United States: Unknown Problem Plus Nonobvious Solution Cannot Render Patent For Sublingual Formulation Of Asenapine Obvious

The District Court for the District of Delaware found Forest Labs' patent for sublingual or buccal compositions of asenapine and methods of using such compositions to treat mental disorders, including schizophrenia and mania, infringed and not invalid. Forest Labs., LLC v. Sigmapharm Labs., LLC, et al., Civ. No. 16-cv-914 RGA, (D. Del. June 30, 2017) (Robinson, J.). 

Forest Labs markets Saphris®, an antipsychotic containing asenapine maleate approved for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder. Saphris is the only antipsychotic that is administered sublingually. 

Development of the Patented Invention

Asenapine was not initially developed as a sublingual tablet but, instead, as a standard conventional tablet given orally. Early studies published by Organon, the company that first developed asenapine for use in humans, demonstrated that asenapine was safe and clinically effective at relatively low doses. Encouraged by these early studies, Organon continued to perform dose ranging and pharmacokinetic studies with asenapine. Studies were conducted to assess the safety and tolerance of asenapine administered intravenously, and to obtain preliminary data on the bioavailability of orally administered asenapine. The IV studies (which were not published) showed serious adverse side effects such that the investigators concluded IV infusion of asenapine was not well tolerated. After the IV study, Organon scientists focused on an oral tablet formulation. Further tests with the oral tablet formulation also demonstrated serious toxicity side effects not previously shown in the earlier published studies. These further tests of the conventional oral tablet were also not published.  

After brainstorming to develop possible avenues of further research, Organon scientists, including the inventors of the patent-in-suit, postulated using a buccal/sublingual route of administration to solve the problems associated with the cardiotoxic side effects encountered in previous studies focused on IV and oral routes of administration. After further testing, Organon determined that asenapine administered sublingually eliminated the cardiovascular side effects associated with oral and IV administration. Based on this discovery, the inventors filed an application that issued as US Patent No. 5,763,476 (the '476 patent).  

Sigmapharm Laboratories, LLC (Sigmapharm), Breckenridge Pharmaceutical, Inc. (Breckenridge), Hikma Pharmaceuticals, LLC (Hikma), Alembic Pharmaceuticals, Inc. (Alembic) and Amneal Pharmaceuticals, LLC (Amneal), each submitted an abbreviated new drug application (ANDA) in an attempt to market generic versions of asenapine before expiration of the '476 patent. The defendants all conceded infringement of claim 1 of the '476 patent; however, two of the defendants, Sigmapharm and Breckenridge, contested infringement of claim 4. All defendants contended that the '476 patent was invalid for being obvious. 


Claim 4 of the '476 patent is directed to a method for treating: (1) tension, excitation, anxiety, and psychotic and schizophrenic disorders, comprising (2) administering sublingually or buccally an (3) effective amount of asenapine or a pharmaceutically acceptable salt thereof. The issue of infringement of claim 4 boiled down to a single question: whether defendants infringed claim 4 even though their generic asenapine products are indicated only for the treatment of "manic episodes" associated with bipolar I disorder. Forest Labs argued that to the extent there are any differences between the treatment of manic episodes associated with bipolar I disorder with asenapine and the treatment of excitation with asenapine as recited in claim 4, such differences are insubstantial. That is, the treatments are equivalent. Forest Labs relied solely on the testimony of its expert who opined that excitation is the defining feature of manic episodes and, therefore, treating excitation is equivalent to treating manic episodes. The court noted that there was no mention of bipolar I disorder or maniac episodes associated with bipolar I disorder in the '476 patent. Further, while acknowledging that excitation is a symptom of manic episodes, no reference relied upon by Forest Labs' expert literally described excitation as the defining feature of mania. Instead, the references refer to excitation as one of several criteria that must be present to properly diagnose a manic episode of bipolar I disorder. Accordingly, the court found that Forest Labs had not carried its burden to prove direct infringement under the doctrine of equivalents, especially when Alembic's and Breckenridge's proposed labels limit the indication of use to manic and mixed episodes of bipolar I disorder. 

Although there can be no indirect infringement in the absence of a direct infringer, the court addressed Forest's evidence of indirect infringement nonetheless. The court found no intent on the part of Alembic and Breckenridge to induce infringement of the '476 patent. The court's finding was largely based on the fact that after the court issued its claim construction ruling, Alembic and Breckenridge submitted new proposed labels to the FDA for their generic products removing schizophrenia as an indication. The court specifically rejected Forest's off-label infringing use argument to establish intent of inducement. 


The defendants argued that the prior art of record would have motivated persons of ordinary skill in the art to formulate asenapine (a new and promising antipsychotic in 1994) as a rapidly disintegrating composition with a reasonable expectation of success. Defendants' primary invalidity theory was that skilled artisans would have been motivated to develop a sublingual formulation of asenapine because there was a bioavailability concern with conventional, orally administered asenapine. The court rejected this theory and stated that the evidence at trial demonstrated that skilled artisans reviewing the publically reported clinical studies would have understood that orally administered asenapine was safe, bioavailable and clinically effective. The publically available prior art further showed that Organon was in the process of conducting a large scale Phase II trial with a conventional oral tablet. The court noted that there was nothing in the prior art that would have indicated that the oral tablet had significant side effects, and ultimately concluded that there was no motivation from the record evidence to completely change the route of administration to a sublingual formulation—especially since a sublingual administration had never before been used for an antipsychotic drug. 

The court also found that the objective indicia of nonobviousness weighed in favor of the validity of the '476 patent. Particularly, the court found that the record was full of evidence demonstrating that it was a surprising and unexpected result of the claimed invention that the sublingual route of administration successfully resolved the serious side effects encountered during the development of the invention and as described in the '476 patent. Moreover, prior to the claimed invention, typical antipsychotics used in the treatment of schizophrenia and mania possessed debilitating side effects. The court found that the claimed sublingual administration meet this unsolved need for a much safer treatment of schizophrenia and mania.

Unknown Problem Plus Nonobvious Solution Cannot Render Patent for Sublingual Formulation of Asenapine Obvious

The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.

To print this article, all you need is to be registered on Mondaq.com.

Click to Login as an existing user or Register so you can print this article.

In association with
Related Video
Up-coming Events Search
Font Size:
Mondaq on Twitter
Register for Access and our Free Biweekly Alert for
This service is completely free. Access 250,000 archived articles from 100+ countries and get a personalised email twice a week covering developments (and yes, our lawyers like to think you’ve read our Disclaimer).
Email Address
Company Name
Confirm Password
Mondaq Topics -- Select your Interests
 Law Performance
 Law Practice
 Media & IT
 Real Estate
 Wealth Mgt
Asia Pacific
European Union
Latin America
Middle East
United States
Worldwide Updates
Mondaq Ltd requires you to register and provide information that personally identifies you, including what sort of information you are interested in, for three primary purposes:
  • To allow you to personalize the Mondaq websites you are visiting.
  • To enable features such as password reminder, newsletter alerts, email a colleague, and linking from Mondaq (and its affiliate sites) to your website.
  • To produce demographic feedback for our information providers who provide information free for your use.
  • Mondaq (and its affiliate sites) do not sell or provide your details to third parties other than information providers. The reason we provide our information providers with this information is so that they can measure the response their articles are receiving and provide you with information about their products and services.
    If you do not want us to provide your name and email address you may opt out by clicking here
    If you do not wish to receive any future announcements of products and services offered by Mondaq you may opt out by clicking here

    Terms & Conditions and Privacy Statement

    Mondaq.com (the Website) is owned and managed by Mondaq Ltd and as a user you are granted a non-exclusive, revocable license to access the Website under its terms and conditions of use. Your use of the Website constitutes your agreement to the following terms and conditions of use. Mondaq Ltd may terminate your use of the Website if you are in breach of these terms and conditions or if Mondaq Ltd decides to terminate your license of use for whatever reason.

    Use of www.mondaq.com

    You may use the Website but are required to register as a user if you wish to read the full text of the content and articles available (the Content). You may not modify, publish, transmit, transfer or sell, reproduce, create derivative works from, distribute, perform, link, display, or in any way exploit any of the Content, in whole or in part, except as expressly permitted in these terms & conditions or with the prior written consent of Mondaq Ltd. You may not use electronic or other means to extract details or information about Mondaq.com’s content, users or contributors in order to offer them any services or products which compete directly or indirectly with Mondaq Ltd’s services and products.


    Mondaq Ltd and/or its respective suppliers make no representations about the suitability of the information contained in the documents and related graphics published on this server for any purpose. All such documents and related graphics are provided "as is" without warranty of any kind. Mondaq Ltd and/or its respective suppliers hereby disclaim all warranties and conditions with regard to this information, including all implied warranties and conditions of merchantability, fitness for a particular purpose, title and non-infringement. In no event shall Mondaq Ltd and/or its respective suppliers be liable for any special, indirect or consequential damages or any damages whatsoever resulting from loss of use, data or profits, whether in an action of contract, negligence or other tortious action, arising out of or in connection with the use or performance of information available from this server.

    The documents and related graphics published on this server could include technical inaccuracies or typographical errors. Changes are periodically added to the information herein. Mondaq Ltd and/or its respective suppliers may make improvements and/or changes in the product(s) and/or the program(s) described herein at any time.


    Mondaq Ltd requires you to register and provide information that personally identifies you, including what sort of information you are interested in, for three primary purposes:

    • To allow you to personalize the Mondaq websites you are visiting.
    • To enable features such as password reminder, newsletter alerts, email a colleague, and linking from Mondaq (and its affiliate sites) to your website.
    • To produce demographic feedback for our information providers who provide information free for your use.

    Mondaq (and its affiliate sites) do not sell or provide your details to third parties other than information providers. The reason we provide our information providers with this information is so that they can measure the response their articles are receiving and provide you with information about their products and services.

    Information Collection and Use

    We require site users to register with Mondaq (and its affiliate sites) to view the free information on the site. We also collect information from our users at several different points on the websites: this is so that we can customise the sites according to individual usage, provide 'session-aware' functionality, and ensure that content is acquired and developed appropriately. This gives us an overall picture of our user profiles, which in turn shows to our Editorial Contributors the type of person they are reaching by posting articles on Mondaq (and its affiliate sites) – meaning more free content for registered users.

    We are only able to provide the material on the Mondaq (and its affiliate sites) site free to site visitors because we can pass on information about the pages that users are viewing and the personal information users provide to us (e.g. email addresses) to reputable contributing firms such as law firms who author those pages. We do not sell or rent information to anyone else other than the authors of those pages, who may change from time to time. Should you wish us not to disclose your details to any of these parties, please tick the box above or tick the box marked "Opt out of Registration Information Disclosure" on the Your Profile page. We and our author organisations may only contact you via email or other means if you allow us to do so. Users can opt out of contact when they register on the site, or send an email to unsubscribe@mondaq.com with “no disclosure” in the subject heading

    Mondaq News Alerts

    In order to receive Mondaq News Alerts, users have to complete a separate registration form. This is a personalised service where users choose regions and topics of interest and we send it only to those users who have requested it. Users can stop receiving these Alerts by going to the Mondaq News Alerts page and deselecting all interest areas. In the same way users can amend their personal preferences to add or remove subject areas.


    A cookie is a small text file written to a user’s hard drive that contains an identifying user number. The cookies do not contain any personal information about users. We use the cookie so users do not have to log in every time they use the service and the cookie will automatically expire if you do not visit the Mondaq website (or its affiliate sites) for 12 months. We also use the cookie to personalise a user's experience of the site (for example to show information specific to a user's region). As the Mondaq sites are fully personalised and cookies are essential to its core technology the site will function unpredictably with browsers that do not support cookies - or where cookies are disabled (in these circumstances we advise you to attempt to locate the information you require elsewhere on the web). However if you are concerned about the presence of a Mondaq cookie on your machine you can also choose to expire the cookie immediately (remove it) by selecting the 'Log Off' menu option as the last thing you do when you use the site.

    Some of our business partners may use cookies on our site (for example, advertisers). However, we have no access to or control over these cookies and we are not aware of any at present that do so.

    Log Files

    We use IP addresses to analyse trends, administer the site, track movement, and gather broad demographic information for aggregate use. IP addresses are not linked to personally identifiable information.


    This web site contains links to other sites. Please be aware that Mondaq (or its affiliate sites) are not responsible for the privacy practices of such other sites. We encourage our users to be aware when they leave our site and to read the privacy statements of these third party sites. This privacy statement applies solely to information collected by this Web site.

    Surveys & Contests

    From time-to-time our site requests information from users via surveys or contests. Participation in these surveys or contests is completely voluntary and the user therefore has a choice whether or not to disclose any information requested. Information requested may include contact information (such as name and delivery address), and demographic information (such as postcode, age level). Contact information will be used to notify the winners and award prizes. Survey information will be used for purposes of monitoring or improving the functionality of the site.


    If a user elects to use our referral service for informing a friend about our site, we ask them for the friend’s name and email address. Mondaq stores this information and may contact the friend to invite them to register with Mondaq, but they will not be contacted more than once. The friend may contact Mondaq to request the removal of this information from our database.


    From time to time Mondaq may send you emails promoting Mondaq services including new services. You may opt out of receiving such emails by clicking below.

    *** If you do not wish to receive any future announcements of services offered by Mondaq you may opt out by clicking here .


    This website takes every reasonable precaution to protect our users’ information. When users submit sensitive information via the website, your information is protected using firewalls and other security technology. If you have any questions about the security at our website, you can send an email to webmaster@mondaq.com.

    Correcting/Updating Personal Information

    If a user’s personally identifiable information changes (such as postcode), or if a user no longer desires our service, we will endeavour to provide a way to correct, update or remove that user’s personal data provided to us. This can usually be done at the “Your Profile” page or by sending an email to EditorialAdvisor@mondaq.com.

    Notification of Changes

    If we decide to change our Terms & Conditions or Privacy Policy, we will post those changes on our site so our users are always aware of what information we collect, how we use it, and under what circumstances, if any, we disclose it. If at any point we decide to use personally identifiable information in a manner different from that stated at the time it was collected, we will notify users by way of an email. Users will have a choice as to whether or not we use their information in this different manner. We will use information in accordance with the privacy policy under which the information was collected.

    How to contact Mondaq

    You can contact us with comments or queries at enquiries@mondaq.com.

    If for some reason you believe Mondaq Ltd. has not adhered to these principles, please notify us by e-mail at problems@mondaq.com and we will use commercially reasonable efforts to determine and correct the problem promptly.

    By clicking Register you state you have read and agree to our Terms and Conditions