Tuesday, January 05, 2016

WIRED takes on the CRISPR patent interference matter

A story by Sarah Zhang at Wired on the coming CRISPR patent interference battle is titled:
An Arcane Patent Law May Decide Crispr’s Big Legal Fight

Of the money aspect:

The money is getting as real as the lab results. The gene-editing company Editas, which licenses the Broad’s patent, filed for a $100 million IPO on Monday. If the interference proceeding negates the Broad’s patent, that could spell the end of Editas (and all that capital!) while clearing the way for several other companies that have licensed the competing, Berkeley-originated patent. A lot is at stake.

Of dates:

Representatives from UC Berkeley declined to comment, but the interference proceeding clearly works in the university’s favor. Berkeley had filed the earliest patent on Doudna’s Crispr/Cas9 work on May 25, 2012—but the patent office initially awarded the patent to the Broad, which had paid to fast-track its later application. The provisional patents on both sides both made it in before the March 16, 2013 date when a new patent law took effect.

Some background from Doudna et al's US patent application 20140068797 :

[0004] About 60% of bacteria and 90% of archaea possess CRISPR (clustered regularly interspaced short palindromic repeats)/CRISPR-associated (Cas) system systems to confer resistance to foreign DNA elements. Type II CRISPR system from Streptococcus pyogenes involves only a single gene encoding the Cas9 protein and two RNAs--a mature CRISPR RNA (crRNA) and a partially complementary trans-acting RNA (tracrRNA)--which are necessary and sufficient for RNA-guided silencing of foreign DNAs.

[0005] In recent years, engineered nuclease enzymes designed to target specific DNA sequences have attracted considerable attention as powerful tools for the genetic manipulation of cells and whole organisms, allowing targeted gene deletion, replacement and repair, as well as the insertion of exogenous sequences (transgenes) into the genome. Two major technologies for engineering site-specific DNA nucleases have emerged, both of which are based on the construction of chimeric endonuclease enzymes in which a sequence non-specific DNA endonuclease domain is fused to an engineered DNA binding domain. However, targeting each new genomic locus requires the design of a novel nuclease enzyme, making these approaches both time consuming and costly. In addition, both technologies suffer from limited precision, which can lead to unpredictable off-target effects.

[0006] The systematic interrogation of genomes and genetic reprogramming of cells involves targeting sets of genes for expression or repression. Currently the most common approach for targeting arbitrary genes for regulation is to use RNA interference (RNAi). This approach has limitations. For example, RNAi can exhibit significant off-target effects and toxicity.

[0007] There is need in the field for a technology that allows precise targeting of nuclease activity (or other protein activities) to distinct locations within a target DNA in a manner that does not require the design of a new protein for each new target sequence. In addition, there is a need in the art for methods of controlling gene expression with minimal off-target effects.

This application was filed on March 15, 2013 , but claims priority to provisional 61652086 (filed May 25, 2012).
One should note that priority is claimed to FOUR provisionals in all, including 61716256, 61757640, and 61765576.
Priority of a claim is assessed on a claim-by-claim basis, and with a priority date assigned when the claim is fully supported by a given disclosure. For example, if a claim in US 20140068797 required the support of provisional
61765576, the priority date for that claim would be Feb 15, 2013.

**Of the Zhang patent, as noted in an IPBiz post in March 2015 [ CRISPR is high profile in science, patents; competitor labeled a mere second comer ]:

US 8,945,839 issued on February 3, 2015. A "Track I" request had been made on 18 April 2014. A final rejection was issued on 18 Nov. 2014, with claims 1-28 rejected as anticipated over Jinek, WO'772 (later identified as Doudna). There was an issue of whether or not the priority documents to WO 2013/176772 supported the later disclosure. In this, there was an issue that the patent applicant had presented only arguments of counsel, with the examiner citing to In re Huang, 100 F.3d 136, 139 (CAFC 1996 ) and In re De Blauwe, 736 F.2d 699, 705 (CAFC 1984 ). Applicant brought up arguments made to the EPO about a Jinek journal publication, which were not of interest to the USPTO.
In a response filed 1 Dec. 2014, applicant was especially harsh to the Doudna application: "Doudna is nothing more than a mere 'second comer' and had no CRISPR-Cas invention prior to Feng Zhang."

One notes that the non-provisional application underlying Zhang's 8,945,839 patent was filed April 18, 2014.
The priority claim in the patent states

This application is a continuation of U.S. application Ser. No. 14/183,429 filed Feb. 18, 2014, which is a continuation of U.S. patent application Ser. No. 14/054,414 filed Oct. 15, 2013, now U.S. Pat. No. 8,697,359, which claims priority to U.S. provisional patent application 61/842,322 having Broad reference BI-2011/008A, entitled CRISPR-CAS SYSTEMS AND METHODS FOR ALTERING EXPRESSION OF GENE PRODUCTS filed on Jul. 2, 2013. Priority is also claimed to U.S. provisional patent applications 61/736,527, 61/748,427, 61/791,409 and 61/835,931 having Broad reference BI-2011/008, BI-2011/008, Broad reference BI-2011/008, and BI-2011/008 respectively, all entitled SYSTEMS METHODS AND COMPOSITIONS FOR SEQUENCE MANIPULATION filed on Dec. 12, 2012, Jan. 2, 2013, Mar. 15, 2013 and Jun. 17, 2013, respectively.

**Of separate relevance to the controversy is an October 2015 post in Wired The Battle Over Genome Editing Gets Science All Wrong

The post was about a prediction by Thomson Reuters, later established to be incorrect, that CRISPR might win this year's Nobel Prize:

Thomson Reuters bases its predictions on how often key papers get cited by other scientists. Here, the paper in question has as its authors Jennifer Doudna, a molecular biologist at UC Berkeley, and Emmanuelle Charpentier, a microbiologist now at the Max Planck Institute for Infection Biology. Missing is Feng Zhang (no relation to this writer), a molecular biologist at the Broad Institute and MIT, who actually owns the patents for CRISPR/Cas9 and says that he came up with the idea independently. So let’s say Thomson Reuters gets it right. Could the patent for a discovery go to one scientist, and the Nobel prize for the discovery to someone else?

Part of the article could have been taken from Lemley's "myth of the solo inventor":

But putting aside all the lawyers and all the money for a moment, obsessing over finding the one true origin of Crispr/Cas9 gets science all wrong. Casting the narrative as Doudna versus Zhang or Berkeley versus MIT is a misapprehension of history, creativity, and innovation. Discovery comes not from a singular stroke of genius, but an incremental body of research. “I’m not a great believer in the flash-of-genius theory. If you are a historian—” says Mario Biagioli, who is in fact a historian of science at UC Davis1—“you quickly will realize exactly how many times there are independent discoveries of the same thing.” The dispute over credit for CRISPR/Cas9 is not the result of exceptional coincidence and disagreement. In fact, it illuminates how science always works.

IPBiz notes that Chester Carlson's xerography invention is a strong counterpoint to Biagoli and Sarah Zhang.
The 1906 patent of the Wright Brothers illustrates a different point: while there might be a strong body of incremental research, not everyone puts the pieces together in the same way. Langley did not even understand the problem to be solved, much less the solution, but he, not the Wrights, was funded by the federal government, based
upon a (false) perception of who would "win."

Zhang brings up Merton:

History is full of parallel discoveries: Isaac Newton and Gottfried Leibniz independently discovered calculus in the late 17th century and then spent years fighting over who got there first. Charles Darwin and Alfred Russel Wallace both came up with the theory of evolution through natural selection, though these two had a more amiable relationship. Back in 1922, the sociologists William Ogburn and Dorothy Thomas catalogued 150 examples of independent discovery and invention. Merton even went so far as to say single discoveries are the real oddities. Scientists naturally flock to the interesting scientific problems of their time, and again naturally, they use the tools of their time to solve them. No wonder they often come up with the same solutions.

Zhang writes:

The problem is, though, is that Nobel prizes go to a maximum of three people, and patents only to one group of inventors.

True as to Nobels, but not exactly true as to patents.

If Feng Zhang keeps working on improvements (e.g., better enzymes), Zhang might obtain a patent on the preferred
CRISPR composition/method, and one could have the diode/triode story revisited.

As to Nobels, there is an urban legend about "why" neither Edison and Tesla got a Nobel prize, involving their dislike for one another.

Separately, recall that Paul Ehrlich and Élie Metchnikoff received the 1908 Nobel Prize for Physiology or Medicine
From NEJM [ N Engl J Med 2002; 346:870March 14, 2002 ] :

Ehrlich also had a long-running, often bitter, disagreement with Élie Metchnikoff, discoverer of the macrophage, about the primacy of antibodies (Ehrlich) or phagocytes (Metchnikoff) in immunity. Ironically, the 1908 Nobel prize was awarded to both men.


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