"Antibiotic Resistance: Global Report on Surveillance" released by the WHO in April 2014 shows that today there is an increasingly serious trend of infection by mutating and antibiotic resistant bacteria which is posing a major threat to public health. In this regard, Keiji Fukuda, the WHO's Assistant Director-General for Health Security, said: "Unless we take significant actions to improve efforts to prevent infections and also change how we produce, prescribe and use antibiotics, the world will lose more and more of these global public health goods and the implications will be devastating. "

In response to this enormous challenge facing the world, major global pharmaceutical companies are stepping up their research on new drug-resistant antibiotics. Among them is CUBICIN (daptomycin) developed by Cubist Pharmaceuticals (hereinafter "Cubist") which exhibits strong bactericidal activity against common clinical and more toxic Gram-positive bacteria such as Staphylococcus aureus, and will not result in skeletal muscle toxicity in patients by improving the administration method of adriamycin. In connection with these research results, Cubist filed with China's State Intellectual Property Office the invention patent application entitled "Method for Administration of Antibiotics" which was granted patent number: ZL99812498.2 (hereinafter the "Disputed Patent").

In April 2009, upon hearing the application for invalidation filed by the Claimant, the Patent Reexamination Board, State Intellectual Property Office (hereinafter "PRB") made an examination decision on the Disputed Patent to hold that the dosage, dosing interval and other features related to use are information pertaining to the medication process, independent of the pharmaceutical process, and has no defining effect on the drug itself, which cannot distinguish the pharmaceutical use of the invention from the known uses of the prior art, and to declare that the Disputed Patent is entirely invalid on the ground that it is not novel. The subsequent first and second instance administrative proceedings ruled in favour of the PRB. In November 2013, the Supreme People's Court ruled on the application for retrial filed by Cubist in relation to this case, to once again uphold the PRB's decision, giving clear standards on whether "dosage" and other technical features in the medication process have defining effects on pharmaceutical-use invention claims.

Administration Method Improved; Successful Clinical Trial

Ever since the advent of penicillin in the 1940s, infections caused by more toxic Gram-positive bacteria represented by Staphylococcus aureus have been better controlled. However, with the widespread use of penicillin, some Gram-positive bacteria gradually developed resistance to penicillin. After further research by scientists, vancomycin began to be used as the preferred drug to treat Gram-positive bacteria in clinical practice, but vancomycin-resistant Staphylococcus aureus has been currently isolated in many countries, raising an urgent need to develop new drug-resistant antibiotics.

Daptomycin, which is considered to be an effective alternative for vancomycin, was first developed by Eli Lilly, a US company.

However, Eli Lilly has encountered a bottleneck in further clinical studies, finding that when patients with profound bacterial infection are treated using daptomycin, some develop short-term muscle weakness, pain and other adverse reactions, accompanied with skeletal muscle toxicity, after a period of high frequency of administration. As a result of such severe toxicity, Eli Lilly not only could not be approved by the US Food and Drug Administration for clinical applications, but it also ultimately abandoned further study of the drug.

Subsequently, Cubist took over the research on daptomycin from Eli Lilly. Through sustained efforts and numerous experiments, it found that the skeletal muscle toxicity caused in patients could be minimized when administered at low frequency and high concentration.

In September 1999, Cubist filed an invention patent application to the State Intellectual Property Office in relation to its research results which was granted in May 2004. The claims in the Patent Grant Publication refer to the use of daptomycin in the preparation of medicaments for treatment, without skeletal muscle toxicity, of bacterial infections of patients having such needs, and define the dosage and dosing interval.

Cubist found that the skeletal muscle toxicity can be avoided by adjusting the dose and dosing interval, which enables daptomycin to have medication safety in the treatment of serious Gram-positive bacterial infections, and, therefore, have therapeutic uses and pharmaceutical industry uses, with a very important progress in clinical applications.

At the end of 2003, the US Food and Drug Administration approved daptomycin for injection, under the brand name "CUBICIN", through an expedited review procedure. After it came on the market, the drug caused a widespread impact in clinical applications and the industry, and achieved huge commercial success. According to available information, global sales of CUBICIN will reach $1 billion since its launch on the market, making it the fastest selling antibiotic in US history.

No Change to Pharmaceutical Process; Disputed Patent Invalidated

China's supply of daptomycin products mainly relies on imports. In June 2008, XIAO Hong, the Claimant, filed an application for patent invalidation with the PRB on the ground that the Disputed Patent had not met the requirements of the Patent Law, before the registration certificate was issued by the China Food and Drug Administration for CUBICIN manufactured by Cubist.

Recently, the Claimant's attorney, HUANG Ze-xiong, Senior Partner, Beijing Boss & Young Patent & Trademark Attorneys was interviewed by a reporter in relation to this case. "Basically, the grounds for invalidation filed by us can be divided into three points: firstly, the claims do not clearly define the bacterial infection to the extent of serious Gram-positive bacterial infections, that is to say, the indications are not clear; secondly, as skeletal muscle toxicity will not be caused by administration to non-seriously infected patients at conventionally high frequency and low doses, "non-skeletal muscle toxicity" does not have specific defining effects on the pharmaceutical use for the preparation of medicaments to treat serious Gram-positive bacterial infections; lastly and most importantly, the claims of the Disputed Patent is the administration use in disguised form of "pharmaceutical use", which is the method for treatment of disease and should not be patentable," said Huang, being straight to the point.

During oral hearings, Cubist's attorney maintained that the Disputed Patent is a pharmaceutical-use invention patent, the claims of which are defined by features, i.e., daptomycin, uses, dosage and dosing interval. The features in dosage and dosing interval reflect the use to be generated which are, in turn, related to the uses to treat, without skeletal muscle toxicity, bacterial infections of patients having such needs, and all the above are closely related to the pharmaceutical process.

Reportedly, according to an examiner of the Collegial Panel for this case, whether the dosage, dosing interval and other features in connection with the use of the drug as included in the claims of the Disputed Patent would change the pharmaceutical use, and, therefore, lead to the finding of novelty, has been designated by the Collegial Panel during the hearing as the most controversial and difficult issue.

"For example, if the patentee changes the preparation steps and process conditions of daptomycin, which is reflected in the pharmaceutical enterprise's pharmaceutical process, this change will have defining effects on the pharmaceutical process; on the other hand, what the patentee has changed in the Disputed Patent is the method for administration of daptomycin, which is the choice and judgment to be made by a doctor in treating patients, independent of the pharmaceutical process," explained the examiner to the reporter. In other words, the later prescription will not affect the preceding pharmaceutical process, which has no defining effect on the pharmaceutical process.

After the invalidation decision was rendered, Cubist filed administrative proceedings with the Beijing First Intermediate People's Court, and then appealed to the Beijing Higher Court after it failed in the first trial, but it ultimately failed again in the second trial. In November 2013, the Supreme People's Court ruled on the application for retrial filed by Cubist in relation to this case, to once again uphold the PRB's decision.

Invalidation Decision Upheld; Lessons Learned from the Rationale of the Trial

Like most countries in the world, China's patent law provides that the method for diagnosis and treatment of diseases is not patentable. Then how is it possible to protect the medical use of substances? The industry generally believes that China provides protection for this issue by reference to the written form of the "Swiss-type claim" in the patent examination practice. However, a new issue would emerge: what technical features may be included in such claims? In particular, whether the method for administration and other medication features are technical features in the "Swiss-type claim" has been a highlighted issue for discussion in the industry.

"One view is that 'how many pills each time and how many doses a day to be taken by the patient' is the choice to be made by a doctor in the course of treatment, and the features which are only reflected in the medication behaviour, such as those in this case, are not the technical features that can change the pharmaceutical use, and, therefore, have no defining effect on the pharmaceutical method itself which is claimed to be protected in the claims. The PRB has always held this view," said the examiner in the case. "Another view is that the nature of the medicinal use invention is method of use, which should include all the processes for the drugs before they leave the factory, and, of course, also include the 'administration features'; therefore, the 'administration feature' on how to use the drugs should also be included in the claims."

To solve these disturbing issues, the Enlarged Board of Appeal of the European Patent Office made a decision in 2010 to cease to allow the reasonableness of the "Swiss-type claim", but instead to use other means to protect the medical use invention of substances. However, the "Swiss-type claim" remains used in China. As such, the decisions and rulings made in relation to the Disputed Patent will undoubtedly play an important guiding role in protecting medical use invention patents in the future.

The examiner in the case said: "The results of this case suggest how to write 'Swiss-type claims' in the future and clarify what technical features would have defining effects on the technical solution." However, this also indicates that, within the context of the current law, medical use inventions having improvement points in regard to medication features are still very difficult to be patented in China.

After the case was settled, many industry insiders have expressed their views, in particular, JIANG Jian-cheng, General Manager, Peksung Intellectual Property Ltd., who said that the most noteworthy core point in the case is that the retrial decision will apply to patent applications, whether they are filed before or after 2006, even if the patent has been granted. In other words, the criteria for the State Intellectual Property Office to review this issue has been explicitly supported by the Supreme Court, and this view is likely to be generally followed by lower courts in the future.

It is worth noting that the ruling by the Supreme Court shows that it shares the same view with the PRB on how to determine the nature of the claims of a pharmaceutical-use invention patent, and it has expressed, for the first time, its attitude as to whether the medication features have defining effects. This has an important guiding significance for the pharmaceutical industry that is extremely dependent on patents to protect innovations.

(Source: State Intellectual Property Office)

【Comments】

Freder J. Shen : when looking throughout the "Daptomycin Patent Invalidation Case", what is very clear is that the attitude of the Supreme Court towards the "Swiss-type claim" is consistent with that of the PRB: specifically, administration method, dosage and other features in the Switzerland type claim, may be considered in judging novelty or inventiveness only if it can have defining effects on the pharmaceutical process; on the other hand, the technical features merely reflected in the medication process cannot make the use become novel.

Since China's implementation of the "Patent Law" in 1985, the diagnosis and treatment method of disease has been non-patentable. According to the descriptions in the "Patent Review Guidelines", this is due to "humanitarian considerations and for reasons of social ethics that doctors should have the freedom to choose methods and conditions in the diagnosis and treatment process. In addition, these methods are directly implemented on living human or animal bodies and have no industrial applicability; therefore, they do not constitute an invention under Patent Law".

In order to circumvent the obstacles that the diagnosis and treatment of diseases are not patentable, the current common practice is to use what is now called a "Swiss-type" use claim (Swiss-type use claim), the typical way of writing of which is: "use of compound X for preparation of a medicament for diagnosis or treatment of disease Y." In China, when new diagnostic and therapeutic uses of known substances are discovered, they will also be given protection if their use claims are written in the "Swiss-type" format. The "Patent Review Guidelines" have laid down rules for "claims for medical use of substances" as follows: "however, as drugs and preparation methods thereof can be patentable under law, a medical use invention of substances does not fall under the circumstances set forth in Paragraph (c), Article 25 of the Patent Law if its patent application is filed as a drug claim, or as the medicament method-type use claim such as 'use in medicament' or 'use in preparation of a medicament for treatment of a disease'. "

In a typical Swiss-type use claim, novelty can be granted for diagnostic or therapeutic uses of usually known substances. However, when the point of invention consists in the defining of a diagnostic or therapeutic process, e.g., defining of the dosage, can the dosage and other features contribute to the novelty for a Swiss-type use claim? Clearly, the Supreme Court's ruling in this case gives a negative guiding opinion, and this also means that the "pharmaceutical process" is interpreted narrowly in China, i.e., it only includes raw materials, preparation steps, preparation conditions, and other features, and does not include the route of administration, dosage, usage, medication objects and other features (on the contrary, many developed countries, especially those with powerful pharmaceutical industries, have adopted a broad interpretation of "pharmaceutical process", for example, the European Patent Office holds that as the pharmaceutical composition, functions, route of administration, dosage, usage, medication objects, etc., are accomplished in the drug development process, and reflect the behaviour of pharmaceutical enterprises in the development and preparation of drugs, they should be considered as the features that define the "pharmaceutical process". However, it should be noted that, in Europe, the protection by Swiss-type claim is currently not acceptable either; it is, instead, switched to more direct protection by a second use of the known drug.)

Then, under the Supreme Court's guidance tendency, the Chinese Patent Office, the review committee and the criteria for judging lower courts will certainly be consistent, objectively speaking; this will be the pharmaceutical industry innovations regarding which administration of patent applications has some impact. For such effects, I think that it is required to analyze and understand, before the patent application is submitted, the risk that it may be rejected in the future, so as to determine the application strategy. If a pharmaceutical enterprise determines to file a patent application, it can take certain techniques, at the time of the initial writing, to avoid the risk as much as possible. For example, it can try to change the "dosage" feature in the medication process into "unit dose" feature, and have a detailed description in the specification that such unit dosage has brought unexpectedly good effects or has overcome certain technical bias. Although the risk of being rejected remains, at least it can gain a relatively good position to argue in future.

For patent agencies, when a client instructs them to file a medical-use type patent application, they need to early and timely communicate with the client, fully inform it of the risks, and suggest changing or abandoning the application, to enable the client to ultimately decide whether there is a reason to proceed with the application. This is what Kangxin has been doing and will continue to do, and we firmly believe that a professional service is not only reflected in the level of knowledge, but also in good faith established based on the considerations of the benefit of the client and down-to-earth attitude.

Mary Y. Zhang : as is generally known, this case, known as "Daptomycin Patent Invalidation Case", is regarded by the Patent Reexamination Board, State Intellectual Property Office (hereinafter "PRB") as one of the top 10 PRB cases in 2013. This, from a certain level, reflects that not only the PRB highly weighs the fact findings, application of law and invalidation results in this case, but also the Supreme Court highly weighs the fact findings and application of law in the ruling rendered on the application for retrial filed by Cubist in relation to this case.

As is generally known, Chinese Patent Law, although having undergone several rounds of changes, has always maintained that the diagnosis and treatment methods of diseases are not patentable under Patent Law ever since its implementation in 1985. In examination practice, the dosage, dosing interval and other features related to the use are information pertaining to the medication process, independent of the pharmaceutical process, and have no defining effect on the drug itself, which cannot distinguish the pharmaceutical use of the invention from the known uses of the prior art and, therefore, are not patentable.

However, as, in our patent practice, different examiners have different criteria to understand such features, a number of such patent applications were granted during the patent examination process a few years ago.

In view of the current invalidation decision in this case and the fact that the Supreme Court ruled in favour of the PRB on the application for retrial filed by Cubist in relation to this case, giving clear standards on whether "dosage" and other technical features in the medication process have defining effects on pharmaceutical-use invention claims, it can be expected that the patents which were granted in the patent practice a few years in relation to the "dose" and / or "dosing interval" will face a series of patent invalidation and related litigation in the near future if it refers to a drug that can bring good market effects and profits.

On the one hand, future patent invalidation and related litigation could bring opportunities to patent agencies and/or law firms specialized in intellectual property cases who, as the attorneys, may represent the applicants claiming invalidation to file the invalidation claims, or represent patent holders as a respondent, during the process of which, how to follow the standards set by the Supreme Court, as well as to find out the reasons and facts to the contrary to respond to the case represented can reflect the professional capacity of patent agents and lawyers.

On the other hand, in the legal context that only Swiss-type claims can be protected in the current patent practice, how to draft claims for relevant patent applications according to the standards set by the Supreme Court so as to subsequently secure a vigorous patent protection, has raised higher requirements for patent agents.

I hope this opportunity will be taken to further enhance the professional capabilities and service capabilities of patent agents in the related fields, provide more quality services to the clients, and further enhance the professional capabilities and service capabilities of the agents, so as to contribute to establishing China as an innovative country.