Patent watch

Label warnings and patent infringement

The US Court of Appeals for the Federal Circuit (CAFC) has issued an injunction that prevents generics manufacturer Apotex from launching a generic version of AstraZeneca's Pulmicort Respules (budesonide inhalation suspension) in the United States. At the heart of the case was whether inclusion of a compulsory safety warning on the label of the proposed generic product meant that this otherwise non-infringing product now infringes on the patents for AstraZeneca's drug.

AstraZeneca's owns two US patents (US 6,598,603 and US 6,899,099) that protect Pulmicort Respules (the so-called 'respule' is a vial containing a single dose of budesonide suspended in a sterile liquid, which is administered using a nebulizer), an anti-inflammatory corticosteroid used in the maintenance treatment of asthma. The patents describe a method of treating asthma that involves administering budesonide using “not more than one daily dose.”

Corticosteroids can affect the hypothalamic–pituitary–adrenal axis. The label of Pulmicort Respules — which are available as 0.25mg, 0.5 mg and 1 mg dosage forms — carries a warning that patients should “titrate the dose downwards” to the lowest effective dose of the medication to avoid any adverse effects from excessive use. Indeed, the US Food and Drug Administration (FDA) requires that all inhaled corticosteroids include this language on the drug label.

Apotex sought regulatory approval to sell a generic version of budesonide for twice-daily administration, a method of use that was not claimed in either the '603 or '099 patents. Moreover, its proposed label for generic budesonide would contain no explicit mention of once-daily administration, in order not to infringe AstraZeneca's patents. However, the proposed label had to retain the FDA-mandated downward-titration language.

So, even though the label of generic budesonide would contain no mention of the once-daily dosing, the CAFC had to decide whether inclusion of the FDA-mandated warning could mean that the dosing regimen might be altered in such a way that the generic product might be administered once daily, which would infringe AstraZeneca's patents.

Apotex asserted that the generic's label would not instruct users to titrate down from a specific starting dose; instead, the label would contain a general recommendation of dose reduction that is applicable to any dosing regimen. But the Court decided that the language on the label would inevitably lead to some consumers to perform the patented method of once-daily dosing. As highlighted in earlier court proceedings, this was because the lowest available dosage form of the Apotex's product was 0.25mg of drug in a 2 ml vial. So, because there was no way of decreasing the amount of each dose below 0.25 mg (opened vials cannot be stored), the downward-titration language would necessarily lead patients to use a 0.25 mg vial of the drug once daily.

Apotex argued that they faced a dilemma: either to comply with the FDA and face patent infringement, or to remove the titration wording, which would result in their generic not receiving regulatory approval. But the Court disagreed; the path they should have taken was to wait until the '603 and '099 patents expire (in 2018).

The case now proceeds to trial, with the injunction preventing Apotex marketing its generic product in the meantime.

AstraZeneca versus Apotex

Sanofi–Aventis and BMS awarded US$442m in Plavix case

Apotex is counting the cost of an 'at risk' launch after Sanofi–Aventis and Bristol-Myers Squibb (BMS) were awarded $442,209,362 in damages as a result of prevailing over the generics company in the long-running patent dispute over the antithrombotic Plavix (clopidogrel bisulphate).

The case began in 2001, when Apotex filed an application with the FDA to market its own version of the product, alleging that the Plavix patent (US 4,847,265) was invalid, largely because they felt that that separating enantiomers of a previously disclosed racemic compound was obvious. This triggered a court case, and although a controversial agreement between Sanofi–Aventis/BMS and Apotex to delay the launch of the generic was reached, this fell through. Apotex then proceeded with an at-risk launch, whereby a company launches a generic product in the hope that it will win subsequent patent infringement cases.

However, this strategy did not pay off as the '265 patent was upheld by the CAFC (Nature Rev. Drug Discov. 8, 101; 2009), resulting in the award of damages — which amount to 50% of net sales — and monetary interest in the current hearing.

Sanofi–Aventis Bristol-Myers Squibb holding partnership versus Apotex

Temodar patent reinstated

The CAFC has overturned a ruling by a lower court that had held that the patent protecting Temodar (temozolomide) — used in the treatment of brain cancer — was invalid because of delays in obtaining the patent (Nature Rev. Drug Discov. 9, 184–185; 2010).

In a patent validity dispute involving Barr Pharmaceuticals (now Teva), the district court held that the ∼10-year delay was unreasonable and invalidated the patent. But on appeal, the CAFC said that one thing was missing from the district court analysis — in addition to unreasonable delay there must be a finding of “prejudice” — that is, Teva must have suffered harm attributable to the delay. Because Teva's application to market was filed more than 13 years after the issuance of the patent and more than 7 years after approval of Temodar, coupled with the lack of evidence that the delay had deterred anyone from entering the market for temozolomide, the Court held that the delay had only limited consequences to Teva and the public. So the patent was held valid.

However, the implications of this case might be limited, as there is now more incentive for inventors not to delay in obtaining a patent following the adoption of the World Trade Organization Trade-Related Aspects of Intellectual Property Rights (TRIPS) agreement in 1995, in which patent terms are now measured from the effective filing date.

Cancer Research Technology and Schering Corporation versus Barr Pharmaceuticals

Patent advisors

Daniel M. Becker: Dechert, Mountain View, CA, USA.

Luke Kempton: Wragge & Co., London, UK.

Leslie Meyer-Leon: Bromberg & Sunstein, Boston, MA, USA.

George W. Schlich: Schlich & Co., London, UK.

John A. Tessensohn: Shusaku Yamamoto, Osaka, Japan.

Philip Webber: Frank B. Dehn & Co., London, UK.

Translocator protein (18 kDa) ligands

The translocator protein (18 kDa) (TSPO; previously known as the peripheral-type benzodiazepine receptor and the mitochondrial benzodiazepine receptor) is a five transmembrane domain protein that is localized primarily in the outer mitochondrial membrane and is expressed predominantly in steroid-synthesizing tissues. TSPO is a biomarker of brain inflammation and reactive gliosis that are associated with various neuropathologies, and so various TSPO ligands have been developed as neuroimaging agents. The potential of TSPO ligands as therapeutic agents is beginning to be explored following the discovery of TSPO ligands with in vivo efficacy in models of neurodegeneration and in anxiety. In their Review on page 971, Rupprecht and colleagues describe the biology and pathophysiology of TSPO as a target in the nervous system and discuss the properties of the available TSPO ligands, with the aim of providing a basis for future discussions on the development of TSPO ligands for the diagnosis and treatment of neurological and psychiatric disorders. Here in Table 1, we summarize patent applications published in the past year related to TSPO ligands. Data were researched using the SureChem database from Macmillan Publishers.

Table 1 Recent patent applications related to translocator protein (18 kDa) (TSPO)