Long post follows:
About a month ago, the UK Chancery division patents courts (England and Wales) rendered an opinion (Justice Floyd) regarding claim construction in defining size of particles of an anti-narcoleptic drug, modafinil, in pharmaceutical compositions. The patent court construed patent claims to determine whether there is an infringement, if any.
Facts: The dispute involves three patents related to the drug modafinil, used to treat sleep disorders such as narcolepsy. Orchid Europe is the manufacturer of generic modafinil and Mylan intended to manufacture the drug in UK. Cephalon is the proprietor, an exclusive licensee in the UK and a sub-licensee of the patents involved (European Patents (UK) Numbers 0 731 698 (“698”), 0 966 962 (“962”) and 1 088 549 (“549”)). These patents contain a very similar disclosure with differentiated claims, and they all claim a priority date of 6th October 1994.
Mylan denied infringement and challenged the validity of all three Cephalon patents on the grounds of lack of inventive step and insufficiency.
Background: Modafinil, the active substance, was discovered and developed by a French company, Lafon. Cephalon licensed modafinil in the USA in 1994 and conducted further tests on it to bring it to the market as an agent to treat sleep disorders. In the course of the tests in the US, modafinil caused more side effects than in Europe in corresponding trials involving equivalent doses. The cause was traced to smaller particle size of the input active pharmaceutical ingredient (“API”) of the lots used in the US trials.
In the first human trials performed on non-commercial samples of modafinil (“early lots”), the median particle size diameter was between 80 and 150 µm. The studies in US involved “late lots”, revealed unanticipated side effects at doses of 800 mg per day. These late lots employed a particle size of 30 to 50 µm. This led the patentee to conclude that the late lots could be more readily absorbed than the early lots, and therefore leading to an increased plasma concentration (increased bioavailability) of modafinil.
Claims: Each patent claimed different formulations of modafinil, with different particle sizes. The relevant portions of the first independent claims of each patent are reproduced below.
….comprising …. modafinil particles, wherein at least about 95% of the cumulative total of modafinil particles in said composition have a diameter of less than about 200 micrometers (µm).
…. comprising modafinil particles having a median particle size of about 2 to about 60 µm…
… wherein at least about 95% of the cumulative total of said modafinil particles in said composition have a diameter of less than about 200 µm and wherein the median particle size is about 10 to 60 µm.
Issue: “Whether the claims were referring to the particle size within the composition (Cephalon’s contention) or whether they were referring to the particle size in the active ingredient used to make the composition (Mylan’s contention).” Additionally, during the tabletting process, the size of the particles in the final finished tablet differed from that in the API from which the tablets are made. Therefore, the sizes of the particles in the API did not correspond to the size of the particles in the finished tablets, and vice versa.
Claim construction and analysis: In the claim construction, both sides pointed to claim language that supported their particular construction. For example, Cephalon pointed to the ‘698 patent, which claimed ‘compositions comprising’ modafinil particles and hence referring to the size of the particles in the final tablets. Mylan pointed to the claims in the ‘962 patent for use of ‘modafinil particles …at least about 95% of the cumulative total of said particles have a diameter of less than about 200 micrometers for the manufacture of a pharmaceutical composition …” and hence points to the particle size in the input API, as it is used in the manufacturing process.
Several industry practices were listed to aid in the interpretation of claims, one of which was, “[A] general practice in the pharmaceutical industry was not to measure particle size in a solid formulation, but to make measurements on the input API.”
Conclusion: Based on the common knowledge, the Judge concluded that the patentee must have meant particle size to be measured on the bulk API. “Particle size is never measured in the dosage form, and the skilled person would not know how to do so.” Although it routine industry practice to measure the particle size of API, the particle size in finished tablets could not have been measured at the priority date of the patents (1994). Additionally, particle size of the API has a direct correlation with bioavailability in the final tablet.
Therefore contentions of Mylan were accepted.
Infringement: Both parties agreed that if Mylan’s construction of the claims was the correct one, there was no infringement.
Obviousness: Mylan contended that the patents were invalid in view of prior publications, ‘Drugs of the future, and Nguyen, a PCT application applied for by Lafon.
On the basis of ‘common general knowledge’ and the knowledge of the relationship between lower particle size and improved plasma concentration or bioavailability, it was held that it would be routine to investigate the particle size to improve the bioavailability of a compound, with the expectation that this investigation would be fruitful. Hence Cephalon patents were obvious in view of the first publication. As regards the Nguyen publication, no dosage for modafinil specified but it did provide a formulation with a particle size of 2–5 µm. J. Floyd rejected the contention that it would require significant experimentation/investment to the results of Nguyen to reach an appropriate dosage for modafinil.
“The skilled person is entitled to implement a disclosure in a technically obvious way, even if doing so might not appear commercially attractive. Had I not come to the conclusions I had already reached in relation to obviousness, I would have required the claims to be limited so as to avoid the attack.”
Significance to Indian scenario:
Shamnad, in a previous post, referred to a need for having broad guidelines for defining ‘efficacy.’ In that post, the question was whether increased bioavailability would constitute as a significant enhancement in efficacy. If this case was decided under the Indian law, increased bioavailability and (therefore efficacy) would have been the argument to counter a 3(d) opposition and it would have overcome the challenge. This case therefore highlights when the patent office should undertake the 3(d) analysis: Only when the basic issues (inventive and non-obvious) should the Controller decide the issue of patentability under section 3(d). This case also highlights whether it makes sense to equate bioavailability to efficacy. The exclusionary test may perhaps make more sense in such a scenario for formulation applications like the one described here.