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.

ZS Per­spec­tive: 3 Pre­dic­tions on the Fu­ture of Cell & Gene Ther­a­pies

The field of cell and gene therapies (C&GTs) has seen a renaissance, with first generation commercial therapies such as Kymriah, Yescarta, and Luxturna laying the groundwork for an incoming wave of potentially transformative C&GTs that aim to address diverse disease areas. With this renaissance comes several potential opportunities, of which we discuss three predictions below.

Allogenic Natural Killer (NK) Cells have the potential to displace current Cell Therapies in oncology if proven durable.

Despite being early in development, Allogenic NKs are proving to be an attractive new treatment paradigm in oncology. The question of durability of response with allogenic therapies is still an unknown. Fate Therapeutics’ recent phase 1 data for FT516 showed relatively quicker relapses vs already approved autologous CAR-Ts. However, other manufacturers, like Allogene for their allogenic CAR-T therapy ALLO-501A, are exploring novel lymphodepletion approaches to improve persistence of allogenic cells. Nevertheless, allogenic NKs demonstrate a strong value proposition relative to their T cell counterparts due to comparable response rates (so far) combined with the added advantage of a significantly safer AE profile. Specifically, little to no risk of graft versus host disease (GvHD), cytotoxic release syndrome (CRS), and neurotoxicity (NT) have been seen so far with allogenic NK cells (Fig. 1). In addition, being able to harness an allogenic cell source gives way to operational advantages as “off-the-shelf” products provide improved turnaround time (TAT), scalability, and potentially reduced cost. NKs are currently in development for a variety of overlapping hematological indications with chimeric antigen receptor T cells (CAR-Ts) today, and the question remains to what extent they will disrupt the current cell therapy landscape. Click for more details.

Graphic: Kathy Wong for Endpoints News

What kind of biotech start­up wins a $3B syn­di­cate, woos a gallery of mar­quee sci­en­tists and re­cruits GSK's Hal Bar­ron as CEO in a stun­ner? Let Rick Klaus­ner ex­plain

It started with a question about a lifetime’s dream on a walk with tech investor Yuri Milner.

At the beginning of the great pandemic, former NCI chief and inveterate biotech entrepreneur Rick Klausner and the Facebook billionaire would traipse Los Altos Hills in Silicon Valley Saturday mornings and talk about ideas.

Milner’s question on one of those mornings on foot: “What do you want to do?”

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Hal Barron, Endpoints UKBIO20 (Jeff Rumans)

'Al­tos was re­al­ly a once-in-a-life­time op­por­tu­ni­ty': Hal Bar­ron re­flects on his big move

By all accounts, Hal Barron had one of the best jobs in Big Pharma R&D. He made more than $11 million in 2020, once again reaping more than his boss, Emma Walmsley, who always championed him at every opportunity. And he oversaw a global R&D effort that struck a variety of big-dollar deals for oncology, neurodegeneration and more.

Sure, the critics never let up about what they saw as a rather uninspiring late-stage pipeline, where the rubber hits the road in the Big Pharma world’s hunt for the next big near-term blockbuster, but the in-house reviews were stellar. And Barron was firmly focused on bringing up the success rate in clinical trials, holding out for the big rewards of moving the dial from an average 10% success rate to 20%.

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Executive Director of the EMA Emer Cooke (AP Photo/Geert Vanden Wijngaert)

Eu­ro­pean Par­lia­ment signs off on strength­en­ing drug reg­u­la­tor's abil­i­ty to tack­le short­ages

The European Parliament on Thursday endorsed a plan to increase the powers of the European Medicines Agency, which will be better equipped to monitor and mitigate shortages of drugs and medical devices.

By a vote of 655 to 31, parliament signed off on a provisional agreement reached with the European Council from last October, in which the EMA will create two shortage steering groups (one for drugs, the other for devices), a new European Shortages Monitoring Platform to facilitate data collection and increase transparency, and on funding for the work of the steering groups, task force, working parties and expert panels that are to be established.

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FDA+ roundup: FDA's neu­ro­science deputy de­parts amid on­go­ing Aduhelm in­ves­ti­ga­tions; Califf on the ropes?

Amid increased scrutiny into the close ties between FDA and Biogen prior to the controversial accelerated approval of Aduhelm, the deputy director of the FDA’s office of neuroscience has called it quits after more than two decades at the agency.

Eric Bastings will now take over as VP of development strategy at Ionis Pharmaceuticals, the company said Wednesday, where he will provide senior clinical and regulatory leadership in support of Ionis’ pipeline.

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Sec­ondary patents prove to be key in biosim­i­lar block­ing strate­gies, re­searchers find

While the US biosimilars industry has generally been a disappointment since its inception, with FDA approving 33 biosimilars since 2015, just a fraction of those have immediately followed their approvals with launches. And more than a handful of biosimilars for two of the biggest blockbusters of all time — AbbVie’s Humira and Amgen’s Enbrel — remain approved by FDA but still have not launched because of legal settlements.

Hal Barron (GSK via YouTube)

GSK R&D chief Hal Bar­ron jumps ship to run a $3B biotech start­up, Tony Wood tapped to re­place him

In a stunning switch, GlaxoSmithKline put out word early Wednesday that R&D chief Hal Barron is exiting the company after 4 years — a relatively brief run for the man chosen by CEO Emma Walmsley in late 2017 to turn around the slow-footed pharma giant.

Barron is being replaced by Tony Wood, a close associate of Barron’s who’s taking one of the top jobs in Big Pharma R&D. He’ll be closer to home, though, for GSK. Barron has been running a UK and Philadelphia-based research organization from his perch in San Francisco.

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Troy Wilson, Kura CEO

FDA lifts par­tial hold on Ku­ra's Phase Ib AML pro­gram as biotech re­dou­bles mit­i­ga­tion ef­forts

Kura Oncology is clear to resume studies for its early-stage leukemia program after the FDA lifted a clinical hold Thursday afternoon.

Regulators had placed the hold on a Phase Ib study of KO-539, an experimental oral treatment for some genetic subsets of acute myeloid leukemia last November after a patient died while taking the drug. Kura expects to begin enrolling patients again imminently, CEO Troy Wilson told Endpoints News.

A Sen­ate bill wants to even an 'un­lev­el play­ing field' for do­mes­tic, for­eign in­spec­tion drop-ins amid back­log

Amid geopolitical tensions between the US and China, two Republican senators are calling for a bill that would aim to strike a balance on domestic and foreign inspection requirements from the FDA.

Sens. Mike Braun (R-IN) and Joni Ernst (R-IA) have penned a bill called the Creating Efficiency in Foreign Inspections Act. It contains a bit of rhetoric, highlighting “communist China” not once, but twice in the release, but states that the goal is to even the playing field between foreign and American manufacturers.

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