History of Chemically Modified Cyclodextrins from a Patent Perspective No controversial patent issues surrounding the natural (, , and ) Cyclodextrins are noted in the literature. The technical literature discussing these compounds gradually filled with public domain information. In 1891, while working on rotting potatoes, Villier’s discovered ß-Cyclodextrins, so that over the next 70 years, it became increasingly difficult to avoid prior art in the scientific literature when contemplating patent applications. Most of the patents issued covered specific CGTases and processes for manufacturing the natural Cyclodextrins.
Early patents filed on the natural Cyclodextrins concerned methods for separating the three different Cyclodextrins that all CGTases made. The most useful patents for separating Cyclodextrins described methods that eliminated the use of non-aqueous solvents, and that used enzymes producing greater yields of a given Cyclodextrin.
The derivatives of the Cyclodextrins created the most interesting and controversial patenting situations.
As early as 1969, Corn Products Co. (CPC) in the US was issued patents in which hydroxypropyl derivatives of Beta Cyclodextrin were described (US 3,426,011). In subsequent patents CPC even alluded to complexes of these derivatives with chemicals, including drugs (US 3,453,259-1969, UK 1,193,197-1970). In 1971 Wiedenhof, in UK 1,244,990 described derivatives that resulted from the reaction of epichlorohydrin with ß-Cyclodextrin. In 1978 Boger, Corcoran and Lehn elucidated the “Selective modification of all primary hydroxyl groups of alpha, beta, and gamma Cyclodextrins in Helvetica Chimica Acta: 61; 203; p. 2190. In the 1980’s, Szejtli and his laboratory workers in Hungary identified the low molecular weight portion of the epichlorohydrin reaction with ß-Cyclodextrin as a hydroxypropyl derivative; this group also showed that this portion was able to complex drugs. In 1983, Craft and Bartsch in Tetrahedron: 39; 9; p. 1417 published a comprehensive collection of synthetic reactions by which Cyclodextrins could be modified.
An aside from the main point the author is making is that CPC did not follow up their early foray into chemically modified Cyclodextrins and even today (1999) they still do not manufacture Cyclodextrins. Also, Szejtli’s group in Hungary chose to pursue the methylated derivatives, which proved to be not as suitable for pharmaceutical uses as the hydroxypropyl derivative.
In any case, it appears that the literature cited above would make it obvious to scientists who were familiar with the art and literature surrounding Cyclodextrins that derivatization increased the aqueous solubility of the Cyclodextrins, especially ß-Cyclodextrin, and that this increase in solubility permitted greater amounts of hydrophobic drugs to be complexed. Not so! On December 20, 1984 a European patent application was filed and assigned to Janssen Pharmaceutica in Beerse, Belgium that claimed improved water solubility of the hydroxypropyl derivative of ß-Cyclodextrin with a greatly improved capacity for solubilzing highly insoluble drugs in water. A more general patent application claiming all derivatives of all Cyclodextrins with all drugs was filed in the US on April 25, 1985.
Credit must be given to the European Patent Office examiners who twice rejected all claims in the Janssen patent application. However, they lost all the kudos from here when they caved in to the irrelevant submission of appended data showing less hemolytic activity (a feeble effort to inject something new, useful and unobvious into the application). The obvious face – saving requirements of eliminating retinoids and all but methyl, hydroxypropyl, and mixtures of these two adducts do nothing to make the cave-in any more justifiable.
In the five years it took the Janssen folks to get their patent approved, the US Patent office was evaluating an NIH patent that didn’t belabor the obvious as the Janssen patent did, but was making very broad claims – “all derivatives of all Cyclodextrins with all drugs”. The US patent application did at least satisfy the novel, useful and unobvious tests for patentability in the explanation of the aqueous solubilizing enhancements created by Cyclodextrins. Amorphousness was the reason!
Note the differences in the two filing dates – Janssen, 12/20/84 NIH, 04/25/85. This 4 month precedence was seized upon by Janssen to institute an interference claim against the US Patent. Janssen’s attorneys were well aware that the rules for precedence in the US are different from those in Europe. In the US, ultimate precedence is given to the “first-to-invent”, while in Europe the “first-to-file” wins. It was clear early on that the resolution of this action would be in favor of the US for jurisdiction in the US. No matter, Janssen’s intent was to create enough legal uncertainty to inhibit any serious effort to develop Cyclodextrin containing formulations by rival pharmaceutical companies while Janssen worked diligently to perfect an oral formulation of HPBCyclodextrin with its antifungal, itraconazole. Janssen succeeded in delaying the incorporation of Cyclodextrin’s in drug formulations for 5-10 years; i.e. instead of not having commercial drug formulations containing Cyclodextrins until 1998, it is likely that there could have been several formulations containing Cyclodextrins in commercialized pharmaceuticals by the early 90’s. The losers were the end users who could have had much more efficacious treatments of their diseases sooner.
Credit must be given to Janssen, however, in the professional and thorough way in which they got their own antifungal formulation approved by the US FDA. They broke new ground with the US FDA and established standards for other pharmaceutical companies to meet in getting new Cyclodextrin containing drug formulations approved.
The controversy was not just US vs. Janssen. In early 1990 when the European Janssen patent issued, a German manufacturer of Cyclodextrins, Wacker Chemie, decided to defend its marketing position; they contended that the Janssen patent was not worthy of patentability and filed an opposition. By filing the opposition within 12 months of issuance, Wacker was able to contest the validity of the patent in all EPO Countries at once.
The research division of Wacker Chemie, Consortium fur Electrokemisch Industrie, had been developing Cyclodextrin manufacturing technology since the early 80’s. By 1990, the Consortium was manufacturing and selling commercial quantities of chemically modified Cyclodextrins, the most important of which was HPBCyclodextrin. Wacker initially felt that the Janssen patent was sufficiently weak that it could be substantially limited if not completely invalidated. If the opposition could be successfully executed at an acceptable expense, Wacker felt that its Cyclodextrin customers’ rate and volume of Cyclodextrin usage would increase enough to justify and pay back the legal costs.
It soon became clear how dedicated Janssen was to this quest of control of the patent rights to the particular chemical modification that produced hydroxypropyl ß-Cyclodextrin. The HPB patent became a classroom example of how even a weak patent can provide enough of a facade of proprietariness through dogged and relentless litigious activity to prevent outside development; a lesson in how controversy can be used to inhibit competition.
Wacker shortly made the business decision to accept the minimal restrictions offered by the EPO on the European Janssen claims. This decision was justified because Wacker had developed a proprietary position in the manufacturing of gamma Cyclodextrin and felt that this Cyclodextrin (and not ß-Cyclodextrin) is where it could better apply its funds in creating a market for proprietary GCyclodextrin products.
Perhaps Wacker would have persisted to an invalidation of the Janssen patent had they known that Janssen had already filed a patent that would inhibit Wacker from selling its hydroxypropyl BCyclodextrin in some parts of the world. In October of 1990 WO 90-12035 was published describing how BCyclodextrin could be regioselectively hydroxyalkylated by using known concentrations of base.
Here again we have an example of the loss of common sense in the application of patenting principles. The regioselective patent described the usual, well-known, and uniformly-practiced method of hydroxylating BCyclodextrin using sodium hydroxide and propylene oxide. The “new, useful, and unobvious” improvement was that the percentage of base used was now correlated to whether substitution took place on the primary or the secondary face of the Cyclodextrin molecule. Notwithstanding that these exact concentrations of base had been used in the previous 10 years of making hydroxypropylated Cyclodextrin’s; now that the concentrations were delineated in a patent, the owner of this patent could legally exclude others from doing what they had been doing for years prior. This is not the original intent of patent laws, but rather a common occurrence resulting from a creative legal interpretation.
As a result of this regioselective patent, Wacker discontinued sales of its hydroxypropyl BCyclodextrin to the US for several years in the early 90’s. Finally around 1996, Wacker convinced itself that common sense would stand up in legal proceedings and they again began supplying HPBCyclodextrin to the US.
One final example of the non-sensical convolutions that occurred during Janssen’s quest for patent control of HPBCyclodextrin and then we will leave this chapter of patent lunacy for history to digest into the expected products of digestion.
In the late 80’s, (approximately 1989), the NTIS (patent licensing arm for NIH) licensed the inventions described in US 4,727,064 (Pitha patent covering chemical modifications of Cyclodextrin’s for use with drugs) coexclusively to Cyclex, Inc. and Pharmatec Inc. At this time Cyclex was a desk in a room and Pharmatec was a small, struggling pharmaceutical research company. Pharmatec actively pursued obtaining the license, but the NTIS could not bring itself to grant an exclusive to a company like Pharmatec, whose prospects for success seemed so limited. So, Pharmatec brought Cyclex to the table and this satisfied the NTIS; the license was granted. At this time no other companies showed interest in the Pitha patent.
Within a year or two the NTIS was notified that Janssen had filed an opposition to 4,727,064 claiming that several of its claims infringed on claims made in its European patent previously issued. The argument was that since the Janssen European patent was filed before the Pitha patent, the offending claims in the Pitha patent should be invalidated giving Janssen worldwide rights to the inventions (primarily HPBCyclodextrin technology) so claimed.
An understaffed and underfinanced OTA legal staff enjoined the battle on behalf of the US.
To increase its chances of success, Janssen, a company with corporate offices in Beerse, Belgium, decided to create a New Jersey based sales office. This move is important because foreign companies are not allowed to purchase American companies when the object of that purchase is to obtain US patent rights owned by the purchased American company. Now, Janssen, a subsidiary of the US fortune 500 company, Johnson and Johnson, could claim that it was legitimately a US company and thereby was not violating the letter of US business law in acquiring Cyclex. The acquisition was made by Janssen so that now Janssen owned ½ the US licensing rights to a patent that it was opposing. They paid much too much for Cyclex, Inc.; but, bravo to Cyclex for being at the right place at the right time.
The real convolutions are soon to come. After about two years of legal fees, the OTA legal staff asked to meet with the coexclusive licensees of the patent that was being opposed by Janssen. The meeting had to occur separately between the OTA / Pharmatec and OTA/Janssen (remember Janssen had purchased Cyclex). The purpose of these meetings with the OTA was for the OTA to secure funding from the licensees to allow the OTA to complete the litigation that they were quite sure would result in getting the opposition thrown out.
What do you think Janssen said? Consider – Janssen was being asked to contribute financially to the legal costs that would invalidate its claims of legitimate interference. Have you ever heard of a legal action in which the defendant and the plaintiff are the same legal entity. Curious?… but it occurred. Further, the OTA promised additional licensing rights to the party that would agree to provide such funding. These additional rights were interesting because at this point the co-exclusive nature of the license permitted one licensee to exclude everyone else but the other co-exclusive licensee. A situation not very comforting to a licensee that one of the two co-exclusive licensees was negotiating with. The extended rights offered by the OTA to a donating co-exclusive licensee was that the NTIS would not consider for licensing to any other potential licensor (including the non-donating co-exclusive licensee) any HPB complex already submitted by the donating co-exclusive licensee. The legal enforcement of this arrangement was to be on a “trust-me” basis under the authority of the Director of the NTIS.
It was at this point that this author absented himself from further activity in these matters and embarked upon a sane, common sense approach to developing Cyclodextrin applications.