Repurposed pharmaceuticals are attractive candidates for clinical development, but only with sufficient marketing exclusivity. Patents that focus on the uses and compositions in the product label can provide up to 20 years of exclusive marketing rights.
In recent years, particularly since the Dot-com stock market crash in 2000-2001, venture capitalists have been increasingly reluctant to fund US companies engaging in drug development. Such investments are often considered to be too risky, too capital-intensive, and to take too long to fit the new, more conservative venture capital model. Indeed, it has been estimated that only 1 in 100 preclinical drug candidates and only 1 in 10 drugs that enter US FDA clinical trials ultimately receive FDA approval. The average cost of developing a drug through FDA approval is approximately US$ 1 billion, and it takes up to 15 years from discovery to product launch. This combination of time, money, and risk has sent venture money fleeing for safer, quicker investments, albeit with a lower upside potential.
One bright spot for start-up pharma companies and venture investors has been speciality pharmaceuticals (or repurposed drugs). Such products include drugs that previously fell out of clinical trials and new uses for old drugs. By starting with a drug that has already been in the clinic, risk is reduced in each category of concern. Approval time is shortened for drugs that have already been proven safe. The cost of the clinical trials is less, because pre-existing ADME and safety data can substitute for expensive research and trials. The risk of failure is also reduced for drugs having known safety and pharmacology. For all of these reasons, repurposed drugs are attracting more and more early-stage investment dollars.
The exclusivity problem
A major drawback to the development of repurposed drugs is lack of exclusivity. These drugs simply will not be developed without sufficient exclusivity to allow a reasonable return on investment. For New Chemical Entities (NCEs), this is usually not a problem, because the typical 20-year patent term (measured from filing) is sufficient. However, for repurposed drugs, the NCE patents often have little or no term left. Moreover, US patent term extension and European Supplementary Protection Certificates apply to the first approval or marketing authorisation of a drug, and so are not available for previously-approved repurposed drugs. Finally, the period of data exclusivity in the US FDA (during which a generic application will not be approved) is five years for NCEs, but only three years for repurposed drugs that are not NCEs (See exclusivity chart). Because a three-year exclusivity period is generally insufficient, development of repurposed drugs hinges on the availability of adequate patent protection.
The FDA, drug patents, and generic drug approval
Generic drug approvals in the US are subject to a detailed regulatory scheme set up by the Hatch-Waxman Act in 1984. Applicants seeking approval of a generic drug typically do so with an Abbreviated New Drug Application, or ANDA. The primary scientific data required in an ANDA is the demonstration that the generic product is bioequivalent to the originally-approved drug. Expensive clinical trials are not required, because ANDAs rely on the safety and efficacy data generated under the original New Drug Application, or NDA, of the original innovator. However, if the original drug product or its use is covered by patents listed in the FDA’s Orange Book, generic marketing approval is effective only after the patents expire. The exception is when the ANDA-filer certifies that the relevant patents are invalid or not infringed. Such certification opens the generic drug company to patent litigation, and an automatic 30-month stay of ANDA approval when the patent infringement suit is filed. Thus, having Orange Book-listable patents is a major consideration when investing in drug development.
The importance of the FDA-approved label
In the course of approving an NDA, the FDA carefully reviews and approves a drug label (also known as the package insert). This label includes information relating to indications and usage, dosage and administration, dosage forms and strengths, contraindications, warnings and precautions, special populations, drug interactions and use in specific populations. With minor exceptions, the ANDA-filer must adopt the approved label. The Orange Book also focusses on the label, listing only patents for approved NCEs, drug formulations, and methods of use that appear in the label. Close coordination between regulatory and patent professionals can enhance correspondence between patent claims and the label.
Extending exclusivity through label patents
A “label patent” is any patent that covers a method or product recited in the FDA-approved label. Because the ANDA-filer must adopt the product label, careful attention should be given to patenting new, non-obvious methods disclosed in the label. Repurposed drugs typically target a new patient population, new indication, or include a new dosage form, dosing regimen or route of administration. Corresponding methods of use in the label are all potentially patentable. Unlike the rule in most countries, methods of medical treatment are patentable in the US. In short, any time the label instructs the patient or physician to do something, consider whether that method is patentable. The patent term for such new patents is 20 years from date of filing, which can significantly extend the period of exclusivity for the repurposed drug.
Those developing repurposed drugs should not overlook the possibility of obtaining patents on seemingly minor improvements or innovations that are reflected in the label. Unlike traditional patent strategies, which focus on obtaining broad patents to cover potential modifications, label patents only need to cover the exact method disclosed in the label. This, in turn, can improve patentability by allowing inclusion of very specific details in the patent claims that are not obvious in light of the prior art. Obtaining several such patents enhances the odds of having a patent that is held valid and infringed at the conclusion of ANDA litigation.
It is desirable to identify potential label patent opportunities prior to public disclosure. When reviewing new clinical data, one should look carefully for unexpected or unpredictable results. In addition, it is helpful to ask what changes will be made in the label or the use of the drug as a result of the new data. Each of these areas represents fruitful ground for obtaining label patents.
A word of caution: in case of public companies, clinical trial results are often disclosed very quickly, leaving little time to prepare patent applications on new observations. In this situation, close coordination with highly-responsive patent counsel is important. Although there is a one-year grace period for filing patents in the US, most non-US countries have an absolute novelty requirement. Thus, filing the US application before any public disclosure can preserve foreign patent opportunities.
Label patents are not necessarily easy to obtain
In the US, patents can only be obtained for inventions that are both novel (new) and non-obvious. In the pharmaceutical area, novelty problems often arise when trying to patent a newly-recognised property of a drug. A result that inherently occurred in the prior art is not considered novel, even if that result was unrecognised. In dealing with inherency issues, is it helpful to ask whether something different is done as a result of the discovery. If the answer is in the affirmative, then including those new actions in the claim can usually overcome the inherent novelty rejection.
Obviousness can be a major issue for label patent claims. In 2007, the US Supreme Court decided KSR vs. Teleflex, which overturned the requirement that the prior art must contain a teaching, suggestion, or motivation to make the new invention. This case makes patents harder to get and easier to invalidate. Although some subsequent cases suggest that inventions made through routine experimentation may well be obvious, such a rule may not apply to unpredictable technologies, such as pharmacology. The very simplicity (and to some, triviality) of some label patent claims may result in obviousness rejections. Good strategies for overcoming those rejections include emphasising the unpredictability of the new discovery, presentation of comparative data (usually available from the clinical trials), long felt need, clinical importance, and lack of suggestion in the prior art. The ability to write very narrow claims (as narrow as the label language) can also help overcome an obviousness rejection, because it is more difficult to show obviousness of all the details of such a claim.
In addition to overcoming these bona fide legal issues, applicants may face less tangible psychological issues in obtaining and defending label patents. Pharmaceutical inventions in general and follow-on patents in particular may be reviewed more closely in both the Patent Office and the courts. Although the original NCE and method of use patents are often well respected, the same does not always hold true for follow-on patents. The latter are often filed as part of a drug life cycle management strategy with the objective of delaying or preventing generic competition. In light of the negative image of pharmaceutical companies and the public interest in the availability of low-priced generic drugs, exclusivity-extending patents receive enhanced scrutiny.
Patents for repurposed drugs have a very different purpose from Big Pharma’s life cycle management patents. They often serve a gating function; in other words, without the patent, the repurposed drug will never be developed or available to the public. However, because of the overlap between patent strategies for protecting repurposed drugs and those for product life extension, repurposed drug patents may suffer from the same negative perceptions in the Patent Office and the courts.
Despite these perception issues, in the end, the Patent Office and the courts are bound to follow the same rules of patentability in all cases. Label patent applications do make it through the Patent Office, and the resulting patents provide major value to innovators, drug developers, investors, and the public who receive the benefits of new and otherwise unavailable therapies.
Examples of label patent claims