(19)
(11)EP 2 760 493 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
22.07.2020 Bulletin 2020/30

(21)Application number: 12780263.5

(22)Date of filing:  01.10.2012
(51)International Patent Classification (IPC): 
A61L 31/00(2006.01)
A61L 31/08(2006.01)
A61L 31/18(2006.01)
A61L 31/02(2006.01)
A61L 31/14(2006.01)
(86)International application number:
PCT/GB2012/052429
(87)International publication number:
WO 2013/045956 (04.04.2013 Gazette  2013/14)

(54)

BIOSORBABLE ENDOPROSTHESIS

BIORESORBIERBARE ENDOPROTHESE

ENDOPROTHÈSE BIORÉSORBABLE


(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

(30)Priority: 30.09.2011 GB 201116879

(43)Date of publication of application:
06.08.2014 Bulletin 2014/32

(73)Proprietor: Magnus Flow Limited
London WC1R 4AG (GB)

(72)Inventors:
  • MARTIN, John Francis
    London N8 8RJ (GB)
  • MATHUR, Anthony
    London N8 8RJ (GB)

(74)Representative: Potter Clarkson 
The Belgrave Centre Talbot Street
Nottingham NG1 5GG
Nottingham NG1 5GG (GB)


(56)References cited: : 
WO-A2-2004/093643
WO-A2-2008/034050
WO-A2-2008/034030
WO-A2-2010/145842
  
  • MANGUAL J O ET AL: "Biodegradable nanocomposite magnetite stent for implant-assisted magnetic drug targeting", JOURNAL OF MAGNETISM AND MAGNETIC MATERIALS, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 322, no. 20, 1 October 2010 (2010-10-01), pages 3094-3100, XP027135544, ISSN: 0304-8853 [retrieved on 2010-05-25]
  • SCHINHAMMER M ET AL: "Design strategy for biodegradable Fe-based alloys for medical applications", ACTA BIOMATERIALIA, ELSEVIER, AMSTERDAM, NL, vol. 6, no. 5, 1 May 2010 (2010-05-01), pages 1705-1713, XP027039391, ISSN: 1742-7061 [retrieved on 2009-08-03]
  • PISLARU S V ET AL: "Magnetically Targeted Endothelial Cell Localization in Stented Vessels", JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, ELSEVIER, NEW YORK, NY, US, vol. 48, no. 9, 7 November 2006 (2006-11-07), pages 1839-1845, XP028006442, ISSN: 0735-1097, DOI: 10.1016/J.JACC.2006.06.069 [retrieved on 2006-11-07]
  
Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


Description

Field of the Invention



[0001] This invention relates to a kit comprising a biosorbable magnetisable endoprosthesis and magnetisable cells capable of repairing an artery in particular a kit comprising coronary stents for use in therapy.

Background of the Invention



[0002] Cardiovascular disease is the largest cause of death in the UK. This condition is characterised by a disease process called atherosclerosis, which is a thickening and hardening of the coronary arteries supplying blood to the heart. This often leads to chest pain (partial obstruction of blood flow) or a heart attack (a complete obstruction of blood flow, which is fatal in 50% of cases). Obstructive narrowing due to atherosclerosis can be relieved by 'ballooning' open the narrowing and inserting a stainless steel scaffold (coronary artery stent, which may also be used to stent other 'tubes' in the body) to prevent the narrowing from returning. This procedure, termed percutaneous angioplasty and stent insertion, is performed under local anaesthetic, and is considered routine in the treatment of people with heart disease.

[0003] After angioplasty and stent insertions, narrowing of the coronary arteries returns in up to 30% of people. This process, i.e. restenosis, occurs within the stent itself. As part of the body's natural healing process, a functional endothelial layer is formed over the stent. This may be a relatively slow process, however, and can allow scar tissue to build up over the stent (restenosis). Various methods have been used to try to reduce this complication. The emergence of drug-eluting stents (coated with an anti-cancer agent) has dramatically reduced the incidence of in-stent restenosis. This therapy interferes with the natural healing response by preventing, the "scarring" process around the stent and therefore delays restenosis. Although more expensive than conventional stents, the improvement in long-term outcome leads to a reduction in overall costs in certain patients. However, this delay in healing can also lead to the formation of blood clots within the stent. This can completely stop blood supply and cause a heart attack.

[0004] Recently, the existence of circulating endothelial progenitor cells (EPCs) has been identified as a key factor for re-endothelialisation. While delaying the formation of a functional endothelial layer may prevent restenosis (as the formation of scar tissue is also delayed), the early establishment of a functional endothelial layer after vascular injury has been shown to assist in the prevention of neointimal proliferation (restenosis process) and thrombus formation (blood clot). As the endothelial layer is formed quickly, there is no time for significant scar tissue to form over the stent.

[0005] WO03/065881 discloses antibody-coated stents. These attract EPC cells and promote the formation of a functional endothelial lining. However, an antibody is not necessarily specific, and it may react with other cells as well as its environment. A non-specific effect may be observed and the efficiency of the system is unclear.

[0006] Polyak et al., PNAS 2007, 105, 698-703, discloses the concept of targeting endothelial cells to a magnetic stent. The stent must be in the presence of a magnetic field in order to be magnetised (paramagnetic). Once magnetised, the stent attracts magnetised bovine aortic endothelial cells, promoting healing of the blood vessel into which it has been inserted.

[0007] Biosorbable stents have also been used to repair arteries after angioplasty. Examples of biosorbable stents are stents made from a magnesium alloy or polymers such as polylactic acid. Biosorbable stents are popular as they overcome problems of stent size mismatch, and can prevent lumen expansion. A feature of biosorbable stents is that they are difficult to visualise using X-rays. This can make stent placement difficult. However, it also means that these stents can be used with MRI scans. This is a unique feature of biosorbable stents.

[0008] WO2008/034030 discloses a magnetised bioerodible endoprosthesis. The endoprosthesis (which is a stent) has a magnetised portion to aid stent placement and a separate bioerodible portion for drug elution. The stent, in its entirety, is not bioerodible.

[0009] Although bioerodible stents are useful, they are not very effective at preventing restenosis, which can and does occur before the stent has degraded. PISLARU S V ET AL: "Magnetically Targeted Endothelial Cell Localization in Stented Vessels", JOURNAL OF THE AMERICAN COLLEGE OF CARIOLOGY, ELSEVIER, NEW YORK, NY, US, vol 48, no.9, 7 November 2006 (2006-11-07), pages 1839-1845, XP028006442, DOI: 10.1016/J.JACC.2006.06.069 relates to a method of magnetically localising endothelial cells to the site of a stent, which is composed of stainless steel coated with nickel.

Summary of the Invention



[0010] Biosorbable endoprostheses are not very efficient at preventing restenosis. The present invention overcomes this problem by providing a kit comprising an endoprosthesis, which is both biosorbable and magnetisable and magnetisable cells capable of repairing an artery. Such materials were not previously thought to exist. This allows the endoprosthesis to attract magnetisable cells capable of repairing an artery.

[0011] According to a first aspect, the present invention is a kit comprising a biosorbable magnetisable endoprosthesis comprising a magnesium alloy; wherein a portion of the endoprosthesis can be absorbed by the body, such that the structural integrity of the endoprosthesis is lost between 6 and 12 months after placement in the body; wherein the endoprosthesis further comprises magnetic particles comprising iron, within a biosorbable material comprising a biosorbable polymer, and magnetisable cells capable of repairing an artery.

[0012] According to a second aspect, the kit as defined above is useful in therapy.

Description of Preferred Embodiments



[0013] The endoprosthesis may be a stent or similar prostheses. Preferably, the endoprosthesis is a stent.

[0014] The endoprosthesis of the invention is magnetisable, which allows it to attract magnetisable cells to its surface.

[0015] The endoprosthesis is biosorbable. Suitable biosorbable materials from which the endoprosthesis may be constructed are magnesium alloys, polymers including polylactones, and iron alloys. Preferably, the entire endoprosthesis is magnetisable and/or biosorbable. A material which is both magnetisable and biosorbable is an iron alloy. Alternatively, the endoprosthesis comprises separate biosorbable and magnetised portions.

[0016] At least a portion of the endoprosthesis can be absorbed by the body, such that structural integrity of the stent is lost between 6 and 12 months after placement of the stent in the body. By loss of structural integrity, it is meant that the original shape of the stent is lost. The stent may not have been completely absorbed by the body by the time structural integrity has been lost. In a preferred embodiment, at least 30% of the stent has been absorbed between 6 and 12 months after placement in the body. More preferably, that figure is at least 40%, 50%, 60%, 70%, 80% or 90%. It is believed that this allows optimum regeneration of the artery. Before being completely absorbed by the body, the magnetic properties of the endoprosthesis allow it to attract certain cells, to aid in the formation of a functional endothelium and prevent restenosis.

[0017] Biosorbable endoprostheses are known in the art. A known biosorbable endoprosthesis can be magnetised according to the description herein, to form a biosorbable magnetisable stent according to the invention. In a preferred embodiment, a stent is absorbed between 6 to 12 months after placement in the body. The skilled person is able to choose a suitable material and/or thickness of the material in order to achieve this.

[0018] An example of a biosorbable stent that can be used in the invention is disclosed in US 2012/0143318.

[0019] In a preferred embodiment, an endoprosthesis is made from a metallic material comprising a magnesium alloy consisting of at least 96% w/w of magnesium, at least 1% w/w, of manganese and at least 0.5% w/w of at least one metal of the rare earth group.

[0020] Preferably, rare earth metals in this context are scandium, yttrium and lanthanum as well as the elements of the periodic table of elements following lanthanum, i.e. so-called lanthanides. These elements are in particular cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium and lutetium, with preference being given to cerium.

[0021] According to the invention the metallic material of the implants may consist of solid structures, lattice structures, wire or fabric structures as well as of metal foam or porous metal.

[0022] Spongy or porous structures offer advantages in that they permit a higher resorption speed, with the existing pores being conducive to the ingrowth of the body's own tissue. This allows the use of magnesium sponge bodies as placeholders, for example for the treatment of fractures and to augment bone or other tissue of the body.

[0023] The structure and strength of the metallic material used for the inventive implants are adapted to suit their placement site and purpose, for instance as far as their mechanical properties and/or use as drug delivery systems are concerned.

[0024] The implants proposed by the present invention may consist altogether or partly of such a resorbable metallic material. Aside from the inventive resorbable metallic material such materials may be other resorbable or non-resorbable metallic or non-metallic materials. Such further components may in particular also be plastic materials consisting of a resorbable substance, for example a polylactide or polyglycolide.

[0025] Resorbable plastic materials of this nature are often used for the purpose of coating stents. Moreover, chitin and chitosan biopolymers can be used for coating purposes as well. Coatings frequently serve as substrate for medical substances which by this method are gradually released and dispensed into the surrounding area.

[0026] Preferably, the resorbable magnesium alloy according to the invention consists of 96 to 97.9% w/w of magnesium, 1.6 to 2% w/w of manganese and 0.5 to 2% w/w of rare earth metal. For this purpose, neodymium or cerium is preferably used as rare earth metal. In particular, a composition comprising 97.45% w/w of magnesium, 1.8% w/w of manganese and 0.75% w/w of cerium is preferred.

[0027] The biosorbability time can be controlled by adjusting the manganese content as desired, i.e. the lower the manganese content the higher the resorption speed.

[0028] The construction of biosorbable endoprostheses are known in the art. In an exemplary embodiment, stents may be cut from tubes manufactured from the relevant magnesium alloy, for example by means of an extrusion process.

[0029] Having cut the stent to size it can be crimped onto a dilatation balloon by means of a method known in the art and together with said balloon transferred to the placement site.

[0030] It will be understood by the skilled person that the endoprosthesis of the invention can be coated with a polymer material with a view to influencing their dissolving behavior or dispensing a medical substance out of the polymer layer. Such drug eluting stents (DES) have been known for a long time and in many cases provided with proliferation-inhibiting medical agents.

[0031] In a further preferred embodiment, maximal magnetic effect is present for a period of at least one week (and preferably about one week) after placement in the body. Preferably, further magnetism can be applied to the stent via magnet external to the body, or positioned within the oesophagus.

[0032] In a particularly preferred embodiment, the stent is constructed according to US 7691142. This describes a stent, which has high stability, in particular radial strength, while allowing good utilization of material. The stent described in this publication has a tubular support frame which is expandable from an initial state to a support state. The support frame is made of ring segments which are arranged sequentially in longitudinal stent axis and formed by struts which are joined continuously in a wave-like manner in circumferential direction of the support frame. Adjacent ring segments are linked by differently long connectors with U-shaped compensating sections. All these compensating sections point in the same circumferential direction. Connectors of different length alternate in circumferential direction as well as in longitudinal stent axis.

[0033] The design of the stent described in US7691142 is configured in such a manner that the immobile struts, which converge respectively with their ends in nodal points that act as friction-free joints, establish a type of self-stabilizing framework structure. Radial forces acting from outside to load the stent are absorbed in the nodal points and deflected there into the various strut directions.

[0034] For the purpose of this specification, the term "magnetic" includes "magnetisable", e.g. a stent whose properties can be influenced in situ. The stent can be paramagnetic or superparamagnetic.

[0035] As used herein, magnetisable is preferably "magnetic". For example, a magnetiseable stent is one that can be magnetised in situ. A magnetic stent is one that has been magnetised.

[0036] In a preferred embodiment, the endoprosthesis comprises a biodegradable polymer. Preferably, the biodegradable polymer is poly(lactic-co-glycolic acid) (PLGA). This polymer may be coated onto a biosorbable stent platform, i.e. a magnesium alloy stent. The biodegradeable polymer may comprise magnetisable particles, which are described in more detail below.

[0037] The endoprosthesis comprises a magnesium metal or alloy. A magnesium endoprosthesis may allow controlled degradation of the medical device in the body, with release of magnesium to the blood-contacting surface of the device.

[0038] In a preferred embodiment, the endoprosthesis comprises a biosorbable matrix, with magnetic particles embedded in, or situated on, the surface of the matrix.

[0039] Magnetic particles suitable for use in the invention are may comprise of any magnetic particles of which many are known, specifically, superparamagnetic iron oxide particles (SPIO), such as MRI contrast agents, magnetic beads or particles based on magnitite. In a preferred embodiment, the endoprosthesis is a stent, which preferably comprises magnetic iron nanoparticles embedded within a biodegradable matrix.

[0040] Preferably, the magnetic particles are magnetite, which is a ferrimagnetic mineral with chemical formula Fe3O4.

[0041] In a preferred embodiment, the magnetic particles, e.g. magnetite, is loaded onto a polymer, preferably PLGA. The polymer may form nanoparticles. The polymer may then be sprayed onto a biosorbable stent, or embedded within a biosorbable stent.

[0042] The endoprosthesis may also be drug-eluting. Examples of drugs which may be eluted by such a stent include antiproliferative drugs, such as sirolimus or paclitaxel.

[0043] A magnetic biosorbable stent embodying the invention can be constructed in a number of ways. In one embodiment a stent can be coated with a high concentration of a polymer-based biodegradable metallic/magnetisable coating. This will confer magnetism sufficient to attract magnetised cells to the stent. The stent may either be a high mechanical strength Mg-based biosorbable stent or a polymer based compound e.g. polyglycolic acid, poly-I-lactic acid, poly d,l-lactide/glycolide copolymer, polyorthoester or polycaprolactone.

[0044] A stent may comprise a polymer including a magnetisable material. The magnetiseable material can be provided as a coating on the polymer, or within the polymer body. The magnetisable material can be magnetised by applying a magnetic field or current. The magnetisable material preferably comprises magnetic particles, as defined above.

[0045] In addition, a stent may be coated with an iron oxide-based biodegradable polymer, or similar magnetisable coating, according to standard coating methods, should the required magnetic effect not be sufficient from the stent alone. Single-layer or multilayer systems may be created (e.g., a base coat, drug coat or topcoat layers or striations).

[0046] In a preferred embodiment, magnetite is used as the magnetic material to coat, or include in, the stent. Magnetite is a ferromagnetic mineral with chemical formula Fe3O4,

[0047] Preferably, the endoprosthesis includes an X-ray maker, such as tungsten carbide.

[0048] In a preferred embodiment, the endoprosthesis comprises a delivery system for a gene therapy. For example, a viral gene transfer product may be within a coating, e.g. a polymer coating, or it may be present on the surface of the stent, using for example encapsulated viral particles.

[0049] According to the invention, a combination of an endoprosthesis as defined above and magnetisable cells capable of repairing an artery is provided. Such cells will be well known to those skilled in the art and include monocytes, multi and pluripotent stem cells and progenitor cells. In a preferred embodiment, the cells are endothelial progenitor cells.

[0050] Means for magnetising (or making magnetisable) such cells are known in the art, and include incorporating iron nanoparticles into the cells.

[0051] According to the invention, a kit is provided, which comprises a biosorbable magnetisable endoprosthesis and magnetisable cells capable of repairing an artery.

[0052] The kit may be used in therapy. The therapy it may be for the disease of a blood vessel, the repair or regeneration of the coronary arteries after angioplasty, for example for the prevention or treatment of restenosis. The kit may also be used for the repair or regeneration of other blood vessels. The kit of the invention may be useful in the therapy of stent thrombosis and/or restenosis.

[0053] The following Examples illustrate the invention.

Example



[0054] Magnetic particles suitable for use in the invention are constructed as follows, and loaded into PLGA to form nanoparticles. The resulting nanoparticles are sprayed onto a biosorbable stent (constructed from a magnesium alloy comprising 96 to 97.9% w/w of magnesium, 1.6 to 2% w/w of manganese and 0.5 to 2% w/w of a rare earth metal), to form a biosorbable magnetisable stent according to the invention. The designed biosorbability time-frame is achieved by adjusting the thickness of the stent accordingly.

[0055] Synthesis of magnetite: Iron acetylacetonate (Fe(acac)3) (0.396 g, 1.56 mmol), oleic acid (1.47 mL, 4.64 mmol), oleylamine (1.02 mL, 3.09 mmol), 1,2-hexadecanediol (2.005 g, 7.76 mmol) and benzyl ether (10 mL) were added to a single-neck round bottom flask equipped with a magnetic stir bar and a condenser and deoxygenated for an hour. The reaction was gradually heated at 3°C /min to 200 °C and held at that temperature for 3 hours and then allowed to cool room temperature. A final black solution was observed. The reaction mixture was precipitated in ethanol and centrifuged twice. Ethanol was decanted and the product was dried via nitrogen purge leaving a black powder.

[0056] Preparation of magnetite-loaded into PLGA: PLGA is dissolved in chloroform (2 mL) and then added drop-wise to a vortexing solution of 5% poly-vinyl alcohol (PVA) (4 mL) and the resulting mixture was sonicated three times for 10 s at an amplitude of 38% (TEKMAR VCW 400 W). The mixture was then added drop-wise to 100 mL of 0.2% PVA and left stirring for 3h to evaporate the solvent. Particles were collected by centrifugation at 12,000 RPM for 10 min at 4 °C and then washed three times with de-ionized water. The particles were lyophilized and stored at -20 °C until use. Particles functionalized on the surface with avidin were prepared in identical fashion with avidin-palmitate incorporated into the 5% PVA solution. Nanoparticles that encapsulating C-6 and functionalized with avidin were manufactured using a modified double emulsion variation of the water-oil-water technique. Nanoparticles encapsulating magnetite and MTX (dissolved in DMSO) were prepared using a single emulsion. Nanoparticles encapsulating magnetite and Clod were manufactured in a similar fashion using a double emulsion, water-oil-water technique.


Claims

1. A kit comprising a biosorbable magnetisable endoprosthesis comprising a magnesium alloy; wherein a portion of the endoprosthesis can be absorbed by the body, such that the structural integrity of the endoprosthesis is lost between 6 and 12 months after placement in the body; wherein the endoprosthesis further comprises magnetic particles comprising iron, within a biosorbable material comprising a biosorbable polymer, and magnetisable cells capable of repairing an artery.
 
2. The kit according to claim 1, wherein the endoprosthesis is a stent.
 
3. The kit according to any preceding claim, wherein the magnesium alloy consists of at least 96% w/w of magnesium, at least 1% w/w of manganese and at least 0.5% w/w of at least one metal of the rare earth group.
 
4. The kit according to any preceding claim, wherein the cells are progenitor cells, preferably endothelial progenitor cells.
 
5. The kit according to any preceding claim, wherein the cells comprise iron.
 
6. The kit according to any of claims 1 to 4, for use in therapy.
 
7. The kit according to claim 6, wherein the therapy is of a disease of a blood vessel, stent thrombosis, restenosis or for the repair or regeneration of a blood vessel after angioplasty.
 


Ansprüche

1. Kit, umfassend eine bioabsorbierbare, magnetisierbare Endoprothese, umfassend eine Magnesiumlegierung;

wobei ein Teil der Endoprothese vom Körper absorbiert werden kann, so dass die strukturelle Integrität der Endoprothese zwischen 6 und 12 Monaten nach dem Einsetzen in den Körper verloren geht;

wobei die Endoprothese ferner magnetische Partikel umfasst, die Eisen umfassen, innerhalb eines bioabsorbierbaren Materials, das ein bioabsorbierbares Polymer umfasst, und magnetisierbare Zellen, die in der Lage sind, eine Arterie zu reparieren.


 
2. Kit nach Anspruch 1, wobei die Endoprothese ein Stent ist.
 
3. Kit nach einem beliebigen vorhergehenden Anspruch, wobei die Magnesiumlegierung aus mindestens 96 Gew.-% Magnesium, mindestens 1 Gew.-% Mangan und mindestens 0,5 Gew.-% mindestens eines Metalls aus der Gruppe der Seltenen Erden besteht.
 
4. Kit nach einem beliebigen vorhergehenden Anspruch, wobei die Zellen Vorläuferzellen sind, vorzugsweise endotheliale Vorläuferzellen.
 
5. Kit nach einem beliebigen vorhergehenden Anspruch, wobei die Zellen Eisen umfassen.
 
6. Kit gemäß einem der Ansprüche 1 bis 4 zur Verwendung in der Therapie.
 
7. Kit nach Anspruch 6, wobei die Therapie eine Erkrankung eines Blutgefäßes, eine Stentthrombose, eine Restenose oder die Reparatur oder Regeneration eines Blutgefäßes nach einer Angioplastie betrifft.
 


Revendications

1. Trousse comprenant une endoprothèse magnétisable biosorbable comprenant un alliage de magnésium ; dans laquelle une partie de l'endoprothèse peut être absorbée par le corps, de telle sorte que l'intégrité structurelle de l'endoprothèse soit perdue entre 6 et 12 mois après son placement dans le corps ; dans laquelle l'endoprothèse comprend en outre des particules magnétiques comprenant du fer, dans un matériau biosorbable comprenant un polymère biosorbable, et des cellules magnétisables capables de réparer une artère.
 
2. Trousse selon la revendication 1, dans laquelle l'endoprothèse est une endoprothèse.
 
3. Trousse selon l'une quelconque des revendications précédentes, dans laquelle l'alliage de magnésium est constitué d'au moins 96 % p/p de magnésium, d'au moins 1 % p/p de manganèse et d'au moins 0,5 % p/p d'au moins un métal du groupe des terres rares.
 
4. Trousse selon l'une quelconque des revendications précédentes, dans laquelle les cellules sont des cellules progénitrices, de préférence des cellules progénitrices endothéliales.
 
5. Trousse selon l'une quelconque des revendications précédentes, dans laquelle les cellules comprennent du fer.
 
6. Trousse selon l'une quelconque des revendications 1 à 4, destinée à être utilisée en thérapie.
 
7. Trousse selon la revendication 6, dans laquelle la thérapie concerne une maladie d'un vaisseau sanguin, une thrombose d'endoprothèse, une resténose ou est destinée à la réparation ou à la régénération d'un vaisseau sanguin après angioplastie.
 






Cited references

REFERENCES CITED IN THE DESCRIPTION



This list of references cited by the applicant is for the reader's convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description




Non-patent literature cited in the description