从Myriad案谈基因专利的正当性及美国对基因专利授权实质性要件分析

按照专利制度构建的本质,基因专利的作用在于激励产业创新,促进基因研究的发展。但基因专利从产生以来就一直存在着争议。2011年美国Myriad案对分离DNA序列的可专利性具有不同的观点,从Myriad I案认为分离的DNA是不可专利的客体,到Myriad II上诉案中联邦巡回上诉法院推翻地方法院的观点,认为分离的DNA具有不同的化学结构,满足专利客体的适格性,但同时也反射出了对DNA序列可专利性的怀疑。Myriad案引起了美国、欧洲和澳大利亚司法审判中就基因专利适格性问题的较大争议。本文结合美国Myriad案来分析DNA序列作为专利客体的适格性以及目前美国对基因专利授权的实质性条件。     

Evaluation of brazilian biotechnology patent activity from 1975 to 2010

The analysis of patent activity is one methodology used for technological monitoring. In this paper, the activity of biotechnology-related patents in Brazil were analyzed through 30 International Patent Classification (IPC) codes published by the Organization for Economic Cooperation and Development (OECD). We developed a program to analyse the dynamics of the major patent applicants, countries and IPC codes extracted from the Brazilian Patent Office (INPI) database. We also identified Brazilian patent applicants who tried to expand protection abroad via the Patent Cooperation Treaty (PCT). We had access to all patents published online at the INPI from 1975 to July 2010, including 9,791 biotechnology patent applications in Brazil, and 163 PCTs published online at World Intellectual Property Organization (WIPO) from 1997 to December 2010. To our knowledge, there are no other online reports of biotechnology patents previous to the years analyzed here. Most of the biotechnology patents filed in the INPI (10.9%) concerned measuring or testing processes involving nucleic acids. The second and third places belonged to patents involving agro-technologies (recombinant DNA technology for plant cells and new flowering plants, i.e. angiosperms, or processes for obtaining them, and reproduction of flowering plants by tissue culture techniques). The majority of patents (87.2%) were filed by nonresidents, with USA being responsible for 51.7% of all biotechnology patents deposited in Brazil. Analyzing the resident applicants per region, we found a hub in the southeast region of Brazil. Among the resident applicants for biotechnology patents filed in the INPI, 43.5% were from S?o Paulo, 18.3% were from Rio de Janeiro, and 9.7% were from Minas Gerais. Pfizer, Novartis, and Sanofi were the largest applicants in Brazil, with 339, 288, and 245 biotechnology patents filed, respectively. For residents, the largest applicant was the governmental institution FIOCRUZ (Oswaldo Cruz Foundation), which filed 69 biotechnology patents within the period analyzed. The first biotechnology patent applications via PCT were submitted by Brazilians in 1997, with 3 from UFMG (university), 2 from individuals, and 1 from EMBRAPA (research institute).     

Intellectual Property: a powerful tool to develop biotech research

Today biotechnology is perhaps the most important technology field because of the strong health and food implications. However, due to the nature of said technology, there is the need of a huge amount of investments to sustain the experimentation costs. Consequently, investors aim to safeguard as much as possible their investments. Intellectual Property, and in particular patents, has been demonstrated to actually constitute a powerful tool to help them. Moreover, patents represent an extremely important means to disclose biotechnology inventions. Patentable biotechnology inventions involve products as nucleotide and amino acid sequences, microorganisms, processes or methods for modifying said products, uses for the manufacture of medicaments, etc. There are several ways to protect inventions, but all follow the three main patentability requirements: novelty, inventive step and industrial application.     

A patent landscape on application of microorganisms in construction industry

Construction biotechnology includes research and development of construction materials and processes that make use of various microbes. The present technology landscape gives a perspective on how microbes have been used in construction industry as cement and concrete additives by analyzing patents filed in this technology arena. All patents related to the technology of interest published globally to date have been reviewed. The earliest patent filing in this technology domain was recorded in the year 1958 and the patenting activity reached its peak around mid to late 1990s. The early technology was mainly focused on microbial polysaccharides and other metabolic products as additives. Year 2002 onwards, biomineralization has taken precedence over the other technologies with consistent patent filings indicating a shift in innovation focus. Japan has been the global leader with highest number of patents filed on application of microbes in construction industry. Southeast University, China has topped the patent assignee list with maximum number of filings followed by Kajima Corp. and Shin-Etsu Chemical Co., Ltd. Most patent applications have claimed microbe based bio-products. Construction-related microbial technologies are mainly based on activity of different microorganisms such as urease-producing, acidogenic, halophilic, alkaliphilic, nitrate and iron-reducing bacteria. Sporosarcina pasteurii has been the most widely used microbe for biomineralization.     

Patentes fúngicas: de Pasteur a nuestros días

At the end of the 19^th century, the American Patent Office granted the patent known as “Pasteur's application”, claiming the protection of a yeast strain. Since that date, the debate around biotechnology patents, especially for those that affect living organisms or part of them, has grown exponentially.In the present article, the Patent Law is reviewed, pointing out the particular problems about fungi or parts of them. Also, some of the fungus patents are discussed from the perspective of the ethical, economical, social and environmental aspects of these kind of patents.     

Patenting genome research tools and the law

Patenting genes encoding therapeutic proteins was relatively uncontroversial in the early days of biotechnology. Controversy arose in the era of high-throughput DNA sequencing, when gene patents started to look less like patents on drugs and more like patents on scientific information. Evolving scientific and business strategies for exploiting genomic information raised concerns that patents might slow subsequent research. The trend towards stricter enforcement of the utility and disclosure requirements by the patent offices should help clarify the current confusion.     

KSR Int'l Co. v. Teleflex, Inc.: no obvious changes for the biotechnology market

With the advent of molecular biology, genomics, and proteomics, the intersection between science and law has become increasingly significant. In addition to the ethical and legal concerns surrounding the collection, storage, and use of genomic data, patent disputes for new biotechnologies are quickly becoming part of mainstream business discussions. Under current patent law, new technologies cannot be patented if they are “obvious” changes to an existing patent. The definition of “obvious,” therefore, has a huge impact on determining whether a patent is granted. For example, are modifications to microarray protocols, popular in diagnostic medicine, considered “obvious” improvements of previous products? Also, inventions that are readily apparent now may not have been obvious when discovered. Polymerase chain reaction, or PCR, is now a common component of every biologist’s toolbox and seems like an obvious invention, though it clearly was not in 1983. Thus, there is also a temporal component that complicates the interpretation of an invention’s obviousness. The following article discusses how a recent Supreme Court decision has altered the definition of “obviousness” in patent disputes. By examining how the obviousness standard has changed, the article illuminates how legal definitions that seem wholly unrelated to biology or medicine could still potentially have enormous effects on these fieldsJust what is obvious or not is a question that has provoked substantial litigation in the Federal Circuit, the appellate court with special jurisdiction over patent law disputes. Under U.S. patent law, an inventor may not obtain a patent, which protects his invention from infringement by others, if the differences between the subject matter sought to be patented and the prior art are such that “the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill” in the patent’s subject matter area [1]. However, what was “obvious” at the time of invention to a person of ordinary skill is hardly clear and is, in effect, a legal fiction designed to approximate objectivity. As illustrated by Chief Justice John Roberts of the Supreme Court in a moment of levity, “Who do you get to ... tell you something’s not obvious … the least insightful person you can find?” [2] Despite the apparent objectivity provided by a “person of ordinary skill” obviousness standard, the difficulty lies in that such a standard is still susceptible to multiple interpretations, depending on the point of view and knowledge ascribed to the “ordinary person.” As such, how obviousness is defined and interpreted by the courts will have important implications on biotechnology patents and the biotechnology business.The issue of obviousness arose in April 2007 when the Supreme Court handed down its decision in KSR Int’l Co. v. Teleflex, Inc. [3] The facts of the case were anything but glamorous; in the suit, Teleflex, a manufacturer of adjustable pedal systems for automobiles, sued KSR, its rival, for infringement of its patent, which “describe[d] a mechanism for combining an electronic sensor with an adjustable automobile pedal so that the pedal’s position can be transmitted to a computer that controls the throttle in the vehicle’s engine.” [4] Teleflex believed that KSR’s new pedal design was too similar to its own patented design and therefore infringed upon it [5]. In defense, KSR argued that Teleflex’s patent was merely the obvious combination of two pre-existing elements and, thus, the patent, upon which Teleflex’s infringement claim was based, was invalid.Patent law relies on the concept of obviousness to distinguish whether new inventions are worthy of being protected by a patent. If a new invention is too obvious, it is not granted a patent and is therefore not a legally protected property interest. However, if an invention is deemed not obvious and has met the other patentability requirements, a patent will be granted, thereby conferring exclusive use of the invention to the patent holder. This exclusive right prohibits others from making, using, selling, offering to sell, or importing into the United States the patented invention [6]. Essentially, the definition of obviousness sets the balance between rewarding new inventions with exclusive property rights and respecting old inventions by not treating minor variations of existing patents as new patents. In this manner, the law seeks to provide economic incentives for the creation of new inventions by ensuring that the property right conferred by the patent will be protected against insignificant variations. The importance of where the line for obviousness is drawn and how clearly it is drawn is especially important in the biotechnology industry. Studies have shown that the development of a new pharmaceutical therapy can take up to 14 years with costs exceeding $800 million [7]. Such an enormous investment of time and money would not be practical if it did not predictably result in a legally enforceable property right.The standard for what constitutes a patentable discovery has evolved over the last 150 years. In 1851, the Supreme Court held in Hotchkiss v. Greenwood that a patentable discovery required a level of ingenuity above that possessed by an ordinary person [8]. Lower courts treated the Hotchkiss standard as a subjective standard, whereby courts sought to determine “what constitute[d] an invention” [9] and a “flash of creative genius” [10]. However, the attempts at imposing the Hotchkiss standard proved unworkable, and in 1952, Congress overrode the case law with the Patent Act, “mandat[ing] that patentability be governed by an objective nonobviousness standard.” [11] This new statutory standard moved the courts away from subjective determinations and toward a more workable, objective obviousness standard.While the Patent Act laid the foundation for the current obviousness standard, the Supreme Court in Graham v. John Deere Co. interpreted the statutory language in an attempt to provide greater clarity as to what exactly “obvious” meant [12]. The Supreme Court determined that the objective analysis would require “the scope and content of the prior art ... to be determined; differences between the prior art and the claims at issue ... to be ascertained; and the level of ordinary skill in the pertinent art resolved.” [13] In addition to analysis under this three-part framework, the Supreme Court called for several secondary considerations to be weighed, including “commercial success, long felt but unresolved needs, [and the] failure of others [to solve the problem addressed].” [13]Unsurprisingly, lower courts were unsatisfied with the Supreme Court’s attempts to clarify the obviousness standard and sought to provide “more uniformity and consistency” to their evaluation of obviousness than the Supreme Court’s jumble of factors provided [14]. In search of consistency, the Federal Circuit created the “teaching, suggestion, or motivation” test (TSM test) “under which a patent is only proved obvious if ‘some motivation or suggestion to combine prior art teachings’ can be found in the prior art, the nature of the problem, or the knowledge of a person having ordinary skill in the art.” [14] Through implementation of the TSM test, the Federal Circuit sought to maintain the flexibility envisioned by the Supreme Court in Graham, while at the same time providing more certainty and predictability to obviousness determinations.The issue before the Supreme Court in KSR Int’l Co. v. Teleflex, Inc. was whether the Federal Circuit’s elaboration on the statutory language of the Patent Act, the TSM test, was consistent with the terms of the Patent Act itself and the Supreme Court’s own analysis in Graham. The Supreme Court determined that while the TSM test was, on its terms, consistent with the framework set out in Graham, the rigid manner in which the Federal Circuit had taken to applying that standard was inconsistent with the flexible approach established by Graham [15]. More generally, it appears the Supreme Court was mainly interested in restoring a more rounded, thorough inquiry to the evaluation of obviousness: “Graham set forth a broad inquiry and invited courts, where appropriate, to look at any secondary considerations that would prove instructive.” [16] As stated by the Supreme Court, “[r]igid preventative rules that deny factfinders recourse to common sense, however, are neither necessary under our case law nor consistent with it.” [17] As such, the Supreme Court reversed the findings of the Federal Circuit, which had found the Teleflex patent valid, and remanded the case back to the lower court with directions to analyze, without rigid adherence to the TSM test, whether the Teleflex patent was obvious [18].The Supreme Court’s ruling in KSR Int’l Co. v. Teleflex, Inc. that the Federal Circuit apply its TSM test less rigidly may have implications for those seeking biotechnology patents in the future. As discussed above, the large investments necessary to develop a marketable biotechnology product demand that entrepreneurs making those investments be reasonably assured that they can predict any future legal hurdles in patenting their invention and in ultimately protecting their patent. As explained by the Biotechnology Industry Organization in its amicus curiae brief in KSR Int’l Co. v. Teleflex, Inc., “[i]nvestment thus is predicated on an expected return on investment in the form of products or services that are protected by patents whose validity can be fairly determined.” [19] Therefore, the Supreme Court’s insistence that the Federal Circuit no longer rigidly rely on the TSM test could increase uncertainty in the grant of future patents. However, the Supreme Court’s refusal to completely dismiss the TSM test, while in fact endorsing its continued use, albeit on a less rigid basis, has to be viewed as a profound victory for an industry with a significant stake in maintaining the status quo. Moreover, it is unclear how much the Supreme Court’s holding in KSR Int’l Co. v. Teleflex, Inc. will truly change the legal analysis of the lower courts, given the evidence that lower courts already were independently shifting away from rigid adherence to the TSM test before the Supreme Court’s ruling [20].More importantly, several aspects of the Supreme Court’s reasoning in KSR Int’l Co. v. Teleflex, Inc. seem to directly address relevant concerns of the biotechnology market in favorable ways. First, the Supreme Court made clear that though a product is the result of a combination of elements that were “obvious to try,” it is not necessarily “obvious” under the Patent Act. Retaining the possibility that “obvious to try” inventions still may be patentable is extremely important to the biotechnology industry in particular because “many patentable inventions in biotechnology spring from known components and methodologies found in [the] prior art.” [21] Rather than foreclosing all “obvious to try” inventions as being obvious, and therefore not patentable, the Supreme Court instead explained that where there is “a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions,” it is more likely that a person of ordinary skill would find it obvious to pursue “known options.” [22] Thus, the proper inquiry, as stated by the Supreme Court, is “whether the improvement is more than the predictable use of prior art elements according to their established functions.” [23] While this reasoning may prevent some “obvious to try” inventions from being patented, it is unlikely to have a substantial effect on inventions in the biotechnology market because “most advances in biotechnology are only won through great effort and expense, and with only a low probability of success in achieving the claimed invention at the outset.” [24] In other words, it would be hard to characterize the use of prior art in the biotechnology context as predictable based on the inherent unpredictability of obtaining favorable results. As such, most biotechnology inventions would presumably fall outside the Supreme Court’s “obvious to try” reasoning due to the very nature of the industry, meaning they would remain patentable under the Supreme Court’s KSR Int’l Co. v. Teleflex, Inc. decision.Second, the Supreme Court recognized the “distortion caused by hindsight bias” and the importance of avoiding “arguments reliant upon ex post reasoning,” though it lessened the Federal Circuit’s rigid protection against hindsight bias [24]. Hindsight bias requires that obviousness be viewed at the time the invention was made, because what may seem revolutionary at the time of invention may, upon the passage of time, seem “obvious.” Cognizance of hindsight bias is crucial for biotechnology patents because “there often is a long ‘passage of time between patent application filing and litigation with biotechnology inventions [that] can exacerbate the problem’ of hindsight bias.” [25] The problem is further exacerbated by the “significantly longer durations of commercial utility” biotechnology inventions enjoy as compared to those in other fields [25]. The more time between the filing of a patent and the subsequent litigation over its validity, the greater the risk that “reliable accounts of [the] context” in which the discovery is made will no longer exist [26]. As such, inventions that were not obvious when they were created will be inescapably colored by the passage of time and by new knowledge and discoveries; the likelihood of this occurrence is higher the further removed the litigation is from the patent filing date. Once again, however, it seems clear that despite the Supreme Court’s abandonment of the TSM test’s rigidity, strong protections against hindsight bias still were emphasized in the Supreme Court’s KSR Int’l Co. v. Teleflex, Inc. decision. In fact, lower courts applying KSR Int’l Co. v. Teleflex, Inc. acknowledge they are “cautious” to avoid “using hindsight” in biotechnology obviousness determinations [27].Finally, the Supreme Court seems to believe that the imposition of a more flexible approach will be more likely to benefit markets not directly at issue in KSR Int’l Co. v. Teleflex, Inc. The Supreme Court asserted, “[t]he diversity of inventive pursuits and of modern technology counsels against limiting the analysis” to the rigid TSM test of the Federal Circuit [28]. This language suggests that the Supreme Court expects lower courts to take into consideration the special considerations facing unique markets, such as the biotechnology market. As such, the specific concerns of the biotechnology market discussed above may receive more attention under the flexible framework asserted by the Supreme Court in KSR Int’l Co. v. Teleflex, Inc.Leading up to the oral argument in KSR Int’l Co. v. Teleflex, Inc., there was widespread speculation that the case could result in a watershed moment, significantly altering the definition of obviousness in patent law. For many, including those in the biotechnology industry, there was ample reason to be concerned. Any change in the definition of obviousness would effectively shift property rights from new patent holders to old, or vice versa. However, the Supreme Court acted with restraint. While the decision purports to make substantial changes by doing away with the Federal Circuit’s TSM test, the opinion seems more like a mild-mannered rebuke of lower courts that had become too complacent in the implementation of their beloved test. If anything, the Supreme Court’s insistence on a more flexible formula is simply a call for lower courts to employ common sense, in addition to considering the factors from Graham and the TSM test. Accordingly, the Supreme Court’s opinion in KSR Int’l Co. v. Teleflex, Inc. is unlikely to have a pronounced effect on the biotechnology market, despite the widespread concern generated before the actual decision was handed down.     

The development of synthetic biology: a patent analysis

In the past decades, synthetic biology has gained interest regarding research and development efforts within the biotechnology domain. However, it is unclear to what extent synthetic biology has matured already into being commercially exploitable. By means of a patent analysis, this study shows that there is an increasing trend regarding synthetic biology related patent applications. The majority of retrieved patents relates to innovations facilitating the realisation of synthetic biology through improved understanding of biological systems. In addition, there is increased activity concerning the development of synthetic biology based applications. When looking at potential application areas, the majority of synthetic biology patents seems most relevant for the medical, energy and industrial sector. Furthermore, the analysis shows that most activity has been carried out by the USA, with Japan and a number of European countries considerably trailing behind. In addition, both universities and companies are major patent applicant actor types. The results presented here form a starting point for follow-up studies concerning the identification of drivers explaining the observed patent application trends in synthetic biology.     

United States patents and fungal cultures

Summary Fungal biotechnology has generated a voluminous amount of technical literature and scientific data. Patents probably contain the most complete and detailed information about the use of fungal cultures in biotechnology. This article contains a brief review of the United States patent system where microorganisms form an integral part of the disclosure and explains the role of the American Type Culture Collection (ATCC) as a patent culture depository. A list based on the application of the ATCC fungal strains which have been cited or used in US patents and the names of the inventors, the titles of the inventions, and their patent numbers are included. This provides resource material particularly for developing countries as they begin to establish their own biotechnology.     

农业生物技术领域专利态势分析

专利是技术的有效载体,通过专利态势分析可以在一定程度上有效掌握技术发展脉络及发展趋势。基于专利信息,采用定量数据、定性调研与专家智慧有机结合的方法,从申请趋势、保护市场、领域分布、重要专利权人等多维度分析视角进行农业生物技术领域专利技术态势分析。通过专利态势分析掌握全球农业生物技术专利保护概貌,指出重点方向。在此基础上结合中国农业生物技术领域专利法律状态和专利转让许可状况探讨中国农业生物技术专利保护现状及存在问题,以期支撑中国农业生物技术领域的创新决策。     

Patent protection for protein structure analysis

Three national patent offices have consulted on patents that cover protein three-dimensional structural data and pharmacophores, with significant implications for the biotechnology industry.     

特殊酵母工业应用专利发展态势分析

特殊酵母作为区别于传统酵母之外的一类生物资源,具有广泛的工业应用前景。基于incoPat数据库收录的专利数据,以特殊酵母工业应用领域的专利为研究对象,从专利分析的角度,揭示了全球特殊酵母工业应用领域技术创新的发展态势、技术分布、主要申请机构、研究热点以及各类特殊酵母的应用优势等。结果表明:全球特殊酵母工业应用领域的专利公开数量在2001~2020年期间整体呈不断增长的趋势,并在2019年达到峰值;专利保护区域主要为美、中、韩、日、欧等国家或地区,其中国内外申请机构的研发侧重点各有不同,以帝斯曼、纳幕尔杜邦、诺维信等为代表的国外工业生物技术公司注重特殊酵母基础技术的知识产权保护,以江南大学为代表的国内科研院校比较注重毕赤酵母应用技术的开发。重点分析了特殊酵母工业应用领域近年来各类特殊酵母在不同技术分支和创新程度上的差异,旨在为我国特殊酵母工业应用领域科研决策和科研工作提供参考。     

Patenting human genetic material: refocusing the debate

The biotechnology industry has become firmly established over the past twenty years and gene patents have played an important part in this phenomenon. However, concerns have been raised over the patentability of human genetic material, through public protests and international statements, but to little effect. Here we discuss some of these concerns, the patent authorities' response to them, and ways in which to address these issues and to move the debate forward using current legal structures.     

生物能源领域国际相关专利分析

随着石油资源的日益枯竭,近年来生物能源技术的开发引起了全球各界的广泛重视,加之专利保护意识的增强,生物能源领域的专利数量迅速增长,对专利信息的分析可以了解生物能源技术的发展现状和趋势,为技术创新和战略发展提供参考。本文选取目前生物能源中的三种重要技术――生物乙醇、生物柴油和生物制氢技术,利用专利计量分析的方法对其发展态势进行了研究。研究内容包括：专利申请的时间分布和空间分布,被引专利情况,主要技术领域,以及重要专利权人及其相关信息,从专利分析的角度揭示近年来这三种生物能源技术的研发状况。     

基于专利分析的3D生物打印产业发展态势研究

目的:揭示3D生物打印产业技术研发态势和专利布局,以期为相关机构提供竞争情报,为行业发展提供数据支撑。方法:基于3D生物打印领域产业调研和技术分解,构造检索式获取数据,多维度量化分析领域专利。结果:3D生物打印产业发展可分为孕育期、萌芽期和高速发展期;该产业集中度较低,处于分散竞争阶段;申请人多依据地缘因素选择合作对象,合作方之间多为不同类型的机构;中国申请人的专利申请量占全球的比重已接近50%,但美国申请人的专利篇均被引频次仍远超中国;美国申请人更关注海外市场。结论:3D生物打印产业尚未形成规模效应,有必要整合业内资源,打造产业集群;中、美两国在该产业都具有优势地位,中国亟待加强海外专利布局;综合权衡专利数量和质量,美国申请人的专利竞争力仍高于中国,中国需培育更多核心专利。     

国际生物技术专利计量分析

目的:通过对近10年全球生物技术专利的文献计量分析,了解其年度分布、国家/地区分布、机构分布和技术热点分布等,结合产业现状,讨论我国在生物技术专利方面的实力和在全球的位置,以期为我国生物技术的研发和产业发展提供参考。方法:在Derwent Innovation Index数据库中检索2001～2010年的生物技术专利,用TDA软件进行数据分析。结果:国际生物技术专利的数量从1996～2002年呈快速增长趋势,2002年后缓慢下降;生物技术专利中的80%分布在美国、日本和中国,集中程度高;申请数排名前20位的专利权人主要分布在美国、日本和中国;专利的技术热点有方法研究、生物医药和治疗研究、生物大分子研究等。美国、日本、欧洲研究机构的专利基础性较中国强,且更加注重产品开发。结论:我国的生物技术专利数量排名靠前值得欣喜,然而在专利的基础性及专利应用于产品转化方面,与美、日、欧等发达国家/地区仍有差距,我国生物技术研发应更加重视基础性研究,同时不断推动生物技术专利的转化。     

Gene patents and capital investment

Will the US Supreme Court''s ruling that genes can no longer be patented in the USA boost venture capital investment into biotech and medical startup companies?Three years ago, Noubar Afeyan, managing partner and CEO of Flagship Ventures, an early-stage venture capital firm in Cambridge, Massachusetts, USA, was working with a biotech start-up company developing techniques for BRCA gene testing for breast cancer risk that avoided the patents held by Myriad Genetics, a molecular diagnostics company in Salt Lake City (Utah, USA) and the only operator in the field. However, despite the promise of the start-up''s techniques, investors were put off by Myriad''s extensive patent portfolio and fiercely defensive tactics: “A lot of investors were simply not willing to take that chance, even though our technology was superior in many ways and patentably different,” Afeyan said. The effort to launch the start-up ultimately failed.…it is also not clear how the Supreme Court''s ruling will affect the […] industry at large, now that one of the most contested patents for a human gene has been ruled invalidAfeyan believes the prospects for such start-ups improved on the morning of 13 June 2013 when the US Supreme Court ruled in an unanimous vote that Myriad''s fundamental patents on the BRCA1 and BRCA2 genes themselves are invalid, opening up the field to new competitors. The court''s ruling, however, validated Myriad''s patents for BRCA cDNA and methods-of-use.The court''s decision comes at a time when venture capital investment into the life sciences is projected to decline in the years ahead. Some believe that the court''s decision sets a precedent and could provide a boost for products, diagnostics and other tests under development that would have been legally difficult in the light of existing patents on human and other DNA sequences.The US Patent Office issued the original patents for the BRCA 1 and BRCA2 genes in 1997 and 1998 for the US National Institute of Environmental Health Services, the University of Utah and Myriad Genetics. One year earlier, Myriad had launched its first diagnostic test for breast cancer risk based on the two genes and has since aggressively defended it against both private and public competitors in court. Many universities and hospitals were originally offering the test for a lower cost, but Myriad forced them to stop and eventually monopolized BRCA-based diagnostics for breast cancer risk in the USA and several other countries.“Myriad did not create anything,” Justice Clarence Thomas wrote in the Supreme Court''s decision. “To be sure, it found an important and useful gene, but separating that gene from its surrounding genetic material is not an act of invention.” Even so, the court did uphold Myriad''s patents on the methodology of its test. Ron Rogers, a spokesman for the biotech firm, said the Supreme Court had “affirmed the patent eligibility of synthetic DNA and underscored the importance and applicability of method-of-use patents for gene-based diagnostic tests. Before the Supreme Court case we had 24 patents and 520 claims. After the Supreme Court decision, we still have 24 patents. […] [T]he number of our patent claims was reduced to 515. In the Supreme Court case itself, only nine of our 520 patent claims were at issue. Of the nine, the Supreme Court ruled that five were not patent-eligible and they ruled that four were patent-eligible. We still have strong intellectual property protection surrounding our BRCA test and the Supreme Court''s decision doesn''t change that.”Within hours of the ruling, capitalism kicked into high gear. Two companies, Ambry Genetics in Alieso Viejo, California, and Gene by Gene Ltd in Houston, Texas, USA, announced that they were launching tests for the BRCA1 and BRCA2 genes for less than the US$3,100 Myriad has been charging privately insured patients and US$2,795 for patients covered by Medicare—the government health plan for the elderly and disabled. Several other companies and universities also announced they would be offering BRCA testing.Entrepreneur Bennett Greenspan, a managing partner of Gene by Gene, explained that his company had been poised to offer BRCA testing if the Supreme Court ruled against Myriad. He said, “We had written a press release with our PR firm a month before the release of the Supreme Court with the intention that if the Supreme Court overruled the patent or invalidated the patent that we would launch right away and if they didn''t, we would just tear up the press release.” His company had previously offered BRCA gene testing in Israel based on guidelines from the European Union.Myriad Genetics has not given up defending its patents, however. On 9 and 10 July 2013, it slapped Ambry and Gene by Gene with lawsuits in the US District Court in Salt Lake City for allegedly infringing on patents covering synthetic DNA and methods-of-use related to the BRCA1 and BRCA2 genes. Rogers commented that the testing processes used by the firms “infringes 10 patents covering synthetic primers, probes and arrays, as well as methods of testing, related to the BRCA1 and BRCA2 genes.”On 6 August 2013, Ambry countersued Myriad, arguing that the company “continues a practice of using overreaching practices to wrongfully monopolize the diagnostic testing of humans'' BRCA1 and BRCA2 genes in the United States and to attempt to injure any competitor […] Due to Myriad''s anticompetitive conduct, customers must pay significantly higher prices for Myriad''s products in the relevant market, often nearly twice as high as the price of Ambry''s products and those of other competitors” [1].Just as the courts will have to clarify whether the competitors in this case infringe on Myriad''s patents, it is also not clear how the Supreme Court''s ruling will affect the biotech and diagnostics industry at large, now that one of the most contested patents for a human gene has been ruled invalid. In recent years, venture capital investment into the life sciences has been in decline. The National Venture Capital Association and the Medical Innovation & Competitiveness Coalition reported from a survey that, “An estimated funding loss of half a billion dollars over the next three years will cost America jobs at a time when we desperately need employment growth” [2]. The survey of 156 venture capital firms found that 39% of respondents said they had reduced investment in the life sciences during the previous three years, and the same proportion intended to do so in the next three years. “[US Food and Drug Administration] FDA regulatory challenges were identified as having the highest impact on these investment decisions,” the report states, adding that many investors intended to shift their focus from the US towards Europe and the Asia/Pacific region.Another report from the same groups explains how public policy involving the FDA and other players in “the medical innovation ecosystem”—including the US patent system, public agencies, tax policy, securities regulation, immigration laws and private groups such as insurers—affect the decisions of investors to commit to funding medical innovation [3].Some investors think that the court decision about the patentability of human DNA will increase confidence and help to attract investors back to the life sciencesSome investors think that the court decision about the patentability of human DNA will increase confidence and help to attract investors back to the life sciences. “The clarity is helpful because for the longest time people didn''t do things because of ambiguity about whether those patents would be enforceable,” Afeyan said. “It''s one thing to not do something because of a patent, it''s another to not do something because you know that they have patents but you''re not sure what it''s going to stop you from doing because it hasn''t been really fully fleshed out. Now I think it is reasonably well fleshed out and I think you will see more innovation in the space.”Others also appreciate the clarification from the Supreme Court about what is a patentable invention in regard to human genes and DNA. “The Myriad decision was a very solid reading of the underlying purpose of our patent law, which is to reward novel invention,” commented Patrick Chung, a partner with New Enterprise Associates, a venture capital firm in Menlo Park, California, which invested in 23andMe, a personal genomics company based in Mountain View (California, USA), and who serves on the 23andMe board.But not everyone agrees that the Supreme Court''s decision has provided clarity. “You could spin it and say that it was beneficial to create some certainty, but at the end of the day, what the Court did was reduce the scope of what you''re allowed to get patent claims on,” said Michael Schuster, a patent lawyer and Intellectual Property Partner and Co-Chair of the Life Sciences Group at Fenwick & West LLP in San Francisco, California, USA. “It''s going to be a continuing dance between companies, smart patent lawyers, and the courts to try to minimize the impact of this decision.”Kevin Noonan, a molecular biologist and patent lawyer with McDonnell Boehnen Hulbert & Berghoff LLP in Chicago, Illinois, USA, commented that he does not expect the Supreme Court decision will have much of an impact on venture investments or anything else. “This case comes at a time fortunately when biotechnology is mature enough so that the more pernicious effects of the decision are not going to be quite as harmful as they would if this had happened ten, 15 or 20 years ago,” he said. “We''re now in the ‘post-genomic'' era; since the late ‘90s and turn of the century, the genomic and genetic data from the Human Genome Project have been on publicly available databases. As a consequence, if a company didn''t apply for a patent before the gene was disclosed publicly, it certainly is not able to apply for a patent now. The days of obtaining these sequences and trying to patent them are behind us.”Noonan also noted that the Myriad Genetics patents were due to expire in 2014–2015 anyway. “Patents are meaningless if you can''t enforce them. And when they expire, you can no longer enforce them. So it really isn''t an impediment to genetic testing now,” he explained. “What the case illustrates is a disconnect between scientists and lawyers. That''s an old battle.”George Church, professor of genetics at Harvard Medical School (Boston, Massachusetts, USA) and Director of the Personal Genome Project, maintains that the Supreme Court decision will have minimal influence on the involvement of venture capitalists in biotech. “I think it''s a non-issue. It''s basically addressing something that was already dead. That particular method of patenting or trying to patent components of nature without modification was never really a viable strategy and in a particular case of genes, most of the patents in the realm of bio-technology have added value to genes and that''s what they depend on to protect their patent portfolio—not the concept of the gene itself,” he said. “I don''t know of any investor who is freaked out by this at all. Presumably there are some, because the stock oscillates. But you can get stock to oscillate with all kinds of nonsense. But I think the sober, long-term investors who create companies that keep innovating are not impacted.”Church suggests that the biggest concern for Myriad now is whole-gene sequencing, rather than the Supreme Court''s decision. “Myriad should be worrying about the new technology, and I''m sure they''ve already considered this. The new technology allows you to sequence hundreds of genes or the whole genome for basically the price they''ve been charging all along for two genes. And from what I understand, they are expanding their collection to many genes, taking advantage of next generation sequencing as other companies have already,” he said.Whatever its consequences in the US, the Supreme Court''s decision will have little impact on other parts of the world, notably Europe, where Myriad also holds patents on the BRCA genes in several countries. Gert Matthijs, Head of the Laboratory for Molecular Diagnostics at the Centre for Human Genetics in Leuven, Belgium, says that even though the US Supreme Court has invalidated the principle of patenting genes in America, the concept remains in Europe and is supported by the European Parliament and the European Patent Convention. “Legally, nothing has changed in Europe,” he commented. “But there is some authority from the US Supreme Court even if it''s not legal authority in Europe. Much of what has been used as arguments in the Supreme Court discussions has been written down by the genetics community in Europe back in 2008 in the recommendations on behalf of the European Society for Human Genetics. The Supreme Court decision is something that most of us in Europe would agree upon only because people have been pushing towards protecting the biotech industry that the pendulum was so way out in Europe.”Benjamin Jackson, Senior Director of legal affairs at Myriad Genetics, commented that Myriad holds several patents in Europe that are not likely to be affected by the Supreme Court''s ruling. “The patent situation both generally and for Myriad is a lot clearer in Europe. The European Union Biotech Directive very clearly says that isolated DNA is patentable even if it shares the same sequence as natural DNA,” he said. “Right now, it''s pretty uncontroversial, or at least it''s well settled law basically in Europe that isolated DNA is patentable.” However, while the Directive states that “biological material which is isolated from its natural environment or produced by means of a technical process” might be patentable “even if it previously occurred in nature”, the European Patent Office (EPO) in Munich, Germany, requires that the subject matter is an inventive step and not just an obvious development of existing technology and that the industrial application and usefulness must be disclosed in the application.Myriad has opened a headquarters in Zurich and a lab in Munich during the past year, hoping to make inroads in Europe. In some EU countries, Myriad offers its BRCA test as part of cancer diagnosis. In other countries, BRCA testing is conducted at a fraction of what Myriad charges in the USA, either because institutions ignore the patents that are not enforced in their jurisdictions, or because these countries, such as Belgium, were not included in the patent granted by the European Patent Office. Moreover, in various countries BRCA testing is only available through the healthcare system and only as part of a more extensive diagnosis of cancer risk. In addition, as Matthijs commented, “[t]he healthcare system in Europe is very heterogeneous and that''s also of course a big impediment for a big laboratory to try and conquer Europe because you have to go through different reimbursement policies in different countries and that''s not easy.”Ultimately, it seems the Supreme Court''s decision might turn out to have little impact on biotech firms in either the USA or Europe. Technological advances, in particular new sequencing technologies, might render the issue of patenting individual genes increasingly irrelevant.     

Polymorphs and Prodrugs and Salts (Oh My!): An Empirical Analysis of “Secondary” Pharmaceutical Patents

Background

While there has been much discussion by policymakers and stakeholders about the effects of “secondary patents” on the pharmaceutical industry, there is no empirical evidence on their prevalence or determinants. Characterizing the landscape of secondary patents is important in light of recent court decisions in the U.S. that may make them more difficult to obtain, and for developing countries considering restrictions on secondary patents.

Methodology/Principal Findings

We read the claims of the 1304 Orange Book listed patents on all new molecular entities approved in the U.S. between 1988 and 2005, and coded the patents as including chemical compound claims (claims covering the active molecule itself) and/or one of several types of secondary claims. We distinguish between patents with any secondary claims, and those with only secondary claims and no chemical compound claims (“independent” secondary patents).We find that secondary claims are common in the pharmaceutical industry. We also show that independent secondary patents tend to be filed and issued later than chemical compound patents, and are also more likely to be filed after the drug is approved. When present, independent formulation patents add an average of 6.5 years of patent life (95% C.I.: 5.9 to 7.3 years), independent method of use patents add 7.4 years (95% C.I.: 6.4 to 8.4 years), and independent patents on polymorphs, isomers, prodrug, ester, and/or salt claims add 6.3 years (95% C.I.: 5.3 to 7.3 years). We also provide evidence that late-filed independent secondary patents are more common for higher sales drugs.

Conclusions/Significance

Policies and court decisions affecting secondary patenting are likely to have a significant impact on the pharmaceutical industry. Secondary patents provide substantial additional patent life in the pharmaceutical industry, at least nominally. Evidence that they are also more common for best-selling drugs is consistent with accounts of active “life cycle management” or “evergreening” of patent portfolios in the industry.