https://www.j-platpat.inpit.go.jp/c1801/PU/JP-3713237/15/en
Intellectual Property High Court Case No. 10090 (Gyo-ke) 2023, October 31, 2024 “Fulvestrant Formulation” Case (Presiding Judge Nakadaira)
Summary of the Judgment and Some Considerations
The corrected invention 1 is “a pharmaceutical preparation for administration to humans by intramuscular injection” and “a pharmaceutical preparation suitable for intramuscular injection.” On the other hand, the invention of Exhibit 1 is “a test composition for verifying FGF autocrine activity as a mechanism of tamoxifen-resistant breast cancer, administered subcutaneously to ovariectomized tumor-bearing mice injected with fibroblast growth factor (FGF)-transfected breast cancer cells (MCF-7 cells).”
(1) Common Technical Knowledge 1 (Regarding intramuscular injections of Fulvestrant)
The pharmaceutical preparation containing fulvestrant was in clinical trials at the time of the priority date and had not yet been approved in any country. Therefore, it cannot be acknowledged that fulvestrant was established as a breast cancer treatment drug. Thus, it cannot be acknowledged that Common Technical Knowledge 1 (regarding intramuscular injections of fulvestrant) existed.
On the other hand, based on the results of pharmacokinetic (PK) studies and clinical trials conducted on fulvestrant at the time of the priority date … it is possible that, at the time of the priority date, fulvestrant was undergoing clinical trials as a potential drug for treating breast cancer, and it was common technical knowledge that it was administered by intramuscular injection in those trials.
However, even assuming such common technical knowledge exists, it cannot be recognized that a person skilled in the art would readily recognize that the composition administered to mice as an antiestrogen drug in Exhibit 1 could be used as a pharmaceutical preparation for immediate intramuscular injection into humans in its original composition.
(2) Common Technical Knowledge 2 (Regarding subcutaneous injection into mice)
Even if common technical knowledge exists to the extent that “pharmaceutical preparations administered to humans by intramuscular injection may sometimes be administered via subcutaneous injection in experiments using mice,” it cannot be recognized as common technical knowledge to administer to humans by intramuscular injection a drug with the same composition as that administered subcutaneously to mice. Moreover, the fulvestrant administered to mice in the invention of Exhibit 1 is used as an auxiliary agent to eliminate estrogenic activity in experiments for verifying a hypothesis. Therefore, it cannot be said that there is a motivation to administer to humans by intramuscular injection a drug with the same composition as that of fulvestrant.
(1) Regarding Inventive Step of The First Medicinal Use Invention
The determination of inventive step is based on whether the differences between the present invention and the main cited invention could have been easily conceived by a person skilled in the art at the time of filing. Putting aside the question of whether the first medicinal use invention is right or wrong, court decisions on applications are particularly pro-patent, and it is extremely difficult to obtain a court ruling denying inventive step. (While beyond the scope of this paper, it is difficult to say that use and dosage patents are necessarily pro-patent.)
When the inventive step of a first medicinal use invention is in question, at the time of filing the primary considerations are: ① if the results of Phase 1 clinical trials have not yet been published, animal studies and the like often become the main cited invention; and ② if the results of Phase 1 clinical trials have been published, the Phase 1 results often become the main cited invention.
In situation ① above, if the results of animal studies and the like are favorable, and if the active ingredient and the target disease to be treated are the same, the question of whether it would have been easily conceived to administer the same composition to humans becomes an issue.
This case is one such case. The court found that although the results of administering a composition identical to the patented invention to a breast cancer mouse model were published in the academic journal “Clinical Cancer Research”, it could not be acknowledged that the same active ingredient (fulvestrant) had been established as a breast cancer treatment drug because it was prior to approval. As such, the court found that there was no common technical knowledge of administering the same composition to humans by intramuscular injection, and acknowledged the inventive step of the present invention.
In this judgment, the court stated that due to the fact that mice have less muscle mass, there exists common technical knowledge only to the extent that “even if a pharmaceutical preparation is administered to humans by intramuscular injection, it is sometimes administered by subcutaneous injection in experiments using mice.” Based on this, the court, finding that “it cannot be acknowledged as common technical knowledge to administer to humans by intramuscular injection a drug having the same composition as that administered subcutaneously to mice,” denied obviousness (and affirmed inventive step).
According to the reasoning above, it becomes nearly impossible to deny inventive step based on the results of animal studies using mice.
In the present case, the Defendant AstraZeneca itself provided fulvestrant formulations to researchers before the filing, and because those researchers published the test results in the journal “Clinical Cancer Research”, it became a rare case where the composition of the cited reference and the present invention were identical. Even so, in this case, inventive step was acknowledged, which shows the high hurdle for denying inventive step of a first medicinal use invention.
As an example of situation ② above, there is a case in which inventive step was acknowledged because, “even if the cited invention has reached Phase 2 clinical trials, the success rate of Phase 2 is only 33%”: namely, Case No. 10019 (Gyo-ke) 2023 “Method for treating atopic dermatitis by administering IL-4R antagonists” (Presiding Judge Miyasaka).
Phase 1 clinical trials are safety tests conducted on healthy subjects and are not intended to confirm pharmacological effects. Subsequently, Phase 2 clinical trials are conducted to confirm the pharmacological effects on a small number of patients suffering from the target disease, and Phase 3 clinical trials are conducted to confirm the pharmacological effects on a large number of patients suffering from the target disease.
Accordingly, even if Phase 1 clinical trials have been completed, it cannot necessarily be said that pharmacological effects have been confirmed; however, if Phase 2 clinical trials have been completed, it can be said that pharmacological effects have been confirmed. In fact, there is a court case in which inventive step was denied where Phase 2 clinical trials had been completed; see Case No. 10094 (Gyo-ke) 2020 “Agent for preventing recurrence of reflux esophagitis”.
Regarding first medicinal use inventions, at the conclusion of Phase 1 clinical trials, in addition to usage and dosage inventions, one possible strategy may be to file a use invention without claiming priority, thereby prolonging the term of the use invention.
(2) Regarding Support Requirement of First Medicinal Use Invention
If it is before clinical trials, satisfaction of the support requirement is often acknowledged on the basis of results of animal studies and other evidence. Here, on the grounds that “a person skilled in the art cannot recognize that pharmacological effects will be acknowledged by administering to humans by intramuscular injection a drug having the same composition as that used in the animal study examples,” the support requirement is not denied. Accordingly, even if the concept by a person skilled in the art is not the same for inventive step and the support requirement, there may remain doubts as to whether both can be explained consistently. In fact, the only examples described in the patent specification in this case are animal studies using rabbits.
In regard to the support requirement, the court states that in the present specification, with respect to formulation F1, it was confirmed that when intramuscularly injected into rabbits, precipitation did not occur at the site of injection and the formulation was sustained-release, and that formulation F1 can solve the problem of “providing a sustained-release pharmaceutical preparation containing at least 45 mg/ml fulvestrant, administered to humans by intramuscular injection.” Thus, the court readily acknowledged the support requirement.
In this judgment, the court made the following determination regarding the support requirement and readily acknowledged the support requirement:
“In the present specification, with respect to formulation F1, it has been confirmed that when intramuscularly injected into rabbits, no precipitation occurs at the injection site and sustained-release properties are exhibited.
With respect to formulation F1, it has been specifically confirmed that the problem of providing a sustained-release pharmaceutical preparation containing at least 45 mg/ml fulvestrant for administration to humans by intramuscular injection can be solved.”
As described above, in this judgment, the court recognized that the problem to be solved by the present invention is to provide the claimed pharmaceutical preparation, and does not require pharmacological effects. This is precisely because it is a first medicinal use invention.
In this case, since the examples in the specification were intramuscular injections into rabbits and the cited example was subcutaneous injection into mice, it is possible to consistently understand each determination regarding inventive step and the support requirement.
However, if the cited example in this case had involved intramuscular injection into rabbits, would it be possible to say that the court would never deny easily conceived property (that is, affirm inventive step), finding that “it cannot be acknowledged as common technical knowledge to administer to humans by intramuscular injection a drug having the same composition as that injected intramuscularly into rabbits”? Conversely, if the example in this case had involved subcutaneous injection into mice, would the court have found a violation of the support requirement?
However, after the commencement of clinical trials (even considering Case No. 10019 (Gyo-ke) 2023), it becomes difficult to secure novelty and inventive steps, so it is necessary to file a patent application with animal studies as examples prior to clinical trials. Since it would be problematic if the support requirement were denied in such cases, the current practice and operation are likely to be realistic.
Writer: Hideki TAKAISHI
Attorney at Law & Patent Attorney