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Genetic Testing: An Analysis of US Patent Trends
(Genetic Testing: Dead Duck or Golden Goose)
January 2002

This report was written after analysis using what would now be called prototype systems. None the less, the answers that were derived from the analysis proved accurate for nearly four years after it was written. This report, while very dated, is still available from MarketResearch.com.

As you read the following, remember that it is January 2002 as this was written!

      Background.

The Human Genome Project changed the rules for genetic testing, and inspired development of new analytical technologies led by the nucleic acid array and amplification methods. It fostered renewal for "older" detection technologies such as fluorescence and chemiluminescence. As a result of the changes, speculation about next steps and future developments abound.

A genetic test consists of four major steps:
      (1) sample processing to separate DNA or RNA from other cellular materials,
      (2) amplification to produce more copies,
      (3) detection in which appropriate products of the amplification are measured, and
      (4) results are calculated using algorithms to give an analytical result.
For each step, devices and systems have been developed to enable the step to be performed. But, which ones are really ready for product development?

      Purpose of the Study.

The purpose of this report is to determine which technology development options are sufficiently advanced to support the claims made for product development in genetic testing.

To meet expectations, fully integrated, cost-effective solutions for genetic testing are needed. For fully integrated, new products to emerge, technology to run each step in a genetic test must be ready for commercial development, but which technology elements of a genetic test are really ready for commercialization? Which companies own leading or lagging technologies. How will the new area of genetic testing develop?

      Sample Purification and Preparation Observations.

Over 190 U.S. patents describe sample purification methods. Sample purification technologies can be divided into several areas for study: (1) integrated and microfluidic devices, (2) adsorption-elution chromatographic methods, (3) microparticle based methods, (4) electrophoresis methods and (5) formulations primarily for nucleic acid precipitation. There are four technologically distinct approaches to separating DNA or RNA from other cellular materials, the first step in performing a genetic test, and two major areas of device development. However, none of the approaches are completely dominant.

The oldest methods of nucleic acid purification describe formulations for selective precipitation of DNA or RNA, freeing the nucleic acids from destructive enzymes and other cellular debris. Key area participants include Becton, Dickinson and Company, AVI BioPharma, The Genetics Institute, E. I. du Pont de Nemours and Company, and Ambion.

In contrast to capillary electrophoresis, preparative electrophoresis for DNA or RNA sample purification is a small, undriven area. Some early intellectual property in the area belongs to Lifecodes, but Invitrogen and Perkin-Elmer have explored the area as well.

genetic testing bar chart 1

Technology developments using microparticles to purify nucleic acids has occurred fairly recently. Activity in the approach is growing fairly rapidly, making it a technology to watch carefully. Since microparticles are widely used in other integrated, automated diagnostic testing systems, application of microparticle nucleic acid would represent a small technology leap for many major diagnostics area participants. Toyo Boseki Kabushiki Kaisha, the Whitehead Institute for Biomedical Research, Promega, Gen-Probe and others have explored microparticles as nucleic acid separation media.

DNA or RNA separation methods based on column chromatographic separation methods is the largest area in nucleic acid sample preparation. Some recent technology developments describe attempts to automate sample purification by chromatographic methods. Becton Dickinson, Quiagen and Transgenomic have been major participants in the area, but a host of other players have explored the approach.

Technological development of devices designed to automate sample preparation or to integrate sample preparation with other steps in genetic testing are in a very early stage of development, primarily exploration. Membranes and ultrafilters are most often used as part of other devices. Whatman, Schleicher & Schuell, Becton Dickinson, Nanogen, Roche and a large number of smaller companies have explored integration.

Technology development for sample processing is a fragmented area, and several future paths are possible. However, the area to watch is microparticle-based separations. Developments in sample purification and in integrating sample purification with other steps in genetic testing could be a technological bottleneck that slows full implementation of genetic testing

      Amplification Technologies.

PCR (polymerase chain reaction) is by far the most prevalent nucleic acid amplification method described in the U.S. patent literature. PCR is a core technique in genetics and has many applications outside medical diagnostic testing. The over 500 PCR patents that are relevant to the diagnostics area were sifted from thousands of patents that mention PCR in titles, abstracts or claims. While PCR is the most prevalent amplification method, other amplification methods include the ligase chain reaction, rolling-circle amplification and strand displacement amplification. Patenting leaders in amplification technology include Abbott, Becton Dickinson, Hoffman LaRoche, J&J Clinical Diagnostics, Perkin-Elmer, and Roche Molecular Systems.

Amplification technologies are the second largest area in the study. The patenting pattern for PCR indicates a maturing technological area. The PCR area appears to be split into several technological focus areas, each of which also appears to be technologically mature. In a mature area, new patents are expected to focus on improvements but not on large technology leaps. Rolling Circle Amplification and Strand Displacement amplification methods appear to be amplification improvement methods that bear watching to see if they offer significant improvements over standard PCR methods.

In a mature area, investment opportunities exist primarily with technology improvements. Thermal cycling, a key technological element of PCR methods, is an evolving area. Thermal cycling times limit the throughput of PCR, but investigation of alternatives to thermal cycling is still small emerging research area. However, if successful, isothermal amplification methods could revolutionize testing.

Surprisingly, only a few patents specifically describe contamination control methods, a widely acknowledged problem in PCR and other amplification methods. Organizations with solutions to contamination control could dramatically influence the speed of commercialization of genetic testing. In the amplification area, there is an evolving focus on miniaturization and integration of amplification steps with microfluidic or capillary devices. Abbott Laboratories, Affymetrix, Becton Dickinson, Boston University and Caliper Technologies are key players in this area, but other organizations with the requisite skill could play a major role in this evolving area.

Homogeneous assay methods that do not depend on arrays are a hidden theme in the amplification patent area. Many patents mention homogeneous assays in their claims. Since homogeneous assays depend on technologies that are similar to existing clinical chemistry systems, they may represent a direct pathway into the clinical chemistry laboratory after appropriate "markers" are discovered by expression analysis studies. Homogeneous assays appear to represent a major alternative to more expensive array technology. Homogeneous assay methods appear to represent a "sleeper" technology.

      Major Detection Technologies.

Over 600 patents represent core detection method patents. Detection method patents can be divided into several broad areas for further study: (1) intercalation methods, (2) chemiluminescent methods, (3) fluorescent methods and (4) alternative detection methods which include mass spectrometry, capillary electrophoresis, Raman, surface plasmon resonance and atomic force microscopy. Patenting activity describing intercalation methods appears strong, but the current strong growth is primarily due to improvements in the rate of patent examination.

Fluorescence and chemiluminescence are the detection methods mentioned most often in U.S. patents describing genetic testing methods. Fluorescent detection methods have been combined to form hybrid methods with interacalation and chemiluminescence. Fluorescent and chemiluminescent detection methods have a long patenting history, and some sources for early patent art might be surprising- Amoco, Enzo Biochem, Cetus, Du Pont, Perkin-Elmer, Miles and MediSense.

Patenting activity in mass spectrometry is increasing slowly, but patenting rate increases in other alternative detection methods appears to be due more to faster processing of patent applications recently than to real increases in the patenting rate.

Patenting in major detection technologies is the largest and most complex patent group in the study. As a result of the complexity, investments in detection methods must be carefully placed to derive any significant competitive benefit. Fluorescence and chemiluminescence appear to be poised to dominate near-term developments. The future role of mass spectrometry is not currently clear, but it does not appear to be ready to replace fluorescence or chemiluminescent detection methods any time soon. Raman, SERS and AFM appear to be research tools, but seem unlikely to play a role in the evolution of genetic testing technology. Detection technology improvements that facilitate multiple, simultaneous assays could positively impact the future direction of genetic testing technology.

      Supporting Technologies.

Supporting technologies include nucleic acid array technologies, nucleic acid placement methods, covalent and other attachment methods, capillary electrophoresis, microfluidics, and integrated systems. Over 440 core technology patents were identified and studied for this report. For study, the area can be divided into the following groups: (1) covalent coupling methods, (2) arrays and solid supports, (3) nozzles, jetting and droplet formation methods, and (4) channels and capillaries. Patenting activity in array technologies appears to have slowed recently, suggesting that a reorganization of the area is taking place. Patenting activity leaders in the area include Affymetrix, Affymax, Aglient, Caliper, Hewlett-Packard, and the University of California

The patenting pattern in array technologies suggests a maturing technology area. In a maturing area, technology improvements can be expected, but investments must be carefully placed to derive competitive benefits. Key next steps for array technology might be devices for low cost array production, fully self-contained fluidic systems, integrated devices & instruments and novel, low cost solid supports. It appears that the supporting technologies area is ready for to "shake out" with winning technology emphasizing flexibility and low production costs.

      Algorithms and Bioinformatics.

Calculations or algorithms are used to convert signal data to concentration information and to relate concentration information to a disease diagnosis. The calculation and algorithm area can be divided into several areas for study: (1) signal processing, (2) data mining, (3) databases and (4) other methods.

Over 200 U.S. patents describe algorithms, database applications or statistical methods that appear to be central to medical diagnostic and genetic testing methods. Overall, patenting activity has increased since about 1995. However, patenting activity is strongest among patents describing methods to retrieve sequence information from a database or to compare results to data stored in a database. The major data mining tool in the area is the neural network. Markov models, Bayesian method and fuzzy logic are much less frequently mentioned than might have been expected from other published literature. Area patenting leaders include Affymetrix, Applied Spectral Imaging, Curagen, Hitachi and the University of California.

Patenting activity in algorithms and bioinformatics is the second smallest area studied. In size, the algorithms and bioinformatics areas is just slightly larger than sample processing, but the impact of the algorithm and bioinformatics area on genetic testing in medical diagnostics is smaller than for sample processing. The area's impact is limited because many of the patents in this area are more focused on sequence detection and managing databases than on actual calculations that are central to processing data for genetic testing.

Signal processing and "simple" calculation algorithms are a small subset of algorithm patents. Both areas are small and emerging slowly, with little "drive" behind them. While the areas are small and undeveloped, they are important to genetic testing measurements. Improvements in signal processing methods that are specifically tailored to genetic testing could provide new products with some useful, unique features.

Applications of powerful statistical methods to array signal data is in an early phase, and improvements seem likely. Organizations with the skills to utilize or to tailor advanced statistical methods to array signal data could benefit. As genetic testing matures further, the algorithms and bioinformatics linkages could be substantially more important that it appear to be in the near-term future.

      Hidden Factors and Emerging Trends.

Research suggests that there may be fewer genes than were originally expected. As a result, processes for determining gene expression will be more important than originally expected. Technology developments for gene expression are already beginning to appear in the patent literature, anticipating the completion of the human genome project.

Homogeneous methods, a hidden theme in genetic testing technology developmnet, represent assay methodology that is equivalent to current clinical chemistry assay methods. Since these methods are compatible with current clinical chemistry instruments, we believe that homogenous methods will ultimately be winners over arrays as more a detailed correlation between genetic markers and disease states emerges.

Isothermal amplification is a method that bypasses the slow heating and cooling steps required by PCR, the dominant amplification method. If successful, this trend also leads toward assays that can be run at room temperature and potentially in a standard clinical laboratory instrument.

      Summary & Main Conclusions as of 2002

R&D investments in genetic testing have been heavily focused on development of amplification and detection technologies and on supporting devices (Fig.1), resulting in mature technology approaches that are likely to dominate near-term commercial product developments. For example, array technology has been aggressively pursued and is now approaching technological maturity. PCR is clearly the dominant amplification technology. Fluorescence and chemiluminescence are clearly dominant detection systems. Challengers such as rolling-circle amplification or mass spectrometry are still trying to emerge as alternatives, but must overcome the momentum of the dominant methods.

genetic testing bar chart 1

Sample processing technology and algorithms have received little R&D investment focus recently and may limit the type of near-term products that can emerge. In sample processing, purification by older column chromatography methods and by newer microparticle based methods are competing, and mircroparticle based methods seem the likely winner. Commercial developments in algorithms are primarily focused on signal processing issues.

Other hidden trends such as homogeneous assays or isothermal amplification may eventually alter the development path for genetic testing, but not without additional development.

Research Area Focus Recommendations
Near-term (as of 2002) research in genetic testing should address issues that currently limit the development of genetic testing including:
    - Automation for sample preparation,
    - Contamination control in amplification,
    - Initial system integration
    - Signal processing.
    - Array quality to reduce need for sophisticated signal processing methods.

Mature Research Areas to Avoid
Past research as addressed these now mature technology areas
    - Amplification - PCR dominates
    - Detection as fluorescence, chemiluminescence dominate
    - Array developments

      Projected Evolution of Genetic Testing as of 2002

Taken together, the observations lead to the expectation that genetic testing will continue to evolve along a path leading toward one-up assays that can be run in the clinical laboratory. Market forces for cost containment and reduced reimbursements support the expectation. It seems likely that array technology and expression analysis will likely highlight new markers in a research setting, but they seem unlikely to play an overwhelming role in routine clinical laboratory testing in the near future.

Expected Evolution of Genetic Testing as of 2002

genetic testing chart 3
      ADDED NOTE:

This study was conducted almost nine years ago as a system test. The predictions contained in the study have proven remarkably accurate. Indeed, experts have told us that he area was still developing as we expected even four years later!

The heart of this story is that with MEASUREMENTS of technology trends, you can see well into the future. Isn't a warning of 3-4 years enough time for you or your company to see a disruptive signal and make plans for the change that is coming?

Analysis of technology trends can do the same for you in your industry.