United States: Patent Trial And Appeal Board Denies Inter Partes Review Of Patent Claiming The Deuterated Form Of A Known Compound

In Neptune Generics, LLC v. Auspex Pharmaceuticals, Inc., IPR2015-01313, Paper No. 25 (PTAB Dec. 9, 2015) ("Neptune"), the Patent Trial and Appeal Board ("the Board") issued an opinion denying institution of inter partes review of U.S. Patent No. 7,456,317 B2 ("the '317 patent"). The '317 patent claims an analog of venlafaxine (Effexor®) in which nine carbon-hydrogen (C-H) bonds are replaced with carbon-deuterium (C-D) bonds. ('317 patent, col. 5:61-67) Claim 1 is representative:

Venlafaxine's mechanism of action and metabolism have been studied extensively (id. at col. 4:6-19), and both venlafaxine and its active metabolite have half-lives that are much shorter than that "regarded as ideal for this class of compounds by most clinicians." (Id. at col. 4:41-50) Venlafaxine is a serotonin and norepinephrine reuptake inhibitor approved for the treatment of depression, generalized anxiety disorder, panic disorder, and social anxiety disorder. As the '317 patent acknowledges, "[d]euteration of pharmaceuticals to improve pharmacokinetics (PK), pharmacodynamics (PD), and toxicity profiles has been demonstrated previously with some classes of drugs." (Id. at col. 3:47-49)1

The '317 patent describes nearly 100 deuterated venlafaxine analogs, including the claimed one (id. at col. 10:51–col. 26:45), and states that enriching for deuterium alters the ratio of active venlafaxine metabolites, reduces unwanted metabolites, and increases the half-life of the parent drug and its metabolites. (Id. at col. 6:27-33)

The Petitioner challenged claim 1 of the '317 patent as being obvious over Fogelman2 in view of Miwa.3,4 The Petitioner primarily relied on Fogelman's disclosure that the major metabolites of venlafaxine are O-desmethylvenlafaxine ("ODV"), N-desmethylvenlafaxine ("NDV"), and N,O-didesmethylvenlafaxine ("N,O-DV"), depicted below.

(Neptune, Paper 25 at 9.) Fogelman states that "ODV has a receptor affinity profile similar to its parent compound [venlafaxine], while the latter two metabolites have little if any affinity for the . . . receptor sites." (Id. at 6) Fogelman further states that "approximately 90% of total intrinsic clearance was accounted for by the O-demethylation pathway," in which the venlafaxine methoxy group is converted to a hydroxy. (Id. at 7, 11)

The Petitioner relied on Miwa for the "teaching that for some drugs, isotope substitution (i.e., from hydrogen to deuterium) may reduce the rate of drug metabolism, and, therefore, may reduce the rate of clearance of the drug from the body." (Id. at 8) According to the Petitioner's expert, one of ordinary skill in the art would have been motivated to "deuterate the methyl groups involved in the primary metabolic pathways. . . . in order to reduce the rate of venlafaxine metabolism, reduce the clearance of venlafaxine from the body, and improve the duration of action and peak plasma levels of venlafaxine." (Neptune, Ex. 1002 at 10)

In its Preliminary Response,5 the Patent Owner relied on several references to support its argument that the '317 patent's claims are nonobvious over the cited prior art because it is not possible to predict whether any given isotope effect will provide a beneficial change in metabolism without extensive testing. (Neptune, Paper 25 at 10)

In particular, the Patent Owner presented evidence that a primary deuterium kinetic isotope effect "will only be observed if the breaking of the carbon-hydrogen bond is the rate-limiting step."6 (Id.) The Patent Owner also provided evidence that even if the breaking of the carbon-hydrogen bond is the rate-limiting step, the ordinary artisan would not have been able to predict the magnitude of the deuterium substitution effect.7 The Patent Owner pointed to Miwa – cited by the Petitioner – for teaching that "isotope substitution may not give rise to significant isotope effects in metabolism or clearance." (Id. at 11)

The Patent Owner also submitted evidence establishing that deuteration of three different drugs does not result in a beneficial change in metabolism. In paroxetine8 – another serotonin reuptake inhibitor – deuteration resulted in increased metabolism rather than decreased metabolism. (Id. at 11-12) In phentermine,9 no deuterium effect was observed with an N-di-(tri-deuteromethyl) group – one of the same types of groups found in the claimed analog. (Id. at 12) And tramadol10 (which, like venlafaxine, is metabolized via O- and N-demethylation) "exhibited reduced in vitro metabolism, [and] none of the prepared deuterated versions were superior to tramadol in terms of potency or duration of effect, clearance was not reduced and half-life was not increased." (Id.)

In denying institution of the inter partes review, the Board agreed with the Patent Owner, finding that the Petitioner had not demonstrated that the ordinary artisan would have combined Fogelman with Miwa with a reasonable expectation of arriving at the invention claimed in the '317 patent. (Id. at 13)

The Board was persuaded by the Patent Owner's evidence that a deuteration "strategy will usually not result in significant alterations in overall metabolic clearance of the substrate" and that it "is difficult to predict a priori which effect deuterium may have on a drug's metabolism." (Id. at 14) The Board also found that the Petitioner did not adequately explain why a skilled artisan would seek to prevent metabolism of venlafaxine into ODV, venlafaxine's longer-lived, active metabolite, rather than focus on one of venlafaxine's nonactive metabolites. (Id.) Therefore, the Board concluded that "the ordinary artisan would not have had a reasonable expectation that substitution of all of the nine hydrogens at those sites for deuterium would result in a deuterated [venlafaxine] derivative having enhanced bioavailability and which maintains its activity for a longer period of time." (Id. at 15)

The Board also rejected the Petitioner's allegation that it would have been "obvious to try" to deuterate venlafaxine at the claimed positions, relying upon In re O'Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988). (Id. at 19-20[11]) Here, the Board noted that there are approximately 124,217,727 possible deuterated forms of venlafaxine. And even though Fogelman suggests that metabolism occurs at two main sites, one skilled in the art "would not have had a reasonable expectation that deuteration of those sites would result in enhanced bioavailability" and a maintenance of biological activity for a longer period of time. (Id. at 20-21) The Board noted that the ordinary artisan "would be left with trying the over 100,000,000 possible deuterated forms of [venlafaxine] until possibly arriving at a successful result."


1 "Since deuterium (D) is two-fold more massive than hydrogen (H), it follows that a C-D bond is stronger than the corresponding C-H bond. . . . If a C-H bond is broken during a rate determining step in a chemical reaction . . . then substituting a deuterium for that hydrogen will cause a decrease in the reaction rate, and the process will slow down. This phenomenon is known as the Deuterium Kinetic Isotope Effect (DKIE)." ('317 patent at col. 2:45-58)

2 Fogelman et al. ("Fogelman"), O- and N-demethylation of Venlafaxine In Vitro by Human Liver Microsomes and by Microsomes from cDNA-Transfected Cells: Effect of Metabolic Inhibitors and SSRI Antidepressants, 20 Neuropsychopharmacology 480-490 (1999).

3 Gerald T. Miwa and Anthony Y. H. Lu ("Miwa"), Kinetic Isotope Effects and 'Metabolic Switching' in Cytochrome P450-Catalyzed Reactions, 7 BioEssays 215-19 (1987).

4 The Petitioner also challenged claims 2 and 8 as being obvious over Fogelman, Miwa, and U.S. Application No. 2003/0190351 to Platteeuw and claims 3-7, 9, and 10 as being obvious over Fogelman, Miwa, Platteeuw, and U.S. Patent No. 6,197,828.

5 The Patent Owner did not submit an expert declaration.

6 Citing to Fisher et al., The Complexities Inherent in Attempts to Decrease Drug Clearance by Blocking Sites of CYP-Mediated Metabolism, 9 Current Opinion in Drug Discovery & Development 101-109 (2006).

7 Scott L. Harbeson and Roger D. Tung, Deuterium in Drug Discovery and Development, 46 Annual Reports in Medicinal Chemistry 403-417 (John E. Macor, Ed., 2011).

8 Citing Harbeson and Tung at 413-414.

9 Citing Allan B. Foster, Deuterium Isotope Effects in the Metabolism of Drugs and Xenobiotics: Implications for Drug Design, 14 Advances in Drug Research 1-40 (1985).

10 Citing Shao et al., Derivative of Tramadol for Increased Duration of Effect, 16 Bioorganic & Medicinal Chemistry Letters 691-94 (2006).

11 According to In re O'Farrell, there are two situations in which an "obvious to try" rationale is improper. (Neptune, Paper 25 at 20) The first situation is where one must "vary all parameters or try each of numerous possible choices until one possibly arrived at a successful result where the prior art gave either no indication of which parameters are critical or no direction as to which of many possible choices is likely to be successful." (Id.) The second situation is where one must "explore a new technology or general approach that seemed to be a promising field of experimentation, where the prior art gave only general guidance as to the particular form of the claimed invention or how to achieve it." (Id.)

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
Check to state you have read and
agree to our Terms and Conditions

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.

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 by clicking here .

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.


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.