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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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March 3, 2009

How Good (or Bad?) Are Patent Procedures, Anyway?

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Posted by Derek

All the comments on the Lundbeck / Dr. Reddy's imbroglio got me to thinking: how good are patent procedures, anyway? I said in that earlier post that I didn't think that they were that much different from procedures in the open literature, but I'd like to throw the issue open for comment.

You might think that patent procedures would be better, actually. There are potential legal implications to bad patent writeups that don't apply to lousy procedures published in a journal. You're supposed to teach how to make the new chemical matter (or how to do the new process) that you're claiming, and if your patent's details really are insufficient to fulfill that requirement, you have a problem. Patents have been invalidated over such disputes. If you thought your invention worth the trouble of patenting, you'd presumably be motivated to provide sufficient detail to make sure the patent is granted, and that it holds up if challenged.

That said, not all that many patents get seriously challenged over such issues. It takes lot of time and a lot of money, and the number of cases where it's worth the trouble are limited. And a patent has to be pretty lousy (or pretty deceptive) to truly fail to teach what its procedures outline. I guess what I'm asking about is the wide middle ground - the various procedures that aren't necessarily make-or-break for the validity of the patent, but are in there as parts of synthetic schemes. What's your success rate following these? And is it better or worse than your success rate trying to reproduce things out of, say, The Journal of Organic Chemistry?

Comments (21) + TrackBacks (0) | Category: Life in the Drug Labs | Patents and IP


1. Petros on March 3, 2009 11:25 AM writes...

It's hard to think of (major) cases where process patents have played a significant role with synthetic drugs but Amgen's biotech process portfolio has effectively given it about 30 years protection for Epogen.

And detecting process infringments is likely to prove difficult in practice

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2. milkshake on March 3, 2009 11:45 AM writes...

My typical patent procedure quality is outstanding but the rest of the patend literature is a low-grade gravel. Now seriously, disregard patent procedures that lack NMR and when the yelds are not given this is another warning sign. A vague experimental written in present tense is a sign of a prophetic example = science fiction stuff. (Btw I have seen some Vertex p38 kinase patents full of prophetic examples.)

Patent procedures are not peer-reviewed, and most medchem procedures are written in hurry because of the submission deadlines, on series of marginal- importance compounds that are meant to demonstrate the scope of composition-of-matter claims. Even 1% yield is sufficient for the purpose.

You don't want to spend too much time on some micromolar compound, made three years back for which the notebook entries are sketchy so some missing experimental details are "re-invented" on the fly or worded around a bit. I have seen this over and again.

I have had serious difficulties with my previous two bosses here at the institute who urged me "not to spend over too much time" on writing the patent example procedures. One of them asked me to provide experimentals only on the active compounds, so I left out the two that were inactive. But my ex-boss failed to remove the two inactive ones from the examples list, and when the patent lawyers found out they were missing experimental examples on two compounds on their list they asked their in-house expert to write them for me as "prophetic examples" without letting me know. I found out only after the stuff was published...

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3. cookingwithsolvents on March 3, 2009 11:54 AM writes...

My sample size is pretty small, but I'd say about 80%-ish of the procedures worked pretty much as advertised. That's pretty good considering I'm usually working at 1/10 or 1/100 the scale of the patent. The oldschool organic type industrial preps worked the best, by far. Can't beat industry for fire and brimstone aromatic substitution "it always works this way" chemistry.

Of course, the fire-and-brimstone preps usually result in mixtures so you'd better do the prep on a big enough scale to easily separate what you want. I've found the isolation procedures, especially crystallization, to be super WHEN they are given, though.

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4. Petros on March 3, 2009 11:59 AM writes...

On other tacks I've had occassion to get multi-gram quantities of reference drugs prepared by custom synthesis based on patent procedures.

In one case, for a marketed drug, the only process then described was a poor multi-step one so it had to cost more since we needed the sample for biological reference purposes and didn't have the time to do it ourselves.

I can't recollect noticing prophetic examples per se but I do remember some Aventis combi-chem type approaches to compounds that listed pages of fragments A, B and C and implied that all the combos had been prepared, although strictly speaking that is unlikely to be an issue in the vlidity of the patent

As for his examples added, I've had an inventor add themselves. They were liasing with the patent attorney, as both both were based in the WDF's home country, and having submitted all the specifications to the patent department I subsequently found that this colleague had added an additional example plus themselves as an inventor

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5. PatentBuster on March 3, 2009 12:34 PM writes...

During my graduate years, my boss would occasionally ask me to consult on patent dispute cases where the "teachings" were at issue (great way to supplement your graduate income!). I think in almost every case I examined, the reaction(s) worked somewhat, but not as advertised, and not without significant experimentation. The strange thing was that I never knew if I was working for the people who wanted the patent to work, or the people who wanted to show it didn't work. I could usually figure it out when I reported the findings (comments like "are you sure there isn't something obvious you're missing?" tend to give it away).

In my own research, I would say the reactions have performed worse than literature preps for sure. Usually due to inadequate experimental details. I think if you listen to Milkshake's suggestions, however, your success rate should be much higher.

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6. Hap on March 3, 2009 12:54 PM writes...

I haven't tried to reproduce patent procedures but I've seen lots of egregious errors in them, enough to question their utility. There are usually enough missing details as well to make you hunt around for your sanity, and I tend to wonder after awhile whether the obfuscation is intentional or due to incompetence. The reviewer for OPRD usually has a few good choice comments, and these are (theoretically) the best and most useful patents.

The question to ask might be whether BMCL procedures or patent procedures are better.

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7. MTK on March 3, 2009 1:21 PM writes...

In general the patent literature is OK. It might take a few times to get things to work as well as you want. In that respect I find it a little less reliable than the literature, but I usually don't mind to be honest with you. My expectations are less, because the purpose is different.

A patent is a legal document. Nothing more, nothing less. The peer-reviewed paper is a scientific document. In the peer-reviewed paper it's reasonable to expect that given enough detail that one should be able to exactly replicate the results as described.

In a patent, however, the goal is usually to get as much coverage as possible. Given that, procedures are often times written in a more general sense to expand the obviousness net.

I have no problem with that. The objectives, standards and obligations are different and so are my expectations.

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8. Nevada Born on March 3, 2009 2:07 PM writes...

Patent procedures (By US law) are not required to be explicitly reproducible. A certain degree of experimentation on the level of one of ordinary skill in the art is assumed. So long as the experimentation is not excessive.

If you look at software patents you often won't see much code, just flow charts. Why? Because it's assumed someone of ordinary skill can produce the code. Likewise, it's assumed you'll be able to know or find the conditions to reduce that ketone.

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9. Cat Herder on March 3, 2009 2:13 PM writes...

I've had pretty much equal success with patent and literature preps. However, when I was an undergrad I was trying to follow a patent procedure for a displacement on 2,5-dibromothiazole with an amine and found that I could reproducibly obtain the wrong regioisomer in the reported yield. Looks like the patent authors never actually made what they said they did...

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10. CMC Guy on March 3, 2009 3:31 PM writes...

I have already expressed skepticism regarding (some) Patent procedures and again think it depends on perspective and objective. If one is attempting just to make a particular compound Patents are generally reliable (as good as JOC)(although have heard a few stories of prophetic molecules that failed) . If however one has concerns about safety, conditions, scales, yields, reproducibility and ultimate practical implementation (i.e Process) many times can be very frustrating to repeat (not up to Org Syn Preps) even if is a Process Patent. IMO "Ordinary skilled in the art" must have a rather broad definition and while might expect some "reasonable experimentation" needed to (enable) duplicate results reported there seems to be vast approaches to what such efforts involve. I thought there is also supposed to be a "Best Practices" doctrine that means if you know there are better ways you must provide and typically that is where most concern comes: if the Best Practices are so lousy is this real at all? There have been several times I knew the Patent was not representative of how the materials was actually being made in the "real world".

MTK is correct Patents are legal documents and that often that is what creates problems for a chemist who does not understand the game. Patent Lawyers will add "clutter" normally a chemist would avoid in a paper, sometimes boiler plate fashion, for purposes of protection and coverage that will disguise the actual procedure. For example suppose THF works much better that anything else but will include 4-5 other solvents (may or my not tried in lab) in application. On the other hand the lawyers may edit "minor" details that can mean a lot to the getting it done right (such as heating/cooling times). Some "Examples" provided seem to be the alternate procedure because wish not to disclose what better routes are. So again beware that is a chance the full story is not what you have in a Patent.

Thanks for the soap-box Derek.

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11. gyg3s on March 3, 2009 4:16 PM writes...

Nevada Born (comment 8) is on the money. I'd also refer you to the links that I posted in your previous post about the Lundbeck paper.

I'll comment more if you're interested.

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12. andrew on March 3, 2009 10:13 PM writes...

Re: Petros "On other tacks I've had occassion to get multi-gram quantities of reference drugs prepared by custom synthesis based on patent procedures.

In one case, for a marketed drug, the only process then described was a poor multi-step one so it had to cost more since we needed the sample for biological reference purposes and didn't have the time to do it ourselves."

Might it actually be cheaper and easier to just buy the drug and extract it out of all the excipients?

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13. andrew on March 3, 2009 10:14 PM writes...

Re: Petros "On other tacks I've had occassion to get multi-gram quantities of reference drugs prepared by custom synthesis based on patent procedures.

In one case, for a marketed drug, the only process then described was a poor multi-step one so it had to cost more since we needed the sample for biological reference purposes and didn't have the time to do it ourselves."

Might it actually be cheaper and easier to just buy the drug and extract it out of all the excipients?

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14. Martin on March 3, 2009 10:20 PM writes...

my experience of patent experimentals is for the most part OK. Of course it's very project specific. One comment I would make is that I see a lot of preps of the kind "500g of cyanogen bromide was added to..." in patents. In academic labs here in .au, try even getting hold of half a kilo let alone getting that quantity through your friendly OHS/risk assessment procedures. Of course we can scale down if you're towards the end of a linear sequence of reactions, but what if it's going to be your SM or scaffold of choice; (Yes Mr benzimidazole, I'm looking at you...)

Many reagents of this type obviously don't store well so we tend to buy in small quantities and it takes a long time to ship if you do need a lot for the first step in a linear process. If you are in a larger enterprise then your turnover is probably high enough to get comfortable with purchasing large quantities. But I seem to be forever running into patent procedures that begin with stuff like this. So we might end up going the long way round to get to things based on avoiding long shipping times, not synthetic expediency.

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15. Pat Pending on March 4, 2009 1:31 AM writes...

I always tell my scientists that if they want to publish their research after the patent is filed they need to write the experimental in J Med Chem style and that the patent experimental and published experimental will be the same. In the specification alternative solvents and conditions will be described to broaden the patent's coverage and of course prophetic examples are in present tense and are prophetic so beware.

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16. processchemist on March 4, 2009 3:49 AM writes...

"And detecting process infringments is likely to prove difficult in practice"

Sure, if you talk about process conditions. But, in case of small molecules, patented intermediates plays a key role, mostly if they can't be excluded from the GMP part of the synthesis.

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17. RB Woodweird on March 4, 2009 9:21 AM writes...

Hey Nevada Born - I spent some time in the Silver State. What county you from?

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18. NH_chem on March 4, 2009 9:31 AM writes...

Having been part of the process, the goal is to submit something that works with as little detail as possible and NOT provide what you are actually doing or the best experimental conditions. That is my experience.

BTW- I don't like that attitude but the patent attorney called the shots not me.

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19. Chemjobber on March 4, 2009 10:46 AM writes...

Uh-oh: Supreme Court ruled 6-3 against Wyeth.

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20. Don B. on March 4, 2009 12:03 PM writes...

We were trained in Discovery Med. Chem. to write our experimental in J. Org.Chem. detail with supporting analytical data. In Development, we were trained to do the same but also to be certain that our latest "improvements" were included in the process patent. We aleways included solid analytical data on all isolated intermediates.

I have told our patent group that every chemist should be "practise deposed" on at least one of their, the chemist's, patents. It would tend to clean up notebooks. Being deposed for real is not a pleasant process even when you KNOW you are in the right & have all the data.

I have only "heard" of cases where the chemist's boss & his/her boss would be added as inventors. We were taught that constitutes FRAUD on the Patent Office!

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21. Robert on March 5, 2009 3:31 AM writes...

I'm with Milkshake as regards reproducability of patent procedures... My experience is that after applying a "does this look real or not" filter (eg NMR ,yields, purities), they tend to be pretty good...

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