Patenting Molecular Diagnostics

The patent eligibility in every jurisdiction differs in content and form. It perhaps finds its justification in the stage of development the country is placed in relation to inventions of new technology or its adoption by the state technology groups. One such grey area that is hotly debated and least understood in the patent administrative set-up is the patenting of the molecular diagnostic process/method. In advanced countries like the US where patent office rejections are vigorously tested by the federal courts, the rules of rejections are tuned to the precedents set by the courts. When BRCA1, the most controversial gene patent in terms of its alleged impact on molecular diagnostics, was granted in the US, it opened the door for patent eligibility of molecular diagnostic inventions particularly those associated with BRCA testing.

Molecular diagnostic is a fast-growing medical diagnostic process of identifying a disease by studying molecules, such as proteins, DNA, and RNA, in a tissue or fluid. In the context of patents on molecular diagnostics, we also refer to disease-gene patents. It covers patents on a genetic mutation and all related methods of diagnosing a genetic condition. In other words, genetic testing is emerging as a pre-emptive treatment medical measure to identify disease-gene and obtain patents. As the commercial application of molecular diagnostics gained acceptance in personalised medicine circles the debate on patenting of the molecular genetic discoveries heated up.

Divergent Views on Patentability

The European Union’s Biotechnology Directive 98/44/ clarified that patents on DNA sequences were allowable. Therefore, gene product patents remain permitted in Europe and so are the patents on genetic diagnostics if they fulfil the normal patentability criteria. In the USA and Australia, the scope of some gene patents has been curtailed to be limited to man-made genes. In Association for Molecular Pathology v. Myriad GeneticsInc., 569 U.S. 576 (2013) case when AMP sued Myriad Genetics to challenge patents relating two genes, BRCA1, BRCA2 associated with breast cancer, the Supreme Court was called into question whether isolated genetic material is itself patentable. The US Supreme Court held that a naturally occurring DNA segment is a product of nature and is not patentable merely because it has been isolated. In the Myriad case, the court ruled that because isolated DNA is not markedly different from DNA as it exists in nature, it constitutes an unpatentable subject matter. In this case, the US Supreme Cot, while ruling partially in favour of Myriad, cleared some mist on diagnostic inventions when the court ruled that a naturally occurring gene sequence could not be patented but c DNA, which is a man-made genetic construct, is a patentable subject matter. It means that isolated DNA without further alteration or manipulation is not patent-eligible. Similarly, in Australia, Myriad BRCA1 And BRCA2 gene patent enforcement hit similar questioning of the patentable nature of genetic material.

It is pertinent to note that European Patent No. 0994963, was granted by the European Patent Office, with terms that are substantively similar to the corresponding US patent 6,258,540. The Australian High Court in D’Arcy v Myriad Genetics Inc [2015] HCA 35 at [6] held that isolated gene sequences were not patentable because they were not something made or brought about by human action. The court observed that the substance of the claims was the information embodied in the sequence, which is not made but discerned. In Ariosa Diagnostics v Sequenom 788 F.3d 1371 (2015), where the claimed invention was for prenatal testing methods, the Federal Court found that the claimed invention is patent ineligible even when it was a truly meritorious innovation according to Judge Linn. The Supreme Court of the USA declined to grant certiorari, so the patent remains invalid [Sequenom v Ariosa Diagnostics, Inc 136 S.Ct. 2511 (2016).]. The Federal Court of Australia on the other hand has upheld a decision to allow patents to diagnostic methods involving the practical application of natural phenomena (including nucleotides) in the case of Ariosa Diagnostics, Inc v Sequenom, Inc (Sequenom 2021). This decision contrasts with the (Ariosa Diagnostics, Inc. v. Sequenom, Inc. 788 F.3d 1371 (Fed. Cir. 2015)) case in the US. As discussed, ante some members of the US Court of Appeals for the Federal Circuit (CAFC) while recognising the contribution of the invention, expressed misgivings but felt bound by precedent to rule that the subject matter was patent ineligible. Interestingly, this Australian decision is in line with the earlier ruling of the UK court regarding the validity of an equivalent UK Patent (Illumina, Inc v Premaitha Health Plc [2017EWHC 2930). In the Illumina case, the UK court speaking on the contention of mere discovery ruled that:

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.

In a recent molecular diagnostic case Federal court found in CareDx, Inc. v. Natera, Inc., — 4th — (Fed. Cir. 2022) that the claimed invention is not patent eligible. The technology in this case is somewhat similar to the prenatal testing methods in the Illumina and Sequenom cases. The only difference is that in Illumina and Sequenom cases, the prenatal technology looked for fetal DNA floating in the mother’s bloodstream and the CareDx case the graft technology looked for DNA of the transplanted organ floating in the stream. The inventors found that the amount of Donor DNA floating in the bloodstream of the recipient is indicative of whether the transplant is being rejected. The rejection of the patent, in this case, was for a different reason. The district court ruled that claimed invention is directed to a patent-ineligible natural phenomenon as the claims are directed to “the presence of donor cfDNA in a transplant recipient and the correlation between donor cfDNA and transplant rejection.” The court held that the particular techniques used to obtain and analyze the cfDNA were all conventional, and hence nothing in the claims transformed their nature into a patent-eligible invention. On appeal, the Federal Circuit affirmed, holding that “[t]his is not a case involving a method of preparation or a new measurement technique.” All these cases suggest we have a mixed bag of patent eligibility for inventions relating to molecular diagnostics.

Molecular Diagnostics Patents

In medicine, the molecular diagnostic technique is emerging as a useful tool to diagnose and monitor disease, detect risk, evaluate patients’ response to drugs and decide the informed course therapies that would be best suited for an individual patient. Thus, analysis of the specific conditions of the patient and their disease condition molecular diagnostics offers the best course for personalised medicine. Encouraged by the grant of patent and their possibility to stand the invalidity test in court like Myriad patents on molecular diagnostic tools comprising BRCA1, and BRCA2 associated with breast cancer many diagnostic patent applications are filed worldwide. In India, many patent applications relating to molecular diagnostics have now been examined.

Position of Gene and Genetic Material Patenting in India

The mystery surrounding the patentability of genes and genetic material in India as well raised some pertinent questions in the Parliament and the Government of India set a Technical expert group headed by Dr Mashelkar (2006) to look into the issue inter alia “whether it would be TRIPS compatible to exclude micro-organisms from patenting.” and resolve it in the context of the Patents Act amendments, particularly in respect of the amended section 3 (j ). This group concluded with the recommendations inter alia that:

“5.19 Microbiological inventions include new products, processes, uses and compositions involving biological materials. These inventions cover methods to isolate and obtain new organisms, improve their character, modify them and find their new and improved uses.

5.20 Patenting of new micro-organisms is based on their differences with the characters and uses of micro-organisms as available in the prior art. Known microorganisms are restricted to new uses, wherever patent law permits such protection. The same is the case with genetically modified microorganisms.

Genes and gene products are treated similarly to chemical compositions. Patenting of animal and human genes quite often attracts issues regarding public order and morality. “

This report acknowledged that isolated genes and nucleotide and polypeptide sequences are treated in the same way as other chemical compounds in the examination for the grant of patents under the patent law. They are considered patentable when they qualify for novelty, inventive step, and industrial applicability requirements under the law. However, the extent to which the patent eligibility can extend remained shrouded with mystery as patent offices around the world including India kept raising the bar on the eligibility of patents on molecular diagnostics.

Coverage of Disease-Gene Patent

The work of examining disease gene patent applications is the most complex as gene patent claims are highly variable. These claims can be for

a) Whole gene sequences to partial sequences
b) Isolated corollaries of naturally occurring sequences to recombinant sequences,
c) entire protein-coding sequences to hybridisable probes, regulatory regions and fragments of unknown function.
d) Wild-type sequences to disease-related mutations and other polymorphisms that do not necessarily affect the function.
e) Claims can be specific to the identified nucleotide sequence, or broad enough to cover some or all of the possible variants that code for a particular polypeptide sequence, or, even more broadly, all of the nucleotide variants that code for all of the functional variants of a particular polypeptide sequence.
f) Vectors, cell lines and host cells.
g) Products and processes can be claimed.

Diagnostic Process: Non-Patentable

Section 3 (i) was amended in 2002 when the terms “diagnostic, therapeutic” was inserted. It was meant to exclude patents on any diagnostic process of human beings to render them free of disease. Thus, diagnostic processes were kept outside the purview of patentable inventions. But neither the diagnostic process was defined nor any limits to this exception set except that the use of such a diagnostic process should not directly lead to rendering the patient free of disease. This means the interpretation of the diagnostic process would be left to the understanding and interpretation of the patent office. When we see the patent application on molecular diagnostics we come across disease-gene patent applications as well. It covers inventions on a genetic mutation and all related methods of diagnosing a genetic condition. In other words, genetic testing is emerging as a pre-emptive treatment medical measure to identify disease-gene and obtain patents. The patentability of gene/DNA or part thereof in India is linked to exceptions under section 3(c) and section 3(j).

Position of Life Forms and Genes

Section 3 (c) of the Indian Patents Act, 1970 as amended in 2002 specifically excludes “discovery of any living thing or non-living substances occurring in nature.” Additionally, section 3(j) put a bar on patentability on “plants and animals in whole or any part thereof other than microorganisms”. These exceptions allow micro-organisms as patentable subject matter, provided they fulfil the prescribed criteria under section 3. The Calcutta High Court in Dimminaco AG vs. Controller of Patents (2002) ruled that the Act did not preclude a living end product from being patented. The Technical group recommendation opened the way for the grant of patents on the modified microorganism, but the question of patent eligibility of higher life forms and genes and genetic material was not addressed by them sufficiently to pave the way for guidelines on their patentability. The Patent Office in the absence of guidelines on biotech inventions kept on changing the fields of exclusions on life forms/gene/DNA based not on any court precedence in India, but on the understanding and interpretations of the Controllers. In the 2008 draft, some clue was given when it was stated that ‘any living entity, even one of artificial origin and any part thereof, is not patentable.’ In the same draft when the question of the patentability of recombinant DNA is answered, it is stated that recombinant DNA is patentable only where there is substantial human intervention in its creation. So far as the genes and genetic material are concerned the 2008 draft elaborated that:

“The following can be claimed when a genetically modified gene sequence/amino acid sequence is novel, involves an inventive step, and has industrial application.

(a) Gene sequence/amino acid sequence
(b) A method of expressing the above sequence
(c) An antibody against that protein/sequence
(d) A kit made from the antibody/sequence

This paves the way for patenting of genes and other nucleic acid sequences as their creation is subjected to a microbiological or non-biological process, like gene sequencing. Gene sequencing is a standard process that is acceptable under patentable subject matter under the patent laws for invention in India and elsewhere. However, patenting of genomes is linked to the question of the function of the genomes. It is understood that the genome per se can do nothing by itself. The function of the genome in any living entity cannot be considered separately from the totality of the entity. This aspect of the patentability of the genome is hit by the provision of section 3 (j), where plants, animals and parts thereof are excluded from patent eligibility in India. It implies that a gene is patentable, provided that it exists in sequences and is recombinant and its creation involved human-induced alterations. While the manual of the patent office clarifies the patenting of life forms and genes to a certain extent it leaves a lot to be determined by the Controller on a case-to-case basis. When the Act is silent about gene patenting, one line of argument would be that genes constitute part of DNA, hence part of the plant or animals that are excluded from the patentability under section 3 (j). Another argument is genes /DNA are the building block of life and hence are living things excluded from the patent when they are found in nature. However, modified genomes and artificially produced genes are treated as patentable subject matter. Since these genes are inserted artificially by humans and such modified genes are in the isolated form, they are not constituted as ‘part’ of any living beings under section 3 (j) and hence they are considered a patentable subject matter.

Gene Patents

There is no doubt that we find many gene and gene-related inventions find favour with the Indian patent office. Many such patents have been granted. However, their legality may remain contentious till it is subjected to the scrutiny of the courts in India. Moreover, the patent office in India keeps discoveries and products of nature outside the purview of the patentability under section 3 (c). Nonetheless, the elements of isolation and purification of parts of living organisms are sufficient to bring them in the fold of patent eligibility as isolated genes, nucleotides and polypeptide sequences are considered like other chemical compounds.

Molecular Diagnostics Patent Rejected in India

Though many patent applications on molecular diagnostics were refused under section 3(i), the outcome of the appeal against recent refusals like EMD Millipore’s patent application for ‘devices and methods for infrared (IR) based quantitation of biomolecules’ (1026/DEL/2012) and Sequenom’s patent application for ‘processes and compositions for methylation-based enrichment of fetal nucleic acid from a maternal sample useful for non-invasive prenatal diagnoses’ (3139/DELNP/2012) would be worth watching when the high court will take up these matters this year.

Looking Forward

Molecular diagnostic is a fast-growing medical diagnostic process of identifying a disease by studying molecules, such as proteins, DNA, and RNA, in a tissue or fluid. BRCA1 perhaps is considered the most controversial gene patent in terms of its impact on patent eligibility of molecular diagnostics inventions associated with BRCA testing. It is another matter that in Europe this patent was invalidated on technical grounds. However, isolated genetic material is considered patentable in Europe. No doubt genetic testing is emerging as a pre-emptive treatment medical measure to identify disease-gene, and more and more diagnostic companies are joining the race to obtain patents. The fate of the appeal on the Sequenom patent application in India will set the precedence on the patent eligibility of molecular diagnostic inventions. In the absence of a Mayo-like ruling in India, we can perhaps expect it may favour the inventor as in the words of Judge Linn “it was a truly meritorious innovation.” If the High Court goes the Australian or the UK way, we can expect the possibility of molecular diagnostic patents in India as well. In the meantime, we may keep our fingers crossed on this appeal and the appeal on the EMD Millipore application that the court will hear together.