7 cool recent CRISPR articles

CRISPR Model Jacob Corn

CRISPR Model from Jacob Corn

So everyone is buzzing about the CRISPR patent court decision (which BTW I think was flawed but that’s for another post), but the research roars on at warp speed.

Here are 7 recent CRISPR articles that caught my attention.

What are your favorite recent CRISPR papers?

Genome surgery using Cas9 ribonucleoproteins for the treatment of age-related macular degeneration. Do you think the term “genome surgery” is appropriate?

Efficient CRISPR/Cas9-assisted gene targeting enables rapid and precise genetic manipulation of mammalian neural stem cells. CRISPR on the brain.

Muscle-specific CRISPR/Cas9 dystrophin gene editing ameliorates pathophysiology in a mouse model for Duchenne muscular dystrophy. CRISPR pre-clinical promise.

The CRISPR/Cas9 system efficiently reverts the tumorigenic ability of BCR/ABL in vitro and in a xenograft model of chronic myeloid leukemia. CRISPR vs. cancer.

Expanding the CRISPR Toolbox: Targeting RNA with Cas13b. CRISPR systems continue to evolve.

CRISPR/Cas9-AAV Mediated Knock-in at NRL Locus in Human Embryonic Stem Cells. CRISPR’ing ES cells.

Interspecies Chimerism with Mammalian Pluripotent Stem Cells. I blogged on this one here and did an opinion piece at WaPo here.

A role for nationalism in science?

we're #1One of the rewarding things about being a scientist is the opportunity to connect and even collaborate with other scientists around the world., but at the same time there is nationalism in science too.  Some nations, perhaps most of them, and some scientists feel a sense of competition against others at least some of the time.

In fact science is very competitive whether it is the colleague just down the hall in some instances or somewhere else on the same campus, same city, state, or country. But when competition in science pits one country against another, things can go to a whole other level. In times of war or even in peace but when countries are adversarial there might be good reasons for science to be woven into a sense of nationalism or at least national self-preservation. Who in American for instance would have wanted Germany to make an atomic bomb first?

Today in most countries we are not openly at war with other countries, but there are still nation-focused threads to science. For instance, in the stem cell field’s area focused on clinical translation there is a growing narrative thread that America must be more competitive with Japan or risk falling behind.

From talking to some colleagues in Japan they likewise have indicated a sense in Japan of wanting to be the #1 leader in stem cells. China is also very competitive on the stem cell front. The UK wants to lead the world it seems in certain reproductive technologies such as 3-person IVF and in other ways including certain areas of stem cell work. Is this kind of competition based on national identity healthy? Toxic? More complicated than such binary ways of thinking?

Does it matter than Japan has a strong and dominant IP position over IPS cells, while arguably many companies in the US do not? Or that pharma companies in Japan recently bought a few notable stem cell biotechs? Does it make a difference to the world that the US is poised to have almost complete control of the IP on CRISPR?

At the same time we need to also keep in mind that there are thousands of collaborations going on between scientists in these and countless other countries too. What if these collaborating scientists’ countries are from a broader perspective fierce competitors with each other? Do individual scientists need to think about that? Worry about it? Embrace it?

I believe collaboration makes science better and it should transcend national boundaries so I’m not a big fan of nationalism in science. What do you think?

CRISPR Update: Patents, Embryos, & IPOs, oh my

It’s been a busy few weeks for the CRISPR arena so I’ve made a CRISPR Update. I’ve listed below links to some commentaries and key developments.Joanne Manaster

 

Fun Video interview on Read Science! with Joanne Manaster on my new book on CRISPR in humans, GMO Sapiens.

CRISPR: Pursuit of profit poisons collaborationNature piece by Jacob Sherkow

HIV Fights Off CRISPR Gene-Editing Attack. HIV adapts when CRISPR attacks.

2nd group CRISPR’s human embryos and things don’t go well. More Indels than precise gene edits, mosaicism and more.

CRISPR biotech Intellia strikes licensing deal with Regeneron, readies IPO. It’s interesting that there are these CRISPR IPO’s when the CRISPR patent situation remains entirely up in the air.

George Church versus Marcy Darnovksy on human modification in the WSJ

CRISPR/Cas9 Used to Create Knockout Chickens. Bock bock adoodle moo

A hunch on that CRISPR patent battle as it heats up

CRISPR patent dispute

Adapted from NIH image

Who really invented CRISPR?

If it was many people and labs, who did it first and who deserves the credit?

When things like Nobel Prizes and Patents get decided on CRISPR-Cas9, who will be for lack of a better way of putting it, the winners and the losers?

It’s not a trivial question and despite what some argue that CRISPR shouldn’t be patented at all, someone will get the decisive patent and the fight to see who prevails in the CRISPR patent battle is getting more intense. For more background in what’s at stake on CRISPR and human gene editing, check out my new book GMO Sapiens.

The signs suggest that there cannot really be a kumbaya approach to credit for things CRISPR even if there were multiple key contributors. For Nobel Prizes, there are only 3 lots. For patents, in many cases even if they are scads of patents related to one thing as seems certain for CRISPR-Cas9-related technology, often only one patent dominates.

The patent situation on CRISPR has really become a battle between the UC system (disclaimer, I’m a UC employee) and the Broad Institute.

I am not going to choose sides or predict the outcome, but I do have a hunch and that is that despite all the different complicated, but important details and potential maneuvers now emerging this week in this patent dispute, what it will all boil down to in the end is just one thing.

The lab notebooks.

What is in the lab notebooks of the various parties involved, how conclusive is this material, and what are the dates on those notebooks?

Patent expert weighs in on CRISPR dispute between UC & Broad

CRISPR dispute patent

Adapted from NIH CRISPR-Cas9 image

The patent dispute on CRISPR between UC/Jennifer Doudna and The Broad/Feng Zhang has been the subject of major attention including in a recent piece on Stanford Center for Law & Biosciences Blog. There is a lot of confusion over this important CRISPR dispute so I turned to a patent expert for their take on this via an interview below.

The interview with this anonymous expert provides some helpful, informed assessments on the CRISPR patent dispute including fresh perspectives. This person has different views than those expressed in other media outlets and in some instances from those in that recent piece on the Stanford Law/Bioethics Blog.

(1) Are there elements to this patent situation that most people are overlooking?

Answer: Probably the most important thing that people are overlooking is the scope of the claimed subject material of the Doudna patent application (and also the Zhang patents in question); only Cas9 is claimed. The claims do not cover other nucleases that could work with CRISPR (such as Zhang’s recently published Cpf1, which is “smaller and easier to program than Cas9”) and thus would not exclude someone from using other nucleases. Therefore, I think that even if the Doudna patent is issued and the Zhang patents are pulled, the Doudna patent would still not exclude someone from using CRISPR/Cpf1 (or CRISPR with other non-Cas9 nucleases that may be eventually discovered or engineered). Similarly, the current Zhang patents also would not exclude someone from using CRISPR with non-Cas9 nucleases, although I assume that Zhang and the Broad Institute will now also be applying for patent coverage for Cpf1. Indeed, the Broad Institute’s press release for the discovery of Cpf1 mentioned that “The Broad Institute and MIT plan to offer non-exclusive licenses to enable commercial tool and service providers to add this enzyme to their CRISPR pipeline and services” and “We see much more to come, even beyond Cpf1 and Cas9, with other enzymes that may be repurposed for further genome editing advances.” Interestingly, this means that if the Doudna patent is issued and the Zhang CRISPR/Cas9 patents are pulled, Zhang and the Broad Institute (and their licensees) will still be able to use CRISPR/Cpf1, whereas if the Doudna patent application is rejected and the Zhang CRISPR/Cas9 patents are left intact and Zhang then patents CRISPR/Cpf1, then Zhang and the Broad Institute could potentially control the entire current CRISPR intellectual property landscape (at least until someone finds or engineers yet another CRISPR-compatible nuclease). Of course, I should also point out that all of this is assuming that there will be no settlement between the UC and the Broad Institute in the current interference proceeding; some kind of settlement could still happen. These aspects regarding the actual scope of the patent claims have been largely ignored by most media reports and were not mentioned in the Stanford Law blog. Therefore, although the outcome of the CRISPR/Cas9 patent battle is indeed important as this is the first wave of patents for this technology, it is important to keep things in perspective, and some assertions from the Stanford Law blog such as “needless to say, this is a monumental event for patent attorneys, molecular biologists, the PTO, and the world” and “the biotech patent dispute of this century” feel to me somewhat overstated.

(2) Do the recent developments chronicled on the Stanford Law Blog favor Doudna’s patent claim?

Answer: The recent developments chronicled in the Stanford Law blog simply amount to the initiation of the interference proceeding, which I think that people have been expecting for a while, perhaps ever since the Zhang patents were issued and it was known that the Doudna application was still under examination. The USPTO’s decision to actually institute the interference proceeding means that the USPTO supports the Doudna team’s position that the scope of the inventions claimed by Doudna and Zhang overlaps and that the claims are in conflict. This is a step forward for Doudna’s team because it opens up the possibility that the Doudna patent could be issued and that the Zhang patents could be pulled. However, the initiation of the interference proceeding itself does not favor or disfavor Doudna’s patent claim; indeed, the entire purpose of having the interference proceeding is to determine whether or not Doudna’s patent claims can be allowed, and as the Stanford Law blog pointed out, decisions to institute interference proceedings are largely pro forma. Basically, we still have no idea who will come out on top, except that it should be whoever can show that they invented CRISPR/Cas9 first.

Regarding the reporting in the Stanford Law blog, though, I disagree with trying to draw a difference between Zhang and Doudna with regard to the modification of eukaryotic cells; Doudna specifically recites it in the originally filed claims (see, e.g., original claim 95), not to mention discussing it in the originally filed specification. Genome editing of human cells is explicitly presented in Doudna’s Example 2, and in vivo genome editing in mice is described in Example 7. Thus, the argument that Doudna did not contemplate eukaryotic applications and the suggestion that Zhang’s claims might thus somehow be more worthy, valuable, or patentable (on this basis) is incorrect. Furthermore, it should be noted that patent claims allow the patent owner to exclude someone else from practicing the invention; they do not give the owner a right to practice what is claimed. Therefore, even if hypothetically Doudna had not explicitly contemplated eukaryotic applications (which is not the case), the broader scope of the resulting claims (which would basically cover any genomic editing by CRISPR/Cas9, not just in eukaryotic cells) might even be considered to make the Doudna patent more (and not less) valuable than the Zhang patent.

Despite disagreeing with some elements of its analysis of the actual patents, I do however think that the Stanford Law blog did a great job of describing what happens in interference proceedings, which are mysterious even to many patent practitioners.

(3) What could be the deciding factor in this patent dispute?

Answer: Because the application was filed under the first-to-invent rule, I think that in the end that it will come down to establishing the actual date of invention on both sides, i.e., at what point both sides achieved what they are claiming. If Doudna has lab data showing that she invented CRISPR/Cas9 before Zhang, then her patent should be allowed and Zhang’s patents should be pulled. If Zhang instead has lab data showing that he invented CRISPR/Cas9 first, then his patents should stand and Doudna’s application should be rejected.

However, Doudna’s team could also go after Zhang’s patents or vice versa by attacking the patentability of the claims themselves under the written description and enablement requirements, i.e., by saying that the invention is not described sufficiently to indicate that Doudna/Zhang was actually in possession of the claimed matter at the time of filing/invention or to enable one of ordinary skill in the art to actually practice the invention. The outcome would be to invalidate Zhang’s patents or reject Doudna’s application on that basis. It should be noted, though, that the enablement and written description aspects were already considered to not be an issue by the examiners for both Zhang’s patents and Doudna’s application. The patentability of the claims over the prior art could also potentially be made an issue, although similar to the enablement and written description aspects, the examiners already found Zhang’s patents and Doudna’s application to be clear of any prior art, and any prior art that one side further attempts to apply would probably also apply to the other side in terms of date, as the dates of invention and the claimed subject material seem to be so similar.

Another possibility is that if the claims of either Doudna’s application or Zhang’s patents, or both, could be amended so that the claimed material no longer overlaps, then Zhang could keep his patents and Doudna’s patent could still be issued. However, given that they are both claiming the same fundamental CRISPR/Cas9 technology, I think that this is unlikely. Still another possibility is that some other kind of settlement could be reached, although it seems as though they have already been trying to settle without success, and as the Stanford Law blog rightly notes, settlement is discouraged in interference proceedings. Thus, I predict that in the end it will probably amount to who has the earliest lab records to determine whether Doudna’s application is issued and Zhang’s patents are pulled or whether Doudna’s application is rejected and Zhang keeps his patents (unless there is a settlement of some kind).

(4) There have been some suggestions that the original UC attorneys were outplayed by those at the Broad. What do you think?

Answer: I don’t really think so. The strategies used are different, but it is difficult to say that one is better than the other. The Broad Institute attorneys opted for the fast track to ensure early granting and as a result had to limit what they were claiming (hence the limiting of the claims to eukaryotic cells) and submit relatively few claims. The UC attorneys submitted lots of claims with a broader scope and more coverage, but then had to deal with the longer conventional prosecution process. I think that one could argue, though, that in the end the pathway used wouldn’t make a much of a difference with regard to total patent coverage that could eventually be obtained, as subsequent applications with broader claims could be filed to increase coverage in the case of Zhang, or an interference proceeding can be requested if the patent prosecution process takes too long and someone else patents the invention first in the case of Doudna.

Furthermore, I think that the question of whether or not the UC’s original attorneys were outplayed by the Broad’s may not even be relevant because the outcome of this patent dispute will likely not depend on whose patents were issued first or on whose patent claims initially had a broader scope. For example, if Doudna’s attorneys had instead filed a fast-track application where the patent was granted before Zhang’s but Zhang believed that he had invented CRISPR/Cas9 before Doudna, then Zhang could have requested the interference proceeding and we would still basically be where we are today. Rather, I think that the quality of the initial attorneys and what they did will only impact the interference proceedings if written description or enablement issues come up, because the resolution of such issues would depend on how solidly the patents/patent applications were written. I think that the arguments made by the currently litigating attorneys will have a greater impact, but the greatest impact will probably come from the dates in the lab records.

(5) What about the “mysterious third party” in this patent situation?

Answer: It could be anyone. However, a couple of things to note:

(a) Whoever it is used a solo attorney (not a firm) who doesn’t seem to do much (if any) life science/biotech work, so I am guessing that (like the Yamanaka patent challenge) they are not serious and are not major players in the field.

(b) The attorney is based out of the San Francisco Bay Area, so I think that whoever it is probably is from the Bay Area, too. I think that it’s highly unlikely that someone from Boston, New York, DC, or another major city (or another country, for that matter) would turn to a local solo non-biotech practitioner who is not from their own locality for this. A look at the patent applications handled by the former firm of the attorney confirms that almost all are from Bay Area inventors. However, another possibility would be if the third party is a friend or relative of the attorney.

(c) Most importantly, the “prior art” cited in both 3rd party submissions was largely filed or published after Doudna’s effective filing date, and thus well after her presumed invention date; the only documents that predate her filing/invention date only generally describe the CRISPR/Cas system as it exists naturally in bacterial cells, which would not render obvious what Doudna did in turning it into a bioengineering tool by including the targeting RNA and activator RNA and then using it in other cell types. Therefore, none of the documents are actually applicable as prior art, and so it is really unclear why the “mysterious third party” would have thought that filing these submissions would affect the granting of Doudna’s patent. The examiner working on this thought the same thing, as she did not consider a single one of the references supplied by the third party to be applicable to reject Doudna’s application.

(d) Furthermore, some of the documents in the 3rd party submission (for example, WO2013141680, which is the main patent application cited) were even already disclosed in the information disclosure statements originally filed with Doudna’s application- so the USPTO had already even been informed about some of these documents by Doudna’s own team. Therefore, I think that the “mysterious third party” submissions were never really an issue, although the fact that someone was actively trying to prevent Doudna’s patent from being issued is indeed interesting.