JP2010187700A - 保存されたナイセリア抗原 - Google Patents
保存されたナイセリア抗原 Download PDFInfo
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- JP2010187700A JP2010187700A JP2010108832A JP2010108832A JP2010187700A JP 2010187700 A JP2010187700 A JP 2010187700A JP 2010108832 A JP2010108832 A JP 2010108832A JP 2010108832 A JP2010108832 A JP 2010108832A JP 2010187700 A JP2010187700 A JP 2010187700A
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Abstract
【解決手段】最大の株間認識および反応性を確実にするために、異なるナイセリア種、血清群および株の間で保存されるタンパク質の領域が、使用され得る。本発明は、大部分のナイセリア属、特に、N.meningitidisおよびN.gonorrhoeaeに共有されるアミノ酸配列の伸長物を含むタンパク質を提供する。ナイセリアタンパク質のフラグメントを含むタンパク質であって、ここでこのフラグメントが、7以上の連続した保存されたアミノ酸から構成され、但し、このタンパク質は、全長ナイセリアタンパク質ではない。
【選択図】なし
Description
本発明は、Neisseria細菌由来の保存された抗原に関する。
Neisseria meningitidisおよびNeisseria gonorrhoeaeは、非運動性のグラム陰性双球菌であり、ヒトにおいて病原体である。
(項目1)ナイセリアタンパク質のフラグメントを含むタンパク質であって、ここで該フラグメントが、7以上の連続した保存されたアミノ酸から構成され、但し、該タンパク質は、全長ナイセリアタンパク質ではない、タンパク質。
(項目2)前記フラグメントが、20以上の連続した保存されたアミノ酸から構成される、項目1に記載のタンパク質。
(項目3)前記保存されたアミノ酸が、少なくとも50%以上のナイセリア属参照集団において見出される、項目1または2に記載のタンパク質。
(項目4)前記参照集団が、複数の異なるナイセリア種を含み、好ましくは、N.meningitidisおよびN.gonorrhoeaeを含む、項目3に記載のタンパク質。
(項目5)前記参照集団が、複数の異なるN.meningitidisの血清群を含む、項目4に記載のタンパク質。
(項目6)前記参照集団が、N.meningitidis A、株Z2491;N.meningitidis B、株NG6/88;N.meningitidis W、株A22;およびN.gonorrhoeae、株Ng F62を含む、項目3または4に記載のタンパク質。
(項目7)前記参照集団が、N.meningitidis A、株Z2491;N.meningitidis B、株NG6/88;およびN.meningitidis W、株A22を含む、項目5に記載のタンパク質。
(項目8)WO99/24578、WO99/36544、WO99/57280またはWO00/22430に開示されるタンパク質のフラグメントを含む、項目1〜7のいずれかに記載のタンパク質。
(項目9)ORF4、ORF40、ORF46、タンパク質225、タンパク質235、タンパク質287、タンパク質519、タンパク質726、タンパク質919およびタンパク質953のうちの1つ以上のフラグメントを含む、項目8に記載のタンパク質。
(項目10)Tettelinら[Science(2000)287:1809−1815]に開示されるタンパク質のフラグメントを含む、項目1〜7のいずれか1項に記載のタンパク質。
(項目11)項目1〜10のいずれかに記載のタンパク質をコードする、核酸。
(項目12)医薬品としての使用のための、項目1〜10のいずれか1項に記載のタンパク質または項目11に記載の核酸。
(項目13)ナイセリア細菌に起因する感染を処置または予防するための医薬品の製造における、項目1〜10のいずれか1項に記載のタンパク質または項目11に記載の核酸の使用。
(項目14)多特異的診断試薬の製造における、項目1〜10のいずれか1項に記載のタンパク質または項目11に記載の核酸の使用。
(項目15)以下のアミノ酸配列:
(本発明の記載)
最大の株間認識および反応性を確実にするために、異なるナイセリア種、血清群および株の間で保存されるタンパク質の領域が、使用され得る。従って、本発明は、大部分のナイセリア属、特に、N.meningitidisおよびN.gonorrhoeaeに共有されるアミノ酸配列の伸長物を含むタンパク質を提供する。
・N.meningitidis A、株Z2941
・N.meningitidis B、株NG6/88
・N.meningitidis W、株A22
・N.gonorrhoeae、株Ng F62。
・N.meningitidis A、株Z2941
・N.meningitidis B、株NG6/88
・N.meningitidis W、株A22。
本発明の実施は、他に示されなければ、分子生物+学、微生物学、組換えDNA、および免疫学の従来技術を使用し、これらは当該分野の技術の範囲内である。このような技術は以下の文献で十分説明されている(例えば、Sambrook Molecular Cloning:A Laboratory Manual 第2版(1989);DNA Cloning,第I巻および第ii巻(D.N Glover編 1985);Oligonucleotide Synthesis(M.J.Gait編 1984);Nucleic Acid Hybridization(B.D.HamesおよびS.J.Higgins編 1984);Transcription and Translation(B.D.HamesおよびS.J.Higgins編 1984);Animal Cell Culture(R.I.Freshney編 1986);Immobilized Cells and Enzymes(IRL Press,1986);B.Perbal,A Practical Guide to Molecular Cloning(1984);the Methods in Enzymologyシリーズ(Academic Press,Inc.),特に第154巻および第155巻;Gene Transfer Vectors for Mammalian Cells(J.H.MillerおよびM.P.Calos編 1987,Cold Spring Harbor Laboratory);MayerおよびWalker,編(1987),Immunochemical Methods in Cell and Molecular Biology(Academic Press,London);Scopes,(1987)Protein Purification:Principles and Practice,第2版(Springer−Verlag,N.Y.)、およびHandbook of Experimental Immunology,第I巻−第IV巻(D.M.WeirおよびC.C.Blackwell編 1986)。
Xを含む組成物は、組成物中の全X+Yの少なくとも85重量%がXであるとき、Yを「実質的に含まない」。好ましくは、Xは、組成物中の全X+Yの少なくとも約90重量%を、さらに好ましくは少なくとも約95重量%または99重量%さえをも含む。
ナイセリアヌクレオチド配列は、種々の異なる発現系;例えば、哺乳動物細胞、バキュロウイルス、植物、細菌、および酵母と共に使用される発現系において発現され得る。
哺乳動物発現系は当該分野において公知である。哺乳動物プロモーターは、哺乳動物RNAポリメラーゼを結合し得、そしてコード配列(例えば、構造遺伝子)のmRNAへの下流(3’)転写を開始し得る任意のDNA配列である。プロモーターは、転写開始領域(これはコード配列の5’末端の近位に通常位置する)およびTATAボックス(転写開始部位の25〜30塩基対(bp)上流に通常位置する)を有する。TATAボックスは、その正しい部位においてRNAポリメラーゼIIにRNA合成を開始させるよう指示すると考えられている。哺乳動物プロモーターはまた、TATAボックスの100〜200bp上流以内に通常位置する上流プロモーターエレメントを含む。上流プロモーターエレメントは、転写が開始され、そしていずれかの方向において作用し得る割合を決定する(Sambrookら(1989)「Expression of Cloned Genes in Mammalian Cells」 Molecular Cloning:A Laboratory Manual、第2版)。
タンパク質をコードしているポリヌクレオチドはまた、適切な昆虫の発現ベクター内に挿入され得、そしてそのベクター内で、制御エレメントに作動可能に連結される。ベクターの構築には、当該分野で公知の技術を使用する。一般に、その発現系の構成要素として、以下を含む:バキュロウイルスゲノムのフラグメント、および発現させる異種遺伝子の挿入用の簡便な制限部位の両方を有する転移ベクター(通常は細菌ベクター);転移ベクター内のバキュロウイルスに特異的なフラグメントに相同性のある配列を有する野生型バキュロウイルス(これは、バキュロウイルスゲノム内への異種遺伝子の相同組換えを可能にする);ならびに適切な昆虫宿主細胞および生育培地。
当該分野で公知の多くの植物細胞培養物および全植物の遺伝子発現系が存在する。例示的な植物細胞遺伝子発現系としては、米国特許第5,693,506号;米国特許第5,659,122号;米国特許第5,608,143号のような特許に記載されるものが挙げられる。植物細胞培養物における遺伝子発現の別の例は、Zenk,Phytochemistry 30:3861−3863(1991)に記載されている。植物タンパク質のシグナルペプチドの記載は、上記の参考文献に加え、以下に示すものの中においても確認される;Vaulcombeら,Mol.Gen.Genet.209:33−40(1987);Chandlerら,Plant Molecular Biology 3:407−418(1984);Rogers,J.Biol.Chem.260:3731−3738(1985);Rothsteinら,Gene 55:353−356(1987);Whittierら,Nucleic Acids Research 15:2515−2535(1987);Wirselら,Molecular Microbiology 3:3−14(1989);Yuら,Gene 122:247−253(1992)。植物ホルモン(ジベレリン酸およびジベレリン酸により誘導される分泌酵素)による植物遺伝子発現の調節の記載は、R.L.JonesおよびJ.MacMillin,Gibberellins:Advanced Plant Physiology,Malcolm B.Wilkins編 1984 Pitman Publishing Limited,London,21−52頁の中に確認され得る。他の代謝調節性遺伝子が記載される参考文献は、以下である;Sheen,Plant Cell,2:1027−1038(1990);Maasら,EMBO J.9:3447−3452(1990);BenkelおよびHickey、Proc.Natl.Acad.Sci.84:1337−1339(1987)。
細菌の発現技術は、当該分野で公知である。細菌のプロモーターは、細菌のRNAポリメラーゼに結合し得、そしてコード配列(例えば、構造遺伝子)の下流方向(3’方向)へのmRNAへの転写を開始し得る任意のDNA配列である。プロモーターは、通常、コード配列の5’末端に近接して配置される転写開始領域を有する。この転写開始領域は、通常、RNAポリメラーゼ結合部位および転写開始部位を含む。細菌のプロモーターはまた、オペレーターと呼ばれる第二のドメインを有し得、これはRNA合成が始まる近接のRNAポリメラーゼ結合部位と重複し得る。オペレーターは、遺伝子リプレッサータンパク質が、オペレーターに結合し、そのため特定の遺伝子の転写を阻害し得るような、負の調節された(誘導性の)転写を可能にする。構成的発現は、オペレーターのような負の調節エレメントの非存在下で起こり得る。さらに、正の調節は、遺伝子アクチベータータンパク質結合配列により達成され得、その配列は、存在する場合には通常、RNAポリメラーゼ結合配列の(5’)側に近接している。遺伝子アクチベータータンパク質の例としては、カタボライト活性化タンパク質(CAP)があり、それはEscherichia coli(E.coli)におけるlacオペロンの転写の開始を補助する(Raibaudら(1984)Annu.Rev.Genet.18:173)。従って、調節される発現は、正または負のいずれかであり、それによって転写を増強するかまたは低下し得る。
酵母発現系もまた、当業者に公知である。酵母プロモーターは、酵母RNAポリメラーゼに結合可能であり、そしてコード配列(例えば、構造遺伝子)からmRNAへの下流の(3’側の)転写を開始し得る、任意のDNA配列である。プロモーターは、通常、コード配列の5’末端の近位に位置する転写開始領域を有する。この転写開始領域は、通常、RNAポリメラーゼ結合部位(「TATAボックス」)および転写開始部位を含む。酵母プロモーターはまた、上流アクチベーター配列(UAS)と呼ばれる第2のドメインを有し得、これは、もし存在するならば、通常、構造遺伝子とは遠位である。このUASは、調節される(誘導できる)発現を可能にする。構成的発現は、UASの非存在下で生じる。調節される発現は、正または負のいずれかであり得、それによって転写を増加させるかまたは減少させるかのいずれかであり得る。
196 056を参照のこと。別の例はユビキチン融合タンパク質である。このような融合タンパク質は、外来タンパク質からユビキチンを切断するプロセシング酵素(例えば、ユビキチン特異的プロセシングプロテアーゼ)のための部位を好ましくは保持する、ユビキチン領域を伴って作製される。従って、この方法を通じて、ネイティブな外来タンパク質は、単離され得る(例えば、WO88/024066)。
あるいは、上記成分のうちのいくつかは、組み立てられて形質転換ベクターになり得る。形質転換ベクターは、通常、上記のように、レプリコンにおいて保持されるか、または組み込みベクターに開発されるかのいずれかである、選択マーカーから構成される。
本明細書で用いるとき、用語「抗体」は、少なくとも1つの抗体結合部位を含むポリペプチドまたは一群のポリペプチドをいう。「抗体結合部位」は、抗体の抗原との結合を可能にする抗原のエピトープに相補的な内部表面形状および荷電分布をもつ三次元結合空間である。「抗体」は、例えば、脊椎動物抗体、ハイブリッド抗体、キメラ抗体、ヒト化抗体、改変抗体、一価抗体、Fabタンパク質、および単一ドメイン抗体を含む。
薬学的組成物は、本発明のポリペプチド、抗体または核酸のいずれかを含み得る。薬学的組成物は、請求項に記載された発明のポリペプチド、抗体、またはポリヌクレオチドのいずれかの治療的有効量を含む。
一旦処方されると、本発明の組成物は被験体に直接投与され得る。処置されるべき被験体は動物であり得;特に、ヒト被験体が処置され得る。
本発明によるワクチンは、予防的(すなわち感染を防ぐ)または治療的(すなわち感染後疾患を処置する)のいずれかであり得る。
哺乳動物中の発現のためにこの哺乳動物に送達される、本発明の治療剤のコード配列を含む構築物の送達のための遺伝子治療ビヒクルは、局所的または全身的のいずれかで送達され得る。これらの構築物は、インビボまたはエキソビボ様式のウイルスまたは非ウイルスベクターアプローチを利用し得る。このようなコード配列の発現は、内因性哺乳動物プロモーターまたは異質プロモーターを用いて誘導され得る。インビボにおけるコード配列の発現は、構成的または調節されるかのいずれかであり得る。
一旦処方されると、本発明のポリヌクレオチド組成物は、(1)被験体に直接);(2)エキソビボで被験体由来の細胞に送達されて;または(3)組換えタンパク質の発現のためにインビトロで、投与され得る。処置される被験体は、哺乳動物または鳥類であり得る。ヒト被験体もまた処置され得る。
上記に記載の薬学的に受容可能なキャリアおよび塩に加えて、以下のさらなる薬剤がポリヌクレオチド組成物および/またはポリペプチド組成物とともに使用され得る。
1つの例は、限定することなく以下を包含するポリペプチドである:アシアロオロソムコイド(ASOR);トランスフェリン;アシアロ糖タンパク質;抗体;抗体フラグメント;フェリチン;インターロイキン;インターフェロン;顆粒球マクロファージコロニー刺激因子(GM−CSF)、顆粒球コロニー刺激因子(G−CSF)、マクロファージコロニー刺激因子(M−CSF)、幹細胞因子およびエリスロポエチン。ウイルス抗原(例えば、エンベロープタンパク質)もまた、使用され得る。また、他の侵襲性生物由来のタンパク質(例えば、RIIとして知られるPlasmodium falciparumの環境スポロゾイト(circumsporozoite)タンパク質由来の17アミノ酸ペプチド)。
薬学的組成物に包含され得る他の群は、例えば、ホルモン、ステロイド、アンドロゲン、エストロゲン、甲状腺ホルモン、またはビタミン、葉酸である。
また、ポリアルキレングリコールが、所望のポリヌクレオチド/ポリペプチドとともに薬学的化合物に含有され得る。好ましい実施態様において、ポリアルキレングリコールは、ポリエチレングリコールである。さらに、モノサッカリド、ジサッカリド、またはポリサッカリドが含有され得る。この局面の好ましい実施態様において、このポリサッカリドは、デキストランまたはDEAEデキストランである。また、キトサンおよびポリ(乳酸−コ−グリコリド)が、薬学的化合物中に含有され得る。
所望のポリヌクレオチド/ポリペプチドはまた、被験体またはそれに由来する細胞への送達の前に、脂質中にカプセル化され得るか、またはリポソーム中にパッケージングされ得る。
さらに、リポタンパク質が、送達されるポリヌクレオチド/ポリペプチドと共に含まれ得る。利用されるリポタンパク質の例としては、キロミクロン、HDL、IDL、LDL、およびVLDLが挙げられる。これらのタンパク質の変異体、フラグメント、または融合物もまた、使用され得る。また、天然に存在するリポタンパク質の改変体(例えば、アセチル化されたLDL)が使用され得る。これらのリポタンパク質は、リポタンパク質レセプターを発現する細胞へのポリヌクレオチドの送達を標的化し得る。好ましくは、リポタンパク質が、送達されるポリヌクレオチドと共に含まれる場合、他の標的化リガンドはその組成物中には含まれない。
ポリカチオン性薬剤は、送達される所望のポリヌクレオチド/ポリペプチドを有する組成物中に、リポタンパク質を伴って、またはリポタンパク質を伴わずに含まれ得る。
本発明のNeisseria抗原は、抗体レベルを検出するためのイムノアッセイにおいて使用され得る(または、逆に抗Neisseria抗体は抗原レベルを検出するために使用され得る)。充分に規定された組換え抗原に基づくイムノアッセイは、侵襲性の診断方法と置き換えるために開発され得る。生物学的サンプル(例えば、血液サンプルまたは血清サンプルを含む)内のNeisseriaタンパク質に対する抗体が検出され得る。このイムノアッセイの設計は、多くのバリエーションの対象であり、そして種々のこれらは当該分野で公知である。イムノアッセイのプロトコルは、例えば、競合アッセイ、または直接反応アッセイ、またはサンドイッチ型アッセイに基づき得る。プロトコルはまた、例えば、固体支持体を使用し得るか、または免疫沈降であり得る。ほとんどのアッセイは、標識された抗体またはポリペプチドの使用を含み、その標識は、例えば、蛍光分子、化学発光分子、放射性分子、または色素分子であり得る。プローブからのシグナルを増幅するアッセイはまた公知であり;これらの例は、ビオチンおよびアビジンを利用するアッセイ、ならびに酵素標識および酵素媒介イムノアッセイ(例えば、ELASAアッセイ)である。
「ハイブリダイゼーション」とは、水素結合による2つの核酸配列の互いの会合をいう。代表的には、一方の配列は、固体支持体に固定され、そして他方は溶液中で遊離している。次いで、この2つの配列は水素結合に好ましい条件下で互いに接触して配置される。この結合に影響を与える因子は以下を含む:溶媒のタイプおよび容量;反応温度;ハイブリダイゼーションの時間;撹拌;液相の配列の固体支持体への非特異的な付着をブロックする薬剤(Denhardt試薬またはBLOTTO);配列の濃度;配列の会合の速度を増大させる化合物(硫酸デキストランまたはポリエチレングリコール)の使用;およびハイブリダイゼーション後の洗浄条件のストリンジェンシー。Sambrookら(前出)第2巻、第9章、9.47〜9.57頁を参照のこと。
Tm=81+16.6(log10Ci)+0.4[%(G+C)]−0.6(%ホルムアミド)−600/n−1.5(%ミスマッチ)。
ここでCiは塩濃度(一価イオン)であり、そしてnは塩基対内のハイブリッドの長さである(MeinkothおよびWahl(1984)Anal.Biochem.138:267−284からわずかに改変した)。
一般的に、50%ホルミアミドの存在下で都合よいハイブリダイゼーション温度は、標的フラグメントに95%〜100%相同であるプローブについて42℃、90%〜95%相同性では37℃、85%〜90%相同性については32℃である。より低い相同性については、ホルムアミド含量が低くされ、そして上記の式を用いてそれに応じて温度が調整されるべきである。プローブと標的フラグメントとの間の相同性が未知である場合、最も単純なアプローチは、いずれもストリンジェントではないハイブリダイゼーション条件および洗浄条件で開始することである。オートラジオグラフィー後に非特異的バンドまたは高いバックグラウンドが観察される場合、フィルターは高ストリンジェンシーで洗浄され得、そして再び曝露され得る。曝露のために必要な時間がこのアプローチを非実用的にする場合、いくつかのハイブリダイゼーションおよび/または洗浄ストリンジェンシーが並行して試験されるべきである。
(実施例1)
WO99/36544の実施例1は、「ORF40」といわれるナイセリアタンパク質のクローニングおよび発現を開示する。A血清型およびB血清型のN.meningitidis由来のタンパク質およびDNA配列が開示され、そして完全なタンパク質配列は、601アミノ酸(aa)の重複部分にわたり83.7%の同一性を示す。
WO99/24578の実施例26は、「ORF4」といわれるナイセリアタンパク質のクローニングおよび発現を開示する。A血清型およびB血清型のN.meningitidis由来のタンパク質およびDNA配列が、N.gonorrhoeae由来の配列と共に開示される。アミノ酸レベルでの配列の間の同一性は以下である:
WO99/57280の実施例16は、「225」といわれるナイセリアタンパク質のクローニングおよび発現を開示する。A血清型およびB血清型のN.meningitidis由来のタンパク質およびDNA配列が、N.gonorrhoeae由来の配列と共に開示される。
WO99/57280の実施例16は、「235」といわれるナイセリアタンパク質のクローニングおよび発現を開示する。A血清型およびB血清型のN.meningitidis由来のタンパク質およびDNA配列が、N.gonorrhoeae由来の配列と共に開示される。
WO99/57280の実施例16は、「287」といわれるナイセリアタンパク質のクローニングおよび発現を開示する。A血清型およびB血清型のN.meningitidis由来のタンパク質およびDNA配列が、N.gonorrhoeae由来の配列と共に開示される。
WO99/57280の実施例16は、「519」といわれるナイセリアタンパク質のクローニングおよび発現を開示する。A血清型およびB血清型のN.meningitidis由来のタンパク質およびDNA配列が、N.gonorrhoeae由来の配列と共に開示される。
WO99/57280の実施例16は、「919」といわれるナイセリアタンパク質のクローニングおよび発現を開示する。A血清型およびB血清型のN.meningitidis由来のタンパク質およびDNA配列が、N.gonorrhoeae由来の配列と共に開示される。
WO99/23578の実施例55は、「ORF46」といわれるNeisserialタンパク質のクローニングおよび発現を開示する。血清型AおよびB N.meningitidis由来のタンパク質およびDNA配列を、N.gonorrhoeae由来の配列と一緒に開示する。
WO99/57280は、「726」といわれるNeisserialタンパク質のクローニングおよび発現を開示する。血清型AおよびB N.meningitidis由来のタンパク質およびDNA配列を開示する。
WO99/57280は、「953」といわれるNeisserialタンパク質のクローニングおよび発現を開示する。血清型AおよびB N.meningitidis由来のタンパク質およびDNA配列を、N.gonorrhoeae由来の配列と一緒に開示する。
図8は、6つの遺伝子フラグメントのMLST[Maidenら(1998)PNAS USA 95:3140から採用]に基づく、107のN.meningitidis菌株の間の遺伝的関係を示す樹状図である。この樹状図は、meningococcus血清型B(矢印)の代表的な菌株を選択するために使用され得る。5つの付加的な菌株(これについて、高度に病原性の系統に対する遺伝的指示(genetic assignment)が、Wangら[J.Infect.Dis(1993)167:1320]、Seilerら[Mol.Microbiol.(1996)19:841]、およびVirjiら[Mol.Microbiol.(1992)6:1271]によって独立して決定される)を、この樹状図上に上書きし、そしてアスタリスクによって示す。MenBの22の菌株に加えて、MenAの3つの菌株、MenCの2つの菌株、およびMen Y、X、ZおよびW135の各菌株の1つを使用した。これらを、名前の前に太字の文字で示した。系統発生データが入手できない場合、菌株を樹の外側に示した。高度に病原性の菌株ET−5、ET−37およびIV−1を示した。
図9aは、N.meningitidisの、タンパク質225、235、287、519、919、ORF4およびORF40についてのアミノ酸配列の可変性の概略表示である。横軸は、MC58の配列を表す。MenB菌株内のアミノ酸の差異を、横軸の上の垂直の線によって示す;血清型A、C、Y、X、ZおよびW135内の差異を、この軸の下の線によって示す。この垂直の線の高さは、アミノ酸の差異を有する菌株の数を表す。従って、ピークは可変領域を示す。225および287の下のバンドは、いくつかの菌株から欠けている配列セグメントを表す。
抗原ORF4、225、235、519および919を、種々の菌株についてウエスタンブロットによって分析した。その結果を図20に示す。225の場合、このブロットは異なる菌株における異なるサイズのフラグメントを示し、矢印は正確なサイズのバンドを示す。225は、規定された反復の欠失および挿入の領域を含み、そしてこのブロット上のフラグメントのサイズは、遺伝子可変性データに一致する。
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- 明細書中に記載の発明。
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- 2000-04-28 MX MXPA01010924A patent/MXPA01010924A/es active IP Right Grant
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- 2000-04-28 EP EP10179801.5A patent/EP2278007B1/en not_active Expired - Lifetime
- 2000-04-28 US US09/980,602 patent/US7368261B1/en not_active Expired - Fee Related
- 2000-04-28 AU AU43096/00A patent/AU4309600A/en not_active Abandoned
- 2000-04-28 RU RU2001132331/13A patent/RU2245366C2/ru not_active IP Right Cessation
- 2000-04-28 EP EP00922818A patent/EP1228217B1/en not_active Expired - Lifetime
- 2000-04-28 NZ NZ530640A patent/NZ530640A/en not_active IP Right Cessation
- 2000-04-28 ES ES00922818T patent/ES2397918T3/es not_active Expired - Lifetime
- 2000-04-28 CN CNB008096244A patent/CN100392082C/zh not_active Expired - Fee Related
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- 2000-04-28 BR BR0010130-3A patent/BR0010130A/pt not_active Application Discontinuation
- 2000-04-28 DK DK00922818.0T patent/DK1228217T3/da active
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2007
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2009
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2010
- 2010-05-10 JP JP2010108832A patent/JP2010187700A/ja not_active Withdrawn
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2013
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- 2013-06-13 JP JP2013124476A patent/JP2013215200A/ja active Pending
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CY1113650T1 (el) | 2016-06-22 |
CA2372235A1 (en) | 2000-11-09 |
EP1228217B1 (en) | 2012-11-21 |
CN1451046A (zh) | 2003-10-22 |
US20100041868A1 (en) | 2010-02-18 |
JP2013215200A (ja) | 2013-10-24 |
EP1228217A2 (en) | 2002-08-07 |
ES2397918T3 (es) | 2013-03-12 |
ES2522667T3 (es) | 2014-11-17 |
PT1228217E (pt) | 2013-01-28 |
NZ530640A (en) | 2006-06-30 |
WO2000066741A3 (en) | 2002-06-13 |
WO2000066741A2 (en) | 2000-11-09 |
RU2001132331A (ru) | 2005-01-27 |
US7368261B1 (en) | 2008-05-06 |
US20080132448A1 (en) | 2008-06-05 |
EP2278007A1 (en) | 2011-01-26 |
DK1228217T3 (da) | 2013-02-25 |
EP2290083A1 (en) | 2011-03-02 |
RU2245366C2 (ru) | 2005-01-27 |
EP2278007B1 (en) | 2014-04-16 |
US9169301B2 (en) | 2015-10-27 |
ES2477194T3 (es) | 2014-07-16 |
AU4309600A (en) | 2000-11-17 |
JP2003518363A (ja) | 2003-06-10 |
NZ581940A (en) | 2011-07-29 |
MXPA01010924A (es) | 2002-05-06 |
NZ571167A (en) | 2010-05-28 |
BR0010130A (pt) | 2002-06-04 |
CN100392082C (zh) | 2008-06-04 |
US7604810B2 (en) | 2009-10-20 |
EP2290083B1 (en) | 2014-08-20 |
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