The Most-Cited Research Papers in Patents Reveal the Science Behind Modern Innovation
More than 50 years ago, biochemists Georges Köhler and César Milstein helped launch a medical revolution. In a landmark 1975 paper, they described a method for mass-producing monoclonal antibodies—proteins engineered to identify and bind to highly specific molecular targets.1
Their research transformed biological science and laid the foundation for blockbuster treatments for cancer, autoimmune diseases and infectious conditions. The paper concluded that antibody-producing cell cultures “could be valuable for medical and industrial use.” That prediction proved remarkably accurate.
Köhler and Milstein’s Antibody Research Became a Patent Powerhouse
Köhler and Milstein’s work has been cited in more than 17,000 academic publications, placing it among the 1,000 most-cited scientific studies worldwide. Its influence is even more pronounced in industry: the paper has appeared in more than 13,000 patent applications.
That ranking places it fifth among scholarly works most frequently cited in patents—documents filed to obtain legal protection for potentially commercial inventions.
Patent citations provide one way to track how academic discoveries move into commercial products. To examine this connection, Nature analyzed the research papers cited most often in patents. The results highlight the scientific foundations of biotechnology, pharmaceuticals, software and agriculture.
Some of the findings are expected. Köhler and Milstein’s antibody research is clearly linked to major commercial developments, and the scientists shared the 1984 Nobel Prize in Physiology or Medicine. Other Nobel Prize-winning discoveries also appear among the most patent-cited studies.
However, the rankings also contain surprises. Some frequently cited papers have relatively little influence in academic literature, and some researchers are unsure why their work appears in so many patent applications.
“Causality in knowledge flows between scholarly work and patents is not a simple matter,” says Richard Jefferson, founder and former director of The Lens Project, a database of patents and scientific publications.
Even with these limitations, patent-citation analysis provides an important insight: much of the research most influential to industry was produced through publicly funded science.
Why Patent Applications Cite Scientific Papers
References in patents serve a different purpose from citations in academic papers. To receive a patent, an inventor must demonstrate that an invention is new and would not have been obvious based on existing knowledge.
For this reason, patent applicants—or the lawyers and technology-transfer specialists preparing the application—typically list publications and previous patents that describe the current state of the field. Patent examiners can also add references when assessing whether an invention meets legal requirements.
These references often appear on the first page of a patent application, sometimes called the front page. Ideally, they create a record of the scientific and technological knowledge leading to an invention.
In practice, the system can produce unusual results. Well-written reviews and technical commentaries may be cited more frequently than original breakthrough studies because they offer patent examiners a clear explanation of an established method or concept.
Reviews Can Outrank Breakthrough Discoveries
A 1977 review by scientists at Pfizer ranks second among the research works most frequently cited on the front pages of patents, according to data from The Lens. The article explains how drugs can be converted into salt forms. By March, it had received more than 16,000 patent citations but only a few hundred citations in academic publications.
Another example is a 1994 antibody review by biochemist Peter Colman. The paper has only five citations in academic literature but has been referenced more than 4,467 times in patents, placing it 30th in the patent-citation ranking.
Colman’s review explains how changing a single amino acid in an antibody’s protein sequence can produce unpredictable changes in the antibody’s function. That information is particularly relevant to patent examiners.
In the past, patent applicants could sometimes seek protection not only for the antibody they described but also for numerous structural variants. As researchers learned that small sequence changes could alter an antibody’s activity, patent examiners began limiting protection more narrowly to the structures and sequences specifically disclosed.
As a result, Colman’s article became a useful reference for examiners evaluating the scope of antibody patents.
These examples show why patent citations should be interpreted carefully. A paper’s high citation count does not necessarily prove that it directly caused a commercial invention. However, large-scale datasets can reveal broader patterns in how research influences industry.
Publicly Funded Research Drives Commercial Innovation
Economist Adam Jaffe, who studies technological innovation, has emphasized that citations in patents may reflect legal requirements as much as scientific inspiration.
Jaffe worked with The Lens team to develop In4M, a ranking system designed to measure the influence of academic research on innovation. In a 2018 study, the system showed that Scripps Research in La Jolla, California, had the highest number of patent citations per research article after accounting for differences between scientific fields.4
Köhler and Milstein’s antibody work illustrates both the benefits and complications of publicly funded research. Their study was supported by the Medical Research Council Laboratory of Molecular Biology in Cambridge, UK.
Although Milstein reportedly spent considerable time encouraging the MRC to patent the discovery, the organization declined. Researchers in the United States eventually patented the technology and received the associated royalties.
Why Antibody Research Dominates Patent Citations
Most of the scientific papers most frequently cited in patents relate to the life sciences. This reflects the size of the biotechnology and pharmaceutical industries, as well as the tendency of some scientific disciplines to cite academic research more heavily in patent applications.
More than a dozen of the top 100 patent-cited papers describe methods for producing, modifying or analyzing antibodies. Many of these studies addressed technical obstacles that initially prevented antibodies from becoming practical medicines.
Humanized Antibodies Made Biologic Drugs Possible
Köhler and Milstein produced antibodies using mouse cells. Although these antibodies were effective research tools, the human immune system could reject them when used repeatedly as medicines.
Later research solved this problem by creating humanized antibodies. Scientists grafted the small portion of a mouse antibody responsible for recognizing a target protein onto a human antibody framework. The first papers describing this approach rank ninth and 11th among the studies most cited on patent front pages.6,7
Other highly cited studies introduced single-chain antibodies—smaller, simpler antibody fragments. These papers rank 12th and 16th on the list.8,9
Two 1991 publications describing methods for screening large collections of antibodies to identify the strongest binders rank 20th and 21st.10,11 This method, known as phage display, became a major tool for antibody discovery and development.
Phage Display Led to Major Drug Discoveries
Biochemist Greg Winter, who was also based at the MRC Laboratory of Molecular Biology, shared the 2018 Nobel Prize in Chemistry for his work on phage display.
Winter founded the company that developed Humira, or adalimumab, an injectable antibody treatment for inflammatory diseases. The drug has generated more than US$200 billion in sales. He also received royalties in the past from Keytruda, or pembrolizumab, a leading cancer treatment and one of the world’s best-selling medicines.
Winter is one of the most frequently represented authors in The Lens’ list of the 100 most patent-cited papers. He co-authored nine studies on the list.
Paul Carter, a biochemist at Genentech, estimates that more than 200 distinct antibody-based medicines have been approved, alongside approximately 400,000 scientific papers and 16,000 patents involving antibodies.
One of those medicines is Herceptin, an anti-cancer treatment developed from work co-authored by Carter. The research was published in 1992 and ranks 41st among the most patent-cited studies.12
“There aren’t many technologies which are so profoundly impactful in a relatively short period of time,” Carter says.
BLAST Is the Most-Cited Research Tool in Patents
Antibody research is not the only major scientific influence on patented technology. Eight papers in The Lens ranking describe methods for comparing DNA or protein sequences.
Sequence-comparison tools help researchers determine whether a DNA segment or protein is genuinely new. They can also reveal evolutionary relationships and provide clues about biological function.
The 1990 publication introducing the Basic Local Alignment Search Tool, better known as BLAST, is the most frequently cited scientific paper on the front pages of patents.13 It is also one of the most-cited studies in academic research.
BLAST allows users to submit a DNA or protein sequence and rapidly search genetic databases for similar sequences. The software then aligns the matching sequences with the original query.
“It’s like Google for DNA and protein,” says Stephen Altschul, a co-author of the original BLAST paper.
Two additional studies on sequence comparison—including a 1997 update to BLAST—rank third and fourth among the most patent-cited papers.14,15
When early versions of BLAST were released, users received the software on CD-ROM. At the time, biotechnology companies were beginning to patent naturally occurring genes, a practice later prohibited by the US Supreme Court.
Researchers recognized that genomics was entering a period of rapid commercial growth. More than three decades later, BLAST remains essential for identifying and analyzing DNA and proteins.
By 2023, the global market for biologic medicines—including antibody therapies—had exceeded $400 billion. Despite major changes in molecular biology and biotechnology, BLAST continues to be widely used.
Scientific Papers Cited Inside Patent Text
Scientific references do not appear only on the front page of a patent. They can also be included throughout the body of the document. These are known as in-text patent citations.
Inventors often add in-text citations to explain the origins of an idea or to provide background information that helps a skilled reader reproduce the patented method. Unlike front-page references, these citations are usually embedded in sentences rather than presented in an organized list.
In-text references can also be difficult to identify. A patent might mention an author and year—for example, “Smith 1992”—without providing enough information to connect the reference to a specific publication.
Machine-learning tools have made it easier to locate and match these citations. One project, Reliance on Science, is led by entrepreneurship researcher Matt Marx of Cornell University and computer scientist Aaron Fuegi of Boston University.
The researchers found that slightly more than 30% of scientific citations appear only in the body text of patents. These references would be missed by analyses that examine front-page citations alone.16
Ignoring in-text citations can significantly underestimate the commercial influence of academic research. One earlier study estimated that 31% of US National Institutes of Health grants had some commercial impact, based on whether related research papers were cited in patents. When in-text patent citations were included, the figure increased to 44%.
Different Databases Produce Different Patent-Citation Rankings
For its analysis, Nature examined a publicly available Reliance on Science dataset covering citations through 2023. The analysis identified the works most frequently referenced in patents overall and separated front-page citations from in-text citations.
The results were compared with data from The Lens. The two databases do not produce identical rankings because they use different source materials and extraction methods.
For example, multiple editions of Molecular Cloning: A Laboratory Manual, first published in 1982, collectively make it the most frequently cited work in the Reliance on Science dataset. However, the book does not rank as highly in The Lens data, apparently because many patent references were not linked to a formal scholarly-work record.
Despite these differences, both datasets identify similar leaders. Antibody research and biological software appear consistently among the most patent-cited scientific works.
Plant Science Has a Larger Commercial Role Than Front-Page Citations Suggest
The biggest differences between the datasets emerge lower in the rankings. Only two plant-biology papers appear among the top 100 works cited on the front pages of patents. When in-text citations are included, however, 28 plant-science papers enter the Reliance on Science ranking.
Many of these papers describe methods used in plant breeding, genetic engineering and the production of transgenic crops. Others focus on plant metabolism or biological mechanisms involved in disease resistance.
The strong presence of plant science in patent text is not surprising to patent professionals. Agriculture generates a consistent flow of patent applications, particularly in areas involving crop genetics and biotechnology.
CRISPR gene-editing technology provides one example. Although the medical applications of CRISPR receive significant media attention, agricultural uses are also commercially important. Corteva Agriscience, based in Indianapolis, Indiana, holds the largest number of US patents related to CRISPR technology. The company was formed following the merger of Dow and DuPont.
Patent attorneys suggest that plant-science papers describing biological techniques are frequently cited to direct readers toward essential methods. This may explain why such research appears more often in the body text of patents than on their front pages.
What Patent Citations Tell Us About Scientific Impact
Patent citations are not a perfect measure of commercial success. Some references are added because they satisfy legal requirements, while others are included by patent examiners rather than inventors. A highly cited review may be more useful for establishing the background of an invention than for demonstrating a direct scientific breakthrough.
Nevertheless, large-scale patent-citation analyses reveal clear trends. The most commercially influential research often provides practical tools, repeatable methods and technical foundations that can be adapted across industries.
Monoclonal antibodies, humanized antibody design, phage display, sequence-comparison software and plant biotechnology all demonstrate how publicly supported research can influence medicine, agriculture and global markets.
From Köhler and Milstein’s antibody-producing cells to BLAST’s ability to search genetic databases, the papers most cited in patents show that the path from academic discovery to commercial innovation is often built on methods that make future discoveries possible.
Source: www.nature.com