DCT
1:22-cv-01597
Scale Biosciences Inc v. Parse Biosciences Inc
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Scale Biosciences, Inc. (Delaware) and Roche Sequencing Solutions, Inc. (Delaware)
- Defendant: Parse Biosciences, Inc. (Delaware)
- Plaintiff’s Counsel: Richards, Layton, & Finger, P.A.
- Case Identification: 1:22-cv-01597, D. Del., 08/30/2023
- Venue Allegations: Venue is alleged to be proper in the District of Delaware because the Defendant is a Delaware corporation and therefore resides in the district.
- Core Dispute: Plaintiffs allege that Defendant’s single-cell gene expression analysis kits and related products infringe four patents related to single-cell combinatorial barcoding technology.
- Technical Context: The dispute centers on single-cell combinatorial indexing, a technology that enables researchers to uniquely label the genetic material of millions of individual cells simultaneously for large-scale sequencing and analysis.
- Key Procedural History: The complaint alleges Defendant received pre-suit notice of infringement for U.S. Patent No. 10,982,256 on or about June 10, 2021, and for U.S. Patent No. 10,626,442 on or about March 1, 2022. Notice for U.S. Patent No. 11,512,341 is alleged via service of the original complaint on December 15, 2022.
Case Timeline
| Date | Event |
|---|---|
| 2011-01-31 | Earliest Priority Date for all Asserted Patents |
| 2020-04-21 | U.S. Patent No. 10,626,442 Issues |
| 2021-02-18 | Accused Evercode WT Products Commercially Launched (approx.) |
| 2021-04-20 | U.S. Patent No. 10,982,256 Issues |
| 2021-06-10 | Defendant Notified of Alleged ’256 Patent Infringement (approx.) |
| 2022-03-01 | Defendant Notified of Alleged ’442 Patent Infringement (approx.) |
| 2022-11-29 | U.S. Patent No. 11,512,341 Issues |
| 2022-12-15 | Defendant Notified of Alleged ’341 Patent Infringement (approx.) |
| 2023-02-07 | Accused Evercode TCR Products Commercially Launched (approx.) |
| 2023-04-25 | U.S. Patent No. 11,634,752 Issues |
| 2023-08-30 | First Supplemental Complaint Filed |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 10,626,442 - "Methods of Identifying Multiple Epitopes in Cells", issued April 21, 2020
The Invention Explained
- Problem Addressed: The patent's background describes a need for methods to accurately detect and quantify multiple different molecules (such as proteins or nucleic acids) from individual cells within a large, complex population, without requiring expensive, specialized equipment to first isolate each cell (Compl. ¶11; ’442 Patent, col. 1:33-46). Prior methods were limited in scale by the number of available fluorescent labels or unique tags (Compl. ¶12).
- The Patented Solution: The invention proposes using the cell itself as a reaction compartment for attaching unique molecular barcodes to target molecules (Compl. ¶11). It employs a "split-pool" method where a population of cells is repeatedly split into separate reaction volumes, a unique barcode segment is added in each volume, and the cells are then pooled back together. Successive rounds of this process build a unique combinatorial barcode on the molecules within each cell, allowing for massive-scale analysis (’442 Patent, col. 2:45-53, Fig. 4).
- Technical Importance: This combinatorial barcoding approach allows single-cell sequencing to proceed at a "vastly greater scale than prior methods" (Compl. ¶11).
Key Claims at a Glance
- The complaint asserts independent Claim 1 (Compl. ¶36).
- The essential elements of Claim 1 are:
- Coupling a common linker sequence to target molecules within a plurality of cells.
- Dividing the cells into at least two primary reaction volumes.
- Providing different primary nucleic acid tags to each primary reaction volume.
- Coupling the common linker sequences with the primary nucleic acid tags.
- Pooling the primary reaction volumes.
- Splitting the combined volume into at least two secondary reaction volumes.
- Providing different secondary nucleic acid tags to each secondary reaction volume.
- Coupling the target molecules with the secondary nucleic acid tags.
- The complaint does not explicitly reserve the right to assert dependent claims for this patent.
U.S. Patent No. 10,982,256 - "Methods of Identifying Multiple Epitopes in Cells", issued April 20, 2021
The Invention Explained
- Problem Addressed: As with the related ’442 Patent, this invention addresses the need for scalable, cell-specific molecular analysis that avoids cumbersome and expensive pre-isolation of individual cells (Compl. ¶11).
- The Patented Solution: This patent claims a method of assembling "cell originating barcodes (COB)" on target-bound "unique binding agents (UBA)" using successive rounds of "split pool synthesis" (’256 Patent, Claim 1). The process explicitly "does not include a step of isolating each cell," reinforcing the concept of using the cell as the reaction vessel (’256 Patent, Claim 1(c)[3]). The specification describes how assayable polymer subunits (APSs) are added in an ordered manner to create unique codes representing the identity of individual cells (’256 Patent, col. 2:45-53).
- Technical Importance: The technology enables single-cell sequencing at a much larger scale than previously possible, making it more accessible to researchers (Compl. ¶11, 14).
Key Claims at a Glance
- The complaint asserts independent Claim 1 (Compl. ¶69).
- The essential elements of Claim 1 are:
- Binding unique binding agent (UBA) nucleic acid tags to nucleic acid targets in a plurality of cells.
- Extending the UBAs bound to the targets.
- Assembling cell originating barcodes (COB) on the extended UBAs by adding multiple assayable polymer subunit (APS) oligonucleotides in an ordered manner during successive rounds of split pool synthesis.
- This assembly involves APS oligonucleotides from one round annealing to and covalently linking with the APS from a previous round.
- The method does not include a step of isolating each cell.
- The complaint does not explicitly reserve the right to assert dependent claims for this patent.
U.S. Patent No. 11,512,341 - "Methods of Identifying Multiple Epitopes in Cells", issued November 29, 2022
Technology Synopsis
This patent, from the same family as the '442 and '256 patents, claims a method for barcoding complementary DNA (cDNA) within cells or cell compartments (Compl. ¶101). The method involves producing the cDNA and then adding oligonucleotide barcodes through at least two barcoding steps, where each step comprises splitting the cells, adding oligonucleotide subunits to the cDNA, and then pooling the cells (Compl. ¶99).
Asserted Claims
Independent Claim 1 (Compl. ¶99).
Accused Features
The Accused Products are alleged to perform a method of barcoding cDNA by first generating cDNA within cells via an in-cell reverse transcription reaction, and then adding barcodes through multiple "split-pool combinatorial barcoding steps" that involve splitting, adding barcode subunits via ligation, and pooling (Compl. ¶¶102-104).
U.S. Patent No. 11,634,752 - "Kit for Split-Pool Barcoding Target Molecules that Are in or on Cells or Cell Organelles", issued April 25, 2023
Technology Synopsis
This patent claims a kit for performing the split-pool barcoding technology disclosed in the related patents (Compl. ¶¶129, 132). The kit comprises at least two sets of "assayable polymer subunit (APS) oligonucleotides" and one or more "linking oligonucleotides" that are configured to link the APS oligonucleotides from different sets together in an ordered fashion, forming a barcode (Compl. ¶129).
Asserted Claims
Independent Claim 1 (Compl. ¶129).
Accused Features
The Accused Products are marketed and sold as kits for "barcoding & library prep" that utilize "split-pool combinatorial barcoding technology" (Compl. ¶132). The complaint alleges these kits contain the claimed sets of APS oligonucleotides (barcodes provided in multi-well plates) and linking oligonucleotides designed to facilitate their ordered assembly (Compl. ¶¶133-138).
III. The Accused Instrumentality
Product Identification
The "Accused Products" are identified as Parse Biosciences' single-cell gene expression kits and related products, including the "Evercode Whole Transcriptome" (WT) product line, the "Evercode TCR" product line, and add-on products such as "Gene Capture" and "CRISPR Detect," along with their associated reagents, consumables, software, and instructional materials (Compl. ¶¶15-19).
Functionality and Market Context
The Accused Products are alleged to provide researchers with a complete workflow for single-cell analysis based on a technique called "SPLiT-Seq" (split-pool combinatorial barcoding) (Compl. ¶20). The complaint alleges this workflow involves fixing cells or nuclei, then "progressing cells through four split-pool combinatorial barcoding steps" to append unique barcodes to each transcript within a cell (Compl. ¶¶22, 23). A diagram provided in the complaint illustrates this multi-step process, which includes reverse transcription to apply a first barcode, followed by successive rounds of pooling cells, splitting them into new reaction wells, and ligating additional barcodes. (Compl. p. 10). The resulting barcoded molecules are then prepared for sequencing (Compl. p. 10). The complaint alleges these products enable users to analyze anywhere from 10,000 to one million single cells (Compl. ¶21).
IV. Analysis of Infringement Allegations
U.S. Patent No. 10,626,442 Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| (a) coupling a common linker sequence to target molecules within the plurality of cells; | The accused workflow applies "sample-specific barcodes" to transcripts (target molecules) in fixed cells via an in-cell reverse transcription (RT) reaction using "barcoded RT primers" which are alleged to include a common linker sequence. | ¶39 | col. 18:28-34 |
| (b) dividing the plurality of cells into at least two primary reaction volumes... | Samples containing the cells are distributed into the wells of a plate for the initial barcoding step. | ¶40 | col. 25:39-44 |
| (c) providing primary nucleic acid tags to the at least two primary reaction volumes, wherein the primary nucleic acid tags provided to the first reaction volume are different from the primary nucleic acid tags provided to a second reaction volume; | The accused workflow pools the cells and then splits them across a new plate, where "well-specific barcodes" are provided to each well (reaction volume), ensuring the tags in different wells are different. | ¶41 | col. 25:45-51 |
| (d) coupling the common linker sequences within each of the at least two primary reaction volumes with the provided primary nucleic acid tags; | An in-cell ligation reaction appends the second barcode (the primary nucleic acid tag) to the DNA linker from the first step. | ¶42 | col. 25:52-55 |
| (e) pooling the at least two primary reaction volumes; | After the second barcoding round, the cells from each well are pooled together. | ¶43 | col. 25:56-57 |
| (f) splitting the combined primary reaction volumes into at least two secondary reaction volumes... | The pooled cells are split again across a new plate for a third barcoding round. | ¶44 | col. 25:58-63 |
| (g) providing secondary nucleic acid tags to each of the at least two secondary reaction volumes, wherein the secondary nucleic acid tags... are different...; and | A third set of "well-specific barcodes" is applied, with each well in the new plate receiving a different barcode tag. | ¶45 | col. 25:64-26:2 |
| (h) coupling the target molecules within each of the at least two secondary reaction volumes with the provided secondary nucleic acid tags. | A third barcode is applied via another in-cell ligation after the cells are split across the plate. The complaint's visual evidence shows this barcode is coupled to the previously added barcodes, which are in turn coupled to the target molecule. (Compl. p. 23). | ¶46 | col. 26:3-6 |
Identified Points of Contention
- Scope Questions: Claim 1 recites a method with "primary" and "secondary" reaction volumes and tags. The complaint alleges the accused product uses a four-round process (Compl. ¶22). A question for the court may be how the accused product's third and fourth barcoding rounds map to the claim language, specifically whether they fall within the scope of the claimed "secondary" steps or represent additional, unclaimed steps.
- Technical Questions: The first "coupling" step is alleged to be performed by reverse transcription (Compl. ¶39), while subsequent coupling steps are by ligation (Compl. ¶42). A question may arise as to whether "coupling" as used in the patent can be construed to cover both distinct biochemical reactions in the manner alleged.
U.S. Patent No. 10,982,256 Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| (a) binding to the nucleic acid targets in the plurality of cells a plurality of unique binding agent (UBA) nucleic acid tags; | The accused workflow applies "sample-specific barcodes" attached to reverse transcription (RT) primers, which bind to mRNA targets (nucleic acid targets) in the cells. The barcoded RT primer is alleged to act as a UBA nucleic acid tag. | ¶72 | col. 28:13-16 |
| (b) extending the UBAs bound to the targets, and | The RT primers (UBAs) are extended by the in-cell reverse transcription reaction, which generates cDNA from the mRNA target. | ¶73 | col. 28:17-18 |
| (c) [1] assembling cell originating barcodes (COB) on the extended UBAs by subsequently adding multiple assayable polymer subunit (APS) oligonucleotides... in an ordered manner during successive rounds of split pool synthesis | The accused method uses "combinatorial barcoding technology" with successive rounds of split-pool synthesis where barcodes (APS oligonucleotides) are sequentially appended via ligation to create a cell-specific combination of barcodes (COB). A diagram from a cited scientific paper illustrates this ordered assembly. (Compl. p. 32). | ¶74 | col. 28:19-24 |
| [2] wherein the APS oligonucleotides in each round anneal to the APS from a previous round and are covalently linked to the adjacently annealed APS to create unique codes... | In the accused workflow, barcodes are appended sequentially via ligation. This is allegedly facilitated by a "universal linker strand with partial complementarity to a second strand containing the unique well-specific barcode sequence," enabling annealing and covalent linkage. | ¶75 | col. 28:25-30 |
| [3] wherein the method does not include a step of isolating each cell in the plurality of cells. | The accused "SPLiT-seq" method is alleged to rely on the cells themselves as compartments and does not require partitioning single cells into individual compartments like droplets or microwells. | ¶76 | col. 28:31-33 |
Identified Points of Contention
- Scope Questions: Claim 1 recites "binding... unique binding agent (UBA) nucleic acid tags" and then "extending the UBAs." The complaint alleges this is met by a barcoded RT primer and the reverse transcription reaction itself (Compl. ¶¶72-73). A key question for construction will be whether a standard RT primer used for cDNA synthesis constitutes a "unique binding agent (UBA)" as that term is understood in the patent.
- Technical Questions: What evidence does the complaint provide that the accused product's use of a "universal linker strand" (Compl. ¶36, citing Rosenberg) for ligation performs the specific function of "anneal[ing] to the APS from a previous round" as required by the claim? The functionality appears to match the claim language, but the precise molecular mechanism may be a point of dispute.
V. Key Claim Terms for Construction
For the ’442 Patent
- The Term: "coupling"
- Context and Importance: This term appears in claim elements (a), (d), and (h) and is central to how barcodes are attached. Its construction will determine whether different biochemical reactions—specifically, reverse transcription and ligation—can satisfy the same claim term. The complaint's theory requires "coupling" to be broad enough to cover both (Compl. ¶¶39, 42, 46).
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The claims do not specify a particular method of coupling. The specification states that the tag can comprise components "linked by ligation" or "capable of being linked [by] Click chemistry," suggesting more than one method is contemplated (’442 Patent, col. 2:47-52).
- Evidence for a Narrower Interpretation: Many embodiments and descriptions focus on ligation as the method for linking barcode subunits together after the initial step (’442 Patent, Abstract; col. 2:47-48). A party might argue that in the context of linking barcode segments to each other, "coupling" should be limited to methods like ligation.
For the ’256 Patent
- The Term: "unique binding agent (UBA)"
- Context and Importance: This term in claim 1(a) defines the initial molecule that attaches to the nucleic acid target. The complaint alleges that a barcoded reverse transcription primer meets this limitation (Compl. ¶72). The viability of the infringement case depends on whether a primer can be considered a "UBA."
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The specification provides a broad definition, stating a UBA can be selected from a group including "antibody, peptide, aptamer, peptoid and nucleic acid" (’256 Patent, col. 18:20-21). A barcoded primer is a nucleic acid, which may support the plaintiff's interpretation.
- Evidence for a Narrower Interpretation: The patent's title refers to identifying "epitopes," and several figures depict the UBA as an antibody-like structure that binds to a target (e.g., ’256 Patent, Fig. 2). A defendant might argue that in the context of the invention, a "UBA" implies a molecule that binds with high specificity to a complex structure like an epitope, not a simple primer that hybridizes to a poly(A) tail.
VI. Other Allegations
Indirect Infringement
The complaint alleges inducement of infringement for all four patents. The basis is that Defendant provides the Accused Products with instructional materials, technical brochures, tutorials, customer training, and support that allegedly guide and encourage customers to use the products in an infringing manner (Compl. ¶¶55, 85, 114, 146). The complaint also alleges contributory infringement, stating the Accused Products have no substantial non-infringing use (Compl. ¶¶57, 87, 116).
Willful Infringement
Willfulness is alleged for all four patents. For the ’442 and ’256 patents, willfulness is based on alleged pre-suit knowledge via notice letters dated March 1, 2022, and June 10, 2021, respectively (Compl. ¶¶53, 83). For the ’341 patent, willfulness is based on knowledge from the service of the original complaint on December 15, 2022 (Compl. ¶112). For the ’752 patent, willfulness is based on alleged knowledge from monitoring the patent family and continued infringement after its issuance on April 25, 2023 (Compl. ¶144).
VII. Analyst’s Conclusion: Key Questions for the Case
- A core issue will be one of claim construction and technical mapping: can the terminology of the asserted claims, which includes terms like "unique binding agent," "coupling," and a "primary/secondary" step structure, be construed to read on the specific multi-round, reverse transcription- and ligation-based "SPLiT-Seq" process used by the Accused Products? The outcome will depend on whether the court adopts a broad, functional definition of these terms or a narrower one tied to specific embodiments in the patents.
- A second key issue will be one of damages and intent: given the specific dates of pre-suit notice alleged for the '442 and '256 patents, a central question for damages will be whether Defendant's conduct after receiving these notices was willful. The court will need to evaluate Defendant's actions in light of its alleged knowledge of the patents to determine if any infringement was objectively reckless, potentially leading to enhanced damages.