BMS Hepatitis Patent Invalidated: A Viral Effect for India?

In a development with significant ramifications for India, a US district court recently invalidated a pharmaceutical patent covering Baraclude (Entecavir), a leading anti-viral drug for Hepatitis B patients. The drug brings in more than a billion dollars each year for BMS! 

The invalidation was pursuant to a law suit bought by BMS (the patentee) against Teva, a leading Israeli generic company. This drug is of particular interest to India, given a roaring patent contest on this front between BMS and Ranbaxy before the Delhi High Court. However, it bears noting that while the US patent (Number 5,206,244) covers the "parent" or "basic" Entecavir compound, the Indian patent only covers an alleged dosage "improvement". This is owing to the fact that Entecavir is a pre-TRIPS molecule and at the time of BMS's US patent application (in the year 2000), India did not grant pharma product patents.

As the Indian patent specification notes:

"This invention is directed to pharmaceutical compositions containing a low dose of entecavir and the use of such low dose composition to safely and effectively treat hepatitis B virus infection."

The Indian judge refused to grant an interim injunction  to BMS at the first instance, noting that the patent was “vulnerable”. The case has since been posted for "trial", and as I understand it, evidence is currently being recorded. For those interested, the Indian patent number is 213457 and the case details are: Bristol-Myers Squibb Company v. Ramesh Adige & Anr (Ranbaxy) C.S. (O.S) No. 534 of 2010.
 

As I’ve advocated here, in all cases where there is a strong challenge to the patent (which is in 90% of all pharmaceutical patent cases), courts must desist from granting injunctions. Rather, they must dispense with the interim phase and move straight to trial. In most pharmaceutical patent cases at least, this route will ensure that patients and generic manufacturers do not stand to suffer a "bad" patent in the "interim", a suffering that is well beyond "monetary" computation. 

"Working" of Entecavir:

It bears noting that we'd prominently featured Baraclude (Entecavir) in our Form 27 investigation some years ago, showing that "working" statements had not been filed in full for this drug. However, what we gathered is that the drug brought in more than 20 crores for BMS each year. We’ve not reviewed the recent statements by BMS, but assume that there has been better compliance on this front. As Sai Vinod noted recently, the Indian Patent Office (IPO) has again indicated that it is serious about compliance with working statements and Form 27. However, we need to re-examine the "efficacy" of the current format of the Form 27 statement.

For those interested, well known pharma blog, Pharmalot has a good review of the US invalidity decision, as also a link to the text. The decision is interesting for several reasons:  

1. This is not a classic ever-greening case and the drug compound (a carboxy nucleoside analog) is not a mere new form of a known compound. Rather, it is a new compound altogether and was approved by the FDA as an NCE (new chemical entity). To this extent, section 3(d) of the Indian Patents Act will not apply directly to this case.  

2. The US court applied a rigorous obviousness standard and held that although this may be a new compound, it fails the obviousness test since it was essentially an obvious modification of an existing natural compound. The two part analysis can be summarised as below:

i) it would have been obvious to a person skilled in the art to work with the closest known prior art compound (a naturally-occurring nucleoside commonly referred to as "2-CDG") with known anti viral properties.

ii) it would then been obvious to modify the existing compound (2-CDG) by substituting the oxygen atom with a carbon carbon double bond at the sugar portion. A skilled person would have a reasonable expectation that this modification would yield improved antiviral properties.

In other words, although the drug is based on a new compound, the said compound is not patentable, since it was obtained by modifying a known natural substance in a "stock in trade" manner.

The judgment which runs into 170 pages is a wonderful read, with a delightful interspersing of snippets of the cross examination. Sample this:

Tevas counsel: Now, you would agree that if you are looking for conservative changes that could be made, one place you would look at is the periodic table, is that right?
 

Dr Schneller (BMS’ key expert witness): Well, you almost have to, because all molecules are made from elements that are on that periodic table. So there no magic lamp someplace that’s going to come up with new ideas.

Tevas’ counsel: And the periodic table…it’s the chemists’ stock in trade?

Dr Schneller: Yes, sir

An "Alien" Patent Standard in India?

 

This decision helps dislodge the now prevalent presumption that the US almost always reflects “low” patent standards. As this case demonstrates (much like its earlier predecessor Pfizer vs Apotex), US courts do apply a rigororous patentability threshold from time to time. And to this extent, one might actually find that the ostensibly high Indian standards are actually not all that “alien”.

Of course, this is a district court decision and will certainly be appealed to the CAFC (Court of Appeals for the Federal Circuit), reputed to be more "patent friendly". 

One is not certain of the fate of the secondary patent in India. However, one might hazard a guess that, in the light of the "therapeutic efficacy" standard under section 3(d) that now informs most Indian decisions (unless the Supremes alter it in the much awaited Novartis Glivec ruling), BMS' claim to an improved "dosage" regimen is extremely vulnerable.