American Society for Gene and Cell Therapy (ASGCT)


On April 29th I will be presenting our research this year at the American Society for Gene and Cell Therapy at the Washington Hilton in Washington DC for Talee Bio, Inc:

Abstract Title: Delivery of AAV-CFTR to Bronchial Epithelial Cells from Cystic Fibrosis Patients Augments Functional Recovery of Chloride Conductance
Session Title: Pulmonary Gene Therapy
Date/Time: Monday April 29th, 11.15-11.30am
Location: Heights Courtyard 3.

On the same day our co-founder and University of Iowa professor, John Engelhardt will be presenting some of his cool data from ferrets. Details here:

Scientific Symposium: Pharmacologic Rescue and Gene Therapy Endpoints in Ferret Models of Cystic Fibrosis
Session Title: Novel Strategies for Lung and GI Tract-directed Genetic Therapies - Organized by the Respiratory & GI Tract Gene & Cell Therapy Committee
Date/Time: Monday April 29th, 8.00-8.30am
Location: Georgetown Room

My colleague will also be presenting his work in a poster that day:

Abstract Title: Study of the Neutralizing Antibody after rAAV.TL65 Transduction in Ferret Airway
Session Title: Immunological Aspects of Gene Therapy and Vaccines
Date/Time: Monday April 29th, 5.00-6.00pm
Location: Poster session, Board no. 130  

This will be the first time I attend this meeting and I look forward to potentially networking with some leading scientists as well as companies working to develop gene therapy products. Since Talee Bio, Inc does not have a social media or publicity machine in place yet (and personally neither do I!) I will put this message out for our company. However, as a disclaimer all of the views I have expressed on this website, in my previous posts and in my subsequent posts reflect my sole opinions and do not reflect that of my biotech company.

Those who know me well will remember that I have family in the DMV area and that I will be staying at home in Virginia from April 27th to May 4th. I welcome any suggestions to network and meet up in the local area.


    Alzheimer’s Drug Failure - Ending Biotech’s Disastrous Love Affair with Beta-Amyloid


Last week another potential blockbuster Alzheimer’s drug failed and two late Phase 3 clinical trials have had to be cancelled. Aducanamab, an antibody drug designed to target beta-amyloid, a pathological hallmark of Alzheimer’s disease, has failed to meet its clinically significant endpoint. Biogen and Eisai, the sponsoring companies behind this latest Alzheimer’s endeavor has suffered a great loss with its stock prices plunging. But the human cost to Alzheimer’s patients, communities and their clinicians, who were expecting to see a cure, will be even greater as they pick up the pieces of another failed promise. There are nearly 6 million people who suffer from Alzheimer’s Disease in the US and at least 50 million people world wide.

Nearly twenty years ago, when I first learnt about Alzheimer’s disease in university, people were talking about beta-amyloid and tau. Beta-amyloid forms deadly plaques in the brain and tau accumulates as neurofibrillary tangles inside neurons, contributing to the death of brain cells. The trigger for Alzheimer’s disease was thought to come from build-up of either beta-amyloid or tau (or both) and these were the most dominant theories. Decades later, after so many biotech companies have tried throwing anti-beta-amyloid drugs into clinical trials to treat patients, none have shown efficacy and not one has been approved by the FDA during that time (trials that have tried to target tau have not faired much better). Large companies from Merck and Eli Lilly to Pfizer, Johnson&Johnson and Roche have all fallen short of bringing a cure to the table.

As Matthew Herper from STATnews recently commented on The Readout Loud podcast, the drug industry has had “a disastrous love affair with beta amyloid. It was like Amyloid would come into the bar and they would meet one drug company and it would end terribly. Everybody else would see it but the next day, somebody else would come in and fall head over heals for Amyloid again.” The latest failure of Biogen’s drug could now put a nail in the coffin for the beta-amyloid hypothesis in spite of its ardent supporters.

The end of Biotech and Beta-Amyloid's love affair?

There are a number of other treatments for Alzheimer’s that are still being worked on in clinical trials. Chief among these are BACE inhibitors (AMG520 by Amgen and Novartis), NMDA receptor antagonists and serotonin / norepinephrine agonists (AXS-05 by Axsome and AVP786 by Avanir). There is even talk of a gene therapy trial to test for targeting the subpopulation of patients who have the APOE4 gene mutation. However these clinical trials are all trying to beat tough odds. In 2017 an Alzheimer’s drug named Interpirdine, a 5HT-6 antagonist, failed to show clinical efficacy. Pulling this drug off the pipeline caused a major setback for the sponsoring company Axovant, which had gone public with the most lucrative IPO in biotech history.

Surely for Alzheimer’s disease, biotech exuberance must give way to scientific reality - they must go back to the drawing board at the research bench and figure out the basic science behind what is actually causing Alzheimer’s. For a multifactorial disease that is so complicated it seems unlikely that a single magic bullet cure would ever work.


Images: Schnabel J, Alzheimer's Theory Makes a Splash, 2009, Nature (459; 310)

Brooks K, The Cut, Failing at trying to have an affair. 2018


Motley Fool:



    Changing Your Habits


When I first started working in my current job at this biotech startup I wanted to see if I could bring something new to the way I organized my experiments and shed some of my old academic habits of doldrum. I decided to jump onto the bandwagon of Electronic Laboratory Notebooks (ELNs). I quickly signed onto SciNote, one of the leading ELNs and, after talking with the management team, decided to stay with using it for the duration of my time in the lab.

ELNs are essentially online cloud storage platforms that are set to replace the traditional lab notebook - think of them as Dropbox for the lab. Instead of writing down protocols, large amounts of data and administrative rules for the lab in a physical book you can now upload everything onto the cloud. This allows everyone who has secure access to be able to see your lab book instantly. Potentially this could help share data between lab personnel and between collaborators more quickly and accurately. Online reviews of ELNs have hailed them as the future of knowledge-sharing platforms. But traditionalists and labs that have settled into a fixed way of managing projects will probably detest the idea.

Here are some advantages of ELNs I can think of:

- ELNs have been granted the same validity as paper records.
- 17% of all research data is lost in physical lab notebooks.
- You can search through your entire lab book for a specific query on a piece of data quickly.
- Upload different files (word, ppt, txt, jpeg, tiffs) instantly.
- Upload large amounts of data directly from a computer integrated with the ELN cloud.
- You will not have to worry about reading illegible handwriting anymore.
- Generate reports and even use the platform to help formulate a manuscript quickly.
- Experimental lab records must be signed and validated in order for drug product development to move through the FDA approval process. This is part of a regulation that must be satisfied for Good Laboratory Practices (GLP) Studies (21 CFR Part 11).

Here are some disadvantages of ELNs:

- Privacy could potentially be breached by bad actors / hackers. Given the number of issues we now have with personal data breaches and sharing with third party advertisers this could be a big concern for many people moving into online repositories of data.
- Updating electronic notebooks can still be as manually intensive and tedious as writing notes in paper lab books.
- Changing from a system of written notes to electronic notes takes a long time for larger labs that are used to doing things a certain way. This can also be time-consuming.
- You must have access to the internet and an electronic device at all times to read the notes.
- ELNs can charge a lot for their premium services, such as larger amounts of data storage and validation signatures.
- Adding extra people onto an ELN platform can also incur extra costs. This could be frustrating when just one or two new people join a lab and want to briefly look at your old data.

A traditional laboratory notebook in the lab:

My SciNote ELN with various windows open showing my workflow through various projects:

How ever you look at it, ELNs are probably here to stay for good. There is an increasing push in our culture to automate dull and mundane work as well as to share our growing amounts of data with a wider range of audience. There may well be a day when the more tedious jobs of pipetting and pouring liquids at the laboratory bench are totally eliminated for human beings (thus eliminating the need for technicians, graduate students and postdocs). But when that day comes, ELNs will provide a vital role for scientists managing projects to make the important Go-No-Go decisions on innovative experiments.


Image from: Kowk R, How to pick and electronic laboratory notebook, Nature 560, 269-270 (2018)



    How to Write Effectively and Get People to Care


"You have a problem with something and it needs to be solved. I will show you where your problem is and provide you with a solution!”. That, according to Larry McEnerney of the University of Chicago, is how we should all start a piece of writing in order to be effective. Looking back at all of my previous blogs I am kicking myself and realizing that although I have constructed some interesting, well-written articles about science, law, policy and healthcare, it has all been written primarily for myself. I have disregarded you, the audience (whoever you are), and am being punished with having relatively few readers. But the problem goes deeper than that and it affects many writers from all areas of society. A lot of people write blogs, papers and even grant proposals expecting everyone to read it and expecting the world to change. In fact the world ignores these articles or just rejects them out right because no one actually cares. We, the ineffective writers, have forgotten the principle rule of writing - to cater to the right audience with things they care about. It turns out that while writing is done by ourselves, locked away in a room, the purpose of writing is to start a relationship with the audience, continuing an interactive dialogue. Only then do we present a possibility of providing value, giving them a sense that the article is worth reading on. With that I will jump straight into what I have learnt from watching a couple of McEnerney’s videos on how to write effectively. You can watch the videos here and here.

1. Your writing must be Valuable.

We have all been taught that writing should be persuasive, organized, clear and somewhat valuable. However, the most important aspect is creating VALUE! We have to identify the target audience and write in a language that the audience wants emotionally. If we write just for ourselves, it’s all over for the audience. People get annoyed, bored and stop reading - but please don’t do that here!

2. You write for the readers, not for yourself.

Everything we have ever been taught by our English teachers up to high school has been WRONG (except for spelling and basic grammar). We have been trained to write out our ideas, submit it as text into the world and everyone will read it. But our readers in school have always been teachers (or parents) who are paid to care about what we think or know. However, in the real world, the function of text is to cause readers’ minds to change. Readers will not care about what I think. Readers only care about what they think or do! The text must flow with the audience’s expectations, not with my own experience.

3. Pamper the audience.

What is important to the reader? There are two types of audiences that we, the writers, have often failed to satisfy. One is the general public and the second is the expert in academia. Let’s start with the academic because they are most familiar to me.

(i) The expert in academia who decides whether to fund your grant proposal

We were taught in school about a “Positivistic World”. We were taught that knowledge is built up over time and every time we found out a bit about something we did not know, we could just add it to the existing pool of knowledge. We thought that as long as knowledge grows in any shape or form, everybody will be happy. This is inconsistent with the real world! In the real world there are a bunch of people who get to decide what knowledge is and what is important. Who are they and why do they get to decide? Well, they are the experts in your community and they just get to do it. Their conversations matter and luckily their conversations will change over time. Over time, some knowledge gets accepted and some knowledge gets left behind. However, when you submit a paper or a grant, you have to deal with these experts, to convince them that you can also join in on the conversation. You must get to know who the experts are in your field and what they did to become so important.

Learn the code: In order to join in on their high level conversation and get your findings published, you have to learn the code. The code is to begin every paper with a variation of an ego massage, ie. “Wow are you smart! You have contributed to the community in fabulous ways! Your work is excellent!….. BUT, there is this little tiny thing you got wrong…” then come in with your argument. Then you point to the anomaly but you leave it open to explanations. Only then will the expert reviewer or grant referee decide to maybe read on. Never introduce your paper by saying “There is something I want to add to the field…”. No expert will want to read it.

(ii) The average reader of the New York Times, CNN and Medium

Unlike in school, readers in the real world do not care about your objective arguments. People read in order to be entertained on some level. Entertainment is the value they seek and the bread and butter of major news outlets (I know, this sounds cynical). Often, New York Times articles are written in shorter sentences. This allows the reader who is on the move, reading on the train, on the smartphone, to get the idea quickly. The longer your sentences are, the more you will interfere with the reader’s thinking processes. If your writing interferes with their thinking, they will get annoyed, bored and stop reading. People like to have their attention captured and if it’s shocking or bad, it will attract people even more. This leads onto the final point:

4. Create valuable tension

Always sprinkle your first few paragraphs with words that cause tension. Tension is valuable to the reader because they will be attracted to it. McEnerney gave an example of five words:


(Notice how I have added these words into the above paragraphs!!)

These words, among others, create instability for the reader and get them engaged. It highlights a problem you are introducing. If you know the readers in your community, you can address them directly and find a polite way to say, “Hey readers, I have read your stuff. I know what you think. But, you are wrong!!! Here is why… and here is how to solve it…” Obviously it is impolite to directly write this in the introduction. Therefore you must learn the code, write something that validates the community’s past thinking, appreciate their previous work and then hit them with what has been missing. People love to have a problem presented to them and see it become enriched. The most effective papers are not structured purely as the classic “Introduction, Middle and Conclusions”. The best literature reviews enrich a problem and create instability.

After watching McEnerney’s writing classes I have to agree with him that some of these ideas seem controversial, even verging on Fascist. You are not being encouraged to think for ourselves or to be brave about broadcasting our thoughts to the world. However, if your career depends on a grant proposal, a paper or a news media article, you have to play by the rules of this society. Ultimately, you have to give the people what they want.



Youtube videos of Larry McEnerney



    We Need to Talk About Mental Health for Graduate Students


As I sat in at a small church group last Friday evening listening to people discuss their anxieties and their struggle to find meaning, two people started talking about their emotional stress stories of dealing with failed experiments in their laboratories.  One person recounted a near mental breakdown at one point and how they cried in that moment of despair.  Another described a feeling of loneliness when pushed to over work at the bench.   Both were biomedical scientists in the early stages of their careers perhaps facing turmoil with their thesis advisors and within the academic system. During my drive back home I pondered about how I could relate to their situation. I remember feeling the same way when I was in graduate school and during parts of my postdoc.  It also echoes what I have been hearing for years at career development meetings and online in science careers columns.

I don’t consider myself as someone who has endured extraordinary hardship.  From a high level perspective I have had it relatively easy, having gone through graduate school and an early career in academia without suffering too much stress. I always had plenty of support from my mentors and my family.  Indeed there were times when I felt challenged and depressed towards the end of my PhD studies, while rushing to finish up my dissertation, but this is just what every graduate student goes through in some way or another.  However, I have seen the toll that graduate school takes on people who have not been as fortunate as me or who lacked the network of emotional support.  For many young academics, especially those who are the first generation of their family to attend graduate school, it is important to find support when dealing with emotional turmoil while they undergo technical and personal challenges.

In March this year, Nature Biotechnology published a report of mental health and clinical anxiety in over 2,000 graduate students in PhD and Masters programs covering everything from biological/physical sciences to humanities and the social sciences.  The results showed that graduate students were six times more likely to experience depression and anxiety than the general population.  39% of graduate students were scored as moderate to severely depressed compared to just 6% in the general population.  Up to 56% of students sampled disagreed with the statement, “I have a good work-life balance”. Up to 50% of those in the anxiety/depression group disagreed with the statement that their PI or advisor provided “real” mentorship or support while only 36% agreed with the statement.  Furthermore, the report provided strong data to show women and transgender students are under increased risk of depression and anxiety compared to men.

It has long been known that people with higher level graduate degrees are more susceptible to depression and feelings of alienation.  Only recently, however, has this been recognized as a crisis and has anyone attempted to address the issues from a national and institutional level.  The NIH introduced the “Broadening Experiences in Scientific Training (BEST)” award program within the NIH campus at the Office of Intramural Training and Education.  This has helped broaden the career aspirations of scientists within their campus.  NIH grants now include mandatory sections for mentors to address how they will help trainees better develop their careers.  Certain training grants, such as the K - grants mandate principle investigators (PIs) to serve a minimum of 75% professional effort on research, development and mentoring.  Many local institutions have graduate school programs that try to help with professional development by introducing individual development plans (IDPs), something that has been offered by Science for a number of years now.  At the postdoctoral level I was intimately familiar with the National Postdoctoral Association.  I personally worked at setting up nationally recognized Postdoctoral Associations during my training to introduce career development at my old school - admittedly without much success!

However, all of these institutional groups still fall short when it comes to solving the mental health crisis.  At issue are two things that, in part, are a reflection of our changing society.  The first is the problem of modern work culture.  The second is economic turmoil that has led to geopolitical division.  I will focus on the former, since the latter requires an altogether different blog – suffice to say it has resulted in a manifestation of nationalism and alternative facts that denigrate everything we strive for in knowledge development. 

The academic system is built on the backs of many hard-working junior scientist who serve a few prominent PIs in order to drive innovative research.  In the old days an academic career was straight forward.  At the end of a productive graduate school and postdoctoral training, one was able to attain a tenure track faculty position in a university as a full professor.  Today, the sheer number of people graduating with a PhD has saturated the job market while research funding, especially within academia, has shrunk, without even accounting for rising inflation.  The guarantee of finding meaningful employment as a tenure track faculty, doing globally impactful research is simply a lie.  It is therefore difficult for career development institutions that work under the NIH and within universities to fundamentally challenge the academic culture that feeds them.  Thus, many graduate students and postdocs in their early career fall through the cracks of emotional support during times of need.

Shortly after the mental health report was published, hundreds of scientists contacted Nature to contribute their personal stories.  One individual, Robbie Hable, a PhD student in engineering, wrote about how he was hospitalized for depression in graduate school.  He then mentioned finding out about the Cheeky Scientist Association (CSA), created by Isaiah Hankel. The CSA provides a platform for PhD students and postdocs to support each other both technically and emotionally as they look for jobs in industry, transitioning out of academia.  On their forum there is a common thread of success stories which researchers post during the interview and transition process designed for encouragement, often during times of rejection.  In the UK there are national frameworks set up, such as #stepchange, which works to improves mental health of faculty and students in higher education.  There are also mental-health charities, such as Student Mindswhich seek to help students psychologically.

For those who are open to the idea, there is always sanctuary in religion, if all other methods seem out of reach.  This may seem counter-intuitive to many people in higher education STEM fields, myself included, who come from atheist families with secular upbringings.  What use is God and a chronicle of bizarre miracles if you champion intellectual philosophers borne out of the enlightenment era to rationally explain your problems?  Religion, however, as I have discovered in recent years, brings with it a form of comfort and community not offered by university or secular institutions.  There are therapeutic stories such as in Mark 4:38-39, Jesus calms the storm in the Sea of Galilea and asks his disciples to stay calm, have faith in him. These stories have a remarkably calming effect on one's personal nature in times of stress. In fact it is often the small bible study groups and communal potlucks that bring nourishment to those who suffer the most.  Deep friendships and bonds can form when people come together to discuss major questions of life – why are we here? / where are we going?.  When one focuses on those big issues, all other life worries tend to seem trivial.  At a time when nations have become protectionist and when political divisions have grown ever larger, religion may yet see its return as a key player for unity.

That is not to say that joining a religion or even joining a cult is the be all and end all to the mental crisis currently faced by graduate students.  Those staunchly opposed to religion may find relief in therapy or simply in school counselling.  A secular movement named "The School of Life", started by the outspoken atheist philosopher, Alain de Botton, has in recent years gained traction around the world. The School of Life provides an endless slew of fascinating videos on Youtube which dish out advice to those searching for meaning in life while going through crises. Each video is designed to teach you a part of a wider curriculum of life lessons that include love, marriage, relationships, philosophy, history, art and psychotherapy. Alain de Botton's radical idea that high art and culture can replace God when it comes to soothing a troubled person's soul may seem elitist and too out of reach for most of us. However, between his famous lectures on why you will marry the wrong person and his books on how to choose a job you love much of his philosophy deals with the same issues the church originally had to do: how to face mundane life problems and how to go on in life in spite of massive emotional setbacks.

The consequences of not seeking help can often be devastating.  The University of Iowa, where I am currently located, bears a painful memory of what happens when graduate student mental illness is not treated quickly.  In 1991, a student named Gang Lu, shot and killed four faculty and a postdoc in the Physics department before committing suicide.  His main grievance was that he was pasesed over for a departmental prize in particle physics and, potentially, not being able to stay on in America.  His problem of deteriorating mental health had been noticed by colleagues for some time but no one took action.  The killing at the university sent shockwaves across the US.  It has even been dramatized by Hollywood into a movie (Dark Matter, starring Meryl Streep). Not surprisingly, after 27 years, the events of that day still echo in the back of people’s minds. 

Interestingly, it has been the local church community, not the university itself, that has gathered together every few years to commemorate this tragedy and move towards healing people from their emotional wounds.  That contrasts with my experience of living in larger metropolitan areas where people often have more choice from secular help groups and charities. Ultimately, there are a multitude of ways for people to seek help in times of mental hardship.  As the crisis of mental illness in graduate students enters into our collective consciousness it will come down to both a matter of personal responsibility and of social institutional support to seek a solution before things spiral out of control. 



Evans TM, Bira L, Gastelum JB, Weiss LT, Vanderford NL, Evidence for a mental health crisis in graduate education. Nature Biotechnology 36, 282-284 (2018):

Nature Career Feature, May 2nd 2018: Feeling overwhelmed in academia? You are not alone, Chris Woolston:

#Stepchange initiative:

Student Minds Charity:

The Cheeky Scientist Association:

Jesus calms the storm by Ludolph Backhuysen:

The School of Life by Alain de Botton:

Dark Matter movie starring Meryl Streep and Ye Liu:

Scream painting by Edvard Munch:



    Chapter 10 - The Limits of Biotechnology Inventions in Patent Eligibility


Over the last 10 blog chapters I have summarized a few interesting topics I learnt about pharmaceutical and biotech patents back when I was doing my Food and Drug Law class.  At the end of that class I realized that the pharmaceutical industry puts a great deal of effort into applying for and maintaining eligible patents.  The US Supreme Court has repeatedly struck down many patent validity appeals for biotechnology products in the past years after they arrived at the US Patent and Trademark Office (USPTO).  Some lawyers have even commented on how the Supreme Court has destroyed the overall US patent system over the last decade.

At issue is that case law defines an eligible patent to be “any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof” under 35 U.S.C. § 101.  However, the law is vague when it comes to defining eligibility of patents which fall under laws of nature, natural phenomena, and abstract ideas.  The bulk of modern biotechnology and pharmaceutical innovations are likely to fall into these narrowly defined categories, which, while not patentable under strict interpretation, have extremely useful applications that do merit eligibility.  For example, a recent patent application (Patent Application No. 20140194345) was rejected despite being a potentially life saving treatment for antibiotic resistance in lethal bacterial infections.  Inventors in biotech companies must put a lot of energy and resources into a discovery.  However when the final patent is deemed a mere law of nature, natural phenomenon or abstract idea, patent protection is lost and pricing decisions become controlled by the market, leaving inventors unable to recuperate their financial losses.

Examples of the Supreme Court’s decisions invalidating patents for this very reason include:

Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S. ­­­___, 132 S.Ct. 1289 (2012).  The courts invalidated the patent claim of using 6-thioguanine as an indicator of whether a drug dose should be modified.  They decided the indication could be defined as a natural phenomenon.

Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. ___, 133 S.Ct. 2107 (2013).  The courts ruled that isolating genomic DNA associated with BRCA genes in breast cancer was not an act of invention because DNA is naturally occuring.  However, cDNA, which lacks the non-coding regions of genomic DNA, was held to be patentable because it is synthesized outside the body.

Alice Corp. v. CLS Bank Int’l, 134 S.Ct. 2347 (2014).  The courts ruled against patent eligibility for 4 patents concerning electronic methods, computer systems, and program code because they were considered abstract ideas.

Each of these Supreme Court decisions spurred the USPTO to issue a new set of guidelines setting forth rules on patent eligibility.  A study, by Gaudry, Grab & McKeon LLC carried out careful statistical analysis of the Supreme Court decisions on patent eligibility rejections under 35 U.S.C. § 101 over the last three years.  The results cast a grim shadow on the pharmaceutical industry.  They show a trend in the courts to increasingly reject patent eligibility from “select art unit groups” including molecular biology, immunology and protein chemistry technologies.  That means, from the time of the Mayo case in 2012 until 2015, there has been a steady rise in patent rejections from 11.2% to 32.5%.  Furthermore, the number of patent claim appeals for biotechnology inventions has risen by 25% over the last three years, suggesting that it is getting harder to secure a patent.  The study then found that following 35 U.S.C. § 101 rejections, firms usually did not appeal to the Patent Trial Appeal Board because the rapid new changes issued by USPTO guidance documents dis-incentivize companies from doing so.

Graph showing percentages of patent office actions (OAs) 
OAs issued during the time period that included a Supreme Court 35 U.S.C. § 101 rejection were calculated for each art unit group in TC 1600.  Art unit groups 1640, 1650 and 1660 (red box) focus on molecular biology, immunology and protein chemistry technologies.  The proportion of OAs with rejections have increased subsequent to each Supreme Court ruling and guideline publication.  Graph made by Gaudry, Grab & McKeon LLC:

What does this mean for the biotech inventor?

In spite of the doom and gloom in patent validity judgments, it is important to keep an eye out on patent reform and to push the agenda for patent protection for essential medical innovations when possible.  A few months ago President Obama signed the America Invents Act (AIA) into law which helped align the US patent system with modern day requirements.  This legislation has instituted sweeping reform into patent applications, including the “first to file” provision which protects the first inventor who files the patent.  In recent months four other major proposals for patent reform have been under consideration by Congress.  These include the Innovation Act, The TROL Act, the STRONG Patents Act and the PATENT Act.  Each of these acts, if approved by Congress, will serve to ease the burden of the patent review system and reduce the number of litigations in future providing a more just and verdant patent protection system.  It is hoped that one day the Supreme Court can be convinced by some of these new reforms to allow a broader definition of patent validity to cover biotech patents.



    Chapter 9 - The longest patent extension battle in history


A pharmaceutical company named The Medicines Company (MDCO) made news in 2015 when it lost a court battle for the rights to its patented drug.  This is a warning story that has been told many times before by patent lawyers regarding inventions, even serving as a punch line in books such as “Don’t File a Patent!”  The saga began way back in December 2000 when MDCO filed a patent term extension (PTE) request for its anticoagulant drug Angiomax (bilvalirudin) U.S. Patent No. 5,196,404

The right to file a PTE is codified under the Hatch-Waxman Act of 1984 to help companies retain market exclusivity for their products because of time lost in the early years developing and testing a new drug as well as time taken at the end of drug development waiting for NDA review approval.  Since a patent only lasts 20 years and it takes up to 15 years to bring a drug to the market, companies often require patent extensions to remain competitive.  Under the patent term extension rules of the US Patent and Trademark Office (USPTO) 35 USC 156, a company can file a PTE within 60 days of receiving FDA approval for a drug.  However, MDCO’s PTE request arrived at the USPTO on the 61st day (Feb 2001) by a stroke of bad luck.  After many years of appeal to the District Courts for the recognition of the PTE, MDCO repeatedly got denied.

In 2010, when MDCO’s patent expired, they found themselves in an infringement lawsuit with a generic company named APP who filed an ANDA for the generic version of bilvarudin.  The US Court of Appeals heard the motion from APP and decided finally to settle the case in favor of MDCO, giving them the PTE for 1728 days.  This meant their patent was now extended from 2010 to December 2014. MDCO went on to sue its intellectual property consultants, Fish & Neave LLP and Ropes & Gray LLP for legal malpractice because they did not carefully calculate the PTE request deadline and made MDCO miss out on the crucial 60-day deadline.  MDCO won a summary judgment against the law firm and settled all its cases in 2012.  This was all well and good for the company at the time.

However, MDCO was embroiled in another lawsuit, a few years later, against a company named Hospira, who were ready to market its generic version of bilalvirudin.  Hospira was in charge of Ben Venue Laboratory, subcontracted by MDCO to manufacture bilvalirudin for many years.  Ben Venue Laboratories had used the patented methods, “adding a pH-adjusting solution during the compounding process minimize the Asp9-bivalirudin impurity to less than 0.6%” filed under US Patent 7,582,727 and 7,598,343 by MDCO. MDCO filed suit claiming that Ben Venue Laboratories used this method of manufacturing bivalrudin before the patent expiration and exploited the drug for marketing, committing a commercial violation.  When the case was reviewed by the District Court this time, they found that Ben Venue did not violate patent infringement and that MDCO’s claims were invalid under on-sale bar.  Thus MDCO went on to face a recurring situation where its pioneer drug was threatened in the market by a generic.  After the Hospira challenge, the company was not able to appeal for further patent extensions because its extra 1728 days also expired.  Later in 2016, the case was brought to the Court of Appeals for the Federal Circuit and two years later, they affirmed the District Court’s non-infringement findings.  However, the Federal Circuit overturned the on-sale bar determining that a distribution agreement constituted a commercial offer-for sale, since the product did pass hands.

The moral of the story is to respect filing deadlines when submitting a patent and to choose your intellectual property lawyers wisely.  When filing a patent for the first time in preparation for marketing a product it is advisable to do some research in order to keep track of the filing dates and to keep ahead of the game.


The Medicines Company v APP and initial PTE denial

The Medicines company v Hospira

When can you file a Patent Term Extension

Lawsuit against IP law firm

On-sale bar



    Chapter 8 - Invasion of Patent Trolls into the Biotech Sector


Over the years the Supreme Court has become more favorable to biotech companies in patent litigation cases where a patent is attacked either by bogus companies or by plaintiffs trying to reduce the costs of drugs.  Just last year, Kyle Bass, the famous hedge fund manager of Hayman Capital Management, lost a litigation case where he tried to invalidate Biogen’s Tecfidera patent.  In the same month, Kyle Bass also lost a similar patent case against the Acorda Therapeutics multiple sclerosis drug, Ampyra.  Intellectual Ventures, another patent troll company, has also lost a string of patent challenges against tech companies, over 80 of which ended up on the Federal court. 

Since writing my original blog I have realized that patent trolls, which seek to invalidate existing patents, can be a boon in the short-term, by lowering the prices of drugs and encouraging the growth of generics.  However, the long-term effects of patent trolling are devastating for the pharma and biotech industry because it reduces the financial war chest needed to bring newer, more innovative treatments from the development pipeline to the market.



Blog from 2015:

The high tech sector has for many years been plagued by patent troll litigations.  Ever since the 1980s, rapid technological innovation has brought great wealth to the industry and it has incentivized certain companies to grab a share of the spoils by filing lawsuits.  However increasingly, patent trolls are invading the biotech and pharmaceutical market and a recent report from Steptoe&Johnson LLP law office highlights the need to recognize such threats.

Patent trolls acquire patents with no intention of using or selling the underlying technology.  They usually have low operating costs because they do not manufacture anything and they do not have to ensure they are infringing on existing patents when filing.  Instead they aggressively target real businesses that file patents arguing patent infringement and earning money by settling legal action in or out of court.  Many of these plaintiffs are known as non-practicing entities (NPEs) and have now become publicly traded companies due to their cunning ability to make money.  Such companies often hide their identities behind shell companies and require defendants to sign non-disclosure agreements.

Total NPE Defendants by Industry Sector:

NPEs operate by filing a vague patent early on (e.g. adding a flash drive to a medical device) and waiting for the medical device industry to “catch up”, investing millions of dollars into the actual innovation.  Once the technology becomes marketed and profitable, the NPE sends out batches of infringement notices to the biggest company in the sector to demand licensing fees.  Companies with the biggest profit margins that are financially well endowed are the most popular targets.  Often it is cheaper for the accused company to settle the licensing fee out of court since prolonged litigation fees cost much more.  NPEs can file many different licensing fees this way and grow their companies quickly.

According to Jay Nuttal, a managing partner of Steptoe&Johnson who wrote the report in In Vivo magazine, 90% of venture capital companies have been hit by patent troll licensing demands but only 13% of pharmaceutical and medical devices investors have received such letters.  However, while only 9 medical devices patent infringement cases were filed in 2009, 93 were filed in 2014.  This marks a rapid rise in such cases and the numbers are projected to increase even further in future years.  Part of the growth in cases can be explained by an increasing number of patents filed by medical device companies (a rise of 15%-20% over the past few years).  The other aspect is that when the plaintiff wins an infringement case they typically get rewarded between $15 to $16 million in damages.  Furthermore, NPEs have generally been successful in litigation cases, winning nearly 40% of medical device cases, as compared to 33% in all other industries.  This statistic has driven NPEs to construct patent portfolios for medical device technologies.  One company, named Intellectual Ventures, has an estimated 1000 individual patents filed across multiple categories.

Medical Device and Service Patent Cases on the rise from 2009 to 2014:

How do you protect your company from patent trolls?

A list of offenders in life sciences litigation cases have been identified, including: Acacia Research Corp., WiLan Inc., Intellectual Ventures Inc., IPNav, My Health Inc. and DE Partners Golden Rule LLC.  There are certain measures one can take to avoid these patent trolls. Jay Nuttal gives a list of things a company can do:

1. Know the landscape – do some research about which patents are held by which companies before submitting your first patent.  Foster collaboration with other companies to protect patents, perhaps by cross-licensing them.  Publish your innovations in peer reviewed journals before filing the patent to create prior art hurdles.

2. Be an aggressive defendant – Make sure you quickly respond to a patent troll once you get letters demanding a licensing fee.  Make your claims early in your defence.

3. Press your advantage – File an inter partes review (IPR) before the patent trial and appeal board to attack the validity of the patent troll’s licenses.  Have the patent office take another look at your patentability claims.  Educate the court about your technology.

4. Do some research about the suspected patent troll – Did the plaintiff really own the patent? Has the same patent company previously filed claims before?  Has the plaintiff done due diligence to research facts about the patent in question before sending out their license demand letters? 

5. Seek attorney’s fees – Build up your reputation as a strong defendant for your patent claims.  Hire strong lawyers to win cases and seek attorney fees from the plaintiff once you win the case.  This would strongly dis-incentivize future patent troll litigations.

In March 2015 Congress passed a bill called the STRONG Patents Act to discourage patent trolling.  This bill introduced steps to prevent abusive demand letters and to simplify the post-grant proceedings at the US Patent and Trademark Office.  It is hoped that this new act will limit the power of patent trolls in future, but only time will tell.

Interestingly, there are also companies which appear to be patent trolls but turn out to be genuine entrepreneurial startups that have failed.  Such companies, known as “Formerly Manufacturing Entities” (FMEs), can easily be confused with patent trolls because they also file license fee demands under NPEs.  In a recent case, Gene Reader LLC vs Agilent Technologies Inc, the plaintiffs (Agilent) filed a patent many years ago for a DNA microarray chip reader but was never able to bring the product to market.  Now that the technology has been licensed to Gene Reader, Agilent may have a viable claim to their patent because they put resources into the development of their technology.  This goes to show the complexity of spotting patent trolls from firms that have genuine patent claims.


Patent Trolls in Biotech

Jay Nuttall (Steptoe and Johnson), Feb 2015: The Patent Trolls Are Coming...To Medtech. In Vivo: the Business and Medicine Report.

Gene Reader LLC vs Agilent Technologies Inc

Formerly Manufacturing Entities

STRONG Patents Act

Patent Troll cartoon courtesy of Inc.



    Chapter 7 - Direct-to-Consumer Genomic Testing - The Pros and Cons


I am often reminded of how quickly the biotech world moves as I look back at my FDA law blogs from 3 years ago.  This week I am re-publishing my article about Direct-to-Consumer (DTC) genomics testing.  DTC genetics testing and counseling is now a veritably large industry, having been given an increasingly and has grown up from its controversial beginnings a few years ago.  DTC companies essentially market genetics tests on TV, print advertisements or the internet.  Customers can send the company a sample of their DNA and a short time later they receive results.  These can be tests for a variety of purposes from genealogy tracing to searching for blood relatives to providing information about healthy lifestyles. 

The most contentious has been the tests for disease risk and health.  Genetics testing can reveal a variety of diseases you may carry in your genes such as cystic fibrosis, sickle cell anemia, celiac disease, Parkinson disease and Alzheimer disease.  The NIH has provided a set of well-written, easy to understand guidelines to teach people considering whether they should use the test.  The implications are huge for health insurance companies since they could benefit from charging a premium for those who merely carry genes for pre-existing diseases.  Right now, health insurance policies generally do not cover DTC testing.  Only if a doctor prescribes the test kit can insurance cover some of the costs.

Today, there are dozens of leading DTC testing companies that offer testing for diseases – not just ancestry.  Chief among these is 23andMe, a Silicon Valley biotech that has been at the center of much FDA wrangling over the years. The FDA has officially approved up to 16 genetic disease tests for 23andMe as part of an initiative to keep up with the times.  Ten of those tests were approved in April 2017 and the genetic tests for breast cancer genes, BRCA1/BRCA2 were approved earlier this year.

Back when I wrote this blog, 23andMe had just been barred by the FDA from distributing whole genome genetic testing for consumers.  This, of course, did not stop me! I went ahead and ordered my own genetic test just to see what diseases I had a higher chance of getting. Details of how I did that can be found here:

It remains to be seen where the FDA will go with this matter.  As many have remarked it is not practical for the agency to approve only one single genetic test for one disease at a time.  Sooner or later DTC will have to be available to consumers for the whole genome, for all diseases.


Blog from 2015:

DNA testing has emerged in recent years as a powerful diagnostic tool for physicians to use in the race to find better cures for intractable diseases.  The advantages of more precise diagnoses based on a patient’s underlying genotype and the ability to prescribe drugs tailored to an individual’s genetic makeup have made personal DNA testing an attractive new industry. Spurred on by government initiatives under the Obama administration to enhance personalized medicine and technological innovations both in software and in molecular biology, there has been an unprecedented growth in DNA diagnostic companies all over the world.  One company, the Louisiana based Renaissance RX, was, until recently, tipped as a rising star in the pharmacogenomics sector. 

Renaissance started out in 2012 as a small toxicology laboratory called UTC laboratories which took cheek swabs, and saliva for DNA analysis.  As the company grew, it started to enroll patients into a wide variety of studies, testing for an individual’s propensity to develop adverse reactions to pain killers and anti-clotting drugs.  The program was called “Diagnosing Adverse Drug Reactions Registry (DART)” and it made money by charging patients $75 to sequence every sample.  Renaissance aimed to enroll 250,000 patients for its studies and had garnered $130 million from Medicare as well as $55 million from a venture capitalist company TPG.  This allowed the company to grow its workforce to 800 people by 2014 and gather grant money from the New Orleans City Council to further expand its operations, as part of the region’s tech industry rejuvenation initiative.

Signs that the company faced trouble emerged shortly after the TPG investment last year when Medicare withdrew its investment support following a routine review.  The DART study was stopped shortly afterwards causing a layoff of hundreds of employees.  While many physicians happily participated in the program, sending out multiple patient samples, one physician named Scott Wilson, discovered that Renaissance was engaging in fraudulent behavior, ignoring regulations.  According to Wilson,

“[Renaissance Rx] generated revenue by and through each ‘swab’ it/they conducted within the context of the DART Study, including, without limitation, by and through the use of erroneous and/or fraudulent Codes on the eCRFs to fraudulently bill the conduct of the trials to Medicare/Medicaid,”

Wilson found out that he was signed on as the Regional Principle Investigator for the DART study without his knowledge.  Furthermore, his signature was faked on thousands of additional patient samples illegally enrolled in the study and through this practice Renaissance may have earned an estimated $10 million on top of its regular revenue.  Wilson is suing Renaissance for misappropriation of his name and potential civil liability for the loss of his ability to practice medicine.  The case is due to be held at the United States District Court for the District of Rhode Island, where Wilson is registered as a physician.

In recent years, federal regulators have become increasingly worried about the lack of regulation of Direct-to-Consumer (DTC) testing.  In 2014, the Office of Inspector General for the Department of Health and Human Services stated that many laboratories could be committing fraud to recruit doctors and patients into DNA studies.  Companies often offer huge amounts of money enticing doctors to enroll patients on studies, rather than paying them the small amount necessary for reimbursement.  Part of the problem is that Medicare has not applied a stringent oversight on these companies as it went ahead in funding such operations.  Medicare should pay due diligence to where its funding goes because its function is to generally back proven treatments rather than experimental tests.  Another problem lies in the fast growth of genomic technology.  Contractors who work for Medicare cannot keep up with reviewing all the details within each company since their technology has evolved so rapidly and there are now so many of them.  At some time national guidelines must be set up by the FDA to promulgate rules for regulating testing at these facilities. 

Interestingly, the FDA has taken initial steps towards this challenge.  Recently a company called 23andMe, one of the first consumer genome sequencing companies in the US, was banned by the FDA from offering customers general genetic disease diagnoses based on genomic information submissions using its health algorithm.  The FDA sent a warning letter in 2013 stating that 23andMe had failed to gain market clearance or approval to assure their tests were accurate.  On the other hand, the FDA granted authorization to the company this year to carry out specific Bloom Syndrome carrier reports.  This was the first direct-to-consumer genomic test that the FDA has ever approved through a regulatory framework.  According to Alberto Gutierrez, a director at the Center for Devices and Radiological Health of the FDA, “The FDA believes that in many circumstances it is not necessary for consumers to go through a licensed practitioner to have direct access to their personal genetic information”.

While the promise of genetic testing holds great value for many diseases such as cancer, diabetes and Alzheimer’s disease, more work needs to be done by the regulatory authorities and by the federal government to ensure consumer protection.  It seems likely that DNA diagnostics kits may one day be sold and marketed as over-the-counter drugs given the ease with which they can be used.  Thus the same regulations will need to be applied to them for safety and efficacy.


Renaissance Rx Lawsuit


Blood Syndrome carrier reports

Direct to Consumer Genomics Testing

Obama’s Precision medicine initiative

NIH Guidelines

FDA Guidelines for DTC in Breast Cancer and 23andMe




    Chapter 6 - The Supreme Court's Dilemma - Isolated Gene Patenting and Laws of Nature


Laws of Nature

In the past few months the Supreme Court of the United States has been in the headlines for all the wrong reasons. With the swearing in of Brett Kavanaugh as the newest justice and the bitter battle that raged through his confirmation hearings, I have to conclude that the partisan politics of Washington DC and the polarization of America's citizens are preventing the Supreme Court and the government from making actual policy decisions that affect real change. In spite of this backdrop it is important to remember that the Supreme Court has been quietly and conscientiously making non-partisan (or less partisan) decisions on healthcare and technology lawsuits that influence how we do science and business. The Supreme Court has made judgements on a long list of patent litigations over the years. Three years ago I wrote about one such case, AMP v Myriad, Naturally occurring isolated DNA is not patentable subject matter; cDNA is (2013 case). This case had wide ranging consequences and stood out for me as a landmark because it drew the line in biotechnology between what is patentable (a gene that has been altered in the lab) vs what is not patentable (a naturally occuring gene in its native unaltered form). It is a shame that such cases are not highlighted more in the media, on social media or draw out huge crowds of protestors.


A few years ago a company named Myriad Genetics filed 23 patents for breast cancer genes their scientists had isolated, known as BRCA1 and BRCA2.  Myriad offers a business to exclusively carry out diagnostic testing for the BRCA genes which would indicate a person's propensity for developing cancer. The patent would have given Myriad exclusive rights to charge a premium on breast cancer diagnosis and grow the company.  However, many people opposed this patent, citing issues of patent infringement and arguing that licenses would impinge restrictions on other diagnostic healthcare services. Groups such as the Association of Molecular Pathology (AMP) together with the University of Pennsylvania's Genetic Diagnostic Laboratory filed suit with the American Civil Liberties Union against Myriad's BRCA gene patent.

This case was initially brought to the District Court in 2010 in which the plaintiffs (AMP) were of the position that isolated genes are "unpatentable products of nature" and that diagnostic claims or drug screening claims by Myriad are just describing the basic process of doing science.  Myriad argued in defense that the BRACA genes were man-made "isolated sequences" just like chemical compounds and that any isolated DNA sequences are rendered a different character from DNA present in the human body. To some extent, Myriad are correct. Current medical research has shown that genes in the human body are subject to epigenetic modifications which depend on the environment, lifestyle and situation the person is in. If the gene is isolated from the body and placed into a test tube, it would behave differently because it would not be subject to those epigenetic changes. In a laboratory, one could also modify isolated genes using chemicals to synthesize something analogous to epigenetic modifications in the body.

However, the case by Myriad was rejected by the District Court who ruled that the existence of DNA in isolation does not alter its fundamental quality as existing in the body. Myriad appealed to the Federal Circuit Court and in 2011, the Federal Circuit overturned the District Court's decision.  In response, AMP petitioned for a writ of certiorari to the Supreme Court asking for a review of their case.  In 2013, Justice Clarence Thomas ruled that naturally occurring DNA could not be patent eligible unless it had been altered outside the body.  Furthermore, Myriad had not created any new innovative methods to isolate this DNA, nor had they altered the natural genetic code in any way to satisfy patent eligibility.  Thus, all the Supreme Court justices at the time ruled unanimously against Myriad's patent file.

Differing public opinions

The differences of opinion between the Federal Circuit Court, the District Court and the Supreme Court reflect the high level of contention over gene patenting technology in the general public.  Although there are now over 5,000 US patents on human genes, many people believe that genes, passed along as traits from one generation to the next, should not be patentable because they are in some sense, private property. Breast cancer advocates often argue that a successful patent on BRACA genes would give Myriad the sole power to dictate all scientific and medical uses of the gene. This would take away power from cancer patients to choose where and how they get diagnosed.  On the other hand, many argue that gene patenting would allow greater competition among genetic diagnostic companies, such as Myriad and this would spur economic growth. Use of the patent system would also help disseminate information to society within the bounds of the legal system, providing a better framework for future innovation. Furthermore, a ruling in support of patenting genetic disease diagnosis could fund investment incentives to improve personalized medicine, an initiative prioritized by the National Institutes of Health.  Interestingly when this case against Myriad was raised in Australia, the courts held in Myriad’s favor.

The fact that the US Supreme Court, comprising judges from non-scientific backgrounds with relatively little knowledge about the latest discoveries in medical sciences are put through the test ruling on topics such as gene patenting, adds fuel to the controversy.  When Justice Thomas gave his decision for the AMP v Myriad Case he wrote that, "A naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated…" However, he later wrote on the same judgment, "by the fact that isolating DNA from the human genome severs chemical bonds and thereby creates a nonnaturally occurring molecule…" His two sentences contradict one another, suggesting that isolated DNA claims could simultaneously cover naturally occurring and nonnaturally occurring molecules. Thus one is led to believe Justice Thomas does not truly understand what a gene is.  It is also conceivable that the Supreme Court is not familiar with the field of epigenetics which would add another layer of complexity to whether a naturally occurring gene can be patented when it is completely altered inside of the body!  Then again one can argue that having judges who do not have scientific training decide on legal issues concerning science is good practice since they can apply an unbiased opinion when making rulings.

Whatever the public opinion may be on isolated gene patentability, one thing is for sure, more patents will be filed in the future as more discoveries are made about diseases caused by faulty genes. Thus the legislative issues of AMP vs Myriad are likely to remain at the forefront.

How does this affect you?

If you are a scientist planning to file patent on a new disease associated gene, you must familiarize yourself with AMP vs Myriad and with similar cases, such as Mayo vs Prometheus and the Australian court ruling on Myriad.


AMP vs Myriad,_Inc.

Myriad case in Australia

Mayo vs Prometheus,_Inc.


NIH Grant funding priorities


    Chapter 5 - The Dark Web, An Unlimited Resource for Unregulated Drugs


Deep Web

The illegal drug market is worth over $300 billion a year in the US and up to $36 trillion globally.  Much of it can now be found online in the "dark web", "dark net" or the "deep web".  Naturally, this is now a source of contention for federal law enforcement and the FDA will have to play a game of "catch-up" in the coming years in order to regulate this new uncharted territory.  Back when I wrote this series of blogs I focused my Dark Web story on Silk Road as the epitome of illegal drug markets, which was shut down in 2013.  Since then, many other underground online drug market places have emerged and have been shut down also (AlphaBay and Hansa are just two recent examples).

What is the Dark web?
99 percent of the internet is the dark web, none of which is indexed by major search engines such as Google and Yahoo.  Users can join the Tor network, or use the Deep Web Harvester to access data online without the possibility of government or commercial surveillance.  Websites on the dark web do not rely on cookies to track users so people can access sites and set up websites anonymously.  It is a very easy process to install the Tor browser and enter into the dark web.

Diagram explaining the Dark Web:

Dark Web 1

My own Tor browser which I downloaded and accessed within a few minutes:

This can be a good thing and a bad thing. For lawyers, journalists and researchers, the dark web can provide a wealth of metadata about virtually any subject or person, all of which can be searched with a guarantee of freedom and privacy. Lawyers gathering information for evidence in litigation cases can find a host of resources leading to unpublished court cases and documents that could help them win legal battles.  On the other hand, criminals can use the dark web for a vast variety of illegal activities, including the marketing of weapons and drugs.  Worse still, payments for all items are done through Bitcoins, an online peer-to-peer currency which is mostly untraceable.

In 2013 the FBI and the Department of Justice shut down Silk Road, the biggest online distributor of illegal drugs. The mastermind behind the website, Ross Ulbricht (also known as Dread Pirate Roberts) has now been sentenced to life in prison.  As soon as the original Silk Road was taken off, Silk Road 2.0 and other sites emerged to take its place and since then there has been a huge increase in online underground drug markets.  For example, Evolution Market Place became a major drug distributor after Silk Road and gained notoriety when it suddenly vanished in March this year, taking away $15 million in Bitcoin payments from customers.

Drug listings on illegal websites since 2013:

Dark Web 2

Agora was the biggest underground drug retail website to emerge after Silk Road (at its peak they owned 82% of that market).  Digital Citizens' Alliance, which monitored illicit online markets, reported that as of April 2015, up to 4 major dark web drug-market websites, including Agora, Nucleus, Black Bank Bitcone and Alphabay, listed over 43,000 illegal drugs.  All of these market place websites have since been shut down but new ones have emerged to replace the inexorable demand by consumers for illegal drugs. A list of top 40 illegal online market places can be found here today.

Supply and demand
The continued growth of underground online drug markets, even after the shutdown of the original Silk Road, is suggestive of an inexorable demand for unregulated drugs.  Of all the items being sold on the dark web, drugs occupy the largest proportion.

Data analysis of the Dark Web:

Dark Web Usage

While some users of these websites are indeed addicts looking for a faster way to acquire risky medication away from street dealers, many online buyers simply cannot afford medical insurance, or are genuine patients trying to buy therapeutic drugs at a hugely discounted price.  Online dealers often sell drugs that originate from the same pharmaceutical companies as those found in an ordinary pharmacy or hospital but at prices that are not competitive on the legal market by industry standards.  There are also terminally ill patients who cannot gain access to the drugs they want before FDA approval.  Often such patients desperately seek drugs that do not qualify for treatment INDs, expedited development designations or drugs that have been approved in other countries that have yet to gain approval in the US.  What is most remarkable about the system of buying drugs on the dark web is that customers can leave feedback anonymously about the seller and rate them out of 5.  According to The Telegraph in the UK, “Over the course of three months, around 120,000 pieces of feedback were left on Silk Road 2.0… and on average, “buyers left a score of 4.85.” This leads one to believe that most people who bought drugs on the website were actually very happy with the results and that they would continue to use such services. The power of choosing drug products lies completely in the hands of the buyer rather than the drug manufacturer, the regulatory agency or the government.  Of course if the consumer were to experience adverse reactions brought along by fraudulent, ineffective drugs they would not be protected by US laws.

How does this affect drug patents and FDA regulation?
A lot of potential exists for criminals to tap into the illegal drug market, selling drugs without NDA approval.  It would not be surprising if most of the drugs being sold on the Tor network have already violated patent protection laws in the US.  A slew of legislation concerning cyber information and privacy has been passed in the last few years under the jurisdiction of the Federal Trade Commission.  Some of these include the Fair Credit Reporting Act and Protecting Cyber Networks Act, which provide a process for the pubic to voluntarily share cyber data that could be threatening to national security.  However, I have searched high and low on the (visible!) web but have not come across any Federal statutes or FDA regulations for guidances regarding underground online drug markets. In order to reach a balance between the prohibition of illegal narcotics and the availability of affordable, lifesaving, unapproved prescription drugs for terminally ill patients, Congress should grant FDA some authority over the regulation of dark web drug markets.  There are several ways this can be done.  For example, just as the Protecting Cyber Networks Act enables collaboration between the Departments of Justice, Commerce, Treasury, Energy and the Office of the Director of National Intelligence, a new act could be legislated to enable collaboration between the FDA and the aforementioned government agencies, increasing vigilance on cyber drug regulation.  Another way would be to increase the online surveillance resources at the FDA specifically to target fraudulent drugs on the dark web.  In light of the ever-changing landscape of the modern internet as a global market place, the FDA will have to work more closely with organizations such as the Center for Safe Internet Pharmacies and the Digital Citizens' Alliance to ensure patient safety and public education are held to the highest standards.

What can you do?
The arena for regulating underground drug markets on the internet is ripe for new legislation.  Find out the latest news and public education materials from the Center for Safe Internet Pharmacies and Alliance for Safe Pharmacies about ordering drugs safely online.  You can monitor and report suspicious activity to the Federal Trade Commission in underground drug markets by joining the Tor network – it is free.


The Dark Web:

Video Documentary:

Buyer and Seller feedback on the Dark Web:

Center for Safe Internet Pharmacies:

Cybersecurity legislation:


    Chapter 4 - Gaming the Hatch Waxman Act and a Solution through Inter Partes Review


Gaming Hatch-Waxman

What is Hatch-Waxman?

The Hatch-Waxman Amendment of 1984 was originally issued by Congress to speed up the approval of generic drugs through Abbrieviated NDAs (ANDAs).   The intent of Congress for this act was to promote pioneering research in the development of new drugs and to bring down the cost of competing generic drugs on the market.  A generic manufacturer who can establish that a new drug has bioequivalence to a previously approved drug can speed through the approval process with an ANDA.  They can “piggyback” on studies previously submitted in the NDA by the original brand drug company. Companies who apply for the ANDA must make four certifications regarding the patent that applies to the drug in question as required by Hatch-Waxman:

(i) No such patent information has been submitted to the FDA

(ii) The patent has expired

(iii) The patent is set to expire on a certain date

(iv) The patent is in valid or will not be infringed by the drug covered in the ANDA

When a generic drug manufacturer successfully files an ANDA, they gain a 180-day exclusivity period and a 30-month stay of FDA approval pending any subsequent litigation.  This reward is given only to the first generic manufacturer to file the ANDA so any subsequent generic manufacturers would not be allowed onto the market at all.

The Gaming Problem

Paragraph IV certifications are a source of much legal contention.  Every time a generic drug manufacturer files an ANDA under the paragraph IV certification, the owner of the original branded drug patent can institute infringement proceedings.  However, because no other generic manufacturers would be entitled to file an ANDA after the first company filed it, patent owners often settle the dispute with a large sum of money to the first generic drug manufacturer.  The result is that the generic manufacturer agrees not to enter the market and gets a handsome “reverse payment”, while the brand drug manufacturer gains monopoly (or sometimes an oligopoly) of the market to satisfy their company shareholders.  Thus, the original intent of the Hatch-Waxman act to speed up generic drug marketing has been subverted.  This has become an increasingly frequent occurrence in the industry and is not likely to go away soon.

Inter Partes Review (IPR) of pharmaceutical patents

Inter Partes Review (IPR) was introduced by the America Invents Act (AIA) of 2012 as a counterpart to post-grant review at the US Patent and Trademark Office.  Both IPR and post-grant review are procedures used to challenge the validity of patent claims on an existing patent. A detailed review of the IPR and post-grant review can be found here.  Once an IPR is filed the review happens before a Patent Trial and Appeal Board (PTAB) and the patent owner can respond.  IPR was initiated as a way to challenge new patents after the 9-month eligibility window of post-grant review expired – ie. IPRs can be used for any patents filed after 2012.  In 2015, 32 IPRs were filed concerning Hatch-Waxman litigations by generic manufacturers.  Today, hundreds of IPRs have since been filed and biotech IPRs tend to have a higher success rate than IT and other IPRs.  Most IPRs are filed challenging the licenses to pharmaceutical composition, formulations and methods of treatment.  Of the 150 pharmaceutical IPRs surveyed by Foley and Lardner, a leading intellectual property law firm, 75% have been instituted (begun the process of litigation) and 22% have been settled for generic drug manufacturers.

Data on IPRs from Foley and Lardner LLP:

IPR petitions filed by each major generic drug manufacturer

The outcome of IPR petitions filed by generic drug manufacturers to date:


On the face of it, IPRs have added another layer of complexity in the effort to bringing generics drugs to market efficiently.  Last week, several Senators voted against a new bill called the Protecting American Talent and Entrepreneurship Act (PATENT Act), which contains requirements concerning IPRs.  Senators Chuck Grassley, Chuck Schumer and John Coryn stated concerns that the language of new IPR rules would enable companies to game the Hatch-Waxman act.  This comes on the back of challenges like Kyle Bass, who have petitioned the use of IPRs to invalidate drug patent claims as a way to short company stocks.

Why IPRs could in fact be a solution to gaming Hatch-Waxman

There are some who argue that IPRs do not make it difficult for generic drugs to enter the market.  In fact a successful IPR on a pharmaceutical patent would render it invalid, enabling other generic manufacturers to immediately enter the market.  It would also make it impossible for generic manufacturers to sue the federal district court whenever they dispute a patent claim.  This would place a roadblock on the system of “reverse payments” through Hatch-Waxman litigations.  Thus, in a way, the IPR process would be detrimental for generic manufacturers who are looking for a quick way to make money through the court system – one wonders whether some Senators who are concerned with the new IPR rules are in fact protecting the monopoly held by drug companies within their constituents.  Never the less, instituting IPRs would pave the way around the dysfunctional Hatch-Waxman Act for generic drugs to become competitive in the market, bringing prices to more affordable levels for consumers.

What can you do?

If you are planning to become a generic drug manufacturer and file your first ANDA today, it is essential you recognize the pitfalls in legal proceedings that can affect your drug approval.  The best way to avoid delays in getting your generic drug to the market is to fully understand the latest bills affecting patent issues. Please refer to the PATENT Act for more information.  From the perspective of a consumer or a patient seeking the cheapest drugs it is essential you place pressure on the government.  Write letters to your state’s Senator and Congressmen to ask for amendments to the Hatch-Waxman Act and to the IPR procedure to prevent companies from gaming the system.  You should also reach out to the Public Patent Advisory Committee of the USPTO and aim to attend their monthly public meetings online or in Alexandria VA.


Gene Quinn, IPWatchdog; Senators mistaken, IPRs do not frustrate Hatch-Waxman. June 4 2015

Gene Quinn, IPWatchdog; Patent abuse or genius? Is Kyle Bass abusing the patent system? April 8 2015.

Christopher Noyes, Law360, New York; When Inter Partes Review Meets Hatch-Waxman Patents. September 09, 2014

Fish and Richardson; Inter Partes Review

The PATENT Act 2015

Upcounsel IPRs:

Biotech sector IPRs:

Foley and Lardner LLP:


    Chapter 3 - The Brave New World of Biosimilars



The FDA has been debating for many years over whether to approve biosimilars, cheaper versions of expensive and complex biological drugs used to treat a multitude of diseases.  Biological products are large protein molecules generally derived from living organisms and have chemical modifications that are very different depending on what cells are used to make them.  Biosimilar products are biologicals that are approved based on high similarity to the brand reference product, with very little differences in terms of safety, efficacy and clinical impact. 

In 2010, Congress passed the Biologics Price Competition and Innovation Act (BPCI Act) which created a new pathway for the reference drugs of biologics, biosimilars, to be approved.  This act was intended to pave the way for cheaper biologics rather like the Hatch-Waxman Act established a way for cheaper small molecule generic drugs to be approved once they show the same effectiveness as brand drugs.  This year, the FDA published the first Biosimilars Action Plan detailing the agency’s vision on how to innovate new cheap biosimilars, while keeping the industry competitive in the market.

A pretty interesting read for those interested in product development in this area:


In 2015 when I first wrote this blog series, the FDA had just approved its first biosimilar drug Zarxio by Sandoz, a generic biological drug version of Neupogen by Amgen prescribed for leukemia patients.  By that time, the EMEA in Europe had already approved 21 biosimilars.  Today the FDA has approved 12 biosimilars, following a worldwide explosion in this area of the drug industry.  The biosimilars market is now expected to reach $61.47 million by 2025, an increase from the prediction three years ago.  Major biologics like Rituximab and Trastuzumab from Roche (approved in 1997 and 1998 respectively) have now come off patent and multitude of pharma companies are vying to develop the next biosimilar.

List of approved biosimilars in the US as of today:


In coordination with the industry, the FDA has written a list of guidance documents for biosimilar manufacturers to adhere to as well an education program to teach all parties about how biosimilars are developed, marketed and prescribed to patients.

As developed markets see their patents expire in the next few years, there will be a rapid shift in consumer spending toward new generic medicines such as biosimilars.  A 2015 report from the IMS Institute for Healthcare Informatics estimated that up to 2% or $6 billion of global healthcare expenditure will be accounted for by biosimilars (part of the $200 billion global spending on biologics market).  In the US, biosimilars are estimated to impact between $27 and $58 billion by 2021.  

The following is based on what I wrote about the Zarxio approval in 2015 and about  a Citizen’s Petition from Abbvie for one of the Biosmilar guidance documents demanding clearer labels to differentiate between brand biologics and biosimilars:


In March 2015, the FDA released news for the approval of Zarxio, a biosimilar produced by Sandoz Inc (the generic arm of Novartis).  It is similar to the reference drug Neupogen (Filgrastim) licenced to Amgen Inc in 1991.  Neupogen has been prescribed to leukemia cancer patients undergoing harsh chemotherapy regimes who suffer from weakened immune systems.  Neupogen is used to boost the immune system of patients by producing recombinant human granulocyte colony stimulating factor to induce neutrophil production.  Sandoz Inc. filed the biosimilar application under the new Biologics Price Competition and Innovation Act (BPCI Act, 2009) and also under the Public Health Service Act’s section 351(k) provision (PHS Act § 351(k)).  The current regulations require biosimilars to show equivalence to a “reference product” without having to go through the full set of preclinical and clinical study necessary for traditional BLAs. 

According to the FDA’s guidance:

“A biosimilar product can only be approved by the FDA if it has the same mechanism(s) of action, route(s) of administration, dosage form(s) and strength(s) as the reference product, and only for the indication(s) and condition(s) of use that have been approved for the reference product. The facilities where biosimilars are manufactured must also meet the FDA’s standards.”

Sandoz Inc managed showed that in a clinical trial involving 388 people with breast cancer, 174 people using Zarxio were able to break it down in the body in a similar way to the Neupogen drug without provoking an adverse immune response.  Zarxio is predicted to cost 40-50% less than Neupogen.  The approval of Zarxio opens the door for companies to start applying for more biosimilars in the United States and allows consumers to buy cheaper biologics in the coming future.

Despite the green light from the FDA, Sandoz will be fighting Amgen over patent laws with regard to its new drug.  US law requires Sandoz to reveal their manufacturing protocols to Amgen in order to ensure licenses for manufacturing methods have not been violated.  Unfortunately Sandoz wants to keep its manufacturing techniques confidential so that they can file their own patents.  Such licensing laws do not exist in Europe hence the approval of biosimilars has been so rapid and convenient in that region.  Furthermore, Advisory Committees and groups like the Generic Pharmaceutical Association (GPhA) have voiced concerns over whether generic names for new biosimilars will be used to replace brand names that originally existed, causing confusion for patients shopping for cheaper drugs in future.

Another issue has recently come to surface over the biosimilars guidance document.  AbbVie sent a Citizen Petition to the FDA demanding a change to the guidance entitled “Scientific Considerations in Demonstrating Biosimilarity to a Reference Product”.  The guidance removed the requirement in the 351(k) provision for sponsors to show labeling of bioequivalence to a reference product (as described above) and also removed the need to indicate whether it is “interchangeable with the reference product”.  AbbVie challenged this guidance demanding that the FDA require all biosimilars to differentiate themselves from a reference product. 

Abbvie wants to see new language in the guidance containing:

- A clear statement that the product is a biosimilar and that the biosimilar is licensed for fewer than the reference product’s conditions of use.

- A clear statement that FDA has not determined that the biosimilar product is interchangeable with the reference product

- A concise description of the data that supports license of the biosimilar and a comparison with data from studies of the reference biological product.

Abbvie contends that biosimilars, unlike generic drugs, are complex products and substitution of established biological drugs could be much riskier, result in very different clinical outcomes and are less interchangeable compared to generic drug substitutions of branded chemical drugs.  They argue that employing a “Same Labeling” approach for biosimilars as for generics in the ANDA requirements is unsound law.  Interestingly, Abbvie alleges that FDA is violating the Administrative Procedure Act (APA) by removing the provision § 351(k) that was originally in the 2012 draft version of the guidance for biosimilar products.  This could premise future litigations.
Is your company affected by the new regulations for biosimilars?

Since biosimilars are likely to become an increasingly prominent product in the industry, changes in legislation concerning these products are likely to affect your company.  The murky area of patent rights for licensing biosimilars, rights to naming the products and rights to manufacturing techniques is likely to affect your company’s future decisions.

For more information, please carefully read FDA’s latest version of Scientific Considerations in Demonstrating Biosimilarity to a Reference Product and Abbvie’s latest Citizen Petition to FDA


Ledford H, First biosimilar drug set to enter US market. Nature, In Focus News; 517:253-254 (2015).

IMS Institute for Healthcare Informatics, The Global Use of Medicines Outlook Through 2016 (July 2012)

FDA Law Blog, Hyman, Phelps and McNamara June 03 2015

FDA Press Release March 2015

Patent Docs blog

List of Biosimilar Guidances

Biosimilars market today:




    Chapter 2 - Patent Protection and Drug Development Strategies


Senators Orrin Hatch and Henry Waxman who introduced the Acts to encourage generic drug price competition


Drug patents are legal devices that grant inventors market exclusivity over their drug product or device.  Patent holders have a huge economic incentive to hold onto patents because this provides them with monopoly over their inventions.  The entities that file patents require this in order to recoup the huge amounts of time and capital to market a drug and to invest in innovative new therapies for a pipeline.  Drug patents typically last for 20 years from the date of filing to the patent office. 

Typically, the process for obtaining a patent goes like this:  A person or company files their invention to the U.S. Patent and Trademark Office (USPTO).  The inventor must file as soon as possible in order to claim rights to that invention, lest a competitor nabs that claim (which happens more often in science than one would expect).  The patent filer usually asks a registered patent attorney to file a utility patent application with the USPTO.  An examiner at the USPTO then performs a prior art search to determine whether the patent satisfies legal requirements for patentability.  The examiner then sends an “office action” to the applicant asking the applicant to amend any issues with the patent.  The applicant must respond by correcting the patent to prevent a rejection.  This process goes back and forth a few times, a bit like submitting a peer review for a manuscript to journal editors.  Once the patent is deemed eligible, the examiner issues a “Notice of Allowance”.  Following the issue of the patent, the applicant can exclude others from making, selling the claimed invention for 20 years from the date it was filed.  Patent fees must then be paid at year 3.5, 7.5 and 11.5 years.

Timeline for Patent and Product Approval / Profit Maximizing Options:

After the patent expires, other companies can submit abbreviated new drug applications (ANDAs) to the FDA for generic drugs - drugs with therapeutically equivalent safety and effectiveness as the original brand-name drug but which are cheaper.  The Hatch-Waxman Amendments to the FD&C Act were introduced in 1984 to ensure that brand-name drug manufacturers could have a fruitful patent protection period and to ensure that consumers would eventually benefit from lower-priced generic versions of the innovative drugs.  However, companies often see the 20-year patent cliff as an obstacle since they have to make as much money as possible from their brand-name drug to cover the costs of development.

In December 2014 Senator Orrin Hatch (R-UT) introduced the Dormant Therapies Act.  This act was intended to "remove the 'ticking patent clock' that forces companies to prioritize research based on which drugs can be marketed more quickly.  Then in 2015, the 21st Century Cures Act was released which contained a new provision in its Subtitle M, Title I.  Subtitle M creates a guaranteed 15-year "protection period" for new drugs and biologicals approved for "dormant therapies" (as opposed to the current 5 years for new drugs).  Dormant therapies is defined as any medical research being done to treat "unmet medical needs".  Any drug that falls under this protection would have an extended period of exclusivity, rendering the sponsor immune from competition of any ANDAs or new NDAs and BLAs for drugs which contain "forms of the active moiety of the dormant therapy and highly similar active moieties".

One reading of the provisions of Subtitle M statutory text could be that any old patent which is reasonably related to a drug or biologic classified under dormant therapies could be "protected" for 15 years from any new competition. The sponsor could simply apply for multiple designations of dormant therapies for the same patent and thus create an "everlasting patent".

However, another reading of the provisions is that a dormant therapy can benefit from only one protection period, "measured from the first day of the first approved indication for a therapy" which cannot be further extended. In such a case the patent cannot be further extended. The applicant sponsor would therefore not gain exclusivity for the patent beyond the initial 15 year protection period. Furthermore according to another provision of Subtitle M, even if the same patent were ever to be extended a second time because a different active moiety was added, the "Hatch-Waxman limitations" would be enforced, limiting the extension terms.

Thus, while the dream for sponsor companies to retain unlimited exclusivity over all of their most valuable patents remains just that, the 21st Century Cures Act has opened up a new debate over whether patent exclusivity should be extended for longer periods of time for urgent medical treatments and for how long such extensions should be allowed.


From a drug development point of view the best way to preserve market exclusivity and ensure the patent does not expire is to expedite the drug approval process at the FDA.  Ever since 1997 after the FDA Modernization Act, the agency has been building pathways for fast-tracking drugs to the market, particularly for drugs designed to target serious illnesses for which there are no clinical treatments available.  There are now four established expedited review processes for drug manufacturers to speed up development and availability of their drugs: Fast Track designation, Breakthrough Therapy designation, Accelerated-Approval Pathway, Priority-Review designation.  Here is a breakdown of what each pathway does to speed things up and how to qualify for each pathway:

4 Different expedited drug review processes at the FDA (Sherman et al., 2013):


4 Different expedited review processes at the FDA (Hwang et al., 2017):



A list of drugs with Breakthrough Designations from 2013:


Drug candidates that qualify for these expedited pathways usually fall into the Orphan Drug category, for which treatment is targeted at a disease population smaller than 200,000 people in the US.  Increasingly these drugs are large molecular entities, diagnostics and biologics.  Sometimes the beneficial effects of the drug in clinical trials are so obvious in early stage clinical trials that there is no necessity to continue testing a larger patient group (Exondys 51 is an example).  Once a drug is placed onto an expedited pathway the FDA will commit to working closely with the sponsor to do things as efficiently as possible.  Certain pathways even come with added incentives, such as the “voucher” system for drugs designated in a Priority Review.  These vouchers (already granted to drugs for Duchenne Muscular Dystrophy and Zika virus) can be sold by the sponsor for up to $125 million to other biotech companies vying to geth their non-expedited drugs to the market. A fifth expedited pathway has recently been issued by the FDA called the Regenerative Medicine Advanced Therapy Designation.  This is the newest pathway for cell and gene therapy products designed to treat rarer genetic disorders.  Given the rise in popularity of gene therapy and stem cell therapy as novel treatment strategies, companies are clambering over each other to apply for this pathway.

There is no shortage of strategies for biotech and pharma companies to license their therapeutic technologies quickly and gain the largest market while their patents are still valid.  Expedited drug review pathways at the FDA are not without their flaws and disadvantages.  A common risk is that drug candidates are not put through rigorous trials lasting longer than 6 months or tested in more than 100 patients.  This leads to the possibility of adverse events affecting patients in years to come.  Another issue is that surrogate endpoints are often used to interpret short-term data and these results do not always correlate with patient survival or quality of life outcome.  

However, it is important for every institution developing novel drug therapies to understand these pathways, to come up with a way of using them while developing a product that is safe and efficacious.  In today’s environment where so many drugs have high price tags and public money from Medicare or Medicaid programs are needed in order to give patients affordability, the onus is on industry to develop drugs quickly before costs of development skyrocket.


Hatch-Waxman Amendments 1984:

FDA Law Blog, ever lasting patent renewal:

RAPs Regulatory Explainer: The (Updated) 21st Century Cures Act:

Gupta H, Kumar S, Roy SK, Gaud RS. Patent Protection Strategies; J Pharm Bioallied Sci. 2010 Jan;2(1):2-7. doi: 10.4103/0975-7406.62694.

Sherman RE, Li J, Shapley S, Robb M, Woodcock J. Expediting drug development--the FDA's new "breakthrough therapy" designation; N Engl J Med. 2013 Nov 14;369(20):1877-80. doi: 10.1056/NEJMp1311439.

FDA Expedited review programs, 2012-2016:
Hwang TJ, Darrow JJ, Kesselheim AS.  The FDA's Expedited Programs and Clinical Development Times for Novel Therapeutics, 2012-2016; JAMA. 2017 Dec 5;318(21):2137-2138. doi: 10.1001/jama.2017.14896.

FDA’s Traditional Expedited Pathways:

FDA’s RMAT Designation:

Risks and Benefits of Expedited Review:



    Chapter 1 - Who Owns CRISPR-Cas9?


The past few years has seen CRISPR/Cas9 emerge as the driving force that could revolutionize gene therapy, precision medicine and many other biological problems.  It has been heralded as the technology that could cure anything from cystic fibrosis to muscular dystrophy to HIV. It also promises to revolutionize agriculture, reduce infectious diseases and save global animal extinction. The implications of this technology are so huge that Science magazine dedicated a special edition to it in 2015 as breakthrough of the year.  The biotech world as well as Wall Street are now invested in some tantalizingly opportunities that this technology can bring.  With the start of the first clinical trials utilizing the CRISPR system this year, many investors are in an uproar over its commercial applications.  Furthermore, one only has to look to Hollywood and bingeable TV such as Rampage, Luke Cage and C.R.I.S.P.R. (I kid you not!) to know that it has entered the mainstream consciousness of our society.

Rampage, the Hollywood movie starring D.T.R.Johnson and CRISPR-imaginary monsters:

Yet the real action movie fight for CRISPR has been going on behind the scenes in a long drawn-out court battle between two rival academic institutions, the Broad Institute in Cambridge Massachusetts and the University of California at Berkeley.  The fight centers around who owns the patents rights to CRISPR/Cas9 gene-editing.  With so much at stake, it is little wonder this patent litigation battle has become “the most heated ever between two educational institutions” according to New York law expert Jacob Sherkow.

Two main scientists on either side of the CRISPR battle, Jennifer Doudna (left) and Feng Zhang (right):


Here is a brief background:

CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats, or segments of DNA used by bacteria to cut out unwanted invading DNA from phages (viruses that invade bacteria).  Cas9 (CRISPR associated protein 9) is a protein which aids the function of CRISPR to cut out undesirable foreign genes.  A few years ago it was found that CRISPR-Cas9 could be engineered to edit the entire genomes of a panoply of organisms from bacteria all the way to mammals and humans, thus potentially curing many genetic diseases.  As with any discovery many teams of scientists worked to uncover mechanisms CRISPR-Cas system.

In April 2014, a broad U.S. patent was awarded to Feng Zhang, a scientist at the MIT-Harvard Broad Institute who claims to have discovered the effectiveness of CRISPR-Cas9 on gene editing in human cells.  Zhang filed his patent with a priority date of Dec 2012.  Just a few months later, a Breakthrough Prize was awarded to Jennifer Doudna and Emmanuelle Charpentier from UC Berkeley and Vienna, Austria, for their contribution to the discovery of CRISPR.  Doudna and Charpentier filed a patent with a priority date of May 25, 2012, which includes 155 claims, encompassing numerous applications of the system for a variety of cell types.

The Takeaway:

The biggest difference between the two patents was that Doudna’s involved modifying just prokaryotic cells while Zhang’s included the use of CRISPR on eukaryotic cells in vivo, enabled him to potentially apply it in human trials.  Although the Broad patent was filed a few months later than the UC patent, the Broad patent was awarded first based on the “First to File” system and on Zhang’s expedited review payment. In early 2016, UC Berkeley requested that a patent interference be initiated claiming that the Doudna / Charpentier team invented CRISPR first. In February 2017 the USPTO Appeals Board rejected this claim. Furthermore, the board concluded that Zhang’s work in eukaryotic and mammalian cells was not an “obvious extension” of Doudna’s work so he had no “reasonable expectation” of success. This decision meant that the Broad Institute patent remained valid and the UC Berkeley team had to file their case with the US Court of Appeals for the Federal Circuit.  This week, as of September 10th, the Federal Circuit court awarded the pivotal intellectual property to the Broad team and upheld the previous decision from the USPTO. It looks like the Broad Institute team have won the overall court battle and things are coming to a close.

Three Main issues with the CRISPR patent dispute:

At the time of the original patent dispute in 2014, several challenges arose.  Firstly, Doudna and Charpentier argued that they filed the patent documents for CRISPR before Zhang because they had an earlier priority date but Zhang was awarded the patent first.  Zhang was awarded the broad patent because he had a laboratory notebook demonstrating his group was doing CRISPR genome editing in human cells before anyone else and also because he paid for an expedited patent review.  Patent lawyers have disputed over the nuances of “First to file” ever since the America Invents Act was signed in 2011.  Thus, the obscurity of the definition contributed to the argument right at the beginning.

Secondly, hundreds of patents which make use of the CRISPR-Cas9 technology have now been filed by leading scientists around the world.  If the patents filed by Zhang are broad enough this could land many scientists with patent infringements if CRISPR-Cas9 were licensed.  In June this year, the USPTO granted Doudna and the UC team a reprieve by awarding them two of the original CRISPR-Cas9 patents (patent 1 and patent 2) they had filed for editing short nucleotide regions of genomes.  Unfortunately these may have little commercial value.

Thirdly, biotech patents that deal with genes and genetic engineering have often been contentious.   Intellectual property that use DNA technology which has already existed in bacteria for millennia and can seem “obvious” for many scientists who can now easily use it in their laboratories.  In a sense CRISPR was in fact “invented” by nature and not by any individual, so claiming a patent over the mechanism would be an act of god.  However, the courts have now clearly decided that the invention was not obvious and therefore is valid.

Historically biotech patents have found different solutions to disputes.  For example, when small interfering RNAs (siRNA) and when polymerase chain reaction (PCR) were first discovered debates arose in the science community about whether people could use the technology without a license.   With the discovery of recombinant DNA, Stanford University was assigned the Cohen-Boyer patent which allowed Stanford to non-exclusively hold the patent, enabling non-profit research institutes to use the technology without a licence.  Stanford also developed a graduated royalty system with small companies to ensure some share of profits if companies used their technology effectively.  For the discovery of siRNA, MIT was awarded the “Tuschl” patent, which also granted nonexclusive licences to companies selling the technology and allowed academic scientists to work on the molecules with no licence.  Similarly, with the invention of the PCR, patents were adapted through a strategy known as “rational forbearance” to prevent researchers from being sued for patent infringement everytime they used the technology and to allow adaptive licences to be held by business partnerships. 

Startups Galore

Since the initial filing, all parties have founded startup biotech companies in the race to develop CRISPR as a viable clinical drug.  Zhang co-founded Editas Medicine with his lab director, George Church at Harvard. Jennifer Doudna was also a co-founder for Editas before she dropped out to found Caribou Biosciences and Intellia Therapeutics.  Charpentier is the founder of CRISPR Therapeutics but has now sold the rights for that company. Her co-founder Roger Novak now runs as President of the firm. CRISPR have teamed up with Vertex, the biotech company that came of age developing drugs for cystic fibrosis in a $100 million deal to develop its technologies for primarily for their pipeline.  Various CRISPR/Cas9 patents have since been filed in Europe and the rest of the world in preparation for commercial use by these firms.  In total, venture capitalists have now invested over a billion dollars in various CRISPR startups, with millions of dollars being paid to lawyers for the patent fight. What makes it interesting is that each CRISPR biotech has overlapping applications and many of the founding scientists hold stakes in rival companies.

A diagram published in Science Magazine in 2017 showing how each researcher or licensee is connected to the major CRISPR startup companies and what applications they have in the pipeline.

This year, Vertex and CRISPR Therapeutics have been given the go-ahead to launch the first CRISPR/Cas9 clinical trial to treat beta-Thalassemia in Europe.  The therapeutic candidate, CTX001, is designed to treat a deficiency in hemoglobin production by cutting the gene BCL11A that represses fetal hemoglobin production.  It is of note that the FDA has ordered a clinical hold on this trial in the US based on safety concerns with the IND filing. German hospitals, however have given it a green light to start by the European Medicines Agency.

Given all of the hype around CRISPR-Cas9 it is important to bear in mind that research is still being done to develop our basic understanding for this molecular machine.  Already this year, two groups (here and here in Nature Medicine) have reported on the potentially worrying link between CRISPR and the cancer preventing gene, p53, which sent biotech investors into a panic and stock prices diving. Normally, p53 serves to prevent cancer formation by correcting genes that have been edited and changed, thus preventing malignant cell division.  It appears that CRISPR-Cas9 works best by targeting cells that lack the functional p53 and therefore selects for cells that develop cancer.  This has been a huge stumbling block for clinical trials using CRISPR-Cas9 thus far from progressing to a larger scale.

Never the less there is optimism that CRISPR-Cas9 therapy could be engineered to work effectively once we gain a foothold of our scientific and mechanistic understanding.  In the meantime, I for one am going to advocate adding CRISPR biotech stocks to your investment portfolios.  There is money to be made in the new frontier of biology!



Rampage Image:

Feng/Doudna Image:

Shwerkow JS, Law, history and lessons in the CRISPR patent conflict, Nature.  Vol 33 (3): 256-257, 2015.

Regalado A, Who Owns the Biggest Biotech Discovery of the Century? MIT Technology Review, Dec 4 2014.

How the battle lines over CRISPR were drawn, Cohen S, Science, 2017:

STAT News/Scientific American:

Pivotal CRISPR Patent Battle won by Broad:



    FDA Law Blog 2.0


Food, Drug and Biological patent disputes in the 21st Century

Three years ago, as part of my FDA law class for my Regulatory Affairs degree program, I set out to write a series of blogs about biotech patent disputes and issues.  Before taking this core curriculum class, I found law particularly daunting and boring. I blindly followed the academician’s typical way of thinking: “why should I care if it’s not about publishing experimental science?”.  But that approach to thinking was leading me down a dead-end in life.  I was not heading anywhere just by publishing and working on my own niche area of academic science.  After 3 months of intensive discussions with my law professor and hours of digging through Hutt et al.’s Food and Drug law text book, I surprised myself and changed my perspective. I gained an appreciation for drug law and of a deeper understanding for the law profession with respect to how it fits into the life science industry.

The series of blogs I wrote was based on a project our professor set for our class discussions.  For this scenario we had to become a subject matter expert for biotech law and give advice to small biotech firms who may be seeking to market their new drug products.  Every week we had to research a topic, write about it and present it in class.  I am going to republish and update my series of 10 blogs. Nowadays more than ever before, drug patents play an increasingly powerful role as drug companies begin to commercialize on an exponentially evolving universe of innovative disease treatments.

Let’s begin with my original introduction to the blog series:
When a company submits a new patent to the U.S. Patent and Trademark Office (USPTO) and it gets approved, it is the responsibility of the sponsoring company to submit the patent information to the FDA’s database of Approved Drug Products with Therapeutic Equivalence Evaluations, otherwise known as the “Orange Book” within 30 days (21CFR314.53).  However, since multiple companies and laboratories are often tackling the same problems with the same available resources, similar patents are often filed by different parties at the same time.  Furthermore, the FDA itself does not review drug patents since the Agency’s statute only requires the publication of patent information.  With patent rights for drugs usually lasting 20 years (with the exception of Title II of the Hatch-Waxman Amendments of 1984) and with time taken for drug development typically lasting over 10 years, it is natural for sponsors to scrupulously guard a patent in order to make good on financial returns once the drug can be marketed.  Thus in our current landscape of technological innovation and financial competition it is not hard to see how patent disputes can often arise between rival companies.

This blog series is intended for researchers and scientists from small biotech companies who have or are about to file their first patent to gain some advice and knowledge about navigating the legal world.

My first focus was on the little-known technology, CRISPR-Cas9 and the patent dispute between two parties.  In the subsequent blogs I dug into a variety of issues surrounding patent law such as patent protection length, brand companies gaming the Hatch-Waxman act, the importance of “obviousness” in gene patents and the scourge of patent trolls that haunt intellectual property.  This week I will begin again with the CRISPR patent dispute and all the updates to the saga.



    Theranos - Moral Lessons for the biotech industry



This week I have been reading Bad Blood - Secrets and Lies in a Silicon Valley Startup by John Carreyrou. I highly recommend this book to anyone working in the biotech startup world as a guide for avoiding a toxic work place. The book details the now infamous rise and fall of Theranos, the biotech startup company in Silicon Valley, once valued at $9 billion with over 800 employees, which has gone under liquidation. The former CEO of Theranos, Elizabeth Holmes, was indicted on federal wire fraud charges by the Northern District of California in mid-June and could face a sentence of 20 years in prison. The former COO and Holmes’ one-time boyfriend Ramesh “Sunny” Balwani faces similar charges.

Theranos was once the darling of Silicon Valley startups, promising to deliver a blood testing kit using a simple skin prick that would revolutionize laboratory diagnosis. Holmes was at the helm of the company from the beginning as the charismatic young visionary who saw herself as the “Steve Jobs” or “Bill Gates” of a burgeoning medical device world. Her ability to charm people and indomitable ambition led to huge investments from top technology companies in Silicon Valley. However, the blood testing device, later named “Edison”, proved to be inconsistent at best and often failed completely to work. Later versions of the device rolled out the “miniLab” which was just as fraught with problems.

Elizabeth Holmes at Theranos in 2015 (Photo from the NY Times):

Diagram of the miniLab from Theranos:

Despite repeated warnings from those working on the device the company went ahead to cover up product defects, sometimes by using existing blood testing kits sourced from other firms. The various engineering, research and finance departments within the company were often segregated so that defects in the Edison and the Minilab were kept a secret from employees. Holmes cultivated a “culture of fear”, enforced non-disclosure agreements on everyone and threatened litigation against fired employees who might reveal the truth.

In the current climate there has been no shortage of bad behavior from Silicon Valley and the Pharma/biotech industry as a whole. We only have to look at Mark Zuckerburg being called to testify in Congress for Facebook’s illegal usage of private data or Martin Shkreli being indicted on securities fraud a year after hiking the price of Daraprim from $13.50 to $750.

As a scientist working at a small biotech company I feel I am in a position to list some moral lessons we should learn from the blunders of failed, fraudulent tech companies.

1. Patience is a virtue - Biotech companies are not Tech companies. It takes many more years to develop a drug or medical device than it does a computer or a piece of software. Drugs require years of clinical trials, safety data and adverse event reporting before the FDA can give the go-ahead to market. The same applies to medical devices. Theranos wanted to apply the Silicon Valley computer tech development model of high speed, straight-to-market model for its medical device and that was a fiasco. Having said this, I think tech companies like Facebook and Google could benefit from FDA-like oversight when it comes to regulating its data collection products. I would like to see clinical trials for social network usage to test for severe adverse events!

2. Have some humility and recognize your mistakes. Elizabeth Holmes dreamed big and indeed achieved stardom when she grew her company so rapidly. However her inability to admit to mistakes in the product development compounded by her manic style of management ultimately led to the company’s downfall. By covering up failed versions of the Edison machine and then keeping this a secret from various departments who could have helped with improving the design, the company was destined to fail. At the core of Elizabeth Holmes’ failure was her ego. Her precocious talent for selling ideas to raise money and her network of wealthy investors blindsided her ability to see her mistakes. It then led to repeated cycles of employee turnover so that she could surround her company with yes-men.

3. Focus on the cure for the patient, not on the profits. This may seem obvious but certain companies lose sight of this when they start rolling in money. There was a time at Theranos when engineers saw that the Edison device seemed to work partially on the first blood draw but failed on subsequent draws. They took the device to hospitals anyway to use it on cancer patients, claiming it would help with their blood tests. The employees agonized over seeing these people about to die but lying to them about the effectiveness of the product. Ultimately no one spoke out because of the terrifying culture at the company. The primary goal of a biotech is to find cures for diseases so to shift the aim to profits, by promoting the product before it is ready, defeats the purpose.

4. Center yourself and ignore the hype. Pretty much all investment works on some level of hype. Theranos was built on hype when Elizabeth Holmes campaigned to get initial venture capital funding to start her company. The company then grew on the myth built around this magical diagnostic/therapeutic machine so more investors piled in. Similarly, there is currently a lot of hype in my field, in gene therapy, gene-editing and CRISPR-Cas9. Much of this hype is driving biotech investors on Wall Street into a frenzy. The science of gene therapy is more solid compared with the Edison device at Theranos - gene therapy research has been building up over many decades. However, like everything else in the world, interest will wax and wane and so will investments. Much research needs to be done before we can use gene therapy to treat a wider range of diseases. In the mean time, many companies will surely rise and fall.

5. Listen to your community carefully. Learn from management who have more years of experience than you and learn from technicians who work for you on the minutiae. Treat people with equal respect, whether they be external stakeholders who you want to collaborate with, company scientists who have been working on the same project for years or patient communities you are working to treat. In biotech the stakes are naturally higher because people’s health is at risk. Therefore treatments must be developed with the patient in mind and communication between different people is a key. When Theranos segregated departments and made every employee sign lengthy non-disclosure agreements it ensured that essential communication would be stopped.

In the biotech industry so many of our decisions are governed by FDA guidances. But many times in life we also need moral guidance. When the stakes are raised and we face insurmountable pressures, that is when we realize how important moral guidances are.


Bad Blood - Secrets and Lies in a Silicon Valley Startup by John Carreyrou



    Gene Therapy for Spinal Cord Injury


After a devastating spinal cord injury the most important thing a paralyzed person wants to gain back is control of their hands. It is not so much about recovery of the legs or the recovery of a walking gait. Wheel chairs and exoskeletons can already support that function. What patients really want is to return to independence. That fine motor control that allows your opposable thumbs to move, to dress yourself, to do up buttons, to pick up a knife and fork, to twist a door knob - that is what gives people hope for independence. To that end scientists working in the nerve regeneration field have sought for decades to help patients recover their hand function and forearm motion.

Last week, a team from my alma mater, King's College London, published a report in Brain detailing the use of gene therapy to promote functional recovery of forehand motion in paralyzed rats. They reported that rats could recover the use of their forepaws to pick up sugar cubes after a contusion spinal injury. The spinal cord is made up of densely bundled nerves carrying messages from the brain to the rest of the body. Injuries to the spinal cord result in two principle barriers that prevent axon regeneration and recovery. First is the scar tissue that forms immediately after injury, made of chondroitin sulfate proteoglycans that wrap around the damaged area. Second is the inflammatory response that lasts from weeks to months and comes into play as part of the body's repair system. This gene therapy being tested is a new lentivirus that encodes chondroitin sulfate proteoglycans ABC (ChABC), an enzyme that digests the scar tissue. The lentivirus is regulated by an inducible vector system made up of two plasmid components: one is the doxycycline-inducible ChABC vector system, where upon addition of Doxycycline, ChABC can be activated. The second vector is the GARrTA transactivator vector which helps the ChABC vector system activate without causing a T-cell mediated immune response. The researchers in this report have named it dox-i-ChABC. and claim to see positive effects in rat models in as little as 2.5 weeks of applying the gene therapy. The report in Brain showed improvements in behavioral assessments of rat forepaw function as well as evidence of increased activity in the sensory and motorneuron tracts along the spinal cord after treatment.

This group, led by Professor Elizabeth Bradbury, has for many years championed the use of ChABC as a way to stimuate damaged axons to re-grow. The latest iteration of delivering ChABC into the contused spinal cord in this two-vector lentivirus system is an exciting one. However, spinal cord injury and paralysis is not a disease that lends itself well to gene therapy. It is not a monogenic disorder. Axon growth requires a multiplicity of factors to be in place and a multi-pronged approach will be needed for human treatment. It will be interesting to see whether this gene therapy makes it to early clinical trials.





    FDA Prepares for a Golden Age in Gene Therapy


Last week the Commissioner of the Food and Drug Adminstration (FDA), Scott Gottlieb, announced that he expects to see 40 new gene therapies approved by 2022. This comes from a recent MIT report which predicts cures in diseases like blindness, sickle cell anemia and hemophilia within 10 years. Gottlieb wants to push the agency to come up with six new guidance documents to help with development, manufacturing and approval process of gene therapies. Many of the guidance documents from the FDA currently being followed by biotech companies, such as our own, are already outdated and require re-thinking.

The optimism of the FDA comes on the back of three recently approved gene therapy products (also mentioned in my previous blogs): Novartis’ Kymriah, a Car-T cell therapy for acute lymphoblastic leukemia (ALL), Gilead’s Yescarta, a Car-T cell therapy for adult B-cell lymphoma and Spark’s Luxturna, an AAV therapy for the treatment of a retinal disease resulting in blindness.

Gottlieb stated that in contrast to traditional small molecule drug development, where most of the FDA review process is focussed on the clinical trials and relatively little is needed for developing the chemical product, gene therapy requires the opposite approach where a substantial amount of resources are needed to establish the gene therapy production process and less is needed to establish early clinical efficacy in a small number of patients. Part of the reason stems from the fact that gene therapy has so far been targeted to small patient populations with rare genetic disorders. However, with more than 7,000 different rare diseases that affect the country, tens of thousands of people could benefit from gene therapy.

In a statement at Alliance for Regenerative Medicine’s Annual Board Meeting, Gottlieb detailed two aspects that need to be addressed if gene therapy is to see success in commercialization.
(1) The gene therapy vector production process must be standardized through “continuous manufacturing”. Otherwise the current processes in place for making lentivirus and AAV will be too inefficient and will depend too heavily on academic laboratories. With improved financing in the coming years, it is hoped more of the smaller biotech companies can shift production reliance towards more established CROs.

(2) The manufacturing paradigm of developing gene therapies must be restructured. It is often difficult for biotech companies to guide a gene therapy product from an early stage pilot process in the laboratory to a later stage clinical trial process that is used for commercialization.
Technical advances will be needed to help scale up capabilities of companies to generate viruses from the laboratory level (which is non-GLP and non-GMP) to the clinical level (which requires GMP quality products).

Gottlieb also announced that he expects to accept more uncertain gene and cell therapies through the FDA’s new accelerated approval pathway called Regenerative Medicine Advanced Therapy (RMAT) designation. RMAT was opened up under the 21st Century Cures Act as part of the FDA’s initiative to speed up reviews for both cell and gene therapy products intended to treat life threatening conditions. At the end of April this year there had already been 62 RMAT designations.

With the closing of last week’s BIO 2018 convention, (one of the biggest annual deal-making conventions of the biotech business), the industry has been set ablaze by optimism for gene therapy developments. Can gene therapy do to rare genetic diseases what immunotherapy and antibody drugs did for cancer therapy and other common disorders? One can only wait to see what happens once the hubris settles.



MIT Report:

Alliance Speech:




1 . 2 . 3 . 4 . 5 . 6 . 7 . 8 . 9 . Next -->





Previous Posts


Alzheimer's Drug Failure

Changing Your Habits

How to Write Effectively

Mental Health in Graduate Students

Chapter 10 - Limits of Biotech inventions

Chapter 9 - Longest PTE in history

Chapter 8 - Invasion of the Patent Trolls

Chapter 7 - Direct-to-Consumer Genomics Testing

Chapter 6 - Supreme Ct and Laws of Nature

Chapter 5 Law - The Dark Web

Chapter 4 Law - Gaming the Hatch Waxman Act

Chapter 3 Law - Biosimilars

Chapter 2 Law - Patent Protection and Drug Development

Chapter 1 Law - CRISPR-Cas9

FDA Law Blog 2.0

Theranos - Moral Lessons for the Biotech Industry

Gene Therapy for Spinal Cord Injury

FDA - Golden Age for Gene Therapy

Pricing Gene Therapy

Lentivirus - Not just Retro Chique


AAV - An Awesome Vehicle!

The Year of the Gene Therapy

Masters in QARA

Industry High Castle


Regeneration Paper Out

Oligonucleotide Therapeutics

Brain-Spine Neural Interface

Black Mirror

A Journey into my Genome (2): Volunteering my DNA

ImPACT Traumatic Brain Injury

Retiring the Mouse Model Gold Standard

Brexit Britain I weep for you


Seven Years in Visaland

Photo Website

Restimulating the Party

Start Talking Science

A Journey into my Genome

Patent Law IX, The Limits of Biotech Patents

Patent Law IX, The Longest Patent Extension Battle

Patent Law VIII, Invasion of Patent Trolls into Biotech

Patent Law VII, DTC Genomic Testing

Patent Law VI, Supreme Court and Laws of Nature

Patent Law V, The Dark Web

Patent Law IV, Gaming the Hatch-Waxman Act

Patent Law III, The Brave New World of Biosimilars

Patent Law II, The Everlasting Patent

Patent Law I, CRISPR-Cas9

FDA Law Intro

The Big Idea

Accountability for Retractions

Neuroscience Drugs

Locked-in Syndrome

SCI scar Inhibitor




Neuropathic Pruritus

Mitochondrial Disease, 3 parent baby

Multiple Sclerosis and Axon Injury

Pint of Science Philadelphia

The Mesoscale Connectome

Tracing Neuronal Circuits

Pint of Science


The Brain Initiative

Two more online courses done

Fellowship Awarded

One week

Shriners Fellowship

PVA Fellowship

SfN Itinerary

Online Course Certificates

Systems Biology