DCT
1:14-cv-01317
Amgen Inc v. Sanofi
Key Events
Amended Complaint
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Amgen Inc. (Delaware)
- Defendant: Sanofi (France); Sanofi-Aventis U.S. LLC (Delaware); Aventisub LLC (Delaware); Regeneron Pharmaceuticals, Inc. (New York)
- Plaintiff’s Counsel: Young Conaway Stargatt & Taylor, LLP; McDermott Will & Emery LLP
- Case Identification: 1:14-cv-01317, D. Del., 11/17/2014
- Venue Allegations: Venue is alleged to be proper in the District of Delaware because several Defendant entities are organized under the laws of Delaware, conduct business in the state, and have previously availed themselves of the forum by filing lawsuits there.
- Core Dispute: Plaintiff alleges that Defendants' anti-PCSK9 antibody, alirocumab, developed for treating high cholesterol, will infringe three of its patents covering monoclonal antibodies that bind to the PCSK9 protein.
- Technical Context: The technology concerns a class of biologic drugs (monoclonal antibodies) that inhibit the protein PCSK9 to lower LDL ("bad") cholesterol, representing a significant therapeutic alternative or supplement to traditional statin drugs.
- Key Procedural History: The complaint notes a long-standing collaboration between Defendants Sanofi and Regeneron, dating back to at least November 2007, for the research and development of antibody products, including the accused alirocumab. This action was filed as a declaratory judgment action in anticipation of Defendants' imminent submission of a Biologics License Application (BLA) to the FDA and subsequent commercial launch.
Case Timeline
| Date | Event |
|---|---|
| 2007-11-28 | Sanofi and Regeneron collaboration agreement executed |
| 2007-12-21 | Earliest Priority Date for '698 and '741 Patents |
| 2008-08-04 | Earliest Priority Date for '165 Patent |
| 2013-10-22 | U.S. Patent No. 8,563,698 Issues |
| 2014-08-28 | Amgen submits BLA for its own anti-PCSK9 antibody, evolocumab |
| 2014-09-09 | U.S. Patent No. 8,829,165 Issues |
| 2014-10-14 | U.S. Patent No. 8,859,741 Issues |
| 2014-11-17 | Complaint Filed |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 8,563,698 - Antigen binding proteins to proprotein convertase subtilisin kexin type 9 (PCSK9)
- Patent Identification: U.S. Patent No. 8,563,698, Issued October 22, 2013.
The Invention Explained
- Problem Addressed: High levels of low-density lipoprotein cholesterol (LDL-C) are a primary cause of cardiovascular disease (Compl. ¶27). The protein PCSK9 circulates in the body and binds to LDL receptors on the surface of liver cells, causing the receptors to be degraded (Compl. ¶30). The degradation of LDL receptors reduces the liver’s ability to remove LDL-C from the blood, leading to elevated cholesterol levels (’698 Patent, col. 1:53-65).
- The Patented Solution: The invention is an isolated monoclonal antibody that specifically binds to the PCSK9 protein (’698 Patent, Abstract). By binding to PCSK9, the antibody acts as an antagonist, preventing PCSK9 from interacting with LDL receptors. This interference allows more LDL receptors to remain on liver cell surfaces to clear LDL-C from the bloodstream, thereby lowering a patient's cholesterol (Compl. ¶31; ’698 Patent, col. 2:9-13).
- Technical Importance: This approach provided a novel biological mechanism to treat high cholesterol, particularly for patients who do not respond well to or cannot tolerate traditional statin therapies (Compl. ¶28).
Key Claims at a Glance
- The complaint does not identify specific asserted claims but makes a general allegation of infringement (Compl. ¶65). Claim 1, as the broadest independent claim, is representative of the patent’s scope.
- Claim 1 of the ’698 Patent requires:
- An isolated monoclonal antibody
- wherein, when bound to PCSK9, said monoclonal antibody binds to at least one residue within the sequence set forth by residues 153-172 of SEQ ID NO:3
- and wherein said monoclonal antibody reduces binding between PCSK9 and an EGFa domain of LDLR
- and antagonizes PCSK9 inhibition of cellular LDL uptake.
U.S. Patent No. 8,829,165 - Antigen binding proteins to proprotein convertase subtilisin kexin type 9 (PCSK9)
- Patent Identification: U.S. Patent No. 8,829,165, Issued September 9, 2014.
The Invention Explained
- Problem Addressed: As with the related '698 Patent, this invention targets the role of PCSK9 in degrading LDL receptors, which leads to elevated LDL-C levels (’165 Patent, col. 1:55-66).
- The Patented Solution: The patent discloses specific monoclonal antibodies that bind to a particular region (epitope) on the PCSK9 protein, thereby blocking its ability to bind to the LDL receptor (LDLR) (’165 Patent, col. 2:10-14). This inhibition preserves LDL receptor function and promotes the clearance of LDL-C from the blood (Compl. ¶31).
- Technical Importance: By identifying specific binding residues on the PCSK9 protein, the invention provides a defined structural basis for designing effective antibody therapies against a key target in cholesterol metabolism.
Key Claims at a Glance
- The complaint does not identify specific asserted claims but makes a general allegation of infringement (Compl. ¶70). Claim 1 is representative of the patent's scope.
- Claim 1 of the ’165 Patent requires:
- An isolated monoclonal antibody that binds to PCSK9
- wherein the isolated 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 where the monoclonal antibody blocks binding of PCSK9 to LDLR.
U.S. Patent No. 8,859,741 - Antigen binding proteins to proprotein convertase subtilisin kexin type 9 (PCSK9)
- Patent Identification: U.S. Patent No. 8,859,741, Issued October 14, 2014.
Technology Synopsis
This patent, part of the same family as the '698 and '165 patents, also claims monoclonal antibodies that inhibit PCSK9 to lower cholesterol (’741 Patent, col. 1:55-66). It defines its antibodies by their binding to a specific epitope on the PCSK9 protein, thereby blocking the interaction between PCSK9 and the LDL receptor (’741 Patent, Abstract).
Asserted Claims
The complaint does not specify which claims are asserted (Compl. ¶75). Claim 1 is representative, requiring an isolated monoclonal antibody that binds an epitope on PCSK9 comprising at least one of residues 237 or 238 of SEQ ID NO: 3, and which blocks the binding of PCSK9 to the LDL receptor.
Accused Features
The accused feature is the alirocumab antibody product (Compl. ¶75).
III. The Accused Instrumentality
Product Identification
The accused instrumentality is Defendants’ monoclonal antibody known by the compound name "alirocumab" (also referred to as "REGN727" and "SAR236553") (Compl. ¶1, ¶43). Defendants intend to market the product under the brand name "Praluent" (Compl. ¶56).
Functionality and Market Context
Alirocumab is alleged to be a fully human monoclonal antibody that targets the PCSK9 protein (Compl. ¶43). Its alleged mechanism of action is to bind to PCSK9 and block its interaction with LDL receptors, which increases the recycling of those receptors and thereby reduces LDL cholesterol levels in the blood (Compl. ¶44). The complaint alleges that Defendants are preparing for a commercial launch in the United States in the second half of 2015 and have begun "building inventory" of the product (Compl. ¶54, ¶58). Alirocumab is positioned as a direct competitor to Amgen’s own anti-PCSK9 product, evolocumab (Compl. ¶60, ¶62).
No probative visual evidence provided in complaint.
IV. Analysis of Infringement Allegations
The complaint does not provide a detailed mapping of claim elements to the features of alirocumab. The infringement theory is based on the general allegation that alirocumab is a monoclonal antibody that performs the same function as the claimed inventions (Compl. ¶44-45).
'698 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| An isolated monoclonal antibody... | Alirocumab is described as a "fully human monoclonal antibody product" and "a monoclonal antibody to PCSK9." | ¶43, ¶44 | col. 401:1-2 |
| ...when bound to PCSK9, said monoclonal antibody binds to at least one residue within the sequence set forth by residues 153-172 of SEQ ID NO:3... | The complaint makes a conclusory allegation that alirocumab is "a monoclonal antibody as claimed in Amgen's '698...Patent[]" but provides no specific facts regarding binding to this residue range. | ¶45 | col. 401:2-5 |
| ...and wherein said monoclonal antibody reduces binding between PCSK9 and an EGFa domain of LDLR and antagonizes PCSK9 inhibition of cellular LDL uptake. | Alirocumab is reported to "block the interaction of PCSK9 with LDL receptors" and "reduces LDL cholesterol levels in the blood." | ¶44 | col. 401:5-9 |
'165 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| An isolated monoclonal antibody that binds to PCSK9... | Alirocumab is described as a "monoclonal antibody to PCSK9." | ¶44 | col. 428:44-45 |
| ...wherein the isolated 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... | The complaint makes a conclusory allegation that alirocumab is "a monoclonal antibody as claimed in Amgen's...'165...Patent[]" but provides no specific facts regarding binding to this specific list of residues. | ¶45 | col. 428:46-52 |
| ...and where the monoclonal antibody blocks binding of PCSK9 to LDLR. | Alirocumab is reported to "block the interaction of PCSK9 with LDL receptors." | ¶44 | col. 428:52-53 |
Identified Points of Contention
- Evidentiary Questions: The complaint does not provide any factual evidence (e.g., from scientific publications or clinical trial data) demonstrating that alirocumab actually binds to the specific amino acid residues or epitopes recited in the claims of the '698, '165, and '741 patents. The central technical dispute will likely concern epitope mapping and binding analysis to determine if the accused antibody meets these precise structural limitations.
- Scope Questions: The claims are directed to an "isolated" monoclonal antibody. The litigation may explore whether the accused product, as manufactured, formulated, and administered, meets the legal definition of "isolated." Further, the functional requirement to "block" or "reduce" binding will likely be a point of contention regarding the degree and method of measurement required to meet the claim limitation.
V. Key Claim Terms for Construction
The Term: "binds to at least one residue within..." ('698 Patent, Claim 1) and "binds to at least one of the following residues..." ('165 Patent, Claim 1)
- Context and Importance: These terms are central to defining the patents' scope. The infringement analysis will depend entirely on whether alirocumab can be proven to bind to the specific amino acid locations on the PCSK9 protein recited in the claims. Practitioners may focus on these terms because the case will turn on the scientific evidence (e.g., X-ray crystallography, binding assays) used to prove or disprove that the accused antibody binds to these exact locations.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The specification suggests that binding can be determined by various methods, including assays that measure a reduction in binding affinity to mutant PCSK9 proteins where a key residue has been altered. This may support an argument that direct atomic contact is not required, and a functional or proximate interaction is sufficient (’698 Patent, col. 59:22-67).
- Evidence for a Narrower Interpretation: The patents provide crystal structure data for exemplary antibodies and identify "core," "boundary," and "contact" residues with high precision (e.g., within 5 angstroms) (’698 Patent, col. 101:53-col. 102:45). This may support an argument that "binds to" requires a direct, structurally defined interaction with the specified residue(s).
The Term: "blocks binding of PCSK9 to LDLR" ('165 Patent, Claim 1) / "reduces binding between PCSK9 and an EGFa domain of LDLR" ('698 Patent, Claim 1)
- Context and Importance: This functional language is critical for infringement and validity. The dispute will likely focus on how much "blocking" or "reducing" is required to infringe.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The specification describes a range of possible inhibition levels. Language discussing antibodies that reduce binding by "at least about 20-30%" could support a construction that does not require complete or near-complete blockage (’698 Patent, col. 35:28-31).
- Evidence for a Narrower Interpretation: The patents describe specific assays for measuring binding inhibition and provide examples of antibodies with high blocking activity (e.g., greater than 90%) (’698 Patent, col. 79:59-col. 80:26). This data may support a narrower construction requiring a specific, high threshold of blocking activity to meet the claim limitation.
VI. Other Allegations
Indirect Infringement
The complaint includes boilerplate allegations of infringement under 35 U.S.C. § 271(b) and (c) but does not plead specific facts to support the requisite knowledge and intent for either induced or contributory infringement (Compl. ¶65, 70, 75).
Willful Infringement
The complaint does not explicitly allege "willful infringement." However, it does allege that the case is "exceptional" and seeks an award of attorneys' fees under 35 U.S.C. § 285 (Compl. ¶68, 73, 78). The complaint does not allege any facts regarding pre-suit knowledge of the patents.
VII. Analyst’s Conclusion: Key Questions for the Case
This dispute appears to be a classic "race to market" between two major biopharmaceutical companies involving a blockbuster class of drugs. The litigation will likely center on highly technical, evidence-intensive questions of protein structure and function.
- A core issue will be one of epitope specificity: Can Amgen produce evidence to prove that Sanofi's alirocumab antibody binds to the precise amino acid residues on the PCSK9 protein that are explicitly recited in the asserted patent claims? The complaint makes only a conclusory allegation on this point.
- A second key question will be one of functional scope: What degree of "blocking" or "reducing" the PCSK9-LDLR interaction is required to infringe the claims, and does alirocumab's mechanism of action meet that standard? The answer will likely depend on how the court construes these functional terms based on the patent's specification.
- A threshold jurisdictional question is one of immediacy: Given that alirocumab was not yet FDA-approved or commercially sold when the complaint was filed, do Defendants' actions—including completing Phase 3 trials, announcing intent to file a BLA, and manufacturing inventory—create a controversy sufficiently "actual" and "immediate" to support the court's power to issue a declaratory judgment?