Repurposing - finding new uses for old (and patented) drugs: bridging the "Valley of Death," to translate academic research into new medicines.

AuthorSem, Daniel S.
  1. INTRODUCTION II. DRUG REPURPOSING A. Growth of Drug Repurposing B. Academic Drug Development and the "Valley of Death" C. Repurposing to Traverse the Valley of Death--Is There Sufficient Exclusivity? D. Repurposing to Traverse the Valley of Death--Can I Find New Uses for Your Drug? III. PATENT LAW AND REPURPOSING A. Statutory Law and History B. Statutory Interpretation and Common Law 1. Creation of 35 U.S.C. [section] 271(e)(1) 2. Eli Lilly v. Medtronic: Setting the Stage for Merck v. Integra 3. Merck v. Integra a. The facts in Merck v. Integra b. The issue of safe harbor protection scope c. Scope includes research directed to IND and NDA filing d. The scope of the safe harbor protection extends beyond safety studies e. Scope not limited to studies included in IND, NDA or ANDA filings 4. After Merck v. Integra C. Summary of Current Law the Legal Issue IV. APPLYING THE LAW TO DRUG REPURPOSING A. Repurposing Research B. Implications of Merck and Momenta (M&M) for Repurposing Research C. Public Policy Considerations for Repurposing Research 1. Society Needs New Medicines - Repurposing Serves the Greater Social Good 2. From Fairies to Financial Bias 3. Innovation - To Advance Science and the Useful Arts Such as Medicine V. CONCLUSION I. INTRODUCTION

    Most people have experienced the pain of seeing loved ones suffer, and perhaps die, from diseases that no adequate treatments exist for. We all understand, in very personal ways, the need for new and better therapies. However, the pipeline of new medicines from the pharmaceutical industry has been dwindling as research and development costs increase, and as productivity has been declining. (1) As a society, we now face a serious problem--indeed, a tipping point. While the pharmaceutical industry was once viewed as a growth industry embodying the spirit of innovation, its pipeline of new medicines is drying up. Could it be that the pharmaceutical industry, at least in its current form--focused on "blockbuster drugs"--has made that fateful transition from a growth--i.e. innovation-driven--industry, to a mature industry? If that is the case, where will the new medicines come from, especially for currently untreated diseases--the "unmet medical needs"? This comment will present legal and public policy arguments in support of one solution to this problem: drug repurposing; in particular, drug repurposing that is performed in university research labs and directed towards unmet medical needs. This comment will also include a fairly detailed description of the drug development process and analysis of the pharmaceutical industry. This is in part a bias of the author, who has previously worked in the pharmaceutical and biotechnology industries in drug development and co-founded two biotechnology companies, one of which is focused on drug repurposing.

    Drug repurposing, sometimes referred to as repositioning, is increasingly being pursued as a solution to the problem of dwindling pharmaceutical pipelines; it is being proposed in both industrial and academic drug development settings. (2) Repositioning is the process whereby a drug that is patented for treating a particular disease is discovered to be useful for treatment of a second disease, and then is developed further for that purpose. (3) But can a researcher explore new uses for a patented drug without infringing on the patent owner's patent under 35 U.S.C. [section] 271? The answer to this question is a qualified "yes."

    This comment will present background as to why drug repositioning, and especially repurposing, has moved to the forefront of public--e.g. university, government-funded research--and private drug development efforts. Then, the various intellectual property and business issues surrounding repurposing will be presented. Case law will be reviewed to address the key legal question: to what extent can a person or company perform research directed towards repurposing another company's patented drug, under the protective umbrella of the safe harbor protection provided by 35 U.S.C. [section] 271(e)(1)? To help answer the question, this comment will review the judicially created guiding principles that establish when repurposing research is permitted safe harbor protection.

    Since the courts have concluded that the 35 U.S.C. [section] 271(e)(1) safe harbor protections apply to an expanding array of repurposing research activities, this comment will conclude with a look forward at this continuing trend. An argument is made that the expanding protections afforded repurposing research is good public policy when balanced against the fact that pharmaceutical companies are not adequately pursuing certain unmet medical needs of society. It is argued that allowing repurposing research serves the broader interests of society by advancing science and the useful arts, such as medical practice. Lastly, the expanding scope of the safe harbor protection of repurposing research should continue because university researchers and small companies will pursue diseases that larger pharmaceutical companies will not explore with their patented drugs, such as diseases that afflict smaller populations of people or those with limited financial resources.


    Drug repositioning is the process of finding a new use for an existing drug. The repositioning process is sub-categorized as: (a) Repurposing, if the first drug is already approved for clinical use in humans after achieving New Drug Application (NDA) approval, and (b) Rescuing, if the first drug did not yet achieve NDA approval, so is not in commercial use. (4) The more common situation, and the focus of this comment, is drug repurposing.

    1. Growth of Drug Repurposing

      Despite consistently increasing spending on drug development in the U.S., the number of new drugs--or New Chemical Entities (NCEs)--produced by the pharmaceutical industry (pharma) has been decreasing for the last twenty years. (5) Initially, this decrease led to a series of mergers and acquisitions (M&A's), as companies attempted to populate their drug development pipelines by acquiring innovation from other companies. Notable examples have been GlaxoWellcome and SmithKline Beecham in 2000, and multiple M&A's in 2009, including Pfizer/Wyeth and Merck/Schering-Plough. (6) Eventually, this lack of innovation leading to NCEs had an even more profound impact on the industry as blockbuster drugs (7) began to come off patent, in what has been referred to as the "patent cliff." (8) As market exclusivity was lost and generic drugs replaced patented drugs, revenue dropped and the industry experienced the most dramatic downsizing in its history. (9)

      As the pharmaceutical industry emerges from this massive downsizing and restructuring, it is struggling both to redefine itself, as well as to find future sources of new medicines for patients. One strategy that pharma is embracing is an increasing trend of in-licensing potential NCEs from biotechnology companies or universities. (10) Meanwhile, the public sector is stepping in to fill this gap in pharmaceutical innovation. Recognizing the public health implications of this dearth of innovation in pharma, President Obama provided funding in 2012 to launch the National Center for Advancing Translational Sciences (NCATS) within the National Institutes of Health (NIH). (11) NIH Director Francis Collins stated that:

      This action marks a major milestone in efforts to revolutionize the science of translation. NCATS provides our nation with an opportunity to forge a new paradigm for translational research that involves government, academia, industry, philanthropy, and patient advocacy groups.... I believe we can work together to achieve our common goal: speeding the movement of scientific discoveries from the lab to patients. (12) B. Academic Drug Development and the "Valley of Death"

      Pharma experts, including former Chairman and CEO of Merck, Roy Vagelos, argue that the public sector--universities and the NIH--have little experience in drug development and should leave drug development work to the pharmaceutical industry. In testimony before the United States House of Representative's Committee on Appropriations, Dr. Vagelos stated that the NIH and NCATS should focus on funding basic research and avoid getting involved in drug repurposing:

      [T]rying to find a use for a drug that has not been approved is a fishing expedition that has a very low probability of success. As for repurposing of drugs, I would recommend that the NIH not support clinical studies of marketed drugs. Such studies that are aimed at obtaining additional claims for drugs already being sold should be funded by the company that owns the drug and will benefit financially from the additional claim. (13) Is Dr. Vagelos correct? Should university researchers and the NIH stay out of drug repurposing research? While he has some valid points, a case can be made that his recommendation is both biased and wrong.

      While academic (i.e. NIH-funded) researchers are adept at identifying new proteins that can be pursued as drug targets, and identifying initial drug lead molecules that bind to these proteins, they often lack the knowledge and expertise needed to go from these basic research discoveries through the various pre-clinical studies, to reach a drug lead molecule in human clinical trials. Indeed, of 5000, pre-clinical drug candidates, on average only five will make it into human clinical trials. Of these, only one will make it to NDA approval. (14) This gap between basic research discovery and the molecule that makes it into the clinic has been called the "valley of death," in part because there is a weeding out in going from 5000 to five drug candidates, in a process that is only traversed by those who have the appropriate skill set, which is typically those in industry. (15) However, because repurposed drugs have already had pre-clinical studies performed on them for another disease indication, they...

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