Disclosure of Drug Patent Data in Pharmaceutical Data Protection

第14期 杜文华 中国国家知识产权局专利局 医药生物发明审查部,[Patent]

Two different methods are available for protecting the intellectual property (IP) of pharmaceuticals: protecting pharmaceutical data and protecting the drug patent. The method of protecting pharmaceutical data can be adopted when a drug is registered. A drug that is under a patent protection application, especially the data about its effects, must be fully disclosed for confirmation of its effects. The degree of its disclosure is an academic issue. The following ideas are expounded from the perspective of pharmaceutical data protection in relation to patent disclosure.

I. Protection of Pharmaceutical Data

1.1 The concept of protection of pharmaceutical data

In the course of drug registration, a drug developer must submit relevant undisclosed data to the authorized governmental agency in order to guarantee the safety and effectiveness of the drug. In order to obtain such data, the drug developer has to invest substantial time and money. Currently, a developer needs to spend 10-12 years and USD800 million on the research, development and successful sales of a new drug. To protect the pharmaceutical data is to provide effective protection for the undisclosed data in the course of drug registration by prohibiting future drug protection applicants from relying directly or indirectly on the prior data in their own application for drug registration, so as to protect the developers’ enthusiasm to investment huge amounts for the development of new drugs. At present, the state administrative departments attach great importance to the protection of pharmaceutical data. Article 35 of the Regulations for the Implementation of the Law on Pharmaceutical Administration, which came into force on September 15, 2002, provides that the State protects the independently acquired and undisclosed experiment data and other data submitted by drug manufacturers or sellers that have obtained production or marketing approval for drugs containing new chemical ingredients. Any unjustified commercial use of the said data is forbidden.

1.2 Characteristics and status quo of pharmaceutical data protection

Generally speaking, protection of pharmaceutical data comes in the form of intellectual property rights (IPR) protection after the application for the patent has been filed. As far as the protection provider is concerned, the main responsibility of protecting pharmaceutical data lies with the governmental departments. This is different from patent protection. As to the term of data protection, the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) has no express provisions and most countries provide a time limit of 5-10 years for the approval of the new chemical ingredient. At the time of its joining the World Trade Organization (WTO) China agreed to provide, under Article 39.3 of TRIPS, effective protection for the undisclosed data of drugs and agricultural chemical products containing new chemical ingredients under market license application in order to prevent unfair commercial use. The Measures for the Administration of Pharmaceutical Registration  (hereinafter referred to as the "Measures") (Trial) implemented in China as of December 1, 2002, expressly provides that the term of data protection shall be six years from when the drug administrative department gives the green light for sale of the drug. Other applicants shall submit the data acquired by themselves, promise that all the experimental data was acquired by themselves and guarantee their authenticity when applying for registration. This can properly reward the drug developer who provides undisclosed data, offer convenience to the registration of ‘me-too’ drugs at the expiration of the data protection term, reduce the time and cost of research and development of ‘me-too’ drugs and quicken their entry into the market.

There is a tendency for data protection in the global development of the medical industry. However, it is still a relatively new field to China and its application is almost blank. Most domestic enterprises still take a wait-and-see attitude in data protection, as it is still uncertain as to how the law shall be ultimately enacted. The existing laws are not very influential, so the future legislation becomes a focal point. The future Measures might stipulate that applicants shall provide evidence to prove that the data they provide were all acquired by themselves; applications without such evidence shall not be accepted, and applications without such evidence shall not be approved even if they have been accepted.

1.3 Scope of pharmaceutical data protection

Protection of pharmaceutical data, aimed to protect undisclosed data in the course of drug registration, involves the safety and clinical effectiveness of drugs. Let's first take a look at the data needed to apply for registration of a new drug: Article 29 of the Pharmaceutical Administration Law, enforcement of which came into effect in China on December 1, 2001, provides that "For producing a new medicine, the samples and related materials of production methods, quality indices, and results of pharmacological and toxicological tests, must be submitted as required by the pharmaceutical supervisory and administrative department of the State Council. Only upon approval can clinical tests be carried out. A certificate for new medicine shall be issued by the pharmaceutical supervisory and administrative department of the State Council after the same agency's approval of the new medicine that has gone through clinical tests.

Article 16 (Chapter 3 "Pre-clinical Laboratory Study of Drugs") of the Measures (Trial), the enforcement of which began on December 1, 2002, provides: "The scope of pre-clinical study of a drug for registration includes synthetic process, extraction methods, physical-chemical properties and purity, dosage form selection, screening of formulas, preparation process, inspection methods, specification, stability, pharmacology, toxicology and pharmacokinetics study of animals. For preparations of traditional Chinese medicine, information such as the source and the processing of raw materials should also be included. For biological products, information such as quality standard, storage condition, genetic stability and immunology study of such starting materials as bacterium strain and cell strain as well as biological tissue, should also be included".

Article 25 (Chapter 4 "Clinical Study of Drugs") of the Measures provides that: "Clinical trials and bio-equivalence trials shall be conducted for the registration of a new drug".

Article 26 provides: "Clinical trials are divided into Phase I, Phase II, Phase III and Phase IV. Clinical trials of Phase I, Phase II and Phase III are needed for a new drug application. In some cases only Phase II and Phase III clinical trials, or only Phase III clinical trials, are needed for a new drug application. Included: clinical pharmacology, human safety and effectiveness evaluation studies, observing tolerance in human bodies and pharmacokinetic parameters, as well as dosages".

The protection of pharmaceutical data, as a follow-up protection of drug patents, includes mainly the best formulation and processing related to the safety of a drug, data in such aspects as pharmacokinetics, toxicology and clinical research of drugs of animals and human beings. Therefore, the disclosed data by the patent are, of course, not within the scope of protection. The Measures(Trial), which came into force in China on December 1, 2002, introduces clauses related to China's Patent Law. For instance, Article 11 provides: For the drug or its formulation and manufacture processing, the applicant shall submit documents explaining his patent and ownership of the patent in China, and a letter of guarantee on avoidance of infringement upon others’ patent rights, and commit himself to assuming liability for any possible infringement. Article 13 provides: For a drug subject to patent protection in China, another applicant may apply for registration within two years prior to the patent expiration. The State Food and Drug Administration (SFDA) shall review the application according to the Measures and, after expiration of the patent, approve the production or import application that meets requirements. In this way, the protection of pharmaceutical data and the protection of drug patents form a whole, and constitute an effective protection of drugs. The full disclosure of the data of drug patents will in return influence the contents of pharmaceutical data protection.

In order to strengthen the IPR protection in the course of the examination and approval of drug registration, and to raise the efficiency of drug registration, it is planned that in the next revision of the Measures, the responsibility of related departments shall be clarified, a data platform for drug patents shall be established in the network of the SFDA, and the data shall be provided jointly by the Patent Office of SIPO and the patentees. Other applicants shall submit the evidence of non-infringement if their applications for registration relate to the patents in the data platform. The patentee shall submit the proposal on patent right issued by SIPO, or the ruling rendered by the people's court. The SFDA shall suspend the work of examination and approval thereby, and inform the applicant of the reason of suspension for the parties to resolve their dispute by themselves. For those that have already been approved, the drug approval number shall not be cancelled.

II. Full Disclosure of Drug Patent

2.1 Criteria of full disclosure of drug patent

Protection of pharmaceutical data does not contradict the patent requirements of full disclosure. The purpose for disclosing drug patent data is to obtain a patent, and protection of pharmaceutical data, as a kind of post-patent protection, perfects the IP system. Full disclosure is the prerequisite to obtain patent, and the patent law of every country provides detailed regulations on it. Article 29 of TRIPS provides for the obligations and conditions on patent applicants: Members shall require that an applicant for a patent shall disclose the invention in a manner sufficiently clear and complete for the invention to be carried out by a person skilled in the art and may require the applicant to indicate the best mode for carrying out the invention known to the inventor at the filing date or, where priority is claimed, at the priority date of the application.

Article 26.3 of the Patent Law and Article 2.1.3 of Part II of the Guidelines for Patent Examination require that the patent application shall be disclosed to the degree that a person skilled in the art can carry it out, which means that a person skilled in the art can carry out the technical mode of the invention or utility model in light of the specification, and solve their technical problems and produce the anticipated technical effect. In addition, one situation where the implementation cannot be fulfilled is provided. For example, the specification provides a concrete technical scheme without experimental evidence, while the scheme cannot be realized without confirmation by the experimental result. The above-mentioned situation often occurs during application for a drug patent because medication is an experimental science, and invention in this field is characterized by its heavy reliance on experimental evidence. Generally speaking, the establishment of a reliable invention in the medicinal field must be built on a suitable experimental foundation instead of speculation alone. This is common sense in the medicinal field. That is, to put forward a hypothetical technical scheme to solve relevant technical problems in accordance with the status and rules of the prior art, to validate through experiment whether the scheme is feasible and whether it can solve the technical problems, and then to proceed to conclusion. The inventor, when filing the application, must have mastered the relevant experimental evidence, and must have the ability to record the experimental evidence into the specification, if he has indeed accomplished the invention himself. Therefore, full disclosure of invention of chemical products required by Article 3.1 of Chapter 10 in Part II of the Guidelines for Patent Examination by SIPO is that: If a person skilled in the art cannot forecast from the prior art that the invention can achieve the use and/or effect of use described, the description shall also contain data of qualitative and quantitative experiments, which are, to those ordinarily skilled in the art, sufficient to prove that the technical mode of the invention can achieve the use described or achieve the desired effect. The new pharmaceutical compounds and pharmaceutical compositions shall contain particular medicinal use, pharmacological efficacy, effective amount, and method of use.

2.2 Characteristics of drug patents

The objects of protection of drug patents mainly include new chemical compounds, new medicinal preparations and compounds, new manufacturing process, and new medicinal use of the improved and known drugs, etc. The birth of a new chemical drug needs to go through two stages: "screening" and "development". The work at the screening stage includes preparation of compound, pre-clinical pharmacological study, pre-clinical safety study, and clinical pharmacological study and safety study. This stage might need 1-2 years. Generally speaking, at the end of this stage the enterprise might apply for patent protection. After the screening stage finishes the subsequent stage might be a very long development—the stage of clinical trials. This stage might last for 10 years or so. Therefore, an application for a patent is forward-looking. In fact, in other countries among the great number of patent applications raised by enterprises every year, only about 10% are actually implemented, and the rest are filed just to prepare for future changes in the market.

2.3 Importance of experimental data concerning drug patents

Because of the characteristics of drug patents, the essential experimental data needs to be disclosed when applying for drug patents in order to prove that the invention has been completed at the filing date or at the priority date. This is the primary requirement of patent disclosure. In addition, the experimental data needs to be disclosed in order to support the scope of protection for the claim. The data that prove the effectiveness of the drug may be the result of cell experimentation or animal experimentation, and they can also be the clinical data, which also conforms to the characteristics of the drugs development.

When a patent application is filed for a new chemical compound, it is undoubtedly unfair to the public to grant the desired scope of protection if the scope of the claim of its use is very broad, and the experimental data, if there is any, cannot support so many functions or such broad fields of treatment, or if only a few compounds are invented but compounds of general formula with wider scope are claimed. Therefore, even if the structure of the compound is a pioneer structure, its use also needs sufficient support by certain representative embodiments. The following two examples are used to illustrate the insufficient disclosure of a drug patent:

Example 1: The patent with the application number of 02818189.1 asks for protection of a new derivative of 4,5-dihydro-1H-pyrazle as well as use of the drugs prepared for all diseases related to cannabis (CB1) receptor. The prior art discloses that the pyrazole derivatives are effective CB1receptor antagonist, and that the obstacle of the cannaboid system is related to many kinds of diseases. The description only discloses the preparation and confirmation of 4,5-dihydro-1H-pyrazle. As to the use of the product, paragraphs 2-3 on page 5 of the Description only mentions that the affinities of CB1 receptor with the present compounds were determined using CHO cells having CB1 eceptor, and the change of the quantity of cyclic adenylate was used to determine the vitro antagonism of the compounds. There is no description of the compound actually used, the quantity of the experimental dosage, or the result. At the same time, this application does not mention data about the effectiveness of these compounds to specific diseases either. Therefore, those ordinarily skilled in the art cannot evaluate the amount of the affinities of 4,5-dihydro-1H-pyrazle of this invention with cannaboid receptor CB1, the quantity of dosage needed, and types of interaction between dihydropyrazole derivatives and cannaboid receptor CB1, and thus, those ordinarily skilled in the art cannot judge whether the technical mode is established at the filing date; and also the invention does not provide any description of the effective quantity and its method of use. In sum, those ordinarily skilled in the art cannot carry out the invention according to the content recorded in the Description.

The above example is typical of insufficient data disclosure.

Let's look at Example 2: The patent with the application number of 02812039.6 demands the protection of a kind of sulfonamides, medicinal combination containing them as well as the use of antagonist of urotensin II. The Description discloses the preparation and confirmation of the sulfonamides, but gives no definite dosage and definite compound of the chemical product in the experiment determining the activity of the product. As to the type of dosage of the combination, the dosage per day of the compound is disclosed to be 0.01mg-40mg/Kg. It is obvious that such a wide range does not conform to "the extent to which the effective quantity and method of use should be disclosed so that those ordinarily skilled in the art can carry it out" in accordance with Article 4.1.3 of Part II, Chapter 10, of the Guidelines for Patent Examination. The applicant was hence required to disclose the concrete experimental dosage in its pharmacological embodiment, and the best and optimized dosage if possible.

In sum, most of the data of the new medicinal compound acquired prior to clinic use needs to be disclosed to prove the achievement of the invention patent, support the scope of its protection, and consequently make effective protection accessible to the patent.

2.4 Extent of permitted disclosure of drug patent application

At present, stipulations on Chinese patents do not require the applicants to disclose the best mode they know to implement their invention. Therefore, part of the know-how is allowed to be reserved in the patent application. For instance, temperature, pH value, reagent quantity and effective quantity, etc., involved in the technical plan disclosed in the claim and the description can be stated in a suitable range. The requirement is satisfied so long as those ordinarily skilled in the art can carry out the technical plan of the invention according to the description provided, and it is not necessary to disclose the best numerical value. That is to say, the requirement of "inventiveness" for patent application is lower than the requirement of "pursuing the best embodiment" in research and development. It is satisfied so long as the achievement of research and development, compared with the prior art, "possesses prominent substantive features and represents a notable progress".

However, the applicant should be cautious not to reserve those essential technical features as know-how. Otherwise, the disclosure of patent application would be insufficient. Moreover, the best embodiment is always the best evidence of inventiveness, so we do not think highly of know-how reservation.

III. Further Disclosure of Patent Data Required by the Development of Chinese Drug Market

At present, competition in the international drug market is turning from capital competition to laboratory competition, i.e. scientific and technological competition. The manufacture of drugs in China still focuses on imitation, and most of the innovations are in processing. It is necessary to have certain pharmaceutical IPR protection strategies to effectively protect national scientific interests, benefit the popularization and application of the invention, realize the legislation purpose of promoting scientific advancement and innovation; help the development of "daughter patent" on the basis of the foreign "basic patent", so as to reach the final goal of protecting self-innovation fruits in China. Under conditions when there is no violation of the natural rule of patent, applicants may be required to further disclose the data of drug patents in order to prove completion of the invention and to support the scope of protection of the claim, which will benefit the patent applicants in China by allowing them to obtain protection of pharmaceutical data by themselves.

Acknowledgement: Sincere thanks to Mr. Zhao Xiyuan of the Department of Medicinal and Biological Invention Examination, SIPO, for taking time from his busy schedule to go through this article and advance valuable suggestions.

Abuout the author
    Du Wenhua, Department of Medicinal and Biological Invention Examination, State Intellectual Property Office (SIPO), P.R. China

                                                                                             (Translated by Ma Jing)

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