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Pipeline Shift

Thu, 07/03/2008 - 9:04am
Michael Fuller, MS, JD, Intellectual Property Analyst Irene Zajac, MS, Life Sciences Analyst Emma Palmacci, PhD, Portfolio Management Analyst Nerac, Inc.
The last two decades have seen a major shift in the type of therapeutic agents being developed for pharmacological applications, and the changes are far from over. This well-documented shift away from small molecule development in the therapeutic agent pipeline has come from the emergence of so-called large molecule therapeutics that live microorganisms synthesize.

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Even so, there are indications that it is not that simple. Small molecule development remains a significant aspect of Big Pharma's business, although large molecule development is taking a larger role. Beyond that, however, is the fact that biotech companies, which might be expected to focus on developing large molecule therapeutics, are also developing significant numbers of small molecule therapeutics.

The question is how much effort "Big Pharma" is investing in large molecule R&D, and alternatively, how much effort biotechnology companies are investing in small molecule R&D. A review of the patenting activity since 2003 of three representative companies from each sector provides answers. The rationale is that both sectors will tend to patent anything of possible value that emerges from their R&D efforts. By examining these companies’ patenting activity, it is possible to not only see where these companies were focusing their R&D efforts around the time of filing their patent applications and how their pipelines may look in the future. In addition, it is possible to gain insight into how these patented pharmacological agents, once commercialized, could impact the treatment of various diseases.

Figure 1. PCT applications filed by case study companies since 2003. (Source: Nerac)
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Figure 1. PCT applications filed by case study companies since 2003. (Source: Nerac)

Patent Cooperation Treaty (PCT) patent applications that were assigned to six prominent pharmaceutical and biotechnology companies and filed since 2003 and were compiled into an Excel spreadsheet using proprietary methods. The selected pharmaceutical companies—Pfizer, AstraZeneca, and Sanofi-Aventis—and the biotechnology companies—Amgen, Genentech, and Genzyme—all are developing small and large molecule therapeutics. In addition, each company's patent activity is vigorous;  all have active pipelines, and high revenues. These patent applications were futher segregated according to international patent classification (IPC) codes and disease states claimed. These patent references were then analyzed using Excel-compatible graphing programs to identify trends in patenting activity among the six companies of interest.

General trends emerge
PCT application filing activity for the six companies in the case study is shown in Figure 1. The pharmaceutical giants, AstraZeneca and Pfizer, each filed over 1,000 PCT applications since 2003. Sanofi-Aventis rounds out the top three, yet filed less than half the applications of its pharmaceutical counterparts. Biotechnology leaders Genentech and Amgen, along with the pharmaceutical company sanofi-aventis, filed similar numbers of applications. Genzyme filed the fewest PCT applications in the case study.

Figure 2. Total PCT filings for large molecule and small molecule therapeutics by case study companies. (Source: Nerac)
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Figure 2. Total PCT filings for large molecule and small molecule therapeutics by case study companies. (Source: Nerac)

The pharmaceutical group as a whole filed two to three times the number of PCT applications as the biotechnology group. Aside from corporate size, the difference could reflect corporate philosophy regarding PCT applications, since costs associated with national stage patent prosecution in multiple countries is very high. It is possible that biotechnology companies are filing more non-PCT applications to manage costs of applying for patents in multiple countries. Given the importance of patent protection for market success, it is unlikely that companies with lower filing numbers have an unwillingness to file patent applications. Relative budgets for patent filings may also vary between companies.

Figure 3. Five year (2003-2008) PCT filing trends for case study companies. (Source: Nerac)
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Figure 3. Five year (2003-2008) PCT filing trends for case study companies. (Source: Nerac)

For the whole group examined in this case study, PCT applications for small molecule therapeutics have increased gradually since 2003 (Figure 2). Large molecule applications have also risen, but the number is roughly one-fourth that of small molecule applications

When PCT filing trends for the six case study companies are viewed over time (see Figure 3), it is evident that Pfizer’s filings peaked in 2005 and dropped each year since. AstraZeneca’s filings dropped from 2004 to 2005 but have increased subsequently. Sanofi-Aventis’s filings almost doubled between 2005 and 2006 and then plateaued into 2007. PCT filings from the biotechnology company Amgen have risen steadily since 2005 compared to Genentech filings, which have generally risen year-to-year with the exception of 2007. Genzyme’s have remained at a low, but constant level.

Table 1. Case Study Companies
Pharmaceutical Companies
Pfizer
AstraZeneca
Sanofi-Aventis
 
Biotechnology Companies
Amgen
Genentech
Genzyme

Overall, the biotechnology companies are still leading in large molecule development, but all six companies are strong contenders in this market segment. As seen in Figure 4, patent filings were evenly dispersed among the companies in 2003 with the exception of sanofi-aventis. Since 2003, the three biotechnology companies have increased filings to about two times the total pharmaceutical filings. Amgen’s and Genzyme’s filings have risen steadily since 2003, while filings from Genentech, the largest biotech player, peaked in 2006 before dropping significantly in 2007. Pfizer’s filings are trending downward, consistent with the company’s overall PCT filings since 2005. Interestingly, sanofi-aventis, which came into the large molecule patent space in 2005, has steadily increased its development activity and has become leading player in this area in early 2008.

Figure 4. Large molecule therapeutics PCT filing trends for case study companies. (Source: Nerac)

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Figure 4. Large molecule therapeutics PCT filing trends for case study companies. (Source: Nerac)

Pharmaceutical and biotechnology company groups have very different track records for small molecule filings, as shown in Figure 5. Not surprisingly, the pharmaceutical companies dominate with more than 85 percent of the total filings in any given year. Within the group of biotechnology companies, Amgen has steadily increased its patent filings over time. Although Amgen still holds less than 10 percent of the total small molecule filings of all the companies studied, a visual comparison of Figures 4 and 5 shows that Amgen is the closest to having a 50-50 split between large and small molecule therapeutics in the pipeline. Genentech’s patent filings peaked in 2004, dropped dramatically in 2005, but have since increased slowly in the same irregular pattern seen with other Genetech filing trends.

Figure 5. Small molecule therapeutics PCT filing trends for case study companies. (Source: Nerac)
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Figure 5. Small molecule therapeutics PCT filing trends for case study companies. (Source: Nerac)

Clinical indications differ
The patent data in the database were segregated based on six clinical indications (Table 2) and combinations of those indications. Figure 6 illustrates the extent to which each indication claim or claim combination was made as a percentage of total claims. The graph presents the pairing of clinical indications with either small molecule or large molecule therapeutic drugs, as well as changes in this landscape over time.

Table 2. Clinical Indications
Central nervous system (CNS)
Metabolic
Inflammation
Cardiovascular
Cancer
Infectious Disease
In 2003, the primary indication claimed for large molecules was cardiovascular. However, large molecule cardiovascular claim filings virtually disappeared after 2003. No fewer than 25 percent of all large molecule claims since 2003 have been for cancer treatment, which in 2007 represented 43 percent of all claims and likely reflects development of antibody-based therapies. Claims for inflammation treatments alone or in combination with other indications are also prominent. Claims linking large molecules to CNS disorders appeared briefly in 2004 but dwindled significantly thereafter. We speculate that success rates were marginal due to inherent difficulties with transport of large molecules across the blood-brain barrier.

The most frequent indication claims for small molecules were inflammation, cancer and CNS disorders, totaling more than 50 percent of the claims each year. CNS indications will continue as the preferential domain of small molecules because of the relative ease with which they cross the blood-brain barrier compared to large molecules. The most frequently claimed combination of indications for small molecules was inflammation plus CNS, but the significance of this combination, if any, is unclear.

Figure 6. Clinical Indications for large molecules and small molecules from case study companies. (Source: Nerac)

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Figure 6. Clinical Indications for large molecules and small molecules from case study companies. (Source: Nerac)
When indication claims were categorized by assignee, a view of the white space among these companies becomes apparent. In Figure 7, small, large, and other therapeutics were segregated by company and single clinical indication. Data for drugs with multiple indication claims were excluded from this view. The biotechnology companies, Genentech, Genzyme, and Amgen have limited activity in cardiovascular, CNS, and infectious disease indications. The prevalence of large molecule therapeutics in the biotechnology companies’ pipelines explains the relative lack of activity in CNS because of the blood-brain barrier challenge. The lack of biotechnology company activity in infectious disease indications is surprising, however, given the ability of large molecule antibodies and vaccines to fight infection. Genentech and Genzyme are also light in metabolic disorder activity, whereas this appears to be a focus area for Amgen.

Figure 7 also illustrates how pharmaceutical company pipelines have more breadth (e.g., circles in more clinical indication cells) and more depth (more circles in each indication cell) than the biotechnology companies, due to their longer history of participation in the market. Infectious disease and cardiovascular indications were the least represented indications for sanofi-aventis and AstraZeneca, whereas Pfizer was least represented in metabolic disorder and cardiovascular indications. On the other hand, clinical indications for cancer, CNS, and inflammation appear to be crowded with small molecules.

Figure 7. Single clinical indications for large molecules (red) and small molecules (green) for case study companies. (Source: Nerac)
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Figure 7. Single clinical indications for large molecules (red) and small molecules (green) for case study companies. (Source: Nerac)
Across all six companies in the case study, the most patent white space occurs in drugs for cardiovascular and infectious disease indications. Biotechnology companies appear to be preferentially working on drugs with cancer and inflammatory disease indications. The pharmaceutical companies in this case study have broad balanced pipeline portfolios relative to clinical indications.

In conclusion, the patent data suggests a more measured approach towards large molecule drug development by the pharmaceutical companies than what was anticipated based on informal impressions of activities within each sector over time. The case study biotechnology companies lead large molecule development, but the pharmaceutical companies are strong contenders. The biotechnology companies were more aggressive filing patent applications for small molecule therapeutics than pharmaceutical companies were for large molecule therapeutics, though the pharmas continue to dominate small molecule development. Both small and large molecule therapeutics will find future applications in inflammation and cancer therapies. Small molecule drugs will continue to dominate central nervous system and infectious disease treatments. Based on market value projections, small molecule drugs will continue to dominate the market for the foreseeable future.

About the Authors
Michael Fuller is a USPTO registered attorney with a master’s degree in pharmacology and experimental therapeutics. As part of the Immunophilin biochemistry group at Guilford Pharmaceuticals, he focused on neurodegenerative diseases, enzyme cloning, and high-throughput assay development. He has authored or co-authored 28 scientific publications and abstracts.

Irene Zajac has 25 years of pharmaceutical industry experience, including work as a researcher or bench scientist at the National Institute of Environmental Health Sciences, Glaxo, Pfizer, Argonex, PRA International, and Spotfire. She is a member of the American Chemical Society and the Society of Competitive Intelligence Professionals.

Emma Palmacci, PhD, co-developed the first automated oligosaccharide synthesizer and researched new methods for the total synthesis of complex biomolecules such as heparin and chondroitin sulfate. She worked in the medicinal chemistry group at Thios Pharmaceuticals and has authored and co-authored publications in chemistry.

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