08 July 2010

Pharmaceutical Extensions and International Inequities

H Lundbeck A/S v Alphapharm Pty Ltd [2009] FCAFC 70 (11 June 2009)
Ortho-McNeil Pharmaceutical, Inc. v. Lupin Pharmaceuticals, Inc., No. 09-1362 (Fed. Cir. May 10, 2010)

"White powder" (or, indeed, powder or other chemical substances of any colour) is not within Patentology's usual area of expertise, and we generally rely upon various colleagues to educate us in this area.

Yet we could not help but notice two recent decisions, one in Australia and one in the US, which resulted in completely opposite outcomes in otherwise analogous circumstances.  We will therefore endeavour to explain our take on these decisions.

In order to do so, we will need to provide a little background, firstly on the provisions for extending the term of pharmaceutical patents, and secondly on the specific chemical issues in these cases.  If you are familiar with this background, click here to jump to the conclusions.

PHARMACEUTICAL EXTENSIONS OF TERM

Although the details largely elude us, the general policies and procedures underlying pharmaceutical extensions of term (PET's) are not difficult to appreciate.

Drugs and other therapeutic products may take a long time, and a great deal of money, to trial, prove, and gain approval for sale.  At the same time, corresponding patents must be filed early in the process to ensure that the applicant is first-to-file (other than in the US), and that the claimed product is novel in view of subsequent disclosures occurring during the product development, trial and approval process.

Registers of approved drugs are maintained by goverment authorities, and specifically the Food and Drug Administration (FDA) in the US, and the Therapeutic Goods Administration (TGA) in Australia.

By the time a drug is actually on the market, the associated patent might be somewhat long in the tooth, and the period within which the patentee is able to capitalise on its investment is then significantly reduced.

To provide compensation for this problem, many jurisdictions allow patentees of pharmaceutical inventions to apply for an extension of the patent term beyond the nominal 20 years from filing.  There are various time limits and procedural requirements, but in essence the expiry of the patent may be extended by a period corresponding with the delay associated with obtaining regulatory approval.  (The extension period is typically capped, eg at five years.)

However, to prevent companies from unfairly extending their patent monopolies, there are restrictions on the cases in which an extension of term may be granted.  In particular, it is generally the case that an extension is only available on a patent subsequent to the first inclusion on the register of approved drugs.  Thus a subsequent patent, directed for example to an improved formulation (ie a better way of delivering the same drug to a patient), would not be eligible for extension if the underlying drug had previously been registered in its own right.

Both of the cases we are looking at - one in Australia and one in the US - address the issue of exactly what must be covered by the first registration in order to trigger a later prohibition on extending patent term.

STEREOCHEMISTRY, ENANTIOMERS AND RACEMIC MIXTURES

Molecules, including those of pharmaceutical compounds, have three-dimensional structures.  Some compounds which have the same chemical formula may exist in different and distinguishable three-dimensional forms.  To borrow an example outline in the Australian Lundbeck decision, bromochlorofluoromethane exists in two distinct forms, which are mirror images of each other, as illustrated below.


The mirror-image molecules are called the "enantiomers" of the compound.  Depending upon the circumstances, either one may exist in isolation, or they may generally exist as a mixture in either equal or unequal proportions.  Such a mixture is known as a "racemate" or "racemic mixture".

In the case of pharmaceutical products, different enantiomers may have different bioactivity, that is one or other of them may be more or less effective as a drug.  In such cases, the racemic mixture may be a useful pharmaceutical product, since it includes the effective enantiomer.  However, it would be desirable to identify and isolate the more-effective enantiomer, if possible.  Both of these steps (identification and isolation) may be easy, or they may be hard.

It is therefore not uncommon for an initial patent to cover a particular pharmaceutical product, in terms of its general chemical formula, and a subsequent patent to cover a specific enantiomer, once the more bioactive molecule has been identified and successfully isolated.

RACEMATES, ENANTIOMERS AND PET'S

The Lundbeck case in Australia relates to the antidepressant drug citalopram, which comprises two enantiomers of which one, escitalopram was ultimately isolated and found to be the more effective.  Citaolopram was covered by Australian patent no. 509,445, and was duly entered on the TGA register of therapeutic goods.  Escitalopram was subsequently covered by Australian patent no. 623,144, and was also entered on the TGA register.

The US Ortho-McNeil case relates to the anti-microbial agent ofloxacin, which also comprises two enantiomers of which one, levofloxacin was ultimately found to be more effective, and covered by US patent no. 5,053,407.  Ofloxacin was initially approved by the FDA, with levofloxacin being subsequently approved.

INCONSISTENT OUTCOMES

In both cases the question was the same: whether a later enantiomer patent is entitled to an extension of term based on approval/registration of the enantiomer, or whether an extension is precluded due to the fact that earlier approval/registration of the racemate was the relevant first approval by virtue of its inherent inclusion of both enantiomers.

However, the outcome in each of the US and Australian cases was completely opposite.

In Australia, the Federal Court majority opinion (penned by Justice Bennett) concluded, at paragraph [224], that escitalopram was encompassed by the earlier registration by the TGA of the racemate, and that this was therefore the first relevant registration  As a result, the time period for requesting an extension of term for the escitalopram patent had expired, and the extension of term was denied.

In the US, the Federal Circuit appeals court concluded that "the enantiomer is a different drug product from the racemate ofloxacin, and was subject to regulatory approval before it could be commercially marketed and used" (slip op. p 7, emphasis added).  Thus the relevant first approval was that relating to the enantiomer, and the extension of term was upheld.

COMMENT AND CONCLUSION

The adverse outcome in Australia is widely considered to be inconsistent with the intended policy behind the legislation.  It is clearly inconsistent with the law in the US - one of Australia's major trading partners.

However, it is also considered to be a legitimate interpretation of the wording of the statute.  An application for leave to appeal the decision to the High Court of Australia was subsequently refused (see transcript here).

Any correction in Australia would therefore now appear to lie in the hands of the parliament.  An election is considered highly likely within the next few months, and we therefore do not expect reform in this area to be a priority.

No comments:

Post a Comment