The sofosbuvir conundrum

Few patents get famous enough to make it to the headlines of the general press. Some Apple patents are among them, such as those nicknamed “slide-to-unlock” or “rubber-banding” – especially thanks to the world war waged against Samsung. Other patent celebs include those on blockbuster pharmaceutical drugs.

In this latter category, one patent family in particular has attracted some fuss over the past few years. It is the one which covers the drug sofosbuvir, marketed under the name Sovaldi.

Blockbuster drug patents can beat even patents on blockbusters.
Blockbuster drug patents can even beat patents on blockbusters.

Sofosbuvir has markedly improved the treatment of hepatitis C virus (HCV) infection. But in many countries, in the absence of any generic version of the drug, the price of HCV treatment has skyrocketed as a result. This has aroused vocal protests by a number of NGOs (see e.g. here).

In Europe, the sofosbuvir patent (or at least one sofosbuvir patent) is EP 2203462, owned by Gilead. It was opposed after grant by ten different parties, including the NGO Médecins du monde, a number of generic manufacturers, and a number of straw men. Oral proceedings took place on October 4-5 in Munich. The only public information available as of today on the online register is that the patent was maintained in amended form. The minutes of the oral proceedings and the written decision of the opposition division have not been issued yet.

Tufty the Cat has recently made assumptions on his blog regarding the claims which were uphed by the opposition division. I have now received a confirmation by someone who attended the oral proceedings that Tufty got the claim amendment right.

But there seems to be some confusion, to say the least, after these oral proceedings. Indeed, Gilead and its opponents seem to have different views as to whether the amended patent still covers sofosbuvir or not.

In order to understand how there can be such a controversy, it is necessary to go back to some basic notions of stereochemistry.

There are many examples of chemical compounds having different 3D atom configurations although they share the same 2D chemical formula. These different configurations are referred to as stereochemical forms, or diastereomers, of a given compound.

In the pharmaceutical field, identifying the different stereochemical forms of a compound is of prime importance, as diastereomers often have different pharmacological effects. By way of example, the so-called (S) stereochemical form of ibuprofen is a hundred times more active than the so-called (R) stereochemical form.

Besides, such chemical compounds are generally not synthesized as stereochemically pure compounds, but as a mixture of diastereomers. It is often necessary to further purify this mixture in order to isolate the most active diastereomer.

Gilead’s patent as granted contains six claims, including three independent claims 1 to 3. For once, let’s start with claim 2.

Claim 2 is directed to a compound of the following formula:

sofos-claim-2

This is sofosbuvir.

Then claim 3 is directed to another compound of the following formula:

sofos-claim-3

This other compound looks very much like sofosbuvir, since it is its diastereomer. The difference between the two compounds is highlighted in yellow. In the sofosbuvir formula, the P-O bond is shaded in black and the P-N bond is hatched, which means that, in 3D, the oxygen atom is in front of the phosphorus atom, while the nitrogen atom is behind. It is exactly the opposite in the diastereomer of claim 3.

Now, here is the formula of the compound of claim 1:

sofos-claim-1

In this formula, the relevant P-N and P-O bonds are depicted as simple lines, which means that the 3D configuration is not specified.

Claims 4-6 simply recite a composition comprising the compound of one of respective claims 1-3 and a pharmaceutically acceptable medium.

According to my source, claims 2, 3, 5 and 6 were found by the opposition division to extend beyond the contents of the application as filed. As a result, the patent proprietor filed an auxiliary request in which these claims were deleted, and only granted claims 1 and 4 remained. The opposition division came to the conclusion that this auxiliary request meets all the requirements of the EPC, and made the interlocutory decision of maintaining the patent in this amended form.

The decision should soon be issued in writing, and will be open to appeal by all parties.

And now, here comes the conundrum.

The patent as amended during first instance opposition proceedings no longer contains claims 2 and 5 which were specifically directed to the sofosbuvir compound and the sofosbuvir-containing medicament. The question is whether the remaining claims 1 and 4 still protect sofosbuvir and sofosbuvir-based drugs.

One possible interpretation is that claim 1 is a generic claim which protects both diastereomers. It is broader than claim 2, and therefore the scope of the patent remains completely intact. Quite frankly, I think this is the interpretation that most patent attorneys would consider as the most logical one.

However, another possible interpretation is that claim 1 is directed to a diastereomeric mixture, i.e. a mixture of the compounds of claims 2 and 3 as granted. Arguments in favor of this interpretation could be that: claim 1 does show a 3D configuration in other parts of the molecule; thus, the absence of 3D information around the phosphorous atom means that such information cannot be provided, because both forms are present in the compound; furthermore, granted claims 2 and 3 are independent claims and do not depend on claim 1 which confirms that they are not particular embodiments of claim 1.

According to this second interpretation, a generic sofosbuvir drug would arguably no longer infringe the patent – as the drug would not contain a diastereomeric mixture.

It seems that the description of the patent does not fully clearly support one interpretation over the other.

I could very well see a French court coming to the conclusion that since the claim specifically directed to sofosbuvir was deleted, the patent may not possibly protect this molecule any longer. Maybe the written decision of the opposition division will contain a position as to what claim 1 means. But then, maybe not. And anyway, any position that they may have taken is not binding on national courts.

With that in mind, I would certainly not bet my life on either interpretation. Would readers be keen on taking a vote?

I would like to thank my source for this hot information. I have also been told that a number of interesting topics were discussed during the opposition proceedings, in connection with extension of subject-matter, priority and inventive step. So we should watch for the written decision of the opposition division when it is issued.


CASE REFERENCE: ongoing opposition proceedings against EP 2203462 to Gilead Pharmasset LLC.

2 thoughts on “The sofosbuvir conundrum”

  1. Renaud,

    you are right, there are strong arguments supporting both options, I would not take a bet, we have to wait for the written decision.

  2. Great entry, Renaud. Looking forward to your follow-up.

    Without knowing the facts of the case, I would apply the general principle that claims have to be interpreted in their broadest meaning, as long as this interpretation is reasonable and not absurd.
    This would mean that claim 1, where no stereochemistry of the P atom is specified, would cover the mixture of stereoisomers with any isomer ratio, but also each pure stereoisomer separately. I see it as if claim 1 would include the IUPAC chemical name without specifying the stereochemistry. That would cover any isomer and mixtures of isomers.
    The deletion of claim 2 due to added matter could have been caused by mere formal grounds, but the claim 1 would still cover stereospecific products. I do not see that deleting claim 2 should imply any restriction to the coverage of claim 1.
    I am even thinking now that granted claims 2 and 3 would also cover mixtures of steroisomers, as long as they contain some of the stereospecific compound of the drawing. They are not only directed to pure stereoisomers.

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