INNsight articles by Duncan Curley

OxyContin® is the big-selling controlled release formulation of oxycodone, a second line opioid to morphine in the management of pain and palliative care.  Oxycodone itself is an old drug that was first developed in Germany in the early 20th century.   There has already been extensive litigation on various patents relating to the controlled release form of oxycodone in the USA, involving Endo Pharmaceuticals, Teva, IMPAX and Mallinckrodt.  In Europe, OxyContin® is manufactured by Napp, the owner of European Patent Nos. 0,722,730 B1 and 1,258,246 B1 (“Controlled release oxycodone compositions”).

In the UK, ratiopharm and Sandoz applied for declarations of non-infringement in respect of tablets of oxycodone which contain small particles made up of a number of layers (supplied to the generic companies by Cimex).  The core of these particles is made from sugar crystals.  There is then an inner layer of made up of oxycodone hydrochloride (83% wt), hydroxypropylmethyl cellulose (HPMC, about 8% wt) and talc/macrogol (about 9% wt).  A further polymer layer contains ethyl cellulose, hydroxypropylcellulose and propylene glycol.  The polymer layer controls the release of the oxycodone hydrochloride in the inner layer.  A further outermost layer contains about 96% wt oxycodone hydrochloride and about 4% wt HPMC.  About 20% of the total weight of oxycodone hydrochloride is in the outermost layer. 

Napp responded to the applications for declarations of non-infringement with claims for patent infringement against both parties.   Judgment was given by Floyd, J. in December 2008.  The interesting part of the case was the Judge’s approach to infringement and his determination of what the claims meant (claim construction).   English law used to have a complicated formula for working out the meaning of patent claims, but the approach was simplified in 2004 when the House of Lords held that the task of the Court was to construe patent claims purposively, in each case by determining what the person skilled in the art would have understood the patentee to have been using the language of the claim to mean.

Two of the pertinent claims in the case were as follows:

Claim 1 of ‘246

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;
(d) wherein said dosage form has an in vitro dissolution rate, when measured by the USP Paddle Method at 100 rpm in 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37 °C, between 12.5% and 42.5% (by weight) oxycodone salt released after 1 hour, between 25% and 55% (by weight) oxycodone salt released after 2 hours, between 45% and 75% (by weight) oxycodone salt released after 4 hours and between 55% and 85% (by weight) oxycodone salt released after 6 hours.

Claim 6 of ‘730

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; and
(b) each spheroid being coated with a film coating which controls the release of oxycodone or oxycodone salt at a controlled rate in an aqueous medium. 

It can be seen that the patents relate to similar subject matter, because ‘246 was divided out of ‘730 during the application phase at the European Patent Office. 

Considering first Claim 1 of ‘246, it will be recalled that the Cimex product has particles which consist of an external, outermost layer containing approximately 20% of the oxycodone in the drug which is released immediately (the remaining 80% being controlled by the polymer layer).   Napp claimed however that provided the quantity of oxycodone within the matrix was within the range specified in part (a) of the claim, there would be infringement, i.e. even if there was more oxycodone on the outside.   The Judge disagreed, holding that the oxycodone dosage defined in part (a) of the claim was the total amount of oxycodone in the formulation.  The requirement of part (b) was that the matrix should incorporate all of the oxycodone in the dose.   Similarly, the requirement of part (c) (concerning the “coating on said matrix”) meant that the coating covered all of the oxycodone in the formulation.    The Judge thus held that the skilled person would not conclude that the patentee was seeking to include formulations where a significant part of the oxycodone was outside the film coating. 

Considering Claim 6 of ‘730, the Judge held that there was relevant information in the patent itself on the meaning of “spheronising agent”.  The patent stated that “the spheronisation agent may be any pharmaceutically acceptable material that, together with the active ingredient, can be spheronised to form spheroids”.  Napp argued for a wide construction of “spheronising agent”, suggesting that it meant anything that would assist in the process of making a spheroid.   This included the HPMC in the inner layer of the Cimex product.  The generic companies argued that the term must refer to materials that are incorporated into the formulation in order to give the material the correct degree of plasticity in a spheronisation process.  The Judge held that the term could not apply to materials that are added once the sphere has already been formed.  If Napp’s construction was correct, the claim would extend to a whole host of materials that the skilled person would “never dream” of calling spheronising agents.  
  
The Judge concluded that neither Claim 1 of ‘246 or Claim 6 of ‘730 was infringed.   The claim for infringement brought by Napp therefore failed.  In a subsidiary part of the case concerned with validity (and presumably to protect themselves in case they lost on infringement), ratiopharm and Sandoz applied to revoke both patents on the grounds of obviousness and added matter.  In the event, the Judge upheld the validity of both patents (in the case of ‘246, with amendments).