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Pharmaceutical Compositions Of Teriflunomide And Process For Preparation Thereof

Abstract: Pharmaceutical. compositions comprising a" pyn"midine synthesis inhibitof, process of preparation thereof and method of using the same are provided. Particularly the. present invention ‘relates to pharmaceutical compositions comprising téfiflunomide, process of preparation thereof and method to treat patients sufféring from autoimmune diseases in particular systemic lupus>erythematosus or graft-yersus-host diéease or rheumatoid arthritis or multiple sclerosis.

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Patent Information

Application #
Filing Date
15 December 2015
Publication Number
24/2017
Publication Type
INA
Invention Field
BIO-CHEMISTRY
Status
Email
Parent Application

Applicants

AUROBINDO PHARMA LIMITED
THE WATER MARK BUILDING, PLOT NO.11, SURVEY NO. 9, KONDAPUR , HITECH CITY, HYDERABAD - 500 084,

Inventors

1. SARAVANAN KANNUSAMY
AUROBINDO PHARMA LTD, THE WATER MARK BUILDING, PLOT NO.11, SURVEY NO. 9, KONDAPUR , HITECH CITY, HYDERABAD - 500 084,
2. SAMIR DAS
AUROBINDO PHARMA LTD, THE WATER MARK BUILDING, PLOT NO.11, SURVEY NO. 9, KONDAPUR , HITECH CITY, HYDERABAD - 500 084,
3. NALLA PRIYANKA
AUROBINDO PHARMA LTD, THE WATER MARK BUILDING, PLOT NO.11, SURVEY NO. 9, KONDAPUR , HITECH CITY, HYDERABAD - 500 084,
4. MEENAKSHISUNDERAM SIVAKUMARAN
AUROBINDO PHARMA LTD, THE WATER MARK BUILDING, PLOT NO.11, SURVEY NO. 9, KONDAPUR , HITECH CITY, HYDERABAD - 500 084,

Specification

FIELD OF THE INVENTION The present invention relates to pharmaceutical compositions comprising a pyrimidine synthesis inhibitor as active agent, process of preparation thereof and method of using the same. Particularly the present invention relates to pharmaceutical compositions comprising teriflunomide as active agent, process of preparation thereof and method to treat patients suffering from autoimmune diseases in particular systemic lupus erythematosus or graft-versus-host disease or rheumatoid arthritis or multiple sclerosis. BACKGROUND OF THE INVENTION Autoimmune diseases arise from an abnormal immune response of the body against substances and tissues normally present in the body (autoimmunity). There are as many as 80 types of autoimmune diseases. Many of them have similar symptoms, which makes them very difficult to diagnose. It's also possible to have more than one at the same time. Autoimmune diseases usually fluctuate between periods of remission (little or no symptoms) and flare-ups (worsening symptoms). Commonly known autoimmune diseases are Addison's disease, Celiac disease - sprue (gluten-sensitive enteropathy), Dermatomyositis, Graves's disease, Hashimoto's thyroiditis, Multiple sclerosis, Reactive arthritis, Rheumatoid arthritis, Sjogren syndrome, Systemic lupus erythematosus etc. Systemic lupus erythematosus is a systemic autoimmune disease (or autoimmune connective tissue disease) in which the body's immune system mistakenly attacks healthy tissue. The cause is believed to be an environmental trigger, which results in a misdirected immune response in people who are genetically susceptible. The treatment of SLE involves preventing flares and reducing their severity and duration when they occur. Treatment can include corticosteroids and anti-malarial drugs. Certain types of lupus nephritis such as diffuse proliferative glomerulonephritis require bouts of cytotoxic drugs. These drugs include cyclophosphamide and mycophenolate. Graft-versus-host disease (GvHD) is a common complication following an allogeneic tissue transplant. It is commonly associated with stem cell or bone marrow transplant but the term also applies to other forms of tissue graft. In the clinical setting, graft-versus-host-disease is g t'idlvidaSfhlB TSLCUtSdLndiM:¥hU ferM- The acufc'ol fSlmiSarit Jbfei of tffe'di§e£se (aGvHD) is normally observed within the first 100 days post-transplant, and is a major challenge to transplants owing to associated morbidity and mortality [Acute graft-vs-host disease Pathobiology and management". Experimental Hematology 29 (3): 259-77]'. Rheumatoid arthritis (RA) is a long lasting autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly the wrist and hands are involved with typically the same joints involved on both sides of the body. The disease may also affect other parts of the body. This may result in low red blood cells, inflammation around the lungs, and inflammation around the heart. Fever and low energy may also be present. Often symptoms come on gradually over weeks to months [Rheumatoid arthritis: diagnosis and management". Majithia et al. Am. J. Med. 120 (11): 936-9]. Multiple sclerosis (MS) is a chronic, progressive autoimmune disease that can lead to neurological impairment and long-term disability [Multiple sclerosis: pathogenesis and treatment. Curr Neuropharmacol 9:409-416], MS takes several forms, with new symptoms either occurring in isolated attacks (relapsing forms) or building up over time (progressive forms). Between attacks, symptoms may disappear completely; however, permanent neurological problems often occur, especially as the disease advances [Defining the clinical course of multiple sclerosis: results of an international survey. Goker et al. Neurology 46 (4): 907-11]'. There is no cure for multiple sclerosis. Treatment typically focuses on speeding recovery from attacks, slowing the progression of the disease and managing MS symptoms. Some people have such mild symptoms that no treatment is necessary. Teriflunomide is an oral de novo pyrimidine synthesis inhibitor which inhibits dihydroorotate dehydrogenase, a mitochondrial enzyme involved in de novo pyrimidine synthesis. The chemical name of teriflunomide is (Z)-2-Cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl)-amide. Its empirical formula is C12H9F3N2O2 and its molecular weight is 270.21. The chemical structure is: Teriflunomide is currently marketed as Aubagio® tablets and indicated for the treatment of patients with relapsing forms of multiple sclerosis. The tablet formulation contains 7 mg or 14 mg of teriflunomide. and the following inactive ingredients: lactose monohydrate, corn starch, hydroxypropyl cellulose, microcrystalline cellulose, sodium starch glycolate, and magnesium stearate. The film coating for the 14 mg tablet is made of hypromellose, titanium dioxide, talc, polyethylene glycol and indigo carmine aluminum lake. In addition to these, the 7 mg tablet film coating includes iron oxide yellow. US 5,679,709 patent discloses teriflunomide as the product. WO2011/004282 PCT publication discloses crystalline form I of Teriflunomide sodium with characteristic XRPD data. The said PCT publication further discloses Teriflunomide having particle size D50 less than about 20 jam, and D90 less than about 40 urn. WO2012/110911 PCT publication discloses crystalline form I of Teriflunomide with characteristic XRPD data. WO2015/029063 PCT publication discloses crystalline form M of Teriflunomide with characteristic XRPD and DSC data. US 8,802,735 patent claims an oral preparation comprising 1% to 30% w/w of Teriflunomide, or a pharmaceutical^ acceptable basic addition salt thereof, 5% to 20% w/w of disintegrant, 0% to 40% w/w binder, 0:1% to 2% w/w lubricant, and the remaining percentage comprising diluents; wherein the solid pharmaceutical composition does not contain colloidal silicon dioxide. Further, the said patent covers in other embodiments the pH of the solid pharmaceutical composition which is no more than about 2.2, The said patent publication discloses that during the stability studies of the solid pharmaceutical formulations prepared, it was observed that there was a strong increase in 2-cyano-N-(4-trifluoromethyl- phenyl)-acetamide (a degradant). Further, it was observed that at room temperature storage, 2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide levels of up to 0.2% was reached in the solid pharmaceutical formulation after 12 month storage (Teriflunomide 7 mg tablets, Al/PVC blisters, storage at 25. +-.2° C and 60% relative humidity [RH]). Thus, the major objective of the said patent publication was to provide a solid pharmaceutical formulation without the use ;t,;oFcofbiSa1 lilfelh dio:^ W^ disadvantages of increased concentrations, of 2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide or 4 trifluoromethyl-aniline (4-TFMA). The disclosure made in the prior art result in compositions that do not require the use o colloidal silicon dioxide which further decreases the content of 2-cyano-N-(4 trifluoromethyl-phenyl)-acetamide. Colloidal silicon dioxide is a commonly known glidan with small particle size and large surface area and used in the tablets to optimize the flov properties of powders. Use of colloidal silicon dioxide as a glidant thus would b< advantageous as it improves dosage uniformity and ultimately results in higher throughput Inventors of the instant invention with considerable expense of intellectual effort and carefu experimentation have developed stable, simple, easy-to-prepare, economical and comparabh compositions with regard to the marketed product Aubagio® wherein the composition: comprise teriflunomide with the effective use of colloidal silicon dioxide. Further, th< compositions of the . present invention contain an acceptable level of 2-cyano-N-(4 trifluoromethyl-phenyl)-acetamide (degradant) and thus alleviates the limitations of the prio; art described herein above. SUMMARY OF THE INVENTION An aspect of the present invention provides oral pharmaceutical compositions comprising « pyrimidine synthesis inhibitor as active agent, at least one glidant, optionally with one o more other pharmaceutically acceptable excipient(s). An aspect of the present invention provides oral pharmaceutical compositions comprising teriflunomide as active agent or pharmaceutically acceptable salts thereof, at least on< glidant, optionally with one or more other pharmaceutically acceptable excipient(s). An aspect of the present invention provides oral pharmaceutical compositions comprising teriflunomide as active agent or pharmaceutically acceptable salts thereof, at least one glidan selected from group comprising talc, colloidal silicon dioxide, calcium silicate, magnesiun silicate, silicon hydrogel, cornstarch, corn starch, DL-leucine and the like, optionally witl one or more other pharmaceutically acceptable excipient(s); An aspect of the present invention provides oral pharmaceutical compositions comprising teriflunomide as active agent, a glidant which is colloidal silicon dioxide, optionally with one or more other pharmaceutically acceptable excipient(s). An aspect of the present invention provides oral pharmaceutical compositions comprising teriflunomide as active agent from about 0.1% w/w to about 99% w/w of the composition, at least one glidant in an amount less than about 10% w/w of the composition, optionally with one or more other pharmaceutically acceptable excipient(s) from about 0% w/w to about 99% w/w of the composition. An aspect of the present invention provides oral pharmaceutical compositions comprising teriflunomide as active agent from about 0.1% w/w to about 99% w/w of the composition, colloidal silicon dioxide in an amount less than about 5% w/w of the composition, optionally with one or more other pharmaceutically acceptable excipient(s) from about 0% w/w to about 99%) w/w of the composition. In an aspect, the present invention provides process for the preparation of stable oral pharmaceutical compositions, wherein the process comprises of the following steps: (i) treating teriflunomide with at least one glidant, (ii) optionally adding one or more other pharmaceutically acceptable excipients, and (iii) formulating the material of step (ii) into a suitable dosage form. An aspect of the present invention relates to method of using the compositions of the present invention to treat patients suffering from autoimmune diseases in particular sepsis, allergy, graft-versus-host-reactions and host-versus-graft-reactions; autoimmune disease such as rheumatoid arthritis, systemic lupus erythematodes, multiple sclerosis, psoriasis, asthma, urticaria, rhinitis and uveitis; cancerous diseases such as lung cancer, leukemia, ovarian cancer, sarcoma, Kaposi's sarcoma, meningioma, intestinal cancer, lymph node cancer, brain tumours, breast cancer, pancreatic cancer, prostate cancer or skin cancer. DETAILED DESCRIPTION OF THE INVENTION The term "particle size" unless indicated otherwise in the specification relates to particles of £ Meliflufio%iM>fieSbas£a^ wAJ Ife.^lJarmaceutlcall^ aeceptabl&salt, amorpholisfer crystalline, anhydrous, esters, or isomer or derivative, hydrate, prodrug or solvates thereof. Teriflunomide with specific "particle size" and distribution, or surface area would provide a fast dissolution of the active ingredient, would be easy to prepare and stable while maintaining the beneficial properties with respect to fast solubility and bioavailability. Particularly, according to the present invention, Teriflunomide having an average particle size less than about 200 microns, and/or surface area less that about 5 m /gm are useful. The term "composition" or "pharmaceutical composition" or "dosage form" or "formulation" or "pharmaceutical composition", as used herein or otherwise, synonymously include solid dosage forms such as granules, multiunit particulate systems (MUPS), pellets, spheres, tablets, capsules, mini-tablets, layered tablets, beads, particles and the like; and liquid dosage forms such as solutions, suspensions, emulsions, colloids and the like, meant for oral administration. The term "excipient" means a pharmacologically inactive component such as a diluent, disintegrant, binder, lubricant, carrier, or the like. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for human pharmaceutical use. Reference to an excipient includes both one and more than one such excipient. "Colloidal silicon dioxide" is submicroscopic fumed silica, also known as pyrogenic silica. It is a non-crystalline, fine grain, low density and high surface area silica. Primary particle size is from 5 nm to 50 nm. The particles are non-porous and have a surface area ranging from 50m2/g to 600m2/g such as described in US patent 8802735 and which is incorporated by reference herein. The pH determination of the oral formulation is performed by suspending one tablet in about 1 ml of purified water. The pH of the supernatant is determined with a pH sensitive probe such as described in US patent 8802735 and is incorporated by reference herein. * "Degradant" refers to any drug-based materials generated after the preparation of the unit dosage form. Analysis of impurities and degradant is done using reverse phase HPLC techniques on extracted samples or techniques known to the person skilled in the art. The term "teriflunomide" unless indicated otherwise in the entire specification, refers to teriflunomide in its free base form, or as a pharmaceutically acceptable salt, amorphous or crystalline, anhydrous, esters, or isomer or derivative, hydrate, prodrug or solvates thereof. Preferably teriflunomide is in the form of base. The phrase "substantially pure polymorphic form of teriflunomide or its salt thereof, unless otherwise specified is to be understood as a substance free of other polymorphic and/or pseudopolymorphic forms at amounts detectable with typical analytical methods such as X-ray powder diffraction and/or solid state infrared absorption,, i.e. containing less than 10% of other polymorphic and/or pseudopolymorphic forms. The present invention provides oral pharmaceutical compositions comprising a pyrimidine synthesis inhibitor as active agent, at least one glidant, optionally with one or more other pharmaceutically acceptable excipient(s). In an embodiment, the present invention provides oral pharmaceutical compositions comprising teriflunomide as active agent, at least one glidant selected from group comprising talc, colloidal silicon dioxide, calcium silicate, magnesium silicate, silicon hydrogel, corn starch, DL-leucine and the like, optionally with one or more other pharmaceutically acceptable excipient(s). In one of the embodiments, the present invention provides oral pharmaceutical compositions comprising teriflunomide as active agent, a glidant which is colloidal silicon dioxide, optionally with one or more other pharmaceutically acceptable excipient(s). In an embodiment, the present invention provides oral pharmaceutical compositions comprising teriflunomide as active agent from about 0.1 % w/w to about 99% w/w of the composition, at least one glidant in an amount less than about 5% w/w of the composition, optionally with one or more other pharmaceutically acceptable excipient(s) from about 0% w/w to about 99% w/w of the composition. In yet another embodiment, the present invention provides oral pharmaceutical compositions . comprising teriflunomide as active agent from about 0.1% w/w to about 99% w/w of the composition, colloidal silicon dioxide in an amount less than about 5% w/w of the — L i -r- .-. i—. i—-. -r-. . J—■ rr- J~- I.I. rr*' k I .*..!■. i-i .1-. A. .1. .. -1. '-*.. .. ■-■...,->. A .--v .rs.. —r. _.. .■•>.. f*i composition, optionally with one or more other pharmaceutically acceptable excipient(s) from about 0% w/w to about 99% w/w of the composition. In a further embodiment, the present invention provides oral pharmaceutical compositions comprising teriflunomide as active agent, from about 0.1% w/w to about 99% w/w of the composition, colloidal silicon dioxide in an amount less than about 5% w/w of the composition, optionally with one or more other pharmaceutically acceptable' excipient(s) from about 0% w/w to about 99% w/w . of the composition and wherein the oral pharmaceutical composition contains no more than about 5% by weight of 2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide or no more than about 2% by weight of 2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide or no more than about 0.5% by weight of 2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide. In an embodiment, the present invention provides oral pharmaceutical compositions comprising teriflunomide as active agent from about 0.1 % w/w to about 99% w/w of the composition, colloidal silicon dioxide in an amount less than about 1.0% w/w of the composition, optionally with one or more other pharmaceutically acceptable excipient(s) from about 0% w/w to about 98.9% w/w of the composition and wherein the oral pharmaceutical composition shows a pH in a range from about 2 to about 8 or from about 2 to about 6. In one of the embodiments, the present invention provides oral pharmaceutical compositions comprising teriflunomide as active agent, a glidant, and an acidic compound.. In another embodiment, the present invention provides pharmaceutical compositions comprising teriflunomide having an average particle size of about 1 urn to about 500 urn or about 1 jim to about 200 urn or about 1 \im to about 100 urn. In an embodiment, the present invention provides process for the preparation of oral pharmaceutical compositions, wherein the process comprises of the following steps: (i) treating teriflunomide with glidant, (ii) optionally adding one or more other pharmaceutically acceptable excipient(s), and (iii) formulating the material of step (ii) into a suitable dosage form. As used herein, unless indicated otherwise, references to total weight of the .pharmaceutical composition refers to the total weight of the active agent(s) and pharmaceutically acceptable excipient(s). "Pharmaceutically acceptable excipient(s)" are components that are added to the pharmaceutical formulation other than the active ingredient teriflunomide. Excipients may be added to facilitate manufacture, enhance stability, enhance product characteristics, enhance bioavailability, enhance patient acceptability, etc. Pharmaceutically acceptable excipient(s) includes, but not limited to, one or more of diluents/fillers, binders, disintegrants, lubricants, glidants, compression aids, colors, sweeteners, preservatives, surfactants, suspending agents, dispersing agents, film formers, flavors, printing inks, and any other excipient known to the art for making pharmaceutical formulations. It will be appreciated by the person skilled in the art that a particular excipient may perform multiple roles in the pharmaceutical composition, such as for example, it can act as both a binder and filler, or as a binder and filler and disintegrant. Binders hold the ingredients in the composition together. Exemplary binders according to the present invention are selected from, but not limited to, cellulose and its derivatives including, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose, povidone, starches such as corn starch, potato starch, modified . starches, sugars, guar gum, pectin, wax binders, methylcellulose, carboxymethylcellulose, hydroxyethyl cellulose, copolyvidone, carboxymethylcellulose sodium, ethyl cellulose, gelatin, liquid glucose and pregelatinized starch, polyvinyl pyrrolidone, sodium alginate, acacia, alginic acid, tragacanth, xanthan, and the like used either alone or in combinations thereof. The binder may be used in the range of about 0.5-10% by weight of the composition. Diluents increase the bulk of the composition. Diluents according to the present invention are selected from but not limited to group comprising lactose, sucrose, dextrose, mannose, fructose, galactose; sugar alcohols such as sorbitol, mannitol, erythritol, xylitol, lactitol, . starlac, starch, modified starches, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, calcium sulfate, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, magnesium carbonate, magnesium oxide, magnesium alumino metasilicate and the like used either alone or in combinations thereof. The diluent may be £ Miiled iStSrra^leIf aooulW$W$\3/ weignt o^the c©rhp3sli^nP 1 7' ■" Q"&" Disintegrants according to the present invention are selected from but not limited to group comprising cellulose and its derivatives including low-substituted hydroxypropyl cellulose; cross-linked polyvinylpyrrolidone; sodium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, calcium carboxy methylcellulose, microcrystalline cellulose; sodium starch glycolate; ion-exchange resins; starch and modified starches including pregelatinized starch; formalin-casein; used either alone or in combinations comprising one or more of the foregoing disintegrants. In an embodiment, the disintegrant may be used in the range of about 1 -20% by weight of the composition. Lubricants and glidants aid in the processing of powder materials. Exemplary lubricants are selected from, but not limited to, calcium stearate, glycerol behenate, magnesium stearate, mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, vegetable oil, and zinc stearate, used either alone or in combinations comprising one or more of the foregoing lubricants. Exemplary glidants include, but not limited to talc, colloidal silicon dioxide, calcium silicate, magnesium silicate, silicon hydrogel, corn starch, DL-leucine and the like used either alone or in combination thereof. Surfactants are compounds which are capable of improving the wetting of the drug and/or enhancing the dissolution. The surfactants can be selected from hydrophilic surfactants or lipophilic surfactants or mixtures thereof. The surfactants can be anionic, nonionic, cationic, and zwitterionic surfactants. Surfactants according to the present invention are selected from, but not limited to, polyoxyethylene alkylaryl ethers such as polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether; polyethylene glycol (PEG) fatty acid esters such as PEG monolaurate, PEG dilaurate, PEG distearate, PEG dioleate; polyoxyethylene sorbitan fatty acid ester such as polysorbate 40, polysorbate 60, polysorbate 80; sorbitan fatty acid mono esters such as sorbitan monolaurate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, polyoxyethylene castor oil derivates such as polyoxyl castor oil, polyoxyl hydrogenated castor oil, sodium lauryl sulphate and the like, used either alone or in combination thereof. Acidic compound according to the present invention is selected from a group comprising citric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, ascorbic acid, maleic acid, £ ?;,lifdro9>feia1eIc^aiid, £enWid';^i

Documents

Application Documents

# Name Date
1 6917-CHE-2015-Other Patent Document-151215.pdf 2016-02-02
1 Correspondence By Applicant_Form3_27-03-2017.pdf 2017-03-27
2 Form3_After Filing_27-03-2017.pdf 2017-03-27
2 6917-CHE-2015-Form 2(Title Page)-151215.pdf 2016-02-02
3 Amended Claims_As Filed_02-01-2017.pdf 2017-01-02
3 6917-CHE-2015-Form 1-151215.pdf 2016-02-02
4 Correspondence by Applicant_Form2 Form5_02-01-2017.pdf 2017-01-02
4 Form5_As Filed_14-12-2016.pdf 2016-12-14
5 Form5_After Filing_02-01-2017.pdf 2017-01-02
5 Form2 Title Page_Complete_14-12-2016.pdf 2016-12-14
6 Description Complete_As Filed_14-12-2016.pdf 2016-12-14
6 Abstract_As Filed_14-12-2016.pdf 2016-12-14
7 Correspondence by Agent_CS After PS_14-12-2016.pdf 2016-12-14
7 Claims_As Filed_14-12-2016.pdf 2016-12-14
8 Correspondence by Agent_CS After PS_14-12-2016.pdf 2016-12-14
8 Claims_As Filed_14-12-2016.pdf 2016-12-14
9 Description Complete_As Filed_14-12-2016.pdf 2016-12-14
9 Abstract_As Filed_14-12-2016.pdf 2016-12-14
10 Form2 Title Page_Complete_14-12-2016.pdf 2016-12-14
10 Form5_After Filing_02-01-2017.pdf 2017-01-02
11 Correspondence by Applicant_Form2 Form5_02-01-2017.pdf 2017-01-02
11 Form5_As Filed_14-12-2016.pdf 2016-12-14
12 Amended Claims_As Filed_02-01-2017.pdf 2017-01-02
12 6917-CHE-2015-Form 1-151215.pdf 2016-02-02
13 Form3_After Filing_27-03-2017.pdf 2017-03-27
13 6917-CHE-2015-Form 2(Title Page)-151215.pdf 2016-02-02
14 Correspondence By Applicant_Form3_27-03-2017.pdf 2017-03-27
14 6917-CHE-2015-Other Patent Document-151215.pdf 2016-02-02