LI Jun-li, WEN Qi, YU Pei-ming

(College of Pharmacy, Henan University, Kaifeng 475004, China)

Patent Status of Antidepressants: Duloxetine

LI Jun-li, WEN Qi, YU Pei-ming

(College of Pharmacy, Henan University, Kaifeng 475004, China)

Objective To study the patent status of duloxetine and to provide references for the strategic development of pharmaceutical companies in China. Methods Patent status of duloxetine in China were analyzed by quantitative and qualitative methods of research. Results and Conclusion Generic manufacturers can produce duloxetine legally when the administrative protection ends on December 11, 2013. But crystal and process patents should be paid attention to avoid infringement. The generic manufacturers can analyze the patents of synthesis process and pharmaceutical formulations, to obtain the best processing route to reduce production cost or to apply for patents on their own. There is still great potential for pharmaceutical companies in China to make new breakthroughs by absorbing technology in previous patents.

antidepressant; duloxetine; patent analysis

Duloxetine Hydrochloride, manufactured and marketed by Eli Lilly Company, is a selective serotonin norepinephrine reuptake inhibit or (SNRI). It was first approved for the treatment of major depressive disorder by FDA in August 2004. That same year, it was also approved for the treatment of neuropathic pain (DPNP) associated with diabetic peripheral neuropathy; it was approved for the treatment of generalized anxiety disorder in 2007 and fibromyalgia in 2008, a new indication approved by FDA in 2010 which was used for the treatment of chronic musculoskeletal pain[1]. It has been sold in more than 70 countries since it was launched in 2004. The Annual global sales of the drug reached $1.3 billion in 2006, $2.1 billion in 2007 and $2.7 billion in 2008[2]. The sales in 2011 and 2012 were surprisingly up to $4.161 billion and $4.994 billion respectively and even it ranked tenth in the top 20 best-selling drugs of 2012[3]. As we know, duloxetine has wide range of clinical use and huge market potential. Domestic generic pharmaceutical companies should pay close attention to the research and development of it. This paper analyzed the patents information of duloxetine in China from 1987 to 2012 to provide references for the domestic pharmaceutical companies.

1 Data sources

We get information from the following database: Searching duloxetine as keywords on China Patent Information Center Retrieval System; Searching A61P25/24 (Antidepressant) as classification number on State Intellectual Property Office Of The P.R.C and then finding out patents of duloxetine; Searching duloxetine as keywords on CNKI Patent Retrieval System; Searching duloxetine as Active Ingredient on Orange Book of FDA and then searching patent family to get China patents of duloxetine; Retrieval date was June 2nd, 2013. Several methods were used to prevent omissions and the patents of utility models and designs were eliminated.

2 Quantitative analysis of patents of duloxetine

2.1 Analysis of patents application

The number of patents applications of duloxetine in China is 78, and the distribution is shown in figure1. The initial application happened in 1987 and all other subsequent patents concerning pharmaceutical use were applied by Eli Lilly Company in the following twelve years. The number of patents applications increased year after year from 2003 and peaked in 2007. This may be related to competitive advantage of the drug since it was listed in 2004 and some big drug companies and research institutions in the world invested so much ti me and resources to expand the research. According to Article 34 of “the Patent Law of the people’s Republic ofChina” (2008), an application for a patent for invention received by the Patent Office should not be opened to the public unless it has undergone a period of 18 months or the applicant requests publication of it. So some patents applications of 2012 can’t be found via patent website and applications numbers can’t be accurate. But we can predict that the applications in 2012 will not be less than that in 2011 considering the development potential of the drug and research information ref l ected by pharmaceutical companies.

Domestic applicants began to apply for the relevant patents in 2003. The first domestic applicant, Beijing Shangdi New Century biological medicine research institute, applied for a patent about an important intermediate and synthesis method of duloxetine[4]. In 2004, Shanghai Institute of pharmaceutical industry applied for three patents, involving synthesis method and new pharmaceutical formulations of duloxetine[5-7], and then domestic universities and enterprises begun to research and applied for patents of this drug.

Figure 1 Changes of the number of patents applications by years

2.2 Analysis of the nature of patents applicants

We analyzed the nature of the applicants (companies, individuals, research institute, university) in excel and found that companies were the main patents applications. 58 patents were owned by companies, accounting for 72% of the total applications, and the distribution is shown in Figure 2. It shows that companies became the main force of the technological innovation. By analyzing the companies, we found that domestic companies applied 22, accounting for 36% of the total number and foreign companies applied 39 patents, 64% of the total number. From Figure 3, we can see that the number of the patents applications owned by domestic companies is less than the foreign companies. The reason is that domestic companies began to research on the drug later than the international leading companies. After all, the earliest patents application of domestic company was Beijing D-Venture Pharmaceutical Technology Co., Ltd in 2005.

Figure 2 Analysis of the nature of patents applicants

2.3 Legal status of the patents application

Legal status of the patents of duloxetine includes the following items: disclosure; substantive examination; rejection after the publication of the application for a patent; withdraw after the publication of the application; a uthorization; termination of a patent right without paying the annual fee; termination of a patent expiration. Statistical analysis of the legal status was carried on in Excel and we got figure 4, it shows that only 19 authorized patents are valid; 36 patents are invalid; 1 patent expired; 2 patents were rejected after the publication of the application; 28 patents were deemed to be withdrawn; 5 patents was terminated for not paying the annual fee; 15 patents are in substantive examination stage. Therefore, the patent owner should pay fees on time in order to maintain the validity of the patent. Domestic pharmaceutical companies can also learn technology information from the invalid patents so as to make innovations. As to the patents in substantive examination, it might be rejected or narrowed the scope of patent protection before reexamination or judicial proceedings required by the domestic pharmaceutical companies that seeks to protect th eir market positions with the reason that the applications are not in conformity with the detailed rules of “the Patent Law of the people’s Republic of China”[8].

Figure 3 Comparison of the number of patents between domestic and foreign companies

Figure 4 Legal status of the patents of duloxetine

Figure 5 Content analysis of the patents of duloxetine

3 Qualitative analysis of the patents of duloxetine

3.1 Content analysis of the patents of duloxetine

By analyzing the claims of duloxetine patents in China, the content protection is confirmed. Statistical analysis of the content was carried on in Excel and the result is shown in f i gure 5. It can be found that the synthesis process patents and the pharmaceutical formulations patents take up 58%. Drug Company can refer to the patents above for getting best preparation process and saving cost.

3.2 Analysis of the basic patent of duloxetine

By downloading patents list on the Orange Book of FDA, the patents protection strategy of brand-name drugs can be seen in details. The complete patents list is shown in Table 1. In order to extend the market monopoly period, the drug was multi-level protected through the compound patents, formulation patents and drug use patents.

Once drug patents expired, lots of generic drugs approved by FDA will be marketed and the price will drop to 20% without the drug market monopoly right. In order to extend the market monopoly period, the original company will apply to extend the patents period through the existing laws and regulations[9]. US5023269 is the compound patent of duloxetine, applied on March 27, 1990, authorized on June 11, 1991[12]. It should expire on June 11, 2008 according to the patent law of the time, but the Hatch-Waxman Act (Drug Price Competition and Patent Term Restoration Act of 1984) Article 35 U.S.C156 states that patent period of validity should be compensated for no more than 5 years, so the patent should expire on June 11, 2013, but the period was extended for 6 months again through the exclusive right by the administration for children regulations, and the f i nal expiring date is December 11, 2013[10,11]. The patent family of China, CN87108175, only protects the manufacturing method of the product[13]. This is because patent application at the time was only awarded to method protection, not invo lving the product protection. “The Patent Law of the P.R.C”revised in 1992 began to give the product protection. In order to expand economic and technical exchange and cooperation with foreign countries, administrative protection was given to foreign drugs. The drug obtained the protection on August 14, 2006 would expire on February 14, 2014 in accordance with the administrative protection period of 7.5 years, but “pharmaceuticals administrative protection regulations” Article 15 points out that the patent right shall cease before the expiration of its duration if exclusive right is expired or patent is invalid in their own country. It means that the administrative protection of the drug will expire at the same time with the patent US5023269 (December 11, 2013). Therefore, generic companies can apply for the marketing the drugs when the protection expires.

US5508276 protected the enteric pill of the product, which will expire on January 18, 2015[14], and the patent family of China is CN95108414, which will expire on July 18, 2014[15]. US6596756 refers to persistent pain treatment[16], and the patent family of China is CN99810830, which will expire on September 10, 2019[17]. In addition, generic companies should also pay attention to other salts and polymorphs patents to avoid infringement. For salts and crystal patents of duloxetine, see Table 2.

4 Conclusions

The total number of the application and the authorized patents is small. It has experienced nearly 20 years of quiet period from the f i rst patent application. The main reason forit is that a certain period of time is usually needed for a new drug to f i nish preclinical and clinical research and obtain a marketing approval. And more time is needed for the drug to make a prof i t and catch the attention of whole industry. But the number of applications went up sharply from 2007 and most of applications came from foreign companies. Obviously, the domestic pharmaceutical companies were less sensitive and began their research and development program later than foreign companies. After investigating all the patents of the drug, we can see that the number of granted patents is relatively small and there are lots of invalid patents. So there are still great potential for domestic pharmaceutical companies to obtain new technological brea kthroughs by absorbing technology in the invalid patents.

Table 1 Patents list of duloxetine on the Orange Book of FDA

Table 2 Salts and crystal patents of duloxetine

Duloxetine has got administrative protection but not compound patents in China. Domestic generic manuf acturers should get ready to produce this drug at the first time when the protection ends on December 11, 2013. At the same time, the generic manufacturers should also analyze the patents of synthesis process and pharmaceutical formulations carefully to obtain the best processing route to reduce production cost and apply for patents timely on their own. But we should still pay attention to crystal and method patents to avoid infringement in the course of research and development. We can also build our own patents protection net by further development of safer and more effective derivative drug product like the original drug research company.

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Author’s information: YU Pei-ming, Associate professor, PhD. Major research area: Pharmacy administration and regulations. Tel: 13223806998, Email: ypm@henu.edu.cn