Illumina Inc v. Billiontoone Inc

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Illumina, Inc. (Delaware)
  • Defendant: BillionToOne, Inc. (Delaware)
  • Plaintiff's Counsel: McCarter & English, LLP
• Case Identification: 1:26-cv-00531, D. Del., 05/07/2026
• Venue Allegations: Venue is alleged to be proper in the District of Delaware because Defendant is a Delaware corporation and has thus committed acts of infringement in the District.
• Core Dispute: Plaintiff alleges that Defendant's non-invasive prenatal testing services infringe three U.S. patents related to methods for determining the fraction of fetal DNA in a maternal blood sample.
• Technical Context: The technology at issue is non-invasive prenatal testing (NIPT), which analyzes cell-free DNA (cfDNA) from a pregnant mother's blood to screen for fetal genetic abnormalities.
• Key Procedural History: The complaint does not mention any prior litigation, inter partes review (IPR) proceedings, or licensing history related to the Asserted Patents.

Case Timeline

Date	Event
2010-01-19	Earliest Priority Date for '096, '760, and '373 Patents
2016-10-20	'096 Patent Filing Date
2019-01-01	Approximate Publication Date of "Tsao 2019" Paper
2020-04-03	'760 Patent Filing Date
2020-04-07	'096 Patent Issue Date
2020-04-27	'373 Patent Filing Date
2024-11-12	'760 Patent Issue Date
2025-01-01	Approximate Publication Date of "Wynn 2025" Paper
2025-05-16	Date of BillionToOne Press Release
2025-10-07	'373 Patent Issue Date
2026-05-07	Complaint Filing Date

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

U.S. Patent No. 10,612,096 - "Methods for Determining Fraction of Fetal Nucleic Acids in Maternal Samples" (Issued Apr. 7, 2020)

The Invention Explained

• Problem Addressed: The patent describes a need for methods to determine the fraction of fetal nucleic acid in both male and female pregnancies, as prior methods were often limited to detecting fetal-specific loci, such as the SRY locus on the Y chromosome for male pregnancies '096 Patent, col. 2:8-28
• The Patented Solution: The invention discloses methods for quantifying the fraction of fetal DNA in a maternal sample by amplifying a plurality of polymorphic target nucleic acids (such as those containing single nucleotide polymorphisms, or SNPs) from the mixed fetal and maternal cfDNA, and then using massively parallel sequencing to determine the relative quantities of the different alleles present '096 Patent, abstract '096 Patent, col. 2:37-56 This quantification allows for a gender-independent calculation of the fetal fraction, which can then be used to help determine the presence of fetal aneuploidies '096 Patent, abstract Figure 1 illustrates the overall workflow, from cfDNA purification (120) through massively parallel sequencing (140) to fetal fraction determination (160) '096 Patent, FIG. 1
• Technical Importance: This approach provided a crucial, gender-independent quality control metric for NIPT, enabling assessment of whether a sample contains sufficient fetal DNA for an accurate aneuploidy diagnosis.

Key Claims at a Glance

• The complaint asserts at least independent claim 1 and dependent claims 2-3, 6-9, 11-12, and 15-18 Compl. ¶34
• Claim 1 recites a method with the essential elements of:
  • (a) isolating the mixture of cfDNA;
  • (b) amplifying a plurality of predetermined polymorphic target nucleic acids comprising at least one SNP;
  • (c) preparing a sequencing library;
  • (d) performing massively parallel sequencing to provide polymorphic sequence reads;
  • (e) mapping sequence reads to polymorphic sites in a reference genome;
  • (f) quantifying sequence tags aligned to allelic sequences;
  • (g) identifying informative SNPs based on the difference in allelic sequences and tag counts; and
  • (h) calculating the fraction of fetal cfDNA from the quantitative values Compl. ¶15

U.S. Patent No. 12,139,760 - "Methods for Determining Fraction of Fetal Nucleic Acids in Maternal Samples" (Issued Nov. 12, 2024)

The Invention Explained

• Problem Addressed: As with the parent '096 Patent, the invention addresses the need for a gender-independent method of determining the fraction of fetal nucleic acid in a maternal sample '760 Patent, col. 2:8-28
• The Patented Solution: The '760 Patent describes similar methods to the '096 Patent, involving the amplification of polymorphic target nucleic acids from a mixed cfDNA sample, followed by massively parallel sequencing and computational analysis to quantify the relative abundance of fetal versus maternal DNA '760 Patent, abstract The patent emphasizes that this approach enables accurate, non-invasive quantification of the fetal fraction through this process '760 Patent, col. 4:1-4
• Technical Importance: This technology refines and continues the development of gender-neutral NIPT quality control, a critical component for the reliability of prenatal screening tests.

Key Claims at a Glance

• The complaint asserts at least independent claim 1 and dependent claims 2-3, 6-9, and 11-13 Compl. ¶38
• Claim 1 recites a method with the essential elements of:
  • (a) isolating the mixture of cfDNA from the sample;
  • (b) amplifying a plurality of predetermined polymorphic target nucleic acids in the mixture, wherein each target comprises at least one SNP;
  • (c) preparing a sequencing library using at least a portion of the amplified product;
  • (d) performing massively parallel sequencing of at least a portion of the library;
  • (e) mapping a plurality of the sequence reads to polymorphic sites in a reference genome;
  • (f) quantifying sequence tags aligned to allelic sequences;
  • (g) identifying a plurality of informative SNPs; and
  • (h) for each informative SNP, calculating the fraction of fetal cfDNA from the quantitative values obtained Compl. ¶21

U.S. Patent No. 12,435,373 - "Identification of Polymorphic Sequences in Mixtures of Genomic DNA" (Issued Oct. 7, 2025) - Multi-Patent Capsule

• Technology Synopsis: The '373 Patent is directed to methods for identifying multiple polymorphisms (such as SNPs) in a first genome (e.g., fetal) from a blood sample that contains a mixture of cfDNA from a first and a second genome (e.g., fetal and maternal) Compl. ¶26 The method involves massively parallel sequencing of amplicons, mapping sequence tags, and quantifying the tags for different alleles at polymorphic sites to classify them as informative or non-informative, which can then be used to determine fetal DNA abundance Compl. ¶27
• Asserted Claims: The complaint asserts at least independent claim 1 and dependent claims 2-4 and 10-13 Compl. ¶42
• Accused Features: The accused features are Defendant's UNITY tests, which allegedly perform massively parallel sequencing and computational analysis to identify polymorphisms and determine fetal DNA abundance Compl. ¶30 Compl. ¶31

III. The Accused Instrumentality

Product Identification

• Defendant's UNITY prenatal testing products, including the UNITY Complete® screen and UNITY Fetal Risk™ Screen (the "UNITY tests") Compl. ¶30

Functionality and Market Context

• The UNITY tests are described as non-invasive prenatal screening tests that use cfDNA from a maternal blood sample to screen for chromosomal aneuploidies and single-gene disorders Compl. ¶30
• The complaint alleges that the methods used in the UNITY tests are described in published, peer-reviewed papers, which state that the approach "integrates measurements of (i) fraction of fetal DNA present in cfDNA, (ii) molecular counts of assayed cfDNA, (iii) allele fraction of the maternal variant, and (iv) allele fraction of any variants that are not present in the maternal genotype" Compl. ¶31 This indicates a process of sequencing cfDNA to analyze allelic differences and quantify fetal DNA fraction Compl. ¶31
• The complaint points to a press release stating the UNITY test provides "precise fetal risk assessment for up to 14 prevalent and actionable recessive and X-linked conditions, in addition to aneuploidies" Compl. ¶31
• No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

'096 Patent Infringement Allegations

Claim Element (from Independent Claim 1)	Alleged Infringing Functionality	Complaint Citation	Patent Citation
a method for determining the fraction of fetal cfDNA in a maternal blood sample...comprising the ordered steps of: (a) isolating the mixture of cfDNA;	The UNITY tests use cfDNA from a maternal blood sample to screen for disorders Compl. ¶30	¶30	col. 13:1-2
(b) amplifying a plurality of predetermined polymorphic target nucleic acids comprising at least one single nucleotide polymorphism ("SNP");	The UNITY tests involve analyzing cfDNA for variants, which implies amplification of target regions containing polymorphisms like SNPs Compl. ¶31	¶31	col. 13:3-6
(c) preparing a sequencing library;	The peer-reviewed papers describing the Defendant's methods are based on high-throughput sequencing, a process that requires library preparation Compl. ¶31	¶31	col. 15:11-20
(d) performing massively parallel sequencing to provide polymorphic sequence reads;	The UNITY tests are described as utilizing a "High-Throughput Molecular Counting Method," consistent with massively parallel sequencing Compl. ¶31	¶31	col. 15:30-34
(e) mapping sequence reads to polymorphic sites in a reference genome;	The Defendant's alleged method involves measuring allele fractions, which requires mapping sequence reads to known polymorphic sites Compl. ¶31	¶31	col. 19:45-51
(f) quantifying sequence tags aligned to allelic sequences;	The complaint alleges Defendant's method includes measuring "molecular counts of assayed cfDNA" and "allele fraction," which corresponds to quantifying tags for different alleles Compl. ¶31	¶31	col. 19:52-54
(g) identifying informative SNPs based on the difference in allelic sequences and tag counts;	The Defendant's method is alleged to analyze allele fractions of maternal and paternally inherited variants, which is the basis for identifying informative SNPs Compl. ¶31	¶31	col. 19:55-62
(h) calculating the fraction of fetal cfDNA from the quantitative values.	The complaint alleges that Defendant's approach for NIPT explicitly "integrates measurements of (i) fraction of fetal DNA present in cfDNA" Compl. ¶31	¶31	col. 20:3-12

• Identified Points of Contention:
  • Technical Questions: A central question will be whether the specific computational steps BillionToOne uses to identify informative SNPs and calculate the fetal fraction, as described in its publications Compl. ¶31, are the same as, or equivalent to, the steps recited in the claims. The complaint relies on these publications to establish a prima facie case, and any deviation in the actual commercial process could be a point of dispute.
  • Scope Questions: The claims of the '096 Patent are directed to a sequence of "ordered steps." The court may need to consider whether BillionToOne's process performs all the claimed steps and in the recited order.

'760 Patent Infringement Allegations

Claim Element (from Independent Claim 1)	Alleged Infringing Functionality	Complaint Citation	Patent Citation
a method for determining the fraction of fetal cfDNA in a maternal blood sample...comprising: (a) isolating the mixture of cfDNA from the sample;	The UNITY tests use cfDNA isolated from a maternal blood sample Compl. ¶30	¶30	col. 13:1-2
(b) amplifying a plurality of predetermined polymorphic target nucleic acids in the mixture, wherein each target nucleic acid comprises at least one single nucleotide polymorphism ("SNP");	The Defendant's described methods involve assays of cfDNA, which would require amplification of target polymorphic regions Compl. ¶31	¶31	col. 13:3-6
(c) preparing a sequencing library using at least a portion of the amplified product;	High-throughput sequencing methods, which the complaint alleges Defendant uses, necessitate the preparation of a sequencing library from the amplified DNA Compl. ¶31	¶31	col. 15:11-20
(d) performing massively parallel sequencing of at least a portion of the library...;	The Defendant's "High-Throughput Molecular Counting Method" is alleged to be a form of massively parallel sequencing Compl. ¶31	¶31	col. 15:30-34
(e) mapping a plurality of the sequence reads to polymorphic sites in a reference genome...;	The alleged analysis of "allele fraction of the maternal variant" and "paternally inherited variants" requires mapping reads to known polymorphic sites Compl. ¶31	¶31	col. 19:45-51
(f) quantifying sequence tags aligned to allelic sequences;	The complaint alleges Defendant's method includes "molecular counts of assayed cfDNA" which corresponds to quantifying tags for specific alleles Compl. ¶31	¶31	col. 19:52-54
(g) identifying a plurality of informative SNPs; and (h) for each informative SNP, calculating the fraction of fetal cfDNA from the quantitative values obtained.	The complaint alleges Defendant's method explicitly integrates measurements of "fraction of fetal DNA" based on analysis of maternal and paternally inherited variants Compl. ¶31	¶31	col. 20:3-12

• Identified Points of Contention:
  • Technical Questions: Given the substantial overlap in claim language and technology between the '760 and '096 Patents, the points of contention are similar. The analysis will likely focus on whether the specific laboratory and computational steps of the UNITY tests, particularly the method for identifying "informative SNPs" and the subsequent calculation, fall within the scope of the claims.
  • Scope Questions: The '760 Patent, like the '096 Patent, claims a multi-step method. Infringement will depend on evidence that BillionToOne practices each and every step of the claimed method.

V. Key Claim Terms for Construction

For U.S. Patent No. 10,612,096 and 12,139,760

• The Term: "informative SNPs"

• Context and Importance: This term is critical because it defines which genetic markers are used for the fetal fraction calculation. The claims functionally define it as being based on "the difference in allelic sequences and tag counts" Compl. ¶15 Practitioners may focus on how this determination is made, as it is a core analytical step of the invention.

• Intrinsic Evidence for Interpretation:

  • Evidence for a Broader Interpretation: The specification describes the general principle that informative SNPs are those where the mother is homozygous and the fetus is heterozygous, allowing the paternally-inherited fetal allele to be distinguished '096 Patent, col. 20:3-12 This may support an interpretation covering any method that identifies such genetic differences.
  • Evidence for a Narrower Interpretation: The specification provides specific examples and calculations for determining informativeness, which could be argued to limit the scope of the term '096 Patent, col. 19:55-67 '096 Patent, FIG. 2 A defendant might argue the term is limited to the specific statistical or quantitative thresholds disclosed in the patent's embodiments.

• The Term: "calculating the fraction of fetal cfDNA"

• Context and Importance: This term represents the final output of the claimed method. The dispute may turn on whether the defendant's specific algorithm for calculating the fetal DNA percentage is covered by the claim language.

• Intrinsic Evidence for Interpretation:

  • Evidence for a Broader Interpretation: The patent states that the fraction can be calculated as a ratio of the fetal-specific allele counts to the maternal allele counts, a general principle that could be read broadly '096 Patent, col. 20:3-12 '096 Patent, col. 62:45-58
  • Evidence for a Narrower Interpretation: The patent provides specific exemplary formulas for the calculation, including one that involves doubling the fetal-specific allele counts to account for the biallelic nature of the fetal genome '096 Patent, col. 62:55-65 A party could argue that the term should be limited to these specific disclosed calculation methods.

VI. Other Allegations

• Indirect Infringement: The complaint does not plead a separate count for indirect infringement. However, it alleges that BillionToOne "marketed, advertised, promoted, and/or supported" the accused UNITY tests Compl. ¶32 These allegations could potentially be used to support a theory of induced infringement, although specific facts demonstrating an intent to encourage infringement by others are not detailed.
• Willful Infringement: The complaint makes a standard request for enhanced damages under 35 U.S.C. § 284 and attorneys' fees under § 285 (Compl. p. 11, prayers B, E). However, it does not plead specific facts to support a claim of willful infringement, such as alleging that Defendant had pre-suit knowledge of the Asserted Patents.

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

1. A central issue will be one of claim construction and scope: How broadly will the court construe the specific, ordered laboratory and computational steps recited in the claims, such as "identifying informative SNPs" and "calculating the fraction of fetal cfDNA"? The outcome may depend on whether these terms are given a broad, functional meaning or are limited to the specific formulas and embodiments disclosed in the patents.
2. A key evidentiary question will be one of technical equivalence: Does the methodology employed in BillionToOne's commercial UNITY tests, as potentially detailed in its internal documentation versus its academic publications, perform every step of the patented methods? The case will likely require a step-by-step comparison of the accused process against the claim limitations.
3. Given the similarity between the asserted patents, which stem from the same original application, a significant question for the litigation will be the validity and potential redundancy of the claims. The court may examine whether the claims across the three patents are patentably distinct and whether they represent non-obvious improvements over the prior art at the time of invention.