In the early 1800s, a chemical compound known as salicin was first isolated from willow bark. Salicin is a close structural analogue to aspirin and is converted into a precursor (salicylic acid) to aspirin upon being metabolized in the body. The reaction scheme is shown below. In reality the hydrolysis and oxidation steps may be reversed, but the below scheme summarizes the gist of the reaction.
Purified salicin and salicylic acid started to be used in the late 1800s as pain relievers, but a significant drawback was that these compounds were severely irritating to the stomach. It was eventually found that if salicylic acid was acetylated, the resulting compound (aspirin - i.e., acetylsalicylic acid) was much more tolerable to the stomach, and thus the miracle drug aspirin was born.
Aspirin appears to have been first synthesized by Charles Frederic Gerhardt in 1853, but Gerhardt apparently did not market the compound, nor use it in any way as a medical treatment. However, in 1897, a German chemist working for Bayer named Felix Hoffmann synthesized aspirin in a Bayer laboratory and recognized its potential as an analgesic/antipyretic drug. Aspirin was the name for the drug originally coined by Bayer, and was actually trademarked at some point, but Bayer eventually lost the rights to the Aspirin trademark for various reasons. This loss of rights to the trademarked name is the reason why you can go out to the store today and find the name "aspirin" on every bottle of the drug, including generics.
Dr. Felix Hoffmann filed a U.S. patent application directed to acetylsalicylic acid (aspirin) on August 1, 1898, and the patent issued on February 27, 1900 as U.S. Patent 644,077. Interestingly, aspirin was ineligible for patent protection in Germany, and a patent was briefly granted in Britain before being overturned a few years later. Perhaps the fact that that the compound was known from Gerhardt in 1853 and Kraut et al. in 1869 (see below) was the reason these European countries would not allow aspirin to be patented.
Hoffmann's U.S. patent claims aspirin itself, i.e., the article of manufacture, instead of any method of making or use thereof. The claim is as follows:
Hoffmann proceeded to discuss the results of various tests he performed on his own acetylsalicylic acid compared to the results of the same tests reported in the journal article by Kraut et al. The results of these chemical tests suggest that Kraut et al.'s product was mainly salicylic acid (without explicitly stating as much), whereas Hoffmann's product was the acetylated version of salicylic acid, i.e., acetylsalicylic acid (aspirin). Given the facts set forth in two court decisions (discussed below), it is likely that Kraut et al. had actually produced a mixture of salicylic acid and aspirin, perhaps weighted more towards salicylic acid.
In the Hoffmann patent, it is noted that Kraut et al. reports that boiling their product in water, even after a long period of time, does not produce acetic acid, whereas Hoffmann states that his product does produce acetic acid upon boiling in water. Of course, in this test the acetyl group in Hoffmann's aspirin hydrolyzes to form salicylic acid and acetic acid, whereas Kraut's compound apparently does not have an acetyl group. Next, Hoffmann reports that mixing Kraut et al.'s product in an aqueous solution of ferric chloride results in a violet color (a well-known test for the presence of phenols), whereas Hoffman asserts that an aqueous solution of his product with ferric chloride does not turn violet. Salicylic acid has a free phenol, whereas aspirin does not (it is acetylated), such that the results of the ferric chloride test are reasonable. Last, Hoffmann notes that Kraut's "body" solidifies at around 118 C upon cooling from a melted state, whereas Hoffmann's product solidifies at a much lower temperature of 70 C. Hoffmann concludes that "[i]t follows from these details that the two compounds are absolutely different." Since NMR and mass spectrometry had not yet been invented in 1900 (or at least not yet in use as the analytic tool we know and rely on today), the foregoing tests described in the Hoffmann patent were all he could really rely on.
The Hoffmann patent has a litigious history. Around 1909, the patent owner Farbenfabriken of Elberfeld Co. (a precursor company of Bayer) sued Edward Küehmsted in District Court for infringing the aspirin patent. Küehmsted contended that aspirin was a known compound that was disclosed in Kraut et al., and thus the aspirin patent was anticipated by Kraut et al. and therefore invalid. In a decision that was issued on August 11, 1909 (171 F. 887), the District Court upheld the validity of the aspirin patent, found that Küehmsted infringed the patent, and issued an injunction against Küehmsted. Küehmsted appealed to the Seventh Circuit Court of Appeals in 1910. Interestingly, the District Court's decision references the events pertaining to an English patent on aspirin:
An English patent on the Hoffman invention was taken out by one Newton December 22, 1898. In 1905 an infringement suit was heard in the Chancery Division of the High Court of Justice before Mr. Justice Joyce, and resulted in the patent being declared void for anticipation. From the evidence in that case the court found that:The District Court, however, found that the facts of the English patent differed from those of the U.S. case, and even if the facts were the same, the differences between the patent laws of the U.S. and England precluded attributing any authority to the English court's decision.
"The crystalline mass is substantially acetyl salicylic acid. Almost the whole of it is the compound acetyl salicylic acid completely formed. For practical purposes the whole may be taken to be and be used as acetyl salicylic acid. Its general and therapeutical characteristics are the same those of pure salicylic acid."
Upon appeal in the U.S., the Seventh Circuit affirmed the decision by the District Court. The Seventh Circuit's decision (179 F. 701) issued May 11, 1910 contained two concurring opinions from Circuit Judges Grosscup and Kohlsaat (apparently the third judge on the panel, Baker, dissented). The court's decision is an interesting read and essentially held that Hoffmann's pure form of aspirin is useful as a therapeutic agent, whereas Kraut et al. likely produced an impure form of aspirin that could not be used as a therapeutic agent. Thus, Hoffman's pure aspirin is patentable over the aspirin gemisch reported by Kraut et al. A fitting soundbite from the decision is as follows:
Hoffmann has produced a medicine indisputably beneficial to mankind - something new in a useful art, such as our patent policy was intended to promote. Kraut and his contemporaries, on the other hand, had produced only, at best, a chemical compound in an impure state. And it makes no difference, so far as patentability is concerned, that the medicine thus produced is lifted out of a mass that contained, chemically, the compound; for, though the difference between Hoffmann and Kraut be one of purification only - strictly marking the line, however, where the one is therapeutically available and the others were therapeutically unavailable - patentability would follow. In the one case the mass is made to yield something to the useful arts; in the other case what is yielded is chiefly interesting as a fact in chemical learning.It appears the Seventh Circuit's decision on the patentability of a pure compound over an impure compound was nowhere near the first of its kind, at least in view of the various other court decisions cited as support in both the Seventh Circuit's and the District Court's opinions in this case. Even today, a pure product can be patentable over a prior art impure product, provided that the pure product is unobvious (see M.P.E.P. 2144.04 (VII)).
Aspirin has been the subject of many patents over the years since Hoffmann's first aspirin patent. A brief Google Patent search for aspirin (or variations thereof) in the titles of issued patents and patent application publications turns up around 3,300 hits (not a perfect measure, but it'll suffice). Many of these applications appear to be directed to increasing the stability of aspirin, creating an aspirin pill with desirable release characteristics (e.g., sustained release), and/or an improved production method.
One of the most recent issued patents directed to aspirin (US 8,017,368, issued September 13, 2011) claims a method of permeabilizing a cell membrane with aspirin in order to allow molecules not normally able to cross a cell membrane to make it across. Apparently after the cell membrane has been permeabilized with aspirin, the integrity of the membrane is regained. The examples demonstrate the success of this method using the fluorescent molecule calcein (easy to track in the experiments), but the patent notes that this method could work with other species, such as elements, charged species/compounds, chemicals, drugs, proteins, and nucleic acids.