JP2022163076A - 癌検出のための方法 - Google Patents
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Abstract
Description
本出願は、2016年11月22日出願の米国仮特許出願第62/425,549号の利益を主張し、該仮出願は、その全体において引用により本明細書に組み込まれる。
本明細書中の出願公開、特許、及び特許出願は全て、あたかも個々の出願公開、特許、或いは特許出願がそれぞれ参照により組み込まれるように具体的且つ個々に指示されるように同じ程度まで、参照により組み込まれる。
エキソソームはまた、細胞膜又は内膜のいずれかに由来する、任意の流出(shed)膜結合粒子を含み得る。エキソソームは更に、原形質膜の一部の脱出性膨出(herniated evagination)(例えば、ブレブ形成)分離及び封止(sealing)により生じる、又は、腫瘍由来マイクロRNA又は細胞内タンパク質を含むがこれらに限定されないエキソソーム内腔に含まれる分子と共に腫瘍由来タンパク質に選択的に結合する宿主循環に由来する表面結合分子等の腫瘍起源の種々の膜結合タンパク質を含む任意の細胞内膜に囲まれた小胞構造の搬出により生じる、脂質二重層膜によって囲まれた細胞由来構造を含み得る。
アダプターは、互いに結合して環状DNAを形成可能となるように修飾され得る。III型制限酵素(例えばEcoP15)を加えることができ;EcoP15は、Ad3の左側のDNA26bp、及びAd2の右の26bpを切断することができる。この切断は、DNAの大きなセグメントを除去し、DNAを再び線状化することができる。右及び左のアダプターの第4巡(Ad4)を、DNAにライゲートすることができ、DNAは(例えば、PCRによって)増幅され、且つ、互いに結合して完成した環状DNA鋳型を形成するように修飾され得る。ローリングサークル複製(例えばPhi29 DNAポリメラーゼを使用する)を使用して、DNAの小さなフラグメントを増幅することができる。4つのアダプター配列は、ハイブリダイズ可能なパリンドローム配列を含有することができ、一本鎖は、それ自体の上へと折りたたまれて、平均で直径およそ200~300ナノメートルとなり得るDNAナノボール(DNB(商標))を形成することができる。DNAナノボールは、マイクロアレイ(配列決定フローセル)に付けることができる(例えば、吸着により)。フローセルは、二酸化ケイ素、チタン、及びヘキサメチルジシラザン(HMDS)、並びにフォトレジスト材料でコーティングされたシリコンウエハであり得る。配列決定は、DNAに蛍光プローブをライゲートすることによる、連鎖しない配列決定によって実施することができる。問い合わせられた位置の蛍光の色は、高解像度カメラによって可視化することができる。アダプター配列間のヌクレオチド配列の同一性を決定することができる。
高速キャッシュ(501)は、プロセッサ(502)により最近使用された、或いは頻繁に使用される指示又はデータのための高速メモリを提供するプロセッサ(502)に接続、又はその中に組み込むことができる。プロセッサ(502)はプロセッサバス(505)によってノースブリッジ(506)に接続される。ノースブリッジ(506)はメモリバス(504)によってランダムアクセスメモリ(RAM)(503)に接続され、プロセッサ(502)によってRAM(503)のアクセスを管理する。ノースブリッジ(506)もチップセットバス(507)によりサウスブリッジ(508)に接続される。サウスブリッジ(508)は次に、周辺バス(509)に接続される。周辺バスは、例えばPCI、PCI-X、PCI Express、又は別の周辺バスであり得る。ノースブリッジ及びサウスブリッジは頻繁に、プロセッサチップセットと称され、周辺バス(509)上でプロセッサと、RAMと、周辺コンポーネントとの間のデータ転送を管理する。幾つかのコンピューターアーキテクチャシステムにおいて、ノースブリッジの機能性は、別個のノースブリッジチップを使用する代わりにプロセッサに組み込まれ得る。
ソフトウェア及びデータは、外部記憶装置モジュール(513)に保管され、プロセッサにより使用のためにRAM(503)及び/又はキャッシュ(501)へとロードされ得る。コンピューターアーキテクチャシステム(2300)は、システムリソースの管理のためにオペレーティングシステムを含み得る。オペレーティングシステムの非限定的な例は、以下を含む:Linux(登録商標)、Windows(商標)、MACOS(商標)、BlackBerry OS(商標)、iOS(商標)、及び他の機能的に同等のオペレーティングシステム。幾つかの実施形態において、オペレーティングシステムはオペレーティングシステムの上部で実行されるアプリケーションソフトウェアであり得る。
図6は、複数のコンピューターシステム(602a及び602b)、複数の携帯電話及び個人用携帯情報端末(602c)、及びNAS装置(601a及び601b)を有するコンピュータネットワーク(600)を示す図である。幾つかの実施形態において、システム(602a)、(602b)、及び(602c)は、データ保存を管理し、NAS装置(601a及び602b)上で保存されたデータに対してデータアクセスを最適化することができる。数学モデルは、コンピューターシステム(602a及び602b)及び携帯電話及び個人用携帯情報端末システム(602c)を介する分布された並列処理を使用して、データを評価するために使用され得る。コンピューターシステム(602a及び602b)及び携帯電話及び個人用携帯情報端末システム(602c)はまた、NAS装置(601a及び601b)上で保存されたデータの適合データ再構築に並列処理を提供することができる。
図7は、共有仮想アドレスメモリ空間を用いる、マルチプロセッサーコンピュータシステムのブロック図である。システムは、共有メモリーサブシステム(702)にアクセス可能な複数のプロセッサ(701a-701f)を含む。システムは、メモリサブシステム(702)に複数のプログラマブルハードウェアのメモリアルゴリズムプロセッサ(MAP)(703a-703f)を組み込む。各MAP(703a-703f)は、メモリーカード(704a-704f)及び1つ以上のフィールドプログラマブルゲートアレイ(FPGA)(705a-705f)を含むことができる。MAPは設定可能な機能ユニットを提供する。アルゴリズム又はアルゴリズムの一部は、それぞれのプロセッサと密に協働して処理するためにFPGA(705a-705f)に提供され得る。幾つかの実施形態において、MAPは各々、プロセッサ全てにより世界的にアクセス可能である。幾つかの実施形態において、MAPは各々、関連するメモリーカード(704a-704f)にアクセスするためにダイレクトメモリアクセス(DMA)を使用することができ、それにより、各マイクロプロセッサ(701a-701f)とは別個に、且つこれらから非同期的にタスクを実行することが可能となる。幾つかのこの構成において、MAPは、パイプライン処理(pipelining)及びアルゴリズムの並列実行のために別のMAPに直接結果を供給することができる。
公的に入手可能なデータを使用して、遺伝子共発現ネットワークを分析する。18の可能なバイオマーカーを多数の疾病に対して発見した。バイオマーカーを、乳癌、結腸癌、肺癌、神経変性疾患、及び炎症性障害を含む疾病に対して発見した。
遺伝子発現レベルを、10の乳癌被験体及び10の対応する健康な対照から得た唾液サンプルを使用して分析した。この研究は、10の患者及び10の対照サンプルの発見データセットからのマイクロアレイデータを使用して、唾液ベースの乳癌検出に概念実証を提供した。サンプルは、例えば人種、BRCA及び非BRCA、高密度なサンプル、及び非高密度なサンプルの混合集団を含んでいた。
実施例2で同定されたバイオマーカーの初期の検証を、9-遺伝子バイオマーカーパネル(例えば図4における遺伝子)について60の患者サンプルに実行した。サンプルは、例えば人種、BRCA及び非BRCA、高密度なサンプル、及び非高密度なサンプルの混合集団を含んでいた。デンスブレスト組織の存在など、マンモグラムに合併症があったとき、9-遺伝子アッセイからのデータを使用して、更なるスクリーニングの必要性を方向付け、検出率を大幅に増大させた。
バイオマーカーレベル(例えば、実施例2からの9つのバイオマーカー遺伝子の転写レベル)を、乳癌の形成及び進行に関係すると知られるそれら遺伝子に相関させる。バイオマーカーに関連する倍率変化の差異を、癌の被験体及びサブクラスと、健康な被験体及びサブクラスとの間で調べ、サブクラスは年齢、人種、身体状態、乳癌のタイプ又は段階、及び乳房組織密度に関連する。この情報を使用して、乳癌の形成及び進行に関係すると知られる遺伝子及び関連経路の遺伝子オンコロジー検索を誘導する。この情報に基づいて、バイオマーカーの発現レベルのランク付け及び重み付けを決定し、試験の感度を改善させた。
標準治療の化学療法薬を用いて、及びそれを用いずに、培養物中で増殖される不死化乳癌細胞株(例えばMDA-MB-231及びMCF7)から放出されたエキソソームのmRNA内容物を、調べる。エキソソームのmRNA内容物から得られたデータを使用して、遺伝子発現値の重み付けを更に洗練させ、試験結果の測定を改善する。
盲検唾液サンプル(例えば、癌があるかわからない30のサンプル、対照情報)を分析し、実施例4及び実施例5から収集された新たな重み付けの最適化を使用して実施例4におけるようにスコア付けした。
図26は、唾液遺伝子試験に対して最適化されたワークフローを示す。5mLの唾液を30分内に50mLの収集チューブに集め、チューブを診断研究所(2601)に運んだ。サンプルを4℃で15分間、2600gで遠心分離した。上清を集めた。5μL(即ち100ユニット)のsuperase阻害剤を唾液上清1mL当たりに加え、サンプルを保管した(2602)。その後、RNAを唾液サンプルから単離した(2603)。唾液上清サンプルを解凍した。200μLの解凍されたサンプルをサンプルチューブに直接移した。標準MagNAプロトコルに従って全RNAを単離した。RNAサンプルを-80℃で保管した。RNAを逆転写し、表3と表4に示される実験パラメータを使用して1工程の反応で予め増幅させた(2604)。
乳癌を抱える10人の患者と正常な10人の患者の唾液から集めたRNAを使用して、癌及び正常な表現型に対する相関性を算出した。これを使用して、癌サンプルと正常サンプルとの間で差次的に発現される遺伝子を判定した。図29は、ヒートマップの形で研究の結果を示す。図29において、最初の10のカラムは癌患者の唾液からのデータを示し、次の10のカラムは正常サンプルの唾液からのデータを示す。各行のボックスは、20人の患者における遺伝子の発現を示す。青色のボックスは、遺伝子発現が下がっていることを示した。赤色のボックスは、遺伝子発現が上がっていることを示した。
女性被験体はマンモグラムを受ける。被験体は、デンスブレストがあることを伝えられている。マンモグラムは、癌に対する陰性の指標を示す。被験体にデンスブレスト組織があるため、医療サービス提供者は、乳癌バイオマーカーアッセイ(例えば実施例4に記載される9-遺伝子アッセイ)を推奨する。
図2は、正確な癌診断のためにマンモグラム画像化と協働した唾液ベースのバイオマーカーアッセイの使用を示す。女性被験体(201)はマンモグラム(202)を受け、医療サービス提供者に唾液サンプル(204)を提出する。マンモグラムを分析し(203)、癌を検出する。同時に、本開示の方法を使用して唾液サンプルを分析し(205)、バイオマーカーパネルからの遺伝子の転写のレベルを判定する(例えば、実施例4に記載される9-遺伝子アッセイ)。被験体は、マンモグラム及びバイオマーカーアッセイからのデータの分析に基づいた診断を受ける(206)。
被験体は毎年、乳癌についてのスクリーニングを希望する。被験体は、画像化の前に、郵送で、又は個人的に唾液サンプルを提供する。被験体のサンプルをバイオマーカーパネルについて分析する。(例えば、郵送により又は個人的に伝達された)結果に基づいて、バイオマーカーは被験体をリスクカテゴリーへと分類する。これらカテゴリーは癌のリスク及び追跡の頻度を特定するために使用され得る。結果は更に、マンモグラム、MRI、及び/又は、唾液結果が非常に高リスクを示す場合のより広範な監視による、追加のスクリーニングに対する推奨を提供することができる。
被験体は毎年、スクリーニングマンモグラムのために医療サービス提供者を訪れ、同時に唾液サンプルを提供する。2つの試験を個別に分析する。結果を組み合わせて、癌に対する単一の組み合わされた確率スコアを生成し、これは何れかの試験単独よりも強健な乳癌リスクの推定値であり得る。
被験体は毎年、スクリーニングマンモグラムのために医療サービス提供者を訪れ、「曖昧な結果」の読み取りを含むマンモグラムを得る。およそ1/7のマンモグラムが曖昧であり得る。被験体は唾液サンプルを提供し、これを本開示のバイオマーカーアッセイを使用して分析する。バイオマーカーアッセイ及びマンモグラムからの結果を組み合わせて、反復マンモグラム、MRI、生検又は、唾液サンプル試験、マンモグラム、或いはその両方による監視頻度の増加などの追跡の進行に被験体を優先させる。
被験体はスクリーニングのために訪問し、サンプルを提供する。サンプルを分析し、試験結果は患者の身体中の癌を同定する。被験体は、乳房などの特異的な体組織に癌を位置づけるために本開示のバイオマーカーアッセイなどの追跡試験を受ける。
被験体はマンモグラムの回避を希望する。マンモグラムには、デンスブレストを持つ被験体、若い被験体(例えば18~40の年齢層、40歳未満、又は35歳未満)、又は乳癌のリスクが高い被験体などに対する、高い偽陰性及び偽陽性の割合がある。若い被験体は、より高い頻度のデンスブレストを有し得る。被験体は34歳であり、デンスブレストを有する。被験体は、本開示の唾液ベースのバイオマーカーアッセイを受ける。被験体は、乳癌のリスクスコア、追加の試験への推奨、及び今後のスクリーニングの頻度を示される。
以下の非限定的な実施形態は、本発明の例示的な実施例を提供するが、本発明の範囲を限定するものではない。
a)被験体にスクリーニング試験を実行する工程であって、スクリーニング試験は健康状態を発達させるリスクに対して被験体を評価することを含む、工程;
b)被験体の生体サンプルを得る工程;
c)被験体の生体サンプル中のバイオマーカーのサンプルレベルを定量する工程;
c)バイオマーカーのサンプルレベルをバイオマーカーの基準レベルと比較する工程;
e)スクリーニング試験の結果と比較を組み合わせる工程;及び
f)比較に基づいて被験体の健康状況を判定する工程
を含む、方法。
a)被験体の唾液サンプルを得る工程;
b)バイオマーカーを放出するために唾液サンプルのエキソソーム分画を実験的に溶解する工程;
c)バイオマーカーのサンプルレベルを定量する工程;及び
d)バイオマーカーのサンプルレベルをバイオマーカーの基準レベルと比較する工程であって、基準レベルは乳癌を抱える被験体から得られる、工程
を含む、方法。
a)被験体にマンモグラムを実行する工程;
b)被験体の唾液サンプルを得る工程;
c)被験体の唾液サンプル中のバイオマーカーのサンプルレベルを定量する工程であって、バイオマーカーはエキソソーム由来である、工程;
d)バイオマーカーのサンプルレベルをバイオマーカーの基準レベルと比較する工程であって、基準レベルは乳癌を抱える被験体から得られる、工程;及び
e)被験体の健康状況を判定するためにマンモグラムと比較の結果を組み合わせる工程
を含む、方法。
a)被験体にスクリーニング試験を実行する工程であって、スクリーニング試験は健康状態を発達させるリスクに対して被験体を評価することを含む、工程;
b)被験体の生体サンプルを得る工程であって、被験体は、スクリーニング試験からの陽性、陰性、又は曖昧な結果を持つ被験体の集団である、工程;
c)被験体の生体サンプル中のバイオマーカーのサンプルレベルを定量する工程であって、バイオマーカーは健康状態に関連付けられる、工程;
d)バイオマーカーのサンプルレベルを健康状態に対するバイオマーカーの基準レベルと比較する工程;及び
e)比較の結果に基づいて健康状態に対する偽陽性又は偽陰性として、スクリーニング試験の結果を同定する工程
を含む、方法。
Claims (33)
- 被験体の健康状況を判定するための方法であって、
a)被験体から唾液サンプルを提供する工程;
b)唾液サンプルからバイオマーカーのサンプルレベルを定量する工程であって、バイオマーカーは唾液サンプル中のエキソソーム由来である、工程;
c)バイオマーカーのサンプルレベルをバイオマーカーの基準レベルと比較する工程であって、基準レベルは乳癌を抱える被験体から得られる、工程;及び
d)比較に基づいて乳癌に対する被験体のリスクスコアを判定する工程
を含む、方法。 - 被験体の乳房組織を画像化する工程を更に含む、請求項1に記載の方法。
- 画像化する工程はマンモグラムを使用して実行される、請求項2に記載の方法。
- マンモグラムからの結果に基づいて被験体のリスクスコアを調整する工程を更に含む、請求項1に記載の方法。
- 工程b)の前にバイオマーカーを放出するためにエキソソームを溶解する工程を更に含む、請求項1に記載の方法。
- 溶解前に唾液サンプルのエキソソーム分画を富化する工程を更に含む、請求項4に記載の方法。
- 富化の後にエキソソーム分画を安定させる工程を更に含む、請求項1に記載の方法。
- バイオマーカーは無細胞核酸である、請求項1に記載の方法。
- 無細胞核酸はRNAである、請求項8に記載の方法。
- RNAはmRNA又はmiRNAである、請求項9に記載の方法。
- mRNAは、LCE2B、HIST1H4K、ABCA1、ABCA2、TNFRSF10A、AK092120、DTYMK、ALKBH1、MCART1、Hs.161434、及びそれらの任意の組み合わせから成る群から選択された遺伝子の転写産物である、請求項10に記載の方法。
- 定量する工程はRNAを逆転写する工程を更に含む、請求項9に記載の方法。
- 定量する工程はポリメラーゼ連鎖反応(PCR)を実行する工程を含む、請求項1に記載の方法。
- PCRはqPCRを含む、請求項13に記載の方法。
- 定量する工程は配列決定を実行する工程を更に含む、請求項1に記載の方法。
- 配列決定は超並列配列決定を含む、請求項15に記載の方法。
- 乳癌に対する被験体のリスクスコアを判定する工程は、少なくとも90%の精度により実行される、請求項1に記載の方法。
- 乳癌に対する被験体のリスクスコアを判定する工程は、少なくとも90%の特異性により実行される、請求項1に記載の方法。
- 乳癌に対する被験体のリスクスコアを判定する工程は、少なくとも80%の感度により実行される。請求項1に記載の方法。
- エキソソームの起始細胞は乳房細胞である、請求項1に記載の方法。
- 被験体はデンスブレスト組織を有する、請求項1に記載の方法。
- 被験体はスクリーニングマンモグラムからの曖昧な結果を持つ、請求項1に記載の方法。
- 被験体は50歳未満である、請求項1に記載の方法。
- バイオマーカーは、癌の特徴に関連付けられる遺伝子の転写産物である、請求項1に記載の方法。
- 癌の特徴は、成長抑制因子の回避、免疫破壊の回避、複製の不死化の促進、腫瘍を促進する炎症、侵入及び転移の活性化、血管新生の誘導、ゲノム不安定性及び突然変異、細胞死に対する耐性、細胞のエネルギー学の調節解除、増殖性シグナル伝達の保持、及びそれらの任意の組み合わせから成る群から選択される、請求項24に記載の方法。
- 癌の特徴に関連付けられる遺伝子は、LCE2B、HIST1H4K、ABCA2、TNFRSF10A、AK092120、DTYMK、ALKBH1、MCART1、Hs.161434、及びそれらの任意の組み合わせから成る群から選択される、請求項24に記載の方法。
- 癌の特徴に関連付けられる遺伝子は、ABCA1、ABCA2、TNFRSF10A、DTYMK、ALKBH1、及びそれらの任意の組み合わせから成る群から選択される、請求項24に記載の方法。
- バイオマーカーは、癌の特徴に関連付けられる遺伝子と同様の発現プロファイルを持つ遺伝子の転写産物である、請求項1に記載の方法。
- 乳癌に対する偽陽性又は偽陰性の結果の数を減らすための方法であって、
a)被験体の生体サンプルを提供する工程であって、被験体は、スクリーニングマンモグラムからの陽性、陰性、又は曖昧な結果を持つ被験体の集団である、工程;
b)被験体の生体サンプル中のバイオマーカーのサンプルレベルを定量する工程;
c)バイオマーカーのサンプルレベルをバイオマーカーの基準レベルと比較する工程;及び
d)比較の結果に基づいて乳癌に対する偽陽性又は偽陰性として、スクリーニングマンモグラムの結果を同定する工程
を含む、方法。 - 被験体の健康状況を判定するための方法であって、
a)被験体の生体サンプルを提供する工程;
b)被験体の生体サンプル中の少なくとも2つのバイオマーカーのサンプルレベルを定量する工程であって、少なくとも2つのバイオマーカーは、LCE2B、HIST1H4K、ABCA2、TNFRSF10A、AK092120、DTYMK、ALKBH1、MCART1、Hs.161434、及びそれらの任意の組み合わせから成る群から選択される、工程;
c)少なくとも2つのバイオマーカーのサンプルレベルを少なくとも2つのバイオマーカーの基準レベルと比較する工程;及び
d)比較に基づいて被験体の健康状況を判定する工程
を含む、方法。 - 被験体の健康状況を判定するための方法であって、
a)被験体にマンモグラムを実行する工程;
b)被験体の唾液サンプルを得る工程;
c)唾液サンプルからのバイオマーカーのサンプルレベルを定量する工程であって、バイオマーカーはエキソソーム由来であり、LCE2B、HIST1H4K、ABCA2、TNFRSF10A、AK092120、DTYMK、ALKBH1、MCART1、Hs.161434、及びそれらの任意の組み合わせから成る群から選択される遺伝子の転写産物である、工程;
d)バイオマーカーのサンプルレベルをバイオマーカーの基準レベルと比較する工程であって、基準レベルは乳癌を抱える被験体から得られる、工程;及び
e)乳癌に関連付けられる被験体の健康状況を判定するためにマンモグラムと比較の結果を組み合わせる工程
を含む、方法。 - a)被験体から唾液サンプルを提供する工程;
b)唾液サンプルからのバイオマーカーのサンプルレベルを定量する工程であって、バイオマーカーは癌の特徴に関連付けられる遺伝子の転写産物である、工程;
c)バイオマーカーのサンプルレベルをバイオマーカーの基準レベルと比較する工程であって、基準レベルは癌を抱える被験体から得られる、工程;及び
d)比較に基づいて癌に対する被験体のリスクスコアを判定する工程
を含む、方法。 - 癌の特徴は、成長抑制因子の回避、免疫破壊の回避、複製の不死化の促進、腫瘍を促進する炎症、侵入及び転移の活性化、血管新生の誘導、ゲノム不安定性及び突然変異、細胞死に対する耐性、細胞のエネルギー学の調節解除、増殖性シグナル伝達の保持、及びそれらの任意の組み合わせから成る群から選択される、請求項32に記載の方法。
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JP2008073304A (ja) * | 2006-09-22 | 2008-04-03 | Gifu Univ | 超音波乳房診断システム |
GB201000688D0 (en) * | 2010-01-15 | 2010-03-03 | Diagenic Asa | Product and method |
WO2011100472A1 (en) * | 2010-02-10 | 2011-08-18 | The Regents Of The University Of California | Salivary transcriptomic and proteomic biomarkers for breast cancer detection |
CA2803266A1 (en) * | 2010-07-08 | 2012-01-12 | Prime Genomics, Inc. | System for the quantification of system-wide dynamics in complex networks |
WO2012115885A1 (en) * | 2011-02-22 | 2012-08-30 | Caris Life Sciences Luxembourg Holdings, S.A.R.L. | Circulating biomarkers |
KR101335034B1 (ko) * | 2011-08-25 | 2013-12-02 | 주식회사 바이오인프라 | 유방암 진단을 위한 엑소좀 내의 ANT2 mRNA의 이용방법 |
US20170175197A1 (en) * | 2014-01-29 | 2017-06-22 | Caris Mpi, Inc. | Molecular profiling of immune modulators |
WO2015187727A2 (en) * | 2014-06-04 | 2015-12-10 | Atossa Genetics Inc. | Molecular mammography |
WO2016004387A1 (en) * | 2014-07-02 | 2016-01-07 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Gene expression signature for cancer prognosis |
-
2017
- 2017-11-22 MA MA046927A patent/MA46927A/fr unknown
- 2017-11-22 US US16/462,699 patent/US20200081008A1/en not_active Abandoned
- 2017-11-22 MX MX2019006005A patent/MX2019006005A/es unknown
- 2017-11-22 WO PCT/US2017/063157 patent/WO2018098379A1/en unknown
- 2017-11-22 JP JP2019527223A patent/JP2020511933A/ja active Pending
- 2017-11-22 CN CN201780084170.4A patent/CN110198711A/zh active Pending
- 2017-11-22 CA CA3044257A patent/CA3044257A1/en active Pending
- 2017-11-22 EP EP17873722.7A patent/EP3544605A4/en active Pending
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2022
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CA3044257A1 (en) | 2018-05-31 |
US20200081008A1 (en) | 2020-03-12 |
EP3544605A4 (en) | 2020-11-25 |
EP3544605A1 (en) | 2019-10-02 |
MA46927A (fr) | 2019-10-02 |
WO2018098379A1 (en) | 2018-05-31 |
CN110198711A (zh) | 2019-09-03 |
JP2020511933A (ja) | 2020-04-23 |
MX2019006005A (es) | 2019-10-02 |
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