Enzo Life Sciences Inc v. Hologic Inc

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Enzo Life Sciences, Inc. (New York)
  • Defendant: Hologic, Inc. (Delaware)
  • Plaintiff’s Counsel: Farnan LLP; Desmarais LLP (Of Counsel)
• Case Identification: 1:16-cv-00894, D. Del., 10/03/2016
• Venue Allegations: Venue is alleged to be proper based on Defendant being a Delaware corporation and having sold, advertised, marketed, and distributed the accused products in the district.
• Core Dispute: Plaintiff alleges that Defendant’s nucleic acid diagnostic assay products, which utilize a "target capture" technology, infringe a patent related to processes for isolating nucleic acids of interest from a sample.
• Technical Context: The lawsuit concerns molecular diagnostics, specifically methods for capturing and isolating target DNA or RNA sequences from a biological sample for detection and analysis.
• Key Procedural History: The complaint alleges that Defendant had pre-suit knowledge of the patent-in-suit as early as June 2005, based on its wholly-owned subsidiary, Gen-Probe Inc., repeatedly identifying the patent as prior art in Information Disclosure Statements (IDS) filed with the U.S. Patent and Trademark Office during the prosecution of its own patents. The complaint also alleges notice via a letter dated September 30, 2016, three days before the suit was filed.

Case Timeline

Date	Event
1984-04-27	'581 Patent Priority Date
2001-04-24	'581 Patent Issue Date
2005-06-29	Hologic subsidiary Gen-Probe allegedly first cited '581 Patent in an IDS
2009-11-25	Hologic subsidiary Gen-Probe allegedly cited '581 Patent in an IDS
2010-07-28	Hologic subsidiary Gen-Probe allegedly cited '581 Patent in an IDS
2011-04-14	Hologic subsidiary Gen-Probe allegedly cited '581 Patent in an IDS
2013-03-07	Hologic subsidiary Gen-Probe allegedly cited '581 Patent in an IDS
2016-09-30	Plaintiff allegedly sent a letter to Defendant providing notice of '581 Patent
2016-10-03	Complaint Filing Date

II. Technology and Patent(s)-in-Suit Analysis

U.S. Patent No. 6,221,581 - “Processes for Detecting Polynucleotides, Determining Genetic Mutations or Defects in Genetic Material, Separating or Isolating Nucleic Acid of Interest from Samples, and Useful Compositions of Matter and Multybrid Complex Compositions”

The Invention Explained

• Problem Addressed: The patent describes conventional nucleic acid detection methods, such as Southern blot hybridization, as requiring multiple steps including electrophoresis and transfer to a filter, which can be complex and time-consuming (’581 Patent, col. 1:26-52). The background also identifies a need for methods to detect genetic material in a solution without requiring immobilization procedures (’581 Patent, col. 1:53-64).
• The Patented Solution: The invention provides a process for isolating a target nucleic acid from a sample by forming a "multi-hybrid complex" (’581 Patent, Abstract). This is achieved by using a "bridging" or "first" nucleic acid strand that has two different regions: one that can bind to the "third" strand (the target nucleic acid of interest in the sample) and another that can bind to the "second" strand (which is fixed to a solid support) (’581 Patent, col. 4:18-44; Fig. 1). This three-part structure allows the target nucleic acid to be "captured" onto the solid support and thereby isolated from other components in the sample (’581 Patent, col. 33:31-col. 34:36).
• Technical Importance: This approach provided a method for capturing and separating specific nucleic acid sequences from complex mixtures in a single process, a foundational technique for modern molecular diagnostics (Compl. ¶9).

Key Claims at a Glance

• The complaint asserts at least exemplary independent claim 158 (Compl. ¶26).
• The essential elements of independent claim 158 are:
  • A process for separating or isolating a nucleic acid of interest in a sample, comprising the steps of:
  • 1. providing three or more nucleic acid strands: (a) a first strand capable of forming a complex with at least two other strands, one of which is the nucleic acid of interest; (b) a second strand fixed to a solid support and capable of hybridizing with the first strand; and (c) a third strand in a sample, which is the nucleic acid of interest.
  • 2. forming a mixture of the first and third strands under hybridizing conditions to form a first complex.
  • 3. capturing the first complex to a solid support by contacting it with the second strand, thereby isolating the nucleic acid of interest.
• The complaint does not explicitly reserve the right to assert dependent claims but refers to infringement of "one or more claims" (Compl. ¶26).

III. The Accused Instrumentality

Product Identification

The accused instrumentalities are products sold by Hologic under the brand names PROGENSA® PCA3, APTIMA®, and PROCLEIX®, which are described as capture assays used to detect nucleic acids of interest (Compl. ¶21).

Functionality and Market Context

• The complaint alleges these products operate using Hologic's "target capture, Transcription-Mediated Amplification (TMA), and Hybridization Protection Assay (HPA) technologies" (Compl. ¶21).
• The specific accused functionality is the "sample preparation/target capture" step (Compl. ¶22). In this step, a target nucleic acid from a sample is hybridized to a "capture oligomer." This complex is then captured onto magnetic microparticles via hybridization between another region of the capture oligomer and oligonucleotides fixed to the magnetic particles (Compl. ¶¶22-23). The resulting structure is described as a "multi-hybrid complex" comprising three nucleic acid strands: the target, the capture oligomer, and the strand fixed to the magnetic particle (Compl. ¶24).
• The complaint describes Exhibit 2, an APTIMA® HPV Assay Package Insert, as teaching that a capture oligomer:target complex is captured out of solution when a temperature reduction allows hybridization between the capture oligomer and molecules attached to magnetic particles (Compl. ¶27(1)(a)).

IV. Analysis of Infringement Allegations

'581 Patent Infringement Allegations

Claim Element (from Independent Claim 158)	Alleged Infringing Functionality	Complaint Citation	Patent Citation
1) providing three or more nucleic acid strands: (a) one or more first nucleic acid strands, each such strand being capable of forming a complex comprising at least two hybrids with at least two other of said nucleic acid strands... one of said at least two other nucleic acid strands being a nucleic acid of interest...	The accused assays provide "capture oligomers" which allegedly serve as the "first nucleic acid strands." These capture oligomers are described as forming two hybrids: one with the target molecule and one with the strand fixed to the magnetic particle. The complaint references Exhibit 2, a product package insert, to support this allegation.	¶27(1)(a)	col. 34:2-10
(b) one or more second nucleic acid strands, each such strand being fixed or immobilized to a solid support... and said one or more second nucleic acid strands being capable of forming at least one hybrid with said one or more first nucleic acid strands (a);	The accused assays provide "poly-deoxythymidine molecules that are covalently attached to the magnetic particles." These serve as the "second nucleic acid strands" fixed to a solid support and are capable of hybridizing with a "deoxyadenosine region on the capture oligomer."	¶27(1)(b)	col. 34:11-17
(c) one or more third nucleic acid strands contained in a sample, said third nucleic acid strand comprising a nucleic acid of interest... and said one or more third nucleic acid strands being capable of forming at least one hybrid with said one or more first nucleic acid strands (a);	The accused assays process samples containing the target nucleic acid, such as "HPV mRNA target molecules," which serve as the "third nucleic acid strands." These are alleged to hybridize with the capture oligomers.	¶27(1)(c)	col. 34:18-24
2) forming a mixture comprising said first and third nucleic acid strands (a) and (c) under hybridizing conditions to form at least one first complex comprising one or more hybrids;	During the accused assay's hybridization step, the "capture oligomers" (first strands) bind to "specific regions of the HPV mRNA target molecule" (third strands) to form a complex.	¶27(2)	col. 34:25-29
3) capturing or collecting said at least one first formed complex to a solid support, by contacting with one or more second nucleic acid strands (b), thereby separating or isolating said nucleic acid of interest in the sample.	The "capture oligomer:target complex" is captured to magnetic particles (the solid support) when temperature reduction allows hybridization between the capture oligomer and the "poly-deoxythymidine molecules" (second strands) fixed to the particles.	¶27(3)	col. 34:30-36

Identified Points of Contention

• Scope Questions: A central question may be whether the accused "capture oligomer" meets the claim limitation of a "first nucleic acid strand... capable of forming a complex comprising at least two hybrids." The defense may argue that the claim requires a pre-existing complex, whereas the accused process forms hybrids sequentially.
• Technical Questions: The infringement read depends on mapping Hologic's components to the claimed "first," "second," and "third" strands. A question for the court will be whether the "capture oligomer" is properly construed as the "first nucleic acid strand" and not, for instance, a combination of the "first" and "second" strands described in other embodiments of the patent.

V. Key Claim Terms for Construction

• The Term: "a complex comprising at least two hybrids"
• Context and Importance: This term is central to defining the structure of the captured entity. The Plaintiff alleges Hologic's three-part assembly (target-oligomer-support) forms such a complex (Compl. ¶24). The defense may argue that this structure does not meet the definition intended by the patent, or that the "hybrids" are not formed in the manner required. Practitioners may focus on this term because the validity of the entire infringement theory rests on this characterization.
• Intrinsic Evidence for Interpretation:
  • Evidence for a Broader Interpretation: The patent abstract describes forming "double hybrid or multihybrid probes." The detailed description explains that a "multihybrid" can be formed when a "double hybrid" is interconnected, suggesting a broad and flexible structural definition (’581 Patent, col. 4:39-44).
  • Evidence for a Narrower Interpretation: Figure 1 of the patent illustrates a "multihybrid" (40) where a target strand (14) is bridged by multiple distinct probe segments (34, 36) attached to particles (32). A party could argue this figure, described as a "preferred scheme" (’581 Patent, col. 2:46-47), implies a more specific structure than what is alleged to be used by Hologic.

VI. Other Allegations

Indirect Infringement

The complaint alleges induced infringement under 35 U.S.C. § 271(b), stating that Hologic provides product manuals and package inserts (e.g., Exhibits 2, 3, and 4) that instruct customers and third parties to use the accused products in a manner that directly infringes at least claim 158 (Compl. ¶¶36-37). It is alleged that Hologic provides these instructions with the specific intent to cause infringement (Compl. ¶37).

Willful Infringement

Willfulness is alleged based on both pre-suit and post-suit knowledge. The complaint asserts pre-suit knowledge dating to at least June 29, 2005, based on Hologic’s subsidiary, Gen-Probe, citing the ’581 patent as prior art in IDSs for at least five of its own patent applications (Compl. ¶¶29-33). It is also alleged that Hologic received a notice letter dated September 30, 2016, and continued its infringing conduct thereafter (Compl. ¶¶34-35).

VII. Analyst’s Conclusion: Key Questions for the Case

• A core issue will be one of structural and procedural equivalence: can the accused process—which involves the sequential hybridization of a target nucleic acid to a capture oligomer, followed by the capture of that pair to an immobilized strand—be construed as the claimed process of providing three distinct strands and forming "a complex comprising at least two hybrids"? The case may turn on whether the court finds the accused three-part assembly to be the same as the "multihybrid complex" contemplated by the patent.
• A second key question will be one of corporate knowledge and intent: does the knowledge of a subsidiary (Gen-Probe), evidenced by its citation of the '581 patent in multiple IDSs during its own patent prosecution, legally constitute pre-suit knowledge for the parent corporation (Hologic) for the purpose of establishing willful infringement?