The Revival of Phage Therapy to Fight Antimicrobial Resistance (AMR) – Part III: What about patent protection and alternative incentives?

In Part II of this blog on legal issues relating to the revival of phage therapy I discussed the US Supreme Court’s decisions in Myriad and Prometheus, which might present major obstacles to the patentability of phage-related technology (a more detailed analysis of the Myriad and Prometheus decisions is available here).

Yet, all is not lost. As indicated in Part II, Myriad does not directly affect the patentability of synthetically modified biological compounds and Prometheus would still allow patents on inventive applications of natural processes and correlations that add new features to “natural laws”. Thus there still seems to be considerable leeway for patenting within the area of page therapy.

One example, mentioned in a recent Nature article, could be the skillful selection and precise combination of different phages in order to attack one specific type of bacteria. Such selections, however, would face a tough battle to overcome the “additional features that add significantly more” and “not identical” thresholds set by Prometheus and Myriad. Another example with even better prospects for patentability relates to genetically modified phages that are – due to human intervention – enabled to target only specific bacteria. This technology was recently presented by MIT researchers at the 2014 American Society for Microbiology Meeting. The researchers led by Timothy Lu had genetically engineered phages that use a DNA-editing system called CRISPR to target and kill only antibiotic-resistant bacteria while leaving other susceptible cells untouched. The significant engineering and alteration of natural products and processes involved in such inventions would most likely meet both the Myriad and Prometheus standards.

Yet, while the USPTO has recently issued new patent eligibility guidance and the CAFC has begun to directly apply Prometheus and Myriad to reject patent claims in biotech cases (e.g. In re Roslin), many questions remain unsolved. In particular, it is still not sufficiently clear exactly how much modification is required to render a molecule or method sufficiently distinct from naturally occurring product and processes. And even if the patent-eligibility threshold could be met in extraordinarily circumstances, the claimed invention would still have to fulfil other patentability requirements such as novelty, non-obviousness and the written description-requirements. The threshold for these requirements, however, have been heightened in recent years (see e.g. KSR v. Teleflex (2007) , Nautilus (2014) etc.). Considering that phage therapy is almost a century old with a substantial common general knowledge and a state of the art employing routine methods, these crucial requirements might still prevent the patentability of many useful applications.

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The Revival of Phage Therapy to Fight Antimicrobial Resistance – Part II: What about patent protection and alternative incentives?

Three days ago I commented on a couple of legal issues raised in the recent Nature report “Phage therapy gets revitalized”  by Sara Reardon. One challenge concerns the reluctance of pharma companies to broadly invest in the development of phage therapies. As pointed out in the report, this does of course very much (but not only) relate to the question of patentability. Various aspects might present obstacles to the patentability of technology relating to phage therapy. To not complicate the discussion and considering recent developments I decided to focus on some of aspects under US patent law.

Like in Europe, the first door to patentability that phage-related technology would need to pass concerns patent eligibility. In the last years the US Supreme Court has rendered an astonishing number of fundamental patent-decisions, including not less than four (!) landmark judgments on patent eligibility, i.e. Bilski v. Kappos (2010), Mayo v. Prometheus (2012) , AMP v. Myriad (2013)  and Alice v. CLS (2014). Most relevant in this context are the decisions in Prometheus and Myriad.

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The Revival of Phage Therapy to Fight Antimicrobial Resistance – Part I: What are the legal implications?

Last week I blogged about recent publications concerning the global battle against anti-microbial resistance (AMR). I did not mention a recent paper published in the June 2014 issue of Nature, which describes how European and U.S. researchers and authorities are increasingly considering clinical research in unconventional areas to fight AMR. The news-report “Phage therapy gets revitalized” by Sara Reardon concentrates on the use of viruses (bacteriophages) to battle bacteria. The idea is not new, but apart from some applications in the former Soviet Union, it never was established as a major research area elsewhere. In particular the paper examines the European Phagoburn project, which is the first large, multi-centre clinical trial of phage therapy for human infections, funded by the European Commission. It involves a phase I-II trial of using viruses for the treatment of bacterial infection following burns. The European Union (EU) is contributing €3.8 million (US$5.2 million) to the Phagoburn study demonstrating that it is taking the approach seriously. Meanwhile, the US National Institute of Allergy and Infectious Diseases announced in March 2014  that it regards phage therapy as one of seven key areas in its strategy to fight antibiotic resistance.

So far Western practice has concentrated on treating complex or unidentified infections with broad-spectrum antibiotics. These antibiotics would typically eliminate multiple types of bacteria, including those who have beneficial effects to the human organism. Despite resulting in direct negative consequences for patients, e.g. gastrointestinal disorders, these “atomic bomb” approaches can result in biological niches where resistant “bad bugs” can prosper. This is the reason why scientists are turning towards more targeted approaches. This is where phage therapy comes into play. Like “guided missiles”, phage-therapy has the ability to kill just species of bacteria or strain. Quoting the US virologist Ryland Young and the head of the scientific council at the Eliava Institute in Tblisi (Georgia), Mzia Kutateladze, the Nature report explains how nature offers an almost unlimited source of different phages and that so far no identical phages have ever been found. For this reason it is fairly simple to identify a particular phage for a bacterial target. If the bacterium should become resistant against that particular phage, researchers would modify the viral cocktails that are used for treatment by adding or substituting phages. At the Eliava Institute such updates occur – according to the report – approximately every 8 months and the scientists would not be fully aware of the precise combination of phages in the cocktail.

In light of these advantages the recent interest of US and EU stakeholders in phage therapy comes as no surprise. However, the scientific and legal challenges confronting these projects are complex. After all we are talking about viruses here, which triggers alarm bells with regard to public perception, safety concerns, and the regulation of relevant research. It also appears questionable if – or under what circumstances – regulatory authorities would be willing to grant market approval for such a rapidly changing product like in the case of e.g. influenza vaccines. Another significant problem for the development of new phage therapies, also addressed in the paper, lies in the reluctance of pharmaceutical companies to invest into the field. The potential obstacles for more private involvement in phage therapy are many and range from considerable risks of failure, reputational damage, and unforeseeable side-effects to insufficient certainty with regard to intellectual property protection and guarantees of a profit.

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The Fight Against Antimicrobial Resistance: Important recent publications

One of my previous blogs discussed the growing threat of antimicrobial resistance (AMR). I concluded that antimicrobial resistance is a growing and complex threat involving multifaceted legal, socio-economic and scientific aspects. This requires sustained and coordinated action on both global and local levels.

A recent medical review on drug resistant tuberculosis supports these findings and provides further fodder to the debate. In their study, which was published in April 2014 in The Lancet – Respiratory Medicine, the authors analyzed the epidemiology, pathogenesis, diagnosis, management, implications for health-care workers, and ethical and medico-legal aspects of extensively drug-resistant tuberculosis and other resistant strains. In particular, the authors discussed the increasing threat of functionally untreatable tuberculosis, and the problems that it creates for public health and clinical practice. The paper concludes that the growth of highly resistant strains of tuberculosis make the development of new drugs and rapid diagnostics for tuberculosis—and increased funding to strengthen global control efforts, research, and advocacy—even more pressing.

This was also recognized in the recent WHO’s Global Surveillance Report on AMR, which was published this April. It is the first WHO report that studied the problem of AMR on a global level. Noting that resistance is occurring across many different infectious agents, the report concentrates on antibiotic resistance in seven different bacteria responsible for common, serious diseases such as bloodstream infections (sepsis), diarrhoea, pneumonia, urinary tract infections and gonorrhoea. The results demonstrate a wide-spread growth of resistance to antibiotics, especially “last resort” antibiotics. In particular the report reveals that this serious threat is no longer a mere forecast for the future. AMR is a contemporary problem in every region of the world and has the potential to affect anyone, of any age, in any country. Consequently the WHO report concludes that antibiotic resistance is now a major threat to public health that needs to be tackled on a global level.

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Bumps on the Road Towards Clinical Trials Data Transparency- A recent U-Turn by the EMA?

By Timo Minssen

In a recent blog I discussed the benefits and potential draw-backs of a new “EU Regulation on clinical trials on medicinal products for human use,” which had been adopted by the European Parliament and Council in April 2014. Parallel to these legislative developments, the drug industry has responded with its own initiatives providing for varying degrees of transparency. But also medical authorities have been very active in developing their transparency policies.

In the US, the FDA proposed new rules which would require disclosure of masked and de-identified patient-level data. In the EU, the EMA organized during 2013 a series of meetings with its five advisory committees to devise a draft policy for proactive publication of and access to clinical-trial data. In June 2013 this process resulted in the publication, of a draft policy document titled “Publication and access to clinical-trial data” (EMA/240810/2013).

Following an invitation for public comments on this document, the EMA received more than 1,000 submissions from stakeholders. Based on these comments the EMA recently proposed “Terms of Use” (TOU) and “Redaction Principles” for clinical trial data disclosure.

In a letter to the EMA’s executive director Dr. Guido Rasi, dated 13 May 2014, the European Ombudsman, Emily O’Reilly, has now expressed concern about what seems to be a substantial shift of policy regarding clinical trial data transparency. Continue reading

Summer Course for Professionals in “Pharma Law & Policy” at the University of Copenhagen

Stay abreast with recent developments and trends determining the legal and regulatory framework of the European pharmaceutical industry.

What are the most significant current issues shaking and shaping the pharmaceutical industry today? The business environment and legal framework relevant to the pharmaceutical industry continues to change rapidly in the face of constant challenges posed by competition, politics and technological innovation. Considering the highly lucrative and competitive nature of the industry, it is more important than ever for professionals working with legal and regulatory aspects of drug development to stay abreast of the most recent developments.

This course provides a broad and practical understanding of the ‘hot topics’ and will present and analyse these topics from scientific, legal and policy perspectives.

Further information about the course is available here.

Course content

The course begins with a general overview of the current scientific and legal trends in pharmaceutical R&D, organisation and policy. This is followed by a review of the hot topics through a combination of lectures, discussions, group work and case studies. The course is designed to allow room for the issues and challenges crucial to the participants’ daily work and practice.

Participants

The course is designed for professionals working with legal issues and/or regulatory aspects of drug development, decision-makers, administrators and health care practitioners within both the public and private sectors, e.g.:

  • Legal departments in the pharmaceutical industry.
  • Law firms dealing with patent and competition law in the pharmaceutical industry.
  • Branch organizations in the pharmaceutical sector.
  • Health care professionals and decision makers.
  • Bank and finance consultants working with risk and investment in the pharmaceutical industry.

Credit – especially for lawyers and trainee solicitors

This course meets the Danish requirements for compulsory supplementary training for lawyers and trainee solicitors.

Course dates

5 days, 18 – 22 August 2014, 9:00 – 17:00 at the University of Copenhagen, Frederiksberg Campus.

Course director

Timo Minssen, Associate Professor, Dr., LL.M., M.I.C.L., Centre for Information and Innovation Law, Faculty of Law, University of Copenhagen

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A More Transparent System for Clinical Trials Data in Europe – Mind the Gaps!

Following the approval of the European Parliament (EP) earlier last month, the Council of the European Union (the Council) adopted on 14 April 2014 a “Regulation on clinical trials on medicinal products for human use” repealing Directive 2001/20/EC.  As described in a press-release, the new law:

“aims to remedy the shortcomings of the existing Clinical Trials Directive by setting up a uniform framework for the authorization of clinical trials by all the member states concerned with a given single assessment outcome. Simplified reporting procedures, and the possibility for the Commission to do checks, are among the law’s key innovations.”

Moreover, and very importantly, the Regulation seeks to improve transparency by requiring pharmaceutical companies and academic researchers to publish the results of all their European clinical trials in a publicly-accessible EU database. In contrast to earlier stipulations which only obliged sponsor to publish the end-results of their clinical trials, the new law requires full clinical study reports to be published after a decision on – or withdrawal of – marketing authorization applications. Sponsors who do not comply with these requirements will face fines.

These groundbreaking changes will enter into force 20 days after publication in the Official Journal of the EU. However, it will first apply six months after a new EU portal for the submission of data on clinical trials and the above mentioned EU database have become fully functional. Since this is expected to take at least two years, the Regulation will apply in 2016 at the earliest (with an opt-out choice available until 2018).

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New regulatory pathways and incentives for sustainable antibiotics: Recent European & US Initiatives

Please find attached a ppt presentation on “New regulatory pathways and incentives for sustainable antibiotics: Recent European & US Initiatives” given on March 7, 2014 at the Broad Institute of MIT and Harvard.  The presentation was followed by a discussion moderated by US patent attorney Melissa Hunter-Ensor, Partner at Saul Ewing, Boston.

I started out by emphasizing increasing problems of antimicrobial resistance (AMR) on a global level, providing new statistics and facts. This was followed by a discussion of main reasons for these alarming developments, such as inappropriate use in agriculture and medicine, insufficient precautions, lack of education, climate change, travel behavior, insufficient collaboration and funding of R&D, scientific complexities, and the problem that incentives provided by the traditional innovation system model often fail in the case of antibiotics.

Next the presentation focused on a variety of solution models that could be discussed to fight AMR. These include both conservational and preventive approaches comprising use limitations, increased public awareness, and better hygiene, but also reactive push & pull strategies, such as increased investments, new collaborative models for R&D in antibiotics, prizes, “sui generis” IP-related incentives, regulatory responses and new pathways for approval.

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Our Bodies, Our Cells: FDA Regulation of Autologous Adult Stem Cell Therapies

By Mary Ann Chirba, J.D., D.Sc., M.P.H. and Alice A. Noble, J.D., M.P.H.

Stem cells have been an endless source of fascination and controversy since Dolly the sheep was cloned in 1996. This month’s announcement of a cloned human embryo from a single skin cell [1] came on the heels of Sir John B. Gurdon and Dr. Shinya Yamanaka’s receipt of the 2012 Nobel for Physiology and Medicine for their work with induced pluripotent stem cells. Pluripotent stem cells can be embryonic or induced. Embryonic stem cells (ESCs) can generally be obtained from human embryos or by cloning embryos through somatic cell nuclear transfer (SCNT), as was done for Dolly.  Gurdon and Yamanaka demonstrated that pluripotent cells may also be formed by reprogramming adult cells to an embryonic state, resulting in induced pluripotent stem (iPS) cells without having to use eggs or cloning, or destroy embryos. However derived, pluripotent cells are capable of differentiating into virtually any cell type in the human body. This imbues them with great promise for scientific breakthroughs and medical advances, but also raises serious ethical, legal and safety concerns about their use.

Less controversial are “multipotent” adult stem cells (ASCs) which do not involve embryos or raise as many safety concerns as pluripotent cells.  ASCs are found throughout the body.  Their ability to differentiate is more limited than pluripotent cells but is vast nonetheless. The NIH’s clinicaltrials.gov site lists some 4500 ASC trials as compared with 27 for embryonic stem cells and 21 for induced pluripotent stem cells. Recent announcements of new stem cell treatments usually involve ASCs, such as last month’s news that a toddler born without a trachea received a new one made from her own adult stem cells.  It is therefore no surprise that ASCs have captured the attention of researchers, investors, physicians, patients and – increasingly – regulators, both here and abroad.

A growing number of physicians routinely offer treatments involving ASCs to their patients which can be performed in their offices.  Autologous adult stem cells, used to treat a variety of conditions, are harvested from the patient, processed, and returned to the same patient. It is no surprise that moving ASCs from laboratories to physician offices raises complex questions of law. We consider one of the more pressing ones: to what extent can the FDA regulate a physician’s ability to treat a patient with that patient’s own stem cells?  In the coming months, the D.C. Circuit Court of Appeals will hear oral arguments on this very issue in United States v. Regenerative Sciences.[2]

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A Decade’s Quest for Safer Drugs: Congressional Committee Green Lights Regulation of Drug Supply Chains and Compounding Manufacturers

By Mary Ann Chirba and Alice A. Noble

On May 22. 2013, the Senate Health, Education, Labor and Pensions (HELP) Committee unanimously approved S.959, “The Pharmaceutical Compounding Quality and Accountability Act,” and S.957, “The Drug Supply and Security Act,” (now incorporated into S. 959 as an amendment).  Congressional efforts to enact comprehensive legislation to improve drug safety and secure the nation’s drug supply chain have lingered for over a decade. The lack of federal uniformity has allowed a patchwork of state legislation to emerge, attracting the less scrupulous to those states with the lowest security. The issue finally gained traction among HELP Committee members when 55 people died and 741 more became ill after contracting fungal meningitis from contaminated steroid injections made by the New England Compounding Center (NECC). Committee member Sen. Pat Roberts (R-KS) stated that given prior reports of problems with NECC, this tragedy could have been averted but for a “shocking failure to act” by NECC, state and federal regulators, and Congress.

As NECC’s role in the meningitis outbreak came to light,gaps in regulatory oversight did, too. The federal Food Drug and Cosmetic Act (FDCA)[1] currently recognizes only two categories of pharmaceutical manufacturers: commercial pharmaceutical companies and compounding pharmacies. To qualify as the latter under federal law, the entity must make individual or small batch, patient-specific drugs and do so only with a physician’s prescription for that patient.  Compounded drugs must be either be unavailable in the commercial market or needed in commercially unavailable doses or combinations. The FDCA exempts such compounders from its pre-marketing requirements applicable to commercially manufactured drugs. Thus, federal law clearly covers commercial pharmaceutical manufacturers, state law just as clearly oversees and licenses pharmacies but as the NECC case demonstrates, there is nothing clear about the responsibility for inspecting, licensing or otherwise overseeing compounders that do not fill prescriptions on a per patient basis.

Instead of compounding in response to an individual prescription, the New England Compounding Center made large batches of drugs for institutional buyers such as hospitals. Many of its drugs were commercially unavailable but some were knock-offs of marketed FDA-approved drugs – a practice which is clearly unauthorized. NECC’s business model was certainly not unique; neither was the limited and erratic response of state and federal regulators to complaints about the facility’s unsafe manufacturing practices. Congress knew that large-scale compounders existed along with concerns about their safety. Several members of the Senate HELP Committee had worked on curative legislation for over ten years, but made few inroads until the NECC crisis prompted the  HELP Committee to shift from park into drive.

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Google, Whole Foods, and … Big Pharma?

Nadia N. Sawicki

Google’s informal corporate slogan is “Don’t be evil.”  Whole Foods is a Fortune 500 company with a net revenue of 10 billion dollar that prides itself on a commitment to social responsibility.  Both companies have pledged to do long-term good in the world, even at the expense of short-term gains, and both are wildly successful.

If corporations can be profitable as a result of their commitments to social justice and corporate ethics, why can’t this doctrine be extended to the pharmaceutical industry?  Someday, a company called GoodPharma might reach the Fortune 500 on the basis of a pledge to improve access to medicine, conduct international research trials in accordance with the highest standards of research ethics, engage in research on orphan diseases, publish negative research findings, promptly report information about adverse effects, and generally act as a model for ethical industry practices.  If this business model hasn’t been explored, it should be.

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The Prescription Drug Abuse and Overdose Crisis: Focus on the Supply Chain

By Scott Burris

There’s so much we still don’t know about the prescription opioid problem. The partial remedies advanced so far reflect this:

  • Prescription Drug Monitoring Programs, which in essence define the problem as doctor-shopping patients;
  • treatment guidelines, which define the problem as doctors without expertise; and
  • crackdowns on “pill-mills,” which see the issue as physician corruption. Each of these diagnoses has an element of truth, but not necessarily enough to make the treatments effective.

One huge part of the problem has gotten far too little attention: the pharmaceutical supply chain where all these drugs start and along which they are distributed. Now, John Coleman, a former DEA officer, has given us a thorough and compelling primer on the supply chain, describing it and showing where the pressure points are for action. He is not happy about what he sees: DEA is overwhelmed, and too secretive with its data;  and the distributors are too interested in profits and far too unwilling to police paying customers. But he also sees room for action and even hope. This article is well worth a read if you are interested in the overdose problem and how to solve it:

Coleman, John J. “The Supply Chain of Medicinal Controlled Substances: Addressing the Achilles Heel of Drug Diversion.” Journal of Pain and Palliative Care Pharmacotherapy 26, no. 3 (2012): 233-50.

P.S. — One of the hopeful signs he sees was Florida’s legislation beefing up state-level monitoring and controls. This takes me back to the successful Wisconsin Cancer Pain Initiative in the 70s and 80s, which articulated the Principle of Balance in drug control and demonstrated that it was possible to have good access to pain medicine and effective control. In those days, David Joranson, the state drug controller, worked closely with DEA, using state regulatory authority to shut down docs and pharmacies who were acting outside the law. The possibility of history repeating itself is a ray of sunlight in the cloudy skies of this issue. (If you are interested in the story, here’s one place to start: Joranson, D., and J. L. Dahl. “Achieving Balance in Drug Policy: The Wisconsin Model.” In Advances in Pain Research and Therapy, edited by CS Hill Jr. and WS Fields. 197-204. New York: Raven Press, 1989.)