DCT
1:18-cv-02434
Novartis Vaccines Diagnostics Inc v. Regeneron Pharma Inc
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Novartis Vaccines and Diagnostics, Inc. (Delaware); Novartis Pharma AG (Switzerland); Grifols Worldwide Operations Limited (Ireland)
- Defendant: Regeneron Pharmaceuticals, Inc. (New York)
- Plaintiff’s Counsel: Mauriel Kapouytian Woods LLP; Rakoczy Molino Mazzochi Siwik LLP
- Case Identification: 1:18-cv-02434, S.D.N.Y., 07/20/2018
- Venue Allegations: Venue is alleged to be proper in the Southern District of New York because Defendant is a New York corporation with its principal place of business, research and manufacturing facilities, and numerous employees within the state.
- Core Dispute: Plaintiffs allege that Defendant’s manufacturing process for the drugs Eylea and Zaltrap infringes a patent directed to a vector system used for producing proteins in mammalian cells.
- Technical Context: The technology concerns recombinant DNA expression vectors, a fundamental platform technology in the biopharmaceutical industry for manufacturing therapeutic proteins and antibodies.
- Key Procedural History: The asserted patent was subject to an Ex Parte Reexamination, which confirmed the patentability of the asserted claims. The complaint alleges infringement occurred prior to the patent's expiration and seeks damages, including lost profits from foreign sales under the theory affirmed in WesternGeco v. ION Geophysical. The complaint also references prior litigation by Novartis involving similar technology against other parties.
Case Timeline
| Date | Event |
|---|---|
| 1984-10-31 | '688 Patent Priority Date |
| 1997-11-18 | '688 Patent Issue Date |
| 2006-06-30 | FDA approves Lucentis (Plaintiffs' competing product) |
| 2011-11-18 | FDA approves Eylea (accused product) |
| 2012-08-03 | FDA approves Zaltrap (accused product) |
| 2018-07-20 | First Amended Complaint Filing Date |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 5,688,688 - "Vector for Expression of a Polypeptide in a Mammalian Cell," issued November 18, 1997
The Invention Explained
- Problem Addressed: The patent background describes the difficulty in obtaining sufficient quantities of viral polypeptides, such as those from the Human Immunodeficiency Virus (HIV), for use in diagnostic assays and the development of potential vaccines. Producing these proteins by culturing live virus was considered inefficient and potentially hazardous (’688 Patent, col. 2:16-24).
- The Patented Solution: The invention provides a highly efficient system for producing a desired "heterologous" (foreign) polypeptide in a host cell. The core of the invention is an expression vector—a circular piece of DNA used to introduce a gene into a cell—that combines several key genetic regulatory elements. These include a powerful promoter/enhancer from the human cytomegalovirus (hCMV) to initiate high-level gene expression, an SV40 origin of replication to allow the vector to be copied within the host cell, and an SV40 polyadenylation signal to properly terminate the genetic message (’688 Patent, Abstract; col. 27:29-28:15). Figure 29 provides a map of a plasmid, pCMV6a, that illustrates the claimed arrangement of these components (’688 Patent, Fig. 29).
- Technical Importance: This specific combination of regulatory elements creates a robust and versatile platform for achieving high-yield production of recombinant proteins in mammalian cells, a critical capability for the commercial-scale manufacturing of modern biologic drugs (Compl. ¶¶20-21).
Key Claims at a Glance
- The complaint provides an exemplary analysis of Independent Claim 1 (Compl. ¶45).
- The essential elements of Claim 1, as amended by an ex parte reexamination certificate, include:
- A non-human mammalian host cell expression system for improved expression.
- This system comprises a non-human mammalian host cell containing a vector.
- The vector comprises a polynucleotide sequence that includes:
- a) an upstream SV40 origin of replication;
- b) a downstream SV40 polyadenylation region;
- c) a transcription regulatory region from hCMV (including the IE1 intron), which is "interposed between" the SV40 origin and polyadenylation region and directs transcription; and
- d) a polypeptide coding sequence for a heterologous polypeptide, which is operably linked downstream of the hCMV regulatory region.
- The complaint reserves the right to assert other claims of the patent (Compl. ¶45).
III. The Accused Instrumentality
Product Identification
- The accused instrumentalities are the processes and systems used by Regeneron to manufacture the active pharmaceutical ingredients for the drugs Eylea® (aflibercept) and Zaltrap® (ziv-aflibercept) (Compl. ¶¶43-44).
Functionality and Market Context
- The complaint alleges that Regeneron manufactures aflibercept and ziv-aflibercept, which are recombinant fusion proteins, using a "non-human mammalian host cell expression system" (Compl. ¶44). Specifically, the process is alleged to use Chinese Hamster Ovary (CHO) cells into which the "Lonza pEE14 Expression Vector" is introduced to produce the desired protein (Compl. ¶¶48, 54).
- Eylea is a VEGF inhibitor approved for treating several eye disorders, including wet age-related macular degeneration (AMD) (Compl. ¶23). The complaint positions Eylea as a direct competitor to Plaintiffs' product, Lucentis®, which treats similar conditions (Compl. ¶¶31-32). Zaltrap, which the complaint states uses an identical active ingredient, is approved for treating metastatic colorectal cancer (Compl. ¶¶38, 42).
IV. Analysis of Infringement Allegations
'688 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A non-human mammalian host cell expression system for improved expression comprising a non-human mammalian host cell with a vector for expression of a polypeptide in a mammalian cell... | Regeneron is alleged to use a system for manufacturing aflibercept that comprises introducing the Lonza pEE14 Expression Vector into non-human mammalian host cells, specifically Chinese Hamster Ovary (CHO) cells. The complaint presents a two-column claim chart mapping the elements of Claim 1 to paragraphs alleging infringement (Compl. ¶55). | ¶¶44, 54, 55 | col. 12:47-52 |
| a) an upstream SV40 origin of replication; | The Lonza pEE14 Expression Vector, allegedly used by Regeneron, is described as comprising an SV40 origin of replication. | ¶52(a) | col. 27:56-59 |
| b) a downstream SV40 polyadenylation region; | The Lonza pEE14 Expression Vector is alleged to comprise an SV40 polyadenylation signal. | ¶52(e) | col. 27:56-59 |
| c) a transcription regulatory region from human cytomegalovirus immediate early region HCMV IE1, wherein the transcription regulatory region includes the first HCMV IE1 intron... is interposed between the SV40 origin of replication and the SV40 polyadenylation region, and is capable of directing the transcription of a polypeptide coding sequence... | The Lonza pEE14 Expression Vector is alleged to contain "The major immediate-early gene promoter-enhancer of the human cytomegalovirus, including the leader intron." | ¶52(c) | col. 28:1-12 |
| d) the polypeptide coding sequence encoding a heterologous polypeptide operably linked downstream of the transcription regulatory region. | Regeneron is alleged to have inserted a "heterologous polypeptide coding sequence"—the DNA coding for aflibercept—into the Lonza pEE14 Expression Vector downstream of the CMV promoter. | ¶53 | col. 12:41-46 |
- Identified Points of Contention:
- Evidentiary Questions: The complaint's allegations regarding the composition of Regeneron's manufacturing system rely heavily on public documents, including another patent assigned to Regeneron (the '959 patent) and a scientific publication, to describe the Lonza pEE14 vector (Compl. ¶¶48, 52). A central question will be whether these public descriptions accurately reflect the proprietary process Regeneron actually used to manufacture Eylea and Zaltrap during the relevant time period.
- Technical Questions: The complaint lists the components of the alleged vector as including not only the claimed elements but also a "GS minigene" (Compl. ¶52(b)). The location of this minigene between the SV40 origin and the hCMV promoter raises the question of whether the hCMV promoter is "interposed between the SV40 origin of replication and the SV40 polyadenylation region" as strictly required by the claim language.
V. Key Claim Terms for Construction
- The Term: "interposed between"
- Context and Importance: This term defines the required spatial relationship of the key regulatory elements on the vector. The complaint alleges the accused vector contains an additional genetic element (a "GS minigene") located between the SV40 origin and the hCMV promoter (Compl. ¶52). The definition of "interposed between" will therefore be critical to determining if this alleged structure meets the limitation of Claim 1(c).
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: Plaintiffs may argue that "interposed between" simply requires the hCMV region to be located somewhere after the SV40 origin and before the SV40 polyadenylation region, without precluding other elements from also being present in that span. The claims focus on the functional relationship of the elements, and a broader structural reading may be consistent with that purpose.
- Evidence for a Narrower Interpretation: Defendant may point to patent figures, such as Figure 29, which depicts the "HCMV IE1 enh/pro" element situated directly between the "SV40 ori" and "SV40 polyA" elements, without any other major functional regions between them ('688 Patent, Fig. 29). This could support an argument that the term requires a more direct or immediate positioning.
VI. Other Allegations
- Indirect Infringement: The complaint alleges direct infringement by making and using the patented system in the U.S. (Compl. ¶72). It also alleges infringement under 35 U.S.C. § 271(f), asserting that Regeneron manufactured the aflibercept active ingredient (a component of a patented invention) in the U.S. and supplied it to its partner, Bayer, for incorporation into the final Eylea drug product sold outside the U.S. (Compl. ¶35). The complaint explicitly cites WesternGeco LLC v. ION Geophysical Corp. to support a claim for lost profits on these foreign sales (Compl. ¶37).
- Willful Infringement: Willfulness is alleged based on Regeneron's purported knowledge of the '688 patent. The complaint alleges this knowledge stems from multiple sources, including Regeneron's awareness of prior Novartis litigation over the same patented technology, public SEC filings identifying Novartis as a key competitor with potentially dominant patents, and admissions in Regeneron's own court filings in the instant case (Compl. ¶¶57-64).
VII. Analyst’s Conclusion: Key Questions for the Case
- A core issue will be one of claim construction: can the term "interposed between", as used in Claim 1, be interpreted to read on a vector that allegedly includes an additional functional gene ("GS minigene") between the SV40 origin and the hCMV promoter? The outcome of this construction could be dispositive for literal infringement.
- A key evidentiary question will be one of proof: can Plaintiffs demonstrate that the specific, proprietary manufacturing process used by Regeneron for Eylea and Zaltrap during the damages period is accurately described by the public disclosures cited in the complaint, such as Regeneron's own '959 patent?
- A significant legal battle will likely concern the scope of damages: assuming infringement is found, the case will test the application of WesternGeco to the biopharmaceutical industry, specifically whether Plaintiffs can recover lost profits on foreign sales of their competing drug (Lucentis) based on Defendant's domestic manufacture of the aflibercept active ingredient.