PTEs for Enantiomers are Possible in Some Cases Notwithstanding an Earlier Marketing Authorization of a Racemate

The availability of a patent term extension (PTE) of a patent covering an enantiomer based on a registration of a drug containing it, notwithstanding past registration of a drug containing the racemate, was the subject of a recent Patent Office decision. It was ruled that where the earlier registration was for a drug containing a racemic compound, as opposed to a racemic mixture, a PTE for a drug containing one of the enantiomers may be possible. This decision opens the door for patentees to obtain a PTE in some cases believed to be hitherto not possible following a past ruling by the Supreme Court.

Introduction

The term of an Israeli patent that protects, inter alia, a substance contained in a pharmaceutical drug[1] may be extended under certain conditions. One of these conditions is that the registration of the drug be the first one in the Register of Pharmaceuticals that enables use of the substance in Israel for medical purposes.[2]

The question of whether a registration is the first registration, within the meaning of the Patents Law, was raised in various contexts in Israeli case law.[3] Of relevance for this case is the question of whether a prior registration in the Register of a drug containing a racemate[4] bars a subsequent PTE (referred to in the Patents Law as an “extension order”) based on a later registration of a drug containing an enantiomer[5] of that racemate. This was discussed and unequivocally decided on by the Israeli Supreme Court in Lundbeck in 2010.[6] This was a case that started at the Israeli Patent Office (ILPO) and made it all the way up to the Supreme Court, where the Supreme Court upheld the decision by the Registrar of Patents and ruled that a previous registration of a racemate prevents a patentee from fulfilling the “first registration” condition and consequently prevents a PTE for a drug containing one of the enantiomers as its active pharmaceutical ingredient (API) from being issued.

This issue came up again in a recent case brought before the ILPO by Takeda Pharmaceuticals Company Ltd. In this case the Registrar ruled in favor of Takeda and extended the term of Takeda’s patent while distinguishing the Takeda case from the Lundbeck ruling based on the differences between different forms of racemates.

Factual Background

Takeda[7] sought to extend an Israeli patent based on the registration of its drug DEXILANT®. The API in DEXILANT® is dexlansoprazole, a new-generation proton pump inhibitor. DEXILANT® is used for the treatment of gastroesophageal reflux disease (GERD) by applying a dual-delayed release technology (DDR) that combines two different types of granules into one pill.

After DEXILANT® was registered in the Israeli Register, Takeda submitted a PTE request for extending the term of IL patent no. 145996,[8] due to expire on June 15, 2020. dexlansoprazole is the R enantiomer of racemic lansoprazole. A drug containing lansoprazole as the API was previously registered in the Register (commercially known as PREVACID®). 

The Israeli examiner’s decision and the administrative appeal

In the Lundbeck ruling, a previous registration of a drug that included a racemate as the API barred a PTE based on a later registration of a drug with an API that was one of the enantiomers of the racemate. Lundbeck sought to obtain a PTE for an Israeli patent based on the registration of its blockbuster antidepressant drug, CIPRALEX™, the API of which is the S enantiomer, or escitalopram, of the racemate which was the API of an earlier Lundbeck antidepressant drug CIPRAMIL^® registered in the Israeli Register. Initially, the Registrar, later the District Court of Appeal and eventually the Supreme Court, refused Lundbeck’s PTE request ruling that CIPRALEX™’s registration is not the first registration that enables the medical use of escitalopram.

Considering the Lundbeck ruling and considering the former registration of lansoprazole, the Israeli examiner refused Takeda’s PTE request and decided that it does not fulfill the “first registration” condition. Takeda submitted an administrative appeal on the examiner’s refusal and argued, inter alia, that a distinction should be made between a racemic mixture[9] and a racemic compound.[10] It was argued that lansoprazole is a racemic compound, namely a material in which each crystal unit of lansoprazole is comprised of both its R enantiomer (dexalansoprazole) and S enantiomer. This is different, it was argued, from Lundbeck in which the earlier registration of CIPRAMIL^® was of a racemic mixture that comprises single crystals of either the R enantiomer or the S enantiomer, the racemate then consisting of a mixture of the two different crystals. Hence, dexlansoprazole, being an isolated single crystalline enantiomer, did not exist in the registered lansoprazole.

Based on this exposition of the underlying science, Takeda argued, and the Registrar agreed, that the Takeda case must be distinguished from the Lundbeck ruling[11] because a previous registration of a drug containing a racemic compound as the API did not enable the medical use of any of its enantiomers (in this case dexlansoprazole). Thus, and in light of further evidence submitted to support Takeda’s position, the Registrar held that Takeda met the burden of proof required to demonstrate that the previous registration of lansoprazole did not enable the use of dexlansoprazole and that, accordingly, Takeda’s PTE request fulfilled the requirements of the Patents Law and its patent is therefore eligible for a PTE.

This decision, thus, opens the door for PTE requests in some cases where PTEs were previously believed to be unavailable.

End Note

Before its final grant a PTE order is published for public opposition and third parties may therefore still oppose the intended grant of the PTE order, in which case Takeda’s arguments may be subject to further scrutiny. The final word on this topic may still not have been heard.

[1] Under Section 64D of the Israeli Patents Law, 5727-1967, to be eligible for a patent term extension, a patent (a ‘Basic Patent’ in the language of the Law) must relate to a ‘Substance’, defined in the Law as “the active ingredient of a pharmaceutical preparation or the salts, esters, hydrates, or crystalline forms of such ingredient,” or to a medical device.

[2] Section 64D(3) of the Patents Law. The Register is a register of drugs that received a marketing authorization.

[3] For example, whether former registration of a drug, containing a certain active pharmaceutical ingredients (API) (referred to in the Patents Law as “a Substance”), for veterinary purposes negates the possibility of obtaining a PTE based on a later registration of a drug, containing the same API, for treatment in humans; whether a former registration of a drug, containing a certain API, negates the possibility of obtaining a PTE order based on later registration of a combination drug containing said API; and so on.

[4] A racemate is an equimolar mixture of a pair of enantiomers. It does not exhibit optical activity (see – International Union of Pure and Applied Chemistry (IUPAC) Gold Book).

[5] One optical isomer of the racemate.

[6]  ALA 5267/09 H. Lundbeck v. Unipharm Ltd et al. [2010].

[7] The largest Japanese and Asian pharmaceutical company and one of the top-20 pharmaceutical companies in the world (2016).

[8] National application of PCT application PCT/JP/2000/003880 (International Publication no. WO/2000/078745).

[9] According to IUPAC

[10] In order to establish these differences Takeda submitted a scientific article by Alan J. Mitchell titled “Racemic Drugs: Racemic Mixture, Racemic Compound, or Pseudoracemate?” Pharm. Pharmaceut. Sci (1998) 1(1): 8-12 . Mitchell explains, inter alia, that “in a racemic mixture each enantiomer has a greater affinity for molecules of its own kind than for those of the other enantiomer and the two enantiomers crystallize in separate phases, in a racemic compound the unit cell of the crystal contains an equal number of molecules of each enantiomer; thus, the product is a true addition compound“.

[11] The Supreme Court’s judgment in the Lundbeck ruling was thus narrowed to the circumstance where the racemate, which was previously approved was a racemic mixture, rather than a racemic compound. In his decision in Takeda, the Registrar did not make an explicit finding that the Lundbeck ruling concerned a racemic mixture. However, a review of the Registrar’s decision in Lundbeck shows that the patentee there used the term “racemic mixture”; Takeda referred to this fact in its arguments filed to the ILPO. Thus, we can only assume that in Lundbeck the racemate was indeed a racemic mixture and not a racemic compound.