Alnylam Wins Important Battle in Kreutzer-Limmer Patent Fight

The Kreutzer-Limmer (KL) patent estate, exclusively owned by Alnylam and very broadly claiming double-stranded RNAs (dsRNAs) for gene silencing in human cells (up to 15-49 base pair dsRNAs), won an important battle at an oral hearing last week at the European Patent Office. This comes after Kreutzer-Limmer has suffered a number of setbacks at the EPO about one and a half years ago. The resuscitation of KL means that Alnylam may leverage this patent as potentially gate-keeping as it looks to enter additional non-exclusive licensing partners for its dominant RNAi Therapeutics patent portfolio, also as a potential backstop in the unlikely event that Alnylam loses the fight for the key Tuschl inventions.

The decision reversed an earlier rejection based on technical objections, mainly by Sirna/Merck and Silence Therapeutics, that some of the claims in the daughter application at issue had been incorrectly drawn from the parental application. In general, the main claim describing the structure of gene silencing short dsRNAs are somewhat clumsily constructed and not as straight-forward as one might imagine. This could be the result of having to take into account the embodiments underlying this claim.

If it were not be so important, reading the deeply philosophical arguments of what it means to be 'double-stranded' can be quite amusing, but unfortunately also very time-consuming and distracting, as are these drawn-out patent back-and-forths. Especially for smaller companies like Silence Therapeutics it may actually be worth focusing on developing the enabling delivery technologies and their therapeutic pipelines instead of having their lead scientists waste their creative juices taking part in these battles.

It is likely that the patent will go back again, but this time to be challenged on other issues such as novelty. Regardless, Alnylam should benefit from last week's decision to uphold Kreutzer-Limmer in that it adds to the appearance that, no matter how the individual patent chips fall, Alnylam has so many patent options that making some kind of licensing arrangement with the company would be required if one wanted to securely develop RNAi Therapeutics. Recent progress in systemic delivery should add to the urgency and may even make waiting for the outcome of the Tuschl Tussle a difficult decision.

The Wall Street Journal Reports that ‘Big Pharma Faces a Grim Prognosis’- In what Form will it take its RNAi Pill?

As I am procrastinating about what to write in a review about the ‘Business of RNAi’, I have tried to get more into the heads of Big Pharma rather than seeing the world from the RNAi company’s point of view as I used to. In a nice front-page article of the Wall Street Journal this week (http://online.wsj.com/article/SB119689933952615133.html?mod=googlenews_wsj), Barbara Martinez and Jacob Goldstein vividly painted a dark portrait about looming patent expirations and generic competition, declining drug approval rates, and a research enterprise that has just gotten too bureaucratic to respond to the new pressures.

To go biotech, which is now producing many of the most innovative and high-margin drugs and which has so far largely avoided similar pressures and proven quite profitable if you invested in the right platforms such as monoclonal antibodies and recombinant proteins, appears to be one of the last options left for Big Pharma to survive. As the likes of Merck, Pfizer, and AstraZeneca jostle to become the leading biotech company of the future, RNAi as one of the few broad technology platforms with a unique mechanism of action has to be up very high on their priority list. So how will Big Pharma get into the game?

There are the early adopters such as Merck, Novartis, and Pfizer which have been quite public about their RNAi efforts. Merck initially played the nice guy that wanted to help companies like Alnylam translate the science of RNAi into drugs. However, with the acquisition of Sirna Therapeutics and later difficulties with Alnylam, it is clear that Merck had grander ambitions than just being a humble licensee. Pfizer on the other hand has been trying this and that as if they first wanted to confirm the clinical viability of RNAi and then make their move. Eventually, unless of course RNAi fails (which I tend not to believe), they will all have to, because even though you are now allowed to use patented technologies with the intent of developing commercial drugs, the moment you hit the market, you have to pay in one form or another, and it is common practice that the earlier you license the less it will cost you.

As I’ve been trying (in vain) to find out which Prior Art was cited in the EPO decision as a reason to restrict the scope of Kreutzer-Limmer to 15-21 base-pair double-strand RNA in 2006 (if somebody can help me here, please contact me), I have come across a webpage on the EPO site where some of the opposition history of K-L is documented. I found it quite interesting that initially, the opposition included the likes of ISIS Pharmaceuticals, now Alnylam’s modification partner for RNAi Therapeutics, and Novartis, the second Big Pharma after Merck to take a broad license from Alnylam. Both of them dropped their opposition and instead joined Alnylam. On the other side there are the likes of Sanofi-Aventis, AstraZeneca, and Atugen (now Silence Therapeutics), and we know that AstraZeneca eventually took a license from Silence, probably the cheaper option.

It therefore appears that in the not-so-distant future we will see Big Pharma split into two camps- those with Alnylam, and those against Alnylam. The rationale for the latter either being the belief that they can find a way around Alnylam’s IP estate, or at least avoid some of the royalties by trying blunt-end dsRNA of longer than 21 base-pairs should K-L’s scope not stand. Of course, the higher the going rate for the license fees, the more the temptation to go that route, and maybe Alnylam bravely does not even mind it that way too much, since a sense of exclusivity probably makes the terms of the licenses more attractive for them. Nevertheless, for somebody with the balance sheet of many in Big Pharma, this would not only appear to be scientifically quite risky, but also penny-wise and pound-foolish. As the WSJ documented so well, the times have probably come to realize that a lot of the innovation has happened outside their research labs and no matter the correlation between wallet size and ego, being humble at the right time may help you survive the next 10 years. The same EPO website also says that Janssen Pharmaceutica, a subsidiary of Johnson and Johnson, has dropped their opposition- what do you conclude?