That (es)citalopram patent yet again

The IPKat seems to somehow have missed the latest installment in the series "is Lundbeck's escitalopram patent valid?" (it should be properly called by now "are the SPCs based on that patent valid?", as the patent term has expired). As previously reported, the product claims of this patent had been declared invalid by Mr Justice Kitchin at the High Court in a judgment of 4 May 2007. The method claims were deemed valid. The Dutch first instance court had invalidated all the claims of the Dutch part of the patent in a judgment of 8 May 2009 for lack of inventive step.

The German Bundesgerichtshof, in a judgment of 10 September 2009, came to a different conclusion regarding the validity of the SPC based on the German part of Lundbeck's escitalopram patent. The grounds for the decision have only been published just recently.

In the first instance, the German Federal Patent Court had invalidated the escitalopram patent on the grounds that the substance citalopram was already known at the priority date and the skilled person would have recognized that is was composed of two enantiomers (S-citalopram and R-citalopram). The Federal Patent Court stated that it was “easily” possible for the person skilled in the art to separate the substance, thus achieving the pharmaceutically more effective S-enantiomer (escitalopram). Even if the common method of forming diastereomeric salts with a chiral acid was inadequate for resolution, the skilled person would employ the chiral chromatography method known to him and established pre-priority (referring to I.W. Wainer, Trends in Analytical Chemistry 6 (1987) 125-134 for commercially available chiral stationary phases which the skilled person would use at the priority date). The ability to obtain S-citalopram was further evidenced by later published documents reporting chiral separation of citalopram. In contrast to the UK, the German Federal Patent Court held that analytical amounts were sufficient. The testing of commercially available chiral stationary phases, including selecting the appropriate parameters, was not considered unreasonable in terms of the tests and analyses the skilled person would conduct, whereas the UK court considered this to extend the common general knowledge too far.

The Bundesgerichtshof reversed. Firstly, it held that prior art that discloses the racemate of a chiral molecule without explicitly disclosing the enantiomers was not novelty destroying for the S-enantiomer. The person skilled in the art may well recognize that citalopram contains carbon and is chiral. However, that is not enough to destroy the novelty of the isolated S-enantiomer if it is not explicitly disclosed in the prior art (citing T 296/87).

The person skilled in the art had reason to try isolating the S-enantiomer at the priority date, but success was not certain and the effectiveness of the isolated S-enantiomer could only be tested empirically. There was no obvious way to isolate the enantiomers of citalopram. The usual method, by forming diastereomeric salts with a chiral acid (namely DPTTA), was not working. The separation using high performance liquid chromatography was successfully used on citalopram racemate at the priority date. However, it was unclear which techniques would yield commercially useful results. In 1988, there was namely no reason to expect that Chiralcel OD, which had just become available, would provide the decisive breakthrough (Mr Justice Kitchin had come to the same conclusion).

The Bundesgerichtshof further held that the second method of manufacturing S-citalopram, stereoselective synthesis using 4-(4-dimethylamino)-1-(4 min -fluorophenyl)-1-(hydroxybutyl)-3-(hydroxymethyl)benzonitrile, was also not obvious. The "Baldwin rules" might have indicated that a ringclosure reaction was not excluded, but that does not mean that there was reasonable expectation of success. The "Baldwin rules" did not indicate which reaction was likely, only which ones were impossible.

The BGH finally held that S-citalopram was a different product than citalopram in the sense of art. 3(d) Regulation 1768/92 concerning the creation of a supplementary protection certificate for medicinal products. The racemate of citalopram is not S-citalopram with a purity of 50%. The R-citalopram of the racemate is also pharmaceutically effective, the mixture of the enantiomers therefore a different active substance from its components.

S-citalopram will therefore remain protected in Germany until the expiration of the SPC on 1 June 2014. The escitalopram preparation Cipralex® is, commercially speaking, Lundbeck’s most important product by far. Cipralex®, which is distributed in the USA under the trademark Lexapro®, is the most often prescribed non-generic antidepressant in Europe and the USA. It generates an annual turnover of more than 1 billion Euros and is being distributed in 93 countries.

Lundbeck was represented by Hoffmann Eitle. Should any reader have an English translation of the decision, the IPKat will post it.

ADDED MATTER: Hoffmann Eitle has again come up trumps, with an excellent English translation. Once again, the IPKat offers his deep gratitude.

Government U-turn on downloaders; parallel imports blames for pharma shortages

Government revives downloader cut-off proposal

The IPKat has learned from the BBC that the Department for Business Innovation and Skills is to consult on whether the forthcoming Digital Economy Bill should include a requirement that ISPs cut off persistent downloaders. Although Lord Carter's Digital Britain report recommended that Ofcom should explore the issue thoroughly before such a measure was taken, this would take until 2012. The Government feels that this the threats posed by online infringement could mean that this would be too long to wait. To take account of the change in position, the Digital Britain consulation period has been extended to 29 September.

The IPKat isn't hugely impressed. What's the point of commissioning such a report if you're going to brief against its measured recommendations? And wouldn't it have been more sensible to have put this proposal forward at the beginning of the consulation period, rather than halfway through?

BIS press release here.

Parallel imports lead to UK drug shortages

Also from the BBC, the news that a survey by Chemist and Druggist magazine has revealed that 90% of pharmacies have experienced difficulties in obtaining stocks of branded medicines. Some patients have suffered health problem as a result (either physical problems, or caused by anxiety when the correct drug cannot be obtained). A good deal of the blame has been placed on parallel imports into other countries of medicines intended for the UK market.

The IPKat wonders if this is another effect of the credit crunch, with the weakish pound making the UK a good place to source goods for export. He wonders if a similar phenomenon is apparent is other products. The problem though is a serious one. He has a dim and distant recollection of an ECJ case saying that sales of parallel imported goods could be stopped on competition grounds where parallel trade leads to a shortage on the exporting market, but he never thought that the UK would be affected in this way.

Appeal judges awake to Napp patent issues

On Wednesday, while much of the IP world was amusing itself with April Fool pranks, the Court of Appeal (England and Wales) had more serious matters to resolve when it gave its decision in Napp Pharmaceutical Holdings Ltd v ratiopharm GmbH/Napp Pharmaceutical Holdings Ltd v Sandoz Ltd [2009] EWCA Civ 252. In what is now becoming something of a regular occurrence a Lord of Appeal in Ordinary dropped down from the House of Lords to sit with the Lords Justices of Appeal, the court consisting of Lord Justice Jacob (who delivered a judgment to which all members of the court contributed), Lord Neuberger himself and Lord Justice Lawrence Collins.

In short (you can read the background to the appeal in greater depth where the IPKat covers the trial decision here) this case involves actions concerning two of Napp's divisional patents (246 and 730) for oxycodone ("a known opioid killer").  The trial judge held the patents valid but not infringed. Both parties appealed. 

The Claim 1 of 246 was for

'a controlled release oxycodone dosage form for oral administration to human patients, comprising: (a) oxycodone salt in an amount equivalent to 10 mg to 160 mg of the oxycodone hydrochloride salt; (b) a matrix incorporating said oxycodone salt; (c) a coating on said matrix controlling the release of said oxycodone salt'.

Claim 6 of 730 was for

'a controlled release oxycodone formulation for administration to human patients, comprising: (a) an analgesically effective amount of spheroids comprising oxycodone or a salt thereof and a spheronising agent; (b) each spheroid being coated with a film coating which controls the release of the oxycodone or oxycodone salt at a controlled rate in an aqueous medium'. 

Napp said that the defendants' Cimex tablets infringed these claims. They had small particles which were made up of a number of layers, where an external layer contained around 20% of oxycodone salt which they released immediately. It was common ground that the release of the remaining 80 per cent was controlled by the film coating. 

Sandoz and ratiopharm said the patents were invalid in respect of added matter under Article 123 of the European Patent Convention ("(2) A European patent application or a European patent may not be amended in such a way that it contains subject-matter which extends beyond the content of the application as filed") and under the Patents Act 1977 ("Since our provisions mean the same as Art 123(2) there is no point in referring to them"). The argument of invalidity was that parts of the specification and/or claims of 730 had not been disclosed clearly and unambiguously in Napp's PCT application and/or that they did not provide a technical contribution. 

The Court of Appeal allowed Napp's appeal and held the patents infringed, but dismissed the generics companies' challenge to their validity.  Their Lordships however emphatically endorsed the statement of the trial judge that

"[122] ... the test for added subject matter remains that set out in the Convention and the Act. The reason that disclaimers of accidental and deemed anticipations do not offend is that they do not add subject matter relevant to the invention. If a disclaimer introduced by a divisional application does not add subject matter relevant to the invention, but merely excludes subject matter from protection, then it too will not offend against the provision."

The IPKat notes that the same patents are currently being litigated in Germany, where (see paragraphs 63 to 67) the litigation has taken a rather different turn and the patent claims have been given a different construction.  Is this yet another example of a justification for a unified approach to patent litigation in Europe, or  -- as Merpel wonders -- just an inconvenient blip that can be overlooked since it's just a small price to pay for the efficient localisation of expensive and complex litigation?

Access to medicine; memorial service

Cheaper drugs for developing countries

The IPKat apologies for having missed the fact that GSK has announced that it will cut drug prices in 50 countries in the developing world (reported here in the BBC). Patented formulas and processes owned by GSK under patent will be shared with researchers. GSK will also reivest 20% of the firm's profits in the developing world in hospitals and clinics there.

The IPKat welcomes this announcement. Yes, a patent can be used in any way its owner wants, and yes it can be used to gain a monopoly rent, but a patent owner also has the right to use his patent in an altruistic way. GSK has raised the game here and the IPKat wonders whether competitors will follow suit.

Memorial

The IPKat draws his readers' notice to the following announcement:

LADDIE, Hugh Ian Lang, a Thanksgiving for
the Life and Work of Professor Sir Hugh Laddie
will take place at Middle Temple Hall, EC4 9AT
on 4 March 2009 at 6pm. Reception follows.

ratiopharm/Sandoz v Napp Pharmaceuticals

Last week, Mr Justice Floyd delivered his judgment in the case of ratiopharm & Sandoz v Napp Pharmaceuticals, but the IPKat has been taking a while to digest this very long and complicated judgment.  The case related to two of Napp's EP(UK) patents for sustained release formulations for the painkiller drug oxycodone, more commonly known (at least to Rush Limbaugh) by the trade mark OxyContin.  

Sandoz and ratiopharm (not to be capitalised, apparently) had applied to revoke the two patents, EP0722730 and EP1258246 (derived from a common priority application) on the grounds that the claimed invention in both was obvious. Napp counter-claimed for infringement.  The invention, which was not at all easy to identify, came down to the particular way in which the claimed formulation provided an extended release of oxycodone over time, apparently allowing a more controlled dosage within specified limits.  This was achieved by having an oxycodone salt mixed into a resin matrix in the form of a spheroid, with an outer coating to control release of the salt.  

Strangely enough, given that the case was kicked off by actions for revocation, the main issue came down to whether the alleged infringing product, in the form of a multi-layered particulate form of oxycodone (pictured left in cross-section) did actually infringe any of the claims in question.  The alleged infringement was based on a central (non-pharmaceutical) core, surrounded by three layers having different functions, the first and third of which (inner and outer layers in the picture) contained oxycodone. The outer layer, containing about 20% of the total amount of oxycodone, would provide an initial dose, while the rest of the drug, bound up in the inner layer, would release over time by diffusing out through the polymer layer. 

Probably the easist of the claims in question to understand was the following one, claim 6 from EP0722730:

A controlled release oxycodone formulation for administration to human patients, comprising:
(a) an analgesically effective amount of spheroids comprising oxycodone or a salt thereof and a spheronising agent;
(b) each spheroid being coated with a film coating which controls the release of the oxycodone or oxycodone salt at a controlled rate in an aqueous medium.

Construction of the claims was a question best answered with reference to the familiar approach offered by Lord Hoffmann in Kirin Amgen:

"Construction, whether of a patent or any other document, is of course not directly concerned with what the author meant to say. There is no window into the mind of the patentee or the author of any other document. Construction is objective in the sense that it is concerned with what a reasonable person to whom the utterance was addressed would have understood the author to be using the words to mean. Notice, however, that it is not, as is sometimes said, "the meaning of the words the author used", but rather what the notional addressee would have understood the author to mean by using those words. The meaning of words is a matter of convention, governed by rules, which can be found in dictionaries and grammars. What the author would have been understood to mean by using those words is not simply a matter of rules. It is highly sensitive to the context of and background to the particular utterance. It depends not only upon the words the author has chosen but also upon the identity of the audience he is taken to have been addressing and the knowledge and assumptions which one attributes to that audience." (paragraph 32)

Floyd J concluded, after extensive analysis of the wording of the claims, that the claims in question required either all the oxycodone to be included in the matrix, and not in the outer layer, or that a spheronising agent (i.e. something that allowed a spherical particle to be formed) was required in the formulation. Neither of these constructions could be used to cover the alleged infringement, since the particle did not have a spheronising agent (the central non-active core was pre-made, and not judged itself to be such an agent), and a significant proportion of the active ingredient was in the outer layer of the particle.

Floyd J went on to conclude that the patents were valid, and not obvious in light of the cited prior art (though the IPKat wonders how valuable they are now, if they can be worked around so easily).

The IPKat thinks that this case demonstrates that there are cases where meticulous verbal analysis is definitely required to figure out what a patent actually claims, as otherwise it would be difficult to show where the boundaries of the invention lie. It didn't help, however, in this case that some of the claims were apparently (in the words of Floyd J) "very poorly drafted", making the task of figuring out what they meant even more difficult than usual. This might be an effect of hindsight, but the IPKat wonders why, for such an important (i.e. money making) drug, the claims in this case were not drafted better.  Could Napp not afford a patent attorney who understood how to draft dependent claims? And how did this get past Article 84 requirements at the EPO?