Bimatoprost - UK

On May 03, 2019, UK high court found low dose Lumigan® patent invalid under obviousness.

Allergan markets product containing 0.1 mg/ml (0.01%) bimatoprost for ophthalmic administration for the treatment of glaucoma under the trade mark Lumigan® 0.1 mg/ml. This replaced an earlier product called Lumigan® 0.3 mg/ml that contained 0.3 mg/ml (0.03%) bimatoprost.  Allergan is the proprietor of European Patent (UK) No. 1 753 434 entitled "Enhanced bimatoprost ophthalmic solution". In essence, the invention claimed in the Patent is a formulation containing a lower concentration of bimatoprost (in particular 0.01%, rather than 0.03%) and a higher concentration of a preservative called benzalkonium chloride ("BAK") (in particular, 200 ppm or 0.02% rather than 50 ppm or 0.005%). Aspire Pharma Ltd and Accord Healthcare Ltd (Defendants) obtained marketing authorisations for generic versions of Lumigan 0.1 mg/ml. Defendants do not dispute the infringement, however, they contend that the Patent is invalid on the ground that the claimed inventions were obvious over Laibovitz et al.

The main dispute was whether it was common general knowledge that BAK enhanced the corneal permeability, and hence bioavailability, of ophthalmic drugs. It is common ground that the inventive concept of claim 18 is a formulation of 0.01% bimatoprost with 0.02% BAK (i.e. 200 ppm) for treating glaucoma. It is also common ground that the key difference between claim 18 and Laibovitz is that, whereas Laibovitz discloses the use of 0.01% bimatoprost to treat glaucoma, it does not disclose the use of 0.02% BAK.

Court said that the Defendants' case is straightforward. It starts from the proposition that the skilled ophthalmologist would be interested in reducing the incidence of conjunctival hyperaemia observed with Lumigan 0.3 mg/ml. Allergan do not to dispute this proposition. The skilled ophthalmologist would see from Laibovitz that 0.01% bimatoprost was reported to lower IOP by 20.7%, which the skilled ophthalmologist would regard as sufficient to be clinically useful for the treatment of glaucoma and ocular hypertension. The skilled ophthalmologist would expect that a lower dose of bimatoprost than 0.03% would reduce the incidence of hyperaemia, but would note that the quality of the hyperaemia data reported in Laibovitz was poor. An obvious course would therefore be to repeat the study with a better methodology for recording and scoring hyperaemia and more patients in order to generate better hyperaemia data and to confirm the IOP lowering efficacy of the bimatoprost doses, and in particular the 0.01% dose.

The Defendants also contended that it would be obvious to use a preserved formulation, and in particular a formulation preserved with BAK. Allergan disputed this. Counsel for Allergan accepted that it would be obvious in the light of Laibovitz to produce a formulation of 0.01% bimatoprost with 50 ppm BAK for a commercial product, but submitted that it would not be obvious to use 50 ppm BAK for the purpose of repeating Laibovitz because of the possibility that BAK would affect the incidence of hyperaemia. Court said that this is a hopeless argument. The question is whether the inclusion of BAK would be an obvious choice from a technical point of view. Laibovitz makes it clear that the only reason why preserved formulations were not used in the original study is because they were not available – it was not a deliberate decision for any scientific reason. When repeating Laibovitz, it would obviously be convenient to be able to use multi-use containers, which would require the use of a preserved formulation. Since BAK was the most commonly used preservative, it would be the obvious choice. For the reasons discussed above, the skilled team would think that the hyperaemia associated with Lumigan 0.3 mg/ml was due to the bimatoprost, and not to the BAK. Accordingly, they would have no reason not to include BAK when repeating Laibovitz.

The Defendants also contended that the inclusion of anywhere from 50 ppm to 200 ppm BAK as a preservative would be obvious given the use of that range in the commercially available PGA eye drops. Allergan again disputed this. Allergan argued that, even if they included preservative at all, the skilled team would not include more than the minimum level of BAK i.e. 50 ppm. Court said that the inclusion of anywhere from 50 ppm to 200 ppm BAK was an entirely obvious choice. It was common general knowledge that BAK was generally used in the range from 40 ppm to 200 ppm. It was also common general knowledge that BAK was used in the range 50 ppm to 200 ppm in the commercially available PGA eye drops. Furthermore, the skilled team would have no reason to think that the inclusion of 200 ppm BAK in either 0.01% or 0.03% bimatoprost would have any adverse impact on the efficacy of the bimatoprost.

In the alternative, even if it was not obvious to include 200 ppm BAK purely as a preservative, the Defendants contended that it would have been obvious to try to optimise the bioavailability of bimatoprost by using BAK's additional property as a corneal permeation enhancer. This would be particularly useful for the lower doses of bimatoprost, given that Laibovitz indicates that they are not as efficacious as the 0.03% dose. The skilled team would expect that increasing the level of BAK from 50 ppm to 200 ppm would not only be safe and tolerable, but also would be likely to enhance the corneal permeation of bimatoprost, and hence its bioavailability and efficacy. Court agreed with Defendants & held that the inclusion of 200 ppm BAK in the lower doses of bimatoprost in order to increase the bioavailability of bimatoprost was obvious to try when repeating Laibovitz, and the skilled team would have a good expectation of success. Therefore, the Patent is invalid.