Case in which the inventive step of a pharmaceutical invention characterized by the time necessary for intravenous administration was admitted

TERACHI, Takumi
Japan Patent Information Committee

– Heisei 26 (2014) (Gyo-Ke) No. 10045, A case seeking revocation of a trial decision –

In the subject case, the Japan Patent Office rendered a trial decision to reject a pharmaceutical invention whose invention specifying matter was the time necessary for intravenous administration, and being dissatisfied with this trial decision, the plaintiff filed a suit for revocation of the trial decision with the Intellectual Property High Court, which then revoked the trial decision. The Court’s judgment was to admit the grounds for revocation claimed by the plaintiff because no person skilled in the art can recognize an improvement for renal safety, which is the technical objective to be attained by the invention of the subject application, based on the disclosures of the cited documents, and disclosures of the cited documents provide no motivation for any person skilled in the art to set the above-noted administration time (the judgment rendered on December 26, 2014).

(1) Subject Application

The subject application is Japanese Patent Application No. 2001-585739 (Title of Invention: Use of zoledronate for producing medicaments for the treatment of bone metabolic diseases; Filing Date: May 9, 2001 (Priority Date: May 19, 2000), and Claim 1 pending at the time when the trial decision of rejection was rendered reads as follows:

[Claim 1]
A treatment agent comprising 2-(imidazol-1-yl)-1-hydroxyethane-1,1-diphosphonic acid (zoledronic acid) or a pharmaceutically acceptable salt thereof as an active ingredient, characterized in that 4 mg of zoledronic acid is intravenously administered to a subject in need of bisphosphonate treatment over a time of 15 minutes.

(2) The trial decision by the Japan Patent Office

In the trial decision, the inventive step was rejected based on the following three documents.

A. Citation 1: Cancer Investigation, Jan 2000, vol. 18, no. suppl. 1, pp. 68-69, (Japanese title: Phase II trial of zoledronic acid vs. pamidronic acid in multiple myeloma and breast cancer)
B. Citation 2: Cancer, 1997, vol. 80, no. 8, suppl., pp. 1699-1701
C. Citation 3: Endocrine Reviews, 1998, vol. 19, no. 1, pp. 80-100

In the trial decision, it is held that the only difference between the invention as disclosed in Citation 1 and the invention of the subject application is about the time for intravenous administration which is “5 minutes” in the former whereas it is “15 minutes” in the latter, and the inventive step was judged as follows:

Being a document that relates to a phase II trial of zoledronic acid, Citation 1 states that as a result of said trial, zoledoronic acid was judged to have certain effects and it also mentions an advance to a phase III trial, so it might be possible for a phase III trial to experience  some adverse effects that were not observed in the phase II trial, and setting the dosage and administration in such a way as to avoid this problem is something that is usually performed by those skilled in the art; based on this premise, Citation 3 states to the effect that in the intravenous administration of bisphosphonate, rapid infusion causes renal failure, so  it is preferable to perform a slow infusion with a large amount of liquid, and Citation 2 states that zoledoronic acid was administered by an infusion for 5 to 30 minutes, with the serum calcium level being effectively lowered by a 20-minute infusion; hence, for any person skilled in the art who looked at Citations 1-3 together, arriving at the time of 15 minutes in the process of slowing down the infusion time from the 5 minutes of cited invention 1 is something that could have been accomplished as appropriate by experimentation.

(3) The argument made by the plaintiff

The plaintiff pointed out the following three points as the grounds for revocation of the trial decision:

1. The passage quoted by the trial decision appears in Abstract of Citation 2 and it is clear from the main text of Citation 2 that the 20-minute administration was not performed for the doses of 4 mg and 8 mg.

2. Citation 1 presents the result of a 5-minute intravenous administration of 4 mg zoledronic acid (phase II clinical trial) whereas and Citation 2  shows the result of a 5-minute intravenous administration of zoledronic acid at a maximum dose of 8 mg (phase I clinical trial). Since both citations state that no toxicity on the kidney was observed, it was difficult in the first place to recognize the existence of the objective of improving renal safety based on the disclosures of these documents.

3. Citation 3 relates to first-generation bisphophonates, and the disclosures of Citation 3 clearly are not applicable to zoledronic acid which is a third generation bisphosphonate having a much higher activity, so the inventions as disclosed in Citation 1 and Citation 2 in no way suggest the objective of the invention of the subject application, and even if these inventions are combined, it is difficult to understand the objective of the invention of the subject application and the invention of the subject application as a means to attain this objective cannot be easily reached; hence, there is found no motivation for combining Citations 1 to 3.

(4) The judgment made by the Court

The Court accepted the plaintiff’s argument and judged as follows:

First, concerning the rapid administration of zoledronic acid, renal safety was considered to be one of the problems involved and a check was also made of this point in the phase I clinical trial of Citation 2; after the phase II clinical trial (Citation 1) and in the subsequent phase III clinical trial, there was the possibility that a different result might arise concerning renal safety  but in the phase I and phase II clinical trials in Citations 1 and 2, no result was confirmed  to cast doubt on the renal safety of the 5-minute administration of 4 mg zoledronic acid; secondly, at the time of the priority date of the subject application, the disclosures of Citation 3 were also understood not to be immediately applicable to zoledronic acid that is a third generation bisphosphonate; accordingly, the 5-minute administration of 4 mg zoledronic acid which was prima facie verified to be safe in Citations 1 and 2 is not considered to offer a motivation for further elongating the administration time to 15 minutes.