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.

Health­care Dis­par­i­ties and Sick­le Cell Dis­ease

In the complicated U.S. healthcare system, navigating a serious illness such as cancer or heart disease can be remarkably challenging for patients and caregivers. When that illness is classified as a rare disease, those challenges can become even more acute. And when that rare disease occurs in a population that experiences health disparities, such as people with sickle cell disease (SCD) who are primarily Black and Latino, challenges can become almost insurmountable.

Jacob Van Naarden (Eli Lilly)

Ex­clu­sives: Eli Lil­ly out to crash the megablock­buster PD-(L)1 par­ty with 'dis­rup­tive' pric­ing; re­veals can­cer biotech buy­out

It’s taken 7 years, but Eli Lilly is promising to finally start hammering the small and affluent PD-(L)1 club with a “disruptive” pricing strategy for their checkpoint therapy allied with China’s Innovent.

Lilly in-licensed global rights to sintilimab a year ago, building on the China alliance they have with Innovent. That cost the pharma giant $200 million in cash upfront, which they plan to capitalize on now with a long-awaited plan to bust up the high-price market in lung cancer and other cancers that have created a market worth tens of billions of dollars.

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David Meek, new Mirati CEO (Marlene Awaad/Bloomberg via Getty Images)

Fresh off Fer­Gene's melt­down, David Meek takes over at Mi­rati with lead KRAS drug rac­ing to an ap­proval

In the insular world of biotech, a spectacular failure can sometimes stay on any executive’s record for a long time. But for David Meek, the man at the helm of FerGene’s recent implosion, two questionable exits made way for what could be an excellent rebound.

Meek, most recently FerGene’s CEO and a past head at Ipsen, has become CEO at Mirati Therapeutics, taking the reins from founding CEO Charles Baum, who will step over into the role of president and head of R&D, according to a release.

FDA hands ac­cel­er­at­ed nod to Seagen, Gen­mab's so­lo ADC in cer­vi­cal can­cer, but com­bo stud­ies look even more promis­ing

Biopharma’s resident antibody-drug conjugate expert Seagen has scored a clutch of oncology approvals in recent years, finding gold in what are known as “third-gen” ADCs. Now, another of their partnered conjugates is ready for prime time.

The FDA on Monday handed an accelerated approval to Seagen and Genmab’s Tivdak (tisotumab vedotin-tftv, or “TV”) in second-line patients with recurrent or metastatic cervical cancer who previously progressed after chemotherapy rather than PD-(L)1 systemic therapy, the companies said in a release.

Dave Lennon, former president of Novartis Gene Therapies

Zol­gens­ma patent spat brews be­tween No­var­tis and Re­genxbio as top No­var­tis gene ther­a­py ex­ec de­parts

Regenxbio, a small licensor of gene therapy viral vectors spun out from the University of Pennsylvania, is now finding itself in the middle of some major league patent fights.

In addition to a patent suit with Sarepta Therapeutics from last September, Novartis, is now trying to push its smaller partner out of the way. The Swiss biopharma licensed Regenxbio’s AAV9 vector for its $2.1 million spinal muscular atrophy therapy Zolgensma.

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Volker Wagner (L) and Jeff Legos

As Bay­er, No­var­tis stack up their ra­dio­phar­ma­ceu­ti­cal da­ta at #ES­MO21, a key de­bate takes shape

Ten years ago, a small Norwegian biotech by the name of Algeta showed up at ESMO — then the European Multidisciplinary Cancer Conference 2011 — and declared that its Bayer-partnered targeted radionuclide therapy, radium-223 chloride, boosted the overall survival of castration-resistant prostate cancer patients with symptomatic bone metastases.

In a Phase III study dubbed ALSYMPCA, patients who were treated with radium-223 chloride lived a median of 14 months compared to 11.2 months. The FDA would stamp an approval on it based on those data two years later, after Bayer snapped up Algeta and christened the drug Xofigo.

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Rafaèle Tordjman (Jeito Capital)

Con­ti­nu­ity and di­ver­si­ty: Rafaèle Tord­j­man's women-led VC firm tops out first fund at $630M

For a first-time fund, Jeito Capital talks a lot about continuity.

Rafaèle Tordjman had spotlighted that concept ever since she started building the firm in 2018, promising to go the extra mile(s) with biotech entrepreneurs while pushing them to reach patients faster.

Coincidentally, the lack of continuity was one of the sore spots listed in a report about the European healthcare sector published that same year by the European Investment Bank — whose fund is one of the LPs, alongside the American pension fund Teacher Retirement System of Texas and Singapore’s Temasek, to help Jeito close its first fund at $630 million (€534 million). As previously reported, Sanofi had chimed in €50 million, marking its first investment in a French life sciences fund.

Mi­rati tri­umphs again in KRAS-mu­tat­ed lung can­cer with a close­ly watched FDA fil­ing now in the cards

After a busy weekend at #ESMO21, which included a big readout for its KRAS drug adagrasib in colon cancer, Mirati Therapeutics is ready to keep the pressure on competitor Amgen with lung cancer data that will undergird an upcoming filing.

In topline results from a Phase II cohort of its KRYSTAL-1 study, adagrasib posted a response rate of 43% in second-line-or-later patients with metastatic non-small cell lung cancer containing a KRAS-G12C mutation, Mirati said Monday.

As­traZeneca, Dai­ichi Sanky­o's ADC En­her­tu blows away Roche's Kad­cy­la in sec­ond-line ad­vanced breast can­cer

AstraZeneca and Japanese drugmaker Daiichi Sankyo think they’ve struck gold with their next-gen ADC drug Enhertu, which has shown some striking data in late-stage breast cancer trials and early solid tumor tests. Getting into earlier patients is now the goal, starting with Enhertu’s complete walkover of a Roche drug in second-line breast cancer revealed Saturday.

Enhertu cut the risk of disease progression or death by a whopping 72% (p=<0.0001) compared with Roche’s ADC Kadcyla in second-line unresectable and/or metastatic HER2-positive breast cancer patients who had previously undergone treatment with a Herceptin-chemo combo, according to interim data from the Phase III DESTINY-Breast03 head-to-head study presented at this weekend’s #ESMO21.

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