Drafting and Researching on Examination for Pharmaceutical Polymorphic Patent Application
Polymorphism refers to the presence of at least two or more different molecular arrangements in the solid state of a compound, resulting in the formation of crystals in many different states.
As an effective means for pharmaceutical companies to expand the pharmaceutical patent pool, prolong the life cycle of pharmaceutical patents and set up technical barriers, pharmaceutical crystal type patents have gradually become one of the focus of competition among various pharmaceutical companies. Pharmaceutical polymorphism research has become a hot field in pharmaceutical research in recent years. At the same time, pharmaceutical crystal type patent applications have been increasing year by year, especially in the past 10 years, there has been an explosive growth.
The pharmaceutical crystal type patent is essentially a patent with a protection theme of chemical products, which has both the general commonality of chemical product patents, but also has the particularity of characterization. This article will introduce drafting and examination in various countries from the aspects of clarity, novelty, inventive step, full disclosure, support, and unity of polymorphic invention application.
1. Polymorphic Naming
For polymorphs, there is currently no universally accepted standard nomenclature. The industry often uses numbers (such as I, II, III) or letters (such as A, B, C) to name polymorphs. When a claim is written in a form such as "Form III of Compound X" (where X is a generally accepted name for a compound), the claim does not satisfy the requirement for clarity according to Patent Law. Claims concerning polymorphism must be characterized in different ways as explained later
2. Polymorphic Characterization
（1）Basic principles and recommended ways
As a general principle, the method of measuring parameters should be defined in the claims. For various reasons, it is recommended to use multiple parameters (such as the parameters obtained by several independent analysis methods) to characterize. When a compound is known to exist in one or more solid forms, subsequent applicants are actually forced to provide comparative data to prove that the required crystal form is novel relative to the solid state of the prior art. It is recommended that applicants proactively and preferably provide these data on the application date to speed up the review process.
X-ray diffraction on single crystals or powdered solids is very suitable for characterizing polymorphs. The single crystal method provides the highest level of information about crystals and molecular structure, while X-ray powder diffraction (XRPD) is used for quantitative detection and routine characterization of polymorphs.
It is particularly important to note that in Chinese patent practice, crystalline type inventions usually use "the crystal has an X-ray powder diffraction pattern as shown in Figure 1", but in European patent practice, the claims should not contain references to the drawings unless absolutely necessary, which may easily cause those skilled in the art to wonder whether the peaks mentioned in the claims are sufficient to characterize polymorphs individually.
Common solid-state spectroscopy methods include infrared spectroscopy (IR), the use of Raman spectroscopy, and solid-state 13C-NMR.
Thermal analysis measures the nature of the sample as it changes with the outside temperature. The most commonly used thermal analysis methods in solids inspection are thermogravimetric analysis (TGA), differential thermal analysis (DTA) and related differential thermal scanning calorimetry (DSC).
（5）Characterize by method
If it is impossible to characterize more clearly, a chemical product can be defined as a product characterized by a method in the claims. However, this characterization method is allowed only if the product meets the patentability requirements.
Generally, the countries have the following examination strategies for polymorphism novelty:
1. It is disclosed in the prior art about a compound with the same structure as the present application or a preparation method (the preparation method may or may not be similar), and it is disclosed in the prior art that structural characterization data of the compound (for example: melting point, nuclear magnetic, infrared, elemental analysis, etc.) did not provide any XPRD and other crystal characterization parameters. At this time, the examiner will believe that the crystal form claimed in this application cannot be distinguished from the known compound based on one or more prior art disclosures. The crystal form of the compound disclosed in the prior art may be the same as the crystal form claimed in the present application, it is presumed that the crystal form claimed in the present application is the same as the known compound, and the crystal form claimed in the present application is not novel.
2. The measurement method or measurement conditions of the crystal form parameters disclosed in the prior art are different from this application, because this application limits the physical characterization parameters (for example: the use of lattice parameters, particle size and distribution, angle of repose, volume density, etc.) cannot be directly compared with the prior art. At this time, according to the disclosure of the prior art, those skilled in the art cannot distinguish the crystal form claimed in this application from the known compound, it is presumed that the crystal form claimed in this application is known compounds are the same.
3. The crystal form disclosed in the prior art is the same as the crystal form claimed in this application, and at least XPRD is disclosed, and the parameter determination method in the citation is the same as this application. At this time, the two can be directly compared. The disclosed crystal is the same as the crystal form claimed in this application or the difference between the XPRD parameters is within the error range, and it can be estimated that the novelty. It should also be noted that the conflicting application can also comment on novelty.
When drafting a polymorphic patent application, the following points should be noted about novelty:
- It must be properly characterized and disclose in detail what is the difference between this crystal feature and the known crystal. If necessary, IR, NMR and other data can be limited in the claims; the more parameters defined in the application, the easier it is to proceed with the prior art in contrast, the easier it is to judge the novelty.
- The crystal data claimed in the claims should be significantly different from the data disclosed in the citation or have data that clearly exceeds the error range. If the error between the cell parameters of the crystal disclosed in the citation and the claimed crystal is within 1%, the claimed crystal is not novel.
- When the citation discloses a solid compound whose chemical structure is the same as the chemical structure of the claimed crystal drug or the citation does not provide crystal characterization parameters and does not indicate that the compound is amorphous, only the preparation method (sometimes) is disclosed (even if the parameters such as melting point are also disclosed), the crystal application applied for at this time may not be novel.
- When the applied compound is a selective compound crystalline form, such as providing evidence of different properties or effects, such as improved biological activity, more favorable physical properties, etc., such an application is novel.
- When the applied compound is a brand-new compound, in order to obtain more protection, the crystal of one or more new compounds developed can be protected in one application at the same time, such application is also novel.
Countries' judgments on inventive step are also very similar, mainly based on the three-step method. Between compound crystals and derivatives of known compounds, their salts or esters, since they all have the same active structure, they are considered to be structurally close, and between new crystals of the same compound and known crystals, they have the exact same chemical structure, but only different in microstructure, and they can also be considered to be close in structure. It is very important to determine whether a crystalline compound is inventive or not, because in general, it is determined that the crystalline compound has a inventive structure, because in general, the claimed crystal product has a compound that is structurally close to the prior art. Only when there is an unexpected use or effect can it be inventive.
When drafting a polymorphic patent application, the following points should be noted about inventive step:
- If the applied crystal drug is only the same compound with the same purpose, but only provides a crystal prepared by another method, and there is no beneficial effect and/or unexpected technical effect, then such a crystal is not inventive.
- When applying for a patent application, the applicant should focus on the unexpected technical effects of the claimed crystalline drug relative to the polymorphic form of the prior art. In other words, what properties may be improved by the claimed new physical form of crystal drug, such as the bioavailability, solubility, chemical physical stability, density or fluidity of the applied crystal drug. It can also be clarified that the existing solid state is difficult to make a formulation due to its shape or hygroscopicity, or the solid needle-like crystal is very viscous and has poor fluidity due to a lot of static electricity. In this way, it is stated that the change in physical form brings unexpected effects to the known polycrystalline compounds, but these technical effects must be supported by sufficient evidence.
In order to be granted, an invention must be disclosed in a manner sufficiently clear and complete to those skilled in the art to enable those skilled in the art to reproduce the invention. In this case, it is important that the original application must clearly describe the method used to determine the parameters for the crystalline compounds.
In the field of compound crystals, whether a compound has a crystal form, how many crystal forms exist, and which crystal forms are not predictable. The acquisition of a new crystal form generally needs to be determined by experimental results, but this is not necessarily the case. This means that a complete X-ray diffraction pattern must be used to characterize the corresponding crystal. If only one or a few diffraction peaks in the XRPD pattern of the specific crystal disclosed in the specification are recited in the claims, it is difficult to determine whether they represent only the specific crystal form claimed by the one or a few diffraction peaks. Those skilled in the art cannot usually determine that the crystal characterized by only one or a few diffraction peaks is the specific crystal actually prepared by the applicant, which may also include other forms prepared by the applicant who are not disclosed in this application, the claim should not be supported by the description.
Although unity does not jeopardize the patentability of the application, when one wants to completely protect several polymorphic forms, this issue involving costs becomes a very important issue.
Organic compounds in crystalline form may have multiple crystal forms. Therefore, especially when first studying the polymorphism of products, multiple polymorphs and solvates may be discovered at once.
Evaluating whether a group of inventions belong to a general inventive concept is not only based on the way in which these inventions are related to each other, but the teaching of the prior art is also important. Generally, (1) if the compound itself has novelty and inventive step, then the claimed different forms of aggregation states and/or multiple crystals have the same or corresponding "technologies" with specific technical characteristics to satisfy the unity requirement. (2) If the compound itself is known, as the prior art has disclosed the "non-crystalline" compound (oil or amorphous solid) or disclosed one or more crystals of the compound, or the compound is new in itself but not inventive, then multiple independent claims cannot be written in parallel between the various crystals claimed at this time, otherwise there is no unity among the independent claims.
VIII．Countries inwhich polymorphic patents cannot be accepted
In particular, the Indian Patent Law specifically excludes the following patent protection objects: salts, esters, polymorphs, metabolites, pure forms, particle sizes, isomers, isomer mixtures, complexes, conjugates, or other derivatives should be considered the same substance unless they produce particularly obvious effects. Therefore, patent applications for protection of polymorphic forms should avoid entering India as much as possible.
As we knew in China, promoted by factors such as drug examination policy, economy, and law, polymorphic patents have become an important aspect of drug patents. In China, drug evaluation agencies often recognize that two or more crystal forms of a compound are equivalent drugs. Compared with the huge cost of new drug compound research, the cost of screening polymorphs is much smaller. As for the market monopoly of patented drugs, polymorphic patents are not inferior. This article analyzes the clarity, novelty, inventive step, full disclosure, support, and unity of polymorphic inventions, hoping to provide reference for subsequent polymorphic patent drafting and examination.