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A Process For Preparation Of An Intermediate Of Silodosin

Abstract: The present invention relates to a process for preparation of an intermediate of Formula III by purification involving simple process and use of said intermediate in the synthesis of the known pharmacologically active agent silodosin. The present invention further relates to the recovery of intermediate of Formula III that is lost in the mother liquor during the purification process.

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Patent Information

Application #
Filing Date
28 October 2016
Publication Number
18/2018
Publication Type
INA
Invention Field
CHEMICAL
Status
Email
Parent Application

Applicants

MANKIND PHARMA LTD
208 OKHLA INDUSTRIAL STATE PHASE 3, NEW DELHI-110020 INDIA

Inventors

1. BHAVSAR, JIGAR TARUN KUMAR
MANKIND RESEARCH CENTRE, 191-E, SECTOR-4-II, IMT MANESAR-122050, HARYANA, INDIA
2. GANGWAR, KULDEEP SINGH
MANKIND RESEARCH CENTRE, 191-E, SECTOR-4-II, IMT MANESAR, HARYANA-122050, INDIA
3. BHASHKAR, BHUWAN
MANKIND RESEARCH CENTRE, 191-E, SECTOR-4-II, IMT MANESAR, HARYANA-122050, INDIA
4. KUMAR, ANIL
MANKIND RESEARCH CENTRE, 191-E, SECTOR-4-II, IMT MANESAR, HARYANA-122050, INDIA

Specification

FIELD OF THE INVENTION The present invention relates to a process for preparation of an intermediate of Formula III which is useful in the synthesis of the known pharmacologically active agent silodosin wherein said intermediate is prepared by employing a simple purification process. The present invention further relates to isolation of compound of Formula III with optical purity of about 65-80% d.e. (diastereomeric excess). H3a O OH 0 HO' T T°H P OH O Formula III Moreover, the present invention further relates to recovery of intermediate compound of Formula III that is lost in the mother liquor during the purification process. BACKGROUND OF THE INVENTION Silodosin is a well-known pharmaceutically active ingredient with the IUPAC name l-(3-hydroxypropyl)-5-[(2R)-({2-[2-[2-(252?2-trifluoroethoxy)phenoxy]ethyl} amino)-propyl]indoline-7-carboxamide having the chemical Formula I. Formula I Silodosin is useful for the treatment of dysuria and similar diseases, in particular dysuria associated with benign prostatic hyperplasia. Silodosin is a highly selective inhibitor of the alA-adrenergic receptor, and it causes practically no orthostatic " I P O D E L H I I Z - I Q . - 2 & I 2 I S ' : 4 22 hypertension. Presently, silodosin is marketed in the US under the trade name Rapaflo. Silodosin was first disclosed in EP0600675 A, where a process for producing the compound is also disclosed. However, since silodosin is an optically active compound (a single enantiomer) and has a complex chemical structure, its synthesis is rather complex requiring a number of different synthesis steps and purification steps including an optical resolution. Several patent applications have been filed for improved processes for preparing silodosin. One synthesis route proceeds through an intermediate of Formula III" H3C«^NH2 O Formula III" which is coupled with a compound of formula V X. . OCH2CF3 Formula V (wherein X is a leaving group) to give a protected intermediate. The obtained protected intermediate is then converted to silodosin. This route of synthesis is disclosed in EP 1806340, JP 2002265444 and JP 2001199956 and solves many problems of the prior art, in particular, the optical resolution to a single enantiomer occurs relatively early in the production process. This is advantageous from an economic point of view. However, the preparation of the intermediate compound of Formula III" which is a single enantiomer, is a complex process. JP 2001199956 discloses a process for the CD G) co Q. CN* E o LL © CO O CO o ft- % 7 1 & I. 4 2 7 diastereomeric mixture containing a compound of formula III having an optical purity of about 65-80%) d.e. It is observed by the inventors of the present invention, that high optical purity of compound of Formula III (i.e. 85%> or above) is not required to produce optically pure Silodosin. Hence, the present invention is focused to prepare compound of Formula III with reasonable optical purity of about 65%) d.e. to about 80%» and more focused towards the recovery of lost compound of Formula III from the mother liquor. It is another object of the present invention to produce diastereomerically pure compound III using simple solvent purification methods and its conversion to optically pure Silodosin. SUMMARY OF THE INVENTION In main aspect, the present invention provides a process for preparation of Silodosin intermediate of Formula-Ill with optical purity of about 65-80%) diastereomeric excess (d.e.); H 3 CV^NH2 OH O \ = y 0 Formula-Ill which comprises the steps of: a) reacting compound of Formula II HI -Gi- W FormuIa-II with L-tartaric acid in presence of acetonitrile and water to get a reaction mixture; b) cooling the reaction mixture to ambient temperature; c) filtering the reaction mixture to get a wet cake; d) washing the wet cake with mixture of acetonitrile and water; e) adding the wet cake in acetonitrile and water followed by heating and then cooling and filtering of the wet cake; f) optionally repeating the process of step d) and e); and g) drying the wet cake to obtain compound of Formula III. In another aspect, the present invention provides a process of recovery of compound of Formula III from the mother liquor. DETAILED DESCRIPTION OF THE INVENTION The present invention will now be explained in details. While the invention is susceptible to various modifications and alternative forms, specific embodiment thereof will be described in detail below. It should be understood, however that it is not intended to limit the invention to the particular forms disclosed, but on the contrary, the invention is to cover all modifications, equivalents, and alternative falling within the scope of the invention as defined by the appended claims. The steps of a method may be providing more details that are pertinent to understanding the embodiments of the present invention and so as not to obscure the disclosure with details that will be readily apparent to those of ordinary skill in the art having benefit of the description herein. Further characteristics and advantages of the process according to the invention will result from the description herein below of preferred exemplary embodiments, which are given as indicative and non-limiting examples. T IT- i: n- - -> n t T t d u J* •> 9 CD G) Q. CD E o Accordingly in one embodiment, the present invention provides a process for preparation of Silodosin intermediate of Formula-Ill with optical purity of about 65- 80% diastereomeric excess (d.e.); O OH HO' which comprises the steps of: a) reacting compound of Formula II FormuIa-II with L-tartaric acid in presence of acetonitrile and water to get a reaction mixture; b) cooling the reaction mixture to ambient temperature; c) filtering the reaction mixture to get a wet cake; d) washing the wet cake with mixture of acetonitrile and water; e) adding the wet cake in acetonitrile and water followed by heating and then cooling and filtering of the wet cake; f) optionally repeating the process of step d) and e); and g) drying the wet cake to obtain compound of Formula III. The compound of Formula II can be obtained by any process disclosed in prior art such as IN 880/DEL/2010. Moreover, the step a) is carried out at temperature in the range of 50-80°C. It is found by the inventors of present invention that by purification and repeated purification using acetonitrile and water, any desired level of optical purity can be achieved. Preferably the compound of formula III is obtained with optical purity of about 70% d.e., more preferably 80% d.e. In other embodiment, the acetonitrile and water used in the above reaction may be taken in a ratio of 1:1 to 3:1. In another embodiment, every step involving filtration and washing of wet cake such as step c) to f) involves isolation of wet cake as solid mass and a filtrate i.e. mother liquor containing acetonitrile and water. Moreover, washing of wet cake of compound of Formula III results into loss of some amount of compound of Formula III in mother liquor wherein the compound of Formula III present in the mother liquor is optically impure. The optically pure intermediate of Formula III thus obtained can be converted into Silodosin by using any prior art method especially as disclosed in EP 1806340, JP 2002-265444 and JP 2001-199956. In further embodiment, the heating of the wet cake in step e) is carried out at a temperature in range of 60-80°C, preferably at a temperature of 70-75°C. In one another embodiment, the present invention relates to a process for preparation of Silodosin intermediate of Formula-Ill with optical purity of about 65-80% diastereomeric excess (d.e.); H3°V^NH2 \ = / c Formula-Ill which comprises the steps of: a) reacting compound of Formula II NH2 V CN Formula-H with L-tartaric acid in presence of acetonitrile and water to get a reaction mixture; b) cooling the reaction mixture to ambient temperature; c) filtering the reaction mixture to get a wet cake and washing the wet cake with mixture of acetonitrile and water; d) adding the wet cake in acetonitrile and water followed by heating and then cooling and filtering of the Wet cake; e) optionally repeating the process of step c) and d); f) drying the wet cake to obtain compound of Formula III; and g) recovering compound of Formula III from filtrate containing acetonitrile, water and lost amount of compound of Formula III. In a preferred embodiment, the filtration of reaction mixture and washing of wet cake in step c) to e) provides a filtrate which is collected separately as a mother liquor wherein said mother liquor comprises of acetonitrile, water and some amount of compound of Formula III that passes into the mother liquor during filtration. In another embodiment, the recovering of compound of Formula III from filtrate in step g) is performed by a process comprising the steps of: a) distilling acetonitrile from the filtrate containing acetonitrile, water and compound of Formula III to get a reaction mass; b) filtering the reaction mass to obtain viscous mass of compound of Formula III; c) hydrolyzmg the viscous mass with base in a solvent mixture comprising water and water immiscible solvent to get free base of compound of Formula III"; d) treating the compound of Formula III" with D-tartaric acid in acetonitrile and water to get a reaction mixture; e) cooling the reaction mixture to get a wet cake, filtering and washing the wet cake i with acetonitrile and water; and f) drying the wet cake to get compound of Formula III wherein said compound of Formula III is having d.e. of about 65-80%. In further embodiment, the base used for hydrolyzing the salt is selected from liquor ammonia, aqueous sodium hydroxide or organic tertiary amines such as triethyl amine and pyridine. Preferably the base used is liquor ammonia. In a preferred embodiment, the water immiscible solvent is selected from carboxylic acid ester such as ethyl acetate, isoprppyl acetate, n-butyl acetate, isobutyl acetate and mixture thereof. In one more embodiment, the present invention further relates to a process for preparing optically pure silodosin of formula I: Formula I comprising the steps of: a) producing compound of Formula III V-NHu: T- t 7 - j n - p f t ] 7 t c - yii > 13 &_,. i> B> -o* Formula III with optical purity of about 65-80% d.e. b) reacting the compound of formula III or its base of formula III" with a compound represented by formula V OCH2CF3 Formula V wherein, X represents a leaving group, to obtain a compound represented by the general formula VI: Formula VI c) de-protecting the compound of formula VI and conducting a hydrolysis reaction to afford silodosin; and d) purifying the silodosin obtained in step (c) by crystallization from a solvent to obtain optically pure silodosin of formula I. In accordance to other embodiment of the present invention, the condensation of compound of Formula III or III" with compound of Formula V is carried out in an organic solvent selected from the group comprising of benzene, toluene, o-xylene, m-xylene, p-xylene, acetonitrile, dimethyl sulfoxide, methyl isobutyl ketones, dioxane, dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidone and/or mixture thereof. More preferably, the solvent selected is toluene and/or dimethyl sulfoxide. In accordance to other embodiment of the present invention, the condensation of compound of Formula III or III" with compound of Formula V is carried out in presence of base comprising of hydroxides, carbonates, alkoxides, phosphates, such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, cesium carbonate, or mixture thereof. More preferably, the base is dipotassium hydrogen phosphate. In further embodiment, the above said condensation is optionally carried out in presence of phase transfer catalyst which is selected from crown ether, triglyme, tetrabutyl ammonium bromide, tetrabutyl ammonium chloride, tetrabutyl ammonium iodide, potassium fluoride and the like. Preferably the phase transfer catalyst is tetrabutyl ammonium iodide. ' Moreover, the purification of silodosin can be carried out by any of the conventional methods. In one more embodiment, the silodosin of Formula I obtained by the process of the present invention can be crystallized in organic solvent(s), preferably in the solvents selected from the group comprising of esters, alcohols, cycloalkanes, substituted or unsubstituted alkanes, halogenated solvents or mixture thereof. In preferred embodiment, the silodosin obtained by the process of the present invention is isolated in two different crystalline forms such as Form a and P wherein (1) Form a is characterized by XPRD peaks at 5.5°±0.2°, 6.1°±0.2°, 9.8°±0.2°, ll.lo±0.2°, 12.2°±0.2°, 16.4°±0.2°, 19.7°±0.2° and 20.0°±0.2° 29; and (2) Form p is characterized by XPRD peaks at 7.0°±0.2°, 12.5°±0.2°, 18.5°±0.2°, 19.5°±0.2°, 20.7°±0.2° and 21.1°±0.2° 29. In other embodiment, the silodosin of Formula I obtained in step d) is optically pure with purity of 95% e.e. or above and preferably, 99% e.e. or above. H I 1 1 - 1 0 " 2 0 : 1 7 1 6 : 4 2 15 In another embodiment, the silodosin of Formula I obtained by the process of the present invention is characterized by particle size distribution wherein,.d9o is 0.1 ^im to 200|am. In a preferred embodiment, the silodosin of Formula I obtained by the process of the present invention is characterized by particle size distribution wherein, d9o is 2.0 (im to 150^im. In a preferred embodiment, the silodosin of Formula I obtained by process of present invention is In another embodiment, the compound of formula III is optically pure with about 70% d.e. In one another embodiment, the compound of formula III is optically pure with 70 % d.e to not more than 80% d.e. In yet another embodiment, the compound of formula III is optically pure with about 70 % d.e. or above. In still another embodiment, the present invention provides a pharmaceutical composition comprising silodosin prepared via an intermediate of compound of Formula III. In further embodiment, the present invention provides a pharmaceutical composition comprising silodosin prepared via an intermediate of compound of Formula III wherein said intermediate of Formula III is prepared as per the process of the present invention. In another embodiment, the present invention provides a pharmaceutical composition comprising silodosin prepared via an intermediate of compound of Formula III wherein said intermediate of Formula III is optically pure with purity of about 65-80% d.e. t The present invention further relates to a process for recovering compound of formula III, II or its base (R-isomer) from mother liquors of the above mentioned purification process, the process is described in below mentioned examples. In one more embodiment, the present invention provides use of silodosin in the treatment of dysuria associated with benign prostatic hyperplasia wherein said silodosin is prepared by using compound of Formula III prepared by the process of the present invention. The invention is illustrated with the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention. EXAMPLES: Preparation of compound of Formula III; Example 1: Charged acetonitrile (4590 ml) to 5-[2-Aminopropyl]-l-[3- (benzoyloxy)propyl]-2,3-dihydro-lH-indole-7-carbonitrile-2,3-dihydroxy butanedioate (500.0 gm) and DM water (860 ml) at 25-30°C. Heated the mass to 55- 60°C. Stirred for 15 minutes and charged L-(+) - tartaric acid (206 gm) at 55-60°C. Stirred for 1 hour and cooled the reaction mass to 28-32°C. Stirred for 3 hours and filtered the product. Washed the wet cake with mixture of acetonitrile (190.0 ml) and DM water (60.0 ml) and charged the wet cake to the round bottom flask. Added acetonitrile (1095.0 ml) and DM water (252.0 ml) to round bottom flask and heated the mass to 55-60°C. Maintained for 2 hours at 55-60°C followed by cooling down to 32-34°C. Stirred the reaction mass for 1.5 hours at 32-34°C. Filtered the product and washed the wet cake with mixture of acetonitrile (170.0 ml) and DM water (60.0 ml). Dried the wet cake so obtained in air oven at 55°C for 4-5 hours to get 165.0 gm of 5-[(2R)-2-Aminopropyl]-l-[3-(benzoyloxy)propyl]-2,3-dihydro-lH-indole- 7-carbonitrile(2R,3R)-2,3-dihydroxy butanedioate.tartarate . Enatiomeric excess (ee): 79.10 % d.e. ** 1? t . ' J J . £ 1 G. - .AO 17 Example 2: Charged acetone (2000 ml), 5-[2-Aminopropyl]-l-[3- (benzoyloxy)propyl]-2,3-dihydro-lH-indole-7-carbonitrile-2:,3-dihydroxy butanedioate (245.0 gm) and DM water (750 ml) at 25-30°C. Heated the mass to 55- 60°C. Stirred the reaction mass for 15 minutes and charged L-(+) - tartaric acid (101 gm) at 55-60°C. Stirred for 1 hour and cooled the reaction mass to 28-32°C. Stirred the reaction mass so obtained for 3 hours and filtered the product. Washed the wet cake with mixture of acetone (96 ml) and DM water (28.0 ml) and charged the wet cake to the round bottom flask. Added acetone (480 ml) and DM water (200 ml) to round bottom flask and heated the mass to 55-60°C. Maintained the temperature for 2 hours and then cooled the reaction mass to 32-34°C. Stirred for 1.5 hours at 32- 34°C followed by filtering the product and washing of the wet cake with mixture of acetone (96 ml) and DM water (28.0 ml). Dried the product so obtained in air oven at 55°C for 4-5 hours to get 85.0gm of 5-[(2R)-2-Aminopropyl]-l-[3- (benzoyloxy)propyl]-2?3-dihydro-lH-indole-7-carbonitrile(2R33R)-2?3-dihydroxy butanedioate.tartarate. Enatiomeric excess (ee): 72.52 % d.e. Example 3: In 5 L round bottom flask, charged compound of formula II (350 g) to acetonitrile (3.5 L) and water (1.05 L) at room temperature. After rising the temperature of reaction mass to 60-65°C, L (+) tartaric acid (144 g) was added. The reaction mass was cooled gradually to 35-25°C. The reaction mass was filtered and washed with mixture of acetonitrile and water. The wet cake thus obtained was charged in acetonitrile (840 ml) and water (280 ml) at room temperature. The temperature of reaction mass was raised to 70-75°C.The reaction mass was cooled gradually to 35-25°C. The reaction mass was filtered and washed with mixture of acetonitrile and water. The wet cake so obtained was dried under vacuum to get 135 g of compound of Formula III. Optical Purity: 80% d.e. Example 4: In 5 L round bottom flask, compound of formula II (500 g), acetonitrile (5 L) and water (2.0 L) were charged at room temperature. After rising the •r * y - u p - >Ql y i- e? * J*>18 temperature of reaction mass to 60-65°C, L-(+) tartaric acid (144 g) was added. The reaction mass was cooled gradually to 35-25°C. The reaction mass was filtered and washed with mixture of acetonitrile and water. The wet cake thus obtained was charged in acetonitrile (1.2 L) and water (0.4 L) at room temperature. The temperature of reaction mass was raised to 70-75°C. Thereaction mass was cooled gradually to 35-25°C. The reaction mass was filtered and washed with mixture of acetonitrile and water. The wet cake thus obtained was charged in acetonitrile (950 ml) and water (950 ml) at room temperature. The temperature of reaction mass was raised to 70-75°C. The reaction mass was cooled gradually to 35-25°C. The reaction mass was filtered and washed with mixture of acetonitrile and water. The wet cake thus obtained was dried under vacuum and 142 g of compound of Formula III was obtained. Optical Purity: 98 % d.e. Example 5: The mother liquors from Example 1 or 2 was taken and acetonitrile was distilled out completely to obtain aqueous reaction mass. The aqueous mass was filtered to obtain L (+) tartrate salt. The wet salt was charged in water (1.5 L) and ethyl acetate (1.5 L). The pH of the reaction mass was adjusted to 8.5 to 9.0 using liq. Ammonia. Separated the layers and distilled off the ethyl acetate layer to get 290 g of free base as a brown color oil. The recovered free base was charged in acetonitrile (2.9 L) and water (870 ml) and the raised the temperature to 60-65°C. Added 120g of D(-) tartaric acid and the reaction mass was gradually cooled to 25-35°C. The reaction mass was filtered and washed with mixture of acetonitrile and water. The wet cake thus obtained was dried under vacuum and 255 g of tartarate salt of formula III was obtained with optical purity of 80.0 to 85.0 % d.e. Acetonitrile was distilled from the mother liquor and 400 ml of ethyl acetate was added. The pH of aqueous residue was adjusted to 8.5-9.0 using liq. ammonia. The layers were separated and the organic layer was washed with brine solution. Ethyl r i T ? - i n . - - j > f t i T i ft ;• 4 ? 19 J L . ™fl>. *' ta&* W Am. %mf- A •*'- J»-W —=fr £— acetate was distilled out completely and 95 g of compound of formula II was obtained with optical purity of 40.0% e.e. Preparation of Silodosin Example 6: To a round bottom flask was added 3-(5-(R)-2-aminopropyl)-7- cyanoindolin-l-yl)propyl benzoate)tartarate (71.5 g, compound of formula III), DM water (350 ml), ethyl acetate (350.0 ml) and aqueous ammonia (71.0 ml) and stirred at 20-25°C till completion of reaction. The layers were separated and distilled the organic layer to get free base, 3-(5-(R)-2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate) (Compound of formula III"). To the solution of 50.0 g of 3-(5-(R)-2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate) (Compound of formula III") in 500.0 ml toluene was added 72 g of dipotassium hydrogen orthophosphate and 41g of 2-[2,2,2-trifluoroethoxy)phenoxy] ethyl methane sulfonate followed by addition of 5.0 g of tetrabutyl ammonium iodide and stirred at 90-110°C till completion of reaction. The reaction mass was cooled followed by addition of water. Separated the layers and distilled the organic layer to get a crude mass. Methanol was added to the crude mass thus obtained followed by addition of sodium hydroxide solution (11.34 g sodium hydroxide in 75.0 ml water). Stirred the reaction mixture followed by addition of water and toluene to the reaction mixture. Separated the organic layer and distilled out to get a reaction mass. DMSO (400 ml) and sodium hydroxide (11.Og sodium hydroxide and 50 ml DM water) were added to the reaction mass which is then followed by addition of 43 g of hydrogen peroxide. The reaction mass was stirred at 20-25°C till reaction completion and added sodium sulphite solution. The reaction mass was extracted E with ethyl acetate and distilled out the ethyl acetate layer and crude Silodosin thus obtained was purified with ethyl acetate. WE CLAIM 1. A process for preparation of Silodosin intermediate of Formula-Ill with optical purity of about 65-80% diastereomeric excess (d.e.); Formula-Ill which comprises the steps of: a) reacting compound of Formula II Formula-II with L-tartaric acid in presence of acetonitrile and water to get a reaction mixture; b) cooling the reaction mixture to ambient temperature; c) filtering the reaction mixture to get a wet cake; d) washing the wet cake with mixture of acetonitrile and water; e) adding the wet cake in acetonitrile and water followed by heating and then cooling and filtering of the wet cake; f) optionally repeating the process of step d) and e); and g) drying the wet cake to obtain compound of Formula III. 2. The process as claimed in claim 1, wherein said heating of the wet cake in step d) is carried out at a temperature in the range of 60-80°C. 3. The process as claimed in claim 1, wherein said acetonitrile and water used in step a) is in a ratio of 1:1 to 3:1. 4. The process as claimed in claim 1, wherein said filtration of reaction mixture and washing of wet cake in step c) to f) provides a filtrate collected separately as a mother liquor comprising of acetonitrile, water and some amount of compound of Formula III. 5. The process as claimed in claim 1, wherein said process further comprises of recovering of compound of Formula III from filtrate wherein the process comprises of: a) distilling acetonitrile from the mother liquor containing acetonitrile, water and compound of Formula III to get a reaction mass; b) filtering the reaction mass to obtain viscous mass of compound of Formula III; c) hydrolyzing the viscous mass with base in a solvent mixture comprising water and water immiscible solvent to get free base of compound of Formula III"; Formula III" d) treating the compound of Formula III" with D-tartaric acid in acetonitrile and water to get a reaction mixture; e) cooling the reaction mixture to get a wet cake, filtering and washing the wet cake with acetonitrile and water; and f) drying the wet cake to get compound of Formula III wherein said compound of Formula III is optically pure with about 65-80% d.e. > 6. The process as claimed in claim 5, wherein said base used in step c) is selected from the group comprising of liquor ammonia, aqueous sodium hydroxide, triethyl amine or pyridine. 7. The process as claimed in claim 5, wherein said water immiscible solvent of step c) is selected from the group comprising of ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and mixture thereof. 8. The process as claimed in claim 1, wherein said compound of Formula III is used for the preparation of optically pure silodosin of Formula I.

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# Name Date
1 201611037060-Other Patent Document-171017-.pdf 2017-10-25
1 201611037060-Other Patent Document-281016.pdf 2016-11-02
2 201611037060-Form 2(Title Page)-171017.pdf 2017-10-24
2 201611037060-Form 5-281016.pdf 2016-11-02
3 201611037060-Form 26-281016.pdf 2016-11-02
3 201611037060-Form 26-171017.pdf 2017-10-24
4 201611037060-Form 3-171017.pdf 2017-10-24
4 201611037060-Form 2(Title Page)-281016.pdf 2016-11-02
5 201611037060-Form 5-171017.pdf 2017-10-24
5 201611037060-Form 1-281016.pdf 2016-11-02
6 201611037060-Power of Attorney-310717.pdf 2017-08-11
6 201611037060-Other Patent Document-171017.pdf 2017-10-24
7 201611037060-OTHERS-310717.pdf 2017-08-11
7 201611037060-Form 6-310717.pdf 2017-08-28
8 201611037060-Other Patent Document-310717.pdf 2017-08-11
8 201611037060-Form 1-310717.pdf 2017-08-11
9 201611037060-Form 2(Title Page)-310717.pdf 2017-08-11
9 201611037060-Form 5-310717.pdf 2017-08-11
10 201611037060-Form 2(Title Page)-310717.pdf 2017-08-11
10 201611037060-Form 5-310717.pdf 2017-08-11
11 201611037060-Form 1-310717.pdf 2017-08-11
11 201611037060-Other Patent Document-310717.pdf 2017-08-11
12 201611037060-Form 6-310717.pdf 2017-08-28
12 201611037060-OTHERS-310717.pdf 2017-08-11
13 201611037060-Other Patent Document-171017.pdf 2017-10-24
13 201611037060-Power of Attorney-310717.pdf 2017-08-11
14 201611037060-Form 1-281016.pdf 2016-11-02
14 201611037060-Form 5-171017.pdf 2017-10-24
15 201611037060-Form 2(Title Page)-281016.pdf 2016-11-02
15 201611037060-Form 3-171017.pdf 2017-10-24
16 201611037060-Form 26-171017.pdf 2017-10-24
16 201611037060-Form 26-281016.pdf 2016-11-02
17 201611037060-Form 2(Title Page)-171017.pdf 2017-10-24
17 201611037060-Form 5-281016.pdf 2016-11-02
18 201611037060-Other Patent Document-281016.pdf 2016-11-02
18 201611037060-Other Patent Document-171017-.pdf 2017-10-25