From the viewpoint of a medicine-business strategy, for example, a life cycle management strategy, many pharmaceutical companies are interested in the filing of (and actually have filed) patent applications relating to a novel crystalline form of a known compound. It is possible to obtain a patent for such a novel crystalline form in Japan, but unfortunately, it is not easy. Recently, a court decision, IP High Court No Hei 23 (Gyo-Ke) No. 10445, was issued, which dismissed the Japanese Patent Office’s (JPO’s) decision indicating that Warner-Lambert’s patent (i.e., Pfizer’s patent; Pfizer acquired Warner-Lambert in 2000) with respect to a novel crystalline form of atorvastatin (product name: Lipitor®; an antihyperlipidemic agent) is valid. This court decision shows the difficulty of obtaining a patent for a novel crystalline form of a known compound.
Below, the background of the above case is described. Sandoz, a major generic company, planned to launch a generic product of Lipitor® in 2011. A basic patent concerning Lipitor® expired in 2011, while a crystalline polymorphism patent (Japanese Patent No. 3296564) was still in force. Therefore, Sandoz requested an invalidation trial, Invalidation Trial No. 2010-800235, against claims 1 and 2 of this patent before the JPO on December 17, 2010. Sandoz argued that the inventions according to granted claims 1 and 2 (hereinafter, referred to as the “granted inventions”) are invalid due to a failure to satisfy the enablement requirements, and due to lack of inventive step.
Claims 1 and 2 of this patent are as follows:
(Claim 1)
Crystalline Form I atorvastatin hydrates characterized by the following X-ray powder diffraction pattern expressed in terms of the 2θ, d-face spacings, and relative intensities with an intensity of >20% measured by after 2 minutes of grinding using CuKα radiation:
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(Claim 2)
Crystalline Form I atorvastatin hydrates characterized by the following solid-state 13C nuclear magnetic resonance spectrum wherein chemical shift is expressed in parts per million:
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The JPO issued a Trial Decision stating that the granted inventions are valid and Warner-Lanbert (Pfizer) won the invalidation trial before the JPO. Sandoz lodged a suit with the IP High Court against the JPO’s trial decision. The IP High Court concluded that the JPO’s trial decision should be overruled due to the JPO’s misjudgments regarding the enablement requirements and inventive step.
Enablement Requirements Judged by the IP High Court
The JPO’s trial decision focused on Method 2 disclosed in the specification and concluded that the enablement requirements are satisfied based on Method 2. However, the IP High Court stated that Method 2 does not specify factors such as a pH value, slurry concentration, temperature, and other additives, which strongly affect crystallization, and concluded that it cannot be recognized that a person skilled in the art could determine specific conditions concerning the above factors and obtain the crystalline form I atorvastatin hydrate of the granted inventions without excessive trial and error.
Inventive Step Judged by the IP High Court
The JPO’s trial decision concluded that the granted inventions have inventive step over the invention disclosed in Citation 1 (Japanese Unexamined Patent Application, First Publication No. H03-58967). However, the IP High Court overruled this conclusion by the JPO. Specifically, the IP High Court indicated that since Example 10 of Citation 1 discloses crystallized atorvastatin, the granted inventions and the cited invention are different in that the granted inventions are a crystalline form I atorvastatin hydrate whose crystalline form is specified by the X-ray powder diffraction pattern or 13C nuclear magnetic resonance spectrum, while the crystalline form of the crystallized atorvastatin disclosed in Citation 1 is not specified and it is unclear whether it is hydrated.
Regarding this difference, the IP High Court stated that since a crystallized substance generally has superior effects with respect to stability, purity, ease of handling, and the like in the field of pharmaceutical compounds, there would have been a strong motivation to crystallize a non-crystallized substance, and a person skilled in the art would have ordinarily studied conditions for crystallization and checked crystalline polymorphism. Therefore, the IP High Court indicated that a person skilled in the art would have been motivated to study crystallization conditions and analyze thecrystalline form produced so as to obtain the crystalline form I atorvastatin. Furthermore, the IP High Court stated that it is common technical knowledge that a hydrate crystalline form is desirable as a crystalline form of a pharmaceutical compound, and thus a person skilled in the art would have ordinarily attempted to obtain the hydrate using a solvent including water. As a result, the IP High Court concluded that as long as a complicated procedure is not necessary to obtain crystalline form I atorvastatin hydrate of the granted inventions, this would have been obtained through trial-and-error that a person skilled in the art would have ordinarily carried out.
This court decision provides us with insight into how we can obtain a patent for a crystalline-form invention in Japan. For example, if a claimed invention relates to Compound X having specific crystalline form Y, the following two points should be considered.
Point 1: In order to avoid an objection concerning enablement requirements, the originally-filed specification must disclose at least one example showing that the claimed crystalline form was actually obtained, wherein the reaction conditions such as pH value, slurry concentration, temperature, and other additives are clearly specified.
Point 2: Assuming that a prior art document discloses crystallized Compound X, even if a specific crystalline form is not disclosed in the prior art document or a crystalline form obtained in the prior art document is not crystalline form Y, there is a possibility that the inventive step will be denied because the JPO concludes that a person skilled in the art would have ordinarily studied conditions for crystallizing Compound X so as to obtain that having crystalline form Y.
Under Japanese patent practice, whether a claimed invention has remarkable effects is viewed as an important factor in determining the inventive step of the claimed invention. Therefore, it is very important to show with experimental data that Compound X having crystalline form Y has remarkable effects in comparison with Compound X having another crystalline form. However, assuming that the originally-filed specification does not include any disclosures concerning these effects, even if experimental data is submitted when responding to an Office Action, the JPO will not accept the data. Furthermore, since some Examiners at the JPO believe that experimental data must be disclosed in the originally-filed specification, there is a risk that post-filing experimental data will not be accepted. Therefore, it would be most preferable that the data is included in the originally-filed specification
