The Need to Perform ‘Complex, Time-Consuming and Expensive’ Clinical Trials Does Not Make a Patent Invalid

Patents play an important role in the development of new pharmaceutical compounds, and therapies based upon the use of such compounds.  The primary global model for drug development is based upon private enterprise and competition.  Within this model, the carrot of a potential patent ‘monopoly’ provides an incentive for companies to deploy the considerable resources – with costs commonly estimated in the billions of dollars – necessary to discover, research, trial, and market new drugs and therapies.  Although not everyone agrees that this is the best approach, it is difficult to dispute that it has, nonetheless, contributed to the delivery of great benefits to humanity over the past century or so.

Within the realm of conventional ‘small molecule’ drugs (i.e. setting aside, for present purposes, recent developments in biotechnology and biologics) four broad categories of patent protection can be identified.

1. New compounds.  When an innovator discovers or synthesises a compound that was not previously known to exist and/or to have any useful therapeutic effect, a patent may be obtained for the compound itself.
2. Formulations.  While it is one thing to identify a biologically-active compound, it is often another altogether to find a safe and effective way of delivering it to a patient.  When an innovator develops a new and/or more effective formulation (e.g. a particular tablet or other oral dosage form), a patent may be obtained for that formulation, even if the active ingredient is well-known and no longer patentable.
3. New therapeutic effects.  When an innovator discovers that a compound already known to have one or more therapeutic effects has a further, and unforeseen, therapeutic use (e.g. in the treatment of a different disease or condition), a patent may be obtained for a method of using or making the compound specifically for the new therapeutic purpose.
4. Improved methods of treatment.  When an innovator discovers that a known compound with a known therapeutic use can be made even more effective, e.g. by combining it with other compounds or therapies, or using a different dosing regime, a patent may be obtained for the new method of treatment.

Of course, a patent will only be validly granted in any of these cases if all of the legal requirements for patentability – novelty, inventive step, sufficiency of description, and so forth – are all satisfied.  These requirements are intended to balance the rewards available to innovators against the rights of the broader community to access knowledge and to engage in free competition.

From a policy perspective, getting the balance right is particularly important in the case of pharmaceutical products.  If it is too difficult to obtain a valid patent, there may be insufficient incentive for companies to invest billions of dollars in new drug development.  On the other hand, it is important to keep in mind that, one way or another, it is the wider community – either individually, or through taxes in countries where healthcare is substantially subsidised by government – that ultimately pays for that development, through the higher prices charged for patented drugs.  Allowing patents to be granted too easily therefore may therefore represent a significant social cost.

A major component of the cost of bringing a drug to market is the need to conduct extensive clinical trials in order to prove the effectiveness and safety of the drug, and thus to obtain regulatory and marketing approval.  Such trials typically take years to complete, following the initial discovery of a new compound, or of a new use for an existing compound.  However, a patent application must be filed as early as possible to ensure that any available protection is secured in the event that the trials are successful.

A recent appeal decision of a Full Bench of the Federal Court of Australia sheds light on how the balance between an innovator’s need to file early, and the community’s right to receive a full disclosure of the invention, is struck in the case of a patent for a new therapeutic use of a known compound: Warner-Lambert Company LLC v Apotex Pty Limited (No 2) [2018] FCAFC 26.  The court has confirmed that the fact that the clinical trials required to establish an effective and safe dosage of a drug for a new therapeutic use may be ‘complex, time-consuming and expensive’ will not render invalid a patent that was filed prior to conducting this essential research.

Background

The patent at issue in Warner-Lambert is Australian patent no. 714980 (also known as AU1997036024 under the current numbering system).  This patent in fact expired on 16 July 2017, however infringement proceedings originally commenced back in 2013.  The patent relates to the use of a drug known as pregabalin, which was previously known as an antiseizure therapy for central nervous system disorders, for the treatment of chronic pain disorders.

The patentee, Warner-Lambert, sued generic manufacturer Apotex for threatening to infringe.  Apotex claimed that the patent was invalid on the basis, among other reasons, that it failed to ‘describe the invention fully’, as required by section 40(2)(a) of the Patents Act 1990 (as it was prior to the commencement of the Raising the Bar law reforms back in 2013).  This requirement is commonly known as ‘sufficiency of description’, or simply ‘sufficiency’.

Case for ‘Lack of Sufficiency’

Apotex had a number of arguments, which can generally be reduced to the contention that while Warner-Lambert was broadly claiming any ‘method for treating pain comprising administering a therapeutically effective amount of [pregabalin]’, the patent specification did not identify with sufficient specificity exactly what would constitute a ‘therapeutically effective’ (and safe) amount of the drug.  Anybody wishing to put the invention into effect would therefore need to conduct extensive research and experimentation – essentially equivalent to clinical trials – in order to do so.  While Apotex abandoned the argument that this may require ‘new inventions or additions’ to what was disclosed in the patent specification, it maintained that working the invention would require ‘prolonged study of matters presenting initial difficulty’, and would constitute an ‘undue burden’.

(Patent attorneys and lawyers following along may recognise the ‘new inventions or additions’ and ‘prolonged study of matters presenting initial difficulty’ tests from the Australian High Court’s reasoning on sufficiency in Kimberly-Clark Australia Pty Ltd v Arico Trading International Pty Limited [2001] HCA 8, at [25].)

While the patent was directed to the treatment of mammals generally, including humans, it describes only tests performed on rats, consisting of giving them doses of pregabalin one hour prior to injecting formalin into their paws which (unsurprisingly) causes them to exhibit pain behaviours.  The tests established that pregabalin was effective in reducing these behaviours, indicating that it provided some level of pain relief in rats.

Apotex argued that a skilled person could not simply work within the broad dose range disclosed for rats to establish a suitable dose in humans.  At the time of the original application, it said, pregabalin was a relatively new chemical entity that had not been tested in humans.  Therefore, before it could be ‘administered to a human in need of pain treatment, it would be necessary to undertake further research and study to obtain an understanding of the safety and toxicity profile of the drug’ (at [30]).  This was said to constitute an ‘undue burden’.

Court Rejects ‘Undue Burden’ Test

As you might appreciate, if the ‘undue burden’ standard applies, then many patents for further therapeutic uses of known compounds would be invalid.  Almost by definition, a patent application must be filed when knowledge of the further use is new, e.g. after initial testing in animals, and before it can be discovered by a competitor and/or become public, e.g. as a result of conducting clinical trials.  An exception might be when the compound is already well-known and characterised in humans, as a result of trials performed in relation to earlier therapeutic uses.  However, it would be a bizarre outcome if it were not possible to obtain a valid patent for the early discovery of additional therapeutic uses while the same discovery made some years later might be patentable!

It is fortunate, then, that the Full Court rejected Apotex’s arguments, which it did for three main reasons.

Firstly, the court noted that Apotex had derived the notion of an ‘undue burden’ test from UK case law, and that to accept its application in Australia would ‘expand the scope of operation of s 40(2)(a) in a way not envisaged by the High Court in Kimberly-Clark, by reference to a little-explained and somewhat indeterminate standard’ as well as running ‘counter to the High Court’s caution [in Lockwood Security Products Pty Limited v Doric Products Pty Limited [2004] HCA 58] against an uncritical adoption of post-1977 United Kingdom cases on provisions that are, at best, only broadly similar to provisions in our own Act’ (at [113]).

Secondly, the court considered the character of the invention claimed in the patent.  The court found that it ‘is a broad one directed to the application of known compounds to a new therapeutic use.  It is not directed to more specific matters, such as a new and inventive dosage regimen or dosage form for the administration of the compounds in treating pain in, say, humans’ (at [123]).  In other words, once the inventors have disclosed the new knowledge, i.e. that pregabalin is effective for the treatment of pain, it is a matter of routine to administer the compounds to human subjects for this purpose.

Thirdly, the court noted the important difference between the ability to work the invention as required by section 40(2)(a) of the Patents Act, and the ability to obtain regulatory approval and market a pharmaceutical product based on the invention (see at [125] to [132]).  The court identified three related aspects of this difference.  First, that the disclosure requirements of the patent law are of a different character to the requirement to prove the safety and efficacy of a compound for regulatory and marketing approval purposes, and the two should not be conflated.  Second, the fact that a clinician would (probably) not administer pregabalin to a human patient to treat pain, without the specific dosages and safety and toxicity profiles that would be obtained through clinical trials, does not mean that someone could not do so based on the disclosure in the patent specification.  Third, section 40(2)(a) is concerned with matters of description and not proof.  There was no allegation that the specification was wrong in its teaching that pregabalin is effective for the treatment of pain in mammals, including humans.  It was therefore not relevant that it did not go further, to disclose the level of detail and proof of safety and efficacy that a clinician would require.

Conclusion – Would Tougher Laws Have Assisted Apotex?

As explained at the outset, there are a number of different circumstances in which it may be possible to obtain a further patent in relation to a known compound with one or more existing therapeutic uses.  In the present case, the patent was granted for the discovery that a drug – pregabalin – already known for treatment of seizures, had previously unknown pain relieving properties.  The court found that demonstration of this analgesic effect in rats was sufficient to support relatively broad claims directed to the new therapeutic use of the known compound.  While it was true, as Apotex argued, that a significant amount of work remained to be done to identify safe and effective dosages for use in human subjects, this was not pertinent to the invention that was actually disclosed and claimed in the patent.

As I have noted, the decision in Warner-Lambert is based upon the law prior to commencement of the Intellectual Property Laws Amendment (Raising the Bar) Act 2012, which raised the standard of disclosure required in a patent specification.  Where section 40(2)(a) previously required the specification to ‘describe the invention fully’ – which came to mean that the description must enable a skilled person to produce something falling within the scope of each of the claims – the current version requires the specification to ‘disclose the invention in a manner which is clear enough and complete enough for the invention to be performed by a person skilled in the relevant art’.  This language is, intentionally, very similar to Article 83 of the European Patent Convention (EPC), and section 14(3) of the UK Patents Act 1977.

It is therefore interesting to consider whether Apotex’s arguments in relation to ‘undue burden’, which are supposedly derived from European and UK case law, might have been successful had the current Australian law applied in this case.  As yet, we have no judicial consideration of the new provisions, although we have seen cases of the Patent Office applying the current version of section 40, both in favour of, and against, the patent applicant.

For the following reasons, however, I think it unlikely that Apotex would have been assisted by the change in the law.  Firstly, in its consideration of the character of the invention, the court appears to have been happy to accept that it was effectively enabled across the full scope of the claims, i.e. that the discovery of the application of known compounds to a new therapeutic use justifies broad claims that are not limited to practical details, such as dosage regimes.  Secondly, in referring to the ‘undue burden’ test as ‘a little-explained and somewhat indeterminate standard’, the court did not appear to be entirely convinced that this is a valid approach in any event.  Thirdly, to the extent that there is a ‘burden’, the court was fairly clear that this is related to generating clinical proof, and obtaining regulatory and marketing approvals, rather than meeting the disclosure requirements of the Patents Act.  Finally, I am not aware of patents on further therapeutic uses of known compounds being routinely invalidated in Europe or the UK on grounds of insufficiency of disclosure, in similar circumstances, which suggests that even if an ‘undue burden’ test exists, it does not apply in such cases.

There is no doubt that, one day, this precise question will come before the Australian courts.  When that day comes, it will be interesting to learn whether their answer is the same as mine.

Tags: Australia, Enablement, Pharmaceuticals, Sufficiency