JP4354184B2 - 核酸の配列決定のための装置および方法 - Google Patents
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Description
本発明は、核酸の配列を決定するための装置および方法に関する。
多くの疾患は、特定のDNA配列に関連する。このDNA配列は、しばしば、DNA多型と呼ばれ、非罹患個体における対応するDNA配列と異なる疾患状態に関連するDNA配列を示す。DNA配列多型は、例えば、1つの配列における、第2の配列と比較してのヌクレオチドの挿入、欠失、または置換を含み得る。特定のDNA配列多型の例は、ヒトゲノムの特定の位置での、5’−ATGG−3’に対する5’−ATCG−3’である。後者の配列における第1ヌクレオチド「G」は、前者の配列においてヌクレオチド「C」で置換されている。前者の配列は、特定の疾患状態に関連し、後者の配列は、その疾患に罹患していない個体において見出される。従って、ヌクレオチド配列「5’−ATCG−3’」の存在は、個体が特定の疾患を有することを示す。この特定の型の配列多型は、配列の差が、1つのヌクレオチドにおける変化に起因することから、単一ヌクレオチド多型(SNP)として公知である。
本発明は、一部、核酸の配列を決定するためのアレイの使用に基づく。
本明細書中に記載される方法および装置は、最初に核酸をクローニングする必要性なしに、核酸配列情報の決定を可能にする。さらに、この方法は、高感度であり、そして核酸の出発集団においてほんの数コピー存在する鋳型核酸のヌクレオチド配列を決定するために使用され得る。さらに、この方法は、多量の核酸の配列を同時に決定するために使用され得る。
本発明は、核酸を配列決定するための装置を提供し、この装置は、一般に、配列決定反応を行うための1個以上の反応チャンバ、この反応チャンバにかまたはこの反応チャンバから反応物を送達するための手段、および配列決定反応事象を検出するための手段、を備える。別の実施形態において、この装置は、試薬送達キュベットを備え、このキュベットは、平面上に複数の空洞を備える。好ましい実施形態において、この装置は、この装置の個々の構成要素を制御するため、ならびに配列反応事象の検出から得られる情報を保存および/または分析するための、少なくとも1つコンピューターに接続されている。
任意の材料の表面がプライマーの安定な結合および核酸配列の検出を可能にする限り、この任意の材料は、固体支持体材料として使用され得る。固体支持体材料は、平面であり得るか、または空洞形成され(cavitated)得る(例えば、光ファイバーの空洞形成された末端においてか、またはエッチングされたか、成形されたか、さもなければ、例えば、超小型電気機械系の構成において通常使用される技術を使用して平面内に微細加工された、ミクロウェルにおいて)。例えば、Rai−Choudhury,HANDBOOK OF MICROLITHOGRAPHY,MICROMACHINING,AND MICROFABRICATION,VOLUME 1:MAICROLITHOGRAPHY,Volume PM39,SPIE Press(1997);Madou,CRC Press(1997),Aoki,Biotech,Histochem.67:98−9(1992);Kaneら、Biomaterials.20:2363−76(1999);Dengら、Anal.Chem.72:3176−80(2000);Zhuら、Nat.Genet.26:283−9(2000)を参照のこと。いくつかの実施形態において、固体支持体は、光学的に透過性(例えば、ガラス)である。
基材材料は、好ましくは、反応事象の検出を容易にする材料から作製される。例えば、代表的な配列決定反応において、dNTPの、配列決定されたサンプル核酸への結合は、配列決定反応において遊離されたホスフェートに対する酵素作用によって生じる光子を検出することによって、モニタリングされ得る。従って、透過性材料または光学的に(すなわち、光)導線性の材料から作製される基材材料を用いると、光子の検出が容易になる。
1つの局面において、本発明はアレイを包含し、このアレイは、その上に配置された複数の反応チャンバを有する平面を備え、ここで、この反応チャンバは、5〜200μmの中心間距離を有し、そして各チャンバは、0.3μmと100μmとの間の、少なくとも1つの寸法幅を有する。いくつかの実施形態において、このアレイは、その上に複数の空洞を備える平面であり、ここで、各空洞は、分析物反応チャンバを形成する。好ましい実施形態において、このアレイは、スライスされた光ファイバーバンドル(すなわち、溶接された光ファイバーケーブルのバンドル)から作製され、そしてこの反応チャンバは、その光ファイバー反応アレイ(「FORA」)の1つの表面をエッチングすることによって形成される。この空洞はまた、エッチング、成形または微細加工によって、基材に形成され得る。
上記反応チャンバーに反応物を送達するための手段の例は、本発明の灌流チャンバーであり、図3に示される。この灌流チャンバーは、透明の上部スライドおよび下部スライドをもつシールされた区画を備える。これは、基板表面の表面上の溶液の流れを可能にし、そして試薬の迅速な交換を可能にするように設計されている。従って、これは、例えば、ピロリン酸配列決定反応を実施するために適切である。このチャンバーの形状および寸法は、バルク流れ交換、拡散的交換、または層流または乱流措置いずれかの両方を含む試薬交換を最適化するために調節され得る。
輸送の対流成分は、一であること(unity)と比較してPeclet数Peが大きい状況において、拡散成分より優勢であることが予期され得る。逆に、輸送の拡散成分は、一であることと比較してPeclet数Peが小さい状況において、対流成分より優勢であることが予期され得る。Peclet数が1よりかなり大きいか、またはかなり小さいかのいずれかの極端な状況では、輸送は、対流単独によるか、または拡散単独によるかのいずれかで生じると、それぞれ、正確に推測され得る。最後に、推定されたPeclet数が一であることのオーダーである状況では、そのときは、対流および拡散の両方が、輸送プロセスの全体に顕著な役割を演じていることが予期され得る。
灌流チャンバー基板を、コネクターと直接接触して配置することによって達成され得る。あるいは、従来の光学が、例えば、I−I拡大複数孔レンズシステム(magnification high numerical aperture lens system)を用いることによって、光ファイバー基板の外側からの直接CCDセンサーへの光を画像化するために用いられ得る。この基板が光ファイバーとの組み合わせを提供しない場合、レンズシステムはまた、上記のように使用され得、この場合、基板または灌流チャンバーカバーのいずれかは、光学的に透明である。例示的なCCD画像化システムは、上記の通りである。
この反応事象(例えば、ルシフェラーゼにより発生された光子)は、種々の検出装置(例えば、光電子増倍管、CCD、CMOS、吸収光計(absorbance photometer)、ルミノメーター、電荷注入デバイス(charge injection device)(CID)、または他の固体状態検出器および本明細書中に記載される装置)を用いて検出および定量され得る。好ましい実施形態において、出力された光子の定量は、融合された光ファイバーバンドルに適合したCCDカメラの使用によって達成される。別の好ましい実施形態において、出力された光子の定量は、マイクロチャネルプレート増強装置に適合したCCDカメラの使用によって達成される。背部を薄くした(back−thinned)CCDが、感度を増加させるために用いられ得る。CCD検出器は、例えば、Bronksら、1995.Anal.Chem.65:2750−2757に記載される。
本発明はまた、核酸の配列決定をするための方法を提供し、この方法は、一般的に、以下:(a)複数の反応チャンバーまたは空洞内に配置された、1つ以上の核酸アンカープライマーおよび複数の一本鎖環状核酸テンプレートを提供する工程;(b)少なくとも1つの一本鎖環状テンプレートに有効量の核酸アンカープライマーをアニーリングして、プライマーが結合されたアンカープライマー−環状テンプレート複合体を産生する工程;(c)プライマーが結合されたアンカープライマー−環状テンプレート複合体と、ポリメラーゼを組み合わせて、環状核酸テンプレートに相補的な複数コピーの核酸を共有結合された伸長アンカープライマーを形成する工程;(d)1コピー以上の共有結合された相補的核酸に有効量の配列決定プライマーをアニーリングする工程;(e)ポリメラーゼおよび予め決定されたヌクレオチド三リン酸を用いて配列決定プライマーを伸長し、配列決定産物、および予め決定されたヌクレオチド三リン酸が配列決定プライマーの3’末端に組み込まれる場合、配列決定反応副産物、を生成する工程;および(f)配列決定反応副産物を同定する工程であって、これにより核酸の配列を決定する工程、を包含する。1つの実施形態において、配列決定副産物は、PPiである。別の実施形態において、dATPアナログまたはddATPアナログがデオキシアデノシン三リン酸またはジデオキシアデノシン三リン酸の代わりに用いられ得る。このアナログは、ポリメラーゼの基質としての役割を果たし得るが、PPi検出酵素の基質としての役割を果たし得ない。この方法は、水性環境における、別々の並行する一般的な反応において実施され得る。
本発明のアンカープライマーは、一般的に、軸領域および少なくとも1つのアダプター領域を含む。好ましい実施形態において、このアンカープライマーは、少なくとも2つの連続するアダプター領域を含む。軸領域は、アンカープライマーの5’末端に存在し、そして固体基材にアンカープライマーを付着させるためのヌクレオチドの領域を含む。
アンカープライマーは、増感部位で固体基材に連結される。連結されたプライマーを含む固体基材の領域は、本明細書中で、アンカーパッドと呼ばれる。従って、固体支持体上での増感状態を特定することによって、アンカーパッドのアレイまたはマトリクスを形成することが可能である。これらのアンカーパッドは、例えば、固体支持体上に等間隔でエッチングされた小さい直径のスポットであり得る。アンカーパッドは、この基材が空洞作成されているか、エッチングされているか、または上で議論されるような他のミクロ機械加工されている場合、空洞またはウェルの底部に配置され得る。
本発明に従って配列決定され得る核酸テンプレート(例えば、核酸ライブラリー)は、一般に開環核酸分子または閉環核酸分子を含み得る。「閉環」は、共有結合的に閉じられた環状核酸分子(例えば、環状DNA分子または環状RNA分子)である。「開環」は、5’リン酸基および3’ヒドロキシル基を有する線状一本鎖核酸分子である。1つの実施形態において、一本鎖核酸は、少なくとも100コピーの核酸配列を含み、各コピーは、末端と末端で共有結合している。いくつかの実施形態において、開環は、線状の2本鎖核酸分子からインサイチュで形成される。所定の開環核酸分子の末端は、DNAリガーゼによって連結され得る。開環分子の5’末端および3’末端での配列は、第2の核酸分子中の隣接するヌクレオチドの2つの領域(例えば、アンカープライマーのアダプター領域、または第2のDNA分子に密接に隣接している2つの領域)に相補的である。従って、開環分子の末端は、DNAリガーゼを用いて連結され得るか、またはギャップ充填反応においてDNAポリメラーゼによって伸長され得る。開環は、Lizardi,米国特許第5,854,033号に詳細に記載される。開環は、DNAリガーゼ(DNA用)またはRNAリガーゼの存在下で、例えば、アンカープライマーへの開環のアニーリング後に閉環に転換され得る。
核酸のライブラリーは、認識された技術を用いてアンカープライマー配列にアニーリングされる(例えば、Hatchら、1999,Genet.Anal.Biomol.Engineer.15:35〜40;Kool,米国特許第5,714,320号およびLizardi,米国特許第5,854,033号を参照のこと)。一般に、アンカープライマーをテンプレート核酸配列にアニーリングさせるための任意の手順は、アダプター領域、またはアンカープライマー配列中の領域とテンプレートライブラリーに特異的(すなわち、完全、またはほぼ完全)な相補性の形成を生じる限り、適切である。
上記のような核酸テンプレートの増幅は、アンカープライマーに共有結合した複数コピーのテンプレート核酸配列を生じる。1つの実施形態において、配列決定産物のある領域は、テンプレート核酸のある領域に対する配列決定プライマーのアニーリング、次いで、DNAポリメラーゼおよび既知のヌクレオチド三リン酸(すなわち、dATP、dCTP、dGTP、dTTPまたはこれらのヌクレオチドの1つのアナログ)と、配列決定プライマーとを接触させることによって決定される。この配列は、以下に記載されるような配列決定反応副産物を検出することによって決定され得る。
理論による束縛を所望しないが、反応条件の最適化は、以下の分析の基礎をなす仮定を使用して実施され得ると考えられる。
KM=[E][S]/[ES]、
速度=Vmax[S]/(KM+[S])、
Vmax=kCAT[ET]
ここで、[S]は、基質の濃度であり、[E]は、遊離酵素の濃度であり、[ES]は、酵素基質複合体の濃度であり、そして[ET](=[E]+[ES])は、酵素の全濃度である。
−d[S]/dt=kCAT[ET][S]/(KM+[S])
基質の有効濃度は、複製されたDNA分子の大きさ(せいぜい(10μm)3)およびコピー数(約10,000)から評価され、約17nMの濃度を得る。この値は、前に記載された酵素のKMより小さく、従って、この速度は、以下のように評価される:
−d[S]/dt=(kCAT/KM)[ET][S]
従って、偽1次反応速度論を使用すれば、基質の消滅についての速度定数は、所定の酵素についての定数である、kCATおよびKMならびに[ET]に依存する。従って、文献中に報告されている同じ酵素濃度を使用して、同様の速度を生じる。
(1/3)exp(−kPt)[pa2/b2]exp(−b2/2DPt)によって近似され得る。因数1/3は、1/4のDNA配列がIヌクレオチドを組み込み、次いで1/4のDNA配列が第2ヌクレオチドを組み込むなどであり、従って、このシリーズの合計は、1/3である。第1アンカーパッドおよび第2アンカーパッドの上方のPPiの量は、2DPtがおよそb2と等しい場合に同等の大きさになり、これにより、分子が拡散するRMS距離は、隣接のアンカーパッドの間の距離に等しいことを示す。従って、本発明の実施において利用されるアッセイ条件を基に、このアンカーパッドはおよそ50μm以上離して配置されなければならず、そして好ましくは、少なくとも3倍以上さらに離して(すなわち、150μm)配置される。
薄いウェハーのファイバー光学アレイの末端を、Healeyら、Anal.Chem.69:2213−2216(1997)によって記載されるように、酸の中にこの末端を入れることによって空洞化する。
開環ライブラリーテンプレートのライブラリーを、70bpのSau3A1−MspIフラグメントの単一の核酸形態を含むと推定される核酸集団から調製する。このテンプレートは、アンカープライマーに相補的であるアダプター、配列決定プライマーに相補的である領域、および特定されるべき挿入配列を含む。ゲノムDNAを消化するためのSau3A1およびMspIを使用して、ライブラリーを作製した。約65〜75ヌクレオチドのインサートを選択して、そして12ヌクレオチド長のアダプターオリゴヌクレオチドにライゲーションした。アダプターオリゴヌクレオチドは、実施例1に記載されるように、基材表面に結合したアンカープライマーの配列に相補的な配列を有する。
実施例2に記載されるように、増幅された核酸を含むファイバー光学アレイのウェハーを、灌流チャンバー内に配置して、これらファイバーはそれ自体が1600万画素のCCDカメラに連結されたファイバー光学アレイの束に取り付けられる。配列決定プライマーを灌流チャンバー内に送達して、そして増幅された配列とアニールし得るようにする。次いで、スルフリラーゼ、アピラーゼおよびルシフェラーゼを、ビオチン−アビジンを使用して空洞化された基材に取り付ける。
配列5’−gAC CTC ACA CgA Tgg CTg CAg CTT−3’(配列番号2)を有するプライマーを、配列5’−TCg TgT gAg gTC TCA gCA TCT TAT gTA TAT TTA CTT CTA TTC TCA gTT gCC TAA gCT gCA gCC A−3’(配列番号1)を有する88ヌクレオチドのテンプレート分子にアニールさせた。プライマーへのテンプレートのアニーリングは、テンプレート分子の5’末端および3’末端の並列を生じた。アニーリングされたテンプレートをリガーゼに曝し、この結果、環状分子を生成するために、テンプレートの5’末端および3’末端のライゲーションを生じた。
DNAビーズ:デオキシオリゴヌクレオチド−ggggAATTCAAAATTTggC(配列番号9)をアニーリングしてプローブを捕捉し、これを5’末端でビオチン化して、次いでDynal M−280(Dynal)またはMPGビーズ(CPG)(ビーズ濃度は1mg/mlであった)のどちらかの上に固定した。ビーズを30分間一定量のオリゴヌクレオチドとインキュベートすることによって固定化を実施した。インキュベート中に使用されるオリゴヌクレオチドの量を変化させることによって、オリゴヌクレオチドの異なる装填物(loading)を得た。インキュベーション後、ビーズをそれぞれの容量のTE緩衝液中で洗浄し、そして等容量のTE中に懸濁した。
試薬:配列分析用で、かつコントロールとしての試薬は、4つのヌクレオチドであり0.1μMのピロリン酸(PPi)を、基質溶液中に作製し、ここで、基質とは、300μMのルシフェリンおよび4μMのアデノシン5’−ホスホスルフェート(APS)の混合物をいい、これらはPPi、ルシフェラーゼおよびスルフリラーゼを関連付ける反応のカスケードのための基質である。基質はアッセイ緩衝液中で作製される。酵素を試験して、そしてチャンバーを通る試薬のバックグラウンドのレベルを決定するために使用されるPPi濃度は、0.1μMであった。ヌクレオチドdTTP、dGTP、dCTPの濃度は、6.5μMであり、そしてαdATPの濃度は50μMであった。各々のヌクレオチドは、100U/mLの濃度のDNAポリメラーゼ、クレノウと混合した。
本発明は、その詳細な説明と共に記載されているが、前述の記載は例示のために意図されるものであって、本発明の範囲を限定するものではなく、本発明の範囲は、添付の特許請求の範囲の範囲によって定義されることが、理解されるべきである。他の局面、利点および改変は、その特許請求の範囲の範囲内である。
Claims (39)
- 核酸を配列決定するためのアレイであって、
複数の個々の光ファイバーの束から形成されている空洞性の光ファイバーウエハを含み、各個々の光ファイバーが3μmと100μmの間の直径を有し、前記ウエハが上面および底面を含み、前記上面が400,000個より多い反応チャンバを含み、前記反応チャンバが空洞性の光ファイバーウエハの上面中にエッチングされ、且つ上面と底面の間の厚さが0.5mmと5.0mmの厚さの間であり;
前記各反応チャンバの深さが個々の光ファイバーの1/2の直径と個々の光ファイバーの3倍の直径の間の範囲にあり;ならびに、
前記空洞性のウエハの上面にある複数の反応チャンバが中に核酸を有し、且つ前記反応チャンバの50%〜100%が配列決定酵素が固定された可動固体支持体を有する、
前記アレイ。 - 前記核酸が反応チャンバまたは可動固体支持体に固定されている、請求項1に記載のアレイ。
- 前記空洞性の光ファイバーウエハにおける各個々の光ファイバーの直径が6〜50μmの間である、請求項1または2に記載のアレイ。
- 前記反応チャンバが50〜100μmの間の中心間距離を有する、請求項1〜3のいずれか1項に記載のアレイ。
- 前記反応チャンバが10〜150μmの間の中心間距離を有する、請求項1〜3のいずれか1項に記載のアレイ。
- 前記アレイが空洞性の光ファイバー表面と反対の研磨された光ファイバー表面を有し、且つ前記研磨された表面が第二の光ファイバーへの光学カップリングを可能にする、請求項1〜5のいずれか1項に記載のアレイ。
- 前記空洞性の光ファイバーウエハがコーティングされている、請求項1〜6のいずれか1項に記載のアレイ。
- 前記コーティングがプラスチック、長鎖チオールアルカンの自己アセンブリングした単層を有する金の層、オルガノシラン剤、光反応性リンカー、親水性ポリマーゲル、およびポリスチレンまたはシラン処理されたガラス表面のいずれかに特異的に吸収されるポリエチレンオキシド−ポリプロピレンオキシド−ポリエチレンオキシドトリブロックコポリマーからなる群より選ばれる、請求項7に記載のアレイ。
- 配列決定酵素がルシフェラーゼである、請求項1〜8のいずれか1項に記載のアレイ。
- 配列決定酵素がスルフリラーゼである、請求項1〜8のいずれか1項に記載のアレイ。
- 核酸の配列決定のための装置であって、請求項1〜10のいずれか1項に記載のアレイと、反応物を反応チャンバにまたは反応チャンバから送達するための手段と、ならびに配列決定反応事象を検出するための手段とを含む、装置。
- 前記装置が、5〜200μmの中心間距離を有する、請求項1に記載のアレイが配置されたフローチャンバ、
中に配置された核酸が試薬に曝露されるように、1つ以上のリザーバーから該フローチャンバまで処理試薬を送達する流体手段;ならびに、
該反応チャンバの各々から光学的シグナルの配列を検出するための検出手段であって、該検出手段が前記反応チャンバと連絡しており、前記配列の各光学的シグナルが処理試薬と該反応チャンバ中の核酸との間の相互作用を示す、検出手段、
を含む、請求項11に記載の装置。 - 前記空洞性の光ファイバーウエハにおける各個々の光ファイバーの直径が6〜50μmの間である、請求項11または12に記載の装置。
- 前記検出手段がCCDカメラである、請求項11、12、または13に記載の装置。
- 前記空洞性の光ファイバーウエハがコーティングされている、前記請求項11〜14のいずれか1項に記載の装置。
- 前記コーティングがプラスチック、金の層、オルガノシラン剤、光反応性リンカー、親水性ポリマーゲル、およびポリスチレンまたはシラン処理されたガラス表面のいずれかに特異的に吸収されるポリエチレンオキシド−ポリプロピレンオキシド−ポリエチレンオキシドトリブロックコポリマーからなる群より選ばれる、請求項15に記載の装置。
- 配列決定酵素がルシフェラーゼである、請求項11〜16のいずれか1項に記載の装置。
- 配列決定酵素がスルフリラーゼである、請求項11〜16のいずれか1項に記載の装置。
- 前記核酸が反応チャンバまたは可動固体支持体に固定されている、請求項11〜18のいずれか1項に記載の装置。
- 前記反応チャンバが50〜100μmの間の中心間距離を有する、請求項11〜18のいずれか1項に記載の装置。
- 前記反応チャンバが10〜150μmの間の中心間距離を有する、請求項11〜18のいずれか1項に記載の装置。
- 請求項1〜10のいずれか1項に記載のアレイおよび/または請求項11〜21のいずれか1項に記載の装置を使用することを含む、核酸を配列決定するための方法。
- 前記アレイがフローチャンバに配置され、前記反応チャンバが5〜200μmの間の中心間距離を有し、ならびに
前記方法が、中に配置された核酸が試薬に曝露されるように1つ以上のリザーバーから前記フローチャンバまで処理試薬を送達すること、および前記反応チャンバと連絡しており、前記配列の各光学的シグナルが処理試薬と該反応チャンバ中の核酸との間の相互作用を示す検出手段を用いて、反応チャンバの各々から光学的シグナルの配列を検出すること、を含む、
請求項22に記載の方法。 - 前記核酸が反応チャンバまたは可動固体支持体に固定されている、請求項24または23に記載の方法。
- ピロリン酸が配列決定の副産物として生成する、請求項22〜24のいずれか1項に記載の方法。
- 前記ピロリン酸が、ATPの形成が可能な条件下で配列決定の副産物をスルフリラーゼと接触させることにより検出される、請求項25に記載の方法。
- スルフリラーゼが熱安定性スルフリラーゼである、請求項26に記載の方法。
- 未反応のヌクレオチド三リン酸を分解するためにアピラーゼを加えることをさらに含む、請求項25に記載の方法。
- 前記配列決定試薬の送達後に拡散性の配列決定試薬を洗浄緩衝液で洗浄することをさらに含む、請求項25に記載の方法。
- 前記緩衝液がアピラーゼを含む、請求項29に記載の方法。
- 前記空洞性の光ファイバーウエハにおける各個々の光ファイバーの直径が6〜50μmの間である、請求項22〜30のいずれか1項に記載の方法。
- 前記反応チャンバが10〜150μmの間の中心間距離を有する、請求項22または23に記載の方法。
- 前記反応チャンバが50〜100μmの間の中心間距離を有する、請求項32に記載の方法。
- 前記検出手段がCCDカメラである、請求項22〜33のいずれか1項に記載の方法。
- 前記アレイが空洞性の光ファイバー表面と反対の研磨された光ファイバー表面を有し、且つ前記研磨された表面が第二の光ファイバーへの光学カップリングを可能にする、請求項22〜34のいずれか1項に記載の方法。
- 前記空洞性の光ファイバーウエハがコーティングされている、請求項22〜35のいずれか1項に記載の方法。
- 前記コーティングがプラスチック、金の層、オルガノシラン剤、光反応性リンカー、親水性ポリマーゲル、およびポリスチレンまたはシラン処理されたガラス表面のいずれかに特異的に吸収されるポリエチレンオキシド−ポリプロピレンオキシド−ポリエチレンオキシドトリブロックコポリマーからなる群より選ばれる、請求項36に記載の方法。
- ピロリン酸配列決定酵素がルシフェラーゼである、請求項22〜37のいずれか1項に記載の方法。
- 前記配列決定酵素がスルフリラーゼである、請求項22〜37のいずれか1項に記載の方法。
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- 2002-03-21 JP JP2002575327A patent/JP4354184B2/ja not_active Expired - Fee Related
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- 2002-03-21 WO PCT/US2002/008700 patent/WO2002077287A1/en active Application Filing
- 2002-03-21 ES ES02715174T patent/ES2348435T3/es not_active Expired - Lifetime
- 2002-08-15 US US10/222,298 patent/US20070092872A1/en not_active Abandoned
- 2002-08-15 US US10/222,592 patent/US7335762B2/en not_active Expired - Fee Related
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Also Published As
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US20030100102A1 (en) | 2003-05-29 |
CA2441603A1 (en) | 2002-10-03 |
AU2002247390B2 (en) | 2007-01-25 |
EP1381693A4 (en) | 2005-12-21 |
US7335762B2 (en) | 2008-02-26 |
US7264929B2 (en) | 2007-09-04 |
WO2002077287A1 (en) | 2002-10-03 |
CA2441603C (en) | 2012-01-10 |
EP1381693B1 (en) | 2010-05-26 |
ES2348435T3 (es) | 2010-12-07 |
US20030068629A1 (en) | 2003-04-10 |
AU2002247390B9 (en) | 2007-03-22 |
AU2002247390A1 (en) | 2002-10-08 |
US7244559B2 (en) | 2007-07-17 |
US20030148344A1 (en) | 2003-08-07 |
US20020012930A1 (en) | 2002-01-31 |
DE60236502D1 (de) | 2010-07-08 |
JP2005505748A (ja) | 2005-02-24 |
US20070092872A1 (en) | 2007-04-26 |
EP1381693A1 (en) | 2004-01-21 |
ATE468915T1 (de) | 2010-06-15 |
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