The Patentability of Medicinal Inventions Related to Personalised Medicine in Japan.

By Itsuki Shimbo, Research Priority Committee Riken, Andrew Cobden, Lovells Tokyo Office and Koichi Sumikura, National Graduate Institute for Policy Studies (GRIPS)

SEVERAL AMENDMENTS OF THE EXAMINATION GUIDELINES FOR MEDICINAL INVENTIONS MAY BE GOOD NEWS FOR PHARMACEUTICAL COMPANIES

As the difficulties in producing new chemical entities continue for pharmaceutical companies, their research strategies have recently emphasised not only the development of new medicines, but also life cycle management. This process is designed to forestall the emergence of generic medicines by protecting related inventions, such as those that expand the range of applicable diseases or optimise methods of administering a medicine, after the expiration of the original basic patent. An example of expanding the range of applicable diseases is the immunosuppressant FK506, which was originally used for organ transplantation and was later developed for use in an atopic dermatitis medicine. Patents have already been granted for a "medicinal invention intended to specify by the mode of medical treatment" (see Table 1, Claim 2), which is designed to increase the medicinal effect, or to reduce side effects. An example of a patent for a combination of known medicinal ingredients is a patent for a combination therapy for hepatitis C using interferon a and ribavirin1. Research is being done on methods of administration matched to the patient's genetic polymorphism of the patient's condition based on biological information obtained through biochemical diagnosis - thereby increasing the promise of personalised medicine.

Many pharmaceutical companies contend that uses of medicine, as well as the medicines themselves, should be covered by patent protection. However, patents for methods of using medicines come under "inventions relating to medical treatment methods", which are not considered patentable in Japan. The Japanese Government Intellectual Property Policy Headquarters has been considering this issue and various parties have given their opinions regarding inventions related to medical activity2. Following this work, in April 2005, the Japan Patent Office ("JPO") clarified its Examination Guidelines for "inventions related to the use of medicines"3.

PATENTABILITY OF MEDICINAL INVENTIONS

In Japan, patentable inventions are stipulated as being "industrially applicable inventions",4 whereas inventions relating to surgery or therapy and diagnostic methods practised on the human body - so-called inventions for medical treatment methods - are not patentable because they are not considered to be industrially applicable. Therefore, a claim in the form "Use of substance or composition X for the treatment of disease Y-" will be regarded as relating to an invention for medical treatment methods, and excluded from patentability. A similar provision is provided in Article 52(4) of the European Patent Convention (EPC).5

Table 1

Examples of claims involving a combination of medicines or the optimisation of dosing interval and given dose

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Source: Table 1 is cited in modified form from the Japan Patent Office Examination Guidelines. Case numbers in the tables are those in the Examination Guidelines

However, "an invention of a product" (a product invention) such as a pharmaceutical or medical device, even though its objective is for medical treatment, still meets the requirement of industrial applicability. In the EPC, the same general concept is made clear in the current provisions of Article 52(4) EPC.

In Japan, a patent for a medicinal invention can be obtained directly as "an invention of a product". Patents for medicinal inventions can be granted when a specific medicinal use of a known compound is discovered. It is not an invention of the substance itself but rather the substance and its particular medical use which is the invention. In other words, a medicinal invention is understood to be "a product invention" based on finding a property of a specific pharmacological function in one compound or one group of compounds, and finding a new medicinal use of applying the property to a new specific disease.

In the United States' patent systems, unlike the Japanese and European, if an invention is for a known product but limited to a novel medical use, because the product itself is the same, it will not have novelty as a product invention and will be deemed unpatentable.6 However, inventions for medical treatment methods can be patented just like inventions in any other technical field. Therefore, if a medicinal use is discovered for a known chemical substance X, a patent can be obtained by claiming "Use of chemical substance X for the treatment of disease Y".

Novelty of medicinal use inventions

Novelty of medicinal inventions can be judged by classifying the inventions into one of the following categories:

first medicinal use, where a medicinal use for either a novel or a known chemical substance is discovered for the first time and

second medicinal use invention, where another new medicinal use is discovered for a publicly known medicine.

In Japan, for a first medicinal use invention, if somebody is first to discover the use of chemical substance X as a medicine, and if that chemical substance is a novel substance, that person can obtain two patents - one for chemical substance X itself, and the other for a medicine containing chemical substance X. On the other hand, in the case of a known chemical substance, only a medicine containing chemical substance X may be patented. As for a second medicinal use invention, a claim will be in the form "A medicine for disease Z comprising a medical ingredient Y", which is more limited than for a first medicinal use invention.

Novelty is therefore judged from two viewpoints: the compound per se and the medicinal use of such compound applied to a specific disease based on a particular property. A characteristic of the JPO approach is that novelty will be evaluated without distinguishing between first medicinal use inventions and second medicinal use inventions. A characteristic of the Japanese patent system is that a product invention limited by use - not just in cases of medicinal inventions - can have novelty because an association with a newly discovered use will be considered as a part of the invention, even where the medical ingredient is known.

Under Article 54(5) of the EPC, a claimed first medical use invention involving a known product can have novelty as a product invention based on an express exception regarding novelty, whereas for a claimed second medical use invention, this exception does not apply. In principle, an invention related to a novel use of a known product may be patentable using a claim directed to that specific use. A difficulty arises, however, in respect of medical use inventions because of Article 52(4). This problem has been overcome to allow patents for second medical use inventions with a Swiss-type claim: "use of (known) substance X for the manufacture of a medicament for therapeutic application Y"7. The need for Swiss-type claims for second medical use inventions should be removed as Article 54(5) of the EPC was amended in November 2000 (ref.88). After implementation of the amended article, it is expected that the EPC approach will be the same as that in Japan.

Furthermore, first medicinal use inventions have a greater significance for a patent strategy compared to second medicinal use inventions. This is because, so long as the substance is recognised to be effective against a single disease, even if it may not be effective against many other diseases, the JPO will allow a broad claim to a medicine containing that substance, not limited to treating a specific disease. In the European Patent Office (EPO) as well, a first medicinal use invention can generally obtain a patent for the medicine itself, which is in the form "X for use in therapy"9. Although allowed by the EPO, there is some doubt as to the validity of such wide claims in the UK, if the claim extends beyond the technical contribution made by the inventor.10

OPTIMISATION OF THE COMBINATION OF MEDICINAL INGREDIENTS, DOSING INTERVAL AND GIVEN DOSE

Sometimes, the combination of several medicinal ingredients may be discovered to have a synergistic effect or a remarkable efficacy that could not be obtained with the individual medicinal ingredients, or it may be discovered that changing the mode of medical treatment, such as the dosing interval and given dose, from the prior art enhances the prior art effects or reduces harmful side effects. It would be more natural to claim these kinds of inventions as "an invention of a method," but method claims will not be allowable because they will be regarded as medical treatment methods. Therefore, in practice, these inventions have been claimed as product inventions. A patent with the objective of optimising the frequency of administration and dosage of Taxol is an example of this (see Table 1, Claim 2). However, it is difficult to distinguish methods, such as combining medicines or optimising dosing intervals and given dose, from prescription and medicine administration activities of physicians. Thus the Intellectual Property Policy Headquarters has explicitly indicated that there should be patent protection "for the manufacture and sale of medicines" so as not to include the activities of a physician, and has proposed that these should be protected as "an invention of a product." Accordingly, the JPO has clarified in its amended examination guidelines that "medicinal inventions intended to specify the mode of medical treatment such as the frequency of administration and dosage" and "combinations of medicinal ingredients" are to be patented as product inventions. Table 1 shows some claims for these inventions: combination of medical ingredients (Claims 3 and 4) and optimisation of dosing interval(s) and given dose(s) (Claims 1, 2 and 5).

The EPO allows patents containing Swiss type claims for inventions that specify the frequency of administration and dosage of a medicine or the method of use of a medicine (Claim 6). More recently, claims have been allowed when the sole feature of novelty was the mode of drug administration (subcutaneous injection instead of the known intramuscular injection)11 and also where novelty resided only in the frequency of administration (nifedipine crystals for oral treatment of hypertension, to be administered once or twice daily).12 However, in the UK, a patent for a medicinal invention specifying the frequency of administration and dosage was invalidated on grounds that it was in reality a method of treatment and would substantially monopolise the activity of physicians.13

The approach used in Japan for determining the novelty of claimed inventions concerning combination or optimisation is as follows: according to the amended examination guidelines, when the mode of medical treatment such as dosing interval and given dose is indicated, novelty of the invention is determined differently depending on whether the mode of treatment is reflected in a dosage form or a spatially separated and packaged kit (Claims 1 and 2), or not (Claim 5). As explained above, novelty of a medicinal invention is judged from two viewpoints: the compound per se and the medicinal use. Therefore, when the mode of treatment is reflected in a dosage form or a kit, if the specified ingredient constitution in the dosage or the kit is novel, even though it is a known medicine, the compound itself is considered novel. On the other hand, when the mode is not reflected in a dosage form or a kit, if the compound is a known medicine, even though they have the novel mode of medical treatment, the novelty of the compound is denied.

Thus, the novelty of the medicinal use, such as specifying target patients, is required for the invention to have novelty (Claim 5).

However, we consider that novelty should not be judged differently, depending on whether or not the mode of treatment is reflected in a dosage form or kit. The description of modes of treatment, such as dosing interval and given dose, given in claims can be information on administration written on the package of a medicine or an instruction document in general. This document brings the medicine used in the mode of treatment within the claim. For this reason, we suggest that the description of the mode of treatment can be a constituent feature of an invention. Moreover, as a compound can perform the required medicinal effect only when it is used with the specific dosing interval and given dose, we consider that the compound itself is just an element of the invention. Taken together, if the mode of treatment is novel, the invention should be regarded as novel. Otherwise, for cases where the mode of treatment is optimised for a combination of publicly known medicinal ingredients, only claims for a dosage form or a kit will be available, which seems to result in too narrow a scope of rights to obtain adequate protection.

CONCLUSIONS

Personalised medicine achieves a finely tuned treatment by differentiating the patients to whom medicines will be administered based on each patient's genetic expression status and gene polymorphism or on some biochemical diagnosis. The Examination Guidelines have made it clear that a medicinal use invention where the target patients are different from those of the known medicines can be protected. In cases where side effect information on a medicine is obtained by analysis of genetic polymorphism, there is also the possibility of being able to obtain a patent for a medicinal invention by specifying the class of patients, so as to exclude those adversely affected. Furthermore, the new guidelines have also made it clear that combinations of medicines and optimisation of dosage and frequency of administration will be protected as "an invention of a product". We consider that the new guidelines, by giving enhanced patent protection to these inventions, will have a great impact on pharmaceutical companies and have an effect on their research strategies.

ACKNOWLEDGMENTS

We thank Toshio Miyake of Kato Patent Firm for advice on this article. First published in Nature.

Footnotes

1 Patent Nos. JP H10-506640 and US 6299872.

2 Intellectual Property Policy Headquarters. "Regarding the state of patent protection for methods related to medical activity." November 22, 2004.

3 Japan Patent Office. Examination guidelines for patent and utility model in Japan, Part VII: Examination guidelines for specific technical field, "Medicinal Inventions." 15 April 2005.

4 Japan Patent Law, Article 29, Subsection 1.

5 Article 52 of the EPC was amended on 29 November 2000. When the amended provisions are implemented, the methods of treatment currently in Article 52(4) EPC will become an exception to patentability under Article 53 EPC, rather than being regarded as not susceptible to industrial application under the present Article 52 EPC.

6 In re Schoenwald, 946 F.2d 1122 (Fed. Cir. 1992).

7 G5/83-EISIA/Second Medical Use [1985] O.J. EPO, 64.

8 Under the new Article 54(5) EPC, patentability will not be excluded on the ground of lack of novelty for any substance or composition, comprised in the state of the art, for any specific use in a method referred to in the present Article 52(4), provided that such use is not comprised in the state of the art.

9 T128/82 Hoffmann-La Roche/pyrrolidine-derivatives [1984] O.J. EPO, 164.

10 UK Patent Office. F. Hoffmann-La Roche AG BL 01/192/04 7 July 2004.

11 T51/93 Serono.

12 T570/92 Bayer (see also T56/97 Takeda).

13 Bristol-Myers Squibb Company v Baker Norton Pharmaceutical Inc [2001] RPC 1.

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