Presentation to the C5 Pharma & Biotech Patent Litigation Conference, Amsterdam, 18 February 2009

1. Supplementary Protection Certificates - targets for litigation Dr Duncan Curley Director, Innovate Legal www.innovatelegal.co.uk C5 Pharma & Bio Patent Litigation Conference Amsterdam,18 February 2009

2. Overview of presentation 1. Introduction – the pharmaceutical industry, yesterday and today 2. The key operative provisions of Council Regulation (EEC) No.1768/92 3. Some cases: atorvastatin , levofloxacin , galanthamine 4. Conclusions

3. The pharmaceutical industry, yesterday and today The research-based pharmaceutical industry is going through a painful transition. Throughout the 1970s and 1980s, the pharmaceutical industry relied on a steady flow of small molecule blockbuster drugs to bring in significant profits – enough to achieve double digit growth. Patent expiries are now threatening sales both of small molecule products and the pioneering biotech products that were discovered in the 1980s and early 1990s. “ An intellectual property meltdown ” – The Times , 17 January 2009

4. The pharmaceutical industry, yesterday and today Despite significant extra investment on R&D, many of the research-based companies are having difficulty in sustaining their output of new products. In 2007, the FDA approved only 19 new drugs, the fewest in 24 years*. The overall growth rate for the industry was 7% in 2006 (the same as 2005, which was in turn down slightly from 2004)**. *Figures from the Tufts Center for the Study of Drug Development **Figures from IMS Health

5. The pharmaceutical industry, yesterday and today Projects based on new therapeutic targets often take longer to deliver a novel drug candidate into clinical development than projects that are extensions of existing targets. Many of the research-based companies have been putting effort into such lower risk activities – “incremental innovation”, rather than focusing on traditional drug discovery. This has led to criticisms e.g. from the European Commission in its Pharmaceutical Sector Inquiry - Preliminary Report (28 November 2008).

7. The pharmaceutical industry, yesterday and today The research-based pharmaceutical industry has come to expect vigorous competition from companies that manufacture drugs in generic form when they go off-patent. What this means is that one may observe an abrupt cut-off date at the end of the 20 year patent monopoly for a small molecule drug.

8. Background to the introduction of SPCs Following the thalidomide disaster in the 1960s, procedures were put in place to trial new drugs thoroughly for safety and efficacy prior to their use in the general population. Directive 65/65/EEC governing the grant of marketing authorisations for pharmaceutical products [now superseded] The requirement to obtain regulatory approval prior to product launch means that the effective patent monopoly for small molecule pharmaceutical products is significantly reduced: “ patent term erosion”

9. Background to the introduction of SPCs In 1984, patent term extension legislation was introduced in the USA (Waxman-Hatch). The aim was to balance patent term extensions awarded to the research-based industry with concessions to the generic industry, in terms of speedier post-patent expiry authorisations for generics (“Bolar” exemption). Patent term restoration was introduced in Japan in 1988, with no statutory provision for the speedy authorisation of generics. The European Commission made its first proposals for a Supplementary Protection Certificate for medicinal products in 1990.

10. Background to the introduction of SPCs The basic objectives of the European Commission’s proposals were set out in an Explanatory Memorandum: “ The basic objectives of this proposal for a Regulation...concern the requirements relating to the proper functioning of the internal market, improvement of our competitiveness as compared with that of our trade partners and the encouragement of research and development in the health field ” Explanatory Memorandum, paragraph 8

11. Background to the introduction of SPCs The European Commission’s proposals were not universally well-received: “ [The pharmaceutical] industry has been spending the equivalent of 10 to 15% of its turnover on research and close to 30% on promotional efforts, and for all that, is one of the most profitable sectors. Obvious alternatives [to SPCs] – less spending on promotional activities, for example – are...ignored ” The Committee on Economic and Monetary Affairs and Industrial Policy, commenting on the Commission’s draft proposals for SPCs

12. Background to the introduction of SPCs The fear was voiced in some quarters of a “cost explosion” - higher prices for new drugs. - See the discussion in Redwood (1990) and the CLIP (Common Law Institute of Intellectual Property) Report on SPCs of 1991 Others said that the additional cost to national health systems would be marginal and the long-term benefit of SPCs would be likely to outweigh any cost savings from prescribing more generic medicines, if SPCs were not introduced.

14. Overview of Council Regulation (EEC) No. 1768/92 Main operative provisions: Articles 1-5 Article 1: Definitions Article 2: Scope Article 3: Conditions for obtaining a SPC Article 4: Subject-matter of protection Article 5: Effects of a SPC Other provisions deal with deadlines, content of applications for SPCs, grant, publication and transitional arrangements

17. The active ingredient must be protected by a basic patent Note the importance of the basic patent. If the basic patent is invalidated, the SPC will fall too. Article 15(c) of Regulation 1768/92: “ The SPC shall be invalid if the basic patent is revoked or limited to the extent that the product for which the certificate was granted would no longer be protected by the claims of the basic patent ”

18. The active ingredient must be protected by a basic patent Example: Seretide ® in the UK The combination of salmeterol and fluticasone was the subject of UK patent no GB2235627 to Glaxo Group Limited. A UK SPC for a combination of salmeterol and fluticasone propionate was granted on 2 September 1999 that would have expired in 2013, but the basic patent was revoked on 5 April 2004 in patent invalidity proceedings brought by CIPLA and others... ...and the SPC fell with the basic patent

19. SPCs: combination products What about combination products? What must be disclosed in the basic patent in order to get a SPC? This is not usually an issue when the basic patent claims a combination of active ingredients as such. For example, Claim 1 of Glaxo’s granted European Patent 0513917 (“ Antiviral combinations containing nucleoside analogues” ) is to: A combination comprising [lamivudine] or a pharmaceutically acceptable derivative thereof and [AZT] or a pharmaceutically acceptable derivative thereof. The combination of active ingredients is explicitly claimed, hence there was no issue with the grant of SPC/GB98/019 for combivir.

20. SPCs: combination products In the UK, it was previously thought that in order to get a SPC for a combination product, the basic patent must explicitly disclose the combination of active ingredients, i.e. it was not sufficient if only one of the actives in a combination was disclosed. Re: Takeda Chemical Industries SPC Applications Takeda made six applications for SPCs protecting various combinations of lansoprazole and an antibiotic. All of them were refused because the patents only protected lansoprazole, not the combination of lansoprazole + antibiotic.

21. SPCs: combination products - recent UK case ( Gilead) Gilead Sciences, Inc. applied for a SPC in respect of a combination of two active ingredients, tenofovir disoproxil and emtricitabine. The basic patent designated in the application was EP 0915894 but emtricitabine was not mentioned anywhere in the basic patent . The applicant therefore relied on a subsidiary claim (27) to: “ A pharmaceutical composition comprising a compound according to any one of [the previous claims] together with a pharmaceutically acceptable carrier and optionally other therapeutic ingredients ”.

23. SPCs: combination products – recent UK case ( Gilead ) Kitchin, J. thought that Takeda may have been wrongly decided, but in the end he was content to conclude that Gilead’s second, narrower argument was correct. In determining whether a combination product was eligible for a SPC, the test was: “ … to identify the active ingredients of the product which are relevant to a consideration of whether the product falls within the scope of a claim of the basic patent. It is those ingredients, and only those ingredients, which can be said to be protected within the meaning of the Regulation”.

24. SPCs: combination products – recent UK case ( Gilead ) In the case of a product consisting of a combination of ingredients A and B and a basic patent which claims A, it is only A which brings the combination within the scope of the monopoly. Hence it is A which is protected and not the combination of A and B. However, Gilead’s subsidiary claim (27) was directed to a composition comprising tenofovir together with a carrier and optionally other active ingredients. The combination product fell within this claim and it did so as a result of the presence of both tenofovir and emtricitabine. Held: SPC allowed. Further reading: BioScience Law Review, 9(5) (2008), pages 194-196.

25. SPCs: combination products - Gliadel But...what is claimed in the basic patent must be a combination of active ingredients Gliadel® MIT applied for a SPC for Gliadel ® in Germany designating European Patent (DE) No. 0260415 B1 (“ Synthesis and application of high molecular weight polyanhydrides ”) as the basic patent. Gliadel consists of carmustine - an old anti-cancer agent - in a biodegradable matrix called polifeprosan. It is used in the treatment of recurrent brain tumours.

26. SPCs: combination products - Gliadel Gliadel - Case C-431/04, European Court of Justice The Court of Justice held that a combination in the SPC Regulation means a combination of active ingredients. Although necessary for the therapeutic effectiveness of Gliadel, polifeprosan was inactive, therefore Gliadel was ineligible for protection by means of a SPC.

28. Atorvastatin Marketed as Lipitor ® in the UK. The active ingredient is atorvastatin calcium, in pure, enantiomeric form. European Patent No. 0,247,633 B1 claimed a family of statin compounds, without specifying stereochemistry . This patent expired on 29 May 2007 but atorvastatin has the benefit of SPC/GB97/011 in the UK that lasts until 6 November 2011.

29. Atorvastatin In Ranbaxy UK Limited v Warner-Lambert Company , Ranbaxy sought a declaration of non-infringement in relation to the active enantiomer of atorvastatin, asserting that the claims covered only the racemic mixture. The issue: was the claim limited to the racemate or did it also cover enantiomers? Note also that Ranbaxy argued that SPC/GB97/011 was granted contrary to Article 3(a) of Council Regulation (EEC) No. 1768/92... ...because the active ingredient in Lipitor® - enantiomerically pure atorvastatin calcium - was not protected by European Patent No. 0,247,633 B1(designated as the basic patent in the application for the SPC)

30. Atorvastatin Held: the claim was to be construed through the eyes of the skilled person. The court refused to accept that the skilled person would read the claim as excluding the active, enantiomeric form. The active ingredient was therefore covered by the claims of the basic patent. Result: the SPC complied with Article 3(a) of Regulation 1768/92 and was valid. Further reading: Patent World Issue #186 pages 10-11 (October 2006)

31. Levofloxacin The background facts of the case of Generics [UK] v Daiichi Sankyo [2008] EWHC 2413 were as follows. Ofloxavin is a member of the quinolone class of anti-microbial agents. It is a racemic compound, consisting of two enantiomers: the (-) enantiomer ( levofloxacin ); and the R( + ) enantiomer.

32. Levofloxacin On 16 March 1990, UK marketing authorisations were granted in respect of the racemate, ofloxacin. On 23 October 1997, Daiichi was granted UK marketing authorisations for the (-) enantiomer, levofloxacin. Daiichi then applied for and was granted a SPC for levofloxacin on 13 July 1998. The SPC is due to expire on 19 June 2011. Generics [UK] contended that the levofloxacin SPC did not comply with Article 3(d) of Regulation 1768/92, because the marketing authorisation for levofloxacin was not the first authorisation to place levofloxacin on the market as a medicinal product.

34. Galanthamine Synaptech Inc. own a second medical use patent claiming galanthamine for use in treating Alzheimer’s disease. A SPC was obtained in the UK, no. SPC/GB00/033 for ‘ Galantamine or acid addition salts thereof ’, specifying the second medical use patent as the basic patent. The SPC is due to expire on 15 January 2012. Generics [UK] claimed that galanthamine had previously received marketing authorisations in the EU in respect of a product called Nivalin® for the treatment of polio.

35. Galanthamine Generics [UK] contended that the term of the SPC should be limited, ending on 31 December 2008. They sought to reply on Article 13 of Regulation 1768/92, which governs the duration of the term of a SPC: “ The certificate shall take effect at the end of the lawful term of the basic patent for a period equal to the period which elapsed between the date on which the application for a basic patent was lodged and the date of first authorization to place the product on the market in the Community , reduced by a period of five years”.

36. Galanthamine The issue in the case was thus the correct meaning of first authorization to place the product on the market in the Community in Article 13. Generics [UK] contended that the first authorisation was one of the previous authorisations for galanthamine, issued in either Austria or Germany. Note: neither of these authorisations was granted under the (then) EU Directive governing the grant of marketing authorisations for pharmaceutical products in the EU, Directive 65/65, referred to elsewhere in the SPC Regulation. Synaptech contended that the first Directive 65/65 “compliant” authorisation was a Swedish marketing authorisation for the product Reminyl® (for treating Alzheimers).

37. Galanthamine The decision At the time of writing, this is awaited... ...in the meantime, there are more “second medical use” cases on SPCs in the pipeline

39. Thank you for listening Further reading: Extending rewards for innovative drug development A Report on Supplementary Protection Certificates for pharmaceutical products available from the Intellectual Property Institute: http://www.ip-institute.org.uk/pub.html

40. Questions? Dr Duncan Curley Innovate Legal 107 Fleet Street London EC4A 2AB Tel: +44(0)20 7936 9056 Fax: +44(0)20 7936 9111 Email: info@innovatelegal.co.uk www.innovatelegal.co.uk