Xiang LIU, Patent Attorney

In the field of chemical materials, crystal form patents are receiving more and more attention. Especially in the field of medicine, the importance of crystal form patents is more prominent. This is because the research and development of new drugs often takes a lot of financial resources and time, and crystal form patents can extend the patent term and the market life of drugs. If the original compound patent expires and the crystal form patent possibly does not, then the generic drug company cannot imitate the same crystal form. In this way, it is possible for crystal form patents to seek more commercial benefits for original pharmaceutical companies.

In recent years, one of the great challenges encountered in the process of applying for patent for crystal form is the issue of inventive step. As this author's practical experience shows, the key to the success of defending inventive step for a crystal form patent application lies in the necessity to prove that the new crystal form of a known compound has achieved unexpected technical effects. The unpredictability of whether a compound has a crystal form, how many crystal forms exist, and what crystal form exists cannot be equated with non-obviousness in inventive-step examination. In addition to being clearly presented in the original application documents, the unexpected technical effects that can be considered in the inventive step evaluation should also be technical effects confirmed with corresponding experimental data.

This article will be discussing the techniques for defending matters of inventive step in the process of crystal form patent application based on the author's practice.

Case One

Chinese Patent Application No. 201711075793.3

Claim 1 of the present application claims an Iprafluazin magnesium salt crystal form A, wherein the Ipramirazin magnesium salt crystal form A uses Cu-Kα radiation, and X-ray powder diffraction pattern expressed at an angle of 2θ has characteristic absorption peaks at 4.795, 12.295, 12.710, 14.684, and 15.887.

In the first office action, the examiner commented that the reference document D1 (WO2011/071314A2) disclosed an ilaprazole magnesium salt tetrahydrate, and pointed out that since the TGA, DSC and XRD powder diffraction of the crystals of ilaprazole magnesium salt tetrahydrate was not determined in D1, therefore making it impossible for the present application to be compared with it, and therefore it could not be proved based on the available evidence that the crystal form A of the magnesium salt of iprazole in the present application was different from the ilaprazole magnesium salt tetrahydrate in D1. Thus, claim 1 is presumably not novel. At the same time, the examiner also pointed out that since the mass-related properties of iprazole magnesium tetrahydrate were not disclosed in D1, there was no evidence that the present application had an unexpected technical effect over D1.

In the process of responding to the office actions and requesting reexamination, the applicant further limited the XRD full spectrum of ilaprazole magnesium salt crystal form A in claim 1 and the preparation method thereof, and supplemented the XRD diagram of the ilaprazole magnesium salt tetrahydrate in D1 to prove the difference in crystal structure between the crystalline form A of the present invention and the ilaprazole magnesium salt tetrahydrate in D1. Additionally, the applicant also elaborated the unexpected technical effect achieved in the present invention.

However, the examiner and the reexamination panel did not accept the above responses and amendments from the applicant. The examiner believed that: first of all, for drug crystals, the superior drug crystals are more reflected in stability or bioavailability, and the improvement in crystal purity is usually not an unexpected technical effect; secondly, XRD spectra is a method for characterizing the internal structure of crystals, which usually cannot be used to characterize crystal purity, so XRD alone does not indicate that the crystal purity or crystallinity in D1 is not good. The reexamination panel pointed out: (1) D1 did not give data on the chemical purity, heat resistance, high temperature stability, and fluidity effect of the crystal form of ilaprazole magnesium salt tetrahydrate in Example 14, and in the case as the applicant did not provide better technical effects in chemical purity, heat resistance, high temperature stability, and fluidity compared with D1, it could not be determined that the technical solution of claim 1 of the present application had prominent substantive features and made significant progress compared with D1; and (ii) in commenting on the product claims of claim 1, there is no evidence to show that the process features have a defining effect on the product itself, and the process features did not define the product claims. Therefore, differences in method features did not make the product claims themselves inventive.

For this reason, in responding to the reexamination notification, the applicant focused on supplementing the comparative experiments of the present invention in terms of fluidity, stability and purity of the ilaprazole magnesium salt crystal form A and the magnesium salt tetrahydrate in D1, to prove that the ilaprazole magnesium salt crystal form A of the present invention achieved unexpected technical effects compared with the ilaprazole magnesium salt tetrahydrate of D1. The above arguments were accepted by the panel. As a result, the panel revoked the decision of the CNIPA on rejecting the application, and this application was ultimately granted the patent.

From the above case, the following experience can be summarized for future practice in such cases: (i) It is not enough to prove that the crystal structure of the material of the present invention is different from the crystal structure of the material disclosed in the prior art by supplementing the XRD diagram, and it is also necessary to further prove that the crystal structure of the material of the present invention has unexpected technical effect relative to the crystal structure of the material disclosed in the prior art; (ii) when proving the unexpected technical effects of the present invention relative to the closest prior art, it is necessary to prove from the aspects recognized in the art, such as the technical effects of drug crystal forms are more reflected in stability or bioavailability; of course, these technical effects must have been mentioned in the initial application documents; and (iii) at the stage of drafting, the application documents should correctly characterize and disclose in details the difference between the crystal features and the known crystals; and the applicant should avoid presenting only a single technical effect, and should describe multiple technical effects. For example, the technical effects may be solubility, dissolution, dissolution rate, hygroscopicity, stability, flowability, purity, and bioavailability. Presenting multiple technical effects would make it possible, in the later stage, to argue for the simultaneous improvement of multiple technical effects, and probable for the inventiveness higher than that of a single technical effect to be recognized. At the same time, presenting more technical effects may make it more possible to subsequently supplement data, and to prove the inventive step by supplementing experimental data from more dimensions.

Case Two

Chinese Patent Application No. 202011548589.0

The present application claims an all-organic pyroelectric material having the following chemical formula: A_1-xA’_xB_1-yB’_y, wherein A is protonated amantadine; B is formate ion; A' is selected from one or more of ... protonated methyl amantadine ... B' is selected from one or more of ... hypophosphite ions, acetate ions ... 0≤x≤0.3, 0≤y≤0.3.

In the office action, the examiner noted that the reference document D1 (CN103588648A) disclosed an amantadine formate that fell within the scope of A_1-xA’_xB_1-yB’_y in claim 1, namely A is protonated amantadine, B is formate ion, and x=0, y=0. The two claim the same technical solution for the same technical field, solve the same technical problem, and achieve the same technical effect, so claim 1 of the present application does not possess novelty.

In the process of responding to the first and second office actions, the applicant further defined the space group and lattice constant of the all-organic pyroelectric material in claim 1 to further define the crystal structure of the material. To prove that the all-organic pyroelectric material of the present invention differed from the material disclosed in D1 in crystal structure, the applicant did not provide a crystal structure characterization of the material in D1, but from the difference in the preparation method of the two materials (such as crystallization temperature) and the physical and chemical properties embodied in the material, it is proved that the amantadine formate of D1 lacked the crystal structure of the present invention. Specifically, the applicant additionally submitted experimental data to show the sublimation temperature of amantadine formate of the present invention. Example 1 of the present invention of amantadine formate sublimation temperature under normal pressure was 140℃, and did not have a melting point. That is, the amantadine formate of present invention was directly sublimated, without the process of melting. The melting point of amantadine formate in D1 was 238℃. It could be seen that the amantadine formate of present invention was completely different from that of D1 in physical properties. Thus, those skilled in the art have reason to infer that the amantadine formate compared to D1 has no crystalline structure of the present invention. To illustrate the technical effect of the all-organic pyroelectric material of present invention relative to the material of D1, the applicant stated: “It is well known in the art that the structure plays an important role in the performance, and the pyroelectric properties are dependent on the structural features of the material; so those skilled in the art have reason to believe that when the material structure of the reference differs from the present invention, its performance and the present invention are not comparable." These arguments were accepted by the examiner, and the application was ultimately granted the patent.

It can be seen from this case: (1) when it is not convenient for the applicant to supplement the characterization data of the crystal structure of D1, the physical and chemical properties of the materials of the present invention can be compared with those disclosed in D1 to prove that the crystal structure of present invention is different from that of the prior art; and (2) if, in the art, the performance of the material depends in particular on the crystal structure of the material (especially if the structure of the material is changed, it brings completely new properties), even if the applicant cannot provide experimental data to prove that the material of the reference does not have the performance of the material of the present invention, the material of present application has opportunity to be patented.

In conclusion, for a crystal structure in an application to be patented, in addition to ensuring that the crystal structure is different from the prior art, it is also necessary to ensure that the difference in the crystal structure brings unexpected technical effects.

Author:

Ms. Xiang LIU

Ms. Liu received her Bachelor degree from Shandong Normal University in 2011 and her Master degree from the Beijing University of Chemical Technology in 2014. She joined Panawell in 2018, and specializes in patent drafting and prosecution in chemical engineering, materials, and etc.