1. 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 Schertenleib Avocat & Solicitor Partner Hirsch & Associés Paris France ds@hirschlex.com

2. H I R S C H & P A R T N E R S Dr Denis Schertenleib HIRSCH & PARTNERS 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

3. H I R S C H & P A R T N E R S Dr Denis Schertenleib HIRSCH & PARTNERS There is a real pressure for Originators to increase the duration of their monopoly beyond 25 years. Generics to break that monopoly.

4. H I R S C H & P A R T N E R S Dr Denis Schertenleib HIRSCH & PARTNERS 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.

5. H I R S C H & P A R T N E R S Dr Denis Schertenleib HIRSCH & PARTNERS Second generation patents - examples Second therapeutic use Crystalline polymorphs Single enantiomers

6. H I R S C H & P A R T N E R S Dr Denis Schertenleib HIRSCH & PARTNERS 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.

7. H I R S C H & P A R T N E R S Dr Denis Schertenleib HIRSCH & PARTNERS 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.

8. H I R S C H & P A R T N E R S Dr Denis Schertenleib HIRSCH & PARTNERS 2 nd therapeutic use – EPC 2000 EPC 2000 clearly removed any ambiguity as to validity of 2 nd therapeutic use. EPC 2000 allows straightforward drafting of 2 nd therapeutic use claim: Product X for treating illness Y

9. H I R S C H & P A R T N E R S Dr Denis Schertenleib HIRSCH & PARTNERS 2 nd 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

10. H I R S C H & P A R T N E R S Dr Denis Schertenleib HIRSCH & PARTNERS 2 nd therapeutic use – dosage regimen Problem with EPC as methods of therapy are not patentable. Is a dosage regimen a method of therapy in disguise?

11. H I R S C H & P A R T N E R S Dr Denis Schertenleib HIRSCH & PARTNERS 2 nd 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

12. H I R S C H & P A R T N E R S Dr Denis Schertenleib HIRSCH & PARTNERS 2 nd 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

13. H I R S C H & P A R T N E R S Dr Denis Schertenleib HIRSCH & PARTNERS 2 nd 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

14. H I R S C H & P A R T N E R S Dr Denis Schertenleib HIRSCH & PARTNERS 2 nd 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

15. H I R S C H & P A R T N E R S Dr Denis Schertenleib HIRSCH & PARTNERS Cristalline polymorphs Complex molecules can crystallize in may ways: Diamond, coal and carbon nanotubes are different crystal structure of the same compounds

16. H I R S C H & P A R T N E R S Dr Denis Schertenleib HIRSCH & PARTNERS Cristalline polymorphs Different crystal structure can result from:  Crystallization parameters (solvent, temperature )  Hydration  Cristal partners (co-crystals)

17. H I R S C H & P A R T N E R S Dr Denis Schertenleib HIRSCH & PARTNERS 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 ® )

18. H I R S C H & P A R T N E R S Dr Denis Schertenleib HIRSCH & PARTNERS 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.

19. H I R S C H & P A R T N E R S Dr Denis Schertenleib HIRSCH & PARTNERS 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

20. H I R S C H & P A R T N E R S Dr Denis Schertenleib HIRSCH & PARTNERS Cristalline polymorphs – Xray data Atorvastatin: form V form VI

21. H I R S C H & P A R T N E R S Dr Denis Schertenleib HIRSCH & PARTNERS 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.

22. H I R S C H & P A R T N E R S Dr Denis Schertenleib HIRSCH & PARTNERS 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”

23. H I R S C H & P A R T N E R S Dr Denis Schertenleib HIRSCH & PARTNERS 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.

24. H I R S C H & P A R T N E R S Dr Denis Schertenleib HIRSCH & PARTNERS 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?

25. H I R S C H & P A R T N E R S Dr Denis Schertenleib HIRSCH & PARTNERS 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”

26. H I R S C H & P A R T N E R S Dr Denis Schertenleib HIRSCH & PARTNERS Enantiomers Molecules can have asymmetric shapes so that a mirror image of them is different form the original They are called chiral

27. H I R S C H & P A R T N E R S Dr Denis Schertenleib HIRSCH & PARTNERS 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 ).

28. H I R S C H & P A R T N E R S Dr Denis Schertenleib HIRSCH & PARTNERS 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.

29. H I R S C H & P A R T N E R S Dr Denis Schertenleib HIRSCH & PARTNERS 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.

30. H I R S C H & P A R T N E R S Dr Denis Schertenleib HIRSCH & PARTNERS 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.

31. H I R S C H & P A R T N E R S Dr Denis Schertenleib HIRSCH & PARTNERS 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.