A federal judge in Indianapolis upheld Eli Lilly’s patent on Zyprexa,(USP 5,605,897) a treatment for schizophrenia that was among the top-selling drugs in the United States last year, with $2.4 billion in sales.

Judge Young’s verdict comes more than a year after the trial in the case. Lilly sued Zenith Goldline Pharmaceuticals, Dr. Reddy’s Laboratories, and Teva Pharmaceuticals, which had filed applications with the Food & Drug Administration to make generic olanzapine, the active chemical in Zyprexa.

Lilly had sued three generic drug companies to protect its patent, after the generic companies claimed that the patent was invalid because Zyprexa is too similar to other chemical compounds whose patents have already expired. In a 224-page ruling, Judge Richard L. Young of Federal District Court backed Lilly’s position, finding Zyprexa different from the other compounds and worthy of protection.
The verdict protects Lilly’s monopoly on selling Zyprexa in the United States until 2011, when its patent expires.

Ivax had the most at stake. The company had obtained the right to six months of exclusive sales on five separate dosages of Zyprexa in exchange for being the first to file a challenge to the olanzapine patent. Dr. Reddy’s had the right to marketing exclusivity on one dosage. Teva didn’t actively participate in the lawsuit and agreed to abide by Young’s ruling.

Ivax and Dr. Reddy’s said they will appeal. The case is headed to the U.S. Court of Appeals for the Federal Circuit in Washington, which specializes in U.S. patent law. The Federal Circuit threw out the Prozac patent in 2000 after Lilly won the original case in Indianapolis.

The three companies claimed that Lilly’s American patent on Zyprexa was invalid because olanzapine was very similar to other compounds it had already patented, including flumezapine, a chemical that Lilly studied in the early 1980’s as a potential schizophrenia medication.
The generic drug makers used five different arguments in their attempt to prove the patent invalid, but the judge found for Lilly on each one.

A main argument of the generics was that “[a]ny skilled scientist could have easily discovered olanzapine based on flumezapine and the other compounds.”

Ivax and Dr. Reddy’s also argued that olanzapine was covered by a patent that expired in 1995, the year before Zyprexa was first prescribed. They claimed that Lilly was only able to extend its patent monopoly by misleading the patent office with a flawed clinical study on beagles.

Lilly argued that the patent was properly issued because olanzapine had unexpected properties that weren’t covered by the first patent. The drug’s commercial success and its use by millions of patients was an indication that other companies would have marketed the drug had they known of those characteristics, Lilly says.

In the end, Judge Young sided with Lilly, noting that “olanzapine lacks a fluorine atom present in flumezapine. Scientists at Lilly had considered fluorine or chlorine to be crucial ingredients in antipsychotic medicines, so Lilly’s discovery that olanzapine worked despite its lack of fluorine was a novel, important finding worthy of patent protection.”

Both olanzapine and flumezapine are substituted benzodiazepines. Let’s look at their structures:


I don’t know about you, but these two compounds at issue look very similar to me, with that single atom exception.

One of the arguments put forth by Lilly was that many/most (atypical?) antipsychotics are fluorinated. Lets look at some of the most popular antipsychotics on the market today: clozapine, a benzodiazepine-based compound is not fluorinated; quetiapine, a benzthiodiazapine is non-fluorinated; risperidone, a quinoline-based drug is fluorinated; and aripiprazole(abilify), another quinoline-based antipsychotic, is non-fluorinated. By my count that’s 1 fluorinated and 3 non-fluorinated compounds used as atypical antipsychotics. Hmmmm… The fluorinated flumezapine does not work well, so lets try the non-fluroinated counterpart? I guess that’s why chemistry is one of those unpredictable sciences.

As an organic chemist, I tend to overanalyze the nuances of chemical structures. I also worked with fluorinated and non-fluorinated aryl azides as photoaffinity labeling agents. These two sets of compounds behaved both physically and chemically very differently from each other. So, how far of a stretch is it to remove a fluorine atom and see what happens? After all, look at the atypical antipsychotics that are non-fluorinated benzodiazepine-derived.

I am digressing too far for a Friday, let alone tax day (see Stephen’s earlier post – I need to get to the beach, lie back in that hammock, and start sipping those well-deserved Long Island iced teas!)

All I can say for the appeal, is “let the games begin.”

(The case is Eli Lilly v. Zenith Goldline Pharmaceuticals, 01cv443, U.S. District Court in Indianapolis)

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