The Valcyte Decision – An Analysis

1. The Valcyte Decision – An Analysis Srividhya Ragavan sragavan@ou.edu Feroz Ali Ali Associates

2. IN 207232 Patentee: F.Hoffmann-La Roche AG

3. The Invention Drug: Valganciclovir Hydrochloride Hydrochloride salt of the L-valyl ester of ganciclovir L-valyl ester prodrug of ganciclovir (two diastereomers) Diastereomers → ganciclovir (intestinal esterases)

4. Chemical Structure Chemical Name: 2-(2-amino-1, 6-dihydro-6-oxo–purin-9-yl) methoxy-3-hydroxy -1-propanyl –L-valinate

5. Patent History in India Patent application: 27 July 1995 FER: 17 May 2006 Pre-grant Opposition: 12 July 2006 Grant published: 29 June 2007 Patent Expiry: 27 July 2015

6. Pre-grant Opposition Oct 2008: Pre-grant opponent files writ in Chennai Dec 2008: Order setting aside the grant; hear opponent Patentee → Supreme Court : hear opponent Jan 2009: Controller dismisses pre-grant opposition

7. Pre-grant Opposition Pre-grant Opponent → Supreme Court Challenged the decision of Controller March 2009: SC order to combine both the SLPs Pre-grant opponent intervene in post-grant proceeding

8. Post-grant Opposition Five post-grant oppositions Ranbaxy, Cipla, Bakul Pharma, Matrix, DNPP (NGO) Sep 2008: Roche sues Cipla in Mumbai Apr 2010: Order rejecting product patent

9. Some Facts Ester form of a known drug Ganciclovir known since the 1980s (US 4,355,032 ) Product claims: 1 to 9; 10 to 12 for process Main Grounds: Lack of Novelty Lack of Inventive Step Not an invention under section 3(d) Non-compliance with section 8

10. Prior Art EP 0375329 (‘329) US 5043339 (‘339) US 6083053 (‘053) US 4355032 (‘032) US 4957924 (‘924) Beauchamp et al, Drugs of the Future, 1993, 18(7): 619,-628 Beauchamp et al, Antiviral Chemistry and Chemotherapy (1992), 3(3), 157-164

11. Lack of Novelty Anticipated by US ‘339 Held, an anticipating prior art document should name the claimed compound individually and should contain sufficient description, which would enable a person of ordinary skill in the art to arrive at the invention without further experimentation. Neither ‘339 or ‘329 disclose or contain an enabling disclosure to carry out the claimed invention so as to render the US ’339 as anticipating the claimed invention. Held, US ‘339 or EP ‘329 do not specifically disclose the mono-(L)-valinate ester of ganciclovir either expressly or inherently. Although both the patents generally disclose the existence of mono esters as a part of a large class of compounds, it does not particularly disclose the compound or other property of the said compound . the information provided may be relevant but not appropriate to obtain the compound of the claimed invention.

12. Comparing the Novelty Analysis US Standard Four Corners Rule for novelty determination: All the elements of the claimed invention should be found within the ambit of a single prior art reference

13. Valcyte Novelty Question • First prior art: US ‘339 discloses L valinate ester of glanciclovir • Second Prior art: EP ‘329- discloses the mono esther form of the application material Counsel for patentee: but, with a 3 fold excess of the activated amino acid Such an argument would not work for novelty purposes in the US since the requirement is that all the elements have to be disclosed in a single prior art. It was argued that a skilled person in the art would have been able to accordingly appreciate the reduction

14. A test that is reminiscent of the TSM test to prove non-obviousness – not a novelty standard • Counsel for patentee argued that US ‘339 is not a valid prior art because:

15. An Enabling Reference • Citing from the Novartis (Glivac) application: In the US too, a reference has to be fully enabled in order to anticipate. Generally, to take care of the objectives of the patent system

16. Citing from Union Carbide [1992] EPOR 312: Inventiveness has to be determined at the time of the invention (and not at the time of evaluation of the patent) The same principle is codified in the statute under Title 35, §103: “A patent may not be obtained unless… the subject matter…would have been obvious at the time the invention was made …

17. Lack of Inventive Step Opponents: US’924 discloses valine esters of acyclovir that exhibit more bioavailability than acyclovir. Drugs having poor absorption are converted into ester to make the drug more bioavailable when administered orally. The amino acid ester of ganciclovir, preferable D-L and DL amino acids. It also teaches bis-(l-valinate) ester of ganciclovir and example 6(b) teaches the process to get mono-(L-alaninate) ester along with bis-(L-alaninate) ester of ganciclovir in the ratio of 1:9. US ‘032 discloses ganciclovir and pharmaceutically acceptable salts which are active against Herpes Simplex virus I and II and related virus such as cytomegalovirus, Epstein-Barr Virus and Varicella Zoster virus. The oral form of parent drug ganciclovir has been commercially known from the US Patent ‘032. The L valine ester of acyclovir has improved bioavailability than the acyclovir after oral administration. A skilled person in the art follows the route of L-valine ester of acyclovir, i.e., valacyclovir and apply same to ganciclovir to get valganciclovir. Valacyclovir and valganciclovir are nucleoside analogs having similar structure and used for similar treatment.

18. Lack of Inventive Step Beauchamp in 1992 and 1992 disclosed the best amino-acid ester for acyclovir. L-valyl ester was the best prodrug amongst 18 amino acid esters sysnthentised and tested as potential prodrugs. Valacycolvir, the prodrug of acyclovir is more bioavailable than acyclovir that is proved to be rapid hydrolysis in vivo than the parent compound. Various forms of esters are prepared using hydroxyl group of the purine ring and the side chain of acyclovir with amino acids. The modifications made to the purine ring was toxic and the modifications made to the acyclic chain resulted in improved effect. Acycolvir and ganciclovir are structurally similar and functionally similar nucleoside analog. It is obvious to a person would try for similar ester which is alresdy proved with improved effect. US ‘924 patent discloses the L-valinate ester of acyclovir and hydorcholorde sasl of the L-valinate ester. The disease targeted by the two drugs, L-valinate ester of acyclovir and ganciclovir are similar. L-valine is a chiral compound, its derivative L- valinate ester of ganciclovir inherently will be a chiral molecule, therefore (R) or (S) diastereoisomers can be expected by a skilled artisan. A person skilled in the art would combine the teachings of Beauchamp’s publications, US 032, US 339 and EP 329 and US 924 to prepare the compound in the alleged invention. Patentee - Combining the prior art, Beauchamp’s publications with US 924, a person skilled in the art will be motivated to block all the free OH groups resulting in bi-ester.

19. Lack of Inventive Step Controller held that the nucleosides such as acyclovir, penciclovir show low aqueous solubility and low bioavailability when administered orally. To increase oral bioavailability many modifications were done to the purine ring and acyclic side chain. Conversion of acyclovir into L-valine ester of acyclovir was suggested by ‘924 patent. The ‘329 patent discloses di-valyl amino acid ester of ganciclovir. Prior art suggests that many similar nucleosides are converted into ester of amino acids, preferably L-valine to increase oral bioavailability. The preferred ester forming compounds suggested by ‘329 patent and ‘924 patent are aminoacids, particularly valine, more particularly, L-valine to overcome the problem of oral drug delivery. Beauchamp suggests and motivates the involvement of stereospecific (L- vs D-) transport process using common branched chain amino acids, L-valine and L-isoleucine, particularly L-valine ester which makes the drug more bio available. A skilled person would have been motivated to prepare mono L-valine ester of ganciclovir from the teachings of ‘329, ‘924 and the Beauchamp articles. Claim 1 and its dependant claims are not inventive.

20. Lack of Inventive Step Ex 9 of the patent does not show the improvement in oral bioavailability of the esters of ganciclovir Comparison made between esters and HCl salt as an improvement with regard bioavailability is not scientific and results provided are not proper to meet the patentability requirement. Since the object of the invention is to provide a prodrug of ganciclovir with improved oral bioavailability, the comparison provided in the specification to show such improvement is not scientific Improved oral bioavailability not proved in the complete specification Most drugs listed in the pharmacopoeias are in the salt forms, because salt forms of the drugs influences the solubility for better therapeutic effect.

21. Process patent inventive Neither ‘339 nor ‘329 specifically mentioned the process for the preparation of the compound of the claimed invention. Identification of the compound of the invention from ‘329 is obvious, but the method for the preparation of such a compound requires extensive research work. Even though the method of hydrolyzing one of the ester group of ‘329 patent or any other steps involved in the preparation is by conventional method, it could not have been ascertained before it was produced. Process claim allowed but restricted to a single process.

22. Not an invention [section 3(d)] New form of a known compound already disclosed in US ‘339 Ester form of a known substance should show significant enhancement in efficacy to merit a patent grant Novartis v Union of India – efficacy means therapeutic efficacy (High Court and IPAB) – ‘Efficacy’ and ‘bio-availability’ are two different concepts. Data provided in Ex 9 of the specification pertains to bioavailability but not therapeutic efficacy. The compound and its pharmaceutically acceptable salts, isomers, crystalline form and composition do not fulfill the requirement of the Act.

23. Inventive Step Issue • Opponents traced the journey of L-valine ester for acyclovir to arrive at L-valine ganciclovir. • Note that acyclovir and ganciclovir are nucleoside analogs • Test used – suggestion and motivation from prior art

24. After KSR, the US has moved to a broader standard Reason?? POSITA would solve a problem by looking at prior arts that solves different problem. When a claimed invention implements a predictable variation of the patent, then §103 bars it

25. Efficacy Issue • Proposition 1: Therapeutic efficacy is different from bioavailability (property) and clinical efficacy 2 Questions: What is the US position on this? The “teaching away” controversy

26. Pfizer v. Apotex (Fed Cir) (2007) : Pfizer sued Apotex for infringing the patent on Norvasc - besylate form of amlodipine. Norvasc is used to treat hypertension and forms of angina. Apotex alleged that Pfizer’s earlier ‘909 patent over amlodipine anticipated the patent over amlodipine besylates – (salt form of amlodipine). Federal Circuit agreed with Apotex on the grounds that the besylate form lacked enhanced utility from the base compound. The Federal Circuit reiterated an established principle that salts of known compounds are deemed obvious unless there is an unexpected utility or improvement or efficacy!! What is the US position on this? Given this, the post-grant decision is commendable in clarifying the constituents of the efficacy requirement

27. The “teaching away” controversy • Where the controversy comes from? • “Teaching Away” – A secondary factor • Secondary factors are employed where court is unable to conclude using the basic test for determining inventiveness • “Teaching Away” – is persuasive but need not tip the case towards the presence of inventive step • Further, I did not see any teaching away.

28. In Re Dillon (Fed Cir) (1991) : Dillon claimed tetraorthoesters Prior art taught triorthoesters Fed. Circuit held that a compound can be prima facie obvious if the examiner can show: Structural similarity, or, Suggestion or expectation that the prior art and claimed compound will have same or similar utility The Teaching Away Controversy In the Valcyte dispute, acyclovir and ganciclovir seems to have demonstrated structural similarity and similar utility.

29. Other findings Patent filed Form 4 declaring the status of the US Patent Application as ‘pending’ – application was abandoned on 16.06.1995 – this amounts to furnishing false information. Patentee has met the requirements under section 8 of the Patents Act. Photocopy of prosecution history of US application was taken from the USPTO website submitted during the proceedings as evidence is not an authenticated document and hence not considered. Amendment of statement of opposition not allowed    Since claim 1 is not inventive, making a composition of known drug with known excipients cannot be considered as an invention. Therefore Claim 9 is a mere admixture resulting only in aggregation of known properties. Controller ordered to amend the patent to process claims restricted to a single process – within 15 days of the decision

30. Locus Standi • Very important issue to determine the course of intellectual property issues for the country

31. Individual farmers, animal husbanders and nonprofit organizations, raised moral and ethical concerns regarding patenting living organisms. • Under Article III, § 2 of the US Constitution, standing is established only for parties with either a threat of personal injury or an actual personal injury. • The injury to farmers as a class, the Federal Circuit held, was due to increased competition from commercialization of genetically improved animals and not from the grant of patents. • Since the appellants asserted no other adverse effects on any individual rights under the patent statute, the suit was dismissed for lack of standing. Animal Defense Fund (Fed. Cir) (1991)

32. The European Position • Europe handled it differently; EPC has a morality provision • In the case involving Relaxin, a patent application for a DNA fragment encoding human H2-relaxin (and its precursors), was opposed as offending the provisions of “morality” and “ordre public” in Article 53(3) of EPC. • With reference to the famous LabCorp case, that dealt with a patent on a diagnostic methods, in Europe, it is expected that the invention would be scrutinized to determine whether it could be characterized as a method ‘‘of treatment of the human or animal body by surgery or therapy and diagnostic methods practiced on the human or animal body.’’ EPC Art. 53(3). • But, the chief tribunal of the European Patent Office, the Enlarged Board of Appeal, has interpreted this exception narrowly in Diagnostic Method G 1/04 (Dec. 16, 2005). • A claimed method is deemed an unpatentable ‘‘diagnostic method’’ within the meaning of Article 53(3) only if each of its steps involves the mental activity of attributing particular symptoms to a disease.

33. Other Controversies Can the procedure for post-grant be different from the revocation proceeding? US: Re-examination is completely different from the pre-grant opposition – designed to prevent the registration of a patent US: Re-examination procedurally completely different from the proceedings in courts - designed to achieve the exact same result Art. 14 – equal protection – does not apply because the objective with post-grant is administrative removal of patents as opposed to judicial removal. Administrative procedures are meant to be less burdensome as a rule.

34. Arguments Relating to Evidence Should the evidence statute be implicated? Both in the US and Europe, administrative procedures rarely implicate the evidentiary requirements. There has to be a reason for India to do that.