The average timeline for patent filing
In the next step, the non-provisional patent or patent corporation treaty (PCT) application is filed. Within 3 months of a PCT application, or 9 months from the priority date, the inventor(s) will receive an international search report and an examination report, sometimes referred to as the International Search Opinion or the Written Opinion of the International Searching Authority. This report will assist the inventor(s) in refining a patent strategy since the reports will explain in detail the validity of the patent application and identify similar inventions.
The inventor(s) will then be allowed to amend any claims stated in the PCT within 2 months of receiving the written report or within 16 months of the earliest priority date. There are typically ownership disputes and oppositions, as well as queries on patent claims requiring resolution. This stage can take 3–5 years to resolve and is usually handled by patent attorneys, thus adding to the costs of PCT filing. Once resolved, a standard PCT is then valid for 20 years from the priority date. However the inventor(s) are required to pay ongoing annual maintenance fees. Despite the time and costs involved, this process is important for the protection of the intellectual property and allows the inventor(s) a legal avenue to pursue infringement.
3 Implications of a Patent
Patents are often described as legal monopolies. A patent gives the patent holder exclusive rights over an invented product/process including marketing, hiring, selling or disposing of the products. These are summarized in Box 32.1. The patent holder may, for a limited period of time, prevent anyone else from making, constructing, emulating, using, or selling the patented invention, or any other invention that achieves substantially the same result in substantially the same manner. These exclusionary rights help to encourage competitiveness in the field. Consequently, biotech companies invest heavily in their research and development. For example, Michael West, CEO of BioTime Inc., and his colleagues patented a method for derivation of chondrogenic cell lines from embryonic progenitors, which can be expanded for over 40 passages and retain site-specific purity .
Box 32.1: The Rights of a Patent Holder
The marketing, hiring, selling, or disposing of the product
Offering to make, sell, hire, or dispose of the product
The use or import of the product
The keeping of the product for any of the above reasons
However, biotech companies do not rely solely on intellectual property developed within company walls nor do they always retain exclusivity of their patent rights. For instance, Advanced Cell Technology has extensively licensed its patent rights to BioTime Inc. and International Stem Cell Corp. Such arrangements are reflective of the commercial value of any given patent. Another level of complexity is added when one considers that as biotech companies grow, they often develop subsidiary companies which they then license their proprietary technology. License holders of patents may also be allowed to sublicense a patent if this is stipulated in the license agreement.
A patent holder may also seek to maximize profit potential by entering into an agreement with a third party allowing that party to exploit their invention in the most commercially viable way. For example, Izadyar and colleagues from the University Medical Center, Utrecht, Netherlands, published their work on the development of a cryopreservation protocol for spermatogonia . While developing this protocol, Izadyar and colleagues entered an agreement with PrimeGen Biotech LLC, which resulted in a patent that was jointly filed . Such arrangements allow biotech companies to invest in academic projects with potential commercial value. Similarly, collaborating academics that are often resource-poor are able to access funds for the project and patent application. The patent is then shared between both parties and allows protection of their joint intellectual property.
Patent law is intended to strike a balance between two conflicting interests: the individual interest of the inventor/investor, which seeks financial recognition, and the promotion of public interest, which also stands to benefit from economic prosperity. Ongoing public debates illustrate the public view that there is currently an imbalance favoring the interests of the inventor/investor which is inherent to patent law, especially where stem cell patents are concerned . Public debate and the inclusion of such concerns in political agendas may lead to restoration of balance in the legal domain.
4 Requirements for the Grant of a Patent
In order for an invention to be patented, it needs to fulfill a number of criteria (Box 32.2). These include novelty, usefulness, an inventive step, full disclosure of the invention, and that the patent relates to a manner of manufacture. In return for the grant of a limited term of commercial exclusivity, the patent holder must disclose the invention in a manner that will enable others to replicate the invention of experimental purposes during the life of the patent and use it freely when the term of exclusivity has expired. This ensures that others can utilize and build on an existing innovation to further develop new and useful technologies . Overall, the patent system attempts to distribute property rights equally between all the inventors who contributed to the overall development process in a manner that encourages exclusivity, efficiency, and wider commercial exploitation without creating barriers to the progress of science .
Box 32.2: Criteria for an Invention to be Patent-Worthy
Involves an inventive step
Details of the invention are sufficiently well disclosed/described
A manner of manufacture, not a product of nature
5 Recent Patent Activities
The term ‘manner of manufacture’ means that a patent must relate to an artificial state of affair. Some argue that genes and DNA are natural parts of the body and should be categorized as products of nature. They are thus unsuitable for patent protection since products of nature can only be discovered, not invented. It is generally accepted that isolated and purified products are patentable if their new form is substantially different from their natural form .
The requirement for novelty is to ensure that a patent is only granted for an invention that is truly new, in the absence of being not previously known in a given field of knowledge. Thus, at the time of the application for a patent, the details of the invention must not have been published . The requirement that an invention involves an inventive step is fundamental to the patent system, as it ensures that an incentive is not awarded for knowledge that was obvious or that would have been available at the time of the patent application .
As of May 2013, we found 56,300 patent applications pertaining to perinatal stem cells on the Google Patent database. Of these, 2,230 applications were approved in the past decade (2003–2013). Currently, 645 patents pertain to amniotic fluid stem cells, 1,100 to stem cells from the placenta and fetal membranes, 616 to umbilical cord blood stem cells, and 1,280 to umbilical cord stem cells. The USA remains a world leader in patenting new technologies regardless of whether one considers all patents filed across all disciplines (Fig. 32.2) or patents filed only in the area of stem cell-related technologies (Fig. 32.3). Patent applications can be found in a number of databases and we have listed some of the major databases in Box 32.3.
Total number of patents approved (1000s) from the top five most active countries in stem cell patents
The top five inventor countries
Box 32.3: A List of Online Patent Databases
World Intellectual Property Organization (WIPO), www.wipo.int
Google Patents, www.google.com
United States Patent & Trademark Office, www.uspto.gov/
European Patent Office, worldwide.espacenet.com
Patent Lens, www.patentlens.net/
Patent Data Analytics Services, www.freedopatentonline.com
Stem cell patents, www.stemcellpatents.com
The patent system is relatively uniform across a number of countries, following many years of efforts to harmonize intellectual property system. This reflects international cooperation in economic and trade development. For the purposes of this chapter, we will review recent patents on stem cells that have been granted to the top five inventor countries—the USA, Germany, UK, Canada, and Australia (Fig. 32.3). We will only review patents that have been granted a publication number. Therefore, inventors/researchers that may have lodged a patent through World Intellectual Property Organization (WIPO) but have not been granted a publication number are not mentioned in this chapter. Each of the following subsections will describe a group of perinatal stem cells, where patents describing the methods of isolation, preparation, and application will be discussed.
6 Patents on Amniotic Fluid Stem Cells
Amniotic fluid stem cells are a multipotent cell source associated with minimal ethical and legal considerations involved in their collection and use. Amniotic fluid stem cells have been differentiated along the adipogenic, osteogenic, myogenic, endothelial, neuronal, and hepatic lineages [9–12]. In preclinical studies, they have been shown to be efficacious in the treatment of bone defects , heart disease , kidney disease , neurodegenerative disease , lung disease , blood , and immune disorders .
A patent on amniotic fluid stem cell banking was granted to Martin Haas in 2005 . His patent describes a method of cell banking that allows for easy access to transplantation antigen-compatible amniotic stem cells, which could then be used postnatally for regenerative medicine. Atala and De Coppi were the first to file a patent on methods of isolation, expansion, and differentiation of stem cells from the amniotic fluid and their therapeutic use . A separate patent by Tsai and Hwang describes a method that contacts the cells isolated with an apoptosis inducing agent under conditions which are apoptotic to non-stem cells and non-apoptotic to stem cells, thereby selecting the stem cells from a heterogeneous population of cells . The selected stem cells may then be used for a variety of applications including transplantation and differentiation .
7 Patents on Stem Cells from the Placenta and Fetal Membranes
Gestational tissues, such as the fetal membranes, have had a history of allograft applications in regenerative medicine. One of the earliest descriptions of allografts of gestational tissues was published almost 70 years ago by Sorsby and Symons, who described the grafting of amniotic membranes in caustic burns of the eye . Amniotic membranes remain recognized as a superior biological dressing for wound management . Beyond their mechanical properties, cells derived from the amniotic membranes retain many characteristics that are ordinarily associated with stem cells. These include pluripotency, proliferative ability, and relative lack of immunogenicity. Additionally, stem cells and stem-like cells obtained from gestational tissues maintain a higher proliferative capacity when compared to their adult stem cell counterparts .
Also in the past decade, there has been growing interest in the reparative properties and potential use of amniotic membrane stem cells in addressing organ injury, including the treatment of adult neurodegenerative or acute-onset brain disorders [27, 28]. The amniotic membrane plays a key function during pregnancy and embryonic development. It has anti-inflammatory and immunological properties that contribute to the suppression of the maternal immune response against the fetus. These unique features of the placental membranes have been exploited in a patent that describes the use of methods of transplanting tissues and organs comprising administration of placental stem cells to prevent or inhibit immune-mediated rejection .
The cell populations within the amniotic membrane demonstrate pluripotent properties, reflective of their derivation prior to gastrulation. Their immunomodulatory properties, reflective of their biological role during pregnancy, contribute to the basis for their clinical applications . For example, the human amniotic membrane has been used clinically to promote epithelialization in burns and skin ulcers, and as a dressing for skin grafts . In keeping with this wound healing property of the amniotic membrane, John Daniel hold a patent that describes a method for preparing fetal membranes as tissue grafts . His patented technique includes a method for processing a placenta with its associated fetal membranes, cleaning and separating the chorion tissue from the amniotic membrane, and preparing the selected layer into a plurality ready for desired tissue grafts. These tissue grafts include the Schneiderian membrane repair (i.e., sinus lift), guided tissue regeneration, general wound care, and a primary closure membrane.
On a related clinical subject, Herzberg and Gurney patented an application of placental stem cells for the treatment of neuropathic pain, which involves the local or systemic administration of a “therapeutically effective amount of tissue culture plastic adherent placental stem cells” . Furthermore, a patent on the wound healing properties of placental stem cell work has been granted to Smith and colleagues . In their patent, they described the use of conditioned media from amnion derived epithelial cells applied topically across a spectrum of wounds. These included infected chronic wounds, surgical sites to prevent keloid scar formation, burns, fractures, and congenital wounds such as epidermolysis . However, it is important to note that similar patents on the wound healing properties of adipose derived stem cells exist in two separate iterations [35, 36].
In another related medical application, the use of placental stem cells for angiogenesis was recently patented by Abbot and colleagues . Their patent describes the use of stem cells to treat individuals with circulatory system disorders (e.g., diseases or disorders associated with or resulting from, inadequate vascularization or blood flow) by improving angiogenesis. Other patents held by Abbot and colleagues include a method for producing placental stem cells enhanced by RNA molecules to treat individuals having condition caused by, or relating to, an unwanted or harmful immune response . In brief, their patent included methods for increasing the immunomodulatory activity of placental stem cells using oligomeric or polymeric regulatory molecules such as modulatory RNA. The enhanced stem cell could then be used to treat individuals suffering from a disease that involves an inflammatory or immunological component.
7.1 Amnion Epithelial Cells
Miki and colleagues were the first to report a stem cell-like population, isolated from the term amnion, termed human amniotic epithelial cells (hAECs) . hAECs express traditional stem cell markers including Oct 4 and Sox 2, and are capable of multipotential differentiation. Miki and colleagues filed a patent on the therapeutic use of placental derived stem cells and their differentiated counterparts including hepatic, pancreatic, and nervous tissue [40, 41]. Tseng and colleagues filed a patent method on the isolation and ex vivo expansion of amnion cells of animal (nonhuman) origin. Their patented method retains pluripotency and selectively enriches the stem cell population . Subsequently, Kang and colleagues were granted a patent on a unique method for isolating and culturing stem cells derived from human amnion . The method used by Kang and colleagues promises high yields of hAECs, involves the treatment of the amnion with dithiothreitol and a low concentration of trypsin, and then culturing the hAECs in a medium containing a Rho-associated kinase inhibitor .