The con­tin­u­ing CRISPR patent saga

Biotech Voices is a collection of exclusive opinion editorials from some of the leading voices in biopharma on the biggest industry questions today. Think you have a voice that should be heard? Reach out to senior editors Kyle Blankenship and Amber Tong.

CRISPR has the po­ten­tial to be one of the most rev­o­lu­tion­ary (or dan­ger­ous) ge­net­ic ma­nip­u­la­tion tech­nolo­gies ever de­vel­oped.

It pro­vides re­searchers with the abil­i­ty to “ed­it” ge­net­ic in­for­ma­tion (in­clud­ing both struc­tur­al genes en­cod­ing pro­teins as well as reg­u­la­to­ry se­quences that con­trol when a gene is ex­pressed, how much, and in what tis­sue) in ways hereto­fore on­ly more crude­ly prac­ticed; for ex­am­ple, by in­tro­duc­ing a het­erol­o­gous gene in­to a new cel­lu­lar en­vi­ron­ment. It thus has im­pli­ca­tions for agri­cul­ture — in­creas­ing yield, for ex­am­ple, or re­duc­ing al­ler­gens like gluten — as well as hu­man med­i­cine.

CRISPR was first re­port­ed by Jen­nifer Doud­na and Em­manuelle Char­p­en­tier in 2012, as an out­growth of their work on bac­te­r­i­al im­mu­ni­ty at the Uni­ver­si­ty of Cal­i­for­nia at Berke­ley and the Uni­ver­si­ty of Vi­en­na. They did not ex­plic­it­ly show that CRISPR could ed­it genes in eu­kary­ot­ic cells — i.e., al­most every type and species of cell ex­cept bac­te­ria — in their ear­li­est pub­lished work (al­though ap­ply­ing CRISPR to eu­kary­ot­ic DNA was en­vi­sioned) and there is some ev­i­dence that the ear­li­est ef­forts in achiev­ing eu­kary­ot­ic CRISPR were un­suc­cess­ful. The first sci­en­tif­ic pub­li­ca­tion demon­strat­ing that CRISPR could be ef­fec­tive­ly prac­ticed in eu­kary­ot­ic cells was by Zhang and col­leagues at The Broad In­sti­tute, MIT and Har­vard Uni­ver­si­ty; there­after, sev­er­al groups re­port­ed suc­cess­ful eu­kary­ot­ic CRISPR re­sults.

Both the Broad and “CVC” (Cal­i­for­nia, Vi­en­na, Char­p­en­tier) groups ac­com­pa­nied their sci­en­tif­ic work with patent ap­pli­ca­tions. This is be­cause both groups, and their uni­ver­si­ties, re­al­ized that in or­der to bring this tech­nol­o­gy to mar­ket there must be a rea­son­able like­li­hood of be­ing able to re­coup a suf­fi­cient­ly ro­bust re­turn on in­vest­ment to make that in­vest­ment worth­while, and this rea­son­able like­li­hood de­pends on hav­ing patent pro­tec­tion.

Both groups claimed in­ven­tor­ship over CRISPR ap­pli­ca­tions to eu­kary­ot­ic cells (which en­com­pass­es most of the most promis­ing ap­pli­ca­tions of the tech­nol­o­gy), and in the face of their com­pet­ing claims, the Patent Tri­al and Ap­peal Board (PT­AB)  in­sti­tut­ed an in­ter­fer­ence pro­ceed­ing to make the de­ter­mi­na­tion of who in­vent­ed eu­kary­ot­ic CRISPR  first.

Two years ago, the out­come of the first of these in­ter­fer­ences seem­ing­ly re­solved the ques­tion, al­beit im­per­fect­ly: the PT­AB de­cid­ed that the Broad In­sti­tute and their col­lab­o­ra­tors had the rights to eu­kary­ot­ic CRISPR ap­pli­ca­tions and that rights to CRISPR more gen­er­al­ly were owned by the Uni­ver­si­ty of Cal­i­for­nia at Berke­ley, the Uni­ver­si­ty of Vi­en­na and Em­manuelle Char­p­en­tier as an in­di­vid­ual.

This out­come had the ben­e­fit of cer­tain­ty in iden­ti­fy­ing who owned the rights to eu­kary­ot­ic CRISPR but suf­fered from the con­se­quence that any third par­ty wish­ing to bring CRISPR-mod­i­fied eu­kary­ot­ic or­gan­isms to mar­ket — or prod­ucts made by such or­gan­isms — would like­ly need a li­cense from both the Broad and CVC, which could re­sult in de­lays in com­mer­cial de­vel­op­ment (be­cause any third par­ty would re­quire li­cens­es from both CVC and the Broad).

In June 2019, the PT­AB de­clared an­oth­er in­ter­fer­ence be­tween these same par­ties, in­volv­ing again who has the rights to eu­kary­ot­ic ap­pli­ca­tions of CRISPR. Af­ter not pre­vail­ing in the first in­ter­fer­ence the CVC group had filed ap­pli­ca­tions di­rect­ed more nar­row­ly at eu­kary­ot­ic CRISPR em­bod­i­ments, and the PTO de­clared an in­ter­fer­ence be­tween these ap­pli­ca­tions and most of the same Broad patents and ap­pli­ca­tions in­volved in the first in­ter­fer­ence.

Hav­ing com­plet­ed the pre­lim­i­nary phase of the in­ter­fer­ence (with­out any sub­stan­tive change in the pos­ture of the par­ties re­gard­ing the pre­sump­tion that the Broad as Se­nior Par­ty is en­ti­tled to pri­or­i­ty based on the par­ties’ re­spec­tive fil­ing dates) the cur­rent in­ter­fer­ence is in the pri­or­i­ty phase, with both par­ties hav­ing filed ev­i­dence for their dates of con­cep­tion and dili­gence in re­duc­ing to prac­tice eu­kary­ot­ic em­bod­i­ments of CRISPR.

CVC has shown ev­i­dence of con­cep­tion as ear­ly as March 2012, and ev­i­dence of dili­gent ef­forts to show suc­cess­ful eu­kary­ot­ic CRISPR ex­per­i­ments from that time un­til its ear­li­est pri­or­i­ty date rec­og­nized by the PT­AB — Jan. 28, 2013. The Broad’s ear­li­est date of con­cep­tion is lat­er than CVC’s, in June 2012, with as­sert­ed re­duc­tion to prac­tice in Ju­ly 2012. This time­line would or­di­nar­i­ly in­di­cate that CVC should win the pri­or­i­ty bat­tle, but the Broad has as­sert­ed a nu­anced counter-ar­gu­ment; the Broad con­tends that the un­pre­dictabil­i­ty of us­ing CRISPR in eu­kary­ot­ic cells is suf­fi­cient­ly high that on­ly by ac­tu­al­ly re­duc­ing the in­ven­tion to prac­tice in a eu­kary­ot­ic cell could the in­ven­tion be con­ceived.

If the PT­AB agrees with this ar­gu­ment the Broad should pre­vail. Fur­ther com­pli­cat­ing this in­ter­fer­ence is that the PT­AB has grant­ed per­mis­sion for CVC to de­pose two oth­er sci­en­tists thought to have in­for­ma­tion re­lat­ing to whether Broad sci­en­tists de­rived their in­ven­tion from the CVC in­ven­tors. Ini­tial res­o­lu­tion of the pri­or­i­ty ques­tion should be made some­time this year. But be­cause what­ev­er the out­come the PT­AB’s de­ci­sion is sure to be ap­pealed to the Fed­er­al Cir­cuit Court of Ap­peals, fi­nal res­o­lu­tion is at least a year away.

A fur­ther com­pli­ca­tion is that the PT­AB de­clared two ad­di­tion­al in­ter­fer­ences, nam­ing Ko­re­an com­pa­ny Tool­Gen as Se­nior Par­ty — and pre­sump­tive first to in­vent — against CVC and Broad, sep­a­rate­ly. These in­ter­fer­ences are in the ear­ly, so-called mo­tions phase, and will not reach the pri­or­i­ty phase (if ei­ther of them reach this phase) un­til this fall, with fi­nal res­o­lu­tion un­like­ly un­til some­time next year. In ad­di­tion, an­oth­er par­ty, Sig­ma Aldrich, al­so has a claim to pri­or­i­ty for eu­kary­ot­ic CRISPR, al­though these claims are bot­tled up in a pro­ce­dur­al morass in the PTO that has pre­vent­ed Sig­ma from join­ing the fray de­spite their ar­gu­ment that join­ing them to the ex­ist­ing in­ter­fer­ence would give the Of­fice (and the par­ties) a chance to re­solve the own­er­ship is­sue more ex­pe­di­tious­ly.

These cir­cum­stances leave the own­er­ship sta­tus of eu­kary­ot­ic CRISPR tech­nol­o­gy in lim­bo for at least the fore­see­able fu­ture. This state of af­fairs rais­es clear im­ped­i­ments to com­mer­cial de­vel­op­ment, at least un­til and if the par­ties de­cide some way to cross-li­cense CRISPR to third par­ties.

While the chal­lenges of de­vel­op­ing CRISPR tech­nol­o­gy over the next decade will un­doubt­ed­ly be pre­dom­i­nant­ly sci­en­tif­ic and tech­no­log­i­cal, eco­nom­ic re­al­i­ties man­date that own­er­ship con­sid­er­a­tions will have a prac­ti­cal ef­fect on what com­pa­nies com­mer­cial­ize var­i­ous as­pects of the tech­nol­o­gy, where this com­mer­cial­iza­tion oc­curs, and the li­cens­ing costs and com­plex­i­ties that arise in the process.

Voting in the 2020 election (AP Images)

The right to vote is fun­da­men­tal — a let­ter from biotech­nol­o­gy in­dus­try lead­ers

Biotech Voices is a collection of exclusive opinion editorials from some of the leading voices in biopharma on the biggest industry questions today. Think you have a voice that should be heard? Reach out to senior editors Kyle Blankenship and Amber Tong.

We oppose all attempts to introduce laws that reduce the rights of US citizens to vote or that restrict them from exercising that right. The right to vote is fundamental to democracy. States that have enacted, or are proposing to enact, legislation to restrict voting are undermining our democracy and posing a threat to our nation. As leaders of the life sciences industry, we stand for what we believe is right for our country, our enterprises, our employees and those who benefit from our work. We join the first groups of business leaders who have challenged these laws and will continue to make our collective voices heard on this matter.

BY­OD Best Prac­tices: How Mo­bile De­vice Strat­e­gy Leads to More Pa­tient-Cen­tric Clin­i­cal Tri­als

Some of the most time- and cost-consuming components of clinical research center on gathering, analyzing, and reporting data. To improve efficiency, many clinical trial sponsors have shifted to electronic clinical outcome assessments (eCOA), including electronic patient-reported outcome (ePRO) tools.

In most cases, patients enter data using apps installed on provisioned devices. At a time when 81% of Americans own a smartphone, why not use the device they rely on every day?

Pascal Soriot (AstraZeneca via YouTube)

Af­ter be­ing goad­ed to sell the com­pa­ny, Alex­ion's CEO set some am­bi­tious new goals for in­vestors. Then Pas­cal So­ri­ot came call­ing

Back in the spring of 2020, Alexion $ALXN CEO Ludwig Hantson was under considerable pressure to perform and had been for months. Elliott Advisers had been applying some high public heat on the biotech’s numbers. And in reaching out to some major stockholders, one thread of advice came through loud and clear: Sell the company or do something dramatic to change the narrative.

In the words of the rather dry SEC filing that offers a detailed backgrounder on the buyout deal, Alexion stated: ‘During the summer and fall of 2020, Alexion also continued to engage with its stockholders, and in these interactions, several stockholders encouraged the company to explore strategic alternatives.’

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Near­ly a year af­ter Au­den­tes' gene ther­a­py deaths, the tri­al con­tin­ues. What hap­pened re­mains a mys­tery

Natalie Holles was five months into her tenure as Audentes CEO and working to smooth out a $3 billion merger when the world crashed in.

Holles and her team received word on the morning of May 5 that, hours before, a patient died in a trial for their lead gene therapy. They went into triage mode, alerting the FDA, calling trial investigators to begin to understand what happened, and, the next day, writing a letter to alert the patient community so they would be the first to know. “We wanted to be as forthright and transparent as possible,” Holles told me late last month.

The brief letter noted two other patients also suffered severe reactions after receiving a high dose of the therapy and were undergoing treatment. One died a month and a half later, at which point news of the deaths became public, jolting an emergent gene therapy field and raising questions about the safety of the high doses Audentes and others were now using. The third patient died in August.

“It was deeply saddening,” Holles said. “But I was — we were — resolute and determined to understand what happened and learn from it and get back on track.”

Eleven months have now passed since the first death and the therapy, a potential cure for a rare and fatal muscle-wasting disease called X-linked myotubular myopathy, is back on track, the FDA having cleared the company to resume dosing at a lower level. Audentes itself is no more; last month, Japanese pharma giant Astellas announced it had completed working out the kinks of the $3 billion merger and had restructured and rebranded the subsidiary as Astellas Gene Therapies. Holles, having successfully steered both efforts, departed.

Still, questions about precisely what led to the deaths of the 3 boys still linger. Trial investigators released key details about the case last August and December, pointing to a biological landmine that Audentes could not have seen coming — a moment of profound medical misfortune. In an emerging field that’s promised cures for devastating diseases but also seen its share of safety setbacks, the cases provided a cautionary tale.

Audentes “contributed in a positive way by giving a painful but important example for others to look at and learn from,” Terry Flotte, dean of the UMass School of Medicine and editor of the journal Human Gene Therapy, told me. “I can’t see anything they did wrong.”

Yet some researchers say they’re still waiting on Astellas to release more data. The company has yet to publish a full paper detailing what happened, nor have they indicated that they will. In the meantime, it remains unclear what triggered the events and how to prevent them in the future.

“Since Audentes was the first one and we don’t have additional information, we’re kind of in a holding pattern, flying around, waiting to figure out how to land our vehicles,” said Jude Samulski, professor of pharmacology at UNC’s Gene Therapy Center and CSO of the gene therapy biotech AskBio, now a subsidiary of Bayer.

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Launched by MIT grads, a small start­up gets $20M to back a ro­bot­ics rev­o­lu­tion in cell ther­a­py man­u­fac­tur­ing

As co-director of an experimental cellular therapy process development and manufacturing group at UCSF specializing in T cell therapies for autoimmune conditions, Jonathan Esensten has learned a lot about the challenges involved when his group hand-fashions a cell therapy. Esensten — who was a postdoc in Wendell Lim’s lab and counts the legendary Jeffrey Bluestone as a mentor — gives them all high marks at being great at what they do, but time and again there are variations in the treatments they construct.

Anand Shah (FDA)

For­mer head of FDA’s med­ical and sci­en­tif­ic af­fairs on Covid: ‘FDA has nev­er been test­ed like this’

Anand Shah has served the American public in a unique way, crisscrossing over the last two administrations between serving as an attending radiation oncologist focused on prostate cancer at NIH, serving as CMO at the Center for Medicare and Medicaid Innovation, and most recently, leading the FDA’s operations on medical and scientific affairs from within the commissioner’s office.

Shah, who stepped down from the FDA in January, caught up with Endpoints News in a phone interview on Tuesday afternoon, offering his thoughts on the agency’s latest decision to pause the J&J vaccinations in the US, and reflecting on his time at an agency during this once-in-a-lifetime pandemic.

UP­DAT­ED: J&J paus­es vac­cine roll­out as feds probe rare cas­es of blood clots

The FDA and CDC have jointly decided to stop administering J&J’s Covid-19 vaccine after reviewing data involving six reported US cases of a rare and severe type of blood clot in individuals after receiving the vaccine.

CDC will convene a meeting of its Advisory Committee on Immunization Practices on Wednesday to further review these cases and assess their potential significance. “FDA will review that analysis as it also investigates these cases. Until that process is complete, we are recommending a pause in the use of this vaccine out of an abundance of caution,” Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research and Anne Schuchat, Principal Deputy Director of the CDC, said in a joint statement Tuesday morning.

Patrizia Cavazzoni, new CDER director

Pa­trizia Cavaz­zoni named per­ma­nent di­rec­tor of CDER, adding to ques­tions around where Wood­cock will end up

Patrizia Cavazzoni on Monday became the permanent director of the FDA’s Center for Drug Evaluation and Research, which puts to rest the idea that Janet Woodcock, Cavazzoni’s predecessor, might return to lead CDER if she isn’t made permanent commissioner.

Woodcock, who’s currently serving as acting commissioner and principal medical advisor to the commissioner, a position she was detailed to last year, may not make the move to permanent commissioner because of lingering questions from Senate Democrats. She previously served as director of CDER since 1994. Cavazzoni took over as acting director of CDER when Woodcock moved over to Operation Warp Speed to run the therapeutics side of the Trump-era program.

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Barbara Weber, Tango Therapeutics CEO (Tango)

It takes two to Tan­go: The biotech us­ing CRISPR to dis­cov­er new can­cer gene tar­gets rides a $353M SPAC deal to Nas­daq

Editor’s note: Interested in following biopharma’s fast-paced IPO market? You can bookmark our IPO Tracker here.

The latest biotech-SPAC deal has arrived, and it’s dancing its way to Nasdaq to the tune of several hundred million dollars.

Tango Therapeutics and its CRISPR-focused search for new cancer genes is reverse merging with Boxer Capital’s blank-check company, the biotech announced Wednesday morning. With a spotlight on three lead programs, Tango expects total proceeds to equal about $353 million in the deal, which includes the roughly $167 million held in the SPAC and an additional $186 million in PIPE financing.