Posts Tagged ‘Intellectual property’

OpenAI and ChatGPT face unique legal challenges over CopyRight Laws

Reporter: Stephen J. Williams, PhD

In previous weeks on this page and on the sister page ChatGPT applied to Cancer & Oncology, a comparison between ChatGPT, OpenAI, and Google large language model based search reveals a major difference between the algorithms with repect to citation and author credit.  In essence while Google returns a hyperlink to the information used to form an answer, ChatGPT and OpenAI are agnostic in crediting or citing the sources of information used to generate answers to queries.  With ChatGPT the source data, or more specifically the training set used for the AI algorithm is never properly cited in the query results.

This, as outlined below, is making a big problem when it comes to copyright law and intelectual property.  Last week a major lawsuit has been filed because of incorrect and citing, referencing, and attribution of ownership of intellectual property.


As Miles Klee reports in The Rolling Stone

“OpenAI faces allegations of privacy invasion and violating authors’ copyright — but this may be just the tip of the iceberg”


The burgeoning AI industry has just crossed another major milestone, with two new class-action lawsuits calling into question whether this technology violates privacy rights, scrapes intellectual property without consent and negatively affects the public at large. Experts believe they’re likely to be the first in a wave of legal challenges to companies working on such products. Both suits were filed on Wednesday and target OpenAI, a research lab consisting of both a nonprofit arm and a corporation, over ChatGPT software, a “large language model” capable of generating human-like responses to text input. One, filed by Clarkson, a public interest law firm, is wide-ranging and invokes the potentially “existential” threat of AI itself. The other, filed by the Joseph Saveri Law Firm and attorney Matthew Butterick, is focused on two established authors, Paul Tremblay and Mona Awad, who claim that their books were among those ChatGPT was trained on — a violation of copyright, according to the complaint. (Saveri and Butterick are separately pursuing legal action against OpenAI, GitHub and Microsoft over GitHub Copilot, an AI-based coding product that they argue “appears to profit from the work of open-source programmers by violating the conditions of their open-source licenses.”)

Saveri and Butterick’s latest suit goes after OpenAI for direct copyright infringement as well as violations of the Digital Millennium Copyright Act (DMCA). Tremblay (who wrote the novel The Cabin at the End of the World) and Awad (author of 13 Ways of Looking at a Fat Girl and Bunny) are the representatives of a proposed class of plaintiffs who would seek damages as well as injunctive relief in the form of changes to ChatGPT. The filing includes ChatGPT’s detailed responses to user questions about the plots of Tremblay’s and Awad’s books — evidence, the attorneys argue, that OpenAI is unduly profiting off of infringed materials, which were scraped by the chat bot. While the suits venture into uncharted legal territory, they were more or less inevitable, according to those who research AI tech and privacy or practice law around those issues.


“[AI companies] should have and likely did expect these types of challenges,” says Ben Winters, senior counsel at the Electronic Privacy Information Center and head of the organization’s AI and Human Rights Project. He points out that OpenAI CEO Sam Altman mentioned a few prior “frivolous” suits against the company during his congressional testimony on artificial intelligence in May. “Whenever you create a tool that implicates so much personal data and can be used so widely for such harmful and otherwise personal purposes, I would be shocked there is not anticipated legal fire,” Winters says. “Particularly since they allow this sort of unfettered access for third parties to integrate their systems, they end up getting more personal information and more live information that is less publicly available, like keystrokes and browser activity, in ways the consumer could not at all anticipate.”

Source: https://www.rollingstone.com/culture/culture-features/chatgtp-openai-lawsuits-copyright-artificial-intelligence-1234780855/

At the heart of the matter is ChatGPT and OpenAI use of ‘shadow libraries’ for AI training datasets, in which the lawsuit claims is illegal.


An article by Anne Bucher in topclassactions.com explains this:

Source: https://topclassactions.com/lawsuit-settlements/class-action-news/class-action-lawsuit-claims-chatgpt-uses-copyrighted-books-without-authors-consent/

They say that OpenAI defendants “profit richly” from the use of their copyrighted materials and yet the authors never consented to the use of their copyrighted materials without credit or compensation.

ChatGPT lawsuit says OpenAI has previously utilized illegal ‘shadow libraries’ for AI training datasets

Although many types of material are used to train large language models, “books offer the best examples of high-quality longform writing,” according to the ChatGPT lawsuit.

OpenAI has previously utilized books for its AI training datasets, including unpublished novels (the majority of which were under copyright) available on a website that provides the materials for free. The plaintiffs suggest that OpenAI may have utilized copyrighted materials from “flagrantly illegal shadow libraries.”

Tremblay and Awad note that OpenAI’s March 2023 paper introducing GPT-4 failed to include any information about the training dataset. However, they say that ChatGPT was able to generate highly accurate summaries of their books when prompted, suggesting that their copyrighted material was used in the training dataset without their consent.

They filed the ChatGPT class action lawsuit on behalf of themselves and a proposed class of U.S. residents and entities that own a U.S. copyright for any work used as training data for the OpenAI language models during the class period.

Earlier this year, a tech policy group urged federal regulators to block OpenAI’s GPT-4 AI product because it does not meet federal standards.


What is the general consensus among legal experts on generative AI and copyright?


From Bloomberg Law: https://www.bloomberglaw.com/external/document/XDDQ1PNK000000/copyrights-professional-perspective-copyright-chaos-legal-implic

Copyright Chaos: Legal Implications of Generative AI

Contributed by Shawn Helms and Jason Krieser, McDermott Will & Emery

Copyright Law Implications – The Ins and Outs

Given the hype around ChatGPT and the speculation that it could be widely used, it is important to understand the legal implications of the technology. First, do copyright owners of the text used to train ChatGPT have a copyright infringement claim against OpenAI? Second, can the output of ChatGPT be protected by copyright and, if so, who owns that copyright?

To answer these questions, we need to understand the application of US copyright law.

Copyright Law Basics

Based on rights in Article I, Section 8 of the Constitution, Congress passed the first copyright law in 1790. It has been amended several times. Today, US copyright law is governed by the Copyright Act of 1976. This law grants authors of original works exclusive rights to reproduce, distribute, and display their work. Copyright protection applies from the moment of creation, and, for most works, the copyright term is the life of the author plus 70 years after the author’s death. Under copyright law, the copyright holder has the exclusive right to make copies of the work, distribute it, display it publicly, and create derivative works based on it. Others who want to use the work must obtain permission from the copyright holder or use one of the exceptions to copyright law, such as fair use.

The purpose of copyright law is to incentivize authors to create novel and creative works. It does this by granting authors exclusive rights to control the use of their work, thus allowing them to financially benefit from their works. Copyright law also encourages the dissemination of knowledge by allowing others to use copyrighted works under certain conditions, such as through the fair use doctrine, which allows for limited use of copyrighted material for the purposes of criticism, commentary, news reporting, teaching, scholarship, or research. By protecting the rights of authors and creators while also allowing for the use of copyrighted works for the public benefit, copyright law aims to strike a balance between the interests of authors and the public.

Inputs – Training ChatGPT with Copyrighted Material

ChatGPT was trained on a large training dataset sourced from the internet, including a vast amount of text from websites, articles, books, social media posts, and academic papers. Importantly, ChatGPT was not aware of the source of the data, it only saw the text and learned the patterns and relationships between the words, phrases and sentences. The vast majority of the text used to train ChatGPT was certainly subject to copyright protection—except for text that is in the public domain like facts or discoveries or works whose term of copyright protection has ended.

Did the ChatGPT training process violate the copyright of the original authors? To answer that question we must determine: if during the training process OpenAI copied the underlying works—because copyright infringement requires an act of copying works that are protected by copyright; is the output of ChatGPT a “derivative work” under copyright law; and would such copying or production of a derivate work fall under the “fair use” exception of copyright law.

Copying During Training

We are not aware of publicly available information regarding whether, during the training process, the training text for ChatGPT was copied or simply referenced. Therefore, we asked ChatGPT and received this answer:

Prompt: During the ChatGPT training process, was the underlying training text copied into a OpenAI database?

Answer: During the training process, text from various sources is used to train the ChatGPT model. It is likely that the text was copied into an internal database at OpenAI for the purpose of training the model. However, the training text is typically preprocessed to remove any sensitive information such as personal identifiers, copyrighted text, etc. In addition, the text is also used to train the model and not stored in a database. The model uses the text to learn patterns and structure of the language and once the training is done, it doesn’t require the text anymore.

So, it seems that during the training process, text was copied. It is also interesting that ChatGPT stated that the training text was “preprocessed” to remove any copyrighted text. That seems highly unlikely since otherwise nearly all text would have been removed.

Is ChatGPT Output a Derivative Work?

Under US copyright law, the owner of a copyright has the exclusive right “to prepare derivative works based upon the copyrighted work.” A “derivative work” is “a work based upon one or more preexisting works.” ChatGPT is trained on preexisting works and generates output based on that training.

As Daniel Gervais, a professor at Vanderbilt Law School who specializes in intellectual property law, says, the definition of a derivative work under copyright law “could loosely be used as a definition of machine learning when applied to the creation of literary and artistic productions because AI machines can produce literary and artistic content (output) that is almost necessarily ‘based upon’ a dataset consisting of preexisting works.” Under this view, it seems that all ChatGPT output is a derivative work under copyright law.

On a related point, it is worth noting that in producing its output, ChatGPT is not “copying” anything. ChatGPT generates text based on the context of the input and the words and phrase patterns it was trained on. ChatGPT is not “copying” and then changing text.

What About Fair Use?

Let’s assume that the underlying text was copied in some way during the ChatGPT training process. Let’s further assume that outputs from Chatto are, at least sometimes, derivative works under copyright law. If that is the case, do copyright owners of the original works have a copyright infringement claim against OpenAI? Not if the copying and the output generation are covered by the doctrine of “fair use.” If a use qualifies as fair use, then actions that would otherwise be prohibited would not be deemed an infringement of copyright.

In determining whether the use made of a work in any particular case is a fair use, the factors include:

  •  The purpose and character of the use, including whether such use is of a commercial nature or is for nonprofit educational purposes.
  •  The nature of the copyrighted work.
  •  The amount and substantiality of the portion used in relation to the copyrighted work as a whole.
  •  The effect of the use upon the potential market for or value of the copyrighted work.

In this case, assuming OpenAI copied copyrighted text as part of the ChatGPT training process, such copying was not for a commercial purpose and had no economic impact on the copyright owner. Daniel Gervais says “it is much more likely than not” that training systems on copyrighted data will be covered by fair use.

In determining if a commercial use will be considered “fair use,” the courts will primarily look at the scope and purpose of the use and the economic impact of such use. Does the use in question change the nature of the underlying copyright material in some material way (described as a “transformative” use) and does it economically impact the original copyright holder?

Without a specific example, it is difficult to determine exactly if a resulting output from ChatGPT would be fair use. The fact that ChatGPT does not copy and has been trained on millions of underlying works, it seems likely most output would be fair use—without using significant portions of any one protected work. In addition, because of the vast corpus of text used to train ChatGPT, it seems unlikely that ChatGPT output will have a negative economic impact on any one copyright holder. But, given the capabilities of ChatGPT, that might not always be the case.

Imagine if you asked ChatGPT to “Write a long-form, coming of age, story in the style of J.K. Rowling, using the characters from Harry Potter and the Chamber of Secrets.” In that case, it would seem that the argument for fair use would be weak. This story could be sold to the public and could conceivably have a negative economic impact on J.K. Rowling. A person that wants to read a story about Harry Potter might buy this story instead of buying a book by J. K. Rowling.

Finally, it is worth noting that OpenAI is a non-profit entity that is a “AI research and deployment company.” It seems that OpenAI is the type of research company, and ChatGPT is the type of research project, that would have a strong argument for fair use. This practice has been criticized as “AI Data Laundering,” shielding commercial entities from liability by using a non-profit research institution to create the data set and train AI engines that might later be used in commercial applications.

Outputs – Can the Output of ChatGPT be Protected by Copyright

Is the output of ChatGPT protected by copyright law and, if so, who is the owner? As an initial matter, does the ChatGPT textual output fit within the definition of what is covered under copyright law: “original works of authorship fixed in any tangible medium of expression.”

The text generated by ChatGPT is the type of subject matter that, if created by a human, would be covered by copyright. However, most scholars have opined, and the US Copyright Office has ruled that the output of generative AI systems, like ChatGPT, are not protectable under US copyright law because the work must be an original, creative work of a human author.

In 2022, the US Copyright Office, ruling on whether a picture generated completely autonomously by AI could be registered as a valid copyright, stated “[b]because copyright law as codified in the 1976 Act requires human authorship, the [AI Generated] Work cannot be registered.” The U.S. Copyright Office has issued several similar statements, informing creators that it will not register copyright for works produced by a machine or computer program. The human authorship requirement of the US Copyright Office is set forth as follows:

The Human Authorship Requirement – The U.S. Copyright Office will register an original work of authorship, provided that the work was created by a human being. The copyright law only protects “the fruits of intellectual labor” that “are founded in the creative powers of the mind.” Trade-Mark Cases, 100 U.S. 82, 94 (1879).

While such policies are not binding on the courts, the stance by the US Copyright Office seems to be in line with the purpose of copyright law flowing from the Constitution: to incentivize humans to produce creative works by giving them a monopoly over their creations for a limited period of time. Machines, of course, need and have no such motivation. In fact, copyright law expressly allows a corporation or other legal entity to be the owner of a copyright under the “work made for hire” doctrine. However, to qualify as a work made for hire, the work must be either work prepared by an employee within the scope of his or her employment, or be prepared by a party who “expressly agrees in a written instrument signed by them that the work shall be considered a work made for hire.” Only humans can be employees and only humans or corporations can enter a legally binding contract—machines cannot.

Other articles of note in this Open Access Scientific Journal on ChatGPT and Open AI Include:

Medicine with GPT-4 & ChatGPT

ChatGPT applied to Cancer & Oncology

ChatGPT applied to Medical Imaging & Radiology

ChatGPT applied to Cardiovascular diseases: Diagnosis and Management

The Use of ChatGPT in the World of BioInformatics and Cancer Research and Development of BioGPT by MIT





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Structure-guided Drug Discovery: (1) The Coronavirus 3CL hydrolase (Mpro) enzyme (main protease) essential for proteolytic maturation of the virus and (2) viral protease, the RNA polymerase, the viral spike protein, a viral RNA as promising two targets for discovery of cleavage inhibitors of the viral spike polyprotein preventing the Coronavirus Virion the spread of infection


Curators and Reporters: Stephen J. Williams, PhD and Aviva Lev-Ari, PhD, RN


Therapeutical options to coronavirus (2019-nCoV) include consideration of the following:

(a) Monoclonal and polyclonal antibodies

(b)  Vaccines

(c)  Small molecule treatments (e.g., chloroquinolone and derivatives), including compounds already approved for other indications 

(d)  Immuno-therapies derived from human or other sources



Structure of the nCoV trimeric spike

The World Health Organization has declared the outbreak of a novel coronavirus (2019-nCoV) to be a public health emergency of international concern. The virus binds to host cells through its trimeric spike glycoprotein, making this protein a key target for potential therapies and diagnostics. Wrapp et al. determined a 3.5-angstrom-resolution structure of the 2019-nCoV trimeric spike protein by cryo–electron microscopy. Using biophysical assays, the authors show that this protein binds at least 10 times more tightly than the corresponding spike protein of severe acute respiratory syndrome (SARS)–CoV to their common host cell receptor. They also tested three antibodies known to bind to the SARS-CoV spike protein but did not detect binding to the 2019-nCoV spike protein. These studies provide valuable information to guide the development of medical counter-measures for 2019-nCoV. [Bold Face Added by ALA]

Science, this issue p. 1260


The outbreak of a novel coronavirus (2019-nCoV) represents a pandemic threat that has been declared a public health emergency of international concern. The CoV spike (S) glycoprotein is a key target for vaccines, therapeutic antibodies, and diagnostics. To facilitate medical countermeasure development, we determined a 3.5-angstrom-resolution cryo–electron microscopy structure of the 2019-nCoV S trimer in the prefusion conformation. The predominant state of the trimer has one of the three receptor-binding domains (RBDs) rotated up in a receptor-accessible conformation. We also provide biophysical and structural evidence that the 2019-nCoV S protein binds angiotensin-converting enzyme 2 (ACE2) with higher affinity than does severe acute respiratory syndrome (SARS)-CoV S. Additionally, we tested several published SARS-CoV RBD-specific monoclonal antibodies and found that they do not have appreciable binding to 2019-nCoV S, suggesting that antibody cross-reactivity may be limited between the two RBDs. The structure of 2019-nCoV S should enable the rapid development and evaluation of medical countermeasures to address the ongoing public health crisis.

Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation
  1. Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA.

  2. 2Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
  1. Corresponding author. Email: jmclellan@austin.utexas.edu
  1. * These authors contributed equally to this work.

Science  13 Mar 2020:
Vol. 367, Issue 6483, pp. 1260-1263
DOI: 10.1126/science.abb2507



New Coronavirus Protease Structure Available

PDB data provide a starting point for structure-guided drug discovery

A high-resolution crystal structure of COVID-19 (2019-nCoV) coronavirus 3CL hydrolase (Mpro) has been determined by Zihe Rao and Haitao Yang’s research team at ShanghaiTech University. Rapid public release of this structure of the main protease of the virus (PDB 6lu7) will enable research on this newly-recognized human pathogen.

Recent emergence of the COVID-19 coronavirus has resulted in a WHO-declared public health emergency of international concern. Research efforts around the world are working towards establishing a greater understanding of this particular virus and developing treatments and vaccines to prevent further spread.

While PDB entry 6lu7 is currently the only public-domain 3D structure from this specific coronavirus, the PDB contains structures of the corresponding enzyme from other coronaviruses. The 2003 outbreak of the closely-related Severe Acute Respiratory Syndrome-related coronavirus (SARS) led to the first 3D structures, and today there are more than 200 PDB structures of SARS proteins. Structural information from these related proteins could be vital in furthering our understanding of coronaviruses and in discovery and development of new treatments and vaccines to contain the current outbreak.

The coronavirus 3CL hydrolase (Mpro) enzyme, also known as the main protease, is essential for proteolytic maturation of the virus. It is thought to be a promising target for discovery of small-molecule drugs that would inhibit cleavage of the viral polyprotein and prevent spread of the infection.

Comparison of the protein sequence of the COVID-19 coronavirus 3CL hydrolase (Mpro) against the PDB archive identified 95 PDB proteins with at least 90% sequence identity. Furthermore, these related protein structures contain approximately 30 distinct small molecule inhibitors, which could guide discovery of new drugs. Of particular significance for drug discovery is the very high amino acid sequence identity (96%) between the COVID-19 coronavirus 3CL hydrolase (Mpro) and the SARS virus main protease (PDB 1q2w). Summary data about these closely-related PDB structures are available (CSV) to help researchers more easily find this information. In addition, the PDB houses 3D structure data for more than 20 unique SARS proteins represented in more than 200 PDB structures, including a second viral protease, the RNA polymerase, the viral spike protein, a viral RNA, and other proteins (CSV).

Public release of the COVID-19 coronavirus 3CL hydrolase (Mpro), at a time when this information can prove most vital and valuable, highlights the importance of open and timely availability of scientific data. The wwPDB strives to ensure that 3D biological structure data remain freely accessible for all, while maintaining as comprehensive and accurate an archive as possible. We hope that this new structure, and those from related viruses, will help researchers and clinicians address the COVID-19 coronavirus global public health emergency.

Update: Released COVID-19-related PDB structures include

  • PDB structure 6lu7 (X. Liu, B. Zhang, Z. Jin, H. Yang, Z. Rao Crystal structure of COVID-19 main protease in complex with an inhibitor N3 doi: 10.2210/pdb6lu7/pdb) Released 2020-02-05
  • PDB structure 6vsb (D. Wrapp, N. Wang, K.S. Corbett, J.A. Goldsmith, C.-L. Hsieh, O. Abiona, B.S. Graham, J.S. McLellan (2020) Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation Science doi: 10.1126/science.abb2507) Released 2020-02-26
  • PDB structure 6lxt (Y. Zhu, F. Sun Structure of post fusion core of 2019-nCoV S2 subunit doi: 10.2210/pdb6lxt/pdb) Released 2020-02-26
  • PDB structure 6lvn (Y. Zhu, F. Sun Structure of the 2019-nCoV HR2 Domain doi: 10.2210/pdb6lvn/pdb) Released 2020-02-26
  • PDB structure 6vw1
    J. Shang, G. Ye, K. Shi, Y.S. Wan, H. Aihara, F. Li Structural basis for receptor recognition by the novel coronavirus from Wuhan doi: 10.2210/pdb6vw1/pdb
    Released 2020-03-04
  • PDB structure 6vww
    Y. Kim, R. Jedrzejczak, N. Maltseva, M. Endres, A. Godzik, K. Michalska, A. Joachimiak, Center for Structural Genomics of Infectious Diseases Crystal Structure of NSP15 Endoribonuclease from SARS CoV-2 doi: 10.2210/pdb6vww/pdb
    Released 2020-03-04
  • PDB structure 6y2e
    L. Zhang, X. Sun, R. Hilgenfeld Crystal structure of the free enzyme of the SARS-CoV-2 (2019-nCoV) main protease doi: 10.2210/pdb6y2e/pdb
    Released 2020-03-04
  • PDB structure 6y2f
    L. Zhang, X. Sun, R. Hilgenfeld Crystal structure (monoclinic form) of the complex resulting from the reaction between SARS-CoV-2 (2019-nCoV) main protease and tert-butyl (1-((S)-1-(((S)-4-(benzylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)carbamate (alpha-ketoamide 13b) doi: 10.2210/pdb6y2f/pdb
    Released 2020-03-04
  • PDB structure 6y2g
    L. Zhang, X. Sun, R. Hilgenfeld Crystal structure (orthorhombic form) of the complex resulting from the reaction between SARS-CoV-2 (2019-nCoV) main protease and tert-butyl (1-((S)-1-(((S)-4-(benzylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)carbamate (alpha-ketoamide 13b) doi: 10.2210/pdb6y2g/pdb
    Released 2020-03-04
First page image


Coronavirus disease 2019 (COVID-19) is a global pandemic impacting nearly 170 countries/regions and more than 285,000 patients worldwide. COVID-19 is caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), which invades cells through the angiotensin converting enzyme 2 (ACE2) receptor. Among those with COVID-19, there is a higher prevalence of cardiovascular disease and more than 7% of patients suffer myocardial injury from the infection (22% of the critically ill). Despite ACE2 serving as the portal for infection, the role of ACE inhibitors or angiotensin receptor blockers requires further investigation. COVID-19 poses a challenge for heart transplantation, impacting donor selection, immunosuppression, and post-transplant management. Thankfully there are a number of promising therapies under active investigation to both treat and prevent COVID-19. Key Words: COVID-19; myocardial injury; pandemic; heart transplant




  • Towler P, Staker B, Prasad SG, Menon S, Tang J, Parsons T, Ryan D, Fisher M, Williams D, Dales NA, Patane MA, Pantoliano MW (Apr 2004). “ACE2 X-ray structures reveal a large hinge-bending motion important for inhibitor binding and catalysis”The Journal of Biological Chemistry279 (17): 17996–8007. doi:10.1074/jbc.M311191200PMID 14754895.


  • Turner AJ, Tipnis SR, Guy JL, Rice G, Hooper NM (Apr 2002). “ACEH/ACE2 is a novel mammalian metallocarboxypeptidase and a homologue of angiotensin-converting enzyme insensitive to ACE inhibitors”Canadian Journal of Physiology and Pharmacology80 (4): 346–53. doi:10.1139/y02-021PMID 12025971.


  •  Zhang, Haibo; Penninger, Josef M.; Li, Yimin; Zhong, Nanshan; Slutsky, Arthur S. (3 March 2020). “Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target”Intensive Care Medicine. Springer Science and Business Media LLC. doi:10.1007/s00134-020-05985-9ISSN 0342-4642PMID 32125455.


  • ^ Gurwitz, David (2020). “Angiotensin receptor blockers as tentative SARS‐CoV‐2 therapeutics”Drug Development Researchdoi:10.1002/ddr.21656PMID 32129518.


Angiotensin converting enzyme 2 (ACE2)

is an exopeptidase that catalyses the conversion of angiotensin I to the nonapeptide angiotensin[1-9][5] or the conversion of angiotensin II to angiotensin 1-7.[6][7] ACE2 has direct effects on cardiac functiona and is expressed predominantly in vascular endothelial cells of the heart and the kidneys.[8] ACE2 is not sensitive to the ACE inhibitor drugs used to treat hypertension.[9]

ACE2 receptors have been shown to be the entry point into human cells for some coronaviruses, including the SARS virus.[10] A number of studies have identified that the entry point is the same for SARS-CoV-2,[11] the virus that causes COVID-19.[12][13][14][15]

Some have suggested that a decrease in ACE2 could be protective against Covid-19 disease[16], but others have suggested the opposite, that Angiotensin II receptor blocker drugs could be protective against Covid-19 disease via increasing ACE2, and that these hypotheses need to be tested by datamining of clinical patient records.[17]





We need your help! Folding@home is joining researchers around the world working to better understand the 2019 Coronavirus (2019-nCoV) to accelerate the open science effort to develop new life-saving therapies. By downloading Folding@Home, you can donate your unused computational resources to the Folding@home Consortium, where researchers working to advance our understanding of the structures of potential drug targets for 2019-nCoV that could aid in the design of new therapies. The data you help us generate will be quickly and openly disseminated as part of an open science collaboration of multiple laboratories around the world, giving researchers new tools that may unlock new opportunities for developing lifesaving drugs.

2019-nCoV is a close cousin to SARS coronavirus (SARS-CoV), and acts in a similar way. For both coronaviruses, the first step of infection occurs in the lungs, when a protein on the surface  of the virus binds to a receptor protein on a lung cell. This viral protein is called the spike protein, depicted in red in the image below, and the receptor is known as ACE2. A therapeutic antibody is a type of protein that can block the viral protein from binding to its receptor, therefore preventing the virus from infecting the lung cell. A therapeutic antibody has already been developed for SARS-CoV, but to develop therapeutic antibodies or small molecules for 2019-nCoV, scientists need to better understand the structure of the viral spike protein and how it binds to the human ACE2 receptor required for viral entry into human cells.

Proteins are not stagnant—they wiggle and fold and unfold to take on numerous shapes.  We need to study not only one shape of the viral spike protein, but all the ways the protein wiggles and folds into alternative shapes in order to best understand how it interacts with the ACE2 receptor, so that an antibody can be designed. Low-resolution structures of the SARS-CoV spike protein exist and we know the mutations that differ between SARS-CoV and 2019-nCoV.  Given this information, we are uniquely positioned to help model the structure of the 2019-nCoV spike protein and identify sites that can be targeted by a therapeutic antibody. We can build computational models that accomplish this goal, but it takes a lot of computing power.

This is where you come in! With many computers working towards the same goal, we aim to help develop a therapeutic remedy as quickly as possible. By downloading Folding@home here [LINK] and selecting to contribute to “Any Disease”, you can help provide us with the computational power required to tackle this problem. One protein from 2019-nCoV, a protease encoded by the viral RNA, has already been crystallized. Although the 2019-nCoV spike protein of interest has not yet been resolved bound to ACE2, our objective is to use the homologous structure of the SARS-CoV spike protein to identify therapeutic antibody targets.

This illustration, created at the Centers for Disease Control and Prevention (CDC), reveals ultrastructural morphology exhibited by coronaviruses. Note the spikes that adorn the outer surface of the virus, which impart the look of a corona surrounding the virion, when viewed electron microscopically. A novel coronavirus virus was identified as the cause of an outbreak of respiratory illness first detected in Wuhan, China in 2019.

Image and Caption Credit: Alissa Eckert, MS; Dan Higgins, MAM available at https://phil.cdc.gov/Details.aspx?pid=23311

Structures of the closely related SARS-CoV spike protein bound by therapeutic antibodies may help rapidly design better therapies. The three monomers of the SARS-CoV spike protein are shown in different shades of red; the antibody is depicted in green. [PDB: 6NB7 https://www.rcsb.org/structure/6nb7]

(post authored by Ariana Brenner Clerkin)


PDB 6lu7 structure summary ‹ Protein Data Bank in Europe (PDBe) ‹ EMBL-EBI https://www.ebi.ac.uk/pdbe/entry/pdb/6lu7 (accessed Feb 5, 2020).

Tian, X.; Li, C.; Huang, A.; Xia, S.; Lu, S.; Shi, Z.; Lu, L.; Jiang, S.; Yang, Z.; Wu, Y.; et al. Potent Binding of 2019 Novel Coronavirus Spike Protein by a SARS Coronavirus-Specific Human Monoclonal Antibody; preprint; Microbiology, 2020. https://doi.org/10.1101/2020.01.28.923011.

Walls, A. C.; Xiong, X.; Park, Y. J.; Tortorici, M. A.; Snijder, J.; Quispe, J.; Cameroni, E.; Gopal, R.; Dai, M.; Lanzavecchia, A.; et al. Unexpected Receptor Functional Mimicry Elucidates Activation of Coronavirus Fusion. Cell 2019176, 1026-1039.e15. https://doi.org/10.2210/pdb6nb7/pdb.



UPDATED 3/13/2020

I am reposting the following Science blog post from Derrick Lowe as is and ask people go browse through the comments on his Science blog In the Pipeline because, as Dr. Lowe states that in this current crisis it is important to disseminate good information as quickly as possible so wanted the readers here to have the ability to read his great posting on this matter of Covid-19.  Also i would like to direct readers to the journal Science opinion letter concerning how important it is to rebuild the trust in good science and the scientific process.  The full link for the following In the Pipeline post is: https://blogs.sciencemag.org/pipeline/archives/2020/03/06/covid-19-small-molecule-therapies-reviewed

A Summary of current potential repurposed therapeutics for COVID-19 Infection from In The Pipeline: A Science blog from Derick Lowe

Covid-19 Small Molecule Therapies Reviewed

Let’s take inventory on the therapies that are being developed for the coronavirus epidemic. Here is a very thorough list of at Biocentury, and I should note that (like Stat and several other organizations) they’re making all their Covid-19 content free to all readers during this crisis. I’d like to zoom in today on the potential small-molecule therapies, since some of these have the most immediate prospects for use in the real world.

The ones at the front of the line are repurposed drugs that are already approved for human use, for a lot of obvious reasons. The Biocentury list doesn’t cover these, but here’s an article at Nature Biotechnology that goes into detail. Clinical trials are a huge time sink – they sort of have to be, in most cases, if they’re going to be any good – and if you’ve already done all that stuff it’s a huge leg up, even if the drug itself is not exactly a perfect fit for the disease. So what do we have? The compound that is most advanced is probably remdesivir from Gilead, at right. This has been in development for a few years as an RNA virus therapy – it was originally developed for Ebola, and has been tried out against a whole list of single-strand RNA viruses. That includes the related coronaviruses SARS and MERS, so Covid-19 was an obvious fit.

The compound is a prodrug – that phosphoramide gets cleaved off completely, leaving the active 5-OH compound GS-44-1524. It mechanism of action is to get incorporated into viral RNA, since it’s taken up by RNA polymerase and it largely seems to evade proofreading. This causes RNA termination trouble later on, since that alpha-nitrile C-nucleoside is not exactly what the virus is expecting in its genome at that point, and thus viral replication is inhibited.

There are five clinical trials underway (here’s an overview at Biocentury). The NIH has an adaptive-design Phase II trial that has already started in Nebraska, with doses to be changed according to Bayesian readouts along the way. There are two Phase III trials underway at China-Japan Friendship Hospital in Hubei, double-blinded and placebo-controlled (since placebo is, as far as drug therapy goes, the current standard of care). And Gilead themselves are starting two open-label trials, one with no control arm and one with an (unblinded) standard-of-care comparison arm. Those might read out first, depending on when they get off the ground, but will be only rough readouts due to the fast-and-loose trial design. The two Hubei trials and the NIH one will add some rigor to the process, but I’m not sure when they’re going to report. My personal opinion is that I like the chances of this drug more than anything else on this list, but it’s still unlikely to be a game-changer.

There’s an RNA polymerase inhibitor (favipiravir) from Toyama, at right, that’s in a trial in China. It’s a thought – a broad-spectrum agent of this sort would be the sort of thing to try. But unfortunately, from what I can see, it has already turned up as ineffective in in vitro tests. The human trial that’s underway is honestly the sort of thing that would only happen under circumstances like the present: a developing epidemic with a new pathogen and no real standard of care. I hold out little hope for this one, but given that there’s nothing else at present, it probably should be tried. As you’ll see, this is far from the only situation like this.

One of the screens of known drugs in China that also flagged remdesivir noted that the old antimalarial drug chloroquine seemed to be effective in vitro. It had been reported some years back as a possible antiviral, working through more than one mechanism, probably both at viral entry and intracellularly thereafter. That part shouldn’t be surprising – chloroquine’s actual mode(s) of action against malaria parasites are still not completely worked out, either, and some of what people thought they knew about it has turned out to be wrong. There are several trials underway with it at Chinese facilities, some in combination with other agents like remdesivir. Chloroquine has of course been taken for many decades as an antimalarial, but it has a number of liabilities, including seizures, hearing damage, retinopathy and sudden effects on blood glucose. So it’s going to be important to establish just how effective it is and what doses will be needed. Just as with vaccine candidates, it’s possible to do more harm with a rushed treatment than the disease is doing itself

There are several other known antiviral drugs are being tried in China, but I don’t have too much hope for those, either. The neuraminidase inhibitors such as oseltamivir (better known as Tamiflu) were tried against SARS and were ineffective; there is no reason to expect anything versus Covid-19 although these drugs are a component of some drug cocktail trials. The HIV protease therapies such as darunavir and the combination therapy Kaletra are in trials, but that’s also a rather desperate long shot, since there’s no particular reason to think that they will have any such protease inhibition against what this new virus has to offer (and indeed, such agents weren’t much help against SARS in the end, either). The classic interferon/ribavirin combination seems to have had some activity against SARS and MERS, and is in two trials from what I can see. That’s not an awful idea by any means, but it’s not a great one, either: if your viral disease has interferon/ribavirin as a front line therapy, it generally means that there’s nothing really good available. No, unless we get really lucky none of these ideas are going to slow the disease down much.

There are a few other repurposed-protease-inhibitors ideas out there, such as this one. (Edit: I had seen this paper but couldn’t track it down, so thanks to those who sent it along). This paper suggests that the TMPRSS2 protease is important for viral entry on the human-cell-side of the process, a pathway that has been noted for other coronaviruses. And it points out that there is a an approved inhibitor (in Japan) for this enzyme (camostat), so that would definitely seem to be worth a trial, probably in combination with remdesivir.

That’s about it for the existing small molecules, from what I can see. What about new ones? Don’t hold your breath, is all I can say. A drug discovery program from scratch against a new pathogen is, as many readers here well know, not a trivial exercise. As this Bloomberg article details, many such efforts in the past (small molecules and vaccines alike) have come to grief because by the time they had anything to deliver the epidemic itself had passed. Indeed, Gilead’s remdesivir had already been dropped as a potential Ebola therapy.

You will either need to have a target in mind up front or go phenotypic. For the former, what you’d see are better characterizations of the viral protease and more extensive screens against it. Two other big target areas are viral entry (which involves the “spike” proteins on the virus surface and the ACE2 protein on human cells) and viral replication. To the former, it’s worth quickly noting that ACE2 is so much unlike the more familiar ACE protein that none of the cardiovascular ACE inhibitors do anything to it at all. And targeting the latter mechanisms is how remdesivir was developed as a possible Ebola agent, but as you can see, that took time, too. Phenotypic screens are perfectly reasonable against viral pathogens as well, but you’ll need to put time and effort into that assay up front, just as with any phenotypic effort, because as anyone who does that sort of work will tell you, a bad phenotypic screen is a complete waste of everyone’s time.

One of the key steps for either route is identifying an animal model. While animal models of infectious disease can be extremely well translated to human therapy, that doesn’t happen by accident: you need to choose the right animal. Viruses in general (and coronaviruses are no exception) vary widely in their effects in different species, and not just across the gaps of bird/reptile/human and the like. No, you’ll run into things where even the usual set of small mammals are acting differently from each other, with some of them not even getting sick at all. This current virus may well have gone through a couple of other mammalian species before landing on us, but you’ll note that dogs (to pick one) don’t seem to have any problem with it.

All this means that any new-target new-chemical-matter effort against Covid-19 (or any new pathogen) is going to take years, and there is just no way around that. Update: see here for just such an effort to start finding fragment hits for the viral protease. This puts small molecules in a very bimodal distribution: you have the existing drugs that might be repurposed, and are presumably available right now. Nothing else is! At the other end, for completely new therapies you have the usual prospects of drug discovery: years from now, lots of money, low success rate, good luck to all of us. The gap between these two could in theory be filled by vaccines and antibody therapies (if everything goes really, really well) but those are very much their own area and will be dealt with in a separate post.

Either way, the odds are that we (and I mean “we as a species” here) are going to be fighting this epidemic without any particularly amazing pharmacological weapons. Eventually we’ll have some, but I would advise people, pundits, and politicians not to get all excited about the prospects for some new therapies to come riding up over the hill to help us out. The odds of that happening in time to do anything about the current outbreak are very small. We will be going for months, years, with the therapeutic options we have right now. Look around you: what we have today is what we have to work with.

Other related articles published in this Open Access Online Scientific Journal include the following:


Group of Researchers @ University of California, Riverside, the University of Chicago, the U.S. Department of Energy’s Argonne National Laboratory, and Northwestern University solve COVID-19 Structure and Map Potential Therapeutics

Reporters: Stephen J Williams, PhD and Aviva Lev-Ari, PhD, RN


Predicting the Protein Structure of Coronavirus: Inhibition of Nsp15 can slow viral replication and Cryo-EM – Spike protein structure (experimentally verified) vs AI-predicted protein structures (not experimentally verified) of DeepMind (Parent: Google) aka AlphaFold

Curators: Stephen J. Williams, PhD and Aviva Lev-Ari, PhD, RN



Coronavirus facility opens at Rambam Hospital using new Israeli tech



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How the ACLU Won the Fight Against Patenting Genes: Article and video on  the History of the Issue of Gene Patents

Curator: Stephen J. Williams, PhD


please see the TED talk below on how ACLU took on the Gene Patenting Industry:

Tania Simoncelli – How I took on the gene patent industry — and won – Ted Talks 2016

This fight started with the patenting of the BRCA1/2 gene mutants, which increase the risk of breast/ovarian cancer in women who harbor these mutation as well as their offspring, which would be the basis for genetic testing services offered by Myriad Genetics.

However, as seen below, these patent fights and the patenting of DNA has been around since the mid 1970’s, with the advent of cloning and other molecular biology techniques.


Robert Cook-Deegan and Christopher Heaney in Annu Rev Genomics Hum Genet. 2010 Sep 22; 11: 383–425.

In April 2009, the U.S. Patent and Trademark Office (USPTO) granted the 50,000th U.S. patent that entered the DNA Patent Database at Georgetown University. That database includes patents that make claims mentioning terms specific to nucleic acids (e.g., DNA, RNA, nucleotide, plasmid, etc.) (64). The specificity of many terms unique to nucleic acid structures makes it possible to monitor patents that correspond to and arise largely from research in genetics and genomics. Patents have been a part of the story of the rise of genetics and genomics since the 1970s, and not just because they can be counted but also because science and commerce have been deeply intertwined, one chapter in the story of modern biotechnology in medicine, agriculture, energy, environment, and other economic sectors. The first DNA patents were granted in the 1970s, but numbers surged in the mid-1990s as molecular genetic techniques began to produce patentable inventions.

This database (Delphion Patent Database) can be reached at (http://www.delphion.com).

From Cook-Deegan, R. and C. Heany. Annu Rev Genomics Hum Genet. 2010 Sep 22; 11: 383–425.

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U.S. Patents: DNA Patents and Patent Applications by Year, 1984–2008. The DNA Patent Database contains patents obtained by searching the Delphion Patent Database (http://www.delphion.com) with an algorithm posted on the DNA Patent Database website that searches for granted U.S. patents (since 1971) and published applications (since 2001) in U.S. patent classes related to genetics and genomics as well as claims that include words specific to nucleic acids, genetics, and genomics. The year 1984 is the first for which more than 100 granted patents are in the DNA Patent Database. Data from Reference 64.

The authors make several points concerning obtaining patents in the genomics field including:

  • Differences in patent practice can be important to scientists working in genetics and genomics. In the United States, a patent goes to the first inventor. If patents or patent applications overlap and the first person to invent is in dispute, then the patent office initiates what’s called an interference proceeding, with intricate rules about deciding priority of invention.
  • Interferences are more than twice as common in biotechnology patents than in any other patent class, six times higher than patents on average (140).
  • The United States also allows a year’s grace period from publication of information pertinent to a patent claim, whereas any public disclosure becomes “prior art” that can defeat patent claims in other jurisdictions.


International harmonization of DNA patents exist including:

  1. 1973 European Patent Convention created the European Patent Office (EPO). EPO can issue a patent valid in signatory countries
  2. 1995 Trade-Related Aspects of Intellectual Property Rights (TRIPS) agreement committed signatory countries to adopt patent standards mainly modeled on the developed-country model of strong patent protection
  3. 1998 Biotechnology Directive: the Directive became an important element of European patent law that binds national governments to comply with it
  4. Both the United States House and Senate of the 111th Congress are considering bills similar to one passed by the House of Representatives (but not the Senate) in the 110th Congress (2007–2008). Two provisions particularly relevant to genetic and genomic inventions are (a) shifting from the current “first to invent” U.S. standard to “first inventor to file,” as in the rest of the world; and (b) establishing a mechanism to challenge patent claims closer to the European opposition process.

top 30 institutions holding patents in the DNA Patent Database. Among them are

  1. Agribusiness and chemical companies (Monsanto and DuPont)
  2. U.S. Government (largely attributable to the large intramural research program at the National Institutes of Health)
  3. Public and private universities (Universities of California and Texas, Johns Hopkins, Harvard, Stanford, MIT, etc.)
  4. Pharmaceutical firms (Novartis, Glaxo SmithKline, Pfizer, Merck, SanofiAventis, Takeda, Bayer, Novo Nordisk, Lilly, etc.)
  5. Established biotechnology firms (Genentech, Amgen, Genzyme, ISIS, etc.)
  6. Firms created to exploit genomic technologies (Incyte, Human Genome Sciences, etc.)
  7. Instrumentation and DNA chip firms (LifeTechnologies, Affymetrix, Becton, Dickinson, etc.)
  8. Academic research institutes (Institut Pasteur, Salk, Scripps, and Ludwig Institutes, Cold Spring Harbor Laboratories, etc.)
  9. Hospitals with research units (e.g., Massachusetts General Hospital)







Top U.S. DNA patent holders. The authors compiled a list of assignees with at least 100 patents, combined different names for the same assignee, and updated names to reflect corporate mergers and acquisitions. Patent counts are from the Delphion Patent Database for U.S. patents granted as of October 26, 2009, using the DNA Patent Database algorithm (64). Data from Reference 64. From Cook-Deegan, R. and C. Heany. Annu Rev Genomics Hum Genet. 2010 Sep 22; 11: 383–425.

And an opinion article by Harvard Law School arguing against the patent-ability of natural products such as DNA:

DNA Sequences as Unpatentable Subject Matter

by  Victor Song & Prof. Peter Hutt

How Merck’s attempt to patent Vitamin B12 may have started a precedent:

In addition to Kuehmsted, the case most frequently cited to support the patentability of “purified and isolated” substances is Merck & Company v. Olin Mathieson Chemical Corporation [44] . In 1958, the United States Court of Appeals for the Fourth Circuit addressed the metes and bounds of the product of nature exception in Merck . The invention at the center of Merck was entitled, “Vitamin B(12)-Active Composition and Process of Preparing Same”.

Prior to the discovery claimed by the patent, vitamin B(12) was unknown to man. What had been known was that patients who had pernicious anemia could mitigate the effects of their condition by consuming cow liver. For years the scientific community analyzed cow liver to determine what in cow liver was the therapeutically active compound. For lack of a better term, scientists named this unknown therapeutic agent the “anti-pernicious anemia” compound.

After a considerable amount of chemical analysis, scientists at Merck isolated the “anti-pernicious anemia” compound in cow liver. They also discovered an alternate source of the “anti-pernicious anemia” compound. Merck scientists were able to harvest the “anti-pernicious anemia” compound from the fermenting eluent of certain microorganisms. After isolating and characterizing the structure of the newly found “anti-pernicious anemia” compound, the scientist renamed it vitamin B(12) for its chemical similarities to the vitamin B family.

Having discovered vitamin B(12), Merck filed for and obtained U.S. patent 2,703,302 (‘the ‘302 patent”) covering both the process of making vitamin B(12) and the actual chemical compound for vitamin B(12). Only the product claims were at issue in Merck [45] . A representative product claim reads:

A vitamin B(12)-active composition comprising recovered elaboration products of the fermentation of a vitamin B(12)-activity producing strain of Fungi selected from the class consisting of Schizomycetes, Torula, and Eremothecium, the L.L.D. activity of said composition being at least 440 L.L.D. units per milligram and less than 11 million L.L.D. units per milligram.[46]

Prior to the appeal, the district court had determined that the product claims were invalid as products of nature. The Court of Appeals for the Fourth Circuit reversed. In reversing the District Court, the Fourth Circuit followed a line of reasoning similar to Kuehmsted.The Court of Appeals reasoned that the product of nature was the unpurified fermenting eluent which had no therapeutic value. However, Merck’s purified fermenting eluent had therapeutic value. Thus, the court believed Merck’s purified product, which was essentially vitamin B(12), was a different from unpurified fermenting eluent. Since Merck’s purified product was different from the product of nature, the court reasoned that it could not be a product of nature.

The main weakness in the Merck decision is similar to weakness of the Kuehmsted decision. Can vitamin B(12) be considered “new” if it always existed in cow liver? In addition, is it necessary to grant Merck both product and process claims? Even without the product claims, Merck will still be able to profit handsomely from the process claims alone. In addition, Merck could have applied for a vitamin B(12) use patent. Merck could have patented the therapeutic use of their vitamin B(12) for treating pernicious anemia.

There are two interesting aspects of the courts decision in Merck . First, in coming to its conclusion that the purified fermentate was not a product of nature the court turned to the phrase “new and useful” contained in section 101. This was an appropriate focus of analysis for the court because it is from this phrase that the product of nature exception is derived. However, in interpreting the phrase “new and useful” the court substituted the patent terms “novelty and utility”.[47]

The threshold for meeting the utility requirement for patentability is very low. Nearly all inventions meet the utility requirement. It is the Fourth Circuit’s reliance on the patent requirement of novelty for the term “new” which is more interesting. The court’s reliance of the novelty standard presents an interesting interpretation because the product of nature exception is not premised solely on the novelty requirement.[48] The product of nature doctrine simply states that products of nature are not patentable because they are made by nature, not by man. Furthermore, since products of nature existed in nature prior to man’s discovery of them, they are not new and thus excluded from patentability.

The novelty standard requires a different analysis. Although the issue of novelty also addresses the question as to whether or not an invention is new, the question of novelty is answered by looking at the prior art. Roughly speaking, the prior art exemplifies man’s entire body of scientific knowledge at the time of invention. In order to be novel, an invention must not be recited in one piece of prior art. For example, to demonstrate a lack of novelty, a single scientific journal article must describe how to extract vitamin B(12) from a fungal fermenting eluent.

The problem with using the novelty requirement to interpret “new” with regard to product of nature purposes is that no product of nature would be found in the prior art before it was discovered. In effect, using the novelty standard eviscerates the product of nature exception. The novelty standard also circumvents the purpose of the product of nature doctrine which is to prevent man from claiming “manifestations of [the] laws of nature”.[49]

For illustrative purposes we can use vitamin B(12) as an example. According to the Fourth Circuit, in order for vitamin B(12) to be considered a product of nature it must lack novelty. To lack novelty, vitamin B(12) must be recited in a single prior art source. Before its discovery by Merck, vitamin B(12) was unknown and hence could not be found in any prior art source. However, vitamin B(12) has always existed as a naturally occurring substance in cow liver (i.e. a product of nature). Despite clear evidence that vitamin B(12) is a product of nature, the Fourth Circuit would permit a patent on vitamin B(12).

This approach nullifies the purpose of the product of nature doctrine. By using the novelty standard, the court never asks the question whether or not vitamin B(12) was made by man. The purpose of the product of nature doctrine is to prevent man from patenting what is made by nature and should thus be accessible to everyone. The Fourth Circuit’s novelty analysis does not consider this.

The second interesting point about Merck is the product claim itself. In claim 1 recited above, vitamin B(12) is claimed only as a product of fermentation. Merck did not claim the vitamin B(12)chemical formula. This is a significant distinction because competitors could design around Merck’s product claim if they could manufacture vitamin B(12) without utilizing the fermenting eluent of fungi. For example, a manufacturer who processed cow livers to obtain vitamin B(12) could sell its version of vitamin B(12) product without infringing Merck’s product claims[50] . With cases such as Kuehmsted and Merck on one side of the product of nature debate, there are several cases which fall on the other side of the debate[51] . In addition to Funk Brothers, General Electric Co. v. De Forest Radio Co. [52] is representative of a court decision upholding the product of nature exception. The invention at the center of General Electric was the chemical element tungsten (W). General Electric was assigned U.S. Patent 1,082,933 (the ‘933 patent) for tungsten.

Is DNA Patentable Subject Matter?

As the cases discussed indicate, it is not entirely clear whether or not DNA sequences are patentable subject matter. What is clear is that processes for isolating DNA sequences are permissible as are product claims that use DNA sequences (such as Chakrabarty’s genetically modified micro-organism). In addition, inventors could get patents for the therapeutic uses of their DNA sequence products.

The Supreme Court’s decision in Chakrabarty indicates an intention by the court to expand the scope of patentable subject matter, but the product of nature doctrine still remains. Whether or not the product of nature exception will apply to DNA sequences depends upon how the courts view DNA sequences. If the courts analogize isolated and purified DNA sequences to aspirin or vitamin B(12), then DNA sequences would be moved outside the product of nature exception and into the scope of patentable subject matter. On the other hand, if DNA sequences are comparable to tungsten or “manifestation of laws of nature” then the product of nature exception would apply.

As the law is currently interpreted by patent practitioners, the product of nature exception to patentable subject matter is considered a technical problem related to drafting DNA sequence product claims. For the patent attorney, all that is necessary to get around the product of nature exception is to not claim a DNA in its naturally occurring form. In order to resolve this technical problem, a patent attorney will claim DNA sequences in an “isolated and purified” form. For example, Amgen’s DNA sequence claim to EPO in United States Patent 4,703,008 reads, “A purified and isolated DNA sequence consisting essentially of a DNA sequence encoding human erythropoietin.”[57]

DNA sequences have been described as molecular strands of genetic information.[59] Information which is so fundamental that it is akin to the natural laws of science. This fundamental information, in the words of Funk Brothers , is “part of the storehouse of knowledge of all men. They are manifestations of laws of nature, free to all men and reserved exclusively to none.”[60] As manifestations of the laws of nature, DNA sequences should be free to all men. By unlocking the hidden secrets of the genetic code, scientists will be able to produce new medical therapies to treat a wide range of illnesses. It is these new therapeutic inventions, their uses, and the processes for making them which should be patented, not the DNA sequences used to implement these inventions.

Although DNA sequences have been analogized to long polymer chains[65] and as a result should be treated similarly to synthesized polymers, this is not entirely correct. The analogy fails because an inventor’s ingenuity plays a part in designing a polymer chain. A chemist will manipulate reaction conditions to produce a polymer with certain characteristics such as strength, durability, and flexibility. This is not the case with DNA. The inventor’s ingenuity, once again, plays no part in designing the DNA sequence as this was the work of nature over thousands of years of evolution.

So the Harvard Law School article concludes:

  1. Patentable subject matter is statutorily defined in 35 U.S.C. Section 101 to include new and useful products (machines, manufactures, and compositions of matter) and processes. However, subject matter which fall outside the scope of Section 101 are products of nature.
  2. There are two general arguments for excluding products of nature from patentable subject matter. First, is that products of nature are the “manifestations of laws of nature”. As the building blocks of science, to grant ownership to these fundamental products would do more harm than good to scientific innovation. Second, is the patent system’s purpose in encouraging inventorship. An inherent aspect of inventorship is interaction of human ingenuity with the natural world. Products of nature are excluded from patentability because they would grant ownership rights to the natural world without any element of human ingenuity. These product of nature patents would reward inventors for nature’s work.

Man has played no part in creating DNA. What required man’s ingenuity was isolating, purifying, and sequencing the DNA. These inventions deserve patent protection.

Other articles on this Open Access Journal on Patents, Patent Fights and Intellectual Property include:

Top Twenty Universities on a list of the top 100 worldwide universities that received the most U.S. utility patents in 2014

The Patents for CRISPR, the DNA editing technology as the Biggest Biotech Discovery of the Century

Innovators can exit with an idea: How to Monetizing Patents and ideas: yazamIP.com launches Idea Lab

RNA related IP Patents Awards

Linus Pauling: On Lipoprotein(a) Patents and On Vitamin C

Recent Patents on Biomarkers

Litigation on the Way: Broad Institute Gets Patent on Revolutionary Gene-Editing Method





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Protecting Your Biotech IP and Market Strategy: Notes from Life Sciences Collaborative 2015 Meeting


Protecting Your Biotech IP and Market Strategy: Notes from Life Sciences Collaborative 2015 Meeting

Achievement Beyond Regulatory Approval – Design for Commercial Success

philly2nightStephen J. Williams, Ph.D.: Reporter

The Mid-Atlantic group Life Sciences Collaborative, a select group of industry veterans and executives from the pharmaceutical, biotechnology, and medical device sectors whose mission is to increase the success of emerging life sciences businesses in the Mid-Atlantic region through networking, education, training and mentorship, met Tuesday March 3, 2015 at the University of the Sciences in Philadelphia (USP) to discuss post-approval regulatory issues and concerns such as designing strong patent protection, developing strategies for insurance reimbursement, and securing financing for any stage of a business.

The meeting was divided into three panel discussions and keynote speech:

  1. Panel 1: Design for Market Protection– Intellectual Property Strategy Planning
  2. Panel 2: Design for Market Success– Commercial Strategy Planning
  3. Panel 3: Design for Investment– Financing Each Stage
  4. Keynote Speaker: Robert Radie, President & CEO Egalet Corporation

Below are Notes from each PANEL Discussion:

For more information about the Life Sciences Collaborative SEE

Website: http://www.lifesciencescollaborative.org/

Or On Facebook

Or On Twitter @LSCollaborative

Panel 1: Design for Market Protection; Intellectual Property Strategy Planning

Take-home Message: Developing a very strong Intellectual Property (IP) portfolio and strategy for a startup is CRITICALLY IMPORTANT for its long-term success. Potential investors, partners, and acquirers will focus on the strength of a startup’s IP so important to take advantage of the legal services available. Do your DUE DIGILENCE.


John F. Ritter, J.D.., MBA; Director Office Tech. Licensing Princeton University

Cozette McAvoy; Senior Attorney Novartis Oncology Pharma Patents

Ryan O’Donnell; Partner Volpe & Koenig

Panel Moderator: Dipanjan “DJ” Nag, PhD, MBA, CLP, RTTP; President CEO IP Shaktl, LLC


Dr. Nag:

  • Sometimes IP can be a double edged sword; e.g. Herbert Boyer with Paul Berg and Stanley Cohen credited with developing recombinant technology but they did not keep the IP strict and opened the door for a biotech revolution (see nice review from Chemical Heritage Foundation).
  • Naked patent licenses are most profitable when try to sell IP

John Ritter: Mr. Ritter gave Princeton University’s perspective on developing and promoting a university-based IP portfolio.

  • 30-40% of Princeton’s IP portfolio is related to life sciences
  • Universities will prefer to seek provisional patent status as a quicker process and allows for publication
  • Princeton will work closely with investigators to walk them through process – Very Important to have support system in place INCLUDING helping investigators and early startups establish a STRONG startup MANAGEMENT TEAM, and making important introductions to and DEVELOPING RELATIONSHIOPS with investors, angels
  • Good to cast a wide net when looking at early development partners like pharma
  • Good example of university which takes active role in developing startups is University of Pennsylvania’s Penn UPstart program.
  • Last 2 years many universities filing patents for startups as a micro-entity

Comment from attendee: Universities are not using enough of their endowments for purpose of startups. Princeton only using $500,00 for accelerator program.

Cozette McAvoy: Mrs. McAvoy talked about monetizing your IP from an industry perspective

  • Industry now is looking at “indirect monetization” of their and others IP portfolio. Indirect monetization refers to unlocking the “indirect value” of intellectual property; for example research tools, processes, which may or may not be related to a tangible product.
  • Good to make a contractual bundle of IP – “days of the $million check is gone”
  • Big companies like big pharma looks to PR (press relation) buzz surrounding new technology, products SO IMPORTANT FOR STARTUP TO FOCUS ON YOUR PR

Ryan O’Donnell: talked about how life science IP has changed especially due to America Invests Act

  • Need to develop a GLOBAL IP strategy so whether drug or device can market in multiple countries
  • Diagnostics and genes not patentable now – Major shift in patent strategy
  • Companies like Unified Patents can protect you against the patent trolls – if patent threatened by patent troll (patent assertion entity) will file a petition with the USPTO (US Patent Office) requesting institution of inter partes review (IPR); this may cost $40,000 BUT WELL WORTH the money – BE PROACTIVE about your patents and IP

Panel 2: Design for Market Success; Commercial Strategy Planning

Take-home Message: Commercial strategy development is defined market facing data, reimbursement strategies and commercial planning that inform labeling requirements, clinical study designs, healthcare economic outcomes and pricing targets. Clarity from payers is extremely important to develop any market strategy. Develop this strategy early and seek advice from payers.


David Blaszczak; Founder, Precipio Health Strategies

Terri Bernacchi, PharmD, MBA; Founder & President Cambria Health Advisory Professionals

Paul Firuta; President US Commercial Operations, NPS Pharma


Panel Moderator: Matt Cabrey; Executive Director, Select Greater Philadelphia



David Blaszczak:

  • Commercial payers are bundling payment: most important to get clarity from these payers
  • Payers are using clinical trials to alter marketing (labeling) so IMPORTANT to BUILD LABEL in early clinical trial phases (phase I or II)
  • When in early phases of small company best now to team or partner with a Medicare or PBM (pharmacy benefit manager) and payers to help develop and spot tier1 and tier 2 companies in their area

Terri Bernacchi:

  • Building relationship with the payer is very important but firms like hers will also look to patients and advocacy groups to see how they respond to a given therapy and decrease the price risk by bundling
  • Value-based contracting with manufacturers can save patient and payer $$
  • As most PBMs formularies are 80% generics goal is how to make money off of generics
  • Patent extension would have greatest impact on price, value

Paul Firuta:

  • NPS Pharma developing a pharmacy benefit program for orphan diseases
  • How you pay depends on mix of Medicare, private payers now
  • Most important change which could affect price is change in compliance regulations

Panel 3: Design for Investment; Financing Each Stage

Take-home Message: VC is a personal relationship so spend time making those relationships. Do your preparation on your value and your market. Look to non-VC avenues: they are out there.


Ting Pau Oei; Managing Director, Easton Capital (NYC)

Manya Deehr; CEO & Founder, Pediva Therapeutics

Sanjoy Dutta, PhD; Assistant VP, Translational Devel. & Intl. Res., Juvenile Diabetes Research Foundation


Panel Moderator: Shahram Hejazi, PhD; Venture Partner, BioAdvance

  • In 2000 his experience finding 1st capital was what are your assets; now has changed to value


Ting Pau Oei:

  • Your very 1st capital is all about VALUE– so plan where you add value
  • Venture Capital is a PERSONAL RELATIONSHIP
  • 1) you need the management team, 2) be able to communicate effectively                  (Powerpoint, elevator pitch, business plan) and #1 and #2 will get you important 2nd Venture Capital meeting; VC’s don’t decide anything in 1st meeting
  • VC’s don’t normally do a good job of premarket valuation or premarket due diligence but know post market valuation well
  • Best advice: show some phase 2 milestones and VC will knock on your door

Manya Deehr:

  • Investment is more niche oriented so find your niche investors
  • Define your product first and then match the investors
  • Biggest failure she has experienced: companies that go out too early looking for capital

Dr. Dutta: funding from a non-profit patient advocacy group perspective

  • Your First Capital: find alliances which can help you get out of “valley of death
  • Develop a targeted product and patient treatment profile
  • Non-profit groups ask three questions:

1) what is the value to patients (non-profits want to partner)

2) what is your timeline (we can wait longer than VC; for example Cystic Fibrosis Foundation waited long time but got great returns for their patients with Kalydeco™)

3) when can we see return

  • Long-term market projections are the knowledge gaps that startups have (the landscape) and startups don’t have all the competitive intelligence
  • Have a plan B every step of the way

Other posts on this site related to Philadelphia Biotech, Startup Funding, Payer Issues, and Intellectual Property Issues include:

PCCI’s 7th Annual Roundtable “Crowdfunding for Life Sciences: A Bridge Over Troubled Waters?” May 12 2014 Embassy Suites Hotel, Chesterbrook PA 6:00-9:30 PM
The Vibrant Philly Biotech Scene: Focus on KannaLife Sciences and the Discipline and Potential of Pharmacognosy
The Vibrant Philly Biotech Scene: Focus on Computer-Aided Drug Design and Gfree Bio, LLC
The Vibrant Philly Biotech Scene: Focus on Vaccines and Philimmune, LLC
The Bioscience Crowdfunding Environment: The Bigger Better VC?
Foundations as a Funding Source
Venture Capital Funding in the Life Sciences: Phase4 Ventures – A Case Study
10 heart-focused apps & devices are crowdfunding for American Heart Association’s open innovation challenge
Funding, Deals & Partnerships
Medicare Panel Punts on Best Tx for Carotid Plaque
9:15AM–2:00PM, January 27, 2015 – Regulatory & Reimbursement Frameworks for Molecular Testing, LIVE @Silicon Valley 2015 Personalized Medicine World Conference, Mountain View, CA
FDA Commissioner, Dr. Margaret A. Hamburg on HealthCare for 310Million Americans and the Role of Personalized Medicine
Biosimilars: Intellectual Property Creation and Protection by Pioneer and by Biosimilar Manufacturers
Litigation on the Way: Broad Institute Gets Patent on Revolutionary Gene-Editing Method
The Patents for CRISPR, the DNA editing technology as the Biggest Biotech Discovery of the Century



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Innovators can exit with an idea How to Monetizing Patents and ideas: yazamIP.com launches Idea Lab

Reporter: Aviva Lev-Ari, PhD, RN

 The IDEA as Entry and as Exit Point

1. yazamIP.com launches Idea Lab, enabling innovators to exit without necessarily establishing a startup.

If you: (A) have a track record of innovation and have a solution for a significant technical problem, and (B) are interested in either of the options below, both have no cost to you: (i) a $1,000,000 “exit” from your idea without necessarily leaving your “day-job”; (ii) having proven innovation, patent and business experts work with you to establish a robust patent portfolio based on your idea. And you maintain the option to spin off the strong portfolio into a startup for you to build the market.

Then yazamIP.com’s Idea Lab is for you. See http://www.yazamip.com/valuations

2. Tel Aviv University’s Ramot raises $17m from Tata & SanDisk.http://yazamip.com/node/84

3. Elvis Presley IP sells. http://yazamip.com/node/82

4. Innovation and patents are helping to increase gun sales.http://yazamip.com/node/85

Want to get a valuation on your patent? See http://yazamip.com/valuations

Do not forget to contact yazamIP.com to inquire about our most generous “referral a patent” fee arrangement.

1. yazamIP.com launches patent valuation service. http://www.yazamip.com/valuations2. yazamIP.com client initiates patent infringement action against Sony.http://www.yazamip.com/node/74

3. Twitter has only 9 patents pre-IPO, a fact that has investors worried.http://www.yazamip.com/node/73

4. Marijuana-related patents? Now that is a market to corner!http://www.yazamip.com/node/77

  1. If the companies are in distress and have US patents then we can sell them for the inventor
  2. If the patents are being infringed upon, we can see how we can help the inventor get compensated
  3. If the inventors have great ideas that they have not turned into companies yet, we would consider investing in them to convert the ideas into patent portfolios

Reply to

“Monte Silver, yazamip.com, Idea Lab” <info@yazamip.com>


From: “Monte Silver, yazamip.com, Idea Lab via LinkedIn” <member@linkedin.com>
Reply-To: “Monte Silver, yazamip.com, Idea Lab” <info@yazamip.com>
Date: Sun, 8 Dec 2013 13:51:06 +0000 (UTC)
To: “Aviva Lev-Ari, PhD, RN” <AvivaLev-Ari@alum.berkeley.edu>
Subject: yazamIP.com launches Idea Lab.  Innovators can exit with an idea

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Reporter: Aviva Lev-Ari, PhD, RN

this post was reblogged on 9/28/2012 by


September 27, 2012 08:30 AM Eastern Daylight Time

Oral Arguments in the UCSF Appeal of United States Patent and Trademark Office Judgment in Favor of InSite Vision Are Scheduled for November 6, 2012

InSite Vision Along with Merck Will Vigorously Defend AzaSite® Patents

ALAMEDA, Calif.–(BUSINESS WIRE)–InSite Vision Incorporated (OTCBB: INSV) today announced that oral arguments are scheduled for November 6, 2012, in Washington, D.C. in connection with the University of California, San Francisco’s (UCSF) appeal of the November 2011 favorable judgment of the United States Patent and Trademark Office (USPTO). The USPTO panel of judges ruled in favor of InSite Vision and confirmed the inventorship of InSite Vision’s U.S. Patent Nos. 6,239,113 and 6,569,443 protecting AzaSite® (azithromycin ophthalmic solution) 1%. The appeal was filed by UCSF with the U.S. Court of Appeals for the Federal Circuit in Washington, D.C. on December 23, 2011, and a cross appeal was filed by InSite Vision on January 4, 2012. Merck, which markets AzaSite in the U.S. for the treatment of bacterial conjunctivitis, is collaborating with InSite on the continued vigorous defense of the AzaSite patents.

“We are highly confident that the UCSF claims are entirely without merit as confirmed by the USPTO judgment last November and we will continue to collaborate actively with Merck to vigorously defend our position”

“We are highly confident that the UCSF claims are entirely without merit as confirmed by the USPTO judgment last November and we will continue to collaborate actively with Merck to vigorously defend our position,” said Timothy Ruane, InSite Vision’s Chief Executive Officer. “We anticipate results of the appeal will be announced in 2013, but we could get a verdict before the end of 2012.”

In 2009, the Regents of the University of California claimed that the inventions contained in the patents were made by a former employee of the University alone and without collaboration with InSite Vision, the assignee of all the named inventors.

About InSite Vision

InSite Vision is advancing new ophthalmic products for unmet eye care needs based on its innovative DuraSite® and DuraSite 2® platform technologies. The DuraSite and DuraSite 2 drug delivery systems extend the duration of drug retention on the surface of the eye, thereby reducing frequency of treatment and improving the efficacy of topical drugs. DuraSite is currently leveraged in two commercial products for the treatment of bacterial eye infections, AzaSite® (azithromycin ophthalmic solution) 1%, marketed in the U.S. by Merck, and Besivance® (besifloxacin ophthalmic suspension) 0.6%, marketed by Bausch + Lomb. InSite Vision is also advancing three novel ophthalmic therapeutics through Phase 3 clinical studies: AzaSite Plus and DexaSite for the treatment of eye infections, and BromSite for pain and swelling associated with ocular surgery. DuraSite 2 incorporates InSite’s proprietary bioadhesive core technology with a cationic polymer to achieve sustained and enhanced ocular delivery of drugs. The DuraSite 2 platform will be applied to InSite’s future pipeline product candidates and available through a broad licensing program for advanced ophthalmic drug development. For further information on InSite Vision, please visit www.insitevision.com.

Forward-looking Statements

This news release contains certain statements of a forward looking nature relating to future events, including InSite Vision’s expectations of a successful outcome in the appeal, the expected timing of a decision by the court, and other plans and expectations with respect to the litigation described above. Such statements entail a number of risks and uncertainties, including but not limited to: that the court may not rule in favor of InSite Vision, the inherent uncertainty of any litigation matter including the court’s decision and the timing of same; InSite Vision’s ability to continue to adequately protect its intellectual property and to be free to operate with regard to the intellectual property of others. Reference is made to the discussion of these and other risk factors detailed in InSite Vision’s filings with the Securities and Exchange Commission, including its annual report on Form 10-K and its quarterly reports on Form 10-Q, under the caption “Risk Factors” and elsewhere in such reports. Any forward-looking statements or projections are based on the limited information currently available to InSite Vision, which is subject to change. Although any such forward-looking statements or projections and the factors influencing them will likely change, InSite Vision undertakes no obligation to update the information. Such information speaks only as of the date of its release. Actual events or results could differ materially and one should not assume that the information provided in this release is still valid at any later date.

AzaSite® and DuraSite® are registered trademarks of InSite Vision Incorporated.

BESIVANCE® is a registered trademark of Bausch + Lomb Incorporated.


InSite Vision
Louis Drapeau, 510-747-1220
Chief Financial Officer
Media and Investor inquiries
BCC Partners
Michelle Corral, 415-794-8662
Karen L. Bergman, 650-575-1509



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Biosimilars: Intellectual Property Creation and Protection by Pioneer and by Biosimilar Manufacturers

Curator: Aviva Lev-Ari, PhD, RN

UPDATED on 5/19/2023

The state of biosimilars in 2023

by Davide Savenije, Editor-in-Chief at Industry Dive

Although the U.S biosimilars market has fallen short of expectations since its first product approval in 2015, more have poured onto the market after a slow start. Greater price competition could emerge as more biosimilars of each drug begin to launch.

  • Big pharma’s looming threat: a patent cliff of ‘tectonic magnitude’
  • AbbVie weathers first months of biosimilar challenge to top-selling Humira
  • Acquired patents aid J&J defense of top-selling drug from biosimilar challenge
Our Trendlines go deep on the biggest trends. These special reports, produced by our team of award-winning journalists, help business leaders understand how their industries are changing.




For Financial Aspects of Biosimilars, go to:

Biosimilars: Financials 2012 vs. 2008



For CMC and Regulatory Affairs of Biosimilars, go to:

Biosimilars: CMC Issues and Regulatory Requirements



In this post we focus on the Legal Scene of Intellectual Property Creation & Protection by Pioneer & by Biosimilar Manufacturers.

The regulatory pathway for biosimilars has an impact on biopharma R&D, M&A and valuation of companies and products. Industry and investors were uncertain if biosimilar will be approved, the impact a new biosimilar will have on rate of return and sales of pioneer innovators which are big pharma with dedicated divisions to biosimilars as well as on new entrants as biosimilar manufacturers.

Biosimilars, aka biogeneric, biocomparable or follow-on biologic are different than traditional pharmaceuticals, aka small molecules produced by chemical reactions, subjected to generic competition. Biosimilars include proteins produced by genetically engineered organisms, have not been challenged by generic competion.The generic  competition provisions of the Drug Price Competition and Patent Term Restoration Act of 1984 (Hatch-Waxman Act) apply to products approved under the Food, Drug, and Cosmetic Act, which include small molecule pharmaceuticals, but not to products approved under the Public Health Service Act, which include biologics.

It is estimated that, within a few years, biologics will be half of the biopharmaceutical market. As a result there have been mounting calls for a biosimilar pathway for companies obtaining Food and Drug Administration (FDA) approval of generic versions of existing biologics based upon lesser showings of safety and efficacy than is required for a pioneer biologic.

Like Hatch-Waxman Act for generic drugs, The Biologics Price Competition and Innovation Act (BPCIA) aka Biosimilar Act of 2009  (1) establishes standards for application and approval; (2) provides a term of data exclusivity; and (3) establishes a scheme for handling patent disputes. The similarities, however, end with these broad constructs, as the details involved with each are quite different.

Patent Disclosure Requirements

The Biosimilar Act imposes completely new disclosure requirements for patents that are demanding and time-sensitive, and it imposes these requirements on both pioneer and biosimilar manufacturers. These requirements will be required after submission of a biosimilar application and will demand sophisticated legal counseling and planning. These requirements are as follows:

• The biosimilar applicant must provide a copy of the application to the pioneer manufacturer (reference product sponsor) within 20 days of being notified that its application has been accepted by the FDA.

• The pioneer manufacturer must provide the applicant with a list of patents that it believes “could reasonably be asserted” with respect to the pioneer product within 60 days of receiving a copy of the application. The list must identify which patents the pioneer manufacturer would be prepared to license to the biosimilar applicant.

• The biosimilar applicant must provide the pioneer manufacturer with a detailed statement describing its opinion that any patent listed is invalid, unenforceable, or will not be infringed by the commercial marketing of the biosimilar, or a statement that it does not intend to begin commercial marketing of the biosimilar before the expiration of the listed patent(s), within 60 days of receiving the list of patents.

• The pioneer manufacturer must provide the biosimilar applicant with a detailed statement describing its opinion that its patent(s) will be infringed by the biosimilar, as well as a response concerning the validity and enforceability of its patent(s) within 60 days of receiving the biosimilar applicant’s detailed statement.

• The biosimilar applicant must notify the pioneer manufacturer 180 days before the first commercial marketing of the biosimilar. The pioneer manufacturer may then seek a preliminary injunction.

After these required exchanges, the act requires good faith negotiations by the parties to agree on which patents will be the subject of any infringement action. Within 30 days of either agreeing on this list of patents, or exchanging each party’s final list of patents, the pioneer manufacturer must bring an infringement action. The pioneer manufacturer also has 30 days to amend this list after the issuance, or exclusive licensing, of a new patent that it believes is infringed by the biosimilar. If the pioneer manufacturer prevails in this action before approval of the biosimilar, the court must enter a permanent injunction prohibiting further infringement.

Failure to bring an infringement action within the 30-day mandate (or bringing an infringement action that was dismissed without prejudice or was not prosecuted to judgment in good faith) will result in the available remedy being limited to a reasonable royalty only. Finally, failure by the pioneer manufacturer to timely include a relevant patent in the exchanged list will preclude the pioneer manufacturer from later bringing an infringement action against the biosimilar applicant with respect to that undisclosed patent.

Intellectual Property Considerations

As a result, it is feasible that a biosimilar may be similar enough to qualify as a biosimilar under the Biosimilar Act but not similar enough to be covered by a patent claim. Accordingly, pioneer manufacturers should take care in obtaining valid claims that afford broad patent protection of their biologics. To do so, pioneer manufacturers should consider, for example, protecting not only the biologic itself but also, if possible, the target molecule(s) of the biologic, methods of use and methods of production. In addition, pioneer manufacturers should also contemplate how their biologics may be modified and consider obtaining patent protection for those modifications. While this is generally a common practice in patent law, it has been less important in pharamceuticals, where the focus has been on the patents that protect the drug itself rather than methods of its manufacture, and on obtaining protection from a generic (a bioequivalent drug, rather than a less equivalent drug that could treat the same condition).

Biosimilar manufacturers, on the other hand, should analyse how the pioneer’s biologic is protected by one or more patents and consider how they may be able to escape patent protection. Biosimilar manufacturers should also be careful of what admissions they make in regard to what is and is not equivalent in an application under the Biosimilar Act. Such admissions may be considered by manufacturers of the pioneer biologic for possible infringement positions. Under the Biosimilar Act, there is a certain amount of protection afforded through data exclusivity for a pioneer biologic. Pioneer biologic manufacturers, however, should not solely rely on this period of exclusivity for protection. Not only may patent protection go beyond the protection afforded by the data exclusivity period for a pioneer biologic, but an additional data exclusivity period may not be available under the Biosimilar Act. As a result, it is important for pioneer manufacturers to consider obtaining patent protection for improvements to their pioneer biologic.

Likewise, biosimilar manufacturers should also seek patent protection for their biosimilars and improvements to them, and consider the pioneer biologic and associated patents in doing so. Patent protection may be available for biosimilar biologics even when data exclusivity under the new act is not. In regard to the patent disclosure requirements, the scheme of the new act appears to avoid many of the problems that have arisen under the Hatch-Waxman Act for generic pharmaceuticals, such as the numerous issues regarding the requirement to list relevant patents in the Orange Book.

However, the completely new patent disclosure scheme for biosimilars will take years for the FDA and the courts to sort out. In the end, it may very well be more burdensome on the  parties than the Hatch-Waxman Act, which has spawned a tremendous amount of litigation. At the very least, the patent provisions of the Biosimilar Act establish demanding and time-sensitive disclosure requirements for both the pioneer and biosimilar applicant. Given the detail required and the complexity of the issues, both parties should conduct the necessary investigation and analysis well before a biosimilar application could be filed. Some steps that may be taken include: identifying all relevant patents, determining expiration dates and potential patent term extensions, and identifying patent owners and licenses. Based on the investigation and analysis, both parties should develop detailed infringement, validity, and enforceability positions before receiving the other party’s patent list or positions. Failing to take early action will likely result in a party rushing to prepare the very detailed statements required by the law for both parties, running the serious risk of making a potentially determinative mistake. Both parties also face penalties for failing to comply with the disclosure requirements.

In all, it will be important for pioneer and biosimilar manufacturers to fully understand their patent portfolios as well as those of their competitors and to review these portfolios regularly. The requirements of the Biosimilar Act will necessitate sophisticated and extensive legal counseling, active portfolio diligence, and time-sensitivity



Greater clarity in the biopharma and pharma market place was achieved on June 28, 2012 when the US Supreme Court has upheld ObamaCare, ensuing that the pathway for biosimilars included with the law will remain intact.

The US paved the way for biosimilar approval in 2012 as part of the Patient Protection and Affordable Care Act (PPACA). A major element of the healthcare reform law is The Biologics Price Competition and Innovation Act (BPCIA) aka Biosimilar Act of 2009 provision of that bill said that biological products that are demonstrated to be highly similar (biosimilar) to or interchangeable with an FDA-licensed biological product may be approved under an abbreviated pathway similar to the process for small molecule generics.

With the upheld ObamaCare, critical parts of the PPACA constitutional, and with it the BPCIA giving the FDA authority to approve biosimilars.

Had the PPACA been stricken in part or in its entirety, it would have presented obstacles to the BPCIA surviving in its present form. The US government has been critical of the 12-year data exclusivity period for Pioneer Innovators, calling for it to be shortened to 7 years (12 years is favorable to Pioneer Innovators and less favorable for Biosimilar manufacturers). The upheld ObamaCare, PPACA and BPCIA, constitutional, has prevented a multiyear delay in biosimilar approval. Thus, it was the best scenario for the biologics industry.

BPCIA provides the approval of biological products as biosimilar or interchangeable (BPCIA 351(k)). As part of the FDA’s approval process, biosimilar products would need to produce the same clinical effect and if a multi-dose product, not present any greater safety or efficacy risk to patients in switching from the reference product. There would have to be “clinically meaningful differences” between the pioneer biologic reference product and the biosimilar product in order to gain FDA approval.

Congress granted the FDA flexibility for approval standards for biosimilars, i.e., what type of clinical studies required, what differences in approval process from biologics license applications (BLA) are appropriate.

1. Pioneer inventors are granted 12 years of data exclusivity, barring FDA approval of a 351 (k) application from “the date on which the reference product was first licensed”

2. An application can’t be submitted to the FDA until 4 years after the date on which the BLA for the reference product was first granted.

3. FDA sets approval requirements unless FDA waives them: analytical studies demonstrating the biosimilar is highly similar to the reference product, animal studies, a clinical study sufficient to demonstrate safety, purity, potency, same mechanism of action, route of administration, dosage form and strength.

Hatch-Waxman Act for generic drugs patent challenge provisions are different from BPCIA‘s patent challenge provisions.

  • BPCIA require “negotiation” of patent disputes and exchanges of patent information between parties prior to instituting patent litigation.
  • BPCIA mandates risk evaluation and mitigation strategy (“REMS”) requirements, shall apply to biosimilars as they do to reference pioneer biologic.
  • Reimbursemwnt for biosimilars is set at Average  Sales Price (ASP) plus 6% of the amount determined for the amount determined for the reference pioneer biologic.
  • BPCIA allows for imposition of user fees to review biosimilars
  • Naming biosimilars: generic vs. proprietary naming requirements for drug safety and/or recalls, tracking adverse events,  as well as reimbursement
  • Unanswered, if a biosimilar applicant needs to provide data on al approved indications of the reference product, and can a biosimilar be better than a reference product (i.e., “biobetters”), if so in what way (e.g., safety or efficacy).

On 2/9/2012 – FDA issued 3 draft guidance documents intended to facilitate the submission of marketing applications for biosimilars

1.  Biosimilars Q&A: provide guidance on the content of 351(k) applications. Recommendations that sponsors meet early with FDA to discuss plans. Guidance sets out the FDA’s current view that comparative animal or clinical data developed using non-US-licensed product can provide evidence that proposed product is biosimilar to a US-licensed reference product.

2. Biosimilars Scientific Guidance – three approaches to establish demonstrated biosimilarity.

a.  “stepwise” approach comparison of proposed product with reference product with respect to structure, function, animal toxicity, human pharmacokinetics (PK) and pharmacodynamics (PD), cinical immunogenicity, and clinical safety and effectiveness.

b.  “totality-of-the-evidence” approach

c.  “general scientific principles” in conducting comparative structural and functional analysis, animal testing, human PK and PD studies, clinical immunogenicity assessment and clinicall safety and effectiveness studies (study design issues)

3.  Biosimilar Quality Guidance provides directions on analytical studies assessing if the proposed biosimilar protein product and the reference product are “highly similar” Guidance suggests that there may be an opportunity for pioneer innovators to argue that current technology does not permit for demonstration of  “biosimilarity” of a potentially competitive product in a manner adequate to gain approval under 351(k), thus necessitating the filing of full BLA.

Outstanding issues under BPCIA’s provisions related to marketing and development could affect biopharma investment:

1.  effects on coverage and reimbursement of the pioneer biologic based on approval of a biosimilar, reimbursement of biosimilars themselves

2. biosimilars and not expressly treated in the new act under Medicare Part B, Medicare Drug Pricing Program, Medicaid, 340B program.

3. non clear is biosimilars will constitute “multi-source drugs.”

Unlike the generic drugs market, the biosimilars market is likely to have a smaller number of entrants, greater costs of applications and testing, less reduction in price from that of a pioneer biologic and necessity of marketing staff.

It is unclear when the cost of the drug will become a switching factor in purchasing a biosimilar. purchaser resistance  note withstanding price advantage did occur in the past. There eexist potential purchaser/payor concerns regarding interchangeability, safety, efficacy (i.e., potency). There is concern over evergreening strategy by pioneer inventors to use drug modifications to extend the exclusivity period thus, deterring the entrance of biosimilars.

In June 2011, the European Medicines Agency (EMA) and FDA issued a joint report noting the interactions between the two agencies, when a biosimilar version of a mococlonal antibody, Remicade was filed in the EU.

Defining Protein Therapeutics

FDA promises a risk-based “totality-of-the-evidence” approach to reviewing biosimilars. Novo Nordisk and Pfizer urged FDA to rethink its definition of proteins as excluding alpha amino acid polymers with fewer than 41 amino acids. Jim Shehan, Novo Nordisk’s corporate vp, legal, government, and quality affairs, noted that the definition clashed with statutes defining biological products as including any polypeptide except for those that are chemically synthesized.

“We believe they have selected an arbitrary cutoff,” Shehan told GEN. “It can conflict with the statutory language and it really isn’t grounded in science either,” an exception, he said, to the guidance’s overall focus on respect for science and patient safety. “In broad strokes, they met the mark in seeming to have a healthy respect for the need to have data in order for biosimilars to come to market.”

F. Owen Fields, Ph.D., Pfizer vp, worldwide regulatory strategy, worldwide R&D, suggested a case-by-case review of proteins with 40 or fewer amino acids. He cited Nisin, a 37-amino-acid polypeptide derivative approved by FDA as a food preservative, as an example among natural peptides best treated as proteins because of their potential for use as substrates for new drug development. “There are structures less than 41 amino acids that present regulatory science issues that are more similar to biologically synthesized proteins than to chemically synthesized peptides,” Dr. Fields pointed out at the hearing.

Keeping Trade Secrets Secret

Abbott called for additional FDA efforts to protect trade secrets of reference drugs during agency review of biosimilar applications. “Safeguards are needed to ensure that the agency doesn’t unintentionally, inadvertently, but nevertheless impermissibly use or disclose to a biosimilar applicant an innovator’s trade secrets,” Neal Parker, an Abbott attorney, said at the hearing.

Among safeguards suggested by Parker were FDA developing IT systems tracking employee involvement with BLAs and biosimilar applications, creating policies and procedures and training employees in them, and preventing FDA reviewers “significantly” involved in reviewing specific U.S.-licensed innovator BLA products from any biosimilar application review activities or any communications with biosimilar applicants seeking to rely on those same reference products.

Abbott recently submitted a citizen’s petition requesting that the agency not consider any applications for biosimilars based on biologic reference products for which a BLA was submitted before March 23, 2010, the date that President Barack Obama signed the Biologics Price Competition and Innovation Act. The request would effectively shield Abbott’s mAb therapeutic and biggest-selling treatment Humira from biosimilar competition. The company is about to spin off its brand-name drug development operations, remaining as a maker of medical equipment and generic drugs.

Fine-Tuning Data Requirements

Kalyan R. Anumala, Ph.D., senior director of Therapeutic Proteins, suggests that the agency should only require Phase II and III trials where it establishes a need after reviewing a submission. He also said the agency should encourage new characterization methods rather than clinical trials.

Also calling for additional characterization methods is the only U.S. company marketing biosimilar drugs, Hospira. Its products include anemia treatment Retacrit in the EU and biosimilar filgrastim product Nivestim, sold in the EU and Australia for stimulating production of white blood cells in patients receiving cytotoxic chemotherapy.

Samant Ramachandra, M.D., Ph.D., Hospira’s senior vp, R&D and regulatory and medical affairs and CSO, also urged FDA to account for reference product variability and clarify the required approach to show clinical immunogenicity assessment.

Dr. Ramachandra and James M. Roach, M.D., svp and CMO of Momenta Pharmaceuticals, urged FDA to permit the use of bridging data in return for allowing non-U.S. reference products. “This is critical if the goal is to implement a global development program that is feasible to conduct,” Dr. Roach added. Eli Lilly’s Gregory C. Davis, Ph.D., pressed FDA for more guidance on the type and extent of bridging data that would be permissible.

Abbott, by contrast, said data from studies involving a foreign comparator product cannot be considered pivotal if the foreign comparator is different from the U.S. reference product. FDA has stated that clinical comparisons with a non-U.S. licensed product do not provide an adequate basis to support interchangeability.

Jay P. Siegel, M.D., chief biotechnology officer and head of global regulatory affairs for Janssen Pharmaceutical, echoed many brand-name drug developers by urging FDA to maintain the draft guidance’s standard for interchangeability. Applicants would have to demonstrate biosimilarity and the ability of the biological product to produce the same clinical result as the reference product in any given patient.

If biosimilarity is established, it should also be extrapolated to pediatric populations, said Karl Heinz Emmert, Ph.D., managing director for Merckle Biotec, a Teva Group member. Dr. Emmert contended that FDA need not require clinical studies of pediatric populations with a biosimilar product. That differs from the thinking of Pfizer, which while supportive of extrapolations between populations within an indication, suggested an exception: diseases where pediatric pathophysiology differs from that of adults.

With regard to manufacturing concerns, Paul Eisenberg, an Amgen svp, argued in part: “Requiring the maintenance of biosimilarity over time would inhibit manufacturing and quality improvements and unduly burden industry without benefiting patients.” Mark McCamish, M.D., Ph.D., head of global biopharmaceutical development for Sandoz Biopharmaceuticals, disagreed.

Determining Label Details

Amgen did not address manufacturing issues in testimony but focused instead, along with several other companies, on how biosimilars should be identified and labeled to ensure accurate tracking and tracing. Suggestions included biosimilar names sharing a common root but having a unique suffix and/or prefix to denote biosimilarity and interchangeability.

“Having unique names will avoid unintended substitution, minimize risk of medication errors, allow for essential elements of pharmacovigilance such as traceability and follow-up of adverse drug reactions, as well as facilitate prescriber-patient decision making,” commented Michelle Rohrer, Ph.D., vp, U.S. regulatory affairs at Genentech.

Teva’s Dr. Emmert and Ahaviah Diane Glaser, vp for policy and strategic alliances with the Generic Pharmaceutical Association (GPhA), noted, however, that while all biologics should be uniquely tracked, biosimilars should not require unique International Nonproprietary Names (INNs) from their reference products. Glaser said different INNs would impede market competition because it would likely require a different marketing campaign, thus raising costs, and would also complicate collection of global safety data and could increase medical errors.

Embracing Biosimilars

Further guidance on naming biosimilars and interchangeables was one point agreed upon by industry and patient groups, so it’s likely FDA will oblige. That’s the easy issue for the agency. Tougher will be how to balance shepherding biosimilars and interchangeable products to market without sacrificing patient safety.

“If FDA issues product-specific guidances with very clear mandates that to get a biosimilar approved, you need to run a Phase III-like trial of X size, evaluating X, Y, and Z, it takes away from the incentive to put that much more time and scientific thought into proving from a structural and functional basis that you have the same compound,” Dr. Roach of Momenta told GEN.

Years ago EMA developed solid scientific guidelines, then product-specific rules that succeeded in bringing biosimilars to Europe. Sandoz’ Dr. McCamish credited EMA’s consistent standards with health authorities embracing biosimilars. It’s a lesson the U.S. will have to learn as FDA builds the pathway for biosimilars to finally reach the American market. 


On February 9, FDA issued long-awaited guidelines designed, according to FDA drug division director Janet Woodcock, M.D., “to help industry develop biosimilar versions of currently approved biological products.” Paul Calvo, Ph.D., a director at Sterne, Kessler, Goldstein & Fox, told GEN, “There were no major surprises” in the guidelines.

“It is clear that FDA wants to move forward with biosimilar approvals and they will be looking to a totality of the evidence as the standard for a determination of biosimilarity.” He also commented that FDA wants a constant dialog with biosimilar sponsors and all the structural and functional data up front. “Their goal for the up-front data is to be involved in design of the clinical trials in order to maximize the data provided.”

FDA’s new documents describe a step-wise approval pathway, starting with extensive analytical, physico-chemical, and biological characterization data that will have to demonstrate a high degree of similarity to the reference product. FDA will evaluate that data and then provide advice to the sponsor on the extent and scope of animal and human testing needed to show biosimilarity. The agency will consider multiple factors in making study determinations, including product complexity, formulation, stability, structure-function relationships, manufacturing process, and clinical experience with the reference product.

While the pathway to the agency’s decision making will be abbreviated, “it will depend on existing data,” Rachel Sherman, M.D., director of the Office of Medical Policy in FDA’s Center for Drug Evaluation and Research, said during a conference call. “We do not want companies repeating studies that do not need to be done.” As to whether most biosimilar applicants will be expected to carry out clinical trials, decisions will be made on a product by product basis.

Another topic of note is that the FDA has said that there could be extrapolation of clinical data to other diseases to give companies developing biosimilars approval for use in multiple indications for a given product. “But for therapeutics like Rituxan with two disparate indications, one for lymphoma and another for rheumatoid arthiritis, two sets of clinical trials will likely be required,” Dr. Calvo explained.

Interchangeability and Exclusivity

Importantly for the industry, the guidance documents indicate that the agency hasn’t settled some important biosimilars policy questions, including requirements for demonstrating interchangeability of a biosimilar with a reference product and terms for establishing the exclusivity period for pioneer biologics.

The Patient Protection and Affordable Care Act, signed into law by President Barack Obama on March 23, 2010, mandated the creation of an abbreviated approval pathway for biosimilars and proposed a 12-year data exclusivity period. The president’s budget proposal for fiscal 2013 released February 13, however, suggests that exclusivity should be lowered to seven years.

With regard to interchangeability, FDA states that it “is continuing to consider the type of information sufficient to enable FDA to determine that a biological product is interchangeable with the reference product.” Dr. Calvo explained that “interchangeability is important because it provides for a period of market exclusivity as well for automatic substitution of the interchangeable for the approved biologic without intervention from the prescribing physician.”

“However,” Dr. Calvo added, “given how new the whole process for biosimilar approval is, it would have been surprising if the FDA would have said there would not be any issues in determining interchangeability.” But, he noted, the agency has said that right now it doesn’t have the scientific ability to approve biosimilars as interchangeable.

An Amgen spokesperson commented that “FDA’s acknowledgement that determining interchangeability is scientifically difficult at this time is important. Patient safety does not stop at approval, and Amgen believes that post-approval activities including ongoing monitoring are essential to patient safety.”

Dr. Sherman believes that the hurdles for interchangeability would be high. Biologic drugs carry the added risk of prompting an immune response, she noted, and the FDA would “almost certainly” require clinical trials in which a patient is switched from the branded drug to the biosimilar and back to rule out the risk of triggering the immune system.

Potential Cost Savings

Dr. Calvo pointed out that “the ability to have a high level of FDA input will likely increase the chance that biosimilars will soon enter the U.S. market.” However, he added, the price erosion that occurs with small molecules “will not happen for biosimilars to even close to the extent that it occurs with small molecules, mainly because there will not be a mechanism for automatic substitution and because clinical studies will be required at least to some degree.”

For more complex products such as antibody conjugates or highly purified protein mixtures, “it is highly likely that more sophisticated manufacturing and analytical methods and possibly clinical trials will be required, therefore increasing costs for biosimilar entrants,” Jefferies analyst Biren Amin said in a note to clients. “This could apply to products like Seattle Genetics’ Adcetris or ImmunoGen and Roche’s T-DM1.”

The Congressional Budget Office still estimates that biosimilars would save the government $25 billion in healthcare spending during the coming decade. While generic chemical compounds like Norvasc and Metoprolol usually sell for less than 20% the cost of the brand product, biosimilars are expected to sell for 60% to 80% of the cost of branded biologics. The difficulty of producing and gaining approval for biosimilars will provide manufacturers increased pricing power and larger margins compared to traditional generic medications.

Biosimilars represent a tremendous opportunity for pharma and biotech companies that can successfully manufacture and market them. The global market for biosimilars will range between $11 billion and $25 billion by 2020, accounting for 4 to 10 percent of the total market for biotech drugs, according to IMS Health. Despite the potential hurdles to both interchangeability and exclusivity, patent expiries in the next two years put around $11 billion in biologic drug sales into play. That kind of potential along with the establishment of a designated approval pathway clears away some lingering doubts about the viability of generic competition.

As for the industry, potential biosimilar manufacturers continue to make deals. While there are no currently marketed biosimilars in the U.S., so-called innovator companies including Amgen, Pfizer, Novartis, and Eli Lilly have joined the ranks of generic firms such as Teva in developing biosimilars. Amgen told GEN that as a leading provider of high-quality biologic medicines, it understands the challenges of developing and manufacturing innovative and biosimilar medicines and appreciates the agency’s efforts on the guidelines, and encourages adoption of a thorough review and approval process.

While it remains to be seen whether approved biosimilars provide the savings in healthcare costs that the Congressional Budget Office optimistically predicted, both the FDA and the industry are moving toward making them a reality in the U.S. As per the three dozen or so requests for meetings, FDA staffers are holding pre-IND meetings with sponsors and encouraging all prospective biosimilar makers to seek early advice. Nine INDs for biosimilar have been filed so far, and the agency is anticipating a full 351(k) application soon.


More than a year after launching a dialogue with industry regarding biosimilars, FDA is holding a morning-long public meeting today. The proposed approval pathway and fees drug developers must pay for the five fiscal years starting October 1, 2012, will be discussed. The agency is soliciting public comment through January 6, 2012

Those comments are expected to shape a final FDA recommendation on biosimilar user fees, which the agency plans to send to Congress by January 15, 2012. On December 7, the agency published “Biosimilar Biological Product Authorization Performance Goals and Procedures, Fiscal Years 2013 through 2017.”

The user fee program is expected to aid FDA in developing the final abbreviated approval pathway for biosimilars, which was required under the Biologics Price Competition and Innovation Act (BPCIA) of 2009. BPCIA was tucked into page 686 of the Patient Protection and Affordable Care Act enacted last year by President Obama. Janet Woodcock, M.D., director of FDA’s Center for Drug Evaluation and Research co-authored a paper published this August in The New England Journal of Medicine that provided some clues on the overall approval pathway.


The initial fee would be 10% of the fee established for a drug application under PDUFA each year from FY 2013 through 2017. The agency would collect only one initial BPD fee per product, regardless of the number of proposed indications.

Sponsors that submit marketing applications would pay fees equal to those established for drug applications under PDUFA minus the cumulative amount of BPD fees. Under PDUFA, 2012 fees for drug products go up as high as $1.84 million.

“By providing FDA with these resources, they would be able to meet with sponsors, provide clear and established guidelines for regulatory action, and as a result that should reduce the barriers to market entry even more than what would be represented through a modest fee like this,” Emmett said. Since established biopharma companies are more likely to produce biosimilars than early-stage companies, “I wouldn’t anticipate that $180,000 would be a significant barrier to market,” Emmett added.

“FDA anticipates a modest level of funding from these sources initially because only biosimilar biological products that are approved for marketing would be subject to these fees,” the agency said.


Biosimilars and Follow-On Branded Biologics

Promoting Innovation and Access to Life-Saving Medicine Act (H.R.1427, a bill from the first session of the 111th Congress) and the FTC’s report titled Emerging Health Care Issues: Follow-on Biologic Drug Competition are intended to provide the rationale for moving access to biosimilars/follow-on biologics and driving the legislative compromise. Of particular interest is the FTC’s projection of what cost savings (10–30%) will actually be achieved, and that the originator biologic manufacturer may likely retain 90% of its market.

When a new human growth hormone (hGH) product tried to compete with  Genentech’s hGH, physicians hesitated to move patients on to it, so its market was just new patients. If there is only a 10–30% price differential for biosimilar/follow-on biologics and they lack an AB substitutability rating, one would anticipate the same reluctance to switch patients.


FDA’s draft guidance for biosimilars drew mostly good marks from industry at the hearing held May 11. Executives from a dozen biopharma companies, however, pressed for greater flexibility in the definition of proteins, tighter standards in naming and labeling follow-on biologics, as well as more details on moving drugs through agency approvals.

Draft Guidance for Industry and FDA Staff: Technical Considerations for Pen, Jet and Related Injectors Intended for Use with Drugs and Biological Products, April 2009.) The Guidance recognizes that these are innovative approaches to deliver drugs or biologics products that may enhance accuracy and patient compliance.

One major significant issue of this Guidance lies in its application to biosimilars, facilitating their conversion into higher-value follow-on branded products. As an example, Novo Nordisk is now introducing its next-generation FlexPen, a prefilled insulin delivery device that the company reports has a 25–41% lower force than the existing SoloStar and KwikPen devices; diabetic patients prefer lower-force insulin injections since they are less painful.

After obtaining FDA approval to market in the U.S., a first-generation biologic may have little commercial value as a commodity product and have a BX rating (not substitutable), since most biopharma companies have developed a second- or third-generation biologic with an innovative delivery system—a specialty product. It is anticipated that specialty products will command prices near or only 10–20% less than that of the originator product, even though they will not have a BX rating. In this scenario, the initial approval of the first-generation biosimilar is really a strategy to rapidly enter the marketplace, then quickly evolve into a higher-value specialty, often called a follow-on branded product.


CMC Issues and Regulatory Requirements for Biosimilars

Dr. Bao-Lu has exposed very important CMC Issues and Regulatory Requirements for Biosimilars in


Chemistry, Manufacturing and Controls (CMC), preclinical and clinical are three critical pieces in biosimilars development. Unlike a small-molecule generic drug, which is approved based on “sameness” to the innovator’s drug; a biosimilar is approved based on high similarity to the original approved biologic drug. This is because biologics are large and complex molecules. Many functional-, safety- and efficacy-related characteristics of a biologic depend on its manufacturing process. A biosimilars manufacturer won’t be able to exactly replicate the innovator’s process. The traditional abbreviated pathway for generic drug approval through the Hatch- Waxman Act of 1984 doesn’t apply for biosimilars as drugs and biologics are regulated under different laws. New laws and regulations are needed for biosimilars approval in the US. The EU has issued biosimilars guidelines based on comparative testing against the reference biologic drug (the original approved biologic). A full scale CMC development is required including expression system, culture, purification, formulation, analytics and packaging. The manufacturing process needs to be developed and optimized using state-of-the-art technologies. Minor differences in structure and impurity profiles are acceptable but should be justified. Abbreviated clinical testing is required to evaluate surrogate markers for efficacy and demonstrate no immunogenic response to the product.

We anticipate the package for a biosimilars approval in the US will be similar to that in the EU and contain a full quality dossier with a comparability program including detailed product characterization comparison and reduced preclinical and clinical requirements.

Biosimilars Become Inevitable

Biologics developed through biotechnology constitute an essential part of the pipeline for medicines available to patients today. Biologic drugs are quite expensive and many of them are top-selling medicines (see Table 1). Since they come at extremely high prices to consumers, some patients may not be able to afford the use of biologics as the best-available treatments to their conditions. The patent protection on a large number of biologics has expired since 2001. These off-patent biologics include Neupogen, Novolin, Protropin, Activase, Epogen or Procrit, Nutropin, Humatrope, Avonex, Intron A, and Humulin. Traditionally, when a drug patent expires, a generic drug will be quickly developed and marketed. Similarly, generic version of off-patent biologic drugs (also referred to biosimilars or follow-on biologics or biogenerics) represents an extraordinary opportunity to companies that want to seize the potentially great commercial rewards in this unexploited territory. Biosimilars not only benefit the biosimilar manufacturers but also can save patients, and insurance companies, substantial cost and allow patients to gain access to more affordable biologics resulting in market expansion. The government can use biosimilars to reduce healthcare costs. Therefore, development and marketing of bosimilars are supported by both manufacturers and consumers.

Differences between Generic Drugs and Biosimilars

Enacted in 1984, the US Drug Price Competition and Patent Term Restoration Act, informally known as the “Hatch-Waxman Act of 1984” standardized US procedures for an abbreviated pathway for the approval of small-molecule generic drugs. The generic drug approval

is based on “sameness”. In comparison to the innovator’s drug, a generic drug is a product that has the same active ingredient, identical in dose, strength, route of administration, safety, efficacy, and intended use. For approval, the generic companies can go through the Abbreviated

New Drug Application (ANDA) process with reduced requirement in comparison to approval for a new drug entity. The generic drugs need to show bioequivalence to the innovator drugs typically based on pharmacokinetic parameters such as the rate of absorption or bioavailability in 24 to 36 healthy volunteers. No large clinical trials for safety and efficacy are required. The generic companies can rely on the FDA’s previous findings of safety and effectiveness of the innovator’s drugs.

However, the abbreviated pathway for generic drugs legally doesn’t apply to biologics as small-molecule drugs and biologics are regulated under different laws and approved through different pathways in the US (Table 2). Small-molecule drugs are regulated under the Food, Drug and Cosmetic Act (FD&C) and require submission of a New Drug Application (NDA) to FDA for drug review and approval. Biologics are regulated under the Public Health Service Act (PHS) and require submission of a Biologic License Application (BLA) to FDA for review and approval. The Hatch-Waxman Act of 1984 doesn’t apply for biosimilars. New laws are needed to establish a pathway for biosimilar approval.

There are some crucial differences between biologics and small-molecule drugs. Small-molecule drugs are made from chemical synthesis. They are not sensitive to process changes. The final product of a small-molecule drug can be fully characterized. The developmentand production of generic drugs are relatively straightforward. Biologics are made from living organisms so that its functional-, efficacy- and safety-related properties depend on its manufacturing and processing conditions. They are sensitive to process changes. Even minor modifications of the manufacturing process can cause variations in important properties of a biological product. Thus it is believed that a biologic product is defined by its manufacturing process. Biologics are 100- or 1,000-fold larger than small-molecule drugs, possess sophisticated three-dimensional structures, and contain mixtures of protein isoforms. A biological product is a heterogeneous mixture and the current analytical methods cannot characterize these complex molecules sufficiently to confirm structural equivalence with the reference biologics.

Laws and Regulatory Pathways for Drug Approval in the US

Law/Application             Small-molecule            Drug Biologics                     

Law             Food, Drug and Cosmetic Act (FD&C)             Public Health Service Act (PHS)

Drug application   New Drug Application (NDA)   Biologic License Application (BLA)

Generic application   Abbreviated New Drug Application(ANDA)   NEW pathways beyond BPCIA, 2009

Differences between small-molecule drugs and biologics

Product characteristics

Small-molecule generics Small, simple molecule

(Molecular weight: 100-1,000 Da)

Biosimilars   Large, complex molecules, Higher order structures, Post-translational, modifications

(Molecular weight: 15,000-150,000 Da)


Small-molecule generics Produced by chemical synthesis

Biosimilars  Produced in living organisms

Analytical testing

Small-molecule  Well-defined chemical structure, all its various components in the finished drug can be determined

Biosimilars  Heterogeneous mixture, difficult to characterize, some of the components of a finished biologic may be unknown

Process dependence

Small-molecule   Not sensitive to manufacturing process changes. The finished product can be analyzed to establish the sameness.

Biosimilars   Sensitive to minor changes in manufacturing process. The product is defined by the process

Identity and purity

Small-molecule Often meeting pharmacopeia or other standards of identity (e.g., minimums for purity and potency)

Biosimilars   Most have no pharmacopeia monographs

immunogenicity issues prior to 1998. When J&J made a change in the Eprex formulation by replacing human serum albumin (HAS) with polysobate 80 and glycine in response to the

request from European health authorities, some patients developed pure red-cell aplasia (PRCA), a severe form of anemia. Eprex induced antibodies neutralize all the exogenous rHuEPO and cross-react with endogenous erythropoietic proteins. As a result, serum EPO is undetectable

and erythropoiesis becomes ineffective. Upon investigation, J&J found that polysorbate 80 might have caused uncoated rubber stoppers in single-use Eprex syringes to leach plasticizers, which stimulated an immune response that resulted in PRCA. Replacing with Teflon coated stoppers resulted in 90% decrease in PRCA by 2003 [3,4]. The effect of neutralizing antibodies has not always resulted in serious clinical consequences. Three interferon beta products, Betaseron, Rebif and Avonex, are marketed by three different companies. These products induce neutralizing antibodies in multiple sclerosis patients from 5 to 50% after one year treatment. Although these antibodies might be associated with loss of efficacy of treatment resulting in some patients to withdraw from the treatment, it seems no other severe adverse effects were detected [5,6].

Regulatory Landscape

The US, the EU and Japan are the three cornerstonemembers of the International Conference on Harmonization (ICH), which intends to harmonize the regulatory requirements for drug or biologic approval in these three regions. With the other two members, the EU and Japan, already have established biosimilar approval procedures (see below), the US lags behind in the biosimilar race. There are no formal approval pathways for biosimilars in the US. Congress needs to establish a legal framework in order for FDA to develop guidelines. Legislation has been under discussion in Congress since 2007. The legislative debate is centered on patient safety and preserving incentives to innovate with introduction of biosimilars. Two bills introduced in March 2009 deserve attentions [7,8]. The Waxman bill (H.R. 1427) proposes 5 years of market exclusivity to the innovator companies and requires no clinical trials for biosimilar development. The Eshoo bill (H.R. 1548) proposes 12 years of market exclusivity to the innovator companies and requires clinical trials for biosimilar development. Obama administration appears to favor a 7-year market exclusivity [9]. Once a legal framework is established for biosimilars, the FDA will likely take a conservative approach using the comparability as an approval principle. Clinical proof of efficacy and safety will be required, probably in reduced scale.

In the EU, the European Medicines Agency (EMEA) issued regulatory guidelines for approving biosimilars in 2005 (Figure 1) [10-16]. These include two general guidelines for quality issues [11] and non-clinical and clinical issues [12] and four class-specific annexes for specific data requirements for Granulocyte-Colony Stimulating factor (G-CSF) [13], Insulin [14], Growth hormone [15] and Erythropoietin [16]. In addition, a concept paper on interferon alpha [17] is also available. So far, there are eleven biosimilar products which received market authorization in the EU and they are biosimilar versions of human growth hormone, Epoetin and filgrastim. It is estimated six to eight years on average for a biosimilar to be developed [18].

The EMEA treats a biosimilar medicine as a medicine which is similar to a biological medicine that has already been authorized (the “biological reference medicine”) in the EU, The active substance of a biosimilar medicine is similar to the one of the biological reference medicine.

A biosimilar and the biological reference medicine are used in general at the same dose to treat the same disease. A biosimilar and the biological reference medicine are not automatically interchangeable because biosimilar and biological reference medicine are only similar but not identical. A physician or a qualified healthcare professional should make the decision to treat a patient with a reference or a biosimilar medicine. Since the biosimilar may contain different inactive ingredients, the name, appearance and packaging of a biosimilar medicine differ to those of the biological reference medicine. In addition, a pharmacovigilance plan must be in place for post-marketing safety monitoring.

Japan’s Ministry of Health, Labor and Welfare (MHLW) issued guidelines for follow-on proteins or biosimilars approval in March 2009. The first biosimilar, Sandoz’ growth hormone Somatropin, was approved in June 2009. The MHLW’s guidelines consider biosimilars drugs which are equivalent and homogeneous to the original biopharmaceuticals in terms of quality, efficacy and safety. Biosimilars are also requested to be developed with updated technologies and knowledge. Biosimilars need to demonstrate enough similarity to guarantee the safety and efficacy instead of absolute identity to the original biologics. Biosimilars’ regulatory approval applications will be categorized separately from conventional generic drugs. In general, the applications should be submitted, as the new drug applications, with data from clinical trials, manufacturing methods, long-term stability and information on overseas use. The MHLW will assess the data on absorption, distribution, metabolism and excretion (ADME) on a case-by-case basis. The applications do not need to provide data on accessory pharmacology, safety pharmacology and genotoxicity.

Biosmilars are already thriving in Eastern Europe and Asia, where regulatory and intellectual property (IP) standards for biosimilars are more liberal. Biosimilars developed in these regions are primarily sold domestically. These markets are considered less controlled. The quality of the biosimilars may not be in full compliance with ICH guidelines although they are often developed through comparative quality testing and clinical trials against the biologics which are already approved in Western countries

 Comparability Demonstration

 A comparability exercise based on the ICH guideline [22] needs to be performed to demonstrate that the biosimilar product and the reference biologic product have similar profiles with respect to product quality, safety, and efficacy. This is accomplished by comparative testing of the biosimilar product and the reference biologic product to demonstrate they have comparable molecular structure, in vitro and in vivo biological activities, pre-clinical safety and pharmacokinetics, and safety and efficacy in human patients. Comparison of quality attributes between the biosimilar and the reference biologic product employs physicochemical and biological characterization. Comparability on physical properties, amino acid sequence, high order structures, post-translationally modified forms are evaluated by physicochemical tests. In vitro receptor-binding or cell-based (binding) assays or even the in vivo potency studies in animals need to be performed to demonstrate comparable activity despite they are often imprecise. Levels of product related impurities (aggregates, oxidized forms, deamidated forms) and process related impurities and contaminants (host cell proteins, residual genomic DNA, reagents, downstream impurities) need to be assessed and quantified. Stability profiles of the biosimilar product and the reference biologic product also need to be studies by placing the products under stressed conditions. The rate of degradation and degradation profiles (oxidation, deamidation, aggregation and other degradation reactions) will be compared. If unknown degradation species are detected, they need to be studied to determine if they affect safety and efficacy. If differences on product purities and stability profiles are present between the biosimilar product and the reference biologic product, these differences need to be justified using scientific knowledge or preclinical or clinical studies. Changes in the impurity profile should be justified as well.

The demonstration of comparability in quality attributes does not necessarily mean that the biosimilars and the reference biologics are identical, but that they are highly similar. In many cases, the relationship between specific quality attributes and safety and efficacy has not been fully established. For example, physicochemical characterization cannot easily predict immunogenicity and slight changes in manufacturing processes or product composition can give rise to unpredicted changes in safety and efficacy. Changes in bioavailability, pharmacokinetics, bioactivity bioactivity, and immunogenicity are the main risks associated with the manufacturing of biosimilars. In vivo studies should be designed to measure the pharmacokinetics and pharmacodynamics relevant to clinical studies. Such in vivo studies should be designed to detect response differences between the biosimilar and the reference biologic not just responses per se. In vivo studies of the biosimilar’s safety in animals may be used to research any concerns into the safety of the biosimilar in human patients. Although extensive clinical testing is not necessary for biosimilars, some degree of clinical testing is needed to establish therapeutic comparability on efficacy and safety between the biosimilar and the reference biologic product [23,24]. This includes using surrogate markers of specific biologic activity as endpoints for demonstrating efficacy, and showing that patients didn’t develop immunogenic responses to the product. In general, the approval of biosimilars will be based on the demonstration of comparable efficacy and safety to an innovator reference product in a relevant patient population. Clinical data requirement for each individual product will be different and will be determined on a case-by-case basis.

Small-molecule Generics versus Biosimilars


  • Approval based on “sameness”


  • Approval based on “high similarity”


  • Replicate the innovator’s process and product and perform a bioavailability study demonstrating similar pharmacokinetic properties


  • Full CMC development with comparative testing, conduct substantial clinical trials for efficacy and safety including immunogenicity


  • Abbreviated registration procedures in Europe and US


  • Regulatory pathway is defined in EU on “Comparability” status, no pathway yet in US under BLA


  • Therapeutically equivalent, thus interchangeable


  • Lack of automatic substitutability


  • $1 to $5 million to develop


  • $100-$200 million to develop


  • Brand-to-generic competition


  • Brand-to-Brand competition


The patent provisions of the Biosimilar Act, 2009 establish demanding and time-sensitive disclosure requirements. ObamaCare upheld by the Supreme Court is a victory for future development of pathways for biosimilar regulatory approval and eventually biosimilar generic drugs.

Biosimilars are defined as biological products similar, but not identical, to the reference biological products that are submitted for separate marketing approval following patent expiration of the reference biological products. As one of the ICH members, the US needs to catch up with the EU and Japan as those two countries have already issued regulatory guidelines for biosimilars. 2009 and 2012 represent milestones in the regulatory provisions for biosimilars in the US.

Once Congress establishes a legal framework, FDA is expected to set up a biosimilar approval pathway which will be similar to those in the EU and Japan and harmonized under ICH. The biosimilar will need a full CMC development package plus demonstration of comparable quality attributes and comparable efficacy and safety to the innovator’s product. Table 5 provides a comparison summary between small-molecule generics and biosimilars. It will take a much bigger effort to develop a biosimilar than a generic drug. Automatic substitution between the innovator product and a biosimilar is not appropriate as a biosimilar is not a generic version of the innovator product and is approved based on comparability to the innovator product.


1. Federal Trade Commission Report, June 2009.

2. Schellekens, H.; Nat. Rev. Drug Discov. 2002, 1: 457-462.

3. Van Regenmortel, M.H.V.; Boven, K. and F. Bader, BioPharm International, August 1, 2005, Vol 18, Issue 8.

4. Locatelli, F.; Del Vecchio, L. and P. Pozzoni, Peritoneal Dialysis International, 2007, 27(Supplement 2): S303-S307.

5. Hartung, H.P.; Munschauer, F. And Schellekens, H., Eur J. Neurol., 2005, 12, 588-601.

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24 Schellekens, H., NDT Plus, 2009, 2 [suppl 1]: i27- i36.

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