In this post, we explore seven momentous partnerships that have been formed for purposes of strengthening company dominance within the induced pluripotent stem cell (iPS cell or iPSC) industry. As you’ll discover, a major theme among the “power players” within the iPSC marketplace is non-exclusive agreements with iPS Academia Japan.
These non-exclusive agreements allow companies access to an absolutely critical iPSC patent portfolio by granting access to the patented discoveries of Dr. Shinya Yamanaka, the scientist who invented induced pluripotent stem cells in 2006.
COLLABORATION #1: Life Technologies, Owned by Thermo Fisher Scientific
Life Technologies Corporation is a global biotechnology company headquartered in Carlsbad, California, that currently offers more than 50,000 products, holds more than 5,000 patents and licenses, and has products that have been cited more than 675,000 times.[1] It is one of the world’s dominant providers of stem cell research products and has been an industry leader in commercializing iPSC technologies, as the company entered into four licensing agreements during 2012 and 2013 pertaining to the development of iPSC products and technologies.
Interestingly, the company was very recently acquired by Thermo Fisher Scientific on February 3, 2014, for approximately $13.6 billion, plus the assumption of $1.5 billion in net debt.[2] It will be interesting to observe what impact this merger has on Life Technologies’ well-established track record of pursuing licensing opportunities for iPSC products and technologies.
Because Life Technologies has actively sought opportunities to strengthen its position within the field of iPSC research, it signed an agreement with Cellular Dynamics International (CDI) on June 12, 2012. As mentioned previously, CDI is the world’s largest producer of fully functional human cells derived from iPSCs.[3]
As such, the partnership between Life Technologies and CDI was structured to “commercialize a set of three new products optimized to consistently develop and grow human iPSCs for both research and bioproduction.”[4] Specifically, the products commercialized through this partnership were:
- Essential 8™ Medium – This is a xeno-free and feeder-free medium optimized for the growth and expansion of human pluripotent stem cells (PSCs).[5]
- Vitronectin – This is recombinant human protein that provides a defined surface for feeder-free culture of human pluripotent stem cells (including iPSCs), designed to be used in conjunction withEssential 8™ Medium.[6]
- Episomal iPSC Reprogramming Vectors – These are a “mixture of three vectors designed to provide the optimal system for generating transgene-free and virus-free induced pluripotent stem cells (iPSCs) in a feeder-free environment.”[7] It is again intended for use with Essential 8™ Medium to allow for defined and feeder-free reprogramming.
For these products, each was originally developed by researchers within the laboratory of James Thompson, who first derived human induced pluripotent stem cells in 2007.[8] (Note: Human iPSCs were derived nearly simultaneously with the research lab of Shinya Yamanaka.[9]) The products were then further optimized within CDI’s research laboratories to ensure the capacity to produce and maintain pluripotency in multiple iPSC lines.[10],[11],[12] Through this joint partnership between Life Technologies and CDI, Essential 8™ Medium, Vitronectin, and Episomal iPSC Reprogramming Vectors have become widely used within the iPSC research community and extensively cited within the scientific literature.
Immediately following that partnership, Life Technologies announced that it had signed a non-exclusive agreement with iPS Academia Japan to license its iPSC patent portfolio.[13] Based on this agreement signed June 15, 2012, Life Technologies has been able to substantially expand its portfolio of research products and services for the iPSC research community. In addition to providing Life Technologies with the right to directly sell iPSCs, the licensing agreement enabled Life Technologies to “provide iPS cell creation, differentiation and screening services for scientists.”[14]
Shortly thereafter, on March 7, 2013, Life Technologies signed a collaborative and licensing agreement with Harvard University pertaining to iPSC characterization assays. Under the agreement, Life Tech has “acquired exclusive rights to further develop a panel of characterization assays designed to rapidly evaluate human induced pluripotent stem cells for their use in a variety of discovery and translational research applications.”[15] As interest in using iPSC for cellular therapy purposes continues to increase, researchers will seek characterization standards that allow them to assess the quality of their cells and the capacity of such cells to differentiate into specific cell types.
Alex Meissner, Ph.D., Associate Professor in the department of Stem Cell and Regenerative Biology at Harvard, developed the assays that were licensed by Life Technologies, and under the terms of the partnership, will continue to explore them in collaboration with Life Technologies.[16] The power of the assays developed by Meissner’s lab is that they can measure gene activity in iPSCs against a prior study’s gene expression range, thereby allowing for accurate assessment of cells capacity to differentiate into particular cell lineages.
Then, on October 15, 2013, Life Technologies announced that it had extended its collaborative agreement with the Japanese firm DNAVEC Corporation to “launch its CytoTune-iPS 2.0 Sendai Reprogramming Kit, a next-generation research technology that enables the most efficient method to develop induced pluripotent stem (iPS) cells from human somatic cells.”[17] The kit uses a benign RNA virus developed by DNAVEC that allows for safer reprogramming than traditional reprogramming methods, in which unwanted genetic mutations were a substantial risk. Life Technologies and DNAVEC have indicated that a series of products will result from the collaboration.
In summary, Life Technologies is the industry leader in the area of iPSC licensing and is expected to continue to launch progressive, cutting-edge products and technologies for the iPSC research community. With its industry dominance further strengthened by its acquisition as a subsidiary of Thermo Fisher Scientific, this will be an interesting company to watch.
COLLABORATION #2: Lonza Group AG
Lonza Group AG is a massive biotechnology company headquartered in Basel, Switzerland, with a specific research products division, Lonza Bioscience. Founded in 1897, Lonza has grown into one of the world’s leading life sciences companies, with more than 40 facilities for manufacturing and research and 10,000 employees worldwide.[18] On August 2, 2012, Lonza added to its market-leading portfolio of cell therapy services and products and demonstrated its commitment to regenerative medicine by entering into a worldwide, non-exclusive licensing agreement with iPS Academia Japan for its iPSC patent portfolio.[19]
The agreement between Lonza and iPS Academia Japan expands Lonza’s substantial portfolio of cell therapy services and products. These products include the manufacture of cells using current Good Manufacturing Practices (cGMP). A critical step in bringing iPSC-based cell therapy to the market is the creation of cGMP-grade cell banks.
COLLABORATION #3: EMD Millipore
On September 17, 2012, EMD Millipore, the Life Science division of Merck KGaA of Darmstadt, Germany, and iPS Academia Japan also announced a non-exclusive global licensing agreement for iPS Academia Japan’s iPSC patent portfolio.[20] This announcement came only two months after Life Technologies announced their non-exclusive licensing agreement with iPS Academia Japan, and six weeks after Lonza announced theirs.
The non-exclusive licensing agreement permits EMD Millipore to continue to manufacture their STEMCCA™ reprogramming stem cell research kits. The STEMCCA™ kits provide an efficient, reproducible process for creating iPSCs and will advance human stem cell based research.
The two key outcomes that resulted from entering into this non-exclusive licensing agreement, as described by EMD Millipore management, are:
- Strengthening of EMD Millipore’s opportunity to offer STEMCCA reprogramming kits for stem cell research
- Access to discoveries by Shinya Yamanaka, a leader in breakthrough research in the field of stem cells.
COLLABORATION #4: Sigma Aldrich
Sigma Life Science, the biological products and services research business of Sigma-Aldrich®, announced that it signed an agreement with Axiogenesis, based in Cologne, Germany, to create application-specific assay kits of mouse induced pluripotent stem cell-derived cardiomyocytes and smooth muscle cells.[21] These assays permit the long-term studies required to accurately predict cardiotoxicity and stand in contrast to the traditional assays which use short-lived, tissue-derived primary cells during drug development. Early prediction of drug interactions will save money and prevent drug candidate failures during clinical trials.
The iPSC-derived cardiomyocytes deliver purities unachievable with assays based on cardiomyocytes derived from animal and patient tissue. The iPSC-based assays allow researchers the luxury of long-term studies of drugs to determine toxicity of compounds that would not be detectable using cardiomyocytes derived from tissue.[22]
COLLABORATION #5: Roslin Cells, Ltd.
Roslin Cells Ltd, based in Edinburgh, Scotland, will participate in a consortium, which includes scientists from the University of Edinburgh’s MRC Centre for Regenerative Medicine as well as scientists from the University of Cambridge, to create human induced pluripotent stem cells to research bipolar affective disorder.[23] The consortium is the winner of a 2011 CRACK-IT Challenge, organized by the National Centre for the Replacement, Refinement and Reduction of Animals in Research.
Currently, animal models used to study human mental illnesses present predictive challenges and raise concern for the welfare of the animal used in research. Utilization of iPSCs in research into bipolar disorder will decrease the number of animal models necessary, and improve the relevance of the results of testing to humans by creating cell systems created from the tissue of affected human patients.
COLLABORATION #6: ArunA Biomedical
ArunA Biomedical Inc., is an Athens, Georgia based company that has traditionally focused on human embryonic stem cell derived products. However, on March 31, 2012, ArunA Biomedical collaborated with Open Biosystems, now part of Thermo Fisher, to launch complete induced pluripotent stem cell kits. These novel kits, viPS™, contain the implements and reagents required to create patient- and disease-specific cell lines for research. The kits, marketed by Open Biosystems, should expedite stem cell research and enable researchers to make significant advances.[24]
Shortly after announcement of the collaboration, in April 2012, ArunA Biomedical and Open Biosystems launched the completed and fully validated induced pluripotent stem cell (viPS) kits, which contain all the tools and reagents necessary to generate patient and disease specific cell lines for use in research applications. The innovative viPS product offerings include two kit formats and additional supplemental kits designed exclusively by the companies.
This strategic collaboration exemplifies ArunA’s commitment to making stem cell research easier, by enabling investigators to efficiently and reliably generate iPSCs.
COLLABORATION #7: CeeTox and Cellular Dynamics International (Owned by Fujifilm Holdings)
On August 14, 2012, the Kalamazoo, Michigan based CeeTox and Cellular Dynamics International, based in Madison, Wisconsin, announced that they developed a new assay for use as a predictive cardiac safety screening service. [25] This innovative, highly predictive assay, the Cardiac Arrhythmia Assessment Screen™ (CAAS), will employ human induced pluripotent stem cell-derived cardiomyocytes to enable early discovery of drug-induced cardiac toxicity during the drug-development cycle. Currently, the FDA requires cardiotoxic safety data before a drug may enter clinical development. Testing methods using animal models or cadaveric cells do not adequately predict the human response to drugs during clinical development and, therefore, may not be indicative of adverse side effects in humans.
The combination of CeeTox’s CAAS™ and Cellular Dynamic’s iCell Cardiomyocytes – iPSC-derived, pure, fully functional human cardiac cells – will create a more reliable and predictive in vitro model. This approach will reduce the need for animal testing and save valuable time and money during the lengthy drug-development process.
As described previously, Cellular Dynamics International also has licensed rights to Dr. Yamanaka’s landmark iPSC patents. Furthermore, it has a license to use Otsu, Japan-based Takara Bio’s RetroNectin product, which it uses as a tool to produce its iCell and MyCell products.[26]
In summary, there has been a significant amount of cross-licensing and collaboration occurring in the iPSC product marketplace throughout the past year. This increase in collaboration reflects the increasing interest in commercial production of iPSC products and the potential necessity of research product companies to engage in future collaboration.
Summary of Collaboration within the iPSC Marketplace
In summary, strategic collaborations can greatly increase a company’s power and influence within the iPSC marketplace. These collaborations can lead to synergistic product development, expanded end-user reach, and in some instances, expanded technological capabilities through intellectual property sharing (as is the case with the companies that enter into non-exclusive agreements with iPS Academia Japan). These seven collaborations represent synergistic, deliberate alliances that have the potential to lead to future innovation within the induced pluripotent stem cell marketplace. I would keep a close watch over the companies involved in these collaborations, due to their intelligent partnering decisions to date.
To learn more, view the “Global Induced Pluripotent Stem Cell (iPSC) Industry Report.”
Footnotes
[1] LifeTechnologies.com (2014). About Us | Life Technologies [Online]. Available at: http://www.lifetechnologies.com/us/en/home/about-us.html. Web. 9 Apr. 2015.
[2] Thermo Fisher Scientific (2014). Thermo Fisher Scientific Completes Acquisition of Life Technologies Corporation [Press Release]. Feb 3, 2014.
[3] CellularDynamics.com (2014). About CDI. Available at: http://www.cellulardynamics.com/about/index.html. Web. 9 Apr. 2015.
[4] Cellular Dynamics International (2012). Life Technologies and Cellular Dynamics International Partner Global Commercialization of Novel Stem Cell Technologies [Press Release]. June 12, 2012.
[5] LifeTechnologies.com (2012). Essential 8™[Online]. Available at http://www.lifetechnologies.com/order/catalog/product/A14666SA. Web. 9 Apr. 2015.
[6] LifeTechnologies.com (2012). Vitronectin [Online]. Available at http://www.lifetechnologies.com/order/catalog/product/A14701SA. Accessed Feb 1, 2014.
[7] LifeTechnologies.com (2012). Episomal iPSC Reprogramming Vectors [Online]. Available at http://www.lifetechnologies.com/order/catalog/product/A14703. Web. 9 Apr. 2015.
[8] Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin II, Thomson JA. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007 Dec 21;318(5858):1917-20.
[9] Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K. and Yamanaka, S. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 2007 Nov 19; 131 (5), pp. 861–872.
[10] LifeTechnologies.com (2012). Essential 8™ Medium (prototype) [Online]. Available at http://www.lifetechnologies.com/order/catalog/product/A14666SA. Web. 7 Apr. 2015.
[11] LifeTechnologies.com (2012). Vitronectin [Online]. Available at http://www.lifetechnologies.com/order/catalog/product/A14701SA. Accessed Feb 1, 2014.
[12] LifeTechnologies.com (2012). Episomal iPSC Reprogramming Vectors [Online]. Available at http://www.lifetechnologies.com/order/catalog/product/A14703. Web. 8 Apr. 2015.
[13] Life Technologies, Corp (2012). Life Technologies Signs Licensing Agreement With iPS Academia Japan For Global Patent Portfolio Rights To Induced Pluripotent Stem Cell Technology [Press Release]. June 15, 2012.
[14] Ibid.
[15] GenomeWeb.com (2013). Life Tech, Harvard to Further Develop iPSC Characterization Assays for PCR, Sequencing Platforms [Press Release]. March 7, 2013.
[16] Ibid.
[17] Lonza.com (2014). Organization [Online]. Available at: http://www.lonza.com/about-lonza/company-profile/organization.aspx. Web. 9 Apr. 2015.
[18] Life Technologies, Corp (2013). Life Technologies Extends Partnership with DNAVEC, Launches Next Generation Stem Cell Reprogramming Solution [Press Release]. Oct 15, 2013.
[19] Lonza Group (2012). Lonza Announces License Agreement With iPS Academia Japan [Press Release]. August 2, 2012.
[20] EMD Millipore (2012). EMD Millipore Obtains Global Licensing Agreement For Induced Pluripotent Stem (iPS) Cell Patent Technology With iPS Academia Japan, Inc. [Press Release]. Sept 17, 2012.
[21] Sigma Aldrich, Inc. (2012). Sigma Aldrich, Axiogenesis Ink Marketing Deal for iPSC-based Assays [Press Release]. Feb 21, 2012.
[22] Sigma Aldrich, Inc. (2012). Sigma® Life Science And Axiogenesis Collaborate To Market More Predictive IPSC-Based Assays And Services For Preclinical Cardiotoxicity Screening [Press Release]. July 31, 2012.
[23] Roslin Cells (2012). Roslin Cells To Manufacture iPS Cells For Bipolar Disorder Research [Press Release]. March 5, 2012.
[24] ArunA Biomedical (2009). ArunA Biomedical Announces Co-development of Fully Validated Induced Pluripotent Stem Cell Kit [Press Release]. March 31, 2009.
[25] Cellular Dynamics (2012). CeeTox And Cellular Dynamics Collaborate To Offer Predictive In Vitro Test For Cardiotoxicity Using Human iPSC-derived Cells [Press Release]. August 14, 2012.
[26] Striklin, D (2014). Three Companies Banking on Regenerative Medicine. Wall Street Cheat Sheet. Retrieved Feb 1, 2014 from, http://wallstcheatsheet.com/stocks/3-companies-banking-on-regenerative-medicine.html/?a=viewall.