Synopsis

In the appeal to the Full Federal Court of the decision handed down by Lindgren J last year, the majority of the Full Federal Court upheld the primary judge's finding that the (+)- enantiomer of citalopram, which was construed as referring to the separate or isolated enantiomer, was not anticipated by the earlier disclosure of the racemate or by mere reference to individual enantiomers. Despite finding for an element of separateness, the Court held that the first registration of goods which contained the (+)-enantiomer was the registration of goods containing the racemate.

FACTS OF THE CASE

Australian Patent No 623144 (“the patent”) to H Lundbeck A/S (“Lundbeck”) was filed on 13 June 1989 and relates specifically to the (+)-enantiomer of citalopram, also referred to as escitalopram. Citalopram is a selective serotonin reuptake inhibitor (SSRI) and is used in the treatment of depression. It contains a single chiral centre, which affords two possible non-superimposable mirror image (enantiomeric) forms, designated as the (+) and (-) forms. These refer to each individual enantiomer's ability to rotate plane polarised light to the right and left respectively. A mixture comprising an equal measure of both enantiomers is referred to as the racemate, or a racemic mixture, and results in no net rotation of plane polarised light. Racemic citalopram was disclosed in Lundbeck's earlier Australian Patent No 5509445 (“the '445 patent”) and was included as citalopram bromide in the Australian Register of Therapeutic Goods (ARTG) on 9 December 1997. The (+)- enantiomer was described in the later patent as being therapeutically more active than the racemate and the (-)-enantiomer.

The patent contained six claims, being directed to the specific (+)-enantiomer per se, addition salts thereof, pharmaceutical compositions comprising the (+)- enantiomer in unit dosage form, as well as to methods for the preparation of the compound. The 20 year term expired on 13 June 2009. Escitalopram oxalate was included on the ARTG on 16 September 2003 and, within the requisite 6 months from that date, on 22 December 2003, Lundbeck applied for an extension of term of the patent. An extension to 13 June 2014 was granted and particulars were entered into the Register. In 2006, a Delegate of the Commissioner held that the first regulatory approval date was in fact earlier than that alleged by Lundbeck and directed, under reg.10.7(7), that the Register be amended to reflect an extension some 18 months shorter, to 9 December 2012.

As reported in our e-mag - IP Update - September 2008 Issue, the Federal Court, at first instance1, held that claims 1-4 and 6 were valid, that Alphapharm had infringed claims 1, 3 and 6 and further ordered that, as the application for extension of term had been made out of time, the Register be corrected by removing from it the (amended) extension of the term of the patent.

THE DECISION Revocation

As at first instance, the novelty of the claims turned on the construction afforded to claim 1. Accordingly, the Full Court also first gave consideration to the meaning of “(+)- enantiomer of citalopram”. The primary judge had accepted that at the priority date, the skilled addressee would construe claim 1 to refer specifically to the (+)- enantiomer, as something separate from a racemic mixture of the (+)-and (-)- enantiomers, favouring an interpretation which required at least 95% pure (+)- enantiomer. On appeal, Alphapharm contended that the primary judge had erred by importing into claim 1 additional integers, namely, an independent existence of the enantiomer, and degree and type of purity. The majority of the Full Court (Bennett and Middleton JJ, with Emmett J dissenting) upheld, in part, the primary judge's finding, i.e. that when read in the context of the specification as a whole, claim 1 refers to the separated or isolated or pure (+)-enantiomer. However, in the absence of a qualification of purity, either expressed in the claim or made clear in the specification, their Honours did not accept that a purity of at least 95% could be read into the claim.

On the basis of their alleged construction of claim 1, Alphapharm contended that the claims lacked novelty in light of the '445 patent and a 1986 article (“the Smith article”) which theoretically predicted that the R-enantiomer of citalopram (which subsequently has been found to be the (-)- enatiomer if citalopram) was more potent than the S-enantiomer. However, given the construction placed on claim 1 by the majority, it was held that disclosure of the racemate in the '445 patent did not anticipate the separated or isolated or pure (+)-enantiomer as defined by claim 1. Furthermore, although the Smith article referred to the existence of both the R- and S-enantiomers, and the skilled addressee would have recognised immediately that one is necessarily the (+)-enantiomer and the other is the (-)-enantiomer, assignment of the (+)- and (-)- designations to the Rand S- forms could not be accomplished until the separate enantiomers were obtained and the ability to rotate plane polarised light to the right or left was measured. Noting that there was no dispute in the appeal that the preparation of the isolated (+)-enantiomer did involve an inventive step, it was held by the majority that the Smith article did not contain disclosure sufficient for obtaining and testing the ability to rotate plane polarised light of each of the separate enantiomers, and that therefore the claims were also novel in light of the Smith article.

Infringement

The full bench of the Court did however agree that the primary judge erred in concluding that Alphapharm infringed claim 6(b) of the patent, which was directed to a method for the preparation of the (+)- enantiomer. Claim 6(b) expressly specified the use of an intermediate cyano-diol intermediate whereas Alphapharm utilized a corresponding bromo-diol intermediate. In finding for infringement, the primary judge accepted that at the priority date, it would have been apparent to the skilled addressee that the cyano-diol of claim 6(b) could be replaced by the bromo-diol without any material difference to the way the process worked. In contrast, the Full Court was of the view that specifying a cyano-group on the intermediate diol compound, signified that this was an essential integer of the claimed method and accordingly, held that the use of a corresponding bromo-diol compound did not infringe the claim.

Extension of term

Despite the majority concluding that the (+)- designation identified an element of separateness, isolation, or purity, the Court was unanimous in upholding the primary judge's finding that the first listing in the ARTG of a good which ”contains” the (+)- enantiomer of citalopram, was the listing of citalopram bromide. The correct timing for applying for an extension of term was therefore to be based on the registration of goods containing the racemate, and consequently Lundbeck's application, made on the basis of the later listing of goods containing the (+)- enantiomer, was held to have been made out of time. On that footing, the Court held that any reference to an extension of term was to be expunged from the Patent Register.

COMMENTARY

Whilst each matter must be decided on the facts peculiar to the case, the finding of the majority is potentially good news for pharmaceutical researchers who through inventive endeavour identify surprising properties belonging to only one enantiomer of a racemate. However, the decision also highlights the need for patentees to exercise caution when applying to register therapeutic goods which effectively contain a mixture of substances, particularly if any individual components of that mixture are or may be the subject of later patents and therapeutic registrations.

In the meantime, the Court has granted a stay on the order for the removal of the currently recorded extension in the Patent Register pending an application for leave to appeal to the High Court. It is noted that prior to the expiration of the patent on 13 June 2009, Lundbeck also filed an application under section 223 for an extension of time (dated from 8 June 1998, being 6 months from the date of registration in the ARTG of goods containing the racemate) in which to lodge their application for an extension of patent term. In order to be granted the extension, Lundbeck must demonstrate that failure to have filed an application to extend the term of the patent by the relevant deadline was due to an error or omission or force majeure circumstances.

As noted above, that the extension of time applied for by Lundbeck is back dated to 8 June 1998. Readers familiar with the extension of term provisions will recognise that they were not in force in 1998 and that even when the provisions were introduced, had Lundbeck at the time recognised that the registration of the racemate was the first registration of goods containing the pharmaceutical substance, the relevant deadline for filing the application was set by the transition provisions, i.e. 6 months from 27 January 1999.

A final point of interest is the order made by the primary and appeal judges that the Patent Register be amended to remove any reference to the extension of term of the patent. Regulation 10.7(7) (previously found not to be ultra vires2) merely compels the Commissioner to amend the Register to insert the correct extension of term if made aware that the first regulatory approval date is earlier than that supplied with the application for extension, but does not extend to any consideration of the circumstances in relation to the making of the application.