Patents and the high cost of medications

 

    "In 1421 builders of the Florence Cathedral needed marble for its construction.  Filippo Brunelleschi devised a boat that would carry the heavy rock up the Arno River and he was granted the right to exclude all new means of transport on the Arno for three years.”  Historians claim this was the first modern patent.

    "In 1449 English King Henry VI granted John of Utynam a 20 years monopoly for a stained glass-making process.

    "During the reign of Queen Anne 1702-1714 the British Crown required a patentee to provide a written description of the invention to be patented and the manner in which it was to be performed.

    The U.S. constitution gave the government the right to issue patents “...limited Times to Authors and Inventors the exclusive Right to their respective Writings,” and in 1790 "Congress passed the first patent statute."

To be eligible for a patent an invention must be novel—unique—different.  It must work and be useful and must not be obvious, not just a simple change to something that's already been invented.

     In 1790 president George Washington signed the first U.S. patent granting Samuel Hopkins the exclusive right to use his process to make potash for a fertilizer.

With regard to medications--Nobel Prize winner Joseph Stiglitz once said “patents are created for each nation’s needs. They give the inventor a monopoly for a number of years. When they are appropriately designed, they promote innovation and societal well-being. When they are not appropriately designed, people die and innovation is suppressed.”

The Canadians who first isolated insulin obtained the American patents for the hormone and sold them to the University of Toronto for one dollar each. At the time the chief researcher, Frederick Banting reportedly claimed they did it because “Insulin belongs to the world, not to me.” 

A human form of the hormone is now produced by a few companies that don’t price compete.  On January 1, 2023, out-of-pocket costs for insulin were capped at $35 per monthly prescription among Medicare Part D enrollees under the Inflation Reduction Act (IRA).  For people who aren't old enough for Medicare the U.S. cost of insulin was (and probably is) higher than it is on the other side of our northern and southern borders.  

Currently the insulin people in our world take is genetically engineered human insuln--, thanks to plasmids..

Plasmids are small circular lengths of DNA and are found in the cytoplasm of some bacteria.  In the 1970s Herb Boyer a researcher at UCSF had a graduate student who discovered an enzyme that sliced the circle at a specific spot and caused the plasmid to have two sticky ends.   

Stan Cohen, then at Stanford, learned how to insert a gene into the cut ends of the plasmid. When the plasmid was inserted into the cytoplasm of certain experimental cells, the gene in the plasmid instructs the cell’s ribosome to make a specific protein.   

Herb and Stan started Genentech.  In 1980 their people created plasmids that instructed cells to make each of the protein chains of the human insulin hormone.  At the time the protein sequence and structure of insulin was known but the gene was unknown, so they created the gene.  They knew that (in each gene) each sequence of three nucleotides, is a codon.  Each codon tells the ribosome to make a specific amino acid.  Working backwards they constructed the genes for the A and B chains of human insulin.  

Over the years a number of companies each developed a slightly different way of producing and delivering human insulin. Each company,then, obtained multiple patents and started charging a lot of money for their version of human insulin.  most of the patents recently expired.

In 2014 three companies had 19 active patents on insulin.  10 were for insulin-containing devices rather than the active ingredient.

"In 1987 the U.S. Patent Office gave Genentech a broad patent covering molecular bio-logical tools used to create proteins from genetically engineered organisms.  The patent encompasses techniques used by the entire biotechnology industry. " 

In 2008, three Genentech drugs had revenues of $7 billion a year.

One, Avastin is a monoclonal antibody that blocks a gene that causes new blood vessels to grow and slows the growth of some cancers.  

The second, Rituxan, is a monoclonal antibody that attaches to a protein only found on B lymphocytes, and that marks them for destruction by macrophages, types of white blood cells that “engulf and digest pathogens.”

The third, Herceptin is a monoclonal antibody that inactivates a protein receptor found on some cancer cells.  Protein receptors tell cells to grow, survive, or die.

In 2009, when Roche paid $46.8 billion to acquire Genentech the annual revenue from all three drugs totaled $7 billion.  As of 2018, the same drugs generated over $21 billion

Do patents and acquisitions play a role in the price of drugs?

 

The chief drug that’s used to kill intestinal parasites recently became a very expensive commodity.  Patented in 1975 by Smith Kline, it was created by Robert J. Gyurik and Vassilios J.Theodorides, after Vassilios, a researcher at Smith Kline and French laboratories, read an article, had a sudden insight, and sketched the chemical structure of the future medication.

The medication he created was introduced in 1977 and was initially only given to animals in Australia and New Zealand.  It was not approved for people in the U.S. because someone at the FDA decided it was carcinogenic.  Vassilios met with scientists at the agency.  He showed them they were using an incorrect mathematical approach when they evaluated the drug’s potential carcinogenicity.  The officials at the FDA agreed and humans started using it in 1982.  

Twenty eight years later the company that owned the drug had merged with two other pharmaceutical giants and became GlaxoSmithKline.

By October 2010, Albendazole had become a financial loser, and the company dumped/sold it and the U.S. marketing rights.  They were picked up by Amedra pharmaceuticals, a small American company.  The details of the deal were not disclosed (or at least I couldn’t find them on the web.)  As part of the agreement GSK agreed to continue manufacturing the medication for Amedra in the short run.   They also renewed their pledge to the World Health Organization.  They would continue to give the organization 600 million tablets per year as their contribution to the struggle to free the world from Lymphatic Filiariasis.  It’s a condition that affects 120 million people in 80 countries, and you can read about it on the internet.  

 The year after Amedra bought Albendazole, the generic drug company Teva, stopped manufacturing the drug’s only U.S. competitor, Mebendazole (brand name-Vermox.  Amedra became the only U.S. player in the intestinal parasite business and the drug then had the potential to become a valuable commodity.  Impax purchased Amedra for $700 million and dramatically increased the amount they charged for the drug.  In late 2010, the average wholesale price was about “$6 per typical daily dose”, and by 2013 it had jumped to almost $120.

In 1947 at age 33 Jonas Salk was given a laboratory at the University of Pittsburg and was funded by the March of Dimes, a charity that was created and promoted by Franklin Roosevelt. He created a vaccine for polio by chemically inactivating live virus.  In the early 1950s it was given to 2 million school children as part of a placebo controlled trial and in April 1955 the nation learned that it was safe and effective.

When the famed journalist Edward R. Murrow asked Salk if he considered patenting the vaccine Salk replied “could you patent the sun?” Some claim the University of Pittsburg lawyers had already concluded the vaccine wasn’t patentable.

The developer of the oral polio vaccine was born in Poland and was fifteen when he and his parents came to the United States. Albert Bruce Sabin eventually went to medical school and he graduated in 1931.  While studying Polio at the Children’s Hospital Research Foundation in Cincinnati, Ohio, Sabin discovered that polio viruses lived in the small intestines before they attacked nerves. He isolated a polio mutant that grew in the intestines and that prevented infections with the wild virus.

Sabin refused to patent the Oral vaccine, and it is currently widely used in the poorer countries of the world. 

Albert Schatz, the PhD who isolated streptomycin, one of the antibiotics that we used for decades for tuberculosis and several other infections, grew up on a New Jersey farm that didn’t have running water, heat or electricity He gave Rutgers the U.S. and foreign patent rights to streptomycin “on the understanding that neither he nor the foundation would profit from the antibiotic.”  He “felt streptomycin was so important it should be made inexpensively available.”  Waksman, the department chief was second author on the paper that announced the antibiotic’s discovery, but he seemed to be claiming all the credit for the discovery.  He apparently told Schatz he was a pawn of the university and had no choice.  “Schatz grew resentful and left Rutgers University bitter and penniless.” When he later learned that some of the royalty he signed away was being channeled back to Waksman’s research institute Schatz sued and the men settled out of court. In 1952 Waksman received the Nobel Prize for the discovery and he didn’t mention Schatz by name in his acceptance speech.

The drug, epinephrine, was one of the world’s first hormones.  Isolated from the adrenal glands of animals in the late 1800s, it was purified and patented in 1902 by Jokichi Takamine a Japanese chemist living in the U.S., and it has long been the antidote for a severe allergic reactions.

A pure injectable form was first used to treat asthma more than 100 years ago.  It remained relatively cheap and available for most of the 20^th century.   

The auto-injector, the device that automatically squeezes epinephrine through a needle and into a body was invented in the mid 1970’s and the FDA approved its use in 1987.  It was presumably no longer patented.

Then between 2007 and 2016 the list price of two injectors full of the epinephrine went from $94 to $609.   The CEO of the responsible drug company was Heather Bresch, the daughter of Joe Manchin, former West Virginia Governor and former U.S. Senator.

As a leader at Mylan Pharmaceuticals, Heather was in charge of EpiPen, an autoinjector containing epinephrine.  Her company purchased EpiPen from Merck in 2007. Once they owned it the company “pushed through legislation that made EpiPen a main stay in schools,” and they dramatically grew its price.

In 2006 Genentech, the company that owned the drug used to treat wet macular degeneration helped the doctors earn money when they made a virtually identical drug and charged a lot of money for it.  Lucentis, like Avastin is an antibody that blocks the growth of new blood vessels.  It’s biologically similar, works as well as Avastin, and is FDA approved for wet macular degeneration. In 2014 Genentech was selling the medication for over $2000, and doctors who used it in their office were able to charge $180 for the visit and the injection. 

Cancer immunotherapy was invented by James Allison, a researcher at the University of California, Berkeley. Once researchers proved it worked, industry took over. Between 2006 and 2016 the U.S. Patent and Trademark Office issued 2,229 patents for various immune related approaches.

Gene therapy—CRISPR—was invented at the University of California and was patented by two opposing groups.

    According to the World Health Organization, “Hepatitis C is an inflammation of the liver caused by the hepatitis C virus, and the virus can cause chronic hepatitis, liver cirrhosis and cancer. Globally, an estimated 50 million people have chronic hepatitis C virus infection, and there are about 1.0 million new infections occurring per year.  In 2022, approximately 242 000 people died from hepatitis C, mostly from cirrhosis and hepatocellular carcinoma (primary liver cancer). 

    Early in the 21st century a startup --Pharmasset-- created a drug that with a second drug cured more tha 95% of persons with chronic hepatitis C in a few weeks. In 2011 Gilead bought the company and its drugs for 11.9 billion and planned to charge about $80,000 for a cure.  When Gilead tried to patent the drug in Egypt, the country's patent judges refused to issue Gilead a patent.  The drug, they claimed, was not unique.  Without a patent Egyptian researchers were able to copy the chemical and provide a cure for infected Egyptians.  In the U.S. individuals and insurance companies were paying about $80,000 for a cure.  Egyptians paid $60.  In the absence of a patent Egyptian leaders were able to save countless lives.

To make pepfar work, to be able to afford to provide needed drugs to infected Africans, U.S. leaders decided to ignore current HIV drug patents.  Pepfar has turned HIV in Africa (once a death sentence) into a chronic condition..

 But, thanks to the patents, the drugs that control HIV and cure hepatitis C remain quite costly in the U.S. and Europe.  For details read these earlier blogs.   

 med-hints.blogspot.com   three posts

Antivirals that control HIV and cure hepatitis C

The next best thing to an HIV vaccine  (the story of lenacapavir)

HIV and the plight of 23 million Africans  (story of pepfar)

“The World Trade Organization’s agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) was negotiated during the1986-94 Uruguay Round.  It introduced intellectual property rules into the multilateral trading system for the first time.”

They defined "Intellectual property" as creations of the mind. The creations can take many different forms and governments grant creators the right to negotiate payment in return for others using them. Eligible inventions can be patented.

The Uruguay Round, the TRIPS Agreement was an attempt to narrow the gaps in the way these rights are protected and enforced around the world, and to bring them under common international rules.

The TRIPS Agreement says patent protection must be available for eligible inventions in all fields of technology that are new, involve an inventive step and can be industrially applied. Eligible inventions include both products and processes and must be protected for at least 20 years. However, governments can exclude diagnostic, therapeutic and surgical methods, plants and animals (other than micro-organisms), and biological processes for their production (other than microbiological processes) from patent protection.

https://www.who.int/news-room/fact-sheets/detail/hepatitis-c

https://www.wto.org/english/thewto_e/whatis_e/tif_e/agrm7_e.htm

BOOK Understanding Modern Healthcare the wonders we created and the potholes we dug by Steve Fredman M.D.

https://pmc.ncbi.nlm.nih.gov/articles/PMC5798424/