Orange Book Blog

At the intersection of Patent and FDA Law

Recent Posts

  • Federal Circuit Revives Mutual’s Antitrust Counterclaims Arising From Temazepam ANDA Litigation

    Tyco Healthcare et al. v. Mutual Pharm. et al., No. 2013-1386 (Fed. Cir.)

        by Aaron F. Barkoff

    In 2006, Mutual filed an ANDA for a generic version of Restoril (temazepam), including a paragraph IV certification to Tyco's U.S. Patent No. 5,211,954.  Tyco filed suit against Mutual under 35 USC 271(e)(2), Mutual responded with antitrust counterclaims (which the court temporarily stayed pending resolution of the case), and the case proceeded to judgment.

    The district court found in 2009 that Mutual did not infringe the '954 patent under section 271(e)(2) because Mutual's product, when manufactured to the ANDA's specification (i.e., where temazepam has a specific surface area of at least 2.2 m2/g), could not infringe the patent (which claims temazepam having a specific surface area of 0.65-1.1 m2/g).

    On August 5, 2009, the day after the district court entered its judgment of noninfringement, Tyco filed a citizen petition urging the FDA to change the criteria for evaluating the bioequivalence of generic temazepam products in order to "help ensure therapeutic equivalence."  On September 8, 2009, while the citizen petition was still pending, the FDA approved Mutual's ANDA.  The FDA denied Tyco's citizen petition in its entirety five months later.

    After the Federal Circuit affirmed the district court's later decision that the '954 patent was invalid for obviousness, the district court lifted the stay of Mutual's antitrust counterclaims.  In an opinion on January 18, 2013, the district court granted summary judgment to Tyco on Mutual's counterclaims, which, according to the Federal Circuit, were based on four arguments:

    1. That Tyco's section 271(e)(2) infringement claim constituted sham litigation that subjected Tyco to antitrust liability for using illegitimate means to keep Mutual's product off the market.
    2. That no reasonable litigant could have expected Tyco's patent to withstand a validity challenge.
    3. That Tyco's citizen petition was a sham.
    4. That Tyco's infringement suit was the product of fraud under Walker Process.

    In a 2-1 decision last week (over Judge Newman's dissent), the Federal Circuit affirmed two aspects of the district court decision and vacated two others.  The court affirmed the summary judgment against Mutual's claim that no reasonable litigant could have expected Tyco's patent to be upheld as valid and affirmed the summary judgment against Mutual's Walker Process fraud claim.  The court vacated the summary judgment that Tyco's infringement claim under 271(e)(2) was not sham and that Tyco's citizen petition to the FDA was not a sham.

    The premise of Mutual's argument that Tyco's 271(e)(2) infringement claim was a sham was that Mutual's ANDA specified that the temazepam in Mutual's ANDA product would have a specific surface area outside of the range claimed in the '954 patent.  The Federal Circuit stated that "it is not unreasonable for a patent owner to allege infringement under section 271(e)(2)(A) if the patent owner has evidence that the as-marketed commercial ANDA product will infringe, even though the hypothetical product specified in the ANDA could not infringe."  But the court found that there was conflicting evidence concerning the specific surface area of the temazepam in Mutual's ANDA product, and remanded for the district court to "determine whether Mutual has shown that the subjective element of the sham-litigation test has been satisfied."

    Similarly, the Federal Circuit found that there were disputed issues of fact precluding summary judgment with respect to whether Tyco's citizen petition was a sham.  The court stated:

    Particularly probative of whether the citizen petition was reasonable is the FDA's response, which denied the petition in terms indicating that, in the FDA's view, it was wholly without merit.  The FDA found that Tyco had "provided no evidence from clinical trials, pharmacokinetic studies, bioequivalence testing, or any other source . . . .  Instead the petition relies entirely on uncorroborated generalities and theoretical speculation to support its critical point."

    The court also noted that "Mutual's expert reviewed the citizen petition and concluded that 'Tyco did not have a scientific basis to conclude that Mutual's production would not be bioequivalent to Restoril.'"  The court concluded, "The testimony of Mutual's expert and the FDA's response to the citizen petition are sufficient evidence from which a reasonable finder of fact could conclude that Tyco's citizen petition was objectively baseless."

    With regard to the subjective prong of the test, the Federal Circuit found it significant that Tyco filed the citizen petition just one day after the district court granted summary judgment of noninfringement.  Mutual argued that "filing the citizen petition at that late date caused the FDA to delay the approval of Mutual's ANDA, and thus resulted in a further period of market exclusivity for Tyco."  Mutual also pointed to an email from Tyco's R&D group stating that a temazepam formulation that was bioequivalent to Restoril could be made from temazepam having a different specific surface area.  The court concluded, "The timing of the citizen petition and the email are sufficient evidence from which a reasonable finder of fact could determine that Mutual had satisfied the subjective element necessary to show that Tyco's citizen petition was a sham."

    The Federal Circuit found, however, that there was an open issue "as to whether the filing of the citizen petition caused any antitrust injury to Mutual."  Thus, the court remanded the case with instructions for the district court to "determine whether Mutual suffered an anticompetitive harm in the form of a delay in the approval of its ANDA due to the filing of Tyco's citizen petition with the FDA."

  • ACI “Women Leaders in Life Sciences Law” Conference, Boston, MA, July 28-29

    We are proud that McAndrews Shareholder Nabeela Rasheed will be one of the featured speakers at American Conference Institute's inaugural "Women Leaders in Life Sciences Law" conference in Boston, July 28-29.  Dr. Rasheed will be speaking on "Thinking Like a Leader: Updates on the Substantive Legal Developments Affecting Life Sciences Companies in 2014 and Beyond."

    The conference will also include these presentations:

    • "Breaking Through the Glass Ceiling: Increasing the Prominence of Women in Leadership Positions in Life Sciences Law"
    • "Being a Successful GC–How to Keep All the Balls in the Air Without Losing Your Mind"
    • "Owning It: Recognizing the Distinct Communication Styles Between Women and Men and Cultivating the Traits That Stand Out in a Leader"
    • "Spotlight on Women Power Players Shaping the Future of Life Sciences Law in the Government"
    • "I Don't Know How She Does It: How Women Leaders in the Increasingly Demanding Life Sciences Legal Space Can Make the Most Out of Both Life and Career"
    • "Interactive Open Floor Discussion on the Challenges and Opportunities Facing Women in Life Sciences Law"

    In addition, ACI will be hosting two post-conference working groups on July 29: "I Wish Someone Had Told Me: Advice from Life Sciences General Counsel on Embracing Influence and Power and Running a Successful Legal Department" and "Combating Gender Sterotypes in the Life Sciences Legal Community: Open Forum and Working Group on Overcoming Implicit Bias."

    Orange Book Blog readers can receive $200 off the registration fee with discount code OBB 200.  For more information or to register, please visit the conference website.

  • Meet Us at BIO 2014 in San Diego!

    A group of twelve attorneys from McAndrews, Held & Malloy will be attending BIO 2014 in San Diego this week, and we're hosting a cocktail reception on Tuesday night.  Please join us if you'll be attending BIO!

      Invite

     

  • ACI “Legal and Regulatory Summit on Generic Drugs,” New York City, July 24-25

    American Conference Institute will be holding its 2nd annual "Legal and Regulatory Summit on Generic Drugs" in New York on July 24-25.  The conference promises to present "comprehensive strategies for the generic pharmaceutical industry's present and future challenges."

    Here is the complete agenda:

    • Unearthing Changes at the Office of Generic Drugs and Understanding Their Impact on the Future Growth and Evolution of the Generic Drug Industry
    • Deciphering GDUFA and Its Impact on ANDA Approvals, Profit Margins, and Performance Metrics
    • Demystifying the FDA's Rulemaking Authority: Exploring How FDA's Proposed Labeling Rule and Other Proposed Rules and Guidances Will Affect the Dynamics of the Generic Pharmaceutical Industry
    • The Changing Paradigm of the Generic Drug Market Entry: Assessing Brand Name Drug Vulnerabilities and New Targets for Generic Drug Manufacturers
    • Operating in the Post-Bartlett Landscape in Light of New Decisions and FDA Rulemaking
    • The Case for Generic Drug Quality: Understanding How Quality Initiatives in Congress and FDA, and DOJ Enforcement Activity Have Impacted the Generic Drug Industry
    • Mitigating the Effects of New Stability Data Requirements to Ensure the Integrity of Generic Drugs
    • Exploring Strategies for Biosimilar Development in the United States: Regulatory, IP & Commercial Considerations Gleaned from the Global Framework
    • Exploring New Developments and Related Tactics in Hatch-Waxman Litigation That Are Impacting the Strategies of Generic Drug Manufacturers
    • Developing Settlement and Negotiation Methods Post-Actavis to Minimize Chances of Costly Government Enforcement Actions
    • View from the Bench: The Judges Speak on Major Developments Affecting the Generic Drug Industry
    • Comprehending How Mergers and Acquisition Activity and Collaborative Partnerships Are Impacting and Changing the Dynamics of the Generic Pharmaceutical Industry
    • Examining Provisions of the Affordable Care Act Impacting Generic Drug Pricing and Reimbursement

    ACI is also offering two pre-conference workshops on July 23: "Understanding and Working with the FDA's Office of Generic Drugs: Jurisdiction, Organization, and Operations" and "OGD Roundtable: Gaining Priceless Insights on the Inner Workings of the FDA's OGD from Former OGD Officials."

    Orange Book Blog readers will receive $200 off registration fees with discount code OBB 200.  For more information or to register, please visit the conference website.

  • Janssen Files Motion to Dismiss Celltrion’s DJ Complaint, Claiming Celltrion is Trying to “Side-Step” the BPCIA

    Celltrion Healthcare v. Janssen Biotech, No. 14-11613 (D. Mass.)

        by Sandra A. Frantzen

    As we previously reported, Celltrion filed a Complaint for Declaratory Judgment against Janssen Biotech on March 31, seeking a declaration of invalidity and unenforceability of three Janssen patents.  In its complaint, Celltrion alleged that Remsima®, a biosimilar version of Janssen's Remicade® (infliximab), "will become the first biosimilar of an antibody drug ever approved in the United States."  Celltrion's DJ complaint, filed before its biosimilar application, states that Celltrion intends to apply for marketing approval of Remsima® during the first half of 2014 and expects FDA approval by early 2015.  Celltrion alleges that because "it expects to face infringement allegations from Janssen, Celltrion wants to start the adjudicative process regarding the invalidity and unenforceability of Janssen's patents."

    Last Friday, May 23, Janssen Biotech filed a motion to dismiss Celltrion’s complaint, alleging that subject matter jurisdiction does not exist under the Declaratory Judgment Act because Celltrion "has not established a real and immediate injury or threat of injury."  Janssen claims that Celltrion "is still in negotiations over the content of its application and that the FDA has already required additional clinical testing of Remsima."  Janssen further argues that "there is no way to know when, if ever, Remsima® will be approved for a use that could potentially infringe" one of its patents, claiming that Health Canada "refused to approve Remsima® for treatment of Crohn's disease."  Janssen also argues that the court should exercise its discretionary authority to decline jurisdiction because "the BPCIA [Biologics Price Competition and Innovation Act] is the appropriate way to resolve any future patent disputes between Janssen and Celltrion."

    The BPCIA created an abbreviated regulatory pathway (the "subsection (k) pathway") for the approval of biosimilar drugs.  Under the BPCIA, a company developing a biosimilar version of a licensed biologic product (or "reference product") may file a subsection (k) application with the FDA for licensure.  Once the FDA notifies the company that its application has been accepted for review, the applicant must then provide certain information about its product and manufacturing process to the reference product sponsor.  Under the BPCIA, the parties then engage in a patent information exchange process which may culminate in a patent lawsuit.  As part of this exchange process, the BPCIA provides limitations on declaratory judgment filings under certain circumstances.

    In its motion to dismiss, Janssen argues that Celltrion should not be permitted "to claim there is jurisdiction for this suit based on Celltrion's status as a future 262(k) applicant just so Celltrion can skirt the express limits on declaratory judgment actions Congress deemed appropriate for 262(k) applicants."  Janssen alleged that "[i]f Celltrion is allowed to side-step the patent dispute procedures of the BPCIA, then every prospective biosimilar applicant will be able to evade the statutory regime by filing a declaratory judgment action immediately before filings its biosimilar application with the FDA."  According to Janssen, "[t]his would clearly frustrate the intent of the BPCIA provisions."

    As noted in our prior posting, Celltrion was the second biosimilar company to file a declaratory judgment action in advance of its biosimilar application.  In the first case, Sandoz v. Amgen, the district court dismissed Sandoz's DJ action on jurisdictional grounds.  An appeal is pending at the Federal Circuit and Amgen recently filed its opposition brief.  Celltrion also filed a DJ complaint relating to Remsima® against Kennedy Trust on March 31.  Kennedy's response is due in July.

  • ACI “Biosimilars” Conference, New York, June 5-6

    American Conference Institute is holding their 5th annual "Biosimilars" conference in New York on June 5-6.  Speakers include in-house counsel from Eli Lilly, Mylan, Sandoz, Amgen, AbbVie, Momenta, J&J, and Actavis.  Also speaking will be representatives of the Federal Trade Commission, GPhA, and PhRMA.

    The agenda includes the following presentations:

    • Minimizing the Uncertainty Surrounding the Untested Pathway: Insight Into FDA's Current Position and Initiatives Regarding Biosimilars
    • Predicting Follow-On Entry and Evaluating the Risk and Commercial Opportunity in the Emerging Biosimilar Landscape
    • New Kid No More: Evolution in Biosimilars Science and Regulations
    • The Holy Grail for Biosimilars: Meeting FDA's Requirements for Biosimilarity and the Heightened Standard of Interchangeability
    • FTC Keynote: Revisiting Competition Issues in the Follow-On Biologics Arena: Substitution and Naming Conventions
    • The Importance of Biologic Manufacturer Accountability: Key Policies for Biologic Substitution and Nonproprietary Names
    • Industry Round Table: Weighing in on the Emerging Controversy on Biosimilars Naming and State Substitution Laws
    • The EU Experience: Regulatory and IP Lessons Learned So Far from the First Biosimilar Antibody Approval in Europe
    • Analyzing the Arguments in the First BPCIA Case, Sandoz v. Amgen: Immediate Action Plans for Innovators and Biosimilars to Prepare Before the First Application is Public
    • The Most Powerful Tool in Your Arsenal: Using Inter-Partes Reveiw at the PTO to Revamp Branded and Biosimilar Litigation Strategies
    • Going Beyond the Hatch-Waxman Comparisons: Delving into Pre-Suit Due Diligence and Pre-Litigation Tactics for Evaluating Patent Strength and Assertion Strategies
    • Platform Patents and Antibodies: Specific Action Plans to Protect or Defend Patents Most Ripe for a Biosimilars First Wave Challenge
    • Key IP Case Law Through the Biosimilars Lens: Top 5 Patent Battles to Consider When Updating Your Biosimilars Prosecution and Litigation Strategies
    • Case Spotlight: Momenta v. Amphastar and Bioequivalence: Understanding the Implications for the Future of Biosimilars
    • Timing is Everything: Managing the Logistics of the BPCIA Exchange Process and Preparing for "Early" and "Late" Phase Litigation
    • Ethics in the Biosimilars Realm: Avoiding Conflicts and Maintaining Confidentiality in the Brave New World

    ACI is also offering a pre-conference primer on June 4 that includes two sessions:  "Biosimilars 101: Comprehensive Deep Dive Into the Relevant Legal, Regulatory, and Scientific Factors Companies Must Now" in the morning and "Biosimilars Around the World: A Regulatory and Patent Cheat Sheet to Maximize Global Biosimilars Market Share and Minimize Risk" in the afternoon.

    For more information or to register, please visit the conference website.

  • District of New Jersey Allows ANDA Filer’s Declaratory Judgment Action to Proceed Despite Covenant Not to Sue

    Purdue Pharm. Products v. TWI Pharms., No. 12-5311 (D.N.J.)

        by Alex Menchaca

    In an opinion last week, the U.S. District Court for the District of New Jersey stymied what appears to be an attempt by Purdue Pharma to prevent TWi Pharmaceuticals from obtaining a final judgment of noninfringement of all four Orange Book-listed patents on Intermezzo® (zolpidem tartrate).  A final judgment could trigger the marketing requirement of the first ANDA filer.  If the first filer does not market its product within 75 days of a final judgment, it will forfeit its 180-day exclusivity.

    Purdue holds the NDA for Intermezzo®, a drug used to treat middle-of-the-night insomnia.  Four patents are listed in the Orange Book in connection with the NDA.  By the time TWi filed its ANDA, four other ANDAs had already been filed and presumably at least one of those is entitled to 180-day exclusivity.  Purdue sued TWi on only two of the patents, and granted TWi a covenant not to sue on the other two.  TWi filed a DJ counterclaim for noninfringement of all four Orange Book-listed patents.

    As simplified by the court, TWi's DJ counterclaim is important because it "could potentially trigger the first ANDA filer's 180-day exclusivity period.  This would have the effect of expediting TWi's ability to market its generic version of Intermezzo®."

    Purdue filed a motion to dismiss TWi's counterclaim, presenting three arguments that no case or controversy exists and therefore the court lacks jurisdiction: (1) the "covenant not to sue rendered moot any such controversy," (2) "the Court cannot redress TWi's alleged injury," and (3) "the dispute is not ripe in light of TWi's inability to obtain tentative approval."

    In response to Purdue's mootness argument, the court stated, "[t]here is ample authority supporting the proposition that a later ANDA filer's declaratory judgment claims involving patents for which the patent holder has given a covenant not to sue are justiciable."  The court therefore held that "the binding principles the Federal Circuit set forth in Dey and Caraco compel this Court to conclude that Plaintiffs' covenant not to sue TWi on the '945 and '628 patents does not moot TWi's counterclaims seeking declaratory judgment that these patents are not infringed."

    With regard to whether TWi's injury is redressable, Purdue argued that "a judgment favorable to TWi on the '945 and '628 patents will not redress any injury arising from delay in TWi's ability to market its generic version of Intermezzo® because such a judgment would not independently trigger the first ANDA filer's exclusivity period as TWi has not received tentative approval from the FDA to market its generic product."  In other words, Purdue argued that because "an applicant in TWi's position cannot trigger the first applicant's exclusivity period through a declaratory judgment action unless it has first received tentative approval," the court cannot redress TWi's purported injury.

    The court noted that the Federal Circuit has not addressed whether a subsequent ANDA filer must first have tentative approval to maintain a declaratory judgment action like TWi's.  Nevertheless, it rejected Purdue's argument based largely on Judge Dow's decision in Seattle Children's Hospital v. Akorn (N.D. Ill. 2011).  The Akorn court recognized that the Hatch-Waxman Act "created a civil action to obtain patent certainty ("CAPC") that could be brought by an ANDA applicant at a time when it likely would not have tentative approval," indicating that other DJ actions similarly do not require that the ANDA filer must have tentative approval.  Following Akorn, the court held that tentative approval is not required for TWi to maintain its DJ counterclaim.

    Finally, the court held that the case is indeed ripe, noting that "delaying judicial consideration of TWi's counterclaims could result in depriving TWi of the ability to trigger the first ANDA filer's 180-day exclusivity period, thus causing TWi to lose profits during the period of time it is excluded from the market.  Accordingly, the court found that "delay in resolving TWi's counterclaims will have an immediate and substantial impact on TWi."

    Although not settled until the Federal Circuit weighs in, based on this case and Akorn it appears that the courts will permit ANDA filers to assert DJ counterclaims even before receiving tentative approval from the FDA and despite having a covenant not to sue from the patent owner.

  • ACI “Paragraph IV Disputes” Conference, New York, April 28-28

    American Conference Institute will be holding their 8th annual "Paragraph IV Disputes" conference on April 28-29 in New York.  Highlights of the conference include a district court judges panel, a magistrate judges panel, and an FTC keynote address.  Here is the complete agenda:

    • On the 30th Anniversary of the Drug Price Competition and Patent Term Restoration Act: Understanding Hatch-Waxman's Transformative Impact on the Pharmaceutical Industry
    • Assessing Pharmaceutical Patent Sustainability and Vulnerability: Strategies and Considerations for Brand Names and Generics in Anticipating, Identifying and Determining Which Patents Will be Ripe for Challenges of Invalidity and Non-Infringement
    • Use of IPR and Other PTO Proceedings in a Paragraph IV Challenge: Strategies for Brand Names and Generics in Navigating PTO Proceedings in ANDA Litigation
    • The Gauntlet Rethrown: The Paragraph IV Certification and Notice Letter
    • Of Prior Art and Double Patenting: Exploring the Dichotomy Between the Federal Circuit and PTO on Obviousness Findings and Potential Impact of the Goodlatte Bill on Obviousness-Type Double Patenting
    • Let the Games Begin: Advanced Strategies for Drafting and Perfecting Pleadings and Effectively Using Dispositive Motions in Paragraph IV Disputes
    • Working With Local Counsel and Within Local Rules: Magistrate and Local Counsel Roundtable
    • A View From the Bench: District Court Judges Panel
    • Claim Construction and Markman Hearings: Standards, Jurisprudential Splits and Strategies for Paragraph IV Litigation
    • FTC Keynote: Reverse Payment Settlements and Other Antitrust Concerns Impacting Paragraph IV Litigation in the Wake of Actavis
    • Perils of the Safe Harbor: Understanding How the Resetting of the Boundaries of 271(e)(1) in the Aftermath of Classen and Momenta is Impacting Paragraph IV Litigation Strategies
    • In the Limelight: Strategies and Theories of Inducement, Contributory, and Divided Infringement in Paragraph IV Litigation Concerning Method of Treatment Patents
    • Assessing GDUFA Implementation and Additional Regulatory Developments of FDA Which Impact Paragraph IV Litigation
    • Looking Beyond 180 Days: New Exclusivity Challenges for Brand Names and Generics and Related Implications for Paragraph IV Challenges
    • A Pros and Cons Analysis of Launching At Risk and Survey of New Developments in Seeking Injunctive Relief and Damages
    • Ethical Considerations for Paragraph IV Matters Before the PTO and District Courts: Inequitable Conduct and More

    In addition to the main conference, ACI is offering a post-conference workshop on pharmaceutical patent settlements.

    Orange Book Blog readers can receive discounted registration with code OBB200.  For more information or to register, please visit the conference website.

  • Second Biosimilar Company Files Declaratory Judgment Action Before Filing FDA Application

    Celltrion Healthcare v. Janssen Biotech, No. 14-11613 (D. Mass.)

        by Sandra A. Frantzen

    On March 31, Celltrion filed a Complaint for Declaratory Judgment in the District of Massachusetts against Janssen Biotech, seeking a declaration of invalidity and unenforceability of three Janssen patents.  In its Complaint, Celltrion alleges that it has developed Remsima®, a biosimilar version of Janssen’s infliximab product, which it claims "will become the first biosimilar of an antibody drug ever approved in the United States."  Celltrion's Complaint states that it intends to apply for marketing approval of Remsima® during the first half of 2014 and expects FDA approval by early 2015.  Celltrion alleges that because "it expects to face infringement allegations from Janssen, Celtrion wants to start the adjudicative process regarding the invalidity and unenforceability of Janssen's patents."     

    Celltrion is the second company developing a biosimilar product to file a declaratory judgment action before filing an application for licensure with the FDA.  Last June, Sandoz filed a declaratory judgment action against Amgen and Hoffman-La Roche in the Northern District of California alleging patent invalidity and noninfringement in a case relating to a biosimilar version of Amgen's Enbrel product.   Like Celltrion, Sandoz filed its case before filing a marketing application with the FDA.  As we discussed in a previous post, the district court dismissed the case, holding that Sandoz's declaratory judgment action was premature as there was not yet a "real and immediate injury" to be addressed.  The court further stated that a lawsuit may not be filed "unless and until" a reference product sponsor and biosimilar applicant engage in the "series of statutorily-mandated exchanges of information" under the Biologics Price Competition and Innovation Act ("BPCIA").

    The BPCIA created an abbreviated regulatory pathway ("the subsection (k) pathway") for the approval of "biosimilar" drugs.  Under the BPCIA, a company developing a biosimilar version of a licensed biologic product (or "reference product") may file a subsection (k) application with the FDA for licensure.  Once the FDA notifies the company that its application has been accepted for review, the applicant must then provide certain information about its product and manufacturing process to the reference product sponsor.  Under the Act, the parties then engage in a patent information exchange process which may culminate in a patent lawsuit.  To date, while two lawsuits involving potential biosimilar products have been filed, no company has publicly announced filing a subsection (k) biosimilar application with the FDA.

    The Sandoz v. Amgen case is now on appeal at the Federal Circuit.  Sandoz recently filed its principal brief.  The Defendants' responsive brief is currently due on May 27.

    UPDATE:  Celltrion filed a second Complaint for Declaratory Judgment relating to its Remsima® product–this one in the Southern District of New York against Kennedy Trust for Rheumatology Research and seeking a declaration of invalidity of three Kennedy patents.  Like its allegations against Janssen, Celltrion alleges that it "expects to face patent infringement allegations from Kennedy" over Remsima® and thus "wants to start the adjudicative process . . . and immediately avail itself of the processes available in the federal judiciary to discover information relating to Kennedy’s patents."

  • Federal Circuit Affirms Validity of Pfizer’s Lyrica (Pregabalin) Patent

    Pfizer Inc. et al. v. Teva Pharms. USA et al., No. 2012-1576 (Fed. Cir.)

    Teva and several other generic pharmaceutical companies each submitted an ANDA seeking approval to market a generic version of Lyrica, for treating seizures and pain. In a unanimous decision last Thursday, the Federal Circuit affirmed the judgment of the U.S. District Court for the District of Delaware by finding claim 2 of U.S. Patent Nos. 6,197,819, covering the active ingredient of Lyrica, pregabalin, infringed and not invalid for lack of enablement, written description, or obviousness.

    Pfizer and Northwestern University initally asserted four Orange Book-listed patents against the ANDA filers, but the case ultimately hinged on claim 2 of the '819 patent, which reads quite simply:

    2. 4-amino-3-(2-methylpropyl) butanoic acid, or a pharmaceutically acceptable salt thereof.

    The compound of claim 2 contains a single chiral center, and may exist, for example, in enantiomerically pure (R)- or (S)- forms or a racemic form, the latter containing equal quantities of both enantiomers. Lyrica and the proposed generic products each contain pregabalin, which is only the S-enantiomer of 4-amino-3-(2-methylpropyl) butanoic acid. Before the district court, the defendants asserted that claim 2 of the '819 patent should be interpreted to cover only the racemic form of 4-amino-3-(2-methylpropyl) butanoic acid (also "3-isobutyl-gamma-aminobutyric acid" or "3-isobutylGABA"). If so construed, the proposed products would not literally infringe the claim. Further, the defendants alleged that claim 2 is invalid for failing the enablement and written description requirements of 35 U.S.C. 112(a) and for obviousness under 35 U.S.C. 103 in view of three asserted prior art references.

    The district court's Markman order construed claim 2 of the '819 patent to encompass all stereochemical forms of 3-isobutylGABA. The parties stipulated to infringment by the defendants' proposed products if claim 2 was found valid and enforceable, as interpreted by the district court. This appeal followed the district court's finding that claim 2 of the '819 patent was enforceable and not invalid for the reasons offered by the defendants. On appeal, the defendants asserted that the district court erred in claim construction and its findings with respect to enablement, written description, and obviousness. The Federal Circuit affirmed the district court on all issues.

    With respect to claim construction and infringement, the Federal Circuit declined to read limitations into claim 2 that were not present in the claim text. After noting that the defendants' expert admitted that claim 2 covers "3-isobutylGABA in any isomeric form," the court stated that the '819 patent made clear that the patent applicants were capable of indicating when individual enantiomers and when racemic forms of compounds were intended, by using the appropriate (R,S)- or (R)- or (S)- prefixes. Nor could the court find any clear disavowal in the '819 patent that would indicate that a lack of stereochemical indication was intended to limit the disclosure to only the racemic form. In view of the lack of any stereochemical limitation within claim 2, the court upheld the district court's interpretation and finding of infringement of claim 2 of the '819 patent.

    On enablement, the ANDA filers asserted that if claim 2 were interpreted to cover all compositions of 3-isobutylGABA, regardless of enantiomeric form, then the specification failed to "teach a skilled artisan how to prepare every conceivable mixture of 3-isobutylGABA’s enantiomer." However, the defendants failed to convince the court that such mixtures were anything other than routine to one of ordinary skill in the art. The court noted that the '819 patent disclosed the method for synthesizing the compound and states that the compound's "enantiomers may be prepared or isolated by methods already well known in the art." Citing In re Hogan, 559 F.2d 595, 606 (CCPA 1977), the court declined to require an applicant to disclose "a detailed recipe for preparing every conceivable permutation of the compound they invented to be entitled to a claim covering that compound."

    For written description, Appellant Sun Pharmaceuticals (only) focused on a lack of disclosure by the '819 patent regarding isolation of the individual enantiomers. Sun proposed that since later application filings by the patentee indicated that enantiomer separation for 3-isobutylGABA may have been less than routine, and that the inventors admitted that at the time of filing of their original applications, they had not yet actually separated the 3-isobutylGABA enantiomers, then the applicants were not in possession of the broader claim scope. However, the court found Sun's focus on the enantiomers to be unpersuasive. Rather, the court focused on whether "relevant identifying characteristics" were provided such that "persons of ordinary skill in the art [] recognize that the inventor invented what is claimed." Here, the court noted that disclosure of the claimed structure (in the absence of stereochemical definition), in vitro and in vivo data for the compound, and a method of synthesizing the compound satisfied the statutory requirements.

    Finally, the ANDA applicants argued that the district court erred in finding claim 2 of the '819 patent not obvious in view of three proffered prior art references. The references were alleged to disclose that 3-isopropylGABA and other homologous compounds may have anticonvulsant activity, that 3-isobutylGABA would have been expected to have similar activity because of its close structural simlarity to the former, and that the anti-convulsant gabapentin, another 3-substituted gamma-amino butyric acid (GABA) derivative, provided motivation to try other substitutions as the 3-position of GABA.

    The court applied the two-part test for obviousness of a chemical compound outlined in Eisai and Takeda by reviewing for (1) whether the asserted prior art compound would have been selected as a lead compound for further modification and (2) whether the prior art would have taught a skilled artisan to make the "specific molecular modifications" necessary to the selected lead compound to yield the claimed compound with a reasonable expectation of success.

    As to the first prong, the court reiterated that more than "mere structural similarity" is necessary for a prior art compound to serve as a lead compound. Rather, other properties, such as chemical activity or potency, inform the lead compound selection. Here, the court was unmoved by the offer of either 3-isopropylGABA or gabapentin as a lead compound. The court found insufficient details in the cited art regarding properties of either compound that would have lead to their selection for further research. With respect to gabapentin, the prior art was vague as to whether the compound was in the prior art at all, and if so, whether any of its relevant properties, such as anticonvulsant activities in the context of other anticonvulsants known at the time would have highlighted the compound for further modification. For 3-isopropylGABA, the court noted that the prior art failed to teach its "mechanisms of action, including whether it has anticonvulsive properties."

    Moving to the second prong, the court noted that even if either compound were selected as a lead compound, the proffered art failed to teach the precise modifications necessary to yield 3-isobutylGABA. Rather, the court noted that the cited art merely suggest "trillions" of compounds "without calling out alkyl groups in particular or singling out isobutyl specifically." The court concluded by agreeing with the district court's finding that the appellees had convincingly established the complicated and unpredictable nature of anticonvulsant field at the time of filing, thereby precluding any reasonable expectation of success in achieving anticonvulsant in 3-isobutylGABA "even if Appellants were able to establish that the prior art taught the substitution of isobutyl at GABA’s 3-position."