Stem Cell Research Patent Landscape (Briefing Note)

What is a patent?

A patent operates as a quid pro quo: the patent owner obtains the exclusive right to make, use, and sell an invention in exchange for publicly disclosing the invention.

Who grants patents?

Different levels of patent jurisdiction exist, but ultimately individual countries grant and enforce patents

WORLDWIDE

The World Intellectual Property Organization (WIPO) operates under the Patent Cooperation Treaty (PCT)

• All major nations are members
• Does not grant patents
• Provides a centralized patent application process that facilitates applications at the regional or national levels

REGIONAL

Several organizations grant regional patents, including parts of Africa and Eurasia

The European Patent Office (EPO) operates under the European Patent Convention (EPC)

• 37 members, including all European Union (EU) countries
• Does not grant a unitary “European” patent
• Confers a bundle of potential national patent rights
• Member countries individually determine a patent’s validity and enforcement according to their own laws

NATIONAL

Most countries have their own patent laws and offices

What do you need to get a patent?

Patent regimes operate according to one of two principles.  US law had a “first-to-invent” principle, where the person with the earliest invention date gets patent protection. By contrast, the rest of the world has adopted the “first-to-file” principle, where the person with the earliest patent filing date gets protection. Recently, however, the US passed the American Invents Act which aligns patent policies to be similar to the “first-to-file” principle used in the rest of the world. There is some debate as to how this law will play out in practical cases. The World Trade Organization (WTO) established the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS), which sets down the basic minimum requirements for patent protection:

1. Subject matter: the invention must fall into a patentable class of things
2. Novelty: the invention must be new
3. Non-obviousness: the invention must involve an inventive step
4. Utility: the invention must be capable of industrial application
5. Enablement: the inventor must disclose enough information to allow a person skilled in the art to practice the invention

All of the major patent regimes include these five requirements in one form or another.  The subject matter requirement is usually a threshold consideration, after which a patent application must meet the other four requirements.  Countries interpret these requirements differently, most notably (for purposes of stem cell research) the subject matter and novelty requirements.

SUBJECT MATTER

• The thrust of the stem cell line patentability question relates to the subject matter requirement
• Countries issue patents for any invention in any field of technology, subject to specific exceptions
• One exception in the patent law of many countries excludes inventions whose use would threaten “public order” or “morality.”  This is relevant for stem cell lines, given the possible implications of utilizing human embryos. This exception has been most notably invoked by the European Patent Office (EPO) in rejecting the Wisconsin Alumni Research Foundation’s (WARF) patent application. Citing Article 53(a) of the European Patent Convention (EPC) which excepts from patentability “inventions the commercial exploitation of which would be contrary to ‘ordre public’ or morality.”   Specific to stem cells, Rule 28(c) of the Implementing Regulations declares “uses of human embryos for industrial or commercial purposes” not patentable.  Interpretations of even the European morality exception vary among member states. These varied responses further contribute to an already complicated patent landscape.
• The US, Canada, and Australia do not have explicit morality restrictions and generally allow for a broader class of patentable inventions
• In addition, the patent laws of most countries prohibit the patenting of natural phenomena, laws of nature and naturally-occurring substances.  These prohibitions have been prominent in recent debates in the U.S., Europe and Australia concerning the patenting of genetic sequence information and isolated genetic material.  While the USPTO has traditionally issued patents covering genetic sequence information and isolated genetic material, a recent Federal District Court decision invalidated patents on the BRCA1/2 genes involved in breast and ovarian cancer.  This case is currently being appealed.

NOVELTY

• Most countries have a strict novelty requirement, under which public disclosure of the invention before patent filing destroys patentability
• Japan allows for a 6 month grace period after public disclosure for patent filing
• The US and Canada allow for a 12 month grace period

Are stem cells lines patentable?

This remains an open question:

• The stem cell field is new, rapidly-developing, and can advance in many different directions: we are not sure what types of stem cell lines, methods, and reagents will ultimately be useful.  For example, it may be easier to patent induced pluripotent stem (iPS) cells than embryonic stem (ES) cells.
• Countries take different stances regarding the patentability of stem cell lines, involving a complex assortment of legal and ethical considerations.  Besides differences in patent law specifics, jurisdictions around the world have adopted a wide variety of stem cell policies, ranging from permissive to prohibitive.  Different cultures have varying attitudes toward the desirability of using stem cells, which likely will affect whether they allow patenting. For example, the EPO specifically cited ethical considerations in rejecting a patent application for human ES cells, with the enlarged board of appeals stating that under the EPC, “It is not possible to grant a patent for an invention which necessarily involves the use and destruction of human embryos.”

Some representative examples:

1. UNITED STATES.  US patent law has no explicit morality clause, and determinations of patentability generally do not consider questions of ethics or morality.  The Supreme Court’s 1980 decision in Diamond v. Chakrabarty established the precedent that living biological material is patentable, interpreting subject matter to include “anything under the sun that is made by man.”  The decision ushered in an era of liberal patentability in all fields of biotechnology.  Notably, the US Patent and Trademark Office (USPTO) has issued a wide range of stem cell patents, including three WARF patents with very broad ES cell claims, known as the ‘780, ‘806, and ‘913 patents.  The WARF patents have been challenged in various re-examination proceedings since 2006 and have been narrowed in scope on prior publication and obviousness grounds.  While conclusions are difficult to draw based on these developments, WARF did revise their policies and adopted a less restrictive stance towards licensing during the course of these proceedings.  The US has also issued one of only three patents worldwide relating to iPS cells. While various cases that are likely to affect the scope of patentable subject matter in the US continue to make their way through the courts, today  stem cell lines remain broadly patentable.
2. CANADA.  Canada, like the US, has no morality exception in its patent law.  The Canadian Intellectual Property Office (CIPO) has recently granted WARF a patent for primate embryonic stem cells mirroring the broad claims in the US patents.
3. EPC.  Article 53(a) of the EPC excepts from patentability “inventions the commercial exploitation of which would be contrary to ‘ordre public’ or morality.”  Specific to stem cells, Rule 28(c) of the Implementing Regulations declares “uses of human embryos for industrial or commercial purposes” not patentable.  The EPO cited this language in denying WARF a patent on its broadest ES cell claims.  In doing so, the EPO emphasized that it was not ruling out all patents on ES cells.  Rather, it issued the rejection because derivation of ES cells at the time of patent filing necessarily involved destruction of human embryos.  The EPO took this to violate Article 53(a) and Rule 28(c).  The current state of stem cell line patenting in the EPC remains in flux.
4. UNITED KINGDOM.  UK patent law contains a morality exception clause whose wording closely follows that of the EPC.  The UK, however, has adopted a more liberal approach to the patentability of stem cell lines in general.  Notably, in an amicus curiae brief to the EPC, the UK argued for the patentability of the WARF claims.  And following the EPC’s rejection of the WARF patent, the UK Intellectual Property Office (IPO) established the current guideline that “on balance the commercial exploitation of inventions concerning human embryonic pluripotent stem cells would not be contrary to public policy or morality in the United Kingdom.”  The UK IPO has issued patents for both ES and iPS cells.
5. GERMANY.  German patent law contains a morality exception clause that is virtually identical to that of the EPC and UK.  In contrast to the UK, Germany has interpreted the morality language more strictly with regards to stem cell line patentability.  Notably, the German patent office issued a patent for a method of generating nerve cells from legally available human ES cells based on the work of Oliver Brüstle.  Greenpeace then challenged the patent on the grounds that it was contrary to public order because it involved the destruction of human embryos, and, in 2006, the German Federal Patent Court ruled in Greenpeace’s favor.  Oliver Brüstle has appealed this ruling and a final decision on the appeal is still pending.
6. JAPAN.  Japanese patent law has a representative morality exception provision, but Japan has been relatively liberal in granting stem cell patents.  This includes the first grant of a patent in iPS cells anywhere in the world.
7. CHINA.  China has granted patents in stem cell research and has the potential for growth in this area.  Interestingly, China has recently amended the morality clause in its patent law to include an additional statement that “no patent will be granted for an invention based on genetic resources if the access or utilization of the said genetic resources is in violation of any law or administrative regulation.”  Although the impact of this language on stem cell line patents remains unclear, it can only act to limit their patentability in the future.  Some countries have called for adding such a “bio-protection” provision to the TRIPS agreement, but powerful members such as the US and Japan have so far opposed the proposal as likely to deter patent applicants.

What are the significant issued patents in stem cell research?

It is very difficult to get a good broad picture of the international patent landscape in stem cell research.  First, we do not know which patent claims are important because the field is still developing and can progress in many directions, potentially bypassing patents that seem important today.  Patents exist for different types of stem cell lines, and at various stages, as well as for methods and reagents to generate and grow them.  For example, a claims search for “stem cells AND pluripotent” yields 510 issued patents and 1995 patent applications in the US alone and 491 PCT applications.  Whether several, one, or even none of these applications will result in patents remains an open question.  Second, patent databases differ in how easy it is to search them, and what search criteria they offer.  As a result, a consistent search of stem cell patents across relevant international databases is not practicable.

The recent literature contains three articles that lay out the general stem cell research patent landscape and include lists of influential patents.  These focus primarily on US patents.

1. UK Stem Cell Initiative Report and Recommendations, 2005.  The authors include an appendix listing 16 of the “most important patents in stem cell research.”  They identified these patents by searching for the term “stem cell” in various patent databases and ranked their importance by the number of citations in other patents.
2. Bergman and Graf, Nat. Biotech., 2007.  The authors list the “50 most important stem cell patent documents published from 1992 onwards.”  They base the selection on the number of forward references in later-issued patents as well as discussion within the stem cell research patent literature.
3. Loring, Nat. Reports, 2007.  The author lists 41 “stem cell patents of interest” based on unknown criteria.
4. Konski and Spielthenner, Nat. Biotech., 2009.  The authors list the “five most dominant patents” in six different areas of stem cell research, as well as the “top 20 important patents identified as brokering knowledge in stem cell research.”  They base the selection on a “network analysis” of “cross-citations between or among the patent[s]” and the relationships between patents in the broad landscape.

Table 1 identifies 111 unique patents that the four sources cite.  None of the patents appear in all four sources.  Six patents make the lists in three sources.  Not surprisingly, these include the two broadest WARF patents.  Patents ‘780’ and ‘806’ are both entitled “Primate embryonic stem cells” and make very broad claims to all ES cell lines and methods to create them. They have been at the center of the stem cell line patentability controversy.  Twenty-one patents appear on lists from two sources and an additional 84 appear in a single source.

Two recent articles lay out the patent landscape specific to iPS cells:

1. Simon, et al., Nat Biotech., 2010
2. Georgieva and Love, Regen. Med., 2010

At the time the papers were published, there were only three iPS stem cell patents:

1. JP 2008283972 issued in Japan, with a publication date of 11/27/2008, and assigned to iPierian.  The patent includes method claims to produce iPS cells from somatic tissue by introducing four pluripotency genes, Oct3/4, Klf4, Sox2, and c-Myc; and product claims to the iPS cells produced by this method.
2. GB 2450603 issued in the UK, with a publication date of 2/10/2010, and assigned to iPierian.  The patent includes method claims to produce iPS cells from postnatal tissue by introducing three pluripotency genes in common with JP 2008283972, Oct3/4, Klf4, and Sox2, but not c-Myc.
3. US 7682828 issued in the US, with a publication date of 3/23/2010, and assigned to the Whitehead Institute for Biomedical Research.  The patent includes broad, non-specific product claims to somatic cells having introduced pluripotency genes.

Most do not consider iPS cells to be as controversial as ES cells because they do not involve the manipulation of human embryos, which has been the basis of morality exceptions to the patentability of ES cells.  Thus, all patent jurisdictions will likely consider iPS cells to be patentable subject matter.  Questions will instead likely arise with regards to individual patents meeting other patentability requirements, especially novelty, non-obviousness, and enablement.  For instance, Simon, et al. suggest that patent US 7682828 may have difficulty satisfying the enablement requirement because of its broad and non-specific language.  In addition, the patent has a very early priority date in 2003, meaning that information in the patent must have enabled people in the field to generate iPS cells a full four years before Yamanaka and Thomson independently first reported iPS cell derivation.

Although the iPS stem cell patent landscape still remains vague in the academic literature, Kyoto University’s Shinya Yamanaka has been granted several patents for his groundbreaking work.  According to iPS Academia Japan, Kyoto University’s business arm responsible for managing CiRA’s intellectual property, a total of 44 patent families, encompassing about 180 applications and 12 granted patents are available for licensing. Though this figure represents a large number of patents, Yamanaka also has patents from his work prior to employment at Kyoto University. Listed below are Yamanaka’s most recent patents from 2011:

U.S. Patents

Patent No.: US7,964,401
Date: June 21, 2011
Inventor: Yamanaka, Shinya
Assignee: Kyoto University; Dainippon Sumitomo Pharma Co., Ltd.
Title: Screening method for somatic cell nuclear reprogramming substance affecting ECAT2 and ECAT3

Patent No.: US8,048,999
Date: November 1, 2011
Inventor: Yamanaka, Shinya; Takahashi, Kazutoshi; Okita, Keisuke
Assignee: Kyoto University
Title: Nuclear reprogramming factor

Patent No.: US8,058,065
Date: November 15, 2011
Inventor: Yamanaka, Shinya; Takahashi, Kazutoshi
Assignee: Kyoto University
Title: Oct3/4, Klf4, cMyc and Sox2 produce induced pluripotent stem cells

Japanese Patents 

Patent No.: JP2011-182720
Date: September 22, 2011
Inventor: Yamanaka Shinya; Nose Toshiaki; Imamura Kiminori
Assignee: Kyoto University; Shiga University of Medical Science; Mitsubishi Chemicals Corp.
Title: Method for differentiation-inducing and amplifying genital stem cell, and medium therefore

Patent No.: JP2011-188860
Date: September 29, 2011
Inventor: Yamanaka Shinya
Assignee: Kyoto University
Title: Induced pluripotent stem cell

World Patent Applications

Patent No.: WO2011158967
Date: December 22, 2011
Inventor: Yamanaka Shinya; Tanabe Koji
Assignee: Kyoto University; Yamanaka Shinya; Tanabe Koji
Title: Method for Efficiently Establishing Induced Pluripotent Stem Cell

Patent No.: WO2011111614
Date: September 15, 2011
Inventor: Yamanaka Shinya; Okita Keisuke
Assignee: Kyoto University; Yamanaka Shinya; Okita Keisuke
Title: Method of selecting induced pluripotent stem cell

Patent No.: WO2011090221
Date: July 28, 2011
Inventor: Yamanaka Shinya; Nakagawa Masato
Assignee: Kyoto University; Yamanaka Shinya; Nakagawa Masato
Title: Method for improving induced pluripotent stem cell generation efficiency

 European Patent Applications

Patent No.: EP2354227(A1)
Date: August 10, 2011
Inventor: Yamanaka Shinya; Kaiho Eiko
Assignee: Yamanaka Shinya; Dainippon Sumitomo Pharma Co.
Title: Genes with ES cell-specific expression

• Significant Patents Table
• Timeline
• Worldwide Stem Cell Patent Applications

Stem Cell Patent Landscape Bibliography

Bergman K, GD Graff. The global stem cell patent landscape: implications for efficient technology transfer and commercial development. Nature – Biotechnology, 2007 April. 25(4): p. 419-424.
The authors provides an overview of the key issues and trends in stem cell patents, including the rate of stem cell patent applications and grants, stem cell patenting activities by country, distribution and concentration of stem cell patent ownership by sector and assignee, technical areas in stem cell patenting, and the most dominant stem cell patents. The authors also propose a solution to the existing patent thicket by means of a “intellectual property clearinghouse mechanism.” The main functions of such a clearinghouse would be to provide a database on available patents for licensing thereby promoting openness and access, as well as a more established set of “best practices” in order to promote ethical and efficient transfer of information. Where there are multiple competing technologies, a clearinghouse will allow transparent competition for the best available product.
see also: Bergman K, Graff GD. Collaborative IP Management for Stem Cell R&D. Center for Intellectual Property, Göteborg, Sweden, and Public Intellectual Property Resource for Agriculture, Davis, California, USA, published online.

Editors. Patenting, Licensing, and Social Responsibility. Journal of the Association of University Technology Managers. 2006 Fall; XVIII(2)
This issue of the AUTM journal contains multiple articles on the topics of patenting, licensing, and social responsibility. In “Human Embryonic Stem Cells: A Review of the Intellectual Property Landscape,” Irene Abrams discusses the complex patenting and licensing world of human embryonic stem cells. The author provides a history of hESCs and outlines the major patents in the hESC field and their availability for licensing in both research and commercial areas.

*Plomer, A., Torremans, P. Embryonic Stem Cell Patents: European Law and Ethics. Oxford: Oxford UP, 2009.
The authors of this book discuss the ethical controls on stem cell research in Europe, and highlight the heterogeneity of European policy. What is found to be problematic is the extension by legal scholars of the concepts of exploitation, objectification and commodification in order to clearly articulate criteria, which would form a consistent basis for judgment to determine the patentability of biological materials. The authors go on to explore the potential risks to the integrity of the legal order when patents are considered morally excludable, yet this judgment conflicts with general consensus outside of the legal system. Opposing viewpoints are presented by different authors concerning the scope and desired role of the legal system in both European and international law

1. Porter, G. The Drafting History of the European Biotechnology Directive
2. Isasi RM and Knoppers BM. Towards Commonality? Policy Approaches to Human Embryonic Stem Cell Research In Europe
3. Kure J. Human Embryonic Stem Cell Research in Central and Eastern Europe: A Comparative Analysis of Regulatory and Policy Approaches
4. Viens AM. Morality Provisions in Law Concerning the Commercialization of Human Embryos and Stem Cells
5. Hellstadius, A. A Comparative Analysis of the National Implementation of the Directive’s Morality Clause
6. Torremans PLC. The Construction of the Directive’s Moral Exclusions under the EPC
7. Plomer, A. Towards Systemic Legal Conflict: Article 6(2)(c) of the EU Directive on Biotechnological Inventions
8. Plomer, A. Human Dignity, Human Rights, and Article 6(1) of the EU Directive on Biotechnology Inventions
9. Engelbrekt, AB. Institutional and Jurisdictional Aspects of Stem Cell Patenting in Europe (EC and EPO): Tensions and Prospects
10. Torremans PLC. A Transnational Institution Confronted with a Single Jurisdiction Model: Guidance for the EPO’s Implementation of the Directive from a Private International Law Perspective
11. Petit E. An Ethics Committee for Patent Offices?
12. Hellstadius, A. The Research Exemption in Patent Law and its Application to hESC Research
13. Porter, Gerard. Human Embryos, Patents, and Global Trade: Assessing the Scope and Contents of the TRIPS Morality Exception
14. Engelbrekt, AB. Stem Cell Patenting and Competition Law

Konski AF, Spielthenner DJ. Stem cell patents: a landscape analysis. Nature – Biotechnology. 2009 Aug;27(8): p.722-6.
The authors used a network or cluster method to analyze stem cell patents, enumerating the dominant patents in several areas: hematopoietic stem cells; culturing hematopoietic stem cells; embryonic-like stem cells; neural stem cells; non-human stem cell research; embryonic stem cells.  They use this method to identify the most significant patents in these areas.

iPSC Patent Landscape Bibliography

Simon BM, Murdoch CE, Scott CT. Pluripotent patents make prime time: an analysis of the emerging landscape. Nature – Biotechnology. 2010 June; 28(6): 557-559.
The authors look at the general patent landscape and consider three patents in iPS to determine their ultimate value in the field.

Georgieva BP, Love JM. Human induced pluripotent stem cells: a review of the US patent landscape. Regenerative Medicine. 2010 July; 5(4): 581-91.
Since iPS cells are not derived from human embryos, they are a less complicated source of human pluripotent cells and are considered valuable research tools and potentially useful in therapeutic applications in regenerative medicine. Worldwide, there are only three issued patents concerning iPS cells. Therefore, the patent landscape in this field is largely undefined. This article provides an overview of the issued patents as well as the pending published patent applications in the field.

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