Patents: A powerful tool in managing Diabetes

Fredrick Banting, is a hero for the Diabetes Community. A hundred years back in 1921 he was the one who found out a method to extract insulin from mammals to use it for the treatment of diabetes mellitus. He was a hero not for finding a way out to isolate insulin and saving countless lives, but for selling his invention which he had protected in the form of a patent to the University of Toronto for a mere price of One dollar, because he believed- “insulin does not belong to me, it belongs to the world.” It is because of him that today we diabetics are able to live a normal life, and not consider it a life- threatening disease.

 

The light that he sparked has cascaded into countless innovations, that make the lives of diabetics a little bit easier. The patent owned by Frederick banting was titled “Extract obtainable from the mammalian pancreas or from the related glands in Fishes, useful in treatment of Diabetes mellitus and a method of preparing it.”  Since the discovery of insulin in 1921, insulin therapy has greatly advanced. It has come a long way from porcine and bovine insulin derivatives to the development of rapid-acting, and then ultra-rapid-acting, insulin analogues, to insulin pump delivery systems as well as Automated Insulin Delivery Systems. This is because innovators are promoted to invest on research and publish their inventions in exchange of a monopoly to exclusively use this invention for a period of 20 years in the form of patents. In this blog, we shall discuss some of these discoveries and the patents through which they are protected. We shall consider two categories, namely, insulin, its analogues; their delivery systems and glucose monitoring devices.

 

INSULIN, ITS ANAGLOUES AND DELVIERY SYSTEMS

 

This last century has been a time of change and innovation in the field of insulin therapy, starting with the isolation of insulin, the purification and concentration of animal pancreatic extracts, the development of formulations with protracted duration of action, and the progression to human insulin and modified insulin analogues made with recombinant DNA technology. The landscape of insulins available today also includes insulin mixtures, concentrated insulins, and insulins with alternate routes of administration, providing a wide array of options for people living with diabetes.

 

The isolation of purification and concentration of animal pancreatic extracts was disclosed in Fredrick Banting’s patent published in October, 1921. Banting and Best could not manufacture insulin to scale using the University facilities so they allowed (i.e., “licensed”) their US patent rights to Eli Lilly, allowing Lilly to apply for its own US patents on improvements to their process. Eli Lilly only filed for patents in the US and Canada on process improvements, and Banting and Best retained rights to their technology for the rest of the world.

 

Outside of Canada and US the university of Toronto was free to allow third parties outside the US and Canada to produce insulin using Toronto’s original technology. Such third parties included Denmark’s Novo Nordisk). Novo improved the original technology adding protamine to insulin and prolonged its action, as well as making further innovations, such as adding zinc to form the crystalline protamine isophane insulin, now known as neutral protamine Hagedorn (NPH), which was patented in 1946. This patent was numbered US2538019 and titled “Crystalline product of insulin and alkaline protein and process of making it” This made it possible to combine longer-acting and short-acting insulin. Many of these improvements resulted in patents being granted.  Soon afterward, Novo Nordisk was able to extend the duration of insulin’s action without protamine.

 

The use of animal based insulin posed many challenges and soon the first recombinant DNA insulin was made in 1978 and Eli Lilly brought the first recombinant human insulins – Humulin R (regular) and Humulin N (NPH) – to the US market in 1982. Novo Nordisk eventually marketed its first recombinant insulin in 1988, and protected it through multiple patents, one such patent is titled “insulin analogues and method of preparing the same”, numbered EP021486A2, filed on 30th august, 1985. Patents on human insulin were now extended into the early part of the 21st century.  Around this time, recombinant DNA technology allowed the substitution and/or alteration of the amino acid sequence of human insulin, resulting in ‘analogues’ such as lispro (1996), one of them filed by Novo named Acylated insulin, numbered US011007A, filed in 1993 and additions to it in 1997, aspart (2000), glargine (2000), glulisine (2004) and detemir (2005). The first patents on these analogues began expiring in 2014-2015.   Unlike small molecule chemical entities, it is difficult to produce an exact copy of a biological product (called a “biosimilar”) that is produced using recombinant DNA technology. Because of the complexity of biosimilar products, patent holders tend to file many patents to protect methods of making, methods of using, as well as the biological product itself.  The major companies having monopoly in the field of Insulin Patents are – Eli Lily, Novo, Sanofi and Pfizer

 

INSULIN DELIVERY SYSTEMS

 

Apart from various insulin and its analogues, various insulin delivery systems have also been developed and patented. After the discovery of insulin, the next challenge that was posed was easy administration of insulin. As there was a wide age group from infants to adults, who depended on insulin; there was a need to provide for its easy administration. The route of administration started from syringes and developed into portable insulin pens in the 1990 and early 2000s, one of the first insulin pens was disclosed in the patent US6585698B1, filed in 1999 and was owned by Benton. This patent was titled “Electronic medical delivery pen having a multifunction actuator.” The insulin pens were a great boon to diabetics, which further encouraged researchers and companies to update these pens leading to the formation of smart insulin pens, which is developed for people on Multiple Daily Injections (MDI). This smart pen integrated system not only provides real-time glucose readings alongside insulin dose information but also gives users everything they need to manage their diabetes in one view. One such smart pen has been disclosed in the patent US20150246179A1, which has been filed in 2014 and titled- “Device and method for drug dosing with administration monitoring, in particular for insulin pen integrated with smart phone apps.”

 

Newer methods of administration of insulin, also include insulin pumps. They deliver a continuous infusion of insulin via a cannula placed in the subcutaneous tissue, sometimes referred to as continuous subcutaneous insulin infusion. One of the first insulin transfusion through pump systems was patented by Medtronic in the year 1999 in the patent US7806886B2, titled “Apparatus and method for controlling insulin infusion with state variable feedback.”

 

Further innovations have led to the development of Automated Insulin Delivery or AID systems (also known as closed-loop, artificial pancreas, or bionic pancreas systems) which use real-time glucose measurements fed into a control algorithm that automatically adjusts the rate of subcutaneous insulin delivery via an insulin pump. One such system is disclosed in Patent US20150352282A1, which has been assigned to Madryn Health Partners filed in 2014 and titled; “Insulin Delivery Systems and methods”

 

 

Figure 1 First insulin pen covered by US6585698B1

 

 

insulin Pump 1:  US7806886B2

 

GLUCOSE MONITORING DEVICES

 

One of the most essential tool in management of type 1 diabetes is- glucose monitoring devices. Patients need to be aware of their glucose levels at all times, for effective management. Glucose monitoring devices have undergone multiple developments, and research in underway to provide easy glucose monitoring systems without the need of needles. The trends have changed from traditional finger stick glucose measurements to continuous glucose monitoring systems (CGMS) to now development of sensor based glucose monitoring systems.

 

The traditional Finger Stick Glucose (FSG) systems have been developed way back in 1990 and early 200s One such patent that disclosed this technology was US7976778B2, filed by Abbott Diabetes in 2001 and is titled “Blood glucose tracking apparatus”. The modification in the traditional FSG systems have been made to make it Bluetooth enabled, which can be paired with smartphone applications, so that patients can track and identify patterns easily, one such patent is US20150264517A1, filed in 2009 by Abbott, titled; “Portable glucose monitor with wireless communications.”

 

 

FSG system: US7976778B2 1

 

The portable glucose monitor systems, then gave rise to the use of Continuous Glucose Monitoring Systems. They work by providing biosensor membranes. They actively transmit glucose information to a dedicated receiver, insulin pump, smartphone/watch, and to a cloud network if desired and can provide real-time information to the user regarding (1) rate of glucose change, (2) hyperglycaemia and hypoglycaemia based on individualized thresholds, and (3) impending hypoglycaemia alarms based on glucose trends. Popular CGM systems in the market include Dexcom G6, Abbott’s Free style libre. The free style libre systems have been covered under a bunch of patents, one of them being US9713443B2 filed in 2016 by Abbott and titled, “Biosensor membranes”

 

The continuous glucose monitors are and improvement over the traditional FSG, and overcome the disadvantage of pricking multiple times a day. However, they still require to be changed and replaced frequently and are costly to use. Hence there was a need to further modify and provide for sensor based systems which do not need to be attached on the body and are easy and convenient use. One such system has been invented and filed for by an Indian start- up called Vivalyf innovations in 2021 and is numbered IN202141012687, titled, “NON-INVASIVE GLUCOSE LEVEL MONITORING DEVICE USING ABSORPTION SPECTROSCOPY WITH AFFORDABILITY “

 

Another such interesting glucose monitoring device is a wearable smartwatch medical device measures and displays glucose level continuously, effortlessly and painlessly. This watch measures glucose concentration by being in contact with the interstitial fluid rather than with the blood which makes it also a blood-free solution. This watch is being developed by Pkvitality in partnership with Beurer Gmbh, and is expected to be rolled into the market in late 2022, or early 2023. This watch is covered in the patent application no WO2019141743A1 and is titled, “Body-monitoring system with adhesive.”

 

The tools and resources for treatment and management of Type 1 Diabetes has come a long way, as we saw. A pivotal role in this has been played by providing monopoly rights through grant of PATENTS. The patent policy came into being for the very purpose of promoting invention and research, which could make human life easier and more convenient, and in case of diabetics; sustainable. However, what has been a point of worry for countries all over is the misuse of these patent policies by some pharmaceutical giants to create a dominant hold over insulin products, thereby making the products unaffordable to a large diaspora of people.  There needs to be a balance between granting monopoly to inventors and making these inventions affordable to the public at large. Steps like the Drug Price Control Order, 1995 as amended in 2013 adopted by India, has been a step forward in the right direction and needs to be adopted by more countries, while safeguarding the interests of genuine inventions and inventors.

 

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– Hasti Chandarana

She is an Intellectual Property Rights Enthusiast and a Pharmacist. Her inspiration behind studying Pharmacy and now inventions is her Type 1 diabetes. She strongly feels that using IP as a tool in the correct direction can lead to finding a cure for the disease itself.

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