Category Archives: Science

National Treasure: H.R. 3043 and Scientific Publications

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On page 14 of the July 30, 2007, issue of C&EN, an article entitled “Bill Mandates Public Access” by David Hanson describes a section of a bill recently passed from the House to the Senate. The relevent text from the bill is as follows-

SEC. 217. The Director of the National Institutes of Health shall require that all investigators funded by the NIH submit or have submitted for them to the National Library of Medicine’s PubMed Central an electronic version of their final, peer-reviewed manuscripts upon acceptance for publication, to be made publicly available no later than 12 months after the official date of publication: Provided, That the NIH shall implement the public access policy in a manner consistent with copyright law. 

Hanson’s article states that the Professional and Scholarly Publishing (PSP) Division of the Association of American Publishers has asked members of Congress to reconsider this bill, or at least the mandatory submission to PubMed. Hanson reports that the PSP claims that-

“This language could serve to undermine the existing system of peer review and scholarly publication which disseminates high-quality research findings throughout the scientific community,” … 

Further down, Hanson gets to the real issue-

Brian D. Crawford, chair of the PSP committee and senior vice president of the Journals Publishing Group at the American Chemical Society (which publishes C&EN), says the House language violates fundamental copyright principles. The bill “would essentially force authors and publishers to, in essence, forfeit their copyrights” without compensation for their investments and would have many negative impacts on private-sector publishers, he says. [Italics by Gaussling]

What is telling is the quote by Brian D. Crawford, who suggests that the publishers stand to lose their copyright on the copy submitted by the NIH funded researchers.  If you are a publisher, should you be worried about this?  Probably.  The gravy train may be leaving the station.

Yes, the publishers have invested large sums in building publishing and distribution systems for the profitable dissemination of information.  But I would add that they have built these publishing engines on a system that hands voluminous copy to them for free.  Unlike other publishers who have to pay their authors for content, academic publishers do not pay contributors who, I might add, provide some incredibly valuable content. Academic publishers have built publishing businesses using content paid for by government granting agencies, and by extension, the public.

It’s easy to fault publishers for taking advantage of a system that hands them publishable content for free. But, on the other hand, circulation numbers for most publications is quite modest.  Even if advertising is used, the typical low circulation of any given specialized scientific journal is so low that only very modest advertising rates could be obtained. Many journals survive on subscription fees alone.  Examples of journals that have come to terms with advertising are J. Chem. Ed., Nature, and Science. 

The scientific publishing system is a sort of a deal with the Devil- the scientist gets the grant, does the work, and then what?  After dinner talks at the Elks Club? Of course not. A manuscript is prepared and in exchange for free printing and distribution, the publisher obtains the copyright. The copyright is the key.  It is a cash cow in the same way that the copyright to the Beatles songs are a cash cow, only with smaller numbers.

I think that Sec. 217 of H.R. 3043 is the right idea. The public has already paid for the research. Why should it be intercepted at no cost by printers who then have an everlasting copyright and control of what is rightly national treasure? The citizens have to pay taxes for the research and then turn around and pay commercial interests for the right to read it.  That is wrong.

If commercial interests want to make a profit on scientific publishing, then they need to find a better model.  The public shouldn’t be barred from access to what they have already paid for. Advertising may be the way to do it.  Perhaps the funding agency should have the copyright and publishers pay a fee to print and distribute it?  Comments?

When can we keep our shoes on?

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Check out Atomic Rocket for a tribute to Heinlein and Clarke and a repository of graphics and themes of space opera. Really a fantastic resource for science fiction writers.

Bruce Schneier interviews TSA Administrator Kip Hawley. Sounds like we’ll be taking our shoes off for quite a while. 

Filipino prisoners do the Algorithm March. The Algorithm March at the airport.

The Odd Relationship of Markush Claims and Obviousness

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This is a long and drawn out post on intellectual property, possibly not suitable for those with attention deficit disorder.

<<<< Warning! This post may cause somnolence or ED. >>>>

In this post, I have attempted to make a case that current practice in granting US patents contains a flaw that may be counter to the public interest. See what you think.

In my view, there is a curious discontinuity between the practice of determining obviousness and the allowance of Markush claims in US Patent law.  A Markush claim in the context of chemistry refers to a claim of a generic chemical structure defined by symbols that represent sets of functionally related moieties or structures.  Very often a core moiety is defined and one or more substructure symbols or other symbols representing various chemical elements are attached. 

As an example of Markush claims, consider US 4,237,133, an expired Pfizer patent dated December 2, 1980.  I “randomly” found this patent by searching under the key words “bromination” and “aromatics” at the USPTO website. This patent is illustrative of the point I want to make and my use here is not meant to defame or otherwise irritate Pfizer. I have no connection to this art in any sense.

The ‘133 patent is a fairly ordinary chemical patent. It contains 10 claims- two independent claims (claims 1 and 10) and 8 dependent claims that are ultimately based on claim 1.  Claim 1 is a Markush claim that defines a set of chemical compositions that the PTO has allowed the assignee, Pfizer, to have a legal monopoly on.   Basically, Pfizer was allowed two varieties of claims: a) a composition of matter,  and b) the process of producing analgesia in mammals, based on the compounds in claim 1.

Claims 2 through 8 are a series of “necking down” refinements to more preferred embodiments that are especially meaningful to the assignee.  Preferred embodiments are specific features that the assignee apparently wished to have clear definition to avoid ambiguity.

A patent must be “enabling”. That is, the patent must teach enough of the art to allow a Phosita the chance to see and avoid the patented art.  This is the whole purpose of publishing a patent.  If the state is to grant exclusive rights to a composition of matter or a process, then the public needs to have a fair chance to avoid infringement. The content ahead of the claim section is called the specification and it must contain information that, when combined with the claims, enable a reader to understand exactly what is being claimed and under what constraints.  In the case of composition of matter, it is common to disclose the procedures used to make the composition so there is no doubt by Phosita as to what conditions lead to the claimed material.

The patent claims a tricyclic ring systen festooned with functionalities, some of which are variable.  Variable groups are R1, R2, R3, R4, Z, and W.  R1 is further subdivided into other moieties, some bearing variable groups R’ and R” and appended to a chain bearing p methylene units -(CH2)-, where p may range from 0 to 4 .  Z and W are also comprised of features subject to variability.

The point is that the set of all claimed species is quite large.  Not surprisingly, one could easily wander into claimed composition space because, ordinarily, CAS does not capture all of the compositions from the Markush claim.

It is not required that the applicant prove that they have prepared each permutation in the set of claims, nor is it required that the enabling procedures specifically address each claimed species. The ‘133 patent has 43 procedures, many of which are for intermediate compounds, at best a number that falls far short of the entire set of claimed compositions.  Usually, it is sufficient for illustrative examples or preferred embodiments to be set forth in procedure.

If you think of each group as a spatial dimension, a generic core species with n variable groups essentially maps out a set of structures occupying a kind of n-dimensional space, subject to specific exclusions. When the variable groups are defined as alkyl, aryl, alkoxy, alkenyl, etc., the number of claimed species can be quite large due to the vast number of possible combinations of groups.  Even limited ranges, i.e., R = C20 alkyl, etc., can result in huge collections of claimed species owing to structural isomerism. 

The concept of obviousness in patent prosecution is one of the most vexing and mercurial ideas I can think of.  The code is set forth in 35 USC 103.  A patent attorney will caution that there is no hard and fast universal definition in advance of litigation because what really matters is how a judge decides the matter.  In a practical sense, though, obviousness depends on how the examiners interpret the code.

On to the point of this posting.  While it is possible for an applicant to claim compositions never made or compositions that should exist by reasonable extrapolation, claims in the reverse sense are more problematic. But what do I mean?

Consider US 7,235,700, a process patent claiming the preparation of a cyclohexenone functionalized on the beta carbon with an enol ether group.  [Disclaimer: again, this patent was “randomly” chosen. I have no specific axe to grind with the assignees or the inventors.  I do, however, have an axe to grind with US patent law.]

This process is a good piece of journeyman organic synthesis featuring the preparation of an alpha/omega functionalized fragment with a Grignard functional group on one end and a silyl-protected oxygen on the other.  From Example 2 of the ‘700 patent, to the Grignard reagent, made in the customary fashion in diethyl ether with dibromoethane as an entrainment additive, was added a THF solution of the cyclohexenone enol ether.  The Grignard added to the enone in 1,2 fashion to afford a tertiary alcohol which upon acid hydrolysis, the resulting alcohol eliminates and the 3-alkoxy enol ether hydrolyzes to afford the product cyclohexenone on workup. 

The patent teaches that the inventors had a poor process before this patented process (column 1, line 37).  So, this must be an improvement, right? It seems to be. But, should it receive a patent?

From my copy of Kharasch and Reinmuth, I see that 1,2-additions of Grignard reagents to cyclohexenone were reported as early as 1941 (Whitmore, Pedlow JACS, 1941, 63, 758-760).  So the knowledge of 1,2- vs 1,4-additions by RMgX nucleophilic additions to cyclohexenones resulting in primarily 1,2-addition is not new. 

The use of nucleophiles with protected incompatible functional groups is not new.  The hydrolysis of enol ethers is not new.  Indeed, nowhere in the description do the inventors state that the disclosed transformations were “surprising” or “unexpected” in their outcome.  As a phosita myself, I look at this patent and see good solid organic synthesis.  I see the results of workers who have undergone training in the usual graduate level chemistry curriculum. Advanced organic synthesis with attention to donors and acceptors, functional group transformations, and protection/deprotection schemes.  They took known transformations and assembled the pieces into the desired molecule.

My objection is this.  Under the convention that Markush claims are allowed under current practices, many compositions of matter can be claimed by virtue of simple declaration despite the fact that homologous series or the usual genus groups of radicals (alkyl, alkenyl, alkynyl, aryl, heteroaryl, etc.) may be rather obvious additions to the list.  A Phosita would reasonably state that if methyl is feasible, then so is ethyl, propyl, butyl, …, alkyl.  Markush claims invoke a kind of obviousness that is allowed. 

However, the same principle may not apply in reverse. That aspect of the body of scientific work teaching that certain generalizations are possible does not seem to be allowed in determinations of obviousness. 

In the instant example, the generalization is that Grignards as a class might be expected to add in the fashion claimed in the ‘700 patent.  Or that enol ethers as a class would be expected to undergo acid catalyzed hydrolysis to ketones.  In the ‘700 patent, elements of the claim are novel only by virtue of being obscure members of a very large set of possibilities.

So, on the novelty and obviousness side of examination, the fact that a claim uses known transformations or schemes on heretofore unreported substrates bearing known features seems to be sufficient to cause an examiner to allow the claim.  The allowance of Markush claims then allows broad generalization into large sets of claimed structures.

But generalization from a broad area of knowledge may not necessarily bar an unreported claim element when acted upon by known influences resulting in transformations that are consistent with the broad knowledge, as in the case of the ‘700 patent.

A patent lawyer reading this might object that the novelty of the substrate and the lack of specific precedence confers novelty and non-obviousness under current precedent.  That lawyers opinion might be internally consistent with precedent and most would leave it at that. 

But the overarching concern that I want to draw attention to is that the current practice in relation to novelty and obviousness may not serve the public interest. I’m seeing far too many patents being allowed for the application of known transformations to substrates that are merely obscure.  What passes for inventorship is often just good craftsmanship. Reacting a Grignard reagent with a ketone followed by elimination is a general process that we might teach to students in a classroom. 

Indeed, the current practice of teaching chemists is to expose the student to systematic generalizations of reaction-types so that they can go out and put generalizations into practice rather that have to memorize countless specifics. 

When these chemists apply their training by reducing generalizations to practice on specific substrates, however, it seems they can claim to have made an invention under US patent law. 

The upshot is that a good deal of technology resulting from ordinary problem solving skills is barred from the public domain for 20 years.  Not that I believe that privately developed inventions should be in the public domain. But I will point out that it is quite easy for a company to get clobbered by an infringement suit for stumbling into claimed art by practicing what their chemists learned to do in graduate school. Reducing general reactions to practice.

I suspect that it is common practice for companies to believe that if something is patentable, then a patent is manditory.  Unfortunately, the current system seems over-generous in granting 20 year monopolies for dubious inventions. When the threshold for obtaining a patent is too low, when practices are too easily removed from the commons, others trying to practice the art are unreasonably restrained.

Reform of matters as basic as the definition of obviousness and novelty cannot come from the USPTO, the courts, or from patent attorneys. Applicants and their attorneys will continue to game the system to the extent allowed by the courts. Fundamental change must come from legislation.

Late Night Thoughts on Twisters

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Now that we are well into tornado season in North America, I thought I’d dredge this old post up out of the cobwebs in the dungeon. As Uncle Al pointed out in the comments, Middle Easterners did have dust devils so a vortex of wind was not unknown there. These, however, are no match for a full-blown F4 tornado.

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One has to wonder what the original inhabitants of North America thought of the tornado (how do you say “WTF” in Lakota?). I have visited a few museums in my travels but have never seen any artifacts or heard of any references to Native American perceptions of the tornado phenomenon.  Without a doubt, Native Americans were visited by tornadoes. The experience must have certainly left an impression. It would be interesting to hear any stories that may be out there.  An internet search just offers a Mulligan stew of hits with tired references to Pecos Bill or to the odd disaster in Kansas.

North America is climatically privileged in that there is the possibility that overland southerly flows of cold dry air from the north can readily contact flows of warm moist air from the Pacific, Gulf of Mexico, or the Atlantic.   Vertical mixing of unstable humid air results in convection cells that are further driven by the latent heat of condensation.  These humid flows are spun up by the coriolis effect and wind shear to afford monster anvil storm cells that can tower to 50,000 ft or higher.

Like many places, here in Colorado we often see lines of isolated storm cells in the early evenings of summer, red in color at low altitude changing to a billowy yellow-white at altitude near sunset. Very often you can see mammatocumulous features signifying violent mixing activity. It’s no place for an airplane.

It is interesting to speculate as to how our modern mythologies and iconographies might have been different if the tornado phenomenon had been common in the Mediterranean and the middle east.  Would Charleton Heston have summoned a tornado to smite Yule Brynner’s Egyptians rather than parting the Red Sea and drowning the buggers?  Perhaps the Pharaohs might have built great stone helices rather than oblisks.  Aristotle might have written a treatise on the handedness of helical flows or whether the air flowed radially into or out of a tornado.

If the tornado had been a common phenomenon in the middle east during the iron age would the “Big Three” Abrahamic religions today feature tornadic themes in their texts and monuments? If so, perhaps the great cathedrals of Europe might today have relief sculptures or stained glass windows portraying the Israelites or Philistines being driven hither and thither by the swirling wrath of the Almighty’s cyclone.

Well, that’s enough of that.

Nitroalkenes

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A nice preparation of nitroalkenes appeared in the latest JOC.  The work was reported by Concellon, et al., JOC, 2007, 72, 5421-5423.

I like the two obvious aspects of this work- catalytic use of NaI and the use of SmI2 for functional group modification.  The use of 0.15 eq of sodium iodide to catalyze the condensation is really clever.  The yields are reported to range from 55 % to 96 %. A few yields are in the mid 50’s range yet no mention is made of dimerization of the bromonitromethane, so I can assume that is not much of an issue. 

Nitroalkene prep

The process uses an excess (2.5 eq) of SmI2 to afford overall 2 electron transfer to the substrate, resulting in loss of Br dot and oxygen, yielding an olefin with good stereospecificity.  For the examples given, the E/Z ratios were all 98/2. 

There are some downsides to the chemistry, I’ll admit. Plant management may not be keen on nitromethane derivatives.  I know that nitromethane has been shown to be shock sensitive in the BOM impact test (personal communication).  Depending on their threshold for these things, the plant safety patrol boys may have misgivings. 

The economic merit of scaling up a process that uses SmI2 depends entirely on the value proposition, which can be readily calculated.  Rare earths are reportedly of low toxicity, though I have not seen a primary reference for that assertion.

Most of the rare earth elements come from FSU or China. There is an accessible supply outside of the usual catalog companies, though you may have to do an electronic funds transfer in advance to some cramped office in Shanghai with a rep named Sylvia or Frank.  Advanced payment and sketchy D&B data will make your accountants skittish. But it could be worth it for bulk material.

I’m increasingly aware of the interesting utility of more than a few of the rare earth elements.  My work post-academia has taken me to many far off and exotic locations on the fabulous periodic table.  The rare earth group is not the featureless corridor of nondescript trivalent cations that this organikker once believed.  Fancy that.

M.S. Kharasch, Merthiolate, and Autism

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One of my most prized books is a tattered copy of Grignard Reactions of Nonmetallic Substances, by M.S. Kharasch and Otto Reinmuth, published in 1954 by Prentice-Hall.  It is a 1384 page tome containing a vast number of examples of Grignard reagent chemistry and reaction chemistry with extensive references through 1954.

Morris Selig Kharasch was a professor at the University of Chicago and is primarily known for his work with free radical chemistry.  To Kharasch is credited much of the early work in sorting out the mechanism of anti-Markovnikov addition of HBr to olefins. Reinmuth was the second Editor of the Journal of Chemical Education (1933-40).  Two coworkers, Frank Mayo and Cheves Walling, went on to make contributions toward the development of vinyl polymerization.

Later in his career Kharasch turned to the examination of the Grignard reagent and many of its reactions.  Among the list of his students and post-docs are H.C. Brown and George Buchi.  Kharasch was instrumental in the founding of the Journal of Organic Chemistry and served on the Editorial Board for many years.

It is interesting to note that Kharasch is credited with the patenting of Thimerosal in 1927, a product also known under the trade name Merthiolate which has been used as an antimicrobial additive in vaccines.

Chemical Safety- Taking the Dragon Out for a Walk

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Safety is something that everyone who handles chemical substances must come to grips with. That’s pretty obvious.  It is possible to structure prudent handling practices into policies that control how people come into contact or proximity with chemicals.  While I can’t speak for the rest of the world, in the US and EU virtually all of academia and industry have rules that govern the use of personal protective equipment (PPE) and hazardous material storage. 

As a group, I have known chemists to span the range of chemical aversion from compulsive chemophobia to stuntman fearlessness.  Most chemists are in the middle ground in regard to what toxicological or energetic hazards they’ll unleash at arms length behind the sash.  

But there is risk and there is perceived risk and the difference can be quite large.   Research laboratories are places where we try to achieve understanding about the unknown.  Material hazards may not be readily apparent in advance of an experiment.  We all have our sensibilities about what’s hazardous- call it “intuition” or just “experience”- but in reality most workers need to get an occasional recalibration.  Our perception of a given risk can be spot on, overly conservative, or overly lax. 

Institutions eventually have to put boundaries on the definition of acceptable risk. In innovative industry, companies want employees to try new things. Being overly conservative with risk can lead to time consuming procedural gymnastics that accomplish only delay.  Being overly lax with risk can lead to the loss of life and facilities.  The necessary administrative skill is to encourage safe innovation. 

Researchers have physical hazards to contend with. Managers must dodge administrative hazards that can blow a project out of the water. Reseachers operate within the bounds of physical law. Managers have the fundamental forces of economics, politics, and CYA (cover your a**) in addition to physics. 

In candid moments, R&D chemists may admit that much of research seems to entail the discovery of new failure modes. The broad search of reaction space can lead the researcher into patches of higher risk activity.  It is quite possible to blunder into energetic hazards or unwittingly generate highly toxic moieties that you were heretofore unaware of.  The abstracts from a SciFinder search don’t always offer notification of such hazards, especially if you are making new chemical compounds.

I know more than a few reasonable chemists who work for companies that have attempted to extract all risk of R&D scale incidents.  All experiments have to be planned and approved by some overseeing body.  Any incident involving a fire or spill is subject to an investigation and disciplinary action is meted out based on the in-house definition of negligence. Large publically-owned commodity producers seem to be the most onerous in this regard. (This is my opinion and the reader is free to take exception).

As is not untypical of large irritable mammals, Th’ Gaussling doesn’t automatically welcome visits by the safety goonsquad.  One of my many festering conceits is that I write procedures, I don’t follow them.  Unfortunately, this is a card that you can play once or twice at most.  The best strategy for long term employment is to stay off the safety radar screen. If you have to take the dragon out for a walk, have your route planned and for gawds sake, keep it on the leash.

The Return of DDT?

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There is serious op-ed talk mulling the return of the insectide DDT, particularly for malaria-infected parts of the world.  What is even more interesting is that this idea has caught on in the ultra-conservative media market and has become the liberal-bashing topic du jour of media darlings like Rush Limbaugh.  Since I don’t waste perfectly good heartbeats listening to that swaggering gas bag, I have missed this “discussion”.  Suddenly, Rush is concerned about the poor and destitute in Africa. 

What has escaped discussion is the possibility that modern methods of high throughput experimentation might find permutations of the DDT “pharmacophore” that would afford something with higher activity and shorter environmental half life.  Who knows, may be this has already been done?  Maybe there is a sample of a DDT analog sitting on a shelf somewhere that has less aptitude for bioconcentration and a greater aptitude for photo or hydrolytic degradation.  Then there is the potential for substantial wealth generation for Limbaugh’s wingnut paymasters.

DDT was clearly effective in suppressing mosquito-born illness for quite a long time.  Surely there are labile analogs that are effective but less objectionable? 

PhD Disease. Gaussling’s 2nd Epistle to the Bohemians.

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As I continue to cross off yet more days behind me in the great calendar of life, I am increasingly aware of just how truly strange and perhaps artificial my station in life is. Occasionally I detach my consciousness from the abstractions of my work and intellectual life and join those who live in the “eternal now” of daily life.  It is the world of real estate, car repair, and weeds. 

Having an advanced degree in anything marks a person as a kind of freak.  Not automatically in a pathological sense, though that is possible.  A freak in that to have gotten from freshman year through PhD is unusual in the statistical sense.  Not a large fraction of the population even try to do it.  To have done this is to be relegated to the far end of the bell curve by virtue of low frequency. 

Many people seem to be overly impressed by someone with a PhD.  To be sure, there are many PhD’s who are extraordinarily bright people.  But it takes more than just smarts for most of us.  It requires focus, tenacity, and endurance.  It takes a willingness to absorb abuse as well.  Getting through grad school has a large political component and a wise player learns how to negotiate with difficult people- advisors, post docs, and other faculty. 

Speaking only for myself, I have become quite aware that my path on this adventure will not be followed by any family members. My love affair with the science of chemistry is my lone passion and the wonders and elegance of its form cannot be fully shared with loved ones. That is a shame.

This lurking sensation of strangeness is especially noticeable at parties.  Say you spent the week trying to isolate a new product; noodled through numerous GCMS fragmentation patterns; or attempted to find meaning in the oddities of phosphorus NMR.  Suddenly friday night you find yourself at a party nursing a Fat Tire in a crowd where most of the people are in construction or real estate.  All of the conversations are about, well, construction or real estate. You find a friendly group and try to fit into the conversation. 

But here is the hard part.  You’re not running a construction site and you don’t deal with construction workers.  The price of copper pipe or the vagaries of the uniform building code have no impact in your life.  You’re just a freakish white collar worker who uses vocabulary that means almost nothing to nearly everyone on earth. You worry about selectivity, isomerization, and line broadening.  It really is a bit odd.

So, after you’ve made a few wry comments and patiently listened to the conversation, someone asks the question “What do you do?”.  This is where everything can fall apart.  You want to be accurate, but concise.  You can’t use obtuse language. If you are a synthetikker, you don’t want to say merely “I’m a chemist” because it is certain that the questioner will imagine that you wear a lab coat while you pour test tubes of “toxins” into the river to mutate the poor fishes.  And, for the love of god, you can’t let them think you’re an … analyst.  Good gravy, what would the neighbors think?

No, you say something to the effect that you make some product or other and it is used for ____.  This is that fork in the road that someone will take to get another beer or suddenly recognize some lost associate across the room.  Others will notice that something is wrong with their watch and pull out the cell phone to get the time, feigning discovery of a voicemail that they have to get. There many ways to eject from a conversation gone bad.  I have seen many of them and invented a few myself.

What I hate to see is the person who wears their PhD degree on their sleeve.  The blatant insertion of this status into the mix is like a turd in a swimming pool. Once it’s spotted, nobody wants to jump in.  For myself, I only use the title of “Dr.” in official company correspondance where I have to establish some credibility to weigh in on a certain range of matters.  Otherwise, I will admit that I have this degree only if people ask. The effect of title dropping on certain groups of people is that they shut down discussion when you walk into the room.  This is bad if the goal is to brainstorm or do a debriefing and the result is that people clam up. 

It’s best to let the strength of your arguments advance your cause. I don’t have a PhD in life- just a thin slice of chemistry.  And that slice seems to get narrower all the time.