Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/22—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/2863—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
  • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
  • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

• the present invention relates to the use of molecules capable of inhibiting the binding between NGF and its receptor, TrkA.
• TrkA a receptor for NGF
• it relates to antibodies that, by blocking the biological activity of NGF, have a prolonged analgesic effect. Owing to the enduring analgesic effect thereof, they provide an advantageous therapy for pathologies with persistent forms of pain, known also as chronic pain, such as but not limited to neuropathic or oncological pain.
• the nociceptive signals afferent to the spinal cord are carried by the fibres A ⁇ and C, the cell bodies of which (primary sensitive neurons) are located in the spinal dorsal ganglia (DRG).
• the primary sensitive neurons release glutamate together with ATP as an excitatory neurotransmitter, and various other substances such as substance P and CGRP (calcitonin-gene-related-peptide), (Hunt and Mantyh, 2001).
• excitatory neurotransmitters are controlled by various classes of receptors present on the afferent terminals including those sensitive to capsaicin (vanilloid receptors, VRl), those activated by GABA, those activated by ATP itself and those activated by cannabinoids (CBl) (Sivilotti and Nistri, 1991; Hunt and Mantyh, 2001; Khakh, 2001; Morisset et al., 2001).
• VIP vanilloid receptors
• CBl cannabinoids
• One of the physiopathological whereby chronic pain occurs is allodynia, i.e. the transformation of stimuli that are not normally painful into painful sensations.
• This phenomenon involves various ionic currents and therefore different channels of the "ligand-gated" type, including the receptor for the capsaicin, VRl, and the ionotropic receptors for ATP (Khakh, 2001).
• the simultaneous activation of the receptors for VRl and of those for ATP on spinal nociceptive interneurons generates a considerable accumulation of the excitatory synaptic signals with reinforcement of the painful stimulus transmission (Nakatsuka et al., 2002). From these observations it is therefore clear that the ATP receptors (especially those belonging to the P2X3 class) play a fundamental role in the pain pathways (Burnstock, 2001).
• nociceptive neurons The development of sensitive nociceptive neurons depends greatly on NGF, and the responses of the adult nociceptors are modulated by the same factor (Julius and Basbaum, 2001). In particular, NGF exerts acute sensitisation to the capsaicin algogenic stimulus (Shu and Mendell, 1999). From a functional standpoint, nociceptive neurons, following chronic inflammation, develop alterations in the frequency and duration of their action potential. These phenomena regress by blocking endogenous NGF, leading to a significant attenuation of the hyperexcitability typical of states of chronic pain (Djouhri et al., 2001).
• NGF action in defining the pain threshold in adult nociceptors is mediated by the TrkA receptor, also through modulation of the response mediated by the VRl receptor present on the nociceptive terminals.
• the TrkA dependent potentiation of the VRl response is thought to occur through the intracellular transduction pathway of the phospholipase C gamma ((PLCgamma, Chuang et al., 2001).
• the peripheral NGF levels are increased in inflammatory processes, while the administration of exogenous NGF has a hyperalgesic effect on rats and produces muscular pain in humans.
• NGF produces hypersensitisation to heat stimulation in humans and mammals in general. NGF is released by mast cells, fibroblasts and other cell types in the peripheral sites where inflammatory processes occur.
• mast cells appear to play a fundamental role (Woolf et al., 1996). As they produce NGF and at the same time express functional TrkA receptors on their surface (Nilsson et al., 1997), they are able to respond to NGF itself, in the presence of lysophosphatidylserine (Horigome et al., 1993; Kawamoto et al., 2002). As a result, the NGF/TrkA system appears to mediate mastocyte activation through an autocrine positive feedback mechanism which allows local amplification of the algogenic inflammatory signal.
• TrkA hereditary recessive autosomic syndrome
• CIPA congenital insensitivity to pain with anhydrosis
• the authors of the present invention make use of antibodies (directed against the TrkA receptor) which are able to block the biological effects of NGF mediated by TrkA.
• the reagents MNAC 13 is of particular interest.
• the MNAC 13 antibody is a mouse monoclonal antibody directed against the human TrkA receptor (Cattaneo et al., 1999; Pesavento et al., 2000), particularly effective in the inhibition of TrkA activation by NGF and the downstream biological functions, both in vitro and in vivo (Cattaneo et al., 1999; Pesavento et al., 2000).
• Anti-TrkA antibodies including the MNAC 13 antibody, having an antagonist activity preventing the functional activation of TrkA by NGF" are disclosed in EP 1.181.318. Derivatives of such antibody are also disclosed in WO2005/061540. However the therapeutic or preventive effect of such molecules on chronic pain is not disclosed.
• the antibodies were characterised in detail from the point of view of the structure (Covaceuszach et al., 2001) and from the molecular interaction with the TrkA receptor (Covaceuszach et al., 2005). On the basis of such in-depth structural knowledge, by means of an innovative method a humanised version of MNAC 13 was generated (Hu- MNAC 13), with the same features of antigen binding as the parental antibody (patent application WO2005/061540).
• cholinergic neurons of the basal forebrain a neuronal population affected by various forms of progressive neurodegeneration, including Alzheimer's disease (Saper et al., 1985), express the TrkA receptor and depend on NGF for correct functioning (Holtzman et al., 1992).
• the international patent application WO 01/78698 proposes the use of an NGF antagonist for preventing or treating chronic visceral pain, but not neuropathic or oncological pain.
• the antagonist can bind both NGF and the TrkA receptor, it is not demonstrated that upon binding of the antagonist to TrkA the receptor is functionally blocked.
• MNAC 13 antibody to block the biological activity of NGF/TrkA
• the antibody and its humanised versions were tested in various animal models of persistent pain, in particular in the "Chronic Constriction Injury” model (CCI, chronic constriction injury of the sciatic nerve), for assessment of chronic pain of neuropathic nature (Bennett and Xie, 1988).
• the object of the present invention is the use of an anti-TrkA antibody that is able to inhibit the binding between NGF and TrkA, for the preparation of a medicament for the treatment of chronic pain.
• the antibody blocks the biological activity of TrkA i.e. is an antagonistic antibody.
• a molecule that blocks the biological activity of TrkA refers to a molecule that acts as an antagonist in terms of the NGF binding to the TrkA receptor, and which can be defined as a synthetic molecule or a monoclonal antibody or a biological/synthetic derivative thereof which: i) binds to TrkA; and ii) inhibits the binding of NGF to the "native" TrkA receptor expressed on the surface of living cells; and iii) blocks the biological activity deriving from NGF binding to the same TrkA receptor.
• blocking the biological activity does not simply mean blocking activation of the receptor, defined as blocking the conversion process of the receptor itself into an “active” state, but also the functional neutralisation of biological consequences downstream of the activation process: second messengers, new gene expression, phenotypic and functional modifications both at cell and system level.
• the molecule of the invention is not only able to block TrIcA in a classic in vitro test (test of neuritic growth in PC 12 cells), but also in vivo (functional block of the cholinergic neurons of the basal forebrain and block of the nociception in a classic "hot plate” test).
• antagonistic TrkA antibodies are disclosed in EP 1181318 and in WO 2005/061540.
• an anti-TrkA antibody capable of inhibiting the binding between NGF and TrkA for the preparation of a medicament for treating and/or preventing chronic pain.
• the antibody is capable of blocking the biological activity of TrkA.
• a method of treatment and/or prevention of chronic pain in a subject comprising administering to the subject an effective amount of an anti-TrkA antibody thereby to treat and/or prevent chronic pain in said subject.
• a kit comprising a composition containing an anti-TrkA antibody together with instructions directing administration of said composition to a subject in need of treatment and/or prevention of chronic pain thereby to treat and/or prevent chronic pain in said subject.
• variable region of the antibody light chain comprises at least one of the complementarity determining regions (CDRs) having the sequence selected from aa. 24 to aa. 33 of SEQ ID No.l; from aa. 49 to aa. 55 of SEQ ID No. 1; from aa. 88 to aa. 96 of SEQ ID No. 1, more preferably two of the above CDRs, most preferably three of the above CDRs.
• the variable region of the antibody light chain may, for example, comprise essentially the sequence of SEQ ID No.l.
• variable region of the antibody heavy chain comprises at least one of the complementarity determining regions (CDRs) having the sequence selected from aa. 26 to aa. 35 of SEQ ID No. 2; from aa. 50 to aa. 66 of SEQ ID No. 2; from aa. 99 to aa. 112 of SEQ ID No. 2, more preferably two of the above CDRs, most preferably three of the above CDRs.
• the variable region of the antibody light chain may, for example, comprise essentially the sequence of SEQ ID No.2.
• the antibody may be in single chain form and comprises a light chain variable region and a heavy chain variable region joined by a linker.
• the antibody may comprise two light chains and two heavy chains.
• the anti-TrkA antibody is a human or humanised antibody.
• the skilled in the art shall select the proper humanisation method to design the antibody, a preferred method is the method as disclosed in WO 2005/061540.
• Exemplary humanised antibodies comprise a light chain variable region which is a humanised derivative of SEQ ID No 1 (a mouse origin sequence).
• Exemplary humanised antibodies comprise a heavy chain variable region which is a humanised derivative of SEQ ID No 2 (a mouse origin sequence).
• variable region of the humanised antibody light chain comprises essentially the sequence from aa. 1 to aa. 106 of SEQ ID No. 3.
• the humanised antibody light chain has essentially the sequence of SEQ ID No. 3.
• variable region of the humanised antibody heavy chain comprises essentially the sequence from aa. 1 to aa. 123 of SEQ ID No. 4 .
• the humanised antibody heavy chain has essentially a sequence selected from SEQ ID No. 4, SEQ BD No. 5, SEQ ID No. 6.
• a still further object of the present invention is the use of a molecule that is able to inhibit the binding between NGF and TrkA and to block the biological activity of the latter to prepare a remedy for the treatment of inflammatory chronic pain.
• the pain is caused by pancreatitis, kidney stones, headaches, dysmenorrhea, musculoskeletal pain, sprains, visceral pain, ovarian cysts, prostatitis, cystitis, interstitial cystitis, post-operative pain, migraine, trigeminal neuralgia, pain from burns and/or wounds, pain associated with trauma, neuropathic pain, pain associated with musculoskeletal diseases, rheumatoid arthritis, osteoarthritis, ankylosing spondilitis, periarticular pathologies, oncological pain, pain from bone metastases, pain from HIV.
• pain is generally defined as "An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage or both".
• the essential element in all forms of pain is the activation of specialized high-threshold receptors and nerve fibers to warn the organism of potential tissue damage.
• the involvement of inflammatory cells and processes is a common element in many pain states.
• acute pain means immediate, generally high threshold, pain brought about by injury such as a cut, crush, burn, or by chemical stimulation.
• chronic pain as used herein, means pain other than acute pain.
• the anti-TrkA antibody of the invention is suitably administered systemically.
• Systemic administration can be performed by injection, e.g. continous intravenous infusion, bolus intravenous infusion, subcutaneous or intramuscular injection.
• other forms of administration e.g. oral, mucosal, via inhalation, sublingually, etc.
• Local delivery of the antibody antibody can be performed by local administration eg intra-articular injection or subcutaneous, intramuscular injection in the vicinity of affected tissues.
• the anti-TrkA antibody will suitably be formulated in a pharmaceutical composition appropriate for the intended route of administration.
• Solutions for injection will suitably contain the antibody dissolved or dispersed in an aqueous medium (eg water for injection) as appropriate containing appropriate buffers and molarity modifiers eg phosphate, salt and/or dextrose.
• Treatment regimen i.e. dose, timing and repetition, can be represented by single or repeated administrations (eg injections) of the product by the chosen administration route.
• the interval of dose administration can be subject to modifications depending on the extent and duration of the clinical response, as well as the particular individual and the individual clinical history.
• the anti-TrkA antibody has a long duration of action.
• the clinical effect of the antibody extends following administration may be as long as 21 days as determined from animal studies.
• preliminary data implies that anti-TrkA antibodies may manifest clinical benefit for a longer period than that in which its presence can be detected in a relevant biological matrix such as serum or plasma following its administration.
• the intended long duration of action i.e.
• the antibody may be administered to subjects at a frequency of not more than once per week eg not more than once per two weeks or once per three weeks or once per four weeks.
• a suitable dose of the anti-TrkA antibody will typically range from O.lmg/kg to 1 Omg/kg body weight
• Novel antibodies and compositions containing them disclosed herein are claimed as an aspect of the invention.
• FIGURE 1 Effect of the anti-TrkA monoclonal antibody MNAC13 (1.4 mg/kg) on neuropathic pain: mechanical allodynia measured by means of a plantar dynamic aesthesiometer; CDl mice subjected to chronic constriction of the sciatic nerve; the antibodies are injected IP. at days 3, 4, 5, 6 after lesion of the sciatic nerve. Observation period: from day 3 to day 14.
• saline (sal) and mouse immunoglobulins (IgG, 1.4 mg/kg) were used. Results are expressed in terms of absolute value (grams) of the threshold force for the hindpaw ipsilateral to lesion.
• the values are subjected to statistical analysis by means of analysis of variance (ANOVA) for repeated measurements, in which both the "treatment” factor and the repeated measurement (days) were significant with p ⁇ 0.01 (at least).
• ANOVA analysis of variance
• FIGURE 2 Effect of the anti-TrkA monoclonal antibody MNAC13 (1.4 mg/kg) on neuropathic pain: mechanical allodynia measured by means of a plantar dynamic aesthesiometer; CDl mice subjected to chronic constriction of the sciatic nerve; the antibodies were injected LP. at days 3, 4, 5, 6 after lesion of the sciatic nerve. Observation period: from day 3 to day 14.
• saline (sal) and mouse immunoglobulins (IgG, 1.4 mg/kg) are used as a percentage, % (ratio between the threshold force of the hindpaw ipsilateral to lesion and that corresponding to the contralateral hindpaw).
• FIGURE 3 Effect of the anti-TrkA monoclonal antibody MNAC13 (2 doses: 0.9 and 2 mg/kg) on neuropathic pain: mechanical allodynia measured by means of a plantar dynamic aesthesiometer; CDl mice subjected to chronic constriction of the sciatic nerve; the antibodies were injected LP. at days 3, 4, 5, 6, 7, 8, 9, 10 after lesion of the sciatic nerve.
• mice immunoglobulins were used (IgG, 2 mg/kg). Results were expressed in terms of the absolute value (grams) of the threshold force for the hindpaw ipsilateral to lesion. The values were subjected to statistical analysis by means of analysis of variance (ANOVA) for repeated measurements, in which both the "treatment” factor and the repeated measurement (days) were significant with p ⁇ 0.01 (at least). The animals treated with MNAC 13 were significantly different from the controls up to the last day of observation (31), from day 5 (greater dose of antibody) or from day 7 (lesser dose).
• ANOVA analysis of variance
• FIGURE 4 Effect of the anti-TrkA monoclonal antibody MNAC13 (2 doses: 0.9 and 2 mg/kg) on neuropathic pain: mechanical allodynia measured by means of a plantar dynamic aesthesiometer; CDl mice subjected to chronic constriction of the sciatic nerve; the antibodies were injected LP. at days 3, 4, 5, 6, 7, 8, 9, 10 after lesion of the sciatic nerve. Observation period: from day 3 to day 31. As a control, mouse immunoglobulins were used (IgG, 2 mg/kg).
• Results were expressed as a % (ratio between the threshold force for the hindpaw ipsilateral to lesion and that corresponding to the contralateral hindpaw).
• the corresponding absolute values were subjected to statistical analysis by means of analysis of variance (ANOVA) for repeated measurements, in which both the "treatment” factor and the repeated measurement (days) were significant with p ⁇ 0.01 (at least).
• the animals treated with MNAC13 were significantly different from the controls until the last day of observation (31), from day 5 (greater dose of antibody) or from day 7 (lesser dose).
• the monoclonal antibody MNAC 13 (variable region light chain SEQ ID No. 1; variable region heavy chain SEQ ID No. 2) may be produced from a hybridoma supernatant, according to standard methods, disclosed above (Galrre and Milstein, 1981; Cattaneo et al., 1988; Cattaneo et al., 1999). The supernatant containing each antibody was subjected to precipitation (29% ammonium sulphate), followed by dialysis against PBS IX (Spectra-Por 12/14K membrane, Spectrum) and affinity chromatography on sepharose protein G column (4-Fast Flow, Amersham Biosciences).
• PBS IX Spectra-Por 12/14K membrane, Spectrum
• anti-TrkA (MNAC 13) antibodies were administered in an entire form (Mab) that were diluted in saline solution (vehicle), as indicated in Table I.
• mouse immunoglobulin was used (IgG), in the same dose as the blocking antibodies (at the greater dose if 2 doses were used), or saline solution.
• N IO animals (unless explicitly stated otherwise).
• Table I Administration protocols and measurement of mechanical allodynia.
• results were expressed in 2 different ways, both as an absolute value of the threshold force value (in grams) that was sufficient for the animal to retract the hind leg that is ipsilateral to the lesion, or in percentage value, as the ratio between the absolute values of the hind legs (ipsilateral/contralateral).
• the values were subjected to statistical analysis by means of an analysis of the variance (ANOVA) for repeated measurements, in which both the "treatment” factor and the repeated measurement (days) were significant with p ⁇ 0.01.
• Adjuvant induced arthritis is elicited in male Lewis rats (175-20Og, 7-8 weeks) by injection of 0.1 ml of Mycobacterium butyricum in mineral oil into the base of the tail.
• MNAC 13 antibody (2 mg/kg in sterile saline vehicle) is administered twice intravenously, at 14 and 20 days after induction of arthritis.
• SISSA PIiD Thesis. Harpf C, Dabernig J, Humpel C (2002) Muscle Nerve 25:612-615.
• Nilsson G Forsberg-Nilsson K, Xiang Z 5 Hallbook F, Nilsson K, Metcalfe DD (1997)

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