Title of Invention

A METHOD FOR THE PRODUCTION OF A BIOLOGICALLY ACTIVE PROSTHETIC DEVICE FOR THE RECONSTRUCTION OF BONE TISSUE AND THE PROSTHETIC DEVICE ITSELF

Abstract

The invention relates to a method for the production of a biologically active prosthetic device for the reconstruction of bone tissue comprising the steps of a CAT (Computerized Axial Tomography) scan of the patient and obtaining a three-dimensional electronic mode] (1) of the part of the bone and of a bone defect (2) to be reconstructed, production by prototyping of a prototype resin mode] (3) of the area of the patient s bone involved, forming of a model (4), of the patient s bone defect to be reconstructed, construction of a netative mould (5), production of a ready sintered ceramic semi-finished product with controlled and interconnected porosity, said semi-finished product being made with dimensions and shape slightly larger than the bone defect mechanical processing and manna] finishing of the sintered semi-finished product, to obtain the precise dimensions and shape of the bone defect, the invention also relating to the prosthetic device obtained using the method described above.

Full Text

WO 2005/094730 PCT/TB2005/000852 1 A method for- the production of a biologica-lly actave pr-osthetxc device for the reconstructaon of bone tissue azid the prosthetic device itself The present invention relates to a method for the production of a biologically active prosthetic device for the reconstruction of bone tissue and the prosthetic device itself. More specifically , the method according to the present invention involves obtaining a made to measure prosthetic device identical to a bone defect or lacuna to be filled m a patient, and which is made of a biologically active material, that is to say, a Ca/P-based ceramic synthesis material (calcium phosphate material, i.e.: stoichiometric hydroxyapatite; non-stoichiometnc hydroxyapatite: carbonated hydroxyapatite (mainly ^ of type B) ; hydroxyapatite enriched with magnesium or fluoride or with strontium or sodium; carbonated hydioxyapatite enriched with magnesium; hydroxyapatire/p tricalcium phosphate in proportions of 50% - 50%, 70% - 30%, 30% - 70%; alpha-tricalcium phosphate (ccTCB) r beta-tricalcium phosphate (f3TCP) ; misiures of alpha-tricalcium WO 2005/094730 PCT/TB2005/000852 2 phosphate (ctTCP) and beta-tri calcium phosphate (jSTCP) with predetermined and interconnected porosity m the 30 - 90% range with bimodal distribution of the dimensions of the pores m the 0.1 - 125 microns and 125 - 2500 microns range The- prosthetic device according to the present invention is obtained with a new production technology and is used for a new bone reconstruction technique. Having achieved the primary objective of saving the patient's life, in its latest scientific and technological evolution, surgery aims in its most advanced area of development to improve the patient's quality of life, making the surgical solutions adopted more acceptable for the patient m functional and aesthetic terms. It is currently possible to carry out operations substituting both hard tissue and very extensive tissue In parallel, biotechnologies, with great progress made in molecular biology, have undergone enormous growth particularly in the last decade. Genetic engineering and prosthetic engineering were a driving force behind research and development of new systems for the production of medical devices, WO 2005/094730 PCT/O32O05/0O0852 3 m terms of both materials and components, to allow clinical solutions whose size and quality are suitable for the individual, specific patient and are the main driving forces m the field of biomedical research for this type of clinical applications. At present in the reconstruction of lacunae in bones, such as parts of the cranium, maxillofacial zones or parts of long bones (for example the femur) , parts of bone are used which are taken from the patient (autologous transplant) or from other persons (heterologous transplant) or artificial materials such as: metals (gold, steel, titanium, tantalum) in the form of plates or meshes or in elongated form, polymers (Nylon, Polyethylene), cements (PMMA polymethyl methacrylate) and porous bio-ceramic materials, for example ceratite and hydroxyapatite. Each of these materials has pros and cons, but as a whole porous bio-ceramic materials have some important advantages. the possibility of practically unlimited supplies, unlike transplants using biological materials (autologous or heterologous bone) xn which the bone to be used must be taken from the patient or a donor, the fact WO 2005/094730 PCT/IB2005/000852 4 chat they are biologically active materials and so promote bone regeneration, and the quality of being recognised as inorganic material not alien to the patient and so free of the problems of rejection. There are basically two types of surgical reconstruction techniques: manual modelling during an operation of the prosthetic device which must be implanted and must fill the lacuna in the bone, or it is possible to implant a prosthetic device already produced and modelled to size for the specific lacuna m the patient's bone before the operation. The fact that a prosthetic device to be substituted is already ready with the shape and dimensions made to measure for the patient's lacuna makes the surgery much faster and simpler, however, the production of a prosthetic device with shape and dimensions already suitable for the patient's specific lacuna involves difficulties, and the current technique for the production of these devices does not yen give satisfactory results when the above-mentioned bio-ceramic materials are used More precisely, due to I the intrinsic characteristics and porosity of tne above- WO 2005/094730 PCT/IB2005/00085; 5 mentioned bio-ceramic materials, when a substitute part for a lacuna in a bone is slip cast using bio-ceraraic material,, it is difficult to obtain a part with the allocated shape and dimensions. In particular,- it is difficult to obtain a part which precisely substitutes a lacuna m a bone to be filled because the above-mentioned bio-ceramic materials are subject to variations m shape and size retraction during both drying after slip casting and after firing. One aim of the present invention is to present an improved method for the production of a prosthetic device for the reconstruction of bone tissue with size and shape characteristics identical to the section of bone missing from the patient without the need for adaptations during insertion of the prosthetic device. Another aim of the present invention is to present an improved method for the production of a prosthetic device for the reconstruction of bone tissue which is made of biologically active material with a controlled-porosity ceramic component In accordance with one aspect of the present WO 2005/094730 PCT/DB2005/000852 6 invention, a method xs proposed for the production of a prosthetic device for the reconstruction of bone tissue as specified m claim 1 Yet another aim of the present invention is the production of a prosthetic device made of biologically active material with a ceramic component having controlled and interconnected porosity m the 30 - 90% range, with bimodal distribution of the dimensions of the pores, m the 0.1 - 125 microns and 125 - 2500 microns ^ range, and with bioactivity characteristics, through the osreoconductive properties of the Ca/P-based material, able to contribute to bone regeneration" mechanisms, so as to promote the laying down and regrowth of bone tissue In accordance with another aspect of the present invention, a prosthetic device is proposed which is made of biologically active material with a porous structure as specified in claim 8. The dependent claims refer to preferred and advantageous embodiments of the invention. Embodiments of the present invention, shown by way of example only and without limiting the scope of the invention, are described .below with WO 2005/094730 PCT/TB2005/000852 7 reference to the accompanying drawingsr m which. - Figure 1 illustrates a computer model of a patient's cranium m which there is a lacuna in the bone, - Figures 2 and 3 illustrate a resin model obtained from the computer model shown in the previous figure, - Figures 4 and 5 illustrate two successive steps of the method m accordance with rhe present invention; - Figure 6 is a cross-section of the cranium illustrated m the previous figures during the step relative to Figure 5; - Figure 7 illustrates another application of the present invention relative to long bones, for example a femur, m particular illustrating a patient's femur with a missing central part; - Figure 8 illustrates the femur shown m the previous figure with a prosthetic device m accordance with the present invention, - Figure 9 is a front view of a computer model of the femur illustrated m the previous figures with the central part missing (a lacuna m the bone) and a control mould for a prosthetic WO 2005/094730 PCT/3B2005/000852 8 device, and Figure 10 is a cross-section of the mould illustrated m the previous figure The method for the production of a prosthetic device for the reconstruction of bone tissue m accordance with ihe invention basically comprises the following steps 1 CAT (Computerised Axial Tomography) scan of the patient and creation of a CAT file representing the three-dimensional electronic model 1 (Figures 1 and 7) of the part of the bone and the bone defect 2 to be reconstructed, 2. based on the data obtained from the CAT (Computerised Axial Tomography) scan of the patient and the CAT file, ^rapid main and interface software system controlled prototyping is used to create a prototype resin model 3 (Figures 2, 3 and 9) of the area of the patient's bone involved, for example the model 3 may be obtained using the three-dimensional stereolithographic technique, 3. this resin prototype is used to make, with slip casting forming technology, the model 4 (in calcium sulphate, resins or silicone rubbers) of the patient's bone defect to be reconstructed; 4. the model m the previous point is used to WO 2005/094730 PCT/EB2005/000852 9 make a mould 5 (Figures 5, 6, 9 and 10) out of calcium sulphate, resins or silicone rubbers which is a negative of the patient's bone defect, again using slip casting forming technology. To obtain this mould a kind of barrier 6 (Figures 5 and 6) or a containment mould 7 (Figure 9} is made using suitable material (for example clay, plasticine or modelling paste) around the bone defect 2 area. The mould 5 made of calcium sulphate, resins or silicons rubbers is then slip cast in this barrier 6 (or containment mould 7) and will serve as a control for the shape and dimensions of the prosthetic device. For said control, the mould 5 has means 8 (Figures 6 and 9) able to detect any points of contact between the semi-finished product and the mould 5. These means 8 may be, for example a coating of tracing paper which can be coloured at points of contact; 5. production of a semi-f mashed product (not illustrated) already sintered, with controlled and interconnected porosity (30 - 90%) having pore dimensions m the 0 1 - 125 microns and 125 - 2500 microns range made of Ca/P-based biologically active ceramic materials. These materials may be the material described m Italian patent IT-1 307 WO 2005/094730 PCT/EB2005/0008S2 10 292 or the material described in the application for a European patent EF-1 411 035 (and in the corresponding application for an Italian patent BO2002A000650). During this step the semi-finished product is made with dimensions larger than and shapes close to those of the model of the patient's bone defect, 6. mechanical processing and manual finishing of the sintered semi-finished product with comrolled and interconnected porosity (30 - 90%) with bimodal distribution of the dimensions of the pores in the 0 1 - 125 microns and 125 - 2500 microns range r made of Ca/P-based ceramic material using as a shape and size comparator the negative mould of the patientr s bone defect (point 4)r to obtain a finished ceramic component corresponding to the patient' s bone defect to be filled, mechanical processing and finishing are carried out by-removing excess material with diamond milling cutters; 7. the final check of the finished ceramic component, that is to say, the prosthetic device 9 (Figure 8), m terms of dimensions and shape, is carried our directly on the resin model of the area of the patient's bone involved - made m point 2 - WO 2005/094730 PCT/EB2O05/OOO852 11 and usang the negative mould 6 or 7 obtained an poxnt 4. It should be noticed that the mechanical processing for removal of material which allows obtainment of the dimensions and shape of the prosthetic device which must fill the bone defect is necessary because Ca/P-based porous ceramic material cannot: - be slip cast directly with the shape and dimensions required because it is subject to retraction and variations in shape which cannot be foreseen. Therefore, a part must be made of porous ceramic material which is close to but slightly larger than the required shape and dimensions of_ the bone defect to be reconstructed The shape and precise dimensions of the prosthetic device 9 will then be achieved by means of successive approximations by manually removing material with diamond milling cutters which turn at high speed. Removal of material must be manual because porous ceramic material does not withstand mechanical processing by machine tools, for example, those of the numeric control type, since it would break. Manual processing to remove material is essential because only an expert operator has the sensitivity "WO 2005/094730 PCT/OB20O5/OOO852 12 required to avoid breaking the ceramic material. The check to ensure that the shape and precise dimensions of the prosthetic device 9 have been achieved takes place as indicated above with successive checks on the resin model 3 and with the aid of the control mould 5 and the means S able to detect any points of contact between the semifinished product and the mould 5 The prosthetic device disclosed is characterised m particular by the following aspects: the shape and dimensions derive from a model of the area of the patient's bone involved, the model^ being obtained using rapid prototyping technology; its structure has a predetermined and interconnected porosity (30 - 90%) with bimodal distribution of the dimensions of the pores m the 0 1- 125 microns and 125 - 2500 microns range, and is made of Ca/P^based ceramic synthesis material (Hydroxyapatite, Tricalcium Phosphate or mixtures of them) using technologies for the impregnation/imbibition of porous supports (cellulose, polyurethane, resin), gel-casting, low pressure injection moulding. The production process flow refers to the following steps WO 2005/094730 PCT/EB2005/000852 13 - CAT scan of the panent and creation of the CAT file (Figure 1); - reading of the CAT file and check of the extent of the bone defect; - production of the model of the area of the patient's bone involved using resin with rapid prototyping (Figures 2 and 3), - production of the model of the bone defect using calcium sulphate,- resins or silicone rubbers {Figure 4); - production of a negative mould of the bone defect using calcium sulphate, resins or silicone rubbers (Figures 5 and 6), - production of a sintered semi-finished product w3,th dimensions greater than and shape similar to the bone defect, having controlled and interconnected porosity (30 - 90%) with pore dimensions m the 0 1 - 125 microns and 125 - 2500 microns range, using Ca/P-based ceramic material; - mechanical processing for removal of material and finishing of the porous ceramic component, - check of the size and shape of the porous ceramic component on rhe resin model of the area of nhe bone involved and wirh the negative of the bone defect; O 2005/094730 PCT/ZB20 05/000852 14 washing, drying and packaging of the porous ceramic component, - sterilisation with gamma rays The materials which can be used to make the prosthetic device disclosed are: stoichiometric hydroxyapatitef non-stoichiometric hydroxyapatite carbonated hydroxyapatite (mainly °f_ type B); hydroxyapatite enriched with magnesium or fluoride or with strontium or sodium, carbonated hydroxyapatite enriched with magnesium; hydroxyapatite/(3 tricalcium phosphate in proportions of 50% - 50%, 70% - 30%, 30% - 70%, alpha-tncalcium phosphate (ctTCP) ; beta-tricalcium phosphate (pTCP), mixtures of alpha-tricalcium phosphate (aTCP) and beta-tricalcium phosphate (J3TCP), finally more specifically the materials mentioned above and forming the subj ect matter of patents IT-1 307 292 and EP-1 411 035 (and the corresponding application for an Italian patent BO2002A000650) The following is a description of several examples of applications of the invention, provided by way of example only and without limiting the scope of the invention In a first example, the made to measure prosthetic PCT/DS2005/000852 WO 2005/094730 15 cievj.ce has the following application: reconstruction of extensive sections of the cranial theca (neurosurgery) . Accidents involving head trauma have become particularly frequent m recent years proportional with the increase m road traffic, accidents at the workplace or during leisure time. Serious head traumas often involve brain function, which takes priority over other lesions, whose future preservation becomes the neurosurgeon's priority. A second cause may be skin tumours or rejection phenomena following the use of other materials, for which the treatment requires surgical removal as a last resort In all of these cases the surgical treatment is based on the removal of extensive sections of bone tissue with consequent primary problems of brain safety and, second in order of priority, aesthetic impla cations. To solve and overcome these clinical problems, for reconstruction of the cranial theca a prosthetic device was produced, which forms the subject matter of the present invention, "made to measure" and identical to the lacuna m the bone to be filled, using hydroxyapatite with controlled and WO 2005/094730 PCT/TB2005/000852 16 interconnected porosity (45 - 65%) with objective clinical evidence showing immediate advantages, from an aesthetic viewpoint, but above all m terms of bn ©compatibility,, which other materials cannot fully guarantee The surgical technique, not innovative in itself, involves detachment pf tissues from the edge of the defect and insertion of the made to measure prosthesis by slotting into place, fixing it with simple wiring thanks to the holes m the "made to measure" prosthesis In a second example, the made to measure prosthetic device has the following application lifting the buccal cavity (dental surgery). Loss of the upper back teeth often leads to vertical bony atrophy of the alveolar ridge to a certain extent, such that titanium implants cannot be inserted. Today, it is already possible to successfully -lift the buccal cavity by means of bone graft according to the Caldewell - Luc technique, but insertion of implants in a single step cannot also be guaranteed. Therefore, m these cases the buccal cavity lift is normally done first, using autologous or homologous bone, then insertion of the implants after 6 WO 2005/094730 PCT/DB2005/000852 17 months. However, observing biological principles, it as possible to use "made to measure prostheses" made of hydroxyapatite with controlled and interconnected porosity (40 - 60%) which allow immediate insertion of the titanium implant, at the same time allowing clotting and its transformation into bone The clinical example involved the use of a prosthetic device disclosed, "made to measure" using hydroxyapatite with controlled and interconnected porosity (40 - 60%) which made it possible to insert the titanium implants in a single step, thus achieving a primary stability that would otherwise be difficult. The surgical technique, also not innovative in itself, involves opening of the buccal caviry from the side and insertion of the made to measure prosthesis in the space obtained. In a third example, the made to measure prosthetic device has the following application ceramic support (scaffold) on which staminal cells can be "sown" for repairing long bones (orthopaedic surgery, maxillofacial surgery) Progress in knowledge of cellular biology and WO 2005/094730 PCT/IB2005/000852 18 improvements in culture techniques make it possible to imagine and m some cases achieve in vitro reconstruction of skeletal tissues able to substitute sick ones. In the specific case for this application a pre-shaped device was produced using hydroxyapatite with controlled and interconnected p6rosity (55 -8 5 %) modelled, with the same design and production criteria as the previous examples, in the dimensions and shape of the sick bone to be substituted and able to be attached to the staminal cells previously taken from the patient's bone marrow then expanded m vitro With this system, hydroxyapatite with controlled and interconnected porosity is used as a ^scaffold" in which the staminal cells (expanded m vitro) are placed. Once they make contact wi-ch the ceramic support, the staminal cells start proliferating, becoming different and generating new bone tissue. The next step, as in the other cases, consists of surgically replacing the sick or damaged bone with this synthetic - organic bone Again, the operating technique, nor innovative in itself, involves substitution of the damaged section with a made to measure prostnesis (to which the autologous WO 2005/094730 PCT/DB2005/000852 19 staminal cells were previously added) secured by a Kirsh thxead or by wiring. The positive results of these transplants are guaranteed by the use of a synthetic material (Ca/P compounds such as- stoichiometric hydroxyapatite, non-stoichiometnc hydrostyapatite, carbonated hydroxyapatite, doped hydroxyapatites, tricalcium phosphate or mixtures of them) chemically similar to the inorganic component of the bone tissue and of cells which the immune system recognises as its own With the passage of tune (several months) the "device" surgically inserted is slowly transformed into bone, binding perfectly with the surrounding tissue This material constitutes, by the interconnections of the channels, the ideal foundation for allowing the growth of bone tissue inside it, since it acts as a vascular support for the newly formed tissue, also promoting bone mineralisation for the specific dimensions of the pores The part of the bone missing is substituted by an identical segment of bone perfectly similar to the part removed, but made synthetically in a laboratory and no longer removed from other individuals. WO 2005/094730 PCT7EB2005/000852 20 Moreover, another advantage of the bone device disclosed is that it may form a support (scaffold) for the connection to it of cells and/or growth factors in order to create an osteomductive effect and/or a support for "drug release" with which drugs ana/or chemotherapeutic substances can be associated in medical or oncological therapies In the case of flat bones (like those of the cranium) the preferred material is a ceramic of the type described m Italian patent IT-1 307 292, that is to say, a ceramic material with less porosity and greater mechanical strength. In the case of long bones (for example the femur) the preferred material is a ceramic of the rype described in the application for a European patent EP-1 411 035 (and in the corresponding application for an Italian patent BO2002A000650) , that is to say, a ceramic material with greater porosity which acts as a scaffold for bone restructuring. The invention described is subject to modifications and variations without thereby departing from the scope of the inventive concept as described m the claims. WO 2005/094730 PCT/IB2005/000852 21 ClajLjns 1) A method for the production of a biologically active prosthetic device for the reconstruction of bone tissue, comprising the following steps CAT (Computerised Axial Tomography) scan of the patient and obtaining a three-dimensional electronic model (1) of the part of the bone and of a bone defect (2) to be reconstructed; creation through prototyping of a prototype resin model (3) of the area of the patient's bone involved, for example using the three-dimensional stereolithographic technique, forming of a model (4) r for example by means of ^slip casting" forming, of the patient's bone defect (2) to be reconstructed, construction of a negative mould (5) , for example using ^slip casting" forming, of the patient's bone defect (2) to be reconstructed, production of a ready sintered ceramic semifinished product with controlled and interconnected porosity (30 - 90%) with pore dimensions m the 0.1 - 125 microns and 125 - 2500 microns range; WO 2005/094730 PCT/TB2005/000852 22 the method being characterised m that the semifinished product obtained by the previous step has dimensions and shape nearing xn excess the ones of the bone defect (2)r and m that it comprises step of mechanical processing and manual finishing of the sintered semi-finished product to obtain the precise dimensions and shape of the bone defect (2). 2) The method for the production of a prosthetic device according to claim 1, characterised m that the mechanical processing and manual finishing are carried out by removing excess material using diamond milling cutters which turn at high speed 3) The method for the production of a prosthetic device according to claim 1 or 2T characterised in that the negative mould (5) of the patient' s bone defect comprises means (8) able to detect any points of contact between the semi-fmished product and the mould (5). 4) The method for the production of a prosthetic device according to claim 3, characterised m that the means (8) able to detect any points of contact WO 2005/094730 PCT/IB20 05/000852 23 between the semi-finished product and the mould (5) comprise a coating of tracing paper which can be coloured at points of contact. i 5) The method for the production of a prosthetic device according to any of the foregoing claims, characterised in that the material used to make it is a Ca/P compound-based biologically active ceramic material. 6) The method for the production of a prosthetic device according to any of the foregoing claims, characterised m that the material used to make the device is a ceramic material selected from the group consisting of: stoichiometric hydroxyapatite, non-stoichiometric hydroxyapatite: carbonated hydroxyapatite (mainly of type B) ; hydroxyapatite enriched wirh magnesium or fluoride or with strontium or sodium; carbonated hydroxyapatite enriched with magnesium, hydroxyapatite/£ tricalcium phosphate m proportions of 50% - 50%, 70% - 30%, 30% - 70%; alpha-tricalcium phosphate (cxTCP) r betaJtricalcium phosphate (pTCP); mixtures of alpha-tncalcium phosphate (aTCP) and beta-tricalcium phosphare (pTCP)r the hydroxyapauite- WO 2005/094730 PCT/TB2005/0008S2 24 based material which forms the subject matter of patent IT-1 307 292r and the hydroxyapatite-based material which forms the subject mater of patent EP-1 411 035 (and the corresponding application for an Italian patent BO2002A000650). 7) The method for the production of a prosthetic device according to any of the foregoing claims r characterised m that it comprises a step of final checking of the prosthetic device component, in terms of dimensions and shape, the check being carried out on the resin model of the area of the patient's bone involved and using the negative mould (6 or 7). 8) A biologically active prosthetic device for the reconstruction of bone tissue obtained according to the method m any of the foregoing claims, characterised m that the shape and dimensions derive from a model of the area of the patient's bone involved, said model being obtained using rapid prototyping technology, for example stereolithography, and also characterised m that it has a structure with predetermined and interconnected porosity (30 - 90%) with bunodal WO 2005/094730 PCT/DB2005/000852 25 distribution of the dimensions of the pores m the 0 1 - 125 microns and 125 - 2500 microns range, being made of Ca/P-based ceramic synthesis material using technologies for the impregnation/imbibition of porous supports (cellulose, polyurethane, resm) r gel-casting, low pressure injection moulding. 9) The prosthetic device according to claim 8, characterised in that it is made of a ceramic material selected from the group consisting of. stoichiometric hydroxyapatite, non-stoichiometric hydroxyapatite carbonated hydroxyapatite (mainly of type B), hydroxyapatite enriched with magnesium or fluoride or with strontium or sodium, carbonated hydroxyapatite enriched with magnesium; hydroxyapatite/b tricalcium phosphate in proportions o'f 50% - 50%, 70% - 30%r 30% - 70%, alpha-tricalcium phosphate (aTCP); beta-tricalcium phosphate (fJTCP) ; mixtures of alpha-tricalcium phosphate (rcTCP) and beta-tncalcium phosphate (|3TCP) r the hydroxyapatite-based material which forms the subject matter of parent IT-1 307 292, and the hydroxyapatite-based material which forms the subject matter of patent EP-1 411 035 (and the W0 2005/094730 PCT/IB2005/000852 26 corresponding application for an Iralian patent BO2002A000650). 10) The prosthetic device according to claim 8 or 9, characterised in that it constitutes a support (scaffold) for the attachment of cells and/or growth factors in order to create an osteoinductive effect and/or a support for "drug release" with which drugs and/or chemotherapeutic substances maybe associated m medical or oncological therapies.

Documents:

02895-kolnp-2006 abstract.pdf

02895-kolnp-2006 claims.pdf

02895-kolnp-2006 correspondenc others.pdf

02895-kolnp-2006 description(complete).pdf

02895-kolnp-2006 drawings.pdf

02895-kolnp-2006 form1.pdf

02895-kolnp-2006 form3.pdf

02895-kolnp-2006 form5.pdf

02895-kolnp-2006 international publication.pdf

02895-kolnp-2006 international search authority report.pdf

02895-kolnp-2006 pctform.pdf

02895.-kolnp-2006-correspondence others-1.1.pdf

02895.-kolnp-2006-form-3-1.1.pdf

02895.-kolnp-2006-gpa.pdf

2895-KOLNP-2006-(04-03-2014)-ABSTRACT.pdf

2895-KOLNP-2006-(04-03-2014)-CLAIMS.pdf

2895-KOLNP-2006-(04-03-2014)-CORRESPONDENCE.pdf

2895-KOLNP-2006-(04-03-2014)-DRAWINGS.pdf

2895-KOLNP-2006-(04-03-2014)-FORM-13.pdf

2895-KOLNP-2006-(10-12-2013)-CORRESPONDENCE.pdf

2895-KOLNP-2006-(12-02-2013)-ABSTRACT.pdf

2895-KOLNP-2006-(12-02-2013)-ANNEXURE TO FORM-3.pdf

2895-KOLNP-2006-(12-02-2013)-CLAIMS.pdf

2895-KOLNP-2006-(12-02-2013)-CORRESPONDENCE.pdf

2895-KOLNP-2006-(12-02-2013)-DESCRIPTION (COMPLETE).pdf

2895-KOLNP-2006-(12-02-2013)-DRAWINGS.pdf

2895-KOLNP-2006-(12-02-2013)-FORM-1.pdf

2895-KOLNP-2006-(12-02-2013)-FORM-13.pdf

2895-KOLNP-2006-(12-02-2013)-FORM-2.pdf

2895-KOLNP-2006-(12-02-2013)-OTHERS.pdf

2895-KOLNP-2006-(12-02-2013)-PA.pdf

2895-KOLNP-2006-(12-02-2013)-PETITION UNDER RULE 137.pdf

2895-KOLNP-2006-CORRESPONDENCE.pdf

2895-kolnp-2006-form 18.pdf

2895-KOLNP-2006-FORM 3.1.1.pdf

abstract-02895-kolnp-2006.jpg