It's a very interesting question. I still do not know whether a patent helps here - whether it's necessary for a compound to be exploited to a multi-ton scale. It depends on what kind of compound it is, and for what purpose. I think fundamentally I don't understand the contrast between private development of a product (which is patented) and public development by a group, funded indirectly by many sources. Again, I think the optimal route must depend on the thing being developed, and the nature of the track that needs to be taken to develop it. - Matthew Todd

Mat in this case the compound is known - only a new preparation method has been patented. It is difficult to see how this isn't a barrier for humanitarian purposes. - Jean-Claude Bradley

Mat left a comment on the blog post: molecular target of praziquantel not known. Seems like an opportunity for Open Science community. - Jean-Claude Bradley

If this method should turn out to be useful at production scales, most of the world's schistosomiasis is in Africa, South America and SE Asia -- so I hope the patent will simply be ignored. - Bill Hooker

"Schistosome calcium ion (Ca+2) channels are the only moiety so far identified as the molecular taget for PZQ, but the evidence remains indirect"! - Current Opinion in Infectious Diseases Issue: Volume 21(6), December 2008, p 659–667; DOI 10.1097/QCO.0b013e328318978f - Khalid Mirza

Bill - even if there is no patent in the countries receiving the medicine, patent rights can be invoked to block manufacture and transportation elsewhere - from http://news.bbc.co.uk/2... "In a letter sent in November, the charity accused Nutriset of invoking patent rights to block a Norwegian competitor from transporting a Plumpy'nut equivalent via Kenya." Also even if these issues do eventually get resolved - it means attorney time for the humanitarian organization. Only the absence (or expiration) of patents for a synthetic route removes that uncertainty. - Jean-Claude Bradley

Bill - also you have to wonder why a German patent was taken out on this. It is expensive and a hassle - generally people file as part of a strategy to recoup costs and profit. Interestingly the assignee is listed as a private individual and the inventor listed as "Inventor will be called later" - Jean-Claude Bradley

Khalid there does appear to be lots of speculation about the mechanism of action but nothing definite - Jean-Claude Bradley

What if the compound were prepared in the country of its use, where no patent existed? - Mr. Gunn

What I meant is what MrGunn said. A German patent is no use against a Brazilian company making pzq for local use, or (say) a Korean company exporting its product to Africa. In theory, patent rights can be extended worldwide -- but go ahead and sue that Korean company, and let me know how that works out for you. :-) - Bill Hooker

MG - it might not make economic or practical sense for a humanitarian organization to do a synthesis in a limited number of countries. This seems to be the main issue under discussion in the BBC article http://news.bbc.co.uk/2... - the patent holder was trying to force the preparation of food to happen in specific countries, which became a problem for a shipment of food to Africa. - Jean-Claude Bradley

MG: "What if the compound were prepared in the country of its use." Ah, this is a beautiful dream of mine. - Matthew Todd

Yeah, I know the economics aren't favorable, but it is possible, especially with all the outsourcing capacity being built in SE Asia these days. - Mr. Gunn

Good point, J-C, but in the case of schistosomiasis I think it could work. You could make pzq in Brazil for all of South America, and in China for all of SE Asia. I'm not sure where you'd go to cover Africa, unless your Brazilian or Chinese facility exported there. As with most NTDs there isn't much opportunity for profit anyway because of the poverty that's co-endemic (is that a word?) with the disease... which, as you say, makes it rather odd to take out a German patent. It could just be bullshit -- lots of patents are taken out to impress investors rather than to protect any genuine commercial advantage. - Bill Hooker

Bill/MG - my point is that it is to the benefit of the Open Science and humanitarian communities to disclose their research as quickly as possible in as much detail as possible. That way it will prevent patents from being awarded in areas of interest and avoid all of these problems. You can come up with ways to circumvent patents and be sure you'll win lawsuits - but that will incur additional legal expense. - Jean-Claude Bradley

JC, I know that some years ago the OpenSource organizations had lengthy talks with the USA and EU patent offices, because Open Source was not acknowledged as prior art; it did not count as 'published'. Since then, I think the POs approved certain central sources of Open Source (not sure which; SF perhaps?), but I doubt that blogs are acknowledged sources of 'prior art'... do you know more on the POs' positions towards blogs? - Egon Willighagen

Egon - according to http://en.wikipedia.org/wiki... "In order to anticipate a claim, prior art is generally expected to provide a description sufficient to inform an average worker in the field (or the person skilled in the art) of some subject matter falling within the scope of the claim. Prior art must be available in some way to the public, and in many countries, the information needs to be recorded in a fixed form somehow" I believe our Open Notebooks and associated raw data meet that criterion, especially when our archives are deposited on Nature Precedings, LuLu, institutional repositories, etc. Hopefully some attorneys will comment - I've asked one to take a look - Jean-Claude Bradley

I agree that NP, Lulu and institutional repositories indeed make the case stronger... but hope too that some legal patent experts can reply too about the acceptability of those as prior art sources. - Egon Willighagen

Also, I don't know if it's the case here, but it's unusual to file a patent application in only one country - usually one is filed in the US, Germany, and Japan, plus others. The situation above doesn't sound like there was a systematic attempt to apply for IP protection world-wide. - Elizabeth Brown

Thinh Nguyen from Science Commons sent me (via John Wilbanks) a detailed response about prior art, which I'll paste below: "“Prior art” generally refers to the conditions of patentability under Title 35 United States Code Section 102, which bars patentability if (a) “invention was known or used by others in this country, or patented or described in a printed publication in this or a foreign country, before the invention thereof by the applicant for patent,” or (b) “the invention was patented or described in a printed publication in this or a foreign country or in public use or on sale in this country, more than one year prior to the date of the application for patent in the United States.” The first clause addresses the situation where the invention was being used in the United States by others (for purposes of this clause, use by others in foreign countries doesn’t count) or described in a “printed publication” anywhere in the world before the inventor made his invention. The second clause is similar to the first clause, except that it establishes a 1 year grace period for the inventor’s public use or disclosure prior to patenting. “Printed publication” isn’t limited to physical printed material but can include electronic sources like databases and Web pages, provided that the publication was accessible to persons concerned with the art to which the document relates. (In re Wyer, 655 F.2d 221). - Jean-Claude Bradley

continued from Thinh Nguyen - the most important part - Prior art disclosures on the Internet are considered publicly available as of the date that the item was posted. MPEP § 901.06(a) <http://www.uspto.gov/web...> , paragraph IV. G. - Jean-Claude Bradley

more from Thinh Nguyen (note that submitting to IP.com is an option for OS but it costs - not sure how much)-"In practice, however, prior art is only effective to block a patent (as opposed to being available to challenge a patent after it has issued) if it can be easily found by the USPTO. USPTO examiners cannot exhaustively find everything on the Internet, and there are places where they are more likely to look. That’s why large prior art repositories that provide easy searching is critical (e.g., IP.com), because they make it easier for the USPTO to locate prior art that may be relevant." - Jean-Claude Bradley

Finally from Thinh Nguyen "Regarding Bill Hooker’s comment on the country of manufacture, unless you have a license, you have to make sure that the country of manufacture AND the importing country are not covered by relevant patents. Inventors are therefore likely seek patent protections at least in those countries with manufacturing capabilities or where manufacturing can be done with economies of scale. " - Jean-Claude Bradley

An interesting finding from IP.com - there is a 2005 patent which covers a Ugi reaction strategy to praziquantel - although it is solid support based http://ip.com/patapp... - Jean-Claude Bradley

If we improve the synthesis by optimizing the solvent would we still be under the patent because we're not changing the reaction just the conditions? - Andrew Lang

What if we could make the last step enantioselective? (Google docs) - Andrew Lang

Changing the solvent would not be enough. I don't know enough about patent coverage on the enantioselectivity of the cyclization step but Mat might. - Jean-Claude Bradley

Oh, sure, the enantioselectivity is our main aim on the Synaptic Leap project. The final step is known, in any case, and a Pictet-Spengler is used in the current industrial synthesis, I think. I would have thought you could patent that last step with an asymmetric catalyst and repatent it with another catalyst ad infinitum if the catalysts are sufficiently different. - Matthew Todd

Thanks for sourcing the expert followup, Jean-Claude! Given TN's and EB's comments about multiple patents being the norm, the application for just the German patent begins to look more and more like PR rather than competitive commerce. Investors are not always as well informed as they should be, and they do like to see a fat patent portfolio, even if the latter is functionally useless... - Bill Hooker

I can't comment on the motivation for the patent, but I can tell you that praziquantel was discovered in Germany in the mid-1970's and was initially produced by Merck and/or Bayer in Germany. Now off-patent, the drug is synthesized in quantity by a South Korean company who sell to the Schistosomiasis Control Initiative which was funded by the Gates Foundation. - Matthew Todd

Good to know Mat. I agree that I don't think we can say much about the motivation for the patent - it would take some work to find out if it is pending or approved in any other countries. - Jean-Claude Bradley

Thanks, JCB. Of course I agree with your main point. Circumvention of patents shouldn't be necessary for humanitarian purposes like this. - Mr. Gunn

@Mat. Have you (or anyone) tried any enantioselectivity of the cyclization step experiments with the Ugi product? - Andrew Lang

@Andrew - Doing it right now. (Actually using achiral acids to get an idea of acid strength needed) http://www.ourexperiment.org/racemic... This is one of the most promising potential routes to enantiopure PZQ for large-scale production. It's exactly the kind of thing where we need help from others with access to potential ligands. http://www.thesynapticleap.org/node... - Matthew Todd

Mat the examples you gave don't involve Ugi product cyclization though - the only example I came across was the article I mentioned in the post http://www.heterocycles.jp/library... Did I miss any? - Jean-Claude Bradley

Ah, I see, with the other amide already in place - sure, we're looking at that too, but I imagine that group making a difference to the reaction through differences in solubility, rather than anything direct. In the Heterocycles paper you mention I think the R group is actually benzyloxycarbonyl, i.e. Cbz, rather than cyclohexanoyl. But the same idea. The synthesis here (http://www.ourexperiment.org/racemic...) is to make the precursor to the cyclization you're talking about. - Matthew Todd

Mat although praziquantel is not used as an example it is mentioned in the introduction of that patent. OK it will be interesting if you can make that Ugi product cyclize entantioselectively. Our interest in that route (via the Ugi method - not the one you are using) is that we can make large libraries of analogs in one step (not counting the cyclization). That's why I was asking about docking. - Jean-Claude Bradley

Well Domling's paper on the synthesis of praziquantel via a Ugi reaction is out: http://www.ncbi.nlm.nih.gov/pubmed... - Guess what - the 100% conversion (done in ethanol) is supported by [34] H. P. Cao, A. Domling, unpublished results! - Jean-Claude Bradley

No access to this journal... - Matthew Todd

"The latest and most convergent addition to the manifold PZQ laboratory syntheses was performed by Cao and Dçmling (Scheme 6).[H. P. Cao, A. Dçmling, unpublished results.]" (Only other data is in the Scheme image: EtOH aq. 100%) "Pictet–Spengler reaction under strongly acidic conditions.[30] Overall, this short two-step process affords PZQ from inexpensive and readily available starting materials in ~70% yield." - Andrew Lang

Just sent you the paper Mat - Jean-Claude Bradley

Mat the R group in compound 10 in the Heterocycles paper is cyclohexanyol - I'll send you the paper - Jean-Claude Bradley