Drug In Focus May 2010

Data and market exclusivity, identified by the Paliperidone Key Patent Indicator (KPI) in Table 2, are currently the greatest barriers to generic competition. Given the relatively recent authorisation of the Invega® products worldwide it's not surprising to find either data or market exclusivity, or both, still in force in many territories, as indicated in the KPI of Paliperidone's Pipeline Selector 'Core' report.

All EU countries listed in the report have a data exclusivity expiry of June 2015 with a further two years marketing exclusivity until June 2017, based on the European 8+2+1 rule for exclusivity. Even without a further 12 months of exclusivity in these territories, which may be gained by demonstrating additional indications for Paliperidone, expiry of patents protecting the molecule per se, in the first KPI family, is already exceeded by the exclusivity expiry dates despite the patents   having granted, 5 year term SPCs. The situation is similar in Canada. The patent protecting the Paliperidone molecule has already expired, due to the absence of patent extension scheme in Canada, however data and market exclusivity do not expire until September 2013 and 2015 respectively, effectively preventing a generic product from entering the Canadian market for another 5 years.

In the US, data exclusivity is due to expire earlier than its European and Canadian counterparts, due to an earlier authorisation date and a shorter new chemical entity (NCE) term, but its application is a little more complex. Data exclusivity, around a new chemical entity NCE, is 5 years from approval, with a further 6 months available for paediatric studies. In the case of Paliperidone this means data exclusivity will expire in December 2011, at the earliest, but possibly 6 months later if authorisation for paediatric use is obtained. Marketing exclusivity for indications has a 3 year term, taken from approval of the indication, also with a further 6 months available for paediatric studies. The exclusivity surrounding Paliperidone used in the treatment of schizoaffective disorder, alone or in combination with antidepressants and/or mood stabilisers, does not expire until July 2012. This means, before this date, generic companies could only market Paliperidone for treatment of schizophrenia and would need to 'carve out' the schizoaffective disorder indication from their packaging and instruction leaflets.

Although data exclusivity generally protects an application for an ANDA for 5 years in the US, generics companies keen to enter this market can file an ANDA with paragraph IV certification one year prior to the expiry of data exclusivity. For Paliperidone this means enthusiastic competitors could file as early as December this year, in preparation for launching as soon as possible thereafter, based on either a successful court case or expiry of the 30 month stay (which may be extended by up to one year to achieve a market exclusivity of 7 1/2 years. Australia, with data exclusivity expiry in September 2012, is the only territory covered in Paliperidone's Pipeline Selector 'Core' report where data exclusivity expires well in advance of the molecule patent.

The Paliperidone KPI identifies 5 patent families protecting the Invega®/Invega Sustenna® products. The first KPI family, discussed above, protects the Paliperidone molecule, acid addition salts and enantiomers. Three related US patents in this family have been granted, US5158952, US5254556 and US6320048 ('952, '556 and '048). The '952 patent protects the Paliperidone molecule and its salts and enantiomers which, due to an s156 extension, will expire in April 2012. The '556 patent claims fatty acid esters of Paliperidone, which includes Paliperidone palmitate, composition and use of these esters. This patent expires in October this year, and would potentially give generics companies access to the Invega Sustenna® product before Invega® itself, if it were not for NDF marketing exclusivity, which expires in July 2012, protecting the Palperidone palmitate injectable product. The '048 patent claims separation of enantiomers and does not expire until November 2018. Generics competitors would need to find alternative methods of producing this enantiomeric product, which may prove difficult given that the use of many conventional chiral acids is protected.

The litigation alert that appears against the US molecule patent '952 actually has no bearing on the Paliperidone molecule. The '952 patent was listed in the Orange Book (OB) by Janssen as relating to Risperidone. They subsequently requested the FDA to de-list the patent, which was done in 2001. Before it was de-listed, however, Teva filed an ANDA with paragraph IV certification, using '952, for generic Risperidone. Teva litigated the de-listing and won, forcing the FDA to re-list the patent. As a result, Teva were awarded 180 days exclusivity for their Risperidone product, since they were the first to file. The exclusivity did not last long, however, as the FDA appealed the District Court of Columbia's ruling and it was subsequently reversed by the Court of Appeals for the D.C. Circuit.

The second KPI family contains patents that claim a platform technology comprising sterile nanoparticles and a therapeutic or diagnostic agent. Since the AU patent has already ceased and the Canadian and European equivalents have been withdrawn, only the granted US patent, with expiry in December 2012, remains. Although it is platform technology in the name of Sterling-Winthrop, the family appears in the KPI because it is listed in the OB, which is just one of the many different selection criteria used to identify patents that are 'key ' in relation to bringing a generic product to market with reduced risk. In this case it should be possible to circumvent the composition, with some R&D from generics companies.

The third and fourth KPI families protects the Invega Sustenna® product by claiming a composition comprising a Paliperidone fatty acid ester suspended in a carrier. The fourth family further specifies the fatty acid ester is crystalline and associated with a surfactant that provides a certain particle size in the suspension. These specific formulation patents possibly indicate that Paliperidone palmitate is difficult to formulate. Generics companies may have to rely on devising suspensions that contain different non-active ingredients to those listed in this patent, but still allow adequate delivery of the active. Patents in the third KPI family all expire at the same time, May 2017, shortly before the currently expected expiry of marketing exclusivity.

The fifth and final KPI family protects the Invega® oral product. The family contains two different PCT applications, WO2004010981 and WO2007050377, the former has 4 corresponding US applications ('631, '995, '132 and '534) and the latter 2 ('605, '635). The first group (WO2004010981) claims Paliperidone in a sustained release osmotic dosage form, which provides strong protection for the Invega® oral product. If the applications are granted then the expected expiry would be July 2023, which is already the case in some EU territories and Canada where the equivalent patents have been granted.  The second group (WO2007050377) claims administration of 2-18 mg of a benzisoxazole derivative in a sustained release oral dosage form. Of the two US equivalents patent '605 has been abandoned, leaving the '635 patent and the AU equivalent still pending.  Although such broad claims are unlikely to be granted, it is important that generics competitors to be aware of and to monitor claims in applications such as these in case they are granted by a patent office, potentially extending the monopoly of the oral sustained release dosage form by a further six to eleven years. 

Generics companies wishing to enter the market as soon as possible will need to scrutinise patents from all 5 families to identify either weaknesses to attack with litigation or loopholes that allow, in the case of the last 3 families, alternative formulations. The DMF section of the Paliperidone Pipeline Selector report shows 2 companies, other than the innovator, that could potentially provide the active ingredient. If the active ingredient could be supplied it would allow interested companies to concentrate on devising alternative formulations.