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Intellectual Property High Court (IPHC) ruling on inventive step of pharmaceutical composition based on clinical trial protocol

1. Background
  On June 15, 2018, the defendants obtained a patent registration for an invention entitled “Methods for treating atopic dermatitis by administering an IL-4R antagonist” (Patent No. 6353838, hereinafter referred to as “the present patent”; the number of claims is 16) with an international filing date of September 4, 2013 (Priority date under the Paris Convention: September 7, 2012, US (and 8 other cases)).
  On January 15, 2021, the plaintiff filed a request for patent invalidation trial (Invalidation No. 2021-800003) for the patent in question (claims 1 to 16). On April 5, 2022, the defendants filed a request for correction to the claims of the patent in question (the number of claims after the correction is 16).
  On January 13, 2023, the Japan Patent Office approved the correction and issued a trial decision (hereinafter referred to as “the present trial decision”) stating that “the request for trial in this case is dismissed.” On February 21, 2023, the plaintiff filed a lawsuit in the IPHC seeking the cancellation of this decision.
  The issues were the inventive step requirement, the support requirement and the enablement requirement, and the IPHC upheld the trial decision finding that all of the requirements were satisfied. Below, the decision only on the inventive step requirement is explained.

2. Inventions of the Present Patent
  The description of claim 1 of the present patent (after the present correction) is as follows (the underlined parts are due to the present correction).
  Note that claims 2 to 16 are dependent on claim 1. Hereinafter, the inventions described in each claim will be collectively referred to as “the present corrected invention.”
  [Claim 1]
  A pharmaceutical composition comprising a therapeutically effective amount of an anti-human interleukin-4 receptor (IL-4R) antibody or antigen-binding fragment thereof for use in a method of treating moderate to severe atopic dermatitis (AD) in a patient, wherein said patient is not sufficiently responsive to treatment with a topical corticosteroid or a local calcineurin inhibitor or said patient is not recommended for said topical treatment.

3. Exhibit Ko 1
  Exhibit Ko 1 (Clinical Trials. Gov archive, History of Changes for Study: NCT 01548404, Study of REGN668 in Adult Patients With Extrinsic Moderate-5 to-Severe Atopic Dermatitis) is a clinical trial protocol (study implementation plan) (output document from information database) submitted by the defendants, who are the sponsors and co-researchers, to the US FDA, the supervisory authority (last updated submission date: April 19, 2012 [Heisei 24]) for “a study of REGN668 in adult patients with moderate to severe extrinsic atopic dermatitis.” REGN668, which is (part of) the investigational drug composition, is an anti-human IL-4R antibody (the antibody in question) and is the same substance as “mAb1” described in the specification in this case as an example of the corrected invention in this case (there is no dispute). Therefore, the corrected invention in this case differs from the invention described in Exhibit 1 in that the former is a pharmaceutical composition while the latter is an investigational drug composition.

4. Decision of the IPHC
4-1. Misunderstanding of common general technical knowledge
  The plaintiff argues that it is against common general technical knowledge to have determined in the present trial decision, as common general technical knowledge on atopic dermatitis, that there are an acute phase and a chronic phase, and that in the chronic phase, production of interferon gamma and IL-12 becomes more dominant than that of Th2 cytokines such as IL-4. However, in light of the statements in the relevant documents, it is found that it was common general technical knowledge as of the priority date of the Patent that atopic dermatitis has a mechanism of action wherein Th2 cells are dominant in the acute phrase when inflammation is strong (acute lesion), whereas Th1 cells become dominant in the chronic state (chronic lesion), and the dominance fluctuates between Th2 cells and Th1 cells (the Th1/Th2 balance changes) depending on the inflamed area and disease stage.
  The plaintiff argues that the very concept of acute and chronic phases of atopic dermatitis is denied. However, in light of the statements in the relevant documents, the “acute phase” and “chronic phase” referred to in the common general technical knowledge on atopic dermatitis as determined in the present trial decision can be understood as meaning “acute lesion” and “chronic lesion” of a rash. Therefore, even in light of the plaintiff’s argument, the determination in the present trial decision regarding the common general technical knowledge cannot be found to be erroneous.

4-2. Error in the determination on whether a person ordinarily skilled in the art could have easily conceived of the corrected invention
  It was common general technical knowledge as of the priority date of the Patent that the Th1/Th2 balance changes depending on the inflamed area and disease stage and it was difficult to understand allergic diseases only on the basis of this balance. Prior to this, those skilled in the art understood that the specific cells and cytokines, including IL-4 and the Th2 cells that produce it, in atopic dermatitis could only provide opportunities for the development of targeted therapies (candidate compounds could be searched for by targeting specific cells and cytokines). It can be said that the existence of compounds (antibodies, etc.) that would enable the treatment of atopic dermatitis by targeting any of the specific cells and cytokines had not yet been elucidated.
  Even though, before the priority date, specific cells and cytokines (Th2/IL-4) were known as antigens that can be targeted by the compounds (antibodies, etc.) which can be used to treat atopic dermatitis, it was known that many other cells and cytokines also work, and it cannot be said that under such circumstances, a person ordinarily skilled in the art could have even been aware of whether inhibiting the action of Th2/IL-4 would be therapeutically effective on chronic atopic dermatitis, including that suffered by the patients in question.
  In addition, the trials in Exhibit Ko 1 are Phase II trials, and in light of the low success rate for the transition from Phase I trials to Phase II trials and the transition from Phrase II trials to Phase III trials, as well as the fact that the information contained in Exhibit Ko 1 is nothing more than a protocol of clinical trials, it cannot be said that a person ordinarily skilled in the art would have understood that the investigational new drug stated in Exhibit Ko 1 is obviously therapeutically effective without looking at the test results.
  Therefore, there is no error in the determination in the present trial decision that the present corrected invention could not have been easily made by a person ordinarily skilled in the art.

5. Comments
  As an issue of the relationship between patent applications and pharmaceutical applications, there is a concern that if a clinical trial protocol becomes publicly known, it may call into question the novelty and inventive step of the pharmaceutical composition. There is also the issue of whether the clinical trial protocol satisfies “the eligibility of cited references”, i.e., whether the pharmaceutical composition is fully disclosed, but there is a court case in which the inventive step was denied based on the description in the clinical trial protocol (IPHC 2020 (Gyo-ke) 10094). There is also the issue of whether the clinical trial protocol is publicly known, but it can be considered to become publicly known by medical professionals or patients (in the case of informed consent) before the clinical trial is conducted.
  In this judgment, the inventive step was disputed based on the clinical trial protocol for a phase II trial submitted by the patent holders themselves, and there was no difference between the active ingredient in the pharmaceutical composition in question and the clinical drug, and the inventive step was disputed regarding the medical use. As a result, the IP High Court affirmed the inventive step, taking into consideration that the success rate of general Phase II trials is low and that Exhibit Ko 1 is merely a clinical trial protocol, on the grounds that the corrected invention is a drug for treating a disease by blocking a pathway different from the common general knowledge at the time of filing derived from other documents. There was a difference in the claims of the plaintiff and defendants regarding their understanding of common general technical knowledge, and this was the main point at issue in this case.
  In the future, in case a patent application is filed after the clinical trial protocol for Phase II trials has become publicly known, proving that the mechanism of action is different from the common general knowledge at the time of filing is considered to be effective for asserting inventive step. However, since this judgment also took into consideration the low success rate of Phase II trials, it is expected that inventive step will be more difficult to be affirmed in case where a patent application is filed after the success of Phase II trials is announced. This case is useful for considering the timing of patent applications and clinical trials.
  In addition, the extent to which the mechanism of action must differ from the common general knowledge at the time of filing to be recognized as inventive step is judged on a case-by-case basis, and it is important to pay attention to future trends in precedent cases.

https://www.ip.courts.go.jp/app/files/hanrei_jp/292/093292_hanrei.pdf