13 min read

In this article we examine how standard polymerase chain reaction (PCR) based testing for the novel coronavirus (SARS-CoV-2) works, explore the new CRISPR-based tests under development and the new rapid point-of-care tests being rolled out, and consider the initiatives by governments and medical device regulators to fast-track the availability of SARS-CoV-2 diagnostic tests.

Diagnostic testing capacity has emerged as a key limitation of our ability to contain SARS-CoV-2, the novel coronavirus responsible for COVID-19 disease. Regulatory barriers and shortages of test kits have impeded effective scale-up of SARS-CoV-2 testing. In response to this health crisis the World Health Organization (WHO) has a simple message for all countries: “test, test, test”.[1] Now governments, regulatory agencies and laboratory-diagnostic and biotechnology companies are responding with multiple new SARS-CoV-2 tests being fast-tracked for use, and production of test kits and reagents being dramatically scaled-up globally.

The identification of symptomatic and asymptomatic at-risk individuals is of immediate importance to enable early case detection and contact-tracing. In these circumstances, diagnostic testing is an essential tool not only to clinical care, but also to tracking and containing the disease in the community.[2] In order to achieve this end, reliable test kits, reagents and laboratory capacity must be readily available. Below, we discuss how these challenges are starting to be met.

Current strategies and the need for scaled-up testing capability and capacity

As a preliminary consideration, there is a distinction between testing for public health surveillance and testing for clinical care. Clinical testing is aimed at diagnosis of individuals with symptoms for the purpose of clinical care, together with a secondary purpose of quarantining and contact-tracing. Surveillance testing is broader community testing for individuals with risk factors such as overseas travel and in high-risk settings such as aged-care facilities, Indigenous communities and for essential-service and healthcare workers. Community surveillance can also occur more generally for early symptoms such as a raised body temperature.

One difficulty with surveillance testing is the prolonged incubation period of SARS-Cov-2, demonstrated to be a mean of 5 days (with a range of between 1 to 14 days),[3] with the effect that a point in time negative result may not rule out infection. Standard molecular testing (known as qRT-PCR, explained further below) is also limited by the type of sample taken (such as a nasopharyngeal swab) as the virus may only be detectable within the lungs. Once an infection is resolved and the virus cleared, the test will also be negative. Detection of past infection instead requires serological blood testing.

It is well documented that testing capacity for SARS-CoV-2 is lacking worldwide, and particularly so in the US and parts of Europe where the disease is spreading rapidly through asymptomatic carriers and individuals with only mild non-specific symptoms. At a WHO forum convened to identify research gaps and priorities for COVID-19 in February, the first of the eight immediate needs identified was for rapid point-of-care diagnostics, recognising the urgent need for accurate and standardised tests which can be deployed in community settings.[4]

Government and regulatory-agency interventions

In Australia, pathology diagnostic tests are regulated by the Therapeutic Goods Administration (TGA) as in-vitro diagnostic medical devices (IVDs). In response to the urgent need to make testing widely available, the Australian Federal Parliament on 22 March 2020 enacted emergency exemptions under the Therapeutic Goods Act 1989 (Cth) permitting the importation, manufacture and supply of SARS-CoV-2 IVDs without prior TGA assessment, for use only by accredited laboratories.[5] Specifically, this exempts SARS-Cov-2 diagnostic tests from regulations including compliance with the TGA’s essential principles for manufacture, conformity assessment certification, and requirement for inclusion on the Australian Register of Therapeutic Goods (ARTG) until 31 January 2021.[6]

While Australia currently has one of the highest rates of per capita SARS-CoV-2 testing, readily accessible community testing is still lacking. The Federal Government has announced a comprehensive AU$2.4 billion funding-package to address COVID-19, which includes Medicare-funded and bulk-billed pathology test for SARS-CoV-2, and AU$2.6 million in research funding to the Peter Doherty Institute for research into the development of improved SARS-CoV-2 diagnostics testing protocols, and for the post-market assessment of the new rapid point-of-care tests.[7]

Similarly, in the US the Food and Drug Administration (FDA) has, as of the date of this publication, provided Emergency Use Authorizations (EUAs) to 20 SARS-CoV-2 tests, including those by Abbott Laboratories, Roche Molecular Systems and ThermoFisher Scientific.[8] This follows the US Federal Government’s declaration of a national emergency,[9] allowing the US Federal Emergency Management Agency to deploy support and provide disaster funds to US state and local governments, including US$50 billion in funding to fight the disease.[10] The manufacturing capacity for SARS-CoV-2 diagnostic testing in the US is expected to be significantly scaled-up as a result of these measures.

SARS-CoV-2 Testing

Diagnostic testing for viral pathogens can be by molecular means to identify viral genetic material (nucleic acid – DNA or RNA) or by serological testing to identify antibodies directed against the virus (Immunoglobulin M (IgM) and Immunoglobulin G (IgG) antibodies). IgM antibodies are produced as a first response to a new infection providing short-term protection. They increase for several weeks and then decline as IgG production begins, with specific IgG antibodies forming the basis of long-term protection against viral pathogens.

Molecular testing by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) is now well established as the gold-standard in testing and is highly sensitive (capable of detecting genetic material from a single viral particle) and specific (capable of distinguishing between similar strains).

Standard qRT-PCR

Diagnostic testing for RNA viruses such as SARS-CoV-2 are routinely performed by qRT-PCR. The PCR reaction alone only amplifies DNA. RT-PCR testing works by first converting viral RNA to its complimentary DNA (cDNA), amplifying the cDNA by standard PCR, and then detecting specific target DNA sequences unique to the virus by fluorescent-labelled probe.[11] Testing encompasses a number of steps and takes at least 4-6 hours in the laboratory, with final results taking up to several days were there is a back log of testing to be performed in the laboratory:[12]

  • A nasopharyngeal swab is used to collect secretions from the back of the nose or throat.
  • The swab is placed into viral transport media and sent to the lab for testing.
  • In the lab the sample is mixed with reagents that release the viral RNA from its capsule, allowing the viral RNA to be isolated.
  • The conversion of RNA into cDNA is facilitated by combining the RNA with deoxyribonucleotides, primers and other reagents. Primers anneal to the RNA strand and provide the reverse transcriptase enzyme with a starting point for DNA synthesis.
  • The cDNA is then used as the template for PCR amplification.
  • The amplified cDNA is labelled with a fluorescent marker that is detected by the real-time PCR machine, which quantifies the amount of fluorescence detected.
  • This value of fluorescence is called the Ct number, and is inversely proportional to the amount of cDNA. Typically Ct values are analysed relative to a ‘housekeeping’ gene to determine whether viral sequences are present in the sample.

The qRT-PCR test is performed in many laboratories worldwide for a variety of different viral pathogens. Since the sequencing of the SARS-CoV-2 genome, many companies have customised their qRT-PCR tests for SARS-CoV-2, using different primers designed to bind to differing target viral genetic sequences.[13]

Serological testing

Serological testing is performed on blood samples analysed by enzyme immunoassay or lateral flow devices and allows for the detection of IgM and IgG antibodies directed against the virus. Viral antibodies take 5 to 7 days to become detectable, making serological testing of more limited use for the diagnosis of acute infection. Antibody tests are also prone to ‘cross-reactivity’ with other similar antibodies (such as antibodies produced by similar strains of seasonal coronavirus causing the common cold), making the test less reliable.[14] Serological testing is however of use in testing for evidence of past resolved infection, and may be used in combination with molecular testing to detect evidence of both current and past infection.

Rapid point-of-care tests

The new rapid ‘point-of-care’ tests use the same qRT-PCR method implemented through a small portable device that can be used in clinics and community-screening settings, and provide results within 5 to 45 minutes depending on the test. Examples of such rapid tests are the Cepheid Xpert Xpress,[15] which in Australia has been included on the ARTG since 22 March 2020, and Abbott’s ID-NOW[16] authorised by the FDA. Similar rapid testing for blood serology by finger prick are also being rolled out, for example VivaCheck Biotech’s VivaDiag SARS-CoV-2 IgM/IgG Rapid test[17] which has been included on the ARTG since 20 March 2020.[18]

CRISPR-Cas tests in development

Two CRISPR biotechnology specialists, Sherlock Biosciences and Mammoth Biosciences, are working with various collaborators to adapt their CRISPR platforms for SARS-CoV-2 diagnosis. Both have developed diagnostic assays using CRISPR technology for the detection of viral pathogens.

CRISPR-associated Cas-proteins developed within bacteria as an evolutionary adaptive immune mechanism to enable bacteria to fight off foreign invaders such as bacteriophages.[19] The discovery of this mechanism led to the development of the CRISPR-Cas system as technology capable of its known use as a genome-editing tool.

The technology is now also being applied to diagnostics, whereby a small segment of ‘guide’ RNA binds to a target sequence of genetic material, followed by use of a Cas12 or Cas13 nuclease for precise target location and cleavage of a ‘reporter’ molecule added to the reaction.[20] This in effect uses CRISPR’s functionality as a means of detecting unique genetic “fingerprints” of virtually any DNA or RNA sequence, in any organism.

Sherlock Biosciences has licensed CRISPR and related technology from the Broad Institute of MIT and Harvard and the Wyss Institute of Harvard[21] to develop a diagnostic test, known as SHERLOCK (Specific High-sensitivity Enzymatic Reporter Unlocking). The test detects two SARS-CoV-2 genes – the S gene and the Orf1ab gene. The test can be adapted to work on a simple paper strip test (similar to a pregnancy test), on laboratory equipment or by electrochemical readout that can be read on a mobile phone.[22]

Mammoth Biosciences has also applied CRISPR-Cas9 gene-editing technology to develop its molecular diagnostic platform called DETECTR (DNA endonuclease-targeted CRISPR trans reporter). As with the SHERLOCK test, DETECTR can be tailored to detect any DNA or RNA target, with results provided in an instrument-free and disposable format within 20 minutes. The technology can also be integrated into other products and platforms. DETECTR is now being developed for identification of the N and E SARS-CoV-2 genes.[23]

These innovations are yet to be validated for clinical use in humans but nonetheless represent a promising development in advanced clinical diagnostics

Currently approved or authorised diagnostic tests

A plethora of SARS-CoV-2 diagnostic tests have been deployed around the world. In Australia 16 SARS-CoV-2 tests have been included on the ARTG as of the date of this publication, including most notably:[24]

  • Cepheid’s Xpert® Xpress (rapid portable RT-PCR test)
  • Roche Diagnostics’ Cobas® (real time RT-PCR test)
  • Becton Dickinson’s VIASURE (real time RT-PCR test)
  • Shanghai ZJ Bio-Tech’s 2019-nCoV (real time RT-PCR test)
  • Viva Check Biotech’s VivaDiag IgM/IgG Rapid (rapid serology test)
  • Hangzhou Clongene Biotech’s COVID-19 IgG/IgM Rapid (rapid serology test)

As of the date of this publication the FDA has provided EUA authorisation to 20 SARS-CoV-2 tests, with a few notable examples not yet available in Australia listed below:[25]

  • Abbott’s ID NOW (rapid portable RT-PCR test)
  • Abbott’s Real Time SARS-CoV-2 assay (real time RT-PCR)
  • ThermoFisher Scientific’s TaqPath (real time RT-PCR)

Concluding remarks

Governments, regulatory bodies and industry are now starting to respond to the immense challenge of meeting the demand for reliable, fast and portable SARS-CoV-2 diagnostic tests in response to this global pandemic, bringing new testing technologies to fruition and scaling up the manufacture of existing tests with increasing urgency. Hopefully, this increased testing capability, together with range of other public health measures currently being implemented, can assist in reducing COVID-19 infection rates in the coming weeks and months.


[1] World Economic Forum, 17 March 2020. “The World Health Organization has called on countries to ‘test, test, test’ for coronavirus – this is why” (https://www.weforum.org/agenda/2020/03/coronavirus-covid-19-testing-disease/, accessed 29 March 2020).

[2] Hellewell J et al, 28 February 2020. Centre for the Mathematical Modelling of Infectious Diseases COVID-19 Working Group. – “Feasibility of controlling COVID-19 outbreaks by isolation of cases and contacts”. Lancet Global Health. February 2020; S2214-109X(20)30074-7. (https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(20)30074-7/fulltext, , accessed 29 March 2020).

[3] Lauer SA et al, 10 March 2020. “The Incubation Period of Coronavirus Disease 2019 (COVID-19) From Publicly Reported Confirmed Cases: Estimation and Application”. Annals of Intern Medicine. 2020. (https://annals.org/aim/fullarticle/2762808/incubation-period-coronavirus-disease-2019-covid-19-from-publicly-reported, accessed 29 March 2020).

[4] WHO, 11-12 February 2020. “COVID 19 Public Health Emergency of International Concern (PHEIC), Global research and innovation forum: towards a research roadmap”. (https://www.who.int/blueprint/priority-diseases/key-action/Global_Research_Forum_FINAL_VERSION_for_web_14_feb_2020.pdf?ua=1, accessed 29 March 2020).

[5] Therapeutic Goods (Medical Devices—Accredited Pathology Laboratories) (COVID-19 Emergency) Exemption 2020 (Cth) (https://www.legislation.gov.au/Details/F2020N00032, accessed 29 March 2020).

[6] As above, note 5.

[7] PM.gov.au Media Release, 11 March 2020. “$2.4 Billion Health Plan to fight COVID-19”. (https://www.pm.gov.au/media/24-billion-health-plan-fight-covid-19, accessed 29 March 2020); Health.gov.au Media Release, 21 March 2020. “$2.6 million for coronavirus research, including a new simpler Australian pathology test” (https://www.health.gov.au/ministers/the-hon-greg-hunt-mp/media/26-million-for-coronavirus-research-including-a-new-simpler-australian-pathology-test, accessed 29 March 2020). ).

[8] FDA, 28 March 2020. “Emergency Use Authorizations” (https://www.fda.gov/medical-devices/emergency-situations-medical-devices/emergency-use-authorizations#covid19ivd, accessed 30 March 2020).

[9] Whitehouse.gov, 13 March 2020. “Proclamation – Proclamation on Declaring a National Emergency Concerning the Novel Coronavirus Disease (COVID-19) Outbreak”. (https://www.whitehouse.gov/presidential-actions/proclamation-declaring-national-emergency-concerning-novel-coronavirus-disease-covid-19-outbreak/, accessed 29 March 2020).

[10] Reuters, 14 March 2020. “Trump declares coronavirus national emergency, says he will most likely be tested”. (https://www.reuters.com/article/us-health-coronavirus-usa-emergency/trump-declares-coronavirus-national-emergency-says-he-will-most-likely-be-tested-idUSKBN2102G3, accessed 29 March 2020).

[11] BioSistemika, 4 July 2017. “Real-Time PCR (qPCR) Technology Basics”. (https://biosistemika.com/blog/qpcr-technology-basics/, accessed 29 March 2020).

[12] Sheridan C, 23 March 2020. “Fast, portable tests come online to curb coronavirus pandemic”. Nature Biotechnology News article. (https://www.nature.com/articles/d41587-020-00010-2, accessed 29 March 2020); Dharmaraj, S (ThermoFisher Scientific). “The Basics: RT-PCR”. (https://www.thermofisher.com/au/en/home/references/ambion-tech-support/rtpcr-analysis/general-articles/rt–pcr-the-basics.html, accessed 29 March 2020); Sharfstein JM et al, 9 March 2020. “Diagnostic Testing for the Novel Coronavirus”. Journal of the American Medical Association (JAMA). (https://jamanetwork.com/journals/jama/fullarticle/2762951, accessed 29 March 2020); Corman V et al, 23 January 2020. “Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR”. Eurosurveillance, 2020;25(3). (https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2020.25.3.2000045, accessed 29 March 2020); Tang Yi-Wei et al, 1 November 1997. “Molecular diagnostics of infectious diseases”. Clinical Chemistry, 1997:43(11),2021-2038. (https://academic.oup.com/clinchem/article/43/11/2021/5640827, accessed 29 March 2020).

[13] Nature News Explainer, 23 March 2020. “Coronavirus tests: researchers chase new diagnostics to fight the pandemic” . (https://www.nature.com/articles/d41586-020-00827-6, accessed 29 March 2020).

[14] Department of Health, 22 March 2020. “PHLN statement on point-of-care serology testing for SARS-CoV-2 (the virus that causes COVID-19”. (https://www.health.gov.au/resources/publications/phln-statement-on-point-of-care-serology-testing-for-sars-cov-2-the-virus-that-causes-covid-19, accessed 28 March 2020).

[15] Cepheid. “Xpert Xpress SARS-CoV-2 has received FDA Emergency Use Authorization”. (https://www.cepheid.com/coronavirus, accessed 29 March 2020).

[16] Abbott. “Abbott launches molecular point-of-care test to detect novel coronavirus in as little as five minutes”. (https://abbott.mediaroom.com/2020-03-27-Abbott-Launches-Molecular-Point-of-Care-Test-to-Detect-Novel-Coronavirus-in-as-Little-as-Five-Minutes, accessed 29 March 2020).

[17] Viva Chek. “VivaDiag SARS-CoV-2 IgM/IgG Rapid Test”. (https://www.vivachek.com/vivachek/English/prods/prod-covid19.html, accessed 29 March 2020).

[18] tga.gov.au, 28 March 2020. “COVID-19 diagnostic tests included on the ARTG for legal supply in Australia”. (https://www.tga.gov.au/covid-19-diagnostic-tests-included-artg-legal-supply-australia, accessed 30 March 2020).

[19] Hille, F et al, 8 March 2018. “The Biology of CRISPR-Cas: Backward and Forward”. Cell. 2018;172(6):1239-1259. (https://www.cell.com/cell/fulltext/S0092-8674(17)31383-1?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867417313831%3Fshowall%3Dtrue, accessed 29 March 2020).

[20] Chiu C, 13 June 2018. “Cutting-Edge Infectious Disease Diagnostics with CRISPR”. Cell Host & Microbe. 2018;23(6):702-704. (https://www.cell.com/cell-host-microbe/fulltext/S1931-3128(18)30270-1?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1931312818302701%3Fshowall%3Dtrue, accessed 29 March 2020).

[21] Broad Institute of MIT and Harvard News Feature, 15 March 2020. “Enabling coronavirus detection using CRISPR-Cas13: Open-access SHERLOCK research protocols and design resources”. (https://www.broadinstitute.org/news/enabling-coronavirus-detection-using-crispr-cas13-open-access-sherlock-research-protocols-and, accessed 29 March 2020).

[22] Sherlock Biosciences. “Better diagnostic testing should be elementary”. (https://sherlock.bio/technology/, accessed 29 March 2020).

[23] Mammoth Biosciences. “The CRISPR-based detection platform”. (https://mammoth.bio/diagnostics/, accessed 29 March 2020); Mammoth Biosciences, 2 March 2020. “A protocol for rapid detection of the 2019 novel coronavirus SARS-CoV-2 using CRISPR diagnostics: SARS-CoV-2 DETECTR”. (https://mammoth.bio/wp-content/uploads/2020/03/Mammoth-Biosciences-A-protocol-for-rapid-detection-of-SARS-CoV-2-using-CRISPR-diagnostics-DETECTR.pdf, accessed 29 March 2020).

[24] As above, note 18.

[25] As above, note 8.

Authored by Duncan Longstaff

6 min read

The urgent need to develop an effective vaccine to provide individuals and populations worldwide with immunity against the COVID-19 disease caused by the novel coronavirus, SARS-CoV-2, has led several biotechnology companies to leverage messenger RNA (mRNA) technology and take a novel approach to vaccine development.

As the COVID-19 pandemic continues to unfold, there are a multitude of biotechnology companies, governments and research institutions concentrating their efforts on developing a prophylactic vaccine against the novel coronavirus known as SARS-CoV-2. Many conventional vaccine development approaches are problematic because they involve prolonged lead times of between 2 to 5 years and require significant capital investment, making them poorly-adapted to responding to a rapidly spreading pathogen. By contrast, mRNA-based vaccines can be developed, clinically trialled and scaled-up into production and distribution relatively quickly – with the possibility of mass-immunisation commencing within 18 months of vaccine development commencing.

The premise of mRNA vaccines is simple: a vaccine that utilises a synthetic strand of mRNA, the minimum genetic instruction that allows human cells to make and express the target viral protein, which then triggers an adaptive immune response against the virus. This approach enables a rapid and scalable response to new viral pathogens as it bypasses the need to work directly with the virus itself.

US-based mRNA pioneers Moderna and Arcturus Therapeutics, as well as Germany’s BioNTech, each have a candidate mRNA vaccine. Moderna’s mRNA-1273 vaccine was produced 42 days following the sequencing of the SARS-CoV-2 genome – a response that is unprecedented in vaccine development. It is the first candidate COVID-19 vaccine to commence human trials, with a Phase I clinical trial under way in the US in collaboration with the National Institutes of Health (NIH). The study is aimed at assessing the vaccine’s safety, reactogenicity (common adverse reactions) and immunogenicity (ability to elicit an immune response) in a limited number of healthy volunteers.[1]

Coronavirus genome and proteins

The coronaviruses are a large family of viruses consisting of spherically-shaped viral particles covered with spike proteins protruding from their surface, which give the virus its crown-like appearance (corona being Latin for crown). The coronavirus uses its spike proteins to attach to and penetrate the surface of host cells by binding to ACE2 receptors on these cells.[2]

Researchers in China have sequenced the genome of the novel coronavirus (SARS-CoV-2), which has allowed mRNA sequences encoding viral proteins to be rapidly developed. Of particular interest has been the genetic sequence encoding the spike protein, which Moderna and Arcturus Therapeutics have incorporated into their respective candidate vaccines.

COVID-19 mRNA vaccine candidates

  • Moderna’s first-in-class mRNA-1273 vaccine encodes for a stabilised form of the spike protein, formulated with a lipid nanoparticle carrier.[3] The US Food and Drug Administration has allowed the vaccine to proceed to a Phase I study in humans under an Investigational New Drug (IND) application filed by the NIH, in parallel with animal studies.[4] The NIH commenced a Phase I trial on 16 March 2020. The study will enrol 45 healthy adults in order to evaluate the vaccine’s safety and immunogenicity at three dosage levels (25mcg, 100mcg and 250 mcg) to be administered by intramuscular injection on a 2-dose vaccination schedule given 28 days apart.[5] If the Phase I trial proves successful, Moderna expects to commence larger Phase II efficacy trials (enrolling several hundred participants) under its own IND filing within a few months.[6] If all Phase II clinical endpoints are met, then Phase III clinical trials may occur towards the end of 2020, but any approved vaccine is anticipated to be 12 to 18 months away by both industry and health authorities.
  • Arcturus Therapeutics and Duke-NUS Medical School have partnered in the development of a candidate self-replicating mRNA vaccine, currently in preclinical testing.[7] The partnership will receive up to US$10 million from the Singapore Government to co-develop the vaccine, which utilises mRNA encoding the viral spike protein, delivered by a lipid nanoparticle delivery system.
  • BioNTech is collaborating with Pfizer to co-develop its mRNA-based vaccine candidate BNT162, leveraging an earlier agreement between the parties to jointly develop an mRNA-based influenza vaccine. The agreement with Pfizer excludes distribution rights within China, where Shanghai-based Fosun Pharma will distribute and market any COVID-19 vaccine developed by BioNTech.[8] BNT162 is currently in pre-clinical testing with clinical trials expected to begin in April 2020.[9]

The rationale for mRNA vaccines

Vaccine platforms using mRNA-based technologies utilise two approaches: non-replicating and self-replicating mRNA. Non-replicating mRNA vaccines only code for the antigen required to elicit the desired immune response (such as the spike protein of SARS-CoV-2), making them relatively simple to develop and often more economical to administer (particularly where direct intradermal injection is feasible). Self-replicating mRNA vaccines include not only the genetic sequence of the antigen required but also the RNA replication machinery required for the mRNA to be amplified, thereby enabling a large amount of antigen production from a small dose, potentially reducing reactogenicity but complicating the development, manufacture and administration of the vaccine.

For both non-replicating and self-replicating mRNA vaccines, the mRNA is formulated with a carrier such as a lipid-nanoparticles that encapsulates the mRNA to protect it from degradation and to allow uptake into human cells. There are various possible modes of delivery of the mRNA to the patient, including direct intradermal injection and more complex cellular therapies (removing, modifying and reintroducing target cells). Once within the cytoplasm of a patient’s host cell, the mRNA is translated by the host cell’s translational machinery (ribosomes) to produce the target protein, which then undergoes further post-translational modifications such as folding to produce a functional protein. This protein mimics the SARS-CoV-2 spike protein and therefore has the ability to elicit an adaptive immune response to the SARS-CoV-2 virus. As noted above, self-replicating mRNA constructs additionally have the ability to be translated by ribosomes to produce the replicase machinery necessary for self-amplification of the mRNA itself.[10]

This mRNA vaccine approach offers potential advantages over conventional inactivated and live-attenuated whole virus vaccines and subunit vaccines (which use a specific part of the virus such as its proteins, sugars, or capsule) in its simplicity and capacity to bring into effect a rapid and scalable response to novel pathogens. There is also likely to be potential for improved vaccine safety and efficacy:[11],[12]

  • mRNA vaccines allow for rapid, cost-effective and scalable manufacture of vaccines as there is no need for viral growth and expansion or the development of viral-specific cell cultures.
  • Once the viral genome has been sequenced, the target mRNA can be produced by a standardised process, rendering production faster and more cost-effective.
  • Delivery of mRNA into a human cell can be achieved by formulating the mRNA onto carrier molecules, allowing for rapid uptake and expression within cells.
  • Modifications to mRNA vaccine constructs can make them more stable and highly translatable.
  • Vaccines containing mRNA are capable of inducing both a T-cell (cellular) and B-cell (antibody) immune response.
  • The use of mRNA confers no risk of infection from the vaccine itself.

This approach also has advantages over DNA-based vaccines because mRNA does not need to enter the host cell nucleus in order to be transcribed. This means the dosage of vaccine can be significantly lower and no special delivery mechanisms are required. Additionally, there is no risk of DNA integrating into the host cell genome, avoiding concerns about the possibility of insertional mutagenesis.

Other candidate vaccines

A number of other COVID-19 candidate vaccines are currently in pre-clinical testing and also hold promise of a viable vaccine being produced during the next 1-2 years, most notably:[13]

  • Janssen’s (Johnson & Johnson) intranasally delivered recombinant adenovirus-based vaccine, incorporating a SARS-CoV-2 protein and utilising the vaccine platform it developed for the Zika and Ebola viruses;
  • Sanofi’s recombinant vaccine expressed in a baculovirus system and incorporating a SARS-CoV-2 protein;
  • LinealRx’s DNA vaccine encoding a SARS-CoV-2 protein;
  • Inovio Pharmaceuticals’ DNA vaccine encoding the SARS-CoV-2 spike protein;
  • Clover Biopharmaceuticals’ and GlaxoSmithKline’s recombinant SARS-CoV-2 spike protein subunit vaccine; and
  • the University of Queensland’s recombinant subunit vaccine incorporating the SARS-CoV-2 spike protein.

A number of these candidates have expectations of moving into Phase I clinical trials within 3 to 6 months.

Concluding remarks

Vaccines utilising mRNA platforms remain an unproven technology, with no vaccine approved for use to date. However, mRNA vaccine technology holds great promise and, if ultimately proven successful, could reduce vaccine lead-time and cost of development and manufacture and thereby shorten the time to product regulatory approval and implementation. While still too early to predict, the outcome of this race to develop a successful COVID-19 vaccine appears destined to yield a variety of improved techniques and new technologies, while also providing important lessons on how best to develop a vaccine in the face of future rapidly emerging epidemics and pandemics.


[1] ClinicalTrials.gov, “Study ID NCT04283461”. (https://clinicaltrials.gov/ct2/show/study/NCT04283461, accessed 22 March 2020).

[2] Tai W et al, “Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine”. Cellular & Molecular Immunology (2020). (https://www.nature.com/articles/s41423-020-0400-4, accessed 22 March 2020).

[3] National Institutes of Health, “NIH clinical trial of investigational vaccine for COVID-19 begins”. (https://www.nih.gov/news-events/news-releases/nih-clinical-trial-investigational-vaccine-covid-19-begins, accessed 22 March 2020).

[4] Moderna, Inc., “Moderna’s Work on a Potential Vaccine Against COVID-19”. (https://www.modernatx.com/modernas-work-potential-vaccine-against-covid-19, accessed 22 March 2020).

[5] As above note 1.

[6] As above, note 2.

[7] Duke NUS Medical School, “Arcturus Therapeutics and Duke-NUS Medical School Partner to develop a coronavirus (COVID-19) vaccine using STARR Technology™”. (https://www.duke-nus.edu.sg/about/media/media-releases/media-releases/arcturus-dukenus-covid-19-vaccine-using-starr-technology, accessed 22 March 2020).

[8] BioNtech SE, “Pfizer and BioNTech to Co-develop Potential COVID-19 Vaccine”. (https://investors.biontech.de/news-releases/news-release-details/pfizer-and-biontech-co-develop-potential-covid-19-vaccine, accessed 22 March 2020).

[9] Pfizer Inc., “Press release – Pfizer and Biontech to co-develop potential COVID-19 vaccine”, 17 March 2020. (https://investors.pfizer.com/investor-news/press-release-details/2020/Pfizer-and-BioNTech-to-Co-Develop-Potential-COVID-19-Vaccine/default.aspx, accessed 22 March 2020).

[10] Pardi, N., Hogan, M., Porter, F. et al, “mRNA vaccines — a new era in vaccinology”. Nature Reviews – Drug Discovery 17, 261–279 (2018). (https://www.nature.com/articles/nrd.2017.243, accessed 22 March 2020).

[11] As above note 8.

[12] Jackson, N.A.C., Kester, K.E., Casimiro, D. et al, “The promise of mRNA vaccines: a biotech and industrial perspective”. Vaccines, 5, 11 (2020). (https://www.nature.com/articles/s41541-020-0159-8, accessed 22 March 2020).

[13] Hodgson J, “The pandemic pipeline”. Nature Biotechnology, News Feature (2020). (https://www.nature.com/articles/d41587-020-00005-z, accessed 22 March 2020).

1 min read

Welcome to Shelston’s wrap-up of the most notable patent decisions in Australia and New Zealand delivered during 2019. It was a busy year for patent jurisprudence with some interesting themes emerging – in particular, it has been a banner year for decisions on the “manner of manufacture” requirement for patentable subject matter.

Read our full report

  • An expanded Full Federal Court clarified the “manner of manufacture” test for computer-implemented methods to be patentable (Encompass), a topic that was also central to several other Federal Court (TettmanRepipeWatson) and Patent Office (Apple) decisions.
  • There were also important “manner of manufacture” decisions in the life sciences space, with single judges finding both a diagnostic method involving a process of detecting genetic material (Sequenom) and use of genetic information to infer traits (Meat & Livestock Australia) to be patentable subject matter.
  • The Full Court confirmed there is no doctrine of patent exhaustion in Australia, the critical distinction being between repairs permitted by implied or express licence terms brought home to the purchaser of a product, and the impermissible re-making of the product beyond the scope of any licence (Calidad (No. 1)).
  • The Full Court confirmed that a permanent injunction framed in general form by reference to the claims of an infringed patent is generally appropriate and may be ordered in addition to a specific injunction describing products or conduct found to infringe (Calidad No. 2).
  • The Full Court overturned an award of additional damages for flagrant patent infringement on the basis that the infringer had believed, on objectively reasonable grounds, that its conduct did not infringe the patent (Oxworks).
  • The tide continued to turn against pharmaceutical patentees being granted interlocutory injunctions (MylanSanofi-Aventis).
  • Patentees learned some harsh lessons as the Full Court dismissed infringement claims based on the construction of the terms “contains” (construed exhaustively in Nichia) and “recognise” (construed broadly in Davies).
  • There were several applications by patentees to amend patent claims and specifications after commencing infringement proceedings (Meat & Livestock AustraliaNeurimBlueScope), with mixed success.
  • Consideration was given in the Patent Office to Australia’s “raised bar” requirements for support and sufficiency (Gary CoxUniversal Polymers).
  • Both clinical trial patient consent forms (InterPharma) and academic conference posters (Regeneron) were considered prior art documents in life sciences cases.
  • There were further decisions regarding families of patents that have been litigated for a decade or more (GlobaltechSNF).
  • There were also decisions regarding the admissibility of “WayBackMachine” evidence (Dyno Nobel), summary dismissal of an infringement case (Pilkin), a successful application for preliminary discovery (MMD), a failed cross-claim for unjustified threats (Liberation), a failed attempt to withdraw admissions relating to infringement (Juno), a “strawman” opponent to a patent application having to pay security for costs in an appeal despite winning the opposition (Toolgen) and a party commencing infringement proceedings despite not being a proper exclusive licensee having to pay indemnity costs (Vald).
  • Two recent decisions issued by the Intellectual Property Office of New Zealand provide new hope that, in certain circumstances, it may be possible to obtain an extension of time to file a divisional patent application (PrimapakMagic Leap).

As 2020 gets underway, we hope this provides a useful and practical resource and, of course, please do not hesitate to take the opportunity to contact our authors, all subject-matter experts in their respective fields, for advice on the issues raised by these important decisions.

Authored by Duncan Longstaff and Onur Saygin

A ‘biosimilar medicine’ or ‘biosimilar’ is a highly similar, but not identical, version of an original biological medicine (‘reference medicine’) – a medicine comprised of large complex molecules derived in some way from a living organism.  In this sense, a biosimilar differs to some extent from a traditional small molecule “generic” medicine, which is commonly understood as a pharmaceutical product that is identical, at least in terms of active ingredients, to the original branded “originator” or “innovator” product.  As the understanding and technology required to develop biological medicines continues to advance rapidly, they are increasingly prominent in the Australian and global pharmaceutical markets. 

Biological medicines are costly to develop, manufacture, store and supply, making their cost to healthcare providers such as the Australian Government through the Pharmaceutical Benefits Scheme (PBS) relatively high compared to conventional “small molecule” medicines.  In 2015, the Australian Government committed AU$20 million to a 3-year awareness campaign to support the increased use of biosimilar medicines by patients, pharmacists and specialists.1  The Government recently granted a further AU$5 million to the Generic Biosimilar Medicines Association (GBMA) to continue the awareness initiative until December 2020.2  The Government hopes its investment in biosimilars will provide significant savings and improve competition.  

In a patent context, the encouragement of biosimilar products may bring with it more litigation as innovators seek to protect the markets for their biological medicines through patent enforcement.  The dynamics of that patent litigation will often be different to conventional “innovator vs.  generic” disputes over small molecule medicines.  Often the party seeking to introduce a biosimilar product is itself traditionally an innovator pharmaceutical company, and the costs of developing both an original biological medicine and a biosimilar are orders of magnitude higher than the costs of developing most small molecule medicines (especially generic versions).  These and other factors will undoubtedly influence parties’ commercial imperatives and their appetite for litigation or settlement, as well as the factual and legal issues that emerge during litigation. 

Biological medicines include antibody-based medicines that treat diseases such as cancer and rheumatoid arthritis, as well as other recombinant proteins that ameliorate conditions such as diabetes.  Biological medicines tend to be significantly more expensive to manufacture than traditional generic medicines that are limited to chemically-synthesised small molecules.  These increased development costs are reflected in significantly higher prices for biological medicines, including biosimilars, compared to most small molecule medicines.  For example, a year of treatment with pembrolizumab (trade name Keytruda, Merck Sharp & Dohme), a selective humanised monoclonal antibody for metastatic malignant melanoma, cost up to AUD $150,000 before it was subsidised by PBS.3  There are currently 24 biosimilar brands listed on the Australian Register of Therapeutic Goods (ARTG), 12 of which are subsidised by the PBS.4  Under the National Health Act 1953 (Cth), Part VII, Division 3A, a statutory price reduction of 25% is applied to existing PBS-listed products on the listing of the first new bioequivalent or biosimilar item that has the same route of administration as an existing brand or item.

Although biosimilars are necessarily highly similar to the innovator biological medicine (“reference medicine”), they are not bioequivalent and do not follow the same regulatory pathways as generic small molecule medicines.  More rigorous testing is required for biosimilars.5  Generic versions of small molecule medicines must contain the same active ingredient as the innovator product, and must also be bioequivalent (the rate and extent of absorption by the body of the same dose of the active ingredient are expected to be essentially the same).6  In the context of small molecule medicines, bioequivalence can generally be reliably proven.  However, as biological medicines are often produced by living cells, differences may exist between different batches of the same medicine.  Their safety and effectiveness can also be affected by small changes in manufacturing and storage conditions.  This necessitates different approval procedures.

The Australian Therapeutic Goods Administration (TGA) has largely adopted the European approach to regulatory approval of biosimilars.7  To obtain TGA approval, each biosimilar must be evaluated using clinical, pre-clinical and laboratory-based comparability studies to generate evidence of similar quality, safety and efficacy of each new biosimilar.  There has been some controversy nationally and internationally about appropriate data threshold requirements for biosimilar regulatory approval.  Concerns have also been expressed regarding patient switching between a reference medicine and a biosimilar, due to, for example, limited long-term efficacy, safety and immunogenicity data.8

Compared to the courts in the US and Europe, which have been busy applying and interpreting the law around biosimilars, and where there are a number of pending biosimilar-related disputes, this space has to date been relatively quiet in Australia.  Litigation is continuing to emerge, though, and this trend is expected to continue in light of the Australian Government’s encouragement of biosimilar medicines.

Over much of the past decade, Australian courts have demonstrated a readiness to grant interlocutory injunctions restraining launch of generic products while patent litigation continued through to at least a first instance (trial) decision on validity and infringement, with the patentee required to give an undertaking to compensate any party for losses arising from the injunction should the patent ultimately be found invalid or not infringed.  This has occurred primarily on the basis that the balance of convenience favoured the innovator/originator in light of the practically-irreversible price drops for PBS reimbursement once a generic product enters the market.  However, in a number of more recent cases, Australian courts have declined to grant interlocutory injunctions to pharmaceutical patentees.  In particular, having recently conducted the first contested trials to enforce the patentee’s undertaking as to damages, the Federal Court has cited “the difficulty, complexity and uncertainty involved in assessing compensation under an undertaking as to damages given in patent infringement proceedings involving the supply of pharmaceutical products in the Australian market” as a factor pointing against the grant of an interlocutory injunction: Mylan Health Pty Ltd v Sun Pharma ANZ Pty Ltd (No 2) [2019] FCA 505 (11 April 2019) at [137].  Accordingly, it has become more difficult to predict whether an interlocutory injunction is likely to be obtained by a patentee seeking to prevent the PBS listing and launch of a biosimilar pending the trial outcome, and each case will turn very much on its own facts regarding the market and also the strength of the patents and nature of the products involved.

The first interlocutory injunction against a biosimilar was granted by the Federal Court of Australia in F. Hoffman-La Roche AG v Sandoz Pty Ltd [2018] FCA 874 (12 June 2018).  Roche is the registered proprietor of several patents relating to methods of use of rituximab, a biologic therapy prescribed in Australia to treat immunological conditions such as chronic lymphocytic leukaemia, lymphoma, and rheumatoid arthritis.  The Federal Court restrained Sandoz from launching its biosimilar, Riximyo, on the basis that there was a prima facie case that such supply would infringe the claims of 5 method of treatment type patents owned by Roche and the balance of convenience favoured preserving the status quo pending the trial outcome.

By contrast, the Federal Court in Sanofi-Aventis Deutschland GmbH v Alphapharm Pty Ltd (No 3) [2018] FCA 2060 (19 December 2018) refused Sanofi’s application for an injunction to prevent Alphapharm from launching and selling its Semglee product.  The Semglee product is a biosimilar to Sanofi’s product, Lantus SoloStar, both of which are new generation insulin products.  Sanofi’s patent relates to the syringe containing a medicine. The Semglee product was intended to be sold with a syringe.  Sanofi applied for leave to appeal to the Full Federal Court (Sanofi-Aventis Deutschland GmbH v Alphapharm Pty Ltd [2019] FCAFC 28) but leave was refused.

As previously reported, Burley J of the Federal Court denied Pfizer’s application (Pfizer Ireland Pharmaceuticals v Samsung Bioepis AU Pty Ltd [2017] FCA 285 (21 March 2017)) for preliminary discovery of documents sought in order to determine whether Samsung Bioepis AU’s biosimilar product (trade name BRENZYS) infringed one or more patents claiming manufacturing processes for Pfizer’s biological medicine, Etanercept (trade name ENBREL).  As we subsequently reported, Pfizer appealed the decision and the Full Federal Court unanimously overturned Burley J’s decision, granting Pfizer preliminary discovery (Pfizer Ireland Pharmaceuticals v Samsung Bioepis AU Pty Ltd [2017] FCAFC 193).  That litigation between Pfizer and Samsung Bioepis AU continues, and Pfizer has recently applied for preliminary discovery from Sandoz with respect to potential infringement of those same manufacturing process patents by Sandoz’s ERELZI etanercept biosimilar products (which have TGA approval but are not yet listed on the PBS).

It appears inevitable that the Australian Government will continue to focus on reducing healthcare expenditure and we will likely see further policies and developments that encourage biosimilars.  We expect a corresponding trend towards litigation activities relating to biosimilars in Australia, as sponsors of original biological medicines seek to protect the markets for their products through their patent portfolios.  Given the technical complexity and unique commercial factors involved in producing and supply biological medicines, such litigation, including the trials and any appeals in the cases that are already underway, will likely produce interesting and important case law on an array of invalidity and infringement grounds.


1 Media release by the Honourable Sussan Ley, Member for Farrer, Minister for the Environment, Pharmaceutical Benefits Scheme to be reformed, <http://sussanley.com/pharmaceutical-benefits-scheme-to-be-reformed/>.

2 Australian Government, Department of Health, Biosimilar Awareness Initiative (02 Dec 2019) <https://www1.health.gov.au/internet/main/publishing.nsf/Content/biosimilar-awareness-initiative>.

ABC News, ‘Revolutionary’ melanoma drug worth $150,000 a year listed on PBS, saving Australian patients thousands (28 Jun 2015) <https://www.abc.net.au/news/2015-06-28/melanoma-drug-listed-on-pbs-saving-patients-thousands/6578554>.

Australian Government, Department of Health, Which biosimilar medicines are available in Australia (02 Dec 2019) <https://www1.health.gov.au/internet/main/publishing.nsf/Content/biosimilar-which-medicines-are-available-in-australia>.

Australian Government, Department of Health, Biosimilar medicines regulation (04 Apr 2018) <https://www.tga.gov.au/publication/biosimilar-medicines-regulation>.

Australian Government, Department of Health, Prescription medicines: registration of new generic medicines and biosimilar medicines (05 Dec 2019) <https://www.tga.gov.au/prescription-medicines-registration-new-generic-medicines-and-biosimilar-medicines>.

Australian Government, Department of Health, EU guidelines (18 Dec 2019) <https://www.tga.gov.au/ws-sg-index?search_api_views_fulltext=CHMP/437/04>.

Thomas Dörner, Vibeke Strand, Paul Cornes, et al, ‘The changing landscape of biosimilars in rheumatology’ (2016) 75 Ann Rheum Dis.  974-982.

Authored by Duncan Longstaff

In July 1969 the United States of America put two men on the moon. Years later in 2011, the then Prime Minister of Australia, Julia Gillard, stood before US Congress and recalled the same moon-landing memory and with acquiescence wept that “Americans could do anything!” Today, the US seems to have entered, what was once described in an episode of Seinfeld as, “Bizzaro world” – Donald Trump is in the White house and, even more astonishingly, researchers are unable to protect what have been described judicially as “truly meritorious” and “ground breaking” innovations in the diagnostics and personal medicine space. Today it is Australia that reigns supreme over the US, as the Federal Court in Sequenom, Inc. v Ariosa Diagnostics, Inc. [2019] FCA 1011 (27 June 2019) confirmed that a non-invasive method of detecting fetal characteristics and abnormalities is patent eligible subject matter in Australia!

The set up

The inventors of the patent-in-suit, Australian Patent No 727919, in the name of Sequenom, Inc., discovered that the cell-free fractions of a pregnant woman’s blood contain surprisingly large amounts of cell-free fetal DNA (cffDNA). Traditionally, this portion of the plasma or serum was discarded as medical waste. This pioneering discovery led to the development of the claimed non-invasive method to determine fetal characteristics and abnormalities, such as Down syndrome. Ariosa Diagnostics Inc, who sought to revoke Sequenom’s Patent, conducts and licenses others to conduct a non-invasive prenatal diagnosis test, marketed under the name “Harmony”, which Sequenom claims infringes their patent.

The significance of the Australian Sequenom decision has been fuelled by the corresponding US case where the claims of the Sequenom’s patent were found to be patent ineligible because they were held to be directed to naturally-occurring matter. The ensuing detrimental impact on US diagnostics industry has subsequently resulted in a proposal for changes to the patentable subject matter legislation, which is currently being considered by US congress.

Issues and findings

Under Australian law, patent eligibility is guided by the principles of the High Court’s decision in National Research Development Corporation v Commissioner of Patents(‘NRDC’) [1959] HCA 67. In that landmark decision, it was held that subject matter was considered patent eligible if it was “an artificially created state of affairs” having “economic significance”.

Ariosa’s case relied heavily on the approach that proved successful in the US, namely that the claims cover a mere discovery, that being the presence of cffDNA, which can be detected in the plasma or serum of pregnant women, and that the end result of each claim is not an artificially created state of affairs. Ariosa further submitted that the claims involve nothing more than the use of well-known techniques to detect cffDNA in maternal blood.

Ariosa also suggested that the Court should follow the US position, which they suggested was in harmony with the Australian Myriad decision. Judge Beach’s response was an emphatic, “I hardly think so”. In fact, in considering the Australian High Court Myriad decision, Beach J emphasised the difference between the gene product claims considered in Myriad and the method defined in the claims of Sequenom’s patent. In particular, he stated that “in nature, the presence of cffDNA in the maternal blood has not and cannot be detected without human action. Accordingly, unlike the claims considered in Myriad, the invention claimed adds to human knowledge and involves the suggestion of an act to be done which results in a new result, or a new process”.

The Court also agreed with Sequenom that the substance of the claimed method is distinct to simply the identification of a natural phenomenon, namely the presence of cffDNA in maternal blood. This, the Judge said, is made clear by the patent specification, which explains that the invention offers a new approach for non-invasive prenatal diagnosis, which only occurs through human intervention and provides a significant advantage over existing fetal DNA detection methods, thus producing a result possessing economic utility.

Consistency with foreign law

Given the intense spotlight that has illuminated patentability issues in the US for diagnostic methods in recent times, the consistency of the Australian decision and the corresponding UK proceedings between Ariosa and Sequenom (Illumina, Inc v Premaitha Health Plc[2017] EWHC 2930), will likely go unnoticed. Those, however, looking for controversy in the conflicting Australian/US findings should look no further than Judge Beach’s swatting away of the issue by stating that the conclusion reached in the US decision is problematic because of the US Court’s dissection of the claims into their constituent parts, which is contrary to Australia’s NRDC and Myriad decisions, – end of story.

Conclusions

This decision, and the recent decision in Meat & Livestock Australia Limited v Cargill, Inc [2018] FCA 51, make it clear that claims directed to practical applications of naturally-occurring phenomena, including gene sequences, used in methods of diagnosis and prognosis are patent eligible subject matter in Australia. This will come as a welcome relief to the diagnostics and personal medicine industry and can be considered as “one small step” forward for Australian patent law but also, hopefully, “one giant leap” that influences beneficial change to the patent eligibility laws in the US.

Non-invasive prenatal genetic testing based on maternal blood sampling is replacing older invasive forms of testing – a paradigm shift in prenatal medicine. The patent rights associated with these methods have been litigated in several jurisdictions, most notably to date the US, UK and Australia. This decision of Justice Beach in Sequenom, Inc. v Ariosa Diagnostics, Inc. [2019] FCA 1011, stands in clear contrast to the US Court of Appeals decision in Ariosa Diagnostics v Sequenom 788 F.3d 1371 (2015) (the Ariosa US decision), and the Supreme Court of the United States which subsequently denied Sequenom’s petition for a writ of certiorari.

The Patent Family

The patent family in question, with patents in the US, Europe and Australia, are in broadly similar terms and arose from research carried out by Professor Dennis Lo and colleagues at Oxford University. Professor Lo’s discovery demonstrated that cell-free foetal DNA (cffDNA) could be detected in the plasma and serum of pregnant women. The patents arising from this discovery are, generally speaking, to methods of detecting this cell-free foetal DNA, using standard techniques, for prenatal diagnosis of genetic anomalies and sex determination.

Sequenom began offering the non-invasive prenatal test in the US in 2011, with a number of other companies following suit, including Ariosa Diagnostics which provided its own “Harmony” test. Illumina, the other major player in the field, produced “Verifi” in the US, and the two companies settled their patent dispute by cross-licensing their patents in 2014.

Background to the Australian Litigation

Sequenom is the patentee of Australian Patent No 727919 entitled “Non-invasive prenatal diagnosis” (the Patent). The claims relate to a method of detecting the presence of nucleic acid of foetal origin in a maternal serum or plasma sample. Sequenom sought relief for infringement in relation to the Harmony test.

The respondents, Ariosa (together with two Australian pathology companies licensed by Ariosa to promote and supply the Harmony test) cross-claimed seeking revocation on several grounds. This article deals exclusively with his Honour’s findings in relation to patent subject-matter eligibility.

The Decision

Genetic Information v Practical Application 

Patent eligibility in Australia requires that the relevant subject matter be a “manner of manufacture”. The leading authorities on interpreting this requirement, High Court decisions in Research and Development Corporation v Commissioner of Patents (1959) 102 CLR 252 (NRDC) and D’Arcy v Myriad Genetics Inc (2015) 258 CLR 334 (Myriad) make clear that there are two essential factors necessary to the characterisation of an invention as a “manner of manufacture”:

(a)   whether the invention as claimed is for a product made, or a process producing an outcome as a result of human action (that is, an artificially created state of affairs); and

(b)   whether the invention as claimed has economic utility.

Ariosa conceded that where a new scientific principle is discovered, its practical application might be patented, even if that application is straight-forward once the new principle is known. However, Ariosa argued, in the instant case, the discovery of the location (in maternal serum) of a known product (foetal DNA), was not the discovery of a new principle, and that the Patent merely claims the use of the discovery for the purposes to which it is inherently adapted. In particular Ariosa contended that there was no claim in the Patent to any new method of detecting cffDNA once it was discovered to be present in the plasma or serum of a pregnant woman.

Second, Ariosa submitted that none of the claims involved the creation of an artificially created state of affairs. The outcome of each claim was merely genetic information about the DNA of the foetus, which is a naturally occurring phenomenon.

Beach J disagreed, finding that the Patent did not contain any claims to cffDNA as a product per se or as genetic information as it existed in nature (as was the case in Myriad), but rather to a method by which the discovery of the existence of cffDNA can be put to practical use. In this way the subject matter of the relevant claims can be seen to fall within the principles of NRDC and affirmed in Myriad, whilst not falling within the impermissible sequence claims rejected in Myriad.

His Honour articulated his reasons in the following terms:

“The invention is undoubtedly an artificial non-invasive detection method involving artificial DNA amplification methods and synthetic probes deriving from the presence of cfDNA in the maternal circulation from both the mother and developing foetus”. 

His Honour concluded that such a “process of detection and discrimination” could only be characterised as artificial and could not be naturally occurring information of a non-patentable character. While not required to do so, his Honour also considered the “other factors” outlined in Myriad and came to the same conclusions on subject matter eligibility.

This decision is not surprising given Justice Beach’s decision in Meat & Livestock Australia Limited v Cargill, Inc [2018] FCA 51 (MLA) discussed here.

The IP Landscape on Patentability

The position in the US

A series of recent decisions in the US have significantly narrowed the patent eligibility for inventions involving diagnostic methods, in particular Mayo Collaborative Services v Prometheus Laboratories Inc 566 US 66 (2012) and Alice Corp. v. CLS Bank International 573 US 208 (2014). The uncertainty and ambiguity created by these decisions for patentees has led the United States Congress to release draft legislation to address patentable subject matter. These matters and the Ariosa US decision are discussed here in further detail.

The position in Europe

The European Courts have taken a more permissive approach to subject matter eligibility, instead restrictively applying criteria for novelty, inventive step, and insufficient disclosure.

Under the European “Biotechnology Directive” (Directive 98/44/EC, Article 5 and Recitals 21-22) where a DNA sequence is isolated from the human body by means of a technical process, the sequence per se becomes eligible for patent protection, even where it is identical to that which exists in nature.

In keeping with this approach, Justice Henry Carr in the corresponding UK proceedings, Illumina, Inc v Premaitha Health Plc [2017] EWHC 2930 (Pat), concluded:

I do not accept that, properly construed, claim 1 is a claim to a discovery as such. The claims are not directed to information about the natural world, but rather to a practical process, namely a “detection method” which uses information about the natural world. Claim 1 is directed to the detection of foetal DNA in a sample of plasma or serum. Such samples do not exist in the natural world and must be artificially created. The claimed method of detection is also an artificial process which does not exist in the natural world. The claim is to a practical process of implementing a discovery, for practical applications. The actual contribution, as a matter of substance, does not fall solely within the excluded subject matter and is technical in nature.

Implications 

The decision in this case, following on from his Honour’s decision in MLA, provides certainty that claims defining practical applications of genetic technologies that are the result of human action are patent eligible subject matter under Australian law. We note that Ariosa has until 18 July 2019 to file an appeal to the Full Court.

It is also evident that the patent eligibility of gene-based applications varies significantly across jurisdictions, and in particular the requirements in the US remain in a state of confusion and flux. It would be highly desirable to have consistency across jurisdictions in this regard, to provide patentees with greater commercial certainty and predictability for their gene and diagnostic based patent portfolios.

Steps are currently being taken by the United States congress to address the issue of patent eligible subject matter that has plagued the United States patent system in recent years.

How we got here?

There is no question that United States Supreme Court decisions such as Mayo Collaborative Services v Prometheus Laboratories Inc, 566 US 66 (2012) and Alice Corp. v. CLS Bank International, 573 US 208 (2014) have changed the Life Sciences patent landscape, particularly with regard to diagnostic inventions based on, for example, measuring various biological components (metabolites, genes, etc.) present in patient’s blood.

A leading example of the impact of these decisions is Ariosa Diagnostics, Inc. v. Sequenom Inc, 788 F3d 1371 (Fed Cir 2015) (“Ariosa”).  The patent at issue in Ariosa, US Patent No 6,258,540, concerned detecting cell-free fetal DNA (“cffDNA”) in maternal plasma to identify fetal characteristics and abnormalities.  This invention replaces invasive pre-natal techniques.  However, the cffDNA was deemed a “natural phenomenon” and its detection an application of routine methods.  Accordingly, the claims were found to be directed to non-patentable subject matter.  Judge Linn concurred in the decision but emphasized that the invention at issue was “truly meritorious” and “ground breaking”, highlighting the illogical result that no patent protection could be awarded despite no one having ever used maternal plasma to detect cffDNA.  As Judge Linn stated:

“But for the sweeping language in the Supreme Court’s Mayo opinion, I see no reason, in policy or statute why this breakthrough invention should be deemed patent ineligible.”

Thus, research into diagnostic methods, which clearly have value to society, would no longer be rewarded with patent protection.

A small area of protection was clawed back by the Federal Circuit decision of Vanda Pharmaceuticals Inc v West-Ward Pharmaceuticals International Limited, 887 F3d 1117 (Fed Cir 2018).  At issue in Vanda was US Patent No 8,586,610, which included claims directed to a method of treatment comprising a diagnostic step based on the genotype of a patient and a step of administering a pharmaceutical in view of the outcome of that diagnostic analysis.  This claim format was enough to overcome the Mayo problem.  Although the tenuousness of this decision is apparent from the dissenting opinion of Chief Judge Prost, who stated that “the end result of the claimed process is no more than the conclusion of a natural law … I see no distinction from Mayo”.

The USPTO embraced the Vanda decision, providing guidance to applicants to formulate patent eligible claims based on a Vanda-style claim. However, since the Vanda claim format includes a diagnostic step and an administration step, the commercial relevance of such claims is questionable since different parties are likely to perform each of the steps.

Now, it seems even Vanda claims may be in danger as the case could be granted certiorari by the Supreme Court as the Supreme Court has requested that the Solicitor General file a brief expressing the view of the United States.

If the Supreme Court should grant certiorari, it would seem to be a negative indication, as it has declined to do so in about 40 post Alice cases.

What is Congress Doing?

In the face of this legal uncertainty, several members of the United States Congress released draft legislation to address the patentable subject matter issue.  The legislation seeks to base patent eligibility on the usefulness of the invention, which is defined to be “any invention or discovery that provides specific and practical utility in any field of technology through human intervention”.  Significantly, the legislation would abrogate the Supreme Court cases applying the natural phenomena criteria to patent eligibility.

The draft legislation served as a starting point for three days of public hearings before the United States Senate Intellectual Property subcommittee, which drew together testimony from a former Chief Judge of the United States Federal Circuit, heads of biotechnology and pharmaceutical concerns, law professors, former directors of the USPTO, and groups such as the American Civil Liberties Union.  Thus, parties on all sides of the patent debate were represented and heard.

The ranking members of the subcommittee released a statement capturing their thoughts on the hearing.  Despite having heard from both sides, the statement appears to weigh more heavily in favour of establishing a system that grants protection to inventions such as diagnostics based on a naturally-occurring correlation.  Significantly, the statement emphasized the misplaced concern surrounding the patenting of human genes and, rather, pointed to the protections afforded by other elements of patentability.  The subcommittee members recognized the need to “incentivize research and development into the exciting prospects of individualized diagnostics and precision medicine” and to “ensure the protections that will enable our innovators to bring these products to market while safeguarding research into the next generation of medical advances”.  Indeed, it should not go unappreciated that the statement refers to the Ariosa decision, which is characterized as the invalidation of claims to “a revolutionary prenatal test … that allowed doctors to avoid invasive procedures”, and quotes from Judge Linn’s concurring opinion.

Thus, the subcommittee appears to fully appreciate that maintaining the current law on patent eligibility is not an option.  While we are only at the beginning of this processes, a return to rewarding inventive effort may be on the horizon.  Stay tuned.

Authored by Michael Christie, PhD

Shelston IP wishes to congratulate Professor Hala Zreiqat from Sydney University, who has recently been named NSW Premier’s Woman of the Year.  She is currently Professor of Biomedical Engineering, where she founded the Tissue Engineering and Biomaterials Research Unit in 2006.

Shelston IP has been providing IP-related services to Sydney University for many years, and has been involved in drafting and prosecution the majority of the patent applications naming Professor Zreiqat as an inventor. The innovative technologies developed by Professor Zreiqat and her teams relate to biocompatible ceramic materials and uses in applications such as bone regeneration, for improving the stability of implantable medical devices, and as synthetic implantable scaffolds. The particular biocompatible ceramic materials covered by her patent applications include materials such as Baghdadite, Strontium-doped Hardystonite, and 2-phase materials comprising metal oxide doped Hardystonites.

Shelston IP is proud to be associated with Sydney University and eminent scientists such as Professor Zreiqat.

Authored by Gareth Dixon, PhD and Serena White, DPhil

The recent Meat & Livestock Australia Limited v Cargill, Inc (MLA) Federal Court decision has brought the significant differences that exist between Australian and US “gene patent” practice into sharp focus. These differences predominantly arise from the peculiarities of the US and AU Myriad decisions as well as the US Mayo v. Prometheus and Ariosa v. Sequenom decisions.

In considering the patent eligibility of isolated naturally-occurring gene sequences, the Australian High Court focussed predominantly on the concept of “genetic information”. Consequently, when the High Court ruled against “gene patents”, the decision excluded from patent eligibility only isolated naturally-occurring gene sequences and non-naturally occurring gene sequences that encompass naturally-occurring genetic information – including artificially created sequences such as cDNA. Under the High Court decision, isolated products of nature other than gene sequences (such as proteins and micro-organisms) remain patent eligible in Australia because they do not encompass naturally-occurring genetic information.  This situation contrasts with the outcome of the US Supreme Court Myriad decision, which resulted in all isolated products of nature being excluded from patent eligibility including, gene sequences, proteins and microorganisms, but not artificially-created gene sequences such as cDNA.

The Australian Myriad decision did not consider the patentability of claims directed to the practical applications of gene sequences. Such claims, however, have generally been confirmed as patent eligible by the recent MLA decision. This contrasts with the US Sequenom v. Ariosa decision where a claim directed to a method of identifying a correlation between a gene sequence and fetal abnormalities was considered ineligible for patent protection, applying the Supreme Court Mayo v. Prometheus decision.

The differences between US and Australian practice are conveniently summarised in the following table. Notably, Australian law in relation to the patentability of gene-based screening methods may evolve after a decision issues in our Sequenom and Ariosa case, which is set down for a hearing in August 2018. Shelston IP will keep you promptly updated in this regard.

Exactly what gene-based inventions are patentable in Australia and the US?

Subject MatterPatent Eligibility in the USPatent Eligibility in Australia
Isolated naturally-occurring gene sequencesNoNo
Isolated naturally-occurring gene sequences having modified nucleotidesYesDependent on whether the modification contributes to the working of the invention
Codon-optimised gene sequencesYesYes
cDNAYesNo
Interfering RNA moleculesYesYes
Isolated naturally-occurring proteinsNoYes
Isolated micro-organismsNoYes
Gene-based screening methods for diagnosis/prognosisLimitedYes

Authored by Paul Harrison

When the Australian High Court ruled against the patentability of isolated naturally occurring genes in the Myriad decision, a number of commentators believed that the decision would ultimately invalidate claims directed to methods involving the practical application of genes. A recent Federal Court decision, however, has confirmed that claims directed to methods involving the correlation of gene sequences to a particular trait in cattle are patent eligible subject matter in Australia.

Background

This case concerns an appeal of an unsuccessful Patent Office opposition, by Meat & Livestock Australia Limited (MLA) and Dairy Australia Limited against Australian patent application 20102022253 (the 253 Application), in the name of Branhaven LLC and Cargill, Inc., directed to animal genomics and the genetic improvement of livestock. The claims relate to methods of identifying beneficial traits in cattle using gene sequence analysis, and specifically the identification of single nucleotide polymorphisms (SNPs).

Gene-based patentable subject matter

The principal attack on the 253 Application involved arguments and evidence that the claims did not define patent eligible subject matter. At the outset, the Judge, Beach J., made it clear that the case did not merely involve the discovery of a correlation between genotype and phenotype. Rather, the Court considered this to be the starting point for the analysis rather than the finishing point in relation to determining patentability.

The submissions made by MLA relied heavily on the findings of the High Court in the Myriad decision. The Court, however, ultimately found these submissions unpersuasive on the basis that the Myriad decision centred on the patentability of claims defining isolated naturally occurring gene sequences per se rather than methods of using gene sequences. The Court therefore concluded that the reasoning of the Myriad decision did not assist MLA. In support of this conclusion, Beach J. indicated that there was no suggestion in the Myriad decision that claims to methods involving the practical application of gene sequences could be dismissed as being, in substance, patent ineligible naturally occurring genetic information.

Patent eligible subject matter under Australian law is required to be an artificially created state of affairs having economic significance. As the claims of the 253 Application cover practical applications of identifying SNPs from a bovine nucleic acid sample and their association with a trait of interest, the Court found that the claims were directed to artificial subject matter resulting from human action, rather than something that exists in nature per se. The decision also makes it clear that it is inappropriate to focus on individual elements of claims, such as SNPs and their association with a particular trait – these being naturally occurring phenomena. For these reasons the claims were found to be “within the plain vanilla concept” of patentable subject matter.

Chilling effect on innovation

MLA further submitted that the claims if granted would have a chilling effect on future research in the livestock industry in Australia contrary to the interests of the Australian public. The “chilling effect” on innovation was one of a number of “other factors” considered by the High Court in the Myriad decision as being important considerations in determining patent eligible subject matter.

In rebutting MLA’s arguments, the Judge identified an Australian granted patent, listing MLA’s experts as the inventors (the AV/Goddard patent) and stated that “if MLA’s chilling effect point was good, then the AV/Goddard patent would be an example par excellence”.

The Judge also clarified that the breadth of claims per se is not indicative of a lack of patentable subject matter. A complaint about the breadth of claims is something that arises under other grounds of invalidity, such as a lack of clarity or a failure to define the invention. The Court concluded that none of the “other factors”, point against patentability – they all consistently point in one direction, namely patentability.

The misaligned Australia/US position on gene-based patentable subject matter

MLA also submitted that as a matter of coherency with US law, the claims should be held to be invalid based on a lack of patentable subject matter having regard to decisions in the US, which have rejected claims to methods of diagnosis based on discoveries or principles of nature; For Example, Mayo Collaborative Services v Prometheus Laboratories, Inc. 566 US 66 (2012) and Ariosa Diagnostics Inc. v Sequenom, Inc.788 F3d 1371 (3d Cir 2015). These submissions were rejected by the Court for three reasons. Firstly, the Judge found that he could not determine coherency with foreign law generally by only considering cherry-picked jurisprudence from one jurisdiction. Thus, consistency with one foreign jurisdiction might produce inconsistency with another foreign jurisdiction. Secondly, the Court found it necessary to apply an evolving concept of patent eligible subject matter in the context of Australian legislation and Australian conditions, not any foreign law approach. Thirdly, the Judge pointed out that the US approach accepts that a method involving the application of a “law of nature” may be patent eligible.

Notably, Beech J said nothing in relation to the US Ariosa Diagnostics Inc. v Sequenom, Inc decision as the corresponding Australian case has been set down before him for August 2018.

Conclusions

Ultimately, the single ground upon which MLA succeeded was that of lack of clarity. The Judge, however, provided a specific indication as to how claim 1 and analogous claims could be amended to render the claims valid. This strongly suggests that the amendments will be allowed, and the patent application granted.

The significance of this Federal Court decision is twofold. Firstly, given the nature of the claims, the 253 Application, once it is granted, may significantly impact the use of genomic analysis in the Australian livestock breeding industry. Secondly, and perhaps more importantly, the decision provides certainty in relation to the patentability of claims defining practical applications of gene sequences, including methods of genetic screening.  In this regard, the decision potentially foreshadows the outcome of the Sequenom and Ariosa case, concerning the patentability of genetic testing methods.

Authored by Paul Harrison