Editing the future: A brief introduction to CRISPR

by Allen & Overy LLP

Allen & Overy LLP

​For those with an interest in life sciences, the rise to prominence of CRISPR has been impossible to ignore.  It seems a day does not go by without the discovery of a new application for the technology or a new variant of one of the essential components of the system, or a yet another twist in the on-going patent dispute between the would-be inventors of the foundational IP. 

On 15 February 2017 the USPTO’s Patent Trial and Appeal Board (PTAB) handed down its decision in the interference proceedings between the Broad Institute of MIT and Harvard (the Broad) and the University of California Berkeley (UCB), discussed further below.  This decision represents perhaps the most significant event in the legal and licensing side of the CRISPR story since the Broad’s key patents were granted ahead of those sought by UCB.

For those not closely following the CRISPR landscape, the pace of developments can be overwhelming and, for those looking to catch up on the latest in the CRISPR field, it can be difficult to know where to look.  This article aims to set out the basic principles behind the technology, why it has taken the scientific world by storm and outline why the patent dispute matters.

What is CRISPR?

CRISPR is short for Clustered Regularly Interspaced Short Palindromic Repeats, a system of adaptive immunity first characterised in bacteria and archaea which has now been harnessed by the scientific community for a host of applications.  Its most well-known application is to facilitate accurate and targeted cutting of DNA to enable editing of genes.

Although there are many variants of the CRISPR system, which differ subtly but importantly from species to species, the first and still most widely used variety is the CRISPR/Cas9 system, which is derived from proteins found in the bacterium Streptococcus pyogenes.  Since then many more CRISPR systems have been discovered and are in the process of being characterised, some of the most promising being the Cpf1 and C2c2 systems.

The power of the CRISPR system lies in the ease with which it can target regions or genes of interest in the genome of target cells.  Unlike existing gene manipulation techniques (i.e. Zinc Finger Nucleases and TALENs), which require entire bespoke proteins to be constructed to interact with a particular target sequence, the CRISPR system simply requires the synthesis of a different 20 base pair RNA guide, which is fed into the relevant protein complex and guides it to the specific target site.  There, the endonuclease activity of the Cas protein (e.g. Cas9) causes a double stranded break which researchers can then take advantage of to remove or insert genetic material, through DNA repair mechanisms such as non-homologous end joining or homology directed repair. 

The CRISPR system had first begun to be characterised in the 80s, but its potential was not realised until 2012 when Jennifer Doudna and Emmanuelle Charpentier developed a method to simplify the RNA guide component of the CRISPR/Cas complex.  Later Feng Zhang and George Church’s labs, separately but simultaneously (in the same issue of Science), were the first groups to publish a method for its use in eukaryotic cells.  This was followed very shortly after by the publication of independent work by other labs, including those of Jennifer Doudna and Jin-Soo Kim, which also described the successful use of the CRISPR system in eukaryotes.

What can CRISPR do?

It is difficult to overstate the realm of potential applications for CRISPR based technology.  Although much of the media coverage to date has tended to focus on the potential medical applications for CRISPR technology, equally there is a wealth of potential applications in the agricultural and bioindustrial sectors.  CRISPR could potentially revolutionise any industry in which molecular biology and genetic technology plays a part. 

In particular, the convergence of the rise of CRISPR technology and personalised medicine is a perfect match – CRISPR enables the accurate and (relatively) inexpensive editing of nucleic acids on a scale which was unimaginable using the previous generation of gene editing techniques.  One of the most exciting early areas of research is in using CRISPR to create “killer” T-cells specifically targeted to antigens displayed by a particular patient’s cancer.  Indeed, a clinical trial involving CRISPR edited T-cells in cancer therapy has already been commenced in China and a similar trial has been approved in the US. 

Genetic modification has never been far from controversy and never has it been so easy to do, or potentially so easy to abuse.  And as much as the power and ease of use of CRISPR technology is a boon to research and development, there is a corresponding risk and concern that such technology may be abused and misused.   

The biggest concern expressed in industry is over the potential for CRISPR to be used to make modifications to the germ line of organisms – i.e. gene edits not to the somatic, adult cells of an organism (which will only affect that organism), but to the reproductive cells, such that those modifications will be passed down to offspring of the organism (and potentially their offspring, and so on down the line).  The spectre of eugenics and uncertainty of the long term consequences of such germ line modification is unlikely to be dispelled any time soon.

Who are the key players?

As with any new transformative technology, questions of access, control, inventorship and ownership are often central, and CRISPR is no exception.  Major patent office disputes are currently underway on both sides of the Atlantic, the outcome of which could have huge implications for the future direction of the technology and the significant economic interests in play.

The protagonists are some of the leading lights in the scientific world today and the powerful academic institutions from which they hail.  They can roughly be divided into one of three camps:

  • Jennifer Doudna, UCB and spin-out companies Caribou Biosciences and Intellia Therapeutics.  Together with the Charpentier group the Doudna group co‑owns the first filed patent applications in the US and Europe in relation to the key components of the CRISPR/Cas9 system currently in use, however their key patents are yet to be granted.

  • Emmanuelle Charpentier, the University of Vienna and spin-out companies CRISPR Therapeutics, ERS Genomics and joint venture (with Bayer) Casebia Therapeutics.

  • Feng Zhang, MIT, Harvard, the Broad Institute and spin-out company Editas Medicine.  The Zhang group owns a range of patents and patent applications concerning the CRISPR process, including granted patents in the US and Europe for the fundamental CRISPR technology in eukaryotes.

Each of these camps has partnered variously with big pharma, venture capitalists and fellow disruptive biotech start-ups in a complex series of exclusive licensing deals, joint ventures and strategic collaborations to commercialise the CRISPR/Cas system.  Each has received substantial funding through early funding rounds and partnerships, and each undertook an IPO in 2016.  Even with the ongoing patent dispute, they represent the vanguard of CRISPR companies, given their stake in the patent dispute and the reputation and expertise of their big name founders.  Leading companies such as Novartis, Regeneron, Bayer and Monsanto have already aligned themselves with one side or the other, and it seems merely a matter of time before others enter the CRISPR field.

Importantly, the Doudna and Charpentier camps share the same estate of foundational CRISPR IP, whereas the Zhang/Broad camp holds a separate, competing portfolio.  This forms the basis of the patent dispute around the globe. On 16 December 2016, the Doudna and Charpentier camps formalised their alliance, signing a global cross-licensing and patent prosecution co-operation agreement.

Why this patent dispute matters

Thus far, most of the focus on the CRISPR patent dispute has been on the US dispute between UCB and the Broad Institute in the interference action before the PTAB.  Commentators have sought to use the PTAB’s 15 February 2017 decision to draw conclusions about the balance of power in the CRISPR dispute more broadly and the future direction of the technology.  

Pursuant to a motion brought by the Broad on 23 May 2016, the PTAB found that there is no interference-in-fact between the Broad’s and UCB’s relevant CRISPR patents and applications, effectively bringing the interference proceedings to an end, subject to any appeal by UCB.  This means that the PTAB considered that the respective inventions claimed by UCB and the Broad are sufficiently different and distinct from one another as to be separately patentable.  The claims of UCB’s patent application cover the use of the CRISPR/Cas9 system in any setting, whilst the claims of the Broad’s patents are limited to the system’s use in eukaryotic cells.  In a separate article, we examine the PTAB decision in detail and its ramifications in the short, medium and long term for the parties and their current and prospective licensees and collaborators.  In particular, we will consider how useful the PTAB decision really is as an indication of how other courts and tribunals may view the patents and the parties’ arguments.

However, whilst the position of the parties’ patents in the US is undoubtedly of key significance, it must be remembered that, in parallel, equally important prosecution and opposition proceedings have been in progress before the European Patent Office (EPO) and a key UCB patent is on the verge of being granted in Europe (Case No. EP2800811).  With so many granted and pending patents, at different stages in prosecution or opposition around the world, and subject to different patent law systems in different jurisdictions, we expect the patent landscape will continue to shift for some time yet.

What is clear, however, is that whilst the Harvard/Broad/MIT camp was not first off the line, in the sense that UCB was first to file, they have since more than caught up, by pursuing a strategy of accelerated patent prosecution and aggressive filing. 

With good reason, life sciences industry press, companies large and small, and even the mainstream media have been keenly observing what has been billed as the biggest biotech patent dispute in history.  The outcome of the dispute in the patent offices will have significant consequences and may come to define the developmental path of this transformational technology.

For those seeking to enter the CRISPR field, uncertainty over the ownership of the foundational IP may delay or deter their entry, thus having a chilling effect on innovation and participation in the CRISPR revolution.  The lack of one clear winner will lead to a fragmented landscape globally or even within a single jurisdiction, with prospective industry entrants forced to take licences from multiple parties unless some single licensing platform or pool could be formed.

For those who have already taken a licence, they will be keen to know whether they have backed the winner in the patent dispute, and how much their licence and/or collaboration is really worth.  Clinical programs being developed in conjunction with a loser in the patent dispute could be jeopardised, and additional licences may need to be sought from the winners.  Significantly, the PTAB’s decision as to the separate patentability of UCB and the Broad’s respective inventions leaves open the possibility that ultimately both UCB and the Broad will retain valid CRISPR/Cas9 patents of broad scope.  In that circumstance, users of CRISPR/Cas9 technology (including UCB and the Broad themselves) will need licences to both CRISPR/Cas9 patent portfolios.  Should this come to pass, we may see more commercially attractive cross-licensing options emerge.

For IP counsel and their external advisors, the dispute will provide plenty to digest, and the way it is fought could set the tone for future breakthrough technologies, either as an example to be followed or a cautionary tale.  By the end, the dispute will no doubt have yielded plenty of lessons to be learned which can be applied more broadly, including:

  • What is the optimal early filing strategy?

  • How should secondary patent protection be developed for biotechnology platforms?

  • How should big pharma approach collaborations with startups holding transformational IP (and vice versa)?

  • How can the risk from such patent disputes be mitigated or accounted for in licensing/collaboration agreements?

At any rate, given the current stage of the case in both the US and Europe and the avenues available to both sides for appeal, oppositions and litigation, barring settlement and cross-licensing, we are unlikely to see any certainty as to the ownership landscape for CRISPR’s foundational IP for some time yet.

DISCLAIMER: Because of the generality of this update, the information provided herein may not be applicable in all situations and should not be acted upon without specific legal advice based on particular situations.

© Allen & Overy LLP | Attorney Advertising

Written by:

Allen & Overy LLP

Allen & Overy LLP on:

Readers' Choice 2017
Reporters on Deadline

"My best business intelligence, in one easy email…"

Your first step to building a free, personalized, morning email brief covering pertinent authors and topics on JD Supra:
*By using the service, you signify your acceptance of JD Supra's Privacy Policy.
Custom Email Digest
- hide

JD Supra Privacy Policy

Updated: May 25, 2018:

JD Supra is a legal publishing service that connects experts and their content with broader audiences of professionals, journalists and associations.

This Privacy Policy describes how JD Supra, LLC ("JD Supra" or "we," "us," or "our") collects, uses and shares personal data collected from visitors to our website (located at www.jdsupra.com) (our "Website") who view only publicly-available content as well as subscribers to our services (such as our email digests or author tools)(our "Services"). By using our Website and registering for one of our Services, you are agreeing to the terms of this Privacy Policy.

Please note that if you subscribe to one of our Services, you can make choices about how we collect, use and share your information through our Privacy Center under the "My Account" dashboard (available if you are logged into your JD Supra account).

Collection of Information

Registration Information. When you register with JD Supra for our Website and Services, either as an author or as a subscriber, you will be asked to provide identifying information to create your JD Supra account ("Registration Data"), such as your:

  • Email
  • First Name
  • Last Name
  • Company Name
  • Company Industry
  • Title
  • Country

Other Information: We also collect other information you may voluntarily provide. This may include content you provide for publication. We may also receive your communications with others through our Website and Services (such as contacting an author through our Website) or communications directly with us (such as through email, feedback or other forms or social media). If you are a subscribed user, we will also collect your user preferences, such as the types of articles you would like to read.

Information from third parties (such as, from your employer or LinkedIn): We may also receive information about you from third party sources. For example, your employer may provide your information to us, such as in connection with an article submitted by your employer for publication. If you choose to use LinkedIn to subscribe to our Website and Services, we also collect information related to your LinkedIn account and profile.

Your interactions with our Website and Services: As is true of most websites, we gather certain information automatically. This information includes IP addresses, browser type, Internet service provider (ISP), referring/exit pages, operating system, date/time stamp and clickstream data. We use this information to analyze trends, to administer the Website and our Services, to improve the content and performance of our Website and Services, and to track users' movements around the site. We may also link this automatically-collected data to personal information, for example, to inform authors about who has read their articles. Some of this data is collected through information sent by your web browser. We also use cookies and other tracking technologies to collect this information. To learn more about cookies and other tracking technologies that JD Supra may use on our Website and Services please see our "Cookies Guide" page.

How do we use this information?

We use the information and data we collect principally in order to provide our Website and Services. More specifically, we may use your personal information to:

  • Operate our Website and Services and publish content;
  • Distribute content to you in accordance with your preferences as well as to provide other notifications to you (for example, updates about our policies and terms);
  • Measure readership and usage of the Website and Services;
  • Communicate with you regarding your questions and requests;
  • Authenticate users and to provide for the safety and security of our Website and Services;
  • Conduct research and similar activities to improve our Website and Services; and
  • Comply with our legal and regulatory responsibilities and to enforce our rights.

How is your information shared?

  • Content and other public information (such as an author profile) is shared on our Website and Services, including via email digests and social media feeds, and is accessible to the general public.
  • If you choose to use our Website and Services to communicate directly with a company or individual, such communication may be shared accordingly.
  • Readership information is provided to publishing law firms and authors of content to give them insight into their readership and to help them to improve their content.
  • Our Website may offer you the opportunity to share information through our Website, such as through Facebook's "Like" or Twitter's "Tweet" button. We offer this functionality to help generate interest in our Website and content and to permit you to recommend content to your contacts. You should be aware that sharing through such functionality may result in information being collected by the applicable social media network and possibly being made publicly available (for example, through a search engine). Any such information collection would be subject to such third party social media network's privacy policy.
  • Your information may also be shared to parties who support our business, such as professional advisors as well as web-hosting providers, analytics providers and other information technology providers.
  • Any court, governmental authority, law enforcement agency or other third party where we believe disclosure is necessary to comply with a legal or regulatory obligation, or otherwise to protect our rights, the rights of any third party or individuals' personal safety, or to detect, prevent, or otherwise address fraud, security or safety issues.
  • To our affiliated entities and in connection with the sale, assignment or other transfer of our company or our business.

How We Protect Your Information

JD Supra takes reasonable and appropriate precautions to insure that user information is protected from loss, misuse and unauthorized access, disclosure, alteration and destruction. We restrict access to user information to those individuals who reasonably need access to perform their job functions, such as our third party email service, customer service personnel and technical staff. You should keep in mind that no Internet transmission is ever 100% secure or error-free. Where you use log-in credentials (usernames, passwords) on our Website, please remember that it is your responsibility to safeguard them. If you believe that your log-in credentials have been compromised, please contact us at privacy@jdsupra.com.

Children's Information

Our Website and Services are not directed at children under the age of 16 and we do not knowingly collect personal information from children under the age of 16 through our Website and/or Services. If you have reason to believe that a child under the age of 16 has provided personal information to us, please contact us, and we will endeavor to delete that information from our databases.

Links to Other Websites

Our Website and Services may contain links to other websites. The operators of such other websites may collect information about you, including through cookies or other technologies. If you are using our Website or Services and click a link to another site, you will leave our Website and this Policy will not apply to your use of and activity on those other sites. We encourage you to read the legal notices posted on those sites, including their privacy policies. We are not responsible for the data collection and use practices of such other sites. This Policy applies solely to the information collected in connection with your use of our Website and Services and does not apply to any practices conducted offline or in connection with any other websites.

Information for EU and Swiss Residents

JD Supra's principal place of business is in the United States. By subscribing to our website, you expressly consent to your information being processed in the United States.

  • Our Legal Basis for Processing: Generally, we rely on our legitimate interests in order to process your personal information. For example, we rely on this legal ground if we use your personal information to manage your Registration Data and administer our relationship with you; to deliver our Website and Services; understand and improve our Website and Services; report reader analytics to our authors; to personalize your experience on our Website and Services; and where necessary to protect or defend our or another's rights or property, or to detect, prevent, or otherwise address fraud, security, safety or privacy issues. Please see Article 6(1)(f) of the E.U. General Data Protection Regulation ("GDPR") In addition, there may be other situations where other grounds for processing may exist, such as where processing is a result of legal requirements (GDPR Article 6(1)(c)) or for reasons of public interest (GDPR Article 6(1)(e)). Please see the "Your Rights" section of this Privacy Policy immediately below for more information about how you may request that we limit or refrain from processing your personal information.
  • Your Rights
    • Right of Access/Portability: You can ask to review details about the information we hold about you and how that information has been used and disclosed. Note that we may request to verify your identification before fulfilling your request. You can also request that your personal information is provided to you in a commonly used electronic format so that you can share it with other organizations.
    • Right to Correct Information: You may ask that we make corrections to any information we hold, if you believe such correction to be necessary.
    • Right to Restrict Our Processing or Erasure of Information: You also have the right in certain circumstances to ask us to restrict processing of your personal information or to erase your personal information. Where you have consented to our use of your personal information, you can withdraw your consent at any time.

You can make a request to exercise any of these rights by emailing us at privacy@jdsupra.com or by writing to us at:

Privacy Officer
JD Supra, LLC
10 Liberty Ship Way, Suite 300
Sausalito, California 94965

You can also manage your profile and subscriptions through our Privacy Center under the "My Account" dashboard.

We will make all practical efforts to respect your wishes. There may be times, however, where we are not able to fulfill your request, for example, if applicable law prohibits our compliance. Please note that JD Supra does not use "automatic decision making" or "profiling" as those terms are defined in the GDPR.

  • Timeframe for retaining your personal information: We will retain your personal information in a form that identifies you only for as long as it serves the purpose(s) for which it was initially collected as stated in this Privacy Policy, or subsequently authorized. We may continue processing your personal information for longer periods, but only for the time and to the extent such processing reasonably serves the purposes of archiving in the public interest, journalism, literature and art, scientific or historical research and statistical analysis, and subject to the protection of this Privacy Policy. For example, if you are an author, your personal information may continue to be published in connection with your article indefinitely. When we have no ongoing legitimate business need to process your personal information, we will either delete or anonymize it, or, if this is not possible (for example, because your personal information has been stored in backup archives), then we will securely store your personal information and isolate it from any further processing until deletion is possible.
  • Onward Transfer to Third Parties: As noted in the "How We Share Your Data" Section above, JD Supra may share your information with third parties. When JD Supra discloses your personal information to third parties, we have ensured that such third parties have either certified under the EU-U.S. or Swiss Privacy Shield Framework and will process all personal data received from EU member states/Switzerland in reliance on the applicable Privacy Shield Framework or that they have been subjected to strict contractual provisions in their contract with us to guarantee an adequate level of data protection for your data.

California Privacy Rights

Pursuant to Section 1798.83 of the California Civil Code, our customers who are California residents have the right to request certain information regarding our disclosure of personal information to third parties for their direct marketing purposes.

You can make a request for this information by emailing us at privacy@jdsupra.com or by writing to us at:

Privacy Officer
JD Supra, LLC
10 Liberty Ship Way, Suite 300
Sausalito, California 94965

Some browsers have incorporated a Do Not Track (DNT) feature. These features, when turned on, send a signal that you prefer that the website you are visiting not collect and use data regarding your online searching and browsing activities. As there is not yet a common understanding on how to interpret the DNT signal, we currently do not respond to DNT signals on our site.

Access/Correct/Update/Delete Personal Information

For non-EU/Swiss residents, if you would like to know what personal information we have about you, you can send an e-mail to privacy@jdsupra.com. We will be in contact with you (by mail or otherwise) to verify your identity and provide you the information you request. We will respond within 30 days to your request for access to your personal information. In some cases, we may not be able to remove your personal information, in which case we will let you know if we are unable to do so and why. If you would like to correct or update your personal information, you can manage your profile and subscriptions through our Privacy Center under the "My Account" dashboard. If you would like to delete your account or remove your information from our Website and Services, send an e-mail to privacy@jdsupra.com.

Changes in Our Privacy Policy

We reserve the right to change this Privacy Policy at any time. Please refer to the date at the top of this page to determine when this Policy was last revised. Any changes to our Privacy Policy will become effective upon posting of the revised policy on the Website. By continuing to use our Website and Services following such changes, you will be deemed to have agreed to such changes.

Contacting JD Supra

If you have any questions about this Privacy Policy, the practices of this site, your dealings with our Website or Services, or if you would like to change any of the information you have provided to us, please contact us at: privacy@jdsupra.com.

JD Supra Cookie Guide

As with many websites, JD Supra's website (located at www.jdsupra.com) (our "Website") and our services (such as our email article digests)(our "Services") use a standard technology called a "cookie" and other similar technologies (such as, pixels and web beacons), which are small data files that are transferred to your computer when you use our Website and Services. These technologies automatically identify your browser whenever you interact with our Website and Services.

How We Use Cookies and Other Tracking Technologies

We use cookies and other tracking technologies to:

  1. Improve the user experience on our Website and Services;
  2. Store the authorization token that users receive when they login to the private areas of our Website. This token is specific to a user's login session and requires a valid username and password to obtain. It is required to access the user's profile information, subscriptions, and analytics;
  3. Track anonymous site usage; and
  4. Permit connectivity with social media networks to permit content sharing.

There are different types of cookies and other technologies used our Website, notably:

  • "Session cookies" - These cookies only last as long as your online session, and disappear from your computer or device when you close your browser (like Internet Explorer, Google Chrome or Safari).
  • "Persistent cookies" - These cookies stay on your computer or device after your browser has been closed and last for a time specified in the cookie. We use persistent cookies when we need to know who you are for more than one browsing session. For example, we use them to remember your preferences for the next time you visit.
  • "Web Beacons/Pixels" - Some of our web pages and emails may also contain small electronic images known as web beacons, clear GIFs or single-pixel GIFs. These images are placed on a web page or email and typically work in conjunction with cookies to collect data. We use these images to identify our users and user behavior, such as counting the number of users who have visited a web page or acted upon one of our email digests.

JD Supra Cookies. We place our own cookies on your computer to track certain information about you while you are using our Website and Services. For example, we place a session cookie on your computer each time you visit our Website. We use these cookies to allow you to log-in to your subscriber account. In addition, through these cookies we are able to collect information about how you use the Website, including what browser you may be using, your IP address, and the URL address you came from upon visiting our Website and the URL you next visit (even if those URLs are not on our Website). We also utilize email web beacons to monitor whether our emails are being delivered and read. We also use these tools to help deliver reader analytics to our authors to give them insight into their readership and help them to improve their content, so that it is most useful for our users.

Analytics/Performance Cookies. JD Supra also uses the following analytic tools to help us analyze the performance of our Website and Services as well as how visitors use our Website and Services:

  • HubSpot - For more information about HubSpot cookies, please visit legal.hubspot.com/privacy-policy.
  • New Relic - For more information on New Relic cookies, please visit www.newrelic.com/privacy.
  • Google Analytics - For more information on Google Analytics cookies, visit www.google.com/policies. To opt-out of being tracked by Google Analytics across all websites visit http://tools.google.com/dlpage/gaoptout. This will allow you to download and install a Google Analytics cookie-free web browser.

Facebook, Twitter and other Social Network Cookies. Our content pages allow you to share content appearing on our Website and Services to your social media accounts through the "Like," "Tweet," or similar buttons displayed on such pages. To accomplish this Service, we embed code that such third party social networks provide and that we do not control. These buttons know that you are logged in to your social network account and therefore such social networks could also know that you are viewing the JD Supra Website.

Controlling and Deleting Cookies

If you would like to change how a browser uses cookies, including blocking or deleting cookies from the JD Supra Website and Services you can do so by changing the settings in your web browser. To control cookies, most browsers allow you to either accept or reject all cookies, only accept certain types of cookies, or prompt you every time a site wishes to save a cookie. It's also easy to delete cookies that are already saved on your device by a browser.

The processes for controlling and deleting cookies vary depending on which browser you use. To find out how to do so with a particular browser, you can use your browser's "Help" function or alternatively, you can visit http://www.aboutcookies.org which explains, step-by-step, how to control and delete cookies in most browsers.

Updates to This Policy

We may update this cookie policy and our Privacy Policy from time-to-time, particularly as technology changes. You can always check this page for the latest version. We may also notify you of changes to our privacy policy by email.

Contacting JD Supra

If you have any questions about how we use cookies and other tracking technologies, please contact us at: privacy@jdsupra.com.

- hide

This website uses cookies to improve user experience, track anonymous site usage, store authorization tokens and permit sharing on social media networks. By continuing to browse this website you accept the use of cookies. Click here to read more about how we use cookies.