Actavis Group PTC EHF and others (Respondents) v ICOS Corporation and another (Appellants)

Cite as:[2019] UKSC 15
Hand-down Date:March 27, 2019
 
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Hilary Term [2019] UKSC 15 On appeal from: [2017] EWCA Civ 1671

JUDGMENT

Actavis Group PTC EHF and others (Respondents) v ICOS Corporation and another (Appellants) before

Lady Hale, President Lord Kerr Lord Sumption

Lord Hodge Lord Briggs JUDGMENT GIVEN ON 27 March 2019 Heard on 19 and 20 November 2018 Appellants Respondents Andrew Waugh QC

Adrian Speck QC Mark Chacksfield Thomas Jones (Instructed by see below for details) Thomas Mitcheson QC

Katherine Moggridge

(Instructed by Allen & Overy LLP)

Intervener (3)

(written submissions) Myles Jelf Annsley Merelle Ward Alan Johnson (Instructed by Bristows LLP) Intervener (4)

(written submissions) Nicole Jadeja (Instructed by Fieldfisher) Appellants:

(1) ICOS Corporation

(2) Eli Lilly & Company

Respondents:

(1) Actavis Group PTC EHF Pinsent Masons LLP (London)

(2) Actavis UK Ltd Bird & Bird LLP

(3) Teva UK Ltd Pinsent Masons LLP (London)

(4) Teva Pharmaceutical Industries Ltd Pinsent Masons LLP (London) (5) Generics (UK) Ltd (t/a Mylan) Taylor Wessing LLP

Interveners: (written submissions)

(1) Medicines for Europe Pinsent Masons LLP (London)

(2) British Generic Manufacturers Association Pinsent Masons LLP (London)

(3) The IP Federation Bristows LLP

(4) UK BioIndustry Association Fieldfisher

LORD HODGE: (with whom Lady Hale, Lord Kerr, Lord Sumption and Lord Briggs agree)

  1. This appeal concerns the application of the test of obviousness under section 3 of the Patents Act 1977 to a dosage patent. In summary, a patent, whose validity is not challenged, identified a compound as an efficacious treatment but did not identify an optimal dosage regime. A pharmaceutical company, which had acquired the patent, conducted extensive research into ascertaining the optimal dosage of the compound. It discovered a dose which not only was safe and effective but also, unexpectedly, could be administered in a new and beneficial manner, because of both the half-life of the compound and its minimal side effects at that dose. A number of generic drug manufacturers challenge the validity of the dosage patent on the basis that it involves no inventive step.

  2. The appeal raises two principal questions. The first relates to the application of the obviousness test to a dosage patent and the second is concerned with whether the Court of Appeal was entitled to reverse the judgment of the judge at first instance on that question in the circumstances of this case.

    The patent under challenge

  3. The dosage patent which is the subject of this appeal is EP(UK) 1,173,181 ("the 181 patent"). It is owned by ICOS and exclusively licensed to Eli Lilly (collectively "Lilly"). It relates to the use of tadalafil in a dosage form for the treatment of sexual dysfunction. It was filed on 26 April 2000 and claims priority from US application no 60/132036P filed on 30 April 1999. It was granted on 15 October 2003. The form of the 181 patent is a B3 specification following centralised amendments made in the European Patent Office ("EPO") on 25 March 2015.

  4. The claimants, who are the respondents in this appeal, raised proceedings to revoke the 181 patent and Lilly defended the claim and counterclaimed that the claimants were threatening to infringe its patent. The earlier phases of this litigation involved challenges to the 181 patent based on (a) priority, (b) added matter, (c) lack of novelty, (d) obviousness and (e) insufficiency. Of those challenges, the principal matter of contention is obviousness. The claimants' challenges on priority, added matter and lack of novelty arise only if this court upholds the appeal by Lilly against the Court of Appeal's finding of obviousness.

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    Factual background

  5. Erectile dysfunction ("ED") is a common medical condition which affects approximately 50% of the male population between the ages of 40 and 70. It is caused by a number of disorders, both physiological and psychological. Unsurprisingly, the discovery of a drug to treat ED, called sildenafil, which was and is sold under the brand name VIAGRA, proved to be a very great commercial success.

  6. The drug, which is the subject of the patent in dispute, is called tadalafil. Tadalafil is the generic name for a drug which is sold under the brand name CIALIS for the treatment of ED and benign prostatic hyperplasia, and under the brand name ADCIRCA for the treatment of pulmonary arterial hypertension. CIALIS has also enjoyed great commercial success. In 2014 worldwide sales amounted to about $2.29 billion and UK sales amounted to about $99m. In that year UK sales of ADCIRCA amounted to about $1m.

    Technical background

  7. I derive my summary of the technical background from the judgment of Kitchin LJ, who wrote the leading judgment in the Court of Appeal [2017] EWCA Civ 1671; [2018] RPC 7, and the findings of the trial judge, Birss J [2016] EWHC 1955 (Pat).

  8. The penis contains smooth muscle. When in its normal resting state, the smooth muscle contracts and so restricts the arteries supplying blood to the penis. When an erection is triggered, the smooth muscle relaxes and no longer restricts the supply of arterial blood, causing the penis to become tumescent. The smooth muscle relaxation which leads to the erection results from a cascade of complex biochemical reactions within the body. Sexual stimulation causes the release of the neurotransmitter nitric oxide ("NO") which enters the smooth muscle cells where it leads to an increase in the production of a second molecule, cyclic guanosine-3', 5'-monophosphate ("cGMP"). cGMP in turn binds to and activates an enzyme which regulates the activity of other intracellular proteins and leads to the relaxation of the smooth muscle. An increase in the intracellular level of cGMP, through NO production, therefore promotes smooth muscle relaxation, while a decrease in the intracellular level of cGMP tends to cause the smooth muscle to return to its ordinary contracted state.

  9. The intracellular concentrations of cGMP and another second molecule, cyclic adenosine-3',5'-monophosphate ("cAMP"), are regulated by a class of

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    enzymes known as cyclic nucleotide phosphodiesterases ("PDEs"). By the priority date in 1999 at least six PDE families had been identified. It was known that the PDE family most prevalent in the penis was PDE5. This binds cGMP and hydrolyses it to its non-cyclic form GMP, so leading to a reduction in smooth muscle relaxation and the prevention of penile tumescence.

  10. It is necessary to mention also the concept of potency. Potency is the amount of the drug required to produce a defined biological effect of given intensity. Potency can be measured as the concentration or dose of a drug required to produce 50% of the drug's maximal effect (EC50 or ED50) as depicted by a graded doseresponse curve. In the context of a drug that inhibits the action of another substance, potency can be expressed as the concentration of a drug required to inhibit a given biological process by half, ie the in vitro concentration of the drug which is required for 50% inhibition (IC50). A higher potency drug will have a lower concentration because less drug will be required to achieve the same effect. As Kitchin LJ illustrated in paras 17 and 18 of his judgment the dose-response curve of a drug is illustrated graphically as a sigmoid (or S-shaped) curve with a flat or gently inclined base at which increasing doses are slow to manifest a significant effect, a steep central part at which increasing doses have an increasing effect, and a plateau at the top at which increasing doses have no increased effect.

  11. The minimum effective dose is the smallest dose in the dose-response curve at which a clinically relevant effect can be seen. The concept of the minimum effective dose would be known to the skilled team, who would be aware that regulators could ask for it to be identified. But they would also know that it is not always required.

  12. The trial judge found that it had not been established that the skilled team would always seek to identify the minimum effective dose for a given drug. It might be sufficient to know that the minimum effective dose was somewhere in a range. In the context of ED, there was no agreed definition of a minimum clinically relevant effect and this had a bearing on the judge's reasoning in relation to obviousness. Identification of the minimum effective dose depends on a value judgment, as the skilled team would know. The primary task of the skilled team was and is to make safe, tolerable and effective medicines.

    Sildenafil and tadalafil

  13. Sildenafil was marketed as an orally administered PDE5 inhibitor, which prevented PDE5 from hydrolysing cGMP to the inactive GMP. cGMP levels remain elevated as a result and this promotes smooth muscle relaxation. This leads to greater

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    arterial blood flow into the penis when it is stimulated and results in penile tumescence.

  14. A disadvantage of sildenafil was its effect on other PDE families and, in particular, PDE6 which was associated with known visual side effects. Sildenafil was also associated with normally mild and transient side effects including flushing, headache and dyspepsia, which were thought to be related to its mode of action as a PDE5 inhibitor. Sildenafil was known to be administered on demand with an onset of action of about one hour and a half-life of about four hours. It was marketed at doses of 25mg, 50mg and 100mg. It was known that broadly efficacy increased with dose and so did side effects. Those were the doses upon which a skilled team would focus although it was also known that a 10mg dose of sildenafil had been investigated in trials and shown to be efficacious.

  15. Sildenafil was a first in class drug which validated the rationale for trying to treat ED using an oral PDE5 inhibitor. Any other PDE5 inhibitor for ED would be known as a second in class...

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