Physician's Experience with Patenting a New Indication for an Existing Drug
By Ralph Wood, DO
ABSTRACT: Most family physicians are not aware that their successful treatments may be new discoveries. This paper will describe the events and process of how the author discovered and received a patent1 for a new indication for an existing medication based on his clinical experience with patients in his practice.
The Complicated Diabetic Patient
Family physicians examine, diagnose and treat a multitude of problems on a daily basis. Most conditions respond as expected, others do not respond, and some respond in ways that are totally unexpected. This paper describes a serendipitous discovery that occurred while treating a gentleman who presented with a litany of co-morbidities, including type 1 diabetes, hypertension, peripheral vascular disease, diabetic foot ulcer, peripheral neuropathy, hyperlipidemia, and erectile dysfunction. The evaluation and subsequent successful treatment of this and other patients, led to the eventual granting of a patent.
This initial patient had been seen for more than 10 years and was typical of diabetic patients in that at times he was poorly compliant with medication and diet, and at other times did quite well. He had developed a foot ulcer where a plantars wart had been, at the base of his third toe. Initially the patient was treated in the office for the ulcer. When the ulcer would not heal, he was referred to a wound clinic, where podiatric and vascular surgical care was provided. After initiating wound care, IV antibiotics, and keeping the patient off his feet, the ulcer healed. However, the ulcer eventually reoccurred, and there was a concern that the patient might require an amputation of the leg. Fifteen percent of diabetics will develop foot ulcers, and of those, approximately 25 percent will require an above or below the knee amputation.2
Follow-up Visits
The patient and his wife of 40 years would come to the office together. While performing the history and review of systems, the wife stated that she and her husband had not had intercourse for several years. She asked about a new medication she had heard about that could help their sex life. Sildenafil (Viagra ©) was prescribed but with a warning that the increased sexual exertion had the potential for precipitating untoward cardiac effects. In response, both stated they understood the risk but were excited about trying the medication. The patient was scheduled to follow up in two weeks.
During the interaction at the next appointment, the couple acted full of life. The patient stated he had used all ten doses of the new prescription over the previous two weeks, without adverse effects of exertion. His blood pressure and glucose were improved and the remainder of the exam identified improvements in other parameters, as well. His legs appeared more pink, and warmer to touch, with more robust circulation, and he appeared to be growing more hair on his legs and feet. The foot ulcer had begun to close. The couple requested additional medication and ten more doses were prescribed. They were to follow up again in two more weeks.
At the next appointment, the foot ulcer had completely healed. It was pink, indented, soft and closed. The patient had grown more hair on his legs and feet and he stated they were less numb.
What was the reason for these improvements? Was it his new medication, the fact that he was spending more time off his feet, or was it due to increased compliance in medication and diet? Given that the only change in the patient’s regimen was the addition of sildenafil, the patient was advised to take sildenafil every day for the next month.
A Review of the Literature
A literature search revealed no studies or reports of using cGMP PDE5 inhibitors in the treatment of peripheral vascular disease, peripheral neuropathy or diabetic foot ulcers. This class of drugs had been used to treat diabetics with erectile dysfunction, but no observations could be found of any effect on their feet in general, or foot ulcers in particular. Local tissue ischemia is a key contributing factor to diabetic foot ulceration.3 Patients with diabetes suffer from poor skin perfusion in at least two ways. First, there is involvement of the non-conduit arteries, which are detrimentally affected by the process of atherosclerosis.3 Second, there is impairment of the microcirculatory control mechanisms that essentially is referred to as small vessel disease.3 When a body tissue suffers some form of trauma, an integral component of the body’s healing mechanism is increased blood flow. When small vessel disease and ischemia are present this increased blood flow response is significantly reduced.3 These peripheral vascular changes combined with the tendency of diabetics to form blood clots in the microcirculatory system during low levels of blood flow, is believed to be an important factor in ulcer pathogenesis.3
Neuropathy is another major complication of diabetes mellitus. Estimates of the prevalence of neuropathy in diabetes vary widely, from a low of 5 percent to a high of 80 percent. This significant variance is due, in part, to the numerous definitions and clinical descriptions utilized when discussing neuropathy.4
The effect of neuropathy is a complex process. Sensory neuropathy in the foot allows for abnormal and prolonged pressure placed upon areas of the foot. Motor neuropathy leads to deformity, further increasing pressure loading on the foot. In autonomic neuropathy, there is a loss of innervation of the sweat glands. This causes dry skin, which then leads to cracks in the skin, resulting in an environment amenable to infection. In this milieu the distribution of micro-circulatory blood flow is altered, directing the flow through shunts and away from the nutritive skin capillaries. These factors, in conjunction with foot trauma, result in skin breakdown and ulcers.3
Nerve damage is believed to be multi-factorial,4 and includes genetic predisposition, metabolic and vascular abnormalities, and lack of perturbation of growth factors.4 The response of the peripheral nervous system to the metabolic effects of diabetes does not appear to differ between type 1 and type 2 diabetes, which suggests a likelihood of similar clinical response to therapies in these two primary forms of the disease. There seems to be a number of susceptibility factors, which operate in the presence of hyperglycemia.3
Other studies have shown that nerve ischemia is involved in the pathogenesis of nerve conduction. Practitioners in the field have theorized that a decrease in nitric oxide levels may be responsible for the decrease in nerve blood flow. Nitric oxide is a short-lived radical with a broad spectrum of metabolic functions, including mediation of vascular tone. The effects of nitric oxide are mediated by cyclic guanosine monophosphate (cGMP). Various therapeutic interventions, all of which increase levels of nitric oxide, have been shown to increase nerve blood flow and nerve conduction.5
There are known cGMP PDE5 inhibitors, such as sildenafil citrate, which are selective inhibitors of cGMP-specific phosphodiesterase (PDE5), known to be responsible for the breakdown of cGMP. Such inhibitor compounds increase intracellular concentrations of nitric oxide derived cGMP, enhancing the effect of nitric oxide, which is responsible for the efficacy of sildenafil in the treatment of male erectile dysfunction.6
The Search Continues
The initial patient’s foot ulcer remained healed as long as he continued to take sildenafil. Other diabetic patients with peripheral vascular disease and diabetic foot ulcers also received the same treatment regimen. As anticipated, their foot ulcers and peripheral vascular disease also showed dramatic improvement. Two non-diabetic patients with peripheral vascular disease were also included, and their peripheral neuropathy improved as well.
After 12 weeks, all of the patients’ wounds were healed or healing. Secondary signs of peripheral vascular disease were improving. Except for some flushing and occasional dyspepsia, no other side effects from taking the medication were apparent. The patients were all impressed with their results. The regional pharmaceutical representative was contacted to determine if the company knew of similar findings.
A Collaboration Develops
After speaking with the pharmaceutical representative, this author received a conference call from the Director of the Diabetic Division in New York City, and the head of research in Sandwich, England. They wanted to know everything about the findings and how they were developed. The author was asked not to discuss the findings with others.
Two days later a certified letter arrived from the pharmaceutical company. It stated the findings as described and listed this author and three other physicians as “inventors.” The letter also stated that the author was receiving payment for the “invention”.
A Change of Plans
This communication raised two questions: 1) Who were these other “inventors”? and 2) What was the payment for? This author sought counsel with a patent attorney in Washington, D.C. All research findings and correspondence were shared with the attorney.
The following morning the patent attorney explained how important it was that a provisional patent be filed.
The attorney explained the timing of filing provisional patent applications is paramount in that the invention is able to be claimed by whomever applies first. Essentially, hours and minutes, or even seconds can make a difference in the outcome. A provisional patent gave rights to the invention following submission of a full patent application within a year.
The provisional patent required a title, an explanation of the field of “invention”, the hypothesis of why it worked, some background about diabetes, peripheral vascular disease, diabetic foot ulcers, and the results of the research. The same afternoon as the discussion with the attorney, the provisional patent was filed with the U.S. Patent and Trademark Office.7
Two days later, the author received a phone call from the pharmaceutical company wanting to know if the agreement was signed. It was explained that a provisional patent had been filed. They too had filed a provisional patent in the author’s name, including the names of the other inventors. They explained they had filed two days prior. The author’s attorney indicated that the author’s provisional patent had in fact been filed about four hours before the pharmaceutical company’s, and thus took precedence.
Negotiating
The pharmaceutical company contested this author’s filing, indicating they had known and documented this usage of cGMP PDE5 inhibitor, which would show their ownership. They also stated they were doing their own research trials in Sandwich, England and the results thus far weren’t promising and that they had pulled their offer. Documentation of ownership was requested from the pharmaceutical company and an agreement was made to not take the invention to any other pharmaceutical company for 90 days.
The next meeting took place in Washington, D.C. about six weeks later. The company agreed that the author owned the provisional patent and stated that current research would most likely not be promising. An agreement on the terms and selling price of the patent would need to be determined.
After five meetings, negotiations broke off. Attorney’s fees and other costs including time out of the office were mounting. The pharmaceutical company recognized this fact, hoping that if they held out long enough, that they could simply buy the patent for the amount of the debt incurred.
Months passed with no further contact and the author proceeded with filing of the permanent patent.
Renegotiations
A few months went by when the pharmaceutical company asked if ownership to the patent could be purchased while maintaining that the research didn’t prove that the invention worked any better than a placebo. This author stated that the patent ownership could still be purchased while disagreeing about its efficacy. The company’s continued insistence that the medication was not efficacious for this indication begged the question of why they still sought ownership.
Attorneys representing both parties began their questions. An attempt was made to imply that this author had used the medication off-label, and not for the indication of erectile dysfunction. They also claimed this author had passed this information without authorization as previously agreed.
After seven hours, the attorneys acquiesced but with the disclaimer that the invention didn’t work, despite threats of a lawsuit stating the patent was illegally filed. Another meeting was scheduled to discuss payment where a settlement was finally reached.
The Osteopathic Philosophy
Osteopathic family physicians are taught a holistic approach to our patients. They know in treating their patients, that they are not just treating the part that is ailing and not functioning properly, but that the treatment and advice will affect the entire patient, and possibly even the extension of the patient, their family8. This foundation allows the osteopathic physician to understand the cause and effect of treatments. The observations which led to the invention described herein improved the quality of life of these patients and their families. Striving to lessen pain and suffering remains a basic tenet of the oath osteopathic physicians take as healers. As an osteopathic physician, there is nothing more compelling than being able to fulfill the principles upon which the essence of our profession is based.
Conclusions
Engaging this patent and confronting all the stressful events encountered while rendering care enlightened the author regarding an area of medicine that most practitioners are not cognizant. The fact that a physician can patent another indication for a medication already on the market is likely a novel concept for most clinicians practicing on the front line. Identifying new uses for medications is usually reserved for the bench researchers at large tertiary care centers and the ivory towers of medicine. However, this tale highlighting the interaction between a physician and his patient emphasizes that what physicians do every day matters to their patients. Who would have known that treating erectile dysfunction would have such an impact on a patient’s feet… an osteopathic family physician did!
Dr. Wood is a 1982 graduate of West Virginia School of Osteopathic Medicine and is Board Certified by AOBFP. He was in private practice in Moundsville, West Virginia for 24 years, and is currently Chair, Department of Family Medicine at Nova Southeastern University, College of Osteopathic Medicine(NSU-COM), Ft. Lauderdale, Florida.
Acknowledgement: Dr. Wood would like to thank Daniel E. Shaw, PhD, Associate Professor of Behavioral Medicine, NSU-COM for his intellectual insight and know-how in developing this scientific paper. He would also like to thank Anthony J. Silvagni, DO FACOFP dist. and Dean of NSU-COM for his support.
References: