Nilotinib Capsule Patent Linkage Case (Novartis AG vs. Suzhou Thery Pharmaceutical Co., Ltd.)
Author: Tina TAI, Jie WEI, and Shudan ZHU
Judgment No: (2022) Jing 73 Min Chu No. 208, 210 Judgment Date: November 10, 2022 Patent at Issue: ZL201080051819.0 Drug at Issue: Nilotinib Capsule API at Issue: Nilotinib Hydrochloride Patentee: Novartis AG Generic drug Applicant: Suzhou Thery Pharmaceutical Co., Ltd. Conclusion: Case dismissed
This is a patent linkage case involving a medical use claim in which it is recited that the API of Tasigna (nilotinib hydrochloride) and pharmaceutically acceptable carriers are dispersed in applesauce. According to the drug leaflet of Tasigna (nilotinib capsule), there is no applesauce in the drug product. The drug leaflet quoted that, “For patients who are unable to swallow capsules, the contents of each capsule may be dispersed in 1 teaspoon of applesauce (puréed apple)”.
There are two key issues involved in the case:
(1) for claim construction, what should be the proper interpretation for the feature of “dispersed in apple sauce”, in other words, should the feature be construed broadly to cover all scenarios that the nilotinib hydrochloride and pharmaceutically acceptable carriers are dispersed in applesauce, or should it be limited to the conduct of drug manufacturer only during drug manufacture, and if the claim is construed broadly to cover all scenarios, could the drug manufacturer be held liable for patent infringement (e.g. indirect infringement by inducement) for manufacturing and selling nilotinib hydrochloride and pharmaceutically acceptable carriers, and at the same time providing instruction in drug description that they may be dispersed in applesauce.
(2) whether the patentee can initiate the current patent linkage case based on Article 76 of the amended Patent Law (introduction of patent linkage system).
The first-instance ruling followed the claim construction of the CNIPA Decision, that the Patent only covered the conduct of manufacture of a medicament where nilotinib was dispersed in applesauce, and because the Patent at Issue did not cover the Tasigna product, it did not qualify for the patent linkage lawsuit pursuant to Article 76 of the amended Patent Law, so the case was dismissed. Because the case was dismissed for not being qualified for patent linkage case, the court did not make determination regarding whether patent infringement could be found based on indirect infringement by inducement, thus did not preclude the possible reliance on indirect infringement theory in future patent infringement civil cases.
2. Procedural history
On September 16, 2021, an ANDA of nilotinib, as the generic product of Tasigna owned by Novartis AG, filed by Suzhou Thery Pharmaceutical Co., Ltd. was published with a Declaration 4.1 (Patent shall be Invalidated) against the Patent at Dispute (ZL201080051819.0).
On September 16, 2021, Suzhou Thery filed an invalidation request against the Patent at Dispute.
On January 27. 2022, the patent linkage lawsuit filed by Novartis AG based on the above Declaration 4.1 was accepted by the Beijing IP Court.
On February 22, 2022, the Board of CNIPA issued the Invalidation Decision No. 54130, announcing the Patent at Dispute valid.
On June 10, 2022, the Beijing IP Court held the court hearing for the patent linkage lawsuit.
On November 10, 2022, the Beijing IP Court issued the rulings (2022) Jing 73 Min Chu No. 208 and (2022) Jing 73 Min Chu No. 210, dismissing the request of Novartis for the reason that the Patent at Dispute does not cover the Tasigna product, thus was not qualified for the patent linkage lawsuit.
3. First-instance ruling
Main arguments of Patentee (Novartis)
(1) Claim construction
The Patent shall at least cover the situations that nilotinib is dispersed in applesauce during drug manufacture, that nilotinib is sold together with applesauce, and that nilotinib is sold alone with drug description indicating that it can be dispersed in applesauce.
(2) Falling within the Scope of the Claims
Since Suzhou Thery’s product has the same way of administration as Tasigna, and for patients who are unable to swallow capsules, the contents of each capsule may be dispersed in applesauce, thus even if Suzhou Thery’s product does not contain applesauce, the drug description has actively induced medical staff and patients to disperse nilotinib in applesauce, thus has committed indirect infringement by inducement. Thus, the generic drug has fallen under the protection scope of the Patent at Issue.
Main arguments of the Generic (Suzhou Thery)
(1) Claim Construction
Following the Invalidation Decision, the Patent only covers the manufacture of a medicament where nilotinib is dispersed in applesauce.
(2) Not falling within the Scope of the Claims
Because the originator drug does not contain applesauce, the Patent at Issue does not cover the originator drug, so the patentee lacks standing to file the current case. Since the Patent at Dispute only covers the manufacture of a medicament where nilotinib is dispersed in applesauce, the generic drug product shall not fall within the scope of the Patent at Issue.
(3) Patent at Issue shall be invalidated
(4) Practicing prior art: The generic is practicing EMA PIP Decision as a prior art.
(1) Claim Construction:
The Beijing IP Court follows the claim construction of the Invalidation Decision, that the Patent at Issue only covers the dispersing of nilotinib in applesauce during manufacture of a medicament, not in drug administration.
(2) Not qualified for patent linkage:
Since the Patent at Issue only covers the manufacture of a medicament where nilotinib is dispersed in applesauce, the originator’s drug product Tasigna shall not fall within the scope of the claims because Tasigna does not contain applesauce. The patent linkage lawsuit is dismissed for not qualified for patent linkage lawsuit pursuant to Article 76 of the amended Patent Law.
Following proceeding after the first-instance judgements
Novartis decided not to appeal the first instance rulings to the Supreme People’s Court.
(1) Regarding the understanding on relevant patent to registered drug
According to Article 76 of Patent Law, relevant patent needs to relate to the drug for which registration is applied in China. According to the purpose of the legislation, the involved originator drug needs to fall under the protection scope of the involved patent, otherwise, the patentee or interested party does not have the right to file an action for determination whether the generic drug falls under the protection scope of the involved patent.
In a patent linkage case, it will be first determined whether the involved patent covers the originator drug received market authorization before determining whether the generic drug falls under the protection scope of the involved patent. If the involved patent does not cover the originator drug, it should not be listed on the patent platform in the first place, and if it has already been listed, the court will dismiss the case and CNIPA will not docket the case.
(2) Claim construction for medical use claim
In the current patent linkage case, the Beijing IP Court follows the claim construction of the CNIPA Decision, that the Patent at Issue only covers the manufacture of a medicament where nilotinib is dispersed in applesauce.
Since the Patent at Issue only covers the manufacture of a medicament where nilotinib is dispersed in applesauce, the originator’s drug product Tasigna shall not fall within the scope of the claims because Tasigna does not contain applesauce. The patent linkage lawsuit is dismissed for not qualified for patent linkage lawsuit.
(3) Applicability of theory of indirect infringement
In the current patent linkage case, because the generic did not actually perform the conduct of dispersing the nilotinib in applesauce, the direct infringement cannot be established due to all-element rule, so the patentee also raised the theory of indirect infringement by inducement. However, the Beijing IP Court dismissed the case based on lack of ground for case filing, and did not make holding regarding the applicability of indirect infringement. Thus, the current case does not preclude the application of indirect infringement theory in future cases, especially in patent infringement civil cases after the market approval of the generic product.
Tocilizumab and Methotrexate Combination Patent Invalidation (Chugai/Roche vs. Bio-Thera)
Author: Tina TAI and Jie WEI
Decision Nos: 560071 and 560488 Decision Dates: March 8 and March 24, 2023 Patent at Issue: ZL200480011401.1 and ZL201511004468.9 Drug at Issue: Tocilizumab Injection API at Issue: Tocilizumab Patentee: Chugai Pharmaceutical Co., Ltd. Generic drug Applicant: Bio-Thera Solutions, Ltd. Conclusion: Patents Maintained
The present case is related to the patent invalidation against Swiss-type claims relating to a pharmaceutical combination therapy of tocilizumab (hereinafter, MRA) and methotrexate (hereinafter, MTX). The patent at issue discloses that MRA and MTX can be used to treat rheumatoid arthritis, with clinical data disclosed in the patent indicating the combination shows better treatment effect than MRA or MTX alone. However, MRA and MTX were administered in different frequency and different administration route in the clinical trial.
There are three key issues involved in the case:
(1) For claim construction, the Board decided that the pharmaceutical combination or pharmaceutical composition for the combination therapy in the Swiss-type claims shall be considered as a packaged drug product, instead of requiring a single dosage form as decided in Alogliptin Decisions (Nos. 38950/38951/38952, Top 10 PRB decision in 2019)
(2) For novelty assessment, the Board further confirmed that mere disclosure of the clinical trial information without any conclusion would not undermine the novelty of the Swiss-type claims.
(3) For inventive step assessment, the Board first time confirmed that synergistic effect is not required for a combination therapy. If the combination therapy shows a better effect over any of the monotherapy, the inventive step can still be established if there lacks teaching in the prior art for the more beneficial effect.
This is the first case that the Board does not require a single dosage form when claiming a pharmaceutical composition or combination wherein the two or more active ingredients are not used in a single dosage form. According to the Decisions, the Board acknowledge the technical contribution of the combination therapy, without requiring the synergistic effect to establish the inventive step.
2. Procedural history and relevant facts
On February 7, 2022, Bio-Thera filed invalidation requests against Chugai’s patents ZL200480011401.1 (CN’401) and ZL201511004468.9 (CN’468). The main invalidation grounds include double patenting, insufficiency of disclosure, lack of support, novelty and inventive step.
On July 25 and July 26, 2022, the oral hearing was held for the two cases.
On March 8, 2022, Invalidation Decision No. 560071 was issued, maintaining the patent right of CN’401 based on the amended claims.
On March 24, 2022, Invalidation Decision No. 560488 was issued, maintaining the patent right of CN’468 based on the amended claims.
The pending claim 1 of CN’401 is as follows.
The use of MRA and methotrexate for the manufacture of a pharmaceutical composition for the treatment of rheumatoid arthritis.
The pending claim 1 of CN’468 is as follows.
The use of recombinant humanized anti-human interleukin 6 receptor monoclonal antibody MRA and methotrexate MTX for the manufacture of a combination of MRA and MTX for the treatment of rheumatoid arthritis,
wherein the MRA is administered intravenously at a dose of 8 mg/kg once/4 weeks; and the MTX is administered orally at a dose of 10 to 25 mg/body/week.
3. Claim construction
The Opponent argued that the present patent is a typical administration regimen patent, since the MRA and MTX as used in the clinical trial are administered separately in different frequency and routes (injection once per 4 weeks and oral administration once per week). The purpose of the patent is to discover the best dosage regimen for MRA in the combination therapy with MTX. However, according to the Chinese Patent Law and the Guidelines, dosage regimen is not protected, and the only way to protect a combination therapy is to form the two or more active ingredients into one single dosage form. Therefore, the “composition/combination” in the Swiss-type claim is not a true technical feature, and the present patent shall belong to unpatentable subject matter under the Chinese Patent Law.
The Board decided that,
(1) Inventions for the manufacture use of substances are method inventions, the claims of which belong to the method type and their technical features should be analyzed in terms of method claims.
(2) Usually, it is the raw materials, the preparation steps and process conditions, the form or composition of the pharmaceutical product, and the equipment that play a role of direct limitation. For features that relate only to the method of using the drugs, if there is no direct link between these features and the manufacture method, they are essentially specific methods of administering the medicine to the human body after the manufacture method has been implemented and the medicine has been obtained, and are not directly and necessarily linked to the manufacture method. Such features, which are only embodied in the act of administering the medicine, are not technical features of pharmaceutical use and has no limiting effect on the claimed manufacture method itself.
(3) In inventions of this type, the feature involving the “drug combination” in the technical solutions can usually be put into effect in the raw materials and preparation process of the drug through ways such as preparing two or more drugs used in combination into compound formulations or kits for the combined use of APIs. In this case, the feature involving the “drug combination” should be considered to be substantially limiting to the manufacture method itself protected by the claim.
(4) According to the present patent, the POSA can conclude that MRA and MTX are not suitable for preparing into one single dosage form. However, it is still possible to choose to prepare a packaged drug product for the joint use of these two drugs. In other words, the “pharmaceutical composition/combination” should be understood as a packaged product comprising the two drugs, and not as a therapeutic regimen in which the two drugs are used separately in a continuous process of administration. As a granted invention, the protection of claim 1 should accordingly be defined as the use of MRA and MTX in the preparation of a packaged drug product for the treatment of RA.
The Opponent cited Nishimoto et al and argued that the prior art has disclosed the combination of MRA and MTX used in the Phase II clinical trial before the priority date, and therefore the novelty shall be undermined.
The Board further confirmed the examination standard for the novelty of Swiss-type claims as established in Gleevec Invalidation and Tasigna Invalidation, that mere disclosure of clinical trial information without any confirmative outcome shall not undermine the novelty of the Swiss-type claims. The novelty assessment shall follow the “four-element rules” including the requirements of the expected technical effects disclosed in the prior art. Given the fact that it is quite uncertain for the outcome of clinical trial, the disclosure of the use in clinical trial shall not be deemed as a disclosure of successful treatment, and thus shall not undermine the novelty of the Swiss-type claims.
5. Inventive step
The Opponent cited Nishimoto et al and Yoshizaki et al and argued that the prior art has disclosed the use of MRA or MTX in the treatment of RA. The present patent only discloses that the combination of MRA and MTX may show synergistic effect only at the dosage regimen of 8 mg/ml of MRA with MTX for ACR70, while it does not show synergistic effect for 2 mg/ml MRA with MTX or 4 mg/ml MRA with MTX. On the other hand, the dosage regimen feature shall not be considered as a true feature in the Swiss-type claims. Therefore, no synergistic effect was achieved over the whole scope of the claims. Without any synergistic effect, the patent shall not involve inventive step according to the established practice in China.
The Board decided that,
(1) The present patent specification clearly states in the SUMMARY OF INVENTION section that “the present invention provides a pharmaceutical composition for the treatment of IL-6 related disease, comprising an interleukin-6 antagonist (IL-6 antagonist) and immunosuppressants”. The representative of interleukin-6-related diseases is RA, and IL-6 antagonist is preferred to MRA and immunosuppressant is preferred to MTX.
(2) The combination of MRA and MTX is compared with MRA alone and MTX alone in the specific embodiment. The data have shown such advantages. The improvement of combination therapy in terms of allergy, antibody production, and hepatotoxicity has been verified many times in the safety comparison.
(3) Furthermore, the invention is of practical value in demonstrating the effectiveness and safety of the combination of antibodies with MTX, given that the serious side effects of high doses of MTX are well known in the field.
(4) The information that a phase II study in combination with MTX is currently underway in several European countries is only an objective fact added to the aforementioned clinical trial study of MRA alone for the treatment of RA. Neither the conclusion nor any clinical data of the aforementioned phase II clinical study was disclosed. It is therefore not possible for those skilled in the art to conclude that this evidence recommends the combination of MRA and MTX for the treatment of RA and to conclude with certainty that MRA and MTX are effective in the treatment of patients with RA. It can be seen that the combination of MRA and MTX in the treatment of RA is significantly more effective than treatment with single drug and is sufficiently safe. Therefore, it is determined that the technical problem actually solved by the solutions protected by claim 1 is to provide a pharmaceutical use of a composition packaged drug product with a curative effect that is significantly better than that of a single component and sufficient safety. The present patent is not obvious when aiming at solving the technical problem.
(1) The Board made a great step on the claim construction of Swiss-type claim for combination therapy as not requiring single dosage form.
The Board decided that the pharmaceutical combination or pharmaceutical composition for the combination therapy in the Swiss-type claims shall be considered as a packaged drug product. This is the first time that the Board does not requires the virtual medicament in the Swiss-type claims as a single dosage form.
Before the present case, the established practice requires the virtual medicament in the Swiss-type claim as a single dosage form, as established in Alogliptin Decisions (Nos. 38950/38951/38952, Top 10 PRB decision in 2019). If the two drugs are not formulated in a single dosage form, it cannot be considered as a true medicament under Swiss-type claim and shall not be protected under the Patent Law.
In the present case, the Board further interpret the virtual medicament for the combination therapy as a packaged drug product, without requiring a single dosage form. This is very meaningful for the combination therapy since the drugs in the real world circumstance are usually used in different frequency with different dosage. This is the first time that the Board acknowledge the inventive contribution of the combination therapy in a substantial manner.
However, it should be noted that, though the Board acknowledged the contribution of the combination therapy, the contribution dosage regimen is still not considered in these cases. We may consider that this would be the intrinsic limitation when applying Swiss-type claims as applied by Chinese practice.
Furthermore, by construing the claims as providing a packaged drug product, as discussed above in the Tasigna case, this would increase the difficulty in the enforcement action, for example the patent linkage proceeding or infringement proceeding, since in many cases, the drug products as manufactured and sold are not in the packaged form, but in a single package with the drug insert indicating the combination therapy.
(2) The Board first made a decision that the inventive step can be established without synergistic effect for combination therapy.
The Board did not make comments on whether the synergistic effect can be achieved, while according to the data in the specification, not all dosage regimen would achieve synergistic effect. The Board merely formulated the technical effect of the present patent based on more beneficial effect without considering the synergy.
In the previous practice, the Board would require the synergy when the two drugs used in the combination therapy were known to be effective in the monotherapy. Therefore, this sets a high threshold for the combination therapy patent to be granted and maintained in the invalidity proceeding.
The present case is the first case that the Board considered the overall teaching in the prior art and acknowledged the unpredictability and difficulty of the combination therapy without requiring synergistic effect. This would be very meaningful in the combination therapy patents and can become a case law in the future.