A clinical trial protocol is a mere plan to conduct a clinical trial. However, if a clinical trial involves combining previously known anti-cancer agents, is the medicinal use for treating a certain cancer inherently disclosed in such a protocol? Further, would a person skilled in the art have a reasonable expectation of success for the clinical trial? In a recent case of first impression, the Korean Patent Court answered no to both of these questions.

Background

Since 2007, anyone planning to conduct clinical trials on humans in the U.S. has been required to post information regarding the clinical trial on the ClinicalTrials.gov database (a public registry maintained by the U.S. National Institutes of Health) immediately after it starts. The European, Japanese, and Korean regulatory authorities have since implemented similar requirements. This means that for dosing regimen inventions with technical features relating to combined administration, secondary medicinal use, dosage, administration route, etc., it is likely that information on the underlying clinical trial will be published on the ClinicalTrials.gov website before patent application filing.

However, patent applications directed to medicinal use inventions in Korea are required to disclose pharmacological data in the original specification that allows identification of the claimed medicinal use (so the invention can be said to be "complete"), unless the pharmacological mechanism was already known. It has generally not been possible to meet this strict "pharmacological data description requirement" for dosing regimen inventions in Korea without including sufficient data from clinical trials in the original application. This has been a problem because mere clinical trial plan disclosures or prophetic examples with no concrete data confirming any pharmacological effects have often been cited as prior art in Korea to deny novelty or inventiveness for patent claims where the supporting data in the specification confirming the medicinal use was obtained through the disclosed clinical trial.

The Patent Application at Issue

The patent application in the recent Patent Court case relates to Perjeta®, an important treatment for women with early stage HER2-positive breast cancer, and claims a therapeutic combination for use in neoadjuvant therapy containing anti-breast cancer antibodies (pertuzumab and trastuzumab) and chemotherapeutic agents (docetaxel and carboplatin). During prosecution, the Korean Intellectual Property Office (KIPO) cited a posting on ClinicalTrials.gov that disclosed that clinical trials would be conducted for the neoadjuvant treatment of early stage HER2-positive breast cancer using pertuzumab, trastuzumab, docetaxel, and carboplatin (the "Cited Reference") to reject the claims for lack of novelty and inventiveness. No in vitro or preclinical studies had been conducted for the claimed invention prior to the Cited Reference.

KIPO issued a Final Rejection of the application despite the patent applicant's arguments that the Cited Reference was merely a plan for a clinical trial from which pharmacological effects could not have been objectively confirmed, and that one skilled in the art would not have been able to predict the superior effect of the claimed therapeutic combination. The applicant appealed the rejection to the Intellectual Property Trial and Appeal Board (IPTAB), but the IPTAB affirmed the rejection, finding lack of novelty on the grounds that the Cited Reference disclosed the same constitution and that the medicinal use was inherent. The IPTAB also denied inventiveness on the basis that ① the Cited Reference clearly stated the same medicinal use, i.e., treating "early-stage HER2-positive breast cancer," and ② the clinical trial described in the Cited Reference was a plan for a Phase 2 clinical trial so the pharmacological effect must have already been ascertained in the previous pre-clinical stage, and therefore one skilled in the art would have had sufficient basis to expect that the claimed therapeutic combination would have a therapeutic effect on early-stage HER2-positive breast cancer. The applicant then appealed the case to the Patent Court.

Patent Court Decision

As a threshold issue, the applicant argued that a reference cannot be prior art if it lacks confirmatory effect disclosures, challenging the general rule in Korea that "incomplete" inventions can still constitute prior art. While the Patent Court did not completely reject the "incomplete" prior art rule, it significantly limited the rule by holding that such reference can only be prior art to the extent that one skilled in the art would have understood the disclosure. The Patent Court noted in this case that Phase 2 clinical trials can be directly conducted without preclinical or Phase 1 clinical trials if what is being tested is merely a combination of known anti-cancer agents. Thus, the Patent Court held that what one skilled in the art would have understood from the Cited Reference is that the claimed medicinal use was not yet confirmed with any preclinical or Phase 1 clinical trials, and that the use was to be confirmed through the Phase 2 clinical trial to be conducted in the future.

The Patent Court then rejected the IPTAB's ruling that the claimed therapeutic combination lacked novelty. While the IPTAB found that the Cited Reference disclosed the same constitution as the invention, and that the medicinal use was inherent, the Patent Court held that the Cited Reference was merely a plan to conduct a clinical trial, and that one skilled in the art would not have been able to objectively confirm any pharmacological effect or medicinal use.

The Patent Court also rejected the IPTAB's ruling that the invention lacked inventiveness on the ground that there was sufficient suggestion that the claimed therapeutic combination might have a therapeutic effect. The Patent Court held instead (i) that two drugs administered concurrently can have a stronger or weaker effect than if each drug is administered alone; (ii) that even if the two individual agents were known to have a treatment effect on cancer, one skilled in the art would not have been able to reasonably predict whether the claimed therapeutic combination had synergistic effects; and (iii) therefore, one skilled in the art would not have been able to reasonably predict what pharmacological effect the claimed invention would exhibit based on the mere fact that a clinical trial was to be conducted in the future.

Significance

Clinical trials for new medicinal uses and dosing regimens are essential parts of the process of developing novel drugs, and trial sponsors in many countries are required to publish clinical trial protocols on public databases. Yet because of the strict pharmacological data description requirement in Korea, where applicants are required to include pharmacological effect data for medicinal use inventions in the original patent specification, innovative pharmaceutical companies have found it challenging to seek patent protection for new medicinal use inventions in Korea. Under the Korean system, medicinal use invention applicants have been faced with a catch-22 situation: either they can delay filing to include confirmatory clinical trial data in the Korean patent application and risk the application being rejected for lack of novelty or inventiveness over the previously-published clinical trial protocol, or file the Korean application before the clinical trial disclosure and likely have the invention rejected for failing to satisfy the strict Korean pharmacological data description requirements.

The Korean Patent Court finally seems to have acknowledged this contradiction, and its new ruling seems to try to strike a new balance between the need to disclose pharmacological effect data for medicinal use inventions and the prior art effect of certain mandated clinical trial information disclosures. The Patent Court's decision gives innovative drug companies a path forward for developing important new uses for key drugs, and is expected to have a positive impact on numerous pending and future cases before KIPO.

This Patent Court decision became final and conclusive on March 3, 2020.