PATENT LIFE CYCLE MANAGEMENT

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PATENT LIFE CYCLE MANAGEMENT

• Strategies for originators and tactics for
  generics
• Dr Denis Schertenleib
• Avocat Solicitor
• Partner Hirsch Associés
• Paris France
• ds_at_hirschlex.com

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25 years is both too long and too short

• Originators are burdened with increasing costs
  for developing drugs
• Originators have less and less blockbuster drugs
  in the pipeline
• The costs of novel drugs are perceived as too
  high even for developed economies

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There is a real pressure for

• Originators to increase the duration of their
  monopoly beyond 25 years.
• Generics to break that monopoly.

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Second generation patents

• These patents seek to protect a drug after the
  original patent on the drug has expired.
• They protect some form of variation or
  improvement.

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Second generation patents - examples

• Second therapeutic use
• Crystalline polymorphs
• Single enantiomers

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Second therapeutic use

• Claims to a further medical use of a substance
  for which a therapeutic use was known.
• E.g. a claim to the use of aspirin for
  fluidifying blood whereas aspirin was known as a
  pain killer for decades.

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Second therapeutic use

• Valid since EPO decision G5/83 if drafted in
  swiss type format
• Use of product X for the manufacture of a
  medicament for treating illness Y
• Until EPC 2000 validity was challenged at
  national level.

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2nd therapeutic use EPC 2000

• EPC 2000 clearly removed any ambiguity as to
  validity of 2nd therapeutic use.
• EPC 2000 allows straightforward drafting of 2nd
  therapeutic use claim
• Product X for treating illness Y

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2nd therapeutic use dosage regimen

• Can dosage regimen be a patentable new use
• Eg Fosamax
• known to use Fosamax every day at 10mg
• Patent on use of Fosamax once a week at 70 mg

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2nd therapeutic use dosage regimen

• Problem with EPC as methods of therapy are not
  patentable.
• Is a dosage regimen a method of therapy in
  disguise?

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2nd therapeutic use dosage regimen

• Under EPC case law unpatentable (T317/95).
• Until T1020/03.
• BUT referral to enlarged EPO Board pending G2/08
• In the UK unpatentable under Bristol-Myer
  Squibbs (2001).
• But now under Actavis UK Ltd v Merck Co Inc CA
  2008 potentially patentable to follow EPO

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2nd therapeutic use valid new uses

• T290/86, T486/01, T189/95, T254/93 and finally
  T1020/03
• New illnesses (sildenafil viagra and now for
  pulmonary hypertension)
• New patient groups (Diovan for adolescents)
• Overall need to open a new field of clinical
  application

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2nd therapeutic use invalid new uses

• T486/01 a claimed use characterised by giving
  more information about a mode of action all
  ready practised was not novel.
• T836/01 - a claimed use which specified a
  different mechanism of action could be novel over
  prior art disclosing the same use as it opened
  new therapeutic possibilities

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2nd therapeutic use - infringement

• It is not the product that is protected but the
  use.
• There is a need to show intended use not merely
  possibility of use.
• Need to resort to evidence such as advertisement,
  marketing authorizations, user notices (Wyeth v
  Abbott Paris Court of Appeal 2004)
• What if stated illness is different from patented
  use
• Allergic rhinitis v hayfever
• Alzheimer v alzheimer caused by a specified
  trauma
• Reducing mortality form illness v treating
  symptoms of illness
• Always remember the validity /infringement squeeze

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Cristalline polymorphs

• Complex molecules can crystallize in may ways
• Diamond, coal and carbon nanotubes are different
  crystal structure of the same compounds

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Cristalline polymorphs

• Different crystal structure can result from
• Crystallization parameters (solvent, temperature
  )
• Hydration
• Cristal partners (co-crystals)

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Cristalline polymorphs relevance?

• New polymorphs can have enhanced
• Stability and Shelf life
• Improved production process and handling
• Biovailability
• Examples include Ranitidine (Zantac),
  Paroxetine (Deroxat), Cefnidir (Omnicef )

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Cristalline polymorphs commercial relevance

• Useful to extend patent monopoly if the market
  switches.
• Generic that uses the old crystalline form can
  be seen as outdated even if no actual benefit
  result.

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Cristalline polymorphs patent definition?

• At present cannot be defined directly by
  structure
• Need to show X-ray or Infrared absorption data.
• These are akin to identification by
  fingerprinting

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Cristalline polymorphs Xray data

• Atorvastatin
• form V form VI

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Cristalline polymorphs Xray data

• The products claimed are defined by selecting
  characteristic peak
• Claim 1 Crystalline atorvastatin hemi-calcium
  characterized by a PXRD pattern having peaks at
  3.8, 8.0, 8.9, and 10.40.2 degrees 2 theta.

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Cristalline polymorphs Issue with validity -
Novelty

• How different should X ray spectra be?
• Should peaks be of different heights, different
  positions?
• Lord Justice Jacob in Laboratoire Servier v
  Apotex 2008 CA
• The individual peaks of the table should not
  have too much significance attached to them it
  is the overall set that matters

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Cristalline polymorphs Issue with validity -
Novelty

• Was the new polymorph already manufactured in
  the past?
• Polymorphs are know to interconvert or revert
  spontaneously to other forms.
• Servier v Apotex
• Patented form a was the inevitable product of the
  prior art protocols.

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Cristalline polymorphs Issue with validity
Inventive step

• Often polymorph patents claim several new forms
  at once but do not state what the new polymorph
  is for?
• Often polymorph patent make vague claims about
  improved stability with no data
• Problems with inventive step under the EPO
  problem/solution approach.
• Is there an invention or a crystalline oddity?

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Cristalline polymorphs Infringement

• What if some peaks are different?
• What if the X ray spectra of the alleged
  infringement is more similar to the prior art X
  ray spectra?
• The novelty/infringement squeeze
• Evidential problems arise easily as excipient
  peaks (such as lactose) easily mask the relevant
  peaks.
• The Lord Chief Justice in Servier v Apotex The
  evidence gave the case the spurious veneer of
  technical complexity

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Enantiomers

• Molecules can have asymmetric shapes so that a
  mirror image of them is different form the
  original
• They are called chiral

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Chiral molecules

• Chiral molecules can exist in the two mirror
  image form. They are called enantiomers.
• A mixture of both enantiomers is called racemic
• The two enantiomers are called the L and the D
  form (or and or S and R ).

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Enantiomers medical relevance?

• Often drugs can exist in the L and the D form.
• One form can be therapeutic and the other toxic.
• Thalidomide one enantiomer was therapeutic and
  the other was teratogenic.

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Enantiomers commercial relevance patent and
switch

• Useful to extend patent monopoly if the market
  switches.
• Generic that uses the old racemic form form can
  be seen as outdated even if no actual benefit
  result.
• Eg Zyrtec racemic form of cetirizine outdone
  by the new L-cetirizine Xyzall.
• Actual clinical benefit still controversial.

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Enantiomers patentability

• Novelty T1046/97 enantiomers can be novel of
  the racemic mixture.
• But are they inventive over growing literature in
  the last 20 years prompting the skilled worker to
  investigate individual enantiomers?
• See T944/04 obvious to try out individual
  enantiomers
• See Ranbaxy attack on Lipitor English Court of
  Appeal skilled worked would investigate the
  properties of the enantiomers.

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Enantiomers defending infringement claims

• Extrinsic evidence of speculative results.
• Some patentee file on the same day pairs
  application each directed to one of the two
  enantiomers.
• But is this an invention or a wild guess?
• Patent require some credible evidence of claimed
  effect see T1329/04, T609/02 and T715/03.