The Federal Court Reverses a Hindsight Reconstruction of An Important Pharmaceutical Invention

by BakerHostetler

In Millennium Pharmaceuticals v. Sandoz,[1] the Federal Circuit reversed the district court’s holding of obviousness of certain claims of Millennium-owned U.S. Patent No. 6,713,446 (the ‘446 patent), finding that the district court improperly applied the lead compound analysis and the inherency doctrine and clearly erred by rejecting objective indicia of non-obviousness.

The disputed claims of the ‘446 patent[2] are directed to Velcade®, a freeze-dried (lyophilized) formulation of D-mannitol N-(2-pyrazine) carbonyl-L-phenylalanine-L-leucine boronate (I) and methods of its preparation and reconstitution. Velcade is Millennium’s oncology product prescribed for multiple myeloma and mantle cell lymphoma. Compound (I) is a mannitol ester of bortezomib. The portion of the molecule depicted in red below identifies the ester linkage between bortezomib and the mannitol sugar.


Claim 20 is representative of the claims on appeal:

  1. The lyophilized compound D-mannitol N-(2-pyrazine) carbonyl-L-phenylalanine-L-leucine boronate.

While bortezomib exhibited efficacy against various cancers, it never achieved FDA approval because of its instability and insolubility. Despite years of research, scientists were unable to solve bortezomib’s problems with a liquid formulation. After failing to develop suitable liquids, the inventor of the ’446 patent investigated a lyophilized formulation, eventually arriving at a process that used mannitol as a bulking agent. The resulting lyophilized product was dramatically more stable and soluble than bortezomib. The reason for the significant improvement was discovered to be the unexpected formation of the mannitol ester during the lyophilization process. This mannitol ester acts as a prodrug, converting to bortezomib upon administration to a patient.

In the district court litigation, it was undisputed that Compound (I) was a new compound with advantageous properties. But the district court concluded that Compound (I) was obvious because freeze-drying was a known process for formulating pharmaceutical compounds, mannitol was known to be used in freeze-drying and the prodrug inherently formed during that process. The Federal Circuit found the district court’s analysis fatally flawed. In so concluding, the court focused its analysis not on whether the process of lyophilizing bortezomib with mannitol would have been obvious but on whether Compound (I) would have been obvious.

The Federal Circuit reasoned that while mannitol was a known bulking agent used in lyophilization – itself a known method of drug formulation – “[t]he prior art contains no teaching or suggestion of this new compound, or that it would form during lyophilization.”[3] The court further noted that there is “no reference or combination of references that shows or suggests a reason to make the claimed compound.”[4]

The Federal Circuit chastised the district court for relying on “inherency” to invalidate the claims, even though “the ester is the ‘natural result’ of freeze-drying bortezomib with mannitol.”[5] The court noted the “high standard in order to rely on inherency to establish the existence of a claim limitation in the prior art in an obviousness analysis.”[6] In this case, the reliance on inherency amounted to hindsight by following the inventor’s path instead of the path that a person of ordinary skill in the art would have followed based on the prior art. The district court’s reliance on the inventor’s path violated Section 103’s admonition that “[p]atentability shall not be negatived [sic] by the manner in which the invention was made.”[7] As to the path that a person of ordinary skill in the art would have followed, the Federal Circuit observed that “[n]o expert testified that they foresaw, or expected, or would have intended, the reaction between bortezomib and mannitol, or that the resulting ester would have the long-sought properties and advantages.”[8]

The Federal Circuit further ruled that the district court clearly erred in its examination of the objective indicia of unexpected results, long-felt need and commercial success. The court found overcoming the problems of bortezomib’s instability and insolubility to be unexpected. The court rejected the district court’s reasoning that the comparison of the claimed invention should have been to other bortezomib esters that, although suggested, were not disclosed, prepared or tested in the prior art. Because bortezomib was not a viable commercial product, the court also found clearly erroneous the district court’s perfunctory reasoning that the invention did not meet a long-felt need and was not commercially successful.

Finally, although an earlier patent encompassed bortezomib formulations until it expired in 2017, leading Sandoz to argue that there was no “failure of others” because they were blocked by that patent, the court stated that the question of failure of others was not before it, because long-felt need, although related, is distinct from failure of others.[9] That ruling suggests that the blocking patent rationale of Merck & Co. v. Teva Pharmaceuticals USA, Inc., 395 F.3d 1364 (Fed. Cir. 2005) does not apply, at least to the secondary consideration of long-felt but unmet need.

Millennium Pharmaceuticals v. Sandoz thus has a number of useful rulings for countering arguments of obviousness based on a hindsight reconstruction of the invention by piecing together separate prior art elements using the claimed invention as a blueprint.

[1] Millennium Pharmaceuticals, Inc. v. Sandoz Inc. et al., 2017 WL 3013204 (Fed. Cir. July 17, 2017).

[2] Claims 20, 31, 49 and 53 were at issue in this appeal.

[3] Millennium, 2017 WL 3013204 at *4.

[4] Id.

[5] Id. at *3.

[6] Id. at *6 (quoting Par Pharm., Inc. v. TWI Pharm., Inc., 773 F.3d 1186, 1195-96 [Fed. Circ. 2014]).

[7] Id. at *7 (quoting 35 U.S.C. § 103).

[8] Id.

[9] Id. at *8 n.5.

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.

© BakerHostetler | Attorney Advertising

Written by:


BakerHostetler 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:
Sign up using*

Already signed up? Log in here

*By using the service, you signify your acceptance of JD Supra's Privacy Policy.
Custom Email Digest
Privacy Policy (Updated: October 8, 2015):

JD Supra provides users with access to its legal industry publishing services (the "Service") through its website (the "Website") as well as through other sources. Our policies with regard to data collection and use of personal information of users of the Service, regardless of the manner in which users access the Service, and visitors to the Website are set forth in this statement ("Policy"). By using the Service, you signify your acceptance of this Policy.

Information Collection and Use by JD Supra

JD Supra collects users' names, companies, titles, e-mail address and industry. JD Supra also tracks the pages that users visit, logs IP addresses and aggregates non-personally identifiable user data and browser type. This data is gathered using cookies and other technologies.

The information and data collected is used to authenticate users and to send notifications relating to the Service, including email alerts to which users have subscribed; to manage the Service and Website, to improve the Service and to customize the user's experience. This information is also provided to the authors of the content to give them insight into their readership and help them to improve their content, so that it is most useful for our users.

JD Supra does not sell, rent or otherwise provide your details to third parties, other than to the authors of the content on JD Supra.

If you prefer not to enable cookies, you may change your browser settings to disable cookies; however, please note that rejecting cookies while visiting the Website may result in certain parts of the Website not operating correctly or as efficiently as if cookies were allowed.

Email Choice/Opt-out

Users who opt in to receive emails may choose to no longer receive e-mail updates and newsletters by selecting the "opt-out of future email" option in the email they receive from JD Supra or in their JD Supra account management screen.


JD Supra takes reasonable precautions to insure that user information is kept private. 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. However, please note that no method of transmitting or storing data is completely secure and we cannot guarantee the security of user information. Unauthorized entry or use, hardware or software failure, and other factors may compromise the security of user information at any time.

If you have reason to believe that your interaction with us is no longer secure, you must immediately notify us of the problem by contacting us at In the unlikely event that we believe that the security of your user information in our possession or control may have been compromised, we may seek to notify you of that development and, if so, will endeavor to do so as promptly as practicable under the circumstances.

Sharing and Disclosure of Information JD Supra Collects

Except as otherwise described in this privacy statement, JD Supra will not disclose personal information to any third party unless we believe that disclosure is necessary to: (1) comply with applicable laws; (2) respond to governmental inquiries or requests; (3) comply with valid legal process; (4) protect the rights, privacy, safety or property of JD Supra, users of the Service, Website visitors or the public; (5) permit us to pursue available remedies or limit the damages that we may sustain; and (6) enforce our Terms & Conditions of Use.

In the event there is a change in the corporate structure of JD Supra such as, but not limited to, merger, consolidation, sale, liquidation or transfer of substantial assets, JD Supra may, in its sole discretion, transfer, sell or assign information collected on and through the Service to one or more affiliated or unaffiliated third parties.

Links to Other Websites

This Website and the Service may contain links to other websites. The operator of such other websites may collect information about you, including through cookies or other technologies. If you are using the Service through the Website and link to another site, you will leave the 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 shall have no responsibility or liability for your visitation to, and the data collection and use practices of, such other sites. This Policy applies solely to the information collected in connection with your use of this Website and does not apply to any practices conducted offline or in connection with any other websites.

Changes in Our Privacy Policy

We reserve the right to change this 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 the Service or Website following such changes, you will be deemed to have agreed to such changes. If you do not agree with the terms of this Policy, as it may be amended from time to time, in whole or part, please do not continue using the Service or the Website.

Contacting JD Supra

If you have any questions about this privacy statement, the practices of this site, your dealings with this Web site, or if you would like to change any of the information you have provided to us, please contact us at:

- hide
*With LinkedIn, you don't need to create a separate login to manage your free JD Supra account, and we can make suggestions based on your needs and interests. We will not post anything on LinkedIn in your name. Or, sign up using your email address.