Scale Biosciences Inc v. Parse Biosciences Inc

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Scale Biosciences, Inc. (Delaware)
  • Defendant: Parse Biosciences, Inc. (Delaware)
  • Plaintiff’s Counsel: Richards, Layton & Finger, P.A.
• Case Identification: 1:22-cv-01597, D. Del., 12/14/2022
• Venue Allegations: Venue is alleged to be proper as Defendant Parse Biosciences, Inc. is a Delaware corporation and therefore resides in the District of Delaware.
• Core Dispute: Plaintiff alleges that Defendant’s Evercode line of single-cell sequencing kits infringes three patents related to methods for uniquely labeling molecules within large populations of cells using combinatorial barcoding.
• Technical Context: The technology at issue addresses single-cell analysis, a critical field in genomics and personalized medicine that allows researchers to study individual cells within complex biological samples.
• Key Procedural History: Plaintiff ScaleBio is the exclusive licensee of the asserted patents, which are owned by Nominal Defendant Roche Sequencing Solutions, Inc. The complaint alleges that Defendant was notified of its infringement of the ’256 Patent in June 2021 and the ’442 Patent in March 2022, prior to the filing of the lawsuit. The ’341 Patent issued just weeks before the complaint was filed.

Case Timeline

Date	Event
2011-01-31	’442, ’256, and ’341 Patents Priority Date
2020-04-21	U.S. Patent No. 10,626,442 Issues
2021-02-18	Accused Products Commercial Launch Date
2021-04-20	U.S. Patent No. 10,982,256 Issues
2021-06-10	Defendant Notified of ’256 Patent
2022-03-01	Defendant Notified of ’442 Patent
2022-11-29	U.S. Patent No. 11,512,341 Issues
2022-12-14	Complaint Filing Date

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 background describes the need for accurate and sensitive methods to detect, identify, and quantify multiple different molecules (e.g., proteins, RNA) within individual cells in a large, complex population, without requiring expensive or complex laboratory equipment for cell separation (’442 Patent, col. 1:29-47).
• The Patented Solution: The invention proposes a method that uses the cell itself as a reaction vessel to build a unique "barcode" on each target molecule. This is achieved through a "split-pool" synthesis process where a population of cells is repeatedly split into different reaction volumes, tagged with a nucleic acid sequence unique to that volume, and then pooled back together. Repeating this process creates a unique combinatorial barcode for the molecules within each cell, identifying both the target molecule and its cell of origin without needing to isolate the cells first (’442 Patent, col. 2:45-56).
• Technical Importance: This approach eliminates the need for specialized equipment to physically compartmentalize single cells (e.g., microfluidic devices), thereby enabling single-cell analysis at a vastly greater scale than was previously practical (Compl. ¶12).

Key Claims at a Glance

• The complaint asserts infringement of at least independent Claim 1 (Compl. ¶30).
• Essential elements of Claim 1 include:
  • 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 to the primary 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 to the secondary tags.
• The complaint does not explicitly reserve the right to assert dependent claims.

U.S. Patent No. 10,982,256 - Methods of Identifying Multiple Epitopes in Cells (Issued April 20, 2021)

The Invention Explained

• Problem Addressed: The patent addresses the same technical challenge as the ’442 Patent: large-scale, multiplexed analysis of molecules in single cells (’256 Patent, col. 1:15-47).
• The Patented Solution: This patent claims a similar split-pool synthesis method but frames the invention using more specific terminology. The solution involves binding a "unique binding agent (UBA)" (e.g., an antibody or primer) to a target molecule and then extending it. A "cell originating barcode (COB)" is then assembled on this extended UBA by sequentially adding multiple "assayable polymer subunit (APS)" oligonucleotides in successive rounds of split-pool synthesis. A key aspect is that the method does not require isolating individual cells into separate compartments (’256 Patent, col. 17:42-56).
• Technical Importance: As with the ’442 Patent, this method allows for massively parallel single-cell analysis by using combinatorial chemistry within the cells themselves, rather than relying on physical partitioning of cells (Compl. ¶12-13).

Key Claims at a Glance

• The complaint asserts infringement of at least independent Claim 1 (Compl. ¶63).
• Essential elements of Claim 1 include:
  • Binding a plurality of 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 during successive rounds of split pool synthesis.
  • Wherein the APS oligonucleotides anneal to the APS from a previous round and are covalently linked to create unique codes identifying individual cells.
  • Wherein the method does not include a step of isolating each cell.
• The complaint does not explicitly reserve the right to assert dependent claims.

U.S. Patent No. 11,512,341 - Methods of Identifying Multiple Epitopes in Cells (Issued November 29, 2022)

• Technology Synopsis: The patent claims a method of barcoding complementary DNA (cDNA) within cells or cell compartments. The method involves producing the cDNA and then adding oligonucleotide barcodes through a process comprising at least two barcoding steps, each of which involves splitting the cells, adding assayable oligonucleotide subunits, and then pooling the cells (’341 Patent, col. 3:50-60).
• Asserted Claims: Independent Claim 1 (Compl. ¶92).
• Accused Features: The complaint alleges that the Accused Products' workflow, which involves producing cDNA via reverse transcription and then performing multiple split-pool barcoding steps, infringes this patent (Compl. ¶95-97).

III. The Accused Instrumentality

Product Identification

The accused instrumentalities are Defendant’s single-cell gene expression products, marketed as "Evercode Whole Transcriptome" or "Evercode WT." This includes kits, reagents, consumables, software, and instruction manuals (Compl. ¶16).

Functionality and Market Context

The Accused Products are alleged to employ a split-pool combinatorial barcoding method known as "SPLiT-Seq" to analyze molecular signatures at the single-cell level (Compl. ¶17). A diagram from the Defendant's website, included in the complaint, illustrates this multi-step process, which involves sequential rounds of splitting cell samples into wells, applying barcodes, and pooling the cells back together (Compl. p. 7). The complaint alleges this technology enables users to process from 10,000 up to one million single cells and that Defendant has "seized a critical early market share" (Compl. ¶16-17). The process is alleged to convert single cells into "individualized reaction compartments" without the need for automated or specialized compartmentalization equipment (Compl. ¶18, 40).

IV. Analysis of Infringement Allegations

10,626,442 Patent 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 user applies "sample-specific barcodes ... to fixed cells or nuclei with an in-cell reverse transcription (RT) reaction." The complaint alleges the barcoded RT primers include a common linker sequence.	¶32	col. 2:57-64
(b) dividing the plurality of cells into at least two primary reaction volumes...	After an initial pooling, cells or nuclei are distributed across a plate into at least two wells, which function as reaction volumes.	¶33	col. 8:20-23
(c) providing primary nucleic acid tags to the at least two primary reaction volumes, wherein the...tags provided to the first...are different from the...tags provided to a second...	"Well-specific barcodes" are provided to the individual wells, which allegedly function as the primary tags. The complaint alleges these tags are different from well to well.	¶34	col. 8:37-43
(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 appends the second barcode" in the workflow, allegedly coupling the primary nucleic acid tag to the previously coupled common linker sequence.	¶35	col. 8:44-46
(e) pooling the at least two primary reaction volumes	After the "in-cell ligation," the complaint alleges that "[c]ells from each well are pooled together."	¶36	col. 8:24-25
(f) splitting the combined primary reaction volumes into at least two secondary reaction volumes...	The complaint alleges that after pooling, a "third barcode is applied...after the cells or nuclei are split across a plate," which constitutes splitting into secondary reaction volumes.	¶37	col. 8:20-23
(g) 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 with another in-cell ligation," which allegedly couples the secondary nucleic acid tags to the target molecules.	¶39	col. 8:44-46

• Identified Points of Contention:
  • Scope Questions: A central question may be whether the sequential steps of the accused SPLiT-Seq process map onto the claim's specific "primary" and "secondary" reaction volume and tagging limitations. The defense may argue a mismatch between the claim's two-stage (primary/secondary) structure and the accused product's alleged multi-stage process.
  • Technical Questions: The claim requires multiple "coupling" steps. The complaint alleges these are performed by both a reverse transcription reaction and a ligation reaction (Compl. ¶32, 35). A point of contention could be whether a reverse transcription reaction, which synthesizes DNA from an RNA template, meets the claim's definition of "coupling a common linker sequence to target molecules."

10,982,256 Patent 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's first step is applying "sample-specific barcodes" via "barcoded RT primers" to mRNA targets through an in-cell reverse transcription reaction. The poly(dT) portion of the primer is alleged to act as the UBA.	¶65	col. 17:15-17
(b) extending the UBAs bound to the targets	The in-cell reverse transcription reaction is alleged to extend the RT primers (the alleged UBAs) that are bound to the mRNA targets.	¶66	col. 17:17-18
(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 workflow uses "combinatorial barcoding technology," which allegedly assembles a "cell-specific combination of barcodes" by adding nucleic acid tags (the alleged APSs) during successive rounds of split-pool synthesis. A diagram from a scientific paper is used to illustrate this sequential ligation process (Compl. p. 28).	¶67	col. 17:42-48
[2] wherein the APS oligonucleotides in each round anneal to the APS from a previous round and are covalently linked ... to create unique codes that represent the identities of individual cells...	The complaint cites a scientific paper describing the accused SPLiT-Seq method, which states that barcodes are "appended to cDNA through ligation," allegedly creating a cell-specific combination of barcodes.	¶68	col. 34:31-35
[3] wherein the method does not include a step of isolating each cell in the plurality of cells	The complaint alleges the SPLiT-Seq method used by the Accused Products "does not require partitioning single cells into individual compartments...but relies on the cells themselves as compartments."	¶69	col. 24:19-22

• Identified Points of Contention:
  • Scope Questions: Practitioners may focus on whether the components of the accused kits meet the specific definitions of "unique binding agent (UBA)" and "assayable polymer subunit (APS)." The complaint maps the UBA to a poly(dT) RT primer and the APS to subsequent barcodes. The defense may challenge this mapping by arguing the claim terms require a different structure or function.
  • Technical Questions: Claim 1(c)[2] requires that APS oligonucleotides "anneal to the APS from a previous round" and are then "covalently linked." The complaint alleges this occurs via ligation (Compl. ¶68). The court may need to determine if the specific chemistry of the accused process, as described in the cited scientific paper (e.g., using a universal linker strand), meets this specific claim limitation.

V. Key Claim Terms for Construction

For the ’442 Patent:

• The Term: "coupling"
• Context and Importance: This term appears multiple times in Claim 1 to describe the attachment of linkers and tags. Its construction is critical because the complaint alleges that both reverse transcription and ligation reactions in the accused process satisfy this limitation. The scope of "coupling" will determine whether both types of biochemical reactions can be considered infringing acts.
• Intrinsic Evidence for Interpretation:
  • Evidence for a Broader Interpretation: The specification describes various ways components can be linked, including ligation, extension via polymerization, and Click chemistry, suggesting "coupling" is not limited to a single chemical method (’442 Patent, col. 7:34-40; col. 21:55-67).
  • Evidence for a Narrower Interpretation: The detailed descriptions of the split-pool synthesis embodiments repeatedly refer to "ligation" as the method for linking components, which might suggest that "coupling" in the context of the claims should be construed as being limited to ligation or similar direct chemical bonding, as opposed to enzymatic synthesis like reverse transcription (’442 Patent, col. 18:3-7).

For the ’256 Patent:

• The Term: "assembling cell originating barcodes (COB) on the extended UBAs"
• Context and Importance: This phrase is the core of Claim 1(c) and defines the inventive process. The dispute may turn on whether the accused product's process of sequentially ligating barcodes to a growing cDNA strand constitutes "assembling" a barcode "on" the extended UBA, especially since the extension (cDNA synthesis) and barcode addition (ligation) are distinct biochemical steps.
• Intrinsic Evidence for Interpretation:
  • Evidence for a Broader Interpretation: The specification states that "tags are formed through polymerization of building blocks in place" and that a COB is "generated with the APSs from the ordered set of APSs," which may support a broad reading that covers any process of sequentially building a barcode structure (’256 Patent, col. 2:1-3; col. 7:35-37). Figure 2 of the patent shows the COB as a polymer assembled from single APS units, which could support the plaintiff's theory (’256 Patent, Fig. 2).
  • Evidence for a Narrower Interpretation: The term "on the extended UBAs" could be interpreted narrowly to require that the barcode is physically built directly onto the UBA structure itself. The defense may argue that in the accused process, barcodes are ligated to the end of a growing cDNA strand, which is a product of the UBA's extension, but not "on" the UBA itself.

VI. Other Allegations

• Indirect Infringement: The complaint alleges that Defendant induces infringement by providing customers with the Accused Products along with "instructional information, dataset examples, tutorials, and support information" that instruct and encourage users to perform the patented methods (Compl. ¶20, 48-49, 78-79). The complaint also alleges the products have no substantial non-infringing use (Compl. ¶50, 80).
• Willful Infringement: Willfulness is alleged for the ’442 and ’256 Patents based on pre-suit knowledge from notice letters dated March 1, 2022 and June 10, 2021, respectively (Compl. ¶25-26, 44, 74). For the ’341 Patent, which issued shortly before the suit, willfulness is alleged on the basis that Defendant was monitoring the patent family and knew of the patent upon its issuance (Compl. ¶104).

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

• A core issue will be one of definitional scope: can the term "coupling" as used in the ’442 Patent be construed to cover both the reverse transcription and ligation reactions alleged to be performed by the accused products, or is it limited to a more specific form of chemical bonding?
• A key evidentiary question will be one of claim mapping: does the multi-round split-pool process of the accused "SPLiT-Seq" method, as described in Defendant's materials, map directly onto the specific "primary" and "secondary" tagging stages of the ’442 Patent's claims and the "UBA," "APS," and "COB" component limitations of the ’256 Patent's claims?
• A central question for damages will be willfulness: given the specific pre-suit notice dates alleged for two of the three patents, the court will need to assess whether Defendant's continued commercial activity after receiving notice was objectively reckless, which could expose it to enhanced damages.