‘For example, the rate of decrease of Cmax in a fed state was 67% and the rate of decrease of AUC in the fed state was 47%, in comparison with those in a fasted state. In this case, Cmax in the fasted state was three times higher than that in the fed state.’
‘Accordingly, in light of the clinical data, the focus for the inventors was to provide a formulation whereby release is less affected by food but without unduly extending the release beyond a point where food effects will no longer be problematic.’
‘From a PK perspective this could be the convolution of the intravenous (‘iv’) plasma concentration time curve with absorption rate to get the extravascular (‘ev’) concentration time curve. Deconvolution can be used to obtain the absorption rate when only iv and ev concentration time profiles are known.’
‘The term ‘rapid release formulation (conventional formulation)’ as used herein means a formulation in which the dissolution rate of the drug from the formulation is 85% or more after 30 minutes from the beginning [of] a dissolution test…’
‘According to the present invention, a pharmaceutical composition for modified release in which the changes in AUC and Cmax caused by food intake can be decreased by controlling a releasing rate of the active ingredient can be provided.’
‘Finally, and most importantly, over-meticulousness is not to be equated to carefulness. Care in working out what the patentee was aiming at when he chose the words he used is absolutely necessary.’
‘Paragraphs [0105] and [0106] set out a dissolution test using formulations prepared according to Examples 2, 8 and 9 and Comparative Example 1. The dissolution profiles of Examples 2, 8 and 9 meet the definitions of “pharmaceutical composition for modified release” and “formulation in which the effects by food are reduced” and the profile for Comparative Example 1 meets the “conventional release” definition.’
‘57 In some cases the second step is the aspect which is a bit more involved. So in Idenix v Gilead, claim 1 was to a Markush class of molecules (see Kitchin LJ para [61]). The claim language did not include any reference to what they were for and so one could not answer the question at the second step by looking at the words of the claim. This is also not unusual. If the compounds are new, then a claim to those compounds will be novel without including a claim feature which refers to what they are actually for. However that does not prevent the reasonable prediction principle being applied. In fact the answer in Idenix was clear from the patent specification. That showed that the point of the invention was to treat infections caused by viruses in the Flaviviridae family. So one can assess the validity of the claim on the basis that it is a claim to compounds with anti-Flaviviridae activity, which is what Kitchin LJ said at paragraphs [113] and [124]. So, in the language coined above, anti-Flaviviridae activity was a step two functional feature. The issue in Idenix arose in the context of inventive step but the same approach applies to reasonable prediction/plausibility. Note that this does not mean that claims to compounds per se are actually limited to using the compounds for treating Flaviviridae infections, but for the purposes of assessing questions like inventive step and reasonable prediction/plausibility, one needs to know what the compounds are supposed to be useful for. In fact in Idenix the outcome of the third step was against the patentee. The court held that it was not plausible that substantially all the claimed molecules would be effective against Flaviviridae infections, and hence it was Agrevo obvious and also insufficient for lack of plausibility for the same reason (see paragraphs [129] and [140]).’
‘Taking this teaching together, the skilled formulator would understand that the time points in claim 1 (understood in the context of the rest of the formulation claimed) were provided to ensure, firstly that the formulation was not an immediate release formulation (by reference to the dissolution requirement at 1.5 hours), secondly, that there was continuous release including some release beyond the stomach (by reference to both dissolution requirements and in light of the gradual and continuous nature of release that would be provided by the claimed excipients), but thirdly, that release wasn’t too extended beyond the upper GI tract - i.e. into the colon (by reference to the dissolution requirement at 7 hours).’
“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.”
“First, it is relevant to consider whether at the priority date something was “obvious to try”, in other words whether it was obvious to undertake a specific piece of research which had a reasonable or fair prospect of success: Conor v Angiotech (above) para 42 per Lord Hoffmann; MedImmune Ltd v Novartis Pharmaceuticals UK Ltd[2012] EWCA Civ 1234 ;[2013] RPC 27 , paras 90 and 91 per Kitchin LJ. In many cases the consideration that there is a likelihood of success which is sufficient to warrant an actual trial is an important pointer to obviousness. But as Kitchin LJ said in Novartis AG v Generics (UK) Ltd[2012] EWCA Civ 1623 , para 55, there is no requirement that it is manifest that a test ought to work; that would impose a straightjacket which would preclude a finding of obviousness in a case where the results of an entirely routine test are unpredictable. As Birss J observed in this case (para 276), some experiments which are undertaken without any particular expectation as to result are obvious. The relevance of the “obvious to try” consideration and its weight when balanced against other relevant considerations depend on the particular facts of the case.”
“One of the matters which it may be appropriate to take into account is whether it was obvious to try a particular route to an improved product or process. There may be no certainty of success but the skilled person might nevertheless assess the prospects of success as being sufficient to warrant a trial. In some circumstances this may be sufficient to render an invention obvious. On the other hand, there are areas of technology such as pharmaceuticals and biotechnology which are heavily dependent on research, and where workers are faced with many possible avenues to explore but have little idea if any one of them will prove fruitful. Nevertheless they do pursue them in the hope that they will find new and useful products. They plainly would not carry out this work if the prospects of success were so low as not to make them worthwhile. But denial of patent protection in all such cases would act as a significant deterrent to research. For these reasons, the judgments of the courts in England and Wales and of the Boards of Appeal of the EPO often reveal an enquiry by the tribunal into whether it was obvious to pursue a particular approach with a reasonable or fair expectation of success as opposed to a hope to succeed. Whether a route has a reasonable or fair prospect of success will depend upon all the circumstances including an ability rationally to predict a successful outcome, how long the project may take, the extent to which the field is unexplored, the complexity or otherwise of any necessary experiments, whether such experiments can be performed by routine means and whether the skilled person will have to make a series of correct decisions along the way.”
“i) There is but one statutory question: was the invention obvious? It is to be answered by reference to the non-exhaustive list of factors identified by Kitchin J in Generics v Lundbeck, including whether it was obvious to try the invention as a solution to a technical problem, as well as the nature of the invention itself. ii) "Obvious to try" is not an independent ground of invalidating a patent under the statute, but one of a variety of factors considered in an overall assessment of inventive step. It must be coupled with a fair expectation of success, the degree of success necessary depending on the other factors present in the individual case. iii) Where an invention is claimed plausibly in terms that it would achieve a technical effect, it is correct to ask whether it was obvious that the invention would achieve that effect, and wrong to ask whether the invention might achieve that effect.”
‘[1] The advantages of controlled-release oral delivery systems, particularly those achieving once-a-day efficacy, have long been recognized. [2] Outcomes can include better therapeutic efficacy via improved control of blood plasma levels and reduced peak-associated side effects. [3] Oral controlled-release dosage forms can also afford advantages in drug stability, patient compliance, and reduced total drug exposure. [4] Applications for once-a-day administration must balance release kinetics, dosage form and in vivo drug stability, absorption kinetics and variable physiologic parameters such as g.i. transit, enzymes, pH, motility and fluid level. [5] In spite of major efforts to develop once-a-day oral dosage forms, relatively few products have been introduced. [6] In many cases, once daily therapeutic efficacy cannot be easily achieved due to poor control of drug release or poor drug absorption in the colon. [7] Food effects can also introduce significant variability. [8] OCAS is an oral controlled absorption gel matrix system that exhibits pH-independent, pseudo-zero order drug release with minimal food effects. [9] The rapid hydration and formation of a rigid gel leads to effective drug release in the colon. [10] Future advances in once-a-day oral delivery systems must address improving drug absorption in the colon and may extend applications of controlled-release technology to biomolecules.’
‘[A] In some cases, controlled-release dosage forms that provided up to 24 hour in vitro drug release do not achieve the same release profile in vivo due to influences from the milieu of the gastrointestinal tract. [B] Also, poor colonic drug absorption can effectively limit the once daily efficacy of dosage forms that otherwise afford 24 hour drug release.’
‘Once-a-day controlled release dosage forms are subject to numerous physiologic influences in the gastrointestinal tract, including pH, bile salts, fluidity, motility, enzyme activity, and absorption windows. Ideally, a once-a-day dosage form should function independent of variations in the parameters shown in Fig 2.’
‘During transit from stomach to lower colon, the pH exposure can range from pH 1.0 to pH 7.5 or greater. Bile salts and degradative enzymes are present in relatively high concentrations in the small intestine. Fluid content and gastrointestinal motility are high in the upper intestine and diminish in a distal direction. In order to reliably control drug release in an extended release product, the formulation would ideally function independent of these changing variables.’
‘Additionally, the decrease in fluid content in the colon, which is a water re-absorption site, can lead to altered drug release profiles (normally a decrease in the release rate if the release mechanism is dependent on the continued presence of high water content).’
‘Several reasons may account for the discrepancies between in vitro and in vivo drug release, including effects of the gastrointestinal milieu on the controlled-release dosage form. In the colon, very little free water exists since the colon is a water absorptive region of the gastrointestinal tract.’
‘The future development of once-a-day dosage forms depends on the ability to design and develop sustained-release dosage forms that will function independent of influences from the gastrointestinal milieu. Since sustained-release dosage forms spend the majority of their residence time in the colon, future once-a-day dosage forms must be designed to release drug in a predictable fashion in the relatively low water content of the colon.’
‘Oral Controlled Absorption System (OCASTM)’, which starts as follows: ‘In an effort to design a sustained-release formulation suitable for once-a-day dosing that will perform reproducibly whether in the small intestine or colon, modifications to gel-forming matrix tablets were investigated. The OCAS system described here contains, as its major components, the active drug, a gel-forming polymer (polyethylene oxide, PEO) and a gel-enhancing agent (polyethylene glycol, PEG). The design concept is to achieve rapid gelation, pseudo first-order drug release, consistent colonic drug release, and ease of manufacturing.’
‘As mentioned in the introduction, the gastrointestinal variables that can impact the performance [of] sustained-release once-a-day dosage forms are generally influenced by the presence of food. Enzyme activity, motility, pH, fluid content, and bile salts are all modified in the fed state versus the fasted state.’
‘The data presented in Table V indicate that significantly greater absorption (AUC) is achieved with OCAS compared to the conventional gel and that the OCAS system is relatively free of food effects (547 vs 681 ng.hr./m1 AUC for fasted vs fed, respectively). By contrast, an approximate 2-fold food effect was observed with the conventional gel formulation. Again, it is likely that the very rapid hydration of the OCAS formulation is an underlying cause for the relative food effect independence.’
“In summary, OCAS is a rapidly hydrating gel matrix tablet that performs relatively independent of the effects of pH, mechanical stress, and location in the gastrointestinal tract. In addition, at least with the model compound employed, food effects appear minimal. As such, the technology represents an advance in sustained release formulations that might have applications in once-a-day drug therapy.”
‘Technologies such as OCAS can achieve effective drug release in the colon. However, until pharmaceutical approaches are available to improve colonic absorption, once-a-day products will be limited to those few drugs that exhibit high colonic permeability. In normal gastrointestinal transit, it can be expected that dosage forms will have approximately 4-6 hours available for drug release prior to arrival at the colon. This time window will continue to limit development of once-a-day dosage forms unless colonic absorption improvement is adequately addressed.’
‘It is essential for the tablet to go through the stomach and small intestine without being damaged by the contractions as ideally it reaches the colon and starts dissolving in a linear way.’
"The 2 rapid hydration and formation of a rigid gel leads to 3 effective drug release in the colon." 4 A. Yes. 5 Q. That is what Fix is all about. 6 A. No, it is not "what Fix is all about"
‘[8] OCAS is an oral controlled absorption gel matrix system that exhibits pH-independent, pseudo-zero order drug release with minimal food effects. [9] The rapid hydration and formation of a rigid gel leads to effective drug release in the colon.’
‘..it follows that the food independence is being taught to be the result of effective drug release in the colon.’
‘Professor Craig’s refusal to accept this was unreasonable and did him no credit. It was classic ex post facto reasoning, driven by the target being aimed at.’ ii) In conclusion on the disclosure of Fix that: ‘Properly understood the teaching of Fix was that the food effect was avoided by extending drug release and absorption into the colon.’
‘As to your comments on solubility data as noted in the document at DXX-KS tab 17, information that mirabegron is soluble in water between neutral to acidic pH comes directly from your client’s Assessment report for Betmiga from the EMA (see page 9 of the Betmiga assessment report). In addition, the information that mirabegron is a BCS class III compound of high solubility and low permeability comes from your client’s NDA. Further it is noted in your client’s Australian PAR that “data provided by the sponsor indicate that it [mirabegron] is Biopharmaceutical Classification System (BCS) Class 3 agent”. We therefore do not see that there is any basis on which to suggest the Sandoz data which demonstrates that mirabegron is soluble in aqueous solutions between neutral and acidic pH is incorrect.’
‘I cannot guarantee but what I will do is I will look at the options and I will make a professional judgment about which ones can be taken forward.’
‘Viewed without any knowledge of the alleged invention, do those differences constitute steps which would have been obvious to the person skilled in the art or do they require a degree of invention?’
‘…the Skilled Formulator would want to take forwards formulations with a range of dissolution rates into in vivo testing. One obvious way to increase the dissolution rate is to decrease the molecular weight of PEO. The next common grade of PEO down has an average molecular weight of 5,000,000. On the basis that the Skilled Formulator would seek to vary the dissolution rates by a material margin, it is not unreasonable to expect that one or more formulations from the routine development may achieve greater than 75% dissolution by 7 hours.’
‘Sandoz promptly disclose all pharmacokinetic data within their control (per the disclosure requirements inCPR 31 and their ongoing duty of disclosure) relating to their Sandoz 25mg and 50mg products in fed and in fasted studies (as well as any data within their control for any immediate-release mirabegron product(s)), pursuant to the confidentiality club agreed between the parties (the “Sandoz PK Data”).’
‘Astellas' position is that the Sandoz PK data sought in Astellas’
‘Sandoz does not hold any PK data for immediate release mirabegron products (i.e., conventional formulations). The PK data Sandoz does hold are bioequivalence data and it holds no data from a fed/fasted cross-over study. These data (i.e., the Sandoz BE data) are therefore irrelevant whichever way the Court resolves the dispute on construction’. ‘On the Defendants’ construction, PK data are only relevant to the extent that they establish the size of the ‘gap’ between the fed and fasted state of a particular parameter for a modified release formulation, which can then be compared to equivalent data for a conventional formulation. That is the means by which a reduction in food effects is to be assessed. However, Sandoz has not conducted any fed/fasted cross-over study with a modified release formulation and does not have any data relating to any conventional mirabegron formulation. What PK data it has for the Sandoz products relate only to modified release formulations, in each case from a single cohort, in a single study, in a single fed or fasted state. In each case, those data are used to determine bioequivalence of the Sandoz generic mirabegron product to Betmiga.’