Israel: A Racemic Compound? A Racemic Mixture? The Fight Over PTE/SPC For Enantiomers Goes On!

Last Updated: 20 May 2019
Article by Tal Band and Yair Ziv

The Israeli Patents Law 1967 (the Patents Law) empowers the Registrar of Patents (the Registrar) to extend the term of 'basic patents' protecting pharmaceutical products, for an additional term beyond the statutory 20-year period of patent protection.

Patent Term Extension (PTE) is granted in Israel only if certain requirements are met as set out in section 64d of the Patents Law. One such requirement is that the marketing approval of the pharmaceutical product is the first marketing approval enabling use of the "compound" contained in the pharmaceutical product for medicinal purposes in Israel ("the first marketing approval requirement"). The term "compound" is defined in the Patents Law as the active ingredient in the pharmaceutical product, or salts, esters, hydrates or polymorphs of said ingredient.

A particularly important Israeli case law in the context of the first marketing approval is the Lundbeck case,1 where it was held that the marketing approval of a pharmaceutical product containing an enantiomeric form, would not be considered the first marketing approval enabling use of the compound contained in the pharmaceutical product for medicinal purposes in Israel, where a pharmaceutical product containing the racemic mixture (namely, a racemate comprising an equal amount of two left and right-handed enantiomers S and R, respectively) has already been approved; this, since the racemate contains the enantiomer.

A decision concerning the first marketing approval in the context of a pharmaceutical product containing an enantiomer was rendered by the Registrar in opposition proceedings initiated by the Manufacturers' Association of Israel (the MAoI).2

The Registrar has applied the Lundbeck case law and refused to grant the applicant, Takeda Pharmaceutical Company Limited (Takeda), a PTE, stating that the marketing approval of a pharmaceutical product containing a "racemic compound"

should likewise be considered as the first marketing approval with respect to a pharmaceutical product containing each of the separated enantiomers. It was held that the classification of a racemate as a "racemic mixture" or a "racemic compound" is not relevant for determining whether the first marketing approval requirement has been fulfilled. Instead, it is relevant to consider whether the molecular structure of the active ingredient remains the same, when the active ingredient is isolated from the racemic compound. In such circumstances, where the active ingredient identity was not affected, no new compound is formed and therefore the first marketing approval requirement is not met.

A. THE BACKGROUND TO THE DECISION

In 2016, Takeda sought to extend the term of an Israeli patent, based on the marketing approval of its pharmaceutical product—DEXILANT®. The active ingredient in the said pharmaceutical product is Dexlansoprazole, the R enantiomer of the Lansoprazole racemate. The Lanzoprazole racemate was previously registered as a pharmaceutical product (Prevacid®).

In its application for PTE, Takeda tried to draw a distinction between its case and the Lundbeck case, by claiming that the ruling in the Lundbeck case concerned a racemic mixture, while the Lansoprazole racemate involves a racemic compound. Takeda further claimed that since the Lansoprazole racemate comprises both the R enantiomer (Dexlansoprazole) and the S enantiomer (Levolansoprazole) in one crystal lattice, that cannot be separated (in the solid state) into two enantiomers; Dexlansoprazole, in its isolated single crystalline form, is a different compound, which was not included in the registered pharmaceutical product containing Lansoprazole.

Based on this argument, the former Registrar held, albeit in ex parte proceedings, that the previous marketing approval of Lansoprazole did not enable the use of Dexlansoprazole and, therefore, Takeda's PTE application for Dexlansoprazole satisfied the requirements of the Patents Law, thus rendering its patent eligible for PTE. The ex-parte decision was reported by Gilat, Bareket & Co., Reinhold Cohn Group (PTEs for Enantiomers are Possible in Some Cases Notwithstanding an Earlier Marketing Authorization of a Racemate). This is no longer the case.

B. THE REGISTRAR'S DECISION IN THE OPPOSITION PROCEEDING

Following the publication of the Registrar's decision holding Takeda's patent is eligible to be granted PTE, the MAoI initiated opposition proceedings.

The Registrar accepted the MAoI's position that the marketing approval of a pharmaceutical product containing a "racemic compound" equally applies to the first marketing approval of a pharmaceutical product containing each of the separated enantiomers. In this context, the Registrar held that it is irrelevant whether the enantiomers in the Lansoprazole racemate may be isolated in the solid as claimed by Takeda or not. Thus, in so far as the molecular structure of the active ingredient remains the same during the separation of the enantiomers, the first marketing approval requirement will be deemed not to have been met. The registrar held that the identity of the active ingredient is not determined by the specific form in which it is contained in the pharmaceutical product.

The circumstances of this case led the Registrar to determine – based on expert opinions and cross examinations of the experts – that the enantiomers included in the Lansoprazole racemate were not linked by means of an-intermolecular bond, thus each of the enantiomers maintains its formal structure in the crystal.

The Registrar also referred to Takeda's additional argument regarding the interpretation of the term "compound", within its meaning in the Patents Law. According to Takeda, the definition of the term "compound" must be interpreted in the context of the dosage form of the pharmaceutical product and, in particular, the state of matter of the active ingredient in the pharmaceutical product.

According to this approach, the active ingredient in previous pharmaceutical products containing the Lansoprazole racemate is a crystal comprising Dexlansoprazole and Levolansoprazole in one lattice, while the active ingredient in the DEXILANT® is a crystal comprising only the Dexlansoprazole molecule.

The Registrar rejected this interpretation. He stated that the term "compound" cannot be considered only in a particular state of matter, as it would lead to a situation in which an active ingredient contained in a pharmaceutical product will be deemed a different active ingredient when dissolved in the human body. This will result in unwarranted effect whereby PTEs will protect only the active ingredient in the form that was actually included in the pharmaceutical product.

In light of the above, the Registrar rejected Takeda's application for PTE, holding that Dexlansoprazole was already contained in a previously registered pharmaceutical product containing the Lansoprazole racemate.

Footnotes

1. MA 223/09 H. Lundbeck A/S v. Unipharm Ltd et al. [2009].

2. Opposition to PTE no. 145996 The Manufacturers' Association of Israel v. Takeda Pharmaceutical Company Limited (Unpublished, 24.5.2018).

2 L/22271/30/6250792/1

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