Drug impurities patent those things

Drug impurities, whether for the original research pharmaceutical factory or imitation pharmaceutical factory, are problems that must be faced, which cannot be avoided or avoided. Accordingly, patents involving pharmaceutical impurities are also an important part of the pharmaceutical patent layout network. Generally speaking, the forms of patent protection for impurities can be divided into the following three types: compound patent form, composition patent form and use patent form.

1.compound patent form

Usually this form of patent protection requires direct protection of the structure of the impurity compound itself. On the surface, this form should be the most widely protected form of patent protection for impurities, but it is also the most controversial form of patent protection for whether it should be granted a patent right.

Due to the object and novelty issues, this form of protection is not feasible in the United States, but based on the current Chinese law, if the impurity itself has new activity or the impurity itself is difficult to find./In the case of identification, it is possible to consider the protection of impurities in this form of protection.

The following will be the patent involved in the dispute between Sihuan Pharmaceutical and Qilu Pharmaceutical.ZL200910176994.1For example, specifically discuss the authorisability, scope of protection and defense of the patent form of the impurity compound.

2.Composition Patent Form

Usually this form of patent protection claims a pharmaceutical composition that includes a certain content below (e. g.0.2%The following) impurity compounds and other substances (such as active substances, etc.). This type of patent form is more commonly used in the United States, but how to overcome the creative problem in China is also a question that needs careful consideration.

In general, if the impurity is known in the prior art, the patented form of the composition is generally not inventive; if the impurity is not known in the prior art, but the patent application does not disclose any special properties of the impurity (such as toxicity) or does not take any special measures to control the content of the impurity, then the patented form of the composition is generally not inventive. It is worth emphasizing that if these compositions are not ordinary dosage forms, but high-tech dosage forms (e. g. liposomes, emulsions or nanoparticles) that require the control of complex preparation processes, then the protection of impurities in the form of composition patents may be easier to argue for inventiveness, and thus easier to obtain authorization, in view of the complexity of controlling impurities.

3.Use Patent Form

Usually this patent form requires protection of the impurity as a reference./Use for quality control. Due to the imperfection of China's evidence disclosure system, the protection of this form of protection is usually weak. However, for original research products or Chinese exclusive products, the corresponding enterprises can use the right to speak on product standards (such as testing indicators), making such use of patents become very exclusive.

Similarly, the following will be the patent in question.ZL200910176994.1For example, specifically discuss the authorizability of the patent form of the use of impurities.

Sihuan Medicinev.s.Qilu Pharmaceuticals, Cinepazide Maleate Patent Dispute

Cinepazide maleate injection is the original product of French Dillon, which is used in1992It was allowed to import into China in 2010, but it was not sold on a large scale.

Four Ring Medicine in2002Year4The company was approved to manufacture cinepazide maleate injections in China in January and2015It has been the only supplier of this product in China for years. According to the annual report of Sihuan Medicine, its2016Total annual revenue is31.86billion yuan, and cinepazide maleate a single variety of revenue accounted for more15%(approx.5billion yuan), in order to prevent other pharmaceutical companies from peeping into the company's core products, Four Ring Pharmaceuticals has adopted a variety of means such as changing drug standards and applying for peripheral patents (such as crystals and impurity-related patents).

Faced with a product market of hundreds of millions of yuan, many domestic companies have declared for the product and subsequently obtained approval, including Qilu Pharmaceutical. From2015After the product of Qilu Pharmaceutical was approved for listing in, Sihuan Pharmaceutical and Qilu Pharmaceutical launched several rounds of confrontation around cinepazide maleate injection. Tort lawsuits, unfair competition lawsuits, invalidity and administrative lawsuits have occurred one after another, so I won't repeat them here.

Patent involvedZL200910176994.1The basic situation

The invention name of the patent involved is "cinepazide nitrogen oxide, its preparation method and use", and the patent number is200910176994.1, the priority date is2009Year08Month17day, the application date is2009Year09Month29The authorization announcement date is2011Year06Month01day. The patent has a total17Claims, which claim.1claim to protect the impurity compound itself, claim2-14The preparation method of the impurity compound is claimed, and the claim is claimed.15The application of the impurity as a standard or control substance is claimed.16Insecticide compositions including impurities are claimed, and claims are claimed.17Claims to protect impurities or insecticidal compositions for the preparation of insecticides, this patent actually covers the patent protection of two impurities, that is, the compound patent form (claims.1) and the use patent form (claims15）。

Qilu Pharmaceuticals has been in2015Year and2016Two invalidation requests were filed in 2010, but were not successful. The patent involved has gone through the process of invalidation and litigation. The following are some related issues to discuss:

1.Whether the impurity compound itself is a patentable object.

It has been argued that impurities are themselves scientific discoveries and therefore not licensable objects. But is it really so?

First, the review guidelines are set out in Section2Part No.1Chapter4.1Section discusses scientific discoveries and excludes the objective existence of substances, phenomena, processes of change and their characteristics and laws in nature from the disclosure of authorized objects. However, the author believes that this provision only excludes the "discovery" itself, but the invention further produced on the basis of the discovery is the object of the authorized patent right. Taking impurity compounds as an example, the mere discovery of the existence of impurity compounds from objective existence may belong to scientific discovery, but if other properties (such as therapeutic activity or toxicity) of the impurity are further discovered so that it can be applied in industry, then the impurity compound itself becomes an invention and thus belongs to the object of the patent.

Secondly, in the Secondary specialized school section of the guide for compounds, only two non-patentable objects are specifically excluded, namely natural substances and the medicinal use of substances. Therefore, for an impurity compound (as a lower concept of a compound), if the impurity compound is considered not to be a natural substance, then it is a patentable object because it does not belong to either of the two non-patentable objects specifically excluded in the compound section; if the impurity compound is considered to be a natural substance, then it will also belong to the authorized object because its "structure, form or other physical and chemical parameters are not known in the prior art, and can be accurately characterized, and have industrial use value.

Thus, where other properties of the impurity (e. g., therapeutic activity or toxicity) are found, the impurity itself should be a patentable object.

2.The Novelty of Impurity Compound Patent

Whether the objectively existing but not yet recognized impurity compounds can destroy the novelty of the impurity compound patent is also one of the main controversial points of the patent involved. Based on the regulations currently in force, the above situation is not sufficient to destroy the novelty of the impurity compound patent.

From the general provisions of the Guide on novelty No.2Part No.3Chapter2.1From the perspective of the identification of the existing technology, novelty means that the invention or utility model does not belong to the existing technology or the content disclosed in the conflicting application, and the existing technology should be the technical content that the public can know before the application date. Since this impurity compound has not yet been recognized, it does not belong to the prior art (regardless of the conflicting application) and is therefore novel.

Specific to Guide No.2Part No.1Chapter5.1In terms of the specific provisions of the novelty of the compound, to destroy the novelty of the compound, the degree of disclosure of the compound in the prior art needs to meet certain requirements, that is, to clearly define or explain the chemical name, molecular formula (or structural formula), physical and chemical parameters or preparation method (including raw materials) of the compound. Based on the above provisions, since the degree of disclosure of the prior art does not meet the above requirements, the impurity compounds are also novel based on the provisions. As for the guidelines in the subsequent No.2Small and No.3The situation that does not destroy the novelty (that is, the compound of the general formula and the natural substance do not destroy the novelty) is particularly emphasized by the small point, because it is only two special examples that do not destroy the novelty, so whether the impurity compound belongs to these two cases or not does not affect whether it has novelty.

Another novelty issue with respect to impurity compounds is whether presumptive novelty should apply. Presumption of novelty, in fact, is to challenge the novelty of the patent application with existing technology that does not fully meet the conditions for destroying novelty in the examination process, and to shift the burden of proof that the patent application is different from the existing technology to the applicant. A workaround. Therefore, the presumption of novelty should be applied cautiously and there should be a clear legal basis for such application. At present, for the chemical field, the review guidelines only stipulate that chemical products characterized by physicochemical parameters or preparative methods can be applied to presumed novelty, and it is not clear whether it can be applied in the invalid stage.

To sum up, based on the current effective regulations in China, the impurity compounds that exist objectively but have not yet been recognized should be novel.

3.Inventiveness of Impurity Compound Patent

Generally speaking, the structure between the impurity compound and the active compound (belonging to the prior art) is relatively similar, so the key to the creativity of the impurity compound lies in whether it produces unexpected technical effects compared with the prior art.

If the impurity compound produces a different type of activity than the active compound, it can generally be recognized that such activity is unexpected, thereby recognizing the inventive step of the impurity compound patent. However, if the impurity compound produces the same type of activity as the active compound or produces a common toxicity, then due to the activity of the impurity compound by the person skilled in the art./Toxicity has certain expectations, so the difficulty of being recognized as an unexpected technical effect is greater.

Therefore, based on the current effective regulations in China, if the impurity compound produces unexpected technical effects, it should be inventive.

4.Patent Protection Scope of Impurity Compounds

In general, the scope of protection of a compound patent covers all compositions comprising such compounds. However, in view of the particularity of the impurity compound, especially in view of the fact that the composition including the impurity compound has been objectively existed in the prior art, the scope of protection of the impurity compound patent should be limited.

As mentioned above, based on the current regulations in China, even if a composition including the impurity compound exists objectively in the prior art, in some cases (for example, the impurity compound itself produces unexpected technical effects), the impurity compound itself can also be patented.

Then the problem arises, if the scope of protection of the impurity compound patent is also interpreted as covering all compositions including the impurity compound, then the patent filed later covers the content of the prior art, which is obviously unreasonable. If there is solid evidence that the impurity must be present in the composition of the prior art (for example, the patentee tetracyclic medicine has admitted in another patent that the impurity is inevitably present in cinepazide and its preparations as harmful impurities), then in this case, the scope of patent protection of the impurity compound seems to be interpreted as not covering the cinepazide injection in the prior art should be more reasonable. Since the Inner Mongolia High Court is already the final judgment, we will see whether the Supreme Court will accept the retrial request and the retrial situation. Let's wait and see if the Supreme Court will limit the scope of protection of impurity compound patents.

However, even in this case, Qilu Pharmaceutical may also infringe the patent of impurity compounds, because according to the requirements of the standard, it is also necessary to purchase the pure substance of the impurity as a reference substance, and to use the impurity as a reference substance for quality control. Therefore, if Qilu Pharmaceutical wants to be completely unaffected by the patent of impurity compounds, it may also need to develop quality control methods that do not use pure impurities.

5.For impurity compound patents, the ban should not be given.

Under normal circumstances, while determining patent infringement, the court will grant an injunction to prohibit the defendant from continuing to implement the patent involved. However, for impurity compound patents, because the defendant actually does not want (but cannot avoid) the products involved to include impurities, and the products involved in the case Including such impurities did not produce any beneficial effect, it seems a little inappropriate to be banned from producing and selling the products involved due to the existence of impurity compounds. According to Article 26 of the Interpretation (II) of the Supreme People's Court on Several Issues Concerning the Application of Law in the Trial of Patent Infringement Disputes, it seems that the plaintiff requested an injunction but the court ordered no injunction only on the grounds of national interest and public interest.

6.Patentability of Impurity Use Patents

In the invalidation decision of the patent in question, for the claim.15The use of the claim, the re-examination board directly based on the compound's creative nature to approve the claim.15creativity, this view is debatable.

Although it is not necessary to doubt the novelty and inventiveness of the use of a compound in the case of novelty and inventiveness in general, this view is not universal in all cases. In this case, for example, the patent in question did not prove that the impurity would produce any particular toxic side effects (I. e., it did not prove why the impurity was selected alone as a quality control impurity), so according to the disclosure of the specification, the claim.15In fact, the technical problem to be solved is only to arbitrarily select an impurity of cinepazide as a reference substance, which is actually obvious to those skilled in the art.

7.Prior Art Defense

The priority date of the patent in question is2009Year8Month17Day, but Sihuan Medicine in2002The product has been sold since the beginning of the year. Thus, the prior art defense is a potential defense.

To determine whether the prior art defense can be established, it is necessary to determine whether all the technical features that fall within the scope of patent protection are the same or equivalent to the corresponding technical features in an existing technical solution (or its simple combination with common knowledge). Therefore, for the compound patent of impurities, the key to judge whether the prior art defense can be established is whether the technical characteristics (I. e. the impurity itself) that have not been recognized in the prior art can become the corresponding technical characteristics of the prior art defense. Where there is clear evidence that such impurities are included in the prior art (e. g., the patentee's admission), the prior art defense should be granted.

8.Standard essential patents in the field of pharmaceuticals

In the course of the confrontation, Qilu Pharmaceutical filed a defense and an unfair competition lawsuit based on the standard essential patent. For pharmaceutical patents, especially for individual varieties, does not applyFRANDPrinciples (fairness, reasonableness and non-discrimination), for the following reasons:

First of all, China's current laws and regulations do not provide for the national mandatory standards (such as drug standards) need to be applied.FRANDThe principle, in this case, should respect the right of the patentee to prevent others from implementing it.

Secondly,FRANDThe principle usually applies to the standards formulated by many enterprises in the industry (so it usually includes the patent rights of many enterprises) and for a large category of products. The most typical example is the communication standard (including the patent rights belonging to many enterprises and aiming at a large category of products), while the usual drug standard is only the standard formulated by one enterprise and aiming at a single variety, moreover, the patent rights related to the standard only exclude other enterprises from entering this single variety, so they are not applicable.FRANDThe need for principle.

Again, the drug standard covers all types of patents, such as the compound structure itself is an important part of the drug standard. Therefore, if the drug standards are applicableFRANDprinciple, then the vast majority of pharmaceutical patents (e. g., compound patents for active substances) would be considered standard essential patents and would apply.FRANDprinciple, which would be a serious blow to innovation in the pharmaceutical industry.

In summary, patents involving drugs, especially those involving only a single variety, should not be applied.FRANDPrinciple.

9.Falsifying data

The premise of the above judgment of the patent in question (especially the judgment of its novelty and creativity) is to believe in good faith that the data recorded in the patent in question and the technical effect are true. If such data and/Or the technical effect is deliberately forged, then the conclusion is completely different.

It is very difficult to challenge the patent fraud involved in the authorization and invalidation stage of the reexamination board, mainly because (a) It is difficult for the invalid requester to prove that the submitted experimental conditions are completely consistent with the experimental records of the patent involved (for example, the patent involved records a preparation method, but it is unlikely that all the temperatures involved in the method are recorded in detail, but the data submitted later must be made at a specific temperature, so it is difficult to prove the consistency between the two); Moreover, (b) The re-examination board is generally unwilling to judge which of the contradictory data submitted by the invalid claimant and the patentee is more true (for example, by appointing an appraisal agency ex officio to independently verify the disputed data), so it generally chooses to believe the original record in the patent text. Therefore, the challenge of data patent fraud may not be known until the administrative litigation stage of the court.

It is worth noting that at present, there are no serious penalties for patent data fraud in China, only in the guidelines for patent infringement judgment (2017) "No.126Article and Article127The article provides that in such cases, a decision may be made to reject the plaintiff's claim.

References:

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