Within my book GMO Sapiens on CRISPR and human genetic modification, I’ve hidden a scientific Easter egg.
There’s more Easter egg info over here including the rules.
If you are the first one to find and properly explain this egg to me after buying the book, you win $250. I had originally limited it to the print edition, but e-version purchase is fine too.
So far no one has gotten the hidden egg right.
To give people a better chance, I’m giving a hint. The clue is: crack the Easter egg code.
This is largely a repost of last year’s Easter piece.
Some months back a USPTO court issued a ruling that most interpreted as meaning the Broad Institute had won the so-called ‘CRISPR patent battle’ in the U.S. and that UC Berkeley, Jennifer Doudna, and Emmanuelle Charpentier had lost. Now this week Berkeley has appealed that ruling. It seems the odds are against Berkeley prevailing in its appeal, but frankly Berkeley deserves the main CRISPR patent and Broad doesn’t. Interestingly, the European Patent Office apparently agrees with this view and disagrees with the USPTO. Update: note that the Berkeley patent application itself also mentions eukaryotic use.
At the heart of the original decision that favored the Broad was an illogical argument by the USPTO court. They said that the research of Doudna and Charpentier did not make the work that the Broad later patented based on the work of Feng Zhang obvious. In my view Doudna and Charpentier’s work in fact did render Zhang’s later work a totally obvious next step.
A hypothetical scenario can help to illustrate this.
Let’s say a colleague tells me something along the lines of “Hey, I found this novel nuclease we are calling ‘DUH1’ that cuts DNA in a nifty new way in a prokaryote and in a test tube” and they publish that. Of course, after that many people are going to want to try DUH1 in eukaryotes. Duh, it’s a no-brainer, right? It’s therefore bizarre that the USPTO would think the step to try CRISPR in eukaryotes was not obvious after Doudna & colleagues groundbreaking work.
Flip it around too and imagine that the hypothetical colleague who discovered DUH1 only reported that it worked in vivo and then someone else was allowed to patent that DUH1 could be used in vitro on plasmid DNA in a tube. Does that make any sense? Someone else could patent the in vitro use of DUH1 over the inventor who discovered DUH1 first and reported how it worked in vivo? Even if was a bit of a challenge to get DUH1 to work in vitro, I don’t think that makes sense.
Back to the real CRISPR world, does the in vivo to in vitro or in vitro to in vivo or prokaryote to eukaryote “directionality” of the research flow matter for a patent? I’m not sure, but in theory it shouldn’t in this case as the next steps were obvious. How obvious?
If you read Doudna and Charpentier’s seminal Science paper, the abstract concludes with a statement for all the world suggesting the use of CRISPR-Cas9 for genomic editing in general and I took that to mean in eukaryotes too:
“Our study reveals a family of endonucleases that use dual-RNAs for site-specific DNA cleavage and highlights the potential to exploit the system for RNA-programmable genome editing.”
and the paper itself ends:
“We propose an alternative methodology based on RNA-programmed Cas9 that could offer considerable potential for gene-targeting and genome-editing applications.”
You’re telling me that these statements were meant to be restricted to only prokaryotes or DNA in a tube? Really? Nope.
Strangely the patent court apparently felt that Doudna’s public statements about it being a challenge to get CRISPR to work in eukaryotes was a big deal in rendering their decision, but again technical difficulty does not equate to an idea being non-obvious. For sure kudos to Zhang, who was technically speaking quite adept to get the CRISPR-Cas9 system to work well in eukaryotes quickly, but even if the Broad ironed out key technical kinks in getting CRISPR-Cas9 to work well inside eukaryotic cells that still doesn’t justify them having the main CRISPR patent. It’s just not conceptually or technically different enough from the earlier Doudna and Charpentier work. To me it’s not even a close call, but USPTO got it totally wrong.
Another exercise reinforces my argument. Can anyone imagine Zhang publishing his first CRISPR work (which by the way cites and heavily relies on the works of Doudna and Charpentier) if he didn’t have those earlier key papers of Doudna and Charpentier to build on moving forward? No way. Could Doudna and/or Charpentier and others have gotten CRISPR to work in eukaryotes without Zhang? Yes and almost certainly it was already inevitable before Zhang even published his key Science paper.
For all these reasons, Berkeley deserves the main patent based on simple common sense, but whether things will turn out that way longer term seems far less clear.
Some may say that no one should get to patent CRISPR, but these days that’s probably a naive perspective. For more on the history of patenting (or lack thereof) of nucleases and in particular restriction enzymes, this is an interesting read.
As a stem cell biologist it’s fun to read new papers on the latest cutting edge research. In that spirit, here is a list of 7 recent stem cell and regenerative medicine papers that caught my eye as particularly notable and that have sparked discussion.
From PLoS Biology:
From Nature Cell Biology:
From Cell Stem Cell:
Stem cell clinic biotech Stemedica has just been sued by one of its own board members based on allegations related to money the company raised, according to CourtHouseNews. The actual suit, filed by an investment company Tiara Holdings and board member Anthony Marlon, can be read here.
“Tiara Holdings II LLC sued Stemedica Cell Technologies Inc. and its top three officers on April 6 in Clark County Court. The officers are CEO and Chairman of the Board Roger Howe, Vice Chairman and CEO Maynard Howe and President and Chief Medical Officer Nikolai Yankovich.”…Dr. Anthony M. Marlon, a medical doctor and businessman, holds 430,000 shares of Stemedica through Tiara Holdings, where he is a member. He also is a member of the board of Stemedica, he says in the complaint.”
Note that “Yankovich” seems to be a typo as the Stemedica leader in question is Nikolai Tankovich.
The allegations in the suit are summarized by CourtHouseNews this way:
“Stemedica’s founders have operated a nearly 10-year investment scheme, wherein they have raised over $110 million dollars from various individual investors for the purported purpose of funding and establishing a stem cell company,” Tiara says in the lawsuit.
Tiara claims the Howes and Tankovich “have used these investor funds, in whole or in part, to benefit themselves and their associates through excessive compensation and lavish personal expenses and related party transactions.”
“Stemedica’s founds have concealed and perpetuated this fraud through purported operating subsidiaries, which permitted them to divert millions to benefit them without raising questions or concerns from Stemedica’s investors and shareholders,” Tiara says.”
“It also seeks damages and punitive damages for fraud, breach of fiduciary duty, unjust enrichment and bad faith.”
Maynard Howe reportedly told CourtHouseNews that the allegations are false.
The Stemedica website still lists Dr. Marlon as a board member (see screenshot above).
Stemedica has seen some other past controversy as in part noted in the new suit related to a KPBS investigation of the San Diego company and ties reported in that piece to the stem cell transplants received by patient Jim Gass, who later developed a spinal tumor. The origin of Gass’s tumor remains unknown to my knowledge and may have had nothing to do with Stemedica’s cells, but the stem cell community would benefit from more clarity on that situation. Stemedica also garnered major media attention further back for its role in a non-FDA-approved stroke treatment received outside the U.S. by hockey legend Gordie Howe (no relation to the company’s Howe brothers).
Another San Diego stem cell businesses, Stemgenex, is also the subject of a lawsuit, in its case related to allegations of improper marketing claims. Additional recent stem cell clinic-related lawsuits have been filed, settled, or remain active as I discuss here and here.
Big HT to Alexey Bersenev.