Recently, the Intellectual Property Tribunal of the Supreme People's Court concluded four administrative disputes involving the invalidation of invention patent rights of the same drug patent products and related cases of disputes over infringement of invention patent rights. The patented product "levonidazole" involved in the four cases is one of the important innovative drugs approved during the "Eleventh Five-Year Plan" period in mainland China, which has attracted much attention. Nanjing Shenghe Pharmaceutical Co., Ltd. (hereinafter referred to as Shenghe Company) is the patentee of two invention patents named "Application of Levonidazole in the Preparation of Antiparasitic Infection Drugs" and "Application of Levonidazole in the Preparation of Anti-anaerobic Bacterial Infection Drugs" (hereinafter referred to as the two patents involved in the case).
Sunwell Company believed that the "levonidazole tablets" drug manufactured by Hunan Warner Pharmaceutical Co., Ltd. (hereinafter referred to as Warner Company) and jointly sold and promised to sell by Warner Company and Dalian CITIC Pharmaceutical Co., Ltd. (hereinafter referred to as CITIC Company) constituted infringement, so it filed two civil infringement lawsuits with the Shanghai Intellectual Property Court.
The Shanghai Intellectual Property Court found in the first instance that Warner and CITIC had infringed the patent rights of Shenghe Company, and ordered Warner Company and CITIC Company to jointly compensate Shenghe Company for economic losses and reasonable expenses totaling 800,000 yuan.
Warner and CITIC were not satisfied and appealed to the Supreme People's Court.
Before Shenghe Company filed two civil infringement lawsuits with the Shanghai Intellectual Property Court, Warner's cooperative company Changsha Huamei Pharmaceutical Technology Co., Ltd. (hereinafter referred to as Huamei Company) filed an invalidation request with the State Intellectual Property Office against the two patent rights involved in The Company. The State Intellectual Property Office (SIPO) made Decisions No. 38074 and 38076 on the Request for Examination of Invalidation (hereinafter referred to as the Decision against The Lawsuit), holding that the patents involved in the two cases were inventive and maintained the validity of the patent rights involved in the two cases.
Huamei Company was not satisfied and filed an administrative lawsuit with the Beijing Intellectual Property Court.
After trial, the Beijing Intellectual Property Court held that neither patent had inventive step and should not be granted a patent right, and ruled to revoke the decision to be sued.
The State Intellectual Property Office and Shenghe Company were not satisfied and appealed to the Supreme People's Court respectively.
The Intellectual Property Tribunal of the Supreme People's Court referred the above-mentioned civil and bank interwoven cases to the same collegial panel for trial to ensure that the collegial panels coordinated their handling of issues such as the validity of patent rights, the determination of the scope of patent protection, and the identification of prior art defenses in the four cases. In administrative cases, the Supreme People's Court held that for pharmaceutical use patents, when judging inventive step, it is necessary to comprehensively and comprehensively consider whether the prior art has given specific and clear guidance. For racemic ornidazole drugs that have been listed, it is necessary to judge whether those skilled in the art will or should not study their chiral enantiomers, and whether they will study the toxicity of chiral enantiomer activities at the same time, which needs to be judged in combination with the overall state of the prior art. If the prior art only gives the general research direction in the field or there is a contrary technical teaching, and there is no clear and specific technical enlightenment on the study of chiral enantiomer toxicity, only based on this to determine that the prior art gives the corresponding technical enlightenment, it is easy to produce the danger of hindsight and underestimate the inventive step of the invention. Accordingly, the second-instance judgment upheld the validity of the patent rights involved in the two cases. On the basis of the administrative case finding that the patent rights involved in the two cases are valid, the collegial panel further clarified in the civil case that the scope of protection of the drug use patent should be subject to the medicinal use clearly recorded in the claims, that is, the activity of the drug, so that the infringement comparison and prior art defense of the patent involved in the case do not need to specifically consider the technical effect of the reduction of the toxicity of levotronidazole.
Upon review, Evidence 1 and Evidence 2 did not disclose the medicinal use of levoonidazole, so the prior art defense claimed by Warner and CITIC could not be established. With regard to the defense of the prior use right claimed by the two companies, since most of the experimental materials submitted by the two companies were later than the date of the patent application in question, and the subject involved earlier than the date was not the two companies, the two companies did not have the subject qualifications to raise the first use right defense with respect to the aforementioned evidence, and the first use right defense could not be established. Based on this, the second-instance judgment found that the allegedly infringing product constituted infringement and upheld the first-instance judgment.
The Intellectual Property Tribunal of the Supreme People's Court has realized the simultaneous trial, coordination and docking and efficient resolution of dispute resolution between administrative cases of confirmation of rights and civil cases of infringement through the "two-in-one" coordinated trial model of unified trial of technical intellectual property administrative and civil appeal cases. On the basis of the coordination and unification of adjudication standards in the two procedures of rights confirmation administration and infringement civil, the four cases realized the balance between the interests of the patentee and the public interest, and finally realized the organic unification of the legal and social effects of the adjudication.
Attached judgment:
Supreme People's Court of the People's Republic
Administrative judgments
(2020) SPC Zhixing Zhong No. 475
Appellant (third party in the first instance, patentee): Nanjing Shenghe Pharmaceutical Co., Ltd. Domicile: No. 9 Huizhong Road, Nanjing Economic and Technological Development Zone, Nanjing, Jiangsu Province.
Legal representative: Wang Yong, chairman and general manager of the company.
Entrusted litigation agent: Tang Tiejun, patent agent of Beijing Wanhuida Law Firm.
Entrusted litigation agent: Liu Qinghui, lawyer of Beijing Anjie Law Firm.
Appellant (defendant in first instance): State Intellectual Property Office. Residence: No. 6 Xitucheng Road, Jimen Bridge, Haidian District, Beijing.
Legal representative: Shen Changyu, director of the bureau.
Entrusted agent ad litem: Chen Yanyan, an examiner of the bureau.
Entrusted litigation agent: Shi Jing, an examiner of the bureau.
Appellee (plaintiff of the first instance and applicant for invalidation): Changsha Huamei Pharmaceutical Technology Co., Ltd. Residence: No. 2423, Pixel Building, No. 109 Guyuan Road, High-tech Development Zone, Changsha, Hunan Province.
Legal representative: Xie Anyun, the general manager of the company.
Entrusted litigation agent: Zeng Di, lawyer of Beijing Zhilin Law Firm.
Entrusted litigation agent: Ma Bowen, lawyer of Beijing Zhilin Law Firm.
The administrative dispute between the appellant Nanjing Shenghe Pharmaceutical Co., Ltd. (hereinafter referred to as Nanjing Shenghe Company), the State Intellectual Property Office and the appellee, Changsha Huamei Pharmaceutical Technology Co., Ltd. (hereinafter referred to as Changsha Huamei Company), over the invalidation of the invention patent rights, involved an invention patent (hereinafter referred to as this patent) in which the patentee is Nanjing Shenghe Company and is named "Application of L-Ornidazole in the Preparation of Anti-Anaerobic Bacterial Infection Drugs". In response to Changsha Huamei Company's request for invalidation of this patent, the State Intellectual Property Office made Decision No. 38076 on the Examination of Invalidation Request (hereinafter referred to as the "Decision to be Sued") to maintain the validity of this patent right; Changsha Huamei Company was not satisfied and filed a lawsuit with the Beijing Intellectual Property Court. The (2019) Jing 73 Xingchu No. 1801 Administrative Judgment rendered by the Beijing Intellectual Property Court on June 10, 2020, ruling: (1) to revoke the decision to be sued by the State Intellectual Property Office; (2) to re-examine the state intellectual property office's request for invalidation of this patent against Changsha Huamei Company. Nanjing Shenghe Company and the State Intellectual Property Office were not satisfied and appealed to this court. After filing the case on October 9, 2020, this court formed a collegial panel in accordance with law and heard the case in public on January 11, 2021 and April 25, 2021. Tang Tiejun and Liu Qinghui, the appellant's entrusted litigation agents of Nanjing Shenghe Company, Chen Yanyan and Shi Jing, the appellant's entrusted litigation agents of the State Intellectual Property Office, and Zeng Di and Ma Bowen, the entrusted litigation agents of the appellee Changsha Huamei Company, attended the court to participate in the litigation. The case is now closed.
The basic facts of this case are as follows: this patent is an invention patent named "Application of Levonidazole in the Preparation of Anti-Anaerobic Bacteria Infection Drugs", the patentee is Nanjing Shenghe Company, the patent number is 200510068478.9, the patent application date is April 28, 2005, and the date of authorization announcement is May 9, 2007. The claims that are the basis for the examination of this case are:
“1． Use of levoonidazole in the preparation of anti-anaerobic infection drugs.
2． The use according to claim 1, wherein the levonidazole is made of a pharmaceutical formulation suitable for clinical use against anaerobic bacterial infection, including oral formulations and intravenous formulations.
3． The use according to claim 2, wherein said oral formulation is a tablet or capsule, the dose of which is administered is 10-40mg / kg / day.
4． The use according to claim 3, wherein said administered dose of 20-30mg / kg / day.
5． The use according to claim 2, wherein said intravenous formulation is sodium chloride injection, glucose injection, sodium chloride - glucose injection, propylene glycol injection or mannitol injection, the administered dose is 5-40mg / kg / day.
6． The use according to claim 5, wherein said administered dose of 10-20mg / kg / day.
7． A pharmaceutical preparation against anaerobic infections, which mainly contains levonidazole as the active ingredient.
8． Pharmaceutical formulations according to claim 7, wherein said pharmaceutical formulation is an oral formulation or an intravenous formulation.
9． The pharmaceutical formulation according to claim 8, wherein said oral formulation is a tablet or capsule.
10． The pharmaceutical formulation according to claim 8, wherein said intravenous formulation is sodium chloride injection, glucose injection, sodium chloride - glucose injection, propylene glycol injection or mannitol injection. ”
On April 2, 2018, Changsha Huamei Company requested the State Intellectual Property Office to declare all the claims of this patent invalid. The main reasons include: (1) this patent specification is not fully disclosed and does not conform to the provisions of Article 26, Paragraph 3 of the Patent Law of the People's Republic of China (hereinafter referred to as the Patent Law), as amended in 2000; (2) claims 1-10 are not supported by the specification and do not conform to the provisions of Article 26, Paragraph 4 of the Patent Law; (3) Claims 1-10 do not have inventive step and do not conform to the provisions of Article 22, Paragraph 3 of the Patent Law.
Changsha Huamei Company submitted the following evidence:
Evidence 1: "Pharmacological effects and clinical applications of ornidazole", Tian Huaiping, Chinese Hospital Drug Evaluation and Analysis, 2002, Vol. 2, No. 5, pp. 303-304, photopic;
Evidence 2: "Lipase-Catalyzed resolutions of both enantiomers of ornidazole and secnidazole", Tian Ping et al., Chinese Journal of Chemistry, 2003, No. 21, pp. 853-857, photocopied and translations Chinese;
Evidence 3: Infection and Experimental Diagnosis of Anaerobic and Microaerobic Bacteria, edited by Zhao Hu, Shanghai Science and Technology Press, January 2005, 1st edition, first printing, cover, title page, copyright page, content summary, table of contents, pages 1-4, 11-13 pages of the main text, back cover, photocopies;
Evidence 4: Experimental Methodology of Pharmacology of Traditional Chinese Medicine, edited by Li Yikui, Shanghai Science and Technology Press, 1991, cover, title page, copyright page, preface, author, table of contents, appendix on page 562, photocopies;
Evidence 5: "Pharmacotoxicology", edited by Zhou Liguo, China Medical Science and Technology Press, first printing of the first edition in August 2003, cover, title page, copyright page, preparation instructions, preface, table of contents, pages 13-14, 148-161 of the main text, photocopies.
In response to the request for invalidation submitted by Changsha Huamei Company, the patentee Nanjing Shenghe Company submitted the following evidence:
Rebuttal 1: "Adverse Reactions of Domestic Tinidazole Tablets", Shi Zongdao et al., Chinese Journal of New Drugs, 1999, Vol. 8, No. 2, pp. 114-115, photocopies;
Counter-evidence 2: Instructions for levonidazole sodium chloride injection, July 15, 2016 (date of last modification), copy;
Counter-evidence 3: "Pharmacokinetics and pharmacodynamics of the nitroimidazole antimicrobials", Kenneth C. Lamp et al., Clin pharmacokinet, May 1999, Vol. 36, No. 5, pp. 353-373, photocopies and partial Chinese translations;
Rebuttal 4: "The Development of Chiral Drugs", He Xuchang, Chinese Journal of Pharmaceutical Industry, 1997, Vol. 28, No. 11, pp. 519-524, photocopies. Among them, page 522 states: "Drug approval authorities in developed countries, such as the FDA in the United States, believe that chiral drugs can better control the disease in the form of a single isomer and simplify the dose-effect relationship." Although drugs applied for racemic are still not excluded, the enantiomers must first be isolated and tested for pharmacology and toxicology, otherwise the enantiomers may be treated as 50% impurities and difficult to approve";
Counter-evidence 5: "Adverse reactions of nitroimidazole drugs", Ma Chuanxue et al., Jiangsu Pharmacy and Clinical Research, 2005, Vol. 13, No. 1, pp. 41-43, photocopied;
Rebuttal 6: "Research Progress on Nitrofurans and Nitroimidazoles", Fu Guo et al., Journal of Qingdao University School of Medicine, December 2003, Vol. 39, No. 4, Photocopies;
Counter-evidence 7: Mechanisms of selective toxicity of metronidazole and other nitroimidazole drugs, David I Edwards, British journal of venereal diseases, 1980, Vol. 56, No. 5, photocopies and translations of Chinese;
Rebuttal 8: "Grundlagen der chemotherapie von trichomoniasis und amoebiasis mit ornidazol", Von R. Richle et al., Arzneimittel forschung drug research, 1978, No. 4, photocopies and translations Chinese thereof;
Rebuttal 9: "Toxicity of ornidazole and its analogues to rat spermatozoa as reflected in motility parameters", W. Bone et al., International journal of andrology, 1997, Vol. 20, No. 6, pp. 347-355, photocopied and translations Chinese;
Counter-evidence 10: The publication date is March 5, 2013, and the disclosure text of the Chinese invention patent application with the publication number CN1400312A;
Counter-evidence 11: National key new product certificate, drug registration approval, new drug certificate, national science and technology major special project acceptance conclusion, copy;
Counter-evidence 12: The "Fact Sheet" issued by Jiangsu Hengrui Pharmaceutical Co., Ltd. and the joint research and development contract signed by Jiangsu Hengrui Pharmaceutical Co., Ltd. and the Shanghai Institute of Organic Research of the Chinese Academy of Sciences, a copy.
On November 28, 2018, the State Intellectual Property Office made a decision to claim that claim 1 of this patent claims protection for the use of levoonidazole in the preparation of drugs against anaerobic infections. Evidence 1 disclosed the pharmacological effect of ornidazole (ONZ), specifically anti-anaerobic effect, of which ornidazole has a strong inhibitory and killing effect on most anaerobic bacteria, and specifically listed the bacteriostatic concentration data of Bacteroides fragilis and Bacillus carboxybidobacteria. In addition, toxicological studies of ornidazole were further disclosed, in which the section on long-term toxicity states that continuous administration of high doses (250 mg/(kg*d)) leads to symptoms of neurotoxicity, and long-term administration of ONZ at the same dose causes later symptoms of neurotoxicity in dogs than metronidazole (MNZ), and its neurotoxicity is a temporary phenomenon and disappears quickly after discontinuation. The pharmacokinetics of ornidazole has also been disclosed.
The conformation of ornidazole is not recorded in Evidence 1, and the chemical name of ornidazole is disclosed in the second paragraph of Evidence 1: 1- (3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole. According to the convention of naming compounds in the chemical field, if no conformation is specified, it is generally believed to refer to racemates, and evidence 1 discloses the racemates of ornidazole. On this point, changsha huamei company and Nanjing Shenghe company did not raise objections. Thus evidence 1 essentially discloses the technical protocol of racemic ornidazole against anaerobic bacteria. The difference between claim 1 and evidence 1 is that levoonidazole is used in claim 1, while in evidence 1 is the racemate of ornidazole.
According to the instructions, the commercially available ornidazole preparations are based on ornidazole racemic as the main drug, and although ornidazole has a good effect on the treatment of anaerobic infections, there are also no small adverse reactions. This patent studies the levotronocyst of ornidazole and finds that in acute toxicological experiments, the LD50 of L-ornidazole is higher than that of racemic ornidazole under various routes of administration, indicating that the safety of L-ornidazole is relatively higher; in the central toxicity experiment, the same amount of levo-ornidazole is compared with dextro-ornidazole and race-canceling ornidazole, and there is no obvious toxic effect on animals in the levo-ornidazole group, and there are manifestations such as salivation and vomiting, which have a certain inhibition of eating and weight, and no obvious case changes are seen in organ histological examination In the dextranidazole and racemic ornidazole administration groups, toxic side reactions such as salivation, vomiting, and convulsions appeared, which had obvious inhibitory effects on eating and body weight, and in the dextro-ornidazole group, there was also a decrease in the number of Purkinye cells and mild deformation. In general pharmacological experiments, the inhibitory effect of levo-ornidazole on the central nervous system was significantly reduced compared with dextro-ornidazole, the effect of racemic ornidazole on the spontaneous activity of mice, and the effect of coordinated equilibrium movement on mice. In addition, in pharmacodynamic studies, the bacteriostatic data of 6 anaerobic bacteria such as Bacteroides and Streptococcus digestion showed that the antibacterial activity of L-ornidazole was basically similar to that of racemic ornidazole. In the course of the oral trial, Nanjing Shenghe Company pointed out that the efficacy of levo-ornidazole and dextrose- and racemic orthotronidazole is comparable; the key to the present invention is to find a decrease in toxicity, especially a lower central toxicity, and the safety is improved. It is thus confirmed that the technical problem actually solved by this patent is to provide a safer anti-anaerobic infection use of drugs that reduce the toxicity (central toxicity) of racemic ornidazole.
Evidence 2 discloses the use of lipase catalyzed methods to split ornidazole to obtain optically pure ornidazole with high enantiomer excess values. Corresponding bioactivity tests are being prepared and the test results will reveal the relationship between the configuration and biological activity of these two chiral drugs. Evidence 2 also discloses that if the active enantiomer of the racemic compound can be used, the dose required thereof can be halved.
Regarding the effect of this patent, when conducting pharmacological experiments, individual differences or experimental errors of animals will affect the experimental results to varying degrees, and to obtain reliable experimental results, it is necessary to avoid the interference of various errors and biases by designing experiments. For acute toxicity experiments, evidence 1 and the toxicity experiments recorded in this patent are carried out under different conditions, respectively, affected by environmental factors, operational factors, animal conditions and other multiple factors, so the LD50 value of the patent's levotronodidazole is directly compared with the LD50 value of racemic ornidazole in evidence 1, which must include the error caused by various factors in different experimental processes. Therefore, it is not possible to conclude that the toxicity of L-ornidazole is comparable or greater than that of racemic ornidazole based on a simple comparison of the absolute values of the two. On the other hand, the acute toxicological experiment carried out in this patent specification is a complete experiment, levo-ornidazole, dextro-ornidazole and racemic ornidazole are experimented under the same conditions to eliminate the system errors that may be caused by the above factors, so by comparing the obtained LD50 values can be concluded that the toxicity of L-ornidazole is less than that of racemic ornidazole.
For the central nervous system toxicity experiment, Changsha Huamei Company converted the dose of dog administration in Evidence 1 to the dose of mice according to Evidence 4 and compared it with the experiments in this patent. First, based on the same reasons described above, considering that the toxicity experiment in evidence 1 is not under the same conditions as the central toxicity experiment of this patent, it is not possible to directly compare the experimental data. Second, due to differences between species, there may be differences in sensitivity between animals for different drugs. For central toxicity models, there are also animal models suitable for different conditions. Evidence 4 is a theoretical value of the equivalent dose ratio table converted according to body surface area, and does not mean that for any drug, especially ornidazole, the dose between various experimental animals such as dogs and mice is strictly converted according to this table. Those skilled in the art in determining the experimental dose, usually on the basis of the table values still need to go through a lot of experimental exploration to determine. On the other hand, the present patent uses the same experimental conditions in the same experiment when performing experiments related to the central nervous system, so by comparing the experimental results it is possible to conclude that the central toxicity of levoonidazole is less than that of racemic ornidazole. Therefore, Changsha Huamei's opinion is not convincing.
Based on the contents of the specification, the purpose of the invention of this patent is how to reduce the toxicity of racemic ornidazole, especially the central toxicity, and not how to split, or how to detect the efficacy and toxicity of the split optical isomer, those skilled in the art generate motivation to select the premise of a particular isomer in the racemic ornidazole, which should be based on the existence of a better technical effect can be achieved by selecting isomers, such as reducing its toxicity, especially the successful expectation of central toxicity. Therefore, the key to whether this patent is inventive is whether the prior art is enlightened in order to reduce toxicity, especially central nervous system toxicity, the use of levotronidazole for pharmaceuticals.
Evidence 1 describes the pharmacological effects, toxicological studies and clinical applications of ornidazole, in which the neurotoxicity is recorded in the experiments on neurotoxicity as a temporary phenomenon, which disappears quickly after discontinuation. In the section on adverse reactions, it is recorded that "the normal dosage of ONZ is relatively safe, and the side effects are mild..." "ONZ as a new drug against anaerobic bacteria, anti-trichomoniasis and anti-amoeba, strong antibacterial power, long half-life, no special toxicity ... Good compliance, low toxicity and low side effects, and good application prospects." It can be seen that evidence 1 believes that the side effects of ornidazole toxicity are mild, and the neurotoxicity is temporary, and it disappears quickly after discontinuation. On this basis, those skilled in the art are not likely to think of further reducing the side effects of ornidazole; and, in evidence 1 does not record how to reduce the central toxicity of ornidazole methods, nor does it involve the mechanism or cause of central toxicity, even for the sake of general drug development considerations, there is no incentive to think of selecting chiral isomers to achieve this purpose. Therefore, evidence 1 itself does not deal with the direction of development on how to reduce toxicity, and does not give enlightenment to reduce central toxicity by selecting chiral isomers.
In the field of toxicology, the toxic effects of chemical substances are the result of their interactions with living organisms and are affected by a variety of factors. From the perspective of the substance itself, the chemical structure determines that it has specific physical and chemical properties and chemical activities. Physicochemical properties such as water solubility, fat solubility, etc. further affect the metabolic conversion process of substances in vivo and thus affect the strength of toxicity. In addition, the pathway by which substances enter the organism may also affect the strength of their toxicity. For drugs, their chemical activity is manifested as both therapeutic activity and toxicity/side effects. It can be seen that those skilled in the art want to reduce the toxicity of known drugs, by changing the structure of the compound, thereby affecting its chemical properties and physicochemical properties, by means of preparation to change its route of administration and / or metabolic processes in vivo and other research and development ideas. The selection of optical isomers is only one of the ideas that may exist, and those skilled in the art will achieve the above purposes through what kind of thinking, need to be combined with the overall situation of the prior art to judge.
In this case, as mentioned earlier, for nitroimidazole drugs, such as ornidazole, metronidazole and tinidazole structurally similar, all include nitro-substituted imidazole rings at the 5-position, the difference is that the N-connected side chains on the imidazole ring are different. The killing effect of such drugs on microorganisms requires the reduction of nitro groups, which subsequently cause DNA strand breakage, and may also include inhibition of DNA repair mechanisms, which in turn exacerbates DNA damage. Metronidazole, tinidazole and ornidazole have similar therapeutic activities and side effects, but differ in degree: for example, page 4 of the rebuttal 3 translation states that ornidazole and other nitroimidazole drugs have the same mechanism of action and antimicrobial activity spectrum for anaerobic microorganisms and protozoles; the disproving 8 Section 3.2.1-3.2.3 test and its test results Table 3-5 show that both Ornidazole and Metronidazole have anti-trichomoniasis, liver amoebic and cecal amoebic activities, while the ED50 and ED90 are not the same The rebuttal 8 translation abstract suggests that neurotoxic symptoms of ornidazole in the high-dose group were also present with other nitroimidazole derivatives, and that ornidazole had later side effects than metronidazole at the same dose. The above facts can prove that the potiodynamic group of nitroimidazole drugs is the nitro group in the molecular structure, and the reduction of nitro is not only the basis for the pharmacological effect, but also the main cause of toxicity. The differences in the side chains and substituents on the side chains of metronidazole, tinidazole and ornidazole lead to differences in their physicochemical properties, for example, the last page of the translation of 8 reverse evidence records that ornidazole is more water-soluble than metronidazole. In summary, metronidazole, tinidazole and ornidazole all have nitro groups on the imidazole ring and the side chains are different, and their efficacy and toxicity are similar but the strength is different. It can be seen that based on the known structure-activity relationship of nitroimidazole drugs, those skilled in the art in order to reduce the toxicity of ornidazole, the usual research and development idea is to modify the structure of the imidazole ring, especially the transformation of the side chain, in the development of nitroimidazole drugs for decades it is along this line of thought that a new generation of drugs such as tinidazole and ornidazole has been obtained.
On the other hand, for the adversarial compound, only the stereo conformation is different, and in general, its physicochemical properties are not different. In this case, the left-handed body of ornidazole is compared to the dextromethosome, and its active group is nitroimidazole, and the active group does not include the chiral center, so the left-handed body and the dextrochanic are only different conformations of the compounds. After the two are split, since the structure of the active group nitro and side chain are the same, combined with the known structure-activity relationship of nitroimidazole drugs, those skilled in the art will expect that their chemical properties and physicochemical properties are similar, without thinking that its activity and / or toxicity will be a large difference. Moreover, Changsha Huamei Company did not provide evidence to prove that the efficacy/toxicity of ornidazole was directly related to the spatial structure of the drug, nor did it prove that the enantiomer had differences in efficacy or toxicity that was foreseeable.
In addition, the abstract of the translation of the disproof 9 also proves that the toxicity of levo-ornidazole and dextro-ornidazole to rat sperm is comparable, further indicating that those skilled in the art tend to derive the toxicity of ornidazole's two optical isomers as expected to be comparable. Thus, based on the foregoing reasons, those skilled in the art on the basis of evidence 1, even in combination with conventional knowledge in the art, can not expect the central toxicity of ornidazole associated with optical isomers, so there is no incentive to think of reducing central toxicity by selecting one of the isomers of ornidazole. Even if those skilled in the art can select isomers of ornidazole by known techniques, it is not expected that the obtained isomers can solve the toxicity of ornidazole, especially the problem of central toxicity. Thus claim 1 is inventive with respect to the combination of evidence 1 and common sense.
Evidence 2 focuses on methods of disassembling racemic ornidazole, but does not measure its biological activity or predict what the activity and toxicity of the isomers will look like. It mentions that "if the active enantiomer can be used, the dose required can be halved", which is only a guess at the active relationship between optical isomers in the general sense, to illustrate the possible advantages of obtaining pure isomers, and does not explicitly reveal what the activity of the two isomers of ornidazole is. Therefore, Evidence 2 also does not give implications for splitting racemic ornidazole and selecting one of the isomers to reduce the central toxicity of ornidazole. Thus those skilled in the art even if on the basis of evidence 1 further combine evidence 2 and the foregoing well-known common sense, can not obtain the technical solution of claim 1 of the present patent. Claim 1 is inventive with respect to the combination of evidence 1, evidence 2 and common sense.
In addition, during the oral trial of Changsha Huamei Company, evidence 4 and evidence 5 were submitted, of which evidence 4 recorded the equivalent dose ratio table between humans and animals according to body surface area, and evidence 5 disclosed the methods and evaluation criteria of acute toxicity experiments. None of the above evidence suggests addressing the problem of central toxicity by splitting the isomers of ornidazole. Claim 1 of this patent is inventive with respect to the combination of evidence 1 and common sense, evidence 1 and evidence 2, and the combination of common sense.
Claims 2-6 are subordinate claims to claim 1, and on the basis that claim 1 has inventive step, claims 2-6 also have inventive step. Claim 7 is inventive with respect to the combination of evidence 1 and common sense, evidence 1 and evidence 2, and the combination of common sense. Claims 8-10 are subordinate claims to claim 7, and on the basis that claim 7 has inventive step, claims 8-10 also have inventive step.
The State Intellectual Property Office hereby decided to maintain the validity of this patent right.
Changsha Huamei Company was not satisfied, and on March 1, 2019, it filed a lawsuit with the court of first instance, requesting: to revoke the decision to be sued and order the State Intellectual Property Office to make a new decision. The facts and reasons are: (1) The decision complained of is wrong in determining the level of personnel in the art and the overall situation of the prior art. Those skilled in the art can think of differences in toxicity and other aspects between the left-handed, dextro-dextrometry and racemic bodies of nitroimidazole drugs based on common sense; the effect of levo-ornidazole recorded in the patent specification does not exceed the reasonable expectations of those skilled in the art; the development of stereochemically pure drugs is a conventional idea in the art, not the initiative of the patentee, and there have been a large number of studies on ornidazole enantiomers in the prior art. (2) The defendant's decision was wrong in determining whether there was technical enlightenment in the prior art. Evidence 2 has been racemic separated to obtain left-handed, dextro-ornidazole, which at the same time has given clear and positive indications of the use of ornidazole enantiomer replacement ornidazole for treatment; evidence 2 "the corresponding biological activity test is being prepared, the test results will reveal the relationship between the configuration of these two chiral drugs and biological activity" has fully demonstrated that those skilled in the art have the motivation to replace ornidazole with ornidazole enantiomer for treatment Although the present patent discloses that there are differences between the toxicity of levo-ornidazole and racemic ornidazole, this discovery does not make the existing technical revelations in the prior art disappear, nor will it prevent those skilled in the art from using levo-ornidazole for the preparation of anti-anaerobic bacterial infection drugs according to the content disclosed in evidence 2, and the difference in toxicity between levo-ornidazole and racemic ornidazole is reasonably expected by those skilled in the art based on common sense, and is not an unexpected technical effect. Thus, claim 1 does not have inventive step, and claim 7 and other claims do not have inventive step.
The State Intellectual Property Office argued that it adhered to the opinions in the decision to be sued, and the decision was to find that the facts were clear, the law was correct, the trial procedure was legal, and the conclusion of the review was correct, and requested that Changsha Huamei Company's litigation claims be rejected.
Nanjing Shenghe Company stated: Agreeing with the opinion of the State Intellectual Property Office, the decision of the lawsuit was clear, the applicable law was correct, and the conclusion of the review was correct, and requested a judgment to reject the litigation claims of Changsha Huamei Company.
The court of first instance determined the above facts after trial. It was also ascertained that during the first-instance trial, Changsha Huamei Company stated that it had no objection to the record of the disclosure of prior art in the decision against the lawsuit, and had no objection to the determination of the distinguishing characteristics of claim 1 relative to evidence 1, but held that claim 1 did not have inventive step.
The court of first instance held that the focus of the dispute in this case was whether claim 1 of this patent complied with the provisions of Article 22,3 of the Patent Law.
Chemistry is an experimental science, drug development is a process of continuous exploration by those skilled in the art under the guidance of existing technology. To determine whether technical solutions such as products or uses involving drugs are patentable, from the perspective of encouraging pharmaceutical companies to innovate and develop and protect the public interest, fully consider the abilities and levels of those skilled in the art themselves, and examine whether those skilled in the art can realize the direction of improvement and find problems on the basis of the closest prior art, and whether there is an incentive to use existing technology to solve the problem.
For chiral drugs, if the compound is known and there is only one chiral center, the disassembly of the racemic compound belongs to the prior art, and those skilled in the art have an incentive to split the compound to seek a better activity or less toxic side effects of the enantiomer, in the absence of unexpected technical effects, the application of the enantiomer compound is generally not creative.
Correspondingly, the State Intellectual Property Office made on July 14, 2019, No. 41175 Invalidation Request Review Decision (hereinafter referred to as Decision 41175) also states: "The prior art has disclosed a racemate of a compound, if the compound has only one chiral center, and the separation of the racemic compound is a conventional technical means for those skilled in the art, and those skilled in the art have the motivation to split the compound to seek a more active enantiomer, then, Even if the enantiomer has relatively better activity than the racemate, the enantiomer compound is still not inventive. "Although the above discussion only involves the characteristics of the activity, according to the usual drug development path, the preclinical study of the drug must include the study of pharmacology and toxicology to determine the scope of action of the drug and the possible toxic reactions, and clinical trials can be carried out after the preliminary approval of the drug administration to ensure the safety and effectiveness of the drug. Therefore, based on the fact that the drugs to be marketed must be studied including efficacy (activity) and safety (toxicity), the above-mentioned statements of the State Intellectual Property Office have similarities with this case.
In this case, claim 1 of this patent seeks to protect the use of levotronidazole in the preparation of drugs against anaerobic bacterial infections, evidence 1 discloses the pharmacological effect of ornidazole (ONZ), and in essence discloses the technical solution of racemic ornidazole against anaerobic bacteria. The difference between claim 1 and evidence 1 is that levoonidazole is used in claim 1, while in evidence 1 is the racemate of ornidazole.
First, the technical implications about Evidence 2. As stated in the decision complained, Evidence 2 discloses the use of lipase-catalyzed methods to split ornidazole to obtain optically pure ornidazole with high enantiomer excess values; the corresponding bioactivity test is being prepared, and the test results will reveal the relationship between the configuration and biological activity of the two chiral drugs; Evidence 2 also discloses that if the active enantiomer of the racemic compound can be used, the required dose can be halved. It can be seen that evidence 2 has been publicly split to obtain a method of obtaining levonidazole, clearly indicating that "if the active enantiomer of the racemic compound can be used, the desired dose can be halved" The effect is expected, on this basis, further states that "the acquisition of ornidazole ... The optical purity of the enantiomer is very necessary." That is, prior to the date of the present patent application, those skilled in the art know that ornidazole has a chiral center, and it is known how to split to obtain a single enantiomer, there is an incentive to split the optical purity of the single enantiomer obtained for subsequent drug development. Evidence 2 describes the splitting of ornidazole recognized that its enantiomers can be used for antimicrobial applications, and that the purpose of its splitting is also to use its enantiomers instead of ornidazole for antimicrobial applications. Therefore, evidence 2 has given technical implications for the use of ornidazole enantiomers instead of ornidazole for antimicrobial applications.
It should be noted that, for those skilled in the art, the starting point of the technical enlightenment is whether or not to study the single enantiomer of ornidazole, rather than specific to how to choose a method to reduce the central toxicity of ornidazole. If those skilled in the art are motivated to study the druggability of ornidazole enantiomers, then the discovery that one of its enantiomers has a higher activity and / or less toxic effect is only an inevitable result of the study, unless such an effect reaches an unexpected degree, otherwise, will not give a particular enantiomer application of creativity. Therefore, to determine whether claim 1 is inventive, the key is to see whether those skilled in the art have an incentive to further develop its single enantiomer into a drug when faced with the racemate of ornidazole described in evidence 1. Since evidence 2 has clearly stated that the single enantiomer of ornidazole has a good development prospect, those skilled in the art are obviously motivated to study its enantiomer, for drug research and development, safety and efficacy are necessary research content.
Second, about the technical effect. First, prior to the date of the present patent application, the art is known to have central nervous system toxic side effects, including headache, dizziness, convulsions and other symptoms. As described above, under the guidance of evidence 2, those skilled in the art have the motivation to split the ornidazole enantiomer and conduct further studies. For those skilled in the art, on the basis of evidence 2, to confirm the efficacy of a single enantiomer and eventually become a drug approved for marketing, it is necessary to know the use of the anti-anaerobic drug prepared by levonidazole claim 1, and it is also necessary to conduct safety tests to understand the safety situation including known central system toxic side reactions. Secondly, in the process of developing levotronidazole, a "head-to-head" comparative study with the known drug ornidazole is a common practice in the art. According to the description of this patent, the order of the size of the central toxic side effects shown is as follows: levo-ornidazole< racemic ornidazole< dextro-ornidazole, but it only confirms the difference in toxic side effects between the racemate and the two enantiomers, and the above difference is only reflected in the amount of observation results of animal tests in 4 Beagle dogs, and the difference in this toxic side effect is difficult to constitute an unexpected technical effect. In fact, it is well known in the art that prior to the date of this patent application, the Drug Evaluation Center has proposed that chiral drugs should strengthen the control of the optical purity of raw materials, for a class of optical isomers, the efficacy and toxicity test data of each optical isomer should be provided, so as to strictly control the toxic isomers in quality standards. That is, prior to the date of the present patent application, those skilled in the art know that chiral drug research and development must be in-depth (R) and (S) enantiomers, and should be carried out corresponding toxic side effects study. Therefore, whether from the perspective of the drug development path, or from the description of this patent specification, the application of levo-ornidazole in claim 1 against anaerobic infection has not achieved unexpected technical effects.
Third, about research and development ideas. The decision pointed out that "those skilled in the art in order to reduce the toxicity of ornidazole, the usual research and development idea is to modify the structure of the imidazole ring, especially the transformation of the side chain, and it is along this line of thought that a new generation of drugs such as tinidazole and ornidazole has been obtained in the decades of the development of nitroimidazole drugs." However, those skilled in the art also know that structural modification has a problem of high risk of research and development, and has relatively large uncertainties in terms of drug efficacy and safety, in contrast, the uncertainty of splitting the study of a single enantiomer will be relatively small. In any case, the separation of a single enantiomer is at least one of the methods of those skilled in the art to reduce racemate toxicity or improve racemate activity, those skilled in the art will not be because of the nitro group in the pharmacodynamic molecular structure of nitroimidazole drugs, and abandon the development of a single enantiomer toxicity.
In summary, prior to the date of the present patent application, those skilled in the art known evidence 1 of the ornidazole has an anti-anaerobic effect, it is also known that ornidazole is a racemate and it has only one chiral center, including a conveniently detachable enantiomer having an optically pure enantiomer, evidence 2 has given the use of ornidazole enantiomer alternatives to ornidazole for antibacterial applications technical implications, and the split single enantiomer as a drug, must confirm its safety and efficacy, The application of levoonidazole in anti-anaerobic infection in claim 1 is not an unanticipated technical effect. Accordingly, the respondent decision found that claim 1 was inventive and that the conclusion was wrong and should be corrected in accordance with law. On this basis, the judgment of the respondent on the determination of inventive step in claim 7 and other claims is also wrong and should be corrected according to law.
In accordance with the provisions of Items 1 and 2 of Article 70 of the Administrative Procedure Law of the People's Republic of China, the court of first instance ruled that: (1) the State Intellectual Property Office made a decision to revoke the examination decision of the request for invalidation of No. 38076 made by the State Intellectual Property Office; (2) the State Intellectual Property Office made a new examination decision against the request for invalidation of the invention patent No. 200510068478.9 submitted by Changsha Huamei Pharmaceutical Technology Co., Ltd. The acceptance fee for the first-instance case is 100 yuan, which shall be borne by the State Intellectual Property Office.
Nanjing Shenghe Company appealed to this court against the first-instance judgment, requesting: 1. Revocation of the first-instance judgment; 2. Upheld the decision to be sued. The facts and reasons are: (i) the court of first instance did not follow the three-step approach in creative judgment. In the process of determining whether the patent has inventive step, the first-instance judgment avoided the technical problems actually solved by the patent, and erroneously determined that the prior art gave corresponding technical enlightenment. In the three-step method, in terms of the technical problems actually solved, the content of the prior art as a whole should and must be fully considered, whether those skilled in the art can based on the teaching of the prior art, obtain the use of distinguishing technical features to improve the inspiration and motivation closest to the prior art. However, in the absence of determining the technical problems actually solved by this patent, the court of first instance talked about the technical enlightenment of evidence 2, the technical effects of this patent and the research and development ideas, especially the interpretation of evidence 2 as a person skilled in the art must study ornidazole isomers under its guidance, and then draw erroneous conclusions. (2) The court of first instance has made an error in determining that the patent does not have inventive step, and the patent is inventive in relation to the combination of evidence 1 and 2 and common knowledge. 1. Those skilled in the art have no incentive to improve and obtain this patent on the basis of evidence 1. According to the content recorded in evidence 1, ornidazole shows good efficacy in anti-anaerobic bacteria, anti-vaginal trichomoniasis and anti-amoeba protozoa, and there is no long-term toxicity, only brief neurotoxicity and disappears quickly after discontinuation. 2. Those skilled in the art can not obtain technical inspiration for reducing the toxicity of racemic ornidazole from evidence 2. First, Evidence 2 is different from the technical issues addressed in this patent. The technical problem to be solved in this patent relative to evidence 1 is to provide a use that reduces the toxicity of racemic ornidazole (especially central toxicity) and makes the use of drugs safer against anaerobic bacterial infections. The technical problem solved by Evidence 2 is how to obtain ornidazole enantiomers with high enantiomer excess values. Secondly, the invention concept of Evidence 2 is completely different from this patent. Evidence 2 was only a split of racemic ornidazole for the purpose of obtaining a single enantiomer, and no further studies were conducted on the pharmacological activity and toxicity of the split single enantiomer, nor did the corresponding pharmacological activity and toxic effect data were obtained. Finally, Evidence 2 does not give technical implications for reducing toxicity. Evidence 2 only mentions that the bioactivity test is being prepared, and does not record the specific method of the bioactivity test, and does not give the corresponding bioactivity effect data. Thus, evidence 2 also does not teach how to solve the technical problem of reducing the toxicity of racemic ornidazole, those skilled in the art can not obtain technical inspiration from evidence 2. 3. Prior art does not give enlightenment to reduce central toxicity by splitting ornidazole optical isomers. (1) Evidence 3 submitted by Changsha Huamei Company disclosed that the biologically active types of chiral drugs have six situations, whether it is pharmacological activity or toxicity, there are large differences. (2) Disproof 9 studied the reproductive toxicity of levo-tron and dextro-ornidazole, and concluded that there was no difference in the reproductive toxicity of L-ox-8-8 unirazole. There are also pharmaceutical companies that have studied the medicinal problem of ornidazole optical isomers, but their focus is only on drug activity. (3) Although the U.S. Food and Drug Administration issued chiral drug guidance (hereinafter referred to as the U.S. FDA guidance document) in 1992, requiring in principle all new racemic drugs applied for marketing in the United States, manufacturers need to provide reports describing the respective pharmacological effects, toxicity and clinical effects of the enantiomers contained in the drug, but this does not mean that those skilled in the art need to do comprehensive testing of the pharmacokinetics, pharmacology and toxicology of each enantiomer of all listed chiral drugs. First of all, ornidazole was listed earlier than the US FDA guidance document. Second, the evidence in the case shows that the enantiomer of ornidazole has been split at least in 1997, but there have been no reports of the use of levotronidazole to solve the central toxicity problem before the date of this patent application. In summary, the prior art does not give enlightenment to reduce central toxicity by splitting ornidazole optical isomers. Those skilled in the art can not expect the technical effect of reducing toxicity achieved by this patent. 4. This patent has unexpected technical effects. First of all, the patent specification records the technical effects of this patent. Toxicity tests and general pharmacological tests of beagle dogs described in this patent specification have shown that levotronidazole can significantly reduce the central toxicity of ornidazole. Second, clinical trial results may further support the effect of the present invention. The results of phase II clinical trials show that while maintaining the therapeutic activity of ornidazole, levotronidazole significantly reduces adverse reactions in humans, especially nervous system adverse reactions such as dizziness, dizziness and headache. Third, the patented product "Levonidazole Sodium Chloride Injection" of Nanjing Shenghe Company is one of the only two approved independent innovation drugs during the "Eleventh Five-Year Plan" period in the mainland, and it is also a major special project of national major new drug creation science and technology, which has won many awards such as the National Key New Product of the Ministry of Science and Technology in 2010 and the 17th China Patent Excellence Award. After the aforementioned patent was granted in the mainland in 2007, it was also granted in Europe and the United States, and the above facts are enough to prove that the patent has achieved unexpected technical effects. Finally, the patent application submitted by Changsha Huamei Company on November 18, 2005 "Pharmaceutical Compositions Containing Levonidazole and Their Applications" and the promotional materials of Changsha Huamei Company's "Levonidazole Tablets" drugs also clearly record the technical effect of levoonidazole can reduce the toxicity of the central nervous system of Ornidazole, thus confirming the technical effect of this patent. (3) Decision 41175 should not be referred to in this case. Decision 41175 was made later than the decision at issue, which has not yet entered into force and which deals with a far cry from the field covered by the present case and is not referable. The first-instance judgment invoked the invalidation decision to evaluate the inventive step of the patent and found that it was wrong.
The State Intellectual Property Office appealed to this court against the first-instance judgment, requesting: 1. To revoke the first-instance judgment; 2. to uphold the decision to be sued. The facts and reasons are: (1) The court of first instance made an error in its determination of the technical enlightenment. The court of first instance did not consider the technical effect of reducing the toxic side effects of ornidazole obtained in this patent, nor did it determine the technical problems to be solved by this patent, but directly determined the starting point of technical enlightenment. Evidence 2 only records the method of splitting ornidazole enantiomers, and does not detect the possible activity and toxicity of ornidazole enantiomers, nor does it analyze and predict their possible activity and toxicity. Those skilled in the art know that the difference in activity between two optical isomers is not always simple equal or unequal strength of these two cases, so evidence 2 is more like aimless speculation, those skilled in the art can not obtain technical inspiration from evidence 2 to study the enantiomers of ornidazole and the corresponding toxicity. (2) The court of first instance has made an error in determining that the patent has not achieved unexpected technical effects. Even if those skilled in the art have an incentive to split the ornidazole racemic in evidence 1, and then test its toxicity and activity, it is also necessary to consider whether those skilled in the art have a reasonable expectation that levonidazole has a reduced toxicity effect. 1. Combined with the understanding and research and development history of those skilled in the art on nitroimidazole compounds, the counter-evidence 6 discloses that the nitro group on the imidazole ring is the source of pharmacological activity and toxicity, while the left-handed and dextro-ornidazole are only different conformations, and do not change the structure of the compound, the structure-activity relationship of the compound has been relatively clear, the key part of the activity and toxicity is in the nitro group and even the group that has an impact on the reduction of the nitro group, and the chiral carbon atoms of ornidazole are not located on the active and toxic center group. 2. The physical and chemical properties of left-handed and dextro-ornidazole are the same, and the reproductive toxicity of the two has been verified to be comparable in counter-evidence 9, based on this, those skilled in the art will also expect that the central toxicity of left-handed and dextro-ornidazole is roughly equivalent, and there is also considerable central toxicity after the formation of racemates. However, the present patent verifies that the toxicity of the two is still quite different under the premise of equal activity of L-ornidazole and racemic, exceeding the general expectations of those skilled in the art, and achieved unexpected technical effects.
Changsha Huamei Company argued: (1) There were errors in the claims of Nanjing Shenghe Company and the State Intellectual Property Office on the technical problems to be actually solved in this patent. 1. The technical problem to be solved in this patent is the therapeutic use of levoonidazole anti-anaerobic bacteria. 2. The technical problems actually solved in this patent have nothing to do with central toxicity. For inventions of use of known products, their technical contribution does not lie in the improvement of the product structure, but in the discovery of new properties of the product and the discovery of new uses resulting from the use of the new properties, i.e., the discovery of new activities, which should be considered in the judgment of inventive step as a technical problem solved by the invention. Toxicity, bioavailability, etc. are only the detection results of the inherent properties of the known product, and have nothing to do with the technical contribution of the invention, and are not technical problems actually solved by the invention. This patent belongs to typical known product uses, central toxicity is not the property that determines whether levoonidazole can be used against anaerobic bacteria, and should not be used as a technical problem actually solved by the invention. 3. Both the Patent Examination Guidelines and previous judicial practices make it clear that the determination of inventive step in the pharmaceutical use of a known product is based on the consideration of activity that has a causal relationship with the medicinal use, not toxicity. (2) The prior art has given clear technical enlightenment, and this patent does not have inventive step. 1. Evidence 2 clearly teaches that ornidazole enantiomer can be used to replace ornidazole for anti-anaerobic bacteria, antiparasitic therapy, for this purpose, levonidazole is split to obtain and instruct those skilled in the art to further detect its activity, and those skilled in the art can know according to common sense that levotronectron, dextronidazole must have at least one therapeutic activity of ornidazole. That is, those skilled in the art are only selected in a very limited range of two choices, and there is a sufficient expectation of success of the results "at least one enantiomer can replace ornidazole for related treatments". 2. Evidence 3 and 4 show that the research and development of chiral drugs has been a hot spot and an inevitable trend in drug research, and those skilled in the art have sufficient motivation to obtain the technical solution of this patent according to the teaching of evidence 2 and common sense. (c) this patent does not produce unexpected technical effects. 1. Central toxicity is not the indication to be treated by levo-ornidazole, whether it has the effect of reducing central toxicity, it does not affect the use of levo-ornidazole for anti-anaerobic bacteria. 2. Even considering central toxicity, the toxicity data of levonidazole did not exceed the reasonable expectations of those skilled in the art, and did not produce unexpected technical effects. The toxic side effects of levotronidazole and ornidazole disclosed in this patent specification are not much different, and there is no technical effect of significantly reducing toxicity. Those skilled in the art based on common sense, can reasonably foresee that there are differences in activity, toxicity, etc. between enantiomers and racemics, etc., and the fact that the central toxicity of levonidazole claimed in the present patent is slightly weaker does not exceed the cognition of those skilled in the art of the toxicity differences of chiral drugs. In summary, the first-instance judgment found that the facts were clear and the law was applied correctly. The first-instance judgment was upheld and the appeal request of Nanjing Shenghe Company and the State Intellectual Property Office was rejected.
During the second-instance trial of this case, none of the parties submitted new evidence, and none of them objected to the first-instance judgment's determination of the authenticity, legality, and relevance of the evidence involved in the case.
After trial, this court ascertained: The facts determined by the court of first instance are true, and this court confirms them.
The Court also ascertained:
(1) The circumstances of this patent
The content of the invention in this patent specification is partially stated: Clinical use shows that ornidazole has a good effect on the treatment of anaerobic infection, but there are also no small adverse reactions. In order to maintain and enhance this therapeutic effect and reduce adverse reactions, the pharmacokinetics, pharmacodynamics, toxicology, general pharmacology and other experimental studies of the left-ionazole of ornidazole were carried out, and it was found that the pharmacokinetic properties of levo-ornidazole were superior to those of de-oxnidazole and racemic ornidazole, and the central toxicity was lower than that of dextro-ornidazole and racemic ornidazole, so it was more practical to use levo-ornidazole for the preparation of anti-anaerobic infection drugs.
(2) Prior art situation
Evidence 1 states that the new nitroimidazole drug ornidazole ONZ was introduced in the 1970s by the Swiss company Roche under the trade name Tiberal and included in the Czech Pharmacopoeia (1991 edition). At present, ornidazole preparations have been listed as four new drugs in the mainland. Other parts of article 1.4 record: Ornidazole has an inhibitory effect on the activity of male rat sperm, reduces rat fertility at high doses, shows a contraceptive effect, and its effect recovers naturally soon after discontinuation, suggesting that ornidazole has no effect on sperm production, and may play a role by affecting epididymis function. The 5th adverse reaction part records: the normal dosage of ornidazole is relatively safe, the side effects are mild, and the acute and subacute toxicity of oral and intravenous injections is low... As a new anti-anaerobic, anti-trichomoniasis and anti-amoeba, ornidazole has strong antibacterial power, long half-life and no special toxicity. Its clinical efficacy is accurate, the applicable population is wide, the compliance is good, the toxic side effects are low, and there are good application prospects.
Counter-evidence 6 records that nitrofurans and nitroimidazole drugs have the same pharmacodynamic group - nitro, and the reduction of nitro is not only the basis for the occurrence of pharmacological effects, but also the main cause of toxicity. The occurrence of chloramphenicol-related dysplasia anemia is associated with DNA damage caused by nitro reduction.
Disproof 9 records that the in vitro toxicity of ornidazole derivatives depends on the presence of halogens and the location of the nitro group, and by direct incubation, the presumed inactive (R)-ornidazole exhibits the same inhibition of sperm motility as the active (S)-ornidazole. This observation and the difference in the ex vivo effects of different ornidazole-like objects show that the different mechanisms of sperm motility inhibition under the two experimental systems... Comparison of (R)-ornidazole and (S)-ornidazole, the motility inhibition effect of direct incubation of sperm for 4h showed no difference between enantiomers.
Disproof 12 Jiangsu Hengrui Pharmaceutical Co., Ltd. issued a "situation note" recorded that the company had commissioned the Shanghai Institute of Organic Chemistry in August 2000 to conduct a separation study of ornidazole racemics. The company conducted drug research and development work, including activity determination, on the separation of the obtained L-Y optical isomers and control of racemic ornidazole. The results showed no significant difference in the activities of levo-ornidazole, dextro-ornidazole and racemic ornidazole, so the Division discontinued the project in December 2003.
Changsha Huamei Company submitted "Chiral Drugs - Research and Application" in the first instance, written by You Qidong and Lin Guoqiang, Chemical Industry Press, January 2004, the first printing of the first edition. Among them, the preamble records that the US Food and Drug Administration (FDA) clearly stipulated as early as 1992 that drugs containing chiral factors tend to develop single enantiomer products; for racemic drugs, detailed biological activity and toxicity studies of stereoisomers are required. In recent years, the Mainland Food and Drug Administration (SFDA) has also made corresponding regulations for the research and development of hand drugs. The biological activity research part of the first part of the chiral drug records that according to the different characteristics of the stereoselectivity of the drug, the biological activity type of chiral drugs is divided into the following types: the two enantiomers have the same effect; the two enantiomers have opposite effects; one enantiomer has pharmacological activity, the other has weak or inactive; the two enantiomers have different pharmacological activities; one enantiomer has pharmacological activity, the other has toxic effects; the enantiomers are complementary.
(3) Other ascertained facts
1. The US FDA guidance document advocates: in the development of new drugs containing chiral factors, it is inclined to develop a single enantiomer product, and the main pharmacological activities of isomers should be compared in vitro and in vivo systems. When using a relatively benign toxicological profile of a racemate, there is no need for a separate toxicological evaluation of a single enantiomer, unless an unintended toxic effect other than a pharmacological effect occurs, and the exposure dose is relatively low compared to the clinically intended dose, a separate toxicity study of the single isomer must be performed to determine which isomer is producing the unintended toxicity that occurs.
2. Before the date of this patent application, the Drug Evaluation Center of the Mainland Food and Drug Administration also proposed that chiral drugs should strengthen the control of the optical purity of raw materials, and for a class of optical isomer drugs, provide the efficacy and toxicity test materials of each optical isomer, so as to strictly control the toxic isomers in quality standards.
3. Article 16 of the Measures for the Administration of Drug Registration (Trial Implementation) (implemented in 2002) of the Mainland Food and Drug Administration stipulates that the preclinical research of drugs for the purpose of applying for drug registration includes the synthesis process, extraction method, physical and chemical properties and purity, dosage form selection, prescription screening, preparation process, testing method, quality indicators, stability, pharmacology, toxicology, animal pharmacokinetics, etc. Traditional Chinese medicine preparations also include the source, processing and preparation of raw medicinal materials, etc.; biological products also include the quality standards, preservation conditions, genetic stability and immunology of starting materials such as bacterial poison species, cell lines, and biological tissues.
The Court held that the patent law amended in 2000 should be applied in this case after the effective date of the Patent Law amended in 2000 (July 1, 2001) and before the effective date of the Patent Law amended in 2008 (October 1, 2009). The focus of the dispute in the second instance of this case was whether the patent possessed the inventive step provided for in paragraph 3 of Article 22 of the Patent Law. Specifically, it mainly includes the following aspects: (1) whether the technical problems actually solved by the patent determined by the lawsuit decision are correct; (2) whether the prior art as a whole gives technical enlightenment.
(1) Whether the technical problems actually resolved in this patent as determined by the decision being sued are correct
The three-step method of inventive step judgment requires that the nearest prior art be determined first, and then the distinguishing technical characteristics between the claimed invention and the nearest prior art are analyzed, and the technical problem actually solved by the invention is determined according to the technical effect that the distinguishing technical features can achieve in the claimed invention. Finally, from the technical problems actually solved above, it is judged whether the claimed invention is obvious to those skilled in the art. The technical problem actually solved by the invention refers to the technical task of improving the prior art in order to obtain better technical results. When specifically determining the technical problems actually solved by the invention, it shall be based on the distinguishing technical characteristics between the patent and the closest prior art, and the technical effects recorded in the patent specification and supported by evidence may be used as a reference for determining the actual solution of the technical problems of the invention.
In this case, Nanjing Shenghe Company and Changsha Huamei Company had no objection to the defendant's decision to use Evidence 1 as the closest prior art to this patent, and to the determination that the distinguishing technical features of the two were "levotronidazole used in claim 1 and racemates used in Evidence 1". However, Nanjing Shenghe Company and the State Intellectual Property Office believe that based on the above-mentioned distinguished technical characteristics, the technical problems actually solved in this patent are to provide a use to reduce the central toxicity of racemic ornidazole and use drugs more safely against anaerobic bacteria infection; Changsha Huamei Company believes that the technical problems actually solved by this patent should not be considered for the reduction of central toxicity of levo-ornidazole, but only provide the anti-anaerobic bacterial infection use of levo-ornidazole. In this regard, our hospital believes that according to the patent specification, ornidazole has adverse reactions in the treatment of anaerobic infections, mainly manifested as central inhibitory effects. This patent aims to maintain and enhance the therapeutic effect and reduce adverse reactions, after the pharmacokinetic, pharmacodynamic, toxicological, general pharmacology and other experimental studies of levo-ornidazole, it was found that the pharmacokinetic properties of L-ornidazole are better than those of racemic ornidazole and dextro-ornidazole, and the central toxicity is lower. The present patent specification also details the toxicity experimental data of intravenous injection of levo-ornidazole, racemic ornidazole and dextro-ornidazole in mice and Beagle dogs. Therefore, in light of the technical characteristics of the difference between this patent and evidence 1, and the technical effect that levonidazole is better than racemic ornidazole and dextronidazole in terms of pharmacokinetics and lower central toxicity, the technical effect of the alleged decision on the actual solution of this patent is to provide a reduction in the toxicity of racemic ornidazole (central toxicity) and a safer use of anti-anaerobic bacteria infection, which is not improper, and the hospital confirms.
(2) Regarding whether the prior art as a whole gives technical enlightenment
In the three-step method of inventive step judgment, when judging whether the prior art gives the revelation of applying distinguishing technical features to the closest prior art to solve the technical problems that exist therein, it should be based on the knowledge and ability of those skilled in the art, and examine whether such revelation will enable those skilled in the art to have the motivation to improve the closest prior art and obtain the invention claiming protection when faced with the technical problems described. If this technological revelation does not exist in the prior art, the invention is non-obvious. Moreover, the technical inspiration that those skilled in the art can obtain from the prior art should, in principle, be specific and clear technical means, rather than abstract ideas or general research directions. Based solely on abstract ideas or general guesses in the field, it is easy to underestimate the inventive step of an invention. Because those inventions that appear to be obvious on the surface may in fact also be inventive, it is necessary to comprehensively, carefully and realistically assess whether a person skilled in the art can easily derive a technical solution for the patent based on all the prior art known to the patent in the face of the technical problems to be solved by the patent.
Especially in the field of pharmacy, invention patents for the use of known compounds are inventions based on the discovery of new properties of known compounds and the use of new properties. The core of protection of invention patents for the use of known compounds lies not in the compound itself, but in the application of new properties of the compound. For a patent for a pharmaceutical use invention of a known compound, if those skilled in the art have no "reasonable expectation of success" for the medicinal use or effect of a known compound, that is, the medicinal use or effect can not be obviously derived or foreseen from the structure, composition, molecular weight, known physicochemical properties of the compound itself and the existing uses of the compound, but utilizes the newly discovered properties of the compound, and produces a beneficial technical effect, exceeding the reasonable expectations of those skilled in the art, The invention of a medicinal use of such a known compound should be considered inventive.
1. Regarding whether the prior art discloses distinguishing technical features
First, about evidence 2. Evidence 2 discloses the use of lipase catalyzed methods to split ornidazole to obtain optically pure ornidazole with high enantiomer excess values. According to the contents disclosed in evidence 2, although it gives clear guidelines for the separation of ornidazole to obtain chiral enantiomers and the detection of ornidazole chiral enantiomer biological activity, it does not disclose the activity data of ornidazole chiral enantiomers, nor does it mention the toxicity of ornidazole, let alone mention the distinguishing technical feature of using levo-ornidazole alone for anti-anaerobic infection. Evidence 2's statement that "if the active enantiomer of a racemic compound can be used, the dose required can be halved" is only a guess by the author about the active relationship between optical isomers in the general sense, and does not explicitly point out or enlighten the difference in activity between the two isomers of ornidazole.
Secondly, regarding the "Chiral Drugs - Research and Application" submitted by Changsha Huamei Company in the first instance. According to the above evidence, the biological activity of chiral drugs has a variety of different situations: two enantiomers have the same effect; two enantiomers have opposite effects; one enantiomer has pharmacological activity, the other is weak or inactive; the two enantiomers have different pharmacological activities; one enantiomer has pharmacological activity, the other has toxic effects; the action of enantiomers is complementary, etc. It can be seen that those skilled in the art can not reasonably expect the biological activity or toxicity of the split levo-ornidazole, nor does it explicitly mention the differential technical characteristics of the levo-ornidazole alone for anti-anaerobic infection.
2. Regarding whether the prior art gives sufficient technical enlightenment to those skilled in the art
First, even under the guidance of evidence 2, those skilled in the art proceeded to determine the biological activity of ornidazole chiral enantiomers, when the measurement found that the activity of left and right ornidazole is quite different, and even the ornidazole anti-anaerobic bacteria activity is provided by only one enantiomer, it is possible to select an active enantiomer to prepare an anti-anaerobic bacteria infection drug, thereby achieving the purpose of halving the dose of the agent. However, according to the present patent, the activity of left-handed, dextro-ornidazole and racemic ornidazole is comparable, according to which it can be supported, those skilled in the art even when measuring the chiral enantiomer activity of ornidazole obtained by splitting evidence 2, will also obtain similar conclusions. Disproof 12 also corroborates the fact that there are no significant differences in the activity of levo-ornidazole, dextro-ornidazole, and racemic ornidazole. In the case where the objective of "if the active enantiomer of the racemic compound can be used, the required dose can be halved" set in evidence 2, and evidence 2 does not expressly indicate that the toxicity of the paraphile is to be further determined, those skilled in the art have no incentive to conduct further research and analysis on the toxicity of the enantiomer of the adversarium. In particular, the rebuttal 9 translation abstract gives the opposite teaching, proving that the toxicity of left-handed and dextro-ornidazole to rat sperm is comparable, further illustrating that those skilled in the art tend to derive the toxicity of ornidazole's two optical isomers equivalent to the expectation. In view of the splitting chiral enantiomer to increase the cost of medicine, those skilled in the art for the low toxicity of the technical effect of levonidazole has no "reasonable expectation of success", will not be split to obtain levotronidazole or dextronidazole alone drug.
Second, even if the content disclosed in Evidence 1 is revisited, there is no clue that can guide those skilled in the art to obtain the technical inspiration of the patent from other prior art. Evidence 1 is a review article on "Pharmacological effects and clinical uses of ornidazole". This paper objectively summarizes and systematically sorts out the pharmacological effects, toxicological studies, pharmacokinetics and clinical application status of ornidazole. Although it is mentioned that ornidazole has a certain degree of toxicity, manifested as "inhibiting the motility of rat sperm", it is also clearly recorded that "the neurotoxicity of ornidazole is a temporary phenomenon, which disappears quickly after discontinuation of the drug." "Moreover, evidence 1 specifically states that normal use of ornidazole is safer, with mild side effects and lower acute and subacute toxicity of both oral and intravenous injections. Its clinical efficacy is accurate, the applicable population is wide, the compliance is good, the toxic side effects are low, and there are good application prospects. It can be seen that those skilled in the art have no incentive to improve the prior art and further reduce the toxicity of ornidazole when reading the information disclosed in evidence 1. Therefore, evidence 1 does not give technical enlightenment to reduce the toxicity of ornidazole, and certainly does not give technical inspiration for finding that levo-ornidazole has a beneficial technical effect with low toxicity and taking L-ornidazole alone.
3. Regarding the influence of research direction on the identification of technical enlightenment in this patent
Changsha Huamei Company advocates that the US FDA guidance documents and the Mainland Food and Drug Administration require that drugs containing chiral factors tend to develop a single enantiomer product, and for racemic drugs to provide detailed biological activity and toxicity research data of stereoisomers, therefore, splitting racemic ornidazole into a single isomer and studying its activity and toxicity is an inevitable research direction and research method. In this regard, this court believes that the requirements of the US FDA guidance document and the Mainland Food and Drug Administration are mainly general requirements and guidelines, and when it comes to the creative judgment of the invention of the medicinal use of levononidazole, a single enantiomer, should be combined with the time and specific content of the above documents and requirements, as well as the characteristics and characteristics of racemic ornidazole, the cognition of those skilled in the art and other factors, comprehensively and comprehensively consider whether the prior art has given specific and clear guidance.
First, ornidazole does not fall within the requirements of the US FDA guidance document and the Continental Drug Review Center to study chiral enantiomers that must be studied for activity and toxicity. The US FDA guidance document advocates that when developing new drugs containing chiral factors, it tends to develop a single enantiomer product, and the main pharmacological activities of isomers should be compared in vitro and in vivo systems. The mainland also attaches more and more importance to the study of chiral enantiomers of chiral drugs, before the date of this patent application, the mainland drug evaluation center also proposed that chiral drugs should strengthen the optical purity control of raw materials, for a class of optical isomer drugs, provide the efficacy of each optical isomer and toxicity test materials, in order to strictly control the toxic isomers in the quality standards. According to the above documents and requirements, in the development of three-dimensional isomer new drugs, both countries advocate strengthening the research and analysis of single isomers. However, the evidence in the case shows that ornidazole has been available as early as the 1970s and has been listed in the mainland as a four-class new drug, so racemic ornidazole is not a new drug to be developed, and it is not necessary to provide a single chiral enantiomer efficacy and toxicity test according to the requirements of new drug development. Therefore, for racemic ornidazole, those skilled in the art are not required to study the efficacy and toxicity of left-handed and dextro-ornidazole.
Secondly, based on the toxic characteristics of ornidazole, those skilled in the art lack motivation for improvement. The US FDA guidance document points out that not all racemates are subject to toxicological evaluation of a single enantiomer, and only in the presence of unintended toxic effects other than pharmacological effects, toxicity studies on single enantiomers must be performed separately to determine the source of toxicity. As mentioned above, evidence 1 discloses the clinical efficacy of racemic ornidazole, drug safety, low toxic side effects and other characteristics, it can be seen that racemic ornidazole does not have serious toxic side effects when clinically used in doses, according to the guidance of the US FDA guidance documents, the racemic drug in this case does not belong to the situation that must be analyzed by single chiral enantiomer toxicology.
Third, the use of optical isomers for disassembly is not the usual direction of improvement of nitroimidazoles. For drugs, their chemical activity is manifested as both therapeutic activity and toxicity/side effects. Those skilled in the art want to reduce the toxicity of known drugs, by changing the structure of the compound, thereby affecting its chemical properties and physicochemical properties, by means of preparation to change its route of administration and / or metabolic processes in vivo and other research and development ideas. The choice of optical isomers is only one idea that may exist. For nitroimidazole drugs, evidence such as counter-evidence 3 and counter-evidence 8 submitted by Nanjing Shenghe Company in the administrative stage of ineffectiveness can prove that the pharmacodynamic group of nitroimidazole drugs is the nitro group in the molecular structure, and the reduction of nitro is not only the basis for pharmacological effects, but also the main cause of toxicity. Metronidazole, tinidazole and ornidazole all have nitro groups on the imidazole ring and the side chains are different, and their efficacy and toxicity are similar but the strength is different. Therefore, based on the known structure-activity relationship of nitroimidazole drugs, those skilled in the art in order to reduce the toxicity of ornidazole, the usual research and development idea is to modify the ring structure of the imidazole, especially the transformation of the side chain, the selection of optical isomers for splitting and use is not the usual practice of such drugs. The development of nitroimidazole drugs for decades also confirms this idea.
Finally, for patents for pharmaceutical use, when judging inventive step, comprehensive consideration should be given to whether the prior art has given specific and clear guidance. Due to the large number of existing compounds and the large differences in activity/toxicity, very few can eventually become drugs. Those skilled in the art in the absence of specific, clear guidance, generally have no incentive to conduct related research on the compound and the compound enantiomer. For racemic ornidazole drugs that have been listed, to determine whether those skilled in the art will or should not study their chiral enantiomers, whether they will study the chiral enantiomer activity at the same time, study its toxicity, need to be combined with the overall situation of the prior art to judge. If the prior art only gives the general research direction in the field or there is a contrary technical teaching, and there is no clear and specific technical enlightenment on the study of chiral enantiomer toxicity, only according to the prior art to give the corresponding technical enlightenment, it is easy to produce the danger of hindsight and underestimate the inventive step of the invention.
In summary, the Court believes that, prior to the date of this patent application, those skilled in the art under the guidance of evidence 1, evidence 2 and well-known common sense in the art, there is no incentive to study the toxicity of levo-ornidazole, and to pharmaceutical it alone, the patented technical solution is not obvious to those skilled in the art. The appeal request of the State Intellectual Property Office and Nanjing Shenghe Company that the prior art did not give a technical enlightenment for the use of L-ornidazole to reduce the toxicity of racemic ornidazole has factual and legal basis, and this court supports it. The court of first instance did not comply with the review principle of the three-step law, and did not judge whether to give technical enlightenment from the overall perspective of the prior art, and this court corrected the error in this determination. The technical solution of claim 1 of this patent is inventive with respect to the combination of evidence 1, evidence 2 and common sense in the art.
Claims 2-6 are subordinate claims to claim 1, and on the basis of the inventive step of claim 1 of the patent, claims 2-6 also have inventive step.
Claim 7 claims protection of a pharmaceutical formulation against anaerobic infection, which contains, inter alia, levoonidazole as the active ingredient. The difference between claim 7 and claim 1 is only that the levoisomer of ornidazole is selected as the active ingredient and made into a pharmaceutical formulation. Therefore, for the same reason as claim 1, claim 7 also has inventive step. Claims 8-10 is a subordinate claim to claim 7, and on the basis of the inventive step of claim 7 of the patent, claims 8-10 also has inventive step.
In addition, Nanjing Shenghe Company also argued that decision 41175 should not be referred to and applied to this case, and in this regard, this court held that decision 41175 and the decision against which the lawsuit is directed at different patents, the comparison documents are different, the technical fields involved are different, and the facts of the case are also different, and decision 41175 should not be referred to and applied to this case. The grounds of appeal of Nanjing Shenghe Company are established and supported by this court.
In summary, the appeal request of Nanjing Shenghe Company and the State Intellectual Property Office is established and should be upheld. This court corrected the error in the application of law in the first-instance judgment. In accordance with the provisions of Article 22, Paragraph 3 of the Patent Law of the People's Republic of China amended in 2000, Article 69 and Article 89, Paragraph 1, Item 2 of the Administrative Procedure Law of the People's Republic of China, the judgment is as follows:
1. Revoke the Administrative Judgment of the Beijing Intellectual Property Court (2019) Jing 73 Xingchu No. 1801;
2. Reject the litigation claims of Changsha Huamei Pharmaceutical Technology Co., Ltd.
The acceptance fee of the first-instance case is 100 yuan, and the acceptance fee of the second-instance case is 100 yuan, both borne by Changsha Huamei Pharmaceutical Technology Co., Ltd.
This judgment is final.
Presiding Judge Zhu Li
Judge Fu Lei
Judge Zhang Xiaoyang
Judge Deng Zhuo
Judge He Jun
December 19, 2021
Assistant judge Bin Yuecheng
Technical Investigator Zhang Xiuli
Clerk Xie Silin
Source: Intellectual Property Tribunal of the Supreme People's Court
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