An Inconvenient Truth about Canadian Patent Law.

The Skilled Addressee in Pharmaceutical Patents

The readers of pharmaceutical patents are not technicians, hobbyists, or simple baccalaureates.  The addressee is not a person with sophisticated manual dexterity and a recollection of all relevant patent disclosures but without a whit of creativity, as the patent law assumes; but a team of information specialists, lawyers, medicinal chemists, doctors, organic chemists; in fact, a team comprising whatever skills are needed in order to properly understand the content of any document that pertains to a medicinal agent.  In particular, the medicinal chemists and organic synthetic chemists, who mostly have interests in pharmaceutical patents, are inventors themselves with well established creativity.

The patent system provides a 20 year monopoly in exchange for a public disclosure of truly breakthrough discoveries of new classes of medicines and with this I have no quibble.

  

However, at the same time it gives 20 years exclusivity for many mundane workman activities which do bring into existence for the first time new subject matter but this information follows inevitably from conventional scientific developments.  Examples of these activities are the discovery of the various polymorphic forms, hydrates, and solvates of a new drug substance and its pharmaceutically acceptable salts. 

Another example of an undeserved patent monopoly is the formulation of such new pharmaceutical salt into a dosage form that has acceptable dissolution in stomach acid that it can serve as an immediate release tablet candidate. Another undeserved patent subject is the formulation of a pharmaceutically acceptable salt into a standard delayed-release or enteric form.  Both these are almost always activities which can be worked out by routine investigations following pre-planned protocols.  There are some particularly difficult instances when a creative solution is required to solve a formulation problem and a patent would be warranted but the putative inventor should be called upon to show to the patent examiner evidence that the standard procedures would not produce the required result and the successful assignee of a granted formulation should be required to forfeit any patents for the formulations that are claimed to be inadequate.

The Common General Knowledge

The law has accepted today that the skilled addressee is actually a team as assembled by a pharmaceutical company.  The natural of the common general knowledge which is allowed to be combined with some prior art in order to assess obviousness has not kept up with the concept of the addressee as a team of inventors with advanced degrees who have access to computer driven scientific literature searching machines. The concept of the common general knowledge is still valid. What is intended is that this common general knowledge is information that is already memorized and available to the reasoning process in the head of one member of the team  That is to say, for example, that knowledge of a particular chemical reaction that is known to PhD organic chemists would be considered part of the common general knowledge.  Thus the common general knowledge would be a function of the graduate curriculum for the specialist who eventually obtains a PhD in the discipline.

The existence of a published protocol for solving the standard problem: making polymorphs, making pharmaceutical salts, formulating a n immediate release tablet, making a delayed release tablet, making an extended release tablet should vitiate claims of creativity in performing these activities.

Purification of Chemical Products by Treatment with Mixtures of Solid Adsorbants: Identifying Useful Absorbants by a Combinatorial Method

Charcoaling as a means of removing small (<2%) amounts of contaminating substances from an organic preparation has long been known. Use of a plug of a solid adsorbant (such as silica or alumina) through which a solution of the slightly impure substance is passed for the purpose of purification is also long known.

There are other similar techniques. The use of these methods has been empirical, trial and error, one-at-a-time testing. In particular, the selection of a solvent to be used in combination with these solid adsorbants is empirical and this is a very real problem because it is often the combination of the correct choice of solvent and the correct choice of solid adsorbant, which produces the required purification.

Kilomentor now suggests the use of statistical methods and /or combinatorial chemistry to solve the problem. Thus although the problem has been long in existence, such a method has not been described and is not part of the common knowledge of those skilled in the art of purification.

The basis for the method---taking several agents and mixing together—is normally very limited because in the case of regular reagents, they as often interact with each other as they interact with the substrate,; however, it has long been known that polymers react extremely slowly or not at all with each other because of the ponderal effect. This has been shown most clearly with organic functionalized polymers (used in Wolf & Lamb reactions) but it can be inferred to be equally true with inorganic polymers such as carbon, silica, Florisil and alumina) for example.  As a consequence the effects of polymers on the removal of impurities from a dissolved sample can be expected to be purely additive. The dissolved substrate will move around between the two insoluble adsorbants with each adsorbant removing what it has attraction for from the solution.  Since the polymers cannot invade each other’s pores, they interact poorly with each other.

This being so, it should be possible to perform a trial separation to purify an organic chemical dissolved in a solvent by mixing the sample with a mechanical mixture of adsorbents such as Norit A, Darco KB, Celite, silica gel, alumina, reverse phase silica, clay, strong acid ion exchange resin, strong base ion exchange resin, macroreticular resin, Florisil, unfunctionalized DEG cellulose, calcium chloride, manganese chloride, lithium bromide or calcium bromide to name a few.   Obviously certain simpler combinations would be better to test. If upon filtration of the sample and reanalysis of the residue the offending impurity has been removed or substantial reduced in a relative sense the job is simply to deconvolute to discover the element or simple combination of adsorbant elements that has the effective action.  If there is no appreciable effect, there is a good likelihood that none of the members of the combination are excellent at the impurity removal.  Another combination of candidate adsorbants and another condition of solvent, temperature and time is tried until a useful positive result is seen.

For many years my research teams have combined Norit A and Darco KB for the purpose of checking on the ability of these carbons to decolourize slightly impure products.  This is my only experimental evidence that this methodology will work. But theoretically it makes sense.

It should be realized that macroscopic properties of the solvent medium such as pH will have their own interactions with each of the adsorbents.