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Table 1. Several authors have highlighted the importance of implementing systems biology approaches for unraveling the mechanisms responsible for plant desiccation tolerance and how these are intertwined, especially when this knowledge has to be transferred to cultivated species and when genetic engineering strategies for improving crop tolerance to drought are involved Moore et al. Since the release of V. In the post-genomics era, future breeding strategies rely on the investigation of abiotic stress tolerance responses and their correlation to genetic traits Cramer, ; Yang et al.

Gene co-expression networks GCN , based in the notion that genes involved in similar or related processes exhibit similar expression patterns under different experimental conditions, are the preferred strategy Wong et al. To this respect, several online platforms have been developed for V. In a pioneering work, Cramer et al. The manual integration of transcript and metabolite data allowed the identification of RuBisCo activase as an early response to water deprivation that was delayed under saline conditions.

Moreover, water stress affected metabolism-associated transcripts whereas salinity had an impact mostly on protein synthesis and fate Cramer et al. The transcript profiling data correlated well with metabolite profiles showing water-deprived grapevine tissues higher concentrations of glucose, malate, and proline than salt-stressed ones. Unfortunately, although this work included metabolite profiling data, no attempt to correlate transcript and metabolite profiling was carried out to provide a more insightful view of the regulatory processes involved in metabolite accumulation.

In a recent work, Corso et al. Transcriptome analysis revealed the WRKY transcription factors TFs -dependent activation of secondary metabolism potentially leading to the accumulation of stilbenes and flavonoids. However, this extent could not be confirmed with a parallel metabolite analysis and no co-expression analysis to unbiasedly correlate specific TF activity with the induction of the biochemical response was attained. In both cases, the use of integrative approaches could have contributed to extract more significant knowledge from already collected data.

Recently, Wong and Matus generated a composite network in grapevine by overlaying co-expression maps between structural and TF genes, integrated with the presence of promoter cis -binding elements, miRNAs, and long non-coding RNAs lncRNA focusing on the phenylpropanoid pathway. This allowed the characterization of novel TFs and miRNAs potentially involved in the regulation of the phenylpropanoid pathway.

Following a similar procedure, but integrating metabolomics, transcriptomics and proteomics data of grapevine berries in different developmental stages, Zamboni et al. Analysis of GCN has been applied in grapevine to identify ripening-associated functional sub-modules under water stress conditions Savoi et al. In this work, GCN revealed major drought stress-regulated gene modules linked to central and specialized metabolites and multiple signal transduction pathways e.

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The activation of both abscisic acid ABA -dependent and -independent pathways may act balancing the regulation of the stress response and the berry ripening program. Sequencing of sweet orange and the major cultivated citrus varieties and related genera including the three parental lines: pummelo, mandarin and citron Xu et al. For instance, the generation of a reference RNA-Seq transcriptome revealed the existence of 3, new genes and increased the number of alternative splicing variants Terol et al.

Annotation of gene function in newly sequenced genomes is not a trivial aspect most efforts are oriented toward the functional annotation of all encoding sequences in the citrus genome. Compared with classical GO surveys, GCN poses the advantage of allowing the annotation of new genes for which no plausible ortholog in better annotated plant species exists Wong et al. As in grapevine, most integrative studies have so far focused on fruit ripening and quality. A PPI analysis inferred from previous work on Arabidopsis thaliana , revealed glycolysis and TCA as functional modules being severely affected in the puffing disorder.

In another work, postharvest disease resistance of thermally acclimated vs. Proteins annotated as glucanases, class III chitinases and a Protein data correlated with increased levels of fatty acids, amino acids, carbohydrates, organic acids, and different secondary metabolites known to be involved in reducing the effects of external stress Yun et al. Focusing on abiotic stress, a recent work studied a co-expression network including both mRNA and non-coding miRNAs and a method to identify miRNA-transcription regulator-target connections in citrus was described Khodadadi et al.

The genus Poncirus with its only representative P. Raf constitutes an example of cold-temperature acclimation in citrus. Hence, the study of cold acclimation in this genotype revealed the involvement of conserved miRNAs and 5 potential novel miRNAs targeting stress-responsive genes Zhang et al. A total of 76 miRNA 47 conserved and 29 novel were altered either by salt stress, desiccation or both. Protein interaction with other proteins and other biomolecules is crucial in every cell process and understanding how these interactions take place is the ultimate goal of systems biology.

To this respect, protein sequence and post-translational modifications PTMs are two essential aspects to consider. In recent works, Tanou et al. In this sense, S and N donors used as priming agents modified the PTMs pattern altering protein biochemical activity and binding affinity. Despite the agricultural and cultural heritage importance of olive tree, the state-of-the-art in -omics toolkits for systems biology in olive is considerably delayed respect to grapevine or citrus and very few reports employing systems biology approaches in this crop exist to date.

Olive trees have a considerable ability to adapt to harsh environments due to their outstanding phenotypic plasticity. Until recently, genomic studies in olive focused mainly on the employment of molecular markers toward identification of genetic variability, olive oil traceability and parental progeny analysis to aid in genetic improvement programs Sebastiani and Busconi, Nevertheless, as in citrus, pre-genomic molecular biology was still possible with different EST collections whose components were functionally annotated by means of ortholog BLAST search.

In a series of experiments carried out using two O. Moreover, the resulting expression data was integrated using network analysis to infer regulatory processes aiming at inducing adaptive responses. In turn, bZIPs appeared to act as master regulators of other TFs within the gene regulatory network, seemingly acting upstream the olive tree ERF homolog. As a result of this study, it was shown that NF-Y TF is located at the uppermost hierarchical position in the regulatory network potentially regulating rewiring of node connectivity in response to salt stress. In general, the salt-tolerant genotype exhibited a more complex TF interaction network than the salt-sensitive, suggesting the existence of a more orchestrated and progressive response to salt stress.

More recently, another in-depth report made by the same authors employing pyrosequencing Bazakos et al. Most recently available studies using systems biology tools in olive have so far relied mainly on transcriptomic approaches focusing on regulatory processes during developmental events, namely flower development Alagna et al. Others aimed to decipher protein regulatory processes during fruit development Bianco et al.

Non-targeted approaches could, however, mine important information that could give significant insight into agronomic issues Ben Ayed et al. A recent study using a non-targeted metabolomic profiling approach in different olive tree tissues revealed 5, metabolite-metabolite correlations and highlighted the upregulation of biosynthetic pathways for phenylpropanoids, monolactams, indole alkaloids and flavonoids especially in young leaves. Considering the well-documented involvement of phenylpropanoids, indole alkaloids and flavonoids in stress protection phenomena, a general defense mechanism was proposed suggesting that metabolites involved in the resistance to biotic and abiotic stresses are mainly biosynthesized in new leaves Rao et al.

The ultimate goal of plant systems biology is to fully understand how plants respond to their environment. What is more, multidimensional interactions involving proteins, protein-nucleic acids and also different metabolites regulatory compounds such as plant hormones, allosteric modifiers, etc. In such a complex regulatory scenario, the integration of —omics within network analysis provides a data-driven and dynamic scaffold to select relevant genes involved in the regulation and development of the phenotype. This extent has been so far poorly investigated in woody crops despite similar approaches proved to be successful in identifying relevant genes in other plant species.

In a pioneering study, Morreel et al. More recently, integration of metabolomics and transcriptomics in co-expression analyses contributed to identify genes involved in side-chain elongation steps of aliphatic glucosinolate biosynthesis Albinsky et al. In woody crops, similar approaches have been applied to the identification of genes controlling acidity in oranges Huang et al. Also in grapevine, integration of transcriptomics and proteomics allowed the identification of transcriptional, post-transcriptional and translational mechanisms involved in the responses of grapevine to high temperatures.

This study revealed that alternative splicing constitutes an important mechanism in the response of grapevine to climate change conditions Jiang et al. Overall, all evidence points out that systems biology approaches are useful data-driven strategies to identify relevant genes involved in different plant processes. The constraints to global food production posed by climate change conditions have become a key issue in agronomy and plant physiology.

Perennial plant species, such as the ones in which this review focuses, are subjected to adverse environmental conditions throughout their entire life cycle, and over consecutive cropping seasons. Therefore, breeding of new varieties more resilient to abiotic stresses with improved performance and productivity traits constitutes a prioritary objective. The development of high-throughput phenotyping platforms complements fruit tree genomics bridging phenotype and genotype, allowing GWAS and network analyses expanding our knowledge on genetic responses linked to the development of particular phenotype traits.

In the field of abiotic stress tolerance, as an example, the integration of -omics for the engineering and selection of abiotic stress-tolerant genotypes has been successfully applied to staple and forage crops Deshmukh et al. Nevertheless, despite the existing technological gap between fruit trees, staple and forage crops and model plants in terms of genomic resources, databases and tools, the situation is changing rapidly and the amount of sequenced genomes and gene association studies increasing. It is therefore desirable that, in the following years, curated databases appear including data from different sources and technological platforms.

Abiotic stress tolerance traits are complex from the genetic point of view involving an intricate interaction of regulator and effector genes. Therefore, the integration of accurate phenotype data along with gene expression, metabolite and protein accumulation in different tissues and germplasm accessions would allow researchers performing in silico gene association studies, as in A. This will undeniably boost any woody crop breeding initiative by narrowing down the number of target gene s and providing a clear gene-to-phenotype association.

CDO and VA conceived and drafted first manuscript organization. All authors revised subsequent drafts of the manuscript and approved final version. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Abberton, M. Global agricultural intensification during climate change: a role for genomics.

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Microclimatic-induced fluctuations in the flower and pollen production rate of olive trees Olea europaea L. Grana 51, — Aissaoui, F. Early water stress detection on olive trees Olea europaea L. Alagna, F. Olive fruits infested with olive fly larvae respond with an ethylene burst and the emission of specific volatiles. Plant Biol. Albinsky, D. Widely targeted metabolomics and coexpression analysis as tools to identify genes involved in the side-chain elongation steps of aliphatic glucosinolate biosynthesis.

Amino Acids 39, — Albrigo, L. Google Scholar. Flower bud induction, flowering and fruit-set of some tropical and subtropical fruit tree crops with special reference to citrus. Acta Hortic. Aleza, P. Tetraploidization events by chromosome doubling of nucellar cells are frequent in apomictic citrus and are dependent on genotype and environment. Allario, T. Large changes in anatomy and physiology between diploid Rangpur lime Citrus limonia and its autotetraploid are not associated with large changes in leaf gene expression.

Tetraploid Rangpur lime rootstock increases drought tolerance via enhanced constitutive root abscisic acid production. Plant Cell Environ. Arroyo-Garcia, R. Multiple origins of cultivated grapevine Vitis vinifera L. Asins, M. QTL analysis of citrus tristeza virus-citradia interaction. Genetic analysis of reproductive, vegetative and fruit quality traits to improve Citrus varieties. Tree Genet. Genomes 11, — Atienza, S. Identification of QTL for agronomic traits of importance for olive breeding. Aubert, B. Avin-wittenberg, T.

Deciphering energy-associated gene networks operating in the response of Arabidopsis plants to stress and nutritional cues. Plant J. Baker, J. Contrasting crop species responses to CO2 and temperature: rice, soybean and citrus. Vegetatio 10, — Baldoni, L.

Vollmann and I. Genetic structure of wild and cultivated olives in the central Mediterranean basin. Barkley, N. Assessing genetic diversity and population structure in a citrus germplasm collection utilizing simple sequence repeat markers SSRs. Barnaud, A. Linkage disequilibrium in wild French grapevine, Vitis vinifera L. Heredity , — Barrios-Masias, F. Differential responses of grapevine rootstocks to water stress are associated with adjustments in fine root hydraulic physiology and suberization.

Baxter, S. Linkage mapping and comparative genomics using next-generation RAD sequencing of a non-model organism. PLoS One 6:e Bazakos, C. PLoS One e Comparative transcriptome analysis of two olive cultivars in response to NaCl-stress. PLoS One 7:e Ben Ayed, R. Database bav Ben-Hayyim, G.

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    Grape Wine Res. Water and salinity stress in grapevines: early and late changes in transcript and metabolite profiles. Genomics 7, — Cruz, F. Genome sequence of the olive tree, Olea europaea. GigaScience 5, 1— Cuenca, J. Fine mapping for identification of Citrus Alternaria brown spot candidate resistance genes and development of new SNP markers for marker-assisted selection.

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    Phylogenetic origin of limes and lemons revealed by cytoplasmic and nuclear markers. Curtolo, M. Dal Santo, S. Distinct transcriptome responses to water limitation in isohydric and anisohydric grapevine cultivars. Dambier, D. Somatic hybridization for citrus rootstock breeding: an effective tool to solve some important issues of the mediterranean citrus industry. Plant Cell Rep. Performance of several models for predicting budburst date of grapevine Vitis vinifera L.

    De la Rosa, R. Deluc, L. Transcriptomic and metabolite analyses of cabernet sauvignon grape berry development. Deshmukh, R. Integrating omic approaches for abiotic stress tolerance in soybean. Desta, Z. Genomic selection: genome-wide prediction in plant improvement. Diez, C. Olive domestication and diversification in the mediterranean basin. New Phytol. Doucleff, M. A genetic linkage map of grape, utilizing Vitis rupestris and Vitis arizonica. Duchene, E. Towards the adaptation of grapevine varieties to climate change: QTLs and candidate genes for developmental stages.

    Elshire, R. A robust, simple genotyping-by-sequencing GBS approach for high diversity species. Essalouh, L. Genomic and EST microsatellite loci development and use in olive: molecular tools for genetic mapping and association studies. Fang, D. Development of molecular markers linked to a gene controlling fruit acidity in citrus.

    Genome 40, — Fares, A. Potential climate change impacts on citrus water requirement across major producing areas in the world. Water Clim. Farneti, B. Genome-wide association study unravels the genetic control of the apple volatilome and its interplay with fruit texture. Fereres, E. Deficit irrigation for reducing agricultural water use. Understanding olive adaptation to abiotic stresses as a tool to increase crop performance.

    Ferrise, R. Navarra and L. Tubiana Dordrecht, NL: Springer , 49— Fitchett, J. Spatio-temporal variation in phenological response of citrus to climate change in Iran: For Meteorol. Forment, J. Fortes, A. Plant stress responses and phenotypic plasticity in the epigenomics era: perspectives on the grapevine scenario, a model for perennial crop plants. Fujii, H. High-throughput genotyping in citrus accessions using an SNP genotyping array. Genomes 9, — Fukushima, A. Gabaldon-Leal, C. Impact of changes in mean and extreme temperatures caused by climate change on olive flowering in southern Spain.

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    Georgiadou, E. Regulation of on-tree vitamin E biosynthesis in olive fruit during successive growing years: the impact of fruit development and environmental cues. Temporal analysis reveals a key role for VTE5 in vitamin E biosynthesis in olive fruit during on-tree development. Gimeno, J. Shared and novel molecular responses of mandarin to drought. Gois, I. Genome wide selection in citrus breeding. Gomez-del-Campo, M. Summer deficit-irrigation strategies in a hedgerow olive orchard cv. Irrigation Sci. Transcriptomic analysis using olive varieties and breeding progenies identifies candidate genes involved in plant architecture.

    Gordo, O. Impact of climate change on plant phenology in mediterranean ecosystems. Green, P. A revision of Olea L. Kew Bull. Greer, B. Polyploidy influences plant-environment interactions in quaking aspen Populus tremuloides Michx. Tree Physiol. Grimplet, J. The grapevine gene nomenclature system. PLoS One 4:e A race to characterize the gene ensued; it was won in by Mark Skolnick, a University of Utah geneticist and cofounder of Myriad Genetics, who quickly moved to patent the isolated gene and its mutations; Skolnick also set up diagnostic testing facilities to detect the sequences in patients.

    He repeated these efforts a year later, when he found the BRCA2 gene, which is likewise associated with early-onset breast and ovarian cancer, on chromosome However, in Myriad began to assert its US patents and clear both the diagnostic and research markets; in , it apparently started to keep information on mutations, correlations with cancer risk, and algorithms for interpreting genetic information as trade secrets.

    From a public relations perspective, these actions proved Myriad's undoing. As studies commissioned by the Health and Human Services Secretary's Advisory Committee on Genetics, Health, and Society SACGHS later found, 34 centralizing genetic testing in a single organization's laboratories eliminated the ability of patients to obtain second opinions a significant problem for a diagnosis that can lead to surgery to remove breasts and ovaries.

    Exclusivity also reduced the incentive to improve the tests or keep them current with advances in the underlying science; it also made it impossible to ensure the quality of the existing test by comparing results from different laboratories. Concerned about freedom of speech and the implications of recognizing exclusive rights over genetic knowledge for patients, researchers, and science, the American Civil Liberties Union challenged these patents in , naming as plaintiffs individuals and organizations with varying relationships to the Myriad patents.

    But because we question the Court's disposition, the opinions generated along the way bear consideration. The trial court quickly focused on the traditional challenges under the Patent Act, rather than the novel claims sounding in constitutional law. According to the court, isolation, including removal of noncoding regions, did not change that fundamental character. In addition, the court held that analysis and comparison of DNA sequences, as described in the diagnostic claims, were abstract mental processes that failed to satisfy the then-prevailing view that a machine or physical transformation was the key to patentability.

    The Federal Circuit agreed that the diagnostic claim was not patentable, 45 but in all other respects, it reversed the trial court. Thus, it was, in his view, patentable. Judge Moore concurred, albeit reluctantly on claims to long gDNA strands. Whereas she thought the short strands were patentable because they were not only markedly different from nature, but also had utilities not found in nature, the longer strands had only the differences in the bonding to distinguish them from nature.

    However, because she recognized a strong reliance interest in DNA patents, she concurred in the result, leaving it to Congress to determine whether such claims promote or inhibit science. Judge Bryson agreed with the others on the disposition regarding cDNA and the method claims. Noting that it referred to a sequence that was 24, nucleotides long with numerous gaps, he argued that: An almost incalculably large number of new molecules could be created by filling in those gaps with almost any nucleotide sequence, and all of those molecules would fall within the scope of [the] claim.

    Included in that set are many important molecular variations to the BRCA1 gene that Myriad had not yet discovered and could not have chemically described. Yet those molecules would share only one unifying characteristic: each codes for the same protein as the naturally occurring BRCA1 gene.

    Given the split decision on the DNA claims, it was not surprising that the Supreme Court agreed to entertain the case. Indeed, in many ways it was primed to hear it. Starting in the early s the Court had become concerned with the impact of patents on scientific and medical advancement. More important, soon after the Federal Circuit's decision in Myriad , the Court reviewed a case that raised the Metabolite issue concerning diagnostics. As foreshadowed by Justice Breyer's dissent in Metabolite , in Mayo the Court invalidated a patent on a method for determining whether a patient was receiving the correct dose of a drug.

    Because Mayo was handed down after the Federal Circuit's decision in the Myriad case, the Court's first step in reviewing Myriad was to ask the Federal Circuit to reconsider its decision in light of Mayo. On remand, Judge Lourie dismissed Mayo as solely concerned with the preemption of laws of nature; 65 Judge Moore stuck to her previous views even though she claimed to consider Mayo applicable; 66 Judge Bryson did not mention the decision at all—and, surprisingly, the Supreme Court barely referenced it in its plenary review. The Court did not, however, reach the same conclusion as Judge Sweet.

    Rather than focus on the question whether information directing the synthesis of proteins is patentable subject matter, the Court relied on the distinction between natural and artificial creation. Because it considered the gDNA naturally occurring, it held it unpatentable. Since the cDNA was synthesized, the Court found it to be statutory subject matter. Once the Court recognized the biological functioning of DNA sequences, it is difficult to understand how it could distinguish between cDNA and gDNA as both encode the identical information.

    Both raise the problem of inhibiting science, which was the focus of Justice Breyer's concern in Metabolite. Moreover, the ownership of what are essentially biological instructions—whether embodied in gDNA or cDNA—ties up principles about the relationships among the nucleotides comprising DNA and the protein chains these nucleotides produce. Since these relationships are at least as fundamental to future innovation as the laws at issue in Mayo , it would seem that the cDNA claims should be equally vulnerable to invalidation.

    Indeed, the informational nature of DNA—the extent to which it encodes a biological process—is arguably why the Court's initial intuition in Myriad was to remand it in light of Mayo.

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    The decision has other problematic features. Although the Court found cDNA patentable, it recognized that sometimes native sequences do not contain noncoding regions. Because detecting these special situations may not be easy and because science may someday identify a use for pseudogenes , these exceptions create an element of unpredictability for other gene-related patents. Even more worrisome is the difficulty in determining the patentability of other substances that are based on nature, such as venoms isolated from animals and used in research on alleviating pain, unmutated genes introduced into patients to stimulate the development of normal proteins, antibodies produced by rats and then treated so that they are close enough to human antibodies to withstand rejection, or proteins and kinases that are used in the development of therapies.

    Since the Court never explained why it ignored the cleaved bonds that were so important to Judge Lourie, it is not clear how far a synthetic molecule must depart from its naturally occurring analog to be considered patentable. The humanized rat antibody is one illustration of the difficulty; another is Dan Burk's example of a peptide nucleic acid, which is entirely artificial yet carries the same sequence information as DNA. Nor is it clear that the inventiveness of the synthesis will matter.

    They instruct examiners to determine whether claims are directed to a statutory category Step 1. From the new life-sciences examples that accompany the guidelines, it is clear that as far as the PTO is concerned, Step 2A is the more critical. The examples include two products derived directly from nature. The first Example 28, a vaccine comprises seven claims, six of which the PTO considers patent-eligible.

    Claim 30 a sweetener includes six claims. For diagnostics, the analysis is similar. While four of the seven claims in Example 29 diagnosis and treatment of a hypothetical disease are considered patent-eligible under Step 2B, still there are two claims in this example that pass muster because of Step 2A.

    Had the PTO considered Step 2B equally determinative, it would presumably have offered more examples of how to use it. The importance of Step 2A is even more evident in the Federal Circuit case law. Of the nearly cases listed by the PTO as of May 3, , only 10 can be classified as involving laws or products of nature. Of the cases involving abstract ideas, the patent holder prevailed in 10; seven because of Step 2A aka Step 1 , two on Step 2B; in the last case, there is considerable ambiguity and a dissent as to how the court decided the claims were statutory subject matter.

    Following Berkheimer , the PTO issued a memorandum that attempts to clarify the analysis. Whether the Supreme Court will approve this approach is an open question and the PTO has asked for public comments. Thus, in Ariosa Diagnostics, Inc. Although the test represents a major breakthrough in prenatal care, cffDNA is a natural phenomenon and so fails to meet the requirement of Step 2A. The diagnosis is a law of nature and therefore cannot save the invention under Step 2B.

    It is also possible that courts and the PTO are reluctant to rely heavily on Step 2B because that test may not serve anyone's purposes. However, if the treatment is not administered by the entity that conducted the diagnosis, then all the steps recited in the patent will not have been performed by the same party. Unless there is a close enough relationship among them to meet the test set out in Limelight Networks, Inc.

    In particular, allowing patentability to turn on a step that later becomes conventional will surely hamper future actors. Putting the emphasis on Step 2A may, however, actually make patent eligibility even harder to predict. In the case of abstractions the bulk of the Federal Circuit case law , a key problem is choosing the level of generality at which to describe the claim.

    For the law of nature cases, there is an analogous problem in that the analysis requires the identification of the law of nature. Whether the claim is markedly different depends on how the decision-maker conceptualizes the law. For example, the law in Mayo was about how a patient metabolizes a pharmaceutical. Since the drug was artificially introduced into the body, it is a law of nature only if that term is broadly conceived.

    In the abstraction cases, imprecision in the starting point of the analysis leads to the result that claims said to be improvements or enhancements are far more likely to be considered patent-eligible, for the focus on the improvement persuades the court that the advance is different from the underlying concept. Consider, for example, Rapid Litig. The trial court found the advance unpatentable because it was directed to the law of nature that hepatocytes are capable of surviving multiple freeze-thaw cycles. Yet it is unclear why the district court was wrong. Why is a better survival through double freezing not itself a law of nature?

    Aside from the predictability problem, this approach elevates the role of drafting, in direct contravention to one of the Supreme Court's concerns in Mayo. For claims to products, the issue is somewhat different. There, Step 2A requires a comparison between the claimed subject matter and material found in nature.

    That, in turn, requires the identification of a basis for the comparison. Although the Court ignored the covalent bonds that influenced Judge Lourie, it still followed his approach of comparing molecular compositions. In re Roslin , which involved the patentability of a cloned sheep, furnishes an example. In holding the sheep was not patentable subject matter because it was identical to a sheep found in nature, the court was unimpressed by differences in mitochondrial DNA or the effect of the environment on the cloned sheep's genotype and physical characteristics.

    In those cases, presumably every embodiment must be different from what occurs in nature, yet it is unlikely that every embodiment can be identified and compared to nature. There are also claims that are drawn to a combination of known elements: is it enough that the combination does not occur naturally, or must the combination also create functional differences in the final product? Thus, the cases do not always clearly differentiate between eligibility by reason of Step 2A or 2B. The bottom line is that it is now extremely difficult to know how to successfully protect advances in the life sciences.

    Kathy Liddell and her co-authors surveyed patent applications published between June and June which included at least one claim to a simple isolated gene sequence. They found that inventors have tried eight different prosecution strategies to differentiate their advances from phenomena of nature. For example, they found that examiners have allowed claims to nucleic acids that differ only slightly from those found in nature, giving the example of adding a fluorescent label.

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    In a sense, it is difficult to fathom how outcomes could be other than haphazard. That requires a theory for why a difference from nature is required at all. While it is clear that the Supreme Court became interested in the question of patentable subject matter out of a concern about inhibiting future innovation, that apprehension appears to have dropped out of the equation. In Myriad , Justice Thomas did not distinguish among claims that specified all the nucleotides in the sequence and those that included many unknown regions, even though Judge Bryson pointed out how much broader the latter claims were.

    Nor did he adopt Judge Moore's suggestion of thinking about long strands with no difference in functionality from nature differently from short strands, which had very articulable and possibly narrow functionalities. Most important, the Court never considered whether the artificiality of cDNA would make rights over it any less chilling of future research than rights over gDNA.

    The failure to consider preemption can be attributed directly to Mayo , where the Court conceded that the law of nature at issue in the case—the relationship between a metabolite of a drug and the appropriate dose of that drug—was extremely narrow and had limited application. Indeed, some judges on the Federal Circuit appear to be approaching the problem this way. Judges Bryson and Moore offered a few clues, as has one of us in previous work. GTG had threatened to enforce the relevant patent against public testing laboratories during and again during The challenge to Patent , was directed to three disputed claims of the 30 total in the patent , which included claims to isolated gDNA, and cDNA coding for identified mutations or polymorphisms.

    The practice of the Australian Patent Office was that isolating DNA sequences from their natural environment was enough to make them patentable subject matter. The Australian Patents Act is one of very few patent statutes to retain this requirement from the first patent statute in the common law. Its inclusion signifies broad judicial discretion to determine whether an invention is within the bounds of patentable subject matter.

    At first instance, Justice Nicholas in the Federal Court of Australia upheld the validity of the disputed claims. His Honor found that the claims in question were to isolated nucleic acids gDNA , and that this isolated gDNA and its counterpart cDNA were structurally different to naturally occurring sequences. Justices Dowsett, Kenny, Bennett, and Middleton held that the isolated product was not only structurally different, but also functionally different to the naturally occurring product.

    Although unanimously holding that the claims in question did not fall within the concept of patentable subject matter, the High Court gave three separate judgments. The plurality returned attention to the NRDC formulation, reiterating that it is not a rigid test. Because the claimed invention fell into what it regarded as a new class of subject matter, the plurality expounded a nonexhaustive list of factors to be taken into consideration: whether patentability would be consistent with the purposes of the Act and, in particular: 1.

    Of these factors, the plurality considered 3, 4, and 6 to be of primary importance. In Cargill Incorporated v Dow Agro Sciences LLC , the patent eligibility of a fungal sequence was confirmed on the basis that the inventors had codon-optimized the sequence, differentiating it from the naturally occurring sequence. Instead, the substance of the invention was a pharmaceutical composition comprising interfering RNA because the particular nucleotide sequences claimed were not critical to the invention, rather the capacity provided by the invention to identify specific target sequences was.

    Finally, in Sun Pharmaceuticals v Tasmanian Alkaloids , the relevant patent claimed the mutagenesis of poppy seeds and screening of progeny plants to produce poppies with a higher output of codeine over other alkaloids. The Patent Office Delegate found no evidence that a mutation producing levels of codeine in line with those claimed in the patent had or would be naturally occurring.

    What this indicates is that it is likely that the factorial approach will only be applied in the rarest of circumstances, for significant new innovations.

    While the lower courts could derive some real benefit from the guidance provided by the High Court in terms of the range of factors to consider in such circumstances, it is disappointing that their opportunities to do so will be so limited. It is even more disappointing that when opportunities have arisen on the boundaries of patent eligibility, there has been some reluctance to engage with them. In this case Myriad failed to establish patentability, but in cases where a finding of patentability remains open, a finding that a new class of claim is implicated is likely, and presumably, the factorial approach would then be applied.

    The plurality's factorial approach effectively legitimizes the approach Australian courts had implicitly taken with respect to determining questions of patentability in areas of new technology. Unlike the Supreme Court in Mayo , the Australian High Court has not yet been given the opportunity to engage with the question of whether methods of diagnostic testing are patentable.

    It has been recognized that diagnostic method claims are capable of producing a greater blocking effect on diagnostic testing than nucleotide sequence claims. But Australia does appear to be having its Mayo moment. These included the argument that the claims failed to satisfy the manner of manufacture test, in that they were drawn to include known methods of identifying bovine traits, and involved DNA sequences that were either not identified or were yet to be identified.

    Servicios Personalizados

    In addition, because the inventors created a high-density map of the bovine genome using variants of specific SNPs and associations that were naturally occurring, MLA asserted a lack of patentable subject matter on the basis that there was nothing man-made or artificially occurring. The case was heard by Justice Jonathan Beach, who brings with him a tertiary education in physical chemistry as well as experience from the bar in intellectual property litigation.

    It also offered little assistance on the question at issue in Cargill , which involved broad methods of identifying bovine traits. Cargill did not involve an assessment of the applicability or otherwise of Mayo. On this point, he found that the claims were not only too broad, but also lacked clarity and were poorly defined, and on this basis he instructed the parties to amend the patent application. It seems a foregone conclusion that the decision will be appealed. It is not difficult to envisage the grounds of appeal focusing on whether the claims in the case can truly be dealt with as methods, despite the characterization of them as such.

    Even if the claims are appropriately classified as method claims, there is a real question as to whether they involve more than the discovery of associations with naturally occurring traits. On this basis, we should expect to see further jurisprudence dealing with this vexed question in the not too distant future. First, is this a policy-driven approach to the assessment of patentability for cases on or beyond the existing boundaries? Second, is this approach properly characterised as purposive or consequentialist or both?

    Third, is there a clear threshold to justify moving into such a space, and if so, what? In some cases reasonable minds might differ as to whether a case is within or without existing boundaries. Fourth, has the plurality just been more transparent about the considerations to be taken into account in assessing whether new or difficult subject matter is a proper subject matter for the grant of letters patent.

    Fifth and further, various issues concerning the priority ranking and weighting to be given to these factors remain to be explored. This approach furnishes an analytical technique that avoids the problems in the two-step Mayo test of determining when a difference is marked, deciding what constitutes significantly more, and finding an inventive concept.

    He did so in three ways. In US parlance, he required the applicant to supply more information under the rubrics of enablement and distinct claiming. Second, to the extent Justice Beach saw himself as dealing with an area where patenting is new—areas where early insights are likely to be fundamental and where rights could, in Justice Breyer's words, impede rather than promote progress—Justice Beach considered the factorial test. He was able to use this approach to look directly at the problem of chilling future innovation instead of, as in CellzDirect , peeking at preemption after struggling with a test that is difficult to apply, not well correlated with the concern, and easily influenced by how a claim is drafted.

    As we will argue later, identifying these borderline cases can also be useful to determine the scope of defenses, should the patent be enforced. In some ways this approach is similar to the suggestion made by Dennis Crouch and Robert Merges that subject matter eligibility should be considered only after other criteria for patentability are evaluated.

    Third, Justice Beach appreciated the difference between attempts to privatize pure communicative material or as the courts call it, information , by claiming the medium in which it is embedded, as opposed to a concrete implementation of that material in a way that can improve social welfare.

    This is illustrated by the way that he dealt with the two product claims in issue in Cargill , a claim to an isolated DNA sequence claim 13 and a claim to a cloned bovine claim 11 , both resulting from methods also claimed in the patent. He did not stop with the similarities between the clone and its mother, as the Federal Circuit did in Roslin , nor did he attempt to decide whether differences in epigenetics or mitochondria were marked or significant enough.

    Instead he reasoned: Now of course the cloned cow in one sense is the same as that which it clones. The submission has a superficial allure, but I reject it. An artificial object of economic significance is produced for its own sake, not merely as a receptacle for its informational content. To be sure, much as this approach presents a valuable way to preserve patentability in areas where incentives are important and concerns around exclusivity are not paramount, it would be somewhat difficult to reconcile with the Supreme Court's pronouncements. But as noted earlier, the distinction Justice Thomas drew in Myriad between man-made and artificial is not as sharp as he maintained.

    As Judge Lourie argued, isolated gDNA involves broken bonds and is thus somewhat artificial especially when the claimed fragments possess the sorts of functions Judge Moore described. At the same time, when it is only the exons coding sequences that matter, cDNA cannot be considered man-made.

    The Landscape of Public Participation on Biotechnology

    In short, supplementary factors will always be necessary to separate patentable and unpatentable subject matter—arguably, that is why the PTO, the Federal Circuit, and the Alice Court ignored the Myriad Court's failure to cite Mayo and instead have relied on its two-step analysis for all subject matter challenges.

    In the February 2, Speech from the Throne which officially opens every. We must apply more of our research and science to help address the most pressing problems of developing countries. Most experts consider biodefense a relatively minor economic driver of biotechnology. As an example of how terrorism-conscious thinking pervades national dialogue even outside the United States, those who are involved with establishing the new national genomics medicine platform in Mexico are aware that such a platform will serve a dual biodefense role see Chapter 2 for details.

    In other words, if genome-specific medicines can be made specifically for use in the ethnically diverse Mexican population, so too can genome-specific bioweapon or bioterrorist agents. Even though biodefense efforts may not greatly impact the absolute growth and spread of technology, they could pose disproportionately greater dual-use risks. For example, a question was raised about whether a greater investment in biodefense might increase the dual-use risk posed by knowledgeable, skilled insiders.

    A question was asked regarding the dual-use potential of agricultural transgenic technology and whether any U. In response, it was mentioned that the USDA recently called for proposals but that only a trivial amount of money was dedicated to the consideration of plant pathogens as biothreats. A similar concern was expressed about plant-based vaccines: if plants can be used as delivery vehicles for vaccines, might they not also. This section summarized comments made by individual workshop participants throughout the course of the workshop.

    Project BioShield. A recent experiment generating considerable attention along these lines involved the engineered expression of insecticidal viruses by plants, in order to kill insect predators that happen upon the plant. No specific cases were mentioned. Along the same lines, concern was expressed that the limited entry of foreign nationals into U. There was concern regarding how the current focus on bioterrorism in the United States may be impacting, perhaps worsening, the general public perception of biotechnology. Does the bioterrorist backdrop make it more difficult to convince people that these products are safe to eat or use?

    For example, technical breakthroughs in the area of rapid diagnostics not only will strengthen biodefense capabilities but may benefit public health generally i. It was noted that the information technology industry was initially a non-commercial endeavor started by the military but was then quickly and ultimately driven by commercial demands. A question was raised about whether the degree to which concern about bioterrorism drives biotechnology investment in Singapore in. Ranjekar, P. Patankar, V. Gupta, R. Bhatnagar, J. Bentur, and P. For example, the CDC-identified category B biological agent Burkholderia pseudomallei is not viewed as a high priority agent of concern by Singaporean authorities, given the ubiquity of this bacterium in the local natural environment.

    In general, naturally occurring emerging infectious diseases are generally considered a greater threat to national security than bioterrorism. For example, because of its strong domestic DNA sequencing and other relevant technology capacities, Singapore was able to contribute to the global SARS response by genetically profiling a number of different viral isolates. The same capabilities could be used in the event of a bioterrorist attack.

    In addition to the more immediate threat posed by naturally emerging pathogens, there is a general sense that chemical e. Singapore has also acknowledged the existence of a black market in the trafficking in these terrorist tools and the difficulty in curtailing the spread of established dual-use agents and advancing technologies. However, the chance that a bioterrorist attack could happen is definitely on the table.

    In April , for example, an outbreak of melioidosis that killed 15 people prompted a genotyping effort to determine whether the strains originated from a single source or a variety of sources, the latter an indication of natural emergence. Generally, even outside the context of the changing global climate with respect to terrorism, Singapore security is very tight; everyone is screened, public institutes require card-key access, and the military has very strict entry guidelines.

    Although bioweapons programs are illegal in accordance with the Biological Weapons Convention, 30 some experts nonetheless consider them a driver of the global proliferation of dual-use agents, knowledge, and technology. There is concern that as the means to acquire or engineer. Some believe that this may already be occurring under the cover of defensive weapons research. The fact that South African troops had been exposed to biowarfare agents in both World Wars, coupled with being privy to British bioweapons secrets, motivated the country to devote resource towards bioweapons research and training and, ultimately, Project Coast.

    In , South Africa dismantled Project Coast, along with its ballistic missile and nuclear weapons programs. But the extent of Project Coast was not publicly known until , when the Truth and Reconciliation Commission hearings coerced many scientists to disclose their involvement with the Project in order to gain immunity. The now transparent history serves as a horrific example of how science can be subverted to undermine entire communities and how scientists can be persuaded to participate in the proclaimed national interest.

    At the time of the Project, research conducted for the sake of the national interest was considered the most important research in the country. At the workshop, three dual-use technologies allegedly produced under the auspices of Project Coast were described:. Up to as many as 45 Bacillus anthracis strains, including a penicillin-resistant strain, were bio-engineered.

    There are disputed claims that South Africa may have played a role in the anthrax epidemic in Zimbabwe formerly Rhodesia , which killed more than 80 people and injured thousands although this occurred before the formal creation of Project Coast. Burgess, S. There is no proof that race-targeting bacterial bioweapons were actually produced, but significant sums of money were spent on the effort and the intent existed. Acquisition of a peptide synthesizer was ostensibly for the purposes of AIDS research, but court testimony indicated that the synthesizer was in fact being used for research on behavior-changing peptides absorbed through the nasal mucus membranes e.

    Although South Africa has dismantled Project Coast and its other weapons programs, and post-apartheid legislative initiatives address the need to regulate dual-use technologies with WMD potential, it is interesting to note that the Non-Proliferation Council does not fall under the Ministry of Defense, presumably because of the realization that such technologies have commercial use.

    As recommended by the international community, the South African government has attempted to keep many of these experts employed under its watch rather than have them take their expertise elsewhere. Based on feedback from you, our users, we've made some improvements that make it easier than ever to read thousands of publications on our website. Jump up to the previous page or down to the next one. Also, you can type in a page number and press Enter to go directly to that page in the book.

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    Stay Connected! Enabling Technologies. Patient- and genome-specific drugs. Gene chips, biomedical databases, computing. Alternative routes for drug administration. Nanotechnology, aerosol technology. Automatic analysis of genomic tests. Biomedical and genome databases, nanotechnology.

    Identify and treat defective genes.