The con­tin­u­ing CRISPR patent saga

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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.

The Fac­tors Dri­ving a Rapid Evo­lu­tion of Gene & Cell Ther­a­py and CAR-T Clin­i­cal Re­search in APAC

APAC is the fastest growing region globally for cell & gene therapy trials representing more than a third of all cell & gene studies globally, with China leading in the region. 

APAC is the leading location globally for CAR-T trials with China attracting ~60% of all CAR-T trials globally between 2015-2022. The number of CAR-T trials initiated by Western companies has rapidly increased in recent years (current CAGR of about 60%), with multiple targets being explored including CD19, CD20, CD22, BCMA, CD30, CD123, CD33, CD38, and CD138.

The End­points 11; blue­bird's $3M gene ther­a­py; Bio­gen tout new neu­ro da­ta; Harsh re­views for can­cer drugs; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

Reading about John Carroll’s pick of biotech’s most promising startups has become a treasured tradition. If you ever get curious about previous classes of the Endpoints 11, you can find all of them (plus a number of our other regular specials) here.

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EMA warns of short­ages of two Boehringer heart drugs due to a spike in de­mand

The EMA is putting EU member states on alert over the shortage of two drugs that counter heart attacks due to an uptick in demand.

On Friday, the EMA sent out a warning that two Boehringer Ingelheim drugs are experiencing a shortage: Actilyse and Metalyse. The drugs are used as emergency treatments for adults experiencing acute myocardial infarction, or a heart attack, by dissolving blood clots that have formed in the blood vessels.

The End­points 11: The top pri­vate biotechs in pur­suit of new drugs. Push­ing the en­ve­lope with pow­er­ful new tech­nolo­gies

Right around the beginning of the year, we got a close-up look at what happens after a boom ripples through biotech. The crash of life sciences stocks in Q1 was heard around the world.

In the months since, we’ve seen the natural Darwinian down cycle take effect. Reverse mergers made a comeback, with more burned out shells to go public at a time IPOs and road shows are out of favor. And no doubt some of the more recent arrivals on the investing side of the business are finding greener pastures.

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Solicitor General Elizabeth Prelogar

Should SCO­TUS hear Am­gen's Repatha case? So­lic­i­tor gen­er­al says no

Back in April, Amgen said it was encouraged by the solicitor general’s anticipated review of its Supreme Court petition to rehear a Repatha patent case. They’re likely much less optimistic about the outcome now.

Solicitor General Elizabeth Prelogar wrote in a recent 27-page brief that Amgen’s arguments “lack merit and further review is not warranted.”

The case traces back to a suit filed in 2014 against Sanofi and Regeneron’s Praluent, which ended up beating Amgen’s PCSK9 blockbuster Repatha to market by a month just a year later.

As­traZeneca, Mer­ck cull one Lyn­parza in­di­ca­tion in heav­i­ly pre­treat­ed ovar­i­an can­cer pa­tients

Just one day after blockbuster Lynparza got access to another indication in China, its Big Pharma owners have decided to withdraw it in certain patients after reviewing Phase III data.

The two companies that work together on Lynparza decided to recall one of the indications several weeks ago in a specific type of ovarian cancer, Lynparza’s first indication when it was first FDA-approved in 2014. Initial data showed that rates of overall survival in patients with at least three rounds of chemo before getting on the PARP inhibitor were lower than in patients with less previous chemo treatment.

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Fu­ji­film con­tin­ues CD­MO ex­pan­sion, break­ing ground on $435M UK site

Fujifilm’s CDMO arm, Fujifilm Diosynth, has been on a roll this month as the company has recently broken ground on a major project in Europe and it appears to be keeping up the momentum.

Fujifilm Diosynth announced that it has kicked off an expansion project for its microbial manufacturing facility at its campus in the town of Billingham, UK, in the northeast of England.

The 20,000 square-foot, £400 million ($435 million) expansion will add clean rooms, purification suites and a packing area along with more space for the manufacturing itself.

An­oth­er Cipla site lands a Form 483 over clean­ing is­sues and QC con­trols

A Cipla drug manufacturing site in India has once again landed in the crosshairs of FDA inspectors.

The facility in question is Cipla’s drug manufacturing facility in the village of Verna, in the state of Goa in India’s southwest. In a sign that foreign inspections might ramp up again, the FDA’s visit from Aug. 16 to Aug. 22 uncovered six observations.

The 11-page report noted that environmental monitoring at the site did not properly ensure that microbial contaminants were not making any impact in the aseptic filling areas. It also found that procedures meant to stop microbial contamination were not adequately conducted in aseptic areas of the facility.

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FDA ad­comm takes down Se­cu­ra Bio's leukemia drug af­ter fi­nal tri­al re­sults show po­ten­tial OS detri­ment

The FDA’s Oncologic Drugs Advisory Committee on Friday voted 8-4 against the benefit-risk profile of Secura Bio’s PI3K inhibitor Copiktra (duvelisib), which won approval in September 2018 as a third-line treatment for relapsed or refractory CLL or SLL, but updated pivotal trial results raised safety questions.

In addition to the serious and fatal toxicities of duvelisib, FDA speakers at the ODAC meeting pointed to an evolved treatment landscape for CLL and SLL, with targeted BTK or BCL2 inhibitors (front-line or second-line), and data pointing to a “potential detriment” in overall survival for duvelisib. But some ODAC members noted that the detriment was likely small and that there is some efficacy even as the data are difficult to interpret.

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