Can approved salt be claimed novel again?
Norvasc® (Amlodipine besylate) Tablets (2006 Sales of $2.8 billions)
Pfizer, Inc. v. Apotex, Inc., No. 2006-1261(Fed. Cir. March 22, 2007)
Parties: Pfizer (brand) and Apotex (generic) Lower Court: The district court ruled in favor of Pfizer that the US Patent No. 4,879,303 is not obvious over US Patent No. 4,572,909. Pfizer sued Apotex on 7/30/03. Decision was issued at about 30 months from the date of Pfizer sued. Pfizer Inc. v. Apotex, Inc., No.03C 5289, 2006 U.S. Dist. LEXIS 95778 (N.D. Ill. Jan. 24, 2006) Appeal Court: The Court of Appeals for the Federal Circuit (CAFC) reversed the district court’s decision and ruled that ‘303 patent is obvious over the ‘909 patent. Decision was ruled on 3/22/07, about 14 months from the lower court decision. Ruling: The novel properties of besylate salt are routine measurement over the prior arts of maleate salt. If it is obvious to try with reasonable expectation of success, it is obvious. Impact: It is unlikely to claim the approved salt as novel salt without extraordinary unexpected properties. Increase solubility, prevent sticking during the manufacturing process, and non-hygroscopic are routine practice, not trial and error procedures. Generic Launch: The generic launch of Norvasc® was a very interesting legal maneuver. An interesting article from the Journal of Generic Medicine discussing this case can be found here. On March 23, 2007, one day after Apotex’s win, Mylan, the first approved generic of Norvasc® launched. Even though Mylan lost its case again Pfizer, the CAFC invalidated the ‘303 patent paving the way for Mylan’s generic launch. Pfizer responded with its own Greenstone authorized generic. You can find the details in the Orange Book Blog here. On April 18, 2007, FDA issued an action letter stating that Mylan’s 180-day exclusivity expired on the day ‘303 patent expired (March 25, 2007). Apotex may receive final approval if the CAFC issued the mandate (when the rehearing is denied.) All other generics are subjected to Pfizer’s pediatric exclusivity till September 25, 2007. On May 21, 2007, the CAFC denied Pfizer’s petition for rehearing and rehearing en banc. Three of twelve judges dissented. On May 24, 2007, Apotex finally launched its generic Norvasc®, two months after Mylan. Its win at the CAFC finally paid off but only enjoy about a month of sales before other generic approvals. On June 22, 2007, the FDA delisted Pfizer’s ‘303 patent per Pfizer’s request. As such, pediatric exclusivity is no longer existed. The reason for Pfizer’s action to crush the market before September 25 is unknown. This paved the way for 21 other generic approvals. (Actavis, Aurobindo, Caraco, Cobalt, Dr. Reddy, Gedeon Richter, Interpharm, Invagen, Kali, Lek, Lupin, Matrix, Mutual, Ranbaxy, Roxane, Synthon, Teva, Upsher Smith, Watson, Wockhardt, and Zydus). On October 1, 2007, the Supreme Court denied Pfizer's certiorari petition. |
This case raises a question of “obvious to try.” Whether a salt exhibiting several advantageous properties over the prior art can claim novel? The Appeal Court in a unanimous decision ruled that if there were finite numbers of choices (available pharmaceutically approved salts, 53 in this case at the time of invention), and predictable solutions with a reasonable expectation of success, it is obvious.
This case involved US Patent No. 4,572,909 of Pfizer. Patent ‘909 was issued on February 25, 1986. The ‘909 patent disclosed the pharmaceutically-acceptable acid addition salts of amlodipine, “such as hydrochloride, hydrobromide, sulphate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate and gluconate salts, and that the preferred salt is maleate.” Even thought, the ‘909 patent did not expressly disclose amlodipine besylate, its claims “literally encompass amlodipine besylate.”
The patent in dispute is US Patent No. 4,879,303 of Pfizer. The claim one of “303 patent states “[t]he besylate salt of amlodipine.” Patent ‘303 was filed on October 13, 1998 claiming priority on March 25, 1987. ‘303 patent was rejected twice as obvious over ‘909 patent and other prior arts. Pfizer filed declaration stated “the besylate salt of amlodipine was ‘found to possess a highly desirable combination of physicochemical properties,’ including good solubility, stability, non-hygroscopicity, and processibility, which properties are ‘unpredictable both individually and collectively.’” This patent was eventually allowed.
According to the 35 U.S.C. §130(a), a claimed invention is unpatentable if the differences between it and the prior art “are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art.”
During the course of development, Pfizer submitted results to FDA to demonstrate that “there was no quantitative difference in efficacy between equivalent doses of amlodipine besylate tablets or capsules and amlodipine maleate capsules.” Additionally, an article titled “Pharmaceutical Salts” in J. Pharm. Sci., 66(1):1-19 (Jan. 1977) by Berge is considered as a prior art. Table 1 of Berge article shows 53 FDA-approved, commercially marketed anions, including benzene sulphonate (besylate salt), that are useful for making pharmaceutically acceptable salts at the time of invention.
The Appeal Court stated that “the prior art provided not only the means of creating acid addition salts but also predicted the results, which Pfizer merely had to verify though routine testing.” This decision indicates that “upon making a new acid addition salt, it was routine in the art to verify the expected physicochemical characteristics of each salt, including solubility, pH, stability, hygroscopicity, and stickiness.” These types of experiments does not “equivalent to the trial and error procedures.” As a result, the ‘303 patent is obvious over the ‘909 patent to a person having ordinary skill in the art at the time of the invention.
Pfizer claims that besylate salt of amlodipine is more stable than maleate salt. Is this a surprise to medicinal chemists or formulators? Let’s review the Michael reaction.
Michael reaction involves conjugate addition. According March’s advanced organic chemistry (5th ed. 2001), compound containing electron-withdrawing groups (Z) add, in the presence of bases, to alkenes of the form C=C-Z.
In this case, the double bond of maleate underwent an addition reaction with amlodipine (a primary amine base) causing the formation of “at least ten degradation products.” Besylate (bezenesulfonic acid) does not have this unsaturated double bond and does not undergo the Michael addition reaction. Improving stability of besylate salt over maleate salt is reasonably expected.
