DCT

1:18-cv-00689

Vanda Pharma Inc v. Apotex Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:18-cv-00689, D. Del., 12/11/2018
  • Venue Allegations: Venue is alleged to be proper in the District of Delaware because Defendant Apotex Corp. is a Delaware corporation, and Defendant Apotex Inc. is a Canadian corporation subject to jurisdiction in any U.S. judicial district.
  • Core Dispute: Plaintiff alleges that Defendants' Abbreviated New Drug Application (ANDA) to market a generic version of Plaintiff's drug HETLIOZ® (tasimelteon) constitutes an act of infringement of seven U.S. patents relating to methods of treating Non-24-Hour Sleep-Wake Disorder and to purified forms of tasimelteon.
  • Technical Context: The technology concerns pharmaceutical treatments for Non-24-Hour Sleep-Wake Disorder, a rare circadian rhythm disorder that primarily affects totally blind individuals who are unable to synchronize their internal body clocks to a 24-hour light/dark cycle.
  • Key Procedural History: This is a Hatch-Waxman action initiated after Plaintiff received Paragraph IV certification notice letters from Defendants on April 3, 2018, and November 16, 2018. Defendants' letters stated their belief that Plaintiff's patents are invalid, unenforceable, and/or will not be infringed by their proposed generic product. The filing of this lawsuit within the statutory 45-day window triggers an automatic 30-month stay on FDA approval of Defendants' generic drug product.

Case Timeline

Date Event
2012-01-26 Priority Date for RE46,604; '995; '234; '913; and '241 Patents
2013-11-12 Priority Date for '910 Patent
2014-01-31 FDA approves Vanda's New Drug Application for HETLIOZ®
2014-02-12 Priority Date for '977 Patent
2015-06-23 U.S. Patent No. 9,060,995 issues
2017-01-10 U.S. Patent No. 9,539,234 issues
2017-01-24 U.S. Patent No. 9,549,913 issues
2017-08-15 U.S. Patent No. 9,730,910 issues
2017-11-14 U.S. Patent No. RE46,604 issues
2018-01-02 U.S. Patent No. 9,855,241 issues
2018-04-03 Vanda receives Apotex's Paragraph IV Notice Letter
2018-09-11 U.S. Patent No. 10,071,977 issues
2018-11-16 Vanda receives Apotex's Supplemental Notice Letter for '977 patent
2018-12-11 Complaint Filing Date

II. Technology and Patent(s)-in-Suit Analysis

U.S. Reissue Patent No. RE46,604 - "Treatment of Circadian Rhythm Disorders"

  • Patent Identification: RE46,604, "Treatment of Circadian Rhythm Disorders," issued November 14, 2017.

The Invention Explained

  • Problem Addressed: The patent addresses Non-24-Hour Sleep-Wake Disorder ("Non-24"), a condition where individuals, primarily those who are totally blind and lack light perception, are unable to synchronize their internal circadian rhythms to the 24-hour day (Compl. ¶39). This results in a "free running" internal clock, causing sleep patterns to drift later each day and leading to cyclical periods of night-time insomnia and daytime sleepiness (’995 Patent, col. 1:47-2:15).
  • The Patented Solution: The invention provides a method to treat Non-24 by administering tasimelteon, a melatonin agonist that binds to melatonin receptors in the suprachiasmatic nucleus of the brain, which acts as the body's master clock (Compl. ¶40; ’995 Patent, col. 2:36-44). Specifically, the patent claims a method of orally administering 20 mg of tasimelteon once daily before a target bedtime to "entrain" the patient's sleep-wake cycle to a 24-hour day (Compl. ¶44).
  • Technical Importance: The invention provides a pharmacological mechanism to entrain the circadian rhythms of patients who lack the primary environmental synchronizing cue of light, addressing a significant unmet medical need (Compl. ¶39).

Key Claims at a Glance

  • The complaint asserts independent claim 1 and dependent claims 6 and 7 (Compl. ¶69, ¶73).
  • The essential elements of independent claim 1 are:
    • A method of entraining a patient suffering from Non-24 to a 24 hour sleep-wake cycle in which the patient awakens at or near a target wake time following a daily sleep period of approximately 7 to 9 hours, and maintaining said 24 hour sleep-wake cycle
    • said method comprising: treating the patient by orally administering to the patient 20 mg of tasimelteon once daily before a target bedtime.
  • The complaint does not explicitly reserve the right to assert other dependent claims for this patent.

U.S. Patent No. 9,060,995 - "Treatment of Circadian Rhythm Disorders"

  • Patent Identification: 9,060,995, "Treatment of Circadian Rhythm Disorders," issued June 23, 2015.

The Invention Explained

  • Problem Addressed: The administration of tasimelteon can be affected by other drugs that inhibit the CYP1A2 enzyme, such as fluvoxamine ('234 Patent, col. 33:65-34:5). Co-administration can lead to a large increase in tasimelteon exposure and a greater risk of adverse reactions (Compl. ¶86).
  • The Patented Solution: The patent claims a specific method for safely treating a Non-24 patient who is currently being treated with fluvoxamine. The claimed method comprises discontinuing the fluvoxamine treatment and then beginning treatment with 20 mg of tasimelteon once daily, thereby avoiding the drug-drug interaction (’995 Patent, Claim 1; Compl. ¶47).
  • Technical Importance: The invention provides a specific safety protocol that allows patients on fluvoxamine to be transitioned to tasimelteon, mitigating the risk of adverse events caused by the known drug interaction.

Key Claims at a Glance

  • The complaint asserts the sole claim of the patent, claim 1 (Compl. ¶90).
  • The essential elements of independent claim 1 are:
    • A method of entraining a light perception impaired patient suffering from Non-24-Hour Sleep-Wake Disorder to a 24-hour sleep-wake cycle...
    • wherein the patient is being treated with fluvoxamine,
    • the method comprising: (A) discontinuing the fluvoxamine treatment and then
    • (B) orally treating the patient with 20 mg of tasimelteon once daily before a target bedtime,
    • thereby avoiding the use of tasimelteon in combination with fluvoxamine.
  • The complaint does not explicitly reserve the right to assert other dependent claims as this is a single-claim patent.

U.S. Patent No. 9,539,234 - "Treatment of Circadian Rhythm Disorders"

  • Patent Identification: 9,539,234, "Treatment of Circadian Rhythm Disorders," issued January 10, 2017.
  • Technology Synopsis: The patent claims methods for treating Non-24 by avoiding the use of tasimelteon in combination with a strong CYP1A2 inhibitor, specifically in a patient who is light perception impaired (LPI) (Compl. ¶49). This addresses the risk of increased tasimelteon exposure and adverse reactions from such drug combinations (Compl. ¶107).
  • Asserted Claims: At least claim 3, which depends from independent claim 1 (Compl. ¶111).
  • Accused Features: The proposed label for Apotex's generic product allegedly instructs physicians to avoid using tasimelteon with strong CYP1A2 inhibitors, thereby inducing infringement of the method claim (Compl. ¶107, ¶111).

U.S. Patent No. 9,549,913 - "Treatment of Circadian Rhythm Disorders"

  • Patent Identification: 9,549,913, "Treatment of Circadian Rhythm Disorders," issued January 24, 2017.
  • Technology Synopsis: This patent claims a method of entraining a patient's cortisol circadian rhythm to a 24-hour cycle by administering tasimelteon (Compl. ¶51). The dysregulation of cortisol rhythms is a physiological consequence of Non-24 (’913 Patent, col. 18:48-52).
  • Asserted Claims: At least claims 1 and 4 (Compl. ¶131).
  • Accused Features: The use of Apotex's product for the treatment of Non-24 is alleged to inherently perform the claimed method of entraining the patient's cortisol rhythm (Compl. ¶129, ¶131).

U.S. Patent No. 9,730,910 - "Treatment of Circadian Rhythm Disorders"

  • Patent Identification: 9,730,910, "Treatment of Circadian Rhythm Disorders," issued August 15, 2017.
  • Technology Synopsis: The patent claims a method for treating a patient with a circadian rhythm disorder who is also being treated with rifampicin (also known as rifampin), a strong CYP3A4 inducer (Compl. ¶53-54). The method involves discontinuing rifampicin and then treating with tasimelteon to avoid reduced exposure to tasimelteon (’910 Patent, Claim 1).
  • Asserted Claims: At least claim 2, which depends from independent claim 1 (Compl. ¶152).
  • Accused Features: The proposed label for Apotex's product allegedly instructs physicians to avoid using tasimelteon with rifampin, which is alleged to induce infringement of the claimed method (Compl. ¶148, ¶152).

U.S. Patent No. 9,855,241 - "Treatment of Circadian Rhythm Disorders"

  • Patent Identification: 9,855,241, "Treatment of Circadian Rhythm Disorders," issued January 2, 2018.
  • Technology Synopsis: The patent claims methods of synchronizing a patient's abnormal cortisol circadian rhythm and abnormal melatonin circadian rhythm with the natural day/night cycle by orally administering an effective amount of tasimelteon (Compl. ¶56).
  • Asserted Claims: At least claim 4, which depends from independent claim 1 (Compl. ¶172).
  • Accused Features: The use of Apotex's product for the treatment of Non-24 is alleged to inherently perform the claimed method of synchronizing the patient's cortisol and melatonin rhythms (Compl. ¶170, ¶172).

U.S. Patent No. 10,071,977 - "Highly Purified Pharmaceutical Grade Tasimelteon"

  • Patent Identification: 10,071,977, "Highly Purified Pharmaceutical Grade Tasimelteon," issued September 11, 2018.
  • Technology Synopsis: This patent addresses the problem that the synthesis of tasimelteon can result in impurities, some of which are potentially genotoxic and must be controlled to very low levels for the drug to be safe and effective (Compl. ¶42). The patent claims processes for synthesizing highly purified tasimelteon and the purified tasimelteon product itself, defined by the absence of certain enumerated impurities above a specific concentration (Compl. ¶58).
  • Asserted Claims: At least claims 1, 18, 22, 23, and 24 (Compl. ¶196).
  • Accused Features: Apotex's ANDA product is alleged to be a highly purified form of tasimelteon that infringes the product claims and is made by a process that infringes the process claims (Compl. ¶191, ¶195).

III. The Accused Instrumentality

  • Product Identification: The accused instrumentality is Apotex's generic tasimelteon oral capsules in a 20 mg strength, for which Apotex seeks FDA approval under Abbreviated New Drug Application (ANDA) No. 211607 (the "Apotex ANDA Product") (Compl. ¶5, ¶12).
  • Functionality and Market Context: The Apotex ANDA Product is intended to be a generic version of Vanda's HETLIOZ® capsules for the treatment of Non-24-Hour Sleep-Wake Disorder (Compl. ¶12, ¶66). As a generic drug, its active ingredient, dosage form, and strength are the same as the branded product (Compl. ¶66, ¶87). The infringement allegations rely heavily on the assertion that the proposed label for the Apotex ANDA Product will "essentially copy" the FDA-approved label for HETLIOZ®, as required by FDA regulations, and will therefore instruct physicians and patients to use the drug in a manner that infringes Vanda's method patents (Compl. ¶69, ¶90). The product is intended to be a lower-cost alternative that will directly compete with and displace sales of HETLIOZ® (Compl. ¶31).

No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

RE46,604 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method of entraining a patient suffering from Non-24 to a 24 hour sleep-wake cycle... Apotex's ANDA seeks approval for a product indicated for the treatment of Non-24-Hour Sleep-Wake Disorder (Non-24). ¶63, ¶66 '995 Patent, col. 2:24-27
...in which the patient awakens at or near a target wake time following a daily sleep period of approximately 7 to 9 hours, and maintaining said 24 hour sleep-wake cycle... The proposed product label allegedly instructs a method of use that achieves this clinical outcome, which is the ultimate treatment goal for individuals with Non-24. ¶39, ¶44 '995 Patent, col. 2:28-35
...said method comprising: treating the patient by orally administering to the patient 20 mg of tasimelteon once daily before a target bedtime. The Apotex ANDA Product is a 20 mg oral capsule of tasimelteon, and its proposed label allegedly instructs physicians that the recommended dosage is 20 mg per day taken before bedtime. ¶64, ¶66 '995 Patent, col. 3:3-11
  • Identified Points of Contention:
    • Scope Questions: The claim includes result-oriented language, such as "entraining a patient" and "maintaining said 24 hour sleep-wake cycle." A potential point of contention is whether the act of administering the drug as instructed on the label is sufficient for infringement, or if infringement requires proof that the claimed "entraining" and "maintaining" results are actually achieved in the patient.
    • Technical Questions: What evidence does the complaint provide that following the alleged instructions on Apotex's proposed label will necessarily result in a patient awakening "at or near a target wake time following a daily sleep period of approximately 7 to 9 hours"? The infringement allegation rests on the premise that the instructed use inevitably produces the claimed outcome.

9,060,995 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method of entraining a light perception impaired patient suffering from Non-24-Hour Sleep-Wake Disorder... Apotex's ANDA Product is indicated for the treatment of Non-24, a disorder that primarily affects light perception impaired patients. ¶39, ¶84 '995 Patent, col. 1:47-53
...wherein the patient is being treated with fluvoxamine... The proposed label allegedly instructs physicians to avoid co-administration of tasimelteon with fluvoxamine, contemplating a patient population that is or could be treated with fluvoxamine. ¶86 '995 Patent, col. 33:65-34:5
...the method comprising: (A) discontinuing the fluvoxamine treatment and then (B) orally treating the patient with 20 mg of tasimelteon once daily before a target bedtime... The proposed label's instruction to "avoid use of HETLIOZ in combination with fluvoxamine" allegedly encourages physicians to perform the claimed method of discontinuing fluvoxamine before administering the 20 mg tasimelteon dose. ¶86, ¶90 '995 Patent, col. 34:1-5
...thereby avoiding the use of tasimelteon in combination with fluvoxamine. The alleged instruction on the proposed label directly teaches avoiding the combination of the two drugs. ¶86 '995 Patent, col. 34:5-7
  • Identified Points of Contention:
    • Scope Questions: Does an instruction to "[a]void use...in combination" (Compl. ¶86) meet the claim limitation requiring the specific, sequential two-step process of "(A) discontinuing... and then (B) orally treating"? The analysis may turn on whether a general warning of avoidance is specific enough to induce infringement of the explicitly claimed sequence of actions.
    • Technical Questions: What factual basis exists for the allegation that Apotex's proposed label will instruct this specific sequence? The complaint quotes the HETLIOZ® label, which gives a general warning. A key question is whether Apotex's proposed label will contain more specific instructions that map more directly onto the claim elements.

V. Key Claim Terms for Construction

  • The Term: "entraining a patient" (from RE46,604, Claim 1)

  • Context and Importance: This term defines the primary purpose and outcome of the claimed method. Its construction will be critical to determining infringement, as it establishes the standard for what must be achieved by administering the drug. Practitioners may focus on this term because it is a result-oriented limitation, and the parties will likely dispute whether the mere act of administering the drug as prescribed is sufficient to "entrain" the patient, or if a specific, objectively measurable clinical outcome is required.

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: The patent's background describes the "ultimate treatment goal" as being "to entrain or synchronize their circadian rhythms into an appropriate phase relationship with the 24-hour day" (’995 Patent, col. 2:28-31). This language suggests a general therapeutic goal, which may support an interpretation where administering the drug for this purpose constitutes "entraining."
    • Evidence for a Narrower Interpretation: The specification of the patent family includes figures showing clinical data where entrainment is measured by objective criteria, such as urinary aMT6s acrophase analysis (’995 Patent, Figs. 1-4). This may support an argument that "entraining" requires achieving a specific, clinically-defined synchronization that can be objectively measured, not just the act of administration.

  • The Term: "avoiding the use of tasimelteon in combination with fluvoxamine" (from '995 Patent, Claim 1)

  • Context and Importance: This phrase appears in the final "thereby" clause of the claim and relates to the claim's two-step body: "(A) discontinuing the fluvoxamine treatment and then (B) orally treating the patient with...tasimelteon." The construction of this term is vital because the infringement allegation relies on a label instruction to "avoid use" (Compl. ¶86). The central question is whether the general concept of "avoiding" is synonymous with the specific sequence of acts recited in the claim body.

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: The final clause itself uses the word "avoiding," which could suggest that the two-step process described in the claim body is one way of achieving the broader goal of "avoiding" combination use.
    • Evidence for a Narrower Interpretation: The body of the claim is structurally clear, reciting two distinct steps in sequence ("discontinuing...and then...treating"). This suggests that infringement requires performance of that specific sequence, and that the final "avoiding" clause merely states the result of performing those steps, rather than defining the scope of the action itself.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges induced infringement under 35 U.S.C. § 271(b) for the method patents. It asserts that Apotex has actual knowledge of the patents-in-suit via the Paragraph IV notice letters it sent to Vanda (Compl. ¶62, ¶83, ¶104). The complaint further alleges that Apotex will induce infringement by physicians and patients through the instructions on its proposed product label, which will allegedly "essentially copy" the HETLIOZ® label and recommend, encourage, or suggest the patented methods of use (Compl. ¶69, ¶90). The complaint also alleges that the Apotex ANDA Product has no substantial non-infringing uses (Compl. ¶70, ¶91).
  • Willful Infringement: The complaint alleges that Apotex's statements regarding invalidity and noninfringement are "devoid of an objective good faith basis in either the facts or the law" (Compl. ¶78, ¶99, ¶120). This allegation appears to be based on Apotex's pre-suit knowledge of the patents via the notice letters and forms the basis for a claim of an "exceptional case" warranting an award of attorneys' fees under 35 U.S.C. § 285.

VII. Analyst’s Conclusion: Key Questions for the Case

  • A core issue will be one of instructional equivalence: will the general warning to "avoid use...in combination" with certain drugs, as allegedly included on Apotex's proposed label, be construed as an affirmative instruction to perform the specific, sequential steps required by method claims such as Claim 1 of the '995 patent, which recites discontinuing one treatment and then starting another?
  • A key question of claim scope will be the interpretation of result-oriented limitations like "entraining a patient" and "maintaining said 24 hour sleep-wake cycle." The case may turn on whether infringement is established by the act of prescribing the drug for its intended purpose, or if it requires objective proof that the prescribed use necessarily achieves the claimed clinical outcome in a patient.
  • For the '977 patent concerning the purified drug substance, a central evidentiary question will be whether Vanda can demonstrate, through discovery and testing, that Apotex's generic product either meets the specific negative purity limitations of the product claims or is manufactured using the patented process.