[go: up one dir, main page]

WO2007145589A1 - Peptides capables de se lier à un peptide bêta-amyloïde - Google Patents

Peptides capables de se lier à un peptide bêta-amyloïde Download PDF

Info

Publication number
WO2007145589A1
WO2007145589A1 PCT/SE2007/050424 SE2007050424W WO2007145589A1 WO 2007145589 A1 WO2007145589 A1 WO 2007145589A1 SE 2007050424 W SE2007050424 W SE 2007050424W WO 2007145589 A1 WO2007145589 A1 WO 2007145589A1
Authority
WO
WIPO (PCT)
Prior art keywords
peptide
amyloid
binding
peptide according
peptides
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/SE2007/050424
Other languages
English (en)
Other versions
WO2007145589A8 (fr
Inventor
Per Arvidsson
Jan Johansson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of WO2007145589A1 publication Critical patent/WO2007145589A1/fr
Anticipated expiration legal-status Critical
Publication of WO2007145589A8 publication Critical patent/WO2007145589A8/fr
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4711—Alzheimer's disease; Amyloid plaque core protein
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to the field of peptide drugs for treatment of diseases involving the formation of amyloid deposits, especially Alzheimer's disease.
  • AD Alzheimer's disease
  • a ⁇ amyloid- ⁇ peptide
  • APP amyloid precursor protein
  • ⁇ - and ⁇ - secretase [2].
  • a ⁇ i_42 the highly aggregation-prone A ⁇ i_42 [3] is the dominant species and it is believed that the peptide and its aggregation into amyloid fibrils plays a major role in the disease.
  • the polymerisation process of A ⁇ in vivo is not fully understood and it is unclear which forms of A ⁇ that are toxic to neurons.
  • amyloid fibrils The ability to form amyloid fibrils has been observed for a number of proteins. Besides AD, about 20 diseases, such as prion diseases, familial amyloid polyneuropathy and Parkinson's disease, are associated with amyloid fibrils formed from specific proteins (reviewed in ref [13]). Amyloid fibrils are highly insoluble aggregates that are composed of ⁇ -strands running perpendicular to the axis of the fibril [14, 15]. The fact that fibrils formed from different proteins show similar morphology indicates that this might be an important structure that all proteins can adopt under certain conditions [16]. Given that several diseases are associated with amyloid formation, finding a therapeutic strategy to modulate this phenomenon is important.
  • amyloid fibrils composed of A ⁇ i -40 [24] and A ⁇ i -42 [25] was recently established. These structures include a ⁇ -strand-turn- ⁇ -strands motif where the ⁇ - strands form intermolecular, parallel ⁇ -sheets.
  • the residues making up the two ⁇ -strands differ slightly between the two structures but both indicate that the first strand comprises residues 18-24 and that residues 31-40 make up the second.
  • the first ⁇ -strand region has been extensively studied and contains a part that has been shown to form fibrils on its own, residues 14-23, whereas the properties of the second ⁇ -strand region is less well known.
  • the present invention is based on the discovery that part of the second ⁇ -strand region, comprising residues 31-40, can be used as a target for blocking of ⁇ -sheet formation.
  • the invention relates to peptides and peptide-like compounds capable of binding to the ⁇ -strand region of residues 31-40 of A ⁇ peptides and inhibiting further assembly of A ⁇ -fibrils.
  • the present invention relates to a peptide having the amino acid sequence He- Ile-Gly-Leu-Met-Val-Gly-Gly- VaI- VaI (SEQ ID NO: 1), or a fragment thereof, capable of binding to amyloid- ⁇ peptide, wherein the N ⁇ -atom of at least one amino acid residue is substituted with a substituent sterically hindering further binding of amyloid- ⁇ peptide, and optionally modified to reduce the polarity of the N- and/or C-terminus.
  • the peptide according to the first aspect has the amino acid sequence Ile-Gly-Leu-Met-Val-Gly (SEQ ID NO: 2).
  • the N ⁇ -atom of at least five amino acid residues are independently substituted with substituents sterically hindering binding of amyloid- ⁇ peptide, e.g. all amino acid residues except Met may be substituted.
  • One or more of the amino acid residues may be the D-enantiomer of the amino acid.
  • the N ⁇ -substituent should be bulky enough to sterically hinder binding of amyloid- ⁇ peptide, yet small enough to allow the peptide to pass cell membranes and the blood-brain barrier.
  • the substituent is preferably selected from the group consisting of Ci -4 alkyl, Ci -4 alkoxy, Ci -4 alkylamino, phenyl, benzyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl.
  • a presently preferred substituent is methyl.
  • the peptide may be modified at the N-terminus, the C-terminus or both the N-terminus and the C-terminus in order to reduce the polarity of the terminal end or ends of the peptide.
  • modifications are routine for a person skilled in the art and usually comprise N-terminal acetylation and C-terminal amidation.
  • the invention relates to a peptide according to the first aspect for use in medicine.
  • the invention relates to the use of the peptide according to the first aspect, or pharmaceutically active salts and esters thereof, for the manufacture of a pharmaceutical composition for the treatment or prevention of diseases involving the formation of amyloid deposits, especially of Alzheimer's disease and to such a composition, optionally further comprising other pharmaceutically acceptable ingredients such as excipients and/or carriers.
  • such a composition may further include other therapeutic agents such as other peptides inhibiting ⁇ -strand formation.
  • Such peptides are i.a. peptides of the sequence
  • KLVFFA (SEQ ID NO: 3) capable of binding to residues 16-22 of amyloid- ⁇ peptide and inhibiting ⁇ -sheet formation as disclosed in WO 01/07473 and WO 01/07474.
  • This aspect also includes a method for treating a patient having, or suspected of having, Alzheimer's disease comprising administering a therapeutically effective amount of such a peptide or composition to said patient.
  • the invention relates to the use of the peptide according to the first aspect, further comprising a reporter group, for diagnosing Alzheimer's disease, or for the production of a composition for use in diagnosis of Alzheimer's disease.
  • the reporter group may be biotin, a fluorescent group, a chromophore or a radioactive atom or group, or any other group that may be incorporated into the peptide and detected in a relevant assay.
  • a radioactive atom may be introduced in a number of ways known to the person skilled in the art. Generally speaking, atoms may be substituted with radioactive isotopes of the same element or isotopes of other elements having similar chemical properties, e.g.
  • amino acid residues used in the production of the peptide may comprise a certain percentage of radioactive hydrogen or sulphur, a percentage of sulphur atoms may be exchanged to selenium atoms etc.
  • Selenomethionine is commercially available and may be used to incorporate selenium as a reporter group into the peptide.
  • This aspect also includes a method for diagnosing Alzheimer's disease using the peptide or the composition according to this aspect.
  • a method for diagnosing Alzheimer's disease using the peptide or the composition according to this aspect may comprise the steps of bringing the peptide comprising a reporter group into contact with a sample from a subject suspected of having Alzheimer's disease and detecting binding of the peptide to A ⁇ peptides in the sample.
  • the method may also be performed in vivo by administering the peptide to a subject suspected of having Alzheimer's disease and detecting binding of the peptide to A ⁇ peptides in the central nervous system of the subject.
  • Figure 1 A: a schematic beta-sheet with interstrand hydrogen bonds between carbonyl oxygens and amide hydrogens.
  • B illustration of how an N-methylated peptide blocks further sheet formation by steric hindrance and loss of hydrogen bonding capabilities.
  • FIG. 2 Electron micrographs of fibrils formed from A ⁇ 1-40 with and without addition of methylated peptides.
  • the invention relates to TV-substituted peptides that targets the second sheet forming part of A ⁇ , i.e. residues 31-40.
  • the following experimental section illustrates one embodiment of the invention and should not be considered to limit the invention, which is defined by the scope of the appended claims.
  • Peptides M2, M4, M6 and M8, corresponding to the 32-37 region of Ap 1 ⁇ 0 , amino acid sequence IGLMVG, containing varying number of N-methyl amino acids were designed.
  • N-methylated peptides Ml, M3, M5 and M7 based on the 17-21 region were also synthesized.
  • Peptides M1-M8 were all synthesized on solid-phase using Fmoc-protected amino acids, as described in the experimental section.
  • all TV-methylated peptides were synthesized on a hyper-acid labile Sieber resin, due to the known instability of poly-N-methylated peptides under strongly acidic conditions [26], with HATU as coupling reagent.
  • the Fmoc-protected TV-methyl amino acids used were synthesized from the corresponding Fmoc-amino acid as previously described [27]. All peptides were obtained in high purity, but were nevertheless purified by preparative reversed phase HPLC.
  • HPLC high pressure liquid chromatography
  • ELSD universal evaporative light- scattering detection
  • the reverse phase HPLC analyses were done using a Phenomenex Gemini C18 (3 ⁇ m, 3.0*150 mm) column (for purity determination) with acetonitrile-water (both containing 0.1 % formic acid) as mobile phase (Gradient: 5-95 % acetonitrile in 6 minutes + 6 minutes at 95%, flow 1.0 ml/min).
  • Preparative HPLC was done using a Grace Vydac Cl 8 (5 ⁇ m, 22* 150mm) column with acetonitrile-water (both containing 0.1 % TFA) as mobile phase (Gradient: 10 - 60 % acetonitrile in 10 min + 6 minutes at 95 %, flow 18.0 ml/min).
  • the Sieber resin was purchased from GL Biochem. All standard Fmoc-amino acids were purchased from Senn Chemicals, and all N-methylated Fmoc-amino acids were synthesized as previously described [27]. All solvents were from Fischer Scientific and all other chemicals from Aldrich, and used as supplied. Synthesis of peptides corresponding to the Ab region 32-37
  • the resin was washed with 1O x DCM before cleavage to wash away residual DMF.
  • the peptide was cleaved from the resin using a cleavage mix 97.9: 2: 0.1 (DCM:TFA:EDT) (5 ml) for 15 min.
  • the cleavage solution was collected into a flask containing 25 ml toluene.
  • the resin was washed with 5 x DCM, 5 x MeOH, 5 x DCM and 5x MeOH to wash out residual cleaved peptide from the resin.
  • the cleavage solution was then evaporated and gave a slightly yellow oil.
  • Peptides M1-M8 were purified by reversed phase HPLC using a binary gradient composed of acetonitrile (containing 0.1% TFA) and water (containing 0.1 TFA), and the solvent was removed by lyophilization.
  • the purity and identity of the peptides were established by running analytical HPLC-MS of the purified peptides.
  • a ⁇ i.40 was purchased from Bachem GmbH (Germany) and stored at -20°C until use. To ensure a monomeric starting solution, the peptide was dissolved, sonicated and vortexed at 1 mg/ml in DMSO (Merck, Germany) and diluted in 10 mM sodium phosphate buffer, pH 7, to the working concentration immediately before use. For the aggregation assay, all methylated peptides were dissolved at 5 mM in DMSO.
  • Aggregation assay A ⁇ i.40, 25 ⁇ M was incubated with or without methylated peptides in 1, 5 or 10 times excess in 10 mM sodium phosphate, pH 7, and 15% DMSO at 37°C with agitation. After 48 hours aliquots of 2 ⁇ l were adsorbed for 1 min on 200-mesh cooper grids. The grids were then stained with 2% uranyl acetate for 30 s and examined and photographed using a Hitachi H7100 microscope operated at 75 kV. The importance of sequence homology for inhibition was demonstrated by the lack of activity of pentameric poly-N-methylated alanine. The results are given in Table 1.
  • Petkova, A.T., et al. A structural model for Alzheimer's beta -amyloid fibrils based on experimental constraints from solid state NMR. Proc Natl Acad Sci U S A, 2002.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Neurosurgery (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Psychiatry (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Hospice & Palliative Care (AREA)
  • Toxicology (AREA)
  • Genetics & Genomics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne de nouveaux peptides capables de se lier à un peptide bêta-amyloïde, l'atome Nα d'au moins un résidu d'acide aminé étant substitué avec un substituant qui produit un encombrement stérique empêchant toute autre liaison du peptide bêta-amyloïde. L'invention concerne en outre l'utilisation desdits peptides dans le domaine médical et des compositions pharmaceutiques destinées au traitement de la maladie d'Alzheimer.
PCT/SE2007/050424 2006-06-15 2007-06-15 Peptides capables de se lier à un peptide bêta-amyloïde Ceased WO2007145589A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE0601310-6 2006-06-15
SE0601310 2006-06-15

Publications (2)

Publication Number Publication Date
WO2007145589A1 true WO2007145589A1 (fr) 2007-12-21
WO2007145589A8 WO2007145589A8 (fr) 2009-07-23

Family

ID=38832008

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE2007/050424 Ceased WO2007145589A1 (fr) 2006-06-15 2007-06-15 Peptides capables de se lier à un peptide bêta-amyloïde

Country Status (1)

Country Link
WO (1) WO2007145589A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2149380A1 (fr) * 2008-07-29 2010-02-03 Medivet Pharma, S.L. Compositions d'immunothérapie vétérinaire pour le disfonctionnement cognitif associé à l'âge
US7834144B2 (en) 2005-09-09 2010-11-16 Novartis Ag Prion-specific peptoid reagents
US20120015883A1 (en) * 2010-06-09 2012-01-19 Sadowski Martin J Peptoid and synthetic oligomers, pharmaceutical compositions and methods of using same
US8349293B2 (en) 2007-03-22 2013-01-08 Guerbet Use of metal nanoparticles in the diagnosis of Alzheimer's disease
US20140039155A1 (en) * 2008-10-06 2014-02-06 Commonwealth Scientific And Industrial Research Organisation Amyloid-beta peptide crystal structure
WO2015043567A1 (fr) * 2013-09-26 2015-04-02 Forschungszentrum Jülich GmbH Peptides se liant aux bêta-amyloïdes et leur utilisation pour le traitement et le diagnostic de la maladie d'alzheimer
WO2017083700A1 (fr) * 2015-11-13 2017-05-18 The Board Of Regents Of The Nevada System Of Higher Education On Behalf Of The University Of Nevada, Las Vegas Thérapie basée sur une phagocytose guidée par ligand pour le traitement de la maladie d'alzheimer et d'autres maladies neurodégénératives
US12018096B2 (en) 2017-09-20 2024-06-25 Councel of Scientific & Industrial Research Potent peptide inhibitors of protein aggregation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6761888B1 (en) * 2000-05-26 2004-07-13 Neuralab Limited Passive immunization treatment of Alzheimer's disease
WO2005028511A2 (fr) * 2003-03-28 2005-03-31 Centocor, Inc. Anticorps anti-amyloides, compositions, procedes et utilisations

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6761888B1 (en) * 2000-05-26 2004-07-13 Neuralab Limited Passive immunization treatment of Alzheimer's disease
WO2005028511A2 (fr) * 2003-03-28 2005-03-31 Centocor, Inc. Anticorps anti-amyloides, compositions, procedes et utilisations

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GORDON D.J. ET AL.: "Inhibition of B-Amyloid(40) Fibrillogenesis and Disassembly of B-Amyloid(40) Fibrils by Short B-Amyloid Congeners Containing N-Methyl Amino Acids at Alternate Residues", BIOCHEMISTRY, vol. 40, 2001, pages 8237 - 8245, XP002980674 *
SCIARRETTA K.L. ET AL.: "Spatial Separation of B-Sheet Domains of B-Amyloid: Disruption of each B-sheet by N-Methyl Amino Acids", BIOCHEMISTRY, vol. 45, 2006, pages 9485 - 9495, XP003018641 *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7834144B2 (en) 2005-09-09 2010-11-16 Novartis Ag Prion-specific peptoid reagents
US8349293B2 (en) 2007-03-22 2013-01-08 Guerbet Use of metal nanoparticles in the diagnosis of Alzheimer's disease
WO2010012749A1 (fr) * 2008-07-29 2010-02-04 Medivet Pharma, S.L. Compositions immunothérapiques pour le traitement et la prévention de l'amylose
EP2149380A1 (fr) * 2008-07-29 2010-02-03 Medivet Pharma, S.L. Compositions d'immunothérapie vétérinaire pour le disfonctionnement cognitif associé à l'âge
US20140039155A1 (en) * 2008-10-06 2014-02-06 Commonwealth Scientific And Industrial Research Organisation Amyloid-beta peptide crystal structure
US9364449B2 (en) * 2010-06-09 2016-06-14 New York University Peptoid and synthetic oligomers, pharmaceutical compositions and methods of using same
US20120015883A1 (en) * 2010-06-09 2012-01-19 Sadowski Martin J Peptoid and synthetic oligomers, pharmaceutical compositions and methods of using same
WO2015043567A1 (fr) * 2013-09-26 2015-04-02 Forschungszentrum Jülich GmbH Peptides se liant aux bêta-amyloïdes et leur utilisation pour le traitement et le diagnostic de la maladie d'alzheimer
EP3049099B1 (fr) * 2013-09-26 2020-06-17 Forschungszentrum Jülich GmbH Peptides se liant aux bêta-amyloïdes et leur utilisation pour le traitement et le diagnostic de la maladie d'alzheimer
EP3747454A1 (fr) 2013-09-26 2020-12-09 Forschungszentrum Jülich GmbH Peptides liants amyloïdes-bêta et leur utilisation pour le traitement et le diagnostic de la maladie d'alzheimer
US10995118B2 (en) 2013-09-26 2021-05-04 Forschungszentrum Juelich Gmbh Amyloid-beta-binding peptides and the use thereof for the treatment and diagnosis of alzheimer's disease
WO2017083700A1 (fr) * 2015-11-13 2017-05-18 The Board Of Regents Of The Nevada System Of Higher Education On Behalf Of The University Of Nevada, Las Vegas Thérapie basée sur une phagocytose guidée par ligand pour le traitement de la maladie d'alzheimer et d'autres maladies neurodégénératives
US11034739B2 (en) 2015-11-13 2021-06-15 The Board Of Regents Of The Nevada System Of Higher Education On Behalf Of The University Of Nevada Ligand-guided phagocytosis based therapy for treatment of Alzheimer's disease and other neurodegenerative diseases
US12018096B2 (en) 2017-09-20 2024-06-25 Councel of Scientific & Industrial Research Potent peptide inhibitors of protein aggregation

Also Published As

Publication number Publication date
WO2007145589A8 (fr) 2009-07-23

Similar Documents

Publication Publication Date Title
WO2007145589A1 (fr) Peptides capables de se lier à un peptide bêta-amyloïde
EP2603600B1 (fr) Macrocycles peptidomimétiques
US5700779A (en) Bradykinin antagonist peptides incorporating N-substituted glycines
CN102655875A (zh) 改善的拟肽大环化合物
CA2737918A1 (fr) Macrocycles peptidomimetiques
CN109942714A (zh) 一种功能多肽及应用
JP5464383B2 (ja) アミロイドβ線維化阻害ペプチド
US7314726B2 (en) Beta secretase exosite binding peptides and methods for identifying beta secretase modulators
CN118772232B (zh) 蛙皮素类多肽化合物及其用途
GB2285047A (en) Polypeptides, rich in proline, which inhibit the NADPH oxidase system
US10208087B2 (en) Peptides
Marseigne et al. Full agonists of CCK8 containing a nonhydrolyzable sulfated tyrosine residue
Olma et al. The biological consequences of replacing hydrophobic amino acids in deltorphin I with amphiphilic α‐hydroxymethylamino acids
EP1858912B1 (fr) Composes destines a reduire l'agregation de beta-peptide amyloide
WO2011144714A1 (fr) Peptides kissorphine pour l'utilisation dans le traitement de la maladie d'alzheimer, la maladie de creutzfeldt-jakob ou le diabète sucré
CN117362388A (zh) 一种激活grp受体的多肽化合物及其用途
CN118085036A (zh) 一种能够自组装形成纳米螺旋的两亲性d/l环肽及其合成和组装方法
US10947272B2 (en) BACE1 inhibitor peptides
WO2015062803A1 (fr) Segments modifiés de polypeptide amyloïde des îlots
WO2003051387A1 (fr) Agents therapeutiques et/ou prophylactiques contre des maladies conformationnelles
CN120818007A (zh) Psd-95 pdz2拟肽类抑制剂及其应用
JP7420361B2 (ja) アミロイド線維の形成を抑制するペプチド
EP1421106B1 (fr) Catalyse de l'isomerisation cis/trans de composes secondaires d'amides et de peptides
Fülöp Aggregation studies, design and synthesis of amyloid aggregation inhibitors for the treatment of Alzheimer's disease
WO2017179647A1 (fr) Peptide pour l'inhibition de la liaison d'amylosphéroïdes (aspd), et procédé d'évaluation et de criblage

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07748584

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07748584

Country of ref document: EP

Kind code of ref document: A1