Takeda has come full circle by winning a Para IV patent litigation and successfully defending the validity and enforceability of US Patent No. 4,687,777 covering pioglitazone hydrochloride, the active ingredient of their oral anti-diabetic drug "ACTOS", against the generic challengers Mylan and Alphapharm. Judge Denis Cote of the US District Court for the southern district of New York, has ruled in favour of Takeda maintaining that 777 patent is valid and enforceable, and thereby preventing Food and Drug Administration (FDA) from approving the abbreviated new drug applications (ANDAs) filed by generics. This victory, however, results from the weak arguments made by generic movers during the court proceeding, miserably failing to meet their homework.

Tempting 'Para IV' generic move
On July 15, 2003 Watson Pharmaceutical, Alphapharm, Ranbaxy, and Mylan all filed ANDAs seeking approval to market 15 mg, 30 mg, and 45 mg pioglitazone hydrochloride tablets. However, Ranbaxy and Watson filed Para III certifications with respect to the 777 patent, not challenging the validity of 777 patent but both filed Para IV certifications relating to the composition claims in the combination use patents where as Alphapharm and Mylan filed Para IV certifications with respect of the 777 patent, claiming that it is invalid. In their Para IV certifications, both Alphapharm and Mylan claimed that the 777 patent was invalid due to obviousness and forwarded notice of Para IV certification to Takeda that included detailed statements under 21 USC 21§ 355 (j) (2) (b) (ii) clarifying the legal basis of their positions. Mylan in their notice described that 777 patent was invalid in the light of Compound 16 of US Patent No. 4,287,200 (200 patent). Mylan also asserted that Compound 16 of 200 patent is identical to a Compound 14 identified in a prior publication of Dr Sohda. Alphapharm also contended in their notice that pioglitazone covered by 777 patent is prima facie obvious over the prior art compound, disclosed in 200 patent and published article of Dr Sohda.

But by the time of trial, each defendant completely altered their approach to the invalidity issue expressed in their statement. Mylan abandoned its obviousness issue, and pursued an inequitable conduct claim at trial whereas Alphapharm altered its obviousness argument in several substantial ways. The trial was based to resolve the challenges made by the defendants to the validity and enforceability of Takeda's 777 patent which took place from Jan. 17 to Jan 30, 2006.

Lacking persuasive evidence
Submission of Alphapharm's Para IV certification statement recognized that during the trial proceeding they have the burden to prove by clear and convincing evidence that the prior art provides some reason or motivation for a person of ordinary skill to make pioglitazone. To substantiate its contention, Alphapharm, identified only two sources of prior art: 200 patent and prior publication of Dr Sohda. But during the trial proceedings they also argued about the divisional patents to the 200 patent and a few articles in scientific journals. Referring to 200 patent, Alphapharm argued that the patent generically disclosed pioglitazone, and identified three compounds related to pioglitazone: compounds 16, 40, and 42, emphasizing particularly on compound 42 which is methyl homolog of the ethyl compounds covered by Claim 1 of the 777 patent, arguing that an exchange of an ethyl group for a methyl group would have been obvious. Coming to Dr Sodha's article, Alphapharm argued that discussion referring to compound 58 would lead one of ordinary skill in the art to choose compound 58 as the lead compound for further development. However, this argument was not part of their Para IV certification statement. Alphapharm argued that the prior art clearly identified compound 58 as a lead compound warranting further investigation, and that the application of a few, obvious chemical processes would have produce pioglitazone. Alphapharm also argued various technical flaws made in 777 patent. Court, however, found that Alphapharm's arguments fails to show any persuasive evidence, much less by clear and convincing evidence, that one with ordinary skill in the art have had any reasonable expectation or motivation based on the prior art for synthesizing pioglitazone.

Declining inequitable conduct
During the trial proceeding, Mylan contended that the 777 patent is invalid because Takeda engaged in inequitable conduct, claiming that Takeda intentionally made material misrepresentations in its presentation made in the 777 patent when applying to the Patent and Trademark Office in 1986. However, this argument was not part of their Para IV certification statement. Mylan also raised few other issues to attack Takeda in its presentation made in the 777 patent. Mylan argues that Takeda fails to disclose to USPTO a compound already disclosed in the prior art, specifically in publication of Dr Sohda, which is parent structure for the left hand moiety of the pioglitazone molecule. Mylan argues that if Takeda had been revealed that prior known compound along with its comparable activity and toxicity to pioglitazone then USPTO "might" have concluded that pioglitazone is not patentable over prior art. But Mylan in their contention failed to prove that Takeda has made any misstatements or has failed to provide the USPTO material information. The Court of law found that Takeda has clearly identified the relevant prior art including both Dr Sohda and 200 patent. Judge Dennis Cote in his 124-page ruling wrote, "Mylan has failed to carry its burden of showing either a material misstatement or omission. It has also failed to present any evidence regarding intent to deceive the Patent and Trademark Office".

Still in the game!
Valid and enforceable 777 patent has shifted the tempting generic move back to innovator Takeda, keeping their faith intact with its patents. The Court's ruling now prevents generic manufacturers from selling and marketing pioglitazone tablets until the 777 patent expires in 2011. Other US patents covering certain methods of treatment using pioglitazone and certain compositions that include pioglitazone will expire in 2016. In another development, Pfizer has successfully defended Lipitor in Finland, after losing it in lower court to Ranbaxy. The Helsinki Court of Appeal has granted a preliminary injunction against Ranbaxy, barring Ranbaxy from selling and marketing generic version of Lipitor. These unfavourable rulings will definitely not affect the Para IV strategy of generic challengers but to win the game they need to restructure it, not technically but in line of Para IV jurisprudential precedents.



(The author is working with a Mumbai-based pharmaceutical company)