“[0024] The presently claimed dosage form preferably is packaged as an article of manufacture for human pharmaceutical use, comprising a package insert, a container, and a dosage form comprising about 1 to about 5 mg of Compound (I) [tadalafil]. [0025] The package insert provides a description of how to administer a pharmaceutical product, along with the safety and efficacy data required to allow the physician, pharmacist, and patient to make an informed decision regarding the use of the product. The package insert generally is regarded as the label of the pharmaceutical product. The package insert incorporated into the article of manufacture indicates that Compound (I) is useful in the treatment of conditions wherein inhibition of PDE 5 is desired. The package insert also provides instructions to administer one or more about 1 to about 5 mg unit dosage forms as needed, up to a maximum total dose of 5 mg per day.”
“135. I will approach the matter of construction focussing on claim 7 or 10 since they include the clinical indication. For this purpose the focus is not on the part of the claim concerned with how much drug is in the tablet, it is on dosing. Subject to the word “maximum”, a skilled reader would understand that what the inventor was using the words of those claims to mean is that the invention is concerned with treating sexual dysfunction by administering a dose of no more than 5mg tadalafil per day to a patient. Doing this provides the efficacy with minimal side effects provided for in the patent. Again subject to the word “maximum”, the skilled reader would not think the inventors intended to exclude the idea that higher doses of tadalafil could be administered to patients if the doctor (and clinical regulators) regarded the balance of efficacy and side effects to be acceptable. Those higher doses would just not be taking advantage of the invention. So marketing authorisation documents from the regulators which approved doses of 2.5 mg per day or 5mg per day as well as 10 mg per day would not mean that a use in accordance with the invention had not been approved by the regulator. On the contrary. It would have been. Both a dose of 2.5 mg per day and a dose of 5 mg per day would take advantage of the discovery presented by the patent. 136. What then of the word “maximum”? The phrase in both claims is “administration up to a maximum total dose of 5mg […] per day”
“The package insert is generally regarded as the label of the pharmaceutical product. The package insert incorporated into the present article of manufacture indicates that the PDE5 inhibitor is useful to treat conditions wherein the inhibition of PDE5 is desired. The package insert also provides instructions to administer one or more 1 to 20mg dosage forms as needed up to a total dose of 20 mg per day. Preferably, the dose administered is 5 to 20mg/day; more preferably 5 to 15mg; and most preferably a 10mg dose form administered once per day, as needed.”
“One such inhibitor, (6R-trans) -6- (1, 3-benzodioxol-5-yl) - 2, 3, 4, 7, 12, 12a - hexahydro-2-methyl-pyrazino [1’,2’:1,6]pyrido [3,4-b] indole-1,4-dione, was demonstrated in human clinical studies to have minimal impact on systolic blood pressure when administered in conjunction with nitrates. By contrast, sildenafil demonstrates a 4 fold greater decrease in systolic blood pressure over placebo, which leads to the contraindications and warnings in certain patients.”
“229. The combination of tadalafil as one of the drugs to which the teaching relates, the content of the dosage forms (15mg drug) and the maximum total dose of 5mg per day are disclosed in the priority document. Based on the general teaching, the reader would understand that what is disclosed is that at all the doses described (including 5mg per day and also up to 20mg per day) the drug will be an efficacious treatment for sexual dysfunction, will have minimal side effects (including vision and flushing) and can be administered without significant interactions with nitrates. The fact that the document is focussed on a wider idea of finding selective PDE5 inhibitors defined by the three criteria does not mean that the more particular disclosures relating to tadalafil are absent.”
“234. Claims 7 and 10 (and the other use claims) are specific to using tadalafil to treat sexual dysfunction. The priority document makes what is claimed plausible because the document provides data showing that tadalafil (Compound 4) is a PDE5 inhibitor and since, as the skilled reader would know but the document explains anyway, sildenafil works to treat this disease by being a PDE5 inhibitor, the basic effect is plausible. The idea that tadalafil would produce efficacy at the doses claimed with minimal side effects is also plausible because the document expressly discloses the doses, sets out a rationale that this effect is due to being a “selective PDE5 inhibitor” based on the three criteria, and explains that tadalafil is a selective PDE5 inhibitor. The claimants did not suggest that the rationale was not credible. The rationale is also supported by Examples 4 and 5. Although Example 5 is not clearly tadalafil, it nevertheless supports the teaching that a selective PDE5 inhibitor based on the three criteria would have the desired effect. If one compound with the desired property does this then it is credible that another will, albeit no doubt tests will be needed. Example 4 supports the general rationale albeit since it is for 10mg tadalafil rather than a 5 mg dose it cannot directly support the claims. Overall in my judgment the use claims are supported by what is disclosed in the priority document and so all the claims (bar claims 2 and 12) maintain priority.”
“The package insert also provides instructions to administer one or more 1 to 20mg dosage forms as needed up to a total dose of 20mg per day. Preferably, the dose administered is 5 to 20mg/day; more preferably 5 to 15mg; and most preferably 10mg dosage form administered once per day, as needed.”
“254. However Stoner is not concerned with monotherapy, it teaches the use of a combination of the two kinds of drug. Dr Brock’s evidence was that the combination with the centrally acting agents drug made a significant difference. He thought the synergistic therapy discussed in Stoner was problematic and said in cross-examination that “all bets are off”
“327. Weighing all this up, the results of the Phase IIb study would require the team to make value judgments. It is not inevitable that a skilled team would investigate lower doses given the plateau in the results of the Phase IIb study, because by identifying a dose (at least 25 mg) which is safe, tolerable and effective they have secured the prime objective of the programme, but it is very likely. Such an investigation would not be quite as routine for the skilled team as the work which has gone before but that cannot be taken too far. Multiple dose ranging studies in general terms are something the skilled team would be familiar with as necessary.”
“335. In other words the skilled team testing a 5mg per day dose of tadalafil (on demand) when carrying out these investigations would not have a reasonable expectation that the drug at this dose would be a useful treatment for erectile dysfunction nor any expectation at all that the drug would produce a clinically relevant effect but with minimal side effects. 336. A skilled team which carried out a dose ranging study including a 5mg dose would discover that this dose was efficacious and had reduced side effects. They would be surprised by this. The team would go ahead to do Phase III studies at 5mg/day and seek clinical approval for a 5mg/day dose of tadalafil.”
“341. The initial Phase IIb dose ranging study which was for daily dosing would probably include a 10mg dose as an additional arm owing to the accumulation factor. It would not include a dose lower than 10mg/day. The team would expect to see a dose response but would see the same plateau in efficacy down to 10 mg and dose response for side effects as discussed already. All the reasoning I have considered above would be the same. Assuming the team decided to conduct an investigation into lower doses in a second, daily dosed, dose ranging study including a 5mg/day dose of tadalafil, they would not have a reasonable expectation that the drug at this dose would be a useful treatment for erectile dysfunction nor any expectation that the drug would produce a clinically relevant effect but with minimal side effects. They would find that it did. They would be surprised.”
“343. However in my judgment a 5mg daily dose of tadalafil as a treatment for erectile dysfunction is not obvious over Daugan. That is for the following reasons articulated having regard to the factors I identified above based in part on Lundbeck: i) In terms of motives to find a solution to the problem the patent addresses, the skilled team would be highly motivated by Daugan and the success of sildenafil to investigate tadalafil as a treatment for erectile dysfunction. ii) As for possible avenues of research, overall tadalafil would be obvious to investigate. In terms of doses however, 5 mg/day is a significantly lower dose than the 50 mg dose exemplified in the Daugan prior art and the marketed doses of sildenafil. It is also significantly lower than the 50 mg dose which would be chosen for the first test of efficacy at Phase IIa. It would not be chosen in the routine first dose ranging study. The team would not have anticipated daily dosing as something to be studied from the outset but once the half-life was discovered it is likely that daily dosing would be included. iii) In terms of effort, overall the programme would involve very substantial resources of time, money and people but it would be pursued. However, by the time the idea of investigating lower doses presents itself, the team would have established safe, tolerable and effective doses of tadalafil at 25mg on demand and 10 mg for daily dosing. At that stage the impetus to investigate lower doses would be reduced but not eliminated. iv) Expectations of success can be considered overall and in relation to particular studies. Overall the team would embark on the project with a reasonable expectation of success in establishing tadalafil as a safe, tolerable and effective treatment for tadalafil. However, the claimants failed to prove that efficacy at 5mg tadalafil was predictable or worth considering by the skilled team based on the properties of tadalafil as compared to sildenafil. The team would know that in principle there would be a minimum effective dose for tadalafil but would also know that its definition depends on a value judgment made by the team. In relation to the dose ranging studies, the team would conduct them hoping for a dose response. Following discovery of a plateau starting at 25 mg or 10mg, there would very likely be a subsequent dose ranging study which included 5 mg. The team would include a 5 mg dose in this study hoping to see a dose response but that does not mean they would have a reasonable expectation that 5mg would produce a clinically relevant effect at all nor one with minimal side effects. Assuming a 5 mg /day dose of tadalafil was tested, it would not be tested with a reasonable expectation of success. v) Considering unexpected or surprising results, the position is as follows. The path to a 5 mg dose requires the discovery of new information such as the half life and the IC 50 vs PDE6. That information would inevitably be found in any clinical programme. The path includes an important result which is unexpected even if it is not actually surprising, i.e. the plateau in the dose response from 10 to 100 mg. There is also a surprising result: the existence of a useful effect with reduced side effects. The claimed 5mg /day dose has that property. vi) A number of value judgments would be required of a skilled team in a programme which reaches the claimed invention. One is to define the level of clinical effect to be regarded as relevant. Another is to embark on investigating daily dosing. An important value judgment is what to do when an unexpected plateau in the dose response has been identified at the same time as a marketable dose.”
“32. So holding is far from saying that in general just specifying a new dosage regime in a Swiss form claim can give rise to a valid patent. On the contrary, nearly always such dosage regimes will be obvious – it is standard practice to investigate appropriate dosage regimes. Only in an unusual case such as the present (where, see below, treatment for the condition with the substance had ceased to be worth investigating with any dosage regime) could specifying a dosage regime as part of the therapeutic use confer validity on an otherwise invalid claim.”
“55. …. In deciding whether the invention was obvious to the skilled but unimaginative addressee at the priority date the court will have regard to all the circumstances of the case including, where appropriate, whether it was obvious to try a particular route with a reasonable or fair expectation of success. What is a reasonable or fair expectation of success will again depend upon all the circumstances and will vary from case to case. Sometimes, as in Saint Gobain, it may be appropriate to consider whether it is more or less self-evident that what is being tested ought to work. So, as this court explained in that case, simply including something in a research project in the hope that something might turn up is unlikely to be enough. But I reject the submission that the court can only make a finding of obviousness where it is manifest that a test ought to work. That would be to impose a straightjacket upon the assessment of obviousness which is not warranted by the statutory test and would, for example, preclude a finding of obviousness in a case where the results of an entirely routine test are unpredictable.”
“Q: We know we are on the top plateau for efficacy and we know that going lower will reduce the side effects. It is really a no brainer, is it not doctor? A: To go to a lower dose? Q: Yes. A: Yes. In this patient population, yes. Q: Indeed, what we see … in the discussion and overall conclusions: “This study confirms that [tadalafil] is safe, well tolerated, and effective when administered as once-daily therapy for the treatment of mild to moderate MED at doses of 10 to 100mg. The results support further investigation evaluating the safety and efficacy of doses < 10mg, which may identify a broader dose range providing a high degree of efficacy with a minimum of undesirable side effects”
“Q: … As I understand your evidence, you think Dr Pullman [one of the two inventors] did something inventive. Yes? A: Yes. Q: Exactly what was that? A: Thinking that a lower dose will need to be tested before the results came out --- before the results of the 10-100 came out. Q: Oh, so you mean thinking to test lower before you saw that LVBG study? A: Yes. Q: Right, because I think you accept that once they came out you would have gone lower anyway. Yes? A: Yes, based on the report, yes.”
“113. Where, therefore, the evidence reveals that to arrive at the invention, the skilled person has to embark on an experiment or series of experiments where there was no fair expectation of success, the conclusion will generally be that the invention was not obvious. … 114. I think that the guiding principle must be that one has to look at each putative step which the skilled person is required to take and decide whether it was obvious. Even then one has to step back and ask an overall question as to whether the step by step analysis, performed after the event, may not in fact prove to be unrealistic or driven by hindsight. … 115. How one would proceed after purely routine steps have been performed may involve more in the way of a value judgment. The mere fact that further steps can be characterised as being performed in order to make an informed decision cannot prevent those steps from contributing to a finding of inventiveness.”
“I think that Mr Birss is right that one must proceed with caution when faced with an obviousness attack based on a suggestion that the skilled person would embark on a research program in the course of which he would discover that a product or compound was effective. This is particularly so where the technical effect is one which is newly discovered, or impossible or very hard to predict. That is because the expectation of success may be zero, or inadequate to drive the research forward. In the end it will all depend on weighing the various factors as they appear from the evidence in the case.”
“The question of whether an invention was obvious has been called "a kind of jury question" (see Jenkins L.J. in Allmanna Svenska Elektriska A/B v. The Burntisland Shipbuilding Co. Ltd (1952) 69 R.P.C. 63, 70) and should be treated with appropriate respect by an appellate court. It is true that in Benmax v. Austin Motor Co. Ltd [1955] A.C. 370 this House decided that, while the judge's findings of primary fact, particularly if founded upon an assessment of the credibility of witnesses, were virtually unassailable, an appellate court would be more ready to differ from the judge's evaluation of those facts by reference to some legal standard such as negligence or obviousness. In drawing this distinction, however, Viscount Simonds went on to observe, at p. 374, that it was "subject only to the weight which should, as a matter of course, be given to the opinion of the learned judge." The need for appellate caution in reversing the judge's evaluation of the facts is based upon much more solid grounds than professional courtesy. It is because specific findings of fact, even by the most meticulous judge, are inherently an incomplete statement of the impression which was made upon him by the primary evidence. His expressed findings are always surrounded by a penumbra of imprecision as to emphasis, relative weight, minor qualification and nuance (as Renan said, la vérité est dans une nuance), of which time and language do not permit exact expression, but which may play an important part in the judge's overall evaluation. It would in my view be wrong to treat Benmax as authorising or requiring an appellate court to undertake a de novo evaluation of the facts in all cases in which no question of the credibility of witnesses is involved. Where the application of a legal standard such as negligence or obviousness involves no question of principle but is simply a matter of degree, an appellate court should be very cautious in differing from the judge's evaluation.”
“Such tests would be performed in ignorance of the results of the testing and in ignorance of whether any particular formulation strategy would have a fair expectation of success. But they would nevertheless be an obvious thing to do. They are obvious because the evidence shows that the skilled person would do them anyway, as part of his routine work.”