Sanofi / regenerant PCSK9 antibody praluent faces a permanent ban on production and sales

Source: biopharmaceutical editor / Jone 2017-1-10 news event on January 5, 2017, because the defendant Sanofi / PCSK9 antibody pratuent of Zaiban infringed the two patents of the plaintiff into repatha, which caused irreparable damage and insufficient monetary compensation to the plaintiff, the Federal District Court of Delaware announced to pratuent With a permanent injunction, Sanofi / SGD cannot produce and sell praluent in the U.S market However, in view of the huge impact of the injunction on on the public and manufacturers, the court decided to postpone the enforcement for 30 days, so that the defendant could have an opportunity to appeal and the federal circuit act could speed up the review of the ruling, or reach an appropriate commercial solution with the plaintiff The praluent (alirocumab) and evolocumab of PCSK9 antibody Sanofi / regenerator are both PCSK9 inhibitors, which prevent them from degrading LDLR and eventually reduce LDL in blood In July and August 2015, they were approved by FDA to control LDL level in high-risk population (such as familial hypercholesterolemia, statin intolerance, etc.) PCSK9 is considered to be a potential lipid-lowering drug Although repatha and praluent have been sold slowly since they came into the market, it does not affect the fierce competition between Amgen and Sanofi First, Sanofi used a $67.5 million priority review coupon to get listed for one month, then Amgen chased Sanofi around the table patent At the beginning and end of the patent dispute, on October 17, 2014, Amgen sued Sanofi / realuent for infringing three patents of repatha (Patent No us8563698, us8829165 and us8859741) On February 22, 2016, Sanofi / realuent admitted infringing some claims claimed in Amgen's patent March 8, 2016 On March 16, 2016, the jury ruled that the claims in the patent of Amgen were valid On March 23-24, 2016, the court heard the evidence provided by the plaintiff's application for a permanent injunction against praluent On January 5, 2017, the court announced that it would grant a permanent injunction to praluent The implementation of the permanent injunction can not produce and sell praluent in the U.S market, and the decision to postpone the implementation of the patent dispute for 30 days involves the protection of PCSK9 binding epitope rather than the traditional antibody structure For details, please refer to the previous article of the small edition "[original] Amgen vs Sanofi: the role of epitope protection seen from the PCSK9 antibody patent dispute" The three patents involved in the dispute are us8563698, us8829165 and us8859741 On February 26, 2009, Amgen applied globally through PCT with wo2009026558 At present, there are nine authorized patents in addition to these three patents in the United States At the same time, there are only one in 2014 in China Authorized on June 25 These patents mainly protect the sequence, epitope and indication of PCSK9 antibody At present, there is no objection to the permanent injunction that Sanofi's praluent infringes the patent of Amgen repatha The dispute between the two sides is whether Sanofi's praluent complies with the permanent prohibition of production and sales Generally speaking, in order to obtain a permanent injunction against the other party, the plaintiff needs to prove the following points: (1) irreparable damage caused to the plaintiff; (2) relief measures provided by law, such as insufficient monetary compensation to make up for the loss; (3) difficult balance between the two parties; (4) the public interest will not suffer irreparable damage due to the permanent injunction Amgen claims that repatha has to face the competition of praluent due to the listing of Sanofi / Zahara's praluent, resulting in market share loss and this trend is expected to continue For example, when an insurance company signs a contract, it must compete with the defendant, which affects the plaintiff's exclusive prescription status, especially when the defendant is the first to list the product And because Sanofi / realuent claimed to be the first PCSK9 inhibitor to be listed at the time of listing, the reputation of the plaintiff was damaged The defendant believed that repatha was known to be the first PCSK9 inhibitor to be submitted to BLA and had been approved, and that even if praluent was not listed on the market, repatha would face price pressure Sanofi / zaharan obviously had insufficient reasons, and the final court supported the plaintiff The plaintiff believed that the patent protection was the basis of his business activities, and his investment in repatha could not be recovered without a permanent injunction Because Amgen wants to obtain market monopoly right through patent protection, he thinks that the money compensation given by law is insufficient in the current situation and that it is a kind of speculative behavior for the defendant to make money compensation at this time And the defendant thinks that the plaintiff has not suffered reputation damage, even if there is one, it can be measured At the same time, the author thinks that the monetary compensation is enough, but the calculation and compensation of reputation damage are not considered In the end, the court supported the plaintiff Both sides spent hundreds of millions of dollars and more than ten years to launch their products If there is no permanent injunction against the defendant, the plaintiff loses the market share of the defendant and faces continuous competition If a permanent injunction is imposed on the defendant, the defendant will lose the right to continue the production and sale of praluent In the end, the court held that the influence of this factor on the two countries was the same and judged as neutral The plaintiff in the public interest is the owner of the patent and the winner of the award The plaintiff pointed out that the FDA approved repatha can treat all patients covered by praluent, so it can alleviate the impact of the ban The defendant pointed out that doctors and patients prefer to use 75 mg dose of praluent (80% of patients use 75 mg dose) and 75 mg dose is also the recommended starting dose approved by the label, so the ban will damage the treatment of patients At this point, the court faces a dilemma, one side is the patent owner and the winner of the ruling, the other side is the public interest, but in the end, the court believes that it supports the defendant in the public interest Conclusion on the basis of the above reasons, the plaintiff proves that the defendant caused irreparable damage to it, and the money compensation given by law is not enough to make up for the loss Although it is in the public interest of the defendant, the court finally announced a permanent injunction against praluent However, considering the potential impact of the injunction on on the public and parties, the court decided to postpone the enforcement for 30 days, give the defendant the opportunity to appeal and speed up the review of the ruling by the federal circuit act, or reach some form of commercial solution with the plaintiff The case reveals that the patent dispute between Sanofi / Zaiyuan and Amgen has basically come to an end Although Sanofi / Zaiyuan claims that Amgen's patent is invalid and appeals, it is unlikely to reverse the plot The licensing of Sanofi / SGD may only be in the public interest, but the compromise plan is to reach a settlement between the two parties and charge a certain amount of compensation fees and royalties The final result will be determined one month later The unexpected termination of Pfizer's PCSK9 antibody bococizumab after the completion of phase III may also have patent infringement considerations in addition to immunogenicity reasons Amgen's patent is extended to the protection of epitopes, which greatly extends the scope of patent protection and creates patent barriers for the latecomers If epitope protection becomes a trend, it can be predicted that bio too antibody will not appear in the market in the future (the difficulty of patent challenge can be imagined), even if there is, it will take a lot of efforts to avoid the protected epitopes with the help of structural biology This change may change the research and development pattern of antibody drugs and even drugs, greatly increasing the difficulty of research and development of antibody drugs with the same target, but at the same time, it will also benefit the research and development pattern of drugs based on other mechanisms, such as antisense RNA and siRNA, which avoid the epitope level In fact, inclsiran, a siRNA drug targeting PCSK9 mRNA by Alnylam, is in phase II clinical stage For more PCSK9 product lines, please refer to "statistics of target drugs for PCSK9 research at home and abroad" Reference: regeneron website: http://www.ded.uscourts.gov/options/amgen-inc-amgen-manufacturing-limited-and-amgen-usa-inc-v-sanofi-sanofi-aventis-us-llc-0