Gedeon Richter Plc v Bayer Schering Pharma AG

By this action, the claimant, Gedeon Richter plc (“Richter”), seeks the revocation of two patents belonging to the defendant Bayer Schering Pharma AG (“Schering”). The two patents in suit are European Patent (UK) Nos. 1,380,301 and 1,598,069 (“the 301 patent” and “the 069 patent” or “301” and “069” respectively). They are both entitled “Pharmaceutical combination of ethinylestradiol and drospirenone for use as a contraceptive”.

Both the patents are under opposition in the EPO. Schering is not seeking to maintain 301 in the form in which it was granted. It has therefore proposed unconditional amendments in this action in order to bring the claims into line with those it is seeking in the EPO. Schering has also put forward a second set of amendments to 301 in this action which are conditional on an added matter attack being successful.

Ethinylestradiol (“EE”) and drospirenone (“DSP”) are two steroidal hormones. EE is an estrogen hormone; DSP is a gestagen hormone. Each of these hormones regulates the female menstrual cycle. DSP has a propensity to isomerise (rearrange its atoms into a different configuration) under the acid conditions in the stomach. The patents are directed to the problem of finding a suitable pharmaceutical formulation of the drugs. Mr Simon Thorley QC and Mr Joe Delaney appeared for Richter. Mr Andrew Waugh QC and Mr Tom Hinchliffe appeared for Schering.

There are the following issues:

Obviousness of each of the patents in the light of four items of prior art:

“Effects of a new oral contraceptive containing an antimineralocorticoid progestogen, drospirenone, on the renin-aldosterone system, body weight, blood pressure, glucose tolerance and lipid metabolism”, Oelkers et al Journal of Clinical Endocrinology and Metabolism (1995) 80:1816-1821 (‘Oelkers’).

“Determination of plasma levels of Spirorenone, a new aldosterone antagonist, and one of its metabolites by high performance liquid chromatography”, Krause and Jakobs, Journal of Chromatography, 230 (1982) 37-45 (“Krause I”).

“Pharmacokinetics of the new aldosterone antagonist, Spirorenone, in healthy volunteers after single and repeated daily doses”, Krause et al Eur. J. Clin. Pharmacol (1983) 25 231-236 (“Krause III”).

US Patent 5,756,490 (“Lachnit”).

Added matter in each of the patents over that contained in the application for the parent patent, WO 01/15701 (“the Parent Application”).

Richter called Professor Graham Buckton who is a Professor of Pharmaceutics at the School of Pharmacy at the University of London. He is a Fellow of the Royal Pharmaceutical Society, the Royal Society of Chemistry, the American Association of Pharmaceutical Scientists and the Academy of Pharmaceutical Sciences of Great Britain. In 2000 he formed Pharmaterials Ltd, a company that provides contract services in the areas of physical form of pharmaceutical materials, materials science, formulation and analytical development.

Schering called Professor Martyn Davies. Professor Davies is a Professor in Biomedical Surface Chemistry at the School of Pharmacy at the University of Nottingham. Over his career he has primarily taught in the field of pharmaceutical technology, physical formulation and advanced drug delivery. He is the founder and chairman of Molecular Profiles Ltd, which is a pharmaceutical development and characterisation company which provides analytical support and consultancy to help find solutions for difficult drug substance and formulation issues.

Both sides criticised the other side’s expert. Mr Waugh made criticisms of Professor Buckton’s approach to the issues, whereas Mr Thorley said that Professor Davies exhibited a self-confidence in his views which would not be that of the ordinary skilled person. I think these questions are better considered in the context of the issues themselves, rather then as ad hominem attacks on the witnesses. Each expert recognised the expertise and academic distinction of the other. Both witnesses were doing their best to give reasons for their genuinely held views about inventiveness. It is for me to form a view as to how closely their reasoning would reflect that of the ordinarily skilled person.

Schering also called two fact witnesses, Dr Tack and Dr Hümpel to give an account of the work conducted at Schering on the pharmaceutical formulation and testing of EE and DSP. At the relevant time, Dr Tack was working in the galenics (pharmaceutical formulation) department of Schering. He was the person given the task of formulating a combination of DSP and EE for Schering’s clinical trials. Dr Hümpel was the head of Schering’s Department of Pharmacokinetics during the development of Schering’s DSP and EE combination formulation. Both witnesses gave their evidence fairly.

Richter also called unchallenged evidence, through a witness statement of their solicitor Abby Minns, reporting on communications with Professor Barry Potter a medicinal chemist at the University of Bath. Professor Potter was asked about whether DSP can form a salt, one of the ways in which one might seek to overcome the acid lability of DSP. Professor Potter’s unchallenged view was that there was no practical way of usefully protecting the molecule by this means. That evidence closed off that particular avenue, and I need say no more about it.

There was not much dispute as to the identity of the skilled team. The patents are both addressed to a team involved in the development of an oral contraceptive. The team would have included a pharmaceutical formulation scientist as well as a clinician with an interest in contraception (and possibly other sex steroid related indications). The formulator would be likely to have a degree in pharmacy (or a related discipline) and would have some industrial experience in pharmaceutical formulation. The clinician would have a good knowledge of sex steroids and their use as contraceptives.

The role of the pharmaceutical formulation scientist, or “formulator” is to design a suitable dosage form of an active pharmaceutical ingredient or API. The goal is to choose a form in which the API can be administered safely and effectively and in a way in which it will become bioavailable for its intended purpose.

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:

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]:

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:

In cross-examination he said that one would use in vitro data to cut down the number of formulations and take 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:

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:

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:

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

“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:

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:

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

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:

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:

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:

The “thrust” of the specification is that a rapidly dissolving formulation should be used: this is the antithesis of an enteric coat;

The dissolution test used in the claims is the test for immediate release formulations, not delayed or enterically coated ones;

The words at [18] and [38] of 301 which refer to rapid absorption/dissolution “on oral administration” are not apt to cover an enteric coated formulation;

There is no disclosure or example of enteric coating: [39] only refers to film coatings which would dissolve rapidly;

The skilled person would know that a particular commercial enteric coat (Eudragit) would not dissolve in water and so would infer that such a coat would not dissolve in the test specified in the claim.

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 fact that a claim covers something does not mean that it discloses it: AC Edwards v Acme Signs & Displays [1992] RPC 131 (see e.g. per Fox LJ at page 143). This fallacy was most recently exposed by Jacob LJ in Napp Pharmaceutical Holdings Ltd v ratiopharm GmbH [2009] EWCA Civ 252, [2009] RPC 18 at [98] – [99]. The point most commonly arises where a claim is widened (as it may be) during prosecution by the omission of a feature.

The mere fact that something is made express in the patent which would be implicit in the application does not amount to added matter: see per Kitchin J in European Central Bank v Document Security Systems [2007] EWHC 600 (Pat) at [100].

Nevertheless, implicit disclosure is to be distinguished from matter which would be obvious to the skilled reader: European Central Bank v Document Security Systems ibid. The distinction is an important one, and can in some cases be difficult to apply. It is not permissible to write into the patent obvious conclusions from the disclosure of the application: they must be expressed or implicit in the disclosure.

An eye needs to be kept on “impermissible intermediate generalisation” as explained by Pumfrey J (as he then was) Palmaz's European Patents [1999] RPC 47, 71 as follows:

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 extension of the disclosure relating to the teaching as to how to obtain good bioavailability. In the Parent Application this was disclosed as being achieved by “rapid dissolution” which “surprisingly” could be achieved by micronisation or spraying, whereas in the 301 patent the teaching is wider, any “rapid dissolution” formulation will achieve good bioavailability.

In the Parent Application there was a definition of what constituted “micronized form”. In the 301 Patent that definition has been deleted so that there is no definition as to what constitutes micronized form.

The definition of “rapid dissolution” has been altered so as to exclude the requirement that the test should be done on a tablet preparation containing 3mg of drospirenone in 900ml of water.

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

The disclosure in the Parent Application was only of the use of a spraying method to apply DSP on to the surface of inert carrier particles to promote “rapid dissolution”, whereas the disclosure in 069 extends to cover any other method of applying the same.

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.

The disclosure in the Parent Application was of two inventions, one being the method of obtaining “rapid dissolution” of DSP, and the other of obtaining a composition within the therapeutic window of DSP. The formulation of inert carrier particles containing DSP on their surface was disclosed as being material to the first invention. In 069, by way of an intermediate generalisation, it is disclosed as being material to the second invention as well.

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:

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

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:

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:

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:

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]:

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:

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

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.

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 :

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:

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:

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 also expressed the view at that meeting that:

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:

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:

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:

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 animal model 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:

Even at face value the rates of isomerisation for SP and DSP are comparable to the mean residence time in the stomach. Krause’s explanation that the acid catalysed isomerisation is relatively slow compared to the possible absorption rate in the stomach is not one which the skilled person would find at all convincing. Moreover it is expressed in an inaccurate way, as drug is not absorbed from the stomach in any event. The skilled formulator would know that the stomach is not the primary site for absorption, a point made by Professor Buckton at the first meeting. What is significant is the residence time in the stomach and the rate at which the drug is emptied.

The rates and half-lives derivable from Krause are based on data obtained at room temperature, when the rates in vivo would be about twice as fast.

The rates of isomerisation of SP and DSP are different: Professor Davies considers, and I accept, that DSP degrades approximately 50% faster than SP at pH 1 at room temperature.

The in vivo tests were on a small scale using unusual water load conditions (although these factors were eliminated for SP by Krause III);

Only SP was administered to patients. Although DSP is formed as a by-product of the metabolism of SP in vivo, DSP would not be exposed to acid in the stomach. Professor Davies points out, therefore, that one cannot conclude from the fact that the isomer of DSP is not visible in plasma that it would not undergo acid catalysed isomerisation in vivo.

The doses of SP being administered were large. Given the poor solubility of SP, and the fact that Krause uses a macro-crystalline form of the drug means that very little will have had the opportunity to dissolve in the stomach. Instead it would have passed through the stomach in a solid suspension. Professor Davies explained this as follows:

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:

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:

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:

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

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

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:

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.