Ramipril and Orange Book Status Ramipril was disclosed in U.S. Patent No. 4,587,258 assigned to Schering Corporation and which later expired on January 27, 2005 (received 632 days patent term extension). Marketed by King Pharms, Ramipril is present in US market under the brand name ALTACE and was approved by USFDA on January 28, 1991 with four strengths (1.25mg, 2.5mg, 5mg, and 10mg). Till date there are two orange book listed U.S. Patents for ramipril --- 5,061,722 and 5,403,856. ‘722 patent covers ramipril isomers, their hypotensive compositions, and their method of use for reducing blood pressure. ‘856 patent covers method of using ramipril for treating cardiac insufficiency. USFDA has approved ramipril to treat hypertension, heart failure, and to reduce the risk of heart attack, stroke, and death from cardiovascular causes. Patent Infringement against Cobalt Para IV Certification On March 14, 2003 King Pharms and Aventis Pharma jointly filed patent infringement lawsuit against Cobalt Pharmaceuticals in the District Court for the District of Massachusetts in response of abbreviated new drug application (ANDA) under Para IV certification submitted on November 22, 2002 with USFDA seeking approval to market generic ramipril capsules. In Para IV certification, Cobalt challenged the validity the ‘722 patent contending that the patent is unenforceable due to Aventis’s inequitable conduct in prosecuting the ‘722 patent before United States Patent & Trademark Office concerning the first-to-invent dispute over ramipril with Schering Corporation’s ‘258 patent. Initially, Cobalt Para IV certification do not include any statement regarding ‘856 patent because it was not listed with Orange Book until Aventis and King filed infringement suit. Upon learning of the ‘856 patent, Cobalt subsequently informed FDA that it was seeking approval for indication covered by the ‘856 patent, that is, treating heart failure. Cobalt also amended its proposed labeling with the FDA and removed the pharmacological information regarding the use of ramipril for treating heart failure and only limit its intention to market generic ramipril solely for treating hypertension and reducing the risk of heart attach, stroke, and death from cardiovascular causes. However, King Pharms & Aventis filed additional patent infringement suit regarding ‘856 patent contending that Cobalt will actively induce or contribute to infringement by others and will indirectly infringe the ‘856 patent because doctors will prescribe generic ramipril for treating heart failure. Summary Judgment for the ‘856 patent Regarding the ‘856 patent, Cobalt moved for summary judgment on Aventis/King contention that Cobalt’s generic ramipril will indirectly infringe the ‘856 patent. Court maintained that there is no genuine dispute regarding the ‘856 patent as Aventis/King has never asserted that the ‘856 patent claims the “reduction of risk” indication, and they have not challenged Cobalt’s assertion that the ‘856 patent does not claim the reduction of risk indication. On this basis, the court granted Cobalt summary judgment of non-infringement of the ‘856 patent. Summary Judgment for the ‘722 patent Aventis & King moved for summary judgment on Cobalt’s affirmative defense of inequitable conduct before USPTO during prosecution of ‘722 patent. Cobalt contended that the ‘722 patent is unenforceable due to Aventis’s inequitable conduct before USPTO, specifically, alleging that Aventis submitted materially false and misleading statements, in several affidavits, to the USPTO during prosecution of ‘722 patent. To counter Aventis/King motion for summary judgment, Cobalt supported their contention with supporting evidence on following facts that - 1) In 1980 Merck introduced enalapril, which was further used by Schering Corporation as a “lead structure” in developing the ramipril compound for which U.S. patent application was filed on July 30, 1984 and against which ‘258 patent was granted on May 06, 1986. 2) In November 1985, Aventis also filed a U.S. patent application for ramipril which was initially rejected by USPTO on the grounds that Schering had been first to develop ramipril against which Aventis responded that the ‘258 patent did not enable a person of ordinary skill in the art to produce ramipril and submitted several affidavits to the USPTO, over a five year period, supporting its claim that the ‘258 patent did not enable synthesis of the ramipril isomer. 3) In November 1986, Aventis submitted the declaration of Dr. Hanjorg Urbach to the USPTO that the method of synthesizing ramipril described in the ‘258 patent did not work. During trial proceedings Cobalt’s expert, Dr. Michael Crimmins asserted that Dr. Urbach’s experiment failed to apply ordinary chemical synthesis protocols when replicating the ‘258 patent process. Further, he also asserted that Dr. Urbach’s statement were materially false because someone skilled in the relevant art of 1981 only needed to know ramipril’s chemical structure to reproduce the compound. 4) In January 1988, in order to determine priority, USPTO declared an interference proceeding between Aventis’s application and Schering’s ‘258 patent. Cobalt contended that Aventis conceded priority to Schering and purchased Schering’s license by taking a license, promising to pay Schering a royalty on Aventis’s future sales. 5) Later, Aventis submitted declarations of Dr. Reinhard Becker to the USPTO asserting new claims to a “superior” and “substantially more effective” version of ramipril-a purer “all S” isomer. Dr. Becker claimed that the purer “all S” isomer was “far superior” to the compounds claimed by the ‘258 patent. During trial proceedings, Cobalt’s expert, Dr. John Caldwell, claimed that Dr. Baker failed to make highly relevant comparisons between the allegedly “superior” ramipril and other ramipril isomers. Further, he also asserted that Dr. Becker misrepresented the sources of test results and failed to disclose the inaccuracy of his test methods. 6) On January 12, 1989, Aventis filed a patent application for these claims to the superior ramipril isomer and yet again had to confront the prior art. In March 1989, Aventis submitted the affidavit of Dr. Volker Teetz to the USPTO claiming that the ‘722 patent did not work and only produced small amounts of ramipril when Teetz employed “extraordinary” procedures not revealed by the prior art. Cobalt’s expert asserted that these statements were false and misleading and the Dr. Teetz’s own laboratory notebooks plainly contradict his conclusions. 7) On October 29, 1991 USPTO granted Aventis the ‘722 patent. Aventis states that Drs. Urbach, Becker, and Teetz submitted declarations to the USPTO attempting to correct some of their earlier mistakes and updating the USPTO with more accurate data and test results. Cobalt insisted that these corrections were either insufficient or misleading. And further argued that that neither Dr. Urbach not Dr. Teetz cured their false testimony regarding the ‘258 patent. Court, however, concluded that elements of materiality and intent are reasonably disputed and thereby denied Aventis/King summary judgment on inequitable conduct of the ‘722 patent. Settlement between Aventis/King and Cobalt After more than a year from obtaining District Court order, on February 27, 2006 Aventis/King and Cobalt agreed to enter into an agreement to dismiss the pending litigation relating to the enforcement of ‘722 patent. The parties agreed that, subject to certain conditions, with 38 days of singing the agreement, will submit a joint stipulation dismissing without prejudice the litigation before the U.S. District Court for the District of Massachusetts. Additionally, King has granted Cobalt a non-exclusive and non-transferable right to enter into the U.S. ramipril market with a generic capsule formulation of ramipril, which would be supplied by King. Lupin --- Another Para IV Filer In July 2005, King/Aventis has filed patent infringement lawsuit against yet another ANDA filer – Lupin in the U.S. District Courts for the District of Maryland and the Eastern District of Virginia in response of Para IV certification made to USFDA seeking approval for generic ramipril capsule. Lupin in its Para IV certification challenged the validity and enforceability of the ‘722 patent. On February 01, 2006 the Maryland and Virginia cases were consolidated into a single action in the Eastern District of Virginia. Trial is currently to begin on June 06, 2006. Long Live King’s Ramipril Whatever may be the outcome between King/Aventis and Lupin patent lawsuit, one thing is sure that 180-days exclusivity is gone with the entry of Cobalt’s generic ramipril but what cannot be ignored is Lupin’s chances of wining this lawsuit, particularly in the light of arguments made by Cobalt during summary judgment for ‘722 patent.