The commentators’ analysis turns on a critical fact: that a skilled person would have been motivated to pursue a di-ester for Gancyclovir and not a mono-ester. To elaborate: Unlike Acyclovir, Gancyclovir has two OH groups. Since these OH group posed phosphorylation problems, it would have been important to block both of them via a di-ester. By coming up with a mono-ester of gancyclovir (blocking only one OH group) and not a di-ester, the inventor taught away from the prior art and can legitimately claim something “inventive”. Apparently, the mono-ester confers surprisingly better properties than the diester …however the skilled person would have been motivated to only go after the di-ester…and to this extent, the inventor of Valgancyclovir did something counter-intuitive!
I haven’t see any published evidence pointing to the certainty of this “fact” (mono ester vs diester phosphorylisation problems etc). And am very keen on hearing what our informed readers who are more well versed in the nuances of chemistry have to say on this.
Anyway, here is what the erudite commentator notes:
“With regard to obviousness, the decision is flawed in as much a chemical formulae cannot be compared like a design or TM even as in this case acyclovir and ganciclovir are both anti-virals and nucleoside analogs.
Its like comparing H2O and H2O2. This seems to be ridiculous argument. One is water the other is hydrogen peroxide.
Small changes make big difference particularly in chemistry and therefore such a comparison is technically incorrect and absolutely flawed. Even legal principles have to adopted and applied keeping in mind the facts of the case and the technology involved.
With regard to this case, all prior art documents taught away from mono ester…pl note ganciclovir has 2-OH groups and acyclovir has one OH.
Prior art suggested di- ester and not mono-ester, as prior art taught that all phosphorylation sites (OH sites) should be blocked in the prodrug. Hence prior art taught away from the monoester.
The present invention surprisingly found that not blocking a phosphorylation site in the pro-durg still led to enhanced and beneficial properties.
The prior art taught several problems with ganciclovir such as:Toxicity; Poor oral bioavailability and Frequent incompatibility with other drugs.
Small changes have huge effect in chemistry as there is no hindsight or prevision.
Previous prodrugs of acyclovir possessing free phosphorylation sites showed significant host cell toxicity and therefore it necessitated blocking of the OH group. As acylocvir has one OH group that was blocked in prior art. In ganciclovir , the prior art suggested blocking both OH groups.
And to this extent, the invention (of blocking just one OH group) was counter-intuitive.”
A patent expert, whom I have tremendous regard for, notes:
“Going by the erudite commentator’s logic, no chemical compound can ever be obvious over any other. Google Petering doctrine and In re Ruschig. These had to do with anticipation, which is a notch above obviousness.
The revoked claims were not granted in the US. At the EPO, there is a very interesting history – GSK opposed the patent -but then settled to sup with Roche.
There is also a 2008 article by Hans Maag, one of the inventors, which is a sort of mea culpa.
I believe your first analysis was bang on target.”
My response to the above patent expert:
I am completely with you on pointing to the flawed jurisprudential underpinnings of the erudite commentator who gave the example of H2O and H2O2. It is a well known legal doctrine now (in US and EU) that structural similarity leads to an inference of obviousness. It is for the inventor to rebut this inference–and in the case of H2O2, this is easily done.
However, in the case of acyclovir and gancyclovir, the structures were similar. And so were the functions (anti viral properties and perhaps both were nucleoside analogs as well?). Therefore it was very reasonable for the examiner to compare them. However, the dispute now centers around the issue of mono ester vs di-ester. I haven’t seen any evidence to support what the commentator proposed in this regard. More importantly, was the Indian patent office presented with such evidence in this regard? i.e. to show that since only one OH was phosphorylated, this was contrary to conventional wisdom?
shamnad,
i wish i wud ve been able to join this debate!!!!!!!!!!!! but alas…..
-aditya kant
Dear Aditya,
would love to have your views on this. Why don’t you come in as one of the many anonymous (es)? 🙂
shamnad,
i wish i could have! but being the ex-handlers of the case, there is no question of my substantive comments on the merits of the case – whether in my name or even as anonymous. lawyer-client privity. n as u must ve discerned by now (thru our brief interaction), how much importance i attach to professional integrity. may b, i belong to the ‘old school’ in this regard.
-aditya kant
Shamnad’s first comment (quoting an email from an anonymous) refers to a 2008 article by Hans Maag, one of the inventors. Can someone please post the full citation?
As one of the inventors involved in the discovery and development of Valcyte, the discovery was serendipitously. We were working purely from the diester approach for oblivious reasons of ease of synthesis and to hopefully maximize exposure. One batch of what would have been a di-valine ester was run in rodent studies before learning that it was in fact a 60:40 mixture of mono and di ester. Rather than stopping the study the data was completed and we found that we had a much higher exposure of gancyclovir than from previous di-valine batches. This is where the discovery of a mono ester was found to be superior.