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.

M&A: a crit­i­cal dri­ver for sus­tain­able top-line growth in health­care

2021 saw a record $600B in healthcare M&A activity. In 2022, there is an anticipated slowdown in activity, however, M&A prospects remain strong in the medium to long-term. What are future growth drivers for the healthcare sector? Where might we see innovations that drive M&A? RBC’s Andrew Callaway, Global Head, Healthcare Investment Banking discusses with Vito Sperduto, Global Co-Head, M&A.

15 LGBTQ lead­ers in bio­phar­ma; Paul Stof­fels’ Gala­pa­gos re­vamp; As­traZeneca catch­es up in AT­TR; 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.

A return to in-person conferences also marks a return to on-the-ground reporting. My colleagues Beth Synder Bulik and Nicole DeFeudis were on-site at Cannes Lions, bringing live coverage of pharma’s presence at the ad festival — accompanied by photos from Clara Bui, our virtual producer, that bring you right to the scene. You can find a recap (and links to all the stories) below.

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AstraZeneca's new Evusheld direct to consumer campaign aims to reach more immunocompromised patients.

As­traZeneca de­buts first con­sumer cam­paign for its Covid-19 pro­phy­lac­tic Evusheld — and a first for EUA drugs

AstraZeneca’s first consumer ad for Evusheld is also a first for drugs that have been granted emergency use authorizations during the pandemic.

The first DTC ad for a medicine under emergency approval, the Evusheld campaign launching this week aims to raise awareness among immunocompromised patients — and spur more use.

Evusheld nabbed emergency authorization in December, however, despite millions of immunocompromised people looking for a solution and now more widespread availability of the drug.

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De­spite a slow start to the year for deals, PwC pre­dicts a flur­ry of ac­tiv­i­ty com­ing up

Despite whispers of a busy year for M&A, deal activity in the pharma space is actually down 30% on a semi-annualized basis, according to PwC’s latest report on deal activity. But don’t rule out larger deals in the second half of the year, the consultants said.

PwC pharmaceutical and life sciences consulting solutions leader Glenn Hunzinger expects to see Big Pharma companies picking up earlier stage companies to try and fill pipeline gaps ahead of a slew of big patent cliffs. Though a bear market continues to maul the biotech sector, Hunzinger said recent deals indicate that pharma companies are still paying above current trading prices.

Abortion-rights protesters regroup and protest following Supreme Court's decision to overturn Roe v. Wade. (AP Photo/Gemunu Amarasinghe)

Fol­low­ing SCO­TUS de­ci­sion to over­turn abor­tion pro­tec­tions, AG Gar­land says states can't ban the abor­tion pill

Following the Supreme Court’s historic decision on Friday to overturn Americans’ constitutional right to an abortion after almost 50 years, Attorney General Merrick Garland sought to somewhat reassure women that states will not be able to ban the prescription drug sometimes used for abortions.

Following the decision, the New England Journal of Medicine also published an editorial strongly condemning the reversal, saying it “serves American families poorly, putting their health, safety, finances, and futures at risk.”

Joe Wiley, Amryt Pharma CEO

Am­ryt Phar­ma sub­mits a for­mal dis­pute res­o­lu­tion to the FDA over re­ject­ed skin dis­ease drug

The story of Amryt Pharma’s candidate for the genetic skin condition epidermolysis bullosa, or EB, will soon enter another chapter.

After the Irish drugmaker’s candidate, dubbed Oleogel-S10 and marketed as Filsuvez, was handed a CRL earlier this year, the company announced in a press release that it plans to submit a formal dispute resolution request for the company’s NDA for Oleogel-S10.

GSK says its drug for chron­ic hep B could ‘lead to a func­tion­al cure’ — but will it be alone or in com­bi­na­tion?

GSK, newly branded and soon-to-be demerged, shared interim results from its Phase II trial on its chronic hepatitis B treatment, one that it says has the “potential to lead to a functional cure.”

At a presentation at the EASL International Liver Congress, GSK shared that in around 450 patients who received its hep B drug bepirovirsen for 24 weeks, just under 30% had hepatitis B surface antigen and viral DNA levels that were too low to detect.

FDA un­veils new draft guid­ance to help with oligonu­cleotide ther­a­peu­tics de­vel­op­ment

While oligonucleotides, a wide variety of synthetically modified RNA or RNA/DNA hybrids that bind to a target RNA sequence to alter RNA and/or protein expression, have been winning approvals in recent years (e.g. Novartis’ cholesterol drug Leqvio), the regulatory agency is offering new draft guidance for those looking to follow a similar path.

The non-binding guidance, titled “Clinical Pharmacology Considerations for the Development of Oligonucleotide Therapeutics Guidance for Industry” deals with pharmacokinetic, pharmacodynamic, and safety assessments required as part of oligonucleotide therapeutics R&D.

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Kelly Martin, Radius Health CEO

VC firms take os­teo­poro­sis drug­mak­er Ra­dius Health pri­vate for al­most $900M

After attacks from activist investors and disappointing returns on share prices, Radius Health has now agreed to new ownership, a direction resulting in leaving the Nasdaq.

Radius Health, a biotech out of Massachusetts with one approved product in its arsenal, announced Thursday morning that it agreed to be acquired by two VC firms: Gurnet Point Capital and Patient Square Capital. The deal, worth around $890 million, will include debt assumption and the payout of $1 CVR per share for investors. And on top of that, OrbiMed is providing debt financing.