Starting from 2011, it is well known that pharmaceutical industries have faced serious financial challenges as large numbers of biggest blockbuster drugs are continuously experiencing patent expiry, a phenomenon known as the patent cliff. For patent life cycle management, pharmaceutical giants (originators) try to maximise patent protection on important compounds by various strategies, such as pursuing additional patents (second generation patents) for new indications, isomers, salts, polymorphisms, formulations, combinations and dosage regimen. Likewise, generic companies are competing for developing and securing patent filings for incrementally modified drugs (IMDs) which are modified in the salt forms, isomers, polymorphs, indications etcfrom the previously approved drugs.
Crystalline polymorphism is a relatively easy approach especially since it can be easily screened and developed by conventional techniques. Further, it is an important patenting strategy, considering that it can be used as an ever-greening strategy for drug patents by the originator, while it can be also employed as a strategy for avoiding the infringement of the originator's patents. Polymorphism is a patentable subject matter in Korea, and thus, it is possible to obtain a patent for a novel crystalline form in Korea. However, it is not easy to satisfy the requirement of inventiveness, which is somewhat similar to other countries. One of the top-selling products of Pfizer, anti-hyperlipidemic Lipitor (atorvastatin) held a strong patent portfolio including second generation patents for single enantiomers, salts and crystalline forms even after the expiry of the original patent. Unfortunately, the crystalline polymorphism patent of atorvastatin was revoked by EPO opposition procedure in 2011, and it was subsequently invalidated in Japan and China.
In Korea, Pfizer's two patents for atorvastatin crystalline forms were not further contended by invalidation trials after the patents for single enantiomers and salts were finally invalidated by a Supreme Court decision in March of 2010. Instead, the Supreme Court decision (2010Hu2865, 2011.7.4) in the patent invalidation case (Recordati Ireland Ltd v Il-dong Pharm) of Lercarnidipine hydrochloride crystalline form was issued, which provides the current standard for determining an inventive step of polymorphism invention.
In that case, the court made the following rulings. First of all, it is commonplace to screen the polymorph of a compound for drug development in the pharmaceutical field. Second, finding a new crystalline form from a known compound lacks technical difficulty. Therefore, as long as there is no special circumstances, an inventive step can be accepted only if qualitatively different or quantitative remarkable effects are acknowledged as compared to those of the prior art compound. In this case, the patentee submitted that the claimed polymorph has remarkable effect, since the solubility of the claimed polymorph is five times higher than the crystals disclosed in the prior art. However, the court held that it is common knowledge in the art that the change of polymorphism can cause five to 10 times difference in solubility. The Court viewed that it is difficult to see what specific pharmaceutical effect can be achieved by the enhanced solubility. As a result, the Court ruled that remarkable effect cannot be acknowledged, based only on the improved solubility. In this regard, the Korean Intellectual Property Office often requires enhanced pharmaceutical activity of the claimed polymorph to establish an inventive step, rather than improved physicochemical properties such as solubility, stability, melting points, etc. However, contrary to this precedent, the Korean Intellectual Property Tribunal has recently issued several decisions that remarkable effects can be acknowledged only with improved physicochemical properties of the claimed polymorphs.
Therefore, if careful attention is paid to the following points when drafting or prosecuting polymorph patent, it is possible to obtain useful polymorph patent protection in Korea:
Under Korean patent practice, whether a claimed polymorph has remarkable effects is considered as a key factor in determining the inventive step. Therefore, it is important to show, by comparative experimental data, the remarkable effect of the claimed polymorph compared to the prior art crystalline forms. In this regard, it is recommended that applicants disclose what pharmaceutical activity is associated with new or improved properties of the crystalline polymorph in the originally filed application. If such disclosure is presented in the originally filed application, it is possible to submit comparative experimental data supporting remarkable effects as post-filed data.
Further, applicants can consider submitting evidence proving special circumstances that it was very difficult to make the crystalline forms or special techniques were required to make the polymorph. If the special circumstances are well supported, finding of new crystalline forms may be acknowledged as a technical difficulty which can be based on an inventive step.
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