JP5254949B2 - 一体型の核酸アッセイ - Google Patents
一体型の核酸アッセイ Download PDFInfo
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- JP5254949B2 JP5254949B2 JP2009500496A JP2009500496A JP5254949B2 JP 5254949 B2 JP5254949 B2 JP 5254949B2 JP 2009500496 A JP2009500496 A JP 2009500496A JP 2009500496 A JP2009500496 A JP 2009500496A JP 5254949 B2 JP5254949 B2 JP 5254949B2
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Description
本願は、米国特許法§119(e)の下、2006年3月15日に出願された米国仮特許出願第60/782,649号および2006年9月14日に出願された米国仮特許出願第60/844,811号の利益を主張し、これらの仮出願は、その全体が本明細書中に参考として援用される。
本発明は、分子生物学および医学の一般的分野、より具体的には、臨床試料から核酸を抽出、増幅、および検出するための一体型マイクロ流体カートリッジに関係する。
臨床検査診断のアッセイ法には、常量法から微量法への目覚ましい変化があり、標本の必要量がミリリットル単位からマイクロリットル単位に減少し、アッセイ時間が、時間単位から分単位に短縮することも可能になった。
全身性の懈怠感をもつ、または胃腸炎や下痢のような特徴のない症候群の患者、または鼻水やリンパ節炎で始まる呼吸器症候群の患者に直面した医師は、一般的に、何を処方すべきかを決定するに当たって、疫学的および統計的な検討を頼りにする。しかし、旅行者が一晩のうちに世界の反対側から到着する世の中では、これらの検討はしばしば役に立たない。
以下の詳細な説明には、例示目的で多くの具体的で詳細な説明が含まれるが、当業者は、以下の詳細に対する数多くの変更および改変も本発明の範囲内に含まれることが理解できよう。したがって、後述する本発明の例示的実施形態は、請求の範囲に記載された発明に対する一般性を損なうことなく、およびそれを限定することなく提示されるものである。
検査試料:代表的な生体試料には、例えば、血液、血清、血漿、軟膜、唾液、傷からの浸出液、膿、肺およびその他の呼吸器の吸引液、鼻腔の吸引液および洗浄液、副鼻腔ドレナージ、気管支洗浄液、痰、中耳および内耳の吸引液、嚢胞吸引液、脳脊髄液、大便、下痢便、尿、涙、乳腺分泌物、卵巣内容物、腹水、粘液、胃液、消化器内容物、尿道分泌物、滑液、腹膜水、胎便、膣液もしくは膣分泌物、羊水、精液、陰茎分泌物などがあり、これらを検査することができる。例えば、咽頭、扁桃腺、歯肉、鼻道、膣、尿道、直腸、下部結腸、および眼の粘膜拭き取り検体など、粘膜分泌物および上皮の代表物である拭き取り検体または洗浄液からのアッセイも、あらゆる種類の組織標本のホモジネート、溶解物、および分解物として許容される。哺乳動物細胞が許容される試料である。生理的溶液以外にも、水、産業廃棄物、食品、ミルク、空気ろ過物(air filtrates)などの試料も検査試料である。実施形態によっては、検査試料を本装置内に直接置くこともあるが、別の実施形態では、解析前処理を想定していることもある。
本発明のアッセイ法は、抽出、増幅、および検出という3つの工程を有する。本明細書で開示されるマイクロ流体装置は、単一の装置に組み込まれた、これらの機能に対応する3つの流体サブ回路から構成されている。
PCRによる増幅は、当技術分野において周知されているように、変性、アニーリング、および伸長の繰り返しである。
ここで、図3の概略図を見ると、検出用サブ回路300が示されている。増幅産物は、まず、マグ混合用チャンバー内で磁気捕捉ビーズと混合される。これらのビーズは、使用時までマグビーズ貯留容器チャンバーに保存されている。ビーズは、アビジンまたはその他の捕捉剤で被覆されている。例えば、アビジンは、ビオチン結合プライマーおよび双尾型単位複製配列を捕捉する。抗ジゴキシゲニンは、ジゴキシゲニン結合プライマーおよび双尾型単位複製配列を捕捉する。
a.試料注入ポート、核酸標的捕捉アセンブリチャンバー、溶解バッファー用チャンバー、洗浄試薬用チャンバー、溶離バッファー用チャンバー、再水和バッファー用チャンバー、ベント型廃液用チャンバー、PCR流体および温度界面アセンブリ、マグ混合装置チャンバー、マグビーズ貯留容器、および検出用チャンバーを含み、さらに、
b.試料ポートと溶解用チャンバーとを流体とバルブによって相互連結している第1のマイクロチャネル、
c.溶解用チャンバーを核酸標的捕捉アセンブリチャンバーに、流体によって相互連結している第2のマイクロチャネル、
d.溶解用チャンバーを溶解バッファーポーチチャンバーに、流体とバルブによって相互連結している第3のマイクロチャネル、
e.核酸標的捕捉アセンブリチャンバーを洗浄バッファーチャンバーに、流体とバルブによって相互連結している第4のマイクロチャネル、
f.核酸標的捕捉アセンブリチャンバーと溶離バッファーチャンバーとを、流体とバルブによって相互連結している第5のマイクロチャネル、
g.核酸標的捕捉アセンブリチャンバーと少なくとも1つのPCR流体および温度界面アセンブリとを、流体とバルブによって相互連結している第6のマイクロチャネル(複数の並列アセンブリは図4に示されている)、
h.少なくとも1つのPCR流体および温度界面アセンブリと、少なくとも1つのマグ混合装置チャンバーとを、流体とバルブによって相互連結している第7のマイクロチャネル、
i.少なくとも1つのマグ混合装置チャンバーと再水和バッファー用チャンバーとを流体とバルブによって相互連結している第8のマイクロチャネルであって、第6のマイクロチャネルが、再水和バッファー用チャンバーとマグ混合装置チャンバーの間に置かれた磁気ビーズ貯留容器をさらに含むマイクロチャネル、
j.マグ混合装置チャンバーと少なくとも1つの検出用チャンバーとを、流体とバルブによって相互連結している第9のマイクロチャネル、
k.核酸標的捕捉アセンブリチャンバーとベント型廃液用チャンバーとを、流体とバルブによって相互連結している第10のマイクロチャネル、
l.検出用チャンバーとベント型廃液用チャンバーとを、流体とバルブによって相互連結している第11のマイクロチャネルを含み、かつ、
ダイヤフラム式バルブおよびベローチャンバーを含む複数の内部空気圧式制御素子であって、外部の制御可能な空気圧作動連結管に接続するための空気圧式相互接続回路を備えた複数の内部空気圧式制御素子をさらに含む一体型マイクロ流体カートリッジ。
a.生体試料から核酸を抽出するための手段、
b.単位複製配列を合成するための手段、
c.単位複製配列を検出するための手段、ただし、
生体試料から核酸を抽出するための手段は、固相によって生体試料から核酸を抽出するための流体サブ回路を含み、単位複製配列を合成するための手段は、機械的な混合素子をもたずに、単位複製配列を合成するための流体サブ回路を含み、かつ、単位複製配列を検出するための手段は、1個の一体型使い捨て部材の中に検出用チャンバーと光学窓をもつ流体サブ回路を含み、また、1個の一体型部材の流体工学を、ダイヤフラム式バルブおよびベローチャンバーを含む複数の空気圧式制御素子であって、外部の制御可能空気圧作動連結管に接続するための空気圧式相互接続回路を備えた複数の空気圧式制御素子によって制御することができる。
図13は、本発明のPCR流体および温度界面アセンブリとして構成されている一対のベローチャンバーの平面図である。2つの固定温度界面を利用するが、その1つがそれぞれのベローチャンバーの下にあって、PCR用の流体と温度の界面を形成している。1個のバルブだけが必要である。左側と右側にある空気圧作動装置の制御下で、流体がチャンバー間を行ったり来たりする。第1のチャンバーに進入した流体は、変性温度条件に遭遇する。第2のベローチャンバーに流れ込むと、温度は、プライマーとアニールさせるために低下している。ポリメラーゼを添加すると伸長が起き、変性条件、すなわち「融解」条件下で鎖が再び分離するまで伸長は続く。2つのダイヤフラムで圧縮と希薄化を交互に行うことによってサイクルが繰り返されて、チャンバー間で周期的な交互の流れが生じる。サイクルを必要回数行った後、増幅された物質がチャンバーから検出ステーションに排出される。
本アッセイ法の開発初期には、変温制御される単一のブロックTECが用いられた。この実施形態においては、ペルティエチップ(Peltier chip)を用いて、PID制御装置の制御下で、適当な大きさのヒートシンクを往復する熱移動を制御する。増幅用のチャネルまたはチャンバーが迅速に反応するよう、マイクロ流体装置の熱質量と熱拡散障壁、およびそれに付いているヒートブロックを小さくして工夫した。そして、二重固定温度ブロックをPCRプロトコールで使用した。増幅に必要とされる量が比較的少ないため、増幅用チャンバー内での混合は、流体の熱対流によって行われる。機械的な混合素子は必要ない。
試料からの核酸抽出は、臨床アッセイ法を開発する上で非常に重要である。困難な標本には、大便と痰がある。血液も、ヘモグロビンが、増幅に用いられるポリメラーゼの活性を阻害するため、問題が多い。
試料中の微生物およびウイルス粒子を溶解するには、試料中のヌクレオカプシド、脂質、およびムコ多糖類を部分的に可溶化する必要があるかもしれない。任意の前処理には、メルカプトエタノール、またはn−アセチル−システインを用いてジスルフィド結合を破壊すること、組織試料について、凍結融解、またはdounce型ホモジナイザー、超音波処理、もしくはフレンチプレスなどの機械的な前処理だけでなく、n,n−ジメチルホルムアミドおよびn−メチルピロリジノンなどの「汎用溶媒」を核酸:タンパク質結合および核酸:脂質結合を破壊するために使用することなどが含まれる。ミニビーズ衝撃式ミルまたは超音波破砕装置も、グラム陽性の球菌、桿菌、または内生胞子に対して使用することができる。
さまざまな病原体の診断的検出が考えられる。血液で運ばれる病原体には、いくつか例を挙げると、腸チフス菌(Salmonella typhosa)、パラチフス菌(Salmonella paratyphi)、炭疽菌(Bacillus anthracis)、ウシ流産菌(Brucella abortus)、ブタ流産菌(Brucella suis)、マルタ熱菌(Brucella melitensis)、ペスト菌(Yersinia(Pasteurella)pestis)、パスツレラ・マルトシダ(Pasteurella multocida)、野兎病菌(Francisella tularensis)、鼠咬症スピロヘータ菌(Spirillum minus)、鼻疽菌(Burkholderia mallei)、黄疸出血性レプトスピラ菌(Leptospirum ictohaemorrhagiae)、コクシエラ・バーネッティ(Coxiella burnetii)、発疹熱リケッチア(Rickettsia typhi)、ハンタウイルス、デング熱ウイルス、黄熱病ウイルス(およびフラビウイルスグループのその他のウイルス)、西ナイルウイルス、B型日本脳炎ウイルス、セントルイス脳炎ウイルス、西部ウマ脳炎ウイルス、ヒト免疫不全ウイルス1および2、ヒトT細胞白血病ウイルス1および2、犬糸状虫(Dirofilaria immitis)、三日熱マラリア原虫(Plasmodium vivax)、熱帯性マラリア、マラリア、卵形マラリア、およびベルゲイなどがある。黒水熱の原因の熱帯性マラリア(P. falciparum)の定量的検出が、血液では重要であろう。
1)第1の標的核酸配列の5’末端に対してハイブリダイゼーション特異性を有する第1のプライマーを選択して、ペプチジルハプテンを結合した第1のプライマーを合成する工程、
2)第1の標的核酸配列の3’末端に対してハイブリダイゼーション特異性を有する第2のプライマーを選択して、リガンドを結合した第2のプライマーを合成し、前記第1と第2のプライマーにプライマー対を形成させる工程、
3)複数の標的核酸配列の各々についてa)およびb)の工程を反復して、プライマー対をプールする工程、
4)プライマー対プールの存在下で双尾型単位複製配列産物を合成する工程、
5)増幅混合産物をリガンド結合因子でコートされた磁気ビーズに接触させて、前記リガンド結合した第1のプライマーを含む双尾型単位複製配列産物を捕捉する工程、
6)増幅混合産物を、各検査用パッドが、固定化された抗ペプチジルハプテン抗体を含む複数の検査用パッドに接触させ、検査用パッド上の双尾型単位複製配列を分子検出複合体の形で捕捉する工程、
7)1つ以上の分子検出複合体を検出することによって、アッセイ結果が、複数の病原体または発病状態について陽性であるとスコアリングする工程。
A)プライマーセットの調製
まず、逆方向プライマーを調製してHPLCで精製した。使用直前にn−末端ヒドラジンでペプチドを修飾した。オリゴヌクレオチドを、ホルムアミド中スクシンイミジル4−ホルミルベンゾエートで処理した後、ヒドラジンで誘導体化したペプチドと反応させて、ハプテンでタグ付けされたプライマーを形成させた。
単分散ストレプトアビジン被覆磁気ビーズ(MyOne Streptavidin Cl Dynabeads)をDynal,Carlsbad CAから購入し、洗浄して、0.5M TRIS(pH8)中80mM MgCl2、0.24%TritonX100、1%BSAの溶液を5%(v/v)含む、0.9×PBS、30mg/mL BSAおよび1%TritonX100に使用直前に再懸濁した。
マイクロ流体装置が、ステンシル裁断した積層板から構築されたが、これは、図9に図示された形の複数の検出用チャンバーを含んでいた。それぞれの検出用チャンバーは、マイクロ流体チャネルによって検出用チャンバーと流体で連結されている注入ポートおよび排出ポートを備えて作られていた。実験のために十分な検出チャネルを作った。
腸内病原菌由来の既知のDNA試料を用いて、PCRを調製されたプライマーセット(上述)で35サイクル行った。増幅には、Platinum Quantitative RT−PCR Thermoscript One−Step System試薬を用いた。増幅がうまく行ったことを、5%アガロースゲル電気泳動法によって確認した。そして、単位複製配列10μLを、10mM MgCl2、0.5%BSA、0.1%TritonX100および5mM TRISバッファー(pH8)を含む、約20μLのバッファーに5μLのビーズ(上述)とともに再懸濁し、この溶液をまとめて検出用チャンバーに入れた。各単位複製配列産物は1つのプライマーセットに対応していたので、これを別々の検出用チャンバーに入れた。
マイクロ流体装置内で以下のとおりにPCR増幅を行った。
溶解バッファー
4.5M グアニジンチオシアネート
5%TritonX100
1%サルコシン
50mM MES(pH5.5)
20mM EDTA
洗浄試薬
無水エタノール
溶離バッファーE11
1%TritonX100
0.1mM EDTA
20mM TRIS(pH8.0)
50U RNAsin(Promega)
再水和バッファー
1%TritonX100
0.5%NaCl
10mg/mL ウシ血清アルブミン
50mM TRIS(pH8.0)。
実施例2の標的を抽出、増幅、および検出したアッセイの結果を図6に示す。
ビオチン化プライマー対およびハプテンでタグ付けされたプライマー対を含む呼吸器パネルを設計する。プライマーを合成してから、装置の別の増幅用チャネルまたはチャンバーに置く。実施例2の手順に続いて、喉頭スワブ洗浄物を解析する。ミニビーズ衝撃式ミルを用いて、解析の前に試料を調製する。結果は、検出チャンバーに表示される。この産物をキットとしてパッケージする。
ビオチン化プライマー対およびペプチジルハプテンのタグ付プライマー対を含む性感染症パネルを設計し、該プライマーを合成する。そして、これらのプライマーを、装置の個別の増幅用のチャネルまたはチャンバー内で沈着させる。実施例2の手順に従って、膣のスワブ、洗浄物を解析する。検出のエンドポイントが、検出用チャンバー内に表示される。この産物をキットとしてパッケージする。
ビオチン化プライマー対およびペプチジルハプテンのタグ付きプライマー対を含む癌遺伝子パネルを設計し、プライマーを合成する。そして、プライマーを共通の増幅用チャネルまたはチャンバー内に沈着させる。PCR増幅の後に、増幅産物を検出ステーション内で検出する。この産物をキットとしてパッケージする。
Claims (12)
- (a)生体試料から核酸を抽出するための手段であって、生体試料から核酸を抽出するための第1の流体サブ回路を備え、前記第1の流体サブ回路が固相の核酸親和性結合基板をもつ、手段、
(b)単位複製配列を合成するための手段であって、単位複製配列を合成するための第2の流体サブ回路を備える、手段、および
(c)単位複製配列を検出するための手段であって、検出用チャンバーと光学窓とをもつ第3の流体サブ回路を備える、手段
を含む一体型マイクロ流体カートリッジであって、
前記第1、第2および第3の流体サブ回路が一個の一体型使い捨て部材の中に形成され、そして、前記第1、第2および第3の流体サブ回路が流体によって相互連結され、かつ、ダイヤフラム式バルブおよびベローチャンバーを含む複数の内部空気圧式制御素子によって制御することができ、そして、前記複数の内部空気圧式制御素子が、外部の制御可能空気圧式作動連結管に接続するための空気圧式相互接続回路を備える、一体型マイクロ流体カートリッジ。 - 請求項1に記載のマイクロ流体カートリッジであって、単位複製配列を合成するための前記手段が、
(a)第2のベローチャンバーに流体によって相互接続している第1のベローチャンバー、
(b)第1のベローチャンバーおよび第2のベローチャンバーを異なった一定温度に保持する温度界面
をさらに含み、ここで、各ベローチャンバーが、前記第1のベローチャンバーと前記第2のベローチャンバーとの間で液体を相互ポンピングするためのダイヤフラムをさらに含む、マイクロ流体カートリッジ。 - 以下の工程(a)〜(f):
(a)前記第1のベローチャンバーの中で、DNA鋳型、プライマー、ポリメラーゼ、dNTP、バッファー、およびマグネシウム塩を含む反応混合液を作成する工程であって、第1の前記ベローチャンバーは二本鎖DNAの変性温度以上の一定の温度に保持されており、かつ第2の前記ベローチャンバーは、前記DNA鋳型と前記プライマーのアニーリング温度以下の一定の温度に保持されている、工程
(b)核酸標的配列を前記第1のベローチャンバーの中に導入する工程、
(c)空気圧を前記第1のベローチャンバーの前記ダイヤフラムに適用して、前記反応混合液を前記第1のベローチャンバーから前記第2のベローチャンバーへ移動させる工程、(d)空気圧を前記第2のベローチャンバーの前記ダイヤフラムに適用して、前記反応混合液を前記第2のベローチャンバーから前記第1のベローチャンバーへ移動させる工程、(e)工程(c)および(d)を多数の温度サイクルの間繰り返して、増幅産物を合成する工程、ならびに
(f)増幅産物を取り出す工程
を含む、請求項2に記載のマイクロ流体カートリッジの中でPCRを行う方法。 - 生体試料について核酸アッセイを行うための装置であって、前記装置は、以下:
(a)前記核酸アッセイのための乾燥試薬および液体試薬を含むプラスチック製の使い捨てカートリッジ本体であって、前記カートリッジ本体が、以下:
(i)前記試料から核酸を抽出するための第1の流体サブ回路;
(ii)単位複製配列産物を合成するための第2の流体サブ回路;
(iii)前記単位複製配列産物を検出するための第3の流体サブ回路;
(iv)衛生廃棄物回収用チャンバー;および
(v)前記第1、第2および第3の流体サブ回路を空気圧式に作動させるためのアームをもつ、空気圧式相互接続サブ回路
を含む、カートリッジ本体と;
(b)前記核酸アッセイを制御するように構成されたマイクロプロセッサの制御下で、前記カートリッジ本体の前記空気圧式相互接続サブ回路に正および負の空気圧のプログラム可能なパルス列を供給するためのアームとソレノイドバルブとをもつ、カートリッジ外の空気圧作動型連結管
とを含み、前記第1の流体サブ回路は、以下:
(a)試料注入ポート;
(b)第1の流体チャネルによって前記試料注入ポートに、そして、第2の流体チャネルによって第2のベローポンプに、流体とバルブにより相互連結している、第1のベローポンプであって、前記第2のベローポンプは、前記サンプルに溶解バッファーをプログラム可能に混合するための壊れやすい溶解バッファー試薬パックを備え、そして、前記空気圧式相互接続サブ回路は、ダイヤフラムと前記第2のベローポンプ内の対向する鋭利なものとの間で前記溶解バッファー試薬パックを圧迫することによって、前記溶解バッファー試薬パックをプログラム可能に破壊するように構成される、第1のベローポンプ;および
(c)核酸を抽出するための、固相の核酸標的捕捉アセンブリであって、前記標的捕捉アセンブリは、前記第1のベローポンプに流体とバルブにより相互連結される、標的捕捉アセンブリ
を備える、装置。 - 請求項4に記載の装置であって、前記第1の流体サブ回路は、さらに、以下:
(a)前記標的捕捉アセンブリに流体とバルブにより相互連結している第3のベローポンプであって、前記第3のベローポンプは、前記標的捕捉アセンブリに洗浄用試薬をプログラム可能に送達するための、壊れやすい洗浄用試薬パックを含み、前記空気圧式相互接続サブ回路は、ダイヤフラムと前記第3のベローポンプ内の対向する鋭利なものとの間で前記洗浄用試薬パックを圧迫することによって、前記洗浄用試薬パックをプログラム可能に破壊するように構成される、第3のベローポンプ;ならびに
(b)廃液用チャネルによって前記標的捕捉アセンブリに、流体およびバルブにより接続される衛生廃棄物貯蔵容器
を備える、装置。 - 請求項5に記載の装置であって、前記第1の流体サブ回路はさらに、以下:
(a)前記標的捕捉アセンブリに流体とバルブにより相互連結している第4のベローポンプであって、前記第4のベローポンプは、前記標的捕捉アセンブリに溶離バッファーをプログラム可能に送達するための、壊れやすい溶離用試薬パックを含み、前記空気圧式相互接続サブ回路は、ダイヤフラムと前記第4のベローポンプ内の対向する鋭利なものとの間で前記溶離用試薬パックを圧迫することによって、前記溶離用試薬パックをプログラム可能に破壊するように構成される、第4のベローポンプ;および
(b)前記標的捕捉アセンブリを前記第2の流体サブ回路に相互連結して、核酸溶出液を増幅のために前記第2の流体サブ回路に運ぶための、第2の流体チャネル
を備える、装置。 - 請求項6に記載の装置であって、前記第2の流体サブ回路は、以下:
(a)マイクロチャネルによって流体により相互連結された第1および第2のベローポンプを備えるPCR流体および温度界面であって、前記PCR流体および温度界面は、前記第1のベローポンプを前記核酸溶出液を変性させるための一定の温度に、そして、前記第2のベローポンプを前記核酸溶出液をアニーリングするための一定の温度に保持するように構成され、前記正および負の空気圧の前記プログラム可能なパルス列は、前記第1のベローポンプと前記第2のベローポンプとの間で前記核酸溶出液を相互ポンピングして、前記核酸溶出液を熱サイクリングさせるように構成される、PCR流体および温度界面;
(b)前記核酸溶出液内で再構成させるためのプライマーを含む、乾燥PCR混合液試薬;ならびに
(c)前記第2の流体サブ回路を前記第3の流体サブ回路にバルブにより相互連結して、前記第2の流体サブ回路の前記単位複製配列産物を検出のために前記第3の流体サブ回路に運ぶための、バルブを備える第3の流体チャネル
を備える、装置。 - 前記乾燥PCR混合液試薬が、前記核酸溶出液内で直接再構成される、請求項7に記載の装置。
- 請求項7に記載の装置であって、前記PCR流体および温度界面の前記第1および第2のベローポンプが、加熱および冷却の手段によって前記一定の温度に保持され、前記加熱および冷却の手段は、前記温度界面と接する第1および第2の加熱および冷却ブロックを備え、前記第1のブロックは、前記第1のベローポンプと作動可能に接触し、そして、前記第2のブロックは前記第2のベローポンプと作動可能に接触する、装置。
- 前記第2のベローポンプが、乾燥ポリメラーゼを含む、請求項7に記載の装置。
- 流体的に前記標的捕捉アセンブリと前記PCR流体および温度界面の前記第1および第2のベローポンプとの間に置かれたcDNA合成チャンバーをさらに備える、請求項9に記載の装置。
- 請求項9に記載の装置であって、前記衛生廃棄物貯蔵容器が、廃棄物のための流入口、前記貯蔵容器内の吸水性パッド、および前記吸水性パッドを覆い、かつ、前記廃棄物貯蔵容器を通気するための外側のベントから前記流入口を分離するフィルムを備える、装置。
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US8772017B2 (en) | 2014-07-08 |
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WO2007106579A3 (en) | 2008-02-28 |
AU2007225038B2 (en) | 2013-08-29 |
US8222023B2 (en) | 2012-07-17 |
HK1126824A1 (en) | 2009-09-11 |
JP2009529883A (ja) | 2009-08-27 |
US20120329142A1 (en) | 2012-12-27 |
EP2007905A2 (en) | 2008-12-31 |
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EP2007905B1 (en) | 2012-08-22 |
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