JP6110304B2 - Fgf21関連障害を処置する方法 - Google Patents
Fgf21関連障害を処置する方法 Download PDFInfo
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- JP6110304B2 JP6110304B2 JP2013539257A JP2013539257A JP6110304B2 JP 6110304 B2 JP6110304 B2 JP 6110304B2 JP 2013539257 A JP2013539257 A JP 2013539257A JP 2013539257 A JP2013539257 A JP 2013539257A JP 6110304 B2 JP6110304 B2 JP 6110304B2
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Description
本発明は、改善された医薬特性を有する線維芽細胞増殖因子21(FGF21)の新規ポリペプチドに関する。また、FGF21関連障害、例えば、肥満、1型および2型糖尿病、膵炎、脂質異常症、非アルコール性脂肪性肝炎(NASH)、インスリン耐性、高インスリン血症、耐糖能障害、高血糖、メタボリック・シンドロームおよび他の代謝障害を処置するための、および重症患者の死亡率および罹患率を減少させることにおける方法も記載する。
線維芽細胞増殖因子(FGF)ファミリーは、7つのサブファミリーにグループ分けされる、22個の遺伝的に異なる同種リガンドにより特徴付けられる。公開文献によると、FGFファミリーは、現在、少なくとも23メンバー、FGF−1からFGF−23からなる(Reussら Cell Tissue Res. 313:139-157 (2003)。
本発明は、改善された医薬特性を有する、例えば、医薬製剤条件下で野生型FGF21よりも、より安定で、タンパク質分解および酵素分解されにくく、複合体を凝集および形成する可能性が低い、線維芽細胞増殖因子21(FGF21)の新規ポリペプチドおよびタンパク質変異体の同定に関する。また、記載されているものは、FGF21関連障害、例えば、代謝状態を処置するための方法である。
タンパク質医薬、例えば、FGF21、例えば、本発明のFGF21タンパク質変異体の開発における重要な挑戦は、それらの物理化学的不安定性に対処することである。タンパク質の組成変化および特性は、特定の性質、例えば、フォールディング、立体配座安定性およびアンフォールディング/変性を定義する。このような特性は、タンパク質水溶液を利用する医薬製剤条件を開発するとき、タンパク質を安定化する必要がある(Wang, W., Int. J. of Pharmaceutics, 18, (1999))。興味ある治療タンパク質、例えば、本発明のFGF21タンパク質変異体を安定化する所望の効果は、タンパク質分解および酵素分解に対する耐性を増加させ、それにより、タンパク質安定性を改善し、タンパク質凝集を減少させる。
種々の定義が、本明細書を通して使用される。多数の用語は、当業者がそれらの用語に帰属すると考える意味を有する。下記で、または本明細書の他の場所で具体的に定義された用語は、全体として、本発明の文脈で提供される意味を有し、一般的には、当業者により理解されるものである。
163Cys。
「部位特異的FGF21突然変異体」または「置換FGF21突然変異体」なる用語は、天然FGF21ポリペプチド配列のアミノ酸配列、例えば、配列番号:1と異なるアミノ酸配列を有するFGF21突然変異体ポリペプチドおよびその変異体を示す。部位特異的FGF21突然変異体は、FGF21ポリペプチドの特定の位置にて、保存または非保存のいずれかでのアミノ酸置換を導入し、天然または非天然アミノ酸を使用することにより作製することができる。
(1)疎水性:ノルロイシン、Met、Ala、Val、Leu、Ile;
(2)中性親水性:Cys、Ser、Thr;
(3)酸性:Asp、Glu;
(4)塩基性:Asn、Gln、His、Lys、Arg;
(5)鎖方向に影響する残基:Gly、Pro;
(6)芳香族性:Trp、Tyr、Phe;ならびに
(7)セレノシステイン、ピロリジン(PYL)およびピロリン−カルボキシ−リジン(PCL)。
本発明の1つの態様は、成熟FGF21ポリペプチド(配列番号:3)の切断形態である。本発明のこの態様は、優れた場合によっては、成熟FGF21ポリペプチドの非切断形態と同様の活性を提供することができる切断FGF21ポリペプチドを同定する努力から生じた。
本発明のいくつかの態様において、N−末端切断は、成熟FGF21ポリペプチドのN−末端からの1、2、3、4、5、6、7または8個のアミノ酸残基を含む。9個未満のアミノ酸残基のN−末端切断を有する切断FGF21ポリペプチドは、個体において血糖を低下させる成熟FGF21ポリペプチドの能力を保持する。したがって、特定の態様において、本発明は、1、2、3、4、5、6、7または8個のアミノ酸残基のN−末端切断を有する成熟FGF21ポリペプチドの切断形態またはFGF21タンパク質変異体を含む。
本発明のいくつかの態様において、C−末端切断は、成熟FGF21ポリペプチドのC−末端からの1、2、3、4、5、6、7、8、9、10、11または12個のアミノ酸残基を含む。13個未満のアミノ酸残基のC−末端切断を有する切断FGF21ポリペプチドは、インビトロ ELK−ルシフェラーゼアッセイ(Yie Jら FEBS Letts 583:19-24 (2009))において野生型FGF21の有効性の少なくとも50%の有効性を示し、これらのFGF21突然変異体が個体において血糖を低下させる成熟FGF21ポリペプチドの能力を保持することを示した。したがって、特定の態様において、本発明は、1、2、3、4、5、6、7、8、9、10、11または12個のアミノ酸残基のC−末端切断を有する成熟FGF21ポリペプチドの切断形態またはFGF21タンパク質変異体を含む。
本発明のいくつかの態様において、切断FGF21ポリペプチドは、N−末端およびC−末端切断の組合せを有することができる。N−末端およびC−末端切断の組合せを有する切断FGF21ポリペプチドは、N−末端またはC−末端切断単独のいずれかを含む対応する切断FGF21ポリペプチドの活性を共有する。言い換えれば、9個未満のアミノ酸残基のN−末端切断および13個未満のアミノ酸残基のC−末端切断の両方を有する切断FGF21ポリペプチドは、9個未満のアミノ酸残基のN−末端切断を有する切断FGF21ポリペプチドまたは13個未満のアミノ酸残基のC−末端切断を有する切断FGF21ポリペプチドと同様またはそれ以上の血糖降下活性を有する。したがって、特定の態様において、本発明は、1、2、3、4、5、6、7または8個のアミノ酸残基のN−末端切断および1、2、3、4、5、6、7、8、9、10、11または12個のアミノ酸残基のC−末端切断の両方を有する成熟FGF21ポリペプチドの切断形態またはFGF21タンパク質変異体を含む。
本明細書において使用される「FGF21融合ポリペプチド」または「FGF21融合タンパク質」なる用語は、本明細書に記載されているいずれかのFGF21タンパク質変異体のN−末端またはC−末端にて1つ以上のアミノ酸残基(例えば、異種タンパク質またはペプチド)の融合を示す。
本発明の1つの態様において、FGF21タンパク質変異体は、ヒトIgGのFc領域の1つ以上のドメインに融合される。抗体は、2つの機能的依存性部分、抗原に結合する「Fab」として知られる可変ドメインおよびエフェクター機能、例えば、補体活性化に関与し、食細胞により攻撃する「Fc」として知られる定常ドメインを含む。Fcは長期血清半減期を有するが、Fabは寿命が短い(Caponら 1989, Nature 337: 525-31)。治療タンパク質と連結されるとき、Fcドメインは、より長い半減期を提供するか、または、Fc受容体結合、プロテインA結合、補体結合および胎盤通過さえも含むような機能を組み込むことができる(Caponら 1989)。
本発明の融合タンパク質を形成するとき、リンカーは必要ではないが、使用することができる。存在するとき、スペーサーとして主に働くため、リンカーの化学構造は重要ではないかもしれない。リンカーは、ペプチド結合により互いに連結されたアミノ酸からなり得る。本発明のいくつかの態様において、リンカーは、ペプチド結合により連結される1から20個のアミノ酸からなり、該アミノ酸は20個の天然アミノ酸から選択される。種々の態様において、1から20個のアミノ酸は、アミノ酸グリシン、セリン、アラニン、プロリン、アスパラギン、グルタミンおよびリジンから選択される。いくつかの態様において、リンカーは、立体的障害のない大多数のアミノ酸、例えば、グリシンおよびアラニンからなる。いくつかの態様において、リンカーは、ポリグリシン、ポリアラニン、グリシンおよびアラニンの組合せ(例えば、ポリ(Gly−Ala))またはグリシンおよびセリンの組合せ(例えば、ポリ(Gly−Ser))である。15個のアミノ酸残基のリンカーがFGF21融合タンパク質に対して特に良く働くことが見出されたが、本発明は、任意の長さまたは組成物のリンカーを考慮する。
本明細書に記載されているFGF21の切断形態を含む本明細書に記載されているFGF21タンパク質変異体の化学的に修飾された形態は、本明細書に記載されている記載を考慮して、当業者により調製することができる。このような化学的に修飾されたFGF21突然変異体は、化学的に修飾されたFGF21突然変異体が、修飾されていないFGF21突然変異体と、FGF21突然変異体に結合された分子の型または位置のいずれかにおいて異なるように改変される。化学的に修飾されたFGF21突然変異体は、1つ以上の天然に結合された化学基の欠失により形成される分子を含むことができる。
FGF21突然変異体を含む治療組成物は、本発明の範囲内であり、具体的には、増強された特性を示すいくつかの突然変異体FGF21配列の同定を踏まえて考慮される。このようなFGF21突然変異体医薬組成物は、投与経路との適合性に対して選択される薬学的または生理学的に許容される製剤との混合物中に治療有効量のFGF21タンパク質変異体を含むことができる。
FGF21タンパク質変異体は、限定はしないが代謝障害を含む、多くの疾患、障害または状態を処置、診断、改善または予防するために使用することができる。1つの態様において、処置される代謝障害は、糖尿病、例えば、2型糖尿病である。別の態様において、代謝障害は肥満である。他の態様は、代謝状態または障害、例えば、1型糖尿病、膵炎、脂質異常症、非アルコール性脂肪性肝炎(NASH)、インスリン耐性、高インスリン血症、耐糖能障害、高血糖、メタボリック・シンドローム、高血圧、心臓血管疾患、アテローム性動脈硬化症、末梢動脈疾患、卒中、心不全、冠動脈性心臓疾患、腎臓疾患、糖尿病性合併症、ニューロパシー、胃不全まひおよび他の代謝障害を含む。
本発明はまた、本明細書に記載されているFGF21変異体または突然変異体の1つ以上および薬学的に許容される担体を含む医薬組成物を提供する。いくつかの態様において、医薬組成物は、液体溶液または懸濁液としてのいずれかで注射用として製造され;注射前に、液体ビヒクルでの溶液または懸濁液に対して適当な固体形態もまた製造することができる。リポソームは、薬学的に許容される担体の定義に含まれる。薬学的に許容される塩、例えば、鉱酸塩、例えば、塩酸塩、臭化水素酸塩、リン酸塩、硫酸塩など;および有機酸の塩、例えば、酢酸塩、プロピオン酸塩、マロン酸塩、安息香酸エステル塩などもまた、医薬組成物に存在することができる。薬学的に許容される賦形剤の徹底的な議論は、Remington: The Science and Practice of Pharmacy (1995) Alfonso Gennaro, Lippincott, Williams, & Wilkinsで利用できる。
別の態様において、本発明のFGF21変異体は、FGF21変異体アミノ酸配列に由来する融合タンパク質またはペプチド化合物に作り替えることができる。このような融合タンパク質およびペプチド化合物は、当分野で知られている標準技術を使用して作製することができる。例えば、ペプチド化合物は、標準ペプチド合成技術を使用する化学合成により作製し、次に、ペプチドを細胞(例えば、リポソームなど)に導入するための当分野で知られている種々の手段により細胞に導入することができる。
実施例1:FGF21変異体タンパク質の調製およびペグ化
FGF21変異体に対する発現構築物:FGF21変異体を、Achmullerら (2007) (Nature Methods 4:1037-1043)に記載されている修飾された大腸菌発現ベクターpET30aにクローニングし、FGF21のN−末端(aa33−209)にヘキサ−ヒスチジンタグ、次に、Npro−EDDIEタグのインフレーム融合物を産生した。
クローニングライブラリー:ベクターpGAPZアルファA(Invitrogen, Carlsbad, CA)を、ベクターのユニークなBamHI部位においてβ−ラクタマーゼ発現カセットを付加することにより修飾した。β−ラクタマーゼ発現カセットは、Hribarら (2008) BioTechniques 44:477-84により記載されているとおりに作製した。アルファ接合因子分泌シグナル配列、6個のヒスチジンアフィニティー精製tag、およびタバコエッチ病ウイルス(TEV)プロテアーゼ認識配列を含むN−末端配列を有するインフレームにおけるグリセルアルデヒド−3−リン酸デヒドロゲナーゼ(GAP)プロモーターの後に、アミノ酸33から209をコードするヒトFGF21 cDNAを、修飾pGAPZアルファAベクターにクローンした。hFGF21構築物のライブラリーを、野生型配列においてCys103およびCys121ならびにシステインに突然変異された2つの野生型アミノ酸を有するそれぞれの構築物で作製した。ライブラリーは、野生型アミノ酸の代わりにシステインをコードするプライマーでhFGF21アミノ酸33−209コード領域のPCRフラグメントを作製することにより作った。PCRフラグメントを、互いに同一の配列の16個の塩基対を共有することができるように、または、直線状修飾pGAPZアルファAベクターを、In−Fusion酵素(Takara Bio Co USA)を使用して結合することができるように設計した。それぞれの構築物を配列確認し、酵母株作製のために使用した。
最近、FGF21は、インスリンの存在および非存在下でマウス3T3−L1脂肪細胞においてグルコース摂取を刺激する、およびob/obおよびdb/dbマウスならびに8週齢ZDFラットにおいて用量依存的に食餌および空腹時血糖、トリグリセリドおよびグルカゴンレベルを減少させることを示し、したがって、糖尿病および肥満を処置するための治療としてのFGF21の使用の基礎を提供する(例えば、特許公報WO03/011213、およびKharitonenkovら (2005) Jour. of Clinical Invest. 115:1627-1635参照)。また、FGF21は、3T3−L1脂肪細胞におけるFGFR−1およびFGFR−2のチロシンリン酸化を刺激することを観察した。
(1)「Fold−WT」は、同じ実験において「直接的」で行われたFGF21−WTに対するFGF21変異体のEC50値の比率である。
ペグ化FGF21変異体と比較して野生型FGF21(FGF21−WT)の血漿安定性を測定するために、血漿安定性アッセイを実行した。十(10)μLのFGF21−WT(4.84mg/ml)および35.5μLのFGF21−V76−154C−PEG(2.12mg/ml)を90μlおよび264.5μLのob/obマウス血漿(90%および88%血漿)に加えた。それぞれのサンプルから5つのアリコートを作り、1時間、4時間、24時間、48時間および72時間インキュベートした。全ての時点からのサンプルを回収するまで、血漿処理サンプルを4℃で貯蔵した。九(9)μLの血漿処理FGF21−WTおよび27μLの血漿処理FGF21−V76−154C−PEGを、750μLの培地(1.2%血漿で300nMのFGF21−WTおよび3.6%血漿で450nMのFGF21−V76−154C−PEG)に加え、培地で1:3に8回連続希釈された。ヒトβ−クロトーで安定にトランスフェクトされたHEK293細胞を、10分間タンパク質で処理、次にpERK ICWの標準プロトコールをした。未処理FGF21−WT、FGF21−V76−154C−PEGならびに1.2%および3.6%マウス血漿もまた、コントロールとして含まれる。これらの実験の結果は、図3Aおよび3Bにより描写されるグラフである。
以下に、本願の当初の特許請求の範囲に記載された発明を付記する。
[1] 表1における配列の群から選択される配列を有するポリペプチド変異体。
[2] 1つ以上の以下の修飾:(a)最大8個のアミノ酸残基のアミノ末端切断;および(b)最大12個のアミノ酸残基のカルボキシル末端切断をさらに含む、[1]に記載の変異体。
[3] ポリエチレングリコール(PEG)またはポリシアル酸に共有結合している、[1]に記載の変異体。
[4] 変異体のシステインに共有結合した分岐状40kDa PEG基をさらに含む、[3]に記載の変異体。
[5] 以下:IgG定常ドメインまたはそのフラグメント;ヒト血清アルブミン(HSA);およびアルブミン結合ポリペプチドの1つからなる異種アミノ酸配列に融合している、[1]に記載の変異体。
[6] 異種アミノ酸配列が変異体のアミノ末端に融合している、[5]に記載の変異体。
[7] 異種アミノ酸配列が変異体のカルボキシ末端に融合している、[5]に記載の変異体。
[8] 少なくとも1つの[1]に記載の変異体からなる多量体。
[9] 多量体がホモ二量体である、[8]に記載の多量体。
[10] 変異体76(V76)を含む、ポリペプチドまたはタンパク質変異体。
[11] 位置154のシステイン残基でペグ化を有する、[10]に記載の変異体。
[12] 位置154で分岐状40kDa PEG基をさらに含む、[11]に記載の変異体。
[13] 表1における配列からなる群から選択される変異体を含む医薬組成物。
[14] 位置154のシステイン残基でペグ化を有する変異体76(V76)をさらに含む、[13]に記載の医薬組成物。
[15] 治療有効量の線維芽細胞増殖因子21(FGF21)ポリペプチドまたはタンパク質変異体を患者に投与することを含む該患者を処置するための方法であって、該患者はFGF21関連障害の1つ以上を示す、方法。
[16] FGF21関連障害が、1つ以上の以下:肥満、1型および2型糖尿病、膵炎、脂質異常症、非アルコール性脂肪性肝炎(NASH)、インスリン耐性、高インスリン血症、耐糖能障害、高血糖、メタボリック・シンドロームおよび他の代謝障害からなる、[15]に記載の方法。
[17] FGF21関連障害が1型糖尿病からなる、[16]に記載の方法。
[18] FGF21関連障害が2型糖尿病からなる、[16]に記載の方法。
[19] 治療有効量の線維芽細胞増殖因子21(FGF21)ポリペプチドまたはタンパク質変異体を含む医薬組成物を患者に投与することを含む該患者を処置するための方法であって、該患者はFGF21関連障害の1つ以上を示す、方法。
[20] 治療有効量の線維芽細胞増殖因子21(FGF21)ポリペプチドまたはタンパク質変異体を患者に投与することを含む該患者を処置するための方法であって、該患者はFGF21関連障害の1つ以上を示し、該変異体は位置154のシステイン残基でペグ化を有する変異体76(V76)をさらに含む、方法。
[21] FGF21関連障害が、1つ以上の以下:肥満、1型および2型糖尿病、膵炎、脂質異常症、非アルコール性脂肪性肝炎(NASH)、インスリン耐性、高インスリン血症、耐糖能障害、高血糖、メタボリック・シンドロームおよび他の代謝障害からなる、[20]に記載の方法。
[22] FGF21関連障害が1型糖尿病からなる、[21]に記載の方法。
[23] FGF21関連障害が2型糖尿病からなる、[21]に記載の方法。
[24] 必要とする患者における高血糖、高インスリン血症、肝臓脂質および体重増加の1つ以上を減少させるための方法であって、治療有効量の線維芽細胞増殖因子21(FGF21)ポリペプチドまたはタンパク質変異体を該患者に投与することを含む、方法。
[25] 変異体が、位置154のシステイン残基でペグ化を有する変異体76(V76)をさらに含む、[24]に記載の方法。
Claims (30)
- 配列番号:39のアミノ酸配列を含む、線維芽細胞増殖因子21(FGF21)ポリペプチド変異体。
- 1つ以上の以下の修飾:(a)最大8個のアミノ酸残基のアミノ末端切断;および/または(b)最大12個のアミノ酸残基のカルボキシル末端切断をさらに含む、請求項1に記載の変異体。
- ポリエチレングリコール(PEG)またはポリシアル酸に共有結合している、請求項1または2に記載の変異体。
- 前記PEGが、変異体のシステインに共有結合した分岐状40kDa PEG基である、請求項3に記載の変異体。
- IgG定常ドメインまたはそのFcフラグメント;ヒト血清アルブミン(HSA);およびアルブミン結合ポリペプチドの1つからなる異種アミノ酸配列に融合している、請求項1または2に記載の変異体。
- 異種アミノ酸配列が変異体のアミノ末端に融合している、請求項5に記載の変異体。
- 異種アミノ酸配列が変異体のカルボキシ末端に融合している、請求項5に記載の変異体。
- 少なくとも1つの請求項1に記載の変異体からなる多量体。
- 多量体がホモ二量体である、請求項8に記載の多量体。
- 配列番号39のアミノ酸配列における残基数154のシステイン残基にペグ化を有する、請求項1または2に記載の変異体。
- 残基数154に分岐状40kDa PEG基を含む、請求項10に記載の変異体。
- 請求項1〜11のいずれか一項に記載の変異体を含む医薬組成物。
- 前記変異体が、残基数154のシステイン残基にペグ化を有する配列番号:39のアミノ酸配列を有する変異体である、請求項12に記載の医薬組成物。
- 治療有効量の請求項1〜11のいずれか一項に記載の線維芽細胞増殖因子21(FGF21)ポリペプチド変異体を含む、患者処置用医薬組成物であって、該患者はFGF21関連障害の1つ以上を示す、医薬組成物。
- FGF21関連障害が、肥満、1型および2型糖尿病、膵炎、脂質異常症、非アルコール性脂肪性肝炎(NASH)、インスリン耐性、高インスリン血症、耐糖能障害、高血糖、メタボリック・シンドロームおよび他の代謝障害の1つ以上からなる、請求項14に記載の医薬組成物。
- FGF21関連障害が1型糖尿病からなる、請求項15に記載の医薬組成物。
- FGF21関連障害が2型糖尿病からなる、請求項15に記載の医薬組成物。
- 患者処置用医薬組成物の製造のための、請求項1〜11のいずれか一項に記載の線維芽細胞増殖因子21(FGF21)ポリペプチド変異体の使用であって、該患者はFGF21関連障害の1つ以上を示す、使用。
- FGF21関連障害が1型糖尿病からなる、請求項18に記載の使用。
- FGF21関連障害が2型糖尿病からなる、請求項18に記載の使用。
- 治療有効量の線維芽細胞増殖因子21(FGF21)ポリペプチド変異体を含む、患者処置用医薬組成物であって、該患者はFGF21関連障害の1つ以上を示し、該変異体は残基数154のシステイン残基にペグ化を有する配列番号:39のアミノ酸配列を有する変異体である、医薬組成物。
- FGF21関連障害が、肥満、1型および2型糖尿病、膵炎、脂質異常症、非アルコール性脂肪性肝炎(NASH)、インスリン耐性、高インスリン血症、耐糖能障害、高血糖、メタボリック・シンドロームおよび他の代謝障害の1つ以上からなる、請求項21に記載の医薬組成物。
- FGF21関連障害が1型糖尿病からなる、請求項22に記載の医薬組成物。
- FGF21関連障害が2型糖尿病からなる、請求項22に記載の医薬組成物。
- 患者処置用医薬組成物の製造のための線維芽細胞増殖因子21(FGF21)ポリペプチド変異体の使用であって、該患者はFGF21関連障害の1つ以上を示し、該変異体は残基数154のシステイン残基にペグ化を有する配列番号:39のアミノ酸配列を有する変異体である、使用。
- FGF21関連障害が、肥満、1型および2型糖尿病、膵炎、脂質異常症、非アルコール性脂肪性肝炎(NASH)、インスリン耐性、高インスリン血症、耐糖能障害、高血糖、メタボリック・シンドロームおよび他の代謝障害の1つ以上からなる、請求項25に記載の使用。
- FGF21関連障害が1型糖尿病からなる、請求項26に記載の使用。
- FGF21関連障害が2型糖尿病からなる、請求項26に記載の使用。
- 必要とする患者における高血糖、高インスリン血症、肝臓脂質および体重増加の1つ以上を減少させる医薬組成物であって、治療有効量の請求項1〜11のいずれか一項に記載の線維芽細胞増殖因子21(FGF21)ポリペプチド変異体を含む、医薬組成物。
- 前記変異体が、残基数154のシステイン残基にペグ化を有する配列番号:39のアミノ酸配列を有する変異体である、請求項29に記載の医薬組成物。
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CA2817786A1 (en) | 2012-05-24 |
CN105837680A (zh) | 2016-08-10 |
CO6791605A2 (es) | 2013-11-14 |
AU2011331166A1 (en) | 2013-06-06 |
EA201390739A1 (ru) | 2013-09-30 |
WO2012066075A1 (en) | 2012-05-24 |
EP3067364A2 (en) | 2016-09-14 |
PE20140574A1 (es) | 2014-05-10 |
EP3067364A3 (en) | 2016-12-07 |
CN103328502A (zh) | 2013-09-25 |
CU20130073A7 (es) | 2013-09-27 |
GT201300131A (es) | 2015-06-02 |
TW201302782A (zh) | 2013-01-16 |
MA34710B1 (fr) | 2013-12-03 |
KR20130115305A (ko) | 2013-10-21 |
CU24115B1 (es) | 2015-08-27 |
JP2017110010A (ja) | 2017-06-22 |
CL2013001410A1 (es) | 2014-03-07 |
US20160051628A1 (en) | 2016-02-25 |
SG190324A1 (en) | 2013-06-28 |
IL226401A0 (en) | 2013-07-31 |
AR083920A1 (es) | 2013-04-10 |
EP2640741A1 (en) | 2013-09-25 |
MX2013005639A (es) | 2013-12-06 |
AP2013006871A0 (en) | 2013-05-31 |
US9023791B2 (en) | 2015-05-05 |
JP2014500880A (ja) | 2014-01-16 |
NZ611108A (en) | 2015-10-30 |
UY33739A (es) | 2012-06-29 |
ZA201303498B (en) | 2014-01-29 |
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