Gedeon Richter Plc v Bayer Schering Pharma AG

The law about the distinction between matter which is part of the common general knowledge, and matter which is merely known or even widely known is stated in Beloit v Valmet [1997] RPC 494-495, relying on the well known judgment of the Court of Appeal in General Tire v Firestone. The matter must be “generally accepted as a good basis for further action”, what Jane Austen would have called “a truth universally acknowledged”, at least within the universe of those skilled in the art. The distinction is important in the law of obviousness because, although it is in general permissible to combine the contents of an individual published citation with matter which is part of the common general knowledge, it is impermissible to make so-called mosaics of individual citations (unless it would be obvious to do so).

Matter which the skilled person would uncover as a matter of routine in the course of work based on a particular disclosure does not form part of the common general knowledge. In ratiopharm v Napp [2008] EWHC 3070 I said this at paragraph 159, relying on what Kitchin J had said in Generics v Daiichi:

“Finally, the common general knowledge does not include knowledge which does not inform the skilled person's approach from the outset. As Kitchin J said in Generics (UK) v Daiichi Pharmaceutical[2008] EWHC 2413 (Pat):

"I can readily accept that, faced with a disclosure which forms part of the state of the art, it may be obvious for the skilled person to seek to acquire further information before he embarks on the problem to which the patent provides a solution. But that does not make all such information part of the common general knowledge. The distinction is a fine one but it may be important. If information is part of the common general knowledge then it forms part of the stock of knowledge which will inform and guide the skilled person's approach to the problem from the outset. It may, for example, affect the steps it will be obvious for him to take, including the nature and extent of any literature search."

Whether knowledge is common and general depends on the considerations explained by Aldous LJ in Beloit. If information does not satisfy that criterion, it does not become common general knowledge by postulating a set of steps that the skilled team might take to find it if they had already embarked on an attempt to solve a particular problem. That is not to say that it is illegitimate, in assessing an obviousness attack, to take account of material which would inevitably be found and treated as reliable in consequence of a step or steps which it is obvious to take. If the material so found is such as would be accepted, then it may assist in showing obviousness of a further step. But what it cannot be used for is in support of an argument that the series of steps being undertaken were obvious from the start.”

Arnold J summarised the current state of the law in KCI v Smith & Nephew [2010] FSR 31 at [112], in a passage approved by the Court of Appeal [2010] EWCA Civ 1260 at [6]:

“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.”

The following matters were established as forming part of the common general knowledge of the relevant team at the priority date of the patents.

The oral route of drug administration requires that the drug pass down the gastro-intestinal tract and be absorbed into the blood stream. For present purposes one can concentrate on the stomach and the small intestine. The stomach is an acid environment with a pH in the range 1 to 3. The stomach lining is coated in mucosa which are not designed for absorption. The primary purpose of the stomach is to process the ingested food into digestible fractions. The contents of the stomach are then emptied into the small intestine either continuously or by means of the so-called “housekeeper” contraction wave.

The small intestine is considerably more alkali than the stomach, with a pH ranging from 5 to 7. The walls of the small intestine have mucosa which have a high surface area and rich blood supply making them ideal for absorption into the bloodstream. The small intestine is therefore the primary site of drug absorption.

A drug spends some time in the stomach and some time in the small intestine before it is absorbed. Liquids and small particles are generally evacuated from the stomach more quickly than large solid particles. A rapidly disintegrating and dissolving drug formulation will therefore spend less time in the stomach than a large solid tablet. The amount of time the drug spends in the stomach depends on a number of patient variables, such as whether the patient is fed or fasted, anxiety state, posture and so on. This is called intra-patient variability. There is also considerable patient to patient, or inter-patient variability.

Both experts speak of a “mean residence time” in the stomach for disintegrated particles of around 90 minutes. Large particles are retained for longer.

A formulator charged with designing a formulation for an API will invariably conduct pre-formulation studies. These are directed at establishing the physico-chemical properties of the API, which is necessary information to inform the subsequent formulation decisions. The studies are designed to establish the solubility (how much dissolves in a given volume) and stability of the API in different environments. The studies would normally include a test of degradation rate as a function of pH to give an indication of whether problems will be encountered in the GI tract. The tests would include studies of the dissolution rate (how quickly the drug dissolves). There are standard tests to determine this in the United States and British Pharmacopoeia. There is a special test for delayed release formulations which includes a preliminary stage in acid to ensure integrity of the coating.

Professor Davies’s evidence was that pre-formulation studies were all carried out in vitro. I did not understand Professor Buckton to disagree, but he went on to say that:

“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 cross-examination he said that one would use in vitro data to cut down the number of formulations andtake four or so formulations forward into a dog study. This gave rise to a significant dispute. Professor Davies said that the skilled person would typically choose a lead formulation based on his in vitro data and hand that on to pharmacologists for testing in animals.

In my judgment it is not possible to say that, as a matter of its common general knowledge, the skilled team would know that it should take a series of formulations into animal studies. No text book reference or other source was cited to support this. The best Mr Thorley could do was a passage from Aulton cited in the judgment of Judge Sheridan giving the decision of the United States District Court for the District of New Jersey in the corresponding case there:

“Dissolution rate data when combined with solubility… provide an insight to the formulator into the potential in vivo absorption characteristics of a drug. However, in vitro tests only have significance if they can be related to in vivo results. Once such a relationship has been established, in vitro dissolution tests can be used as a quality control test.

The passage suggests that in vitro results need to be treated with caution until an in vitro to in vivo correlation (“IVIVC”) is established. Thus in vitro results cannot bear the responsibility for quality control until an IVIVC is established. But neither witness suggested that such studies were of no value in predicting behaviour in vivo or that formulation decisions cannot or would not be taken on the basis of in vitro results. On the contrary, both sides supported their use, and so does the Aulton passage cited. The question of whether more than one formulation should be taken into animal studies is a question which the formulator would decide on the facts of the individual case.

Low solubility APIs present particular difficulties for the formulator. Such APIs run the risk of incomplete absorption. Steps can be taken to improve the dissolution properties of poorly soluble APIs. Those of particular relevance to this case are (a) reducing particle size by micronisation, i.e. fine milling of the drug to produce a higher surface area (for example, icing sugar as against granulated) and (b) applying the API onto the surface of inert carrier particles. These are, however, only examples of the techniques which the skilled formulator would have in his armoury for dealing with poorly soluble drugs as part of his common general knowledge.

A skilled person would be aware that, in the case of a drug which is sensitive to stomach acid, taking steps to increase solubility would be likely to increase the rate at which the drug degraded. This was particularly notable in the case of the antibiotics penicillin G and erythromycin which are highly unstable in the gastric environment, but it is a factor which the formulator would have in mind for any acid labile drug.

Contraceptives have traditionally been formulated as tablets supplied to the patient in blister packs.

A contraceptive has to be formulated so that it is 100% effective at inhibiting ovulation, given that the consequence of an ineffective dose would be an unwanted pregnancy. This is a demanding requirement not met with analgesics or antibiotics. It is therefore necessary to establish a dosage which achieves this degree of reliability. At the other extreme there are known dosage-dependent side-effects which the skilled team would be anxious to avoid by excessive dosing.

Contraceptive reliability is obtained by maintaining an adequate level of drug in the plasma.

Low dose APIs are usually highly potent, so that a small variation in the amount of the dose can have substantial clinical consequences. It is therefore very important to ensure not only that each tablet contains as near as possible the same dose at the point of administration, but also that the dose is not lost on its way to the site of absorption.

If studies show that a drug has a tendency to degrade in acid conditions, it is possible to protect the drug from the acid environment in the stomach by means of an enteric coating. The coating is designed to be insoluble in acid conditions. The formulation is therefore discharged without dissolution from the stomach by the stomach emptying process into the more alkaline environment of the small intestine. The coating is designed to dissolve in those conditions, and the drug is then released for absorption at that stage.

Enteric coatings are also used to protect the stomach lining from the action of a drug, but that application is not directly relevant here. As at 1996 there were 261 drugs on the market with enteric coats, about one third of which were so formulated to protect the drug from acid.

A consequence of the mode of action of the enterically coated drug is that there is a delay in the onset of action while the formulation is discharged from the stomach.

Whilst there is no doubt that enteric coatings overcame the problem of acid degradation in the stomach, they undoubtedly had some problems of their own. The first is the delayed onset of action which I have already mentioned. This is a particular problem in a drug for which there is an urgent need for immediate onset.

A second and related problem with the enteric coating is that the period of delay will be the subject of inter- and intra-patient variability because of the differences in gastric emptying times to which I have referred. One reference suggests that the residence time for a delayed dosage form is between 30 minutes and 4.5 hours. Examples were found of drugs which were delayed even longer, one by up to 12 hours.

By the priority date, however, these problems had been met to a large degree by providing enterically coated granules. Their small size enabled them to pass through into the intestine at a faster and less variable rate. The notion of providing enterically coated granules in a hard gelatine two-part capsule was well established by the priority date. Compressing the granules into a tablet was a slightly different matter. Professor Buckton did not accept that these tablet formulations were part of the common general knowledge, and I conclude that it was not.

It is not suggested that the combination of DSP and EE was part of the common general knowledge. As all the attacks on the patents start from documents which disclose the combination, the point does not matter.

The relevant application for both patents is PCT application WO 01/15701, “the Parent Application”. 301 is a divisional application from the Parent Application, and 069 is a divisional application from 301.

The parent application commences at pages 1-2 with some general background on oral contraceptives, and information on dosage ranges which have been proposed in the prior art for DSP and EE, alone or in combination. The “Summary of the Invention” is then in the following terms:

“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.”

The section then goes on to describe a first aspect of the invention as relating to a combination formulation of DSP at a dose of 2 to 4 mg and EE at a dose of 0.01 to 0.05 mg. This is the invention which is reflected in claim 1 of the Parent Application. I shall call this “the dosage range invention”.

Under the heading “Detailed Disclosure of the Invention” the specification goes on to explain that DSP:

“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.”

At page 4 lines 11 to 24 of the Parent Application it is first recorded that it has been “surprisingly” found that:

“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.”

“Rapid dissolution” is then defined as the dissolution of at least 70% over about 30 minutes, in particular about 80% over about 20 minutes, of DSP from a tablet preparation containing 3 mg of DSP in 900 ml of water at 37^oC determined by USP XXIII Paddle Method using a USP dissolution test apparatus 2 at 50 rpm.

Finally in this passage, the Parent Application points out that as an alternative to micronisation, it is possible to dissolve the active in a suitable solvent and spray it onto the surface of inert carrier particles which make up the composition.

The Parent Application then goes on to point out at page 4 lines 26-31 a theory and an advantage:

“Without wishing to be limited to any particular theory, it appears that the in vitro dissolution rate of [DSP] is connected to the dissolution rate in vivo resulting in rapid absorption of [DSP] in vivo on oral administration of the compound. This is an advantage because isomerisation of the compound in the gastric environment and/or hydrolysis in the intestine is substantially reduced, leading to a high bioavailability of the compound."

Thus far the skilled person would understand that it was advantageous to provide DSP in a form that promotes rapid dissolution because that in turn would promote rapid absorption and thus give less opportunity for degradation in the stomach or the intestine. This leads to “good” or “high” bioavailability. Two particular ways of achieving this are described, namely micronisation and spraying onto inert carrier particles.

At page 5 lines 11 to 12 the Parent Application points out that:

“To obtain a more rapid rate of dissolution, it is preferred to include carriers or excipients which act to promote dissolution of both active substances."

Then at page 9 lines 10 onwards, the Parent Application explains how the “composition of the invention” may be formulated:

“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.”

Claim 1 in the Parent Application was, as I have indicated, directed to the dosage range invention. Claim 2 required the DSP to be in micronised form or sprayed onto inert particles. Claim 8 claimed a dissolution rate (70% released in 30 minutes).

Both patents have a priority date of 31^st August 1999. The specifications (other than the claims) are broadly similar.

In 301, the Background section from the Parent Application has been expanded to include the cited Oelkers document, pointing out that Oelkers does not disclose compositions having a rapid dissolution rate of DSP.

301 then sets out a “Summary of the Invention” as follows:

“[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.”

In broad terms the rapid dissolution test has been introduced into this summary as an additional limitation of the dosage range invention. This is reflected by a corresponding limitation in claim 1.

Turning to the detailed disclosure, 301 repeats at [16] the statements from the Parent Application that DSP is sparingly soluble, and that it isomerises under acid conditions and hydrolyses under alkaline conditions and that, to ensure good bioavailability it should be provided in a form which promotes rapid dissolution.

The draftsman of 301 has been less restrained when he came to the passage at page 4 lines 11 to 24 of the Parent Application. This now reads as follows:

“[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.”

Nevertheless the following paragraph, [18], is left unchanged from page 4 lines 26 to 31 of the Parent Application, pointing out the advantage which flows from rapid dissolution.

[38] is also left unchanged from page 9 line 10 onwards of the Parent Application. [39] identifies some film coats which can be applied to the formulations: none of these is an enteric coat.

069 maintains the same Summary of the Invention at [10] and [11] as the Parent Application, even though all the claims are narrower than the dosage range invention which they purport to summarise.

[16] and [18] of 069 are the same as the same numbered paragraphs of 301 and the corresponding passages in the Parent Application. [17], however, substantially follows the Parent Application rather than 301.

The claims that are alleged to be independently valid are claims 1 and 7 of 301, and 1, 6 and 19 of 069.

Claim 1 of 301 as granted is to the dosage range invention wherein the DSP satisfies the “rapid dissolution” test.

By their unconditional amendment, Schering introduce the 900ml requirement into the “rapid dissolution” test of claim 1, and their conditional amendment would further specify (1) that the composition was a “tablet”, (2) that the amount of drospirenone was 3mg, and (3) that the range for EE was 0.015-0.03mg.

Claim 7 as granted further specified that the DSP is sprayed from a solution onto inert carrier particles. It would become claim 2 in the conditional amendments.

Claim 1 of 069 is to the dosage range invention wherein the DSP is contained on the surface of inert carrier particles. There is no limitation to spraying or dissolution rate.

Claim 6 of 069 further requires that the DSP in the compositions of the preceding claims undergoes dissolution of at least 70% within 30 minutes as determined by USP XXIII Paddle Method II using water at 37^oC and 50 rpm as the stirring rate.

Claim 19 of 069 is dependent solely on claim 1. This claim introduces the requirement that the DSP has been sprayed onto the surface of the inert particles of claim 1.

Schering contends that claim 1 of 301 and claim 6 of 069, properly construed, exclude an enteric coated formulation. Richter contend that this is to read in limitations which are not present.

The approach to construction is not in dispute. It is as stated by Lord Hoffman in Kirin Amgen v TKT [2005] RPC 9. The task for the court is to determine what a person skilled in the art would have understood the patentee to have used the language of the claim to mean.

Mr Waugh submits:

I have no hesitation in rejecting those submissions. The claims are clear. They require a formulation which satisfies a particular dissolution test in vitro. Whilst the skilled person might think it unlikely that an enterically coated tablet would satisfy the test, he would nevertheless understand the patentee to be claiming any formulation that did so. The thrust of the specification is indeed rapid dissolution, but it is rapid dissolution as defined in the test. If it is possible to devise an enterically coated tablet which satisfies the dissolution test and the other features of the claim, then it would infringe. The strongest of Mr Waugh’s points is that the test is not the dissolution test for enteric coatings, but I cannot accept that the skilled person would understand the patentee to be using this language to exclude, for example, a rather thin enteric coat which managed to get through the test.

A patent will be invalid for the objection known as “added matter” if “the matter disclosed in the specification of the patent extends beyond that disclosed in the application for the patent as filed” (Patents Act 1977, section 72(1)(d)). The relevant law has been compendiously summarised by Arnold J in Abbott Laboratories Ltd v Medinol Limited [2010] EWHC 2865 (Pat) at [251] – [253]. The points I would emphasise here are the following:

The Re-Amended Grounds of Invalidity in respect of 301 allege that matter has been added in three respects. These are summarised in Richter’s skeleton argument as follows:

The Re-Amended Grounds of Invalidity against 069 alleged the following:

This is the most important objection, because it is not suggested that it is answered by any of the amendments. It asserts, in essence, that the disclosure of the Parent Application is that good bioavailability may be obtained by micronising/spraying, whereas 301 teaches that it can be obtained by any method which produces rapid dissolution.

I think that, fairly read, the Parent Application teaches that good bioavailability is obtained by any formulation that gives rapid dissolution. Micronisation and spraying are given as examples. I think this is clear from the passages which became [16] and [18] in 301 and which are carried through from the Parent Application unaltered. [16] makes it clear that the patentee considers it an advantage to formulate the product in a form which promotes rapid dissolution. That suggestion of advantage is entirely general, and not linked to the specific means of promoting rapid dissolution. Equally clearly, [18] does not limit the obtaining of high bioavailability to the specific technique used to promote dissolution: it links rapid dissolution to high bioavailability in an entirely general way. Read in context the intervening paragraph (page 4 lines 11 to 24 of the Parent Application, which becomes [17] in granted 301) is providing exemplification of the concept of obtaining high bioavailability by promoting rapid dissolution. Sensibly read, the skilled person would not take that passage as indicating that this was the only way in which he was being told he could put the invention into effect. It is implicit that any method of arriving at a formulation which achieved rapid dissolution would do equally well. This is not something which is only obvious from the disclosure: it what the skilled reader would understand is being said.

When one turns to 301 as granted, references to “the invention” must now be taken as limited to a rapid dissolution form. Thus it is fair to note that [38], whilst unchanged from the text of the Parent Application, is now making a different statement from that which it made in the context of the Parent Application. It now says that the composition of the invention (i.e. rapid dissolution forms) may be formulated in any manner known in the art. When the invention related simply to dosage ranges, this did not imply anything about rapid dissolution or high bioavailability. It now says that rapid dissolution form may be formulated by any known method which achieves rapid dissolution. But that, in my judgment, was the clear disclosure of the Parent Application. In both cases the skilled person would understand the specification as teaching that any known way of achieving rapid dissolution would do. No matter is added in the granted text of 301 in this respect.

This objection is met because, by their unconditional amendment application, Schering offer to reinstate the definition of micronisation. As no objection is taken to the amendments, the amendment will be allowed and the objection to validity falls away.

Insofar as this point relies on the 900 ml of water used in the dissolution test, it is met by the unconditional amendments, and falls away. The 3 mg point remains live (although it would be met by the conditional amendment application). Professor Buckton’s evidence was, as one would expect, that the choice of a 3 mg tablet would yield a different dissolution rate to the choice of a 2 mg or 4 mg tablet. By deleting the reference to the loading of the tablet in the granted patent, Schering have changed the technical disclosure of the paragraph which became [17] in the granted patent. The original paragraph only contained a test for a 3 mg tablet. The test in the granted patent is not specific to any tablet, and suggests for the first time that any tablet loading which passes the test will do. That is additional matter relevant to the invention. The relevant conditional amendment will have to be made.

The objection arises out of the fact that, apart from the dosage ranges, claim 1 of 069 is only limited by the requirement that the DSP be on the surface of the carrier particles. Application of the DSP by spraying is not claimed until claim 19. Thus it is argued by Richter that the granted text of 069 discloses that it is possible to achieve DSP on the surface of a carrier particle by means other than spraying. Richter again relies on [38] and the suggestion that formulation of the composition of the invention may be in any manner known in the art. They submit that “the invention” here is not the dosage form invention summarised in [10] and [11], but the one claimed in claim 1. So they say there is a specific teaching that any method of applying DSP onto the surface, not just spraying, will do.

I agree that [38] refers to the claimed invention. Without [38], the point would be hopeless. Claim 1 does not disclose an inert carrier particle covered by any method other than spraying. It says nothing about how the DSP got there at all. The question is whether [38] is going further than the application in teaching that any method will do. The skilled person reading the Parent Application would understand that what was important was the finished composition. Once the DSP had been applied to the surface it does not matter how it got there. He would see spraying as an example of a process for getting it there, but not as an essential part of the invention of the product. [38] in the granted 069 is therefore merely making explicit that which was implicit in the Parent, namely that other methods of achieving application of DSP onto the surface, if they are known to the person skilled in the art, will do just as well. Accordingly, in my judgment, this objection is not made out.

This objection was that “the disclosure of the Parent Application was that compositions containing inert carrier particles containing DSP on their surface would promote “rapid dissolution” of DSP, whereas the disclosure in 069 is that not all such compositions will do so.” This objection was not much elaborated by Mr Thorley. For my part I cannot see any disclosure in the Parent Application that all compositions which contain inert carrier particles containing DSP on their surface would promote “rapid dissolution” of DSP, or any disclosure in 069 that not all such compositions will do so.

This objection was also not much elaborated. It is founded on the proposition that the skilled person would not see the dosage range invention as connected with formulation. I cannot see how this could be so.

All the added matter points fail, with the exception of that related to the 3mg loading. The 3 mg point is met by the conditional amendments.

Oelkers was published in 1995. Oelkers was a scientist in the Endocrinology Department of the Freie Universität, Berlin. Other clinicians came from the Catholic University of Liege, Belgium. The final author, Heithecker, was from Schering’s Department of Fertility Control and is one of the named inventors of the patents in suit.

Oelkers describes a study in which three groups of 20 women received either: (A) 30µg/3mg, (B) 20µg/3mg, or (C) 15µg/3mg of EE / DSP and as a control (D) 30µg EE and 150µg levonorgestrel (Microgynon). The 3 mg/day dose of DSP used in each of the three groups was chosen to provide a safety margin over the threshold dose of 2mg. Body weight and blood pressure fell in the three test groups, but rose for the control group.

The authors thought this to be the first report on a combined oral contraceptive that leads to a small decrease in body weight and blood pressure. They conclude by saying that:

“…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.”

These findings were of significance because prolonged use of hormonal oral contraceptives can lead to small mean increases in body weight and blood pressure.

Oelkers reveals that DSP was formerly called dihydrospirorenone. There is, however, no information about how to formulate it. The volunteers, it is to be inferred, were given the API in pill form.

Krause I was published in 1982, some thirteen years before Oelkers. It was published in the Journal of Chromatography, which, because of its essentially analytical content, is not a journal regularly read by formulators as part of their work. Krause and his co-worker Jakobs, a laboratory technician, were scientists working at the Department of Pharmacokinetics at Schering in Berlin. Krause I is not about contraception at all. In terms of the drug studied, its principal focus is spirorenone (“SP”) which is an aldosterone antagonist (a type of drug for treating high blood pressure). It works as a diuretic, that is to say by eliminating excess water from the body.

Here it is worth noting some chemistry which, though not part of the common general knowledge, could be readily discovered by a reader of Krause. SP and DSP are complex polycyclic molecules which differ only by the presence of an additional C-C double bond in SP in one of its constituent ring structures. The inactive isomer in each case is caused by the rearrangement of a ring at the opposite end of the molecule. There was no dispute that DSP and SP would be regarded as analogous compounds. Equally one cannot make any assumptions about the behaviour of a molecule merely because it has a similar structure.

Krause reports that SP was currently under investigation in man using subjects with constant oral water loading. During the studies, plasma samples were withdrawn from the two male test subjects for analysis of the SP levels. SP was known from in vitro studies to isomerise in the stomach to a re-arranged compound which was inactive. Krause observed that if substantial amounts of this compound were found in blood, a formulation resistant to gastric juice would have to be developed. The aim was therefore to establish an assay procedure capable of detecting low plasma concentrations and which was able to separate the active and inactive isomers of SP.

DSP (which Oelkers had pointed out was dihydro-SP) is a metabolite of SP. Krause detected the metabolite in his plasma samples.

So far as the in vitro experiments are concerned, Krause reports that both SP and DSP undergo the isomerisation reaction in vitro. His graph shows that about half the SP is converted to inactive isomer in about 150 minutes and about half the DSP is converted in about 90 minutes.

Krause does not expressly say whether these in vitro results are obtained at room temperature, although there is an indication that the chromatographic system was operated at that temperature. Professor Davies would have assumed that it was so operated in the absence of any other explanation. Professor Buckton did not really dispute this.

In relation to these in vitro results he states that:

“…the process of re-arrangement was relatively slow compared to possible absorption rates in the stomach…"

The analysis of the plasma samples from the two test subjects showed that inactive isomerisation product of SP:

“…was not detectable in the plasma, suggesting that the absorption process was much faster than the acid catalysed isomerisation of the drug."

There are no express conclusions about the isomerisation product of DSP in plasma, although it is not visible in the relevant trace. For reasons which Professor Davies explained (see below), one would not expect it to be.

Krause III was published in 1982. Krause’s co-authors on this occasion include clinicians from the Department of Internal Medicine at Schering. Krause III was published in the European Journal of Clinical Pharmacology. This is, again, not a journal which would be read regularly by formulators as part of their work.

The aim of this further work was, firstly, to evaluate the pharmacokinetics of the drug (again as an aldosterone antagonist) in male test subjects who were not given the heavy oral water load. Secondly, the inactivation of SP by isomerisation was to be investigated in a larger number of volunteer males (thirteen instead of two). Thirdly, they were to follow the appearance of the active metabolite (believed to be DSP) after single and repeated doses.

Krause concludes, once again, that the isomerisation product of SP could not be detected in the plasma in either 1 or 14 doses. He also observed that there was a distinct lag time of absorption, and that there was a problem with absorption at higher doses.

There is no detail of the pharmaceutical formulation administered to the subjects, except that it is to be inferred that a macrocrystalline form was used. An express suggestion to use a micronised material in future is therefore made. Professor Davies infers, and I accept, that the use of macrocrystalline material would have restricted the scope for acid catalysed isomerisation to take place in the stomach.

Lachnit is dated May 26^th 1998. It is a Schering US patent with named inventors from Germany and Australia.

Lachnit’s introduction makes reference to the desirability of reducing the doses of oral contraceptives in order to reduce the incidence of unwanted side effects. The object of the invention is said, somewhat globally, to be:

"To make available a combination preparation with an estrogen content that is as low as possible in each individual dosage unit but also with a low total hormone content per administration cycle, whereby with high contraceptive reliability, an incidence of follicular development that is as low as possible and satisfactory cycle control with reliable avoidance of intra-cyclic menstrual bleeding such as breakthrough bleeding and "spottings" are to be achieved and undesirable side-effects are to be avoided.”

The preferred embodiment of the invention is said to be an estrogen/gestagen combination in which the estrogen is selected from a list of 3 compounds (including EE) and the gestagen is selected from a list of 8 compounds (including DSP). Dosage ranges for EE are given as 0.01 to 0.04 mg/day; for DSP as 1.0 to 3.0 mg/day.

Lachnit does not provide any detailed formulation information. But at column 7 line 24 one finds the following passage:

"The formulation of an estrogen and a gestagen for the production of a combination preparation according to the invention is carried out completely analogously to the way already known for conventional oral contraceptives with a 21-day intake period of the active ingredients, such as, for example, Femovan^® (ethinylestradiol/gestodene) or Microgynon^® (ethinylestradiol/levonorogestrel). The formulation of the dosage units that contain only estrogen can also be carried out quite analogously to the way known for already obtained estrogen-containing agents that are intended for oral use, for example, Progynon C^®.”

Femovan and Microgynon were not enteric coated products. But there is no evidence that they were acid labile. The skilled person would not derive from this that he could get away without using an enteric coat if he found that a chosen API was acid labile. He would proceed with tests in the usual way.

Although the attack based on Lachnit was not formally abandoned, in the end Mr Thorley did not maintain that he could get home on Lachnit if he did not get home with his other attacks.

A patent will be invalid on the ground called “obviousness” if the invention is obvious to a person skilled in the art having regard to any matter which formed part of the state of the art: Patents Act 1977, section 72(1)(a), section 1(1)(b) and section 3.

The structured analysis adopted in Pozzoli v BDMO [2007] FSR 37, is a helpful guide to the fact finding tribunal, but is not to be regarded as a substitute for the statutory test. The approach is as follows:

“(1)

(a) Identify the notional "person skilled in the art";

(b)

Identify the relevant common general knowledge of that person;

(2)

Identify the inventive concept of the claim in question or if that cannot readily be done, construe it;

(3)

Identify what, if any, differences exist between the matter cited as forming part of the "state of the art" and the inventive concept of the claim or the claim as construed;

(4)

Viewed without any knowledge of the alleged invention as claimed, do those differences constitute steps which would have been obvious to the person skilled in the art or do they require any degree of invention?”

Kitchin J concisely summarised the law in Generics v Lundbeck [2007] RPC 32 at [72] subsequently approved by the Court of Appeal in that case and the House of Lords in Conor v Angiotech [2008] R.P.C. 28 at [42]:

“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.”

A number of cases have discussed the notion of an invention being “obvious to try”. In the Court of Appeal in Conor v Angiotech [2007] EWCA Civ 5, Jacob LJ said this:

“[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”. Diplock LJ said:

“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.”

I interpolate to say, he failed there! Continuing:

“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 House of Lords Lord Hoffmann, with whom all their Lordships agreed, said this:

“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.”

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.

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 physico-chemical 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.

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 have identified the skilled team and the common general knowledge above. The inventive concept of claim 1 of 301 is a formulation of the two drugs at the given dosage which satisfies the Paddle test for dissolution; that of claim 1 of 069 requires the dosage of DSP to be disposed on inert carrier particles; claim 19 introduces spraying; whereas claim 6 introduces the Paddle test. I propose to consider obviousness first in relation to the claims that include the Paddle test, that is claims 1 and 7 (2 as amended) of 301 and claim 6 of 069 and then return to the other claims.

The difference between Oelkers and the inventive concept of the Paddle test claims is therefore that Oelkers does not disclose any formulation details. The skilled person faced with Oelkers would have to design a formulation, and it would then have to be tested to determine whether it satisfied the Paddle test. I shall assume for the purposes of this part of the case that if the skilled person chose an enteric coating it would not satisfy the Paddle test.

The experts are agreed that, having read Oelkers, and having been tasked with the preparation of a formulation for oral administration of EE and DSP, the skilled formulator would embark on in vitro formulation tests in order to determine the physico-chemical characteristics of the drug. Both experts revealed a strong preference for carrying out these experiments themselves in their own laboratory, rather than hunting down information from the literature.

The evidence establishes that such studies would include an in vitro acid stability test at 37^oC . The results of such a study as performed by Schering were in evidence. These show that after 10 minutes, 21% of the total dose would have isomerised, rising to 29% after 20 minutes and 40% after thirty minutes. At 45 minutes half the dose had isomerised. This is within the mean residence time of the drug in the stomach.

Another way of looking at the data is by looking at the DSP in solution. After 10 minutes 27% of the DSP in solution is isomerised, and then 30% at 20 minutes, 40% at 30 minutes and 50% at 45 minutes.

Professor Davies was very clear that he would take these results as a signal that an enteric coat must be adopted, and that he would not take an immediate release formulation into animal trials. He was cross-examined on the basis that, because enteric coats had their own problems of variability, it would have been sensible to take both formulations forward before a final decision was taken.

“Q. I simply cannot understand, professor, why, with the uncertainties of, on the one hand, the amount of degradation and, on the other hand, the unpredictabilities of enteric coating, you do not say "Let's try both."

A. Because you undertake experiments on formulations that you think will work. You undertake experiments as a group, as a development team. You would look at this formulation and say, "There is going to be a severe issue here. Why would we make a formulation which would not work?" We would not have any expectation it would work. We make a formulation which would work, we are going to do pharmacokinetic studies on that and then into man, see if it has a clinical effect and that is what formulation teams do.

Q. But then you are assuming the result. You are assuming that your in vivo result is going to be the same as your in vitro result.

A. I do not think you are assuming. You are basing your decision, the development team is basing its decision, on clear data which illustrates the problem of degradation and based on their experience, understanding not only the formulation but also the properties of the drug and the clinical effect, you would then make your decision.”

It is answers of this kind which Mr Thorley described as over-confident, and unrepresentative of the more cautious attitude of the skilled person. It is fair to describe Professor’s Davies’ views as confidently expressed. It would also be wrong to assume that Professor Davies’ views would necessarily be those of the ordinary unimaginative skilled formulator. Nevertheless I considered that there was great force in Professor Davies’ evidence. To go forward with animal tests on an uncoated product would be to take a step strongly contra-indicated by the available evidence. Although Mr Thorley put the argument in an attractive way, what he was really doing by his cross-examination was urging the Professor to be more open minded and imaginative. He was unable to shake Professor Davies from the view that this was not how the average skilled team would operate.

Professor Buckton’s evidence was in the opposite sense. In his first report he expressed the view that if a formulator had concerns about degradation of the API in the stomach :

“it would be routine to do a study on the bio-availability of formulations with and without coatings in animals (usually dogs).”

This opinion was arrived at without reference to the actual data from degradation exhibited in the acid dissolution test. In his second report he tackled the degradation figures for the first time. After explaining the degradation rates for the erythromycin and penicillin G examples cited by Professor Davies, he gave this evidence:

“These degradation rates for erythromycin and penicillin G are very much faster than the 21% degradation of drospirenone observed by Schering after 10 minutes, or 50% after 45 minutes… with 50% of the drospirenone remaining after 45 minutes … (which may well be longer than the time it would spend so exposed in vivo) and also having reason to believe from Krause and Oelkers that drospirenone absorbs more rapidly than it degrades, a skilled formulator would have sufficient confidence that enough of it would survive to be absorbed and therefore that an effective immediate release formulation could be investigated."

This, of course, is a very much less powerful statement than that which he made in his first report about routine animal tests. In order to arrive at the conclusion that an effective immediate release formulation could be investigated, Professor Buckton found it necessary to rely on Krause for support. He confirmed this in cross-examination:

A. What I said in the report is that taking everything, you know, that is available to me, what is available to me is the Krause data which shows that spirorenone, which has I would say a broadly similar in vitro degradation rate, spirorenone does not convert substantially in the stomach and gives a reasonable outcome. Based with that information and the other information around, I would think it prudent to go to an animal model to assess the relative merits of an uncoated and a coated formulation. At no point have I said I believe there would be no degradation in the stomach. I suspect it would be something of a miracle if there would be no degradation, there would be some. The question is which one is going to work out better, which one is the better way forward: having an uncoated product which is at risk of degradation or a coated product which we have talked about the concerns for enteric coated tablets.

In the course of the trial a note of the first meeting between Professor Buckton and Richter’s solicitors was disclosed by Richter. It would be wrong to place too much reliance on this. Nevertheless, the view Professor Buckton then expressed was that:

“he might do an experiment whereby he gives a dog the tablet with and without an enteric coating. It was not an issue which would be catastrophic.” (added emphasis).

He also expressed the view at that meeting that:

“for a low dose compound he might be concerned if 10-20% converted in 45 minutes, this is a change which is liable to have a clinical effect”.

In the end, I am not able to conclude that it would be routine to do animal tests on an immediate release formulation. It would be a matter for the skilled judgment of the formulator. The factors he would bring to bear in making that decision are the following:

Firstly the skilled formulator would realise that the in vitro tests had shown a significant degree of degradation in the pH conditions likely to be encountered in the stomach. Whilst there was no established IVIVC, there was also no obvious reason why the drug should not also degrade in the stomach. It would indeed be a miracle if it did not. This would give rise to serious concern.

Secondly this is not a situation where a significant degree of degradation could be readily brushed aside. Contraceptive efficacy cannot be allowed to fall below 100%. The extent of degradation would be variable: varying residence times in the stomach dependent on many variables, coupled with varying stomach pH would ensure that this was so. It would not be sensible to attempt to compensate for this by increasing the dose, and the skilled person would not attempt to do so. Professor Davies explained:

“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.”

Thirdly, the risks involved in the two routes are not really comparable. Whilst the delay in onset of action with an enteric coating is a disadvantage, the skilled team would not consider that it posed a comparable risk to that involved with losing half the dose. Here Professor Davies was again clear:

Q. And so you would have had to say to your team, when you said, "I am going to recommend an enteric formulation, but you must realise that this is going to give a delay which may vary from 30 minutes to several hours and you will find considerable intrasubject and intersubject variation"?

A. Yes, and I think the team would recognise -- that is true, and the team would recognise that what is important is the trade-off between either having loss of potency of the drug byacid degradation versus delay in onset. But in the delay inonset, you could make an enterically coated tablet which wouldallow the drug to be released and in a way that you could get therapeutic effect. There is no reason why, in thisparticular case in contraception, there is not a need forimmediate release; in other words, the drug has to be thereimmediately. It could be delayed after the formulation leavesthe stomach and as long as the dose is delivered to thepatient, sufficient dose, you can achieve a therapeuticeffect, and that is how enteric systems work, and have worked.

A decision to do animal tests on an immediate release formulation would not in my judgment be obvious on the basis of the information which would be acquired by in vitro testing of DSP, following on from Oelkers. As this was an essential step in the obviousness argument presented the attack based on Oelkers alone must fail.

Richter did not advance any independent obviousness attack starting from the Krause papers alone. The case advanced at the trial was that these papers would be found in a literature search and provide encouragement to the skilled person to test an immediate released formulation in animals.

The experts agreed that there was no particular difficulty in conducting a literature search on DSP in 1999. A PubMed search would have produced a list of some 11 papers against DSP as a search term, and some six papers against the alternative name dihydrospirorenone. Krause I would appear in the first list and Krause III in the second.

However, beyond the fact that these two papers could have been obtained by way of a literature search conducted in this way, there was little to persuade me that the skilled formulator would take the trouble to obtain copies of these papers or review their contents.

The results of the literature search would be a list setting out the journal in which each paper is published, the title of the paper, its publication date and the identity of its authors. The skilled person would review this list to see which if any of the papers looked worth reviewing.

Krause I is published in the Journal of Chromatography, a publication which a formulator does not read as part of his work. That does not mean to say that he would not follow up the reference if there were some incentive to do so, but it is not a promising start. The title of the article is “Determination of plasma levels of spirorenone, a new aldosterone antagonist, and one of its metabolites by high performance liquid chromatography”. There is nothing there to excite the interest of the formulator. Spirorenone is not the drug he is concerned with. There is nothing to indicate that the metabolite is DSP. The paper is obviously about analysis of plasma not formulation. Moreover the indication involved is different from that which the formulator would be concerned with.

Krause III is published in the European Journal of Clinical Pharmacology, again not the formulator’s customary reading matter. Professor Davies said that clinical papers rarely had information relevant to formulations. The title is again unpromising. It relates entirely to a different drug for a different indication. He was cross-examined as follows:

“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.”

It was not established that there was anything to catch the interest of the formulator in the title to Krause III.

There was no attempt by Professor Buckton to re-create the thought processes by which he considered that the skilled person would obtain and review the contents of the two Krause papers. This was probably because he was presented with the two papers as part of his initial reading material on his introduction to the case. Indeed he did not appear to have read all the papers produced by the search. Mr Waugh relied on the fact that his reaction to the Krause papers at the first meeting was that he would have been unlikely to have read them and that he would not be concerned with them himself. This might have been directed to a slightly different question, namely whether he would have come across the papers in the ordinary course, and Professor Buckton could not remember the precise context. Nevertheless, in cross-examination he did not support the case that the formulator would obtain the documents and read them: he suspected that other members of the team would. I am left with no clear impression of what impact this might have had on the thinking of the team as a whole.

I am left with no confidence that the results of the literature search would lead the skilled person to read the contents of Krause I or III.

I conclude, therefore, that it is not legitimate to combine Oelkers with Krause I or III for the purposes of an obviousness attack.

In case I am wrong about the combination point, I should consider whether the combination of Oelkers and Krause I and III makes the invention claimed obvious. For this purpose I assume that at the outset of the investigation the skilled formulator had obtained copies of Oelkers, Krause I and Krause III and read them with interest.

The difference between this combination of documents and the inventive concept remains the same, although it must not be forgotten that Krause I and III are mainly concerned with SP, not DSP or EE. Krause III gives a hint that macro-crystalline material has been used, and that a different formulation might be used in future.

Krause I and III do provide evidence that the observed in vitro isomerisation of SP is not being replicated in vivo.

Richter’s case is that, seeing this lack of IVIVC, the skilled person would realise that he should test (or as they put it, be even more inclined to test) an immediate release formulation using an animalmodel either on its own, or in addition to the enteric coated version.

Schering’s answer is to attack the validity of the conclusions which the skilled person would be able to draw from Krause’s work. In essence they say:

I think that the problem with Richter’s case on Krause is that it does not provide a crisp or obvious answer to the problem which will be troubling the formulator, namely whether DSP will survive acid catalysed isomerisation in the stomach if not presented in an enteric coated form. The best that one can say in the light of the data in Krause is that the drug might survive in the final formulation. If it were to do so a number of assumptions about the behaviour of DSP when formulated as a contraceptive would have to turn out to be justified. SP would have to behave like DSP, or at least sufficiently similarly to achieve a similar result. Yet Krause shows that DSP degrades much more rapidly, so there is positive reason to suppose that the result will be different. Moreover Krause’s suggestion to modify the formulation from macrocrystalline form will lead the skilled person to doubt further whether the same result will be obtainable if those steps are taken and the drug is exposed to stomach acid for longer.

The inclusion of an immediate release version in animal tests would in my judgment not be a step which the skilled person would be able to take with the necessary “fair expectation of success”. The skilled formulator would have well in mind that success in this field includes near certainty of efficacy in all patients. The difficulties likely to be encountered if the drug is allowed to pass unprotected into and through the stomach would not be productive of confidence.

The evidence in this case is unusual for another reason. It is common in a patent case, with all the benefits that hindsight brings, to have a clear explanation of how the invention works. Yet none of the witnesses proffered an explanation of why it was that DSP does not degrade in vivo when it does so rapidly in vitro. Mr Thorley proffered the suggestion that the in vitro result at pH 1 is at the extreme acid end of the pH observed in the stomach, and that actual conditions are milder. I do not think that this explanation would satisfy the skilled formulator working to the objectives that oral contraceptives require. It is certainly not one which was advanced with confidence by any witness. I think one has to be particularly aware of the dangers of hindsight in such a case.

Both sides said that the evidence of what occurred at Schering supported their cases. I therefore need to summarise it.

DSP originally attracted Schering’s interest in the late 1970s to early 1980s as a potential competitor to spironolactone which was marketed as a diuretic to treat high blood pressure. The project generated evidence that DSP was a strong progestagen as well.

At a meeting in April 1983 it was decided to pursue DSP as the progestagen component of a combined oral contraceptive, given that there was potential for added value in reduction of blood pressure. Dr Tack was given the task of developing a formulation containing 1 mg active.

Dr Tack had access to and thinks he would have reviewed earlier work done within Schering and in particular a report of a Dr Raptis dated in January 1981 in relation to SP. Dr Raptis had analysed the degradation of SP in vitro at pH 1 at 37^oC and concluded:

"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."

Dr Raptis’ results showed that the half life of SP under these conditions was of the order of one hour.

Shortly after this report of Dr Raptis there is a report of work performed by Dr Krause which corresponds to the in vitro part of Krause I. It is clear from the report that the in vitro work is carried out at room temperature rather than 37^oC. Krause stated his conclusions in his report as follows:

“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…).”

A subsequent report by Dr Krause describes the in vivo part of Krause I. Krause reported that at higher doses the absorption of SP was not complete, and the observed in vitro inactivation was not observed in vivo.

Dr Tack proceeded to design his own formulation experiments for DSP. He did dissolution experiments at pH 1 at 37^oC . His conclusion is as expressed as follows:

“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.”

Dr Tack accordingly wrote to his superiors on 14th of September 1983 with the results of his investigations. He reported that:

“After 20 and 60 minutes, 35% and as much as 50% respectively of the total amount dissolved had isomerized.”

Dr Tack referred back to Dr Krause’s earlier work, saying that:

“The isomerization of [DSP] in hydrochloric acid medium has been known for some time ... but now needs to be discussed anew from the following perspective. Since the solubility of [DSP] is 5-10 mg/l and the gastric fluid volume is accepted to be approx. 100 ml, it has to be assumed that the majority of the planned dosages of 2-4 mg will dissolve and therefore quickly isomerize during gastric transit. This would result in a clear reduction of the bioavailability of the unchanged active substance.

From the Drug Formulation perspective, an enteric-coated tablet formulation ought therefore to be developed."

This document is important. It shows that conclusions drawn by Dr Krause in the context of his work were not regarded as transferable to DSP as an oral contraceptive, but needed to be re-assessed. In particular a low dose oral contraceptive which was shown to be acid labile and to dissolve completely in the stomach was thought to present too much of a risk. The proposal to develop an enteric-coated formulation was accepted by Dr Tack’s superiors, including Dr Hümpel and the clinicians.

Dr Tack also performed some theoretical calculations at the same time to try and determine whether there was an alternative to enteric coating. These calculations showed that between 12.5% and 42.7% of the DSP would be isomerised. He concluded that macrocrystalline forms or sustained release forms might be alternatives.

Schering developed an enteric coated formulation which they took through animal and clinical studies until 1988. In the course of these studies, Schering encountered inter- and intra-patient variability. Dr Tack remained convinced that an enteric coat was necessary. In February 1988 he gave a lecture at the Free University of Berlin on the topic of whether enteric coats were necessary for these compounds. He concluded that they were.

However, in 1988 Schering conducted a clinical trial in which a non-enteric coated pill was given to one group of volunteers and an enteric coated pill to another (a third arm was an intravenous dose: hence it was called the “three-arm study”). The three-arm study showed that there was no statistically significant difference between the enteric and non-enteric formulations.

The genesis of the three-arm study was a suggestion by Dr Düsterberg in light of the variability experienced, made in 1986:

“to test whether, similar to other analogues of this class of effective agents, the acid-catalysed transfer is negligible in vivo”

Mr Waugh submits that the Schering story supports the inventiveness of an immediate release product. Schering did not have the idea of such a product for many years, despite having access to the relevant data.

Mr Thorley submits that, appropriately analysed, the history supports Professor Buckton’s approach.

Mr Thorley takes first the work of Drs Raptis and Krause on SP and DSP in 1981-2. Although Dr Raptis voted for an enteric coating, Schering did not go ahead on this basis. Dr Krause went on to do two sets of in vivo testing to find out if an enteric coat was really necessary.

For my part I do not think there is much support for Richter’s case here. Dr Krause’s work was questioning what might be regarded as the conventional view. The plasma samples tested by Krause were obtained from a trial of heavily water-overloaded human patients, with no comparative enteric coated material. This does not support Professor Buckton’s view that the routine approach would be two test the two formulations alongside each other in animals. I do not think that Dr Krause’s work is typical of how a skilled person would proceed.

Mr Thorley seeks to dismiss Dr Tack’s work on the basis that he and Schering generally were insufficiently skilled in enteric coating, and were therefore unaware of the potential pitfalls of going down that route. I do not accept that submission. Dr Tack was aware of the problems highlighted in the literature with variability, but nevertheless considered that this route was preferable given the degradation problem. Dr Tack’s superiors, including Dr Zimmermann who was a very experienced formulator, approved the decision to coat the product.

Mr Thorley also explains the long period before Schering came up with an immediate release formulation on the same basis. The problems with enteric coats should, he submits, have been predicted much earlier. Again, I do not accept this. The decision to coat the product was one taken in the knowledge of potential pitfalls, but was driven by the far more serious perceived consequences of exposing the drug to acid in the stomach.

Next, Mr Thorley urges me to place great weight on Dr Düsterberg’s suggestion for the three-arm study based on analogy with SP. But this was no more than a research proposal for inclusion of a further arm in a study. There is nothing to indicate any degree of confidence in the likelihood of success of that arm. Professor Davies was surprised by the decision. His evidence, which I accept, is that he would not have taken this decision himself.

Mr Thorley criticised the fact that Drs Krause and Düsterberg were not called to give evidence. This is a fair point, although their role is plainly not as central as that of Dr Tack. In the end I think Schering’s history provides a reasonable measure of support for non-obviousness of the immediate release formulation. But I would have come to the same conclusion without it.

I have decided above that the claim is not limited specifically by reference to the absence of an enteric coat. This gives rise to an argument based on the Free University lecture which Dr Tack gave in Berlin. Figure 4.5 gives in vitro release data for DSP from enteric coated tablets. The enteric coat is Eudragit L. The tablets were first subjected to a pharmaceutical disintegration test called DAB 9 (short for Deutsches Arzneibuch 9). The tablets are exposed to pH 1 for 2 hours to test the enteric coating under the conditions of stomach acid. The tablets are then placed in a dissolution test according to USP XXI paddle method.

In his third report Professor Buckton points out that dissolution test shows that the mean percentage of DSP dissolved from the tablets at 30 minutes is greater than 70%.

Professor Davies’ answer is that the testing reported in Dr Tack’s lecture is not the same as that identified in the claim. It cannot be assumed that the formulations which emerge from the DAB 9 part of the test are identical to those that went into it: the test will cause the enteric coat to have become less robust. Professor Buckton accepted in cross-examination that the acid step could affect the results of the second stage of the testing. He did not know whether this was the case. Critically, he did not know for how much longer the tablet would have survived before it reached 70% if the step had not been performed.

Accordingly, in my judgment the evidence does not establish that the enteric coated tablet tested by Dr Tack falls within the claims limited by the Paddle test.

Mr Thorley also relied on some data in Dr Tack’s report at Bundle 9 tab 6. This data was also not generated under the conditions in the patent test. So I am unable to form any conclusion about that either. If Richter had been serious about showing that an enterically coated tablet which it was obvious to make fell within the claims, they should have performed appropriate tests to prove it. They have not done so.

The consequence of my conclusions thus far is that the claims limited by the Paddle test, that is to say claims 1 and 7 of 301 and claim 6 of 069 are not invalid for obviousness over Oelkers. They are also not invalid over Lachnit, where the argument follows a similar course. That leaves claims 1 and 19 of 069.

Practically no time at the trial was occupied on these claims, I suspect because Richter recognise that to succeed they need to succeed on claim 6 of 069 as well. It is important to recognise, however, that these claims monopolise any composition in which steps are taken to improve the rate of dissolution by surface coating inert particles with DSP (claim 1) by spraying (claim 19).

Mr Waugh’s submission was that no motive had been shown to coat the surface of inert particles. However, Professor Buckton explained during his cross examination that one would want to take steps to achieve rapid dissolution of the API even if one’s aim was to protect the formulation with an enteric coat until it reached the small intestine. If a skilled person were to seek to achieve this, I see no reason why in the case of the poorly soluble DSP he would not use surface coating of inert particles as a means of achieving it. Spray coating of inert particles was recognised to be part of the common general knowledge for achieving rapid dissolution of a poorly soluble API. I therefore consider that claims 1 and 19 of 069 lack inventive step over Oelkers and Lachnit.

Claim 19 will survive, however, if made dependent on claim 6.

I was shown the judgment of the Court of Appeals of the Federal Circuit on the corresponding United States patent: Bayer Scehring Pharma AG and another v Barr Laboaratries Inc. (Unrep August 5 2009). That court upheld the decision of Judge Sheridan sitting in the United States District Court for the District of New Jersey finding the patent invalid for obviousness. The CAFC was divided by two judges to one, Circuit Judge Pauline Newman dissenting. I have not found that decision of assistance in reaching my conclusions here, which are arrived at on the basis of the evidence adduced in this case.

Claim 1 of 301 and claim 6 of 069 are not invalid for obviousness. Claims 1 and 19 (as dependent on claim 1) of 069 are invalid for obviousness over Oelkers and Lachnit.

Subject to amendment of the 301 patent to deal with the 3 mg point, neither patent is invalid for added matter.

Claim 1 of 301 and claim 6 of 069 are not invalid for obviousness. Claims 1 and 19 of 069 are invalid for obviousness over Oelkers and Lachnit.