Why UC Berkeley deserves the main CRISPR patent

crispr nihSome 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.

Why?

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. 

7 cool new stem cell research papers

Yang et al graphical abstract

Yang et al. graphical abstract

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:

From Stem Cells:

From Cell Stem Cell: 

Another stem cell lawsuit: Stemedica sued by board member over alleged mishandling of funds

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.

CourtHouseNews writes:

“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.”

stemedica

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.”

and

“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.

Dr. Anthony M. Marlon Stemedica

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.

Wouldn’t you like to be a RAT too? Stem cell clinics apply for new FDA accelerated approval path

RAT RMAT designationAre stem cell clinics going to somehow get the FDA to approve their stem cell interventions? To get recognized as legit? It seems they are trying now more than ever.

Remember the REGROW Act that would have greatly reduced regulations on investigational stem cells and then how the 21st Century Cures Act passed with some REGROW-related provisions, but more moderate ones?

The status quo of how the FDA regulated stem cell-based regenerative medicine therapies wasn’t working so great in past years so some reforms were (and still are) needed, but the key was hitting the “Goldilocks” sweet spot of just the right amount of regulatory change.

I was worried about REGROW in particular because I viewed it as having overshot by a mile by going for too much reduction in oversight (particularly in its original language, although it moderated somewhat over time) and I had mixed feelings on Cures, but it was at least relatively more balanced. Cures passed, was signed by Obama, and is now law. One of its main provisions on stem cells is so-called Regenerative Advanced Therapy (RAT, an unfortunate acronym choice that it seems the FDA wants to change to RMAT) designation that could speed up vetting of stem cell therapies.

My concerns about the legislative efforts were mainly stemming from the possibility that stem cell clinics would try to take advantage of the less stringent regulations. Could they get their interventions to be designated as RATs? Could some of the clinics get FDA approval?

Now some of the clinics are trying to make that a reality.

I’m hearing from multiple sources that a number of stem cell businesses running clinics have already applied to the FDA for RAT/RMAT designation that puts therapies automatically on the accelerated pathway. Most of these businesses have not publicly announced their applications, but US Stem Cell, Inc., a publicly-traded stem cell clinic company disclosed that it has applied for RAT status. You might recall this businesses as it was associated with the blinding of three of its patients. I’m hearing that other businesses are already applying for RAT too. US Stem Cell wrote:

“Following the passing of the 21st Century Cures Act, U.S. Stem Cell, Inc. has applied to the FDA for RAT Designation. We have recently heard from the FDA, who has requested additional information regarding the MARVEL Phase II/III trial. We have provided all requested information to the FDA and are hopeful that the FDA will continue their expeditious review of our MyoCell product. Thanks to the REGROW component of the Cures Act, the FDA will grant RAT designation for a regenerative medicine therapy that is intended to treat, modify, reverse, or cure a serious or life-threatening disease and demonstrates preliminary clinical evidence that the product has the potential to address unmet medical needs for a disease. We believe that our MyoCell product meets these requirements, as we have demonstrated clinical efficacy in both preclinical and clinical studies…”

Presumably, some of those working on investigational stem cell therapies from non-clinics are going for RAT designation too and some of those are probably not going to get approved. On the other hand, some stem cell clinic and non-clinic applications to the FDA may get the RAT stamp of approval.

Overall, how will the FDA decide what to approve as a RAT and what to reject as not a RAT? How effective will the FDA be able to be on vetting the host of RAT applications it is getting?

Showing how fast this could all happen, the FDA has already granted the now-re-named RMAT designation to some companies including Humacyte, which is in part funded by CIRM and this RMAT designation seems like a positive move.

Hold on to your hat (or chair, or pet rat, or whatever) as we will now all witness a high stakes regulatory experiment unfold in front of us in the coming months and years due to Cures. The outcome is likely to be mixed overall, but we can hope it’ll be on the whole a positive for the field and for patients. There’s no crystal ball on this though.

Splashy SacBee Ad for Stem Cell Clinic Nervana Raises More Questions

This morning my local paper The Sacramento Bee ran a full-page, super splashy ad for the local stem cell clinic, Nervana.

Remarkably the ad says, “As Seen in The Sacramento Bee”, referring to an article by reporter Claudia Buck that ran in the past in the SacBee Insight section that raised many concerns and questions about Nervana. I may have missed it, but it seems like it has been months since the last Nervana ad in the Bee.

What is going on here? It seems like there are few answers still and more questions now.

Nervana SacBee ad

I’ve written before about how Nervana has had a number of big full-page ads in the Bee. Nervana markets non-FDA approved stem cell offerings for neuropathy and other conditions for which in my opinion as a stem cell scientist there is no solid scientific basis for safety or efficacy.

This new ad takes the cake in this series of ads from the company as it has “Stem Cells” in huge blue font across the top and a very large “Neuropathy” below that in red font. In addition to that dash of splash and the odd mention of the clinic having been discussed in the Sac Bee before, importantly the ad makes medical claims that I see as unproven.

For instance, to my knowledge there is no concrete evidence such as published peer-reviewed articles backing up the ad’s claim of essentially a cure by “getting rid” of neuropathy symptoms. It does qualify that I guess with “may be possible”, but I’m not sure that conditional will sink in for patients. It also makes other medical claims that the treatment is “safe and effective”. Is it objectively known for sure to be those things? Could they have rigorous unpublished data that they’ve run by the FDA that serves as a foundation for what they are doing medically?

Finally the ad has a coupon and says, “over 1,000 patients already served”. If indeed they’ve already done experimental stem cell transplants into that many patients at a cost of say roughly $5,000 each then that is $5 million in money taken from patients. Is that serving the community? Is the SacBee an enabler of guiding patients toward potentially risky, unproven, and expensive medical offerings? Is the FDA still basically sitting out regulating stem cell clinics? What about state regulators in California? Who knows?

I’m going to reach out to Nervana itself again too to try to get more clarity on this situation and their perspectives. The company website still lists Dr. Tushar Goradia as the leader so I’ll try to reach him.