哥倫比亞大學 (以下略稱為哥大) 擁有以美國專利第9,718,852號 (以下略稱為 '852專利),Massive parallel method for decoding DNA and RNA,為首的五個專利。具體而言,其內容與核苷酸類似物和使用核苷酸類似物對DNA進行定序的方法有關。
其中代表性請求項如下 (涉訟重點以紅色字體標示):
1. An adenine deoxyribonucleotide analogue having the structure:
wherein R (a) represents a small, chemically cleavable, chemical group capping the oxygen at the 3′ position of the deoxyribose of the deoxyribonucleotide analogue, (b) does not interfere with recognition of the analogue as a substrate by a DNA polymerase, (c) is stable during a DNA polymerase reaction, and (d) does not contain a ketone group;
wherein OR is not a methoxy group or an ester group;
wherein the covalent bond between the 3′-oxygen and R is stable during a DNA polymerase reaction;
wherein tag represents a detectable fluorescent moiety;
wherein Y represents a chemically cleavable, chemical linker which (a) does not interfere with recognition of the analogue as a substrate by a DNA polymerase and (b) is stable during a DNA polymerase reaction; and
wherein the adenine deoxyribonucleotide analogue:
i) is recognized as a substrate by a DNA polymerase,
ii) is incorporated at the end of a growing strand of DNA during a DNA polymer-ase reaction,
iii) produces a 3′-OH group on the deoxyribose upon cleavage of R,
iv) no longer includes a tag on the base upon cleavage of Y, and
v) is capable of forming hydrogen bonds with thymine or a thymine nucleotide analogue.
PTAB則基於「就Metzker揭露表格來說,即便3'-O-allyl之核苷酸的終止效力不完整,相較其他核苷酸類似物,其仍具有足夠好的效力」(見圖 8,其中顯示有部分核苷酸類似物根本是毫無效力的),並引用In re Mouttet案之判決內容「僅僅因為先前技術中存在更好的替代方案,並不代表沒那麼好的組合不適合用於進步性之判斷」(見圖 12)
而且,Metzker也未將以allyl基團作為保護基的實驗描述成一種失敗,相反地,其直接的揭露3'-O-allyl之核苷酸可以被併入單股聚合體中,根據In re Mouttet案的先例,Metzker的揭露內容並未構成反向教示。最後,CAFC認同PTAB「提高核苷酸類似物的反應濃度或延長其反應時間」的論點,肯認其系爭請求項不具備進步性的論點。
究其根源係反向教示已經建立了完整的法理。第一,先前技術中較佳或優選實施例之存在,並不構成對較廣之揭露內容或較不理想之實施例的反向教示 (見於In re Susi案與In re Mouttet案);第二,單純揭露替代技術方案,而無「批評、詆毀或以其他方式阻攔」(criticize, discredit, or otherwise discourage) 的話,揭露替代技術方案亦不構成反向教示 (見於In re Fulton案與DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc.案) 。這兩點都必須藉由全面審視先前技術來達成,或可稱為反向教示正反兩面之定義。