Harry Potter and the Sick Puppies

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By 12:15 AM saturday we had copies of the latest and final installment of the J.K. Rowling franchise, Harry Potter and the Deathly Hallows.  It was an evening of standing-room-only at the local Borders bookstore, elbow to elbow with muggle Potter enthusiasts.  Many were in costume but all were anxious to get their copy of the book and once again enter the magical world of Harry Potter.

As we made our way to the parking lot it became apparent that flyers had been affixed under the wiper blades of cars outside the store.  Under the orange afterglow of the evening we could see the colorful flyers festooned with Potter graphics and the congratulations to the reader on their early purchase of the book.  Then the flyer went on to reveal the the fate of the characters!  These flyers were SPOILERS!#&*@!  It was an unthinkable act of desecration forced upon innocent followers of the story. 

For the love of God!!  What kind of fiendish mind could conceive of this heinous act?!  Someone printed these flyers and then, when the moment was right, quietly planted them when anticipation was at its highest.  What mothers child could do this? Who are these sick puppies, these bomb throwing literary terrorists who could execute such a felonious theft of innocence?  Think of the children.

Well, anyway, we intercepted the flyer and tucked it away to protect some unsuspecting citizen from picking up this booby-trap from the ground and reading it.  Unfortunately, Th’ Gaussling suffered some acute exposure to this bit of printed poison. Bummer.

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.

Does CO2 Lag or Lead the Atmospheric Temperature Rise?

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I keep running into people who claim that atmospheric CO2 levels lag atmospheric temperature rises rather than lead them. That is, higher CO2 levels are a result of global temperature increases rather than a cause.  I’m not a researcher in this area, so my opinion is approximately meaningless. But on basic principles, it would seem that the partial pressure (or mole fraction, really) of CO2 might be expected to increase in the atmosphere over a warming ocean containing carbonate. 

Aqueous CO2 equilibria is complicated by its reaction with water, but one should still expect that the decrease in solubility of CO2 in surface waters might have some bearing on the present atmospheric CO2 levels.  For a given dT of an aqueous system with dissolved CO2, how does the mole fraction of CO2 in the gas phase change? The last time I worked a problem like this Ronald Reagan was president. Sigh.

On the Road in the Land of GM

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Th’ Gaussling has been on the road the last few days visiting one of the states shaped like an oven mit up along the north coast.  This is my first visit to this area during the summer. It is very beautiful country.

We had an inflight medical emergency enroute to a stop in the Windy City.  The call came over the PA “Is there a doctor on the plane?”.  Two vacationing MD’s, one in a fishing vest, rendered aid to a fellow who had a seizure.  They had the poor sod on the floor with a saline i.v. and O2 for 90 minutes. The guy was lucky that he had more than an Untied (Airline name purposely altered) Stewtron to look after him. A business associate had the same experience the same day on the same route, but on a different flight. Curious.  [Note to self: Bring meds on trip.]  

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.

==========

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.

Good Customers and Bad Customers

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Even the biggest pollyanna in the sales group will discover one day that it is possible to have a bad customer.  Yes Johnny, it is a fact that not all customers are desirable.  Oh I know, in sales one is always rabid to close the deal. Get the sale and move on to the next prospect with a pulse. But what is the difference between a good customer and a bad customer if their money spends the same?

Ideally, a “Great” customer comes back for repeat business, is flexible on terms and conditions, pays 30 days net, gives long lead times for delivery, accepts FOB terms, accepts delays and price increases without protest, and picks up the dinner tab when out for a visit.  [~~Sound of needle scraping across phonograph album~~]

If only such compliant customers existed (Sigh).  In reality, most chemical customers are in what I would call the “Good” category.  That is, they have reasonable expectations of price and delivery as well as an understanding of what constitutes fair business practice.

But on occasion one runs into what you might call a “bad” customer.  Such customers are found across the entire spectrum of size and business model. 

A bad customer is one that consumes excessive resources during the course of service.

A small bad customer might want you to do free product development for them, or may try to negotiate bulk pricing only to turn around and try to get bulk pricing on small quantities. Bad customers may finagle front-run samples from you and then disappear for months or years without a peep.

Large bad customers like to throw their weight around.  They know they are above you on the food chain and behave accordingly.  They dangle promises of big and long term sales and wangle free services from you. Services like gratis process development, holding inventory for free, tolling or other business agreements that tie your hands and force you to open your books for their auditors.

Bad customers large and small have other maddening habits that consume resources.  Specifications that change over time, always to the side of higher stringency, are a favorite of bad customers.  Bad customers will discover that they can shave costs by elaborate just-in-time delivery schemes with favored shippers, a circumstance that will require full time attention by logistics people and production managers.

Bad customers want the transaction to follow their particular terms and conditions. Bad customers will want 60 days net- a particularly transparent scheme to float their resources in interest bearing accounts while the vendor has to finance manufacture up front.  The fetid odor of MBA finance people lingers here.

Bad customers will want their vendors to provide indemnity to shield them against any conceivable liability related to the product.  Bad customers will want to own any and all inventions pertaining to process improvements relating to the product. They’ll want to be free to take this improvement and hand it to your competitors in order to generate a tidy little bidding war over their business. 

Practices that I have been calling “bad” are generally accepted in the business world.  On the buy-side they are considered good practices.  On the sell-side they are arguably bad practices because they increase risk and expense related to the transaction. A good buyer tries to implement these bad attributes.  A good seller tries to eliminate or minimize these bad attributes. 

In the real world, one rarely has the option of walking away from bad customers.  But it is possible to stand firm and prevent profit erosion.  Very often a customers apparent demand is just a straw man.  If not entirely a bluff, it might be negotiable to some reasonable concession.  The best practice is to be up front with your concerns and communicate with the customer. They are nearly always reasonable.

The 80/20 rule often applies to customer service:  20 % of your customers will take 80 % of your time. This is life in the fabulous world of sales.  Every sales person must eventually come to terms with it.  Sales consultants talk about “qualifying” sales prospects, but that only applies to real estate and vacuum cleaners.  The world of custom business-to-business chemical sales is such that if someone can identify your product and seek your services, they are almost always a legitimate player.

National Aphorism Day

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Below are a few quotations that patch together is a particular way.  

Here is a great quote lifted from the internet. With any luck it is accurate-

 “They lied to you. The Devil is not the Prince of Matter; the Devil is the arrogance of the spirit, faith without smile, truth that is never seized by doubt. The Devil is grim because he knows where he is going, and, in moving, he always returns whence he came.” (Umberto Eco, The Name of the Rose)

Here is another good one-

“When a government is dependent upon bankers for money, they and not the leaders of the government control the situation, since the hand that gives is above the hand that takes. Money has no motherland; financiers are without patriotism and without decency; their sole object is gain.” (Napoleon Bonaparte)

And then there is this-

“Ask a Soviet engineer to design a pair of shoes and he’ll come up with something that looks like the boxes that the shoes came in; ask him to make something that will massacre Germans, and he turns into Thomas F–king Edison.” (Neal Stephenson, Cryptonomicon)

Neal Stephenson’s book, Cryptonomicon, is quite good though ponderously large.

B-24 Liberator in the Morning Sky

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This morning while on a pleasant bike ride through the countryside I chanced to hear a familiar rumbling noise.  Not seeing anything immediately, I stopped to look at a pony and a mule that had gotten loose from a pasture.  Moments later, over the cottonwood trees there appeared a B-24 Liberator flying overhead not more than 1000 ft above ground.  This is something you don’t see every day. 

Turns out that the owners of this aircraft were flying out of a local airport over the holiday selling $400 rides in this lumbering relic of another age.  Hell, if I could justify it to my wife, I’d have taken a ride too.

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.