DCT
1:25-cv-00263
Cold Spring Harbor Laboratory v. Guardant Health Inc
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Cold Spring Harbor Laboratory (New York)
- Defendant: Guardant Health, Inc. (Delaware)
- Plaintiff’s Counsel: Desmarais LLP
- Case Identification: 1:25-cv-00263, D. Del., 05/01/2025
- Venue Allegations: Venue is alleged to be proper in the District of Delaware because Defendant is a Delaware corporation and therefore resides in the district for patent venue purposes.
- Core Dispute: Plaintiff alleges that Defendant’s liquid biopsy tests for cancer diagnostics and monitoring infringe two patents related to methods for accurately determining genomic copy number information by using unique molecular tags to count original DNA molecules.
- Technical Context: The technology addresses a fundamental challenge in genetic sequencing from small samples by using molecular tags to overcome amplification biases, a technique critical to the accuracy of liquid biopsies that analyze cell-free DNA in blood.
- Key Procedural History: The complaint alleges that Defendant has been aware of the asserted patent family since at least May 2015. It further alleges that Defendant initiated a European opposition proceeding in 2019 against a related European patent, EP2630263, and that a Guardant representative attended the oral proceedings in 2021, facts which Plaintiff presents to support its allegations of pre-suit knowledge and willful infringement.
Case Timeline
| Date | Event |
|---|---|
| 2010-10-22 | Earliest Priority Date for ’589 and ’510 Patents |
| 2014-05-01 | Accused Guardant360 Test Launched |
| 2015-05-01 | Date Plaintiff alleges Defendant became aware of patent family |
| 2019-01-25 | European Opposition Filed Against Related CSHL Patent |
| 2020-08-01 | Accused Guardant360 CDx Test Launched |
| 2021-03-16 | U.S. Patent No. 10,947,589 Issues |
| 2021-03-17 | European Opposition Oral Proceedings Held |
| 2025-02-25 | U.S. Patent No. 12,234,510 Issues |
| 2025-03-06 | Original Complaint Filed |
| 2025-04-25 | Plaintiff’s Counsel Sends Letter Identifying Patents-in-Suit |
| 2025-05-01 | First Amended Complaint Filed |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 10,947,589 - "Varietal Counting Of Nucleic Acids For Obtaining Genomic Copy Number Information"
The Invention Explained
- Problem Addressed: The patent describes a need for a method to determine genomic copy number that is free from distortions caused by the "non-uniform amplification of genomic DNA" inherent in methods like whole genome amplification (WGA), particularly when used on complex or limited samples (’589 Patent, col. 2:29-37). This "amplification distortion" makes it difficult to accurately quantify the original number of DNA molecules in a sample (Compl. ¶27).
- The Patented Solution: The invention proposes a method where segments of genomic material are first tagged with "substantially unique tags" to create a library of tagged molecules. These tagged molecules are then amplified and sequenced. Crucially, the analysis involves counting the number of unique tags that map to a specific location on the genome, rather than counting the total number of sequence reads. This method allows for a direct count of the original molecules present before the distortion-introducing amplification step, thereby obtaining copy number information "unaffected by amplification distortion" (’589 Patent, Abstract; col. 6:1-6).
- Technical Importance: This approach provided a method to obtain accurate copy number information from very small amounts of DNA, a key technical hurdle for realizing the clinical potential of liquid biopsies for early cancer detection and monitoring (Compl. ¶34; ’589 Patent, col. 30:30-42).
Key Claims at a Glance
- The complaint’s infringement count focuses on at least Claim 1 (Compl. ¶84).
- Independent Claim 1 of the ’589 Patent recites the essential elements of a method comprising:
- obtaining segments of genomic nucleic acids from a sample;
- tagging the segments with nucleic acid tags to generate a plurality of unique tagged nucleic acid molecules;
- subjecting the unique tagged molecules to PCR to generate amplified molecules;
- generating sequence reads from the amplified molecules;
- assigning each amplified molecule to a location on a reference genome by mapping; and
- counting the number of unique tagged molecules assigned to the same location on the genome to obtain copy number information.
U.S. Patent No. 12,234,510 - "Varietal Counting Of Nucleic Acids For Obtaining Genomic Copy Number Information"
The Invention Explained
- Problem Addressed: The ’510 Patent addresses the same technical problem as the ’589 patent: the difficulty in obtaining accurate genomic copy number information due to "distortions introduced by non-uniform amplification of genomic DNA," which is a barrier to analyzing complex samples (’510 Patent, col. 2:29-37; Compl. ¶39).
- The Patented Solution: The solution is substantively identical to that of the ’589 Patent. It involves "randomly tagging" segments of genomic nucleic acids with different tags before amplification. After sequencing, the number of unique tagged molecules assigned to various locations on the genome is used to obtain "relative copy number information" (’510 Patent, Abstract; col. 35:40-46). By counting the unique tags, the method bypasses distortions from the amplification process (Compl. ¶39).
- Technical Importance: This method enables accurate copy number analysis from limited biological samples, which the patent notes has clinical applications in determining tumor heterogeneity, detecting cancer recurrence, and measuring cancer load (’510 Patent, col. 30:30-67).
Key Claims at a Glance
- The complaint’s infringement count focuses on at least Claim 1 (Compl. ¶93).
- Independent Claim 1 of the ’510 Patent recites the essential elements of a method comprising:
- obtaining segments of genomic nucleic acids from a sample;
- randomly tagging the segments with different nucleic acid tags to generate unique tagged nucleic acid molecules;
- subjecting the unique tagged molecules to PCR to generate copies;
- generating sequence reads from the copies;
- assigning each unique tagged molecule to a location on a genome by mapping; and
- obtaining relative copy number information based on the number of unique tagged nucleic acid molecules assigned to each of a plurality of locations.
III. The Accused Instrumentality
Product Identification
- The accused instrumentalities are the Guardant360 test and the Guardant360 CDx test (Compl. ¶43, ¶51).
Functionality and Market Context
- The accused products are described as commercial liquid biopsy blood tests that analyze cell-free circulating tumor DNA (cfDNA) to provide genomic profiles, including copy number information (Compl. ¶8, ¶43-44). The complaint alleges the tests perform a multi-step method that includes obtaining cfDNA from a blood sample, tagging the cfDNA fragments with "non-unique oligonucleotide heptamer barcodes" or "inline barcodes," amplifying the tagged DNA via PCR, sequencing the amplified molecules, mapping the resulting reads to a reference genome, and quantifying unique DNA fragments to determine copy number variations (Compl. ¶44-49, ¶52-57).
- The complaint alleges the tests are commercially significant, stating that over 500,000 patient samples have been analyzed and that the tests have generated "hundreds of millions of dollars in revenue" (Compl. ¶78, ¶83). The Guardant360 CDx test is noted as being FDA-approved (Compl. ¶51).
IV. Analysis of Infringement Allegations
No probative visual evidence provided in complaint.
U.S. Patent No. 10,947,589 Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| a) obtaining segments of genomic nucleic acids from a sample | Extracting cell-free DNA (cfDNA) from a patient blood sample. | ¶84.a | col. 5:48 |
| b) tagging the segments with nucleic acid tags, thereby generating a plurality of unique tagged nucleic acid molecules... | Attaching oligonucleotide barcodes to cfDNA fragments to create digital sequence libraries. | ¶84.b | col. 5:49-53 |
| c) subjecting the plurality of the unique tagged nucleic acid molecules to a polymerase chain reaction (PCR)... | Amplifying the barcoded cfDNA fragments using PCR to create libraries suitable for sequencing. | ¶84.c | col. 5:54-55 |
| d) generating tag associated sequence reads by sequencing the amplified tagged nucleic acid molecules... | Sequencing the amplified libraries using an Illumina sequencing platform. | ¶84.d | col. 5:56-57 |
| e) assigning each of the amplified tagged nucleic acid molecules to a location on a reference genome...by mapping... | Using software (e.g., BWA-MEM aligner) to align sequence reads to a human reference genome (e.g., hg19). | ¶84.e | col. 5:58-64 |
| f) at a plurality of locations on the reference genome, counting the number of unique tagged nucleic acid molecules...thereby obtaining copy number information... | Quantifying the number of unique DNA fragments mapping to a given gene or genomic region to ascertain copy number variations. | ¶84.f | col. 6:1-6 |
U.S. Patent No. 12,234,510 Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| a) obtaining segments of genomic nucleic acids from a sample containing the genomic nucleic acids | Extracting cfDNA from a patient blood sample. | ¶93.a | col. 35:17-19 |
| b) randomly tagging the segments of genomic nucleic acids with different nucleic acid tags, thereby generating unique tagged nucleic acid molecules... | Attaching "non-unique oligonucleotide heptamer barcodes" or "inline barcodes" to cfDNA fragments via ligation to create digital sequence libraries. | ¶93.b | col. 35:20-27 |
| c) subjecting the unique tagged nucleic acid molecules to a polymerase chain reaction (PCR)... | Amplifying the barcoded cfDNA libraries using PCR. | ¶93.c | col. 35:28-31 |
| d) generating tag associated sequence reads by sequencing the copies of the unique tagged nucleic acid molecules... | Sequencing the amplified libraries on an Illumina platform. | ¶93.d | col. 35:32-34 |
| e) assigning each of the unique tagged nucleic acid molecules to a location on a genome by mapping... | Aligning sequence reads to a human reference genome using software. | ¶93.e | col. 35:35-39 |
| g) in a plurality of locations in the genome, obtaining relative copy number information...based on the number of unique tagged nucleic acid molecules... | Quantifying unique DNA fragments covering specific genes to determine copy number amplifications and report relative copy number states. | ¶93.f | col. 35:40-46 |
Identified Points of Contention
- Scope Questions: The complaint alleges Guardant uses "non-unique" barcodes (Compl. ¶45). This raises the question of how the term "unique tagged nucleic acid molecules" in both patents will be construed. The dispute may center on whether the claim requires the nucleic acid "tag itself" to be unique, or whether the "resulting molecule" can be rendered unique for counting purposes by combining a non-unique tag with other data, such as the start and end positions of the DNA segment.
- Technical Questions: Claim 1 of the ’510 Patent requires "randomly tagging." A potential point of contention is whether Guardant's alleged process of attaching barcodes using blunt-end ligation (Compl. ¶53) satisfies this "randomly" limitation as it is understood in the context of the patent.
V. Key Claim Terms for Construction
- The Term: "unique tagged nucleic acid molecules"
- Context and Importance: This term is central to the asserted claims of both patents. Its construction is critical because the complaint alleges the accused tests use "non-unique" barcodes (Compl. ¶45). The infringement analysis will depend on whether generating "unique tagged nucleic acid molecules" can be achieved with non-unique tags.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The specification states that after tagging, "[e]very tagged molecule becomes essentially unique" and that the goal is to enable the "counting' of original molecules" (’589 Patent, col. 20:38-39; col. 27:63-65). This language may support an interpretation where the overall molecule's identifiability for counting is the focus, not the uniqueness of the tag in isolation.
- Evidence for a Narrower Interpretation: The Abstract of the ’589 Patent describes the method as "tagging the segments with substantially unique tags," which might suggest that the tags themselves must be the source of uniqueness. An opponent could argue that a process using explicitly "non-unique" barcodes does not meet this limitation.
VI. Other Allegations
- Willful Infringement: The complaint alleges that Defendant's infringement was and continues to be willful (Compl. ¶86, ¶95). The allegations are based on both pre-suit and post-suit knowledge. Pre-suit knowledge is alleged to arise from Defendant's own patent prosecution activities as early as May 2015, as well as Defendant's alleged initiation of and participation in a European opposition against a related CSHL patent between 2019 and 2021 (Compl. ¶61, ¶66, ¶73). Post-suit knowledge is alleged based on the filing of the original complaint on March 6, 2025, and subsequent communications (Compl. ¶74-77).
VII. Analyst’s Conclusion: Key Questions for the Case
- A core issue will be one of "definitional scope": can the claim term "unique tagged nucleic acid molecules" be construed to cover molecules that are made uniquely identifiable by combining an admittedly "non-unique" barcode with other sequence information, such as the start and stop points of the DNA fragment? The resolution of this question may determine whether there is literal infringement.
- A key factual question will be one of "pre-suit knowledge": does Plaintiff's evidence regarding Defendant's alleged patent prosecution research and its involvement in a European patent opposition provide a sufficient basis to establish knowledge of the specific patents-in-suit prior to the lawsuit, thereby supporting the claim for willful infringement?