Title of Invention

A HEMOSTAT TO PROVIDE AND MAINTAIN EFFECTIVE HEMOSTASIS

Abstract

This invention relaters to a hemostat to provide and maintain effective hemostasis, comprising an absorbable foam, an absorbable woven or knitted fabric, and thrombin and/or fibrinogen, wherein the foam comprises carboxymethyl cellulose and albumin, the ratio of carboxymethyl cellulose to the albumin ranges from about 1:8 to 8:1 by weight, wherein the absorbable woven or knitted fabric preferably comprises oxidized regenerated cellulose and may have a basis weight ranging from about 0.001 to 0.2 g/in2, and wherein the thrombin activity on the hemostat ranges from about 20 to 500 IU/cm2, and/or the fibrinogen activity ranges from about 2 to 15 mg/cm2.

Full Text

FIELD OF THE INVENTION The present invention relates to a hemostat. BACKGROUND OF THE INVENTION The control of bleeding, as well as sealing of air and various bodily fluids, is essential and critical in surgical procedures to minimize blood loss, to seal tissue and organ structures, to reduce post-surgical complications, and to shorten the duration of the surgery in the operating room. In an effort to provide dressings with enhanced hemostatic and tissue sealing and adhering properties, therapeutic agents, including, but not limited to, thrombin, fibrin and fibrinogen have been combined with dressing carriers or substrates, including gelatin-based carriers, polysaccharide-based carriers, glycolic acid or lactic acid-based carriers and a collagen matrix. Examples of such dressings are disclosed in USP 6,762,336, USP 6,733,774 and PCT publication WO 2004/064878 A1. Due to its biodegradability and its bactericidal, tissue sealing, tissue repairing, drug delivering and hemostatic properties, it is desirable to utilize cellulose that has been oxidized to contain carboxylic acid moieties, hereinafter referred to as carboxylic- oxidized cellulose, as a topical dressing in a variety of surgical procedures, including neurosurgery, abdominal surgery, cardiovascular surgery, thoracic surgery, head and neck surgery, pelvic surgery and skin and subcutaneous tissue procedures. However, when carboxylic-oxidized cellulose is utilized in combination with thrombin and/or fibrinogen, the acidic moieties that may be present in the cellulose denature the activity of the thrombin and/or fibrinogen. Therefore, it is desirable to shield the thrombin and/or fibrinogen from such acid moieties to maintain their hemostatic activities. SUMMARY OF THE INVENTION The present invention is directed towards a hemostat comprising an absorbable foam, an absorbable woven or knitted fabric, thrombin and/or fibrinogen. DETAILED DESCRIPTION OF THE INVENTION The hemostat described herein provides and maintains effective hemostasis when applied to a wound requiring hemostasis. Effective hemostasis, as used herein, is the ability to control and/or abate capillary, venous, or arteriole bleeding within an effective time, as recognized by those skilled in the art of hemostasis. Further indications of effective hemostasis may be provided by governmental regulatory standards and the like. In certain embodiments, hemostats of the present invention are effective in providing and maintaining hemostasis in cases of severe or brisk bleeding. As used herein, severe bleeding is meant to include those cases of bleeding where a relatively high volume of blood is lost at a relatively high rate. Examples of severe bleeding include, without limitation, bleeding due to arterial puncture, liver resection, blunt liver trauma, blunt spleen trauma, aortic aneurysm, bleeding from patients with over- anticoagulation, or bleeding from patients with coagulopathies, such as hemophilia. The hemostat generally comprises an absorbable foam and a reinforcement fabric. The reinforcement fabric provides a backing to which the foam may be attached, either directly or indirectly, wherein thrombin and/or fibrinogen may be substantially homogeneously dispersed throughout the foam and / or disposed on the surface of the foam. The reinforcement fabric provides strength to the hemostat sufficient to permit the user to place and manipulate the hemostat on or within a wound or directly onto tissue of a patient requiring hemostasis, or tissue sealing and adhering. In embodiments where the foam is directly attached to the reinforcement fabric, fibrinogen may be substantially homogeneously dispersed throughout the foam and/or disposed on the surface of the foam. Alternatively, thrombin may be disposed on the surface of the foam. In embodiments where the foam is indirectly attached to the reinforcement fabric, fibrinogen and/or thrombin may be substantially homogeneously dispersed throughout the foam and or disposed on the surface of the foam. In addition to serving as a carrier for the thrombin and/or fibrinogen, the foam also serves to shield the thrombin and/or fibrinogen from acidic moieties that may be present in the reinforcement fabric, such as is the case where carboxylic-oxidized cellulose is used as the reinforcement fabric. The foam may be a biocompatible, water-soluble, or water-swellable polymer and optionally a foaming agent/surfactant. Preferred biocompatible, water-soluble, or water-swellable polymers used to fabricate the foam include polysaccharides. Such polysaccharides include, without limitation, cellulose, alkyl cellulose, e.g. methylcellulose, alkylhydroxyalkyl cellulose, hydroxyalkyl cellulose, cellulose sulfate, salts of carboxymethyl cellulose, carboxymethyl cellulose, and carboxyethyl cellulose. Additionally, albumin, chitin, carboxymethyl chitin, hyaluronic acid, salts of hyaluronic acid, alginate, alginic acid, propylene glycol alginate, glycogen, dextran, dextran sulfate, curdlan, pectin, pullulan, xanthan, chondroitin, chondroitin sulfates, carboxymethyl dextran, carboxymethyl chitosan, chitosan, heparin, heparin sulfate, heparan, heparan sulfate, dermatan sulfate, keratan sulfate, carrageenans, chitosan, starch, amylose, amylopectin, poly-N-glucosamine, polymannuronic acid, polyglucuronic acid polyguluronic acid, and derivatives of any of the above, may be utilized. Even more preferably, biocompatible, water-soluble, or water-swellable polymers are an alkali or alkali earth metal salts of carboxylmethyl cellulose, most preferably sodium carboxylmethyl cellulose (CMC-Na). The foaming agent/surfactant may be a cationic, anionic, amphoteric, zwitterionic or nonionic surfactant, or natural or modified proteins, including but without limitation, albumin, sodium lauryl sulfate, sodium laureth sulfate, or ammonia lauryl sulfate. A preferred foaming agent/surfactant is albumin, and more preferably, human serum albumin (HSA). The reinforcement fabric is an absorbable woven or knitted fabric and comprises oxidized polysaccharides, in particular oxidized cellulose and the neutralized derivatives thereof. For example, the cellulose may be carboxylic-oxidized or aldehyde-oxidized cellulose. More preferably, oxidized regenerated polysaccharides, including but without limitation oxidized regenerated cellulose, may be used to prepare the absorbable woven or knitted fabric. Regenerated cellulose is preferred due to its higher degree of uniformity versus cellulose that has not been regenerated. Regenerated cellulose and a detailed description of how to make oxidized regenerated cellulose are set forth in USP 3,364,200, USP 5,180,398 and USP 4,626,253, the contents each of which is hereby incorporated by reference as if set forth in its entirety. Examples of fabrics that may be utilized as the reinforcement fabric include, but are not limited to, Interceed® absorbable adhesion barrier, Surgicel® absorbable hemostat, Surgicel Nu-Knit® absorbable hemostat and Surgicel® Fibrillar absorbable hemostat (each available from Johnson & Johnson Wound Management Worldwide or Gynecare Worldwide, each a division of Ethicon, Inc., Somerville, New Jersey). The reinforcement fabric utilized in the present invention may be woven or knitted, provided that the fabric possesses the physical properties necessary for use in contemplated applications. Such fabrics, for example, are described in USP 4,626,253, USP 5,002,551 and USP 5,007,916, the contents of which are hereby incorporated by reference herein as if set forth in its entirety. In preferred embodiments, the reinforcement fabric is a warp knitted tricot fabric constructed of bright rayon yarn that is subsequently oxidized to include carboxyl or aldehyde moieties in amounts effective to provide the fabrics with biodegradability. In an alternative embodiment, the reinforcement fabric comprises oxidized polysaccharide fibers in combination with fibers comprised of aliphatic polyester polymers, copolymers, or blends thereof. Aliphatic polyester polymers include, but are not limited to homopolymers and copolymers of lactide (which includes lactic acid, D-, L- and meso lactide), glycolide (including glycolic acid), epsilon-caprolactone, p-dioxanone (l,4-dioxan-2-one), trimethylene carbonate (1, 3-dioxan-2-one), alkyl derivatives of trimethylene carbonate, delta-valerolactone, beta-butyrolactone, gamma-butyrolactone, epsilon- decalactone, hydroxybutyrate (repeating units), hydroxyvalerate (repeating units), l,4-dioxepan-2- one (including its dimer 1,5, 8,12-tetraoxacyclotetradecane-7,14-dione), 1,5-dioxepan- 2-one, 6,6-dimethyl-1, 4-dioxan-2-one 2,5-diketomorpholine, pivalolactone, alpha, alpha- diethylpropiolactone, ethylene carbonate, ethylene oxalate, 3-methyl-1,4- dioxane-2,5-dione, 3,3-diethyl-1,4-dioxan-2,5-dione, 6,8- dioxabicycloctane-7- one and polymer blends thereof. The reinforcement fabric preferably comprises oxidized regenerated cellulose and may have a basis weight ranging from about 0.001 to 0.2 g/in2, preferably in the range of about 0.01 to 0.1 g/in2, and most preferably in the range of about 0.04 to 0.07 g/in2. In preparing the hemostats, a foam slurry may be prepared from, for example, CMC-Na and HSA, and then spread on the surface of, for example, an oxidized regenerated cellulose fabric. The ratio of the water-soluble or water-swellable polymer to the foaming agent may range from about 1:8 to 8:1 by weight, and preferably from about 2:1 to 1:2 by weight. The foam slurry is then dried either by lyophilization or in an oven at elevated temperature to form a solid foam substrate. The foam substrate may be treated with a chemical cross-1inking agent such as glutaraldehyde for increased strength or may be partly cross-1inked by heating. The density of the hemostat may be from about 5 to 20 mg/cm3. The thrombin and/or fibrinogen may be animal derived, preferably human, or may be recombinant. The thrombin activity on the hemostat may be in the range of about 20 to 500 IU/cm2, preferably about 20 to 200 IU/cm2, and most preferably about 50 to 200 IU/cm2. The fibrinogen activity on the hemostat may be in the range of about 2 to 15 mg/cm2, preferably about 3 to 10 mg/cm2, and most preferably about 4 to 7 mg/cm2. Thrombin powders may be prepared by lyophilization of thrombin solutions. Fibrinogen may be prepared by lyophilizaton of solutions containing fibrinogen, such as those described in USP 6,121,232 and PCT Application Publication No. WO 02/095019. Dry powders of fibrinogen and thrombin suspended in an organic solvent such as PF5060 or HFE 7000—7300 series are then sprayed onto the surface of the foam. Alternatively, the thrombin and/or fibrinogen may be incorporated into the foam during the foam production. In an alternate embodiment, the hemostat may comprise a first foam having incorporated thereon or therein a first therapeutic agent, e.g., fibrinogen, and a second foam separate (unattached) from the first foam that may have upon or incorporated therein powders of a second therapeutic agent, e.g. thrombin. In an alternative embodiment, a hemostat may comprise a reinforcement fabric having a first foam adjacent thereto and second foam on the other side of the first foam. Fibrinogen may be incorporated into or onto the first foam. While either thrombin or fibrinogen may be incorporated into or onto the second foam, thrombin is preferred. In such an embodiment, the foam slurries used to prepare the first and second foams are selected such that the second foam is less dense than the first foam so that it liquefies or melts quickly after coming into contact with blood at the wound site to start the clotting process. The second foam contacts the bleeding site first, then the combined reinforcing layer and first foam keeps the clot from being washed away by the blood flow. In another alternative embodiment, the hemostat may comprise a foam having incorporated thereon or therein thrombin and/or fibrinogen, a nonwoven, and a reinforcement fabric wherein the foam is indirectly attached to the reinforcement fabric via the nonwoven. The nonwoven may be comprised of aliphatic polyester fibers such as those described herein. The hemostat comprising a foam having incorporated thereon or therein thrombin and/or fibrinogen, a nonwoven, and a reinforcement fabric wherein the foam is indirectly attached to the reinforcement fabric via the nonwoven may be prepared in the following manner. A nonwoven comprising a copolymer of lactide and glycolide is needlepunched to the oxidized regenerated cellulose reinforcement fabric. An aqueous solution of about 0.2 to about 1.5% hyaluronic acid and thrombin is prepared. The aqueous solution is then spread upon the surface of the nonwoven such that it partially penetrates the nonwoven. The solution layer is foamed by lyophilization. The nonwoven is made by processes other than spinning, weaving or knitting. For example, the nonwoven may be prepared from yarn, scrims, netting, fibers or filaments that have been made by processes that include spinning, weaving or knitting. The yarn, scrims, netting fibers and/or filaments are crimped to enhance entanglement with each other. Such crimped yarn, scrims, netting fibers and/or filaments may then be cut into staple that is long enough to entangle. The staple may be carded to create nonwoven bats, which may be then needlepunched or calendared. Additionally, the staple may be kinked or piled. Other methods known for the production of nonwovens may be utilized and include such processes as air laying, wet forming and stitch bonding. The hemostat may optionally include without limitation, procoagulant enzymes, proteins and peptides, may be naturally occurring, recombinant, or synthetic, and may be selected from the group consisting of prothrombin, fibrin, fibronectin, heparinase, Factor X/Xa, Factor VII/VIIa, Factor IX/IXa, Factor XI/XIa, Factor XII/XIIa, tissue factor, batroxobin, ancrod, ecarin, von Willebrand Factor, collagen, elastin, albumin, gelatin, platelet surface glycoproteins, vasopressin and vasopressin analogs, epinephrine, selectin, procoagulant venom, plasminogen activator inhibitor, platelet activating agents, synthetic peptides having hemostatic activity, derivatives of the above and any combination thereof. The hemostat described herein may also be used as an adjunct to primary wound closure devices, such as arterial closure devices, staples, and sutures, to seal potential leaks of gasses, liquids, or solids as well as to provide hemostasis. For example, the hemostat may be utilized to seal air from tissue or fluids from organs and tissues, including but not limited to, bile, lymph, cerebrospinal fluids, gastrointestinal fluids, interstitial fluids and urine. The hemostat described herein has additional medical applications and may be used for a variety of clinical functions, including but not limited to tissue reienforcement and buttressing, i.e., for gastrointestinal or vascular anastomoses, approximation, i.e., to connect anastomoses that are difficult to perform (i.e. under tension), and tension releasing. The hemostat may additionally promote and possibly enhance the natural tissue healing process in all the above events. This hemostat can be used internally in many types of surgery, including, but not limited to, cardiovascular, peripheral-vascular, cardio-thoracic, gynecological, neuro- and general surgery. The hemostat may also be used to attach medical devices (e.g. meshes, clips and films) to tissues, tissue to tissue, or medical device to medical device. Example 1. Lyophilized CMC-Na/ HSA foam with ORC fabric In a mixing bowl were added 190 mL of a 2% solution of sodium carboxy methylcellulose (CMC-Na) (Aqualon, catalog No. 7M8SFPH) and 10 mL of a 20% solution of human serum albumin (HSA) (ALBUTEIN™, Alpha Therapeutic Corporation). The mixture was whipped mechanically to generate a foamed slurry. The foamed slurry was transferred to a rectangular frame having a piece of knitted carboxylic-oxidized regenerated cellulose fabric, available from Ethicon, Inc. under the tradename Interceed®, disposed at the bottom. The foamed slurry was then spread evenly across the whole frame to yield a thickness of about 3 mm. The foamed slurry was then lyophilized to remove solvent, thus yielding a solid CMC-Na/HSA foam adjacent and attached to the ORC fabric. Example 2. Heat-treated CMC-Na/ HSA foam with ORC fabric In a mixing bowl were added 190 mL of 2% solution of sodium carboxy methylcellulose (CMC-Na) (Aqualon, catalog No. 7M8SFPH) and 10 mL of 20% solution of human serum albumin (HSA) (ALBUTEIN™, Alpha Therapeutic Corporation). The mixture was whipped mechanically to generate a foamed slurry. The foamed slurry was transferred to a rectangular frame having a piece of carboxylic- oxidized regenerated cellulose fabric, available from Ethicon, Inc. under the tradename Interceed®, at the bottom. The foamed slurry was then spread evenly across the whole frame to yield a thickness of about 3 mm. The foamed slurry was then heated in an oven at 65°C for an hour to remove solvent and thus yielded a solid CMC-Na/HSA foam adjacent and attached to the ORC fabric. Example 3. Reinforced Foams with active clotting factors Hemostatic agents were applied to the constructs prepared in Examples 1 and 2 as below. The constructs were cut into 3" x 4" pieces. Lyophilized thrombin and Biological Active Components 2 (BAC-2) containing fibrinogen were ground to powder separately. The thrombin powder and the BAC-2 powder were passed through a 45-micrometer sieve. The two powders were weighed to provide a final fibrinogen concentration of 6 mg/cm2, 7 mg/cm2 or 8 mg/cm2, and a thrombin activity of 50 IU/cm2. The powders were then mixed and suspended in a per-fluorinated solvent HFE 7000 in a flask. The suspension then was sprayed onto the various constructs and then dried under nitrogen at room temperature for 1 hour. Example 4. Hemostasis test in a swine spleen linear incision model Linear incisions (1.5 cm long and 0.3 cm deep) were made on a swine spleen. After spraying the wound with 0.9% saline solution, various test materials from Example 3 were applied to the wounds. Tamponade was applied for 30 seconds followed by a 30-second observation. When hemostasis was not achieved, additional tamponade was applied to stop the bleeding. A piece of surgical gauze and a commercial product Tachocomb® surgical patch (commercially available from Nycomed Pharma GmbH) were used as controls. Table 1 lists the experimental results. Example 5. CMC-Na/HSA foam with thrombin In a mixing bowl were added 190 mL of a 2% solution of sodium carboxy methylcellulose (CMC-Na) (Aqualon, catalog No. 7M8SFPH) and 10 mL of a 20% solution of human serum albumin (HSA) (ALBUTEIN™, Alpha Therapeutic Corporation). The mixture was whipped mechanically to generate a foamed slurry. A portion of the foamed slurry was transferred to a glass beaker. Thrombin powder was folded into the foamed slurry to yield an estimated activity of 1,000 IU/cm3. The final mixture was lyophilized in aluminum weighing dishes with a height of 0.5 cm to form a solid foam comprising the thrombin dispersed therethrough. Example 6. CMC-Na/HSA foam with fibrinogen In a mixing bowl were added 190 mL of 2% solution of sodium carboxy methylcellulose (CMC-Na) (Aqualon, catalog No. 7M8SFPH) and 10 mL of 20% solution of human serum albumin (HSA) (ALBUTEIN™, Alpha Therapeutic Corporation). The mixture was whipped mechanically to generate a foamed slurry. A portion of the foamed slurry was transferred to a glass beaker. Five grams of fibrinogen powder was folded into the foam. The final mixture was placed in an aluminum weighing dish with a height of 0.5 cm and a having a piece of ORC fabric at the bottom. The foamed slurry then was lyophilized to form a solid foam comprising the fibrinogen dispersed therethrough. Example 7. Hemostasis test with CMC-Na/HSA/Thrombin foam and CMC- Na/HSA/Fibrinogen foam A severe bleeding wound was made on a swine liver. The defect was created by making a triangular cut with a surgical scalpel. Each side measured about 1 inch and the depth measured 5mm. After the triangular liver tissue was removed, CMC- Na/HSA/Thrombin foam (1" x 1") was quickly applied to the wound. A piece of CMC- Na/HSA/Fibrinogen foam was then applied on top of the thrombin foam followed by manual compression. Hemostasis was achieved in 2 minutes. WE CLAIM 1. A hemostat to provide and maintain effective hemostasis, comprising an absorbable foam, an absorbable woven or knitted fabric, and thrombin and/or fibrinogen, wherein the foam comprises carboxymethyl cellulose and albumin, the ratio of carboxymethyl cellulose to the albumin ranges from about 1:8 to 8:1 by weight, wherein the absorbable woven or knitted fabric preferably comprises oxidized regenerated cellulose and may have a basis weight ranging from about 0.001 to 0.2 g/in2, and wherein the thrombin activity on the hemostat ranges from about 20 to 500 IU/cm2, and/or the fibrinogen activity ranges from about 2 to 15 mg/cm2. 2. The hemostat as claimed in claim 1, wherein the foam comprises one or more polymers selected from the group consisting of polysaccharides, albumin, chitin, carboxymethyl chitin, hyaluronic acid, salts of hyaluronic acid, alginate, alginic acid, propylene glycol alginate, glycogen, dextran, dextran sulfate, curdlan, pectin, pullulan, xanthan, chondroitin, chondroitin sulfates, carboxymethyl dextran, carboxymethyl chitosan, chitosan, heparin, heparin sulfate, heparan, heparan sulfate, dermatan sulfate, keratin sulfate, carrageenans, chitosan, starch, amylose, amylopectin, poly-N-glucosamine, polymannuronic acid, polyglucuronic acid polyguluronic acid, and derivatives of any of the above. 3. The hemostat as claimed in claim 2, wherein the foam comprises a polysaccharide selected from the group consisting of methylcellulose, alkylhydroxyalkyl cellulose, hydroxyalkyl cellulose, cellulose sulfate, salts of carboxymethyl cellulose, carboxymethyl cellulose, carboxyethyl cellulose. 4. The hemostat as claimed in claim 1, wherein the absorbable woven or knitted fabric comprises oxidized regenerated cellulose, and the thrombin and/or fibrinogen are incorporated into or sprayed onto the foam. 5. The hemostat as claimed in claim 2, wherein the foam comprises hyaluronic acid or salts thereof and thrombin and/or fibrinogen is incorporated into the foam. 6. The hemostat as claimed in any one of claims 1 to 5, wherein the hemostat is sterilized. 7. The hemostat as claimed in claim 6, wherein the hemostat is sterilized by electron beam sterilization to a sterility assurance level of 10-6 with an absorbed dose from 4 to 25 kGy. ABSTRACT TITLE : "A HEMOSTAT TO PROVIDE AND MAINTAIN EFFECTIVE HEMOSTASIS" This invention relaters to a hemostat to provide and maintain effective hemostasis, comprising an absorbable foam, an absorbable woven or knitted fabric, and thrombin and/or fibrinogen, wherein the foam comprises carboxymethyl cellulose and albumin, the ratio of carboxymethyl cellulose to the albumin ranges from about 1:8 to 8:1 by weight, wherein the absorbable woven or knitted fabric preferably comprises oxidized regenerated cellulose and may have a basis weight ranging from about 0.001 to 0.2 g/in2, and wherein the thrombin activity on the hemostat ranges from about 20 to 500 IU/cm2, and/or the fibrinogen activity ranges from about 2 to 15 mg/cm2.

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01338-kolnp-2007-abstract.pdf

01338-kolnp-2007-claims1.0.pdf

01338-kolnp-2007-claims1.1.pdf

01338-kolnp-2007-correspondence others 1.1.pdf

01338-kolnp-2007-correspondence others.pdf

01338-kolnp-2007-description complete.pdf

01338-kolnp-2007-form 1.pdf

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01338-kolnp-2007-international publication.pdf

01338-kolnp-2007-international search report.pdf

1338-KOLNP-2007-(27-01-2012)-ABSTRACT.pdf

1338-KOLNP-2007-(27-01-2012)-AMANDED CLAIMS.pdf

1338-KOLNP-2007-(27-01-2012)-CORRESPONDENCE.pdf

1338-KOLNP-2007-(27-01-2012)-DESCRIPTION (COMPLETE).pdf

1338-KOLNP-2007-(27-01-2012)-FORM 1.pdf

1338-KOLNP-2007-(27-01-2012)-FORM 2.pdf

1338-KOLNP-2007-(27-01-2012)-PA.pdf

1338-KOLnp-2007-ABSTRACT 1.1.pdf

1338-KOLnp-2007-AMANDED CLAIMS.pdf

1338-KOLNP-2007-ASSIGNMENT.pdf

1338-KOLNP-2007-CORRESPONDENCE 1.1.pdf

1338-KOLNP-2007-CORRESPONDENCE.pdf

1338-KOLnp-2007-DESCRIPTION (COMPLETE) 1.1.pdf

1338-KOLnp-2007-EXAMINATION REPORT REPLY RECIEVED.pdf

1338-KOLNP-2007-EXAMINATION REPORT.pdf

1338-KOLnp-2007-FORM 1-1.1.pdf

1338-KOLNP-2007-FORM 18 1.1.pdf

1338-kolnp-2007-form 18.pdf

1338-KOLnp-2007-FORM 2-1.1.pdf

1338-KOLNP-2007-FORM 26.pdf

1338-KOLNP-2007-FORM 3 1.1.pdf

1338-KOLnp-2007-FORM 3-1.1.pdf

1338-KOLNP-2007-FORM 5.pdf

1338-KOLNP-2007-GRANTED-ABSTRACT.pdf

1338-KOLNP-2007-GRANTED-CLAIMS.pdf

1338-KOLNP-2007-GRANTED-DESCRIPTION (COMPLETE).pdf

1338-KOLNP-2007-GRANTED-FORM 1.pdf

1338-KOLNP-2007-GRANTED-FORM 2.pdf

1338-KOLNP-2007-GRANTED-SPECIFICATION.pdf

1338-KOLNP-2007-INTENATIONAL PUBLICATION.pdf

1338-KOLnp-2007-OTHERS 1.1.pdf

1338-KOLNP-2007-PETITION UNDER RULE 137.pdf

1338-KOLNP-2007-PETITION UNDER RULR 137-1.1.pdf

1338-KOLNP-2007-REPLY TO EXAMINATION REPORT.pdf