Section 7 Flashcards
What is a patent?
A contract between a state and individual(s) or company whereby the individual(s) or company has the right to exclusively benefit from the invention for a fixed period. This is in exchange for a full disclosure as to how the invention can be reproduced.
For a patent to be granted, what must the disclosure be?
Novel (i.e., never been done before)
Inventive (not obvious to one skilled in the art)
Not have been previously disclosed anywhere in the world prior to filing
Must have utility
What is intellectual property?
Creations of the mind, including inventions, literary or artistic work, designs, names etc.
How long does a patent protect an invention?
20 years from when it is filed
Why is the timing of patent filing crucial?
It is important to file a patent early in the discovery process if there is heavy competition in the area to prevent the idea being stolen. However, patents only last 20 years from filing, so by the time the drug comes comes to market and starts generating income, there may only be 7 years or so of exclusive profit left before competitors can produce the drug under a different/generic name and profit from it.
What is the breakdown of the average total cost of a patent?
£3-6k - application
£3-5k - Patent cooperation treaty (ensures patent protection in multiple countries simultaneously)
£4-5k filing in EU and US
£5l examination for EU and US patents
£20k translation fees for EU countries
£75k
What does a patent consist of?
- Introduction (technical field and background)
- Statement of invention (restates the main patent claims i.e., what it is and does).
- Detailed description (including fall-back claims and how to carry out invention).
- Worked examples - preparations and experiments which have been carried out.
- Claims - define the invention and define what the patent should achieve. Usually 1 broad generalised claim backed up by some narrower claims.
What are the different types of claims which can be made in a patent?
- Composition of matter claim/compounds per se - If a compound has never been described before it is possible to claim the compound (per se) and compounds similar to it. This claim will cover the compound in any setting, in any form and for any use.
- First medical use claim - if compound is known but not for medical use.
- Second medical use claim - if compound has a medical use but not for the one in the patent.
- Salt/crystalline form claim - entitles them to all physical forms of a compound if they display beneficial effects.
- Composition of claims and contributions - a combination of the compound with particular excipients or other compounds.
- Dosage regimen claim
- Synthetic processes claim - improved methods of preparing the compound.
How did the broadness of Searle’s patent claim for Celecoxib both benefit and hinder it?
Celecoxib by Searle and Rofecoxib by Merck were 2 selective COX-II inhibitors which were developed around the same time.
Searle sued Merck as in Searle’s patent, claim 1 was for a structure containing an X, Y, R1 and R2 of certain listed functional groups, one of which covered structure which possessed a tautomerised structure of Rofecoxib. They won this claim.
However, since the claim was so broad (due to the extensive listed options for the X, Y, R1 and R2 groups), some of the compounds claimed didn’t have selective COX II inhibitory activity, or any COX inhibitory activity at all. Therefore, Merck filed a countercase stating that since not all the compounds listed were inactive, the patent did not contain an inventive step. The judged granted for the patent to be revoked.
Describe the equilibrium dialysis assay.
This in vitro assay measures the level of plasma protein binding of a drug.
A known concentration of drug is put in a semi-permeable compartment containing plasma and albumin (or other plasma protein). This compartment is placed in a buffer, and the free drug moves from down its concentration gradient from the plasma to the buffer, while bound drug remains in the compartment. The concentration in the buffer indicates the proportion of free drug.
Why is the mu-opioid agonist loperamide used as an anti-diarrhoea agent and not an opioid analgesic?
Morphine and other opioids penetrates the blood brain barrier and acts on mu-opioid receptors in the brain to reduce pain signal transmission.
Loperamide is rapidly transported out of the brain by P-glycoprotein efflux transporters in the brain, preventing it from acting there. Instead it acts on enteric mu-opioid receptors, resulting in reduced gastric motility and increased fluid reabsorption, and therefore constipation (side effect of opioids). This can be used to treat diarrhoea with minimal side effects.
What is toxicity through mechanism-based pharmacology?
When activation of the target causes unwanted effects as well as the desired therapeutic effect.
Why was the immunosuppressant TGN1412 unsuccessful in human clinical trials?
Despite the dose given to volunteers being 500x less than the predicted safe dose (based on previous animal trials), the drug bound to 86-91% of CD28 receptors in the body. This led to cytokine release syndrome which caused multi-organ failure.
Why are electrophiles not desired in drug or metabolite structures?
Nucleophilic attack of electrophiles by nucleophiles in the body (e.g., in proteins or DNA) result in the electrophiles becoming covalently bound which can lead to toxic effects, most commonly hepatoxicity (liver) and genotoxicity (DNA).
How does the aniline functional group cause mutagenicity?
- Aniline oxidised by CYP1A2 to aryl hydroxylamine.
- Aryl hydroxylamine undergoes conjugation via a range of transferases.
- Products of conjugation undergo acid catalysed loss of either acetic acid, water, or sulphate to generate a highly electrophilic nitrenium ion (Ar-NH+).
- Species forms covalent adducts with DNA guanines.
- Persistent mutations caused by intercalation of adducts in hotspots of DNA can lead to frameshift mutations in these hotspots, ultimately leading to cancer.
