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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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« Ranbaxy in Trouble | Main | Hot Chemistry, Low Tech to High »

February 27, 2009

Your Paper Is A Sack Of Raving Nonsense. Thank You.

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Posted by Derek

You don’t often get to see the sort of fistfight that’s detailed in the latest issue of Organic Process Research and Development. Patents whose procedures are hard to reproduce are familiar to every industrial chemist, unfortunately, but coming across one that seems completely mistaken in its most important details is rare. And this is the first time I’ve seen one of these dragged out into the open literature for a give-and-take with the original authors about whether they’re delusional or not. (The editors of the journal seem to be in new territory themselves on this one).

I should add here that the great majority of patent preps I’ve followed have worked pretty much as described, and I don’t think that my success rate in reproducing them is any worse than procedures from the chemical journals. Some journals more than others, of course, (another topic!) but OPRD is known to be very, very reproducible indeed. As it should be: it’s a journal for process chemists, whose livelihood is refining chemical routes until they’re scalable, economical, and (very importantly) until they work exactly the same way every time they’re run.

So here’s the situation. In 2007, the journal published a paper by a group from Dr. Reddy’s Laboratories, a large Indian company that does both generic drugs and has their own drug discovery operation. (There are, I should note, some academic co-authors who seem to have completely disappeared during this current food fight). The paper covered a synthesis of S-citalopram, and it caught the attention of the process chemists at Lundbeck, in Denmark. And well it might – citalopram (Celexa and other brand names), an antidepressant, was discovered there in the late 1980s, and has been generic since 2003.

The original paper (Eliati et al.) described a new alkylation reaction route to produce a key intermediate and a resolution of it (and of citalopram) into pure enantiomers by forming chiral salts. So far, so good – these sorts of things are the heart of process chemistry, and entirely appropriate for a paper in OPRD. But only if they work.

The Lundbeck group (Dancer and de Diego), had tried that exact resolution of citalopram many times themselves, though, without success, so they were rather taken aback to see it published as working just fine. They detail their attempts to reproduce the Eliati procedure, and demonstrate in great detail that it indeed does not work as written. I won’t go into their experimental work, which is very extensive and painstaking, but nothing the Lundbeck team could do resulted in anything better than a 55:45 mixture, which is a rather poor substitute for a pure compound. Midway through their paper, they start putting the word “resolution” in quotation marks when discussing the Eliati procedure, and the arm’s-length-and-holding-the-nose attitude is very successfully conveyed. The phrases “enormous disparity”, “effectively impossible”, “extremely unlikely”, and “not feasible in any meaningful, practical sense” all make appearances.

They also were surprised at the alkylation reaction reported in the Eliati paper, which is the only one of its kind reported in the literature – well, other than a patent by the same team from Dr. Reddy’s, that is. The weird thing about it is that it uses 3-chloropropylamine, apparently as the isolated free base. My chemistry audience will now be raising their eyebrows, because this is not a compound that you’d expect to be very happy as anything but a salt. It should, in fact, start reacting with itself quite vigorously, with plenty of HCl being given off in the process. But the Eliati procedure doesn’t have enough base to allow for anything else, and they use (supposedly) 12 grams of the stuff in 2.5 mL of DMSO. Since no paper or patent has ever reported isolation of this free base, it’s a rather odd compound to drop into your manuscript without explanation.

Another example of the same reaction in the Eliati paper is even weirder. Not only do they use this never-before-seen chloropropylamine, but this time they do the reaction in acetone, at 60 to 65 degrees C, by first adding 7.5 grams of potassium t-butoxide to 40 mL of the acetone. Now that prep should get the attention of the organic chemists in the audience, because that sounds like an excellent way to make a bunch of hot polymerized gunk. For one thing, acetone boils at 56, so how you get it to 65 is a real stumper. And adding a strong base to it is a surefire way to deprotonate it and start the famous aldol condensation (and every other base-catalyzed ketone reaction you can think of, for that matter). The Lundbeck group tried it, out of sheer curiosity, and got:

”. . . a vigorous/violent reaction. . .with the formation of a quantity of a white solid. (It had) an odor of higher ketones/alkenes, and analysis by NMR indicated that it was a complex mixture of products, with peaks consistent with condensation products of acetone.

A solid majority of the chemists reading that sentence, you can bet, finished reading that and added a “No shit” to the end. This is the sort of thing a sophomore undergraduate should be able to spot, and my guess is that whoever reviewed the Eliati paper for OPRD has had some interesting correspondence with the journal. The resolution is one thing – that’s impossible to spot if you haven’t worked with that exact reaction. But this alkylation step is ridiculous.

The journal gave Eliati and co-workers a chance to respond to all this, and followed that with a last word from Dancer and de Diego at Lundbeck. These things are all published back to back; it's like watching a boxing match. The Dr. Reddy’s group runs up the white flag immediately on the chiral salt resolution, actually, agreeing that their published procedure doesn’t work. But they claim that a modified version of the procedure does work, and that they “inadvertently missed incorporating a few words in the text” of the article which would have made this clear. The Lundbeck group isn’t buying this for a minute. They point out that the manuscript would have been had to have been substantially reworked to make it into this different procedure, for one thing. And even worse, the details of it as reported by Eliati are internally inconsistent, with the masses and ratios not even adding up. And finally, they report their own attempts to reproduce the new procedure, and find that it, too, is basically impossible.

And as for the alkylation, Eliati et al. claim that if you work quickly, you can use the chloropropylamine free base as they described. They also present a table showing how long it lasts under different conditions and in different solvents, and claim to have done the best variation of the reaction on a six-kilo scale. The acetone reaction, they admit, wasn’t as clean, but they didn’t spend much time talking about that because their “aim was to isolate the desired product instead of the aldol product.” Dancer and de Diego aren’t very happy with that either, continuing to insist that the acetone procedure is “completely unworkable”. As for the chloropropylamine, they welcome the clarifications in the second Eliati paper, but point out that said details contradict themselves at one point, and at any rate, none of them are to be found in the corresponding Dr. Reddy’s patent application, which continues to talk about using only the free base, and (on top of everything else) in a way that makes no sense.

The final Lundbeck reply has a telling line in the acknowledgements, which is, in its way, even more pointed than anything else in their paper: “One of us (R.J.D.) thanks Sir John Cornforth for inspiration derived from a series of his articles in a similar case some years ago.” That’s the famous “Some Comments on a Paper by Samir Chatterjee” affair, Tetrahedron Letters 1980 709 and 1982, 2213. Cornforth completely demolished some heterocyclic chemistry work by the unfortunate Chatterjee, pointing out by several lines of evidence that the whole thing had to have been faked. Name-dropping this example is about as direct a statement of your opinion as the scientific literature will allow. . .

Comments (43) + TrackBacks (0) | Category: Chemical News | Drug Development | The Dark Side | The Scientific Literature


COMMENTS

1. big biotech on February 27, 2009 10:03 AM writes...

Will the reply to OPRD count as a line item on the authors' CV?

Permalink to Comment

2. Al on February 27, 2009 10:06 AM writes...

Bit of a howler in the graphical abstract to the 2007 Reddy paper as well, which doesn't help inspire confidence in the rest of their work.

Permalink to Comment

3. RTW on February 27, 2009 10:32 AM writes...

Thankfully this is a patent proceedure on a generic companies prep. Had it been the primary patent covering a drug still on patent this situation surely would have resulted in the patent being overturned.

Permalink to Comment

4. Jose on February 27, 2009 10:36 AM writes...

Ah, well, what's a methylene between friends!

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5. DrKai on February 27, 2009 10:50 AM writes...

The most frustrating part of these situations is that the original paper has not been retracted. Even when there is an obvious error or blatant fabrication, as long as the opposing party doesn't propose retraction, how are these junk papers going to get removed?

I know of other (non-chemistry) fabricated papers, which are universally and publicly recognized as complete frauds by people within the field. Yet for some reason, the fear of lawsuits have kept the journals from retracting the papers (or saying outright that they are fabrications). Yes, there are challenges and responses that get published with varying degrees of diplomatic language, but nothing happens when the fraud will not publicly admit they are making things up.

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6. HOMO-LUMO on February 27, 2009 11:21 AM writes...

The acetone alkylation made my day, thanks.

:D

Permalink to Comment

7. processchemist on February 27, 2009 11:30 AM writes...

"Thankfully this is a patent proceedure on a generic companies prep"

Maybe the medchem audience is missing a point. What drives generic companies in filing patents? In the western world, if you produce a generic API (or sell it) you MUST have a Drug Master File filed at FDA and EMEA. The DMF must contain the detailed process used (and analytical methods for final product, intermediates, IPC etc). To file a DMF with a patent infringing process is a suicide. So two are the choices: to use the process of an expired patent, or to patent a process of your own.
A demonstrated inconsistent patent (with faked chemistry) can put the producer OUT of the western world market for the product involved in a blink of an eye.
This case will be discussed not only by lawyers in courts, but probably also at FDA and EMEA.
The combined citalopram/escitalopram markets are not so small...

Permalink to Comment

8. John Doe on February 27, 2009 11:47 AM writes...

That's why you don't want your drugs to be made in India...

Permalink to Comment

9. Nick K on February 27, 2009 11:52 AM writes...

What strikes me is the sheer incompetence of the authors: if you're going to invent completely fictitious chemistry (as seems to be the case with Ranbaxy) the least you can do is make it plausible. Incidentally, what happened in the famous Corey-Schlosser spat (early Eighties) about the lithiation of Wittig reagents? A friend of mine spent many fruitless months trying to reproduce Corey's work.

Permalink to Comment

10. CMC Guy on February 27, 2009 12:01 PM writes...

I, for one, am much more skeptical about repeating Patent Literature(sic) but maybe that is subtle distinction in what is typically found in medchem/composition of matter Filing vs. attempting to duplicate a Process Patent. Its not so much getting the the correct compound that is gist of the former (more typically well reflected in Patent procedure) but to quote want to achieve "scalable, economical, and (very importantly) until they work exactly the same way every time they’re run" processes. Many times seem to be found wanting from that score and in fact appear misleading as although they "work" some it seems would have to stand on your head, point your knees north and pat your tummy to get useful results in a plant. There is apparent "gamesmanship" built is the system that can be frustrating until you recognize it exists.

Unfortunately I have been on both sides as although it violates the spirit, if not directly the law, I have seen lab procedures get obfuscated by the lawyers "to protect the companies value" through selective additions or subtractions to the actual processes.

Permalink to Comment

11. RB Woodweird on February 27, 2009 1:24 PM writes...

I have spent bench time, as many of us have, trying to reproduce some questionable procedure - on a milligram scale. When it does not work, we curse the author and toss the reference in the trash.

If I were a process chemist adding ten liters of t-butyl lithium to five liters of HMPA and then found out that the authors were jerking me around? I'd be waiting in a dark alley in Mumbai with a broken-off two liter EM flask in my hand.

Permalink to Comment

12. Jose on February 27, 2009 1:49 PM writes...

Friday afternoon might just be a prefect time to try the "7.5 grams of potassium t-butoxide to 40 mL of the acetone" trick...

Permalink to Comment

13. RTW on February 27, 2009 1:58 PM writes...

Processchemist: I agree to what you are saying, but the patent process in this instance probably has no barring what so ever to the process they actually use to produce the API or Generic. It doesn't have to. As you point out its what is in the DMF. I also have to take exception with RB. Any process chemist that would take a lit prep as written and start off at such large scales gets what they deserve.

I once tried to reproduce a prep from OrgSyn, a publication from which all preps are checked by other groups. I faithfully followed the prep and all the notes. Ended up with one heck of a mess. I happen to also work with a former grad student of the prof that submitted it. Asked him what do you make of this? He said the guys preps never worked, there where always little things that the prof never recorded and that even his students struggled to reproduce preps. I then asked how they ended up in OrgSyn and how it had passed being reproduced. He said who would reject them? I should add he was a VERY well known chemist in his particular branch of chemistry.

Permalink to Comment

14. Stephen on February 27, 2009 1:59 PM writes...

Is this the industry version of the Hexacyclinol-affair?

Permalink to Comment

15. Retread on February 27, 2009 2:02 PM writes...

This sort of thing is fairly rare in the scientific literature, but common in the medical literature -- which usually isn't fraud but overinterpretation. The consequences are vastly greater (see the vaccine autism correspondence earlier this month) and you might be interested in what happened in Russia in the 90's (see below).

It is a real pleasure to read papers without constantly thinking -- how are these people lying to me?

[ Lancet vol. 338 pp. 1004 '91 ] While the western physician is interested in diphtheria toxin as a molecular biology probe, people are still dying of the disease in Russia. Apparently, the populace, afraid of getting AIDS from a reused needle has been avoiding inoculations of any sort. As of 1 October '91 there had been 16 cases in Rostov on Don, all unimmunized. The fear of contaminated needles is real apparently, as in one county of Moldavia 25% of the population was infected with reusable needles which spread hepatitis B.

[ Science vol. 267 pp. 1416 - 1417 '95 ] Things are getting worse. This story from the 10 Mar '95 issue, notes that 80,000 people have been affected with 2000 deaths. In the past year 30,000,000 of the 150,000,000 people in Russia were immunized. In the USA, immunization levels have slipped, only 44% of children were fully vaccinated in '91 - '92. [ J. Am. Med. Assoc. vol. 273 pp. 1250 - 1252 '95 ] 2 cases are reported in US citizens working in Russia, so our immunizations are low. Since 1980 five or fewer cases have been reported each year. Since 1988 all culture confirmed cases of diphtheria have been imported. However, our immunization levels are quite low, and 20 - 60% of US adults over 20 years of age are susceptible.

[ Arch. Neurol. vol. 58 pp. 1438 - 1442 '01 ] From Russia about the epidemic of '90 - '95. There were 125,000 cases with 4000 deaths, of which 97,000 2500 were in Russia. The latency was 18 - 46 days average 40 weeks. They describe 32 cases with severe neuropathy. 42/32 required ventilation. All had sensory signs and all had autonomic disturbance. Only 2/32 died (of pneumonia). Recovery was complete. Early neurologic symptoms and signs weren't indicative of subsequent neuropathy (such as weak soft palate), but crdiac and renal disturbances were predictive. Interestingly, the longer the latency the more rapid regression. There is lots more.

Permalink to Comment

16. Hap on February 27, 2009 2:31 PM writes...

12 g of amine in 2.5 mL of DMSO? If the solution doesn't expand (unlikely), that's like 60 M in amine, and even if the volumes simply add, that's probably still 7 or 8 M in amine. That seems like a really (almost impossibly) concentrated solution, and since DMSO's a great SN2 solvent and the concentration of amine is so high, it seems like a great way to make polyamine gick.

Permalink to Comment

17. Timothy on February 27, 2009 5:12 PM writes...

This is the sort of thing a sophomore undergraduate should be able to spot, and my guess is that whoever reviewed the Eliati paper for OPRD has had some interesting correspondence with the journal.

As an undergraduate who's midway through his second semester of O-chem, I have to agree. I read the bit about t-butoxide and acetone and cringed a little bit. How'd that slip past an actual expert?

Permalink to Comment

18. Fat Old Man on February 27, 2009 7:20 PM writes...

processchemist:

Great post. Let's take it a step further. Is Reddy's making citalopram/escitalopram? If so, are you suggesting that they would or will make it by a process different than what is in their DMF? I hope no agency comes knocking on their doors for an inspection. Our sites spent more than 6 months last year under inspection from one global agency or another. They would have to fake batch records and analytical results for the whole process. It could be quite a scandal.

Permalink to Comment

19. Fat Old Man on February 27, 2009 8:09 PM writes...

Ok, ok, I posted that before reading the previous day's blog. Looks like Ranbaxy faked some dates on stability samples. I still say that is far from faking a whole process from GMP starting materials to API, including analytical methods, qualification reports, etc.

Permalink to Comment

20. Hap on February 27, 2009 8:28 PM writes...

It still seems like a stupid idea to falsify data submitted to the FDA - you want to increase your credibility with foreign agencies and consumers, not decrease it. Lying about details that don't matter much only makes people wonder what else you might lie about, or whether you will lie when more money is at stake.

Permalink to Comment

21. Anonymous BMS Researcher on February 27, 2009 9:34 PM writes...


When I brought this posting to the attention of my wife, who once was Managing Editor of a pharmacology journal, she immediately exclaimed, "I wouldn't want to be in the shoes of the Managing Editor of this journal!"

Permalink to Comment

22. McChemist on February 27, 2009 9:52 PM writes...

That nod towards Cornforth certainly was interesting, but I was curious as to why they said only Dancer acknowledged him. Could be that Dancer knows Cornforth or that he was influenced by those papers when the came out in the early 80's, but instead I wonder if there may have been some disagreement between the two Lundbeck authors as to whether to put in that statement.

Permalink to Comment

23. BHO on February 27, 2009 10:50 PM writes...

So Obama wants to import pharmaceuticals to control health care costs? With jokers like these guys making your drugs in a back alley of Hyderbad, I must ask the question: Do you feel safe, DO YOU?

Permalink to Comment

24. BCP on February 28, 2009 1:08 AM writes...

I have to say that I quite like the OPRD editor's take. Although his comment at the end "One of the aspects of the physical sciences that first attracted me is that there is an absolute
truth in science." seems a little ironic. It reminds me that while this statement is factually correct, we only have the ability to apprehend this truth through our imperfect ability to interpret what our senses relay to us, or in this case, what the authors wish to share.

Permalink to Comment

25. processchemist on February 28, 2009 2:53 AM writes...

@Fat Old Man,

"I still say that is far from faking a whole process from GMP starting materials to API, including analytical methods, qualification reports, etc."

I don't know if this can be the case. But I can assure you about one thing: it's perfectly possible.
And I'm not talking about a perfect fake.
Who in the world would be such a fool? Someone who thinks that the most dreaded piece of paper in the API manufacturing industry, an FDA warning letter, will never show.
And this someone has good reasons to think so. FDA representatives declared to the US congress that the agency is able to inspect only a little fraction of the asian manufacturers of APIs admitted to the US market.
Honestly, I always had a good opinion about Dr. Reddy's, Jubilant, Dishman, Piramal. We're talking about global players, with operations and facilities now all over the world, and with a solid reputation (this is the reason why these two accidents are so concerning).

Permalink to Comment

26. processchemist on February 28, 2009 3:42 AM writes...

... and Dr. Reddy's is registered for citalopram hydromide tablets with FDA.

Permalink to Comment

27. NS 29 on February 28, 2009 10:33 AM writes...

@ processchemist:

"Who in the world would be such a fool? Someone who thinks that the most dreaded piece of paper in the API manufacturing industry, an FDA warning letter, will never show."

Exactly!

Getting a warning letter from the FDA will have some devastating implications on your business, to put it mildly, especially if you are working in the custom manufacturing business. If you think just brushing up your batch records by backdating a couple of blanks in your batch record will do before an FDA audit since the inspectors will only have a superficial look on your data, you're screwed and you deserve it.

GMP is a quality system that has to be lived by every single employee, from the CEO to shift worker in production plant. It is really a lot of effort to maintain the high quality standards in documenation (GMP = Gimme More Paper, us Germans like to see it as abbreviation for "Grosse Menge Papier").

My two (Euro)cents on that topic.

Permalink to Comment

28. Sili on February 28, 2009 2:25 PM writes...

The phrases “enormous disparity”, “effectively impossible”, “extremely unlikely”, and “not feasible in any meaningful, practical sense” all make appearances.
I really wish I was good enough to get to work for Lundbeck. Permalink to Comment

29. Abhishek Tiwari on February 28, 2009 9:22 PM writes...

Well finding those can not reproduced are not new in organic chemistry or any scientific disciplines, recently there was a study how 7 out of 10 micro arrays experiment published by different labs can not be reproduced, that does not mean they all are faking the papers. Just by taking a particular example and targeting researchers from particular country is not fare, each country had scientist and researchers who published fake papers and caught time to time. So lets concentrate on science. Even no one feel safe when they consume drugs those are totally US made.

Permalink to Comment

30. Aspirin on March 1, 2009 12:05 AM writes...

"So lets concentrate on science."

I thought that's what Derek did above. Even if the enantiomeric ratios could be debated (although after Lundbeck's meticulous study the burden of proof is clearly on Reddy's), the parts about the chloropropyl amine and acetone/t-BuOK reflux seem to be rather glaring and fundamental errors of the sophomore org chem kind.

Permalink to Comment

31. silly on March 1, 2009 12:21 AM writes...

Obviously the paper is a fake.Defending it is just a waste of time.As an Indian, I would just offer this insight...India has a history for granting 'process patents'.The industry gives great emphasis on 'secret processes' that others cannot reproduce..the cheapest process possible guarantees the market.So why would anybody give the full process out to reproduce.Regarding why the journal article was 'published', it might be that it was an 'invited' article and they just tht they will get away with it if they give just some made-up numbers.

Permalink to Comment

32. zippy on March 1, 2009 12:37 PM writes...

Some earlier comments suggested some possible legal implications that may follow from this controversy. A quick check at the USPTO finds quite a few process patents around S-citalopram granted to Lundbeck which are still in force. A carefull reading of the controversial paper from Dr. Reddy's along with the Lundbeck process patents by by a qualified chemist might give a sense of whether Dr. Reddy's is making efforts to bypass the Lundbeck patents. Since I imagine that Dr Reddy's manufactures citalopram in India, any process patents in force in India would be the more relevant information. However, casual efforts to search the Indian Patent Office from my home computer ended in failure.

So, is it possible/likely that the Lundbeck paper might be a prelude to more serious actions, since discrediting the science could have value in later arguments?

Permalink to Comment

33. silly on March 1, 2009 3:29 PM writes...

#32 might be on to something more serious... Is Dr.Reddy using the Lundbeck process patents and reporting that they are using a diff. set of made-up worthless conditions for making their molecules...

Permalink to Comment

34. gyg3s on March 1, 2009 4:48 PM writes...

You chaps should have a read of Synthon BV v SKB; it gives a very interesting explanation as to the way that patents work.

Also, this note may be of interest, "Cephalotaxane and Paclitaxel"

Permalink to Comment

35. Handles on March 1, 2009 9:28 PM writes...

"For one thing, acetone boils at 56, so how you get it to 65 is a real stumper"

Raoult's Law (as stated by Wikipedia): the vapor pressure of an ideal solution is dependent on the vapor pressure of each chemical component and the mole fraction of the component present in the solution.

This means that the presence of a solute raises the boiling point of the solution (and depresses the melting point). So for example, the bp of 50% NaOH is 143 C / 279 F. From Perry's via here.

You could theoretically calculate the effect on boiling point from the ebullioscopic constant (for acetone Kb = 2.67 at Wikipedia). Boiling point elevation is a colligative property so it doesnt matter what solute you use. The answer for the horrible mixture in question would be worthless, as such a solution would be far from ideal (reliable answers could be gained for a dilute solution of deuterated acetone in acetone). Just for kicks I calculated a bp elevation of 5 Kelvin for the imaginary solution of t-BuOK in acetone, rising to 19 Kelvin once you add the amine.

Permalink to Comment

36. Radchem on March 2, 2009 1:32 AM writes...

#15 Retread wrote

"This sort of thing is fairly rare in the scientific literature,"

This is unfortunately true, not necessarily because it doesn't happen (a number of recent posts attests to that) but because it isn't publicised or people are too scared to say anything. These high profile ones are just the tip of the iceberg. If it does get published there appears to be few repercussions. In 5 or 10 years time will anyone remember the authors names if they appear on a CV in front of them?

While nothing on the size of the problem described in this post it has a familiar ring.

Tetrahedron Letters, Volume 48, Issue 32, 6 August 2007, Pages 5585-5588

Permalink to Comment

37. Robert on March 2, 2009 9:59 AM writes...

I am a process chemist; actually the Robert Dancer who was first author on the paper in question from Lundbeck. I loved the article here by Derek (and comments). Also, given some of the very interesting comments that have come up, I have a couple of quick comments/clarifications.

(a) It may be of interest (particularly to #32 and #33) to know that as soon as the original paper by Elati et.al. was published, it was (has been, and still is) used extensively by generic wholesalers around the world in court cases challenging the ligitimacy of our Escitalopram patent. (b) Despite what you may think, I have no criticisms of the reviewers of Elati's original paper. The resolution stuff looks reasonable unless you have actually tried it yourself (which I have; many times!!!), and the dodgy alkylation stuff is not explicitly in the paper, but rather hidden away in the patent. (c) There has been a bit of criticism (implied or otherwise) of the OPRD editors for sitting on the fence. I would like to defend them there a bit, because they should not be judge and jury. Instead, they are the people who should be ensuring that scientific debates can run (which is what happened here). In a similar manner, there have been some comments wondering why the paper hasn't been retracted. Well, it is my opinion that the editors should not be able to unless the original authors request a retraction themselves, otherwise there is a risk of ending up at the top of a slippery slope towards censorship, which should be avoided at all costs. Better to have a good debate where necessary. (d) An eagle-eyed commenter noticed that I was the only one who aknowledged Sir John. Well spotted! I am a chemist, whereas Heidi comes from a background as a crystallographer, and now heads our Physical Characterisation group. As such, I was familiar with Sir John's work (I also met him once many years ago), but Heidi wasn't. When we were nearly finished with our reply I said that I would like to put a personal aknowledgement in, and she said fine by me! (e) A quick comment to #35 regarding bp of acetone etc. In the patent they specifiy that KOtBu was added directly to (pure) acetone at 6o-65 degrees, and the idea was that it should be at 60-65 degrees first... But one thing I can guarantee... If it isn't at a high temperature _before_ you add the KOtBu, it is certainly hot _after_!!!

Once again, thanks to all those with comments. In many ways it is not much fun trying to put together a publication that which casts doubt on someone else's credibility, so I am very happy to see that there are so many that share (at least part of) my/our view!

Permalink to Comment

38. processchemist on March 2, 2009 10:49 AM writes...

@Robert

"challenging the ligitimacy of our Escitalopram patent."

Interesting... I was used to Lundbeck challenging the legitimate of citalopram patents from others * joke mode off*

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39. Jose on March 2, 2009 12:21 PM writes...

Another gem is a Scott Denmark paper-

Angewandte Chemie International Edition
Volume 40, Issue 12, Date: June 18, 2001, Pages: 2255-2256.

...the reported ability of chiral phosphonamide
2 to effect the enantioselective opening of meso epoxides with silicon tetrachloride has not withstood experimental verification. [snip] ... until the questions raised herein are appropriately addressed, all the results described by Buono et al. should be viewed with skepticism.

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40. Robert on March 3, 2009 4:22 AM writes...

I'm not aware of any citalopram or escitalopram patents owned by others that Lundbeck has tried to take down. Our policy is to defend the patents we have, not attack patents of others. We have better things to do with our time. On the other hand, I have heard of so much very dodgy chemistry thrown at us in court cases by generics trying to take down _our_ patents...

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41. zippy on March 3, 2009 9:41 AM writes...

Robert,

I guess the issue would be whether the generic API manufacturers actually violate Lundbeck process patents in the countries that they manufacture.

#34,
Would you give a condensed summary of the relevant information in Synthon BV v SKB? Composition of matter or method of use patents would not appear to be relevant. But, process chemistry patents might.

thanks.

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42. Robert on March 3, 2009 10:10 AM writes...

Zippy,

Good question! I am not a lawyer (thank goodness!), but from what I can gather, patent infingement occurs if (for example) we have a patent covering that process in the country of manufacture, _or_ if we have a patent covering that process in the country of _sale_.

Perhaps another clarification would be in order. The Elati paper was used against us in court because it (the paper) claimed that you could resolve citalopram itself using ditoluoyl tartaric acid (DTT). The legal arguement is slightly more complicated, but the short version is that to patentable it has to be novel and not obvious. Therefore it was argued that it was easy to resolve citalopram, so therefore it was obvious. I knew it wasn't (I had tried it myself). Since this (and the rest of the "fun" chemistry) had appeared in the literature, and not just in a court case, I wanted to make sure that it was also corrected in the literature.

Incidently, our patent that they were attacking was the main "use" patent of Escitalopram...

(-:

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43. processchemist on March 3, 2009 11:12 AM writes...

@Robert

What I was meaning is that Lundbeck defended citalopram in an impressive and effective way. Former VIS, now Lundbeck Pharmaceuticals Italy, is an example.

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