07-15-04 23:27
No 519651
A question that interests Lego for quite a long time.....
One the one hand the ethics and laws of patent regulation forbid to patent impossible or not working procedures and
on the other hand some procedures from patents don't work as advertised and a guy from a chem company told Lego that they usually 'forget' the essential detail ("we don't want to inform the rival companies but to defend our territories").
So what is your opinion?
Does anybody have detailed information from within companies which are involved in patents?
Please don't post comments like 'I tried patent DE08150815 and it didn't work' as many of the experiments, especially the yields of the scientific literature are not reproducible too.
The tendency is to push it as far as you can
(Hive Addict)
07-15-04 23:41
No 519653
What I noticed frequently is that the older patents seem more reliable than the recent ones.
Also, there used to be stated in the beginning of the older patents: "...for which we pray a patent may be granted..." which seems to imply that it was not that easy at all back in the old days.
Now, when I see a patent can be granted for something like this: Post 473601 (Vitus_Verdegast: "Hallucinogen Genus Mixtures from Great Britian", General Discourse) I really doubt what remains of the ethics of patent regulation.
It is understandable when you see how much more patents have been filed the last twenty years compared to the rest of the century. Obviously this makes it also harder to verify the integrity of each patent application.
http://www.mindspring.com/~rathcoombe/ho
(Hive Addict)
07-16-04 08:30
No 519715
For the patents I have practically applied in my little lab, I must agree with Vitus, namely that I have the impression that older patents are "more reliable" than the newer ones. That, however, does not imply that the newer patents are bogus or phantasy. They usually contain the information you should use, but hidden between lines. They will give an example using acetone as a solvent, and it will have a great yield. You apply the method, and your yields are terrible. However, changing the solvent to methanol or ether might give you the "expected" yields. These kind of "catches" are usually hidden in the patent.
I have also read quite some weird things in patents, like e.g. extracting bromide from an aqueous solution with DCM. But I see this kind of bogus rather infrequently (but others might see it all the time). What I see almost in all new patents is that they apply "unnecessary steps" in their procedures, of which I'm sure they didn't do it that way in their lab. For instance, adding A and B in a RB and reflux for 2 h before adding C (while you should add them all three at the same time), distilling with Vigreux colomn (while a simple distillation setup is sufficient), ... It may suffice to follow the patent once as described, and if you have a reasonable amount of practical laboratory experience, you will automatically adapt the patent procedure. A very good example that can be found here on The Hive is the synthesis of 3.4-dihydroxy-5-methoxybenzaldehyde from 5-bromovanillin (or 5-iodovanillin), where they use 16-24h continuous extraction to obtain the desired compound. But you can simply extract it with a few portions of warm DCM or toluene.
And that does also agree with the information I get from people involved in patent publishing. I used to know a few people who own a few patents, and they just give a synthetic procedure that works but they keep the optimal procedure for themselves. They will cover for their procedure in the patent by e.g. stating that other polar solvents than the ones applied in the examples fall within the scope of the patent.
Aztecunnilingus Maximus
(Hive Bee)
07-16-04 12:01
No 519738
I have also read quite some weird things in patents, like e.g. extracting bromide from an aqueous solution with DCM.
Perhaps they meant removal of Br+-ions with DCM - common method for anorganic cation analysis..
But I think too that the important details of patents are often hidden between the lines and require reading the text several times to get the relevant facts..
And that does also agree with the information I get from people involved in patent publishing. I used to know a few people who own a few patents, and they just give a synthetic procedure that works but they keep the optimal procedure for themselves. They will cover for their procedure in the patent by e.g. stating that other polar solvents than the ones applied in the examples fall within the scope of the patent.
Although I don't know any patent owners - that's exactly what I experienced too with patented procedures.. (and newer patents are generally more vague than the older ones, sadly!)
But this is the point where THE HIVE usually comes into play, right?
Greetz, A
"..ein Trank von unterschiedlicher Farbe, in ihm ist Heilung für die Menschen."
(Guardian)
07-16-04 15:25
No 519750
I know a women that is the Principle inventor for over 20 patents. I have noticed that many of the procedures that were described in the patents were copied directly out of a unseasoned technicians laboratory notebook. There was such a rush to get the patent application in that there was no "expert review" of the patent. Just after a brief review of one of the patents I noticed errors such as wildly incorrect terminology, and volume errors i.e. 100mL instead of the proper 100µl. It was not the intention to mislead our competitors just shoddy procedure review from someone that was even less well versed in the subject.
The company has around 100 patents over the last 15 years, and I can also attest that over that short period of time the quality has decreased exponentially. The reason for this I believe is because up until the last four years the company had the money to employ a battery of experts in the field, M.D.'s seasoned PhD's, and people with 10+ years industry experience (we are in a fairly new industry). The patents written back then were flawless, well written and reviewed with a fine tooth comb. The patents that are written now are written by people that are not experts, do not have experience, and most of the patents are usually ripped off in one way or another from someone else. The legal difficulties we have been experiencing from the patents written in the last three years have probably outweighed the legal difficulties that were experienced in the twelve years prior to that. The reason is because without true inventors around, the company has been more or less using everyone elses technology and with the aid of a patent attorney with experience in our field they are able to change the invention just enough to get by. That of course does not always work.
I also find that we are putting more time into challenging competitor patent applications, instead of using our brains and time in order to invent something on our own. This is a very sad way to operate a business. In essence a competitor puts the time and resources into inventing a process and it works very well. Instead of our company respecting that and licensing their process or even spending the time on inventing a process that works better than theirs we waste time and money trying to prove that their patent was "common knowledge" (that is not the term they use it escapes my mind at present).
The pressure from executive management to produce new products and patent processes as fast as possible, utilizing the least amount of resources, has a negative effect on the quality of the products and the patents. I assume that this may be the trend in almost all industries. And that is what I have to say about why patents have gone down hill as of late. Just my thoughts...
regards,
m_e
Unipolar Mania, It's good for life...
(«
»)07-17-04 15:58
No 519893
(Rated as: excellent)
Many bees have reported interesting and strange details to the patent literature, both new and old.
In regards to inventions of mechanical or industrial processes, such as a new method for eliminating pollution from contaminated sites, such examples of the patent literature fall a bit short of detail. This may occur for any number of reasons, the most typical ones perhaps surrounding the necessity of providing limited information about the process, construction, and overall function of the invention itself. My guess is that the vagueness in detail of many current inventions is for the purpose of securing the potential profits said invention may yield through it's application in the global market.
But patents detailing standard chemical processes, such as a new reaction protocol for synthesizing any one of many commercial reagents or substances, typically seem to be quite accurate in that they appear to have only a marginal promise of profitability, and seem more an extension of the inventor's desire to report and promote his/her/their most recent contribution to science. In short, these patents, both new and old, oftentimes are very detailed and, at least on the surface, appear to be accurate, and according to heresay, generally provide positive results.
However, patents detailing potentially "controversial" inventions--that for any one of many reasons, political, scientific, ethical, or perhaps even those based on someone's desire to "hint" to possible future buffs of patent history that they, the researcher, author, transcriber, or sponsor of the patent, knew more about the particular invention in question and, equally importantly, about the manner in which it was published--seem to retain an air of mystery that perhaps the typical casual reader who tends to refrain from probing and asking questions, would miss.
My point is quite simple: Many patents (and scientific articles as well) that I have read have strangely been marred by errors which seem difficult to dismiss as simple oversights. Since the primary focus here at the Hive is to explore various aspects to the drug phenomena, I will cite just a few examples of particularly strange errors in the pharmaceutical and chemical patent literature, that, to the best of my memory, are inexcusable as common and so-called expected "mistakes".
The Parke-Davis U.S. Patent detailing the synthesis of l-methcathinone from l-ephedrine indicates an over-usage of sulfuric acid in the chromic acid oxidation phase. I believe the required decimal point that would have accurately indicated the correct volume/weight of sulfuric acid required to prepare the Jones Reagent, is missing. To the inexperienced experimentor, following the instructions in the patent to the letter/number would likely, as has unfortunately been reported here at the Hive numerous times, lead to an overly acidic reaction which would in turn would make the subsequent processing and purification steps difficult.
Also, it has been reported time and again, that the 4-6 hour length of time mandated in the experimental section of the patent will NOT be enough for the oxidation to reach completion. In other words, an excessive amount of starting material (l-ephedrine, in the case of both the British Patent and U.S. Patent) would be present in the final product in what would likely be in an unacceptably and potentially dangerous excess.
Furthermore, the danger of condensation of two methcathinone base molecules to form the pyrazine derivative is not even hinted at in any of the three patents. This, I suspect, is either because the pyrazine would naturally be expected to be removed by a skilled experimentor through common prudent purification steps accompanied by the appropriate use analytical devices to determine purity. In this light, it is possible that the authors of the patents did not care about--or possibly were not even aware of--the ramifications the pyrazine contaminant would have on the future problem of social methcathinone use/abuse in what is, and has been, and will likely continue to be for quite some time, a drug prohibitionist society. Either way, the authors of the U.S. Patent, at least--if so inclined, and if they were alive--could argue that the inconsistencies found in the final draft of their published patent were a result of their commitment to and respect for the former literature from which they obtained their information, and that, in their view, at least, the simplist explanation to the issue of misreporting, is that they--the reseachers from Parke-Davis--directly copied their information from the previously published British Patent, detailing the same reaction scheme in the same vague and inaccurate way.
The British Patent--again, if I remember correctly--is focused primarily on the chemisty and synthesis of l-methcathinone; the U.S. Patent, on the other hand, appears to actually be a report on l-methcathinone clinical trails with results of toxicity laboratory experiments performed on rats. Maybe the synthesis of l-methcathinone was published in the U.S. Patent just for the sake of maintaining an air of professionality, via, of course, the inclusion of a concise and detailed experimental section. For all we know, the U.S. Patent research staff may have gotten their samples of l-methcathinone straight from the British. Huh. But I doubt that very much.
Strangely enough, the authors of the British Patent got their information from, I believe, a German Patent detailing the synthesis of l-ephedrine from the chromic acid oxidation of d-pseudoephedrine, which was then subsequently reduced by sodium metal (I think) to the l-ephedrine. Basically, the patent is a synthesis of l-ephedrine from d-pseudoephedine. I've done the math, and the exact same proportions of reactants are used in the German patent as are used in the British and U.S. Patents. The only difference is that the German patent uses both a much larger scale of reactants and a standing--yes, STANDING not STIRRING--reaction of six or so days as the time interval required to complete the chromic acid oxidation. The yield was reported to be about 80% l-methcathinone, which actually represented the intermediate to the final l-ephedrine product, which was the main focus of the patent.
The British patent and the U.S. patent use stirring for a 4 to 6 hr period of time to complete the oxidation of l-ephedrine to l-methcathinone. Strangely enough AGAIN, no yields are reported.
According to the much more detailed process of chromic acid oxidation of both ephedrine and pseudoephedrine as reported in the 1994 volume of Journal of Chromatographic Science (J. of C.S.)--I'll get the actual paper later for more details--the chromic acid oxidation should proceed through stirring of the reaction matrix for--if I remember correctly--12 to 18 hrs. However, in the J. of C.S. report, seemingly more useful experimental details are offered that, at least on cursory inspection, appear to fill in the gaps and limitations of the three former examples cited in the patent literature. In point of fact, the suggested reaction time, the purifaction protocol whereby the toluene solution is gassed by anhydrous HCl, distilled off under vacuum until a small quantity of toluene and the solubilized methcathinone-HCl is left. Then, the solution is quenched with anhydrous ether and the precipitated product filtered and recrystallized with IPA/acetone. This report is quite detailed compared to that reported in the former literature. It unfortunately is devoid of the unquestionably beneficial step of adding a minimal quantity of IPA to reduce the excess chromic acid to the amphoteric chromium hydroxide. The completely uniform green or blue solution can then be basified to liberate the methcathinone free base, a step which will also simultaneously solubilize the chromium hydroxide formed. Unfortunately, in lieu of this step, the author of the J. of C.S. adheres to the classic method of basification which, at the completion of the reaction, causes the time and again reported--inconvenient, and tediously removed--insoluble chromium hydroxide to precipitate out as a water insoluble chromium amphoteric hydroxide sludge.
Unfortunately, this article too offers what appears to be an erroneous and likely problematic step wherein a ridiculously excessive amount of sulfuric acid is called for (not a typo like in the British and U.S. Patents; merely a modification--a bad one, in my opinion, that would most likely be scorned by the Hive community at large). Why such a modification was suggested is certainly a good question as the recommended sulfuric acid concentration seems to be so excessive as to perhaps account for about more than 50% of the aqueous solution. As a matter of speculation, perhaps the authors of the J. of C.S. article were actually promoting a very prudent technique that would allow the overall chromic acid oxidation scheme to work in an optimal manner. Although this could be the case, it certainly doesn't look that way.
I would suspect that--based on the current knowledge of the general chromic acid oxidation--the quantity of sulfuric acid called for in the J. of C.S. periodical is either an accidental or intentional mistake. Perhaps in the instances so far mentioned, the authors have been, or presently are, either sympathetic or hostile to the cause of drug experimentation and research; therefore it is logical to assume they possibly had the wisdom to foresee both positive and negative commercial applications of their research.
Or perhaps, even more interestingly, the authors of the publications in question reported their information in such a manner that would allow only those individuals who were both knowledgeable, skilled, and qualified to "read between the lines" and make the necessary inferences about the patents secrets, thus implying the need to take certain productive and intelligent steps based on the available evidence.
Another simple yet compelling theory is that the authors of such patents and scientific articles--then as well as today--are bound by some governmental type of limitations in terms of how the experimental segments of scientific papers (particularly those written about the subject of illicit or potentially future illicit substances) are to be reported. Such a model would obviously favor qualitative evidence as the primary focus of scientific research while quantitative evidence would either be marginalized or altogether absent.
And last but not least, maybe the inventors of said erroneous patents were (are) just lazy about dotting every "i" and crossing every "t", and simply didn't catch the typos. However, in all honesty, I find this last possible explanation hard to swallow as the typo in question had appeared more than once (as a reminder, in both the British and U.S. Patents). The recurrence of such a big mistake, which would obviously affect the outcome of just about any application to research of the information contained therein, would obviously, at the very least, cause time consuming and costly mistakes, and at most, cause harm to a potential experimentor wishing to reproduce the results of the patent's claims.
To me, the whole thing smakes of some undisclosed political or ethical agenda, dating back all the way to the earlier half of the twentieth century.
BTW, this is a little off the subject,but I thought it worth mentioning that the molar ratios of the dichromate oxidation used to convert l-ephedrine/d-pseudoephedrine to l-methcathinone are completely equimolar to eachother in all three patents, meaning that just enough sulfuric acid is added to the sodium or potassium dichromate to make just enough chromic acid to oxidize the exact amount of ephedrine/pseudoephedrine in solution.
As for the stereochemical consistency of the dichromate oxidation of ephedrine/pseudoephedrine, it is correctly reported in the J. of C.S., but suspiciously incorrectly reported in the J. of Forensic Sciences article covering the subject of methcathinone also indicated to be known as "Jeff", "Mulka", and "Ephedrone". It would seem, therefore, that a 100% yield from this reaction would be out of the question, as much of the chromic acid oxidant is reported to consume much of the desired methcathinone product, accounting for the 20% excess of the ephedrine enatiomer starting material left over. But, on the good side, l-ephedrine (1R,2S) and d-pseudoephedrine (1S, 2S) DO both in fact yield, upon direct oxidation with any number of oxidants, the more potent levo isomer of methcathinone. Racemization can occur due to the enolizable carbonyl group, but harsh reaction conditions and/or strongly basic conditions would have to exist for this to occur. This is merely interesting as this property is very much akin to the reduction of ephedrine/pseudoephedrine to the stronger dextro isomer of methamphetamine, in that the enantiomers, ephedrine/pseudoephedrine, upon clean oxidation or reduction, yield only one isomeric product, namely the most potent one.
More interesting but possibly irrelevant and off-topic information for the Hive masses:
Accidental application of excess sulfuric acid in dichromate aminoalcohol oxidations to aminoketones and the subsequent attempt to remedy the situation by basifying a bit to compensate for said excess, and then extending the length of the reaction to twice the amount indicated to compensate for the excessive volume of liquid in the reaction matrix, has been reported to lead to low yields and difficulty in reducing, at the end of the reaction, the excess chromic acid in solution with the standard application of a minimal quantity of 2-propanol (IPA). Surprisingly, and symptomatic of this particular problem, is that the solution does not change its appearance in color to that of the expected opaque green or opaque blue in the expected amount of time (2-3 minutes). Furthermore, the subsequent basification step is rendered difficult due to the formation of solids, most likely the typical insoluble chromium hydroxide salts that normally accompany the classic basification method to the aminoketone base liberation/isolation step essential to this and pretty much any other general alkylamino/aminoketone synthesis.
The above mentioned problem is reported to normally be avoided by the simple use of the appropriate ratio of reagents to that of the substrate (everything appears to be equimolar, according to former calculations). Also, the exact amount of sodium hydroxide required to effect basification (the details of which are absent in all of the patents) falls somewhere--again, according to previous reports--to a dramatically lesser degree than has been both assumed and even reported by members here at the Hive. I believe I read somewhere that the proper amount of base--for both the British and U.S. Patent basification step--is somwhere around 2.1 g of sodium hydroxide in enough water to form a 20% solution. This amount--I'm going by memory as I read these figures a long time ago--is necessary for either every 1 g of sodium or potassium dichromate or for every 1 g of aminoalcohol-HCl used in the oxidation reaction. I don't remember which. More research in this area is obviously called for.
I obviously got sidetracked from the main topic of this thread, but I do have other striking examples of perculiar errors in the patent literature and a host of wild theories as to why they made it to final publication. But I'm tired of typing, so that part of my report will have to wait for now.
Until sometime in the near future, use your time wisely and respond to my post. And, of course, take care!
PK
(Hive Bee)
07-19-04 00:00
No 520147
Starlight: Thanks for the detailed discussion of the patent literature of the cathinone synthesis, it could bee a topic on its own.
Lego asked another guy who is responsible for a lot of patents and he said that the procedure must bee reproducible by an expert. This is an important point as an expert on the topic covered by the patent will immediately see the errors, like mixing µl and ml. He also said that the reproduciblity of the patent strongly depends on the company, he mentioned a big chem company which patents can bee used straigt as they are without any problems, but this is an exception.
Therefore Lego suggest that patents mentioned in the Hive should bee read very careful (posting the experimental details and not just the abstract reaction scheme) and discussed before tried to avoid unnecessary errors.
Another point is the thing Starlight mentioned about patents and drugs of abuse. Lego doubts that there is a special unwritten rule to add an error knowingly in order to confuse the illicit cook. The abusive potential of a substance is usually discovered after its commercial breakthrough. Therefore Lego assumes that the errors in 'drugs of abuse' patents are not different than in other chemical patents.
The tendency is to push it as far as you can
(Hive Bee)
07-20-04 15:00
No 520409
Another point is the thing Starlight mentioned about patents and drugs of abuse. Lego doubts that there is a special unwritten rule to add an error knowingly in order to confuse the illicit cook. The abusive potential of a substance is usually discovered after its commercial breakthrough. Therefore Lego assumes that the errors in 'drugs of abuse' patents are not different than in other chemical patents.
I think the existance of such a "rule" might be true for patented improvements of older methods, i.e. newer patents - its probably the reason why older patents usually work better than newer ones - back then, when they were applied, the substance in question usually wasn't already known to be a drug - so no errors were put in...
(with newer patents, I can very well imagine they "modify" the procedure with the intention to prevent use in drug manufacture - if the inventor knows that the compound in question may related to illicit drug synthesis, or better said if a previous patent is well known for its use in clandestine chemistry, the inventor of a new procedure might want to avoid such use of "his" procedure, by confusing the clandestine chemists a bit..)
Take for example methylamine production: I BET every new patent about its synthesis is subject of DEA investigation, due to MeAm's use in meth production...
But I also bet there was NO investigation whatsoever back in 1928, when this procedure Patent DE468895 was patented - there was no DEA back then...
Greetz A
"..ein Trank von unterschiedlicher Farbe, in ihm ist Heilung für die Menschen."
(Hive Bee)
07-20-04 15:31
No 520412
Take for example methylamine production: I BET every new patent about its synthesis is subject of DEA investigation, due to MeAm's use in meth production...
No way... Methylamine is too trivial a chemical. For a Hive bee it is easy to start thinking that every chemist is always thinking of applications related to making drugs which most likely is a false assumption. P2P might arguably be a different story, but really, in the end the world does not revolve around our way of seeing things. The forensic science journals do that as a profession and the chemical suppliers are forced to do that.
fear fear hate hate
(Hive Bee)
07-20-04 18:36
No 520434
For a Hive bee it is easy to start thinking that every chemist is always thinking of applications related to making drugs which most likely is a false assumption
I'll bet there are literally thousands of drugs which could be 'interesting' in our view. There's more which fits in our brain than only meth. I'd love to wonder through the archives of SmithKlineBeecham. Who knows what treasures are lying there, waiting to be discovered.
07-21-04 04:02
(Rated as: off-topic)
(Stranger)
07-21-04 14:02
No 520589
For the patent as I think is an essential tool for companys or scientist to protect their synthetical way and products. This is the first thing that the "patent" to do. And instructed with this principle no one will tell the rival the essential details.
Its' not to say that their is nothing to get from the patent.First it give you the approximately process.Second as a "Rival" you should boldness dope out the way and to try.Recent I synthesize an compound consult a "Merck Inc" patent, the patent describe that first treat the benzene and then deal with ether... , I do it like this and obtain very pure product but very very low yields.Instantly I just use the water instand of benzene and ether,after that I obtain high yield with the some purity.
So,my opinion is treat the patent as a guidance rather than a "book"
<my english is not very well
>
Fang.Sh
(Stranger)
08-01-04 07:44
No 523039
I did not take a look at the patents in question, but some things to consider:
The patent must be "enabling" for someone "skilled in the art" (of chemistry) to reproduce the process or product (depending on the claim) without "unreasonable experimentation."
Another thing to watch out for is the use of patent language. Notice that in chemical process patents there is often terminology such as "essentially consisting of" and qualifiers like "no more than about." These are not mistakes: the process claims are meant to be as broad as possible and be accurate enough so that someone "skilled in the art" would not require "unreasonable experimentation."
The thing about patents is that the specifications are only for the purpose of enablement and to support the claims. If the temperature or concentration is specified in a claim, than it will be accurate. If not, than the patent is worthless as it does not exclude others from the right to use, make, produce, etc. the process or product.
Chemical process patents have their own language as, unlike mechanical and electrical (the "predictable sciences"), chemistry is rather unpredictable; therefore, claims are made for products by the process by which they are made, seperate rules apply for groupings of elements in a claim, etc. Without looking at the patents in question I can't really tell you what is going on, but my guess is that if the specification isn't enabling, the patent is worthless, and there is no reason to waste the thousands of dollars to submit it.
stabmaster<--- biochemical engineer and patent agent :)
Sometimes I think I'd be better off dead. No, wait, not me, you.