Assessment of novelty and inventiveness for pharmaceutical preparation invention

Introduction
Facts
Decision
Comment

Introduction

In practice, an invention of a pharmaceutical preparation is generally considered to be less creative than an invention of a compound. This usually puts the patentee of a pharmaceutical preparation invention in a disadvantageous position when defending the validity of its patent.

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". Clinically, ibuprofen is known to be widely used as a non-steroidal drug for analgesia, antipyretic and anti-inflammation.

Ibuprofen is usually administered orally, but this may cause a number of side effects, such as indigestion, stomach and duodenal bleeding, gastric ulcers or gastritis. The patent at issue covered the transdermal administration of an ibuprofen prodrug, which effectively avoids the side effects caused by oral administration of ibuprofen and is superior to oral administration of ibuprofen in terms of efficacy. The patented preparation is in the clinical research stage in China.

Facts

Claim 1 of the patent at issue sought protection for a transdermal therapeutic application system containing an ibuprofen prodrug of the structure shown in Figure 1, administered in the form of a solution or spray. Figure 1 shows the structural formula of the ibuprofen prodrugs, consisting of ibuprofen residue (the portion in the red box) and a modifying group (the remainder of the formula).

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Figure 1: structure of ibuprofen prodrugs

The patent description explicitly recorded 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 a better skin diffusion rate, which enables it to penetrate skin barriers quickly and effectively and avoid the side effects attributed to oral administration of ibuprofen. In the meantime, the transdermally administered prodrug 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 Intellectual Property Administration maintained, in its invalidity decision No. 38911 on 30 January 2019, the validity of the patent on the basis of the revised claims. Qi appealed the invalidity decision to the Beijing IP Court, narrowing down his invalidation grounds to 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 entered into effect.

Decision

Novelty
Evidence 2 disclosed an isotonic drug solution containing the compound BF-DEAE (a compound falling within the structural formula as defined in Claim 1), whose anaesthetic effect had 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 pharmaceutics is concerned, transdermal preparation and eye drops were different dosage forms; and
• the purpose of the invention was to improve the penetration rate of ibuprofen to the biomembrane and the skin barrier so that it could be delivered transdermally, thereby avoiding the side effects of ibuprofen. Nevertheless, the eye drops in Evidence 2 were 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 did not include eye drops.

Inventiveness
Evidence 7 disclosed ibuprofen prodrugs in ester form (eg, compounds 36 and 37), which demonstrated superior topical anti-inflammatory activity to ibuprofen in the topical use pathway. Thus, the difference between Claim 1 and Evidence 7 was that the compound in Evidence 7 failed to form salt, whereas the compound in Claim 1 was in the form of salt. Evidence 3 disclosed 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 tested acute toxicity and pharmacological activity (including anti-inflammatory and analgesic activity) of compounds. The results indicated that Compounds 36 and 37 showed 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 was inferior to ibuprofen in analgesic efficacy and acute toxicity. Compound 37 was slightly superior to ibuprofen in analgesic efficacy, but inferior to ibuprofen in acute toxicity in oral administration.
• Evidence 7 recorded that "some of the compounds of the present invention have [a] 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 disclosed the structures of 66 compounds, and Table II of Evidence 7 disclosed the pharmacological effect and acute toxicity of 30 compounds. In examples, the preparation methods of some compounds were disclosed, but all of the compounds disclosed were 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 II, the amino ester derivatives 36 and 37 were not superior to the alkyl ester and aryl ester derivatives, and compounds 36 and 37 were not even mentioned in the preferred examples for the preparation method.
• Evidence 7 provided the esterified derivatives of ibuprofen to achieve the technical effect of reducing toxicity and improving anti-inflammatory potency in topical application, rather than providing a prodrug to improve solubility, safety and skin penetration. Therefore, the technical problem actually solved by Claim 1 was 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 was substantially different from that of ibuprofen in the patent.
• Propranolol, scopolamine, benzocaine and lidocaine, mentioned in Evidence 3, all contained lipophilic parts and amino group in their own structures and did not need prodrug modification. Moreover, Evidence 3 simply mentioned that "using a similar tert-amino group" to modify indomethacin and deoxycorticosterone resulted in a six-to-20 times increase in in vitro transdermal flux, but failed to specify how to modify them.
• Evidence 3 disclosed that the in vitro human skin penetration rate of testosterone prodrug was about 60 times faster than that of testosterone, its in vivo penetration rate was seven times of that of testosterone, and the in vitro transdermal flux of derivatives of indomethacin and deoxycorticosterone increased by six to 20 times. The charged prodrug ibuprofen in this patent, however, had 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 was non-obvious relative to the combination of Evidence 7 and 3 and had achieved an unexpected technical effect. It thus involved an inventive step under article 22(3) of the Patent Law.

Comment

The decision of the Beijing IP Court is significant in its assessment of the novelty and inventiveness of the pharmaceutical preparation. As regards the assessment of novelty, the Court took a holistic approach in considering the definition effect of all technical features in the claim, including that of the subject matter title per se on the product type. As regards the assessment of inventiveness, it analysed in detail whether there was technical teaching in the prior art as a whole, which aligns with the practice in the examination of inventiveness – ie, the obviousness of a claim should be assessed by taking the prior art as a whole:

• The Patent Examination Guideline provides that in an assessment of novelty, whether the invention is found to be identical with the prior art hinges on whether the invention is substantially the same as the prior art in terms of the technical field, the technical problem solved, the technical solution and the desired effect. The Court decision followed this principle, not only focusing on the differences between the technical solutions per se, but also clarifying the substantial differences between the invention and the prior art from the technical field, the technical problem solved and the technical effect. This was an effective rebuttal to the plaintiff's biased approach, which merely dwelt on the structure and composition of the product.
• The assessment of obviousness hinges on the determination of the technical problem actually solved by the invention. To all appearances, pharmaceutical preparation inventions are only slightly different from the prior art, and the distinguishing features are likely to be misconstrued as common knowledge or conventional technical means in the field. In this case, the only difference between Claim 1 and Evidence 7 was that Claim 1 used the compound in the form of salt instead of ester. However, the invalidity decision and the Court decision unanimously elaborated on the technical effect that the distinguishing feature could achieve in the technical solution of the invention based on the disclosure of Evidence 7 and the effect recorded in the patent, so as to identify the technical problem actually solved by the invention.
• In terms of the assessment of obviousness, it has become common practice to take the prior art as a whole in identifying technical enlightenment. In respect of the disclosed contents of Evidence 3, the plaintiff pointed out mere fragments of the evidence. It could therefore not be determined whether the technical solution of the patent at issue was obvious relative to these contents alone. The Beijing IP Court, based on the evidence adduced by the patentee, not only took into account the difference between the testosterone prodrug disclosed in Evidence 3 and the technical solution of the invention, but also demonstrated the teachings given in Evidence 3 in combination with the structures of other compounds disclosed in the evidence, which led to the finding that the patented technical solution was not obvious.
• The actual technical effect of the invention must also be factored in the determination of non-obviousness. This is consistent with the interpretation of the relationship between unexpected technical effect and non-obviousness in the Patent Examination Guideline:

When an invention produces unexpected technical effect, on the one hand, it indicates that the invention has significant progress, and on the other hand, it also reflects that the technical solution of the invention is non-obvious.

The Court, in assessing non-obviousness, took into account the actual technical effect of the invention. The practice could serve as a point of reference in similar cases.

For further information on this topic please contact Wu Xiaoping at Wanhuida Intellectual Property by telephone (+86 10 6892 1000) or email ([email protected]). The Wanhuida Intellectual Property website can be accessed at www.wanhuida.com.