h i r s c h & p a r t n e r s a v o c a t s o l i c i t o r r e c h t s a n w a l t patent life...

H I R S C H & P A R T N E R S

A v o c a t S o l i c i t o r R e c h t s a n w a l t

PATENT LIFE CYCLE MANAGEMENT

Strategies for originators and tactics for generics

Dr Denis SchertenleibAvocat & SolicitorPartner Hirsch & AssociésParis France

[email protected]

HIRSCH & PARTNERSH I R S C H & P A R T N E R S Dr Denis Schertenleib

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


There is a real pressure for

Originators to increase the duration of their monopoly beyond 25 years.

Generics to break that monopoly.


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.


Second generation patents - examples

Second therapeutic use

Crystalline polymorphs

Single enantiomers



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.



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.


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


2nd therapeutic use – dosage regimen

Can dosage regimen be a patentable new use:

Eg: Fosamaxknown to use Fosamax every day at 10mgPatent on use of Fosamax once a week at 70

mg


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?


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


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


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


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


Cristalline polymorphs

Complex molecules can crystallize in may ways:

Diamond, coal and carbon nanotubes are different crystal structure of the same compounds


Cristalline polymorphs

Different crystal structure can result from:

Crystallization parameters (solvent, temperature )

Hydration Cristal partners (co-crystals)


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 ®)


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.


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


Cristalline polymorphs – Xray data

Atorvastatin:

form V form VI


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 10.4±0.2 degrees 2 theta.


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”


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 was the inevitable product of the

prior art protocols.


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?


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”


Enantiomers

Molecules can have asymmetric shapes so that a mirror image of them is different form the original

They are called chiral


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 ).


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.


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.


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.


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.

h i r s c h & p a r t n e r s a v o c a t s o l i c i t o r r e c h t s a n w a l t patent life...

Documents

h i r s c h p

i c i t o r r e c h

nd therapeutic use epc

use of fosamax

therapeutic use claims

use of aspirin

nd therapeutic use claim

medical use