WO1998051217A1 - Vaccin dirige contre les noyaux de lipopolysaccharides - Google Patents

Vaccin dirige contre les noyaux de lipopolysaccharides Download PDF

Info

Publication number
WO1998051217A1
WO1998051217A1 PCT/US1998/009988 US9809988W WO9851217A1 WO 1998051217 A1 WO1998051217 A1 WO 1998051217A1 US 9809988 W US9809988 W US 9809988W WO 9851217 A1 WO9851217 A1 WO 9851217A1
Authority
WO
WIPO (PCT)
Prior art keywords
lps
antigen
bacterium
core
coli
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/US1998/009988
Other languages
English (en)
Inventor
Elliott Bennett-Guerrero
George Robin Barclay
Ian Raymond Poxton
Thomas James Mcintosh
David Scott Snyder
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.)
MEDICAL DEFENSE TECHNOLOGIES LLC
Medical Defence Technologies LLC
Original Assignee
MEDICAL DEFENSE TECHNOLOGIES LLC
Medical Defence Technologies LLC
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 MEDICAL DEFENSE TECHNOLOGIES LLC, Medical Defence Technologies LLC filed Critical MEDICAL DEFENSE TECHNOLOGIES LLC
Priority to EP98922339A priority Critical patent/EP1011440A4/fr
Priority to CA002289760A priority patent/CA2289760A1/fr
Priority to AU74912/98A priority patent/AU7491298A/en
Priority to JP54958998A priority patent/JP2001527562A/ja
Priority to US09/423,546 priority patent/US6749831B1/en
Publication of WO1998051217A1 publication Critical patent/WO1998051217A1/fr
Anticipated expiration legal-status Critical
Priority to US10/819,712 priority patent/US20040219587A1/en
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K39/02—Bacterial antigens
    • A61K39/025—Enterobacteriales, e.g. Enterobacter
    • A61K39/0275—Salmonella
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes
    • 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
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55555—Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the LPS of each type comprises the lipid A structure.
  • the Ra chemotype is characterized by a complete core region
  • the Rb chemotype is characterized by the absence of N-acetyl-D-glucosamine residues
  • the Re chemotype is characterized by the absence of N-acetyl-D-glucosamine and galactose residues
  • the Rd chemotype is characterized by the absence of any residues constituting the outer core
  • the Re chemotype is characterized by the sole KDO region attached to lipid A.
  • the effectiveness of the antisera varies greatly depending upon a large number of factors including, for example, the composition and titer of the specific antibodies, which cannot be easily standardized.
  • the use of these antisera may also carry a risk of transmission of viral infectious diseases.
  • the liposome may include a component to provide stability or alter the compound's charge, selected from the group consisting of: phospholipid, cholesterol, positively charged compounds, negatively charged compounds, amphipathic compounds. Multilamellar type liposomes (MLV) in particular may be used. Small or large unilamellar liposomes (SUVs and LUVs) also may be used.
  • the composition may be administered intramuscularly intravenously, subcutaneously, intraperitonealy, via the respiratory tract, or via gastrointestinal tract.
  • the dose of antigen can be readily determined by standard dosage trials which correlate dosage with titre and/or protection.
  • the antibodies induced by this vaccine preferably react with all common smooth strain isolates, and preferably also with rough strain LPSs of all five core types (Rl, R2 , R3 , R4 , and K12) .
  • the antibodies induced by this vaccine are also reactive with different smooth and rough LPSs of Salmonella. It is possible to achieve a vigorous and effective antibody response using compositions with acceptable levels of (or no) toxicity.
  • the vaccine stimulates the synthesis of antibodies which recognize an epitope in the core region of the LPS molecule and which are cross- protective against endotoxemia caused by at least two different Gram-negative bacterial strains having different LPS structures and in particular are cross- protective against smooth strains as well as complete core rough strains.
  • the purified LPS from one of these strains, a mixture of any combination of these strains, or a different strain of bacteria may be used in any ratio of the individual strains in the case of use of more than one LPS type.
  • an important function of our method of vaccination is to cause an increase in the serum concentration of antibodies which may already be present, but at levels which do not allow for sufficient protection from a toxic exposure of LPS during periods of stress and trauma.
  • the above in no means suggests that there are not patients who will also benefit from vaccination with this invention by means of a primary (i.e. na ⁇ ve) antibody response .
  • the lipid mixture When shaken in the presence of an excess amount of water, the lipid mixture is formed into discrete particles consisting of concentric spherical shells of lipid bilayer membranes which are referred to as multilamellar liposomes (MLV) .
  • MLV multilamellar liposomes
  • LPS incorporated into liposomes from method #3 was purified on a 1.1 x 28.5 cm BioGel A15M column using 4 mM MOPS/153 mM saline as the running buffer and 0.7 ml/min as the flow rate. This step maybe unnecessary since there was no difference in the lymulate ameoba lysate (LAL) activity between purified and unpurified liposomes due to the almost complete (>99.9%) incorporation of the free LPS into the liposomes.
  • LAL ameoba lysate
  • LPS of Escherichia coli as well as smooth and complete core rough LPS of Salmonella. It demonstrated superior binding than sera from rabbits immunized with immunogens from prior art such as the extensively tested Re J5 mutant of Escherichia coli, the Re mutant of Salmonella minnesota, and lipid A.
  • microtitre plates and strips used were ELISA-grade polystyrene (Greiner, medium-binding grade, flat-bottom wells) : some other grades and some other manufacturers microtitre plates may be unsuitable for this assay. Plates were stacked, wrapped in plastic (Clingfilm) , and incubated overnight at 37C. The plates were washed as previously described using phosphate- buffered saline (PBS) with 0.05% (v/v) tween-20. A 5% solution of bovine serum albumin (BSA) in PBS, containing 0.05% sodium azide, was added at 120 microlitres per well. The plates were stacked, wrapped in plastic, and incubated overnight at 37C.
  • PBS phosphate- buffered saline
  • BSA bovine serum albumin
  • LAL limulus amebocyte lysate
  • This assay quantitates the activity of a biologically active LPS, whereas in the presence of protective anti-LPS antibodies there is significant inhibition of the LAL test due to competitive binding and neutralization of the LPS.
  • LAL test kits can be purchased from manufacturers, e.g. Coatest Endotoxin from Chromogenix, Sweden. Different versions of the LAL assay can be used, e.g. gel-clot version or chromogenic version.
  • mouse peritoneal cells (C3H/HeN) are obtained by peritoneal lavage with 0.34 M sucrose in distilled water. Peritoneal cells are seeded at 5xl0 5 cells/ml in 0.2 ml serum free medium (IMDM-ATL, Schreier and Tees, Immunological Methods, Vol. II, Acad. Press (1981) : 263) and cultured for 4 hours at 37 degrees C in the presence or absence of (1) LPS, e.g. LPS from E. coli R3 (0.05 ng/ml) or E. coli 018 (0.05 ng/ml) or S . minnesota wild type smooth (0.05 ng/ml) or S.
  • LPS e.g. LPS from E. coli R3 (0.05 ng/ml) or E. coli 018 (0.05 ng/ml) or S .
  • Cross-Protection from Lethal Dose of Endotoxin Another measure of the effectiveness of this invention is its ability to confer cross-protection against LPS.
  • a mouse lethality model is used in which mice are immunized intraperitonealy on Day 0 with either the invention, appropriate controls, or immunogens described previously such as the Re J5 mutant LPS of Escherichia coli and the Re mutant LPS of Salmonella minnesota.
  • a second dose of antigen is administered on Day 7 and Day 14.
  • endotoxin can be administered intravenously in a 95% lethal dose of a particular LPS to groups of six female C57BL/6 mice, 6-8 weeks old.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Organic Chemistry (AREA)
  • Toxicology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Epidemiology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicinal Preparation (AREA)

Abstract

Selon cette invention, on incorpore à un vaccin se présentant généralement sous forme de liposomes, des lipopolysaccharides (LPS) à noyau complet (dépourvus de chaînes latérales de O-polysaccharide) provenant de bactéries Gram négatif. Le noyau complet de E.coli K12 s'avère particulièrement utile. Lorsqu'on l'administre à un mammifère, ce vaccin stimule la synthèse d'anticorps qui assurent une protection croisée contre les formes lisses et rugueuses de LPS, à partir d'au moins deux souches bactériennes Gram négatif dotées de structures de noyaux différentes.
PCT/US1998/009988 1997-05-16 1998-05-15 Vaccin dirige contre les noyaux de lipopolysaccharides Ceased WO1998051217A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
EP98922339A EP1011440A4 (fr) 1997-05-16 1998-05-15 Vaccin dirige contre les noyaux de lipopolysaccharides
CA002289760A CA2289760A1 (fr) 1997-05-16 1998-05-15 Vaccin dirige contre les noyaux de lipopolysaccharides
AU74912/98A AU7491298A (en) 1997-05-16 1998-05-15 Vaccine against lipopolysaccharide core
JP54958998A JP2001527562A (ja) 1997-05-16 1998-05-15 リポ多糖コアに対するワクチン
US09/423,546 US6749831B1 (en) 1997-05-16 1998-05-15 Vaccine against lipopolysaccharide core
US10/819,712 US20040219587A1 (en) 1997-05-16 2004-04-06 Vaccine against lipopolysaccharide core

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US4668097P 1997-05-16 1997-05-16
US60/046,680 1997-05-16

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US09/423,546 A-371-Of-International US6749831B1 (en) 1997-05-16 1998-05-15 Vaccine against lipopolysaccharide core
US10/819,712 Division US20040219587A1 (en) 1997-05-16 2004-04-06 Vaccine against lipopolysaccharide core

Publications (1)

Publication Number Publication Date
WO1998051217A1 true WO1998051217A1 (fr) 1998-11-19

Family

ID=21944797

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/009988 Ceased WO1998051217A1 (fr) 1997-05-16 1998-05-15 Vaccin dirige contre les noyaux de lipopolysaccharides

Country Status (5)

Country Link
EP (1) EP1011440A4 (fr)
JP (1) JP2001527562A (fr)
AU (1) AU7491298A (fr)
CA (1) CA2289760A1 (fr)
WO (1) WO1998051217A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010023366A1 (fr) * 2008-09-01 2010-03-04 Esa-Matti Lilius Lps rugueuses en tant qu’immunostimulants dans un élevage aquatique
WO2012171077A1 (fr) * 2011-06-17 2012-12-20 Immuron Limited Procédé et composition pour traiter ou inhiber une mucosite associée à une chimiothérapie ou à une lésion causée par un rayonnement
WO2017109733A3 (fr) * 2015-12-22 2017-08-24 Glaxosmithkline Biologicals Sa Procédé
FR3072880A1 (fr) * 2017-10-30 2019-05-03 Institut National De La Sante Et De La Recherche Medicale (Inserm) Formulation liposomale et son utilisation en therapie anti-tumorale

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5417986A (en) * 1984-03-16 1995-05-23 The United States Of America As Represented By The Secretary Of The Army Vaccines against diseases caused by enteropathogenic organisms using antigens encapsulated within biodegradable-biocompatible microspheres
US5730989A (en) * 1995-02-16 1998-03-24 Novavax, Inc. Oral vaccine against gram negative bacterial infection
US5750115A (en) * 1989-08-03 1998-05-12 Akzo Nobel N. V. Escherichia coli vaccine

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE173634T1 (de) * 1994-04-20 1998-12-15 Us Army Impfstoff gegen gram-negative bakterielle infektionen

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5417986A (en) * 1984-03-16 1995-05-23 The United States Of America As Represented By The Secretary Of The Army Vaccines against diseases caused by enteropathogenic organisms using antigens encapsulated within biodegradable-biocompatible microspheres
US5750115A (en) * 1989-08-03 1998-05-12 Akzo Nobel N. V. Escherichia coli vaccine
US5730989A (en) * 1995-02-16 1998-03-24 Novavax, Inc. Oral vaccine against gram negative bacterial infection

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
DALE P A, ET AL: "HUMAN VACCINATION WITH ESCHERICHIA COLI J5 MUTANT INDUCES CROSS-REACTIVE BACTERICIDAL ANTIBODY AGANIST NEISSERIA GONORRHOAEA LIPOOLIGOSACCHARIDE.", JOURNAL OF INFECTIOUS DISEASES. JID, UNIVERSITY OF CHICAGO PRESS., CHICAGO, IL., vol. 166., 1 August 1992 (1992-08-01), CHICAGO, IL., pages 316 - 325., XP002914080, ISSN: 0022-1899 *
FANG I. S., ET AL.: "INHIBITION OF LIPOPOLYSACCHARIDE-ASSOCIATED ENDOTOXIN ACTIVITIES IN VITRO AND IN VIVO BY THE HUMAN ANTI-LIPID A MONOCLONAL ANTIBODY SDJ5-1.17.15.", INFECTION AND IMMUNITY, AMERICAN SOCIETY FOR MICROBIOLOGY., US, vol. 61., no. 09., 1 September 1993 (1993-09-01), US, pages 3873 - 3878., XP002914081, ISSN: 0019-9567 *
GREEN S., ET AL.: "LIPOSOMAL VACCINES", IMMUNOBIOLOGY OF PROTEINS AND PEPTIDES, XX, XX, vol. 383., 1 January 1995 (1995-01-01), XX, pages 83 - 92., XP002914078 *
HODGSON J.C., ET AL.: "PROPHYLACTIC USE OF HUMAN ENDOTOXIN-CORE HYPERIMMUNE GAMMAGLOBULIN TO PREVENT ENDOTOXAEMIA IN COLOSTRUM-DEPRIVED, GNOTOBIOTIC LAMBS CHALLENGED ORALLY WITH ESCHERICHIA COLI.", FEMS IMMUNOLOGY AND MEDICAL MICROBIOLOGY., ELSEVIER SCIENCE B.V., AMSTERDAM., NL, vol. 11., no. 03., 1 January 1995 (1995-01-01), NL, pages 171 - 180., XP002914079, ISSN: 0928-8244, DOI: 10.1016/0928-8244(95)00021-X *
PADOVA F. E., ET AL.: "A BROADLY CROSS-PROTECTIVE MONOCLONAL ANTIBODY BINDING TO ESCHERICHIA COLI AND SALMONELLA LIPOPOLYSACCHARIDES.", INFECTION AND IMMUNITY, AMERICAN SOCIETY FOR MICROBIOLOGY., US, vol. 61., no. 09., 1 September 1993 (1993-09-01), US, pages 3863 - 3872., XP002914082, ISSN: 0019-9567 *
POXTON R.: "ANTIBODIES TO LIPOPOLYSACCHARIDE.", JOURNAL OF IMMUNOLOGICAL METHODS., ELSEVIER SCIENCE PUBLISHERS B.V.,AMSTERDAM., NL, vol. 186., 1 January 1995 (1995-01-01), NL, pages 01 - 15., XP002914083, ISSN: 0022-1759, DOI: 10.1016/0022-1759(95)00123-R *
See also references of EP1011440A4 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010023366A1 (fr) * 2008-09-01 2010-03-04 Esa-Matti Lilius Lps rugueuses en tant qu’immunostimulants dans un élevage aquatique
WO2012171077A1 (fr) * 2011-06-17 2012-12-20 Immuron Limited Procédé et composition pour traiter ou inhiber une mucosite associée à une chimiothérapie ou à une lésion causée par un rayonnement
WO2017109733A3 (fr) * 2015-12-22 2017-08-24 Glaxosmithkline Biologicals Sa Procédé
CN108431049A (zh) * 2015-12-22 2018-08-21 葛兰素史密丝克莱恩生物有限公司 Lps提取工艺
US11186652B2 (en) 2015-12-22 2021-11-30 Glaxosmithkline Biologicals Sa LPS extraction process
FR3072880A1 (fr) * 2017-10-30 2019-05-03 Institut National De La Sante Et De La Recherche Medicale (Inserm) Formulation liposomale et son utilisation en therapie anti-tumorale
WO2019086806A1 (fr) * 2017-10-30 2019-05-09 Institut National De La Sante Et De La Recherche Medicale (Inserm) Formulation liposomale de lipopolysaccharide bactérien combinée à un agent cytotoxique, et son utilisation en therapie anti-tumorale
US12433838B2 (en) 2017-10-30 2025-10-07 Institut National De La Santé Et De La Recherche Médicale (Inserm) Liposomal formulation of bacterial lipopolysaccharide combined with a cytotoxic agent, and use thereof in anti-tumour therapy

Also Published As

Publication number Publication date
CA2289760A1 (fr) 1998-11-19
EP1011440A1 (fr) 2000-06-28
EP1011440A4 (fr) 2003-08-06
JP2001527562A (ja) 2001-12-25
AU7491298A (en) 1998-12-08

Similar Documents

Publication Publication Date Title
AU631377B2 (en) Affinity associated vaccine
US5026557A (en) Adjuvant composition
JP2005514388A (ja) グラム陰性菌由来の外膜小胞およびワクチンとしての使用
AU2001256461B2 (en) Immunotherapeutic methods and compositions
US6749831B1 (en) Vaccine against lipopolysaccharide core
EP0356340B1 (fr) Vaccin à affinité associée
Lee et al. Immunization of burn-patients with a Pseudomonas aeruginosa outer membrane protein vaccine elicits antibodies with protective efficacy
US5013555A (en) Agent for desensitizing man and/or animals against an allergen
Sheikh et al. Generation of antigen specific CD8+ cytotoxic T cells following immunization with soluble protein formulated with novel glycoside adjuvants
US5888519A (en) Encapsulated high-concentration lipid a compositions as immunogenic agents to produce human antibodies to prevent or treat gram-negative bacterial infections
US5897873A (en) Affinity associated vaccine
Childers et al. Mucosal and systemic responses to an oral liposome-Streptococcus mutans carbohydrate vaccine in humans.
WO1998051217A1 (fr) Vaccin dirige contre les noyaux de lipopolysaccharides
Nakhla et al. Serum anti-LPS antibody production by rainbow trout (Oncorhynchus mykiss) in response to the administration of free and liposomally-incorporated LPS fromAeromonas salmonicida
Lipld Rough LPs.
AU667028B2 (en) Lipid A composition as immunogenic agents to prevent or treat gram-negative bacterial infections
WO1990001947A1 (fr) Vaccin a affinite associee
Chaicumpa et al. Immunogenicity of liposome-associated oral cholera vaccine prepared from combined Vibrio cholerae antigens
AU1747097A (en) Compositions and methods for administering borrelia burgdorferi antigens
RU2683027C2 (ru) Поливалентная иммунизирующая и/или терапевтическая композиция для применения при бактериальных инфекциях или пищевом отравлении, в частности сальмонеллёзе, способ получения этой композиции, её применение и вакцина, содержащая эту композицию
Parmar Development and characterization of a liposomal subunit vaccine against Neisseria Gonorrhoeae
CA1334165C (fr) Vaccin avec antigenes associes par affinite
Vitas et al. Protective effect of Brucella outer membrane complex-bearing liposomes against experimental murine brucellosis
EP1766008A1 (fr) Dosage de criblage phage
KR0137360B1 (ko) 인플루엔자 백신과 새로운 보조제

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM GW HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 74912/98

Country of ref document: AU

ENP Entry into the national phase

Ref document number: 2289760

Country of ref document: CA

Ref country code: CA

Ref document number: 2289760

Kind code of ref document: A

Format of ref document f/p: F

ENP Entry into the national phase

Ref country code: JP

Ref document number: 1998 549589

Kind code of ref document: A

Format of ref document f/p: F

WWE Wipo information: entry into national phase

Ref document number: 1998922339

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWE Wipo information: entry into national phase

Ref document number: 09423546

Country of ref document: US

WWP Wipo information: published in national office

Ref document number: 1998922339

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1998922339

Country of ref document: EP