Bertram Rowland and the Cohen/Boyer Cloning Patent

The Attorney: Bertram Rowland was born in 1930 in New York City. He received his B.S. in Chemistry from UCLA in 1950, his Ph.D. in Physical Organic Chemistry from the University of Washington in 1954, and his J.D. from the George Washington University Law School in 1961. He began his patent law career as a Patent Agent in the DuPont Patent Training Program and as a Supervisory Patent Attorney for the Chevron Research Corporation, and has since been a partner in and Of Counsel to a number of law firms, General Counsel for a number of biotech companies, and President and CEO of DrugAbuse Sciences, Inc. He has been associated with the founding of numerous biotech companies, including SyStemix, Inc. and Pharmacopoeia, Inc.

The Cohen and Boyer cloning patent is only one of over five hundred patents that Rowland has written and prosecuted. Other prominent patents include

  • 4,471,130; 4,594,439; and 4,900,847 -- a series of patents concerned with catalytic asymmetric expoxidation, an important step in the synthesis of drugs. The co-inventor, Karl Barry Sharpless, won the 2001 Nobel Prize in Chemistry for this and related work.
  • 5,107,065 -- the first demonstration of the utility of antisense in controlling expression in a eukaryote.
  • 5,061.620 -- claiming the human hematopoeitic stem cell
  • 5,565,324 (written by Rowland and prosecuted by Paul White) -- the basis for combinatorially preparing organic molecules other than oligimers, and the patent on which Pharmacopoeia, Inc. was founded.

For Mr. Rowland's own account of the prosecution of the Cohen/Boyer cloning patent -- 4,237,224 -- see below.

 

The Invention: Herbert Boyer and Stanley Cohen's invention is the "biotechnology tool" now commonly known as recombinant DNA cloning or gene splicing. Under this technology, a gene from a piece of foreign DNA is inserted into a bacterial plasmid. The plasmid is inserted into a living organism, and the organism becomes a cell "factory" capable of reproducing the desired gene in unlimited quantities.

This technology became the core of the fledgling biotechnology industry. Stanford University licensed a total of 467 companies to use this technology. The major products sold under the licensing program include tissue plasminogen activator for heart attacks, erythropoeitin for dialysis patients, insulin for the treatment of diabetes, growth hormone for children with growth deficiencies and interferon for cancer patients. Major licensees included Amgen, Eli Lilly, Genentech, Johnson and Johnson, and Schering Plough.

The Inventors: Dr. Herbert Boyer is professor emeritus of biochemistry and biophysics at the University of California at San Francisco, and co-founder of Genentech, Inc., the San Francisco-based biotechnology company he started with venture capitalist Robert Swanson in 1976. Boyer has also served as director of the graduate program in genetics at the University in San Francisco and as an investigator for the Howard Hughes Medical Institute. He received the Albert Lasker Basic Medical Research Award in 1980, the Golden Plate Award from the Academy of Achievement in 1981 and the Industrial Research Institute Award in 1982. Boyer is an elected member of the California Inventors Hall of Fame, the American Academy of Arts and Sciences and the National Academy of Sciences. He received the National Medal of Science from President George Bush in 1990. Born in Derry, PA, Boyer earned his bachelor's degree in biology and chemistry in 1958 from St. Vincent College in Latrobe, Pennsylvania, and received both his master's (1960) and doctorate (1963) from the University of Pittsburgh.

Former chairman of the Department of Genetics at Stanford University, Dr. Stanley Cohen presently serves as the K.-T. Li professor, professor of genetics and professor of medicine at the School of Medicine. Following training at the National Institutes of Health, Cohen joined the faculty of Stanford University in 1968. He has authored more than 250 scientific publications and is the recipient of numerous awards, including the National Medal of Science, the National Medal of Technology, the Albert Lasker Award for Basic Medical Research, the Wolf Prize in Medicine, the Helmut Horten Foundation Research Award and the Prix de l'Institut de la Vie. He is an elected member of the California Inventors Hall of Fame, the National Academy of Sciences and the American Academy of Arts and Sciences. Originally from Perth Amboy, NJ, Cohen earned his B.S. magna cum laude in 1956 from Rutgers University, and his M.D. in 1960 from the University of Pennsylvania School of Medicine.

The Patent: Here is Bertram Rowland's own account of the patent prosecution, which he graciously provided us:

Here is the story of the '224 patent as I recall it. I had recently done work for Stanford in organic chemistry. The assistant science editor of the New York Times, Mr. McElhenny, called Niels Reimers, manager of the Office of Technology Licensing at Stanford, to inquire about any patent filing on a cloning invention. Reimers was unaware of the invention and called Stanley Cohen of the Stanford faculty to inquire. It appeared that the other coinventor, Herb Boyer, a subsequent founder of Genentech, had given an impromptu presentation at a Gordon conference. While Gordon conferences are to be kept in confidence until the material is published, someone informed Mr. McElhenny.

As I was informed Cohen insisted that the invention had no commercial application, was not patentable, and was really only a minor extension of what had been performed by others. However, he agreed to be a good academic citizen and cooperate if Boyer would go along with the filing. Reimers then called me and asked me if I knew what a plasmid is? I have a Ph.D. in organic chemistry and minor in biochemistry, but I received my degree in 1954 and this was 1974. I told Reimers that I did not know, but would find out. He then suggested that maybe he should find someone else, but I assured him that at that time there were no molecular biologists in the patent field and he was not likely to find anyone else more capable than myself to write the case. He then requested that I speak to Cohen and Boyer and get the information that I needed.

The materials I received were three published papers. After reading them, I was given about a total of two hours to speak to Cohen; Boyer was not available for discussion. I had about three weeks to write the case as one of the references could be seen to be a statutory bar. It was a very interesting exercise and after sending the draft to the inventors for review, I put the application in final form and sent it to the inventors for execution. At this point Cohen asked me why I was limiting the claims to bacteria, as plasmids are also available in eukaryotes or one could use viruses for cloning in mammalian cells. So far as eukaryotic plasmids, there was one yeast plasmid known and viruses had not been previously manipulated and shown to be capable of introducing foreign DNA into a mammalian host and the foreign DNA replicated.

As a side issue, Paul Berg, who subsequently received the Nobel Prize and is a colleague of Cohen's, had tried to clone SV40 DNA using lambda phage. The linking of the SV40 DNA and the lambda phage had been the subject of a paper by Mertz and Davis, who worked with Berg. Before attempting to introduce the construct into a bacterium, Mertz went on to Harvard and reported what she had been doing. I do not recall the name of the professor who heard of the experiment, but he was concerned about introducing the construct into E. coli. SV40 is a fragment of simian virus which is known to be oncogenic. His concern was that putting a cancer causing DNA fragment into a bacterium that populates mammalian guts could be dangerous if the investigator lost control of the organism. Berg was discouraged from proceeding and we will never know whether the experiment would have worked. For reasons I will not explain there is a question whether such construct would have been functional. I spoke with Davis and he believed that in making the construct there was a form made that would have been functional, but no one is going to repeat the experiment and we will never really know. If Davis was right and had proceeded, then Berg would have been the first to clone DNA. Berg adamantly refuses to file patent applications on his work, so there might not have been a '224 patent and Stanford University and the University of California would have been $300 million poorer.

In 1974, we did not have computers, but rather had an original and four carbon copies. Rewriting the case was not an alternative in view of the time pressure. My expedient was to add a claim at the end of the claims to "A cell…" as there was enough language in the application that could be interpreted to support other than bacteria. This was a much simpler time and Alvin Tannenholz who turned out to be the examiner was less proficient than I in molecular biology. As the case gained prominence, in some way he became more accepting and in other ways less accepting of scope. Based on the way that I was claiming he insisted that somewhere in the universe there might be a plasmid that fit the limitations. An important limitation was that the organisms did not exchange genetic information. This is not as clear today as it was in those days. In any event, we finally prevailed and he gave up on the universe rejection.

As you recall in the '70s, it was unclear that living matter could be claimed. The plasmid should have been allowed, but viruses added an additional aspect. Tannenholz had no problem with the method claims so we pursued those until the Chakrabarty case came down. At that point we could claim living cells with the constructs as patentable subject matter and most of the issues of novelty and scope had been resolved during the prosecution of the method claims. Since it would be the transformed cells that made product, from a licensing standpoint it was desirable to have claims to the cells.

Once the licensing program was launched, people started asking for the file history. Niels Reimers requested that I provide copies to those inquiring. After the second copy I informed Reimers that my office was not a copying service and that I would provide him with a complete copy and he could provide the copies. After making a couple of copies he decided that Office of Technology Licensing was not a copying service and inquired whether we could have the PTO open the file and let the potential licensees make their own copies. The PTO graciously agreed and we opened the file. Subsequently, there was an issue of inventorship. When the case was originally filed, under the rule of In re Katz I believe, I sent letters to all of the other authors of the three articles asking them to waive any inventorship interest. Of the nine inquiries, one agreed and the others either did not respond or sent unkind letters about the inventors and Stanford's filing of the application. One professor claimed joint inventorship. I did not pursue this avenue any further, but chose to swear back of the references. The one professor pursued his claim with his Office of Technology Licensing and wrote to me and I requested that he provide me with information supporting the claim. At this point we decided that it would be provident to close the file. Wegner opposed unsuccessfully on the grounds that once the door was open, there was no right to close it. The PTO recognizes the applicant's right to open and close the file. The upshot of the inventorship claim was that I was reprimanded for not bringing it to the PTO's attention, but nothing further came of it as I had asked for support for the allegation and it had not been forthcoming. It is still my contention that unless I have some basis for assuming that someone alleging coinvention has at least a colorable basis, I have no duty to bring the allegation to the attention of the PTO. Furthermore, such individual has an opportunity to bring the claim into court, where the facilities for evaluating such allegation are far greater than at the PTO.

The issue came up whether we should file a terminal disclaimer for the plasmid and cell cases. It was my opinion that we should not, but the client overruled me. There is this tension among academic licensing organizations that their original purpose for existence was to see that technology was exploited commercially. In those instances where the technology would not be exploited without a patent filing, then the technology would be lost. In the case of cloning, it was obvious from the outset that everyone would use and exploit the technology whether a patent existed or not. In fact, there was some grumbling from industry that this was a tax on the industry from an invention made with government money. The grumbling was never very loud and I think that the industry recognized the enormous contribution to their success that academia provided. Furthermore, many of the small companies were founded by academicians and were in no position to be hostile, since their companies were frequently founded based on inventions they made at the universities.

Ultimately, the patent realized about $300 million in revenues.

 


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