[Co-Authors: Liuxin Jin and Yu Bai]
Polymorphism of a pharmaceutical compound refers to its state of existing in different solid forms that is caused by the fact that the molecules of the compound, though being of the same chemical structure, are arranged in the lattice space in different orders. The existence of different crystalline forms of a small-molecule drug may affect its melting point, solubility, physical/chemical stability, bioavailability, and the like, thereby affecting its safety and efficacy. From that point of view, more and more attention has been paid to studies of pharmaceutical crystalline forms. Also, from the point of view of patent values, patents for crystalline forms of pharmaceuticals are of great significance. For manufacturers of originators, crystalline form patents can prolong or reinforce the protection for the medicament; for manufacturers of generics, they can somewhat bypass barriers of existing patents and thus manage to gain a competitive edge in the market by developing different crystalline forms and applying for patent protection. Hereafter we would like to discuss, based on concrete cases, criteria adopted in China in examining inventions of crystalline forms of pharmaceuticals (primarily new crystalline forms of known compounds) as to inventive step, and provide pertinent individuals and entities with suggestions on how to patent crystalline forms of pharmaceuticals.
I. Criteria for Examining Inventive Step of Crystalline Form Inventions
The Guidelines for Patent Examination (2010) do not stipulate anything special about the examination of applications for invention patents for pharmaceutical crystalline forms as to inventive step. Crystalline compounds, though being likely characterized by unusual physicochemical parameters due to special molecular arrangements, still belong under the category of compounds. Therefore, the stipulations on examining inventive step of applications for invention patents for compounds in the Guidelines apply to pharmaceutical crystalline forms.
In earlier years, a crystalline form of a medicament was likely to get patented in China as long as the crystalline form was proven to be different from the prior art and achieved a certain effect [1].
However, as an increasing number of applications for invention patents for pharmaceutical crystalline forms are filed in China and an increasing number of patents for them are granted there, invalidation disputes are also increasing year after year, and some of the patents for medicament crystalline forms have been invalidated because of not involving inventive step. After studying relevant invalidation decisions and verdicts made by the authorities, we find that the reexamination and invalidation department as well as courts at all levels are more likely to be of the opinion that a person skilled in the art, motivated by stability, treatment convenience, and other universal considerations, would be able to attain a new crystalline form having superior properties. They therefore conclude that even a new crystalline form is not necessarily nonobvious. We herein present Case I (The 2011 Case of Administrative Dispute over Invalidation of Patent for Invention “Crystal of Tiotropium Bromide Monohydrate” [(2011) Zhi Xing Zi No. 86]), a typical invalidation lawsuit. In Case I, the Supreme People’s Court (SPC) was in favor of the former Patent Reexamination Board under the CNIPA, saying, in the retrial judgement, as follows: “Not all changes in microscopic crystal structure would inevitably lead to a prominent substantive feature and notable progress, so dissimilarities in structure cannot be determined based merely on dissimilarities in microscopic crystal structure. In the determination of whether a crystal involves inventive step, microscopic crystal structures must be taken into consideration together with whether a change in microscopic crystal structure brings about an unexpected technical effect.”
Correspondingly, the CNIPA was applying an increasingly strict criterion to the examination of inventive step of applications for patent inventions of pharmaceutical crystalline forms. Some of the office actions held that new crystalline forms per se are obvious on the following grounds: as the research and development of medicaments is becoming standardized and internationalized, and techniques for screening crystalline forms are becoming mature, a person skilled in the art would have the motivation to screen out a particular crystalline form; processes for screening crystalline forms are in general the prior art. Since a new crystalline form of a known compound is usually considered to resemble in structure the known compound/a formerly known crystalline form of the compound, whether the new crystalline form achieves an unexpected technical effect is the main consideration in determining whether the new crystalline form involves inventive step. Developing crystalline forms is among ordinary projects of pharmaceutical R & D, and a newly developed crystalline form may find it difficult to come up to such a standard as “unexpected technical effect.” Some of the patent applications for crystalline forms are rejected because of failing to provide sufficient data on their effects. As a result, the patent grant rate of recent years is noticeably lower than that of earlier years.
Recent years have seen that some of the CN patents for pharmaceutical crystalline forms are invalidated for a lack of inventive step, and that some of the CN patent applications for pharmaceutical crystalline forms are rejected and do not throw off the rejections even after the applicants request reexamination of them. There is, for instance, a patent for a crystalline form of the antineoplastic drug “Imatinib Mesylate” that was invalidated due to a lack of inventive step. As another example, the patent application for a crystalline form of “Sofosbuvir” was rejected, and the decision of rejection for the application was upheld by the former Patent Reexamination Board on the same ground. Even after the applicant filed a lawsuit against the Board with the SPC, the SPC still held that the application did not involve inventive step. Such phenomena have aroused in the industry widespread concern and discussion about what data on effects of a crystalline form should be provided in order for the crystalline form to be considered inventive.
In response to the concerns of domestic and foreign innovation entities, the CNIPA issued on December 14, 2020 a decision on amendments to the Guidelines, mainly to chapter 10 of part II, which is Several Stipulations on Examination of Applications for Invention Patents in Chemistry Field) (Announcement No. 391, coming into force on January 15, 2021). For the examination of inventive step of compounds, the amended Guidelines, having deleted those sentences and paragraphs saying that determining whether a compound involves inventive step shall consider whether the compound is similar to a known compound in addition to technical effects, make clear the guiding role that “Three-Step Approach” plays in determining whether compounds involve inventive step, stress the necessity to grasp the relationship between structural modification and use and/or effect, and highlight “unexpected technical effects” as an auxiliary factor for inventive-step determination. It can also be seen, from the office actions and the decisions of rejection issued over the past two years, that in determining whether inventions of new crystalline forms of pharmaceuticals involve inventive step, the examiners consider not only whether the new crystalline forms per se are nonobvious but also whether the overall technical effects achieved by the new crystalline forms are unexpected [2]. Now let’s have a look at Case II, an invalidation case (Invalidation Decision No. 50673) concerning a crystalline form of Entresto (valsartan-sacubitril trisodium salt hemipentahydrate, LCZ696), a Novartis’ blockbuster drug for the treatment of heart failure. According to the collegial panel, there is the general teaching of forming a co-crystal or complex using different organic compounds, or combining two drugs, but applying the general theories to particular compounds and succeeding in doing so are not the same thing as making simple customary choices. Instead, that needs the inventor to do in-depth research on the structure and physicochemical properties of related compounds and verify the result by doing a large amount of experimentation. Moreover, to form a co-crystal or complex from two medicaments, the inventor needs to consider effects of using the two medicaments together on the efficacy, their compatibility, and administration route, among other factors. Although evidence 2 discloses a pharmaceutical composition comprising valsartan and sacubitril, it is not the case that two medicaments usable in combination inevitably form a complex. It would not be easy for a person skilled in the art to think of forming a complex of valsartan and sacubitril in the form of a trisodium salt hydrate without sufficient information on doing so in the prior art.
To sum up, criteria for examining inventions of pharmaceutical crystalline forms in China have stabilized, which would help with the development of the pharmaceutical industry. In this context, we provide pertinent individuals and entities with suggestions on how to get crystalline forms of pharmaceuticals patented more likely and how to make the patents more robust.
II. Suggestions for Patenting Crystalline Forms
For a new crystalline form of a pharmaceutical compound suitable for commercialization that is attainable by customary means, the applicant might as well consider not disclosing or less disclosing, in an application for a patent for the compound, the method of producing the new crystalline form. If the new crystalline form does not achieve a noticeably improved technical effect, it would be better that the applicant files an application for a patent for the new crystalline form before the application for a patent for the compound is disclosed. If, on the other hand, the new crystalline form achieves a noticeably improved technical effect, the applicant can file an application for a patent for the new crystalline form depending on circumstances after the application for a patent for the compound is disclosed, so as to prolong the protection for the compound. In the latter case, however, the applicant needs to provide in the application document data sufficient to establish the unexpected technical effect achievable by the new crystalline form. In the case of a special crystalline form such as a co-crystal, the applicant may need to emphasize in the application document that the new crystalline form cannot be obtained without a special crystallization approach or means so as to highlight non-obviousness of the crystalline form itself. It is also necessary to study crystal transformation. If a crystalline form comes into existence while the compound is left alone, the applicant may try to protect it by a patent or prevent others from applying for a patent for it by disclosing it. All the patent strategies need to match the degree of disclosure of the medicament in research and match the degree of progress of the registration for the medicament [3]. The following are things worth noting in practice.
the applicant can stress differences of the new crystalline form from amorphous forms or other crystalline forms of the known compounds that are disclosed in the prior art, and provide detailed relevant data. It is therefore necessary to find out as many technical effects as possible before applying for a patent. For reference, the technical effects include physical stability, solubility, dissolution rate, hygroscopicity, chemical stability, purity, bioavailability, etc. Describing in the application document multiple technical effects makes it possible to argue in a later prosecution stage that several technical effects can be improved in a balanced manner, at least makes it possible to argue that one of the technical effects is unexpected, and also make it more possible to supplement experimental data in a later prosecution stage. If there are other salt forms with relatively poor effects or other crystalline forms of the same salt form that are obtained in developing a preferable crystalline form, it would be better to record them in the application document so as to highlight the overall unexpected technical effects achieved by the preferable crystalline form.
In defining “unexpected technical effects,” the Guidelines stipulate like this: That an invention achieves unexpected technical effects means that the invention, compared with the prior art, achieves technical effects involving a “qualitative” change, and thus has a new property, or achieves technical effects involving a “quantitative” change that goes beyond people’s expectations. Such a “qualitative” or “quantitative” change cannot be predicted or inferred by a person skilled in the art. For an invention of a crystalline form of a medicament, improvements, over the free base, on physical/chemical stability, solubility, and storage resistance, among other technical effects, brought about by the specific ordered microstructure of the compound crystal, are probably considered in the examination as predictable technical effects. For example, if a pharmaceutical compound has a melting point of 200 °C or more, a difference in melting point that ranges from 8 °C to 10 °C is generally not considered as a “quantitative” or “qualitative” improvement on the stability of the product (see Case V described later). The following are two invalidation cases regarding how technical effect can be regarded as “unexpected technical effects.”
Case III: Invalidation Case of Sitagliptin Dihydrogen Phosphate Crystalline Monohydrate (Invalid Decision No. 48334)
The application document records the thermal stability, crystal stability, and water solubility of sitagliptin dihydrogen phosphate crystalline monohydrate. In determining whether sitagliptin dihydrogen phosphate crystalline monohydrate produces an unexpected technical effect over the prior art, the collegial panel holds the following opinions: First, since the presence of water molecules will make a big difference in property (e.g., stability), determining whether the technical effect achieved by sitagliptin dihydrogen phosphate monohydrate is predictable must be based only on the technical effect achieved by the hydrochloride crystalline monohydrate in evidence 4 and evidence 18. Second, comparing the TGA and DSC curves of the dihydrogen phosphate crystalline monohydrate with those of the hydrochloride crystalline monohydrate in evidence 4 shows that the temperature at which the dihydrogen phosphate crystalline monohydrate loses water is 100 °C or higher, almost twice as much as the temperature at which the hydrochloride crystalline monohydrate loses water. As shown by a comparison between the TGA and DSC curves of the dihydrogen phosphate crystalline monohydrate with those of the hydrochloride monohydrate in evidence 18, the temperature at which the dihydrogen phosphate crystalline monohydrate loses water is also raised significantly. This is unpredictable by a person skilled in the art from the documentary evidence provided by the invalidation petitioner. Data on effects in the application as well as that in evidence 4 and evidence 18 is listed below.
The collegial panel concludes that the technical effect of the significantly improved thermal stability and crystalline form stability achieved by sitagliptin dihydrogen phosphate monohydrate is unexpected by a person skilled in the art, and the documentary evidence teaches nothing about that replacing the chloride anion of the hydrochloride hydrate to the dihydrogen phosphate anion will improve the thermal stability and crystalline form stability of the salt crystal, but the water solubility of sitagliptin dihydrogen phosphate monohydrate is not an unexpected technical effect.
Case IV: Invalidation Case of Crystalline Form of Vortioxetine Hydrobromide (Invalidation Decision No. 54705 and Invalidation Decision No. 48337)
The prior art discloses the free base of vortioxetine/a pharmaceutically acceptable acid addition salt of vortioxetine, not disclosing its physicochemical properties. According to the collegial panel, for a new salt crystal of a known compound, a person skilled in the art would usually study salts formed from the known compound and common acids and crystals of the salts, but this does not mean that a salt crystal of the compound necessarily does not involve inventive step, and the key to the determination is whether the claimed salt crystal solves a certain technical problem and produces an unexpected technical effect. Considerations in determining whether the claimed salt crystal achieves an unexpected technical effect include not only the difference between different salts but also the difference in technical effect between different crystalline forms of the same salt. A comprehensive determination should be based on all the technical effects recorded in the specification. The specification of the application describes, in the examples, melting point, hygroscopicity, and solubility of free base and nine salt crystals (including five crystals of hydrobromide) of vortioxetine. Part of the data is listed below.
As can be found from an analysis of the melting point, hygroscopicity, and solubility of the various salt crystals, the α and β crystalline forms of hydrobromide vortioxetine have a higher melting point (stability) than, a comparable low hygroscopicity (graded as “slightly hygroscopic”) to, and a higher water solubility (graded as “slightly soluble”) than the other salt forms, suitable for medical use. Such comprehensive performance is unexpected by a person skilled in the art from the many salt crystals listed in the application document. The other salts or crystals have a high hygroscopicity or are unstable. For example, of the hydrochlorides, similar in nature to the hydrobromides, the hydrochloride crystal has a high hygroscopicity, and the hydrochloride monohydrate dehydrates even at 50 ℃. The γ crystalline form of hydrobromide vortioxetine, also a hydrobromide vortioxetine, is so unstable that it may have its crystalline form converted at about 100 ℃, and has a high hygroscopicity. The hydrate and ethyl acetate solvate are so unstable that they are prone to lose water or the solvent. The collegial panel therefore accepts the involvement of inventive step in the α and β crystalline forms of hydrobromide vortioxetine.
From the two cases discussed above, we can learn a process for determining “unexpected technical effect,” objects for the comparison, and criteria for determining the “quantitative change” and “qualitative change.” See below for the details.
The process for the determination includes: the first step of confirming the technical effects achieved by the claimed new crystalline form, the second step of confirming the technical effects achieved by the closest prior art, and the third step of comparing the technical effects achieved by the two to determine whether the difference in technical effect is predictable to a person skilled in the art.
The objects to compare with each other are the application and the closest prior art. In many cases, the closet prior is usually concerned with a basic compound such as a free base or numerous pharmaceutically acceptable acid addition salts (mentioned in general terms), without disclosing properties or effects corresponding to the claimed crystalline form. In that case and in a case where the application describes, in the specification, the technical effects achieved by the free base or various crystalline forms, the examiner would usually make a comparison based on the data on the effects. For that reason, comprehensive data for effect comparison recorded in the specification is of great importance. When the patent comes to the invalidation proceedings, the collegial panel generally holds that if the petitioner fails to provide ample evidence capable of refuting the results confirmed by the experiments recorded in the specification of the application, or sufficient evidence capable of establishing the technical effects of the prior art, the petitioner shall bear the legal consequence of failing to prove that the technical effects of the application are predictable.
When it comes to the determination criteria, “unexpected technical effect” may be a significant “quantitative” change like a multifold increase in the water-loss temperature of the product in Case III, or a “qualitative” change like the product’s properties of a low hygroscopicity and a proper solubility in addition to a high melting point. To speak more about a “qualitative” change as “unexpected technical effects,” when a compound turns from the free-base form to a salt, its solubility is usually increased, but when the salt comes into being in the form of a crystal, its solubility is lowered to some extent. A crystal having a high melting point means more regular grains and higher stability, but corresponds to lower solubility and lower hygroscopicity. The claimed crystalline form in Case IV has a high melting point, low hygroscopicity and proper solubility. Such a property combination means that the crystalline form attains a favorable balance between those requirements. Case IV is a typical example of making improvement on various technical effects, and it has been challenged many times but still stands firm. To embody “unexpected technical effects” in the application document, it is necessary for the specification to present experimental data showing that a preferred crystalline form is apparently superior to other crystalline forms in at least one technical effect, when the disclosure in the closest prior art is a mere mention of numerous pharmaceutically acceptable acid addition salts of the known compound.
There are some applications the applicants of which are unable to provide enough original data at the time of filing the applications due to delays in the progress of their R & D. Also, there are some cases where the examiner or invalidation petitioner provides the prior art that is unknown to the applicant/patentee. In those cases, the applicant/patentee can submit supplementary experimental data to prove the claimed invention’s unexpected technical effect at the prosecution stage of substantive examination, reexamination, or invalidation. However, the technical effects that the supplementary experimental data can establish should be contents that a person skilled in the art can derive from the application document. Case V is a successful case where the supplementary experimental data submitted by the applicant was accepted.
Case V: Invalidation Case of Cariprazine (Invalid Decision No. 47087)
The patented product is a crystalline form I of cariprazine monohydrochloride anhydrate. The specification of the application describes as follows: “During the experiments, the inventor has surprisingly discovered that, of the many salts described in the art, the monohydrochloride, dihydrochloride, monohydrobromide, maleate and mesylate exhibit excellent stability, separability, and solubility properties.” “The hydrochloride is particularly preferred because it can be prepared in the highest yield and with the highest purity.” There is a record, in the specification, of the yield, melting point, TG analysis, DSC analysis, and other analyses of the monohydrochloride, but no record of information on the purity.
In the invalidation stage, the patentee supplementarily submitted counter-evidence 1 and counter-evidence 2 (which are documents submitted by the patentee to the EPO in response to the office action for the the EP counterpart, and a Chinese translation of part of the documents). Counter-evidence 2 compares the products obtained in Examples 1-4 and 6 as to purity, total content of impurities, and content of the most characteristic impurity, and proves, by repeating the experiments, that the impurity contents are not measurement errors.
According to the collegial panel, as is determinable from what is described in the specification, a person skilled in the art would be able to get the idea that the higher purity of monohydrochloride than the other salts is a technical effect that the patentee had noticed and should have had studied before the filing date. The patentee supplemented, after the filing date, the experimental data as required by the examination, to prove that the crystalline form I of cariprazine monohydrochloride has higher purity. The supplementary experimental data is eligible for consideration. As shown by the supplementary experimental data, the monohydrochloride has a significantly lower total content of impurities and a significantly lower content of the most characteristic impurity than the other salt forms, and the documentary evidence is no sufficient proof that the contents of impurities are not correlated with which one of the salt forms is selected but are only affected by what method is used to prepare the product. The collegial panel holds that the crystalline form I of cariprazine monohydrochloride, in comparison with the other salt forms, exhibits such high purity that a person skilled in the art would not be able to expect it. With the acceptable stability and improved solubility over the free base also taken into consideration, the collegial panel declares the patent to be valid.
Case V is a showcase of how important it is to record multiple technical effects in the specification. For a technical effect that is mentioned in the specification but lacks experimental data, if a person skilled in the art is sure, based on the whole specification, that the patentee had paid attention to the technical effect and should have had studied the technical effect before the filing date, corresponding experimental data can be supplemented after the filing date, and the supplementary experimental data may be taken as proof of the technical effects achievable by the invention. Incidentally, notarization and certification are not procedures that the patentee must undergo. The documents recording the experimental data that were submitted during the examination of a patent family, though not being notarized and certified, are usually confirmed to be true if there is not sufficient evidence that the relevant data is fraudulent or not true [4].
Generally, applicants apply for patents for their inventions of drug crystalline forms that carry highly commercial potentials, in countries where their products are sold and manufactured. Getting knowledge of the differences between countries in criteria for examining inventions of pharmaceutical crystalline forms helps applicants apply for patents and adopt patent strategies. According to our experience, China and Japan apply a strict criterion. In the two countries, acquiring a crystalline form is generally considered obvious, and more importance is attached to whether the technical effects achieved by the crystalline form reach the level “unexpected”; an allowed claim is in general required to be restricted by multiple characteristic peaks (e.g., five or more characteristic peaks). In the US, an invention of a crystalline form of a pharmaceutical compound can be patented more readily. Arguments for the involvement of inventive step in a crystalline form can be the usual ones, such as whether the prior art teaches the existence of polymorphism in the pharmaceutical compound, whether the crystalline form is attainable by customary experiments and techniques, whether a large number of variable conditions are involved in the crystallization experiment, and whether it is reasonably predictable to succeed in finding the new crystalline form [5]. A claim allowed in the US is usually so broad that only a few characteristic peaks (e.g., three characteristic peaks) are enough. The EPO also gives attention to unexpected technical effects, but requires an allowed claim to be restricted by a few characteristic peaks. Therefore, if applying for patents for a crystalline form of a pharmaceutical compound in multiple countries or regions, the applicant should preferably disclose data to the strictest standard, write the claims to the least strict standard, and include various kinds of subject matter into the specification.
In summary, an invention of a crystalline form of a pharmaceutical compound is an important subject of patent protection in the medical field, either at home or abroad. To get it patented more likely and make the patent more robust, the applicant shall find out technical effects from multiple angles, and record in the application document data on comparing effects of the claimed crystalline form with those of the prior art or other crystalline forms; and might as well have a try if there is a need to submit supplementary experimental data after the filing date. Paying attention to the differences between countries in criteria for examining inventions of crystalline forms of pharmaceutical compounds would help the applicant to adopt appropriate patent strategies in different countries.
References
[1] Inventive-Step Requirements for Inventions of Crystalline Forms of Compounds, Seen from Invalidation Cases in China, Official Account of Linda Liu & Partners, Yu BAI
[2] Strategies for Applying for Patents for Crystalline Forms of Pharmaceutical Compounds 2022, Source: Jingtai Technology XtalPi, Yuanxia LIU
[3] Jingyan Talk | How should pharmaceutical companies create a patent application strategy for a pharmaceutical crystalline form? Source: Jingtai Technology XtalPi
[4] Problems and Trends of Patent Grant, Right Confirmation, and Infringement about Crystalline Forms of Pharmaceuticals, Source: CPIPS 2021, Yongquan LIU
[5] Brief Analysis of Differences between China and US in Criteria for Determining Inventive Step in Inventions for Patents for Crystalline Forms of Pharmaceutical Compounds, Patent Agency, 2017(4): 37-44, Xiyuan ZHENG, Ying ZHANG
