Predicting the unpredictable during pregnancy
A pressing need for more non-invasive prenatal tests is leading to increasing IP activity and commercial interest, say Fran Salisbury and Alice Jefferies of Mewburn Ellis.
For many expectant parents, pregnancy is a time of excitement, yet it can also be riddled with uncertainty. Unexpected complications affect one in five pregnancies, and only one in five pregnancy complications can be predicted by current clinical assessments. To further complicate the situation, many of the tests currently used in the clinic are invasive, risky, and fraught with bias.
Thus, there is a pressing need for a more comprehensive pathophysiological understanding of pregnancy (for both mother and baby) and more rigorous, yet safe, diagnostic procedures.
Safer testing
Performing a liquid biopsy on almost any bodily fluid can identify a plethora of biomarkers originating from many different parts of the body, and these biomarkers can be mapped back to their site of origin. Cell-free RNA (cfRNA) is one of these biomarkers, and cfRNA originating from the foetus or the placenta can be detected in a sample of the mother’s blood – much safer than performing amniotic testing.
Several such non-invasive prenatal tests or screens (NIPTs or NIPS) are well established in the market, such as the SAFE test (St George’s Antenatal Fetal Evaluation test), the NIFTY test (BGI), the Harmony Prenatal Test (Roche) and the Verifi Prenatal Test (Illumina), all designed to determine the presence of chromosomal disorders in the developing foetus.
Populating the field
In recent years, several new approaches have emerged, providing alternative (or in some cases supplemental) tests to the established chromosomal methods.
Research published in The Lancet last year revealed that piRNA (a type of short non-coding RNA) in maternal plasma-derived exosomes can also be detected in a blood sample for the early diagnosis of foetal congenital defects.
Such abnormalities cannot typically be seen during early prenatal ultrasound screening, meaning that any opportunity for prenatal treatment or intervention is missed. Thus, detection of these conditions before they’re formed may allow for therapeutic intervention and preparation for delivery at specialist centres.
Competing prenatal screening platforms by Natera and Invitae evaluate single nucleotide polymorphisms in foetal cfDNA to indicate the risk of common genetic conditions that are caused by extra or missing chromosomes, such as Down syndrome and Prader-Willi syndrome.
Natera also reports to have the only non-invasive prenatal test for triploidy; a condition where foetuses have a complete extra set of chromosomes. Although it is rare for these babies to reach term, the mother’s risk of developing pre-eclampsia and hyperthyroidism is heightened4.
New applications: combining RNA-seq and AI
At the start of 2022, research published in Nature revealed that health technology platform Mirvie’s combination of machine-learning with single-cell RNA-seq analysis of foetal and maternal cfRNA can accurately identify 75% of women who later develop pre-eclampsia; a condition associated with maternal endothelial dysfunction and high blood pressure affecting up to 1 in 12 pregnancies.
Pre-eclampsia is largely responsible for maternal morbidity, and symptoms often don’t manifest until the third trimester. This new liquid biopsy approach, however, allows diagnosis to be carried out at a much earlier stage during the second trimester, opening new therapeutic windows for improving clinical outcomes for both mother and baby.
By identifying gene sets that experience temporal changes in expression during pregnancy and foetal development, this technique additionally helped monitor pregnancy progression and predict increased risk of spontaneous preterm birth, independent of clinical factors.
The study reported in Nature was conducted on a large and diverse cohort (in terms of race, age, ethnicity, health status, BMI), and the results indicate that such factors have a negligible impact on the evaluation of results, unlike current, state-of-the-art methods.
Commercial boom
This potential has attracted substantial commercial interest. The global market for NIPT has been estimated to reach $12.6 billion by 2031, driven in part by increased consumer demand from rising maternal age increases, coupled with an emphasis on early detection and improved availability of advanced screening technologies.
US6258540B1 (granted 2001), initially patented by Isis Innovation (now Oxford University Innovation) and now assigned to Sequenom, lies at the heart of the bustling IP activity within the field of NIPT technologies and the corresponding commercial growth.
The patent was extremely broad when granted, encompassing almost all methods for NIPT. In light of the unpatentability of natural products, the patent was ruled invalid in Ariosa Diagnostics v Sequenom and Illumina 788 F.3d 1371 (Fed. Circ. 2015).
This decision in the US has since triggered litigation, patent pool settlements and licensing agreements, including those between Illumina and Sequenom, and Roche and Ariosa, both in 2014. Last year, Illumina and Roche settled multiple lawsuits relating to sequencing methods used in their NIPT technologies out of court in the US.
Big lawsuits aside, investors are clearly excited by the innovative NIPT technology coming out of start-ups. Mirvie has raised more than $20 million and Cradle Genomics has raised $17 million in Series A financing.
Although the past decade has seen North America and Europe leading the global market, the Asia Pacific is predicted to be the most rapidly expanding market region. Traditionally a market dominated by BGI in China, major companies are looking to enter the Asian market; for example, the partnership between Illumina and Next Generation Genomic Co (NGG Thailand) has introduced the CE-IVD VeriSeq NIPT Solution v2 in Thailand following regulatory approval in November 2020.
Anticipating growth
An overarching theme of these technologies is the ability to anticipate difficulties that may arise during the later stages of pregnancy, delivery, or after birth. While treatment options for conditions detected at the earlier stages may not yet be available, the time to prepare is substantially important for optimising the health and wellbeing of patients, in addition to alerting specialist clinicians and facilities if required.
Furthermore, the availability of an early diagnosis should help accelerate development of more viable treatment options in the future. With that, we are likely to see more patent disputes arise as the commercial importance and licensing of NIPT technologies continues to grow.
Fran Salisbury is a partner at Mewburn Ellis. She can be contacted at: alice.jefferies@mewburn.com
Alice Jefferies is a patent technical assistant, life sciences, at Mewburn Ellis. She can be contacted at: alice.jefferies@mewburn.com
