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26 August 2008
Alphapharm Pty Ltd v H Lundbeck A/S ( FCA 559) involved four separate proceedings (heard together) relating to Lundbeck’s anti-depressant drugs Lexapro and its predecessors. This is the first in a series of recent patent cases concerning claims to enantiomers.
Citalopram, marketed as Cipramil, is the subject of a patent filed by Lundbeck on January 5 1977. Citalopram is a chiral molecule which exists as a racemate, a mixture of two enantiomers in equal measures. The enantiomers of a racemate may be designated as either (S) or (R) based on the arrangement of molecules around the carbon centre of the compound, or (+) or (-) depending on the direction in which the compounds rotate plane polarized light (which can be determined only by experimentation).
On June 13 1989 Lundbeck filed a patent for the (+) enantiomer of citalopram, referred to as escitalopram or (+) citalopram (marketed as Lexapro). The escitalopram patent disclosed that (+) citalopram is therapeutically more active than citalopram itself and 100 times more active than (-) citalopram.
In the patent revocation (and infringement) proceedings Alphapharm (and Arrow) sought to invalidate the escitalopram patent on a number of grounds, including that pursuant to Section 18 of the Patents Act 1990 (Cth), the claims to (+) citalopram:
As a first step, the court considered the proper construction of the claim to (+) citalopram. The court rejected the argument by Alphapharm that the skilled addressee would have understood the claim to refer to the enantiomer as part of the unresolved racemate of citalopram. The court instead held that the use of the (+) symbol would have been understood as a reference to (+) citalopram as a compound that had “an existence independent to that of the racemate” (and which had a purity of at least 95%).
The novelty challenge was based upon two publications. The first publication, a journal article, predicted that the (R) enantiomer was more potent than the (S) enantiomer. The court held that this was not an anticipation as it taught away from the invention.
The second publication relied upon was the original citalopram patent. Alphapharm argued that a person who followed the teaching of the citalopram patent would make the racemic mixture which contained the (+) enantiomer. It also submitted that a person skilled in the art would at once recognize that the chemical formula disclosed in the citalopram patent was a chiral molecule that would exist in the form of two enantiomers. The court accepted that citalopram consisted of the (+) and (-) enantiomers in equal parts, but noted that it was not possible to identify which was which in the racemic mixture in the absence of further experimentation.The court found that in order to anticipate the escitalopram patent, it was necessary that the citalopram patent be an ‘enabling disclosure’, in the sense that it pointed unmistakably to the (+) enantiomer of citalopram as distinct from the racemate “as a drug desirable to make”. The court held that the citalopram patent disclosed the racemate and enabled the making of it, but it did not teach that it was desirable to obtain (+) citalopram in its own right and so was not an enabling disclosure. The escitalopram patent was therefore held to be novel.
Alphapharm also failed in its challenge to the escitalopram patent, on the basis that the claim to (+) citalopram was obvious. The court applied the now well-established principle that for an invention to be obvious it must be shown that a hypothetical addressee (or team) equipped with the common general knowledge would have taken steps towards the invention as a matter of routine in the expectation that the steps might well produce the invention. In applying this test, the court held that it was not necessary for Alphapharm to establish that it was obvious to obtain the (+) enantiomer specifically, because to obtain one enantiomer was to obtain the other.
The court also held that although the obtaining of the separate enantiomers was “conceivable” at the priority date of the escitalopram patent, it would not have been obvious to obtain the enantiomers so as to use one of them for the treatment of depression. In coming to this view, the court appears to have relied on evidence which demonstrated that it was known to be nothing more than a possibility that either enantiomer of citalopram might exhibit advantageous therapeutic properties as compared to citalopram itself. There was therefore no significant need or desire to obtain the enantiomers of citalopram, which was well known to be used successfully for the treatment of depression.
The court also held that the claims to (+) citalopram constituted a manner of manufacture. Significantly, it held that while citalopram formed part of the disclosure of the escitalopram patent, the patent did not acknowledge, either expressly or by implication, that the (+) enantiomer was a compound with known properties. Rather, the escitalopram patent demonstrated (+) citalopram to be a new compound that exhibited unexpected and surprising properties that could not be predicted from the known properties of citalopram.
Lundbeck cross-claimed against Alphapharm for infringement of the escitalopram patent, on the basis of Alphapharm’s manufacture of goods containing (+) citalopram for the purposes of obtaining regulatory approval. The court found that this conduct infringed the escitalopram patent, except to the extent that Alphapharm could avail itself of the defence provided by Section 78(2) of the Patents Act (which, although now repealed and replaced by Section 119A, still applied to the escitalopram patent), which exempts acts done for purposes connected with obtaining inclusion of a substance in the Australian Register of Therapeutic Goods (ARTG).
Further proceedings considered the extension of term of the escitalopram patent.
The Patents Act allows the term of a pharmaceutical patent to be extended under certain circumstances for a maximum of five years in order to compensate for delays in obtaining listing of goods in the ARTG containing the active ingredient of the subject of the patent.
Specifically, Section 70 provides that in order to obtain an extension: (i) one or more pharmaceutical substance per se must in substance be disclosed in the patent (and fall within the scope of a claim of the patent); and (ii) the period beginning on the date of the patent and ending on the first regulatory approval date for the substance must be five years. Section 70(5) defines the ‘first approval date’ (where no pre-Therapeutic Goods Administration approval was granted), to be the date of commencement of the “first inclusion in the ARTG” of goods that “contain or consist of the substance”.
The commissioner of patents had originally granted the maximum five-year extension on the basis that the relevant first regulatory approval date was September 16 2003, the date on which Lexapro was first included in the ARTG. Following a challenge to this decision to the Patent Office by Alphapharm, the commissioner reduced the term of the extension on the basis that the relevant first regulatory approval date was December 9 1997, the date on which Cipramil was included in the ARTG, given that escitalopram, as an enantiomer of citalopram, was "contained in" Cipramil.
The court agreed that Cipramil as a racemate “contained” escitalopram and held that Lundbeck was not entitled to “any” extension of patent term at all, as it had not applied for the extension within six months of the date of the first inclusion of goods containing escitalopram (ie, Cipramil) in the ARTG as required under Section 70(2).
In the protected information (data exclusivity) proceedings Lundbeck sought a declaration that the information that it provided to the secretary of the Department of Health and Ageing as to (+) citalopram in seeking to have the product registered in the ARTG constituted ‘protected information’.
Section 25A of the Therapeutic Goods Act 1989 (Cth) provides that information is protected (for a period of five years) if it is information (which is not publicly available) about the active ingredient of a therapeutic good provided to the secretary in relation to an application to register goods containing the active ingredient. However, information is protected only if no other therapeutic goods “consisting of or containing the active component” were previously included in the ARTG.
The court found that information about (+) citalopram submitted to the secretary by Lundbeck did not constitute ‘protected information’ because goods consisting of (+) citalopram (ie, Cipramil) were previously included in the ARTG.
The case has been appealed to the Full Federal Court.
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