Is “Comparable” the New “Unexpected”? China’s SPC Relaxes Inventive Step Standard for Breakthrough Therapeutics
How the Supreme People's Court Established a New Benchmark for Unexpected Technical Effects in a Landmark Diabetic Nephropathy Case
Proving inventive step for pharmaceutical compounds, especially a second medical use, remains one of the most challenging aspects of patent prosecution in China. When the prior art discloses a compound's general therapeutic properties, how can an applicant demonstrate that a specific new use achieves "unexpected technical effects"?
The Supreme People's Court's (SPC) recent decision in the "Ligustrazine Nitrone Derivative" case offers an answer: If the therapeutic effect of an invention patent application's technical solution for a certain disease is comparable to that of the world's first drug approved for treating that disease after the filing date, such therapeutic effect may serve as an important factor in determining whether the invention patent application has achieved unexpected technical effects.
Background
Qingdao Hai Pharmaceutical Co., Ltd. (herein after "Qingdao Hai Company") filed an invention patent application titled "Application of Ligustrazine Nitrone Derivatives in the Prevention and Treatment of Diabetic Complication Diseases"1 on May 27, 2017.
Claims 1-4 of the application were second medical use (Swiss style) claims directed towards ligustrazine nitrone derivatives (e.g., structure (I), TBN or TN-2) for the manufacture of a medicament for preventing and treating diabetic complication diseases (e.g., diabetic nephropathy).
The prosecution of this case progressed through three stages: CNIPA examination/re-examination, Beijing IP Court (“the First Instance Court”), and the Supreme People’s Court (second instance).
At the CNIPA stage, the application was rejected on the ground of lack of inventive step in view of three prior art references:
- D1 (CN102311396A): Disclosed pyrazine nitrone derivatives (e.g., TN-2) as antioxidants with antithrombotic activity useful for treating diseases caused by excessive free radicals, such as diabetes, glomerulonephritis, and renal failure.
- D2 (CN101468970A): Disclosed that a related molecule, ligustrazine (TMP), has antioxidant effects, and taught that introducing nitrone groups into ligustrazine and its derivatives (leading to TBN, TN-2) enhances antioxidant capacity and cellular protective ability.
- D3: A 2011 academic paper reporting that ligustrazine (TMP) protected against diabetic renal injury through antioxidant mechanisms.
The CNIPA found that the distinguishing feature of claim 1 (for TN‑2) over D1 was the focus on diabetic nephropathy. However, the CNIPA reasoned that a person skilled in the art, combining the teachings of D1-D3, would expect TN‑2, having enhanced antioxidant capacity due to additional nitrone groups, to be effective in treating diabetic nephropathy, making the therapeutic effect predictable.
The case then proceeded to the Beijing Intellectual Property Court, where Qingdao Hai Company primarily challenged the validity and evidentiary value of D3, arguing that its data was unreliable and that the prior art did not provide a reasonable expectation of success. The court determined that D3’s textual disclosure alone provided sufficient technical teaching and upheld CNIPA’s view that combining the prior art would make the invention and its effects predictable.
The Supreme People’s Court reversed and upheld the patent.
The SPC identified several issues with the CNIPA’s reasoning, clarified the proper standard for determining whether a technical teaching existed (inventive step standard), and after reviewing new evidence (including several pieces of post-filing data), upheld the patent.
Post Filing Supplemental Data Accepted by the SPC
At the SPC stage, Qingdao Hai Company supplemented the record with a comprehensive set of new evidence. This included multiple pieces of scientific literature and post-filing experimental results2 demonstrating that the effects of nitrone groups on ligustrazine derivatives are unpredictable, with TBN exhibiting superior performance compared to the other derivatives.
Additionally, Qingdao Hai Company also provided post-filing clinical data (Phase II) that demonstrated TBN's therapeutic effect on diabetic nephropathy was superior to the current mainstream international approved drugs for treating diabetic nephropathy, (i.e., existing drugs empagliflozin and finerenone).3
The SPC accepted all five categories of evidence, confirming that post‑filing supplementary experimental data may be considered, provided that it is supported by the original disclosure and does not attempt to remedy inherent defects in the application as filed.
SPC Considers Inventive Step: Does the Prior Art Provide a “Technical Teaching"
The SPC emphasized that technical teaching must be specific and concrete, not abstract or directional. It determined that the prior art merely suggested an abstract research direction rather than a specific and clear technical teaching, and that the relationship between antioxidant capacity (due to the nitrone groups) and renal protection was not predictable. The reliance on such abstract guidance carries the danger of hindsight and tends to underestimate the inventive step of the invention.
The SPC identified three issues in the CNIPA's reasoning:
First, D2 merely lists dozens of conditions that nitrone compounds might treat, including diabetes, glomerulonephritis, and renal failure. D2 did not specifically disclose diabetic nephropathy as a treatable condition, nor did it provide any mechanistic or efficacy data for these indications.
Second, the D3’s experimental data is unreliable because the experimental data showed consistent results despite inconsistencies in the underlying experimental protocols, thereby undermining both the credibility of the data and the conclusion that ligustrazine confers renal protection through antioxidant and anti‑glycation effects.
Finally, even if SPC considers the content of D3, D3 does not provide specific technical teaching that ligustrazine nitrone derivatives such as TBN can treat diabetic nephropathy. It only concludes that ligustrazine's protection of the kidney is related to ligustrazine's ability to enhance renal antioxidant capacity and inhibit excessive glycation reactions, which is not research on ligustrazine nitrone derivatives. Moreover, the data did not establish a reliable correlation between antioxidant properties and renal protection, as stronger antioxidant effects did not consistently lead to better therapeutic outcomes. For example, D3’s own data showed that at 160mg/kg, ligustrazine had stronger antioxidant capacity than at 80mg/kg, but weaker renal protective effects. As there is no positive correlation between antioxidant properties and renal function, the combination with D2 and D3 merely suggested a general research direction rather than a concrete and predictive technical teaching.
Taken together, these findings showed that the effect of nitrone groups on the efficacy of ligustrazine derivatives in treating diabetic nephropathy is unpredictable.
SPC Considers Inventive Step: Does the Invention Achieve Unexpected Technical Effects
Having found no technical teaching in the prior art, the SPC further assessed whether the invention achieved unexpected technical effects, which is one of the factors to be considered when judging inventive step. An invention achieving unexpected technical effects means that compared with the prior art, the technical effects of the invention produce a "qualitative" change with new properties; or produce a "quantitative" change exceeding people's expected imagination. Such "qualitative" or "quantitative" changes cannot be predicted or inferred in advance by a person skilled in the art.
The SPC's analysis proceeded in two areas:
Evidence 4: Specification Data vs. Existing First-Line Treatment
Qingdao Hai company submitted a detailed analysis of the data in the originally filed specification, comparing TBN to Losartan, an established first-line drug for diabetic kidney disease.
The data showed that TBN significantly outperformed the control group Losartan in various indicators measuring diabetic nephropathy levels, including urinary protein, blood glucose levels, serum creatinine levels, and serum urea nitrogen levels. Therefore, it can be concluded from the specification figures that TBN has a significant therapeutic effect on diabetic nephropathy.
Evidence 5: Post-Filing Clinical Data vs. World's First Approved Drugs
Qingdao Hai company also submitted post-filing4 Phase II clinical trial results comparing TBN to Empagliflozin and Finerenone, both of which were approved for treating diabetic nephropathy after the filing date of the present application.
The post-filing clinical data showed that TBN's therapeutic effect on diabetic nephropathy is not inferior to Empagliflozin and Finerenone. Since these drugs had not yet been approved at the time of filing, such a level of efficacy would not have been reasonably expected by a person skilled in the art, thereby supporting a finding of unexpected technical effects. The SPC concluded that this performance exceeded the expectations at the filing date and thus has reached the level of unexpected technical effects.
The SPC revoked the CNIPA's rejection decision and the Beijing IP Court's judgment, ordering CNIPA to issue a new examination decision. The SPC held that the technical solution where the derivative is TBN "has prominent substantive features and represents notable progress and possesses inventive step."
Eagle IP Thoughts
This decision is quite interesting in that it appears to expand the types of post-filing data acceptable to the court, as well as clarify the standard for what is considered “surprising” when it comes to comparison data.
Types of post-filing data acceptable includes drugs approved after the filing date
The traditional approach assesses unexpected technical effects against the prior art existing before the filing date. This decision confirms that post‑filing evidence, for example, comparisons with drugs approved after the filing date may be considered, provided that the ideas demonstrated by the data are supported by the original disclosure as filed.
In this case, the Court treated the subsequent approval of drugs for the same indication as objective context for what could not have been reasonably predicted at the filing date.
“Comparable” efficacy is sufficient to demonstrative inventive step
Additionally, merely showing that the invention had comparable therapeutic effects with the later-approved drugs (not necessarily better technical effects), was sufficient to support a finding of “unexpected technical effects”. The SPC reasoned that such technical effect, by definition, could not have been predicted when no effective treatments existed.
The strength of such comparative data is quite remarkable. In this case, the world’s first approved drug was not structurally similar to the claimed molecule at all. Yet comparison data showing TBN’s efficacy was comparable to a world’s first approved drug overcame all prior art teachings, including those about an identical structure (TN-2) for use in a very related disease (diabetes).
Particularly for applicants developing breakthrough products in areas with limited or no approved therapies, this new SPC ruling offers an easier way to meet the “unexpected” standard for inventive step.
Comparative data against existing treatments in your original specification
This case also provides strategies for what type of comparison data to include in the specification at the drafting stage, especially when there are no direct comparisons. In this case, even though there were no approved treatments for diabetic neuropathy, the patentees provided comparison data with the “closest” existing drug they could find (Losartan for treating diabetic kidney disease). Additionally, they measured key indicators for the new disease they were trying to treat, e.g., urine protein levels).
In the end, the SPC relied on a number of factors as a whole to reach their ultimate conclusion. However, the original specification’s comparison of TBN with Losartan did help to establish a credible therapeutic effect, helping to provided support for the later submitted post-filing clinical trial data. The case illustrates that including baseline comparisons with clinically relevant drugs in the original filing can strengthen the foundation for demonstrating unexpected technical effects.
What Are the Limits?
Several questions remain for future cases:
- How "comparable" must the effects be?
Although the SPC concluded that TBN was “not inferior to” empagliflozin and finerenone, it did not specify a quantitative threshold, leaving uncertainty as to what degree of comparability (e.g., 80% or 50%) would meet the standard.
- Does this apply only to "world's first" drugs?
The Court’s reasoning places particular weight on the fact that no drugs had been approved for the relevant indication at the filing date, suggesting that comparison with subsequently approved therapies is most persuasive where the field lacked an established treatment benchmark. However, the judgment does not explicitly limit this approach to “first-in-class” drugs, leaving open whether comparisons with later entrants’ drugs would carry the same weight.
Drafting Strategies
These limits will certainly be tested as innovators, learning from this case, begin submitting more and varied types of comparison data. At the drafting stage, applicants should consider more broadly what types of data to include in the specification, encouraging inventors to compare their breakthrough therapies with related (but not identical) products currently on the market. If possible, provide as many measurements and data points as possible from these comparison studies. This will help support post filing data at a later stage.
IP and clinical teams should work closely together to consider what types of measurements and data points from a clinical study can directly match up with data presented in the patent application. In this case, the original comparison data showing TBN’s “therapeutic effect” (e.g., abilities to reduce urinary protein levels) allowed Qingdao Hai to later submit additional clinical studies further showing this same effect with later approved drugs.
Finally, it’s extremely useful to know that data showing a drug has “comparable efficacy” to later approved drugs support a finding of inventive step. This should especially encourage follow-on drug companies to continue developing (and patenting!) new alternatives therapeutics, even if they aren’t necessarily better than existing treatments.
If you would like to have more information on this matter or would like to have our advice, please feel free to contact us at [email protected].
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.
Application No. 20171039xxxx.x. Ligustrazine (also known as tetramethylpyrazine or TMP) is a compound derived from the Chinese herb Chuanxiong, traditionally used for cardiovascular conditions. TBN is a ligustrazine nitrone derivative with one nitrone group; TN-2 has two nitrone groups.
↩︎Evidence 1: Scientific literature structure-activity relationships of Ligustrazine derivatives, demonstrating that the effects of nitrone groups on ligustrazine derivatives are unpredictable.
Evidence 2: Scientific literature suggesting that nitrone compounds may not necessarily confer renal protection.
Evidence 3: Experimental results submitted by Qingdao Hai Company on the protective effects of ligustrazine nitrone derivatives on db/db diabetic nephropathy mice. The experimental data demonstrates that the effect of nitrone groups on the efficacy of ligustrazine derivatives is unpredictable, while TBN exhibiting superior performance compared to the other derivatives.
Evidence 4: Analysis of experimental data already disclosed in the application (Figures 2–4). The data shows that TBN significantly reduces urinary protein levels. Moreover, TBN's effect on reducing urinary protein is superior to the current known first-line drug Losartan.
Evidence 5 (Post-filing clinical data): Phase II clinical trial submitted by the Qingdao Hai Company for treating diabetic nephropathy, including comparative analysis with existing drugs (empagliflozin and finerenone).a The post‑filing TBN clinical trial data shows that TBN's therapeutic effect on diabetic nephropathy is superior to the current mainstream international approved drugs for treating diabetic nephropathy, i.e. empagliflozin and finerenone.
↩︎Empagliflozin has patent filings (WO2014/161919, filed on 3 April 2014) directed to use in patients with renal impairment or chronic kidney disease. Finerenone is covered by earlier compound/use patent protection, including WO2008/104306 and US 8,436,180, filed on 19 February 2008, and was subsequently approved for chronic kidney disease associated with type 2 diabetes.
↩︎The SPC accepted this post‑filing clinical data as valid supplementary evidence because it was supported by the original patent document disclosure and did not serve to remedy inherent defects in the application as filed.
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