Regenerative medicine, which aims at the process of replacing, engineering or regenerating human cells, tissues or organs, so as to restore or establish the normal function of a living organism, is a prospective branch of medicine. Regenerative medicine is popular worldwide in the recent decade, and has broad applications. Many biological companies, research institutions and universities are conducting research in this field. In the same time, a large amount of patent applications in this field have been or are being filed. In this article, we will discuss typical issues in connection with patenting regenerative medicine in China, by referring to reexamination and invalidation decisions.
Key words: regenerative medicine · stem cell · patent ·reexamination · invalidation
I. Current status and challenges in connection with patenting regenerative medicine in China
The patent filing is active in the field of regenerative medicine. Upon a preliminary search, it is found that, the applications in this field are mainly filed by US, European, Japan and Korean applicants. Among the applications, most are associated with stem cells. Considering that stem cells are often obtained from an embryo, and closely associated with living organisms, there are some unique issues regarding the patent applications in this field. Of these issues, patent eligibility of subject matter, practical applicability, as well as social morality or ethnics are of particular interest.
As it is known, in Chinese patent examination practice, if a patent application is rejected, the applicant may request reexamination in front of the reexamination board. During the reexamination procedure, the application will be further examined by a reexamination panel consisting of three re-examiners. Further, any party may challenge the validity of a patent in front of the reexamination board by filing a request for invalidation. Accordingly, the opinion of the reexamination board is authoritative, and may reflect the examination standard to some extent. In practice, some examiners may refer to reexamination or invalidation decisions during their examinations.
We will discuss the above-mentioned issues in detail in the following sections by referring to some representative reexamination and invalidation decisions.
II. Subject matter and patent eligibility
The first question to ask is about which kind of subject matter could be patented. It is well known that, claims include product, method and use claims. This is the same for patent applications based on regenerative medicine. Typically, the patent-eligible subject matter in this field can be divided into the following types.
Product claims may relate to a cell, a tissue, or an organ per se, or a pharmaceutical composition comprising a cell or the extract thereof.
Methods for consideration are, for instance, methods for preparing a specific cell, tissue, or an organ, methods for oriented differentiation, and methods for treatment with a non-diagnosis or treatment purpose.
Although methods for treatment or diagnosis are not patentable in China, Swiss-type use claims are allowable in current Chinese practice. As an illustrative example, the use claim may be drafted in the format of "use of a substance, a cell, a tissue, an organ or a composition in the manufacture of a medicament for the treatment of certain diseases".
III. Ethics and social morality
Principle and Legal Basis
The issue of social morality is the most prominent issue in the prosecution of patent applications on regenerative medicine.
It is prescribed in Art. 5.1 of the Patent Law of China that no patent right shall be granted for any invention-creation that is contrary to the laws or social morality or that is detrimental to public interest.
Further, it is addressed in the Guidelines for Patent Examination of China that, "social morality" refers to ethical or moral norms and rules generally recognized as justifiable and accepted by the public. Its connotation is based on certain cultural background, continuously changes with time and social progress, and varies from region to region. Social morality in the Chinese Patent Law refers to the morality within the territory of China.
Examples of this kind of applications include a process for modifying the germ line genetic identity of human beings or a human being thus modified, a process for cloning human beings or a cloned human being, use of human embryos for industrial or commercial purposes, and a process for modifying the genetic identity of animals which is likely to cause them suffering without any substantial medical benefit to human-beings or animals.
It is worth noting that, in examination, when evaluating whether an application falls within the scope of the conditions under Article 5.1, the examiner will examine all the application documents, including the claims, description, drawings, and abstract. If a patent application is considered partially contravening Article 5.1 since a part of the application contains certain content that is contrary to the laws or social morality and the rest part of the application is not, an applicant may amend the application and delete the part contravening Article 5.1. If the applicant refuses to delete the part that is contrary to the laws, it cannot be granted a patent right.
Representative cases and rulings of reexamination board
Regarding the use of human embryos for industrial or commercial purposes
As discussed in the previous section, the use of human embryos for industrial or commercial purposes is deemed as contrary to the social morality.
What is an "embryo" under Chinese Patent Law?
Some reexamination decisions provide interpretations on the term "embryo."
It is stated in the reexamination decision No.18784 that, the human embryos refer to the embryonic embodiments at any stage from a zygote to a newborn, including cleavage stage, morula stage, implantation stage, and differentiation stage.
Regarding the source of an embryo, it is stated that, the source shall include any source, including blastula discarded after in vitro fertilization, blastula obtained via the transplanting of a body cell nucleus, embryos naturally or manually aborted.
Further, parthenogenetic embryos and parthenogenetic blastocysts also belong to the concept of an "embryo" by referring to reexamination decision Nos. 89657 and 73216.
What is "use of human embryos" under the scenario of "use of human embryos for industrial or commercial purposes"?
In one reexamination decision No. 50837, "use of human embryos" was expounded as "operation" and "contact". The patent in suit is directed to a method of assessing the viability of thawed cells, comprising incubating a grade I embryo in a culture medium and determining the change in concentration of at least one amino acid in the medium. It is contended in the reexamination decision No. 50837 that, such a method definitely involves the steps of culturing an embryo or an embryonic cell, and there is operation and contact with human embryo or embryo cell, and such operation and contact are for developing relevant assessing technology with a commercial purpose.
Further, the "use of human embryos" is irrelevant with whether the embryo is disrupted or not. In particular, even if embryonic cells are obtained from a human embryo without disrupting the human embryo, it also involves the use of human embryos for industrial or commercial purposes.
Inventions involving an embryonic stem cell
The prerequisite for the allowance of inventions involving an embryonic stem cell is that, the invention is merely the further usage of human embryonic stem cell lines which are established, conventional and stable, and the patent application does not contain contents which relate to the direct description and use of human embryo (by referring to reexamination decision No. 103528).
In practice, it is necessary to amend the description of the patent application to cancel contents which relate to the use of human embryos for industrial or commercial purposes. Further, the patent application shall disclose the ways by which the stem cell lines used in the working examples can be obtained without disruption of a human embryo. Also, it may necessary to prove that the cell lines used in the working examples are matured and commercialized before the priority date. As for the claims, it shall be limited to cell lines which are established, conventional and stable.
There are several cases to illustrate this issue.
In one case, the invention is about the differentiation of human embryonic stem cells. It is described in the claims that the pluripotent stem cells are established human embryonic stem cell lines, and there is also similar recitation in the description. Also, it is described in the working examples that "non-limiting examples are established lines of human embryonic stem cells or human embryonic germ cells, such as, for example the human embryonic stem cell lines H1, H7, and H9 (WiCeIl)." During the prosecution, relevant contents concerning the direct use and disruption of a human embryo were cancelled. Accordingly, the reexamination board determined that the invention does not involve the use of human embryos for industrial or commercial purposes, and thus is not contrary to social morality.
Similarly, from a series of other reexamination decisions, we can learn the conditions under which human embryonic stem cells related inventions are patentable. In these reexamination decisions, allowable human embryonic stem cells are specified as "established cell lines which are commercially available", "human embryonic stem cell lines H1, H7, H9 and BG01v", "established embryonic stem cell lines", "established pluripotent stem cell lines", "pluripotent stem cells other than embryonic stem cells, and embryonic germline stem cells from human embryos", and "the source of embryonic stem cells does not include human embryo sources, and the source of the embryo does not include human embryo source", respectively.
The above are cases with positive outcome after reexamination. However, in another case, the reexamination decision No. 97723 was different. Although it was defined in the claims and the description that the sources of the human embryonic stem cells are established cell lines, it was found that the patent application does not state that the human embryonic stem cells used in the working examples are established cell lines, and there is no evidence to prove that these cell lines are mature and commercially available human embryonic stem cell lines before the priority date. The conclusion was made that the invention falls within the scope of Article 5.1 of the Patent Law.
Regarding the "use of human embryos for industrial or commercial purposes," it is an important and debating area. There are multiple reexamination decisions and invalidation decisions to address this issue. Some are directed to totipotent stem cells, and some are directed to pluripotent stem cells.
Inventions regarding totipotent stem cells
In a case related to totipotent stem cells, the reexamination board held that, the totipotent stem cells have the capability to self-renew and differentiate into any type of cells, and also have the potential to develop into an entire human being, and thus belong to a certain stage of a human being, which is not patentable (reexamination decision 87655).
Inventions regarding induced pluripotent stem cells
Induced pluripotent stem cells (iPSCs) are pluripotent stem cells that can be generated directly from adult cells. For the amazing discovery that mature cells can be reprogrammed to become pluripotent, a Japanese scientist, Mr. Shinya Yamanaka from Kyoto University, was awarded a Nobel Prize in 2012. iPSCs are typically derived by introducing an induction factor (for instance, a reprogramming factor) into a given cell type.
One of the cases on iPSCs, which is also the recent and the most influencing one, is regarding a patent entitled "nuclear preprogramming factor." This case is an invalidation case which was selected as top 1 reexamination and invalidation decisions by the Patent Reexamination Board in 2015. The most important reason for this case to be selected is that it is a typical case on the social morality of embryonic stem cells.
The patent was owned by Kyoto University and the inventor is Mr. Shinya Yamanaka. The patent was granted on February 12, 2014, and an opponent filed a request for invalidation on October 29, 2014. One ground for requesting invalidation is that the invention involves the operation on human embryo, and is contrary to social morality.
The independent claim 1 of the patent does not directly relate to iPSCs. Instead, it is directed to a nuclear preprogramming factor of a somatic cell. However, according to the description, in the example of "Establishment of iPS Cells from Embryonic HDFs in Mouse ES Cell Medium", embryonic human dermal fibroblasts (HDFs) were used. The opponent is of the opinion that, "embryonic" may imply that the cells are from human embryo; and under the condition that the patent in suit does not describe that the HDFs are derived from mature and commercially available cell lines, it should be considered that the obtainment of the dermal fibroblasts require the disruption of a human embryo.
Further, the opponent pointed out that, in the description, it was described that when the iPS cells derived from adult dermal fibroblasts were transplanted to the blastocysts, and then transplanted into the uteri of pseudopregnant mice, embryos were obtained. The opponent deduced that, when the method is applied onto human cells, the established iPS cells will have the potential to develop into a human being once transplanted into human uteri.
Upon an oral hearing, the reexamination board made a decision on June 25, 2015.
The main points of the invalidation decision are as follows:
-for an invention related to cells that can either be obtained from an embryo or be commercially available, it shall be determined that the description excludes the contents on directly obtaining the cells from a human embryo, if:
（1）one of the objects of the invention is to avoid the ethical problems due to obtaining some cells from the embryo,
（2）the description does not include any operation on the embryo; and
（3）it can be determined be a person skilled in the art that there are routes to commercially obtain the cells
-for human cells that do not have the totipotency, if the obtainment and preparation thereof do not involve any process on the destruction or usage of human embryo, the cell per se and the preparation thereof do not involve industrial or business application of human embryos, and it cannot be considered that it is contrary to social morality.
Accordingly, the patent was maintained as valid by the reexamination board. After the invalidation decision was issued, the opponent has appealed to the court. A court hearing was held on January 18, 2018, and a further decision has not been issued. The only issue for the appeal is that social morality issue under Article 5.1.
In another case, the invention is directed to a method of preparing the pluripotent stem cells, kit and use. One claim relates to a method for preparing induced pluripotent stem cells, comprising providing induction factors to differentiated cells. During the prosecution, the applicant cancelled the description on embryonic cells, related experiments and data, and merely experiments and data on adult body cells are maintained in the working examples. Based on these facts, the reexamination board concluded in decision No. 77660 that, even though the iPSCs are pluripotent, they are just similar to embryonic stem cells in property, but are not embryonic stem cells. Accordingly, the method as claimed does not involve the preparation of human embryonic stem cells.
IV. Practical applicability
Principle and Legal Basis
Practical applicability is another notable issue that is often raised during prosecution of patent applications related to regenerative medicine.
It is prescribed in Art. 22.4 of the Patent Law that practical applicability means that, the invention or utility model can be made or used and can produce effective results.
It is further explained in the Guidelines for Patent Examination that, the expression "can be made or used" referred to in Article 22. 4 means that it is possible for the technical solution of an invention or utility model to be made or used industrially. A technical solution that satisfies the requirement of practical applicability shall be reproducible. Reproducibility means that, according to the technical contents disclosed, the technical solution adopted in the patent application to solve a technical problem can be implemented repeatedly by a person skilled in the art. Such repeated implementation shall not rely on any random factors and shall have the same result.
In the field of regenerative medicine, methods for surgery on human or animal body for non-treatment purposes do not have practical applicability.
Representative cases and rulings of reexamination board
In line with the principle and legal basis for practical applicability, the core for determining whether an invention has industrial application may be whether the invention is reproducible, and can be made or used in industry. We may see this in some reexamination decisions.
Regarding autologous products
One invention is directed to an autologous serum complex for the nourishment of skin mesoderm, comprising certain weight parts of fresh infertile autologous serum. In the reexamination decision No. 77419, the board is of the opinion that, for the product claim, the preparation of the products lies in a specific individual, and is performed on a specific individual, which cannot be manufactured industrially. The decision was made in view of the disclosure of the description. It was found that, the fresh serum contained in the product as claimed must be autologous, and thus is personalized, has no practical applicability.
In contrast, in another case which relate to the use of autologous transplants, the decision of the reexamination board (reexamination decision No. 88910) is different from the above one. The invention is directed to the use of autologous transplants in the manufacture of a medicament for treating a subject who is in need of liver or pancreas transplantation, wherein the autologous transplants are obtained by a method comprising inoculating a porous matrix comprising a biologically tolerated polymer with cells to form an autologous implant, wherein the cells are obtained from a subject's living liver cells and pancreas cells.
In reexamination decision No. 88910, the Board held that, if an invention complies with the following requirement, it has practical applicability:
-the subject matter is not directed to a surgery method with a non-treatment purpose,
-the technical solution can be reproducibly carried out, not relying individual or other any random factors and achieving the same result.
Turning back to the patent-in-suit, the Board held that:
-the subject matter as claimed is "use of autologous transplants in the manufacture of a medicament", which does not belong to a surgery method;
-even though it is defined that "the cells are obtained from a subject's living liver cells and pancreas cells," this is just to define the source of the cells, and does not comprise surgery steps of obtaining liver cells and pancreas cells, so the assertion of the previous examiner that such a definition implied unavoidably surgery method is an extension of the technical solution as claimed;
-the "autologous transplants" can be generated from different individuals, and thus the technical solution can be reproducibly carried out, not relying individual or other random factors and achieving the same result, i.e., manufacture of a corresponding medicament.
Based on the above, it is believed by the Board that, the technical solution has the possibility of being produced or used in industry. Further, according to the disclosure of the description, the invention achieved advantages effects. So, the technical solutions of the above claim and its dependent claims are considered as having practical applicability.
In a series of other reexamination decisions including reexamination decisions No. 59995, No. 59167 and No. 99488, the Reexamination Board also held that, the expression "can be made or used" under Article 22. 4 means that it is possible for the technical solution of an invention or utility model to be made or used industrially. If the source of a technical solutions as claimed cannot be industrialized, the invention does not practical applicability. For instance, if the donor applied in the invention can only be dominated by a volunteer, such an invention would not be applied in industry.
In the scenario of the invention addressed in reexamination decisions No. 59995, in the prior art, the neural stem cells which must be used in the application has quite limited source. Besides an embryo, the neural stem cells can only be prepared from the tissues donated by volunteers, and the donation of cells or organs normally are limited for medicine and research purposes, which cannot be applied for business, and cannot serve as the source for industrialization. In the meantime, the applicant also failed to provide any evidence that, besides the domination for the volunteers, other sources (for instance, commercially available sources) are available and can be industrialized.
Inventions which depend on individuals and relate to surgery methods
In addition, for the inventions which depend on individuals and relate to surgery methods, the practical applicability for these inventions are difficult to be established.
As an illustrative case, claim 1 of a patent application is directed to the use of bone marrow mesenchymal stem cells in the manufacture of a medicament for treating Crohn's disease, and the steps for preparing the bone marrow mesenchymal stem cells are defined in the claim, including dilution of posterior superior iliac spine bone marrow sprinkled with heparin diluting solution, and taking the cell surface markers of each generations of the bone marrow mesenchymal stem cells and obtaining the bone marrow mesenchymal stem cells with certain property.
In reexamination decision No. 98995, the Board is of the opinion that, for an invention which is directed to the use of a product using bone marrow as a source via specific methods, if there is no evidence to prove that the raw material, i.e., the bone marrow, is commercially available, it is impossible to exclude the step of obtaining the bone marrow via surgery from a specific human body, and thus the technical solution cannot be made or used industrially, and does not have practical applicability.
Turing back to this case, it is believed that, the use as claimed does not have practical applicability, based on the following grounds:
-it is an indispensable step to obtain the bone marrow raw material, so as to carry out the technical solution as claimed;
-the reexamination petitioner failed to provide evidence to prove that the commercial availability of the bone marrow raw material;
-the petitioner failed to demonstrate in the description that the bone marrow obtained from one donor can be applied into multiple patients, and there is no evidence to support the petitioner's opinion that the marrow bone does not rely on an individual; instead, according to the common knowledge in the art, when mesenchymal stem cells are extracted from bone marrow in clinical trials, the bone marrow is extracted from the body before using, which implies that, in each process of the manufacture of a medicament, bone marrow needs to be extracted from a living human body;
-since the source is not commercially available, rendering that the step of extracting bone marrow from a living human body is a necessary step in the manufacture of a medicament, that is, such a process of manufacture relies on a living human being, by carrying out surgery on the human being, so that the technical solution cannot be produced or used in industry.
Inventions on heterologous products
The patent-in-suit is directed to an isolated hair follicle stem cell, which in certain stage of its growth circle, was obtained from mammalian animals.
The main holding of the Reexamination Board is the same as that in the decision No. 88910. Specifically, the Board held that, the invention as claimed, if an invention complies with the following requirement, it has practical applicability:
-The subject matter is not directed to a surgery method with a non-treatment purpose,
-the technical solution can be reproducibly carried out, not relying individual or other any random factors and achieving the same result.
Turning back to the patent patent-in-suit, the Board held that:
-the subject matter as claimed is "isolated hair follicle stem cell", which does not belong to a surgery method;
-the raw material can be obtained as long as a skin can be obtained; and the obtainment of the hair follicle stem cells from a skin can be performed without relying on a living human or animal body, and thus does not relate to a surgery with non-treatment purpose
-the hair follicle stem cell does not require a particular source of skin, and thus the technical solution can be reproducibly carried out, achieving the same result, i.e., manufacture of a corresponding medicament, without relying on a particular individual or other any random factors.
In another similar case, the Board made a similar decision in decision No. 89329. In that case, the source does not rely on a specific source, and is commercially available. And the practical applicability was acknowledged.
V. Other issues
Besides the above issues, some other issues are also worth of noting, for example, the disclosure of genetic resources.As prescribed in Article 26.5 of the Patent Law, where an invention-creation is developed relying on the genetic resources, the applicant shall indicate the direct and original source of such genetic resources; where the applicant cannot indicate the original source, he or it shall state the reasons thereof.
According to the Guidelines for Patent Examination, "genetic resources" referred to in the Patent Law mean the material obtained from such as human body, animal, plant, or microorganism which contains functional units of heredity and is of actual or potential value. The invention-creation is developed relying on the genetic resources means that the invention-creation is developed relying on the use of the heredity function of the genetic resources. Functional unit of heredity refers to a gene, or a DNA or RNA fragment having heredity function of an organism. With regard to an invention-creation, using the heredity function of the genetic resources refers to, for example, isolating, analyzing and/ or processing the functional units of heredity to develop the invention-creation and to realize the value of the genetic resources. "Acquisition or use of the genetic resources is not consistent with the provisions of the laws and administrative regulations" means that the acquisition or use of the genetic resources is not beforehand approved by relevant administrative departments or licensed by relevant right holder in accordance with the provisions of relevant laws and administrative regulations of China.
VI. Future Perspectives
In the above sections, we discussed the typical issues in the patenting of regenerative medicine in China, with a brief review on a series of reexamination and invalidation decisions. These decisions may reflect the examination standard to some extent. In view of our experiences, current examination practice has been pursued in line with the legal principles as well as the gist of the opinions of the reexamination board.
Among the typical issues, patent eligibility, social morality and practical applicability are most important.
Regarding patent eligibility, we suggested several kinds of possible subject matter which could be covered in the claims. An applicant may consider covering diverse types of claims in an application, for instance, a product claim covering a cell, a tissue, or an organ per se, or a pharmaceutical composition comprising a cell or the extract thereof; a method claim covering the process for preparing a specific cell, tissue, or an organ, methods for oriented differentiation, and methods for treatment with a non-diagnosis or treatment purpose; and Swiss-type use claims.
Regarding social morality, the examination will be conducted in view of the specification as an entirety, including the claims, description and drawings. The bottom line seems that, any human embryo could not be involved in the specification. And, it is not allowable to generate an embryo or a cell with totipotency. But it appears that the iPSCs are allowable under many conditions. This would be clearer if the court make a decision in the case regarding "nuclear preprogramming factor" in the future.
Regarding practical applicability, surgery methods are generally considered as having no practical applicability. Further, under some conditions, the obtainment of raw material may also trigger this issue. For instance, for autologous products, the raw material may be deemed as individualized, and cannot be reproduced in industry. And for heterologous products, it seems to be more likely to establish practical applicability. In brief, for every product, the principle is that, whether the invention is reproducible, and whether it can be produced or used industrially.
Particular attention shall be paid to the source of the materials. The source of the material is related to issues of social morality, practical applicability as well sufficient disclosure. It is advisable to set forth different sources of cells in the description and in the working examples. In case some sources are considered as not complying with relevant provisions, the applicant may cancel them from the description, and alternative options are kept. It would also be favorable for an applicant to list the conventional and stable embryonic stem cell lines which are available before the priority date. With the disclosure of multiple sources of materials, particularly the recitation of the conventional and stable embryonic stem cell lines, an application may go more smoothly towards the grant of a patent right.
In summary, when filing an application or during the prosecution of an application, the applicant is suggested to take the above issues into account. The entirety of the application documents is recommended to be considered in details, so as to advance the prosecution.
The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.