Patentability of Circulating Tumor DNA, An Emerging Tool in Precision Technology and Cancer Research

Sofia MakePeace

1. Introduction

   Circulating tumor DNA (ctDNA) has emerged as one of the most promising tools in modern oncology.^[1] Unlike traditional tissue biopsies, ctDNA-based “liquid biopsies” allow clinicians to detect and monitor cancer using a simple fluid sample.^[2] By identifying fragments of tumor DNA outside the cell, these tests can reveal genetic information about a malignancy in a minimally invasive manner.^[3] Presently, liquid biopsies are most reliably used to guide targeted therapies, assess patient treatment response, including drug resistance, and identify recurrence, sometimes months before radiographic evidence would appear.^[4]

   Given the significant clinical promise of ctDNA technologies, commercial development of ctDNA technologies has been accompanied by corresponding efforts to secure intellectual property rights. Legal literature specifically addressing interactions between ctDNA and intellectual property law is limited, but decided and pending litigation will guide this analysis. Namely, Natera, Inc. v. NeoGenomics Laboratories, Inc., directly addresses ctDNA patent disputes.^[5] And, subject-matter eligibility of ctDNA products is on the United States District Court for the District of Delaware’s docket.^[6] 

   ctDNA seemingly falls directly in the category of unpatentable subject matter. ctDNA fragments are naturally occurring DNA molecules shed by tumor cells into the bloodstream. The Supreme Court has unanimously invalidated claims directed to naturally occurring isolated genes.^[7] Even so, clinical use of ctDNA depends on extensive human intervention, including isolation techniques, chemical modification, amplification, sequencing, and computational analysis. Those steps raise the possibility that ctDNA-based inventions may fall in the scope of patent-eligible subject matter under Chakrabarty^[8] and progeny. That is true especially for method claims: claims that direct laboratories on how to prepare ctDNA technologies, like diagnostic tests.

   This paper argues that although ctDNA itself is unlikely to be patentable as a standalone composition of matter, patent law will likely protect claims directed toward engineered ctDNA-related technologies and computational methods.

    

2. Scientific and Doctrinal Foundations of ctDNA Patentability

   1. Scientific Background: What is ctDNA?

      To understand circulating tumor DNA (ctDNA), it is important to distinguish it from circulating cell-free DNA (cfDNA). Of course, the vast majority of human DNA is housed inside each of the body’s cells, contained in the nucleus. However, cfDNA are short fragments of DNA, believed to be released from cells primarily during cell death^[9], that exist outside the confines of the cell walls. cfDNA can be found in plasma, urine, cerebral spinal fluid, pleural fluid, and saliva.^[10]

      Then, ctDNA refers to even shorter fragments of cfDNA that are released exclusively by tumor cells whether through cell death or active secretion via extracellular vesicles or lipoprotein complexes.^[11]  When a tumor is present, fragments with tumor-specific genetic alterations—such as point mutations, insertions, deletions, or characteristic methylation patterns—circulate alongside normal cfDNA.^[12] By identifying these distinctive alterations, clinicians can isolate ctDNA within the broader cfDNA pool and use it as a highly specific biomarker for cancer.

      Since cfDNA is present in a variety of bodily fluids, ctDNA is especially clinically relevant because a person’s tumor biology can be monitored using blood, urine, saliva, or semen^[13] instead of invasive procedures. ctDNA data can be used to detect molecular residual disease (MRD), monitor treatment response, identify emerging resistance mutations from treatment, and screen for cancer at early stages, using only non-solid biological tissues.^[14]

   2. Patent Eligibility Framework, as it relates to ctDNA

      Patent eligibility in the United States is governed by 35 U.S.C. § 101 which makes patentable “any new and useful process, machine, manufacture, or composition of matter. . . .” Although the language reads very broad, the Supreme Court has long recognized several exceptions to patentability: laws of nature, natural phenomena, and abstract ideas. Patent claims directed toward those areas, such as a newly discovered mineral or a naturally occurring DNA sequence, are per se invalid, even though they are, technically, compositions of matter.

      The Supreme Court’s decision in Chakrabarty, reflects those judicially created exceptions in the biotechnology innovation space.^[15] The Court held that genetically engineered , capable of breaking down crude oil, were patentable because they possessed “markedly different characteristics from any found in nature.”^[16]

      Again, in Association for Molecular Pathology v. Myriad Genetics, Inc., the Supreme Court addressed patent eligibility in biotechnology; this time addressing DNA isolation and sequencing techniques.^[17] Claims directed to the ‘natural phenomena’ of isolated DNA segments were held ineligible for patent.^[18] At the same time, claims directed to synthetic DNA molecules, complementary DNA (cDNA) in this case, were held eligible for patent.^[19] The reasoning was that cDNA, synthesized in the 5’ to 3’ direction, was ‘markedly different’ from the naturally occurring mRNA template, which exists only in the 3’ to 5’ direction. Yet, even where eligibility and infringement were established, Myriad’s patents did not truly result in comprehensive market exclusivity.^[20] In subsequent proceedings, courts denied injunctive relief, finding that while Myriad faced “irreparable harm” from market share loss, the “balance of hardships” favored competitors offering broader access to breast cancer testing.^[21]

      In Illumina, Inc. v. Ariosa Diagnostics, Inc., the Federal Circuit clarified that method claims involving DNA preparation can be patent eligible under the Myriad framework if they involve “specific process steps” that, via human-initiated selection, “change the composition of the [naturally-occurring] mixture.”^[22] There, the Majority held that patents claiming methods of preparing an extracellular fraction of cell-free DNA enriched in fetal DNA constituted      patent-eligible subject matter under 35 U.S.C. § 101, even though it was a natural phenomenon that fetal DNA fragments could be separated and amplified based on their size.^[23] In response, practitioners recommended that life sciences claims should be drafted as  of preparing samples or treatment methods, instead of methods to diagnose or detect disease to withstand section 101 scrutiny.^[24]

      The United States Patent and Trademark Office (USPTO) issued specific guidance following Myriad, advising patent examiners that they should “reject product claims drawn solely to naturally occurring nucleic acids or fragments, whether isolated or not, as ineligible subject matter under Section 101.”^[25] However, claims directed to non-naturally occurring nucleic acids or novel methods of detection and production remain patent eligible under the memorandum.^[26]

       

3. The Natera Case and Other Existing Litigation and Patents on ctDNA

   The Federal Circuit has already addressed some patentability issues of claims directed toward ctDNA in Natera, Inc. v. NeoGenomics Laboratories, Inc., 106 F.4^th 1369 (2024). Two competing products, Natera’s Signatera and NeoGenomics’ RaDaR, detect ctDNA shed by cancerous cells to detect molecular residual disease (MRD) for early detection of cancer relapse. Both products are tumor-informed MRD tests, meaning they are based on a tissue biopsy of the patient’s tumor and specialized to the patient’s genome.^[27]

   Natera owns two patents directed toward “methods for amplifying targeted genetic material, such as cfDNA, while reducing amplification of non-targeted genetic material,” and “methods for detecting variations in genetic material indicative of disease or disease recurrence, such as ctDNA.”^[28] They sued NeoGenomics alleging patent infringement. The Federal Circuit affirmed the district court’s decision to grant Natera’s request for a preliminary injunction, barring NeoGenomics from making, using, selling, offering for sale, or promoting, advertising, marketing, servicing, distributing, or supplying their product to induce infringement. That means the court believed the patentee showed not only a likelihood of success of their infringement claim, but that their infringement claim will likely withstand challenges to validity of the patents.^[29] It is important to note, however, that NeoGenomics’ only validity argument was obviousness. The court did not directly address whether methods directed toward ctDNA detection are subject-matter eligible under ection 101, but the grant of preliminary equitable relief suggests that no immediate eligibility defect was apparent to the court. 

   Another biotechnology company, Guardant Health, has been the subject of ctDNA litigation all over the country.^[30] ctDNA methods of liquid biopsy hold significant commercial value in terms of intellectual property rights. For Guardant Health, patents are the primary method of commercializing their liquid biopsy products, with expert testimony indicating that the patents-in-suit “are foundational and essential to the significant commercial success” of the accused products.^[31]

   In a pending case, Guardant Health, Inc. v. Tempus AI, Inc., the court has been asked to address patent subject matter eligibility of ctDNA method claims. Guardant argues their method claims are patentable because they rely on human intervention, including isolation techniques, amplification, and computational analysis. In response, Tempus AI, asserts that Guardant’s method claims are directed to patent-ineligible natural phenomena. They argue that Guardant’s patent claims are “all directed to methods of detecting or monitoring a natural phenomenon, namely “disease” or “residual disease”—in particular, cancer—through observation of another natural phenomenon—naturally occurring cfDNA.”^[32]

4. Implications for ctDNA Patentability

   As reflected in Chakrabarty and its progeny, as well as in the trajectory of pending litigation, ctDNA will likely only be patentable to the extent that its claimed use involves human intervention. To date, method claims have proven to be successful at the patent office. Accordingly, ctDNA technologies should be patented as methods—such as selective isolation techniques, novel amplification strategies that enrich tumor-specific fragments, error-correction algorithms, or computational systems that convert raw sequencing data into clinical applications. Although certain detection claims have survived examination, under Ariosa such claims remain vulnerable where they risk being characterized as directed toward natural phenomena.

   At the same time, patenting in this area should remain attentive to the policy concerns behind Myriad. Broad claiming, even to methods, risks preempting downstream research and, importantly, clinical use at affordable prices. Claim drafting should strike a balance between ensuring commercial reward for technological innovators and avoiding monopolization of fundamental biological information. The current ctDNA legal landscape suggests that courts are willing to uphold and enforce patents that claim ctDNA methods, but the outer boundaries of validity, particularly subject-matter eligibility, remain unsettled.

    

5. Conclusion

ctDNA exists at the intersection of biotechnology innovation and patent law’s longstanding exclusions for natural phenomena. While ctDNA fragments, even isolated, are unlikely to qualify as patentable subject matter, existing precedent indicates that method claims directed to human-engineered processes remain valid under 35 U.S.C. § 101.

            That being said, ctDNA methodology has thus far been tested through obviousness challenges, leaving subject-matter eligibility unresolved. Pending litigation in the District of Delaware may soon address whether such claims survive scrutiny.

            Patent law must balance incentivizing innovation in ctDNA technologies with the risk of impeding downstream cancer research or increasing treatment costs for patients. Ultimately, how that balance is struck will shape the market for liquid biopsy diagnostics and the role of patents in commercializing precision medicine.

^[1] What is circulating tumor DNA and how is it used to diagnose and manage cancer?, Nat’l inst. health: medline plus (July 28, 2021), https://medlineplus.gov/genetics/understanding/testing/circulatingtumordna/.

^[2] Julie Grisham, Liquid Biopsies and Other Blood Tests for Cancer: What You Should Know, mem’l sloan kettering cancer ctr. (2025) (Sept. 15, 2025), https://www.mskcc.org/news/liquid-biopsies-and-other-blood-tests-for-cancer.

^[3] Id.

^[4] Id.

^[5] 106 F.4^th 1369 (2024).

^[6] Guardant Health, Inc. v. Tempus AI, Inc., No. 24-687 (D. Del. Dec. 3, 2025). 

^[7] Assn. for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576, 590 (2013) (invalidating claims directed toward the precise location and genetic sequence of BRCA1 and BRCA2 genes as ineligible subject matter).

^[8] Diamond v. Chakrabarty, 447 U.S. 303 (1980).

^[9] Jahr Sabine et al., DNA Fragments in the Blood Plasma of Cancer Patients: Quantitations and Evidence for Their Origin from Apoptotic and Necrotic Cells, 61 Cancer Rsch. 4, 1659-1665 (2001).

^[10] Caitlin Stewart & Dana Tsui, Circulating cell-free DNA for non-invasive cancer management, 229 cancer genetics 1, 169-179 (2018).

^[11] Sabine, supra note 10.

^[12] Stewart & Tsui, supra note 11.

^[13] Sabine, supra note 10.

^[14] Re-I Chin et al., Detection of Solid Tumor Molecular Residual Disease (MRD) Using Circulating Tumor DNA (ctDNA), 23 Molecular diagnosis & Therapy 1, 311-331 (2019).

^[15] Chakrabarty, 447 U.S. at 303.

^[16] Id. at 310.

^[17] 569 U.S. 576 (2013).

^[18] Id.

^[19] Id.

^[20] In re BRCA1-, BRCA2-Based Hereditary Cancer Test Pat. Litig., 3 F. Supp. 3d 1213, 1219 (D. Utah 2014), aff'd and remanded sub nom. In re BRCA1- and BRCA2-Based Hereditary Cancer Test Pat. Litig., 774 F.3d 755 (Fed. Cir. 2014).

^[21] Id.

^[22] Illumina, Inc. v. Ariosa Diagnostics, Inc., 967 F.3d 1319, 1326 (Fed. Cir. 2020).

^[23] Id.

^[24] Howard S. Suh, Illumina v. Ariosa: Carving Out a New ‘Bucket’ of Section 101 Patent Eligible Claims, fox rothschild (2020), https://www.foxrothschild.com/publications/illumina-v-ariosa-carving-out-a-new-bucket-of-section-101-patent-eligible-claims.

^[25] Memorandum from the Deputy Commissioner for Patent Examination Policy at the USPTO on Guidance to Patent Examiners Following Supreme Court's Myriad Decision to Patent Examining Corps, 1 (June 13, 2013) (on file with author).

^[26] Id.

^[27] Clinicians prefer tumor-informed MRD tests because their specialized nature increase efficacy.

^[28] U.S. Patents Nos. 11,519,035 and 11,530,454 (filed Jul. 21, 2020).

^[29] Purdue Pharma L.P. v. Boehringer Ingelheim GMBH, 237 F.3d 11359, 1363 (Fed. Cir. 2001).

^[30] See Guardant Health, Inc. v. Natera, Inc., 580 F. Supp. 3d 691 (N.D. Cal. 2022) (bringing claims against competitor, Natera, alleging false statements, state and federal false advertising, and state and common law unfair competition); see also Guardant Health, Inc. v. Found. Med., Inc., No. CV 17-1616-LPS-CJB, 2020 WL 2461551, at *1 (D. Del. May 7, 2020), report and recommendation adopted, No. CV 17-1616-LPS-CJB, 2020 WL 5994155 (D. Del. Oct. 9, 2020) (bringing patent infringement claims against Foundation Medicine and Personal Genome Diagnostics); but see Twinstrand Biosciences, Inc. v. Guardant Health, Inc., No. CV 21-1126-GBW-SRF, 2022 WL 18936070, at *1 (D. Del. Oct. 28, 2022), report and recommendation adopted, No. CV 21-1126-GBW-SRF, 2023 WL 1860186 (D. Del. Feb. 9, 2023) (Twinstrand Biosciences bringing patent infringement claims against Guardant Health).

^[31] Guardant Health, Inc. v. Found. Med., Inc., No. CV 17-1616-LPS-CJB, 2020 WL 2461551, at *17 (D. Del. May 7, 2020), report and recommendation adopted, No. CV 17-1616-LPS-CJB, 2020 WL 5994155 (D. Del. Oct. 9, 2020)

^[32] Brief of Defendant at 7, Guardant Health, Inc. v. Tempus AI, Inc., No. 24-687 (D. Del. Dec. 3, 2025).