JP5695287B2 - 微小流体の核酸解析 - Google Patents
微小流体の核酸解析 Download PDFInfo
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Description
即時の通常特許出願は、2002年10月2日に出願された米国仮特許出願番号60/415,407から優先権を主張する。即時の通常特許出願はまた、2003年1月31日に出願された米国仮特許出願番号60/444,022から優先権を主張する。即時の通常特許出願は、2003年8月11日に出願された米国仮特許出願番号60/494,377および米国仮特許出願番号60/494,388からさらに優先権を主張する。従って、これらの以前に出願された仮特許出願の各々が、全ての目的のために本明細書により参考として援用される。
本明細書中に記載されている研究は、部分的に、Army Research Office(No.DAAD19−00−1−0392)およびDARPA Bioflips programからのNSF助成金によって支援されている。従って、米国政府は本発明の特定の権利を有する。
多くの生態系において、微生物の個体集団の99%以上が、実験室の培養に抵抗性であるという証明がある。N.R.Pace「A Molecular View of Microbial Diversity and the Biosphere」、Science 276、734(1997)。これにより、人間の体内での微生物の生態系は、以前に推測していたよりも複雑で、培養不能な微生物のいくらか、または多くは、病原菌であり得るということが示唆される。D.A.Relman「The Search for Unrecognized Pathogens」、Science 284、1308(1999)。
種々の環境から採取された細胞およびウイルス由来の核酸が微小流体の技術を利用して、精製および発現され得る。本発明の1つの実施形態に従って、細胞またはウイルスの個々あるいは小さな集団が希釈、分類および/またはセグメント化によって、微小流体チャンバ内に隔離され得る。隔離された細胞またはウイルスは微小流体チャンバ内で直接溶解され得、その結果得られた核酸が、親和性ビーズに曝露することによって精製される。その後の精製された核酸の溶出の後に、連結および細胞形質転換が続き得る。1つの特定の適用において、細胞の隔離、溶解および核酸精製が、ゲノムDNAおよび相補鎖DNAのライブラリーを作製するために高度に並行化した微小流体アーキテクチャーを利用して行われ得る。
(I.微小製造の概要)
以下の議論は、2003年9月24日に出願された米国特許出願10/___,___号(代理人整理番号20174C−009410US)、2002年10月4日に出願された10/265,473号、2002年4月5日に出願された10/118,466号、2001年4月6日に出願された09/826,585号、2000年11月28日に出願された09/724,784号、および2000年6月27日に出願された09/605,520号に概ね記載されているように、エラストマー物質を利用する微小製造した流体デバイスの構成に関係している。これによって、これらの以前に出願された特許出願は、あらゆる目的のためにその全体が本明細書により参考として援用される。
本発明を製造する例示的な方法が、本明細書中に提供されている。本発明は、これらの方法の1つまたは他の方法による製造に限られないことが理解されるべきである。むしろ、本方法を改変することを含む、本発明の微小構造を製造する他の適切な方法もまた、意図されている。
微小製造は、本発明の実施形態に従って製造されたエラストマー構造の特徴の大きさについて言及している。一般に、微小製造構造のうちの少なくとも1つの寸法の変化はミクロンレベルで、少なくとも1つの寸法が微視的(すなわち、1000μm以下)に制御される。微小製造は一般に、微視的なレベルの特徴の寸法を生産するために設計されるフォトリソグラフィーおよびスピンコーティングのような半導体またはMEMS製造技術を含み、微小製造された構造の寸法のうちの少なくともいくつかは、適度に構造を分解/画像化するためにマイクロスコープを必要とする。
好ましくはエラストマー層は、パターン化されたエラストマー層を含むポリマーに固有である化学的性質を使用して、化学的に共に結合される。最も好ましくは、結合は2つの成分「添加硬化」結合を含む。
Allcockら、Contemporary Polymer Chemistry第2版は、ガラス転移温度と液化温度との間の温度で存在するポリマーとして一般のエラストマーについて記載している。ポリマー鎖は容易にねじれ運動を受けて、力に応じて主鎖を伸ばすことを可能にし、力を欠く場合、先の形状をとるように骨格を再び巻くので、エラストマー物質は弾力性を示す。一般に、エラストマーは力が適用された場合変形するが、次いで力が離れた場合それらの原形に戻る。エラストマー物質によって示された弾力性は、ヤング率によって特徴づけられ得る。約1Pa〜1TPaの間、さらに好ましくは約10Pa〜100GPaの間、さらに好ましくは約20Pa〜1GPaの間、さらに好ましくは約50Pa〜10MPaの間、およびさらに好ましくは約100Pa〜1MPaの間のヤング率を有するエラストマー物質は、本発明に基づいて有益であるが、これらの範囲外のヤング率を有するエラストマー物質もまた、特定用途の必要次第で利用され得る。
ポリイソプレン、ポリブタジエン、およびポリクロロプレンは全て、ジエンモノマーから重合されて、その結果として重合された場合モノマーにつき1つの二重結合を有する。この二重結合は、ポリマーが加硫によってエラストマーに変換されることを可能にする(本質的に、硫黄は熱によって二重結合の間の架橋を形成するように使用される)。このことは、層の不完全な加硫によって同質の多層ソフトリソグラフィーが容易に結合することを可能にする;フォトレジストカプセル化は、同様の機構によって可能である。
純粋なポリイソブチレンは二重結合を持たないが、重合に少量(約1%)のイソプレンを含むことによってエラストマーとして使用されるように架橋される。イソプレンモノマーは、ポリイソブチレン骨格でペンダント二重結合を与え、次いで上記のように加硫され得る。
ポリ(スチレン−ブタジエン−スチレン)はリビングアニオン重合によって生産され(すなわち、反応において自然な連鎖停止段階がない)、「生きた(live)」ポリマーの末端が、硬化されたポリマーの中に存在できる。このことは、本フォトレジストカプセル化システムに対する自然な候補にさせる(硬化された層の上に注がれた液体層の中にたくさんの反応を起こしていないモノマーがある場合)。不完全な硬化は、同質の多層ソフトリソグラフィー(A−A結合)を可能にする。化学的性質もまた、余分なブタジエン(「A」)およびカップリング剤を有する1つの層ならびにブタジエンの無い他の層(「B」)を作ることを容易にする(異質の多層ソフトリソグラフィーにおいて)。SBSは「熱硬化性のエラストマー」であり、これは特定の温度より上で溶けて可塑性(弾性に反対するような)になることを意味する;温度を下げていくと再びエラストマーが生じる。このように、層は熱によって共に結合され得る。
ポリウレタンは、ジ−イソシアネート(A−A)およびジ−アルコールまたはジ−アミン(B−B)から生成される;ジ−イソシアネートおよびジ−アルコール/アミンの多数の多様性があるので、ポリウレタンの異なるタイプの数は莫大である。ポリマーA対Bの性質は、しかしながら、それらをちょうどRTV615のように異質な多層ソフトリソグラフィにとって有効にさせる:1つの層の中の過剰のA−Aおよび他の層の中の過剰のB−Bを使用することによる。
シリコーンポリマーは、おそらく最大の構造多様性を有し、商業的に利用できる製剤の最大数をほとんど確実に有する。RTV615のビニルと(Si−H)の架橋(異質の多層ソフトリソグラフィおよびフォトレジストカプセル化の両方を可能にする)は、すでに述べられているが、これはシリコーンポリマー化学で使用される数個の架橋方法のうちの単なる1つである。
図7Bおよび7Hは共に、第2流動チャネルを加圧することによる第1流動チャネルの閉鎖を示し、図7B(図7Aに相当する流動チャネル32を通して切り取った正面断面図)で、開いた第1流動チャネル30を示し;図7Hで、第2流動チャネル32の加圧によって閉じられた第1流動チャネル30を示す。
そのようなバルブはチャネルの屋根を動かすことによってそれら自身(すなわち:膜25を動かすこと)が作動されるので、この技術によって製造されたバルブおよびポンプは正確にゼロデッドボリュームを有し、この技術によって作られた切り換えバルブはおよそバルブのアクティブボリュームと同等のデッドボリュームを有する、例えば、約100×100×10μm=100pLである。膜を動かすことによって消滅されたそのようなデッドボリュームおよびエリアは、既知の従来の微小バルブよりもおよそ2桁小さい。より小さいおよびより大きいバルブならびに切り換えバルブは本発明に考慮されており、デッドボリュームの範囲の包括的なリストは、1aLから1μL、100aLから100nL、1fLから10nL、100fLから1nL、および1pLから100pLを含む。
(1) w=(BPb4)/(Eh3)、ここで:
w=プレートの偏向;
B=形状係数(長さ対幅およびプレートの端の支持体に依存している);
P=付与される圧力;
b=プレート幅
E=ヤング率;および
h=プレート厚さ
このようにこの極めて単純化した式においてでさえ、圧力に応答するエラストマー膜の偏向は:膜の長さ、幅、および厚さ、膜の可撓性(ヤング率)、ならびに付与された作動力によって変化する。これらのパラメータの各々は、本発明に従う特定のエラストマーデバイスの実寸法および物理組成に依存して広く変わるので、膜厚さおよび弾性、チャネル幅、ならびに作動力の広い範囲は、本発明によって考慮されている。
本発明の流動チャネルは、異なる横断面のサイズおよび形状で必要に応じて設計され得、それらの所望の適用に依存して、異なる利点を提供する。例えば、下方の流動チャネルの横断面の形状は、湾曲した上面(全長に沿った、または上方の交差チャネルの下に配置された範囲のいずれか)を有し得る。そのような湾曲した上面は、以下のように、バルブの密閉を促進する。
図12Aおよび12Bは、1つのオン/オフバルブの図を示し、上記で説明した(例えば、図7A)システムと同一である。図13Aおよび13Bは、図12に見られるが、共にネットワーク化されているような1つのアドレス可能なオン/オフバルブ複数から構成された蠕動ポンピングシステムを示す。図14は、図13の蠕動ポンピングシステムの回転数に対して実験的に達成されたポンピング速度を示すグラフである。図15Aおよび15Bは、1つの制御ラインによって制御可能である複数の流動チャネルの概略図を示す。このシステムはまた、ともに多重化されるが、図12のそれとは異なる配置である、図12の1つのアドレス可能なオン/オフバルブ複数から構成される。図16は、選択されたチャネルを通して流体流動を可能にするのに適用された多重化システムの概略図であり、ともに結合またはネットワーク化された、図12の1つのオン/オフバルブ複数から構成される。
さらに別の新規な実施形態において、流体通路は、2つの垂直な方向のいずれかの流動に選択的に方向づけされ得る。「切り換え可能な流動アレイ」システムのような例が、図17A〜図17Dに提供されている。図17Aは、エラストマー90の第1の層(または任意の他の適切な基板)の下面図を示し、エラストマー90は、固体柱92のアレイによって規定された流動チャネル格子を形成する溝のパターンを有する滑走面を有し、各固体柱は、その周りを通過する流動チャネルを有する。
本発明のなおさらなる適用において、エラストマー構造は、生物体または他の生物学的物質を操作することに利用され得る。図18A〜18Dは、本発明に従う細胞囲い構造の1つの実施形態の平面図を示す。
上記の細胞囲いアレイ4404は、選択された範囲内(すぐにアクセスするためのアドレス可能な位置)で、物質を蓄え得る。しかし、細胞のような生きている生物体は、生き残るために持続的な食物の摂取および水の排出を必要とし得る。したがって、図19Aおよび19Bは、それぞれに、本発明に従う細胞ケージ構造の1つの実施形態の(ライン45B−45B’に沿った)平面および横断面図を示す。
図18A〜18Dに示された交差流動チャネル構造は、記載した細胞囲い以外の機能を果たすために使用され得る。例えば、交差流動チャネル構造は、混合する用途に利用され得る。
本発明の実施形態に従う微小流体制御チャネルおよび微小流体流動チャネルは、閉鎖回路流動チャネルを通して流体を循環させる回転ポンプデザインに方向づけられ得る。本明細書中に使用される用語「閉鎖回路」は、当該分野において周知であり、楕円および長円のような環状ならびにその変形、ならびに三角形、長方形またはさらに複雑な形状によって作られるような、角を有する流動回路経路である構造をいう意味を有する。
前節は、実質的に密封および拡張可能であるモノリシック微小バルブを記載し、これらの微小バルブを製造するための方法もまた記載している。前に記載した比較的単純な微小流体バルブの集合のために、各流体流動チャネルは、その特有の個々のバルブ制御チャネルによって制御され得る。しかし、そのような非一体化制御戦略は、個々にアドレス可能な何千または何万ものバルブを含む、より複雑な集合に対して実際的に実施され得ない。従って、技術の多様性が、単独でまたは組合わせて適用され、個々にアドレス可能なバルブを有する大規模一体化微小流体デバイスの製造を可能にし得る。
ヒトの腸および以前は到達不可能であった他の環境の細菌生態学が、個々の細菌からゲノムDNA(gDNA)ライブラリーを作製するための微小流体チップを利用して、高度に類似の様式で特徴付けられ得、かつ分析され得る。gDNAライブラリーは、高スループットなスクリーニングまたはハイブリダイゼーションアッセイを使用して分析され得る。微小流体構造が個々の細菌から試薬を生成する能力によって、以前は解決不可能であった問題に対処するために機能ゲノム科学の適用が可能になる。
図29Aは、本発明に従う微小流体アーキテクチャーの1つの実施形態の平面図を示す。微小流体チップ6100は、第1のフローチャネル6102を備え、この第1のフローチャネル6102は、第1のクロスフロー注入構造物6104、第2のクロスフロー注入構造物6106、そして第3のクロスフロー注入構造物6108に連続的に通じている。クロスフロー注入構造物6104、6106、および6108は、第1のフローチャネル6102と、分岐6110a、6110b、および6110cを有する第2のフローチャネル6110との交差によって規定される。3つの並行単離が、それぞれクロスフロー注入構造物6104、6106、および6108について、1.6nl、1.0nl、および0.4nlの異なるサンプル容積を用いて利用可能である。図29Bは、クロスフロー注入構造物6104の拡大図を示す。
特定の細胞またはウイルスから核酸を精製し、そして回収するために、細胞またはウイルスはまず、その内容物を曝露するために溶解されなければならない。図29Aに戻ると、第2のフローチャネルネットワーク6110への注入口6110dは、フローチャネルの3つの注入口に流体連絡している。
上記の関連の議論は、細菌細胞の溶解から得た核酸の精製に関する。しかし、本発明に従う実施形態は、この型の核酸の精製に限定されない。他の型の核酸(真核細胞からのメッセンジャーRNA(mRNA)が挙げられるがこれらに限定されない)が、本発明の実施形態に従って単離および精製され得る。
ポリメラーゼ連鎖反応(PCR)は、分子生物学で最も遍在するツールの1つとなり、そしてそれ故、微小流体デバイス中で履行されるべき最も重要な生化学的反応の1つは核酸を増幅する能力である。Liuら、「A Nanoliter Rorary Device for PCR」、Electrophoresis、第23巻、1531頁(2002)は、本明細書中にすべての目的のために援用され、PCRを実施するために先に微小流体構造を創製している。
一旦、核酸が精製されると、それは、細胞内に取り込まれ得、そして次に発現され得る。このような発現プロセスの最初の工程は、この核酸をプラスミドのような宿主ベクター内に連結することである。図33は、精製された核酸のこのような連結および発現のために適切な微小流体アーキテクチャーの1つの実施形態の平面図を示す。図33の微小流体構造6200は、核酸の連結のために用いられる第1のセットの平行混合構造、および連結された、精製核酸での細胞の形質転換のために用いられる第2のセットの平行混合構造を備える。
図33の微小流体構造6200はまた、連結された精製核酸で細胞を形質転換するために用いられる平行混合構造6251、6252、および6253の第2のセットを備える。図33Bは、連結された精製核酸での細胞形質転換を可能にする図33の微小流体アーキテクチャーの領域の拡大図を示す。
一旦、第2の混合構造内の細胞が、熱ショックに曝され、そしてそれによって、精製核酸を含む宿主ベクターを取り込むと、それらは、培養のために出口流れチャネル6179a〜cから流れ得る。1つの実施形態によれば、形質転換細胞は、培養のためにチップから除去され得る。あるいは、形質転換された細胞を培養することは、上記で説明された細胞ペンまたはケージ構造中でチップ上直接行われ得る。
進化のバリエーション:細胞−>gDNA−>PCR−>回収DNA
本発明による核酸精製について1つの適用は、制限されたセットの遺伝子における進化のバリエーションを研究することである。進化の関係は、現在、リボゾームRNAか、または利用可能であるとき、全ゲノム比較のいずれかを主に基礎にして推定されている。本発明の実施形態によれば、サンプルの微小流体操作は、培養することができない細菌における選択された遺伝子についての変異の分布の比例的測定を可能とし得る。この微小流体アーキテクチャーは、サンプルから単一の細菌を単離し、その細菌を溶解し、そして次にこの細菌からゲノムDNAを精製し得る。この微小流体アーキテクチャーは、次いで、PCRを用いて選択された遺伝子(または遺伝子のセット)を増幅し得る。この増幅された物質は、チップから回収され得、再増幅され、そして配列決定される。
本発明による別の実施形態によれば、ゲノムDNAのクローン化ライブラリーが、単一または小数の細菌から創製され得る。希釈サンプルからの個々の細菌は、微小流体チャンバ中に分配され得る。次いで、細菌は溶解され、ゲノムDNAが精製され、消化され、そして次にクローニングベクター中に連結される。これらのベクターは、次いで、図33と組み合わせて記載したように、熱ショックを用いること、および混合することにより、E.coli中に形質転換される。
本発明のなおその他の実施形態によれば、微小流体アーキテクチャーを用いて、単一または小数の細菌からのゲノムDNAのクローン化細菌人工染色体(BAC)ライブラリーを作製し得る。これらのBACライブラリーは、約200kbpのオーダーのかなりより大きな平均挿入サイズを有する利点を提供する。
一世紀にわたって、シロアリの胃内容物は、豊富かつ形態学的に多岐にわたるスピロヘータの顕微鏡観察のための優れた供給源であるとして言及されてきた。スピロヘータは、超微細構造的に別個でありかつ遺伝的に首尾一貫している、原核生物の門レベルの集合である。多くのシロアリの胃において優勢である(時には、直接数のうちの50%程度の多さを占める)が、スピロヘータはまた、「培養可能ではないこと」についての評判を有する。しかし、Leadbetterらは、カリフォルニア湿材(dampwod)シロアリ(Zootemopsis angusticollis)の後腸内容物由来の9株のコレクションを集めた。
微生物生態は、特定の環境と、その環境中に存在する生物学的実体との間の関係を探求する、新たに生まれた研究分野である。そのような環境的生物学的実体の特性および遺伝的構成の調査は、その環境中に存在するペニシリンカビの抗生物質特性の発見により例証されるような、ものすごい利益を提供し得る。
上記の説明は、現在まで、細菌またはウイルスから核酸を精製するための適用に焦点を合わせている。しかし、本発明は、この特定の適用に限定されず、代替的実施形態に従って、哺乳動物細胞型または他の非細菌細胞型に由来する核酸が、2003年8月11日に出願した米国特許仮出願番号60/494,388(すべての目的のために本明細書中に参考として援用される)において詳細に考察されるように、微量流体アプローチを使用して精製され得る。
一実施形態に従って、微小流体チップを設計して、少数の細胞(1個〜1,000個)を取得し、それらの細胞を溶解し、mRNAを精製し、cDNAを生成し、そしてマトリックスの幾何学構造においてTaqman PCRを使用して、特定の転写物の存在を検出し得る。そのような微小流体アーキテクチャーを使用して、mRNA精製およびcDNA合成のパラメーターを最適化し得る。
別の適用において、微小流体チップを設計して、少数の細胞(1個〜1,000個)を取得し、それらを溶解し、mRNAを精製し、T7プロモーターを用いてcDNAを生成し、その後、T7RNAポリメラーゼを使用して、線形増幅された蛍光RNAを生成し得、その後、その蛍光RNAをマイクロアレイにハイブリダイズし得る。このマイクロアレイは、表面ビオチニル化について以前に示された表面誘導体化と類似する方法を使用して、チップ上にインサイチュで製造し得る。
なお別の適用において、微小流体チップを設計して、少数(1個〜1,000個)の細胞から、cDNAクローンのライブラリーを構築し得る。そのようなチップは、上記ライブラリーを構築するためにもとのcDNAチップの方法を使用し得る。
多能性造血幹細胞(PHSC)は、骨髄中に存在し、かつ血液系の動態を維持する、稀な細胞集団である。固有の特徴および環境の影響に従って、これらの細胞は、以下の経路のうちの1つへと移動する:始原幹細胞としての自己再生、分化した造血細胞への成熟、またはアポトーシス。生体の骨髄において、これらの3つの経路の間のバランスは、正常な造血を提供するために維持される。
Claims (11)
- 複数のクロスフロー注入構造物が第1のフローチャネルを介して多段に連結された、細胞を含むサンプルのサブセットをクロスフロー注入構造物ごとに隔離するための微小流体デバイスであって、
該クロスフロー注入構造物の各々は、
a)第1のフローチャネルと、
b)第2のフローチャネルと、
を含み、
サンプルは、最上流のクロスフロー注入構造物の第1のフローチャネルの注入口を通して流され、
該第1のフローチャネルは、該第2のフローチャネルと交差(以下、「第1の交差」という。)を形成し、
そして該第2のフローチャネルの中への該第1のフローチャネルを介する流れを停止するように配置された第1バルブを含み、そして、
該第2のフローチャネルは、次段のクロスフロー注入構造物の第1のフローチャネルと交差(以下「第2の交差」という。)を形成し、
最終段のクロスフロー注入構造物の第2のフローチャネルは、排出口につながる第1のフローチャネルと第2の交差を形成し、
そして該次段のクロスフロー注入構造物の第1のフローチャネルの中への該第2のフローチャネルを介する流れを停止するように該次段のクロスフロー注入構造物の第1のフローチャネルに配置された第4バルブを含み、
最終段のクロスフロー注入構造物は該第4バルブから第1のフローチャネルを介して排出口に連結され、
該第2のフローチャネルは、第2バルブおよび第3バルブを含み、
該第2バルブと該第3バルブとの間に、該第1の交差と、該第2の交差とが位置しており、
該クロスフロー注入構造物の各々は、該第2バルブおよび該第3バルブが閉じている際に該第1バルブおよび該第4バルブが開かれてサンプルを流入させ、
その後、該第1バルブおよび該第4バルブを閉じることにより、第1バルブ、第2バルブ、第3バルブおよび第4バルブで囲まれる部分に該サンプルを保持し、
そしてその後、該第2バルブおよび該第3バルブを開くことにより、該保持されたサンプルを該第3バルブから流出させるように構成されている、
微小流体デバイス。 - 請求項1に記載の微小流体デバイスであって、各クロスフロー注入構造物は、回転式混合構造と流体連絡する、微小流体デバイス。
- 請求項2に記載の微小流体デバイスであって、回転式混合構造において溶解が行われる、微小流体デバイス。
- 請求項1に記載の微小流体デバイスであって、各クロスフロー注入構造物は、核酸精製媒体で充填されたチャネルと流体連絡している、微小流体デバイス。
- 請求項4に記載の微小流体デバイスであって、前記核酸精製媒体が、特定の核酸に親和性を示す、コーティングされたビーズを含む、微小流体デバイス。
- 請求項1に記載の微小流体デバイスを用いて1つ以上の細胞を溶解し、核酸を放出する方法であって:
(a)請求項1に記載の微小流体デバイスを作動させ各クロスフロー注入構造物において、第1バルブ、第2バルブ、第3バルブ、第4バルブで囲まれる部分に該サンプルを保持する工程;
(b)そしてその後、該第2バルブおよび該第3バルブを開くことにより、第2のフローチャネルを介して溶解溶液を導入し該サンプルと組み合わせる工程、
(c)該サンプル中の細胞は、該溶解溶液中で溶解され、核酸が放出される、工程
を包含する方法。 - 請求項6に記載の方法であって、
(d)前記工程(c)の後に、別個の回転式混合構造の中に該サンプルを流す工程
をさらに含む、方法。 - 請求項6に記載の方法であって、
(e)前記放出された核酸を、前記工程(c)の後に、核酸精製媒体と接触させる工程
をさらに含む、方法。 - 請求項8に記載の方法であって、
(f)前記工程(e)の後に、mRNAが、前記核酸精製媒体から溶出される工程
をさらに含む、方法。 - 請求項9に記載の方法であって、
(g)前記精製されたmRNAを逆転写酵素に曝露して、該精製されたmRNAをcDNAに変換する工程
をさらに包含する、方法。 - 前記細胞は、細菌細胞を含む、請求項10に記載の方法。
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US10940473B2 (en) | 2021-03-09 |
EP1546412B1 (en) | 2014-05-21 |
US9579650B2 (en) | 2017-02-28 |
JP2010104373A (ja) | 2010-05-13 |
EP1546412A4 (en) | 2007-10-03 |
US20190009272A1 (en) | 2019-01-10 |
US8871446B2 (en) | 2014-10-28 |
JP2006517095A (ja) | 2006-07-20 |
US20150238960A1 (en) | 2015-08-27 |
WO2004040001A3 (en) | 2004-07-22 |
JP2014168480A (ja) | 2014-09-18 |
WO2004040001A2 (en) | 2004-05-13 |
US20050053952A1 (en) | 2005-03-10 |
US20200147608A1 (en) | 2020-05-14 |
EP1546412A2 (en) | 2005-06-29 |
AU2003299541A1 (en) | 2004-05-25 |
US10328428B2 (en) | 2019-06-25 |
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