The development of China’s approach to patents, especially those in the pharmaceutical and biotech space, has been fascinating to watch. Those of us who have practiced in the area for a long time have been frustrated by the Chinese patent office’s overly strict rules regarding patentability (e.g., high data support standard and refusal to consider post-filing data), while at the same time being more lax on enforcement.
Things have changed a lot in the past five years as China has revamped its patent system in numerous ways. The creation of an entirely new IP court system, the introduction of a new patent law (only the 4th revision in its 40+ year history), the first phase of the US China Economic and Trade Agreement, and recent case law all point in the direction that China is moving rapidly towards upgrading its entire IP infrastructure to be in line with global standards.
The summary of China’s Top 10 IP Cases of 2020 has just been released and there are two cases in the area of life science. Today, we will discuss a patent invalidation request for a second medical use patent owned by University of Bordeaux.
Claim 1 as amended during the invalidation proceedings is shown below.
The petitioner Yabao Pharmaceutical Group Co., Ltd. (“Yabao”) filed for invalidation of the Chinese patent requesting that all claims to be declared invalid. Yabao submitted 23 different academic papers and patent publications as evidence and argued that the patent was invalid for reasons of sufficiency, clarity, novelty, and inventive step.
Sufficiency: How Many Examples and How Much Data is Needed?
Yabao argued that the specification was insufficiently described because it did not provide adequate support for the technical solution that propranolol provided in treating infant capillary hemangioma. Yabao noted that the specification did not disclose any toxicity-related experimental data, thus making it impossible to predict any toxicity or side effects in infants. Furthermore, Yabao argued the specification only contained three examples, two with other medicines. Given that the therapeutic effects of drugs on hemangiomas vary wildly (and some hemangiomas even heal by themselves), it is difficult to predict the therapeutic effect of propranolol alone.
With respect to toxicity, the Panel indicated that no additional toxicity data was needed for a second medical use drug since the first medical use (also in infants) already provided sufficient support for safety.
With respect to data, the Panel emphasized that the law does not require a certain number of examples to satisfy the sufficiency requirement. Instead, the general principle is as follows: one of skill in the art, based on the disclosure and common knowledge, should be able to implement the invention within the full scope of the claims and achieve the effects described.
In this case, based on the clinical trial data in the specification, one of skill in the art would understand how to administer propranolol and would be convinced that propranolol can achieve the therapeutic effect of treating infantile capillary hemangioma. The number of examples in a specification alone is not enough to constitute a reasonable ground for refutation. Accordingly, the Panel concluded that the disclosure is sufficient.
It is interesting to note that the sufficiency data needed for a second medical use drug is actually lower because a lot of the data is already in the prior art. With that comes a higher standard for novelty and inventive step, of course. However, it is helpful to see the Panel’s logic in this case, and we generally agree with the Panel for basing its decision on the standard of what a skilled person would think when evaluating the patent claims as a whole, taking into account the prior art and common knowledge available at the time of filing.
Clarity: Is the term “infantile capillary hemangioma” clear?
Yabao argued that the definition of the claim term “infantile capillary hemangioma” was unclear based on evidence showing that the term “capillary hemangioma” was used to describe two different conditions: strawberry-shaped capillary hemangioma and port-wine stain. Therefore, the claim was unclear.
The Patentees provided counter evidence clearly showing that the term “infantile capillary hemangioma” was not unclear and did not mean two different things. Instead, as clarified in C18 and C19 (both published after the filing date), capillary hemangioma in infantile hemangioma is strawberry-shaped hemangioma, while port-wine stains are classified as “vascular malformations”, a separate parallel condition alongside infant capillary hemangioma. Particularly C19 (a well-respected “treatise” on hemangioma diagnosis and treatment) listed such differences, as did evidence C16 (published before the patent filing date) and the instant application. It was understood that even if there was unclear terminology and vague classification at the time of filing, there was a clear consensus that infant capillary hemangioma was considered strawberry-shaped hemangioma before the application date. Accordingly, the Panel decided that the definition of infantile capillary hemangioma was clear.
Although the Panel even conceded that the term may have been a bit unclear at the time the filing, the Panel relied upon post-filing publications (e.g., the “treatise”) as evidence to confirm that earlier ideas (already present before the filing date) were true, thus determining the language in the patent application was clear.
Boundaries of the Claims: Rule 20.1
Yabao also argued that claim 2, which added the limitation “wherein the β-blocking agent has intrinsic sympathomimetic activity” did not actually narrow down the claims, since it was referring to an intrinsic property of the propranolol itself. As a result, Yabao asserted that the patent was invalid. Yabao also listed other similar reasons to support its argument that the claims were not concise.
Even if Yabao was correct in its assertion regarding claim scope, the Panel indicated that as long as the boundary lines of the claims were clear (i.e. even if two claims within a patent had overlapping / identical scopes), this issue alone was not a ground for invalidating the patent. After all, the patent claim scope was still clear, and this “overlap” did not impact the public’s ultimate rights with respect to the patent scope.
E7: Novelty Issues Due to Clarity Issues?
Yabao argued that the claims were not novel in view of various pieces of prior art. Yabao took advantage of the clarity arguments it used earlier, arguing that Evidence 7 disclosed use of propranolol together with an ECE inhibitor/NEP inhibitor in the manufacture of a medicament for treating arteriovenous malformations and telangiectasias. Yabao argued arteriovenous malformations and telangiectasias fell within the category of hemangioma or capillary hemangioma, thus destroying the novelty of claim 1.
The Panel disagreed, pointing out that arteriovenous malformations and telangiectasias belong to the category of vascular malformations, which is a completely different disease (different pathogenesis and treatment method) compared to hemangioma or capillary hemangioma for at least the reasons discussed earlier in the clarity section.
Yabao also argued that Evidence 8 disclosed the use of Formulae I, II, III in combination with a second compound for use in treating infant capillary hemangioma. Within a large list of “second compounds” was propranolol. Accordingly, E8 clearly disclosed the use of propranolol for treating infant capillary hemangioma.
The Panel in this case disagreed and dug pretty deeply into the scientific rational in its response. The Panel indicated that E8 taught that Formulae I, II, III were used to treat infant capillary hemangioma, while the second compound (which included propranolol) was used to reduce side effects (i.e. to use its first medical use). In essence, the prior art did not disclose the use of propranolol for treating hemangioma. It merely taught the use of propranolol to treat side effects from Formulae I, II, and III, which were used to treat the disease.
Just like E7, The Panel also emphasized that E8 disclosed a series of very different diseases, and a large list of possible second compounds. The Panel asserted that those skilled in the art would not necessarily think that any second compounds disclosed therein could be applied to the treatment of any of the mentioned diseases.
E15: Mechanism of Action Not Needed for Sufficiency of the Claims
Yabao further argued that the claims were not novel in view of E15, a New England Journal of Medicine publication by the inventor disclosing several aspects of the invention. This article was published after the patent’s priority date but before the filing date. Yabao argued the patent was not entitled to its priority date because Example 4 was not present in either priority document.
Example 4 provided details on the mechanism of how the drug treated infant capillary hemangioma. The Panel emphasized that the mechanism of how an invention works is not necessary for making the invention complete. As long as an invention disclosure provides a technical solution to solve a technical problem to achieve a technical effect, the disclosure does not need to explain how or why the solution works. Accordingly, the pending claims were entitled to claim priority to the earliest date, thus predating reference E15.
In general, including mechanism-of-action disclosure in a patent specification to explain why an invention works is always a double edged sword. Although it can potentially provide “support” or “teaching” for additional disclosure that was not explicitly included in the application as filed, it may also teach towards the obviousness of your invention or provide other damaging content that an opponent can attack during an invalidation.
In China, as long as you provide a technical solution to a technical problem and demonstrate unexpected results, there is no need to explain further. As can be seen from this case, this additional “mechanism of action” information added after the priority date served as an easy target for an invalidity claim based on improper priority, making the overall patent more vulnerable to attack in an invalidation.
Yabao argued that the claims lacked inventive step in view of Evidence 10 (closest prior art), Evidence 11, together with common knowledge.
Evidence 10 studied hemangioma cell samples from young children and showed that cell apoptosis and cell proliferation were involved in the regression of hemangioma. The paper speculated that an anti-angiogenic agent that cause apoptosis may attenuate cell proliferation and therefore accelerate the degeneration of hemangioma.
Yabao argued that it would have been obvious for one of skill in the art to arrive at the claimed invention knowing that promoting cell apoptosis could treat hemangioma (Evidence 10) and propranolol was particularly effective at promoting apoptosis (Evidence 11).
The Panel disagreed, concluding that the prior art cited by Yabao was very preliminary in nature. It merely speculated a general direction based on correlation, but did not provide any detailed mechanisms or specific data to support this inference and therefore would not motivate or guide one of skill in the art towards a technical solution. Even though many anti-tumor drugs kill tumor cells by initiating apoptosis, the prior art still lacked sufficient detail and information to convince one of skill in the art that a well-known apoptotic agent could be used to treat infant capillary hemangioma.
With respect to Evidence 11, the Panel further concluded that Yabao’s conclusion was too simplistic. Even though the paper taught that blocking capillary endothelial cell β alone induces apoptosis, the opposite occurs when both vascular endothelial cells and fibroblasts are blocked at the same time. This double blocking actually protects endothelial cells from apoptosis. As such, the Panel concluded that in a complex in vivo environment, Yabao’s assertion that “anti-angiogenic agents reduced apoptosis of proliferating endothelial cells” was unlikely to be always true. Furthermore, the effect was seen in pulmonary cells, and thus yet another leap needed to be made. The Panel rightly concluded that Yabao had over-simplified the situation. If the Panel agreed with Yabao, then very few new anti-tumor drugs would ever be patented.
Evidence 12 (closest prior art) + Evidence 13 + common knowledge
Evidence 12 teaches that β-isozyme-selective protein kinase (PKC) inhibitors can treat tumors and other VEGF-related diseases, including capillary hemangioblastoma. It provides data showing that certain known PKC inhibitors can inhibit VEGF in bovine endothelial cells. There is no specific mention of propranolol.
Evidence 13 teaches that propranolol selectively inhibits PKCα and PKCβ in human neutrophils (PMN).
The Panel concluded that the number of steps needed to arrive at the claimed invention was far-fetched. First, Evidence 12 does not provide teachings on which specific tumors the β-isozyme-selective protein kinase (PKC) inhibitors can treat, nor which inhibitors are effective against which tumors. Further, it does not confirm PKC inhibitory effect against any certain specific tumors, let alone anything relating to hemangioma.
Furthermore, it is unclear whether the effect from neutrophils in Evidence 13 corresponds to endothelial cells, and whether a PKC effect necessarily translates to a VEGF inhibitory effect.
Evidence 14 + Evidence 1-2, Evidence 4-7, Evidence 10-13, Evidence 15, 18-22, or combination of common knowledge
Evidence 14 discloses a therapeutic kit providing doses of vasoactive agents, including β-adrenergic blockers (among others) for treating a large list of diseases including hemangioma. It does not mention propranolol, nor does it specifically mention infantile capillary hemangioma. The panel was quite scientific in its approach here, digging into the actual mechanisms of actions of the various sub-types of hemangioma to determine whether it was obvious to choose a vasoactive agent to treat infantile capillary hemangioma particularly.
The panel considered two main questions:
- Is infantile capillary hemangioma caused by inflammation?
- Does the mechanism of treating vasodilation also treat infantile capillary hemangioma?
The Panel considered numerous documents submitted by the Requestor. These documents taught how propranolol blocks vascular density in cancer cells, eliminates biliary obstruction caused by a portal cavernous hemangioma (similar mechanism as IH), opens mitrochodrial apoptosis-induced channels (MAC) to promote apoptosis in treating cell proliferative diseases, and can combine with an anti-angiogenic agent to treat angiogenesis-related diseases (caused, for example, by hemangioma) without causing hypertension.
The Panel concluded none of the documents mentioned that infantile capillary hemangioma is caused by inflammation. Furthermore, Evidence 14, which focuses on using a vasoactive agent to treat “hemangioma” generally, is not relevant to the specific sub-class of infantile capillary hemangioma. As had been discussed earlier, hemangiomas comprise at least two different classes: port-wine stains (vascular malformations caused by the expansion of the capillary network), and IH (caused by capillary hyperplasia), which are two completely different diseases that work via different mechanisms. A skilled person in the art trying to treat the capillary hyperplasia of infantile capillary hemangioma would not be motivated to choose a drug that is good at treating vascular malformations from port-wine stains. Furthermore, the additional documents (Evidence 1, 2, 4-7, 10-13) are either irrelevant when combined with Evidence 14, or even teach away. For example, Evidence 4 was cited because it suggests propranolol plays a role in diseases where apoptosis is undesirable, even though propranolol promotes apoptosis to treat cell proliferation.
Finally, Evidence 6 and 15 were not considered because they were published after the priority date of the patent application, to which the Panel had decided the pending patent could claim priority.
Evidence 18-22 (common sense)
Similarly, the Panel reviewed Evidence 18-22 and also concluded that these references only generally taught around the subject matter of hemangioma and capillary hemangioma, but none of them discussed infantile capillary hemangioma or propranolol or the mechanism related to propranolol treatment.
Additional supporting evidence provided by the patentee demonstrated that the product has become very successful worldwide and propranolol has become a top therapy for treating infantile capillary hemangioma. These secondary considerations further demonstrate how the invention’s technical solution is such an improvement over what is available in the prior art.
Most notably, this decision is very important in its emphasis on preventing hindsight in an unpredictable field. The Panel in this case dove deeply into the scientific details, really studying closely the mechanisms of various diseases in order to make a scientifically rigorous and logically sound decision on matters of inventiveness, sufficiency, and priority. The Panel members recognized full well the dangers of hindsight, especially in the area of inventions relating to new uses of old drugs. They cautioned against automatically thinking that new, second medical uses would be obvious in view of known pharmacology and physiological mechanisms. They emphasized that hindsight ignores the unpredictable nature of the human body.
For a pharmaceutical invention, proposing a technical solution with a definite curative effect requires careful observation and ingenious conception, or a lot of trial and error. However, once the technical solution has been proposed, it is easy to reconstruct a linear logical path following known pharmacological and pathological mechanisms to arrive at the technical solution. If this “re-tracing” method completely ignores the complexity, diversity, and uncertainty of human physiology and pathology, it is obviously done with hindsight. Such approach will harm the legitimate interests of the patentee.The Panel at the Patent Reexamination Board (translated from Chinese)
The Panel’s subsequent analysis was detailed, rigorous, and fair. They analyzed each prior art document in excruciating detail to truly understand the mechanisms behind each type of hemangioma and the mechanisms taught in each prior art reference, in order to truly determine whether hindsight was involved.
The Panel further explicitly cautioned away from “over-interpretation”, and instead took a very pragmatic approach to interpreting the available evidence in order to make their decision.
Additionally, we welcome how post-filing data was used for determining the definitions of technical terms that were not clearly understood at the time of filing. We agree with the decision stating that even if multiple claims have unclear or duplicate limitations, as long as the boundaries of the claims are clear, such informalities should not be grounds for invalidating a patent.
In summary, we think this is an excellent, well-reasoned result. In fact, we have noticed that decisions coming out of the CNIPA and Chinese patent courts are becoming more and more sophisticated. Not only are the courts more experienced (due partly to the nature of having specialized IP courts), the litigants and respondents are also becoming more advanced, bringing more nuanced arguments, creative approaches, and detailed reasoning. Most importantly, we still don’t see a bias in favor of domestic patentees, which is consistent with what we found earlier. As China aggressively tries to cancel its “abnormal” (i.e., totally invalid, fraudulent, “never-should-have-been-filed”) patents and as domestic companies begin to innovate more and more, this imbalance will most certainly shift over time.
By and large, a decision like this one is great news for patentees in China, particularly foreign ones. Foreigners will be more and more convinced of the value of patents in China as they see firsthand courts conducting rigorous and detailed analyses together reasonable and fair decisions.
- Article 26, paragraph 3, Patent Law ↑
- Article 26, paragraph 4, Patent Law ↑
- Admitted Evidence 18, 19, 20, 21 and 22 ↑
- Article 22, paragraph 2 of the Patent Law ↑
- Evidence 7, 8, and 15 ↑
- Article 22, paragraph 3 of the Patent Law ↑
About the Authors
Jennifer Che, J.D. is Vice President and Principal at Eagle IP, a Boutique Patent Firm with offices in Hong Kong, Shenzhen, and Macau.
Yolanda Wang is a Principal, Chinese Patent Attorney, and Chinese Patent Litigator at Eagle IP, a Boutique Patent Firm with offices in Hong Kong, Shenzhen, and Macau.
This article is for general informational purposes only and should not be considered legal advice or a legal opinion on a specific set of facts