Innovators vs. generic drug makers

Parikshit Bansal and Anand Sharma delve into some of the pertinent issues related to IPR in the concluding part of the article

Recombining drugs in slightly different ways to secure new patents is a real cause of concern for a country like India where the local industry has capabilities to provide competition to global pharmaceutical industry.

According to the Report of the National Institute of Healthcare and Medicines (NIHCM), between 1989 and 2000 incrementally modified drugs (IMDs) constitute 54 per cent of all drugs patented and approved of by the FDA in the USA.

Other case studies and examples

Benefits of ANDA filing to get six months exclusivity:

• In August 2001, Dr Reddy’s Labs (DRL) won a 180-day exclusivity for fluoxetine which netted the company $70 million in six months.
• When ciprofloxacin went generic, 10 players including DRL launched their version of the drug on day one. This was unprecedented and prices collapsed by 95 per cent. Same day filings meant that those 10 companies only and not anyone else had exclusivity rights for six months.

Case 1:Pfizer vs Dr Reddy’s Labs (DRL)

Even after expiry of patents, IPP can be extended to compensate for the loss to the innvator during the approval process

In February 1986, Pfizer was granted a patent on a class of compounds that treats heart disease and hypertension. The patent covered the molecule amlodipine, including two of its salts—amlodipine besylate and amlodipine maleate. In 1987, Pfizer filed another application for amlodipine besylate salt specifically, as studies conducted showed it was superior in treating hypertension, and marketed it as Norvasc. As the patent’s expiry date approached (Feb 25, 2006), Pfizer went ahead and filed a Patent Term Extension (PTE) under the Hatch-Waxman extension rules.

Meanwhile, in 2002, DRL tried to get approval for manufacture of AmVaz under the generics category in view of the significant returns estimated at $200 million over a three-year period. DRL filed an ANDA for same under US FDA’s 505(b)2, seeking marketing pproval after it was found the PTE by Pfizer was only for amlodipine besylate. On October 31, 2002 US FDA granted approval to DRL to go ahead. However, Pfizer sued DRL for patent infringement, insisting that PTE covered the entire scope of amlodipine.

Pfizer lost the case in a New Jersey district court in Dec 2002 but won the same in a higher court in February 2004, thus putting an end to DRL attempts to tap a lucrative market in the generics segment.

The IPR issues in this case touch several facets:

• Extension of IP protection (IPP): Even after expiry of patents, IPP can be extended to compensate for the loss to the innvator during the approval process. Presently, this extension period is restricted to five years. Pfizer was able to get IP protection for its drug amlodipine besylate (Norvasc) even after expiry of the patent.
• Broad nature of IP coverage: The basic patent coverage is quite broad and a generic drug maker may find it tough to manufacture even the generic versions after expiry of the patent term. DRL was not granted permission to manufacture amlodipine beslate (AmVaz) even though the drug had not been covered under the PTE. DRL followed necessary legal procedures and even won in a lower court, but ultimately did not get permission.
• IPR issues extend to generics also: DRL simply wanted to make a drug whose patent term had expired and which the original patent company had not marketed at all. Still it was unable to get permission. - Ethical issues: A pharmaceutical giant, Pfizer is already actively making profits on one version of the drug. It has not undertaken production of the other version, even after 20 years. When it seeks extension, it does so for only the version it has marketed (Norvasc). Yet when another company in the US wants to manufacture the version which has neither been marketed nor applied for under patent extension (AmVaz), Pfizer puts in all out effort to block the same. It loses once. Does not give up. Fights in a higher court and wins the case. Is it ethically correct on part of the company? What in your opinion are the points n favour of Pfizer? After all it did win the case in a higher court.

Case 2:Pfizer vs Ranbaxy Labs:

In Jan, 1983, Pfizer was granted a patent for its anti-fungal drug Diflucan. When Ranbaxy initiated the process for launch of a generic version of the drug, it was sued by Pfizer on grounds of patent infringement. Pfizer also sought PTE for six months for a paediatric version of the drug. The infringement suit against Ranbaxy was terminated on Jan 29, 2003 when the original term of the patent came to an end. However, Pfizer was granted an extension of six months till July, 29, 2003 during which Ranbaxy could not launch the generic version. Diflucan which treats fungal infections had sales of US $1.2 billion in 2003.

Case 3: Aventis SA and Albany Molecular Research vs DRL and others.

Five companies which sought to market generic versions of Allegra, anti-allergy pill were sued by the parent company for infringement of its patents which expire in 2013. Dr Reddy’s Labs (India), Barr Pharmaceuticals, Mylan Pharmaceuticals, Impax Laboratories of US and Israel’s Teva Pharmaceuticals were all sued by Aventis SA, France’s biggest drug maker and partner Albany Molecular Research. Production of generics halted.

Case 4: GlaxoSmithKline vs Cipla Ltd, Ivax (USA) and two other generic firms.

The case pertained to Europe’s biggest drug maker, GlaxoSmithKline. Patent granted to GSK’s biggest selling asthma drug Seretide also called Advair having global sales of US $2.2 billion was challenged by the generic drug makers on grounds of obviousness. The case was fought in the London High Court.

The main grounds on which the patent rested was whether an inventive step was involved in combining two older drugs, Flovent and Serevant to make Advair. Justice Pumfray of the London High Court ruled that the combination was entirely obvious and cancelled the patent. The victory for generic drug makers meant that they could launch cheaper versions of the inhaled asthma treatment as early as October, 2005.

Case 5: UCB vs DRL

Dr Reddy’s Labs has been sued by Belgian pharma major, UCB for patent infringement. DRL had filed ANDA with the USFDA for Levetiracetam tablets (250, 500 and 750 mg). Levetiracetam is the generic version of UCBs Keppra TM, for which patent rights are held by UCB. It is used for the treatment of epilepsy. The brand has annual sales of US $234 billion.

Compulsory licensing of patented drugs

Case 1: Compulsory License granted to Cipla for anti-retroviral (HIV-AIDS) formultions. Cipla became the first company in the world to benefit from the issuance of compulsory license (CL) for import of drugs issued after August 30, 2003.

WTO decision to allow flexibilities in the patent laws to deal with health emergencies.

The CL was issued by the Malaysian government to a national firm, Syarikat Megah Pharma Vaccines, to import specified anti-retroviral patented drugs in different doses from Cipla. These drugs are didanosine and zidorudine. The patent for the first drug is held by Bristol Myer Squibb and the other drug is held by GSK. The drugs have to be supplied to government hospitals in Malaysia for a period of two years.

Case 2: Issue of Compulsory License (CL) by Kenyan government for manufacture of anti-pneumonia drug

The Kenyan government has initiated a process to issue a compulsory license to procure antibiotic azithromycin, a new generation drug for which Pfizer Inc holds patent rights. Indian drug companies who manufacture and market the drug include Wockhardt, Alembic and FDC. The license issued by the Kenyan Government would expect the CL holder to produce azithromycin formulations in quantities that are enough to treat over two million cases of pneumonia in the Sub-Saharan Africa. The market of the drug which is marketed by Pfizer under the brand name Zithromax is close to US $one billion.

Some definitions of generic drugs on the web

A prescription drug, which is chemically equivalent to a band-name product, dispensed under its generic chemical name.

benefitsu.stanford.edu/glossary/glossary.html

Drugs marketed under their nonproprietary name rather than a brand name.

www.hsl.unc.edu/lm/druginformation/glossary.htm

A prescription drug that has the same active-ingredient formula as a brand-name drug. A generic drug is known only by its formula name and its formula is available to any pharmaceutical company. Generic drugs are rated by the Food and Drug Administration (FDA) to be as safe and as effective as brand name drugs and are typically less costly because advertising costs are not included. www.cwru.edu/med/epidbio/mphp439/Dictonary.htm

Copies of innovative products sold by multiple manufacturers once any limited market exclusivity period has expired.

www.canadapharma.org/Patient—Pathways/Glossary—Terms/ Less expensive drugs, but of the same therapeutic value.

Generic medicines appear on the market when the protection of original leading medicines, assured by a patent is expired.

www.euromut.be/uk/lexique.htm

Important site for information on Orange Book

www.fda.gov/cder/ob/default.htm

Parikshit Bansal is with IPR Cell and Anand Sharma is with Dept of Pharmaceutical Management at National Institute of Pharmaceutical Education & Research (NIPER), Punjab. E-mail: pbansal@niper.ac.in