Combination therapy patents: a new front in evergreening

Garth W. Strohbehn; Alec J. Kacew; Daniel A. Goldstein; Robin C. Feldman; Mark J. Ratain

doi:10.1038/s41587-021-01137-6

Combination therapy patents: a new front in evergreening

Garth W. Strohbehn, Alec J. Kacew, Daniel A. Goldstein, Robin C. Feldman, Mark J. Ratain^*

^*Corresponding author for this work

Clinical Departments

Research output: Contribution to journal › Comment/debate

Original language	English
Pages (from-to)	1504-1510
Number of pages	7
Journal	Nature Biotechnology
Volume	39
Issue number	12
DOIs	https://doi.org/10.1038/s41587-021-01137-6
State	Published - Dec 2021

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@article{7ac80e6fb075443bb2d4794b20d62bf6,

title = "Combination therapy patents: a new front in evergreening",

author = "Strohbehn, {Garth W.} and Kacew, {Alec J.} and Goldstein, {Daniel A.} and Feldman, {Robin C.} and Ratain, {Mark J.}",

note = "Funding Information: to achieve FDA approval, rather than identify truly unexpected or scientifically novel results that would overcome obviousness concerns. While such approvals will yield significant financial rewards for the drug sponsor(s), they should not result in extension of exclusivity in the absence of a demonstration of non-obviousness through the discovery of unexpected results. In truth, encouraging combination patents and RCTs that do not aim to identify unexpected results carries societal costs. First, the limited resources that can be dedicated to research and development efforts are directed away from the truly innovative approaches that represent the constitutional goal of the patent system and toward the commercialization of combinations that are, in the context of oncology{\textquoteright}s prior art, non-innovative. Second, even if VEGF–IO patents were to be invalidated in court, the time and expense required to challenge them often deters competitors from entering the market, interfering with the natural competitive forces expected to discipline high prices4. In short, this new frontier in evergreening raises serious societal concerns and requires coordinated action from all involved parties — from the end users who have demand for these products and the government-supported entities that enable patent-seeking research rather than true innovation, through to the executive branch entities responsible for conferring patents. Physicians, as end users of combination therapies, bear a societal responsibility to be thoughtful producers and consumers of biomedical research — industry-sponsored or not. As with any therapy, physicians should reflect on the designs of the relevant combination therapy clinical trials. In the context of cancer, oncologists need to disabuse themselves of the notion that {\textquoteleft}more therapy is better and in the best interests of the patient{\textquoteright}. Learning health systems would be wise to assess the real-world outcomes of patients treated with combination therapies, especially as the gap between performance as observed in clinical trials versus real life yawns. Finally, disclosure of the shortcomings of clinical trial design is an absolutely necessary component in the desired goal of clinical care — shared clinical decision-making. Clinical trialists and institutions have critical roles in the current pharmaceutical research and development landscape; it is this infrastructure that enables both innovative and non-innovative research. Realizing that the potential benefits of a clinical trial redound to patients other than the ones for which they care, clinical trialists must ask themselves, “Is the trial on which I am proposing to enroll patients something new or is it an incremental step?” It is unlikely physicians can do this alone, but demanding more from the research that we and others design and enact is a good first step, along with thoughtful skepticism toward certain types of patent claims. Similarly, the academic research infrastructure, as well as the cachet, on which many non-innovative clinical trials rest is supported in no small part by federal grants. Within the context of oncology, the National Cancer Institute designated 53 Comprehensive Cancer Centers in the United States, with federal grant support (P30) exceeding US$265 million in fiscal year 2020 (ref. 49). Incorporating review of the relative amounts of industry-versus non-industry-sponsored research activity occurring at a given cancer center in the NCI P30 grant renewal process may help to promote truly innovative research. The concept of taxpayers {\textquoteleft}paying twice{\textquoteright} for drug development — once through government-funded research and again in the form of high drug prices — has gained traction during the COVID-19 pandemic and should be seriously considered. As the guardian of the patent and drug-making processes, coordinated federal action on the part of the US Patent and Trademark Office (USPTO) and FDA is important. As the prior arts of medicine{\textquoteright}s subspecialties become increasingly complex, the case for inter-agency collaboration between the USPTO and FDA becomes stronger. The FDA has the capacity to provide information about all registered clinical trials, fully informing the prior art and context that the USPTO requires to make its determinations. The FDA also has a supply of experts who can provide additional perspective for USPTO examiners, who are rarely (if ever) clinicians (for example, physicians, pharmacists) or pharmaceutical scientists — FDA experts would be, to a first approximation, the government{\textquoteright}s best proxy for a well-informed POSITA. In addition, the USPTO is optimally positioned to communicate to researchers and industry the requirements for patentability and to issue guidance on what constitutes unexpected results (positive or negative) in clinical trials. The challenge in designing interagency cooperation is to ensure that the process is meaningful, rather than pro forma or simply burdensome. Fortunately, the USPTO has a model in place to better inform prior art determinations. In 2019, USPTO director Andrei Iancu reported to the Senate Judiciary Subcommittee on Intellectual Property that the USPTO was piloting projects to help examiners better identify prior art by collaboration between multiple USTPO examiners, as well as examiners from foreign patent offices50. This project could be expanded to include expertise closer to home — specifically at the FDA. Such guidance for the USPTO is in the interests of both drug developers (by providing a measure of certainty) and the public (by enhancing the risk–benefit calculus of biomedical research). Similarly, any regulatory standards that emerge at the USPTO could be incorporated by the FDA into its oversight of clinical trials and more fully inform its safety and efficacy determinations. This would allow both agencies to better carry out their mandates in serving the public interest.",

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doi = "10.1038/s41587-021-01137-6",

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volume = "39",

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AU - Ratain, Mark J.

N1 - Funding Information: to achieve FDA approval, rather than identify truly unexpected or scientifically novel results that would overcome obviousness concerns. While such approvals will yield significant financial rewards for the drug sponsor(s), they should not result in extension of exclusivity in the absence of a demonstration of non-obviousness through the discovery of unexpected results. In truth, encouraging combination patents and RCTs that do not aim to identify unexpected results carries societal costs. First, the limited resources that can be dedicated to research and development efforts are directed away from the truly innovative approaches that represent the constitutional goal of the patent system and toward the commercialization of combinations that are, in the context of oncology’s prior art, non-innovative. Second, even if VEGF–IO patents were to be invalidated in court, the time and expense required to challenge them often deters competitors from entering the market, interfering with the natural competitive forces expected to discipline high prices4. In short, this new frontier in evergreening raises serious societal concerns and requires coordinated action from all involved parties — from the end users who have demand for these products and the government-supported entities that enable patent-seeking research rather than true innovation, through to the executive branch entities responsible for conferring patents. Physicians, as end users of combination therapies, bear a societal responsibility to be thoughtful producers and consumers of biomedical research — industry-sponsored or not. As with any therapy, physicians should reflect on the designs of the relevant combination therapy clinical trials. In the context of cancer, oncologists need to disabuse themselves of the notion that ‘more therapy is better and in the best interests of the patient’. Learning health systems would be wise to assess the real-world outcomes of patients treated with combination therapies, especially as the gap between performance as observed in clinical trials versus real life yawns. Finally, disclosure of the shortcomings of clinical trial design is an absolutely necessary component in the desired goal of clinical care — shared clinical decision-making. Clinical trialists and institutions have critical roles in the current pharmaceutical research and development landscape; it is this infrastructure that enables both innovative and non-innovative research. Realizing that the potential benefits of a clinical trial redound to patients other than the ones for which they care, clinical trialists must ask themselves, “Is the trial on which I am proposing to enroll patients something new or is it an incremental step?” It is unlikely physicians can do this alone, but demanding more from the research that we and others design and enact is a good first step, along with thoughtful skepticism toward certain types of patent claims. Similarly, the academic research infrastructure, as well as the cachet, on which many non-innovative clinical trials rest is supported in no small part by federal grants. Within the context of oncology, the National Cancer Institute designated 53 Comprehensive Cancer Centers in the United States, with federal grant support (P30) exceeding US$265 million in fiscal year 2020 (ref. 49). Incorporating review of the relative amounts of industry-versus non-industry-sponsored research activity occurring at a given cancer center in the NCI P30 grant renewal process may help to promote truly innovative research. The concept of taxpayers ‘paying twice’ for drug development — once through government-funded research and again in the form of high drug prices — has gained traction during the COVID-19 pandemic and should be seriously considered. As the guardian of the patent and drug-making processes, coordinated federal action on the part of the US Patent and Trademark Office (USPTO) and FDA is important. As the prior arts of medicine’s subspecialties become increasingly complex, the case for inter-agency collaboration between the USPTO and FDA becomes stronger. The FDA has the capacity to provide information about all registered clinical trials, fully informing the prior art and context that the USPTO requires to make its determinations. The FDA also has a supply of experts who can provide additional perspective for USPTO examiners, who are rarely (if ever) clinicians (for example, physicians, pharmacists) or pharmaceutical scientists — FDA experts would be, to a first approximation, the government’s best proxy for a well-informed POSITA. In addition, the USPTO is optimally positioned to communicate to researchers and industry the requirements for patentability and to issue guidance on what constitutes unexpected results (positive or negative) in clinical trials. The challenge in designing interagency cooperation is to ensure that the process is meaningful, rather than pro forma or simply burdensome. Fortunately, the USPTO has a model in place to better inform prior art determinations. In 2019, USPTO director Andrei Iancu reported to the Senate Judiciary Subcommittee on Intellectual Property that the USPTO was piloting projects to help examiners better identify prior art by collaboration between multiple USTPO examiners, as well as examiners from foreign patent offices50. This project could be expanded to include expertise closer to home — specifically at the FDA. Such guidance for the USPTO is in the interests of both drug developers (by providing a measure of certainty) and the public (by enhancing the risk–benefit calculus of biomedical research). Similarly, any regulatory standards that emerge at the USPTO could be incorporated by the FDA into its oversight of clinical trials and more fully inform its safety and efficacy determinations. This would allow both agencies to better carry out their mandates in serving the public interest.

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Combination therapy patents: a new front in evergreening

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