Pacific Biosciences Of California Inc v. Oxford Nanopore Tech Inc

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Pacific Biosciences of California, Inc. (Delaware)
  • Defendant: Oxford Nanopore Technologies, Inc. (Delaware)
  • Plaintiff’s Counsel: Farnan LLP; Weil, Gotshal & Manges LLP
• Case Identification: 1:17-cv-01353, D. Del., 03/28/2018
• Venue Allegations: Venue is alleged to be proper in the District of Delaware because Defendant is a Delaware corporation.
• Core Dispute: Plaintiff alleges that Defendant’s nanopore-based single-molecule DNA sequencing products and related software infringe three U.S. patents related to controlling nucleic acid translocation, generating high-accuracy consensus sequences, and interpreting sequencing signals.
• Technical Context: The lawsuit concerns single-molecule DNA sequencing, a technology enabling the reading of long, continuous stretches of genetic code, which has significant applications in genomics and diagnostics.
• Key Procedural History: The complaint alleges that in parallel proceedings before the International Trade Commission, Defendant has asserted that nanopore sequencing was "not known in the 2008-2009 timeframe" and was a "later developed technology." The complaint also cites Defendant's own patent filings, which Plaintiff alleges acknowledge the inventive concepts patented by Plaintiff.

Case Timeline

Date	Event
2008-09-24	U.S. Patent No. 9,738,929 Priority Date
2009-04-10	U.S. Patent Nos. 9,678,056 & 9,772,323 Priority Date
2015-01-01	Accused Products commercialization began (approximate timeframe)
2017-06-13	U.S. Patent No. 9,678,056 Issued
2017-08-22	U.S. Patent No. 9,738,929 Issued
2017-09-26	U.S. Patent No. 9,772,323 Issued
2018-03-28	Complaint Filing Date

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

U.S. Patent No. 9,678,056 - "Control of Enzyme Translocation in Nanopore Sequencing"

The Invention Explained

• Problem Addressed: The patent's background section describes the challenge that devices using nanopores to sequence DNA have generally not been capable of reading sequence at single-nucleotide resolution, in part because of the rapid, uncontrolled speed at which the DNA molecule passes through the pore (U.S. Patent No. 9,678,056, col. 1:56-59).
• The Patented Solution: The invention proposes to solve this problem by controlling the rate of DNA translocation using an associated enzyme. Specifically, the enzyme and reaction conditions are selected such that the enzyme exhibits "two slow kinetic steps," which effectively moves the DNA through the nanopore in a more controlled, stepwise fashion, allowing for more accurate electrical measurements for each nucleotide (’056 Patent, Abstract; col. 26:1-20).
• Technical Importance: Controlling the translocation speed of a nucleic acid through a nanopore is a foundational challenge in the field, and achieving such control is a key step toward making the technology a high-accuracy, commercially viable sequencing method (Compl. ¶¶20, 22).

Key Claims at a Glance

• The complaint asserts independent claim 1 (Compl. ¶27).
• Essential elements of Claim 1:
  • Providing a substrate with a nanopore connecting an upper and lower solution, with the nanopore sized to pass a single strand of nucleic acid.
  • Providing a voltage across the nanopore to produce a measurable current.
  • Controlling the rate of translocation of the nucleic acid with a translocating enzyme that exhibits two kinetic steps, where the ratio of the rate constants for those steps is from 10:1 to 1:10.
  • Measuring the current through the nanopore over time as the nucleic acid translates.
  • Determining the sequence of the nucleic acid using the measured current.

U.S. Patent No. 9,738,929 - "Nucleic Acid Sequence Analysis"

The Invention Explained

• Problem Addressed: The complaint describes the problem of inherent inaccuracies in nanopore-based DNA sequencing (Compl. ¶44). The patent background notes the challenge of collecting reliable reaction data from disparate reaction times and the potential for photo-induced damage to reactants in optically-based systems (’929 Patent, col. 2:45-66).
• The Patented Solution: The invention describes a method for improving accuracy by sequencing a double-stranded polynucleotide construct. The system obtains sequence information from both the forward strand and its complementary strand, generating "redundant sequence information." This redundant information is then used to determine a high-confidence "consensus sequence" for the region of interest ('929 Patent, Abstract; col. 38:5-19). The complaint notes that this can be embodied in constructs where the two strands are linked, forming a hairpin or dumbbell shape (Compl. ¶¶48-49).
• Technical Importance: This "proof-reading" capability, generated by sequencing both strands of a DNA molecule, offers a method to dramatically increase the accuracy of single-molecule sequencing, which is critical for applications that require high fidelity (Compl. ¶23, 47).

Key Claims at a Glance

• The complaint asserts independent claim 1 and dependent claims 2, 6-8, and 10-11 (Compl. ¶41).
• Essential elements of Claim 1:
  • Introducing a polynucleotide containing a double-stranded portion with complementary strands to a sequence analysis system that has a nanopore.
  • Applying a voltage across the membrane.
  • Monitoring ionic current variations during "enzyme chaperone-regulated passage" of the polynucleotide through the nanopore.
  • Analyzing the current variations to obtain "redundant sequence information" comprising the sequence of the complementary strands.
  • Determining a "consensus sequence" based on the redundant sequence information.
• The complaint explicitly reserves the right to assert dependent claims (Compl. ¶41).

U.S. Patent No. 9,772,323 - "Nanopore Sequencing Using N-mers"

The Invention Explained

• Technology Synopsis: The complaint alleges that the electrical signal in a nanopore sequencer arises not from a single base, but from a contiguous group of bases, or an "N-mer" (e.g., a 5-mer) (Compl. ¶21). This patent addresses the problem by describing a method to determine a DNA sequence by comparing the measured electrical signal to pre-existing "calibration information" that accounts for the signals produced by all possible N-mer combinations (’323 Patent, Abstract).

Key Claims at a Glance

• Asserted Claims: The complaint asserts independent claim 1 (Compl. ¶64).
• Accused Features: The complaint alleges that Defendant's basecalling software uses calibration information produced by measuring signals from different combinations of bases to interpret the electrical signal and determine the DNA sequence (Compl. ¶¶21, 66).

III. The Accused Instrumentality

Product Identification

• The accused instrumentalities are Oxford Nanopore's single-molecule sequencing products, including at least the MinION, GridION X5, PromethION, SmidgION, and Flongle sequencing instruments, along with the associated reagents, consumables (such as flow cells), and software used with them (Compl. ¶13). Specifically for the ’929 Patent, the complaint identifies reagents and kits for generating "2D reads" and "1D squared reads" (Compl. ¶40).

Functionality and Market Context

• The Accused Products perform DNA sequencing by passing a strand of DNA through a protein nanopore embedded in a membrane (Compl. ¶18, p. 5, Ex. 7). An applied voltage creates an ionic current through the pore, and as the DNA translocates, it disrupts this current, producing an electrical signal that is measured (Compl. p. 8, Ex. 9 text). The complaint includes an image of a MinION device showing a flow cell with a "nanopore array" labeled "C" (Compl. p. 4, Figure 4). The signal corresponds to a contiguous group of bases within the pore at a given time (Compl. ¶21). The system allegedly uses a "motor protein" or enzyme to control the rate at which the DNA moves through the pore (Compl. ¶22). Software then analyzes the measured electrical signal to determine the DNA sequence (Compl. ¶21, 29). The complaint alleges that PacBio and Oxford compete in the single-molecule sequencing market (Compl. ¶12). A diagram provided in the complaint illustrates a strand of DNA being drawn through a pore in a membrane (Compl. p. 7).

IV. Analysis of Infringement Allegations

U.S. Patent No. 9,678,056 Infringement Allegations

Claim Element (from Independent Claim 1)	Alleged Infringing Functionality	Complaint Citation	Patent Citation
[a] providing a substrate having an upper solution above the substrate, a lower solution below the substrate, the substrate comprising a nanopore connecting the upper solution and lower solution, the nanopore sized to pass a single strand of nucleic acid;	Oxford's products include an instrument with a substrate containing a nanopore in a membrane, separating upper and lower solutions containing nucleic acids.	¶29	col. 8:5-20
[b] providing a voltage across the nanopore to produce a measurable current flow through the nanopore;	A voltage is applied across the membrane in Oxford's products to drive a current.	¶29	col. 24:1-5
[c] controlling the rate of translocation of a single stranded portion of the nucleic acid template through the nanopore with a translocating enzyme... such that the translocating enzyme exhibits two kinetic steps wherein each of the kinetic steps has a rate constant, and the ratio of the rate constants of the kinetic steps is from 10:1 to 1:10;	The rate of translocation is allegedly controlled by a translocating enzyme that exhibits two kinetic steps with rate constants falling within the claimed ratio.	¶29	col. 26:1-20
[d] measuring the current through the nanopore over time as the nucleic acid template is translated through the nanopore; and	The current is measured over time as a nucleic acid molecule is drawn through the nanopore, with the current being disrupted and measured by an ASIC chip.	¶29	col. 23:35-40
[e] determining the sequence of a portion of the nucleic acid template as it translates through the nanopore using the measured current over time.	Oxford's basecalling software determines the sequence based on the current measurements as the nucleic acid template is translated through the nanopore.	¶29	col. 25:10-24

• Identified Points of Contention:
  • Technical Question: What evidence does the complaint provide that the "translocating enzyme" used in Defendant's products exhibits the specific "two kinetic steps" with a rate constant ratio between "10:1 to 1:10" as required by the claim? The complaint's assertion on this element is conclusory and will likely require significant factual and expert discovery to substantiate.

U.S. Patent No. 9,738,929 Infringement Allegations

Claim Element (from Independent Claim 1)	Alleged Infringing Functionality	Complaint Citation	Patent Citation
[a] introducing a polynucleotide comprising a region of interest to a sequence analysis system comprising a nanopore in a membrane, wherein the polynucleotide comprises a double-stranded portion comprising complementary strands of the region of interest;	Oxford's products are used to sequence a double-stranded polynucleotide by unzipping the double strand and feeding it through a nanopore in a membrane.	¶45	col. 38:20-25
[b] applying a voltage across the membrane;	A voltage is applied across the membrane to drive a current.	¶45	col. 37:45-50
[c] monitoring variations in ionic current through the nanopore of the sequence analysis system during enzyme chaperone-regulated passage of the polynucleotide through the nanopore;	An enzyme allegedly regulates the passage of the polynucleotide through the nanopore, and variations in the ionic current are measured and monitored.	¶45	col. 37:50-55
[d] analyzing the monitored variations in ionic current to obtain nucleotide sequence information for the polynucleotide, wherein the nucleotide sequence information comprises redundant sequence information for the region of interest, wherein the redundant sequence information comprises the nucleotide sequence of the complementary strands; and	When generating "2D reads" or "1D squared reads," Oxford's analysis allegedly uses redundant sequence information from both the sense and antisense strands of DNA.	¶46	col. 38:5-15
[e] determining a consensus sequence for the region of interest based on the redundant sequence information.	A consensus sequence is determined based on the analysis of the redundant sequence information.	¶46	col. 38:15-19

• Identified Points of Contention:
  • Scope Questions: The infringement analysis may focus on the term "enzyme chaperone-regulated passage." It raises the question of whether the enzymes used in the accused products, which modulate translocation speed, perform the specific function of an "enzyme chaperone" as contemplated by the patent.

V. Key Claim Terms for Construction

For the ’056 Patent

• The Term: "a translocating enzyme... exhibits two kinetic steps wherein each of the kinetic steps has a rate constant, and the ratio of the rate constants of the kinetic steps is from 10:1 to 1:10"
• Context and Importance: This limitation is the central technical feature of the asserted claim, defining the specific biochemical mechanism for controlling DNA translocation. Whether the enzymes in the accused products function in this precise manner will be a dispositive issue for infringement.
• Intrinsic Evidence for a Broader Interpretation: The specification describes the invention as relating to a variety of enzymes, including "polymerases, helicases, and other nucleic acid translocases" ('056 Patent, col. 23:45-50), suggesting the term "translocating enzyme" is not limited to a single type.
• Intrinsic Evidence for a Narrower Interpretation: The specification provides detailed theoretical models, equations, and diagrams (e.g., Fig. 32) describing the reaction cycle with two slow steps ('056 Patent, col. 25:40-67; Fig. 32). A party could argue that the claim term must be interpreted in light of these specific disclosed biochemical mechanisms.

For the ’929 Patent

• The Term: "enzyme chaperone-regulated passage"
• Context and Importance: This term describes the mechanism by which the polynucleotide moves through the nanopore. The definition of this term will determine what type of enzymatic control meets the claim limitation and will be critical for the infringement analysis.
• Intrinsic Evidence for a Broader Interpretation: The specification broadly refers to using "DNA or RNA metabolizing or translocating enzymes" and "DNA or RNA binding proteins" to control translocation ('929 Patent, col. 49:40-55), which may support a broad definition of "enzyme chaperone."
• Intrinsic Evidence for a Narrower Interpretation: While the specification is broad, the use of the specific term "chaperone" could suggest a function more specific than simply a polymerase moving along a template. A party might argue it implies an enzyme whose primary role is to guide the polynucleotide, raising questions about whether a standard sequencing polymerase performs this "chaperone" function.

VI. Other Allegations

Indirect Infringement

• The complaint alleges both induced and contributory infringement for all three patents. It alleges inducement based on Defendant's alleged knowledge and specific intent that its customers' use of the Accused Products constitutes infringement, citing Defendant's promotional materials, website, and distribution channels as evidence (Compl. ¶¶31-34, 54-57, 68-71). Contributory infringement is alleged on the basis that the Accused Products are specialized apparatuses that are a material part of the invention and are not staple articles of commerce suitable for substantial non-infringing use (Compl. ¶¶35-36, 58-59, 72-73).

Willful Infringement

• For each patent-in-suit, the complaint alleges that Defendant has monitored Plaintiff's patent filings and has been aware of the respective patent since its issuance date, but has continued its allegedly infringing activities despite this knowledge (Compl. ¶¶30, 53, 67). Plaintiff seeks a declaration that the case is exceptional and an award of attorneys' fees (Compl. p. 28, ¶E).

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

The resolution of this dispute may turn on several key technical and evidentiary questions for the court:

• A core issue will be one of functional proof: can Plaintiff provide sufficient evidence to demonstrate that the enzymes operating in Defendant's sequencing systems exhibit the specific "two kinetic steps" with the precise ratio of rate constants as required by Claim 1 of the ’056 patent, or is there a fundamental mismatch in the biochemical mechanism of translocation?
• A second key question will be one of definitional scope: can the term "enzyme chaperone-regulated passage" from the ’929 patent be construed to cover the process by which a polymerase moves a DNA construct through a nanopore in Defendant's systems, or does the term imply a more specific guiding function not present in the accused method?
• A final point of interest will be one of evidentiary framing: how might Defendant's alleged statements in a parallel ITC proceeding—characterizing nanopore sequencing as a "later developed technology" not known in the 2008-2009 timeframe—be used by Plaintiff to argue for the non-obviousness and inventive nature of its patented solutions, which claim priority to that same period?