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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: Twitter: Dereklowe

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June 9, 2010

Running Out of Decent Molecules to Patent?

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Posted by Derek

Yancey Ward, who comments over at Megan McArdle's site at The Atlantic, has started a discussion over there on drug patent issues. There are a couple of things worth talking about here (such as how to handle combination therapies), but I wanted to bring up a particular issue first to see what the readership here makes of it:

". . .It is getting increasingly difficult to patent small molecules because their structures are increasingly found in the ever growing patent literature for completely different targets. I know for a fact that a lot of projects begin on a less than optimal structure for reasons of patentability alone."

How much of a problem is this? I know that sometimes it can be a real roadblock, particularly in areas where particular structural motifs get (over)used. I've been in on some of those projects myself. And "useful chemical space with no prior art" is a large (but finite) resource, which we are using up, as people have realized for years.

But it would be very interesting - although probably impossible - to know how many total projects across the industry have to start from a bad position because of patentability issues. That can be partly a problem of your own screening collection, which is something every company has to guard against. If you have some big, long-running projects that have cranked out a lot of similar-looking chemical matter in certain areas, these things are naturally going to be over-represented in your corporate screening files. If they're really useful structures, the challenge (after a while) becomes how to avoid starting off yet another program from the same general structures, in order to avoid their complex IP and shrinking freedom to operate. The less-trampled your compound collection is, the better off you'll be when something hits from it.

That said, the only projects I've been on that came to a halt because of patentability trouble did so because someone else popped up in the middle of things with coverage of exactly what we were working on. It happens! Other projects have gotten rather complex, as the trends in the active compounds kept pushing us closer to someone else's exemplified chemical matter, but we generally can find a way around that. Now, if we tried to total up the amount of time and money spent in that way, in working around other people's claims, that might truly add up to something alarming. . .

Comments (42) + TrackBacks (0) | Category: Patents and IP


1. Des on June 9, 2010 11:44 AM writes...

Any thoughts on what actually constitutes prior art? As I understand it, for a patented structure to be considered as prior art, there has to be enablement. How much of the chemical space has been gobbled up by over-broad patenting of structures that the inventors/authors/patentees have given zero enablement for, and which there is no known or obvious route/synthesis? Has this ever put anyone off pursuing what would otherwise have been a seemingly attractive series?

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2. Evorich on June 9, 2010 11:46 AM writes...

I can honestly say, of the many dozens of projects I've seen, not one has stopped for patent space reasons.

We replace 10-20% of our screening library every year with novel scaffolds. And we do virtual screens. Beyond that, once in H2L, we create virtual libraries for scaffold hopping on every series which, given the enormity of chemical space, usually gives us something good and totally novel even if we didn't have it already. Sometimes it picks out a patent but we usually treat that as proof that the method is working, not that it has failed.

Some start points are better than others and "patent busting" is sometimes part of the game. It's that simple.

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3. OrgMed on June 9, 2010 12:02 PM writes...

Interesting note fromEvorich, I do not believe virtual screening brings any novel/patentable leads. The libraries of over 10-15 MM that every one explored/exploring are all covered in >55 MM Scifinder database.

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4. notalawyerbut on June 9, 2010 12:40 PM writes...

You can always patent a particular structure for a particular target, even if the structure has been patented or published elsewhere for a different reason. But such a case prevents you from claiming all the hypothetical SAR (markush stucture) around such a compound, so the patent would be very narrow. That said, I believe if a structure is published anywhere, for any reason, then the well is poisoned in that a markush structure can never overlap with any previously published compound. I think all this shows how silly markush structures are...

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5. partial agonist on June 9, 2010 12:40 PM writes...

Patentability is a huge and confusing issue. Huge in that bosses I have worked with demand that we abandon a good scaffold falling under a very broad genus in a patent even if the patent has no examples of that compound.

It is frustrating because you see companies developing compounds that seem to violate the broad claims of each others patents all the time. It becomes a judgement call, and the de facto judgement seems to be to only focus on leads with a clear path to patentability even to the exclusion of very broad claims. This eliminates lots of very good compounds from any consideration for optimization, even if the prior art was for a different target, different disease, and was totally unrelated. Broad patent claims being issued are in my opinion a major impediment to progress.

I roll my eyes when claim 1 of a patent application is "A-B" where seemingly A stands for anything and B stands for anything else. These borad claims rarely get issued, but now and again one slips by the examiner.

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6. Canuck Chemist on June 9, 2010 1:16 PM writes...

I'm wondering how many people here have had promising leads terminated by "cover your ass" legal departments who don't want to deal with the future possibility of contesting overly broad and unexemplified claims in a competitor's patent?

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7. kxc on June 9, 2010 1:18 PM writes...

The so called patent white space is simply created by our fellow chemists to confuse ourselves and patent relatively useless molecules. >90% of patents do not lead to clinical compound. Just compare amprenavir and darunavir and one would know that we only need a good drug molecule.

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8. Ben A on June 9, 2010 2:00 PM writes...

I've never heard this as a problem. Sure, kinase inhibitors can be a tangled space. But you can even patent bust in that area.

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9. john on June 9, 2010 2:29 PM writes...

kxc, Amprenavir (and it's pro-drug)and darunavir are covered under the same patent issued to G. D. Searle in the mid 90's. Both compounds are licensed to GSK and J&J who pay royalties to (I guess) Pfizer although amprenavir was taken off the market after the pro-drug was approved.

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10. Pat Pending on June 9, 2010 2:57 PM writes...

As a patent attorney I think you need to look at this problem in two different ways. If you have a drug on the market the important claim is the one that specifically claims the compound because that is the claim that prevents generic entry. The broad Markush claims are valuable to keep other R and D based pharma companies out of your chemical space (you hope) however compare the structure of Viagra and Levitra and even if the molecular structure itself is claimed a company may license or co-promote the drug for example Zithromax. I think the problem arises because most companies do not want to license rights and many patent attorneys may be to lazy to really think through when a blocking patent is going to expire and where will the project be at that time. Foe example if the patent is going to expire in five years and you are in lead development unless you are extraordinarily lucky the patent will expire before your compound is approved and you should be able to get patent protection for your compound and some surrounding space unless your compound itself was previously described in the literature. On a related note this is why in another 10 years or so as patents claiming human genes expire and the human genome project as prior art prevents new patents the problem of claiming human genes will go away.

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11. scientist on June 9, 2010 4:12 PM writes...

In 20 years in industry and time spent pretty close to R&D on 3 marketed products, I've found that if you focus on finding a really great compound and you have decent assays and you know a little bit about organic synthesis and medchem, the 'issue' of patentability usually is solved by actually discovering something useful. If you spend too much time getting your ideas from others ('patent-busting'), don't be surprised if you have some challenges - but in my experience, a real drug is almost always patentable. Worrying about patentable drug space getting used up is a little silly if you've ever watched how the discovery of new reactions (Pd-couplings come to mind) drives new medchem which opens up new space. Many bigger worries than this....

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12. MedChem on June 9, 2010 5:31 PM writes...

Let me guess: poster 2 is not a medicinal chemist and poster 11 never actually led a kinase program in the past 5 years :) No offense if I guessed wrong.

Many people are confusing two difference issues here:patentability and infringement. One might be able to "patent" a molecule but the company can't market it if it infringes on an existing patent, e.g. your molecule falls under others' claim.

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13. JR on June 9, 2010 5:35 PM writes...

If your compounds work well and are novel, you should be able to get claims to them even if they are encompassed by a broad prior art genus. Now, someone might come knocking on your door for royalties, but they also might think twice about trying to enforce a broad claim if it is weak. It is even easier in cases where the prior art is for a different use (less obvious). You can also get a genus that overlaps with a prior art genus, particularly in cases where the prior art use is different. One of the reasons pharma patents (and claims) get written so broadly is because the slow nature of development means it often takes several years before the patent applicant even knows what the invention IS.

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14. barry on June 9, 2010 6:03 PM writes...

If you're just going to stick a hydrogen-bonding donor-acceptor-donor motif into the hinge region of a serine/threonine kinase it's likely that what you're making is not novel, is not non-obvious and is not utile. By the time you have a potent and selective inhibitor of your target you have outrun 99.9percent of the patent claims in the area

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15. MedChem on June 9, 2010 6:08 PM writes...


If you know any hinge binders that don't have the "hydrogen-bonding donor-acceptor-donor motif", I'm all ears.

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16. milkshake on June 9, 2010 7:06 PM writes...

I had bosses who instructed me not to make any molecule that falls within a prior art in someones patent - even if we were at the start of the project. How is one supposed to build a decent SAR "without wasting time on series for which we cannot get IP position" I don't know - I usually ignored people who were saying this kind of stuff, typicaly they were young and insecure. My answer to them was that one only has to look at the structures of competing approved drugs, to see that overlaping patent claims is not such a tragedy.

I think the first order of business is to have a decent series which work in cell assays and animal models, and their PK is tolerable. The patentability issue can be often adressed later on as you understand your SAR better and are re-optimizing your compounds to get a decent bioavailability or target selectivity/dial out tox issues,

Patent busting is easier done than most people think - just adding (or disconnecting) one ring or moving one nitrogen around or swapping one methylene for oxygen means you got a new scaffold. And even if you cannot patent a geneal scaffold you can make a narrower patent for a specific subset of substituents that are of interest. Especially if the substitution pattern is only claimed but not exemplified in the other patents, and if their target is different - you can easily claim that your stuff is new and unexpected.

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17. Alexander on June 9, 2010 9:03 PM writes...

Throwing my hat in the ring:

Selection inventions are a pretty standard way around this. The prior art discloses a huge number of compounds, the current patent discloses a selection and shows that the selected compounds have some property not expected from the broad disclosure. For example, it inhbits the X receptor where the prior art was entirely focused on the Y receptor.

Also, Swiss claims and the like. The EPO just approved the phrasing "(known) Compound X for use in treating (novel use)". More restrictive than the compound unbound, but still pretty decent it seems.

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18. Ronathan richardson on June 9, 2010 9:29 PM writes...

What about pathway/target patents? Could someone explain how these work? E.G., if I read that a company has an exclusive patent covering the targeting of protein X in disease Y, and I do a phenotypic screen and and get a compounds that turns out to hit protein X, do I have to pay royalties?

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19. researchfella on June 9, 2010 9:52 PM writes...

There are bigger challenges than the available chemical space... Selection inventions are not being allowed as readily as in the past. And KSR v. Teleflex (2007) has raised the bar for obviousness. Do a Google search for KSR v. Teleflex and see the discussions on this topic.

(Hey Derek, my last post was accepted and 'held for review', but it never was posted. It certainly wasn't inflammatory in any way... is the website broken or are you filtering comments?)

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20. A Nonny Mouse on June 10, 2010 3:38 AM writes...

Fluconazole, a very large drug for Pfizer, was generically included in an ICI plant protection patent. Pfizer had to get a licence to use it. The chap working on the project at ICI was in trouble for missing the compound as it was about the only one that was not teratogenic!

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21. sgcox on June 10, 2010 3:58 AM writes...

15. Med.Chem : look at 2VAG in PDB.
we will get paper with ic50 data soon...

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22. chris on June 10, 2010 6:55 AM writes...

I've never known a program that was stopped because of patent issues, even when we started with a published compound.
I would have thought the difficulty in identifying a drug far outweighs any difficulty in negotiating any potential royalties that might have to be paid.

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23. MedChem on June 10, 2010 9:37 AM writes...

#16 Milkshake

If you modifications didn't get you out of the said patent's broadest genus, you still haven't broken it. You might very well be able to get a patent on your molecule, but you'd still be infringing. See my previous comments. The mode of operation you described may have been ok a few years ago but is becoming increasing difficult.

I looked at it and thought "so what". One can get a lot of fragments to bind in the ATP site. Another way to look at it is: have you seen a potent ATP competitive kinase inhibitor without engaging in one of the three hinge interactions?

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24. OrgMed on June 10, 2010 9:51 AM writes...

Though its different topic, sgcox very interesting 2VAG, di-Cl aryl ring position to hing?.

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25. JR on June 10, 2010 11:22 AM writes...

Nay- KSR v Teleflex has done little to raise the bar for obviousness in pharma cases. In fact, subsequent cases, citing KSR, have come down that strongly favor the idea of chemical nonobviousness (i.e., it is not necessarily obvious to make a seemingly minor change in a structure to generate a new compound). The two biggest are Takeda v Alphapharm and Eisai v Dr. Reddy's.

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26. Pat Pending on June 10, 2010 3:22 PM writes...

18 Ronathan Richardson

University of Rochester tried this approach against Pfizer and Pharmacia/Searle and was shot down. The court ruled that all Rochester did was to provide a road map and not an actual compound.

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27. kxc on June 11, 2010 9:07 AM writes...

One should not mix up patenting an invention and freedom to operate. Both Vertex and Arun Ghosh secured patents for amprenavir and darunavir which provided them with exclusive right (i.e. exclude other from practicing the art). The matter of cross licensing between two patent holders is not determined by the patent office but by the court.

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28. milkshake on June 12, 2010 1:27 PM writes...

#23 the answer is yes, our c-Met compounds did not bing into the ATP binding site but over it, like a lid over a pot, being sandwiched with Tyr from the activation loop. These were single nM competetive inhibitors.

Re patents: Infringement-liable series is not something you wish for with your patents but it is not such a big deal. In the same way you may not wish for your compound to have chiral centers or active metabolites because it makes the development more expensive. We do not live in ideal world. Sepracor based its business model on patent infringement.

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29. Pharmachick on June 13, 2010 10:54 PM writes...

Hi guys,
howzit? I've been gone a while...

Just wanted to back up Milkshake on several points:
1) How to do SAR without infringing on previously 'SAR-ed' molecules?

2) "And their 'PK is tolerable' " AAAAARRRRGGGGHHHH, whilst on one hand I applaud Milkshake for this statement (do y'all know how many "scientists" put through molecules that have crap PK?)... on the other hand... "tolerable" is not an actual endorsement.... PLLLEEASSSE get a professional PK-ist onboard!!

3) What about process patents, hmmm ?

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30. processchemist on June 14, 2010 3:54 AM writes...


"What about process patents, hmmm ? "

Process patents are one of the most common strategies to protect the product (together with patents covering specific crystalline forms) after the patent covering the compound has expired. Obviously other companies can produce the compound using a synthesis in the public domain, or can patent their own process. In few words, only an unreported NCE can assure the highest returns if approved. More useful to gain an "orphan drug" status, I think.

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31. milkshake on June 14, 2010 6:49 AM writes...

I think process patent-based protection stands a chance in cases of very complex small molecules or protein drugs which have only few possible ways to be accessed, and are made cheaply by fermentation using engineered cells or extracted from natural source by an elaborate process - and even that is very hard to enforce because the burden of proof is on you - you have to convince the court that what someone has been growing or mixing up in his reactors in Hyderabad was based on your process. Litigation like this has been done successfully in the case of Taxol though.

I worked with a guy who developed an alternate way of making Tamoxifen in Prague and ended up sued by ICI for his trouble, ICI was trying to invalidate his patent and have him pay the royalties - he prevailed because the court decided that some steps and especially the choice of solvents were innovative enough that his patent did not infringe the ICI process patents (and composition of matter patents on Tamoxifen were already expired).

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32. petros on June 14, 2010 7:48 AM writes...

Although many process patents are filed, and granted, both the originator companies and generic companies, how many patent infringment cases have succesfully used such patents? (Not biotech examples obviously)

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33. MedChem on June 14, 2010 10:32 AM writes...

Milkshake #28,

I don't know what you meant. The Searle/Pfizer c-Met cmpd most definitely binds to the hinge in the traditional sense.

Regarding your infringement comment, I don't disagree with you in that "infringement" can be fought. I just wish our legal dept sees it the same way. Unfortunately, big pharmas in general are becoming more and more risk-averse, although Pfizer appears to be an expection. Maybe they strategy is to just buy the infringed company out.

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34. milkshake on June 14, 2010 12:50 PM writes...

There are two SUGEN/Pfizer c-Met series. One is classic hinge binder the other one is atypical active site binder as I described above.

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35. MedChem on June 14, 2010 2:24 PM writes...

#33 Milkshake

The two I know 1) SGX type inhibitor 2) Sutent type inhibitor, both bind to the hinge. Were you refering to these two or another chemotype?

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36. milkshake on June 15, 2010 6:42 AM writes... is the hinge binder, aminopyridines based on co-crystal of Kalamazoo aminopyridine HTS hit and older oxindole compounds. Now doing really well in phase III for ALK-positive lung cancer.

"SGX Type" should be called properly SUGEN type because we found them first too:

PCT Int. Appl. (2005), 47 pp. CODEN: PIXXD2 WO 2005010005 A1 20050203

which was based on tetracyclic compounds from SUGEN patent

PCT Int. Appl. (2005), 73 pp. CODEN: PIXXD2 WO 2005004808 A2 20050120 CAN 142:155983 AN 2005:55025

which was based on earlier isatine hydrazone sugen patent

PCT Int. Appl. (2005), 189 pp. CODEN: PIXXD2 WO 2005005378 A2 20050120

which came from high-throughput hit from screening Kalamazoo compound collection

(The isatine hydrazones were emphatically not hinge binders I know this because I was involved in the design that was based on co-crystal X-ray. SUGEN got closed right after and Pfizer did not pursue this second series. SGX and many others only busted our patents when the patents got published. )

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37. Anonymous on June 15, 2010 9:31 AM writes...

"The isatine hydrazones were emphatically not hinge binders"

Really? It certainly could (the oxeindole part).

""SGX Type" should be called properly SUGEN type because we found them first too"

I definitely agree with you on this one. The SGX c-Met has utterly NO creativity and was entirely based on Pfizer's chemotype.

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38. sgcox on June 15, 2010 10:27 AM writes...

milkshake, are you talking about this:
yes, there is an h-bond to hinge

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39. milkshake on June 15, 2010 11:44 AM writes...

isatine hydrazones were not hinge binders - thats what we thought too before a colleague made analogs with Cl or Me group in 7 position, right next to the oxindole NH. They were just as good as unsubstituted ones, and more soluble. There is no space in the hinge to accomodate the 7-substituent. X-ray structure explained everything, with the hydrazones (and later tetracycles analogs) binding perpendicularly over the binding site and pi-stacking with tyrosine from activation loop. By the way thats the reason you need so many nitrogens in these rings - you want flat electron-deficient aromatics to pi-stack with hydroxyphenyl of the tyrosine. Charge transfer interactions are strongest when they happen between two electronically unequal partners, for example tetranitrofluorenone and trimethoxybenzene.

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40. MedChem on June 15, 2010 1:04 PM writes...

"There is no space in the hinge to accomodate the 7-substituent."

Did you get a co-xtal structure of this Cl- analog to prove this?

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41. milkshake on June 15, 2010 4:02 PM writes...

yes - that is what I am trying to explain to you but you just wont accept any input that contradicts your conviction. The X-ray was the starting point of everything we designed

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42. Jonadab the Unsightly One on June 22, 2010 7:45 AM writes...

> I know for a fact that a lot of projects
> begin on a less than optimal structure
> for reasons of patentability alone.

Wait, pardon my layman's ignorance, but do you really want to put all the R&D effort and money into developing a drug and getting it approved, only to have your competitor discover that a more optimal version is possible, which is NOT covered by your patent? I mean, I know they'd have to go through FDA approval before they could do anything with it, but still... it seems like a dangerous position to be in, from a business perspective.

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