synthesis of glatiramer acetate |
CN104098655B (en) * | 2013-04-09 | 2018-01-30 | 深圳翰宇药业股份有限公司 | Target polypeptide in mass spectrum for synthesizing acetic acid copaxone |
EP3147667A1 (en) * | 2015-09-24 | 2017-03-29 | CHEMI S.p.A. | Analysis of the molecular weight distribution of complex polypeptide mixtures |
US10234461B2 (en) | 2015-09-24 | 2019-03-19 | Chemi S.P.A. | Analysis of the molecular weight distribution of complex polypeptide mixtures |
Also Published As
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BR112013002230A2 (en) | 2016-05-24 |
US9109006B2 (en) | 2015-08-18 |
NZ606723A (en) | 2015-11-27 |
CA2806997A1 (en) | 2012-02-02 |
EP2598889A4 (en) | 2014-01-22 |
KR20130043196A (en) | 2013-04-29 |
ZA201300980B (en) | 2014-03-26 |
AU2011282635B2 (en) | 2015-05-28 |
US20130205877A1 (en) | 2013-08-15 |
RU2013108828A (en) | 2014-09-10 |
AU2011282635A1 (en) | 2013-02-28 |
MX2013001150A (en) | 2013-05-30 |
CN103080747A (en) | 2013-05-01 |
CN103080747B (en) | 2016-04-27 |
JP2013535474A (en) | 2013-09-12 |
WO2012016042A3 (en) | 2012-05-31 |
EP2598889A2 (en) | 2013-06-05 |
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