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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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October 30, 2012

JQ1: Giving Up a Fortune?

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Posted by Derek

The Atlantic is out with a list of "Brave Thinkers", and one of them is Jay Bradner at Harvard Medical School. He's on there for JQ1, a small-molecule bromodomain ligand that was reported in 2010. (I note, in passing, that once again nomenclature has come to the opposite of our rescue, since bromodomains have absolutely nothing to do with bromine, in contrast to 98% of all the other words that begin with "bromo-")

These sorts of compounds have been very much in the news recently, as part of the whole multiyear surge in epigenetic research. Drug companies, naturally, are looking to the epigenetic targets that might be amenable to small-molecule intervention, and bromodomains seem to qualify (well, some of them do, anyway).

At any rate, JQ1 is a perfectly reasonable probe compound for bromodomain studies, but it got a lot of press a couple of months ago as a potential male contraceptive. I found all that wildly premature - a compound like this one surely sets off all kinds of effects in vivo, and disruption of spermatogenesis is only one of them. Note (PDF) that it hits a variety of bromodomain subtypes, and we only have the foggiest notion of what most of these are doing in real living systems.

The Atlantic, for its part, makes much of Bradner's publishing JQ1 instead of patenting it:

The monopoly on developing the molecule that Bradner walked away from would likely have been worth a fortune (last year, the median value for U.S.-based biotech companies was $370 million). Now four companies are building on his discovery—which delights Bradner, who this year released four new molecules. “For years, drug discovery has been a dark art performed behind closed doors with the shades pulled,” he says. “I would be greatly satisfied if the example of this research contributed to a change in the culture of drug discovery.”

But as Chemjobber rightly says, the idea that Bradner walked away from a fortune is ridiculous. JQ1 is not a drug, nor is it ever likely to become a drug. It has inspired research programs to find drugs, but they likely won't look much (or anything) like JQ1, and they'll do different things (for one, they'll almost surely be more selective). In fact, chasing after that sort of selectivity is one of the things that Bradner's own research group appears to be doing - and quite rightly - while his employer (Dana-Farber) is filing patent applications on JQ1 derivatives. Quite rightly.

Patents work differently in small-molecule drug research than most people seem to think. (You can argue, in fact, that it's one of the areas where the system works most like it was designed to, as opposed to often-abominable patent efforts in software, interface design, business methods, and the like). People who've never had to work with them have ideas about patents being dark, hidden boxes of secrets, but one of the key things about a patent is disclosure. You have to tell people what your invention is, what it's good for, and how to replicate it, or you don't have a valid patent.

Admittedly, there are patent applications that do not make all of these steps easy - a case in point would be the ones from Exelixis - I wrote here about my onetime attempts to figure out the structures of some of their lead compounds from their patent filings. Not long ago I had a chance to speak with someone who was there at the time, and he was happy to hear that I'd come up short, saying that this had been exactly the plan). But at the same time, all their molecules were in there, along with all the details of how to make them. And the claims of the patents detailed exactly why they were interested in such compounds, and what they planned to do with them as drugs. You could learn a lot about what Exelixis was up to; it was just that finding out the exact structure of the clinical candidate that was tricky. A patent application on JQ1 would have actually ended up disclosing most (or all) of what the publication did.

I'm not criticizing Prof. Bradner and his research group here. He's been doing excellent work in this area, and his papers are a pleasure to read. But the idea that Harvard Medical School and Dana-Farber would walk away from a pharma fortune is laughable.

Comments (33) + TrackBacks (0) | Category: Cancer | Chemical Biology | Drug Development | Patents and IP


COMMENTS

1. ronathan richardson on October 30, 2012 10:11 AM writes...

What makes the Atlantic article even more ridiculous is that JQ1 was discovered by ripping off a Mitsubishi pharmaceuticals patent--this is openly claimed in Bradner's first nature paper on the subject (Pubmed central link below):
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010259/

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2. qetzal on October 30, 2012 10:41 AM writes...

Furthermore, if JQ1 had been a potential drug, publishing without patenting would very likely have hurt its development, not helped. Pharma isn't usually interested in spending $1B to try to develop an API that's in the public domain.

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3. Chemist with Plan B on October 30, 2012 11:08 AM writes...

#2--unless you're Biogen Idec and you're convinced that such molecules as 4-aminopyridine and dimethyl fumarate are worth developing as drugs. The former has turned out to be laughable, but the second appears to be going to make them a mint.

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4. MoMo on October 30, 2012 11:50 AM writes...

Good biology here, although I would be worried about the chemically promiscuous nature of the thienodiazepines.

Flattened, lipophilic and bulky does not a good drug make. Let's see what the future brings for the patented series before drug designers everywhere pounce on what looks like Brick Dust.

Is this the same old academic love story? Boy meets molecule, Boy falls in love with Molecule, Molecule turns out to be Evil and Promiscuous, and soon Boy disappears from the face of the Earth?

BTW, what ever happened to Sirtris?

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5. Anonymous on October 30, 2012 12:07 PM writes...

#3 Biogen's patent rights to BG-12 will expire in 2019 and I'd bet that was a use patent not a substance of matter patent. And 4-aminopyridine was developed and marketed by Acorda and they claim to have lots of use patents on it as well. If JQ1 was later found to have a novel use outside its activity on bromodomains, someone could patent it and develop it even though it's in the public domain.

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6. johnnyboy on October 30, 2012 12:57 PM writes...

Well, I see your point Derek, but keep in mind that one can easily make a fortune in biotech without coming close to bringing any drug to market. With VCs ready to throw their money at any sweet-talking halfwit with a powerpoint business plan and a semblance of a NCE, it's valuable to commend Bradner on not wanting to play that game.

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7. Al on October 30, 2012 1:19 PM writes...

Scientists in our organization, the SGC, are having a great and productive time collaborating with scientists in industry to develop tool compounds for proteins that regulate epigenetic signalling, with a pre-commitment to making them available without restriction (e.g. http://www.thesgc.org/scientists/chemical_probes/GSKJ1; http://www.thesgc.org/scientists/chemical_probes/PFI-1/). Pharma medicinal chemists and biologists (now from 8 different companies) bring invaluable experience and skills to our collaborations - keep your eyes peeled for more chemical probes over the next few years.

We are equally appreciative of the academic scientists (for example, Jian, Frye, Bradner, Gray: http://apps.thesgc.org/chemical_probes/UNC0638/#overview; http://apps.thesgc.org/chemical_probes/JQ1_SGCBD01/#overview) that have also joined the open access party. All brave thinkers!

With JQ1, we are delighted with the science but a tad uncomfortable with way the story is told.

The contributions of GSK and Mitsubishi scientists to the project (Jay fully acknowledges these contributions) are often minimized, or even left out in the popular media, and that is unfair.

The Mitsubishi scientists are particularly under-acknowledged

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8. gippgig on October 30, 2012 1:39 PM writes...

Playing that game takes up a lot of time that could otherwise be used to do more research. If you're more interested in making discoveries than making money it's the obvious choice.

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9. OpenSourced on October 30, 2012 1:46 PM writes...

Interesting post which I have been closely following. From my perspective, the important piece of the story is the free distribution of the JQ1 molecule which has greatly accelerated research on bromodomains. Check out Bradner on TED: http://www.ted.com/talks/jay_bradner_open_source_cancer_research.html

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10. gippgig on October 30, 2012 2:01 PM writes...

The first 2 SGC links don't work.

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11. qetzal on October 30, 2012 2:07 PM writes...

#3 & #5,

Obviously it's not unheard of to develop a drug where the API is unpatentable. But I trust you'll agree that lack of IP on the composition of matter is almost always going to be considered a negative by potential developers.

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12. Anon Academic on October 30, 2012 3:17 PM writes...

In his TED talk he says that he has a startup (Tensha Therapeutics) working on improving the pharmacological properties of JQ1. So much for not patenting and trying to make money...

In that TED talk he made a big deal about publishing the structure. Well, that is what academics do. All academics. Sure, some file provisional patents, but the only reason Bradner didn't file a provisional was because he knew JQ1 wasn't ever going to be a drug.

If he really wanted to be open source, why have a startup company? Just publish the improved compounds and keep patting yourself on your back.

Permalink to Comment

13. Chemjobber on October 30, 2012 5:51 PM writes...

Thanks for commenting on the story, Derek! I am relieved that my thoughts on this were not outside of the fat part of the bell curve.

11: If you click on the link in my handle, it will lead you to a Felix Salmon's comments on TED talks and the people who work with the speakers. They're strongly guided (see below) by the use of narrative and emotion to tell a story.

The real work of the curators, though, often comes down to emotional shading. When Cain first drafted her talk, it was thick with statistics and case-making data. Looking at other TED lectures, though, she decided to replace some of her data points with stories—an inclination that the conference’s curators pushed even further.

I suspect that is what happened with Professor Bradner's TED talk. (I also suspect that this piece from The Atlantic is based on the talk.)

Permalink to Comment

14. Chemjobber on October 30, 2012 5:59 PM writes...

Oops, let's try that again.

Permalink to Comment

15. Jose on October 30, 2012 8:43 PM writes...

The TED talks have "curators" ?? Seriously??!? How staggeringly pretentious! Plus the cost: Regular: $7,500, Donor: $15,000 Patron: $125,000. A nice idea that has gotten far too big for its britches! At least they are free for the common folk.

Permalink to Comment

16. Anonymous on October 30, 2012 8:53 PM writes...

So JQ1 was discovered by Mitsubishi scientists years ago.

Bradner took JQ1 from their patent and published it.

Now he praised for not patenting the same compound.

Permalink to Comment

17. SoCalChem on October 30, 2012 10:57 PM writes...

People can try to downplay JQ1 in these comments regarding patents and such, but it really misses the point. The free distribution of JQ1 to academics has produced a staggering amount of research and papers in a rather unprecedented way. That is what makes this story special. Having seen Dr. Bradner speak, his passion for this science and compassion for patients is unquestionably real.

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18. ty on October 30, 2012 11:01 PM writes...

My understanding is that the SGC was founded on the premise of no IP from the get go, which enabled participation of many pharma companies.

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19. drug_hunter on October 30, 2012 11:17 PM writes...

Absolutely correct that he's accelerated research in this field. And, believe me, he could have found a way to peddle JQ1 to make a fair chunk of cash if he wanted. I don't get why anyone on this board is slamming him. You might think the article *about* him is over the top; that's not his fault.

Permalink to Comment

20. Anonymous on October 31, 2012 5:48 AM writes...

Why do you think he is not trying to cash in ?
Google Tensha Therapeutics

http://211.144.68.84:9998/91keshi/Public/File/49/30-4/pdf/nbt0412-305.pdf

Permalink to Comment

21. aaa on October 31, 2012 6:10 AM writes...

I don't think JQ1 is directly from the Mitsu. patent, just the series in general. Cut JB and his group a little slack.

Permalink to Comment

22. al on October 31, 2012 8:03 AM writes...

Just a note to clarify the origin of JQ1.

JQ1 resulted from a collaboration between Jay Bradner's lab and the SGC. The first author and the co-corresponding last author are from the SGC. The project started with a pre-commitment from us all to place the output (which ended up being JQ1) into the public domain without restriction. This is a fundamental principle of the SGC and we ask a similar pre-commitment from all our collaborators, and Jay bought in to this 100%.

Jay and the SGC have independently given JQ1 to hundreds of labs, and now it is commercially available. We feel it is very important to allow all our chemical probes to be commercially available, without restriction on use, so no one has to disclose what experiments they are doing with the molecule.

It should also be noted that Jay is fantastic to work with, and we can't give enough credit to him, Jun Qi and the rest of his lab.

Finally, as we have stated publicly, we must give credit where credit is due, the impetus to start the project that led to JQ1 came from GSK and Mitsubishi

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23. John Wayne on October 31, 2012 8:13 AM writes...

I'm acquainted with Jay and can confirm that he is really nice, professional scientist that thinks deeply about medicine and biology. His colleagues really appreciate working with his group, and I don't think anybody could realistically say a bad thing about him or his work.

On the other hand, the jobs of the writers at The Atlantic (and other places) is so make a story, so they exaggerated the facts to make a martyr for patients in a field of evil money-grubbing companies. I think that is the source of the negative reactions most of us are having here.

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24. SP on October 31, 2012 8:27 AM writes...

If I'm not mistaken he has a close follow on compound, JQ2, that is in clinical trials for midline carcinoma. So the statement "they likely won't look much (or anything) like JQ1" doesn't seem to be accurate.

Permalink to Comment

25. overthetop on October 31, 2012 8:56 AM writes...

Having had to negotiate IP terms with Harvard Medical School on several occasions, I have no doubt that the only reason for publishing was because they were obliged to do so by their funding contract with SGC. "Noble" and "not motivated by profit" don't really belong in the same sentence as HMS. Nothing wrong with that, but that is the reality, not the selfless picture painted by the Atlantic.

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26. g0pr on October 31, 2012 11:25 AM writes...

Having followed the story bromodomains as targets and the benzodiazapins (& the corresponding thiophene analogs)as promising modulators for quite sometime, I just want to add my 2 cents:
Original Mitsubishi patent (WO2009084693) did have (almost) same molecule as JQ1 drawn out. The difference is methyl ester vs t-butyl ester (in JQ1). If I remember correctly, Bradner said the t-butyl group eliminated some off-target activity at the CNS relating to benzodiazepin receptors. Also, the Mitsubishi patent did mention bromodomains as the targets for their compounds. Bradner having had avid interest in these targets, with Mitsubishi's consent, took one of the compounds in the patent and did a thorough study published in Nature: showed that one enantiomer is overwhelmingly more active than the other, explained the differences with crystal structures, modeling etc. May be they didn't patent because they couldn't - Mitsubushi has the molecule claimed already!

In the meantime GSK published their work in 2011: one J Med Chem paper and a couple of patents. Of course, the main difference here is GSK has benzodiazepin scaffold. ie a benzo ring replacing the dimethylthiophene in Mitsubishi's (& JQ1). I think GSK has a compound in Ph 2 clinicals now.

Bradner started Tensha Therapeutics based his findings published in that Nature paper. Cynics might say, only a Harvard man could manage to raise multi milion dollars based on a compound with no IP! However, having listened to Bradner speak, his passion is genuine. And why should he give out JQ1 for free to those working on this family of targets? And he's always acknowledged Mitsubishi's contributions.

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27. pharma professional on October 31, 2012 11:38 AM writes...

Those of us who know Jay, know that he is an excellent scientist/physician, who is genuinely concerned about advancing science and medicine. By making JQ1 available as a probe, it will only serve to enhance our understanding of epigenetic targets. Harvard and UNC have made probes available to SGC; look for pharma companies (forward thinking ones at least) to do the same.

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28. Rafael Najmanovich on October 31, 2012 4:03 PM writes...

I'd like to emphasize some points made by Al. This new way to see open collaborations is leading to the development of pre-competitive molecules that then can be taken over by however is willing and move to the next stage. In the meanwhile the strategy permits the development of research inhibitors that are indispensable to better understand the usefulness of the target and may be useful as starting point in the generation of lead compounds. Once these molecules exist, they promote a surge in understanding the role of the target and that picks up the interest of pharma and VCs. "Open-access" molecules fill a gap that exists currently in drug development linking academia and industry. Here are DOIs for some papers from the SGC about the idea of open drug design: 10.1038/470163a and 10.1038/nchembio0709-436

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29. sjc on October 31, 2012 5:27 PM writes...

Couple of points:

1. GSK published their work (I-BET/I-BET762) in 2010 in the same issue of Nature as the JQ1 paper (http://www.nature.com/nature/journal/v468/n7327/abs/nature09589.html)

2. Some info on the GSK clinical trial for I-BET762 is here: http://www.gsk-clinicalstudyregister.com/protocol_detail.jsp?protocolId=115521&studyId=8CA80D1C-BFAC-4309-9EA7-9F65BC8197A2&compound=115521&type=GSK+Study+ID&letterrange=All

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30. exscientist on November 1, 2012 3:13 AM writes...

@27, "look for pharma companies (forward thinking ones at least) to do the same"

But that's exactly what happened here. Mitsubishi find a compound and tell the world (in patent form). GSK pick up on the patent because it looks like their own compounds and show it to the SGC, who tell Bradner. Bradner makes a compound from the patent and (reluctantly I'm sure) claims the credit. I think the real credit is due to those involved in the work who are somehow keeping a dignified silence.

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31. Londonlad on November 1, 2012 3:57 AM writes...

#20 keshi91 - that's a mighty fine collection of copyright pdfs you have there - is it OK to copy all of these. My lab can't afford all the journals you seem to have for free. For example browsing around http://211.144.68.84:9998/91keshi/Public/File/ there's lots of cool stuff.

Derek - you may want to take this link down if keshi91 doesn't confirm it's all legit

Permalink to Comment

32. Sili on November 4, 2012 6:59 PM writes...

(I note, in passing, that once again nomenclature has come to the opposite of our rescue, since bromodomains have absolutely nothing to do with bromine, in contrast to 98% of all the other words that begin with "bromo-")
Perhaps it just stinks. Permalink to Comment

33. g0pr on November 5, 2012 1:38 PM writes...

The name bromodomain is derived from the drosophila gene, brahma where it was first identified in...

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