Drug invention patents protect multiple types of invention, including compounds, crystal forms, dosage forms, preparation methods and uses. Known for their high entry threshold, the research and development of drugs can be an expensive and lengthy process that does not necessarily guarantee high returns. Thus, pharmaceutical companies often seek to patent their innovations. New compounds, which are undoubtedly the core patents relating to drugs, are far rarer than improvement inventions (eg, dosage forms).
Nonetheless, in practice, it is difficult to patent improvement drug inventions in China. In proving the patentability of such an invention, patentees often face difficulties in establishing its non-obviousness (inventiveness). Non-obviousness is determined using the following three-step approach set out in the Guidelines for Patent Examination:
- determine the closest prior art;
- ascertain the invention's distinguishing technical features and the technical problem actually addressed by the invention; and
- evaluate the obviousness of the invention (whether there is such technical teaching as to motivate a person skilled in the art to apply the distinguishing technical features to address the technical problem).
Given that improvement drug invention patents are typically slightly different to the prior art, and the distinguishing technical features that are known or conventional could be deemed as constituting technical motivation, such inventions are often erroneously found to be obvious (and thus non-inventive) over the closest prior art.
Therefore, it is vital that the three-step approach is properly employed to assess the technical contribution of an improvement drug invention in order to ascertain its patentability and grant it the protection that it deserves.
This article analyses an invalidation case in order to understand the Patent Re-examination Board's (PRB's)(1) examination methodology for determining the non-obviousness of improvement inventions.
The invalidation case (Decision 38911) concerned an improvement invention patent for ibuprofen. Claim 1 sought to protect a transdermal treatment application system comprising a prodrug of ibuprofen with the following structure (Figure 1) for transdermal administration in the form of a solution or spray.
The inventive aspect of the patent lies in:
- the structural modification to ibuprofen; and
- the dosage form for administration.
The patent's description explicitly records the advantages of administering the prodrug transdermally over administering the parent drug ibuprofen orally. Compared with ibuprofen, the prodrug has considerably improved water solubility and skin diffusion rate, which enables it to penetrate skin barriers fast and effectively and achieve transdermal administration. Thus, it avoids side effects attributed to administering ibuprofen orally. Further, the transdermally administered prodrug is remarkably better than the orally administered ibuprofen in terms of both time to peak and peak concentration of the blood concentration.
In the invalidation proceeding, the petitioner proposed multiple combinations of evidence to negate the patent's inventiveness. The disclosure of the closest prior art varied within the pieces of evidence. For example, some pieces disclosed a wider range of compounds of general formula, some disclosed an identical prodrug compound and some disclosed topical administration formulation comprising the compound which had a similar structure to the prodrug. In reviewing each proposed combination of the evidence, the PRB followed the three-step approach in reaching its decision. The PRB's comments on some typical combinations of evidence shed light on the parameters that the board adopts in ascertaining non-obviousness of improvement drug patents.
Wide range of compounds
Where the closest prior art relates to a wide range of compounds of a general formula, the improvement of the invention embodies aspects of structural modification and dosage form.
In this case, Evidence 1 disclosed a class of compounds of a general formula, covering the prodrug defined in Claim 1. Evidence 1 also specifically disclosed an ibuprofen prodrug, Compound 31, which was modified with the imidazate group and was thus different to the prodrug of the patent. Evidence 1 indicated that the prodrugs therein were more permeable through biological membranes and could be administrated by oral or transdermal formulation. A topical administration method with glyceride triacetate as the carrier was also given.
The PRB analysed the technical effects recorded in the patent's description and, after comparing this with Evidence 1, identified that the technical problem actually solved by Claim 1 was providing a transdermal formulation of ibuprofen prodrug compound which had less side effects but better therapeutic effects than the oral preparation of ibuprofen. On such basis, the PRB found that Evidence 1 indicated that a good biphasic solubility of the derivatives enabled them to be more permeable through biological membranes such as skin, intestine, oral or rectal mucosa, thus making them less irritating compared with the parent drug. While this may provide a higher level of bioavailability, no research on the activity of any specific compound was conducted. Further, as to the administration route or dosage form of the derivatives, Evidence 1 merely indicated that drugs may generally be administrated by oral or transdermal dosage form, without revealing what technical effects could be achieved by transdermal administration of the prodrug over oral administration of the parent drug. Therefore, the PRB concluded that Evidence 1 failed to give corresponding technical insight into the technical problem solved by the patent.
Where the closest prior art discloses an identical prodrug, the improvement of the invention embodies in dosage form.
In this case, Evidence 8, as the closest prior art, disclosed an ibuprofen prodrug of an identical structure and tested its pharmacological activity in oral administration studies. However, it failed to address other properties or the compound's administration route. Evidence 3 disclosed the prodrugs of some known compounds (eg, testosterone, deoxycortone and indomethacin) which share the same modification group with the compound of the patent. Evidence 3 also highlighted the improvement in the permeability of these prodrugs when administered transdermally.
Based on the technical effect recorded in the patent's description, the PRB identified that the technical problem solved by Claim 1 over Evidence 8 was providing a transdermal formulation of an ibuprofen prodrug compound which had less side effects but better therapeutic effects than the oral preparation of ibuprofen.
As to the combination of Evidence 3 and Evidence 8, the PRB found that testosterone and deoxycortone, which were modified in Evidence 3, are considerably different from ibuprofen in terms of the chemical structure and activity. Even indomethacin (a non-steroidal anti-inflammatory drug similar to ibuprofen) has a chemical structure that differs to ibuprofen. Moreover, Evidence 3 failed to address whether transdermal administration was superior to other administration routes in terms of effects, whereas – after modifying ibuprofen to be a prodrug – the patent overcame side effects which resulted from the oral administration of the parent drug by transdermal administration and achieved a better therapeutic effect. In addition, the results of in vivo experiments concerning analgesic, antipyretic and anti-inflammatory effects in the patent reveal that, even though both have the ibuprofen prodrug compound as their active ingredient, transdermal administration achieves better technical effects than oral administration. Such effects exceed the extent that can be reasonably expected based on the disclosure of Evidence 3 by those skilled in the art. According to the information disclosed in Evidence 8 regarding the single compound, it was unlikely that those skilled in the art would come up with the idea of preparing it into transdermal formulation in order to reduce the side effects of orally administered ibuprofen while producing a better therapeutic effect. Thus, the technical solution of Claim 1 was not obvious over the prior art.
Where the closest prior art discloses the topical administration of a prodrug in ester form, the improvement of the invention embodies the salifying of the compound.
Evidence 7 in this case disclosed an ibuprofen prodrug in ester form, which showed better topical anti-inflammatory activity than ibuprofen when administered topically. Claim 1 differed from Evidence 7 in that Evidence 7's compound was not salified, while Claim 1's compound was.
The technical problem solved by Claim 1 over Evidence 7 was providing a transdermal formulation which had better therapeutic effects than the oral preparation of ibuprofen. In addition to the related disclosure in Evidence 3, the petitioner argued that the common knowledge set out in Evidence 10 disclosed substances facilitating diffusion (including monosaccharides, quaternary ammonium salts and amino acids); as such, Evidence 10 provided a motivation for those skilled in the art to prepare the compound of Evidence 7 into a quaternary ammonium salt. However, the PRB found that Evidence 10 merely provided a general teaching; it failed to give specific technical teaching about what effect the specific drug ibuprofen could achieve. The patent's effects exceed the extent that could be reasonably expected based on the disclosure of the evidence by those skilled in the art. When confronted with the technical problem solved by the invention, those skilled in the art would not be motivated to obtain the technical solution of the patent.
Under current practice, the seemingly narrow gap between an improvement invention and the prior art largely gives rise to a trend of distinguishing features per se being perceived as common sense or conventional technical means, particularly with regard to inventions involving a drug dosage form. Dosage forms are generally known and new forms emerge only in rare circumstances. If an assessment of non-obviousness focuses mainly on the dosage form as the distinguishing feature, it would be easy to rush to a conclusion of obviousness. However, the aim of a non-obviousness assessment is not to determine whether the distinguishing features per se are obvious, but rather to assess the technical solution as a whole. The common distinguishing feature is not necessarily equivalent to the common technical solution. In this case, the difference between the patent and Evidence 8 was merely the route of administration, and the difference between the patent and Evidence 7 was merely the form of the compound – the PRB did not arbitrarily treat them as conventional technical means in the field.
To ascertain whether an improvement invention is non-obvious, the technical effect achieved by the technical solution as a whole must be considered – that is, whether the technical assignment accomplished by the invention by introducing the distinguishing feature brings enough contribution and value to the prior art. This is also consistent with the interpretation of the Guidelines for Patent Examination in respect of the correlation between unexpected technical effects and non-obviousness, which state that "if an invention produces an unexpected effect, it means the invention represents notable progress, and also the technical solution of the invention is non-obvious". This perspective was corroborated in the PRB's analysis of Evidence 7 and Evidence 8.
Another important aspect of a non-obviousness judgment is the accurate interpretation of the technical teaching of the prior art. The PRB is prone to consider prior art as a whole in its identification of technical teaching. As in the above case, the examination on Evidence 1 is based on the whole disclosure of Evidence 1. The PRB did not rush to conclude that Evidence 1 gave a related technical teaching when it generally stated that the drug therein was more permeable through biological membranes and could be administered with transdermal formulation.
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