Strategies for Stem Cell Patent Applications in the Light of Recent Court Cases
PATENTING STEM CELL TECHNOLOGIES FOLLOWING GUIDELINES ISSUED BY THE EPO, USPTO, JPO AND SIPO
Stem cells offer the prospect of treatments for diseases and injuries that are currently beyond medical science. Although development of these potential medical marvels has been dogged by their controversial origin, technological developments and guidance from recent judicial decisions have answered and overcome many of these difficulties. In particular the European Patent Office, United States Patent and Trademark Office, Japan Patent Office and State Intellectual Property Office of China have published guidelines covering patenting of stem cell technologies in the
light of recent decisions. We now see a patent landscape where stem cell technologies and related therapies can, with very few exceptions, be protected via patents, provided the appropriate form of claim wording is used.
A peer-reviewed version of this article has been published in Pharmaceutical Patent Analyst (D. E. Eyre and G. W. Schlich, Pat. Anal. (2015) 4(6), 431–441; DOI: 10.4155/ppa.15.29).
Executive Summary / Practice Points
- Stem cell technologies promise to be the next transformative medical technology offering therapies
for conditions and diseases that are currently beyond medical science by creating replacement or supplementary tissues for a patient.
- Stem cell technologies have been dogged by controversy because of objections over the morality of
sacrificing human embryos to produce the first human embryonic stem cell lines. Patent law around the world has now developed to define the
boundaries between stem cell technologies that can be patented and those that cannot.
- Furthermore, alternative, competing, and morally acceptable stem-cell technologies have been
- Stem cell technologies and related therapies can all, with very few exceptions, be protected via patents, provided the appropriate form of claim wording is used.
- To maximize the protection available:
- include different forms of wording to cater for the differing acceptance criteria used in various jurisdictions;
- where possible, provide manufacturing processes that start with stem cells that can only yield adult tissues; and
- if you have a choice of starting material and are forced to use embryonic stem cells to carry out the invention, ensure you describe the use of embryonic stem cells from morally acceptable sources in your patent application.
- include different forms of wording to cater for the differing acceptance criteria used in various jurisdictions;
- The greater legal certainty provided by recent court cases means that patent rights, and the investment they attract, can be secured for human embryonic stem-cell based technologies.
Defined Key Terms
Patentability — Patents are only granted for certain technical creations. For example, patents are not generally granted for mathematical methods or presentations of information.
Morality — The belief that some behaviour is right and acceptable whereas other behaviour is wrong: this belief being founded on the totality of the accepted norms which are deeply rooted in a particular culture1.
Ordre Public — The protection of public security and the physical integrity of individuals as part of society1.
Regenerative Medicine — Replacement or regeneration of cells, tissues or organs, in order to restore or establish normal function2.
Reproductive Cloning — Use of a donor cell to create a new human genetically identical to the donor.
Therapeutic Cloning — Use of a donor cell to create pluripotent stem cells suitable for growing tissues for implantation into the donor or other patient.
Stem cells promise a great many things. They are precursor cells to the development of all adult body tissues; so, being able to manipulate stem cells offers the prospect of generating any form of tissue for medical use1. The field of 'regenerative medicine' is thus now on the horizon. Currently, biologics are the grand new pharmaceutical technology; they are coming on stream and they promise to be very successful and very profitable4,5,6,7. Stem cells may underpin the next generation of pharmaceuticals, with even greater promise for successful treatment of diseases that are intractable or scarcely treatable now.
Furthermore, the medical sphere is investing and becoming organized so as to offer personalized medicine to patients8,9, 10,11,12,13. Some proposed forms of stem cell therapy may yield the ultimate in personalized medicine; reagents made using a patient's own cells used to regenerate disease or damaged tissues14,15, once the stuff of science fiction, may become science fact.
However, development of such technologies is, of course, not a simple matter and requires a vast investment of resources16,17. Furthermore, the first source of stem cell technology is controversial. The first human stem cell techniques relied on cells taken from human embryos18. The acceptability of developing (or attempting to develop) technologies derived from human embryo research varies widely19, 20,21.
With such medical potential, the barriers of cost, time and controversy to development of therapies in this field are being overcome and progress is being made towards stem cell based technologies that offer the promise of regenerative, and/or personalized medicine that might have incredible benefits for patients22.
Embryonic stem cells are derived from the inner cell mass of a blastocyst18. A blastocyst is a stage in embryonic development and is characterized by the embryo comprising a layer of cells surrounding a vacuole with a group of cells, the inner cell mass (ICM) on the inner wall 23. Cells taken from an ICM can be cultured and because of the early stage in development at which they are taken they can be coaxed into differentiating into almost any cell type18. These cells are said to be pluripotent.
Such pluripotent cells were first made from mouse embryos24,25 and were later made from human embryos18. Pluripotent human embryonic stem cells can potentially become any adult human tissue26. However, they cannot become placental or umbilical cord tissue. Thus, they cannot support a pregnancy and independently develop into a human being. Cells that can independently develop into a human being are said to be to totipotent27.
It is these differences in capability that lead to the controversies regarding their use that are discussed below. These controversies arise from differences in opinion as to the extent to which a pluripotent or totipotent cell is an independent human being28.
The depth and strength of the controversy has given extra impetus to research into alternative stem cell technologies. The best known alternative stem cell technologies are induced pluripotent stem (iPS) cells 29,30 and nuclear transfer embryonic stem cells (NT-ESCs) 31. These alternative technologies offer different capabilities from hESCs derived from human embryos and may be useful in different arenas. Absent the controversy then these technologies would not be so well developed now. Consequently, and ironically, the controversies have yielded a three-pronged attack on the diseases and conditions that stem cells may be useful for treating.
iPS cells are cells taken from an adult human being (i.e. from somatic cells) in which transcription factors are induced to reset their differentiated state and return them to a pluripotent state. This newly pluripotent cell can then be cultured and re-differentiated into other cell types and tissues29,30.
The most recent development in stem cell technologies has been the emergence of NT-ESCs. These are stem cells made by injecting the nucleus from a somatic cell into an egg cell from which the original nucleus has been removed. A new pluripotent pseudo-adult cell is thus formed31 .
iPS and NT-ESCs offer the possibility of patient specific embryonic stem cell lines derived from a patient's own cells. Tissue grown from these cell lines and implanted into a patient would not be rejected. Thus one of the major obstacles to regenerative therapies is simply obviated by the origin of the source material used.
In terms of developing stem cell technologies, there are a number of obstacles to overcome, not least concerns about safety; in particular, being assured that the cells act as intended once implanted and do not grow uncontrollably to form a cancer32,33. There is also the technical question as to which type of pluripotent stem cell is best suited for pursuing particular medical treatments in terms of its eloquence of addressing disease and the simplicity of achieving a workable therapy. The short and inconvenient truth is that no-one is certain of the answer at the moment. There are a large number of physiological wrinkles associated with each of the types of stem cells that might mean they are better for some applications and not for others34. Only when these uncertainties have been resolved will we have a truly systematic method of producing stem cell therapies.
A strong and, indeed, primary focus of the law in all jurisdictions is the protection of human life. Such laws are underpinned by the prevailing morality of the people living in these jurisdictions. However, whether a human embryo is a human being or simply a stage in the development of the human being, i.e. not a human being yet, is controversial in some jurisdictions and highly emotive for many people. Consequently, destruction of human embryos to obtain human embryonic stem cells is highly controversial. For some the idea of utilizing embryos in any way, including for medical treatment, is anathema, to others, a point of indifference, and to yet others it is a worthy goal that we should be pursuing with vigour.
Thus, the controversy centres on the identity of an embryo as being human or not. Over the past two decades this issue has been considered and while it has not been universally resolved one primary distinction has become clear. The distinction is that a totipotent cell is considered to be an embryo because it can develop into a human being28. In contrast, a pluripotent cell, that is a cell that is only capable of developing into any adult tissue, is arguably not a human embryo28. The subtleties in the law around the world concentrate on pluripotent cells and the extent to which they are considered to be embryos. That totipotent cells are embryos is an issue that appears to have been decided in all major jurisdictions20,21. Thus, potential stem cell therapies are limited to those that can only yield adult tissues.
This prevailing view of totipotent versus pluripotent stem cells view reflects the view on reproductive versus therapeutic cloning in virtually all jurisdictions20,21.
Reproductive cloning of a human is universally banned. In contrast, therapeutic cloning produces cells that are genetically identical to the donor without the possibility of producing a new and genetically identical human being. However, therapeutic cloning is still controversial; some consider that such cloning is not compatible with the dignity of human beings35,36. The views prevailing around the world are summarized in the map displayed below.
As noted in the key, countries in dark brown allow therapeutic cloning. Countries in light brown allow research on stem cell derived from un-needed IVF embryos but do not allow therapeutic cloning. Countries in grey have restrictive policies regarding stem cell research and development. Countries in yellow have no explicit policy. All countries except the U.S. have banned by law human reproductive cloning20.
Legal Provisions in Major Jurisdictions
Against the background summarized above the law defining patent-eligible stem cell related subject matter has developed.
For patent law a major influence on national patent laws has been the multilateral Trade-Related Aspects of Intellectual Property agreement (TRIPS) 37. TRIPS established the minimum standards for patentability and Articles 27.2 and 27.3 of TRIPS allow the exclusion of certain inventions from patentability: inventions contrary to ordre public or morality, diagnostic, therapeutic and surgical methods for the treatment of humans or animals, plants and animals as well as essentially biological processes for the production of plants or animals. The principles and standards of TRIPS are reflected and implemented in national patent laws to different extents.
However, there is a further complicating factor. As noted above, the development of stem cell technologies requires vast investment and consequently can only realistically be achieved via direct governmental investment. Governments are informed and bound by the ethical grounds reviewed above. Consequently funding by governments is granted with restrictions following those moral and ethical grounds. Similarly, governments pass patent laws and jurisprudence develops to reflect these moral and ethical grounds. We observe, however, that these moral and ethical grounds are not identically applied for funding research and granting patent claims flowing from that research. , We also observe that those jurisdictions with fewer legal restrictions on stem cell research are those with greater patenting activity.
Accordingly, and particularly for therapeutic cloning, subject matter that is considered acceptable for stem cell research funding is more likely to be patentable in a given jurisdiction. Therefore the map above, showing stem cell policy around the world, in general also reflects the relative patentability of stem cell based technologies.
We now turn to look at some of the major jurisdictions in which stem cell patents are being granted with a view to summarizing the philosophy behind their approach to stem cell research and patenting, and as enacted by laws and official guidelines in these jurisdictions.
The legal situation in Europe is characterized by the interplay between decisions of the Courts of Justice of the European Union (CJEU) and the enlarged Board of Appeal (EBA) of the European Patent Office (EPO). The EBA is the highest forum for appeal at the EPO. However, the EBA cannot refer questions of law to the CJEU. . The case where this point was decided is G2/06 ("WARF")38, which is also one of the major cases which underlies the EPO's reasoning and practice relating to stem cell patents. While the EBA was clear in G2/06 that their reasoning could not be further considered by the CJEU, it is nevertheless the case that CJEU rulings and the ratio thereof have been followed by the EPO. Indeed, following Brüstle v Greenpeace39, a major stem-cell decision by the CJEU, the decision was incorporated into EPO practice almost immediately.
In G2/06 the EPO finally and clearly stated that an invention was unpatentable when carrying out the invention at the filing date would necessarily destroy a human embryo36. The result of this decision was that patents could only be granted for inventions relating to human embryonic stem cells "provided that, at the filing or priority date, the invention could be obtained by a means other than the destruction of human embryos".
The CJEU ruling in the case of Brüstle v Greenpeace also has a large effect on EPO practice relating to stem cells. This decision defined the meaning of the term "human embryo", which was not previously defined under European law39. The definition given in this case was that a human embryo is,
"any human ovum after fertilization, any non-fertilisation human ovum into which the cell nucleus from a mature human cell has been transplanted and any non-fertilised human ovum whose division and further development have been stimulated by parthenogenesis [constitute a "human embryo"]".
This decision also mirrored G2/06 in finding that an invention that requires the destruction of an embryo is unpatentable and that this assessment was to be made from the disclosure of the specification as a whole and not only the invention as defined by the claims39.
Following the Brüstle v Greenpeace decision, an embryo was defined in wide terms as being any cell capable of beginning the process of development into a human being39. However, later technical developments demonstrated that parthenotes, and consequently stem cells derived therefrom, were not capable of development into a human being40. Thus, if there was never any possibility of a parthenote embryo developing into a human being, could it ever have been said to have commenced the process of development into a human being? This question was considered by the CJEU in ISCC v Comptroller (C‑364/13)41. In C‑364/13 the CJEU clarified their ruling in Brüstle v Greenpeace to state that,
"unfertilized human ova whose division and further development had been stimulated by parthenogenesis are not included in the term human embryo […] as long as they are not capable of developing into a human being and have not been genetically manipulated to acquire such a capacity."
These cases thus define when a stem cell is a "human embryo" under European practice. They also define the window of time when an invention would necessarily involve the destruction of a human embryo, and so be unpatentable. Preimplantation Genetic Diagnosis, a technique for the indirect and non-destructive obtaining of stem cells from a human embryo to test for chromosome abnormalities was available on or after 10 January 2008 42. Consequently, stem cell inventions that rely on using human embryonic stem cells with an effective priority date after 10 January 2008 are likely to be patentable. Stem cell inventions that rely on these cells with an effective priority date before this date are, on the face of it, not patentable. However, there is an argument that stem cells from acceptable sources were available from January 2006 onwards. This argument is untested as yet but is explored more fully in the authors' article in the CIPA Journal43. A further untested argument of ours supports a date of June 200344.
The national laws relating to stem cell research within Europe are very variable. These range from some of the most permissive available to some of the most restrictive45. In parallel, patent applications made to national offices are judged against widely varying criteria. In contrast, national patents derived from a validated European patent are granted based on the criteria used by the EPO. EPO practice is, however, very influential upon national practice. For example, following the decision in C‑364/13 the UKIPO has updated its Manual of Patent Practice to integrate the ratio into their examination practice46.
However, a marked difference between European and direct national patents is that questions of law regarding direct national patents can be referred to the CJEU. In contrast, controversial questions before the EPO TBA or EBA can be stalled indefinitely and the question is never resolved. This has the result of keeping patent rights in limbo, thus rendering them much less commercially useful. Consequently, while the territorial protection may be greatest when applying for a Europe-wide patent, in order to be able to appeal and argue for more controversial subject matter a national patent application can be a much better forum for gaining granted patent rights - because of the possibility of referring controversial questions of law to the CJEU that this patenting route confers. Furthermore, European patents are validated and enforced as national patent rights. Accordingly, judgements of the CJEU define the extent of enforceability of validated European patents as commercial tools.
The "Myriad"47 and "Mayo"48 decisions define the scope of patent-eligible subject matter that is derived from natural sources or products. USPTO practice relating to these cases is set out in a "guidance paper" for natural products49. The overriding test conducted by the USPTO relating to patentability is that a patentable product must be "significantly different from the product as it occurs in nature".
Late last year the USPTO issued further advice in its '2014 Interim Guidance on Patent Subject Matter Eligibility'49 to assist USPTO staff and the public in determining whether particular stem cell technologies were patent eligible in view of recent Supreme Court decisions, namely Myriad and Mayo.
To summarise the interim guidance, nature-based products are patent-eligible if they possess any characteristics (structural, functional or otherwise) that are different from their natural counterparts. The mere fact that a cell is isolated from nature and described as man-made therefore is insufficient to render the subject matter patent eligible.
Stem cell use and research is particularly controversial in the USA50. However, the controversies relating to stem cell research are largely resolved at the state level rather than the federal level at which patent eligibility is considered and resolved51. Once again, control of controversial stem cell research is done by restricting or allowing funding. The US federal government has strict rules governing funding research on existing cell lines and for making new cell lines52,53. In contrast, under the federal US system, individual states can allow stem cell research and extend funding for that research54. Thus, in the USA restrictions on patentability are separated from restrictions on funding. Consequently, the federal criteria for the patentability of stem cells is more liberal than the criteria for funding stem cell research in many states; a similar situation to that seen in Europe.
The law in Japan relating to stem cells flows from the September 2001 Japanese Government guidelines for "derivation and utilization of human embryonic stem cells"55,56. Theoretically these guidelines are permissive to stem cell research but the regulatory burden for approval and practice of such research yielded a relatively restrictive regime57. However, a number of regulations were relaxed in 2009 by the Council for Science and Technology Policy (a Cabinet Office chaired by the Prime Minister)58. Under the revised guidelines, embryonic stem cells can be derived only from 'spare' IVF embryos subject to informed consent, ethical considerations and the embryos being of less than fourteen days old 55,56. The guidelines ban reproductive cloning but research orientated therapeutic cloning is permitted under a heavy regulatory burden59.
Against this background, Inventions relating to stem cells are patentable in Japan. However, Japanese patent law includes a statutory restriction against patenting inventions that are liable to injure public order, morality or public health60. Violation of public order and morality may occur by using a method for isolating human embryos that presupposes destroying a human embryo every time the invention is carried out, or if embryo use is solely aimed to produce a cloned human being. Consequently, patent applications for such subject matter are likely to be rejected under Article 32 of the Patent Act60.
Stem cell research is governed by the 2003 Ethical Guiding Principles on Human Embryonic Stem Cell Research61. The guiding principles allow for embryonic stem cells to be derived from embryos resulting from in vitro fertilization that are no longer intended for implantation, from embryos created using voluntarily donated gametes, from foetal cells derived from spontaneous or induced abortion, and from embryos created by somatic cell nuclear transfer61. Also research is permitted on existing or imported embryonic stem cell lines61. There are overarching requirements of no growth of embryos in vitro beyond 14 days and gaining the informed consent of donors61.
Article 5 of China's patent law defines subject matter excluded from patentability62. Article 5 (translated) states that, "Patent rights shall not be granted for invention - creations that violate the law or social ethics, or harm public interests. Patent rights shall not be granted for inventions that are accomplished by relying on genetic resources which are obtained or used in violation of the provisions of laws and administrative regulations."
The administrative regulations referred to here are published as the Examination Practices on the Applications Concerning Genetic Resources 63. The guideline sets out that unpatentable inventions will result from violations that include the acquisition or use of genetic resources "not beforehand approved by relevant administrative departments or licensed by relevant right holder in accordance with the provisions of relevant laws and regulations of China". Additionally, the Guidelines for Patent Examination, at Part II, Chapter 10, sections 220.127.116.11 and 18.104.22.168, state that human beings and the human body at various stages of formation and development, including embryonic stem cells are not patentable pursuant to Article 5.1 of the Chinese patent law64. Additionally, embryonic stem cells of animals are also not patentable pursuant to Article 25.1 of China's patent law (see the Guidelines for Patent Examination, at Part II, Chapter 10, section 22.214.171.124)64 .
Applications for Stem Cell Patents around the World
As noted above, European claims to stem cell technologies based on induced pluripotent stem cells and parthenote human embryonic stem cells fall outside the statutory exclusion of patentability. Furthermore, claims to stem cell technologies with an effective filing date after January 2006, and certainly after 10 January 2008, that can arguably be achieved without a use of embryonic stem cells that required destruction of an embryo at any stage in the development of the invention are patentable43. A proviso to the patentability of stem cell based inventions in Europe is that methods of treatment of the human body by surgery or diagnosis are not eligible for patent protection in Europe65. Thus claims to stem cell related inventions must be drafted so as to avoid such subject matter. However, first and second medical use claims to reagents based on and comprising allowable stem cells are patent eligible66. In short, in most cases the prohibition against patenting methods of treatment can be sidestepped by using the correct claim wording.
Regarding the degree of exemplification and supporting data that need to be filed as part of a patent application, recent developments before the Opposition Division of the European Patent Office have indicated that only minimal data from in vivo or in vitro tests need be filed as long as the state of the art at the effective priority date renders the invention plausible with respect to the state of the art67,68. Thus it is possible to file a valid patent application and claim an invention even in the absence of directly demonstrating that invention through data filed in the patent application69. Therefore European practice offers the possibility of earlier and more speculative filings that are nevertheless plausible within the state of the art and can be demonstrated to work by way of supplementary post-filed data.
A further peculiarity of court proceedings regarding European patents and national patents from European countries is, as noted above, that a national patent application can be referred to the CJEU for a final judgement. In contrast, questions of law relating to a European patent cannot be referred to the CJEU for a preliminary ruling and controversial proceedings can be stalled indefinitely at the Technical Board of Appeal or Enlarged Board of Appeal. Thus a consideration for International applications made under the Patent Cooperation Treaty (PCT) is that the application might enter the European regional phase and in parallel enter a limited number of national European phases. This may, of course, lead to double patenting within Europe. This is, in general, prohibited but provisions exist in all EPO countries by abandonment of the European or national application70 . Should a European application fail but a national application succeed then such a conflict is rendered moot but patent rights can still result.
As noted above, following the Myriad47 and Mayo48 decisions of the US Supreme Court, the USPTO issued its modified and revised 2014 Interim Guidance on Patent Subject Matter Eligibility49. This interim guidance is for the assistance of patent Examiners and the public in determining which subject matters might be eligible, including inventions based on stem cells.
The analysis as to whether a stem cell and an invention on which it relies might be excluded from patentability is based on determining whether the stem cell is significantly different from the stem cell as it occurs in nature. To be patent eligible the stem cell must have a "markedly different characteristic" or a structural or functional difference between the claimed product and its natural counterpart49. Notably, the interim guidance indicates that a product such as a stem cell that is purified or isolated will be eligible when there is a significant difference in characteristics from the natural counterpart resulting from the purification or isolation49.
A specific example relating to stem cell inventions is given in Example 9 of the illustrative examples71 issued by the USPTO for use in conjunction with their 2014 Interim Guidance49. This example lists five claims related to stem cell inventions to illustrate the extent of the exclusion to patentability set out by Myriad and Mayo. This example highlights that nature-based products are eligible for patent protection if they possess any characteristics be they structural, functional or otherwise that are different from their natural counterparts and disclosed as such in the patent application. However, the mere fact that a cell is isolated from nature and is thus "man-made" is not enough to yield an allowable patent claim49.
In parallel with the US, laws of nature are not patent eligible in Japan72. However, an isolated gene, a protein, a vector, a transformant or a fused cell are all patent eligible subject matters in Japan73. However, methods of surgery, therapy or diagnosis of humans relating to these reagents or stem cell related reagents are excluded from patentability in Japan72.
Guidelines illustrating the acceptable patent scope of stem cell related therapies are set out in examples 23-1 to 23-3 of part II, chapter 1, of the JPO Examination Guidelines for Patent and Utility Models in Japan72.
Each of these three examples illustrates the point that subject matter where it is intrinsic that materials are removed from the human body to produce medical reagents that are presumed to be returned to the same body are patent eligible subject matter72.
Thus, while methods of treatment are not patentable, and nor are human embryonic stem cells necessarily produced through destruction of an embryo, a wide range of isolated stem cells and reagents based on stem cells for medical therapies are patentable in Japan.
In contrast to the jurisdictions noted above, the Examination guidelines of the State Intellectual Property Office (SIPO) do not explicitly consider the patentability of stem cells or inventions derived from stem cells74.
Thus subject matter within the bounds set out under the laws noted above appear to be patentable. However, methods for the diagnosis or treatment of diseases are not patent eligible under Article 25 of the Chinese Patent Law62. Furthermore, "methods for the diagnosis or treatment of diseases" in China are not limited to those practiced on human bodies, but also encompass those practiced on animal bodies and samples in vitro as long as their immediate purposes are to obtain the diagnostic result of a disease or health condition for the same subject74.
A recent development in prosecution of patent applications in parallel in multiple jurisdictions has been the institution of patent prosecution highway (PPH) agreements75. These allow accelerated examination and grant of a patent based on a parallel patent application being found allowable by a cooperating patent office75,76,77. Such accelerated grant assumes that the scope of the claims in the two parallel applications is substantially similar75,76,77. Obviously, for this option to be pursued then the scope of protection must be adequate in each jurisdiction. Where subject matter does not overlap and therefore cannot be allowed on the basis of similar claims then non-overlapping subject matter will have to be applied for and gained via divisional applications. Thus rapid ground can be gained but not necessarily for the full scope of subject matter required.
International examination of PCT application speeds this process yet further as a positive International Preliminary Report on Patentability is often persuasive to the Examiners in the regional or national phases. Thus rapid grant of a first application in the national or regional phase can yield accelerated prosecution in many other jurisdictions.
The downside of this situation is that amendments made to ensure rapid grant in a first jurisdiction may cause difficulties in securing the broadest scope of protection in other jurisdiction. In particular, we would note that use of disclaimers can yield rapid grant of patent rights in particular subject matter related to stem cells. However, it is envisaged that this might cause large problems for future enforcement of patent rights (see enforcement section below).
Notwithstanding the observations given above about the extent of disclosure required for European patent applications relating to stem cells and second medical use claims, the disclosure burden in many other jurisdictions is high. Consequently, it is strongly recommended that sufficient basis for all aspects of the claimed invention be disclosed in the initial patent application.
Above we alluded to the use of disclaimers in yielding allowed patent protection. As a consequence of the use of disclaimers we can foresee situations where a "moral" patent disclaims subject matter than an "immoral" infringer then uses. For example, the patent claim will only extend to non-human stem cells. An infringer may obtain and use human embryonic stem cells in working the invention. Necessarily their act falls outside of the scope of the claim and in the disclaimed area. Thus the applicant has been forced to concede scope of protection that would otherwise flow from their inventive step because such subject matter is considered to be prohibited from exploitation. In this case the infringer has used subject matter that has been considered unacceptable for exploitation to do an act that without the prohibition would have fallen within the scope of the patentee's claimed subject matter. Consequently, the "infringer" is free to operate their method that would be considered 'immoral' for the purpose of patent protection.
We pose the question whether this act should be prevented and should be considered an infringement. Under these circumstances, the patentee should be free to prevent this exploitation - particularly as they, as the honest actor, have been prevented from so doing by acting in good faith with respect to the law. We note that this situation is as yet untried but is predictable.
Above, we noted that personalized medical technologies are predicted to yield the next great leap in medical treatments. In the past patents have covered technologies that are widely applicable and the more widely applicable the technology the greater the need for protection and profits derived therefrom. However, personalized medical technologies might not follow this particular pattern. While they are expected to be widely applicable, we foresee the reagents produced for use in personalized stem-cell medical technologies are probably only useful to specific individuals. Thus there is less motivation to pursue a personalized stem cell product per se and infringement of a personal stem cell product may be much harder to detect. Under these circumstances, method claims might be more valuable in this arena of medicine. In contrast, currently it is product claims that are, generally, more valuable4,5,6,7.
Emotive technology would appear to be a contradiction in terms. Yet this is what stem cells are - both for their potentially controversial origin and their potential in promising world-changing medical advances.
However, courts around the world have now been asked, and have answered, many questions about the suitability of research into stem cells and how appropriate commercial exploitation of stems cells, in the form of patent rights, is considered to be38,39,41, 47,48. The number of high-level (appellate or above) cases appears to be tailing off and so there is a much greater degree of certainty as to the scope of patentable subject matter. In short, the question as to how we can acceptably commercialize stem cell technologies has largely been answered, and positively. Clearly, however, there are still wrinkles - differences in national philosophy or practice can yield different claim scopes.
It is striking how closely the provisos between countries are. This appears to be because the law and practice has less been shaped by morality objections as to the origins of these new technologies but by the morality objections as to fetters on the medical use of these new technologies. Restricting patenting of medical treatments is a widely-shared goal of patent systems around the world. In contrast, there has developed a reluctance to grant monopoly rights to the raw materials that offer the promise of new medical treatments37,62,65,72.
Stem cell technologies and related therapies can all, with very few exceptions, be protected via patents, provided the appropriate form of claim wording is used. To maximize the protection available: (i) include different forms of wording to cater for the differing acceptance criteria used in various jurisdictions; (ii) where possible, provide manufacturing processes that start with stem cells that can only yield adult tissues; and (iii) if you have a choice of starting material and are forced to use embryonic stem cells to carry out the invention, ensure you describe the use of embryonic stem cells from morally acceptable sources in your patent application.
We thank William Hoffman of MBBNet at the University of Minnesota for his permission to reproduce his World Stem Cell Policy Map. We also thank Dr. Kazuyuki Ohira of Takuya Shindo Soju Partners of Japan, Mr. Yue Long of Jiaquan IP Law Firm in China and Dr. Philip Mountjoy of the UK Intellectual Property Office for their helpful comments on the draft article.
1. EPO TBA Decision T 0356/93 (Plant cells) of 21 February 1995 (Internet). Available from: http://www.epo.org/law-practice/case-law-appeals/recent/t930356ex1.html.
2. Regenerative medicine - Glossary, British Standards Institute PAS 84:2008. .
3. The Promise of Stem Cell Research [Stem Cell Information] NIH (Internet). Available from: http://stemcells.nih.gov/info/media/pages/promise.aspx.
4. Motley Fool. The 5 Best-Selling Medications of 2013 (So Far) (Internet). Available from: http://www.fool.com/investing/general/2013/08/05/the-5-best-selling-medications-of-2013.aspx.
5. 4 out of 5 Best-Selling Medicines for 2013 are Biologics | Zymergi (Internet). Available from: http://blog.zymergi.com/2013/08/4-of-5-top-selling-2013-drugs-biologics.html.
6. The 14 drugs most likely to top global pharma sales in 2015 and 2020 | BioPharma Dive (Internet). Available from: http://www.biopharmadive.com/news/the-14-drugs-most-likely-to-top-global-pharma-sales-in-2015-and-2020/344616/.
7. The 11 biggest drug launches to watch in 2015 | BioPharma Dive (Internet). Available from: http://www.biopharmadive.com/news/the-11-biggest-drug-launches-to-watch-in-2015/344075/.
8. Collins FS, Varmus H. A New Initiative on Precision Medicine. N. Engl. J. Med. 372(9), 793-795 (2015).
9. California Launches Initiative to Advance Precision Medicine (Internet). Available from: http://gov.ca.gov/news.php?id=18921.
10. Andre N, Carre M, Pasquier E. Metronomics: towards personalized chemotherapy? Nat Rev Clin Oncol. 11(7), 413-431 (2014).
11. Intlekofer AM, Younes A. Precision therapy for lymphoma-current state and future directions. Nat Rev Clin Oncol. 11(10), 585-596 (2014).
12. van Gelder T, van Schaik RH, Hesselink DA. Pharmacogenetics and immunosuppressive drugs in solid organ transplantation. Nat Rev Nephrol. 10(12), 725-731 (2014).
13. Haddad AQ, Margulis V. Tumour and patient factors in renal cell carcinoma-towards personalized therapy. Nat Rev Urol. 12(5), 253-262 (2015).
14. Maffioletti SM, Gerli MFM, Ragazzi M, et al. Efficient derivation and inducible differentiation of expandable skeletal myogenic cells from human ES and patient-specific iPS cells. Nat Protoc. 10(7), 941-958 (2015).
15. Willis JCD, Lord GM. Immune biomarkers: the promises and pitfalls of personalized medicine. Nat Rev Immunol. 15(5), 323-329 (2015).
16. UK Trade & Investment. Regenerative Medicine and Stem Cells - UKTI Life Science Investment Organisation (LSIO) (Internet). (2013). Available from: https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/301793/UK_Regenerative_Medicine_Brochure.pdf.
17. Policies for Stem Cell Research (Internet). Available from: http://www.explorestemcells.co.uk/PoliciesForStemCellResearch.html.
18. Thomson JA. Embryonic Stem Cell Lines Derived from Human Blastocysts. Science. 282(5391), 1145-1147 (1998).
19. Appendix E - Overview of International Human Embryonic Stem Cell Laws - The New Atlantis (Internet). Available from: http://www.thenewatlantis.com/publications/appendix-e-overview-of-international-human-embryonic-stem-cell-laws.
20. Stem Cell Policy: World Stem Cell Map (Internet). Available from: http://www.mbbnet.umn.edu/scmap.html.
21. The Hinxton Group: World Stem Cell Policies (Internet). Available from: http://www.hinxtongroup.org/wp.html.
22. Medical potential of stem cells | Wellcome Trust (Internet). Available from: http://www.wellcome.ac.uk/About-us/Policy/Spotlight-issues/Human-Fertilisation-and-Embryology-Act/Stem-cell-basics/WTD040069.htm.
23. Early Mammalian Development - Developmental Biology - NCBI Bookshelf (Internet). Available from: http://www.ncbi.nlm.nih.gov/books/NBK10052/.
24. Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature. 292(5819), 154-156 (1981).
25. Martin GR. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc. Natl. Acad. Sci. 78(12), 7634-7638 (1981).
26. Ulloa-Montoya F, Verfaillie CM, Hu W-S. Culture systems for pluripotent stem cells. J. Biosci. Bioeng. 100(1), 12-27 (2005).
27. Mitalipov S, Wolf D. Totipotency, Pluripotency and Nuclear Reprogramming (Internet). In: Engineering of Stem Cells. Martin U (Ed.). . Springer Berlin Heidelberg, Berlin, Heidelberg, 185-199 (2009) [cited 2015 Aug 5]. Available from: http://link.springer.com/10.1007/10_2008_45.
28. Condic ML. Totipotency: What It Is and What It Is Not. Stem Cells Dev. 23(8), 796-812 (2014).
29. Baker M. Adult cells reprogrammed to pluripotency, without tumors. Nat. Rep. Stem Cells (Internet). (2007). Available from: http://www.nature.com/doifinder/10.1038/stemcells.2007.124.
30. Takahashi K, Tanabe K, Ohnuki M, et al. Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors. Cell. 131(5), 861-872 (2007).
31. Tachibana M, Amato P, Sparman M, et al. Human Embryonic Stem Cells Derived by Somatic Cell Nuclear Transfer. Cell. 154(2), 465-466 (2013).
32. Miura K, Okada Y, Aoi T, et al. Variation in the safety of induced pluripotent stem cell lines. Nat. Biotechnol. 27(8), 743-745 (2009).
33. Knoepfler PS. Deconstructing Stem Cell Tumorigenicity: A Roadmap to Safe Regenerative Medicine. Stem Cells. 27(5), 1050-1056 (2009).
34. Tabar V, Studer L. Pluripotent stem cells in regenerative medicine: challenges and recent progress. Nat. Rev. Genet. 15(2), 82-92 (2014).
35. Council of Europe - ETS no. 164 - Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine (Internet). Available from: http://conventions.coe.int/treaty/en/treaties/html/164.htm.
36. Council of Europe - ETS no. 168 - Additional Protocol to the Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine, on the Prohibition of Cloning Human Beings (Internet). Available from: http://conventions.coe.int/treaty/en/treaties/html/168.htm.
37. WTO | intellectual property (TRIPS) - agreement text - standards (Internet). Available from: https://www.wto.org/english/tratop_e/trips_e/t_agm3c_e.htm#5.
38. EPO - G 2/06 (Use of embryos/WARF) of 25.11.2008 (Internet). Available from: http://www.epo.org/law-practice/case-law-appeals/recent/g060002ex1.html.
The EBA of the EPO held that the invention claimed by WARF required, at the time of filing, destruction of an embryo. Furthermore, this decision set the general principle that, whatever the claims cover, if working the invention necessarily involves the destruction of a human embryo then the application must be refused.
39. C-34/10 - Brüstle CURIA - Documents (Internet). Available from: http://curia.europa.eu/juris/document/document.jsf?text=&docid=111402&pageIndex=0&doclang=EN&mode=lst&dir=&occ=first&part=1&cid=223134.
In this decision the CJEU defined that definition of 'human embyros' in the context of the EU Biotech Directive. They found that "Any human ovum after fertilisation, any non-fertilised human ovum into which the cell nucleus from a mature human cell has been transplanted and any non-fertilised human ovum whose division and further development have been stimulated by parthenogenesis [constitute a 'human embryo']"
40. C-364/13 - International Stem Cell Opinion CURIA - Documents (Internet). Available from: http://curia.europa.eu/juris/document/document.jsf?text=&docid=155123&pageIndex=0&doclang=EN&mode=lst&dir=&occ=first&part=1&cid=223211.
41. C-364/13 - International Stem Cell Decision CURIA - Documents (Internet). Available from: http://curia.europa.eu/juris/document/document.jsf?text=&docid=160936&pageIndex=0&doclang=EN&mode=lst&dir=&occ=first&part=1&cid=223319.
Here the CJEU partially reversed the decision taken in C-34/10 in the light of more detailed technical evidence. The CJEU held that [The EU Biotech Directive] must be interpreted as meaning that an unfertilised human ovum whose division and further development have been stimulated by parthenogenesis does not constitute a 'human embryo' […], if […] it does not, in itself, have the inherent capacity of developing into a human being, this being a matter for the national court to determine.
42. Chung Y, Klimanskaya I, Becker S, et al. Human Embryonic Stem Cell Lines Generated without Embryo Destruction. Cell Stem Cell. 2(2), 113-117 (2008).
The first report of generation of hES cells without destruction of an embyro.
43. Eyre DE, Schlich GW. MORALLY ACCEPTABLE SOURCES OF HUMAN EMBRYONIC STEM CELLS (hESCs): EMBRYOS THAT NEVER WERE, OR COULD NEVER BE. CIPA J. , 505-507 (2014).
44. International Patent Application WO 2003/046141, published 5 June 2003, Methods for Making And Using Reprogrammed Human Somatic Cell Nuclei and Autologous And Isogenic Human Stem Cells, Example 4. (Internet). Available from: https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2003046141&redirectedID=tr
45. Hinxton Group, Europe: Map (Internet). Available from: http://www.hinxtongroup.org/wp_eu_map.html.
46. Manual of Patent Practice (MOPP) (Internet). Available from: https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/436997/mopp.pdf.
47. Association for Molecular Pathology v. Myriad Genetics, Inc., 133 S. Ct. 2107 (2013). .
This case challenged and invalidated claims in granted patents for isolated DNA sequences. The US Supreme Court unanimously held that merely isolating genes that are found in nature does not make them patentable. Claims for such sequences are not inventive because the claimed genetic information is a product of nature.
48. Mayo Collaborative Services v. Prometheus Laboratories, Inc., 132 S. Ct. 1289 (2012).
In this case the US Supreme Court considered whether using the concentration of a natural metabolite as an indicator of a correct drug regimen was patentable. They unanimously held that variation in the metabolite level was a newly discovered law of nature and so unpatentable. Furthermore, the application of a newly discovered law is also normally unpatentable if the application merely relies upon elements already known in the art"
49. USPTO 2014 Guidance on Patent Subject Matter Eligibility (Internet). Available from: http://www.gpo.gov/fdsys/pkg/FR-2014-12-16/pdf/2014-29414.pdf.
50. The Hinxton Group: World Stem Cell Policies, The Americas (Internet). Available from: http://www.hinxtongroup.org/wp_am_map.html.
51. U.S. Patent Act -- 35 USCS Sects. 1 - 376. .
52. Executive Order 13505 of March 9, 2009 - Removing Barriers to Responsible Scientific Research Involving Human Stem Cells (Internet). Available from: http://www.gpo.gov/fdsys/pkg/FR-2009-03-11/pdf/E9-5441.pdf.
53. National Institutes of Health 2009 Guidelines on Stem Cell Research (Internet). Available from: http://stemcells.nih.gov/policy/pages/2009guidelines.aspx.
54. Alberta HB, Cheng A, Jackson EL, Pjecha M, Levine AD. Assessing State Stem Cell Programs in the United States: How Has State Funding Affected Publication Trends? Cell Stem Cell. 16(2), 115-118.
55. Japanese Guidelines for Derivation and Utilization of Human Embryonic Stem Cells (Japanese) (Internet). Available from: http://www.mext.go.jp/b_menu/houdou/26/11/__icsFiles/afieldfile/2014/11/25/1353645_1_1.pdf.
56. Japanese Guidelines for Derivation and Utilization of Human Embryonic Stem Cells (English translation) (Internet). Available from: http://www.lifescience.mext.go.jp/files/pdf/32_90.pdf.
57. Cyranoski D. Japan relaxes human stem-cell rules. Nature. 460(7259), 1068-1068 (2009).
58. Council for Science and Technology Policy 83rd session (Internet). Available from: http://www8.cao.go.jp/cstp/english/policy/83cstp.html.
59. Kawakami M, Sipp D, Kato K. Regulatory Impacts on Stem Cell Research in Japan. Cell Stem Cell. 6(5), 415-418.
60. Japan Patent Act - Article 32 (English translation) (Internet). Available from: http://www.japaneselawtranslation.go.jp/law/detail/?co=1&yo=Patent&gn=&sy=&ht=&no=&bu=&ta=&x=0&y=0&re=02&ky=patent&page=1.
61. People's Republic of China, Ministry of Science and Technology and the Ministry of Health, Ethical Guiding Principles on Human Embryonic Stem Cell Research, 2003 (Internet). Available from: http://www.qmlc.com.cn/edit/UploadFile/info/2009430113029216.doc.
62. Patent Law of the People's Republic of China (English translation) (Internet). Available from: http://english.sipo.gov.cn/laws/lawsregulations/201101/t20110119_566244.html.
63. SIPO Examination Practices on the Applications Concerning Genetic Resources (English translation) (Internet). Available from: http://english.sipo.gov.cn/examination/referencematerialssy/201108/t20110808_614851.html.
64. SIPO Guidelines for Patent Examination, 2010 (Internet). Available from: http://english.sipo.gov.cn/examination/.
65. The European Patent Convention, Article 53 - Exceptions to patentability (Internet). Available from: http://www.epo.org/law-practice/legal-texts/html/epc/2013/e/ar53.html.
66. The European Patent Convention, Article 54 - Novelty (Internet). Available from: http://www.epo.org/law-practice/legal-texts/html/epc/2013/e/ar54.html.
67. Technical Board of Appeal of the European Patent Organisation T 609/02 r.9 (AP-1 complex/SALT INSTITUTE) (Internet). Available from: https://www.epo.org/law-practice/case-law-appeals/recent/t020609eu1.html.
68. Technical Board of Appeal of the European Patent Organisation T 0920/10 (Sebaceous gland disorders/ GENERAL HOSPITAL CORPORATION) (Internet). Available from: http://www.epo.org/law-practice/case-law-appeals/recent/t100920eu1.html.
69. Opposition to European Patent No. 2311869, Interlocutory decision of the EPO Opposition Division of 20 February 2015. .
70. National law relating to the EPC. September 2013. 16th edition, Table X, Miscellaneous, pp 289-291, column 1. (Internet). Available from: http://documents.epo.org/projects/babylon/eponet.nsf/0/EE1929ACFAA82EC3C125725800374350/$File/National_law_relating_to_the_EPC_en.pdf.
71. USPTO Illustrative Examples (Nature-Based Products) (Internet). Available from: http://www.uspto.gov/patents/law/exam/mdc_examples_nature-based_products.pdf.
72. Examination Guidelines for Patent and Utility Model in Japan, Article 2(1) Statutory Inventions, Japan Patent Office (Internet). Available from: https://www.jpo.go.jp/tetuzuki_e/t_tokkyo_e/Guidelines/2_1.pdf.
73. Examination Guidelines for Patent and Utility Model in Japan, Chapter 7.2 Biological Inventions, Japan Patent Office (Internet). Available from: https://www.jpo.go.jp/tetuzuki_e/t_tokkyo_e/Guidelines/7_2.pdf.
74. SIPO Guidelines for Patent Examination 2010, Part II, 4.3 p. 136 "Methods for Diagnosis or for Treatment of Diseases" (Internet). Available from: http://www.sipo.gov.cn/zlsqzn/sczn2010eng.pdf.
75. Global Patent Prosecution Highway simplifies existing network (Internet). Available from: http://www.jpo.go.jp/ppph-portal/globalpph.htm.
76. Patent Prosecution Highway (PPH) Portal - About PPH (Internet). Available from: http://www.jpo.go.jp/ppph-portal/aboutpph.htm.
77. Patent Prosecution Highway pilot programme between the IP5 Offices based on PCT and national work products, European Patent Office (Internet). Available from: http://www.epo.org/law-practice/legal-texts/official-journal/2014/01/a8.html.