CNIPA’s assessment of novelty and inventiveness for transdermally administered ibuprofen could pave way for future similar decisions

Tianjin Xinchen Techfields Pharmaceutical Technology Co, Ltd owns the patent for invention ZL200680055379.X, entitled “positively charged water-soluble prodrugs of ibuprofen with very fast skin penetration rate”. Ibuprofen is widely used as a non-steroidal drug with analgesic, antipyretic and anti-inflammatory properties. It is usually administered orally and may cause a number of side effects, such as indigestion, stomach and duodenal bleeding, gastric ulcers and gastritis. The patent at issue pertains to the transdermal administration of ibuprofen, which effectively avoids these side effects and is superior to oral administration in terms of efficacy. The invention is in the clinical research stage in China.

In practice, an invention of a pharmaceutical preparation is generally considered to be less creative than that of a creation of compound. Patentees of pharmaceutical preparation inventions may find themselves at a disadvantage when it comes to defending the validity of their inventions.

Case brief

Claim 1 of the patent at issue seeks protection for a transdermal therapeutic application system containing ibuprofen prodrugs (see Structure 1), which are administered in the form of a solution or spray. Below is the structural formula of the ibuprofen prodrugs, consisting of ibuprofen residue (in the red box) and a modifying group (remainder of the formula).



The patent description explicitly records the advantages of administering the drug transdermally over orally. Compared with ibuprofen, the prodrug has considerably improved water solubility and skin diffusion rate, which enables it to penetrate skin barriers quickly and effectively. As well as avoiding the usual side effects, it is remarkably superior to the orally administered ibuprofen in terms of therapeutic effects.

On 13 February 2018, Qi filed a request for invalidation of the patent by challenging the clarity, support, novelty and inventiveness of the claims. The China National IP Administration (CNIPA) maintained in its invalidity decision 38911 on 30 January 2019. Qi appealed to the Beijing IP Court, narrowing down the invalidation grounds to the novelty and inventiveness of the claims. On 20 July 2020 the Beijing IP Court rendered a decision to uphold the invalidity decision. The judgment has now become effective.

Court decision

Evidence 2 discloses an isotonic drug solution containing the compound BF-DEAE (a compound falling within the structural formula 1 as defined in Claim 1), the anaesthetic effect of which has been tested by dripping it onto the corneal surface of guinea pigs. As to the novelty of Claim 1 relative to Evidence 2, the court affirmed that:

  • as far as the classification of pharmaceuticals is concerned, transdermal preparation and eye drops are different dosages; and
  • the purpose of the invention is to improve the penetration rate of ibuprofen to biomembrane and skin barrier so that it can be delivered transdermally, thereby avoiding side effects. Nevertheless, the eye drops in Evidence 2 is applied to the cornea, which consists of connective tissue rather than skin and is devoid of a cuticle barrier. Therefore, the "transdermal therapeutic application system" of Claim 1 does not include eye drops.

Evidence 7 discloses ibuprofen prodrugs in ester form (eg, Compounds 36 and 37), which demonstrate superior topical anti-inflammatory activity to ibuprofen. Thus, the difference between Claim 1 and Evidence 7 is that the compound in Evidence 7 fails to form salt, whereas the compound in Claim 1 is in the form of salt. Evidence 3 discloses a testosterone prodrug with the same modifying structure as in Claim 1, with a transdermal rate 60 times faster than testosterone per se.

As for the technical problem actually solved by Claim 1, the court analysed the following aspects:

  • Evidence 7 tests the acute toxicity and pharmacological activity (including anti-inflammatory and analgesic activity) of compounds. The results indicate that Compounds 36 and 37 show similar anti-inflammatory effects to ibuprofen when administered orally, and slightly superior anti-inflammatory effects (one to two times higher) to ibuprofen when administered topically. However, Compound 36 is inferior to ibuprofen in analgesic efficacy and acute toxicity and Compound 37 is slightly superior to ibuprofen in analgesic efficacy, but inferior to Ibuprofen in acute toxicity in oral administration.
  • Evidence 7 records that "some of the compounds of the present invention have high degree of pharmacological activity and low toxicity and, in particular, the topical application of the compounds produces stronger anti-inflammatory effect than Ibuprofen".
  • Table I of Evidence 7 discloses the structures of 66 compounds, and Table II of Evidence 7 discloses the pharmacological effect and acute toxicity of 30 compounds. In the examples section, the preparation methods of some compounds are disclosed, but all the compounds provided are esterified derivatives of carboxyl groups in ibuprofen structure, including alkyl esters, aryl esters and amino esters, among others. Based on the pharmacological activity and acute toxicity data exhibited in Table I, the amino ester derivatives 36 and 37 are not superior to the alkyl ester and aryl ester derivatives, and compounds 36 and 37 are not even mentioned in the preferred examples for the preparation method.
  • In a nutshell, Evidence 7 provides the esterified derivatives of ibuprofen to achieve the technical effect of reducing toxicity and improving anti-inflammatory potency in topical application, rather than providing prodrug to improve solubility, safety, and skin penetration. Therefore, the technical problem actually solved by Claim 1 is to provide a safe and high skin penetration Ibuprofen prodrug preparation.

As for the combination of Evidence 7 and Evidence 3, the court affirmed the following:

  • The prodrug of testosterone disclosed in Evidence 3 is substantially different from that of ibuprofen in this patent.
  • Propranolol, scopolamine, benzocaine and lidocaine mentioned in Evidence 3 all contain lipopilic parts and amino group in their own structures and do not need prodrug modification. Moreover, Evidence 3 simply mentions that "using similar tert-amino group" to modify indomethacin and deoxycorticosterone results in a six to 20 times increase in in vitro transdermal flux, but fails to specify how to modify them.
  • Evidence 3 discloses that in vitro human skin penetration rate of testosterone prodrug is about 60 times faster than that of testosterone, its in vivo penetration rate is seven times of that of testosterone, and in vitro transdermal flux of derivatives derived from modified indomethacin and deoxycorticosterone increases by six to 20 times. However, the charged prodrug ibuprofen in this patent has a 250-fold difference in skin penetration rates in vitro and a 60-fold difference in vivo when compared with ibuprofen, significantly exceeding the scope that could be reasonably expected by a person skilled in the art based on the content of Evidence 3.
  • Claim 1 is non-obvious relative to the combination of Evidence 7 and 3 and has achieved unexpected technical effect, and therefore involves an inventive step under Article 22.3 of the Patent Law.

While the situation remains unclear for patentees of pharmaceutical preparations, it is hoped that this should provide some useful guidance.

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