12 November 2011

Successful Appeal Paves the Way for Generic EFFEXOR-XR

Sigma Pharmaceuticals (Australia) Pty Ltd v Wyeth [2011] FCAFC 132 (28 October 2011)
Appeal from: Sigma Pharmaceuticals (Australia) Pty Ltd v Wyeth Australia Pty Ltd [2010] FCA 1211
See also: Australian Federal Court Blocks Generic EFFEXOR-XR

Validity – ‘external’ fair basis – whether claims entitled to priority date of original US application – whether claims are novel

effexor-xrGeneric pharmaceutical manufacturers Sigma Pharmaceuticals (Australia) Pty Ltd, Alphapharm Pty Ltd and Generic Health Pty Ltd will be free to sell in Australia their own versions of an "extended release" formulation of antidepressant drug venlafaxine hydrochloride (marketed by Wyeth as EFFEXOR-XR), after a Full Bench of the Federal Court of Australia upheld their appeal against a decision issued a year ago by Justice Jagot.

Each of the three generic pharmaceutical companies had previously obtained registration of extended release formulations of venlafaxine hydrochloride on the Australian Register of Therapeutic Goods (ARTG).  According to these registrations, Sigma's product is known as Evelexa XR, Alphapharm's as Enlafax-XR and Generic Health's as "generichealth XR".

In the original case before the Federal Court, the generic manufacturers sought revocation of Wyeth’s Australian Patent No. 2003259586 ("the XR patent"), so that they would be free to market their generic products in Australia.  In response, Wyeth argued that the proposed manufacture and sale of generic drugs would infringe claims 1, 4, 5, 8, 9, 10, 15, 16 and 27 of the XR patent.  Justice Jagot dismissed the generic manufacturers' invalidity claims, and granted an injunction barring them from selling generic extended release venlafaxine hydrochloride in Australia.

On appeal, Justice Bennett, Justice Nicholas and Justice Yates have found that the relevant claims of the XR patent are invalid, and that the primary judge erred in finding that they were entitled to the benefit the priority date of United States Patent Application No 60/14006, filed on 25 March 1996.  In fact, the Full Court has found, the claims are based on amendments filed on 20 December 2006, and are not entitled to any earlier date.  As a result, they are anticipated by the sale of EFFEXOR-XR in Australia since 1999.

Justice Bennett has written the leading opinion of the Full Court, with Justices Nicholas and Yates concurring, and providing their own additional reasons in relation to selected aspects of the case.

THE ‘ORIGINAL’ INVENTION

The main issue before the court was the effect of differences between the original US priority application, and the specification and claims of the XR patent as ultimately granted, which resulted from the amendments made in 2006.

As described in the background section of the original specification, extended release (ER) drug formulations are conventionally produced as compressed tablets by hydrogel tablet technology.  However, when the production of tablets is not feasible, encapsulated drug formulations may be prepared, which provide extended or sustained release properties.  The encapsulated formulations typically comprise spheroids, which may be film-coated to retard dissolution.  Gelatine capsules are filled with the film-coated spheroids in the quantity needed to obtain the desired therapeutic effect.

Prior to the development of an ER formulation, venlafaxine hydrochloride was administered in compressed tablet form in doses ranging from 75 to 350 mg per day.  However, these dissolved rapidly, resulting in a rapid increase in blood plasma levels followed by a decrease in blood plasma levels over several hours as the active compound was eliminated or metabolised, until sub-therapeutic plasma levels were approached about 12 hours following administration, requiring additional dosing with the drug.  These large fluctuations in blood plasma levels had the unpleasant side effects of nausea and vomiting.

It was therefore clearly desirable to produce an ER formulation of venlafaxine hydrochloride, to avoid the level fluctuations, regular dosing, and side effects.

According to the original specification, it had proven extremely difficult to develop a ER formulation of venlafaxine hydrochloride, due to its very high water-solubility.  Numerous attempts to produce ER tablets by hydrogel technology had proved to be fruitless, and efforts to produce spheroid formulations had also been unsuccessful.

This problem was ultimately solved by developing a spheroid formulation in which an additional film coating gives the desired ER dissolution profile.  According to the original specification, a suitable sustained release dosage form of venlafaxine hydrochloride, considered impossible to achieve with hydrogel tablet technology, was achieved with the film coated spheroid compositions of this invention.

The original claims all referred to ‘an encapsulated, [ER] formulation of venlafaxine hydrochloride’.

THE ‘AMENDED’ INVENTION

Claim 1 of the patent – as amended in 2006 – recites:

A method for providing a therapeutic blood plasma concentration of venlafaxine over a 24 hour period which comprises administering orally to a patient in need of venlafaxine a single daily dosing formulation of venlafaxine hydrochloride that provides a peak blood plasma level of venlafaxine in from about 4 to 8 hours after administration.

This method claim thus defines the invention in terms of the result achieved by an ER formulation in general, i.e. a single daily dosage with a relatively uniform blood plasma level which peaks some hours after administration, thereby avoiding the unpleasant side effects associated with large and rapid fluctuations in blood plasma levels. 

There is no reference in the above claim to an ‘encapsulated [ER] formulation’, and it therefore encompasses any method, using any formulation, which produces the claimed (and desired)effect.

A number of further amendments were made to the specification in 2006, with the general effect of playing down the significance of the specific encapsulated ER formulation which had been developed, regarding this instead as just one exemplary approach to implementing the claimed invention.

FAIR BASIS AND VALIDITY OF CLAIMS

The key question was therefore whether there was fair basis for the amended claims in the original priority application.  If not, then the claims would be entitled to a priority date determined by the amendments (i.e. 20 December 2006), and it was common ground that the consequence would be invalidity due to lack of novelty.

The primary judge considered that the amended claims were fairly based on the priority application, which she considered to disclose two inventions, ‘an encapsulated formulation’ and ‘a method for obtaining a certain drug to plasma relationship over time yielding a “tighter plasma therapeutic control” than multiple daily dosing’ (at [15], citing [165] of the first instance decision).

Justice Bennett did not agree that the priority document disclosed a second ‘invention’ comprising a general method for achieving the desired profile of blood plasma level, stating (at [59]) that:

The invention is not the discovery of a new method with any formulation. The method disclosed is the use of the invention, the ER formulation. There is no asserted invention in the measurement of blood plasma levels after administration of the drug. There is no asserted invention in the idea of a sustained release formulation delivering a therapeutic plasma level of the drug over 24 hours. They are the parameters by which the success of the formulation is measured. They are the parameters of the method which is the goal: a therapeutic dosage, measured by the plasma level of the drug, delivered over 24 hours. The goal is not the patentable invention. The invention is the means of achieving the goal.

She therefore concluded (at [74]) that:

…the claims of the Amended Patent are wider than the invention there [i.e. in the priority application] disclosed which, as I found above and as is claimed in claims 1 to 8 of the Priority Document, is limited to the ER formulation described in the body of that specification. The claimed methods of the Amended Patent are not so limited. The subject matter of each of claims 1 to 17 and 27 of the Amended Patent is not fairly based on the matter disclosed in the Priority Document and those claims claim matter in substance disclosed as a result of the 2006 Amendments.

Justice Nicholas reached the same conclusion, via a similar line of reasoning (at [167], and Justice Yates likewise (at [227-8]).

INFRINGEMENT

The generic manufacturers’ proposed products utilise hydrogel tablet technology, which obviously turned out not to be impossible to achieve, after all!

While these products would infringe the claims of the XR patent, which were not limited to an encapsulated ER formulation, the broadening of the patent by way of the 2006 amendments had rendered these claims invalid (paragraph [131]).

CONCLUSION

The generic manufacturers were successful in their appeal.  While their proposed products would infringe certain claims of the XR patent, all of the pertinent claims are invalid as a result of the broadening amendments made on 20 December 2006.

It seems fairly clear that the amendments were made intentionally to broaden the scope of the patent, so as to capture a wider range of prospective infringing formulations.  Most likely Wyeth was aware, by December 2006, that a hydrogel tablet formulation was not an impossibility, and that it would therefore be desirable to have claims broad enough to encompass such a formulation. 

It is understandable that Wyeth would attempt these amendments, considering the high value of the patent monopoly on a drug such as EFFEXOR-XR.  And there was, after all, a sufficiently strong argument in support of the amendments to satisfy a patent examiner, and a single judge of the Federal Court of Australia.

However, with three concurring judgments on appeal, this looks to be the end-of-the-line for Wyeth’s XR patent, and Australian consumers (and taxpayers) can now look forward to reduced prices on venlafaxine hydrochloride, as the generics enter the market.

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