“[0009] Significantly, applicants' clinical studies also reveal that an effective product having a reduced tendency to cause flushing in susceptible individuals can be provided. Most unexpectedly, the product also can be administered with clinically insignificant side effects associated with the combined effects of a PDE5 inhibitor and an organic nitrate. Thus, the contraindication once believed necessary for a product containing a PDE5 inhibitor is unnecessary when Compound (I) is administered as a unit dose of about 1 to about 20 mg, as disclosed herein. Thus, the present invention discloses an effective therapy for sexual dysfunction in individuals who previously were untreatable or suffered from unacceptable side effects, including individuals having cardiovascular disease, such as in individuals requiring nitrate therapy, having suffered a myocardial infarction more than three months before the onset of sexual dysfunction therapy, and suffering from class 1 congestive heart failure, or individuals suffering from vision abnormalities. [0010] The present invention relates to Compound (I) in a unit dosage form.
“The package insert also provides instructions to administer one or more 1 to 20 mg dosage forms as needed up to a total dose of 20 mg per day. Preferably, the dose administered is 5 to 20 mg/day; more preferably 5 to 15 mg; and most preferably a 10 mg dose form administered once per day, as needed.”
“One such inhibitor, (6R-trans) -6- (1, 3-benzodioxol-5yl) - 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.” contraindications and warnings in certain patients.”
“Fused rings. In simple cases the relative stereochemistry of substituted fused-ring systems can be designated by the methods used for monocycles. For the absolute stereochemistry of optically active and racemic compounds the sequence-rule procedure can be used in all cases (see Rule E-4.9 and Appendix 2); for relative configurations.”
"E-3.1. Steric relations at saturated bridgeheads common to two rings are denoted by cis or trans. followed by a hyphen and placed before the name of the ring system, according to the relative positions of the exocyclic atoms or groups attached to the bridgeheads. Such rings are said to be cis-fused or trans-fused."
“123. Where a priority document discloses a numerical range from which the patent claims a sub-range, the appropriate forensic question is whether the sub-range is a novel one. If it is not, then it merely forms part of the disclosure of the priority document, and the claim to the sub-range is entitled to priority.”
“The principle applicable to purpose limited medical use claims must be that the material relied on to establish plausibility must be both sufficiently specific, and have a sufficient breadth of application, to fairly support the claim both in terms of the nature of the agent claimed to have an effect, and in terms of the effect claimed.”
“31. Accordingly on the basis of Eisai alone we would hold that Swiss form claims are allowable where the novelty is conferred by a new dosage regime or other form of administration of a substance. 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 nearlyalways such dosage regimes will be obvious – it isstandard practice to investigate appropriate dosageregimes. 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.”
“… the motive for defending these patents is straightforward. It is to recover in respect of and provide the incentive for the expensive and uncertain research programmes that are entailed in getting a drug to market for the benefit of patients. There is, … far, far more involved in getting a safe and efficacious drug to the patient than just finding the molecule. And in that lengthy and costly process there is every reason to reward the results of that research and development programme.”
“When Mr Thorley was asked what policy reason there should be for on the one hand allowing Swiss form second medical treatment claims for different diseases but not allowing them for the same disease, the only answer he could devise was that the treatment might cost more. Why, he said, should you have to pay morefor a 1mg pill than for an out of patent 5mg pill? Thereason is obvious – the 1mg pill has only come aboutbecause of expensive unpredictable research. Patentedthings often cost more. And the reason is because themonopoly has been given as result of the researchwhich led to it. Research into new and better dosageregimes is clearly desirable – and there is simply nopolicy reason why, if a novel non-obvious regime isinvented, there should not be an appropriate patentreward. Such a reward cannot extend to covering the actual treatment but a Swiss form claim which specifies the new, inventive, regime is entirely in accordance with policy.”
“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. Mr Thorley submitted that one had to distinguish between experiments which were conducted in order to make an informed decision as to what to do, and experiments which are conducted only because it is believed that they will produce the desired end result. The former type could be obvious experiments to do, notwithstanding that they were performed without any prior knowledge of the result, or whether the result would predict a successful outcome of the whole project. There was an independent motive for driving the project forward, namely to find out whether a solution to the problem was possible. 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. Thus to return for a moment to the facts of this case, both sides are agreed that there is nothing per se inventive in embarking on in vitro pre-formulation testing to determine the physicochemical characteristics of the API. 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. 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.”
“The question of obviousness must be considered on the facts of each case. The court must consider the weight to be attached to any particular factor in the light of all the relevant circumstances. These may include such matters as the motive to find a solution to the problem the patent addresses, the number and extent of the possible avenues of research, the effort involved in pursuing them and the expectation of success.”
“Taking [the pharmacokinetic data] into account, the skilled clinician would have counselled the skilled team that a 50mg dose would be the best targeted starting dose to assess safety, tolerability and efficacy. The skilled clinician would discount the 100mg, due to its unfavourable side effect profile (100% occurrences of musculoskeletal pain and myalgia are not clinically acceptable). The skilled clinician would not select a dose as low as 10 mg because as compared to the 10 mg doses the 50mg dose demonstrated significantly higher drug concentrations, making efficacy more likely. Also, based on this study, the 50mg dose appears to have an equivalent (and in some cases more favourable) side effect profile than the 10mg dose.”
“Q. And so what I am suggesting to you, these three factors that the skilled person would positively know about would lead the skilled person to know that there may be other factors that could go one way or the other, but as a starting point on your approach a skilled person without any efficacy data at all would believe that rough and ready the 25 mg of sildenafil should equate to about a 5 mg of tadalafil. A. Using these criteria only as a paper exercise, yes. Q. One thing we can say for sure is that he would certainly predict doses below 20 mg would be efficacious. Yes? A. Yes.”
“56. The principle I derive from these authorities is that the question the court is asking in every case is whether, viewed in all the relevant circumstances, there was a sufficiently strong probability that an injunction would be required to prevent the harm to the claimant to justify bringing the proceedings. In adding the word sufficiently to the word strong I do not mean to put a gloss on the words of Chadwick LJ [in Lloyd vSymonds[1998] EWCA Civ 511 ], rather I am seeking to encapsulate the idea that the degree of probability required will vary from case to case depending on all the circumstances but that mere possibilities are never enough. To justify coming to court requires there to be a concrete, strong and tangible risk that an injunction is required in order to do justice in all the circumstances. 57. If a defendant really does, at the date of the proceedings, have no intention to do the act then in the majority of cases that will be conclusive of the question whether there was a sufficiently strong probability to justify proceedings. (e.g. London Borough of Islington). However it seems to me that the question is not confined to the defendant's subjective intentions. A defendant's overt acts must be capable of being relevant. To take an extreme case, if a man began taking actual preparatory steps to commit some unlawful act seriously damaging to the claimant and in infringement of the claimant's rights and did so in full view of the claimant and well aware that the claimant could see them, he could hardly complain if the claimant started proceedings and the court decided to grant a final injunction to prevent it. A statement at trial that he had never intended to go through with it would get short shrift. 58. I bear in mind that intentions are not necessarily simple. A state of mind need not merely be either one thing or another. Also in this case the defendants are corporate entities to whom an intention can only be imputed.”
“[0005] The poor solubility of many β-carboline compounds useful as PDE5 inhibitors prompted the development of coprecipitate preparations, as disclosed in PCT publication WO 96/38131 and Butler U.S. Patent No. 5,985,326. Briefly, coprecipitates of a βcarboline with polymeric hydroxypropylmethylcellulose phthalate, for example, were prepared, milled, mixed with excipients, and compressed into tablets for oral administration. Studies revealed, however, that difficulties arose in generating precisely reproducible lots of coprecipitate product, which makes use of coprecipitates less than ideal in pharmaceutical formulations. [0006] Additionally, clinical studies involving administration of coprecipitate tablets preliminarily revealed that maximum blood concentration of the βcarboline compound is achieved in 3 to 4 hours, with the average time for onset of therapeutic effect not yet precisely determined. In the treatment of sexual dysfunction, such as male erectile dysfunction or female sexual arousal disorder, however, a more rapid achievement of maximum blood concentration, along with a greater prospect for rapid onset of therapeutic effect, frequently is sought by individuals desiring more immediate and/or less prolonged effects. Accordingly, a need in the art continues to exist for orally administrable β-carboline compounds and β-carbolinecontaining pharmaceutical compositions having an ability to provide a therapeutic effect within a desirable, or at least acceptable, time frame.”
“The specific dose of [tadalafil] administered according to this invention is, of course, determined by the particular circumstances surrounding the case including, for example, the route of administration, the state of being of the patient, and the pathological condition being treated. A typical daily dose contains a nontoxic dosage level from about 1 to about 20 mg/day of [tadalafil]. Preferred daily doses generally are about 1 to about 20 mg/day, particularly 5 mg, 10 mg, and 20 mg tablets, administered as needed.”
“The specific doses of a compound administered according to this invention will, of course, be determined by the particular circumstances surrounding the case including, for example, the compound administered, the route of administration, the state of being of the patient, and the pathological condition being treated. A typical daily dose will contain a nontoxic dosage level from about 1 to 20 mg/day of a particulate compound of the present invention. Preferred daily doses generally will be from about 1 to 10 mg/day, particularly of 5mg and 10mg tablets, administered once per day.”
“But the infringement must be not merely a possible or even likely consequence of performing the invention disclosed by the prior disclosure. It must be necessarily entailed. If there is more than one possible consequence, one cannot say that performing the disclosed invention will infringe. The flag has not been planted on the patented invention, although a person performing the invention disclosed by the prior art may carry it there by accident or (if he is aware of the patented invention) by design. Indeed, it may be obvious to do so. But the prior disclosure must be construed as it would have been understood by the skilled person at the date of the disclosure and not in the light of the subsequent patent.”
“104 I can therefore turn to the case on inevitable result. As I have said, in relation to this issue experiments were performed. This has produced a very large amount of evidence. Inhale has identified every single difference between the description of the process and apparatus in [the prior art] and that used in Quadrant's experiments and argues that the latter are neither a repetition of [the prior art] nor do they prove that a product within the claims of the patent would inevitably be made. Each of the points taken by Inhale has been addressed by Quadrant. However, it is not necessary to go through each of them because, for the reasons set out in the last preceding paragraph, it has not been proved that repetition of the teaching in the document would inevitably have produced something with a Tg above 20°C . Once again, it is overwhelmingly likely that such a Tg would have been achieved, but that is not enough for the purpose of anticipation.”
“85. Is that finding good enough for an inevitable result? The legal requirement is that this feature of the claim be the inevitable result of carrying out the prior teaching. Does that mean that if there is some other possibility, even a fairly remote one, that some other result would follow, I should conclude the result is not inevitable? Or am I concerned to establish what, on the balance of probabilities would in fact occur? In my judgment, it is the latter approach which is correct. The inevitable result test does not require proof of individual facts to a quasi-criminal standard. It may be impossible to establish the relevant technical facts to that standard. It is another matter if the evidence establishes that sometimes one result will follow and sometimes another, depending on what conditions are used. But there is nothing of that kind suggested here. It is simply a question of what occurs in fact.”
“I consider it highly likely that the formulation accordingly to Example 1 of Oren (which contains tadalafil with a d90 particle size of 4 µm) would exhibit Cmax and AUC values with the ranges […] stated by claims 8 and 9.”
“I mention a conventional formulation. I cannot imagine this kind of formulation without a surfactant in it.”
"Mere possible inclusion of something within a research programme on the basis you will find out more and something might turn up is not enough. If it were otherwise there would be few inventions which were patentable. The only research which would be worthwhile (because of the prospect of protection) would be in areas totally devoid of prospect."