19 | 2月 | 2021 | 知的財産専門ニュースを随時更新
  • CAFC Affirms Section 112 Invalidation/ Non-Infringement in Synchronoss v. Dropbox Dispute

    On February 12, the U.S. Court of Appeals for the Federal Circuit (CAFC) affirmed a district court’s conclusion of invalidity under Section 112 and/or non-infringement in Synchronoss v. Dropbox. Synchronoss had appealed the district court’s decision that the asserted claims, which were “drawn to technology for synchronizing data across multiple devices” are either invalid under 35 U.S.C. Section 112 for indefiniteness, or not infringed.” Meanwhile, Dropbox cross-appealed, arguing that the…

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  • Gutting Patents Won’t Speed the COVID-19 Vaccine Rollout

    India and South Africa recently urged the World Trade Organization to suspend intellectual property protections for COVID-19 vaccines and treatments. The claim is that this would allow developing countries to manufacture “cheap” COVID-19 therapeutics and vaccines, hastening the end to the pandemic—at least, that’s what proponents claim. They’re wrong. Dangerously wrong. Gutting IP protections won’t make COVID-19 medications more readily available but it will set a terrible precedent that will…

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  • How can policymakers overcome the hurdles to scaling up antibody manufacturing?

    By Rachel Sachs, Jacob S. Sherkow, Lisa Larrimore Ouellette, and Nicholson Price

    In our last post, we introduced some of the clinical evidence supporting the use of therapeutic antibodies against COVID-19—including Regeneron’s casirivimab and imdevimab and Eli Lilly’s bamlanivimab—and analyzed the existing problems in the distribution and administration of those therapies. Even in just the last few weeks, further clinical evidence has supported the use of these technologies, leading the FDA to issue an additional emergency use authorization for Lilly’s bamlanivimab and etesevimab cocktail. In the near future, though, problems in administering our existing supply of these new drugs may give way to problems producing enough of them—a challenge that is also affecting the vaccine rollout. In this post, we consider the difficult manufacturing issues involved in the therapeutic antibody context (a subject we’ve previously explored regarding vaccines), and what might be done to address them.

    What production challenges arise with the large-scale manufacture of therapeutic antibodies?

    As we have explained, antibodies have been remarkably successful in treating diseases by specifically targeting certain foreign invaders. But antibodies are not simple chemicals that are easy to produce: they are complex proteins that are time-consuming and expensive to manufacture. Your immune system naturally produces antibodies in response to foreign bacteria and viruses; commercial antibody production attempts to replicate this biological process inside living cells.

    The antibody treatments authorized for COVID-19 so far are individual monoclonal antibodies (mAbs) or combinations of mAbs. The “monoclonal” in monoclonal antibodies means that they are produced from a single cloned B-cell line and thus only produce a single antibody. This gives them high specificity to a particular target. Polyclonal antibodies, by contrast, are produced by more than one cloned B-cell line, and thus produce a number of slightly different antibodies with greater target variability. The most common commercial production platform for mAbs is the fed-batch process, in which a closed batch of cells and culture medium is fed additional nutrients as they are consumed, after which the antibodies are isolated and purified. The biopharmaceutical sector is increasingly shifting toward continuous manufacturing processes, with encouragement from the FDA, although regulatory and scientific challenges remain.

    The hurdles to scaling up these processes for COVID-19 therapeutics have been long apparent. A June 2020 analysis from Duke’s Margolis Center for Health Policy noted that setting up new mAb manufacturing capacity typically takes years, and that “the fungibility of the mAb manufacturing capacity depends on the process mode and bioreactor type.” The authors argued that the “federal government could play a coordinating role,” including to help manufacturers of antibody treatments for COVID-19 “reallocate their capacity to the most promising therapies as clinical evidence emerges” without raising the “serious antitrust concerns” that such collaborations would normally raise. 

    Although the federal government didn’t invest in COVID-19 antibody treatments to the same extent as vaccines, in February 2020 it entered an agreement to support Regeneron’s preclinical and clinical COVID-19 treatment development. Then in July 2020 it provided Regeneron $450 million for large-scale manufacturing, supporting the at-risk manufacture of 300,000 doses of the casirivimab and imdevimab cocktail that were allocated to states after FDA authorization in November. The federal government also entered into an advance purchase agreement for Eli Lilly’s bamlanivimab ($375 million for 300,000 doses, with the option to pay $812.5 million more for 650,000 additional doses), although the agreement came only two weeks before authorization, making it less effective for encouraging at-risk manufacturing.

    The complexity of mAb manufacturing also increases costs. Regeneron’s and Eli Lilly’s drugs are cheaper than most antibody therapies, although the prices being paid by the U.S. government—over $1000 per dose for Eli Lilly’s bamlanivimab alone, not including the etesevimab that appears to make it more effective—place it out of reach of many low-income countries. These high prices and the difficulty of scaling manufacturing have raised distributional concerns that these drugs will be less available outside high-income countries. 

    Part of the reason mAb manufacturing is hard and expensive is that many of the process details are kept as trade secrets. The public information about manufacturing Regeneron’s and Eli Lilly’s cocktails is limited. FDA fact sheets indicate that like the majority of commercial mAbs, the antibodies authorized for treating COVID-19 are produced using Chinese hamster ovary (CHO) cell lines. We are unaware of more detailed information about the manufacturing processes—although if you want to see some shiny metal tanks, Lilly does provide B-roll footage of bamlanivimab manufacturing for reporters.

    How can policymakers help scale up antibody manufacturing?

    The most basic step in scaling up antibody manufacturing is recognizing that it is a worthwhile policy goal to pursue alongside other priorities. As noted above, policymakers under the previous administration prioritized the scale-up of vaccine manufacturing, but did not invest to the same degree in antibody manufacturing. In our view, this was a miscalculation. Weighing investment in vaccine versus antibody manufacturing, policymakers may have thought (correctly) that vaccines would be needed broadly to bring about the end of the pandemic, but that antibodies were less crucial, both because vaccines would diminish the need for effective treatments (as fewer people become ill) and because antibodies are merely one among many potential therapeutic interventions. This may be true, but investing in manufacturing scale-up for vaccines versus antibodies need not be an “either or” situation; rather, it is “both and,” especially given that we now have EUAs for multiple antibodies. Given the economic and human toll of COVID-19, we can afford to invest in both, particularly if investments in scaling up the manufacturing technology lead to broader innovations in biologics manufacturing.

    So how does that investment happen? For one thing, policymakers can try to drive knowledge sharing between antibody manufacturers. In the vaccine space, knowledge transfer has emerged as a stumbling block to rapid scale-up, especially on a global scale, though there are other hurdles, especially for the novel mRNA vaccines, involving specialized ingredients and equipment. Knowledge sharing is likely a more important limiting factor for antibody manufacturing, since antibody manufacturing has been going on in some form for decades, and many manufacturers thus already possess the ingredients and equipment needed. Sharing knowledge would allow other manufacturers to increase the supply of existing antibodies, and could also allow for increased understanding and better manufacturing generally (including of other antibodies). Incentives or mandates for increased information sharing could increase innovation and efficiency in antibody manufacturing (and potentially biologic manufacturing more generally), with possible benefits beyond the pandemic. There are some indications that information sharing is happening: six companies involved in therapeutic antibody development sought and received DOJ permission to share development and manufacturing information in August (defusing antitrust concerns). Such collaborations should be lauded and pursued.

    More immediately, policymakers should seriously consider employing global purchasing initiatives for biologic therapies, akin to those of COVAX, the international consortium for global purchasing of vaccines. IAVI, the nonprofit famous for its work on securing and distributing HIV therapies in Africa and India, recently announced it was working on such an initiative in partnership with the Wellcome Trust for biologic therapies, like antibodies. IAVI’s initiative, Expanding Access to Monoclonal Antibody-based Products, seeks to expand access to antibody therapies, including those for COVID-19, to middle and low-income countries, an important component of global health equity. As noted in IAVI’s report, Asia and Africa constitute less than 20% of the global market for antibodies despite comprising more than half of the world’s population and their population’s persistent need for such treatments. At the same time, IAVI’s report is short on details about how to bring about such change, other than harmonizing a number of global regulatory pathways for antibody therapies’ approval that IAVI contends will lower prices by lowering manufacturing costs. Whether such cost savings will indeed be passed on to payers in the short run remains to be seen—but lowering manufacturing costs may give payers more leverage on prices both during this pandemic and the next one (or few).

    Relatedly, policymakers in the US could invest in improving manufacturing domestically. The House Energy and Commerce Committee recently introduced a legislative package that includes $500 million in funds for the FDA “to support the review, facilitate the development and post-marketing surveillance of COVID-19 vaccines and therapeutics.” This could very well be used to support advances in techniques in and regulatory oversight over continuous manufacturing, a possibility that Alexander Gaffney of Politico notes would be of great interest to FDA observers. To be sure, half-a-billion to improve biologics manufacturing seems like a lot of money—but as we’ve noted time and time again, the COVID-19 pandemic is not the time to be penny-wise and pound-foolish. As noted above, manufacturing advantages are one area where the public is likely to see advantages—bang for their collective buck—not just in the United States, but elsewhere, too.

    Among other things, that $500 million fund could be used to invest, specifically, in automating and simplifying the production of biologics in manner akin to those of small molecule drugs. Researchers in the area, like James Swartz at Stanford, have researched some of these possibilities for years, labeling their efforts “cell-free manufacturing.” The necessity of cellular components in biologics manufacturing is a major technical hurdle, a source of both secret and tacit knowledge, and a cost sink. Efforts to improve cell-free manufacturing are under-encouraged, among other reasons, because profit margins for biologics remain enormously high and FDA regulations for cell-free manufacturing are, not yet, up to a sufficient level of specificity. Implementing such guidances would go a long way for both investing in the now—and in the future.

    This post is part of a series on COVID-19 innovation law and policy. Author order is rotated with each post.

    Continue Reading ...
  • How can policymakers overcome the hurdles to scaling up antibody manufacturing?

    By Rachel Sachs, Jacob S. Sherkow, Lisa Larrimore Ouellette, and Nicholson Price

    In our last post, we introduced some of the clinical evidence supporting the use of therapeutic antibodies against COVID-19—including Regeneron’s casirivimab and imdevimab and Eli Lilly’s bamlanivimab—and analyzed the existing problems in the distribution and administration of those therapies. Even in just the last few weeks, further clinical evidence has supported the use of these technologies, leading the FDA to issue an additional emergency use authorization for Lilly’s bamlanivimab and etesevimab cocktail. In the near future, though, problems in administering our existing supply of these new drugs may give way to problems producing enough of them—a challenge that is also affecting the vaccine rollout. In this post, we consider the difficult manufacturing issues involved in the therapeutic antibody context (a subject we’ve previously explored regarding vaccines), and what might be done to address them.

    What production challenges arise with the large-scale manufacture of therapeutic antibodies?

    As we have explained, antibodies have been remarkably successful in treating diseases by specifically targeting certain foreign invaders. But antibodies are not simple chemicals that are easy to produce: they are complex proteins that are time-consuming and expensive to manufacture. Your immune system naturally produces antibodies in response to foreign bacteria and viruses; commercial antibody production attempts to replicate this biological process inside living cells.

    The antibody treatments authorized for COVID-19 so far are individual monoclonal antibodies (mAbs) or combinations of mAbs. The “monoclonal” in monoclonal antibodies means that they are produced from a single cloned B-cell line and thus only produce a single antibody. This gives them high specificity to a particular target. Polyclonal antibodies, by contrast, are produced by more than one cloned B-cell line, and thus produce a number of slightly different antibodies with greater target variability. The most common commercial production platform for mAbs is the fed-batch process, in which a closed batch of cells and culture medium is fed additional nutrients as they are consumed, after which the antibodies are isolated and purified. The biopharmaceutical sector is increasingly shifting toward continuous manufacturing processes, with encouragement from the FDA, although regulatory and scientific challenges remain.

    The hurdles to scaling up these processes for COVID-19 therapeutics have been long apparent. A June 2020 analysis from Duke’s Margolis Center for Health Policy noted that setting up new mAb manufacturing capacity typically takes years, and that “the fungibility of the mAb manufacturing capacity depends on the process mode and bioreactor type.” The authors argued that the “federal government could play a coordinating role,” including to help manufacturers of antibody treatments for COVID-19 “reallocate their capacity to the most promising therapies as clinical evidence emerges” without raising the “serious antitrust concerns” that such collaborations would normally raise. 

    Although the federal government didn’t invest in COVID-19 antibody treatments to the same extent as vaccines, in February 2020 it entered an agreement to support Regeneron’s preclinical and clinical COVID-19 treatment development. Then in July 2020 it provided Regeneron $450 million for large-scale manufacturing, supporting the at-risk manufacture of 300,000 doses of the casirivimab and imdevimab cocktail that were allocated to states after FDA authorization in November. The federal government also entered into an advance purchase agreement for Eli Lilly’s bamlanivimab ($375 million for 300,000 doses, with the option to pay $812.5 million more for 650,000 additional doses), although the agreement came only two weeks before authorization, making it less effective for encouraging at-risk manufacturing.

    The complexity of mAb manufacturing also increases costs. Regeneron’s and Eli Lilly’s drugs are cheaper than most antibody therapies, although the prices being paid by the U.S. government—over $1000 per dose for Eli Lilly’s bamlanivimab alone, not including the etesevimab that appears to make it more effective—place it out of reach of many low-income countries. These high prices and the difficulty of scaling manufacturing have raised distributional concerns that these drugs will be less available outside high-income countries. 

    Part of the reason mAb manufacturing is hard and expensive is that many of the process details are kept as trade secrets. The public information about manufacturing Regeneron’s and Eli Lilly’s cocktails is limited. FDA fact sheets indicate that like the majority of commercial mAbs, the antibodies authorized for treating COVID-19 are produced using Chinese hamster ovary (CHO) cell lines. We are unaware of more detailed information about the manufacturing processes—although if you want to see some shiny metal tanks, Lilly does provide B-roll footage of bamlanivimab manufacturing for reporters.

    How can policymakers help scale up antibody manufacturing?

    The most basic step in scaling up antibody manufacturing is recognizing that it is a worthwhile policy goal to pursue alongside other priorities. As noted above, policymakers under the previous administration prioritized the scale-up of vaccine manufacturing, but did not invest to the same degree in antibody manufacturing. In our view, this was a miscalculation. Weighing investment in vaccine versus antibody manufacturing, policymakers may have thought (correctly) that vaccines would be needed broadly to bring about the end of the pandemic, but that antibodies were less crucial, both because vaccines would diminish the need for effective treatments (as fewer people become ill) and because antibodies are merely one among many potential therapeutic interventions. This may be true, but investing in manufacturing scale-up for vaccines versus antibodies need not be an “either or” situation; rather, it is “both and,” especially given that we now have EUAs for multiple antibodies. Given the economic and human toll of COVID-19, we can afford to invest in both, particularly if investments in scaling up the manufacturing technology lead to broader innovations in biologics manufacturing.

    So how does that investment happen? For one thing, policymakers can try to drive knowledge sharing between antibody manufacturers. In the vaccine space, knowledge transfer has emerged as a stumbling block to rapid scale-up, especially on a global scale, though there are other hurdles, especially for the novel mRNA vaccines, involving specialized ingredients and equipment. Knowledge sharing is likely a more important limiting factor for antibody manufacturing, since antibody manufacturing has been going on in some form for decades, and many manufacturers thus already possess the ingredients and equipment needed. Sharing knowledge would allow other manufacturers to increase the supply of existing antibodies, and could also allow for increased understanding and better manufacturing generally (including of other antibodies). Incentives or mandates for increased information sharing could increase innovation and efficiency in antibody manufacturing (and potentially biologic manufacturing more generally), with possible benefits beyond the pandemic. There are some indications that information sharing is happening: six companies involved in therapeutic antibody development sought and received DOJ permission to share development and manufacturing information in August (defusing antitrust concerns). Such collaborations should be lauded and pursued.

    More immediately, policymakers should seriously consider employing global purchasing initiatives for biologic therapies, akin to those of COVAX, the international consortium for global purchasing of vaccines. IAVI, the nonprofit famous for its work on securing and distributing HIV therapies in Africa and India, recently announced it was working on such an initiative in partnership with the Wellcome Trust for biologic therapies, like antibodies. IAVI’s initiative, Expanding Access to Monoclonal Antibody-based Products, seeks to expand access to antibody therapies, including those for COVID-19, to middle and low-income countries, an important component of global health equity. As noted in IAVI’s report, Asia and Africa constitute less than 20% of the global market for antibodies despite comprising more than half of the world’s population and their population’s persistent need for such treatments. At the same time, IAVI’s report is short on details about how to bring about such change, other than harmonizing a number of global regulatory pathways for antibody therapies’ approval that IAVI contends will lower prices by lowering manufacturing costs. Whether such cost savings will indeed be passed on to payers in the short run remains to be seen—but lowering manufacturing costs may give payers more leverage on prices both during this pandemic and the next one (or few).

    Relatedly, policymakers in the US could invest in improving manufacturing domestically. The House Energy and Commerce Committee recently introduced a legislative package that includes $500 million in funds for the FDA “to support the review, facilitate the development and post-marketing surveillance of COVID-19 vaccines and therapeutics.” This could very well be used to support advances in techniques in and regulatory oversight over continuous manufacturing, a possibility that Alexander Gaffney of Politico notes would be of great interest to FDA observers. To be sure, half-a-billion to improve biologics manufacturing seems like a lot of money—but as we’ve noted time and time again, the COVID-19 pandemic is not the time to be penny-wise and pound-foolish. As noted above, manufacturing advantages are one area where the public is likely to see advantages—bang for their collective buck—not just in the United States, but elsewhere, too.

    Among other things, that $500 million fund could be used to invest, specifically, in automating and simplifying the production of biologics in manner akin to those of small molecule drugs. Researchers in the area, like James Swartz at Stanford, have researched some of these possibilities for years, labeling their efforts “cell-free manufacturing.” The necessity of cellular components in biologics manufacturing is a major technical hurdle, a source of both secret and tacit knowledge, and a cost sink. Efforts to improve cell-free manufacturing are under-encouraged, among other reasons, because profit margins for biologics remain enormously high and FDA regulations for cell-free manufacturing are, not yet, up to a sufficient level of specificity. Implementing such guidances would go a long way for both investing in the now—and in the future.

    This post is part of a series on COVID-19 innovation law and policy. Author order is rotated with each post.

    Continue Reading ...
  • How can policymakers overcome the hurdles to scaling up antibody manufacturing?

    By Rachel Sachs, Jacob S. Sherkow, Lisa Larrimore Ouellette, and Nicholson Price

    In our last post, we introduced some of the clinical evidence supporting the use of therapeutic antibodies against COVID-19—including Regeneron’s casirivimab and imdevimab and Eli Lilly’s bamlanivimab—and analyzed the existing problems in the distribution and administration of those therapies. Even in just the last few weeks, further clinical evidence has supported the use of these technologies, leading the FDA to issue an additional emergency use authorization for Lilly’s bamlanivimab and etesevimab cocktail. In the near future, though, problems in administering our existing supply of these new drugs may give way to problems producing enough of them—a challenge that is also affecting the vaccine rollout. In this post, we consider the difficult manufacturing issues involved in the therapeutic antibody context (a subject we’ve previously explored regarding vaccines), and what might be done to address them.

    What production challenges arise with the large-scale manufacture of therapeutic antibodies?

    As we have explained, antibodies have been remarkably successful in treating diseases by specifically targeting certain foreign invaders. But antibodies are not simple chemicals that are easy to produce: they are complex proteins that are time-consuming and expensive to manufacture. Your immune system naturally produces antibodies in response to foreign bacteria and viruses; commercial antibody production attempts to replicate this biological process inside living cells.

    The antibody treatments authorized for COVID-19 so far are individual monoclonal antibodies (mAbs) or combinations of mAbs. The “monoclonal” in monoclonal antibodies means that they are produced from a single cloned B-cell line and thus only produce a single antibody. This gives them high specificity to a particular target. Polyclonal antibodies, by contrast, are produced by more than one cloned B-cell line, and thus produce a number of slightly different antibodies with greater target variability. The most common commercial production platform for mAbs is the fed-batch process, in which a closed batch of cells and culture medium is fed additional nutrients as they are consumed, after which the antibodies are isolated and purified. The biopharmaceutical sector is increasingly shifting toward continuous manufacturing processes, with encouragement from the FDA, although regulatory and scientific challenges remain.

    The hurdles to scaling up these processes for COVID-19 therapeutics have been long apparent. A June 2020 analysis from Duke’s Margolis Center for Health Policy noted that setting up new mAb manufacturing capacity typically takes years, and that “the fungibility of the mAb manufacturing capacity depends on the process mode and bioreactor type.” The authors argued that the “federal government could play a coordinating role,” including to help manufacturers of antibody treatments for COVID-19 “reallocate their capacity to the most promising therapies as clinical evidence emerges” without raising the “serious antitrust concerns” that such collaborations would normally raise. 

    Although the federal government didn’t invest in COVID-19 antibody treatments to the same extent as vaccines, in February 2020 it entered an agreement to support Regeneron’s preclinical and clinical COVID-19 treatment development. Then in July 2020 it provided Regeneron $450 million for large-scale manufacturing, supporting the at-risk manufacture of 300,000 doses of the casirivimab and imdevimab cocktail that were allocated to states after FDA authorization in November. The federal government also entered into an advance purchase agreement for Eli Lilly’s bamlanivimab ($375 million for 300,000 doses, with the option to pay $812.5 million more for 650,000 additional doses), although the agreement came only two weeks before authorization, making it less effective for encouraging at-risk manufacturing.

    The complexity of mAb manufacturing also increases costs. Regeneron’s and Eli Lilly’s drugs are cheaper than most antibody therapies, although the prices being paid by the U.S. government—over $1000 per dose for Eli Lilly’s bamlanivimab alone, not including the etesevimab that appears to make it more effective—place it out of reach of many low-income countries. These high prices and the difficulty of scaling manufacturing have raised distributional concerns that these drugs will be less available outside high-income countries. 

    Part of the reason mAb manufacturing is hard and expensive is that many of the process details are kept as trade secrets. The public information about manufacturing Regeneron’s and Eli Lilly’s cocktails is limited. FDA fact sheets indicate that like the majority of commercial mAbs, the antibodies authorized for treating COVID-19 are produced using Chinese hamster ovary (CHO) cell lines. We are unaware of more detailed information about the manufacturing processes—although if you want to see some shiny metal tanks, Lilly does provide B-roll footage of bamlanivimab manufacturing for reporters.

    How can policymakers help scale up antibody manufacturing?

    The most basic step in scaling up antibody manufacturing is recognizing that it is a worthwhile policy goal to pursue alongside other priorities. As noted above, policymakers under the previous administration prioritized the scale-up of vaccine manufacturing, but did not invest to the same degree in antibody manufacturing. In our view, this was a miscalculation. Weighing investment in vaccine versus antibody manufacturing, policymakers may have thought (correctly) that vaccines would be needed broadly to bring about the end of the pandemic, but that antibodies were less crucial, both because vaccines would diminish the need for effective treatments (as fewer people become ill) and because antibodies are merely one among many potential therapeutic interventions. This may be true, but investing in manufacturing scale-up for vaccines versus antibodies need not be an “either or” situation; rather, it is “both and,” especially given that we now have EUAs for multiple antibodies. Given the economic and human toll of COVID-19, we can afford to invest in both, particularly if investments in scaling up the manufacturing technology lead to broader innovations in biologics manufacturing.

    So how does that investment happen? For one thing, policymakers can try to drive knowledge sharing between antibody manufacturers. In the vaccine space, knowledge transfer has emerged as a stumbling block to rapid scale-up, especially on a global scale, though there are other hurdles, especially for the novel mRNA vaccines, involving specialized ingredients and equipment. Knowledge sharing is likely a more important limiting factor for antibody manufacturing, since antibody manufacturing has been going on in some form for decades, and many manufacturers thus already possess the ingredients and equipment needed. Sharing knowledge would allow other manufacturers to increase the supply of existing antibodies, and could also allow for increased understanding and better manufacturing generally (including of other antibodies). Incentives or mandates for increased information sharing could increase innovation and efficiency in antibody manufacturing (and potentially biologic manufacturing more generally), with possible benefits beyond the pandemic. There are some indications that information sharing is happening: six companies involved in therapeutic antibody development sought and received DOJ permission to share development and manufacturing information in August (defusing antitrust concerns). Such collaborations should be lauded and pursued.

    More immediately, policymakers should seriously consider employing global purchasing initiatives for biologic therapies, akin to those of COVAX, the international consortium for global purchasing of vaccines. IAVI, the nonprofit famous for its work on securing and distributing HIV therapies in Africa and India, recently announced it was working on such an initiative in partnership with the Wellcome Trust for biologic therapies, like antibodies. IAVI’s initiative, Expanding Access to Monoclonal Antibody-based Products, seeks to expand access to antibody therapies, including those for COVID-19, to middle and low-income countries, an important component of global health equity. As noted in IAVI’s report, Asia and Africa constitute less than 20% of the global market for antibodies despite comprising more than half of the world’s population and their population’s persistent need for such treatments. At the same time, IAVI’s report is short on details about how to bring about such change, other than harmonizing a number of global regulatory pathways for antibody therapies’ approval that IAVI contends will lower prices by lowering manufacturing costs. Whether such cost savings will indeed be passed on to payers in the short run remains to be seen—but lowering manufacturing costs may give payers more leverage on prices both during this pandemic and the next one (or few).

    Relatedly, policymakers in the US could invest in improving manufacturing domestically. The House Energy and Commerce Committee recently introduced a legislative package that includes $500 million in funds for the FDA “to support the review, facilitate the development and post-marketing surveillance of COVID-19 vaccines and therapeutics.” This could very well be used to support advances in techniques in and regulatory oversight over continuous manufacturing, a possibility that Alexander Gaffney of Politico notes would be of great interest to FDA observers. To be sure, half-a-billion to improve biologics manufacturing seems like a lot of money—but as we’ve noted time and time again, the COVID-19 pandemic is not the time to be penny-wise and pound-foolish. As noted above, manufacturing advantages are one area where the public is likely to see advantages—bang for their collective buck—not just in the United States, but elsewhere, too.

    Among other things, that $500 million fund could be used to invest, specifically, in automating and simplifying the production of biologics in manner akin to those of small molecule drugs. Researchers in the area, like James Swartz at Stanford, have researched some of these possibilities for years, labeling their efforts “cell-free manufacturing.” The necessity of cellular components in biologics manufacturing is a major technical hurdle, a source of both secret and tacit knowledge, and a cost sink. Efforts to improve cell-free manufacturing are under-encouraged, among other reasons, because profit margins for biologics remain enormously high and FDA regulations for cell-free manufacturing are, not yet, up to a sufficient level of specificity. Implementing such guidances would go a long way for both investing in the now—and in the future.

    This post is part of a series on COVID-19 innovation law and policy. Author order is rotated with each post.

    Continue Reading ...
  • How can policymakers overcome the hurdles to scaling up antibody manufacturing?

    By Rachel Sachs, Jacob S. Sherkow, Lisa Larrimore Ouellette, and Nicholson Price

    In our last post, we introduced some of the clinical evidence supporting the use of therapeutic antibodies against COVID-19—including Regeneron’s casirivimab and imdevimab and Eli Lilly’s bamlanivimab—and analyzed the existing problems in the distribution and administration of those therapies. Even in just the last few weeks, further clinical evidence has supported the use of these technologies, leading the FDA to issue an additional emergency use authorization for Lilly’s bamlanivimab and etesevimab cocktail. In the near future, though, problems in administering our existing supply of these new drugs may give way to problems producing enough of them—a challenge that is also affecting the vaccine rollout. In this post, we consider the difficult manufacturing issues involved in the therapeutic antibody context (a subject we’ve previously explored regarding vaccines), and what might be done to address them.

    What production challenges arise with the large-scale manufacture of therapeutic antibodies?

    As we have explained, antibodies have been remarkably successful in treating diseases by specifically targeting certain foreign invaders. But antibodies are not simple chemicals that are easy to produce: they are complex proteins that are time-consuming and expensive to manufacture. Your immune system naturally produces antibodies in response to foreign bacteria and viruses; commercial antibody production attempts to replicate this biological process inside living cells.

    The antibody treatments authorized for COVID-19 so far are individual monoclonal antibodies (mAbs) or combinations of mAbs. The “monoclonal” in monoclonal antibodies means that they are produced from a single cloned B-cell line and thus only produce a single antibody. This gives them high specificity to a particular target. Polyclonal antibodies, by contrast, are produced by more than one cloned B-cell line, and thus produce a number of slightly different antibodies with greater target variability. The most common commercial production platform for mAbs is the fed-batch process, in which a closed batch of cells and culture medium is fed additional nutrients as they are consumed, after which the antibodies are isolated and purified. The biopharmaceutical sector is increasingly shifting toward continuous manufacturing processes, with encouragement from the FDA, although regulatory and scientific challenges remain.

    The hurdles to scaling up these processes for COVID-19 therapeutics have been long apparent. A June 2020 analysis from Duke’s Margolis Center for Health Policy noted that setting up new mAb manufacturing capacity typically takes years, and that “the fungibility of the mAb manufacturing capacity depends on the process mode and bioreactor type.” The authors argued that the “federal government could play a coordinating role,” including to help manufacturers of antibody treatments for COVID-19 “reallocate their capacity to the most promising therapies as clinical evidence emerges” without raising the “serious antitrust concerns” that such collaborations would normally raise. 

    Although the federal government didn’t invest in COVID-19 antibody treatments to the same extent as vaccines, in February 2020 it entered an agreement to support Regeneron’s preclinical and clinical COVID-19 treatment development. Then in July 2020 it provided Regeneron $450 million for large-scale manufacturing, supporting the at-risk manufacture of 300,000 doses of the casirivimab and imdevimab cocktail that were allocated to states after FDA authorization in November. The federal government also entered into an advance purchase agreement for Eli Lilly’s bamlanivimab ($375 million for 300,000 doses, with the option to pay $812.5 million more for 650,000 additional doses), although the agreement came only two weeks before authorization, making it less effective for encouraging at-risk manufacturing.

    The complexity of mAb manufacturing also increases costs. Regeneron’s and Eli Lilly’s drugs are cheaper than most antibody therapies, although the prices being paid by the U.S. government—over $1000 per dose for Eli Lilly’s bamlanivimab alone, not including the etesevimab that appears to make it more effective—place it out of reach of many low-income countries. These high prices and the difficulty of scaling manufacturing have raised distributional concerns that these drugs will be less available outside high-income countries. 

    Part of the reason mAb manufacturing is hard and expensive is that many of the process details are kept as trade secrets. The public information about manufacturing Regeneron’s and Eli Lilly’s cocktails is limited. FDA fact sheets indicate that like the majority of commercial mAbs, the antibodies authorized for treating COVID-19 are produced using Chinese hamster ovary (CHO) cell lines. We are unaware of more detailed information about the manufacturing processes—although if you want to see some shiny metal tanks, Lilly does provide B-roll footage of bamlanivimab manufacturing for reporters.

    How can policymakers help scale up antibody manufacturing?

    The most basic step in scaling up antibody manufacturing is recognizing that it is a worthwhile policy goal to pursue alongside other priorities. As noted above, policymakers under the previous administration prioritized the scale-up of vaccine manufacturing, but did not invest to the same degree in antibody manufacturing. In our view, this was a miscalculation. Weighing investment in vaccine versus antibody manufacturing, policymakers may have thought (correctly) that vaccines would be needed broadly to bring about the end of the pandemic, but that antibodies were less crucial, both because vaccines would diminish the need for effective treatments (as fewer people become ill) and because antibodies are merely one among many potential therapeutic interventions. This may be true, but investing in manufacturing scale-up for vaccines versus antibodies need not be an “either or” situation; rather, it is “both and,” especially given that we now have EUAs for multiple antibodies. Given the economic and human toll of COVID-19, we can afford to invest in both, particularly if investments in scaling up the manufacturing technology lead to broader innovations in biologics manufacturing.

    So how does that investment happen? For one thing, policymakers can try to drive knowledge sharing between antibody manufacturers. In the vaccine space, knowledge transfer has emerged as a stumbling block to rapid scale-up, especially on a global scale, though there are other hurdles, especially for the novel mRNA vaccines, involving specialized ingredients and equipment. Knowledge sharing is likely a more important limiting factor for antibody manufacturing, since antibody manufacturing has been going on in some form for decades, and many manufacturers thus already possess the ingredients and equipment needed. Sharing knowledge would allow other manufacturers to increase the supply of existing antibodies, and could also allow for increased understanding and better manufacturing generally (including of other antibodies). Incentives or mandates for increased information sharing could increase innovation and efficiency in antibody manufacturing (and potentially biologic manufacturing more generally), with possible benefits beyond the pandemic. There are some indications that information sharing is happening: six companies involved in therapeutic antibody development sought and received DOJ permission to share development and manufacturing information in August (defusing antitrust concerns). Such collaborations should be lauded and pursued.

    More immediately, policymakers should seriously consider employing global purchasing initiatives for biologic therapies, akin to those of COVAX, the international consortium for global purchasing of vaccines. IAVI, the nonprofit famous for its work on securing and distributing HIV therapies in Africa and India, recently announced it was working on such an initiative in partnership with the Wellcome Trust for biologic therapies, like antibodies. IAVI’s initiative, Expanding Access to Monoclonal Antibody-based Products, seeks to expand access to antibody therapies, including those for COVID-19, to middle and low-income countries, an important component of global health equity. As noted in IAVI’s report, Asia and Africa constitute less than 20% of the global market for antibodies despite comprising more than half of the world’s population and their population’s persistent need for such treatments. At the same time, IAVI’s report is short on details about how to bring about such change, other than harmonizing a number of global regulatory pathways for antibody therapies’ approval that IAVI contends will lower prices by lowering manufacturing costs. Whether such cost savings will indeed be passed on to payers in the short run remains to be seen—but lowering manufacturing costs may give payers more leverage on prices both during this pandemic and the next one (or few).

    Relatedly, policymakers in the US could invest in improving manufacturing domestically. The House Energy and Commerce Committee recently introduced a legislative package that includes $500 million in funds for the FDA “to support the review, facilitate the development and post-marketing surveillance of COVID-19 vaccines and therapeutics.” This could very well be used to support advances in techniques in and regulatory oversight over continuous manufacturing, a possibility that Alexander Gaffney of Politico notes would be of great interest to FDA observers. To be sure, half-a-billion to improve biologics manufacturing seems like a lot of money—but as we’ve noted time and time again, the COVID-19 pandemic is not the time to be penny-wise and pound-foolish. As noted above, manufacturing advantages are one area where the public is likely to see advantages—bang for their collective buck—not just in the United States, but elsewhere, too.

    Among other things, that $500 million fund could be used to invest, specifically, in automating and simplifying the production of biologics in manner akin to those of small molecule drugs. Researchers in the area, like James Swartz at Stanford, have researched some of these possibilities for years, labeling their efforts “cell-free manufacturing.” The necessity of cellular components in biologics manufacturing is a major technical hurdle, a source of both secret and tacit knowledge, and a cost sink. Efforts to improve cell-free manufacturing are under-encouraged, among other reasons, because profit margins for biologics remain enormously high and FDA regulations for cell-free manufacturing are, not yet, up to a sufficient level of specificity. Implementing such guidances would go a long way for both investing in the now—and in the future.

    This post is part of a series on COVID-19 innovation law and policy. Author order is rotated with each post.

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  • Patent Filings Roundup: Porn Sites Head for PTAB; All-or-Nothing Post Grant Review Institution

    Patent Trial and Appeal Board (PTAB) filings have settled into a relatively steady-state of roughly 20-30 petitions, occasionally punctuated by a big burst of litigation-related activity. Notably, five of the 34 petitions filed were post grant reviews (PGRs), as the numbers there continue to (very slowly) creep up from nothing. In the district courts, a relatively typical 76 patent filings hit dockets across the nation, including some newer names—and some old ones just now resurfacing. For…

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  • From Around the Blogs

    1. On Law360, Brian Johnson published an expert analysis titled How Parties Can Prep for Global FRAND Jurisdictional Battles.   The essay touches on several issues of importance in the ongoing SEP wars, including whether antisuit injunctions ever are or should be available to prevent a party from proceeding with litigation in the first-seised forum; the capabilities of the forum; and the question of whether the exercise of jurisdiction to determine global rates can ever constitutes “international coercion.”  He closes with some practical considerations, including the “need to act quickly to obtain [one’s] preferred venue.”  

    For my recent thoughts on these issues, see here.

    2.  On the Kluwer Patent Blog, Matthieu Dhenne published a post titled Pemetrexed in France Act 2: 1 PI + 4 millions.  The post discusses a recent decision in France (which I have not yet obtained a copy of, myself, so I’m going on M. Dhenne’s description here) granting a preliminary injunction against the marketing of (yet another) generic Pemetrexed product, and awarding provisional damages in the amount of  4 million.  The decision to grant the preliminary injunction touches on issues courts in France and elsewhere have addressed in recent years concerning claim construction under article 69 of the EPC.  As for the provisional damages, M. Dhenne is critical of the court’s use of a 25% royalty rate multiplied by the defendant’s turnover.  He describes the rate as having “no basis . . .   except that it is an increased rate compared to a normal one,” and the base (turnover) as having no textual basis in article L 615-7 of the French IP Code, which allows royalties to be awarded as a lump sum.  (But I thought it was common to use turnover as the oryalty base in France, and isn’t 4 million itself a lump sum?)  He also published a follow-up to a post I mentioned recently, this one titled The FRAND Lectures (Part 2): which Judge can order a cross-border injunction?.  In the post, Professor Anne-Catherine Chriariny analyzes EU law relating to cross-border injunctions under the Brussels I Bis Regulation.

    Also on Kluwer are two posts by Vaishali Mittal titled Implementors must be given access to FRAND agreements: Delhi High Court, Part 1, and Implementors must be given access to FRAND agreements: Delhi High Court, Part 2The author discusses the decision of the Delhi High Court in the InterDigital/Xiaomi dispute in which “[t]he Court held that that Xiaomi’s employees must necessarily have access to InterDigital’s third party patent license agreements, so that Xiaomi may put up an adequate defense in the suit filed by InterDigital with respect to the infringement of its 3G, 4G Standard Essential Patents (SEPs).”  This matter also has been the subject of discussion recently on the SpicyIP Blog, including a more critical assessment here.

    3.  On FOSS Patents, Florian Mueller published a post titled European Commission’s expert group report on standard-essential patents uses misnomers “license to all” and “access to all”.  The post discusses the recently published document titled Group of Experts on Licensing and Valuation of Standard Essential Patents ‘SEPs Expert Group’ – full contribution.  While I make my way through the document itself (it’s long, and it’s been a busy month), which I may have more to say about in due time, I’ll just note for now that Mr. Mueller makes what I think may be a very good suggestion, namely that we abandon use of the terms “license to all” and “access to all,” which he views as being somewhat misleading, in favor of “implementer’s choice” and “patentee’s choice.”  I recall that a few years ago someone suggested that I refrain from using the term “FRAND-encumbered,” which sounds kind of negative, in lieu of the more neutral “FRAND-committed,” and I have mostly done so ever since.  Maybe this will be another such change worth making.  

    Mr. Mueller has published one follow-up article here, as well as a follow-up to his recent post on the Munich Court’s referral to the CJEU on a question relating to preliminary injunctions.  

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