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Preparation Of Phenylacetic Acid Derivative

Abstract: Disclosed herein is a process for the preparation of substituted derivatives of 3 - Benzoyl - 2 - amino phenylacetic acid of Formula - I and its pharmaceutically acceptable salts; which comprises the (i) protection of compound 2 - nitro benzophenone of Formula - XV to get the compound of Formula - XVI;(ii) reaction of compound of Formula - XVI with vinyl magnesium bromide to obtain compound (\H~ indol - 7 - yl) phenyl - methanone of Formula - XIII; which is finally converted to isolate substituted derivatives of 3 -Benzoyl - 2 - amino phenylacetic acid of Formula -1.

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Patent Information

Application #
Filing Date
25 November 2008
Publication Number
33/2010
Publication Type
INA
Invention Field
CHEMICAL
Status
Email
Parent Application
Patent Number
Legal Status
Grant Date
2016-10-04
Renewal Date

Applicants

INDOCO REMEDIES LIMITED
INDOCO HOUSE, 166 C.S.T. ROAD, SANTACRUZ (EAST), MUMBAI-400 098, MAHARASHTRA, INDIA.

Inventors

1. VYAS KETAN DHANSUKHLAL
INDOCO REMEDIES LIMITED, R & D Centre, R/92-93, TTC INDUSTRIAL AREA, MIDC RABALE, NAVI MUMBAI-400 701, MAHARASHTRA, INDIA.
2. NAIR RANJEET
INDOCO REMEDIES LIMITED, R & D Centre, R/92-93, TTC INDUSTRIAL AREA, MIDC RABALE, NAVI MUMBAI-400 701, MAHARASHTRA, INDIA.
3. KHABALE SOMNATH AMBADAS
INDOCO REMEDIES LIMITED, R & D Centre, R/92-93, TTC INDUSTRIAL AREA, MIDC RABALE, NAVI MUMBAI-400 701, MAHARASHTRA, INDIA.
4. PANANDIKAR ADITI MILIND
INDOCO REMEDIES LIMITED, INDOCO HOUSE, 166 CST ROAD, SANTACRUZ (EAST), MUMBAI-400 098, MAHARASHTRA, INDIA.

Specification

FORM 2 THE PATENTS ACT 1970 (39 of 1970) AND The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule 13) 1. TITLE OF THE INVENTION: "PREPARATION OF PHENYLACETIC ACID DERIVATIVE" 2. APPLICANT: (a) NAME: INDOCO REMEDIES LIMITED. (b) NATIONALITY: Indian Company incorporated under the Indian Companies Act, 1956 (c) ADDRESS: Indoco House, 166 C. S. T. Road, Santacruz (East), Mumbai - 400 098, Maharashtra, India. 3. PREAMBLE TO THE DESCRIPTION: The following specification describes the invention and the manner in which it is to be performed. FIELD OF THE INVENTION: This invention relates to novel process for the preparation of substituted derivatives of 3 -Benzoyl -2~ amino phenylacetic acid of Formula I; and its pharmaceutical^ acceptable salts. formula-1 Wherein; X is Hydrogen, lower alkyl Ci - C4 group, halogen atom (CI, Br, F, I), trifluoromethyl group. R is - OH, -NH2 & - OM; where M is any metal. BACKGROUND AND PRIOR ART: 3 - Benzoyl - 2 - amino phenylacetic acid and its substituted derivatives are known nonsteroidal anti-inflammatory drugs (NSAIDs), useful in relieving rheumatoid arthritis and pain and / or inflammation after surgery, blood platelet aggregation inhibiting agents, muscle relaxants, and as ophthalmic. Some of the important compounds of 3- Benzoyl - 2 - amino phenylacetic acid derivatives are Nepafenac [Formula - II] Bromfenac Sodium [Formula - III] Amfenac [Formula - IV]. A common structural feature in the above NSAIDs is the presence of 3 - Benzoyl - 2 -amino phenylacetic acid moiety. The preparation of these compounds are described in the published US patent No US4,045,576, US4,126,635 and tJS4,503,073 and by DA. Walsh et al„ in J. Med. Chem. 27, 1379, (1984).The general process described for the preparation of the above compounds uses 2-Aminobenzophenone Formula - V as the starting material. 2-Aminobenzophenone Formula - V is treated with ethyl a-(methylthio) acetate Formula - V] in presence of tert-butyl hypochlorite and dichloromethane at -65°C gives an intermediate which on addition of triethylamine rearranges to give ethyl 2 -(2 - amino - 3 - benzoylphenyl) - 2 - (methylthio) acetate derivative of Formula - VII. The compound ethyl 2-(2 - amino - 3 - benzoylphenyl) - 2 - (methylthio) acetate (Formula - VII) is cyclized using hydrochloric acid in methanol under reflux yields 7-benzoyl- 3 - methylthioindolin - 2 - one derivative of Formula - VIII. 7- benzoy] - 3 -methylthioindolin - 2 - one in tetrahydrofuran is treated with Raney nickel or tin and hydrochloric acid gives 7-benzoyI indolin-2-one derivative of Formula - IX, which on hydrolysis with sodium hydroxide results in substituted derivatives of 3- Benzoyl - 2 -amino phenylacetic acid Formula -1. The scheme of the reaction sequences are given in Scheme -1 as below; Formula-I Formula - IX Formula-VIII Scheme -1 Where; X is Hydrogen, lower alkyl Q - C4 group, halogen atom (CI, Br, F, I), trifluoromethyl group, R= H (Formula I) Other method described by Lo, Y. S, et al in J, Heterocycl. Chem., 1980, 17, 1663 - 4 for the preparation of 7 - Benzoy Undo lone Formula - IX, the precursor for the preparation of the above drugs uses Indoline Formula - X as starting material. Indoline is benzoylated with benzonitrile Formula - XI derivative by modified Friedel-Crafts reaction in the presence of boron trichloride and aluminium trichloride to give 7-benzoyIindoline derivatives of Formula - XII. Oxidation of the 7-benzoyIindoline derivative with activated manganese oxide in dichIoromethane under reflux condition gives 7-benzoylindoIe derivative of Formula - XIII. Brominating the 7-benzoyIindole derivative with N-bromosuccinimide at ambient temperature gives 7-benzoyl-3-bromoindole derivatives of Formula - XIV. Hydrolysis of the 3-bromoindole derivative with phosphoric acid in either 2-methoxyethanol or acetic acid gives 7-benzoylindoIin-2-one Formula - IX derivatives. The reaction sequences are given in Scheme - II as below; Scheme - II Where X is as described above. The major drawbacks of the prior art processes include: 1. Use of tert-butyl hypochlorite which is light sensitive, corrosive, highly flammable and unstable at room temperature which requires storage below 10°C; 2. Temperature of the reaction for preparation of ethyl 2 - (2 - amino - 3 -benzoylphenyl) - 2 - (methylthio) acetate derivative is -65°C which is sensitive, difficult to maintain and not economical to carry out the reaction on industrial scale. 3. Removal of 3 - methylthio group requires use of Raney Ni or Tin / HC1 which results in dehalogenation of derivatives containing bromo, chloro, fluoro or iodo group; 4. Use of manganese oxide results in sludge formation which creates disposal problems on industrial scale; 5. Boron tri chloride is unstable, corrosive and violently reacts with water during work up possess considerable process hazards as well as handling issues when used on an industrial scale. Therefore there remains a need for an improved process which ameliorates the problems of the prior art process and is industrially rugged and useful. The present invention provides a novel process for the preparation of 3 - Benzoyl - 2 -amino phenylacetic acid and derivatives which involves stable reagents, elevated temperature of reaction and therefore industrially useful. Therefore the object of the present invention is to provide a rugged synthetic process for the preparation of 3 - Benzoyl - 2 - amino phenylacetic acid and derivatives of Formula-I and its pharmaceutical^ acceptable salts, esteis and amides which is economical, uses stable reagents and are industrially useful. SUMMARY OF THE INVENTION: The present invention provides a process for the synthesis of substituted derivatives of 3 - Benzoyl - 2 - amino phenylacetic acid of Formula - I and its pharmaceutically acceptable salts; Formula -1 Where X is independently H, lower alkyl Ci - C4 group, halogen atom (CI, Br, F, I), trifluoromethyl group and; R is - OH, - NH2 & - OM; where M is any metal. The process for the preparation of 3 - Benzoyl - 2 - amino phenylacetic acid derivative of Formula -1 and its pharmaceutical^ acceptable salts comprising of; i. reacting 2 - amino benzophenone of Formula - V; Formula - V with an oxidizing agent in presence of solvent to get 2 - nitro benzophenone compound of Formula - XV; Formula - XV ii. protecting the compound of Formula - XV with a carbonyl protecting group to get the compound of Formula -XVI; Formula - XVI where R| is linear or branched aliphatic chain having 2 to 6 carbon atoms. iii. reacting the compound of Formula - XVI with vinyl magnesium bromide in presence of solvent at temperature in the range of-60 to 0°C to isolate (1H -indol - 7 - yl) phenyl methanone compound of Formula - XIII; Formula-XIII iv. brominating the compound of Formula - XIII with brominating reagent to get the compound of Formula - XIV; Formula - XIV v. converting the compound of Formula - XIV to the precursor oxyindole compound of Formula - IX and; Formula - IX ri. hydrolysis of the compound of Formula - IX to isolate the desired derivative of 3 - Benzoyl - 2 - amino phenylacetic acid. The process of the present invention is described herein after in more details substantiating various embodiments and conditions of reaction for better understanding/appreciation of the invention. DESCRIPTION OF THE INVENTION: The present invention discloses a novel process for the preparation of substituted derivatives of 3 - Benzoyl - 2 - amino phenylacetic acid of Formula - I and its pharmaceuticalIy acceptable salts; Formula -1 Where X is independently H, lower alkyl C| - C4 group, halogen atom (Cl, Br, F, I), trifluoromethyl group and; R is - OH, -NH2 & - OM; where M is any metal. The reaction sequence of the present invention is as given in the scheme — III below; Scheme - III Wherein X is independently H, lower alkyl C1 - C4group, halogen atom (CI, Br, F, I), and trifluoromethyl group and R is - OH, -NH2 & - OM; where M is any metal. In one embodiment of the present invention the compound 2 - amino benzophenone of Formula - V [where X is independently H, lower alkyl C, _ c4 group, halogen atom (CI, Br, F, I), and trifluoromethyl group] is subjected to oxidation reaction using trifluoroacetic acid and hydrogen peroxide in presence of chlorinated solvent selected from dichloromethane, dichloroethane, tetrachloroethan^ and chloroform. The preferred chlorinated solvent for oxidation is dichloroethane. The solution of the compound of Formula - V in dichloroethane is added to the cooled mixture of hydrogen peroxide and trifluoroacetic acid in dichloroethane at temperature in the range of 0°C to -30°C. The preferred temperature of addition is between -20° to -15°C. After the addition the temperature of the reaction mass is raised to the reflux temperature of the solvent used and maintained for 2 - 4 hours. Cooled the reaction mass to 20 - 30°C and decomposed by charging water. Stirred and separated the organic layer and washed further with water to neutral pH. Concentrated the organic layer under reduced pressure to isolate 2 - nitro benzophenone compound of Formula - XV. The starting compound 2 - Amino benzophenone of Formula - V is prepared as per the process described in Org. Synth. Coll. Vol. IV, 34 (1963). Scheme - 1. In another embodiment of the present invention the carbonyl group of 2 - nitro benzophenone compound of Formula - XV is protected by reacting with trimethyl orthoformate, triethyl orthoformate, HO - (Ri) - OH , where R] is linear or branched aliphatic chain having 2 to 6 carbon atoms, in presence of catalyst selected from p-toluenesulfonic acid monohydrate, p-toluenesulfonic ac;id monohydrate and molecular sieves, Copper sulfate and Copper chloride; in Solvent selected from aromatic hydrocarbon, toluene, xylene, monochlorobenzene, or polar protic solvents selected from N,N - Dimethylformarnide, N,N - Dimethyl acetamid-bromo-\H-'mdo]-l~y\) (4-bromophenyl) methanone (10 gm). Raised the temperature of the reaction mass to 80 -90°C. Charged phosphoric acid (30 ml) maintaining temperature at 80-85 °C, and maintained at reflux temperature for 10 hrs. After completion of reaction, cooled the reaction mass to 25 - 30 ° C and filtered. Washed the solid with 2- methoxy methanol (20 ml).Wet cake charged in D. M. water (100 ml) and stirred at 25 - 30°C for 1 hr, filtered the solid and washed with D.M. water (50 ml). Dried the solid to get 7-(4-bromobenzoyl)-1, 3-dihydro-2#-indoI-2-one. Dry wt= 7.3 gm. Example- 6: Preparation of Bromfenac sodium sesquihydrate: Charged 7-(4-bromobenzoyl)-l, 3-dihydro-2#-indol-2-e>ne (5 gm) in the flask having mixture of solvents of toluene (35 ml) and ethanol (15 ml). Stirred at 25 - 30°C for 30 minutes, followed by addition of aqueous solution of sodium hydroxide (0.6 gm in 1.2 ml water), with continous stirring for 15 minutes at 25 - 30tJC. Raised the temperature of the reaction mass to 75-78 °C and maintained for 5 hours. Cooled the reaction mass to 25 -30°C and charged DIPE (50 ml) and ethanol (25 ml). CQoled the reaction mass further to 5 - 10 °C, and stirred for 10-12 hours, filtered the solid at 10 °C. Washed the solid mass with 10 ml of DIPE and dried the solid to get crude bromfenac sodium sesquihydrate. Dry wt = 5.2 gm Example-7: Purification of crude Bromfenac sodium sesquihydrate: Charged crude bromfenac sodium sesquihydrate (5 gm) to the flask containing dimethoxy ethane (35 ml) and D.M. water (4 ml) under stirring. Heated to raise the temperature to reflux,maintained 1 hr at 70 - 72°C.Filtered the reaction mass under hot condition to remove un-dissolved particles. Filtrate was concentrated under vacuum and charged DIPE (50 ml) and ethanol (25 ml) to the residual solid. Stirred at 25 - 30°C for 2 hours filtered and washed with DIPE (10 ml). Dried the solid to get pure bromfenac sodium sesquihydrate. Dry wt= 3.7 gm Example- 8: Preparation of 3-amino-4-benzoyIphenyl acetamide (Nepafenac): Charged 7-benzoyl-l, 3-dihydro-2.//-indol-2-one (5 gm) in a R. B. Flask containing toluene (35 ml) and ethanol (15 ml), stirred at 25 - 30°C for 30 minutes. Charged aqueous solution of sodium hydroxide (0.45 gm in 0.9 ml water) and stirred for 10 min at 25 - 30°C. Raised the temperature of the reaction mass to 75-78 °C and maintained for 5 hours. Cooled the reaction mass to 25 - 30°C and charged DIPE (50 mi) and ethanol (25 ml). Cooled the reaction mass further to 5 - 10 °C, and stirred for 10-12 hours, filtered the solid at 10 °C. Washed the filtered solid mass with DIPE (10 ml) to get sodium salt of 3-amino-4-benzoylphenyl acetic acid. The wet mass was then charged to R.B.Flask containing water (50 ml), under stirring. This was followed by addition of concentrated hydrochloric acid to adjust pH to 1. Stirred the reaction mass at 25 - 30°C for 1 hour and extracted the free acid with dichloromethane (3 x 50 ml). Separated and washed the organic layer using brine solution (3 x 50ml) till pH of organic layer was 6.5 to 7. Cooled organic layer to 0 - 5 °C and charged thionyl chloride (4.6 gm). Raised the temperature of the reaction to reflux and maintained for 3 hours. Further cooled the reaction mass to 0°C, and purged ammonia gas at 0 - 5°C till pH of the reaction mass is 8.5 - 9.5. Raised the temperature of the reaction to 25 - 30°C and concentrated the solvent under reduced pressure to get the residual solid. Charged water (50 ml) to the residual solid and stirred for 1 hour at 25 - 30°C. Filtered the solid mass to get 3-amino-4-benzoylphenyl acetamide (Nepafenac). Dry wt= 4.0 gm. Example- 9: Preparation of 3-amino-4-benzoylphenyl acetic acid (Amfenac): Charged 7-benzoyl-l, 3-dihydro-2/f-indol-2-one (5 gm) in a R. B. Flask containing toluene (35 ml) and ethanol (15 ml), stirred at 25 - 30°C for 30 minutes. This was followed by addition of aqueous solution of sodium hydroxide (0.45 gm in 0.9 ml water). The reaction mass was stirred for 10 min at 25 - 30°C. Raised the temperature of the reaction mass to 75-78 °C and maintained for 5 hours. Cooled the reaction mass to 25 -30°C and charged DIPE (50 ml) and ethanol (25 ml). Cooled the reaction mass further to 5 - 10 °C, and stirred for 10-12 hours, filtered the solid at 10 °C. Washed the filtered solid mass with DIPE (10 ml) to give sodium salt of 3-amino-4-benzoylphenyl acetic acid. Charged the wet mass to R.B.Flask containing water (50 ml), under stirring. This was followed by addition of concentrated hydrochloric acid to adjust pH to 1.Stirred the reaction mass at 25 - 30°C for 1 hour, cooled to 10-15°C, pH of reaction mixture adjusted to 6.8-7.0 with aqueous sodium carbonate solution. The product was extracted in dichloromethane (3 x 100ml). Combined all organic layers, dried over anhydrous sodium sulphate and concentrated under reduced pressure at 20 - 25°C to get 3-amino-4-benzoylphenyl acetic acid (Amfenac). Dry wt = 4.5 gm. We claim, 1. A process for the preparation of substituted derivatives of 3 - Benzoyl - 2 - amino phenylacetic acid of Formula - I and its pharmaceutically acceptable salts; Formula -1 Where X is independently H, lower alkyl Ci - C4 group, halogen atom (CI, Br, F, I), trifluoromethyl group and; R is - OH, -NH2 & - OM; where M is any metal. comprising of; with a carbonyl protecting group to get the compound of Formula - XVI; i. protecting the compound 2 - nitro benzophenone of Formula - XV; where R] is linear or branched aliphatic chain having 2 to 6 carbon atoms; ii. reacting the compound of Formula - XVI with vinyl magnesium bromide in presence of solvent at temperature in the range of -60 to 0°C to obtain compound (\H~ indol - 7 -yl) phenyl - methanone of Formula -XI11; iii. converting the compound of Formula - XIII to isolate substituted derivatives of 3 - Benzoyl - 2 - amino phenylacetic acid of Formula -1. 2. The process as claimed in claim 1; comprising the steps of: i. reacting the compound 2 - nitrobenzophenone of Formula XV with a carbonyf protecting group in presence of catalyst and solvent to get the compound of Formula - XVI; Formula - XVI where R, is linear or branched aliphatic chain having 2 to 6 carbon atoms. ii. reacting the compound of Formula - XVI with vinyl magnesium bromide in presence of solvent at temperature in the range of-60 to 0°C to isolate (W-indol - 7 - yl) phenyl methanone compound of Formula - XIII; Formula-XIII iii. brominating the compound of Formula - XIII with brominating reagent to get the compound of Formula - XIV; Formula - XIV iv. converting the compound of Formula - XIV to the precursor oxyindole compound of Formula - IX. Formula - IX v. hydrolysing the compound of Formula - IX to isolate the desired substituted derivatives of 3 - Benzoyl - 2 - amino phenylacetic acid of Formula -1. 3. The process as claimed in claimsl and 2; wherein the solvent for the reaction of vinyl magnesium bromide with the compound of Formula - XVI is selected from tetrahydrofuran, toluene, N, N - dimethylformamide and N - methyl pyrrolidone or mixtures thereof. 4. The process as claimed in claim 3; wherein the preferred solvent for the reaction of vinyl magnesium bromide and the compound of Formula- XVI is tetrahydrofuran. 5. The process as claimed in claims 1 and 2; wherein the preferred temperature for the reaction of vinyl magnesium bromide with compound of Formula - XVI is -40°C to -5°C. 6. The process as claimed in claim 1 and 2; wherein the most preferred temperature for the reaction of vinyl magnesium bromide with compound of Formula -XVI is -20° C to -10°C. 7. The process as claimed in claims 1 & 2; wherein the carbonyl protecting group is selected from the compound having general formula where Ri is linear or branched aliphatic chain having 2 to 6 carbon atoms. 8. The process as claimed in claim 1; wherein the substituted derivative of 3 - Benzoyl -2 - amino phenylacetic acid of Formula - I is 2 - Amino - 3 - benzoyl phenyl acetamide of Formula - II; 9. The process as claimed in claim 1; wherein the substituted derivative of 3 - Benzoyl -2 - amino phenylacetic acid of Formula - I is 2 - Amino - 3 - (4 - bromobenzoyl) phenyl acetic acid sodium salt of Formula- III; 1 0. The process as claimed in claim 1; wherein the substituted derivative of 3 - Benzoyl ~ 2 - amino phenylacetic acid of Formula - I is 2 - Amino - 3 - benzoyl phenyl acetic acid of Formula -IV;

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# Name Date
1 2481 MUM 2008 Amended claims and HIGHLIGHTING THE CLAIMS INDOCO 651.pdf 2018-08-09
1 2481-MUM-2008FORM 2(TITLE PAGE)-(PROVISIONAL)-(25-11-2008).pdf 2008-11-25
2 2481-MUM-2008-FORM 1(15-12-2008).pdf 2008-12-15
2 2481 MUM 2008 REPLY TO F E R INDOCO 648.pdf 2018-08-09
3 2481-MUM-2008-CORRESPONDENCE(15-12-2008).pdf 2008-12-15
3 2481 MUM 2008 REPLY TO F E R INDOCO 649.pdf 2018-08-09
4 2481-MUM-2008-FORM 5(24-11-2009).pdf 2009-11-24
4 2481-mum-2008-abstract.doc 2018-08-09
5 2481-MUM-2008-FORM 2(TITLE PAGE)-(24-11-2009).pdf 2009-11-24
6 2481-mum-2008-form 2(24-11-2009).pdf 2009-11-24
6 2481-MUM-2008-CORRESPONDENCE(12-9-2014).pdf 2018-08-09
7 2481-MUM-2008-DESCRIPTION(COMPLETE)-(24-11-2009).pdf 2009-11-24
7 2481-MUM-2008-CORRESPONDENCE(8-12-2010).pdf 2018-08-09
8 2481-mum-2008-correspondence.pdf 2018-08-09
8 2481-MUM-2008-CORRESPONDENCE(24-11-2009).pdf 2009-11-24
9 2481-MUM-2008-CLAIMS(24-11-2009).pdf 2009-11-24
10 2481-MUM-2008-ABSTRACT(24-11-2009).pdf 2009-11-24
10 2481-mum-2008-description(provisional).pdf 2018-08-09
11 2481-MUM-2008-CORRESPONDENCE(IPO)-(FER)-(20-09-2013).pdf 2013-09-20
11 2481-mum-2008-form 1.pdf 2018-08-09
12 2481-MUM-2008-FORM 18(8-12-2010).pdf 2018-08-09
12 27-06-2014_FORM-2_Complete Application.pdf 2014-06-27
13 2481-mum-2008-form 2(titel page).pdf 2018-08-09
13 27-06-2014_2481 MUM 2008 REPLY TO F E R INDOCO 649.pdf 2014-06-27
14 27-06-2014_2481 MUM 2008 REPLY TO F E R INDOCO 648.pdf 2014-06-27
15 2481-mum-2008-form 2.pdf 2018-08-09
15 27-06-2014_2481 MUM 2008 Amended claims and HIGHLIGHTING THE CLAIMS INDOCO 651.pdf 2014-06-27
16 2481-mum-2008-form 26.pdf 2018-08-09
16 2481-MUM-2008-FORM 2-(GRANTED)-(04-10-2016).pdf 2016-10-04
17 2481-mum-2008-form 3.pdf 2018-08-09
17 2481-MUM-2008-FORM 2(TITLE PAGE)-(GRANTED)-(04-10-2016).pdf 2016-10-04
18 2481-MUM-2008-DESCRIPTION(GRANTED)-(04-10-2016).pdf 2016-10-04
18 2481-MUM-2008_EXAMREPORT.pdf 2018-08-09
19 2481-MUM-2008-CORRESPONDENCE(IPO)-(04-10-2016).pdf 2016-10-04
19 FORM-2_Complete Application.pdf 2018-08-09
20 2481-MUM-2008-ABSTRACT(GRANTED)-(04-10-2016).pdf 2016-10-04
20 2481-MUM-2008-CLAIMS(GRANTED)-(04-10-2016).pdf 2016-10-04
21 2481-MUM-2008-ABSTRACT(GRANTED)-(04-10-2016).pdf 2016-10-04
21 2481-MUM-2008-CLAIMS(GRANTED)-(04-10-2016).pdf 2016-10-04
22 2481-MUM-2008-CORRESPONDENCE(IPO)-(04-10-2016).pdf 2016-10-04
22 FORM-2_Complete Application.pdf 2018-08-09
23 2481-MUM-2008-DESCRIPTION(GRANTED)-(04-10-2016).pdf 2016-10-04
23 2481-MUM-2008_EXAMREPORT.pdf 2018-08-09
24 2481-MUM-2008-FORM 2(TITLE PAGE)-(GRANTED)-(04-10-2016).pdf 2016-10-04
24 2481-mum-2008-form 3.pdf 2018-08-09
25 2481-MUM-2008-FORM 2-(GRANTED)-(04-10-2016).pdf 2016-10-04
25 2481-mum-2008-form 26.pdf 2018-08-09
26 2481-mum-2008-form 2.pdf 2018-08-09
26 27-06-2014_2481 MUM 2008 Amended claims and HIGHLIGHTING THE CLAIMS INDOCO 651.pdf 2014-06-27
27 27-06-2014_2481 MUM 2008 REPLY TO F E R INDOCO 648.pdf 2014-06-27
28 27-06-2014_2481 MUM 2008 REPLY TO F E R INDOCO 649.pdf 2014-06-27
28 2481-mum-2008-form 2(titel page).pdf 2018-08-09
29 27-06-2014_FORM-2_Complete Application.pdf 2014-06-27
29 2481-MUM-2008-FORM 18(8-12-2010).pdf 2018-08-09
30 2481-MUM-2008-CORRESPONDENCE(IPO)-(FER)-(20-09-2013).pdf 2013-09-20
30 2481-mum-2008-form 1.pdf 2018-08-09
31 2481-MUM-2008-ABSTRACT(24-11-2009).pdf 2009-11-24
31 2481-mum-2008-description(provisional).pdf 2018-08-09
32 2481-MUM-2008-CLAIMS(24-11-2009).pdf 2009-11-24
33 2481-MUM-2008-CORRESPONDENCE(24-11-2009).pdf 2009-11-24
33 2481-mum-2008-correspondence.pdf 2018-08-09
34 2481-MUM-2008-CORRESPONDENCE(8-12-2010).pdf 2018-08-09
34 2481-MUM-2008-DESCRIPTION(COMPLETE)-(24-11-2009).pdf 2009-11-24
35 2481-mum-2008-form 2(24-11-2009).pdf 2009-11-24
35 2481-MUM-2008-CORRESPONDENCE(12-9-2014).pdf 2018-08-09
36 2481-MUM-2008-FORM 2(TITLE PAGE)-(24-11-2009).pdf 2009-11-24
37 2481-MUM-2008-FORM 5(24-11-2009).pdf 2009-11-24
38 2481-MUM-2008-CORRESPONDENCE(15-12-2008).pdf 2008-12-15
38 2481 MUM 2008 REPLY TO F E R INDOCO 649.pdf 2018-08-09
39 2481-MUM-2008-FORM 1(15-12-2008).pdf 2008-12-15
39 2481 MUM 2008 REPLY TO F E R INDOCO 648.pdf 2018-08-09
40 2481 MUM 2008 Amended claims and HIGHLIGHTING THE CLAIMS INDOCO 651.pdf 2018-08-09
40 2481-MUM-2008FORM 2(TITLE PAGE)-(PROVISIONAL)-(25-11-2008).pdf 2008-11-25

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