“It follows that, even if information is neither disclosed by a specific item of prior art nor common general knowledge, it may nevertheless be taken into account as part of a case of obviousness if it is proved that the skilled person faced with the problem to which the patent is addressed would acquire that information as a matter of routine. For example, if the problem is how to formulate a particular pharmaceutical substance for administration to patients, then it may be shown that the skilled formulator would as a matter of routine start by ascertaining certain physical and chemical properties of that substance (e.g. its aqueous solubility) from the literature or by routine testing. If so, it is legitimate to take that information into account when assessing the obviousness of a particular formulation. But that is because it is obvious for the skilled person to obtain the information, not because it is common general knowledge.”
“Having acquired the necessary in vitro data described above, the formulator would carry out simple in vivo tests (using animal models) in order to guide the actual formulation of the API that would be used in human clinical trials.”
“In the course of research leading to the present invention, it has surprisingly been found that a hitherto undisclosed minimum dosage level of [DSP] is required for reliable contraceptive activity. Similarly, a preferred maximum dosage has been identified at which unpleasant side effects, in particular excessive diuresis, may substantially be avoided.”
“is a sparingly soluble substance in water and aqueous buffers at various pH values. Furthermore drospirenone is rearranged to an inactive isomer under acid conditions and hydrolysed under alkali conditions. To ensure good bioavailability of the compound, it is therefore advantageously provided in a form that promotes rapid dissolution thereof.”
“when [DSP] is provided in micronized form [to a particular surface area and particle size distribution] in a pharmaceutical formulation, rapid dissolution of the active compound from the composition occurs in vitro.”
“The composition of the invention may be formulated in any manner known in the pharmaceutical art. In particular, as indicated above, the composition may be formulated by a method comprising providing [DSP] ….. in micronized form in said unit dosage form, or sprayed from a solution onto particles of an inert carrier…so as to promote rapid dissolution of the drospirenone on oral administration.”
“[0012] In a first aspect the present invention relates to a pharmaceutical composition comprising, as a first active agent [DSP] in an amount corresponding to a daily dosage, on administration of the composition, of from about 2 mg to 4 mg, and as a second active agent, [EE] in an amount corresponding to a daily dosage of from about 0.01 mg to 0.05 mg, together with one or more pharmaceutically acceptable carriers or excipients, wherein at least 70% of said [DSP] is dissolved from said composition within 30 minutes, as determined by USP XXIII Paddle Method II using water at 37°C as the dissolution media and 50 rpm as the stirring rate.”
“[0017] It has surprisingly been found that when [DSP] is provided in a pharmaceutical composition allowing for rapid dissolution of [DSP] a high oral bioavailability of [DSP] is obtained ("rapid dissolution" is defined as the dissolution of at least 70% within 30 minutes, in particular at least 80% within 20 minutes, of [DSP] from the composition as determined by the USP XXIII Paddle Method using a USP dissolution test apparatus 2 at 50 rpm and using water at 37°C as the dissolution media). This may be achieved by providing [DSP] in micronized form, or by dissolving it in a suitable solvent, e.g. methanol or ethyl acetate, and spray it onto the surface of inert carrier particles followed by incorporation of the particles containing [DSP] on their surface in the composition.”
“If the specification discloses distinct sub-classes of the overall inventive concept, then it should be possible to amend down to one or other of those sub-classes, whether or not they are presented as inventively distinct in the specification before amendment. The difficulty comes when it is sought to take features which are only disclosed in a particular context and which are not disclosed as having any inventive significance and introduce them into the claim deprived of that context. This is a process sometimes called "intermediate generalisation".”
“…it is conceivable that a combination [oral contraceptive] of this new type of progestogen may be of special benefit to women susceptible to weight gain and a rise in blood pressure.”
“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.”
“[39]…what Mr Waugh endeavoured to do was to say that the Judge had wrongly applied an “obvious to try” test. It is necessary to say a little about this. The expression got into the law of obviousness by virtue of the Johns-Manville case,[1967] RPC 479 . The facts were simple: there was a known process. The patent was for the old process using the new agent. It was held obvious as being “well worth trying out”
“It is enough that the person versed in the art would assess the likelihood of success as sufficient to warrant actual trial” [40] More recently, in this court I, with the concurrence of Peter Gibson and Scott Baker LJJ said: "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. The "obvious to try test really only works where it is more-or-less self evident that what is being tested ought to work", St Gobain v Fusion Providahttp://www.bailii.org/ew/cases/EWCA/Civ/2005/177.html[2005] EWCA Civ 177 . [41] Judge Rich in the US Court of Appeal for the Federal Circuit said (I did not know this when I wrote St Gobain) much the same thing in Tomlinson's Appn (1966) 363 F 2d 298 at 931: "Slight reflection suggests, we think, that there is usually an element of 'obviousness to try' in any research endeavour that is not undertaken with complete blindness but rather with some semblance of a chance of success, and that patentability determinations based on that as the test would not only be contrary to statute but result in a marked deterioration of the whole patent system as an incentive to invest in those efforts and attempts which go by the name of 'research'." [42] Mr Waugh submitted that was the correct approach and that it was that approach which was also followed in Australia (Hässlev Alphapharm(2002) 312 CLR 411 ), Canada (Aventis v Apotex (2005) [2005] FC 1504) and the USA (Tomlinson and re O'Farell (1988) 853 F 2d 894 also per Judge Rich). [43] I have to say that I do not discern a shift in the position in this country following the 1977 Act as the majority of the Australian High Court thought had happened. It is perhaps noteworthy that currently Australian courts seem to be taking a very pro-patent view of obviousness and that patents are being upheld there which are not upheld elsewhere. The Hässle case and the Viagra case, Pfizer v Lilley (held by the Federal Court of Appeal non-obvious though invalid on other grounds) are perhaps examples of this. Whether, if that is so, it is good for the Australian economy is not my concern. [44] I also take the view that one can overelaborate a discussion of the concept of “obviousness” so that it becomes metaphysical or endowed with unwritten and unwarranted doctrines, sub-doctrines or even sub-sub-doctrines. This can be coupled with a massive citation of authority (the opinions in the 84 printed page, 203 paragraph judgment, in Hässle have 307 footnotes, many of which are citations of authority); Diplock LJ warned against this in Johns Manville saying: “I have endeavoured to refrain from coining a definition of ‘obviousness’ which counsel may be tempted to cite in subsequent cases relating to different types of claims.”
“Patent law can too easily be bedevilled by linguistics and the citation of a plethora of cases about inventions of different kinds. The correctness of a decision upon an issue of obviousness does not depend upon whether or not the decider has paraphrased the words of the Act in some particular verbal formula. I doubt whether there is any verbal formula which is appropriate to all classes of claims.” [45] That reminder cannot be repeated too often. The words of the law are simply: “An invention shall be considered as involving an inventive step, if, having regard to the state of the art, it is not obvious to a person skilled in the art” (Art 56 EPC). [46] In the end the question is simply "was the invention obvious?" This involves taking into account a number of factors, for instance the attributes and cgk of the skilled man, the difference between what is claimed and the prior art, whether there is a motive provided or hinted by the prior art and so on. Some factors are more important than others. Sometimes commercial success can demonstrate that an idea was a good one. In others "obvious to try" may come into the assessment. But such a formula cannot itself necessarily provide the answer. Of particular importance is of course the nature of the invention itself.” “It is enough that the person versed in the art would assess the likelihood of success as sufficient to warrant actual trial” "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. The "obvious to try test really only works where it is more-or-less self evident that what is being tested ought to work", St Gobain v Fusion Providahttp://www.bailii.org/ew/cases/EWCA/Civ/2005/177.html[2005] EWCA Civ 177 . [41] Judge Rich in the US Court of Appeal for the Federal Circuit said (I did not know this when I wrote St Gobain) much the same thing in Tomlinson's Appn (1966) 363 F 2d 298 at 931: "Slight reflection suggests, we think, that there is usually an element of 'obviousness to try' in any research endeavour that is not undertaken with complete blindness but rather with some semblance of a chance of success, and that patentability determinations based on that as the test would not only be contrary to statute but result in a marked deterioration of the whole patent system as an incentive to invest in those efforts and attempts which go by the name of 'research'." [42] Mr Waugh submitted that was the correct approach and that it was that approach which was also followed in Australia (Hässlev Alphapharm(2002) 312 CLR 411 ), Canada (Aventis v Apotex (2005) [2005] FC 1504) and the USA (Tomlinson and re O'Farell (1988) 853 F 2d 894 also per Judge Rich). [43] I have to say that I do not discern a shift in the position in this country following the 1977 Act as the majority of the Australian High Court thought had happened. It is perhaps noteworthy that currently Australian courts seem to be taking a very pro-patent view of obviousness and that patents are being upheld there which are not upheld elsewhere. The Hässle case and the Viagra case, Pfizer v Lilley (held by the Federal Court of Appeal non-obvious though invalid on other grounds) are perhaps examples of this. Whether, if that is so, it is good for the Australian economy is not my concern. [44] I also take the view that one can overelaborate a discussion of the concept of “obviousness” so that it becomes metaphysical or endowed with unwritten and unwarranted doctrines, sub-doctrines or even sub-sub-doctrines. This can be coupled with a massive citation of authority (the opinions in the 84 printed page, 203 paragraph judgment, in Hässle have 307 footnotes, many of which are citations of authority); Diplock LJ warned against this in Johns Manville saying: “I have endeavoured to refrain from coining a definition of ‘obviousness’ which counsel may be tempted to cite in subsequent cases relating to different types of claims.”
“Patent law can too easily be bedevilled by linguistics and the citation of a plethora of cases about inventions of different kinds. The correctness of a decision upon an issue of obviousness does not depend upon whether or not the decider has paraphrased the words of the Act in some particular verbal formula. I doubt whether there is any verbal formula which is appropriate to all classes of claims.” [45] That reminder cannot be repeated too often. The words of the law are simply: “An invention shall be considered as involving an inventive step, if, having regard to the state of the art, it is not obvious to a person skilled in the art” (Art 56 EPC). [46] In the end the question is simply "was the invention obvious?" This involves taking into account a number of factors, for instance the attributes and cgk of the skilled man, the difference between what is claimed and the prior art, whether there is a motive provided or hinted by the prior art and so on. Some factors are more important than others. Sometimes commercial success can demonstrate that an idea was a good one. In others "obvious to try" may come into the assessment. But such a formula cannot itself necessarily provide the answer. Of particular importance is of course the nature of the invention itself.”
“In the Court of Appeal, Jacob LJ dealt comprehensively with the question of when an invention could be considered obvious on the ground that it was obvious to try. He correctly summarised the authorities, starting with the judgment of Diplock LJ in Johns-Manville Corporation's Patent[1967] RPC 479 , by saying that the notion of something being obvious to try was useful only in a case in which there was a fair expectation of success. How much of an expectation would be needed depended upon the particular facts of the case.”
“it would be routine to do a study on the bio-availability of formulations with and without coatings in animals (usually dogs).”
“Q. … If you can get regularly 50% of your dose to the site of absorption within 30 minutes, then why is it not of interest to you to see if that can be done in vivo, so that instead of administering 2 mg, you administer 4, and you then know you are going to get 2 mg delivered to your site of absorption? A. For the very reason that you know the biological variation in the gastric emptying, even for immediate release systems. You know that it would be difficult to predict that you could accurately get 50% absorbed every time. You just would not be thinking that you would be able to do that based on your formulation experience. If you cannot predict that, then it is an extremely dangerous approach to take. In fact, it is not an approach that formulation scientists or development teams would be at all happy with if they knew from in vitro data, in vitro data that teaches you there is no doubt from the in vitro data that this drug isomerised significantly. Everything that you are taught would teach you that you should protect that drug. You cannot, for a low-dose contraceptive, go for a potential irregular amount of that drug to be absorbed through an immediate release system. It would be madness.”
“Q. With the documents that are in, for example, The European Journal of Pharmacology, are you saying that because it is in that journal, it cannot be of any interest to you? A. No, I did not say that. I said a formulating scientist would not normally look at such journals. Q. No, you would not read them as part of your everyday reading. A. Absolutely. Q. But the fact that an article is in the European Journal of Clinical Pharmacology does not mean to say that you can just rule it out immediately? A. No, I do not think you would, but you would look at the title. You would look to see whether -- for example, if it was a clinical paper or a pharmacological paper, it would probably suggest to you that this would not be something of great interest to you. It would not be something you would come across in the normal run of your activities. You may look at it and review it, but many of those papers in clinical journals have very little information, if at all, on the formulation. They just talk about a tablet or a capsule. Q. You would scan them to confirm your belief that there is likely to be nothing in them of any use? A. You could potentially scan them.”
“Q. Going on, you have then got "Study of plasma levels". It says …“The lactone rearrangement product of spirorenone was not detectable in the plasma, suggesting that the absorption process was much faster than the acid-catalyzed isomerisation of the drug." Just [looking at] that as a statement, why do you think they put that in as an observation from their test? A. I cannot speak to Dr. Krause and why he wrote that. I know it is on a different drug, as we have indicated, for a different particular condition. As a formulator, I would be thinking, "I do not know which form of the drug they have used, what formulation they have used." Q. But you would be alert, would you not, to the fact that there was a possibility that in vivo, the rate of rearrangement was sufficiently low that unreasonable amounts of isomerisation were not being identified? A. I would see that and then I would do my pre-formulation studies on the different drug, drospirenone, and I would need to micronise to improve the dissolution rate and in doing those studies and with the dissolution studies, I would identify at 37°, at a faster rate, that we are getting significant degradation. So I see this for what it is. I do not know anything about the formulation. …”
"On the basis of the trial results available, significant losses of active ingredient during passage through the stomach must be expected. From a formulation point of view, an administration form that is resistant to gastric juice should therefore be used for carrying out the human random trial."
“It does not appear very probable that [SP] is a converted to any great extent into its inactive isomer in the stomach. The reasons for this are as follows: (1) The isomerization takes place relatively slowly. (2) The doses of 10 to 320 mg envisaged for the planned human trial are presumably not completely dissolved in the stomach (volume of gastric fluid: about 120 ml…).” (1) The isomerization takes place relatively slowly. (2) The doses of 10 to 320 mg envisaged for the planned human trial are presumably not completely dissolved in the stomach (volume of gastric fluid: about 120 ml…).”
“In hydrochloric acid at 37°C, [DSP] undergoes rapid, substantial rearrangement into its inactive isomer… If the in vitro results are extrapolated to in vivo conditions, it may be assumed that the predominant part of the dose (solubility of [DSP]: 5-10 mg/l) goes into solution during passage through the stomach (taking the volume of gastric fluid to be 100 ml) and hence undergoes rapid isomerisation. As a result, the biovailability of the unchanged active ingredient is expected to be considerably reduced. The planned studies on the progestational activity of [DSP] were therefore to be carried out with a formulation resistant to gastric fluid.”
“After 20 and 60 minutes, 35% and as much as 50% respectively of the total amount dissolved had isomerized.”
“to test whether, similar to other analogues of this class of effective agents, the acid-catalysed transfer is negligible in vivo”