What is CRISPR?

Some scientists believe the design and development of new biomolecules is as much an art as it is science. The  discussed, and used, by Dr. Pearlman capitalizes on an adaptive immunity system found naturally in bacteria and archaea that uses clustered, regularly interspaced short palindromic repeat (CRISPER) DNA segments to fend off invading viruses. In naturally adapting to a virus invading the cell, CRISPR associated proteins (Cas proteins) will create a spacer unit of genetic code that is unique to the invading virus and incorporate this spacer into the CRISPR region of the cell’s genome. This unique spacer unit will then be transcribed (that is, converted from double stranded DNA to RNA), associate with Cas proteins to form a functional complex, and then target and inactivate the very same type of virus that led to the creation of the spacer unit.

In the laboratory, genome editing uses the functional complex found in this adaptive immunity mechanism to insert or remove genetic code from the genome of a cell. By attaching a synthetic, guiding portion of RNA (sgRNA) to Cas proteins they can be directed to a portion of the genome, through complimentary base pairing with the sgRNA, where Cas will recognize a portion of the genome and cut it to either insert a new region or to remove a portion and disrupt the expression of a gene. By cutting out sections of DNA a gene can be disrupted and lose its functional expression in the cell. In other words, it will no longer be able to produce the molecular products responsible for its former physical trait. By inserting new regions of DNA, the genome can be expanded to confer resistance to invading pathogens, such as viruses, or to express new protein products that can add or enhance the cell’s function. For example, a new portion of DNA may be inserted that codes for a digestive protein not normally found in the cell and, consequently, grant a new molecular digestive mechanism.

What does Genome Editing have to do with Law?

Dr. Pearlman noted that there has been an explosion of scientific literature covering the CRISPR system of genome editing since 2010 and it appears that the momentum will only grow in the coming years. The ability to edit genomes can allow for the expression of new protein products that can be of great commercial value as well as pave the way for new medical treatments that circumvent traditional pharmaceuticals. Additionally, Dr. Pearlman noted that the CRISPR system can be used to produce heritable traits – that is, changes that can be transferred from a parent to their offspring. With this sort of molecular modification becoming more pragmatic, it becomes paramount to have a thorough understanding of the biochemical expression pathways that govern genomic expression to keep an eye on the ethical implications of modification. If human genome editing were to become available, should those with advantageous genomic modifications be treated differently by public health systems? To whom should these technologies be made available, if ever? These questions are beyond the scope of current genomic technology but, with the growing pace of CRISPR methodologies, designs may soon start to reach more readily into the macroscopic domain.

What Makes Scientific Designs Different?

With the cost of biochemical research and development increasing and a billion-dollar entry fee for the drug and biomolecular development market it follows that when an industrially relevant molecule is finally created the developer should be able to recuperate their investment and benefit from their work. Normally, the boundaries of property rights require contextual understanding: what is the nature of comparable products, if the new product’s design is generic or obvious, and if the new product can have a place in its intended market. The differentiating criteria of the sciences become pronounced when considering the esoteric nature of the discipline. How can one reasonably expect a thorough consideration of the distinguishing criteria for obscure scientific concepts, like base pair fidelity, when the requisite knowledge is held only by a few people, like Dr. Pearlman, who have committed years, if not decades, to the study? The nuanced nature of genetics can make innovations in genome editing or CRISPR technology appear to be near imitation; however, the modification of a single nucleotide in the genetic code can have a profound impact on the success and possible application of a biotechnology.

Synthesis, Structure, and Industry

What amount of scientific knowledge is sufficient in legal practice? that a special breed of IP lawyer will arise to confront the high demands of contemporary science and technology patents. Considering the high financial stakes and the significant likelihood that a new molecule or molecular technique will fail the requisite safety tests at any of a multitude of stages, a lot of designs are left in the laboratory. A re-engineering of the approach or scrapping the project in its entirety may follow, meaning product patents should not be initiated until after the molecule has been proven safe for its regular use instead of when it is first designed or synthesized in the lab. Additionally, research and development can indirectly prioritize self-benefit over scientific collaboration since scientists rely on design details to learn about their ever-developing field and most details are kept secret until after a patent has been granted.

This is where innovation becomes conservative and structure becomes especially important. Does a single elemental substitution in the genetic code constitute a new product if the application remains the same? What about changing a single gene to modify a physical characteristic that relies on multiple genes? While certain business practices, such as non-competition deals, are commonly found outside of the sciences, unique can arise from small chemical modifications which effectively extend a patent beyond its expiry date through the issuing of a new patent for a highly similar molecule. Furthermore, patents may be sought for generic parts of biotechnology procedures that are nonessential to its action, prohibiting competitors from including strategies in their approach and significantly , or even demolishing, a competing synthesis. Lastly, meeting the testing and safety demands of different communities poses an for introduction into a global market due to different national regulatory standards.

So, What Makes It My Molecule?

The same fundamental concepts that apply to patents outside of genome engineering also apply to those inside the discipline but with a stringent demand to understand the nuances of molecular design. An integration of mechanistic knowledge may prove to be key when evaluating possible distinguishing criteria among patents filed for similar compounds but it is ultimately up to practicing lawyers to integrate sufficient scientific knowledge to accurately capture the scope of their client’s designs.

Dominic Cerilli is the Content Editor for the IPilogue and a JD Candidate at Osgoode Hall Law School.

[1] Dr. Pearlman's talk was organized by The 91��ɫ Collegium for Practical Ethics and The 91��ɫ Centre for Public Policy and Law under the leadership of Ian Stedman.  Support for the event was provided by IP Osgoode, McLaughlin College, 91��ɫ - Faculty of Health, 91��ɫ - Faculty of Science, and 91��ɫ's Office of the VPRI.

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On November 2, 2011, the United Kingdom Supreme Court (UKSC) in ¹ unanimously reversed the lower court’s decision that Human Genome Sciences (“HGS”) Neutrokine-α was invalid as it lacked industrial application. Thus bringing UK law in line with the European Patent Office’s (EPO) interpretation of industrial applicability.

The five judges of the UKSC ruled that Article 57 of the European Patent Convention (EPC) does not require that patent application for new genes go as far as providing clinical tests as proof of industrial application.

Article 57 of the EPC states that: “An invention shall be considered as susceptible of industrial application if it can be made or used in any kind of industry, including agriculture.”² It is part of the UK and EPC’s utility requirement.

Lord Neuberger wrote the main judgment for the panel of five justices.

Background

In 1996, HGS filed for a patent for Neutrokine-α, which was granted by the EPO in August 2005. Neutrokine-α is a novel human protein and a member of the TNF ligand superfamily of cytokines (proteins that act as inter-cellular mediators in inflammation and other immune responses). The specification in the patent included the encoding nucleotide, the amino acid sequence and certain anti-bodies of Neutrokine-α; it included contentions as to its biological properties and therapeutic activities along with those of its anti-bodies. The contentions were predictions that were substantially based on the proposition that Neutrokine-α is a member of the TNF ligand superfamily. However, nowhere in the Patent was there any data or suggestions of in vitro or in vivo studies. Bioinformatics assays were the basis of its predictions rather than wet lab tests.

After the Patent was granted to HGS, it became the subject of opposition proceedings brought by Eli Lilly (“Lilly”) at the EPO.  After the hearing at the Opposition Division (OD) of the EPO in June 2008, the Patent was revoked. HGS appealed to the EPO Boards of Appeal which allowed the appeal, referring the case back to the OD with the direction that the Patent be maintained.

Lilly also brought parallel proceedings in the UK at the High Court for revocation of the Patent in its jurisdiction. The proceeding was heard by Kitichin J, he revoked the patent based on the conclusion that, (described by Lord Neuberger in summary terms at para 31) in light of the common general knowledge, the notional addressee of the Patent would have concluded that the “functions” of Neutrokine-α “were, at best, a matter of expectation and then at far too high level of generality to constitute a sound or concrete basis for anything except a research project”. HGS appealed this decision at the Court of Appeal. The court dismissed HGS’s appeal, following and approving Kitchin J’s approach.  This ruling by the UKSC was based on an appeal by HGS against the Court of Appeal’s decision.

The Decision

The decision had three main threads of analysis:

a) Consistent Approach: National Courts vs. the EPO

The Supreme Court found that while there is “room for dialogue between the national court and the EPO” and that national courts are free to come to different outcomes than the EPO, the principles behind such decisions must be the same, they must stem from the EPC. The court found that where the EPO has adopted a consistent approach to an issue in a number of decisions, a national court should only rule differently when there are “very uncertain facts to justify” it. The court found that the Technical Board had ruled consistently in its application of Rule 57 to patents for biological material and that there was “little helpful domestic guidance” in the UK on this issue. Therefore, the Court of Appeal and the lower court were wrong in not following EPO’s approach.

b) Wider Policy Concerns

But in making this decision, the court appeared hesitant to overturn the two lower courts ruling, especially since they were consistent with each other, and two patent specialists gave the ruling with extensive trial evidence before them.³ The UKSC’s approach was based on two “strong” policy arguments. Lord Walker elaborates at para 171 that:

The first is to reduce the risk of a chilling effect on investment in bioscience (though here the arguments are certainly not all one way). The other is to align this country's interpretation of the European Patent Convention more closely with that of other contracting states. To my mind these considerations justify this Court in taking what would otherwise be a questionable course.

The court also seemed to agree with the submissions of the BioIndustry Association (BIA), who were interveners in the case. The BIA had argued that it is important that the law is clear and certain in its application of Article 57. The court agreed, especially since it is important for bioscience companies to decide when they need to file for patent protection.  Lord Neuberger outlines why the Court of Appeal’s approach would be a detriment to UK’s bioscience sector. At Para 100-101, Lord Neuberger points out that:

For obvious reasons, the BIA has not set out to support either of the two parties to this appeal in its trenchant written submissions in these proceedings. However, it does suggest that if we agree with the reasoning of the Court of Appeal there is at least a risk that it will "make it appreciably harder for patentees to satisfy the requirement of industrial applicability in future cases." If that were so, it is suggested that this "would cause UK bioscience companies great difficulty in attracting investment at an early stage in the research and development process".

This consequence is said to arise from the reasoning of the Court of Appeal (and hence of Kitchin J), on the basis that there will normally be a need to conduct tests to provide experimental data to establish to the standard they require that a protein (or its antagonists) have therapeutic use. This in turn is said to lead to two problems. First, such tests will or may involve clinical work, which, as I understand it, would be hard to keep confidential, especially in the age of the internet. Secondly, such tests would often be expensive to run, and, as already mentioned, funding would be hard to obtain for a project of this sort which had no protection in the form of a patent application.

c) Standard for “Industrial Applicability”

At Para 108, the court summarizes the Board’s approach in relation to the requirements of Article 57 in relation to biological material. The court held that the industrial application requirement was met because Neutrokine-α was a member of a TNF ligand superfamily and that all the members of the family were associated with important immune response related activity. Lord Neuberger at Para 111 agreeing with the Boards conclusion states that:

The Board's conclusion was effectively this, that the disclosure of what was accepted to be a new member of the TNF ligand superfamily (coupled with details of its tissue distribution) satisfied Article 57, because all known members were expressed on T-cells and were able to co-stimulate T-cell proliferation, and therefore Neutrokine-α would be expected to have a similar function.

The court counters the lower courts argument that the basis for HGS’s patent is “speculative and did not give rise to an immediate concrete benefit”.  Lord Neuberger responds by saying that if a statement “is indeed plausible, then, in the absence of any reason to the contrary, it at least prima facie satisfies the requirements of Article 57 according to the Board”.  He goes on to say that:

I appreciate that the dividing line between "plausibility" and "educated guess", as against "speculation", just like the contrast between "a real as opposed to a purely theoretical possibility of exploitation", can be difficult to discern in terms of language and application, and is a point on which tribunals could often differ... However, as a result of the decisions discussed above, the Board's approach to patents such as that in this case is, I believe, tolerably clear.

The court found that the lower courts were mistaken in interpreting what “immediate concrete benefit means” and that it is enough if the Patent satisfies requirements outlined in its summary of the Board’s case law.

Lord Hope also finds that the Court of Appeal was setting as onerous standard, he states at Para 151 that:

I think that there are indications in these passages that the standard which Jacob LJ was setting for susceptibility to industrial application was a more exacting one than that used by the TBA.

He found that the Board’s approach to industrial application was the use of the molecule for research was sufficient in itself as an industrial activity (Para 155). The court adopted this lower standard on the principle that biotechnology investments should be encouraged in the UK.

Impact on Canada

The case demonstrates that there is a clear functional parallel between the European requirement of “industrial application” and the Canadian utility requirement, which means that Canadian courts and the Patent office can look at UK and EPO jurisprudence on the issue of utility.⁴ But on the point of how far long before a patent should be granted, the Canadian doctrine of Sound Prediction makes it difficult to directly apply European case law on the point, as they don’t have this doctrine.⁵ While harmonizing with EPO law is not a priority for Canadian courts, Professor Siebrasse in his blog points out that “consistency with the law of other jurisdictions is important in light of the practical reality that Canada is effectively just one part of a world-wide patent system”.⁶ Therefore he contends that the principles set out in this case deserve to be seriously looked at in Canada especially on the point of whether patents claiming a new protein and encoding gene satisfy the utility requirement.

Conclusion

The court on the main issue found that HGS’s patent satisfied the requirement of Article 57.  The court also dismissed Lilly’s cross appeal on the insufficiency issue. The case will now be sent back to the Court of Appeal to deal with other outstanding issues.

¹ Human Genome Sciences Inc. v. Eli Lilly and Company, .
² The European Patent Convention, online: <>
³ James Nurton, “Analysis: Why the Supreme Court Overturned Two Patent Specialists” (2011) Managing Intellectual Property Patents.
⁴ Norman Siebrasse, “What does HGS v. Eli Lilly mean for Canada?” Sufficient Description (November 2011), online:  <>
⁵ Ibid.
⁶ Supra note 4.

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In the , the flood of computationally predicted genes has introduced a new challenge for the patent system: How much does a gene patent have to disclose to satisfy the “useful” requirement for patentability? In Human Genome Sciences Inc v Eli Lilly & Co, , the United Kingdom Supreme Court (UKSC) unanimously held that a patent for a gene sequence, without having done any concrete functional experiments, is a valid patent. The decision has significant implications on the scope of disclosure for gene patents and gives rise to far-reaching consequences in the scientific and biotechnology industry.

Background and Facts

Based on bioinformatics, scientists at the Human Genome Sciences (“HGS”) discovered a novel gene called Neutrokine-α and predicted it to be a member of the TNF ligand superfamily. The patent, which was granted by the European Patent Office (EPO) in 2005, claims the nucleotide of Neutrokine-α, the amino acid sequence and its antibodies, which might be useful for the diagnosis or treatment of an extraordinarily large range of immune disorders. However, there is no experimental data to support these suggestions.

Eli Lilly opposed the patent, arguing that the patent did not disclose a practical way of exploiting the gene. , Eli Lilly has already spent $50 million on the development of an antibody to Neutrokine-α and plan on spending another $250 million in clinical trials.

Judicial History

The Opposition Division of the EPO revoked the patent on the basis that the invention did not have a known function. The Technical Board of Appeal held that the patent was valid because a person skilled in the art would have appreciated the general knowledge of the TNF ligand superfamily.

Eli Lilly brought parallel proceedings in the UK Patents Court for revocation of the patent. At the Mr. Justice Kitchin stated that the specification “contains extravagant and sometimes contradictory claims” and struck down the patent. The also invalidated the patent, asserting that “however clever and inventive you may have been in discovering a gene sequence, you cannot have a patent for it or for the protein for which it encodes if you do not disclose how it can be used.”

Issue on Appeal

The primary issue is whether the requirement of industrial applicability in Articles 52 and 57 of the (“EPC”) extends to a patent for biological material. To satisfy the requirement of industrial applicability, the invention must be made or used in an industry.

UK Supreme Court Decision

The UKSC unanimously held that the patent satisfied the requirement of industrial application. Lord Neuberger, penning the leading decision, based his reasons on the policy argument advanced by the BioIndustry Association (BIA) and a desire to be consistent with the EPO jurisprudence.

The BIA, which is an association representing the bioscience sector with an aggregate turnover of £5.5 billion in 2010, intervened as a neutral party. It submitted that following the Court of Appeal decision will “make it appreciably harder” to satisfy the patentability requirement in the future, and will cause the “UK bioscience companies great difficulty in attracting investment at an early stage in the research and development process.”

Even though Lord Neuberger recognized that “it would be undesirable to have a monopoly over a particular biological molecular too early, because it risks closing down competition”, His Lordship ultimately agreed with BIA’s submission and said that “it would be wrong to set the hurdle for patentability too high.”

Next, Lord Neuberger made an effort to align UK patent law “so far as possible” with the EPO jurisprudence. Even though the UK Court of Appeal held, and Eli Lilly argued, that the Board’s decisions should carry less weight because the proceedings were unopposed and without cross-examination, Lord Neuberger rejected the argument and stated that the Board has applied its principle consistently. After reviewing the Board’s approach to Article 57 in relation to biological material, Lord Neuberger stated, among other things, that a “plausible” or “reasonably credible” claimed use, or an “educated guess” on biological function can suffice even without any experimental or wet lab evidence. Since the newly discovered gene belongs to the well-known TNF ligand superfamily, where its members share many common features, finding this new member will have great value and the “educated guess” made in the patent application is plausible. Therefore, the gene patent is held to be valid.

Comments

Whole genome sequencing projects have inundated the bioinformatics world with a vast amount of data. It is expected that the rate of gene discovery will continue to accelerate; yet these newly discovered genes would not be very useful until further functional or therapeutic research is performed. However, allowing a monopoly on gene sequence will reserve this unexplored territory for the patentee, thereby hindering research in the community. The anti-competitive effect may also undermine the quality of experimental data. Without good biomedical research, human health may suffer.

Further, the patent gives the patentee over others who have been actively investigating in the field. For instance, researchers who have worked on the TNF ligand superfamily for years may now have to pay a licensing fee for including the patented gene in a routine experiment. Rather than promoting innovation, this unfair arrangement may become an impediment to scientific progress.

A policy goal of the patent system is to encourage others to perform fair research and make improvements on the patented invention during the monopoly period. However, given the broad patent claims in a gene patent, the line between fair research and patent infringement is blurred. For example, if others discover a genetic variant of the patented gene, it is unclear whether the finding is a patent infringement or not. Such uncertainty in law will inevitably lead to an increased number of patent infringement litigations in the future.

Given that bioinformatics is becoming an increasingly popular method to draw predictions on the function of a gene, and that this is a UKSC decision that many will follow, the trend of gene patenting based on computational predictions will probably continue. Therefore, it is imperative to devise a solution to preserve the quality of granted patents and to prevent clogging up the patent office with unmerited applications.

One possible solution is to set a high threshold of reliability for computationally derived data and grant patents only to those with sufficient accuracy. If computational methods become highly accurate and predicted the function of the gene with 99% accuracy, such gene patents should be allowed. On the other hand, if the prediction has 50% accuracy, then the gene should not deserve patent protection. Setting a clear benchmark will prevent patent applicants from wasting effort to file for patent protection. Until such highly accurate bioinformatics methods become available, a higher standard of disclosure should be required for computationally derived gene patents.

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