Development of biosimilar medicines patent issues Dr Duncan

Overview of presentation Part 1 Introduction Barriers to entry for biosimilar medicines European patent law basics Part 2 Lessons from the public record: epo Part 3 Lessons from the public record: G-CSF © 2008 Innovate Legal Services Limited

Introduction In 2004, a new regulatory framework for the authorisation of biosimilar medicines was passed by the EU legislature: “Where a biological medicinal product which is similar to a reference biological product does not meet the conditions in the definition of generic medicinal products, owing to, in particular, differences relating to raw materials or differences in manufacturing processes of the biological medicinal product and the reference biological medicinal product, the results of appropriate preclinical tests or clinical trials relating to those conditions must be provided. ” Directive 2004/27/EC of the European Parliament and of the Council amending Directive 2001/83/EC on the Community code relating to medicinal products for human use © 2008 Innovate Legal Services Limited

Introduction Biosimilar medicines are now being approved in the EU via the European centralised procedure. The first EU approvals for biosimilars were in April 2006, when the European Commission granted marketing authorisations for Sandoz’s Omnitrope® and Bio. Partners’ Valtropin®. Both of these products are biosimilars of somatropin, a first generation recombinant human growth hormone. © 2008 Innovate Legal Services Limited

Introduction EMEA in its European Public Assessment Report for Omnitrope (2006): “. . . Omnitrope is a ‘biosimilar product’: this means that Omnitrope is similar to a biological medicine already authorised in the EU. . . Omnitrope has been compared to and matches the reference medicine (Genotropin) in terms of quality [i. e. how it is made], safety [for example the side-effects that can occur when receiving similar treatment] and effectiveness. . . ” © 2008 Innovate Legal Services Limited

Barriers to entry – data requirements The Sandoz experience A significant increase in the data requirements were required for the EU authorisation of Omnitrope®, as compared to a “classical generic” “The lever arch file test” 39 lever arch files for the authorisation of Omnitrope® c. f. typically, 8 lever arch files for a classical generic Julia Barth, Global Legal Head, Product Development, Sandoz, at the Pharmaceutical Law Europe Conference in London, 4 October 2006 © 2008 Innovate Legal Services Limited

Barriers to entry – data requirements For clinical safety studies, the regulator will generally require a pre-approval study of 6 -12 months, depending on the product and its indications. The data requirements (safety data in 500 -1000 patients) are a significant commitment for any company seeking EU approval of a biosimilar. The cost of the additional studies required for the EU authorisation of a biosimilar epo has been estimated at € 20 -40 M. Tim Oldham of Hospira at the “Biosimilar Medicinal Products: from Marketing Approval to Commercial Reality” seminar hosted by the BIA in London on 5 December 2006 © 2008 Innovate Legal Services Limited

Other barriers to entry - manufacturing The manufacturing process used to produce a recombinant biological product is much more complex than the process used for synthetic small molecule products. It will usually include numerous extraction, purification and concentration steps that might involve protein denaturisation. Each of these steps can influence the biological activity of the resultant protein. The properties of the product are highly dependent on the production process. A producer of a biosimilar is clearly not in a position to replicate the manufacturing process of the innovator. © 2008 Innovate Legal Services Limited

Other barriers to entry - patents “Rapid access to the market on patent expiry is not a phenomenon that has yet been seen in the context of biosimilars…. …. to date, patents and SPCs have been of less importance – in terms of barriers to entry for competitive products – than the strictures imposed by the regulatory framework” Extending Rewards for Innovative Drug Development – A Report on Supplementry Protection Certificates for the Intellectual Property Institute, August 2007 © 2008 Innovate Legal Services Limited

European patent law basics The patent application process in Europe A European patent application is usually published 18 months after filing. The application is then considered for compliance with the requirements of the European Patent Convention: • is the invention new (novelty)? • is it non-obvious (does it contain an inventive step)? • does the application meet all of the other formal requirements in the EPC? The application process takes place in the public domain, i. e. the European Patent Office’s files are laid open to public inspection. © 2008 Innovate Legal Services Limited

European patent law basics The patent application process in Europe At the end of the examination process, the application is either refused or granted. If the application is granted, a European patent then has effect as a related family of individual national patents, in each of the European countries designated by the applicant for protection. Oppositions For nine months after the date of grant, third parties may file oppositions at the European Patent Office, challenging the office’s decision to allow the grant of the patent. The patent may be opposed on any of the legal grounds contained in the European Patent Convention, e. g. lack of novelty, lack of inventive step. © 2008 Innovate Legal Services Limited

European patent law basics Oppositions Once the European Patent Office’s Opposition Division has given its decision, there is then the possibility of an appeal, usually before one of the European Patent Office’s Technical Boards of Appeal. Once an opposition and/or an appeal has been concluded, all of the written submissions and arguments of the opponents remain on the public record: see www. epoline. org. © 2008 Innovate Legal Services Limited

European patent law basics Patent challenges Decisions of the European Patent Office (both at Opposition Division and Technical Appeal Board level) are not binding on the national courts. National courts are free to revisit a prior decision of the European Patent Office on the validity of a patent, although frequently many of the same arguments on lack of novelty, lack of inventive step (and so on) are re-run, but in more detail. Patent challenges in the national courts are a way of life for a number of generic manufacturers. A number of companies have a good track record of knocking out patents and clearing the way to market for small molecule products. © 2008 Innovate Legal Services Limited

European patent law basics Novelty A patent may only be granted for an invention that is new. This is the requirement of novelty. Whether an invention is new depends upon the state of the art at the priority date of the patent. The state of the art consists of everything (whether it is a product, a process, information, or anything else) that has at any time before the priority date of the patent been made available to the public, by written or oral description, or by use in any other way. Documents (such as scientific papers or patents) that form part of the state of the art are often called prior art documents. © 2008 Innovate Legal Services Limited

European patent law basics Lack of inventive step / obviousness A patented invention involves an inventive step if it is not obvious to a person skilled in the art, having regard to any matter (such as a prior art document) that forms part of the state of the art. The legal test for obviousness therefore requires an assessment of the technical differences between the prior art and the patent under attack. Does the patent contain a genuine technical advance, when viewed through the eyes of the skilled person? If not, the invention is obvious (i. e. lacking in inventive step). © 2008 Innovate Legal Services Limited

European patent law basics Insufficiency A patent must describe an invention clearly enough and completely enough for it to be performed by a person skilled in the art. Put another way, the content of the patent specification must enable the skilled person to make the invention work. If the patent fails adequately to teach how to put the invention into practice, it is insufficient (or inadequately enabled). © 2008 Innovate Legal Services Limited

European patent law basics Added subject-matter The subject matter disclosed in European patent specification must not go beyond what is contained in the application for the patent, as filed. This is a highly technical ground of objection to the grant of a patent - note that the test is much more strict than in the US PTO. © 2008 Innovate Legal Services Limited

European patent law basics Formulating a patent challenge In formulating a patent challenge in Europe, a good starting point is often an examination of the file history at the European Patent Office. What arguments did the Examiner make against the grant of the patent? Was the patent opposed? Was the opposition determined, or was it settled without a definitive conclusion on a legal issue relating to patentablity? © 2008 Innovate Legal Services Limited

European patent law basics Formulating a patent challenge - biopharmaceuticals A number of biopharmaceuticals are already subject to competition amongst the innovators. Often, the same innovators will have fought out the patent issues in the European Patent Office, at an early stage in the life of their patents. The public record can reveal some interesting opportunities. . . © 2008 Innovate Legal Services Limited

Lessons from the public record: epo Erythropoietin (epo) A glycoprotein hormone that regulates red blood cell production. Recombinant epo is used for the treatment of chronic renal failure. Recombinant epo has the highest market volume amongst all therapeutic proteins - it is a blockbuster. © 2008 Innovate Legal Services Limited

Lessons from the public record: epo There a number of recombinant epos already on the EU market: Johnson & Johnson (epoietin alpha, Eprex®) Roche (epoietin beta, Neorecormon®) Amgen (epoietin delta, Aranesp®) Shire / TKT (Dynepo®) Roche (Mircera®: methoxypolyethyleneglycolated epoietin beta). . . and at least one biosimilar epo: Stada / Hospira (epo-zeta: Silapo®, Retacrit. TM) © 2008 Innovate Legal Services Limited

Aranesp® A sizeable proportion of global epo sales are accounted for by Aranesp®, a “sustained release” form of epo. The prolonged bioavailability of Aranesp® over first generation recombinant epos is achieved by the introduction of additional glycosylation sites on the protein’s amino acid backbone. The European launch of another sustained release product (pegylated epo, Mircera®) is likely to put pressure on the market for the first generation epos. © 2008 Innovate Legal Services Limited

Aranesp® Authorised in the EU on 8 June 2001. Protected in various European countries by European Patent 0, 640, 619 B 2: “Erythropoietin analogs with additional glycosylation sites”. Priority: 17 August 1993 (US Patent 108016) European application filed: 16 August 1994, expires: 16 August 2014. In the UK, Supplementary Protection Certificate No. SPC/GB 01/055 expires on 7 June 2016. © 2008 Innovate Legal Services Limited

European patent no. 0, 640, 619 B 2 Granted: 23 July 1997 Grant of the patent was opposed by Roche Diagostics Gmb. H (“Roche”). Grounds of opposition: • added subject matter • lack of novelty • lack of inventive step © 2008 Innovate Legal Services Limited

Technical background Glycoproteins such as epo are carbohydrate-protein complexes in which short oligosaccharide chains are glycosidically attached through the side chain functions of certain amino acids. Several modes of attachment are known, e. g. • O-glycosidic linkage (to Ser, Thr) • N-glycosidic linkage (to N-terminal amino groups, amide nitrogen of Asn, ε-amino group of Lys) The carbohydrate components are for example composed of hexoses (mainly D-galactose, D-mannose, D-glucose) as well as sialic acid (N-acetylneuraminic acid) as terminal components of the chains. © 2008 Innovate Legal Services Limited

European patent no. 0, 640, 619 B 2 Lack of inventive step “Role of glycosylation on the secretion and biological activity of erythropoietin”, Delorme et al. , Biochemistry, 1992, 31, 9871 -9876. The research described in this paper concluded that the deletion of natural glycosylation sites in human epo results in reduced in vivo biological activity. However, it did not suggest that the addition of new N-glycosylation sites would increase in vivo activity. © 2008 Innovate Legal Services Limited

European patent no. 0, 640, 619 B 2 Lack of inventive step The opponent relied upon the following prior art document in its attack based on lack of inventive step: European patent application no. 0, 428, 267 – “Erythropoietin isoforms” This patent application disclosed analogues of human epo with one or more changes in the amino acid sequence of human epo which results in an increase of the number of sites for sialic acid attachment, which is ultimately linked with an increased biological activity. © 2008 Innovate Legal Services Limited

European patent no. 0, 640, 619 B 2 Lack of inventive step European patent application no. 0, 428, 267 – “Erythropoietin isoforms” The opponent argued that in light of this patent application, the skilled person would have appreciated that routine techniques could be used to introduce additional N-glycosylation sites into human epo in order to increase its biological activity. © 2008 Innovate Legal Services Limited

European patent no. 0, 640, 619 B 2 Lack of inventive step European patent application no. 0, 428, 267 – “Erythropoietin isoforms” The Opposition Division rejected this argument. Although it accepted that the skilled person would be given an incentive to look for further human epo analogues by the prior art patent application, the skilled person would not have had a reasonable expectation of success of obtaining an analogue with the surprising properties reported by Amgen for the analogues described in European patent no. 0, 640, 619. © 2008 Innovate Legal Services Limited

European patent no. 0, 640, 619 B 2 Conclusion The grant of the patent was allowed to stand (with amendments to get over other lack of novelty and added matter objections). The granted patent was then re-published as a “B 2” specification. © 2008 Innovate Legal Services Limited

European patent no. 0, 640, 619 B 2 The appeal Roche appealed the Oppositon Division’s decision. In a preliminary opinion given before the main hearing of the appeal, the Technical Board of Appeal noted that if the activity of differently glycosylated (or hyperglycosylated) epo analogues was not predictable, then it could not plausibly be assumed that all of the epo analogues covered by the patent possess the surprising in vivo properties claimed. © 2008 Innovate Legal Services Limited

European patent no. 0, 640, 619 B 2 The appeal The Technical Board of Appeal noted that if it was not credible that substantially all of the claimed compounds possessed the desired activity, then in reality the technical advance provided by the patent was simply the provision of further epo analogues. This was essentially equivalent to the technical advance described in the prior art patent application, European patent application no. 0, 428, 267 – “Erythropoietin isoforms”. So where was the inventive step? © 2008 Innovate Legal Services Limited

European patent no. 0, 640, 619 B 2 Roche’s appeal was withdrawn before the

Lessons from the public record: G-CSF Granulocyte colony stimulating factor A naturally-occurring glycoprotein. Recombinant human G-CSF is used to treat neutropenia, a side-effect of cancer chemotherapy. Helps cancer sufferers to fight potentially life-threatening infections. The market leading recombinant human G-CSF is filgrastim (Amgen’s product Neupogen®). Neupogen had sales of over US$1. 2 billion in 2007, of which US$416 million were outside the USA. Filgrastim has already been a target for biosimilar development, with the Committee for Medicinal Products for Human Use (CHMP) issuing positive opinions on 21 February 2008 for three biosimilar filgrastim products. © 2008 Innovate Legal Services Limited

G-CSF PEG-filgrastim: patent situation Amgen’s pegylated filgrastim product Neulasta® was launched in 2002. This product has a prolonged half-life and therefore requires less frequent administration to patients. Bioimilar versions of Neupogen® compete with Neulasta®. © 2008 Innovate Legal Services Limited

G-CSF PEG-filgrastim: patent situation European patent no. 0, 733, 067 B 1 “N-Terminally Chemically Modified Protein Compositions and Methods”. Priority date: 12 October 1994. © 2008 Innovate Legal Services Limited

G-CSF PEGylation –technical background Polyethylene glycol (PEG) was well known before 1994 as a chemical moiety that could usefully be attached to proteins. See for example: “The Clinical Efficacy of Poly(ethylene glycol)-modified proteins” by F. Fuertges and A. Abuchowski, Journal of Controlled Release, 11 (1990) 139 -148. © 2008 Innovate Legal Services Limited

G-CSF PEGylation –technical background By 1994, a number of proteins had been PEGylated, including: -PEG-L-asparaginase -PEG-superoxide dismutase -PEG-uricase -PEG-adenosine deaminase -PEG-interleukin 2 © 2008 Innovate Legal Services Limited

G-CSF PEG-filgrastim: patent situation During the examination of European patent application no. 0, 733, 067, it was observed that the PEGylation of G-CSF was described in the prior art, specifically the patent application WO 90/04606. An objection was raised for lack of inventive step. © 2008 Innovate Legal Services Limited

G-CSF PEG-filgrastim: patent situation In response, it was said that the patent recited a novel process for the preparation of N-terminally monopegylated G-CSF. “These processes have unexpected and therefore surprising advantages vis-avis the known methods” Amgen’s patent attorney in a communication to the EPO’s Examining Division dated 25 April 1997 © 2008 Innovate Legal Services Limited

G-CSF PEG-filgrastim: patent situation However, the EPO’s Examining Division observed that PEGylation via reductive alkylation (the process used in Amgen’s patent) had already been described in the prior art, specifically a journal article: Bioconjugate Chem. , 5, 133 -140 (1994). © 2008 Innovate Legal Services Limited

G-CSF PEG-filgrastim: patent situation Nevertheless, the patent application was subsequently accepted and granted, without opposition. In the UK, PEG-filgrastim has a supplementary protection certificate that expires on 21 August 2017. © 2008 Innovate Legal Services Limited

Conclusion “Generic companies see their future in the biosimilars segment. More than half of the respondents [to the EU Commission’s Pharma Sector Inquiry] are, or will in the near future be, involved in the biosimilars market. Furthermore, generic companies considered that biosimilar products will achieve fundamental cost savings for national health care systems, as existing biopharmaceutical products are generally highly priced medicines. However, compared to chemical [small] molecules, the savings expected are less prominent due to the high costs involved in the development of biosimilars”. The European Commission Pharmaceutical Sector Inquiry – Final Report (paragraph 104). © 2008 Innovate Legal Services Limited

Questions? © 2008 Innovate Legal Services Limited

Thank you for listening Dr Duncan Curley duncancurley@innovatelegal. co. uk 107 Fleet Street London EC 4 A 2 AB Tel: +44(0)20 7936 9056 Fax: +44(0)20 7936 9111 www. innovatelegal. co. uk © 2008 Innovate Legal Services Limited