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Supplementary protection certificates Keeping pace with drug development

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Title: Supplementary protection certificates Keeping pace with drug development


1
Supplementary protection certificates -Keeping
pace with drug development?
  • Dr Duncan Curley
  • Director, Innovate Legal
  • www.innovatelegal.co.uk
  • 23 January 2008

2
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.

3
The pharmaceutical industry yesterday and today
  • Despite significant extra investment on RD, 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

4
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,
    rather than focusing on traditional drug
    discovery.
  • Much of the discovery work has been done recently
    in the biotech companies. The proportion of new
    medicines launched each year that are based on
    biological products continues to increase.

5
The pharmaceutical industry yesterday and today
  • Many of the larger research-based companies have
    sought to boost their product pipelines by means
    of
  • acquiring smaller biotechnology companies
  • licensing-in drugs from biotech
  • - joint ventures and partnering arrangements
  • While 15 years ago, up to 90 of pharmaceutical
    RD was delivered internally, some companies are
    now buying in 40 of their product pipeline from
    external innovators
  • See Integration and Evolution in the Life
    Sciences publication by the ESRC Genomics
    Network (2007).

6
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 often sees an abrupt
    cut-off date at the end of the 20 year patent
    monopoly for a small molecule drug.

7
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.
  • 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

8
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.

9
Background to the introduction of SPCs
  • In Pharmaceutical patent term restoration for
    the 1990s Heinz Redwood examined the adequacy of
    patent protection in sustaining the acceptance of
    financial risk in pharmaceutical research and
    development in Europe.
  • He found that
  • effective patent life had converged on the narrow
    band of 10.1 to 11.9 years per patented product
  • unexpired patent cover on patented products had
    collapsed in Europe between 1970 and 1988
  • market rejuvenation - the influx of new products
    - was twice as fast in the US and Japan as in
    Europe.

10
The Commissions proposals
  • The European Commission made its first proposals
    for a Supplementary Protection Certificate for
    medicinal products in 1990. The basic objectives
    of its 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
The Commissions proposals
  • The European Commissions 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
    Commissions draft proposals for SPCs

12
The Commissions proposals
  • 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.

13
The compromise
  • ....and so in Council Regulation (EEC) No.
    1768/92
  • the protection to be given by SPCs is limited to
    new medicinal products
  • for a product covered by several patents, the
    applicant for a SPC has to choose only one patent
    the basic patent which is designated in the
    application for a SPC
  • the maximum duration of a SPC is limited to 5
    years

14
The compromise
  • ? A SPC extends the rights conferred by a single
    (basic) patent for up to 5 years after patent
    expiry, for certain pharmaceutical products.

15
The value of SPCs
  • Despite their limitations, SPCs have proved
    vitally important to the research-based industry,
    because they provide up to 5 years extra
    marketing exclusivity after patent expiry, often
    at a time when a product is approaching peak
    sales
  • EG Prozac (fluoxetine) in the UK
  • Prozac was introduced in the UK in 1986
  • Patent protection in the UK expired in 1995
  • The UK SPC expired on 8 January 2000
  • Approximately 80 of Prozacs sales were made in
    the 5 years in which the product was protected by
    the SPC

16
The value of SPCs
Graph courtesy of IMS Health Accessible at
http//www.ims-global.com/insight/news_story/ne
ws_story_000417a.htm
17
SPC versus data exclusivity
  • The principle behind the legislation is that the
    holder of both a patent and a SPC should be able
    to enjoy a maximum of 15 years of exclusivity
    from the date of first market authorisation of a
    drug product in the EEA.
  • But sometimes drug products (eg in the CNS area,
    which often require lengthy clinical trials) do
    not receive marketing authorisation until close
    to the end of the patent term.
  • Note that in these circumstances, the five year
    limit on the maximum SPC term can mean that data
    exclusivity offers longer effective protection
    than a SPC.

18
Brief 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

19
Brief overview of Council Regulation (EEC) No.
1768/92
  • What is required in order to get a SPC?
  • a product meaning an active ingredient or a
    combination of active ingredients of a medicinal
    product that is protected by a basic patent
  • - Article 3(a)
  • a valid marketing authorisation to place the
    product on the market as a medicinal product
  • - Article 3(b)
  • the product must not already be the subject of a
    SPC
  • - Article 3(c)
  • The marketing authorisation must be the first
    authorisation to place the product on the market
  • - Article 3(d)

20
A closer look at the Regulation
  • What is required in order to get a SPC?
  • a product meaning an active ingredient or a
    combination of active ingredients of a medicinal
    product that is protected by a basic patent -
    Article 3(a)
  • a valid marketing authorisation to place the
    product on the market as a medicinal product
  • - Article 3(b)
  • the product must not already be the subject of a
    SPC
  • - Article 3(c)
  • The marketing authorisation must be the first
    authorisation to place the product on the market
  • - Article 3(d)

21
Active ingredient must be protected by a basic
patent
  • Example Lipitor in the UK -
  • The active ingredient is atorvastatin calcium (in
    pure, enantiomeric form).
  • European Patent No. 0247633 claimed a compound
    as shown, without specifying stereochemistry.
  • 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.

22
Active ingredient must be protected by a basic
patent
  • Following the first instance judgment of the
    Patents Court, Ranbaxy amended its case to plead
    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. 0247633 (the
    basic patent)
  • This claim failed, together with the appeal from
    the refusal to give the declaration sought - see
    Court of Appeal judgment, paragraph 31.

23
Active ingredient must be protected by a basic
patent
  • Note that where one patent covers several
    products that each get regulatory approval, each
    product can be the subject of a separate SPC.
  • Example PDL BioPharma Incs European Patent
    0,451,216 to humanised antibodies (recently
    upheld by the EPO)
  • 2 SPCs granted in the UK designating this as the
    basic patent
  • - SPC/GB99/029 daclizumab (Zenapax)
  • - SPC/GB00/032 trastuzumab (Herceptin)

24
Active ingredient must be protected by a basic
patent
  • Note also the importance of the choice of the
    basic patent. If the basic patent can be
    invalidated, the SPC will fall too.
  • NB - Article 15(c) of the SPC Regulation
  • 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

25
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

26
Active ingredient must be protected by a basic
patent
  • Knocking out a SPC by invalidating the basic
    patent
  • Upcoming case Dr Reddys Laboratories v Eli
    Lilly and Company Ltd.
  • Listed for trial in July 2008. Claim is for
    (inter alia) a declaration that SPC/GB96/058
    (Olanzapine optionally in the form of an acid
    addition salt) is invalid, by reason of the
    invalidity of the basic patent (European Patent
    (UK) No. 0454436).

27
Combination products
  • For a combination product, the basic patent must
    disclose the combination of active ingredients
    it is not sufficient if only one of the actives
    in a combination is disclosed.
  • Re Takeda Chemical Industries SPC Applications
  • 2004 RPC 2
  • Takedas applications for SPCs protecting various
    combinations of lansoprazole and an antibiotic
    were refused because the patents only protected
    lansoprazole, not the combination of lansoprazole
    antibiotic.

28
Combination products
  • 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.

29
Combination products
  • Gliadel
  • The European Court of Justice was asked to
    interpret the meaning of a combination of active
    ingredients of a medicinal product and
    specifically whether this could include a
    combination of two substances, only one of which
    has a therapeutic effect of its own for a
    specific indication, the other being necessary
    for the therapeutic efficacy of the first.
  • Note a SPC had already been granted in the UK
    SPC/GB01/013.

30
Combination products
  • Gliadel The Advocate General
  • Combination of active ingredients should not be
    interpreted literally, because this was
    inconsistent with both the thrust of Regulation
    1768/92 and a broader objective being pursued
    within the EU, being the combating of cancer.
  • Gliadel was the kind of therapeutic innovation
    whose development was intended to be encouraged
    by Regulation 1768/92.

31
Combination products
  • Gliadel The Advocate General
  • I consider that research into new applications
    for existing active ingredients should be
    promoted by developing auxiliary substances and
    enabling their use or the enhancement of their
    pharmacological properties for a specific
    indication.
  • If no such research were conducted...many
    patients would have to make do with treatment
    that was not optimal.
  • Paragraph 48 of Advocate General Légers opinion

32
Combination products
  • Gliadel The Advocate General
  • Polifeprosan made it possible ...not only to
    increase significantly the intended therapeutic
    effect of the active ingredient as a result of a
    new and inventive mode of administration, but
    also, through its progressive dissolution, to
    avoid harmful side-effects associated with the
    intravenous administration of simply the active
    ingredient.
  • Paragraph 58 of Advocate General Légers opinion

33
Combination products
  • Gliadel The Advocate General
  • ...the combination at issue represents a major
    innovation, resulting from long, costly research,
    which the regulation seeks precisely to protect.
  • Paragraph 58 of Advocate General Légers opinion

34
Combination products
  • 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.

35
Combination products
  • Fallout from the Gliadel decision - Serevent
  • Glaxo applied for a SPC for salmeterol xinafoate
    CFC-free formulation (Serevent) SPC/GB06/017.
    The product for which protection was sought was
    as follows
  • A combination of salmeterol or a physiologically
    acceptable salt or solvate thereof, such as
    xinafoate, and 1,1,1,2-tetrafluoroethane.

36
Combination products
  • Fallout from the Gliadel decision - Serevent
  • The UK IPOs response
  • ...the only active ingredient present in the
    authorised medicinal product Serevent ...is the
    salmeterol component...
  • 1,1,1,2-tetrafluoroethane is...simply...an
    excipient....
  • The medicinal product Serevent may well require
    a new authorisation but it remains merely a
    reformulation of a known active, salmeterol....

37
Combination products
  • Serevent The UK IPOs response (ctd.)
  • ...The ECJ found in MIT that a combination of
    two substances wherein only one substance has a
    therapeutic effect and the other substance
    enables a pharmaceutical form of the medicinal
    product which is necessary for the therapeutic
    effect of the first substance is not included
    within the definition in Article 1(b) of
    Regulation 1768/92....
  • The definition which you have provided as the
    subject-matter to be protected by the
    certificate...is not a combination of active
    ingredients within the meaning of Article 1(b).

38
Second medical use
  • Yissum - Case C-205/05, European Court of Justice
  • Yissum Research and Development Company sought a
    SPC for a combination of calcitriol with an
    ointment base, based on European Patent (UK) No
    0129003 B2. However, there were other medicinal
    products that had calcitriol as the sole active
    ingredient before the authorisation of Yissums
    ointment product.

39
Second medical use
  • Yissum - Case C-205/05, European Court of Justice
  • Yissum argued that product in Regulation
    1768/92 should be interpreted as meaning the
    active ingredient or combination of active
    ingredients that are the subject of the
    innovation of the basic patent.
  • In a Swiss-form of patent claim (new medical uses
    for old compounds), the innovation in the basic
    patent must incorporate the use, eg the product
    in the Yissum case was calcitriol for the topical
    treatment of psoriasis

40
Second medical use
  • Yissum - Case C-205/05, European Court of Justice
  • The question referred to the European Court of
    Justice was as follows
  • In a case in which the basic patent protects a
    second medical application of a therapeutic
    agent, what is meant by product in Regulation
    1768/92 and in particular does the application
    of the therapeutic agent play any part in the
    definition of product?

41
Second medical use
  • Yissum European Court of Justice
  • The answer
  • In a case where a basic patent protects a second
    medical use of an active ingredient, that use
    does not form an integral part of the definition
    of product in Regulation 1768/92.

42
A valid marketing authorisation
  • What is required in order to get a SPC?
  • a product meaning an active ingredient or a
    combination of active ingredients of a medicinal
    product that is protected by a basic patent
  • - Article 3(a)
  • a valid marketing authorisation to place the
    product on the market as a medicinal product -
    Article 3(b)
  • the product must not already be the subject of a
    SPC
  • - Article 3(c)
  • The marketing authorisation must be the first
    authorisation to place the product on the market
  • - Article 3(d)

43
A valid marketing authorisation
  • For pharmaceutical products, this means an
    authorisation to be placed on the market in
    accordance with Directive 2001/83/EC.
  • Note British Technologys SPC Application
  • 1997 RPC 118
  • A letter granting permission to carry out a
    clinical trial is not sufficient.

44
One SPC per product ?
  • What is required in order to get a SPC?
  • a product meaning an active ingredient or a
    combination of active ingredients of a medicinal
    product that is protected by a basic patent
  • - Article 3(a)
  • a valid marketing authorisation to place the
    product on the market as a medicinal product
  • - Article 3(b)
  • the product must not already be the subject of a
    SPC - Article 3(c)
  • The marketing authorisation must be the first
    authorisation to place the product on the market
  • - Article 3(d)

45
One SPC per product?
  • Biogen v SmithKline Beecham Case C-181/95
  • The question
  • Is it possible for SPCs to be granted to more
    than one holder of a basic patent, where an
    authorised product is covered by several patents
    belonging to different entities?

46
One SPC per product?
  • Biogen v SmithKline Beecham Case C-181/95
  • Advocate General Fennelly
  • Regulation 1768/92 applies simply to a simple
    situation, in which basic research, product
    development, production and marketing are
    vertically integrated where the holder of the
    patent relating to a medicinal product is also
    the holder of the relevant marketing
    authorisation. Regulation 1768/92 was evidently
    drafted on the basis of this classic model.

47
One SPC per product?
  • Biogen v SmithKline Beecham Case C-181/95
  • European Court of Justice
  • 1997 RPC 23
  • Where a medicinal product is covered by several
    basic patents, Regulation 1768/92 does not
    preclude the grant of a SPC to each holder of a
    basic patent.

48
Evergreening
  • What is required in order to get a SPC?
  • a product meaning an active ingredient or a
    combination of active ingredients of a medicinal
    product that is protected by a basic patent
  • - Article 3(a)
  • a valid marketing authorisation to place the
    product on the market as a medicinal product
  • - Article 3(b)
  • the product must not already be the subject of a
    SPC
  • - Article 3(c)
  • The marketing authorisation must be the first
    authorisation to place the product on the market
    - Article 3(d)

49
Evergreening
  • The Pulmicort Turbuhaler case (Draco ABs SPC
    application 1996 RPC 417).
  • Budesonide was the sole active ingredient in two
    medicinal products that were the subject of
    marketing authorisations in the UK in 1981 and
    1982. Although budesonide was still protected by
    a basic patent in 1993, it was an old active
    ingredient and it could not be brought within
    Regulation 1768/92.

50
Evergreening
  • The Pulmicort Turbuhaler case (Draco ABs SPC
    application)
  • The applicant tried to argue that the product
    was a new formulation
  • additive free budesonide in the form of
    aggolmerated micronised particles
  • and that a SPC should be granted on the basis of
    a later marketing approval in 1990 for the
    Pulmicort Turbuhaler device.

51
Evergreening
  • The Pulmicort Turbuhaler case (Draco ABs SPC
    application).
  • The application was turned down by the Patent
    Office. On appeal, it was argued that extensive
    research had been required to adapt the
    formulation of budesonide for the Turbuhaler.
  • This argument was rejected SPCs were not
  • for the general protection of the fruits of
    research
  • per Jacob, J.

52
Paediatric extensions
  • Regulation (EC) Nos. 1901/2006 and 1902/2006 on
    medicinal products for paediatric use (in force
    from 26 January 2007).
  • Paediatric Investigation Plans must be agreed
    between sponsors of clinical trials and the
    Paediatric Committee.
  • The reward a 6 month extension to the SPC term
    on submission of the results of paediatric
    studies, whether or not the drug is shown to be
    efficacious in children.

53
Paediatric extensions
  • Getting a paediatric extension is not a trivial
    matter
  • all of the measures contained in the Paediatric
    Investigation Plan must have been complied with
  • the product must be authorised in all EU Member
    States
  • relevant information on the results of the
    paediatric studies must be included in the SmPC.

54
Paediatric extensions
  • For blockbuster products, the 6 month extension
    to a SPC will be an extremely valuable reward,
    far exceeding the cost of undertaking the
    paediatric studies.
  • Overall, the new paediatric extensions will
    translate to a cost to the NHS drugs bill of
    between 30 million and 120 million a year in
    England alone
  • - UK Government Partial Regulatory Impact
    Assessment

55
Keeping pace with drug development?
  • To summarise
  • SPCs do not provide additional protection for
    reformulations, medical devices or new delivery
    systems.
  • SPCs are not available to extend second medical
    use patents, where the product in question has
    already been the subject of a marketing
    authorisation for a different indication.
  • But a 6 month paediatric extension to a SPC is
    available on completion of paediatric studies,
    even if a paediatric indication for the drug is
    not authorised.

56
Postscript
  • Whilst uncertainty reigns the patentees will
    have practical monopolies unless competitors are
    prepared to take the risk of SPCs being granted.
    It would not be surprising if millions of pounds
    turn on the point, quite a lot of it being public
    money on the National Health Service drugs bill
  • Comments of Jacob, J. in the Pulmicort Turbuhaler
    case

57
Postscript
  • AstraZeneca (under appeal)
  • Facts
  • Losec (omeprazole) was an old product by the
    time that Regulation 1768/92 came into force
  • By using a date for the marketing authorisation
    of Losec in Luxembourg, AstraZeneca managed to
    obtain SPCs for Losec in certain European
    countries under the transitional provisions in
    Article 19 of Regulation 1768/92
  • On 15 June 2005, the European Commission issued a
    decision in which it fined AstraZeneca 60
    million for breach of EC competition law (Article
    82).

58
Postscript
  • ...and on 16 January 2008, the European
    Commission announced a wide-ranging investigation
    into certain practices of the pharmaceutical
    industry
  • The European Commission has launched a sector
    inquiry into competition in the pharmaceuticals
    sector (under Article 17 of Regulation 1/2003),
    and is conducting inspections at the premises of
    a number of innovative and generic pharmaceutical
    companies. The inquiry is a response to
    indications that competition in pharmaceutical
    markets in Europe may not be working well fewer
    new pharmaceuticals are being brought to market,
    and the entry of generic pharmaceuticals
    sometimes seems to be delayed. The inquiry will
    therefore look at the reasons for this.
  • - Commission Press Release

59
Supplementary protection certificates -Keeping
pace with drug development?
  • Questions?
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