United States: Federal Circuit Affirms Tygacil Formulation Patent

In a non-precedential decision in Apotex, Inc. v. Wyeth LLC, the Federal Circuit affirmed the decision of the USPTO Patent Trial and Appeal Board (PTAB) finding that Apotex had failed to show that claims directed to a specific formulation of tigecycline were invalid as obvious. Both the PTAB and Federal Circuit decisions show that while the burden of proof is lower in an inter partes review proceeding than a district court proceeding, it still can be difficult to invalidate a patent. Indeed, Apotex's second attempt to invalidate this Tygacil formulation patent in an inter partes review proceeding was denied institution in September 2015, while this appeal was pending.

The Tygacil Formulation Patent At Issue

The patent at issue was Wyeth's U.S. Patent No. 7,879,828, which is directed to a specific formulation of tigecycline, a tetracycline antibiotic and the active ingredient of Wyeth's Tygacil® product.

  1. A composition comprising tigecycline, lactose, and an acid selected from hydrochloric acid and gentisic acid, wherein the molar ratio of tigecycline to lactose is between about 1:0.2 and about 1:5 and the pH of the composition in a solution is between about 3.0 and about 7.0.

As set forth in the Federal Circuit decision, "[a]ccording to the specification [of the '828 patent], the acid minimizes oxidative degradation, and the carbohydrate stabilizes the tigecycline against epimer formation at acidic pH."

The Inter Partes Review Proceeding

Apotex sought inter partes review of the '828 patent, which was instituted based on the following references:

  • Chinese Patent Publication No. 1390550A, which discloses a minocycline-based powder injection (like tigecycline, minocycline is a tetracycline antibiotic).
  • Naggar et al., "Effect of Solubilizers on the Stability of Tetracycline," 29 PHARMAZIE 126 (1974)
  • Pawelczyk et al., "Kinetics of Drug Decomposition: Part 74: Kinetics of Degradation of Minocycline in Aqueous Solution," 34 POL. J. PHARMACOL. PHARM. 409 (1982)

The Federal Circuit decision summarizes the PTAB's findings as to the disclosures of the cited references as follows:

  • CN '550 discloses a formulation comprising "'minocycline hydrochloride, ... [a] lyophilized powder supporting agent, and a suitable amount of a pH adjusting agent,'" where "[t]he powder supporting agent can be lactose, and the 'pH adjusting agent is an inorganic acid, such as hydrochloric acid.'" The reference teaches that "[t]he composition is stable against "degradation by light, heat, oxygen, and water,'" but does not discuss epimerization.
  • Pawelczyk discusses "the stability of minocycline in solutions over a broad range of pHs, specifically 'teach[ing] that oxidation is the predominant minocycline degradation process above pH 5.'"
  • Naggar discusses "tetracycline epimerization, specifically teaching that 'at a pH of 2–6, tetracycline undergoes a reversible epimerization at the C4 dimethylamino group.'"

The PTAB determined that Apotex has not established obviousness based on these references:

It first reasoned that Apotex failed to explain why a skilled artisan "would have substituted tigecycline for minocycline in the CN '550 composition for any reason, much less in an attempt to make a lyophilized tigecycline composition that was stable against epimerization." .... It then reasoned that Apotex failed to establish why a skilled artisan would have been motivated to combine CN '550, Pawelczyk, and Naggar, and use lactose, as a means for stabilizing tigecycline against epimerization.

Apotex appealed, arguing that the PTAB "wrongly relied on the failure of CN '550 to teach the epimeric stability of its composition," and "failed to consider any motivation to combine the prior art of record beyond the problem the patentee was trying to solve."

The Federal Circuit Decision

The Federal Circuit decision was authored by Judge Lourie and joined by Judges Wallach and Hughes.

The opinion starts with this reminder of the applicable standards of review:

We review the Board's legal determinations de novo, ... and the Board's factual findings underlying those determinations for substantial evidence, .... Obviousness is a question of law based on underlying factual findings, ... such as what a reference teaches, ... and whether a skilled artisan would have had a reason to combine references....

With regard to Apotex's first argument, the Federal Circuit agreed that "the challenged claims do not require epimeric stability," but found no PTAB error in this regard. To the contrary, the PTAB itself "stated that the purported 'obviousness of the claims [could] be demonstrated without a showing of epimeric stability in the prior art.'"

With regard to Apotex's second argument, the Federal Circuit determined that the PTAB had "correctly considered several purported motivations to combine the prior art beyond epimeric stability." For example, while Apotex argued that "the structural similarity of tigecycline and minocycline would have motivated a skilled artisan to replace minocycline with tigecycline in the CN '550 composition," the PTAB "fully considered that potential motivation to combine and found it wanting." In particular, the PTAB "found that no evidence suggested that tigecycline would be as stable in the CN '550 composition," and that "the notion of 'identical A and B rings' alone was insufficient to show that," particularly where Wyeth had proffered evidence that the compounds have different oxidation rates.

The Federal Circuit refused to disturb these findings:

[T]here is not necessarily a motivation to substitute one antibiotic for a structurally related one when the prior-art antibiotic has a favorable stability profile, and there is nothing in the record here to show that the substitution would solve any other problem.

With regard to epimeric stability, the PTAB found that a skilled artisan would not have been motivated to combine the asserted references to stabilize tigecycline against epimerization. The Federal Circuit noted four specific findings underlying this determination:

  1. none of the references discloses tigecycline
  2. Naggar and Pawelczyk do not disclose lactose, much less disclose it as a stabilizing agent against epimerization
  3. CN '550 teaches lactose only as a "powder supporting agent"
  4. Apotex failed to show why a skilled artisan would have been motivated to use lactose in view of Naggar, when Naggar teaches a different polysaccharide, polysorbate 20, as the least effective solubilizer in a larger list of solubilizers, such as urea.

Considering the record as a whole, the Federal Circuit concluded:

[W]hile tigecycline is closely related to minocycline structurally and in terms of benefit, the Board did not err in concluding that there was insufficient basis in the record to show that it would have been obvious to a skilled artisan to substitute tigecycline in the prior art minocycline composition.

If At First You Don't Succeed ...

As noted above, while this appeal was pending, Apotex filed another IPR petition against the '828 patent, based on CN '550 reference and two other references. The PTAB denied institution, finding similar holes in Apotex's case as it found here.

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.