2ry Patent For Protection

The art of using secondary patents to improve protection Received (in revised form): 4th March, 2003

Michael Burdon is Head of Olswang’s sector-focussed Biosciences team and a member of the Intellectual Property Group. His principal area of expertise is patents, especially multijurisdictional disputes. Michael manages the legal requirements of and provides specialist intellectual property and regulatory advice to, participants in all aspects of the biosciences industry. He serves on the Intellectual Property Advisory Committee of the BioIndustry Association, is an associate member of the Chartered Institute of Patent Agents and on the Editorial Board of Patent World. He regularly writes for specialist journals and chairs and speaks at conferences and in the media about biosciences and intellectual property. He has been selected for inclusion in the Euromoney Guide to the World’s Patent Law Experts as well as Law Business Research’s International Who’s Who of Patent Lawyers. He is also ‘Highly Recommended’ in the UK Intellectual Property (Hard) category of PLC’s Global Counsel 3000.

Kristie Sloper is an assistant solicitor in the Intellectual Property Group and a member of the Biosciences team. She works on a variety of contentious intellectual property matters including patent, trademark, copyright and design right disputes. She has particular experience of advising clients in the biotechnology and pharmaceutical sectors on a broad range of intellectual property and regulatory matters.

Keywords patents, secondary patents, legal, patent protection, intellectual property, pharmaceuticals Abstract In an environment where there is ever increasing pressure on innovator pharmaceutical companies to maximise return on investment and where share values may be substantially affected by court decisions in patent litigation between pharmaceutical innovators and generic companies, a key element of pharmaceutical life cycle management strategies is to extend patent protection for as long as possible by filing secondary patents to keep generics off the market. This paper considers the approach taken by the UK courts to the enforcement of secondary patents, focussing on recent decisions of the UK courts and attempting to draw some conclusions from the case law as to the types of secondary patent that may be enforceable in the UK and the implications of the case law for the development of a credible life cycle management strategy.

INTRODUCTION

Michael Burdon Partner, Olswang, 90 High Holborn, London WC1V 6XX, UK Tel: +44 (0)20 7208 8697 e-mail: [email protected]

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There has been a great deal of publicity during the first few months of 2003 concerning the current decline in productivity, as measured by the number of successful new chemical entities reaching market, of the research and development (R&D) departments of the innovator pharmaceutical companies. Despite a large increase in investment in R&D, the number of new chemical entities reaching the market has been in

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steady decline. The annual number of new chemical entities approved by the US’ FDA fell from an all-time high of 53 in 1996 to 24 in 2001. As at September 2002, the number of new chemical entities obtaining approval in 2002 was only 11. Added to this problem of the dearth of new drugs is the problem of patent expiration and/or revocation of the patents protecting existing brand-name drugs. A number of high profile drugs lost patent protection and fell open to generic

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competition during 2001–2002; among them, Eli Lilly’s PROZAC, GlaxoSmithKline’s AUGMENTIN and Akzo Nobel’s REMERON. Such loss of protection often has a devastating effect on sales and share price. Sales of Prozac fell 66 per cent following the loss of patent protection and this shortfall led Eli Lilly to reduce profit estimates three times in one year. It is clear that court decisions in the USA, the UK and elsewhere in patent litigation between pharmaceutical innovators and generic companies can have a substantial effect on share prices. This is well illustrated by the case of PRILOSEC, AstraZeneca’s ulcer drug. The patent on the active ingredient in Prilosec, omeprazole, expired in October 2001 in the USA. The Supplementary Protection Certificate protecting omeprazole in the UK expired in April 2002. Prilosec, which has annual global revenues of approximately US$6bn a year, was widely regarded as one of the best selling drugs in the world. Following the expiry of patent protection on omeprazole, AstraZeneca sought to extend their period of exclusivity and to keep generics off the market using formulation patents for a coating for an oral administration form of Prilosec. Shares in AstraZeneca rose by 13 per cent, after a US court ruled that the US formulation patents on the coating for Prilosec were valid until 2007 and that three of the four companies, which had applied to sell generic versions of Prilosec, were infringing these patents. The US court found that the product of the fourth company, Schwarz Pharma of Germany, did not infringe these patents. Following this ruling Schwarz Pharma’s shares soared by 80 per cent. The unpredictability of patent litigation however, is illustrated by the fact that just 10 days later the UK Court of Appeal found AstraZeneca’s UK formulation patents for the coating on the drug (known as Losec in the UK) to be

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invalid. As the UK accounted for only 4.3 per cent of worldwide sales of Losec, this ruling did not have such a substantial effect on AstraZeneca, but it still resulted in a share price drop. There is thus increasing pressure on innovator pharmaceutical companies to maximise the value obtained from each product in view of the very high R&D costs of pharmaceuticals. Development of a ‘life cycle management’ strategy in relation to successful products to ensure that maximum value can be obtained has therefore become increasingly important. Life cycle management strategies commonly include the tactical use of patent litigation and the proactive strategic use of the regulatory system. A key element of any life cycle management strategy however, is to extend patent protection beyond the basic patent term for as long as possible, by filing secondary patents which are effective to keep generics off the market. This paper provides a brief consideration of the different types of secondary patents that may be available and considers the approach taken by the courts to enforcement of these types of patents. As can be seen from the example given above in relation to omeprazole, there may be differences in the outcome of patent litigation in different jurisdictions. Such differences in outcome may result from a number of factors including differences in the substantive legislation (eg between the UK and USA); differences in the procedural requirements of each jurisdiction; differences in the evidence put before the courts in each jurisdiction and differences in the approach of the courts to interpretation of the relevant provisions of the legislation. This paper focuses primarily on recent decisions of the UK courts and attempts to draw some conclusions from the case law as to the types of secondary patent that may be enforceable in the UK and the

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implications of the case law for the development of a credible life cycle management strategy.

SECONDARY PATENTS The process of converting a new chemical entity into a marketable product involves a great deal of research and investment. During this research process, a number of new and potentially patentable discoveries may result. These discoveries may result in ‘secondary patents’, the aim of which is generally to extend the period of patent protection of the compound and therefore extend the period of exclusivity during which the product can be marketed free from generic competition. Possible types of secondary patent include: . . . . . . .

Composition patents Patents for new polymorphs Patents for new formulations Synthesis patents Patents for new therapeutic uses Patents for new treatment regimes Patents for metabolites/pro drugs.

As the aim in filing secondary patents is to extend the period of exclusivity for the product, such patents must be filed later than the basic patents. This means that the basic patent is generally prior art in relation to the secondary patent. This may give rise to difficulties in validity and enforcement. Set out below are summaries of some recent decisions of the UK courts in relation to some of the types of secondary patents referred to above.

PATENTS FOR NEW POLYMORPHS: SMITHKLINE BEECHAM AND SEROXAT There have been a number of cases involving patents concerned with SmithKline Beecham’s antidepressant product paroxetine, which is marketed as Seroxat in the UK (Paxil in the USA).

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Seroxat is one of SmithKline Beecham’s leading products. Patent protection on the basic compound paroxetine hydrochloride (for which a Supplementary Protection Certificate was obtained on the expiry of the basic patent in the UK) expired in the UK in January 1999. The patent in issue in many of the recent disputes in the UK was GB 2,297,550 which relates to the anhydrous form of paroxetine hydrochloride, its preparation and its use as a therapeutic agent. The specification described the invention as ‘paroxetine hydrochloride anhydrate substantially free of bound organic solvent’. SmithKline Beecham’s Seroxat product is in fact produced from a different form of paroxetine hydrochloride, the hemihydrate. Due to the existence of patent protection on the hemihydrate and other hydrated forms however, a number of generic companies sought to develop paroxetine hydrochloride products that utilise the anhydrate form. Set out below are summaries of some of the recent decisions in this area.

SmithKline Beecham v Generics (UK) Ltd (23rd October, 2001) SmithKline Beecham applied for an interim injunction restraining infringement of GB 2,297,550 by Generics (UK). The matter came before Mr Justice Jacob, who granted the injunction. This case was notable, as it was the first time that an interim injunction had been granted in patent proceedings in the UK for a number of years and was therefore a significant victory for the patentee. In reaching his decision to grant an interim injunction in that case, the judge took into account the fact that the defendant had known about the patent for a long time and therefore could have taken steps (by, eg applying for a declaration of non-infringement, launching a petition to revoke or inviting the claimant to sue) to

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clear its position prior to the intended launch of its product. This decision places a high burden on a generic company planning to launch a product where that company is aware of a competitor’s patent and the possibility of infringement. The proceedings between SmithKline Beecham and Generics subsequently settled before the matter came to a full trial.

BASF v SmithKline Beecham (12th July, 2002) BASF brought proceedings to revoke GB 2,297,550 on the grounds of anticipation and/or obviousness. The main item of prior art relied on was an earlier Beecham Group patent application (the ‘407 application’), which was never published by the UK Patent Office, but was subsequently published in the files of a later application (the ‘403 application’), when that application was published by the EPO. The ‘407 application’ was concerned with the preparation of crystalline paroxetine hydrochloride. It describes the production of three polymorphic forms: the hemihydrate, the anhydrate and paroxetine hydrochloride isopropanol solvate. A method of preparation of the anhydrate form is described. BASF alleged that the patent was invalid for anticipation and/or obviousness in relation to the ‘407 patent’. Issues of construction arose in relation to the meaning of the phrase ‘substantially free of bound organic solvent’. The specification sought to define this as ‘less than the amount of propan-2-ol that would remain solvated, ie bound, within the crystal lattice of the product under conventional vacuum oven drying conditions’. The judge stated that he found this issue of construction very difficult to decide, but he concluded that this passage was to be read as relating to any relevant organic solvent or solvents, rather than merely to propan-2-ol.

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The evidence showed that although at the time the ‘407 application was prepared it appeared that it was possible to produce the anhydrate by following the method set out in this application, subsequently (and prior to the priority date of the patent) it became impossible to reproduce the teaching of the ‘407 application to produce the anhydrate form. The judge found that the experiments performed by the parties in the course of the litigation failed to establish that the anhydrate form could be produced by this method. The result of following the teaching of the ‘407 patent was that a hydrated form of paroxetine hydrochloride was produced. The court held that the claim to paroxetine hydrochloride substantially free of bound organic solvent was therefore not anticipated over the ‘407 patent. Some, but not all, of the process claims however, were found to be invalid on the ground of obviousness. The judge stated that the product claims would have to be limited to the products of the valid process claims. Following this judgment, SmithKline Beecham applied to amend the patent. The amendment proceedings are continuing and are due to be heard in July 2003. In addition, both parties have appealed the judgment. The appeal is due to be heard in May 2003.

SmithKline Beecham v Apotex & others (28th November, 2002) Following their successful application for an interim injunction against Generics in October 2001, SmithKline Beecham applied for a further interim injunction restraining infringement of GB 2,297,550 by Apotex and others. The matter came before Mr Justice Jacob in November 2002. By this date, the patent had been held only partially valid by the decision of Mr Justice Pumfrey in the action against BASF in July 2002. The claim that SmithKline Beecham sought to enforce

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against Apotex, Claim 11, however, was one of the claims that had been held valid by Mr Justice Pumfrey. SmithKline Beecham argued that the defendants’ process infringed this claim and that an interim injunction should be granted restraining infringement pending trial. The defendants argued that the judge should not grant an injunction. They raised a number of points. They stated that their product did not infringe the claim; that since the claimants were not exploiting the patent (as their product in fact involved the hemihydrate and not the anhydrate form) they should not be entitled to damages and therefore no injunction should be granted; that since the patent had been found only partially valid and therefore required amendment, no injunction should be granted; and that damages would be an adequate remedy to SmithKline Beecham, should infringement be established at trial. The judge rejected the defendants’ arguments, considering that it was appropriate to grant an interim injunction in all the circumstances. He reiterated his comments in the earlier case against Generics that the generic company should take steps to clear its position prior to launch of its product, stating that: ‘Where litigation is bound to ensue if the defendant introduces his product he can avoid all the problems of an interlocutory injunction if he clears the way first. That is what the procedures for revocation and declaration of noninfringement are for’.

SmithKline Beecham v Apotex & others (4th February, 2003) This dispute came back before the court on a matter relating to confidentiality of test results and whether the results of tests which had been conducted for the purposes of the UK proceedings could be disclosed or used outside those proceedings.

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SmithKline Beecham had asked the defendants for samples of their product to enable them to ascertain whether or not they infringed the patent. The defendants agreed to provide samples but wanted access to the samples and the results of the tests controlled by certain confidentiality undertakings. SmithKline Beecham objected to the draft undertakings because they imposed restrictions on SmithKline Beecham but allowed the defendants to use the test results in any way they chose. The undertakings were amended, but it became apparent that the defendants thought they could use the test results provided for the purpose of these proceedings by the claimants, in any way they chose. The defendants submitted that if the test results proved to be unhelpful to them, then they could restrain SmithKline Beecham from making use of the samples or results outside the proceedings, but that the defendants could use them in any way they chose. The court held that CPR Part 31.22 applied once the proceedings had commenced. This rule states that a party to whom a document has been disclosed may use the document only for the purpose of the proceedings in which it is disclosed, except where — (1) the document has been read to or by the court, or referred to, at a hearing which has been held in public, (2) the court gives permission, or (3) the party who disclosed the document and the person to whom the document belongs agree. SmithKline Beecham had submitted that if the test results fell outside CPR 31.22, then they could be used in the current US proceedings, although they were generated solely for the purpose of the UK proceedings. The court held that the test results came within CPR 31.22 and should not be disclosed outside the UK proceedings except where the parties agreed or by order of the court.

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Synthon BV v SmithKline Beecham (19th June, 2002; 31st July, 2002; 3rd December, 2002) Synthon brought an action for revocation in relation to a further patent owned by SmithKline Beecham relating to paroxetine, GB 2,336,364. This patent relates to paroxetine methansulphonate in crystalline form. Synthon had filed a patent application in relation to paroxetine methansulphonate in June 1997, prior to the priority date of SmithKline Beecham’s patent in July 1998. Synthon’s patent application was unpublished at the priority date of SmithKline Beecham’s patent. Under section 2(3) of the Patents Act 1977 Synthon’s patent application was therefore deemed to be prior art for the purposes of a novelty attack but not for the purposes of obviousness. The Synthon patent application described paroxetine methansulphonate, a method of making it and an IR spectrum characterising it. The main claim of SmithKline Beecham’s patent was as follows: ‘Paroxetine methansulphonate in crystalline form having inter alia the following characteristic IR peaks [list] and/or the following XRD peaks [list]’

The key difficulty for Synthon was that the product described in the Synthon patent application had a different IR spectrum to that set out in the SmithKline Beecham patent. Synthon claimed that the patent was anticipated by their prior application. SmithKline Beecham argued that Synthon had identified a different polymorph since a different IR spectrum was obtained. Synthon alleged that the IR spectrum set out in their patent application was erroneous and that if the method set out in the patent application was repeated the IR spectrums obtained would be those set out in SmithKline Beecham’s patent.

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Their argument was in essence that there was ‘only one paroxetine methanesulphonate’, as the judge put it and that this was disclosed by their prior application. Synthon made an application to the court in June 2002 to determine the admissibility of experiments carried out to establish that following the method set out in Synthon’s patent application would produce a product having exactly the same characteristics as those disclosed in the patent in suit. SmithKline Beecham argued that the results of these experiments were irrelevant since the ‘inevitable result’ test for anticipation could not apply where the prior art was an unpublished patent application which only constituted prior art under the provisions of section 2(3). They stated that in these circumstances the application could only be novelty destroying if this was clear on the face of the application. The judge dismissed SmithKline Beecham’s argument, stating that it would be bizarre if there were two sorts of novelty, one for actually prior published applications and one for deemed prior published applications. If the inevitable result of using the process described in Synthon’s application was a product within the claims of the patent in suit then experiments proving this were both relevant and admissible. The matter was appealed to the Court of Appeal, who agreed with the judge. The experimental evidence was therefore admitted. The matter came to trial in October 2002 and judgment was given by Mr Justice Jacob on 3rd December, 2002. The judge found on a balance of probabilities that Synthon was correct that there was only one crystalline form of paroxetine methansulphonate. He found on the evidence that the Synthon experiment was not repeatable. He considered however, that if SmithKline Beecham’s patent enabled crystals to be made in all the ways it taught, so did Synthon’s patent

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application. Synthon’s patent application was a general disclosure of a wide variety of methods of making crystalline paroxetine methansulphonate. SmithKline Beecham’s later disclosure was an equivalent wide disclosure. All that could be said for SmithKline Beecham was that the disclosure in their patent was to a readier way of making the crystals, but the disclosure in Synthon’s application was clear enough and amounted to an anticipation. It was Synthon that first invented paroxetine methansulphonate, including the crystals of the SmithKline Beecham form and Synthon gave enough information as to how to make this substance. The patent was therefore held invalid and revoked.

FORMULATION PATENTS: CAIRNSTORES LTD & GENERICS (UK) LTD v AKTIEBOLAGET HASSLE (6th MARCH, 2002; 22nd OCTOBER, 2002) (OMEPRAZOLE) The principal patent in issue in this case concerned a formulation of an oral preparation containing the drug omeprazole, which inhibits the secretion of acid in the stomach and is used in the treatment of gastric ulcers. The basic patent for omeprazole had expired but was the subject of a Supplementary Protection Certificate, which would expire in April 2002. Omeprazole is very sensitive to and can be degraded by acid and therefore had to be in a form which protected it during its passage through the stomach, but which allowed it to be released in the intestine. The invention was a way of orally administering the drug, which was resistant to stomach acid but was bioavailable in the intestines. The solution to this problem in the patent had three parts; the use of a separating layer, which was water soluble or dispersible and the

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use of alkali or alkaline salts in the omeprazole core. The claimants applied to revoke the patent on the basis of common general knowledge and prior art. Mr Justice Laddie held the patent should be revoked on the following grounds: 1

2

The possibility of chemical interaction between a new drug and each of the excipients contemplated for use in the dosage form, including the coating material, would have been recognised by the skilled formulator. Compatibility tests would have been carried out as a matter of course, which would have shown incompatibility between the omeprazole and the coating material. A soluble intermediate layer or coat would have been expected to work by the notional skilled man, or to be sufficiently likely to work to warrant trial. There was nothing that would have deterred him from trying such a separating layer. Therefore Claim 1 and all the remaining claims failed for obviousness and the prior art (various technical leaflets/books) relied on by the claimants also rendered the claim invalid for obviousness.

The defendant appealed to the Court of Appeal. The main ground of appeal was the judge’s conduct. The defendant alleged that the conduct of the judge during the cross examination of the defendant’s expert had been such as to render the trial unfair. In his judgment, the judge had rejected much of this expert’s evidence and stated that he had acted more as an advocate than as an expert for the defendant and that his evidence had become increasingly unconvincing during the course of cross examination. The Court of Appeal noted that some of the questions asked by the judge could be seen as not directed to clarifying or amplifying an answer previously given, but found that there was

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no doubt that when considered in context, the judge’s part in the trial as a whole could not be seen as such to render the trial unfair. The appeal was dismissed.

SYNTHESIS PATENTS: GENERICS BV v SMITH KLINE & FRENCH LABORATORIES LTD (EUROPEAN COURT OF JUSTICE, 9th JULY, 1997) (TAGAMET) This decision of the European Court of Justice is significant in that it was the first decision to confirm that remedies for patent infringement may extend beyond the life of the patent itself. In this case the ECJ confirmed that a post expiry injunction did not amount to an unlawful restraint of trade. The principle of this decision was followed in the UK in the case of Dyson v Hoover in 2001 where the judge awarded a post-expiry injunction against Hoover. On 19th June, 1991, following an application submitted on 4th September, 1973, SKF was granted a Netherlands patent in respect of a manufacturing process for a pharmaceutical preparation having the generic name ‘cimetidine’, which it marketed in the Netherlands under the brand name ‘Tagamet’. That patent expired on 4th September, 1993. In October 1987 and October 1989, Genfarma BV (‘Genfarma’) filed three applications with the assessment board for medicinal products (‘the CBG’) to register 200 mg, 400 mg and 800 mg cimetidine tablets. Samples of those preparations were submitted to the CBG with the applications. Genfarma was granted registration in January 1990 in respect of the first two applications and in December 1992 in respect of the third. Genfarma subsequently transferred those registrations to Generics and, in June 1993, they were entered under Generics’ name in the register of pharmaceutical preparations.

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In August 1993, SKF applied to the Dutch court for an injunction restraining Generics, until November 1994, from offering or supplying cimetidine on the Netherlands market or transferring to third parties the registrations relating to that product. SKF considered that the submission of the samples of cimetidine preparation to the CBG constituted an infringement of its patent under Dutch law. In particular, SKF referred to the judgment delivered by the Supreme Court in Medicopharma v ICI, in which it was held that submission to the CBG of samples of a medicinal product manufactured in accordance with a patented process, by a person other than the patentee, with a view to placing the product on the market after the expiry of the patent, was not covered by the exemption in Article 30(3) of the relevant Dutch law. That paragraph provides: ‘The exclusive right does not extend to acts undertaken solely for the purposes of an examination of the patented object, which must be taken to include a product directly obtained by means of the application of the patented process.’ SKF took the view, therefore, that Generics could not have applied for the registrations until after the expiry of the patent on 4th September, 1993 and that given the duration of the registration procedure in the Netherlands, it would not have obtained them for another 14 months. They therefore asked for the injunction to be extended to 5th November, 1994. The Dutch courts referred to the ECJ for a ruling as to whether the post-patent expiry injunction constitutes a measure which is prohibited by Article 30 of the EC Treaty and which is not covered by the exception contained in Article 36 of the EC Treaty, as being a barrier to intracommunity trade. The ECJ approved the decision of the Dutch courts to grant the injunction,

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stating that if Generics had respected SKF’s patent, they could not have submitted the cimetidine samples until after the patent expired. SKF would therefore have been able to continue marketing its product without competition from the generic product for the period required to obtain the marketing authorisation. The relief imposed by the court, in so far as it sought to place SKF in the position in which it would have been in had its rights been respected, could not be disproportionate.

NEW THERAPEUTIC USES Article 52(4) of the European Patent Convention states that methods of treatment of the human or animal body by surgery or therapy or diagnostic methods practised on the human or animal body shall not be regarded as inventions which are susceptible of industrial application and therefore shall not be patentable. This provision however, goes on to state that this exception does not apply to products, in particular substances or compositions, for use in any of these methods. Article 54(5) in effect provides that first medical uses of substances or compositions will be patentable. This section states that the use of a known compound for a method of treatment may be patentable if the use itself does not form part of the state of the art. Novelty resides in the use itself. Article 54(5) however, effectively precludes a claim to a substance or composition characterised by a medical application if that product has already been described for another medical use (‘further medical use’ or ‘second medical use’ claims). The question therefore arose as to whether such second (or subsequent) medical use claims could be patentable in any circumstances or whether this article precluded the patentability of such claims. In the EISAI case in 1985 (G 5/83) the Enlarged Board of Appeal of the EPO held that second medical use claims were patentable. This decision was subsequently

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followed by the English courts in Wyeth & Schering’s Applications [1985] RPC 545. Novelty was held to reside in the new second (or subsequent) use. In order to claim an invention which involves second or subsequent medical use of a known substance or composition, it has been necessary for the claims to be expressed in a form known as ‘Swiss-type’ claims (because the EPO in EISAI followed a precedent first set by the Swiss Patent Office). ‘Swiss-type’ claims are those directed to the use of a substance or composition for the manufacture of a medicament for a specified new and inventive therapeutic application, ie ‘Use of X for the manufacture of a medicament for the treatment of Y’. Article 54(5) is due to be amended following the Diplomatic Conference held in November 2000 at the EPO. The amended article will specifically allow for claims to second and further medical uses of known substances or compositions and therefore avoid the need for such claims to be expressed as ‘Swiss-type’ claims. Set out below are several recent cases concerning claims to second medical uses.

Lilly ICOS v Pfizer (23rd January, 2002) (VIAGRA) One of the most high profile cases concerned the patent dispute between Pfizer and Lilly ICOS in relation to Pfizer’s second medical use patent covering Viagra (sildenafil citrate). In 1991 and 1992 Pfizer patented a series of compounds, which exhibited selective inhibition of phosphodiesterases (‘PDEs’). The patented compounds included sildenafil citrate. The patents stated that these compounds were useful in the treatment of angina and hypertension. In 1992 and 1993 several research articles were published, which suggested that an inhibitor of PDEs would be useful in the treatment of impotence and male erectile dysfunction (MED).

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Pfizer applied for the patent in suit in June 1994. This patent covered substantially the same compounds, including sildenafil citrate, which had been patented in 1991 and 1992, but this time claimed that the invention was the use of those products as a treatment for impotence and MED. The specification of the patent stated that the compounds had ‘unexpectedly’ been found to operate as inhibitors of PDEs and had the added advantage of being capable of being administered orally, thereby removing the disadvantages associated with the common treatments for impotence and MED, which were administered by injection. The main claim was drafted in the Swiss form. The matter came before Mr Justice Laddie in November 2000. Lilly ICOS argued that the patent was invalid for obviousness in view of the 1992–1993 articles. Pfizer argued that these articles did not suggest the use of PDE inhibitors as an oral treatment for impotence and that the patent was inventive in this respect. The judge found that the only difference between the prior art and the claims in the patent was the suggestion of oral use. He held that this did not constitute an invention. The patent was invalid for obviousness and should therefore be revoked. Pfizer appealed. The Court of Appeal dismissed the appeal. They held that the judge had rightly held the patent to be invalid for obviousness. Anyone reading the prior art would have realised that PDE inhibitors were likely to be effective in the treatment of impotence and MED. There was nothing inventive in trying them out for that purpose. The Court of Appeal rejected the argument that the judge’s conclusion had been arrived at as a result of hindsight reasoning, which was unfair to inventors. The also found that while there were reasons for doubting the ability to administer orally a drug to treat MED, this did not mean that it was inventive to

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decide to do so. Oral was the obvious route of administration and there was nothing in the specification that suggested there was any difficulty to be overcome to adapt the compound for oral use. If it was obvious to try, success was within the reach of the skilled person carrying out routine procedures.

AHP v Novartis (27th July, 2000) (RAPAMYCIN) This case concerned a patent for the use of rapamycin for inhibiting transplant rejection in mammals. Rapamycin was a known compound also known at the priority date of the patent, to be useful as an immunosuppressant. The patent claimed a second medical use of rapamycin, namely its use in the prevention of transplant rejection. Claim 1 was drafted in Swiss form as follows: ‘Use of rapamycin for the preparation of a medicament for inhibiting organ or tissue transplant rejection in a mammal in need thereof’. Derivatives and prodrugs of rapamycin were mentioned in the title of the patent and in the specification, but not in the claims. Novartis’ alleged infringing product was an immunosuppressant known as SDZ RAD, a derivative of rapamycin. AHP claimed that the patent covered the use of rapamycin and derivatives of rapamycin, which exhibited the same immunosuppressive effect as rapamycin, including SDZ RAD. Novartis contended that the patent covered the use of the compound rapamycin only and therefore SDZ RAD did not infringe. At the first instance hearing Mr Justice Laddie concluded that the person skilled in the art would understand the scope of the patent to include such derivatives of rapamycin as exhibited the same type of inhibition to organ rejection as rapamycin itself did. He therefore concluded that Novartis’ product infringed the patent. The Court of Appeal overturned Mr Justice Laddie’s judgment. They concluded

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that the scope of protection of the patent was limited to the use of rapamycin alone and therefore there was no infringement. They found that if Claim 1 had the broader scope contended for by AHP, then the specification would have been insufficient, since to be sufficient the claim must be enabled over its entire scope and the skilled person should not be expected to carry out research to ascertain how the invention is to be performed. For the patent to cover derivatives of rapamycin, it would need to disclose how to perform the invention with such derivatives. Although the patent gave a starting point, the skilled man was left to ascertain by research which derivatives worked; an enormous task since these derivatives would need to be conceived, produced and tested for their effect in the inhibition of transplant rejection. The Court of Appeal therefore concluded that the patent was valid but not infringed. Note that this case was slightly unusual in that the parties had agreed between them that the issues of infringement and sufficiency should be heard separately from the issues of novelty and obviousness. The above decisions related to the case on infringement and sufficiency only, the issues of novelty and obviousness to be heard at a later date. The parties subsequently settled their dispute before the trial on novelty and obviousness took place. As is often the case with patent disputes, parallel proceedings were also ongoing in Germany and the Netherlands. The District Court of the Hague on 29th March, 2000 came to the same view later reached by the English Court of Appeal in this case, ie that the scope of the patent was limited to the use of the compound rapamycin itself and that Novartis’ derivative therefore did not infringe.

NEW TREATMENT REGIMES As stated above in the discussion on second medical use patents, Article 52(4) of the

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European Patent Convention excludes methods of treatment of the human or animal body by surgery or therapy or diagnostic methods from patentability. There are therefore difficulties in trying to obtain a valid patent for new treatment regimes in Europe. As can be seen from the summaries set out below, the current position in the UK is that claims to new treatment regimes are likely to be seen as claims to methods of treatment and therefore unpatentable. In the case of Teva v Merck, however, the judge expressed some reservations as to whether this is in fact the correct approach to take. It will be interesting to see whether the Court of Appeal follow their reasoning in Bristol Myers Squibb v Baker Norton when this question next comes before that Court.

Bristol Myers Squibb v Baker Norton (23rd May, 2000) (TAXOL) This case concerned Bristol Myers Squibb’s taxol product, which is used in the treatment of cancers, particularly breast cancer and ovarian cancer. Taxol was a natural product, which was known to have anti-tumour activity prior to the priority date of the patent. The use of taxol however, was limited by its sideeffects, in particular neutropenia, a reduction in the white blood cell count. Bristol Myers Squibb filed a UK patent in 1993 for the ‘use of taxol . . . for manufacturing a medicament . . . for the administration of 135–175 mg/m2 taxol over a period of about 3 hours or less, as a means of treating cancer and simultaneously reducing neutropenia’. Baker Norton contended that the patent was invalid for lack of novelty and/or inventive step, since the prior art had suggested that taxol may be administered over 3 hours (although the reduction in neutropenia that might result from such administration had not been explicitly stated). They also alleged that the claim, although drafted in Swiss form, was really

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The art of using secondary patents to improve protection

a ‘method of treatment’ claim in disguise and as such was unpatentable due to the provisions of Article 52(4) EPC and the corresponding provisions in the UK Patents Act 1977 (s.4(2)). The Court of Appeal upheld the view of the High Court that the claim was in effect a claim to a ‘method of treatment’ and therefore unpatentable, since the claim to the use of taxol in a new treatment regime did not disclose any new therapeutic method. Following the EISAI decision the Court of Appeal considered that Swiss form claims were only valid where they related to second or further medical uses and the disclosure of a new treatment regime as set out in this case did not constitute a second or further medical use. They also found that the claim in any event lacked novelty since the inevitable result of following the teaching in the prior art was a reduction in neutropenia.

Teva Pharmaceutical Industries Ltd v Merck & others (21st January, 2003) (ALENDRONATE) This case involved an application by three drug companies for revocation of two patents owned by Merck. Both patents concerned a pharmaceutically active compound called alendronate, a biphosphonate. Alendronate is capable of inhibiting bone resorption and as such can be used to treat bone diseases such as osteoporosis. The first patent, which had a priority date of 1982, claimed a pharmaceutical composition containing as its active ingredient alendronate or its salt with an acceptable carrier or diluent. The patent stated that the invention related especially to pharmaceutical compositions suitable for the treatment of urolithiasis and capable of inhibiting bone resorption. A number of matters were agreed to be common general knowledge. These included the fact that there was widespread interest in the clinical use of

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biphosphonates to treat disorders of excess bone destruction and that the oral administration of three biphosphonates (etidronate, clodronate and pamidronate) had been shown to be clinically effective in treating several medical disorders of excess bone destruction, but that these compounds had different efficacies and there was room for a better therapy. The claimants alleged that the patent was invalid for lack of novelty, or alternatively obviousness by reason of ‘Blum’, which was a process patent for making alendronate suitable for pharmaceutical preparations. They also contended that the patent was invalid for obviousness over ‘Kabatchnick’, which was similar to Blum and detailed how to make alendronic acid; and ‘Fleisch’, which reviewed the history and mechanisms of action of bisphosphonates and predicted that further exploration of other types of bisphosphonates could lead to fruitful future development of the compounds. The judge found that a skilled man, being aware of the bisphosphonate pamidronate and its efficacy in the treatment of medical disorders of excess bone destruction, would naturally read Blum as a proposal to use alendronate as the active ingredient in a pharmaceutical. The patent was therefore invalid for lack of novelty and obviousness over Blum. The patent was also obvious over Kabatchnick, which detailed how to make alendronic acid, as it was common general knowledge that the bisphosphonates had clinical uses. Alendronate was also an obvious compound to try after Fleisch. There would be a high expectation of biological activity and a very good chance of increased activity over pamidronate. The second patent had a priority date of 1997. Merck were seeking to amend this patent to claim a new regime for administering the drug to treat osteoporosis. This involved the administration of a 70 mg dose once

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weekly. The previous treatment regime was 10 mg per day to be taken in a particular manner, which led to problems with GI disturbance and also problems in compliance. The claimants argued that this was a claim to a method of treatment of the human body by therapy and therefore incapable of industrial application under section 4(2) of the Patents Act 1977. They also alleged the patent lacked novelty and was obvious over the prior art. The judge considered that the inventive concept of the patent was the preparation of a medicament, which could be used in a 70 mg dosing regime. He stated that, but for the Court of Appeal’s decision in Bristol Myers Squibb v Baker Norton he would not have held this to be a claim to a method of treatment since the monopoly covered the preparation of the dose to be administered but not its actual administration. Following the principle set out in that case however, he considered that he had no choice but to find this to be a claim for a method of treatment and therefore unpatentable. He also found the second patent to lack novelty and to be obvious in the light of the prior art.

CONCLUSIONS It is clear from a consideration of the above cases that secondary patents can be useful in extending patent protection in certain cases. Although it has often proved difficult to maintain the validity of such patents before the UK courts it is by no means impossible and there have been some significant victories for patentees in the UK courts in cases involving secondary patents in recent years. The use by SmithKline Beecham of its secondary patents relating to Seroxat to obtain interlocutory injunctions to keep generics off the market in the SmithKline Beecham v Generics and SmithKline Beecham v Apotex cases described above, was particularly significant. It is clear that patents for novel polymorphs may be valid and enforceable

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and can be very useful in certain cases. The Synthon case highlights the need to consider carefully how much detail to include in the specification, in order to adequately characterise the novel polymorph. In that case it was the inclusion of the IR spectra in Synthon’s earlier application which caused them difficulties in establishing that this application anticipated SmithKline Beecham’s later application, although they were ultimately successful in proving anticipation at the trial. In general it has proved difficult to maintain the validity of formulation patents before the courts. These patents however, can be useful provided validity can be shown and the new formulation is an improvement over existing formulations (otherwise the generics may simply develop generic versions of older formulations on which patent protection has expired). Second and subsequent medical uses of compounds may also be patentable, provided that the new use is sufficiently novel in relation to the known medical use(s). Claims to new treatment regimes however, should be used with caution since the current approach in the UK is that such claims will generally be considered to be claims to a method of treatment and therefore excluded from patentability under the provisions of the EPC (and the corresponding provisions in the Patents Act 1977). Even where the final outcome of proceedings is that the patent is held invalid, the effect of the litigation will have been to delay the generics’ entry to the market. Fighting the litigation may also have ‘warned off’ other generic competition. In any event, for a successful product, the benefit of even a short time of additional proprietary sales may easily outweigh the costs of patent litigation. # Olswang

Henry Stewart Publications 1469–7025 (2003)