Innovative drug patent layout strategy

The value of a drug can be used (Price), sales volume (Volume) and the sales period (Time) is measured by the product of patents, and the impact of patents on these three factors can be said to be crucial.,After all, during the period of validity of the patent right, the drug has exclusive interests, and then it will have to face competition from generic drugs, which will affect the price and sales volume of the drug.

Patent Protection and Extension System

In the pharmaceutical industry, many people think that it is good to wait until they want to apply for clinical trials and then apply for patents together. In fact, unlike other fields, the development cycle of innovative drugs is longer and requires molecular screening, pharmaceutical research,1-3In order to prevent the disclosure of technical information, compound patents need to be widely and generally protected from possible components and uses in the early stage of research and development, and then strengthen the protection of specific chemical structures, drug operation mechanisms, administration methods, etc. in the pre-clinical period. When fully balanced early application(Short post-marketing protection period)and late applications(High risk of technology leakage)After the pros and cons, usually the compound patent is filed before the start of a phase I clinical trial, the instructions should disclose at least one use and preparation method, the effect data generally provides at least cell activity data, as appropriate to add animal test data.

The entry into force of the patent right is calculated from the date of authorization, and the term of protection is generally from the date of application.20years, until the expiration or termination of the patent, and after listing, the actual term of protection is usually only left.10Year or so. In order to compensate for the loss to innovative drug companies caused by delays in approval and clinical data collection, the U.S. Drug Price Competition and Patent Period Amendments(Hatch-Waxman Act)The patent protection period of patented drugs can be extended.5years; EU patent law has a similar system of "supplementary protection certificates"(SupplementaryProtection Certificate,SPC), The extended protection period starts from the date of expiration of the patent protection period, and the maximum can be obtained by applying for the certificate separately to the intellectual property offices of the member states.5In China, due to the lack of a patent extension system and the long time it takes to approve, some imported innovative drugs have a shorter patent protection period in China.

Key Points of Patent Layout Strategy

Another myth is that when applying for a patent for a pharmaceutical ingredient, many people tend to apply for a patent for only one compound, and as a result, when a patent is published, a competitor can avoid the infringement problem by slightly modifying the chemical structure, with different ingredients but the same effect. Therefore, the original research drug companies must have a patent portfolio (Portfolio patent) concept, that is, for the main part of the chemical structure of the various possible derivatives, are also protected by patents, so as not to leave the opponent can take advantage of the opportunity.

For chemical drugs, the original research company usually applies for the basic compound patent protection general structure before the first human test. This patent protects a class of derivatives with the same purpose to the greatest extent. These compounds have a large number and a common structure. The common structure should be novel and inventive compared with the existing technology. Due to the large number of structures protected by the patent of the basic compound, it is possible to avoid premature exposure of the target compound and prevent the opponent from following up. Generally speaking, in addition to the basic compound patent, the applicant may subsequently propose a specific compound patent.(For example, specific salts, isomers, prodrugs, active metabolites)Application. For example, Pfizer's blockbuster lipid-lowering drug Lipitor(AtorvastatinAtorvastatin), its in1986Year5Month30US patent filed onUS4681893, protected the general compound containing atorvastatin and its pharmaceutically acceptable lactone hydrolysis salt, the normal expiration time is.2006Year5Month30Day, after the patent extension application, the protection period is extended.2009Year9Month24Day;Subsequent patent applicationsUS5273995The protection of atorvastatin and its calcium salt(namely atorvastatin calcium), the expiration date shall be2010Year12Month28Day,Due to compliance with pediatric medication(pediatric medication,PED) 6The patent period is extended by six months, with the actual expiration date2011 Year6 Month28day.

In addition to compound patents, the importance of crystal patents is second only to compound patents and is the second line of defense to block the listing of generic drugs. Many innovative drugs are now being developed into crystalline drugs for the following reasons: (1) The unit surface free energy of the amorphous state material is larger, and the drug particles are more easily dispersed in the suspension formed after the disintegration of the solid preparation, which can improve the dissolution rate and increase the bioavailability of the insoluble drug in the body. However, more amorphous drugs are prone to crystallization and other phenomena during processing and storage, thus losing consistency between bioavailability and drug dissolution rate, free energy, etc., and absorption may even be worse than other more stable crystalline drugs; (2) The crystal form of the drug is stable, and some impurities can be removed by recrystallization to reduce the toxic and side effects of the drug; (3) Crystal drugs can be patented, to a certain extent, can restrict some generic drug manufacturers. Although crystalline drugs have many advantages, they are not suitable for all new drugs. Some blockbuster drugs have more advantages than crystalline forms in amorphous form. For example, the century-old classic drug aspirin, the super blockbuster cytotoxic drug paclitaxel, and AstraZeneca's former master Hua Dan esomeprazole, the amorphous state of these drugs has better absorption properties than crystalline forms.

For polymorphic drugs, the original research company applies for crystal forms before the drug is approved.(Listed drugs use crystal form)Patents, but also after the market will actively develop the advantages of crystal type, again apply for a new crystal type patent. For example, imatinib has multiple crystal forms, and the drug is in.2001The first time it was approved for the market, the listed drug uses beta crystal form, Novartis has disclosed the compound's alpha, beta, and beta,F,G,H,I,K, D, e and amorphous morphology(CN98807303.X,CN200680044007.7,CN200880018651.6andCN201010586080.5)The β crystal form is the most stable crystal form, and other crystal forms are easy to change into β crystal form at room temperature, especially in the presence of water, alcohol and ketone. β crystal form in1998Year7Month16day application, the priority date is1997Year7Month18Date, patent grant number:CN1134430C N.CN201010586080.5(Patent name: δ and ε crystal forms of imatinib mesylate)In2006Year08Month24day application,CN200680044007.7(Patent name: imatinib mesylateF,G,H,IandKcrystal form)In2006Year11Month23day application. Shiyao Ouyi Group has independently developed a new crystal form that is more stable with the β crystal form.Mcrystal form, and bypasses the patent protection of the original research company, and in2014Apply for patent to protect their achievements(Application NumberCN201410139481.4)Now that the production approval has been obtained, Shiyao Ouyi has realized a real defensive counterattack here.

In addition to applying for core patents to restrict generic drug developers, the original research company will also apply for peripheral patents, such as composition patents, synthesis method patents, new usage patents, new crystal type patents and new salt patents. On the one hand, it will set up technical barriers for generic drug manufacturers through peripheral patent applications, and on the other hand, it will prevent competitors from developing new technologies to restrict themselves through patent applications. Therefore, the core patent plays the role of attack in the layout, and the main role of the peripheral patent is defense.

Make good use of experimental data protection

In addition to patents, the new drug industry has a special experimental data protection mechanism, that is, for the original research drug company in the process of drug development accumulated test data, to give a preferential period to exclude others from entering the market. Although the data protection period will overlap with the patent validity period, the former is an absolute guarantee, and the manufacturer will not disappear or withdraw after obtaining it. However, the patent right is relative. If the patent right is successfully challenged by competitors in the patent linkage system to invalidate the patent right, at least the exclusive protection period can be used for defense. At present, new drugs are given at least in the United States.5New use of old drugs is3Years of protection period; If orphan drugs for rare diseases are developed (Orphan drug), the protection period is more likely to lengthen7Year. Smart pharmaceutical companies will match exclusive protection periods with patent applications to greatly increase the market value of their drugs. For example, Abei Pharmaceutical Factory (Abbott,RenamedAbbVie) in1998The right to a cardiovascular drug, named it 「Tricorand to market. At that time, the drug's ingredient patent and exclusive protection period had expired, and the market value was quite limited, but in the following.15During the year, Abbott applied for new patents with improved dosage forms again and again, and also obtained exclusive protection periods.-In the first five years, the formula was changed from200Milligrams changed to smaller160Milligrams, and also adjust the dosage, so that even if the scientific name pharmaceutical company successfully challenged the patent, it would not be able to enter the market. Abbott repeated the same strategy three times and even arrived.2009YearTricorThe sales amount also climbed14billion dollar peak.

At present, there are no relevant implementation methods and rules in China, but the State Drug Administration recently drafted the measures for the implementation of Drug trial data Protection (interim) (draft for soliciting opinions), which gives innovative drugs6Protection, improved new drugs are3years of protection.

Conclusion

The patent layout of innovative drugs is a game between the original research company and the generic drug company. A good layout should be offensive and defensive, accurately grasp the timing, and be good at using the priority, divisional application and international patent application in the patent law to ensure the best interests of the applicant. The patent layout is like the arrangement of troops in the World Cup football match. Being good at attacking can help the team win some games, but only with both attack and defense can we go further!

References

https://mp.weixin.qq.com/s/nBi7YXhHlRRPkueObGuQSg