United States: Obviousness Of A Dosage Regiment: Yeda Research And Development Co., Ltd. v. Mylan Pharmaceuticals Inc. Teva Pharmaceuticals USA, Inc. v. Sandoz Inc

Last Updated: December 4 2018
Article by Marina I. Miller

Yeda Research and Development Co., Ltd. ("Yeda") is the assignee of three "Copaxone patents" that describe and claim COPAXONE® 40mg/mL (glatiramer acetate ("GA")), a treatment for relapsing-remitting multiple sclerosis ("RRMS"). For analyzing the obviousness of the Copaxone patents, a key limitation of the claims is the administration of a 40mg GA dose in three subcutaneous injections over seven days. The Patent and Trademark Appeal Board ("the Board") found (and the district court affirmed) that the prior art described all limitations of the claims except for the administration of 40mg GA 3x/week for seven days. However, the Board and the district court concluded that the claimed dosage regiment would have been obvious to a parson of skill in the art (POSITA). Yeda appealed both decisions.

Claim 1 of U.S. 8,232,250 is representative:

1. A method of alleviating a symptom of relapsing- remitting multiple sclerosis in a human patient suffering from relapsing-remitting multiple sclerosis or a patient who has experienced a first clinical episode and is determined to be at high risk of developing clinically definite multiple sclerosis comprising administering to the human patient a therapeutically effective regimen of three subcutaneous injections of a 40 mg dose of glatiramer acetate over a period of seven days with at least one day between every subcutaneous injection, the regimen being sufficient to alleviate the symptom of the patient.

'250 patent col. 16 ll. 35–45.

Yeda Research and Development Co., Ltd. v. Mylan Pharmaceuticals Inc., Nos. 2017-1594, -1596 (Fed. Cir. October 12, 2018) – appeal from the Board

Mylan Pharmaceuticals, Inc. ("Mylan") filed petitions for inter partes review ("IPR"), challenging all claims of the Copaxone patents on the grounds of obviousness over Pinchasi in view of FDA's 1996 SBOA, and over Pinchasi, in view of Flechter.

The Board considered multiple prior art references including WO 2007/081975 ("Pinchasi") that disclose a 40mg GA every other day dosing regimen for the treatment of RRMS. Pinchasi cited to the data from another study to conclude that the increased efficacy observed with 40 mg/day GA in reducing disease activity and a relapse rate indicated that it was well tolerated and could improve the treatment of RRMS patients.  Pinchasi describes that the improvement in efficacy, however, was not accompanied by a corresponding increase of adverse reactions which would be expected upon a doubling of the administered dose. The Board also considered a 2002 study by Flechter that evaluated treatment of RRMS with 20mg of GA administered every other day. Flechter concluded that the alternate-day treatment with GA was safe, well tolerated, and probably as effective as daily GA in reducing a relapse rate and slowing neurologic deterioration. Flechter noted that patient dropout rates decreased when GA was administered every other day as opposed to daily.

The Board also acknowledged that prior to COPAXONE® 40mg/mL, in 1996 FDA approved Teva's New Drug Application for COPAXONE® 20mg injected daily. The FDA recommended that Teva "evaluate the necessity of daily [GA] injections as opposed to more infrequent intermittent administration of the drug," because the daily dosing regimen subjected patients to an excessive amount of discomfort, if it is not necessary to maintain efficacy.

The Board first noted that Pinchasi disclosed every limitation of the independent claims of the Copaxone patents, except for the claimed dosing regimen. The Board found that there would have been a motivation to use a 40mg dose, crediting the testimony of Petitioners' expert, Dr. Green, who noted that Pinchasi demonstrated increased efficacy of 40mg GA compared to 20mg with no significant difference in side effects, and cited a study which concluded that daily administration of 40mg GA was effective, safe, and well tolerated. In reaching this finding, the Board also found that FORTE, a phase III clinical trial comparing 40mg GA and 20mg GA, would not have taught away from using 40mg (as argued by Yeda), because it did not criticize, discredit, or discourage the 40mg GA dose.

The Board next considered whether there was a motivation to modify Pinchasi's 40mg every other day regimen. The Board noted that the difference between the challenged claims (6 doses over 2 weeks) and Pinchasi (7 doses over 2 weeks) was only one less injection every two weeks. The Board had found motivation to eliminate one injection every other week to increase patient compliance, relying in part on Petitioners' expert Dr. Green, who testified that decreasing the frequency of injections helps with patient adherence to the treatment regimen, and FDA's 1996 SBOA, which recommended that the necessity of daily injections, as opposed to less frequent administration, be evaluated. The Board further relied on other prior art references, which showed that the alternate-day dosing of 20 mg was safe, well-tolerated, as effective as daily 20mg, reduced injection reactions, and that patients in the daily-injection group preferred less  frequent dosing. The Board also found Khan 2009 (not prior art) probative of the fact of motivation to investigate dosing regimens of GA with fewer injections to improve patient compliance. The Board then concluded that, in light of the evidence presented, a POSITA would have had a reason to modify Pinchasi's dosing regimen of 40mg GA every other day to 40mg GA 3x/week, thus rendering the claimed 40mg 3x/week limitation obvious.

Regarding a non-prior art reference, Khan 2009, relied upon by the Board in the obviousness determination, the district court pointed out that the question was whether the Board could rely on non-prior art evidence in considering the knowledge, motivations, and expectations of a POSITA regarding the prior art.

The Federal Circuit ("the Court") agreed that the Board properly relied on evidence other than just prior art in this case. The Board had recognized that non-prior art evidence of what was known "cannot be applied, independently, as teachings separately combinable" with other prior art, but "can be relied on for their proper supporting roles, e.g., indicating the level of ordinary skill in the art, what certain terms would mean to one with ordinary skill in the art, and how one with ordinary skill in the art would have understood a prior art disclosure." The Court concluded that Khan 2009 was probative of the fact that those skilled in the art were motivated to investigate dosing regimens of GA with fewer injections to improve patient compliance.

On appeal, Yeda disputed the Board's conclusion of obviousness by also arguing that the Board disregarded certain uncertainties associated with the fact that GA's pharmacokinetic and pharmacodynamic ("pk/pd") profile, mechanism of action, optimal dose, and active species were all unknown. Yeda cited to In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litigation, 676 F.3d 1063 (Fed. Cir. 2012).

The Court clarified that in Cyclobenzaprine, "we held that bioequivalence alone could not establish obviousness because . . . 'skilled artisans could not predict whether any particular PK profile, including a bioequivalent one, would produce a therapeutically effective formulation." 676 F.3d at 1070.  However, in Cyclobenzaprine, "there were no prior art clinical studies to suggest what would be a therapeutically effective formulation. We do not read Cyclobenzaprine as establishing a rigid rule categorically precluding obviousness determinations without pk/pd data. Here, however, the Board committed no such error; the record is replete with prior art that would have taught or suggested a therapeutically effective formulation to a POSITA. The Board pointed to clinical studies that taught the effectiveness of 20mg daily (Copaxone® 20mg), 20mg every other day (Flechter, Khan 2008, Caon), and 40mg daily (Cohen, FORTE), and the Pinchasi application, which suggested that 40mg every other day would be therapeutically effective. The Board's finding that the uncertainty around GA's mechanism of action would motivate a POSITA to stick to dosing regimens with existing clinical support, such as 20mg and 40mg, is supported by substantial evidence from Dr. Green (Petitioner's expert)." The Court concluded that because the expectation of success need only to be reasonable, not absolute, there was no error in these findings.

The Court found no hindsight in the Board's analysis. "Here, far from a 'sea of prior art,' the references before the Board presented a finite and known pool of dose and frequency options easily traversed to show obviousness. The dosages in the prior art that had clinical support for being effective and safe consisted of only two: 20mg and 40mg. The prior art disclosed both daily and every other day administration, and the Board found a motivation for both less frequent injections and a thrice-weekly regimen specifically."  The Court found no clear error in the Board's finding that the "[p]otent and promising activity in the prior art" would have encouraged a POSITA "to traverse the experimental options to produce this invention," given the small field of prior art references with clinical support.

In light of the foregoing, the Court concluded that substantial evidence supported the Board's reliance on the clinical data and its conclusion that a POSITA would have been motivated to combine Pinchasi's 40mg every other day dose with a less frequent dosing regimen, such as 3x/week, and would have had a reasonable expectation of success in therapeutic effectiveness and patient compliance. Accordingly, the Court affirmed the Board's finding that the 40mg GA 3x/week regimen was obvious in light of the prior art.

In a companion case that consolidated five district court cases (ANDA related litigation), Teva Pharmaceuticals USA, Inc. v. Sandoz Inc., No. 17-1575 (Fed. Cir. Oct. 12, 2018), collectively "Teva" and Yeda appealed the decision of the District Court for the District of Delaware invalidating all asserted claims of the patents directed to COPAXONE® 40mg/mL.  The Court of Appeals for the Federal Circuit affirmed.

Teva argued that the district court impermissibly relied on hindsight and an improper "obvious to try" analysis, and analyzed the obviousness of individual claim elements, rather than the invention as a whole. Teva also maintained that the district court's decision was at odds with the  decision in In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litigation, 676 F.3d 1063 (Fed. Cir. 2012).

The Court again explained two categories of impermissible "obvious to try" analyses that run afoul of KSR and § 103: "when what was 'obvious to try' was (a) to vary all parameters or try every available option until one succeeds, where the prior art gave no indication of critical parameters and no direction as to which of many possibilities is likely to be successful; or (b) to explore a new technology or general approach in a seemingly promising field of experimentation, where the prior art gave only general guidance as to the particular form or method of achieving the claimed invention." The Court distinguished the present case and said that it fell into neither of the two impermissible categories. "Here, the prior art focused on two critical variables, dose size and injection frequency, and provided clear direction as to choices likely to be successful in reducing adverse side effects and increasing patient adherence."  The Court pointed out that only two GA dose sizes had been shown to be effective, safe, and well-tolerated (20mg and 40mg).  The Court agreed with the district court that cited prior art that encouraged to pursue a less frequent than daily dosing regimen. The district court properly relied on certain references that were not statutory prior art, as probative references that persons of skill in the art were interested in pursuing less frequent dosing regimens. "Given this motivation, a POSITA had only a limited number of permutations of dose and frequency to explore that were not already disclosed in the prior art."

Teva further argued that the district court narrowed the universe of possible GA regimens and used hindsight. The Court disagreed because "the district court had ample evidence besides hindsight and the disclosures" on which to find a thrice-weekly dosing regimen of 40mg GA to be obvious to try. The Court explained that although the universe of potential GA doses was theoretically unlimited, the universe of dosages in the prior art that had clinical support for being effective and safe consisted of only two doses: 20mg and 40mg. "This is not a situation where the prior art gave no direction in how to reach a successful result; the prior art clearly indicated that less frequent doses should be explored" and that higher doses could increase efficacy while not affecting adverse reactions.  "We recognize that the prior art did not conclusively teach that a regimen of 40mg GA 3x/week would be effective. However, '[c]onclusive proof of efficacy is not necessary to show obviousness. All that is required is a reasonable expectation of success.'"

Teva also argued that prior to the invention, higher doses of GA were not necessarily known to be more effective, GA's pharmacokinetic and pharmacodynamic ("pk/pd") profile was and remains unknown, GA's mechanism of action was still unknown, and the cause of patient's reactions to injections of GA was unknown. Teva argued that the unpredictable nature of GA categorically precluded the obvious-to-try analysis employed by the district court.

The Court replied that "[w]e do not read Cyclobenzaprine as establishing a rigid rule categorically precluding obviousness findings without pk/pd data. Further, Cyclobenzaprine is distinguishable in that, there, the obviousness proof relied entirely on the bioequivalence of certain pharmacokinetic profiles. Bioequivalence is not argued here; instead, obviousness is proven through human clinical studies establishing the safety, efficacy, and tolerability of GA at doses and dose frequencies similar to the claimed regimen. In this case, the evidence shows that pk/pd data was largely irrelevant to the invention. Numerous clinical studies in the prior art describe GA and its effects on the human body. Although the precise mechanism of GA is not known, it is known to be immunomodulating—i.e., it changes the immune system—and is not necessarily measurable in the bloodstream and its levels are not indicative of efficacy. Testimony was given at trial that pharmacokinetic studies for drugs like GA are less appropriate than for small molecule drugs, such as those at issue in Cyclobenzaprine. GA was also known to be "forgiving," in that occasional missed doses would not reduce efficacy, and that fact gave POSITAs further confidence in eliminating one dose every two weeks. Higher doses were clinically shown to be at least as effective as lower doses."

The Court held that the existence of the studies showed a motivation to provide less frequent dose regiments and the 40mg GA 3x/week regimen was obvious in light of the prior art despite the argued lack of expectations of success, hindsight, and failure to follow the minimum effective dose principle. The Court found no clear error in the conclusion that a POSITA would have been motivated to combine the 40mg GA dose, which had proven efficacy, with a 3x/week frequency, which was desirable because the prior art indicated that less frequent administration increased patient adherence while maintaining efficacy.

***

Applicants should search not only for prior knowledge before the priority date, but monitor more recent developments and publications that could be used as probative evidence, e.g., to show motivation to try, a reasonable expectation of success, the level of a skilled artisan, the meaning of terms to one with ordinary skill in the art, and how one with ordinary skill in the art would have understood a prior art disclosure.

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.

Authors
Similar Articles
Relevancy Powered by MondaqAI
 
In association with
Related Topics
 
Similar Articles
Relevancy Powered by MondaqAI
Related Articles
 
Related Video
Up-coming Events Search
Tools
Print
Font Size:
Translation
Channels
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
Password
Confirm Password
Position
Mondaq Topics -- Select your Interests
 Accounting
 Anti-trust
 Commercial
 Compliance
 Consumer
 Criminal
 Employment
 Energy
 Environment
 Family
 Finance
 Government
 Healthcare
 Immigration
 Insolvency
 Insurance
 International
 IP
 Law Performance
 Law Practice
 Litigation
 Media & IT
 Privacy
 Real Estate
 Strategy
 Tax
 Technology
 Transport
 Wealth Mgt
Regions
Africa
Asia
Asia Pacific
Australasia
Canada
Caribbean
Europe
European Union
Latin America
Middle East
U.K.
United States
Worldwide Updates
Registration (you must scroll down to set your data preferences)

Mondaq Ltd requires you to register and provide information that personally identifies you, including your content preferences, for three primary purposes (full details of Mondaq’s use of your personal data can be found in our Privacy and Cookies Notice):

  • To allow you to personalize the Mondaq websites you are visiting to show content ("Content") relevant to your interests.
  • To enable features such as password reminder, news alerts, email a colleague, and linking from Mondaq (and its affiliate sites) to your website.
  • To produce demographic feedback for our content providers ("Contributors") who contribute Content for free for your use.

Mondaq hopes that our registered users will support us in maintaining our free to view business model by consenting to our use of your personal data as described below.

Mondaq has a "free to view" business model. Our services are paid for by Contributors in exchange for Mondaq providing them with access to information about who accesses their content. Once personal data is transferred to our Contributors they become a data controller of this personal data. They use it to measure the response that their articles are receiving, as a form of market research. They may also use it to provide Mondaq users with information about their products and services.

Details of each Contributor to which your personal data will be transferred is clearly stated within the Content that you access. For full details of how this Contributor will use your personal data, you should review the Contributor’s own Privacy Notice.

Please indicate your preference below:

Yes, I am happy to support Mondaq in maintaining its free to view business model by agreeing to allow Mondaq to share my personal data with Contributors whose Content I access
No, I do not want Mondaq to share my personal data with Contributors

Also please let us know whether you are happy to receive communications promoting products and services offered by Mondaq:

Yes, I am happy to received promotional communications from Mondaq
No, please do not send me promotional communications from Mondaq
Terms & Conditions

Mondaq.com (the Website) is owned and managed by Mondaq Ltd (Mondaq). Mondaq grants you a non-exclusive, revocable licence to access the Website and associated services, such as the Mondaq News Alerts (Services), subject to and in consideration of your compliance with the following terms and conditions of use (Terms). Your use of the Website and/or Services constitutes your agreement to the Terms. Mondaq may terminate your use of the Website and Services if you are in breach of these Terms or if Mondaq decides to terminate the licence granted hereunder for any reason whatsoever.

Use of www.mondaq.com

To Use Mondaq.com you must be: eighteen (18) years old or over; legally capable of entering into binding contracts; and not in any way prohibited by the applicable law to enter into these Terms in the jurisdiction which you are currently located.

You may use the Website as an unregistered user, however, you are required to register as a user if you wish to read the full text of the Content or to receive the Services.

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 or with the prior written consent of Mondaq. You may not use electronic or other means to extract details or information from the Content. Nor shall you extract information about users or Contributors in order to offer them any services or products.

In your use of the Website and/or Services you shall: comply with all applicable laws, regulations, directives and legislations which apply to your Use of the Website and/or Services in whatever country you are physically located including without limitation any and all consumer law, export control laws and regulations; provide to us true, correct and accurate information and promptly inform us in the event that any information that you have provided to us changes or becomes inaccurate; notify Mondaq immediately of any circumstances where you have reason to believe that any Intellectual Property Rights or any other rights of any third party may have been infringed; co-operate with reasonable security or other checks or requests for information made by Mondaq from time to time; and at all times be fully liable for the breach of any of these Terms by a third party using your login details to access the Website and/or Services

however, you shall not: do anything likely to impair, interfere with or damage or cause harm or distress to any persons, or the network; do anything that will infringe any Intellectual Property Rights or other rights of Mondaq or any third party; or use the Website, Services and/or Content otherwise than in accordance with these Terms; use any trade marks or service marks of Mondaq or the Contributors, or do anything which may be seen to take unfair advantage of the reputation and goodwill of Mondaq or the Contributors, or the Website, Services and/or Content.

Mondaq reserves the right, in its sole discretion, to take any action that it deems necessary and appropriate in the event it considers that there is a breach or threatened breach of the Terms.

Mondaq’s Rights and Obligations

Unless otherwise expressly set out to the contrary, nothing in these Terms shall serve to transfer from Mondaq to you, any Intellectual Property Rights owned by and/or licensed to Mondaq and all rights, title and interest in and to such Intellectual Property Rights will remain exclusively with Mondaq and/or its licensors.

Mondaq shall use its reasonable endeavours to make the Website and Services available to you at all times, but we cannot guarantee an uninterrupted and fault free service.

Mondaq reserves the right to make changes to the services and/or the Website or part thereof, from time to time, and we may add, remove, modify and/or vary any elements of features and functionalities of the Website or the services.

Mondaq also reserves the right from time to time to monitor your Use of the Website and/or services.

Disclaimer

The Content is general information only. It is not intended to constitute legal advice or seek to be the complete and comprehensive statement of the law, nor is it intended to address your specific requirements or provide advice on which reliance should be placed. Mondaq and/or its Contributors and other suppliers make no representations about the suitability of the information contained in the Content for any purpose. All Content provided "as is" without warranty of any kind. Mondaq and/or its Contributors and other suppliers hereby exclude and disclaim all representations, warranties or guarantees with regard to the Content, including all implied warranties and conditions of merchantability, fitness for a particular purpose, title and non-infringement. To the maximum extent permitted by law, Mondaq expressly excludes all representations, warranties, obligations, and liabilities arising out of or in connection with all Content. In no event shall Mondaq 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 of the Content or performance of Mondaq’s Services.

General

Mondaq may alter or amend these Terms by amending them on the Website. By continuing to Use the Services and/or the Website after such amendment, you will be deemed to have accepted any amendment to these Terms.

These Terms shall be governed by and construed in accordance with the laws of England and Wales and you irrevocably submit to the exclusive jurisdiction of the courts of England and Wales to settle any dispute which may arise out of or in connection with these Terms. If you live outside the United Kingdom, English law shall apply only to the extent that English law shall not deprive you of any legal protection accorded in accordance with the law of the place where you are habitually resident ("Local Law"). In the event English law deprives you of any legal protection which is accorded to you under Local Law, then these terms shall be governed by Local Law and any dispute or claim arising out of or in connection with these Terms shall be subject to the non-exclusive jurisdiction of the courts where you are habitually resident.

You may print and keep a copy of these Terms, which form the entire agreement between you and Mondaq and supersede any other communications or advertising in respect of the Service and/or the Website.

No delay in exercising or non-exercise by you and/or Mondaq of any of its rights under or in connection with these Terms shall operate as a waiver or release of each of your or Mondaq’s right. Rather, any such waiver or release must be specifically granted in writing signed by the party granting it.

If any part of these Terms is held unenforceable, that part shall be enforced to the maximum extent permissible so as to give effect to the intent of the parties, and the Terms shall continue in full force and effect.

Mondaq shall not incur any liability to you on account of any loss or damage resulting from any delay or failure to perform all or any part of these Terms if such delay or failure is caused, in whole or in part, by events, occurrences, or causes beyond the control of Mondaq. Such events, occurrences or causes will include, without limitation, acts of God, strikes, lockouts, server and network failure, riots, acts of war, earthquakes, fire and explosions.

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