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Repatha Vs. Praluent: Will Amgen’s Patents Decide The Race For The Prevailing PCSK9 Inhibitor?

Date:2017-01-07 14:26

Amgen’s Repatha and Sanofi/Regeneron’s Praluent are competing for market share in the new class of PCSK9 inhibitors for high-risk cholesterol patients after both were approved by FDA this summer.
Amgen is seeking to bar Praluent from the market based on a lawsuit alleging that Sanofi and Regeneron are infringing multiple Amgen patents.
A recent claim construction hearing in the patent lawsuit suggests that Sanofi and Regeneron may have an advantage in the case.
The patent case is scheduled for trial in March 2016.

Amgen, Inc. (NASDAQ:AMGN) recently scored a victory in its competition with Sanofi (NYSE:SNY)/Regeneron (NASDAQ:REGN) for the prevailing PCSK9 inhibitor. On November 23, 2015, Amgen got a leg up in that competition on its announcement that Repatha will be the only PCSK9 inhibitor offered by CVS (NYSE:CVS) commercial formularies.

Repatha’s exclusive relationship with CVS will help boost its sales, but other factors will be critical as the companies jockey for the winning PCSK9 inhibitor. This article addresses one of those factors in particular, namely, Amgen’s attempt to box out Sanofi and Regeneron from the market on the grounds their drug infringes Amgen’s PCSK9 patents. Amgen has sued Sanofi and Regeneron for patent infringement in the District of Delaware, wherein Amgen has accused Praluent of infringing multiple patents owned by Amgen. The case is heating up quickly, and it is scheduled to go to trial in March 2016. A permanent injunction hearing is also scheduled in late March, which means if Amgen is successful, Praluent could be off the market by early next year.

Both companies received FDA approval this summer to market a PCSK9 inhibitor for high-risk cholesterol patients. Sanofi’s Praluent was approved on July 24, 2015, and Amgen’s Repatha shortly thereafter on August 27, 2015. This spawned a fierce competition for market share in the burgeoning market for a new class of cholesterol drugs for high-risk patients.

The upcoming patent trial is important to investors because Amgen is seeking an injunction to bar Praluent from the market if successful in the suit. And even if it cannot obtain an injunction, an ongoing royalty rate would potentially allow Amgen to capture some of Praluent’s revenue.

Repatha® vs. Praluent®

Both drugs comprise antibodies that target a protein (PCSK9) that plays a role in increasing “bad” cholesterol (LDL). While statin pills, such as Pfizer’s (NYSE:PFE) Lipitor, remain traditional treatments for high cholesterol, Repatha and Praluent are for those patients who do not effectively respond to statins, and potentially suffer from hereditary high cholesterol conditions, such as hypercholesteralimea. Repatha and Praluent are currently the only two drugs approved in this new class of PCSK9 inhibitors.

As Repatha and Praluent have started fighting for market share, observers have already noted that the comparative merits of the drugs are relatively equal. Further, the prices are currently relatively the same, with Repatha priced at $14,100 per year, and Praluent at $14,600 per year. Thus, other typically less important factors may prove important in the drugs’ competition.

For instance, the dosages are different. Repatha has monthly injections at higher dosages, and Praluent only offers bi-weekly injections. Doctors may view Repatha’s single monthly dosage, which is more potent, as more convenient. Repatha can also be stored at room temperature for 30 days, thus offering another convenience factor over Praluent, which must be refridgerated after 24 hours. On the other hand, Sanofi has a larger marketing force with heart doctors, which may give it an edge. And Sanofi is promoting that it is a leader in injectables.

Amgen’s Patent Lawsuit Against Sanofi and Regeneron

Given the competitive proximity of the drugs, another factor that may prove critical in the battle between Repatha and Praluent is the patent-infringement lawsuit that Amgen recently waged against Sanofi and Regeneron. Amgen commenced the lawsuit on October 17, 2014 in the United States District Court for the District of Delaware with the assertion of U.S. Patent Nos. 8,563,698, 8,829,165, and 8,859,741. Followup suits added additional patents as they issued from the Patent Office.

This included another lawsuit commenced on October 28, 2014 asserting U.S. Patents 8,871,913 and 8,871,914, that issued from the Patent Office the same day. Then, another lawsuit on November 11, 2014 asserting U.S. Patent No. 8,883,983, which issued the same day. And, finally one on November 18, 2014, asserting U.S. Patent No. 8,889,834, which issued on that day.

The cases were subsequently consolidated with the original action (Civil Action No. 14-01317). In total, Amgen originally asserted infringement of seven patents by Sanofi’s Praluent PCSK9 inhibitor drug. In March 2015, the district court ordered Amgen to narrow the number of claims to be tried. Amgen narrowed the case to 18 claims from the first three patents asserted (‘165, ‘751, ‘914 patents).

The stakes of this case are technically large. Amgen is seeking to permanently enjoin Praluent from the market if Sanofi and Regeneron are found to infringe one or more of its patents. In the event that Amgen wins at trial, the district court in Delaware has already scheduled a hearing on March 23 and 24, 2016 to address Amgen’s request for a permanent injunction.

Technically, that means that Sanofi could be barred from selling Praluent as early as March of next year. Apart from an injunction, Amgen is more realistically seeking future royalties on every sale of Sanofi’s Praluent product. This could be a boon for Amgen if, in addition to reaping 100% of its own sales, it can recoup a percentage (most likely a single-digit percentage) of Sanofi’s sales.

The case is currently scheduled for a seven-day jury trial beginning March 7, 2016. This is relatively unusual for a pharmaceutical patent litigation, which are not typically tried in front of a jury, but rather in front of Judge (known as a bench trial.) Yet, that is because most patent litigation between pharmaceutical companies is waged between a brand pharmaceutical company suing under the Hatch-Waxman Act to enjoin generic pharmaceutical companies that have filed Abbreviated New Drug Applications (ANDAs).

By contrast, Amgen’s dispute with Sanofi/Regeneron is not under the Hatch-Waxman Act. The Hatch-Waxman Act applies to small-molecule drugs, whereas Sanofi’s Praluent is a biologics drug. Biologics are regulated under the Biologics Price Competition and Innovation Act (BPCIA), but this dispute is not under that Act either. That is because Sanofi’s Praluent is not a proposed biosimilar version of Amgen’s Repatha. Rather, both companies applied for and received approval from the FDA to sell their own versions of PCSK9 inhibitors. In sum, this is a run-of-the-mill patent dispute between two competitors each selling similar products, and as a result, the case will be tried in front of a jury.

The consequences of having this case heard before a jury rather than a judge are important. Most Hatch-Waxman cases are, for the most part, tried before Judges in Delaware or New Jersey who are well versed in patent law as well as the basic chemistry behind many small-molecule pharmaceutical patents.

This case is housed in Delaware, which in addition to presiding over numerous Hatch-Waxman cases, is also one of the busiest districts in the country for patent cases. The juries there are known for being typically pro-plaintiff. Yet, the cases that reach juries in Delaware are often between a non-practicing plaintiff/patent-holder and a large corporate defendant. By contrast, this case is not a David and Goliath story, and it is unlikely Amgen will have the typical plaintiff’s advantage.

The Claim Construction Order

It remains too early to predict whether Amgen can successfully enjoin Praluent from the market. However, a recent hearing in the case suggests that Sanofi and Regeneron may have gained an advantage. In late October, the district court issued a claim construction order that construed certain terms from the three patents to be tried. Sanofi prevailed on many of its constructions, which for the reasons discussed below, suggest that it may have the upper hand going into trial.

The claim construction process, commonly known as the Markman hearing, is a proceeding unique to patent cases during which the Judge construes certain disputed terms and phrases within the asserted claims. At the back of every patent are a series of claims. Those claims are the most important part of every patent because they, in effect, lay out the meets and bounds of the invention. Proving infringement of a patent requires showing that each element of an asserted claim is present within the alleged infringing product.

Yet, during a patent case, the parties typically dispute the scope of different claim elements. For instance, assume a patent claim is directed to a chair with “multiple legs.” If the accused product has three legs, but the patent only discloses embodiments with four legs, the parties may dispute whether the claim – which only recites “multiple legs” – requires specifically four legs, or just plural legs. That determination can be determinative of whether there is infringement, likewise, whether the patent-holder or the accused infringer prevails in the case.

Yet, claim constructions can also be determinative of whether the claim is invalid. For instance, in the chair example, if the court construes the claim broadly, and finds that the claim is not limited to four legs only, but simply requires multiple legs, then that will make it easier for the plaintiff to prove infringement. Yet, it will correspondingly make it easier for the defendant to show the claim is invalid. That is because, the broader a claim is, the higher the likelihood it falls within prior art. Thus, claim construction is typically a very strategic process during which the plaintiff needs to carefully stake out constructions that will help them on infringement, but not hurt them on invalidity.

Amgen’s case against Sanofi is a case in point. The principal observation from the Markman hearing in this case is that Amgen has primarily pursued broad claim constructions. That suggests that it is more concerned about proving infringement than avoiding invalidity.

Amgen’s patents are directed to antibodies that bind to PCSK9 proteins. Humans with high-risk cholesterol often have high levels of “bad” cholesterol, known as “LDL.” In humans who are not at risk, that “bad” cholesterol is flushed from the body after it binds with LDL receptors that degrade it. By contrast, humans with high-risk cholesterol do not adequately degrade “bad” LDL, yielding high LDL levels. The reason LDL levels are high is because there is an excess of protein PCSK9 that binds to LDL and its receptors. When it does, it prevents the “bad” LDL cholesterol from degrading and flushing from the body. Thus, both Repatha and Praluent work by introducing an antibody into the body that binds with PCSK9, thereby blocking it from binding to LDL and its receptor. By binding to PCSK9, and barring it from binding to LDL and its receptors, the “bad” LDL cholesterol can properly degrade and flush from the body.

Thus, the active ingredients in Repatha and Praluent include specific antibodies that bind to PCSK9. Antibodies are proteins that are made up of chains of amino acids. Each amino acid within the chain, which is a molecule, is commonly referred to as a “residue.” There are only twenty naturally-occurring amino acids, and thus antibodies differ by their arrangement of hundreds of different amino acids.

PCSK9 is also a protein that, like antibodies, is also made of a chain of hundreds of amino acids. In nature, the chains of amino acids that make up antibodies and PCSK9 do not exist in a straight line, but rather in three-dimensional folds of the chains. When they bind together, the three-dimensional folded chain of hundreds of amino acids of the antibody binds to the three-dimensional folded chain of hundreds of amino acids making up PCSK9. The way they actually “bind” is when one amino acid in the antibody forms a non-covalent bond with a corresponding amino acid in PCSK9.

The bonds between these individual amino acids in the antibody and PCSK9 are each relatively weak. Yet, when a sufficient number of amino acids bond between the antibody and PCSK9, the result can add up to a bond between the two proteins that is sufficiently strong. When that happens, the antibody and PCSK9 are described as having a higher “affinity.”

When they have high “affinity,” then the antibody can successfully bind to PCSK9, and block it from binding to LDL and its receptors. Though numerous bonds between amino acids in the antibody and PCSK9 are needed to have a high “affinity,” in practice, only a small portion of the overall three-dimensional antibody binds to, or “recognizes,” a small portion of the overall PCSK9 protein. In other words, the two proteins only need to kiss in order for the antibody to effectively bind to PCSK9 and reduce LDL levels.

Even though Amgen’s Repatha drug itself includes the administration of a specific antibody for binding to PCSK9 proteins, the patents are different. The patents themselves do not necessarily claim that protein. Rather, they are much broader than that, and this may have implications for Amgen’s success in its patent case. For instance, one of the principal claims that has been asserted by Amgen in the case comes from U.S. Patent No. 8,829,165, and is set forth below.

1. An isolated monoclonal antibody, wherein, when bound to PCSK9, the monoclonal antibody binds to at least one of the following residues: S153, I154, P155, R194, D238, A239, I369, S372, D374, C375, T377, C378, F379, V380, or S381 of SEQ ID NO:3, and wherein the monoclonal antibody blocks binding of PCSK9 to LDLR.

As can be seen from his language, this claim does not specify a specific antibody in terms of what it is, i.e., the series of amino acids making up the antibody. Rather, the claim specifies antibody in terms of what it does.Specifically, the claim recites an antibody that binds to PCSK9 at specific “residues.” That means, the claim recites an antibody that binds to specific amino acids in the PCSK9 chain. More importantly, the claim states that the antibody only has to bind “to at least one of the following residues.” In patent parlance, that means that any antibody in the universe that binds to just one of the enumerated amino acid residues in the PCSK9 chain will infringe this patent, and potentially be enjoined from the market.

Overall, Sanofi and Regeneron appear to have prevailed on many of the important claim constructions during the Markman hearing. A listing of the claim terms construed by the district court is set forth below.

On the first term (an isolated monoclonal antibody), Amgen argued that the phrase did not include “fragments” of an antibody, but was limited only to intact molecules. The district court disagreed, and found the claimed antibody can include fragments thereof. This is a win for Sanofi that may prove important. Amgen was effectively trying to narrow the claim, presumably to avoid potentially invalidating prior art. Because the claim has been determined to cover antibody fragments, Sanofi can potentially rely upon prior art of amino acids binding to PCSK9, which is potentially a much large field of art than that disclosing specific intact antibodies.

On the second term (binds to residues), Amgen argued for a broad construction that required only that corresponding amino acids in the antibody and the PCSK9 protein “interact.” That broad construction would presumably have made infringement much easier because, as Sanofi argued, proximity alone between amino acids in the antibody and those in the PCSK9 protein would potentially meet this claim limitation. In other words, if part of the antibody simply covers the PCSK9 protein, without any non-covalent for bonds forming, that may yield infringement under Amgen’s construction. The district court disagreed with Amgen, however, and found that only those antibody amino acids “binding to” residues in the PCSK9 protein that contribute to the “affinity” of the antibody/PCSK9 interaction fall within the claim.

On the third and fourth terms (epitope and functional epitope), these terms only appear in one of the patents at issue during the Markman hearing (the ‘741 Patent). The district court’s constructions, which are slight departures from each party’s proposed respective construction, is broad. This will likely assist Amgen’s proof of infringement for the ‘741 Patent, but also assist Sanofi’s proof of invalidity.

On the fifth term (PCSK9), the parties once again disputed whether the claims cover intact PCSK9 proteins alone, or also include fragments thereof. Amgen argued against including fragments, presumably to narrow the claim and avoid potentially invalidating prior art. The district court disagreed, and found the PCSK9 proteins recited in the claims includes fragments thereof.

On the sixth term (human antibody), the parties disputed whether the claimed antibody must be made from human genes, or can alternatively be made from rabbit or mice genes. In other words, antibodies for administration to humans can technically be made from rabbit or mouse genes, provided certain amino acid chains are replaced so that the resulting antibody “looks human” to the patient. Amgen argued some of the claims encompass these types of antibodies (which is a broad construction, and would presumably make infringement easier to prove.) Sanofi argued that the claimed antibodies must be encoded from human genes. This is a potentially important dispute for some of the claims because Praluent may not be manufactured from human genes alone. The district court has deferred determining this dispute pending more expert discovery.

Upcoming Events

Although Sanofi appears to have prevailed on many of the terms at issue during the Markman hearing, two additional developments in the case suggest it remains at risk.

First, Amgen recently moved for leave to file an amended complaint based upon willfulness evidence it allegedly unearthed during discovery. Amgen alleged that Regeneron previously identified one of the asserted patents (the ‘165 Patent) during prosecution of one of its own patents, thus evidencing knowledge of the asserted patent prior to the case. Amgen also identified numerous documents produced by Regeneron allegedly showing prior knowledge of the ‘165 Patent. These documents are not publicly available, but Regeneron has claimed that they do not even mention the ‘165 Patent.

While the district court will likely grant Amgen’s request to amend its complaint in some respect, it will nevertheless remain difficult for Amgen to prove willful infringement. The bar for doing so is fairly high, and it typically requires more than simply an identification of the patent on an information disclosure statement during prosecution of an unrelated patent. And most of the patents asserted in this case issued the day the complaints were filed. Given all this, based on the information that is publicly available, willfulness is not likely to add to Amgen’s damages.

Separately, the parties recently disputed whether Sanofi/Regeneron were required to produce a technical document showing how its drug contacts and interacts with the residues of the PCSK9 protein. Sanofi opposed production of this document, even though it appears to be highly relevant, on the grounds that it was privileged. The district court disagreed, and ordered its production. The document is not publicly available, and it is not clear whether it will assist Amgen’s proof of infringement. Yet, when a party strenuously opposes the production of a technical document during a patent litigation, there is usually a reason for doing so. The substance of this document may prove helpful to Amgen down the road.

The case is currently completing expert discovery. As the case nears trial in March 2016, we expect more procedural and substantive briefs and motions that will require analysis, and shed better light on the respective merits – and outcome – of this case.

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