用途發明的挑戰 - Merck v. Ono Pharmaceutical 歐洲專利法院案例討論

此案例討論「用途發明」中所採用的元素為已知物質，而先前文獻是否有任何使用此物質解決特定問題（該用途）的動機。特別在醫療領域中，藥物上市前有很多實驗，實驗是否證明有特定療效的成功機會，即便藥品最後可能在不同的用途上，但是這些實驗（或相關領域的實驗）都有可能是阻礙藥品在其他用途的後續專利的證據。

用途發明就看專利說明書是否提出有力的實驗證明該用途。

案件資訊：
專利權人/侵權原告：ONO PHARMACEUTICAL CO., LTD.（日本公司）
侵權被告：Merck Sharp & Dohme Limited

系爭專利：EP1537878 

系爭專利揭露「Immunpotenzierende zusammensetzungen」，這是一種治療癌症的抗體與PD-1受體的技術。

這個曾經被異議而仍存留的專利權，請求項範圍如下，請求項1界定一種「使用發明（use invention）」，使用已經存在的物質的用途發明，專利關於一種使用「反PD-1抗體（anti-PD-1 antibody）」的技術，其抑制用於治療癌症藥的PD-1免疫抑制信號，（不懂沒關係），而其附屬項描述此反PD-1抗體就是人類的反PD-1抗體。其他兩項範圍則是界定此抗體。

1. Use of an anti-PD-1 antibody which inhibits the immunosuppressive signal of PD-1 for the manufacture of a medicament for cancer treatment.
2. The use according to claim 1, wherein the anti-PD-1 antibody is a human anti-PD-1 antibody.
3. Anti-PD-1 antibody which inhibits the immunosuppressive signal of PD-1 for the use in cancer treatment.
4. Anti-PD-1 antibody for the use according to claim 3, wherein the anti-PD-1 antibody is a human anti-PD-1 antibody.

不懂系爭專利沒關係，但是可以明顯知道這是一種已知物質的用途發明，且專利範圍簡單地描述用途。這就是爭議的來源 - 範圍過廣（涵蓋所有癌症治療？）。

被告Merck Sharp製造了「anti-PD-1 antibody pembrolizumab (Keytruda)」，也是一種如系爭專利所述的反PD-1抗體，推出市場後宣稱可以治療不能用手術切除或已經轉移的腫瘤。

有錢也頗為阿沙力（任性），Merck承認，如果專利有效，他的產品確實落於專利範圍中。但也不是直接認栽，而興起一連串專利無效主張，理由包括新增事務（added matter）、揭露不充分（insufficiency）、優先權有誤、缺乏新穎性與進步性等。

不曉得是不是外電撰寫的風格，這回原告Ono Pharmaceutical也頗為乾脆，認為如果專利的優先權錯誤的話，其專利無效，因為其優先權文獻記載了證明抑制PD-1抗體而降低腫瘤生長的記錄。甚至聲明，如果專利侵權成立，也不會對手提起禁制令。

專利有效性的爭議中，「用途發明」危險的地方是，是否相關先前技術（PD-1抗體）有隱含這個用途，是否有此案所稱可以治療癌症的效果？如果先前技術的文獻已經足夠揭示出系爭專利的治療效果，系爭專利應該不予專利，對此案來看，先前技術並未有支持有腫瘤治療效果的實驗產生，無法證明專利缺乏新穎性。這種爭議應該常見於醫療領域的專利。

「優先權」的爭議在於，Merck聲明系爭專利優先權日前的技術顯示不是每種腫瘤都可用免疫系統治療，這樣證明系爭專利可以治療癌症的使用範圍過廣。不過法官認為，癌症與免疫系統的關聯將來可能會有變化，如此不能認定專利無效。

系爭專利在進步性的討論中，就頗為複雜，重點在於是否有先前技術已經揭示出抑制特定免疫信號是否可以降低腫瘤成長？先前小鼠腫瘤實驗證明「PD-1抗體」可以排除自身免疫性疾病，關鍵就在，這個系爭專利是有關「反PD-1抗體」，而此是否阻礙了PD-1抗體的治療效果？這有關相關領域技術人員是否有相關治療效果的期待。

即便有不少先前實驗的證據，法院"正確的"「動機」判斷影響系爭專利是否顯而易見。

(updated on Nov. 20, 2015)『問題在於顯而易見性應可考量事實，法院應考量相關環境中的特別因子，這些可能包括系爭專利是否有動機得出解決問題的方案、可能的研究經費、得到解決方案與期待成功的努力等。』

"The question of obviousness must be considered on the facts of each case. The court must consider the weight to be attached to any particular factor in the light of all the relevant circumstances. These may include such matters as the motive to find a solution to the problem the patent addresses, the number and extent of the possible avenues of research, the effort involved in pursuing them and the expectation of success."

(updated on Nov. 20, 2015)『根據以上證據，認為相關技術領域中具有一般知識的技術者根據優先權日當時文獻可知，如果無法被免疫系統識別的話，反PD-1抗體不會有治療癌症的效果。因此相關技術人員並不會考慮是否此反PD-1抗體會有效，也非已知免疫原性。就此而論，在小鼠中可成功，反PD-1抗體的療性。』

"Taking this evidence together I find that the thinking of a skilled person with their common general knowledge reading the document at the priority date would be as follows.  Obviously an anti-PD-1 antibody cannot have an effect on a cancer if it is not recognised by the immune system but the skilled person would not think that the fact that a cancer had been regarded as unresponsive to existing immunotherapies was determinative of whether anti-PD-1 treatment would work and would not regard “known immunogenicity” as a useful category in this context.  Given the successful results in the mouse models, it is plausible that anti-PD-1 therapy, which is focussed on the immune system, will have the capacity to treat any type of tumour because all tumours express antigens not found in normal cells."

(updated on Nov. 20, 2015)『法院認為，相關領域技術人員從優先權文件可以得到反PD-1抗體對於癌症的療效。即便迄今都認為反PD-1抗體非癌症系統可識別的免疫原性，但系爭專利的思想讓此反PD-1抗體對癌症可能具有療效。』

"I find that a skilled person reading the first priority document would be able to make a sound prediction that anti-PD-1 antibodies would work in cancer generally, irrespective of whether the tumour cells expressed PD-L1 or PD-L2.  The idea that the anti-PD-1 therapy could treat cancers even if they were not hitherto regarded as immunogenic is a plausible one."

結論：
專利有效。

理由是(updated on Nov. 20, 2015)：
1. 優先權日文獻支持系爭專利技術中採用特定抗體的療效，相關領域技術人員也因此可以得出有療效的結論。
2. 相關技術領域的人員從來沒有考慮反PD-1抗體對於癌症的療效。
3. 雖系爭專利專利範圍很廣，但是不能排除其技術貢獻，證據也支持anti-PD-1抗體的療效。
4. 系爭專利為非顯而易知，因為先前技術對anti-PD-1抗體的療效沒有太高期待。
5. 先前技術無法證明系爭專利無效。

1. At the priority date the common general knowledge of the person skilled in the art included the idea that the PD-1 pathway was an important aspect of the immune system with a role in self-tolerance.  It could be a target for therapeutic manipulation.  This knowledge included the concept that PD-1 was an inhibitory receptor.  However it also included knowledge of a debate about the PD-1 pathway.  It was known that ligands to PD-1 also had a co-stimulatory effect and it was known that a proven explanation had not emerged.
2. The in vivo mouse data contained in the first priority document, in which two different kinds of tumour are transferred to PD-1 knockout mice, represent an important advance.  The data make plausible the idea that an agent which blocks the PD-1 receptor can manipulate the immune system in such a way as to treat cancers in general, not only those tumours which express PD-1 ligands.  Nevertheless, while the reasonable prediction which the priority document supports is a wide one, it does not purport to promise that every cancer patient in all circumstances can be treated.  Claims 1 and 3 are plausible and are entitled to priority. 
3. The patent enables the skilled person to make and use anti-PD-1 antibodies as anti-cancer medicines.  Moreover, and crucially, the evidence today shows that anti-PD-1 antibodies have been approved to treat a number of different cancers and are worth investigating in a very wide range of cancers.  The evidence today also shows that anti-PD-1 monotherapy probably does not treat prostate cancer and most colorectal cancers, but this does not demonstrate a lack of technical contribution or undue burden.  The law does not require perfection.
4. The prior art document Dana Farber 557 discloses the idea of manipulating the PD-1 pathway and includes the idea of an anti-PD-1 agent as a therapeutic agent to be used to treat a number of diseases including cancer.  That agent could be an anti-PD-1 antibody.  However the document includes evidence of both the inhibitory effect of the PD-1 receptor and the co-stimulatory effect of PD ligands.  While its disclosure may be enough to support the general idea of using an agent which acts somehow on the PD-1 pathway in medicine, it does not make plausible the specific idea of an anti-PD-1 agent to treat cancer.  The same is true for the prior art Wyeth 499.  Therefore claims 1 and 3 are novel.
5. The claims involve an inventive step over the Latchman paper and Dana Farber 557 because the common general knowledge includes knowledge of the existence of the debate about the cause of the co-stimulatory role of PD-1 ligands.  Although it was known that the PD-1 receptor was inhibitory, the existence of the debate meant that a skilled person who conducted a test of PD-1 blockade against a tumour in a mouse, would not have a fair expectation of success.  The mouse tumour results in the patent were exciting and were not predictable from the prior art.  Claims 1 and 3 are not obvious.
6. The Tchekmedyian and Davis abstracts do not render the claims obvious either.  They are not concerned with the PD-1 pathway at all.  

my two cents:
使用已知物品的用途發明（swiss type）應會面對很多的挑戰，實務上比較少見，但是顯然常見於醫療領域。

(updated on Nov. 20, 2015)

此案例重要結論是，當先前技術無法證明系爭專利是否有可實施性，也就是法官/專利審查官無法證明專利無法達成時，而被告侵權者反而證明專利技術可以成功，使得系爭專利優先權日的技術成為重要議題，這些證據都讓本系爭專利判為有效。

因此，本案例因為優先權文獻證明專利描述的真實性，讓相關領域技術人員可以得出系爭專利是有可能成功的，以及證明在此優先權之前的技術都呈現系爭專利技術「不會成功、沒有成功的期待」，這些證據都證明本案例「用途發明」的非顯而易知性。

另，看不懂內容也要學到知識。

部落格文章：
http://enpan.blogspot.tw/2011/11/swiss-type-claiming-about-claims-xlii.html
（其中也提到Merck！）

參考資料：
http://www.eplawpatentblog.com/eplaw/2015/11/uk-merck-v-ono-pharmaceutical-bristol-myers-squibb-.html（其中有判決原文檔案）

Ron