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New Progress in Examination Practice of Compound Patents

29

JUL

2022

Recently, two typical cases[1] announced by the CNIPA (Top Ten Cases of Reexamination and Invalidation in 2021) provide the examination practice for some complicated issues in compound patents, including determination of priority of compound, evaluation of enablement of table compounds, non-obviousness of compound structure and support of Markush structure-containing claim.

In summary, from the invalidation decisions of the above two cases, in addition to specific embodiments, current invalidation examination would also concern the whole disclosure and teaching of patent specification and the prior art.

In the following part, we will analyze and discuss the examination practice for these complicated issues in detail with reference to the two cases.

I. Determination of Compound Priority

As for determination of compound priority, especially when the priority application refers to a wider general formula, whereas the later application or patent refers to a specific compound or a narrower general formula within the wider general formula, it is hard to determine whether the later application or patent can enjoy priority or not.

As for this issue, Macitentan Case provides an approach to determine whether a specific compound or a narrower general formula can enjoy priority or not, in which it will be determined whether the specific compound or narrower general formula is recited or implied in the prior application, and if not, the priority cannot be enjoyed. This issue will be discussed in detail as follows.

i) Case Introduction

In Maxitentan Case, the independent claim 1 protects compound 104 and Maxitentan. Although it recites a general formula (I) covering compound 104 and Maxitentan, the priority application fails to recite compound 104 and Maxitentan. Therefore, one of the controversial points in this case is whether compound 104 and Maxitentan can enjoy priority based on formula (I).

ii) Decision’s Opinion

The Decision holds that a specific compound cannot enjoy priority based on a Markush formula.

First, Markush formula, as a special form of compounds, is generally regarded as an organic whole formed by various substituents and options, rather than a collection of specific compounds. According to the determination of novelty, the general formula cannot destroy the novelty of a specific compound in the general formula, which means that the Markush formula and the specific compound therein cannot be considered as the same technical solution, and thus cannot constitute the same subject matter.

Second, if the specific compound can enjoy the priority based on a Markush formula, this will disobey the purpose of priority system.

Therefore, a priority can only be enjoyed when the specific compound or narrower general formula is recited or implied in the priority document.

iii) Take-away message

In practice, the key to determine priority is how to determine whether a specific compound or a narrower general formula is recited or implied in the priority document. According to this case, this can be done by evaluating if the specific compound or narrower general formula is novel over the priority application. If not, it will be considered as not being recited or implied in the priority application, and thus cannot enjoy priority.

II. Enablement of Table Compounds

-Generally, since the specification only recites the structures of the table compounds and does not provide preparation example, identification and activity data thereof, there is a risk that the table compounds will be considered as not being enabled. Therefore, whether the table compounds are enabled is hard to be evaluated in practice.

As for this issue, Maxitentan Case provides how to evaluate enablement of a table compound, i.e. if one skilled in the art can confirm its structure, acquire how to prepare it and expect its use/effect based on the patent specification, the compound will be considered enabled. This issue will be discussed in detail as follows.

i) Case Introduction

As shown in Part I, the independent claim 1 protects compound 104 and Maxitentan. As for compound 104, the specification provides its MS data and IC50 values against ETA and ETB, as for Maxitentan, the specification only recites its structure in the form of table compounds, and does not provide any preparation example, identification or activity data.

Compound 104 Maxitentan

The patent specification further discloses the identification and activity data of compounds 115 and 117 which are structurally similar to compound 104 and Maxitentan.

Compound 115 Compound 117

Since the patent specification provides neither preparation of Maxitentan nor its identification or activity data, whether Maxitentan is enabled becomes one of the controversial points.

ii) Decision’s Opinion

According to the invalidation decision, if one skilled in the art can prepare the table compound, confirm its structure and expect its technical effect based on the specification, the compound will be considered enabled.

(1) In this case, as for the preparation and identification of the compound, Maxitentan is very similar to compound 104 in structure, and the only difference lies in the alkyl chain attached to aminosulfonyl group, wherein compound 104 is ethyl, whereas Maxitentan is propyl. According to Scheme 3 of the specification, the alkyl chain is introduced by reacting alkylamine with aminosulfonyl chloride. In the preparation of compound 104, the raw material for introducing ethyl group is ethylamine. When preparing Maxitentan, one skilled in the art only needs to replace ethylamine with propylamine. Moreover, the specification further discloses the preparation of compounds 115 and 117 with similar structures, wherein the alkyl chain of compound 115 is ethyl and that of compound 117 is butyl. To sum up, there is no difficulty in introducing propyl chains, and thus Maxitentan can be prepared.

(2) As for the use and effect of the compound, since there is only one methylene difference between compound 104 and Maxitentan, their structures are highly similar. Therefore, one skilled in the art can reasonably expect that the technical effect of Maxitentan and compound 104 should be similar. Moreover, compounds 115 and 117 are structurally similar to compounds 104 and Maxitentan. There is only one ethylene group difference between compounds 115 and 117, and their technical effects are also similar. This further supports the expectation of the technical effect of Maxitentan to be reasonable. In addition, the patentee submits supplementary experimental data of Maxitentan, which further proves that the technical effects of Maxitentan and compound 104 are similar. Therefore, by comprehensively analyzing the data disclosed in the specification, one skilled in the art can expect the use and activity of Maxitentan.

iii) Take-away message

According to this case, in addition to the technical information of the compound itself, evaluation of enablement of a table compound would also rely on the whole contents of the specification. If one skilled in the art can prepare the table compound and expect its activity based on the whole contents of the specification, such as by means of the preparation and activity information of other similar compounds, the table compound will be considered enabled.

In practice, when facing this issue, we can also make a reference to this case, and find the basis to support the enablement of the table compound by utilizing the preparation and activity data of other similar compounds.

In addition, even if this Case provides an approach to evaluate enablement of table compounds, in view of the risk that the table compound may be considered as not being enabled, we still suggest providing the preparation example and activity data of the compound of interest in the specification.

III. Inventiveness of specific compounds - non-obviousness of compound structure

When evaluating the inventiveness of a compound, if the activity of the compound is not superior over that of the prior art, it is still hard to determine whether the inventiveness can be established only based on the structure modification.

As for this issue, Maxitentan Case indicates that when evaluating the inventiveness of a compound, besides the activity of a compound, whether the prior art provides a specific indication to modify the structure of the compound should also be considered. In other words, the non-obviousness of compound structure is also important for evaluating the inventiveness. This issue will be discussed in detail as follows.

i) Case Introduction

In this case, the petitioner used Compound 7K of Evidence 5 as the closest prior art. By comparison, the activity of compound 104 and Maxitentan is similar to that of compound 7K.

Compound 104 Maxitentan Compound 7k

Since the activity of compound 104 and Maxitentan (i.e., the activity of ETA and ETB receptors) is not superior over that of compound 7k, whether the above compounds involve inventiveness becomes one of the controversial points in this case.

ii) Decision’s Opinion

The invalidation decision holds that the inventiveness of a compound could be established if the prior art fails to provide a specific direction and indication to modify the structure of the compound. As for this case, the prior art (Evidence 5 and Evidence 6) has deeply studied the structure-activity relationship (SAR) of this kind of compounds and finds that the change of substituents on sulfonamide at the 4-position of pyrimidine ring (i.e., the part in the left circle of the compounds) is closely related to the activity of ETA and ETB receptors. Moreover, the change of substituents at the 4-position is directed to attaching to sulfonamide group via carbon. Under such circumstances, one skilled in the art is not motivated to replace the substituent on the sulfonamide group with a substituent which attaches to the sulfonamide group via nitrogen in the patent. Therefore, compound 104 and Maxitentan involve inventiveness.

iii) Take-away message

According to this case, the inventiveness of a compound can also be established on the structure of a compound, provided that the prior art fails to provide the specific direction and indication to modify the structure. In order words, in addition to the activity of a compound, the non-obviousness of its structure is also important for establishing inventiveness. When evaluating the non-obviousness of structure, it is necessary to comprehensively analyze the current situation of the prior art, such as the SAR in the prior art, so as to determine whether the prior art provides a direction to modify the structure of the closest compound in line with the patent. If not, the structure of the compound will be considered as non-obvious and the inventiveness will be established.

To sum up, in practice, if the inventiveness of a compound cannot be established on its activity, an argument from the non-obviousness of the structure may be another option.

IV. Support of Markush compounds

Since Markush formula is usually complicated, it is also hard to determine whether Markush structure-containing claims are supported by the specification.

As for this issue, Baloxavir Marboxil Case provides an approach to analyze the support of Markush structure-containing claims, in which the whole contents of the specification are comprehensively analyzed at first, and then the support of claims from structure, effect and structure-activity relationship is specifically analyzed. This issue will be discussed in detail as follows.

i) Case Introduction

In Baloxavir Marboxil Case, the independent claim 1 protects a compound of formula (I), which is the prodrug of parent compound of formula (II). Claim 1 defines that the compound of formula (I) can be bicyclic or tricyclic. Since the specification does not recite tricylic prodrug compounds but only recites tricylic parent compounds, the petitioner holds that the tricyclic prodrug compounds defined in claim 1 is not supported by the specification.

Parent compound Prodrug compound

ii) Decision’s opinion

The Decision holds that in evaluation of support of a Markush claim, in addition to the specific embodiments, the whole contents of the specification should also be considered.

As for this patent, from the whole contents of the patent specification, the patent is to prodrug the “parent compound”. The patent discloses a general preparation method for prodrug conversion, and 241 prodrug compounds are prepared by prodrugging parent compounds. Therefore, one skilled in the art can convert the parent compounds in the patent into corresponding prodrug compounds according to the disclosure of the patent. Moreover, Test Example 8 of the patent proves that the prodrug compound can be converted back into the corresponding parent compound in vivo. Therefore, one skilled in the art can prepare the parent compounds disclosed in the patent into the corresponding prodrug compounds, and can also confirm that the prodrug compounds could be converted into the corresponding parent compounds in vivo. Thus, the invalidation decision holds that when evaluating support of claim 1, the preparation examples and effects of both prodrug compounds and parent compounds should be considered.

On this basis, the invalidation decision specifically analyzes the support of claim 1 from compound structure, effect and structure-activity relationship.

As for compound structure, the patent discloses hundreds of preparation examples of parent compounds, including some compounds with tricyclic structure, wherein the number of ring atoms and the number and types of heteroatoms are representative. Therefore, one skilled in the art can generalize the tricyclic structure defined in Claim 1.

As for compound effect, the patent verifies the cap-dependent endonuclease inhibiting activity for a large number of parent compounds, and verifies that the prodrug compounds can be converted into parent compounds in vivo. Therefore, the patent verifies that the prodrug compounds can provide cap-dependent endonuclease inhibiting activity in vivo.

As for structure-activity relationship, by analyzing structure and activity of the compounds, it can be concluded that the bicyclic structure shown in the general formula of claim 1 is the basic core structure, and the change of substituents in other positions substantially does not affect the existence of this activity.

To sum up, one skilled in the art can generalize the technical solution of claim 1 and expect the technical effect by considering the whole contents of the specification. Therefore, claim 1 is supported by the specification.

iii) Take-away message

From this case, when analyzing support of Markush structure-containing claim, in addition to specific compounds within the scope of claim, the whole contents of the specification should be considered and analyzed.

Moreover, as for support analysis, in addition to considering whether the structure distribution of the example compounds is reasonable and whether the effect is verified, it is suggested to pay more attention to SAR analysis. If the basic core structure of these compounds can be determined by SAR analysis and this basic core structure is covered by the claim, it can also be indicated that the claim is supported by the specification.

V. Conclusion

In general, according to the decision of the two cases, current examination practice pays more attention to the overall understanding of the patent and the prior art. Therefore, when facing complicated issues such as enablement, support and inventiveness, it is important to analyze the patent specification and the prior art as a whole to avoid the limitation due to mainly merely considering the specific embodiments, so as to make a more reasonable response to complicated issues.


[1] Case 1: Macitentan compound patent invalidation case (Decision No. 48183, Patent No. 01820481.3)

Case 2: Baloxavir Marboxil compound patent invalidation case (Decision No. 47328, Patent No. 201180056716.8)

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