DCT
1:21-cv-00248
Aether Therap Inc v. RedHill Biopharma Inc
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Aether Therapeutics Inc. (Delaware)
- Defendant: RedHill Biopharma Inc. (Delaware)
- Plaintiff’s Counsel: Stamoulis & Weinblatt LLC; Goldberg Segalla LLP
- Case Identification: 1:21-cv-00248, D. Del., 06/08/2021
- Venue Allegations: Venue is alleged to be proper in the District of Delaware because Defendant is a Delaware corporation and therefore resides in the judicial district.
- Core Dispute: Plaintiff alleges that Defendant’s Movantik® product, used for treating opioid-induced constipation, infringes four patents related to the use of neutral opioid antagonists to counteract adverse side effects of opioid agonists.
- Technical Context: The technology addresses the challenge of mitigating negative side effects of opioid painkillers, such as constipation and addiction, without compromising their analgesic efficacy.
- Key Procedural History: The complaint alleges that Defendant RedHill acquired the rights to Movantik® from AstraZeneca after Plaintiff had already filed suit against AstraZeneca for infringement of the same patents-in-suit. This alleged pre-acquisition notice forms the basis of Plaintiff's willfulness allegations.
Case Timeline
| Date | Event |
|---|---|
| 2000-03-15 | ’488 Patent Priority Date |
| 2004-03-30 | ’488 Patent Issue Date |
| 2007-10-18 | ’448, ’817, and ’024 Patents Priority Date |
| 2014-06-10 | ’448 Patent Issue Date |
| 2014-11-11 | ’817 Patent Issue Date |
| 2015-06-23 | ’024 Patent Issue Date |
| 2020-03-18 | Plaintiff files initial suit against AstraZeneca re: patents-in-suit |
| 2020-04-01 | RedHill acquires rights to Movantik® from AstraZeneca |
| 2020-06-11 | Plaintiff files First Amended Complaint in AstraZeneca suit |
| 2021-05-25 | USPTO issues certificate of correction for the ’448 Patent |
| 2021-06-08 | Complaint Filing Date |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 6,713,488 - "Neutral antagonists and use thereof in treating drug abuse"
The Invention Explained
- Problem Addressed: The patent's background describes that traditional opioid antagonists like naloxone and naltrexone, while effective in treating drug overdose and dependency, are "quite aversive" and can induce "intense withdrawal syndrome," which limits their therapeutic utility and patient acceptance (’488 Patent, col. 2:25-39). These antagonists can also cause unwanted side effects, such as respiratory depression, when used to manage chronic pain or reverse opioid-induced constipation (’488 Patent, col. 2:40-58).
- The Patented Solution: The invention proposes the use of specific naltrexone and naloxone analogs that function as "neutral antagonists" at the µ opioid receptor (’488 Patent, Abstract). Unlike traditional "inverse agonist" antagonists which suppress the receptor's baseline activity, these neutral antagonists are described as blocking the effects of an agonist without significantly affecting the receptor's spontaneous activity (’488 Patent, col. 3:39-48). This approach is intended to alleviate adverse effects of opioid use with reduced withdrawal symptoms and aversive effects (’488 Patent, col. 3:1-15).
- Technical Importance: The invention represented a strategy to create safer and more tolerable treatments for opioid dependency and for managing the side effects of opioid analgesics, thereby potentially improving patient compliance (’488 Patent, col. 2:59-65).
Key Claims at a Glance
- The complaint asserts independent claim 25 and dependent claims 26 and 29 (Compl. ¶75).
- The essential elements of independent claim 25 are:
- A method of alleviating adverse effects associated with opioid use by an individual in need thereof
- comprising administration to the individual of a therapeutically effective amount of a naloxone analog or naltrexone analog or a pharmaceutically acceptable salt thereof
- which is a neutral antagonist at the µ opioid receptor.
- The complaint reserves the right to assert additional claims (Compl. ¶92).
U.S. Patent No. 8,748,448 - "Combination analgesic employing opioid agonist and neutral antagonist"
The Invention Explained
- Problem Addressed: The patent addresses the dual problems of opioid analgesics: addiction liability and adverse peripheral effects such as constipation (’448 Patent, col. 1:24-35). Prior art co-formulations using "aversive" antagonists like naltrexone can trigger severe withdrawal and may not be optimized to selectively target peripheral side effects without impairing central pain relief (’448 Patent, col. 1:47-54).
- The Patented Solution: The invention claims a unit dosage composition that combines an opioid agonist with a "non-aversive neutral opioid antagonist" (’448 Patent, Abstract). The key aspects of the solution are twofold: (1) the antagonist is dosed in an amount sufficient to inhibit peripheral effects but insufficient to block central analgesic effects, and (2) the antagonist is selected to have a substantially longer blood half-life than the agonist, which serves to deter abuse through overly frequent administration (’448 Patent, col. 2:55-63).
- Technical Importance: This technology aims to provide an opioid analgesic with a built-in safety mechanism, designed to reduce both addiction potential and common physical side effects, thereby creating a potentially safer and more effective option for pain management (’448 Patent, col. 2:55-63).
Key Claims at a Glance
- The complaint asserts independent claim 1 and dependent claims 2, 4, 5, 9, and 11 (Compl. ¶95).
- The essential elements of independent claim 1 (as corrected) are:
- A unit dosage of an analgesic composition, formulated for oral administration to a subject, comprising:
- (a) an opioid agonist in an amount sufficient to confer analgesia;
- (b) a non-aversive neutral opioid antagonist in an amount sufficient to substantially inhibit peripheral effects and insufficient to block substantial central effects;
- wherein the amounts are selected so a specific weight/weight ratio of morphine equivalent (agonist) to 6.beta.-naltrexol equivalent (antagonist) is at least 1.0;
- and the antagonist has a substantially longer blood half-life than the agonist to deter abuse; and
- (c) a pharmaceutically acceptable carrier.
- The complaint reserves the right to assert additional claims (Compl. ¶116).
U.S. Patent No. 8,883,817 - "Combination analgesic employing opioid and neutral antagonist" (Multi-Patent Capsule)
- Patent Identification: U.S. Patent No. 8,883,817, "Combination analgesic employing opioid and neutral antagonist," issued November 11, 2014 (Compl. ¶37).
- Technology Synopsis: This patent claims a unit dosage analgesic composition combining an opioid agonist and a neutral opioid antagonist. The invention is distinguished by selecting the agonist and antagonist amounts to achieve a specific ratio of biological activities (antinociception ID50 to GI transit ID50) between about 5 and 50, which is intended to ensure inhibition of peripheral side effects without blocking central analgesia (’817 Patent, Abstract; Compl. ¶120).
- Asserted Claims: Independent claim 1 and numerous dependent claims are asserted (Compl. ¶119).
- Accused Features: The complaint alleges that the use of Movantik® with an analgesic results in a combination of active ingredients whose respective biological activities satisfy the claimed ratio (Compl. ¶123-125).
U.S. Patent No. 9,061,024 - "Combination analgesic employing opioid and neutral antagonist" (Multi-Patent Capsule)
- Patent Identification: U.S. Patent No. 9,061,024, "Combination analgesic employing opioid and neutral antagonist," issued June 23, 2015 (Compl. ¶44).
- Technology Synopsis: This patent claims a method of providing analgesia by orally administering a unit dosage composition. The composition includes an opioid agonist and a non-aversive neutral opioid antagonist selected to have weaker access to the central nervous system than the agonist. The method requires that the amounts of the components meet a specified weight/weight ratio of at least 0.15 to inhibit peripheral effects without blocking central effects (’024 Patent, Abstract; Compl. ¶141).
- Asserted Claims: Independent claim 1 and several dependent claims are asserted (Compl. ¶140).
- Accused Features: The complaint alleges that the instructed use of Movantik® (containing the peripherally-acting naloxegol) in combination with an opioid agonist constitutes performance of the claimed method, including meeting the specified ratios (Compl. ¶144-148).
III. The Accused Instrumentality
- Product Identification: The accused product is Movantik®, an oral tablet whose active ingredient is naloxegol (Compl. ¶51, 56).
- Functionality and Market Context: Movantik® is prescribed for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain (Compl. ¶52). Its active ingredient, naloxegol, is identified as a PEGylated analog of naloxone (Compl. ¶57). The complaint alleges, citing the product label and external literature, that naloxegol functions as a peripherally-acting µ-opioid receptor antagonist, thereby decreasing the constipating effects of opioids, and is a "neutral competitive antagonist" (Compl. ¶59-60). The complaint provides a diagram showing the chemical structure of naloxegol oxalate (Compl. ¶58, p. 9). Defendant RedHill markets and sells Movantik® in the United States after acquiring the rights from AstraZeneca (Compl. ¶4-5).
IV. Analysis of Infringement Allegations
’488 Patent Infringement Allegations
| Claim Element (from Independent Claim 25) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A method of alleviating adverse effects associated with opioid use by an individual in need thereof | The use of Movantik® is indicated for the treatment of opioid-induced constipation (OIC), an adverse effect of opioid use. | ¶77 | col. 2:59-65 |
| comprising administration to the individual of a therapeutically effective amount of a naloxone analog or naltrexone analog or a pharmaceutically acceptable salt thereof | Movantik® contains naloxegol oxalate, alleged to be a naloxone analog, and is administered in recommended daily dosages. | ¶78 | col. 5:65-6:43 |
| which is a neutral antagonist at the µ opioid receptor. | Publicly available scientific literature allegedly states that naloxegol acts as a competitive neutral antagonist at the human µ opioid receptor. | ¶80 | col. 3:39-43 |
- Identified Points of Contention:
- Scope Questions: A potential dispute may arise over whether the claim term "neutral antagonist," as defined and understood in the context of the ’488 Patent's disclosure, reads on the specific pharmacological profile of naloxegol. The complaint's reliance on extrinsic evidence (a 2017 article) to meet this limitation suggests this could be a central point of contention (Compl. ¶80).
- Technical Questions: What evidence does the complaint provide that naloxegol does not "significantly effect the level of spontaneous receptor activity," as required by the patent’s definition of a "neutral antagonist"? The case may turn on experimental data comparing naloxegol's activity to that of traditional inverse agonists like naloxone.
’448 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A unit dosage of an analgesic composition, formulated for oral administration to a subject, comprising: (a) an opioid agonist in an amount sufficient to confer analgesia | Movantik® is used concomitantly with a separate opioid analgesic (e.g., morphine), which provides analgesia. | ¶98 | col. 2:55-57 |
| (b) a non-aversive neutral opioid antagonist in an amount sufficient to substantially inhibit peripheral effects and insufficient to block substantial central effects | Naloxegol is alleged to be a neutral antagonist that acts peripherally in the gastrointestinal tract to decrease constipation without interfering with centrally mediated analgesia. | ¶100 | col. 2:57-63 |
| wherein the amounts... are selected so that a weight/weight (w/w) ratio of (1) an amount of morphine equivalent to the opioid agonist divided by (2) an amount of 6.beta.-naltrexol equivalent to the amount of neutral opioid antagonist is at least 1.0 | The Movantik® label describes clinical trials where patients received opioid and Movantik® dosages alleged to fall within the claimed ratio. | ¶101 | col. 7:45-56 |
| and (c) a pharmaceutically acceptable carrier. | The Movantik® label lists tablet core and coat ingredients such as mannitol and cellulose, which constitute a carrier. | ¶102 | col. 10:1-10 |
- Identified Points of Contention:
- Scope Questions: A primary issue for construction will be whether a "unit dosage of an analgesic composition...comprising" an agonist and antagonist requires both components to be in a single physical dosage form. Since Movantik® does not contain an agonist, infringement hinges on whether the instructed co-administration of two separate products can meet this claim limitation.
- Technical Questions: Does the description of patient populations and dosing ranges in the Movantik® label's clinical trial summary provide sufficient evidence that the actual prescribed use of the product meets the specific quantitative ratio required by the claim?
V. Key Claim Terms for Construction
The Term: "neutral antagonist at the µ opioid receptor" (’488 Patent, Claim 25)
Context and Importance: This functional limitation is the central inventive concept of the ’488 patent, distinguishing the claimed analogs from prior art aversive antagonists. The complaint relies on extrinsic evidence to allege that naloxegol meets this definition (Compl. ¶80), making its construction critical. Practitioners may focus on this term because the difference between a "neutral" and "inverse" agonist is a subtle but potentially dispositive pharmacological distinction.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The specification defines "neutral antagonists" as "agents which block the affects of an agonist at the target receptor but do not significantly effect the level of spontaneous receptor activity" (’488 Patent, col. 3:39-43). The inclusion of the qualifier "significantly" may support a construction that allows for some minor, clinically irrelevant effect on spontaneous activity.
- Evidence for a Narrower Interpretation: The patent explicitly contrasts neutral antagonists with "inverse agonists" like naloxone and naltrexone, which "suppress spontaneous receptor activity" (’488 Patent, col. 3:43-48). A defendant could argue that any measurable suppression of baseline activity, however small, makes a compound an inverse agonist and thus outside the scope of the claim.
The Term: "unit dosage of an analgesic composition...comprising" (’448 Patent, Claim 1)
Context and Importance: This term is critical because the accused product, Movantik®, contains only the antagonist, not the agonist. The infringement theory depends on construing this term to cover two separate pills (Movantik® and an opioid) administered together. This construction will determine whether direct infringement of the composition claim is possible.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The patent specification repeatedly discusses the invention in terms of "co-formulation, co-administration or separate, but overlapping administration" (’448 Patent, col. 2:55-63). Plaintiff may argue this language demonstrates the inventors' intent for the claims to cover scenarios where the two components are administered as separate tablets.
- Evidence for a Narrower Interpretation: The plain language of the claim recites "A unit dosage...comprising: (a) an...agonist...; (b) a...antagonist." A defendant may argue that this language unambiguously requires both components to be physically present in a single tablet or capsule, and that the specification's discussion of "separate administration" applies to methods of use, not the claimed composition itself.
VI. Other Allegations
- Indirect Infringement: The complaint heavily pleads induced infringement, alleging Defendant instructs patients and medical professionals, via the Movantik® Label, to use the product in combination with opioid agonists in a manner that directly infringes the asserted claims (Compl. ¶75, 95, 110, 119, 140).
- Willful Infringement: Willfulness is alleged based on pre-suit knowledge. The complaint contends that before acquiring Movantik®, RedHill conducted due diligence and was provided with copies of Plaintiff's prior complaint against AstraZeneca asserting the same patents-in-suit, giving RedHill actual knowledge of the patents and the ongoing infringement allegations (Compl. ¶63-71).
VII. Analyst’s Conclusion: Key Questions for the Case
- A core issue will be one of claim scope versus infringement theory: Can the sale and labeling of Movantik®, which contains only the antagonist, constitute direct infringement of composition claims reciting a "unit dosage...comprising" both an agonist and an antagonist? Or must infringement of these claims rely solely on a theory of inducement, which requires proof of an underlying direct infringement by a third party (e.g., a patient)?
- A key evidentiary question will be one of functional definition: Does naloxegol, the active ingredient in Movantik®, meet the specific definition of a "neutral antagonist" as disclosed and defined within the patents-in-suit? The resolution will likely depend on competing expert testimony and pharmacological data regarding naloxegol's effect on the baseline activity of the µ opioid receptor.
- A central factual dispute will be one of quantitative proof: Do the dosing regimens described on the Movantik® label for its clinical trials provide sufficient evidence that the product, when used as prescribed, satisfies the specific numerical ratios (e.g., weight/weight, ID50) required by the claims of the ’448, ’817, and ’024 patents?