GENE PATENTING: REVISITING FUNDAMENTALS
"One-Fifth of Human Genes Patented", beams the headline of a leading popular science magazine. We never heard of patents on flowers or fireflies pre-empting others from studying those beautiful things of nature. Does patenting of genes mean that a small group of people are out to claim ownership of what is undeniably our collective "natural heritage"? What is this surge towards gene patenting, and why is it even being allowed under the law?
The furor about gene patenting calls for creating fundamental clarity about the patenting system, and how it actually promotes innovation. Scientists and business personnel not possessing intimate knowledge of patent law must not panic. The purpose of this article is to mitigate the chilling effect of such popular science headlines on bioresearch, and to dispel the myths surrounding gene patenting.
You can't patent genes as much as you can't patent the moon and the planets.
A gene - as it exists in nature - is not patentable. "A thing occurring in nature, which is substantially unaltered" is not patentable, see MPEP § 706.03 (a). What is patentable, though, is a product of nature significantly altered by mankind – a "non-naturally occurring manufacture or composition of matter" (35 U.S.C. § 101, MPEP § 2105).
A landmark precedent for biotechnological innovations was set in Diamond v. Chakraborty, where a patent claim on "a new bacterium with markedly different characteristics from any found in nature and one having the potential for significant utility" was deemed patentable subject matter. That patenting in biotechnology is fundamentally no different from that in other domains became clear then onwards. A biologically pure culture of a single microorganism extracted from its soil milieu constitutes patentable subject matter – because in nature it does not exist as "biologically pure", and because man invested effort in creating it. A protein isolated from tissue and purified to a high degree constitutes patentable subject matter. A gene isolated from the genome makes patentable subject matter. "Gene patenting" is a loosely used term – as one does not patent a gene or a nucleic acid sequence per se, but a non-naturally occurring man-made form of it.
A concept that should be understood at the outset is:
By patenting isolated and purified nucleic acid sequences (or genetically modified organisms), a patentee does not claim ownership of the natural world.
Such media headlines are misleading, and affect the public perception of biotechnology research and business entities. Nature's pristine beauty and abundance are in no way being encroached upon.
Then what exactly is being patented here, and why is it so important?
The cardinal importance of nucleic acids in biosciences research :
Almost all biotechnological pursuits involve nucleic acids in some ways or the other. That is a given. These have central importance in research simply because they are at the helm of biological activity! (No wonder some people compare playing around with genes to playing God.) For the purposes of the present article, we'll touch upon a few therapeutic applications of nucleic acids that are under research: gene-based diagnoses and microarrays.
Genes are sentient entities. They "express" themselves. They respond to external stimuli – they get "turned on" or "turned off" (to various degrees), or they remain stolid. What this means is that inside a living cell, several series of biochemical reactions go up or down in response to a stimulus). Scientists use precisely this property of genes, tinkering with them in the lab and observing how their behavior changes in response to drugs. Here is the catch: the signals that normal tissue genes provide are different from those of, say, cancerous cells. Therefore, scientists play around with gene expression trying to find drugs that modulate the "aberrant" genes of the diseased cells. For this purpose, they utilize nucleic acid fragments in the lab.
Towards the goal of individualized therapy, scientists are trying to develop targeted disease mediation using each person's unique patterns of gene expression, for e.g., see Moving Towards Individualized Medicine with Pharmacogenomics. Biotechnology may be an arduous activity, but therapy tailored for each person is no longer a utopian goal. It would be a day of triumph when we get gene-targeted drugs to the clinic for complicated diseases such as tuberculosis and depression.
Herceptin is perhaps the best example of targeted personalized medicine. HER2 is the name of a gene that has a role in cell proliferation. Over-amplification of the HER2 gene is observed in nearly 30 % of early-stage breast cancers; see Molecular Targets for Breast Cancer Therapy and Prevention. Herceptin is provided as therapy to patients in whom HER2 over-amplification is observed. Since Genentech came up with this drug in 1998, numerous therapeutic advantages have come to the fore. For a complete story of the drug, see the book Her-2: The Making of Herceptin, a Revolutionary Treatment for Breast Cancer. HER2 over-amplification is the cause, and a majority of the diagnostic assays rely on using the HER2 gene fragments in the lab.
Similarly, research on delivering correct copies of genes to replace the existing disease-causing ones – gene therapy – makes use of gene fragments in the lab. Development of cells that can produce therapeutic protein drugs called biologics or biopharmaceuticals involves the use of gene fragments in the lab. The list of uses that gene segments are put to in the lab is very long.
All this research is for the greater good of mankind. Therefore, we need an inventor-friendly system that incentivizes biotechnology research, and which ensures that the world also benefits adequately out of it. Here is how the patenting system is designed to do so.
The patenting system is here to ensure a quid pro quo.
- Utility - To get a patent, specific and substantial utility is the "benchmark" for the scientist.
Patents are granted to inventions which have some utility (see 35 U.S.C. § 101). After all, the quid pro quo behind the patenting system is that the inventor discloses, among other things, the utility of her invention, and in return gets exclusive rights under the patent. The public may thereby benefit from the disclosed invention. Patents are not granted to inventions that have no "immediate benefit to mankind", see (
An illustrative example in this case is Fisher's patent application (serial No. 09/619,643). The patent application claimed five ESTs. However, the functions of the genes represented by the ESTs were not known at that time. The benefit of, say, detecting polymorphisms in these genes or looking at their differential expression, was merely contemplative. The application was rejected based on lack of utility as further research would have been necessary to identify or confirm their utilities (see In re Fisher).
For a detailed description of the guidelines used to evaluate the utility requirement in patent applications, please see MPEP 2107 and Revised Interim Utility Guidelines Training Materials.
The bottomline is:
No patent can be obtained for a nucleic acid fragment that you could isolate, purify, and sequence, unless you have determined and shown its "specific and substantial" utility.
Having said that, let us also visit the other ways in which the patenting system ensures a reasonable bargain in case of gene sequence patenting.
- Written Description - Put your finger on what exactly the invention is.
You may have a brilliant idea, and you may have done some work on it too, but if you do not "possess" an invention yet, it might be a good idea to just keep your lab notebook updated regularly. You need to have something tangible in your hands to claim an invention at the Patent Office (see MPEP 2163.02), not something just very well-conceived and not actualized. The written description requirement ensures this (see 35 U.S.C. § 112). The landmark biotechnology case with regard to the written description standard was University of Rochester v. G.D. Searle & Co., 358 F. 3d 916. The plaintiff claimed a method of achieving a biological effect but did not disclose any compound that could accomplish that result. The CAFC ruled that the patent "disclosed nothing more than a hoped for function for an as-yet-to-be discovered compound", and held the patent invalid due to the lack of written description. The rule applies to gene sequence patenting as well. One of the most representative cases here is the Regents of the University of California v. Eli Lilly and Co., 119 F.3d 1559. While the asserted patent claimed a recombinant microorganism having human insulin-encoding cDNA, a written description of the cDNA encoding human insulin was lacking.
See Revised Interim Written Description Guidelines Training Materials for how the USPTO evaluates the written description in patent applications especially with biotechnology-related subject matter.
- Enablement - As you wade through the jungle, leave adequate signposts.
The deal is that not only does a patentee have to describe the invention and show its utility, but she also has to enable the invention. That is, any person reasonably skilled in the art should be able to pick up the patent specification and reproduce the invention in her lab without undue experimentation (see MPEP 2164). Claiming broader than you have enabled (or you could possibly enable!) is disallowed (see MPEP 2164.08), and that is what transpired during the case Amgen, Inc. v. Chugai Pharmaceutical Co. Ltd. 927 f2d 1200. The asserted patent claimed a DNA sequence encoding a polypeptide the sequence of which is sufficiently duplicative of erythropoietin (EPO) in order for it to acquire the biological functions of EPO. The patent was held invalid as it claimed an unusually large number of analogs, and enabled only a handful of them. "It is not sufficient, having made the gene and a handful of analogs whose activity has not been clearly ascertained, to claim all possible genetic sequences that have EPO-like activity", the CAFC held.
The patenting system does not cater to the caprice of researchers. It is meticulously designed to assess whether each patent given out is indeed a square deal.
If a patent on a gene is granted taking in to account the statutory requirements referred to above, then that invention reflects a significant amount of hard work and ingenuity poured in to it by the scientist/s.
It pays to incentivize the inventor as well as the investor.
For inventors, moments when the neural machinery gets its piquant sparks, the so-called "flashes of genius", are as precious as they are rare. These moments often follow arduous, venturesome striving in "the dark". Therefore, they are "prized" moments. A patent incentivizes them to not keep it a secret, and thereby let others develop the idea and take things further.
Some innovations have significantly catalyzed overawing leaps and bounds in biosciences research. The entire landscape of biotechnological research changed drastically due to them. Polymerase chain reaction (PCR), restriction endonucleases, and Sanger's DNA sequencing method are some of the most obvious. Although the widespread impact of these inventions may not have been fully apparent during their conception, the inventors thought it wise to take refuge under the patenting system early on. Contrary to what some people contend, the patenting of such pivotal technologies did not block further research.
For example, the Kary Mullis patent on PCR, the U.S. patent no. 4,683,202 (the "PCR patent") was filed in 1985. About 1700 patents and patent applications filed to date cite to the PCR patent. Of these, only 32 are assigned to Hoffman-La Roche, Inc., the company that eventually bought the PCR patent.
Biotechnology is a unique research area requiring not only immense patience on the inventors' part, but also substantial investments provided usually by large private investors. Take drug discovery, for example. A blockbuster drug may eventually fetch unimaginable returns, but a lot is at stake initially as the drug discovery process is replete with uncertainties, and is painfully slow. Even the drug development phase that follows discovery is not without its share (and variety) of bottlenecks (see the report How Much Does it Cost to Develop a Drug to get an idea of the finances involved in drug development). It is a multi-million dollar industry, and in the given scenario, one of the biggest motivations for investors is that their new technology gets covered by a patent.
Some Real Issues Surrounding Gene Patents
- A large number of sketchy applications still get through during prosecution.
A survey published in Science in 2005 (see Patents on Human Genes: An Analysis of Scope and Claims) revealed quite a high number of gene sequence claims in U.S. patents that, as per the analysts' reviews, did not conform to one or more of the patenting standards such as written description or enablement. The article also pointed to various approaches that may be considered to remedy the problem. These included patent law amendments, policy changes at the USPTO, and alternative licensing mechanisms. As obvious as it may be, the deluge of patent applications (see Backlog, Quotas Overwhelm Patent Examiners) including those containing tall gene sequence claims is at least partially responsible for these lapses in quality. The "letter of the law" is sufficient; its implementation seems to be lacking to a considerable extent.
Oftentimes out of fear of litigation, research organizations do not venture into areas involving protected technologies. Understandably, most do not have the wherewithal to obtain expert validity opinions for concerned patents. This produces a chilling effect on research.
Large-scale revamping of systems and processes at the USPTO to focus on quality output would constitute the best approach to better the situation.
- The Bullying Patentee
More often than not, a biotechnology-related research activity aimed at any objective starts with the use of the nucleic acid sequence concerned. That is a given. Now, a patent covering the concerned nucleic acid sequence isolated and purified in lab represents the first (and major) bottleneck to the whole series of activities (and discoveries) waiting downstream of the gene. For example, a patent on a gene sequence of critical importance in therapeutic and/or diagnostic applications may become a stumbling block for everyone from the "bench researcher" right up to the end consumer that draws the benefit (see the articles AIDS Research: HIV Experts vs. Sequencers in Patent Race and Your Money or Your Life). Knowing full well the importance of such patents, some patent owners take advantage of their position (see The True Cost of Gene Patents).
The world has actually witnessed some cases of menacing patent owners not willing to allow anyone else to carry out their invention or charging extortionate royalties. However, the cry about doing away with gene patenting altogether is an exaggerated response.
First, a patent can be a stumbling block only in case its owner is a difficult entity. If the owner is ready to out-license it at an appropriate fee, it is only reasonable. To rationalize that, try to absorb this fact: Mercator Genetics, owner of two patents that cover the hemochromatosis diagnosis, actually went out of business after spending $ 10 million dollars on developing the diagnostic test (see Diagnostic Testing Fails the Test). Hemochromatosis affects 1 in 200 to 1 in 300 people in North European descent. Should we not care to motivate companies like Mercator towards medically relevant research that might benefit mankind?
Second, the answer to handling the "bullying patentee" might lie in deciding a regulatory framework to take stock of patent misuse. While patent assignees "indulging" in restrictive licensing and monopolization is indeed a real issue, there are probably no quick-fix solutions.
For the hemochromatosis diagnostic test that is reported to have "suffered" due to patenting (see Diagnostic Testing Fails The Test), consider the following hypothetical regulatory framework:
1) If a laboratory is providing the patented test to their customers at a fee, then the patentee gets royalties commensurate with the cost of developing the diagnostic tests.
2) If a laboratory is further developing and/or validating the assay, then nominal or no royalty must be paid. However, if a commerciable improvement step is hit upon during this further developmental stage, then both the laboratory and the patent owner must somehow share the benefits arising out of the improvement (say, become co-assignees on the patent that issues for the improvement).
The above framework may be far from being perfect and complete. However, look at the possible spin-offs of the above:
If you have used your ingenuity and hard work in developing something, it is natural that you would prefer not to share it with anyone. Therefore, the above no.2 regulation motivates the laboratory to only in-license the patent on the test (route no. 1).
If the laboratory can't in-license due to some reason, then the laboratory takes the no.2 route. The no.2 route generates further competition in the future, as then two entities would derive benefits from the same test, and would need to find better ways to minimize the competition.
While this may or may not be viewed as the best and complete solution, what is being stressed here is that the unique set of issues that biotech patenting has brought to the fore entail inventing out-of-the-box approaches. Perhaps it is time we began to conceive of viable counterparts of the USFDA and EMEA for patentable nucleic acids and GMOs.
Acknowledgement: I thank my colleague Mr. Mihir Mahajan for a detailed review and various inputs.
