DCT

1:21-cv-01411

Allergan Inc v. Revance Therap Inc

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Key Events
Amended Complaint

I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: Allergan, Inc. et al. v. Revance Therapeutics, Inc. et al., 1:21-cv-01411, D. Del., 11/24/2021
  • Venue Allegations: Venue is alleged to be proper in the District of Delaware because both Defendants are Delaware corporations and are therefore residents of the district.
  • Core Dispute: Plaintiff alleges that Defendants’ development, manufacture, and stockpiling of their DaxibotulinumtoxinA for Injection product infringes six patents related to botulinum toxin formulations, purification processes, and potency assays.
  • Technical Context: The technology concerns pharmaceutical-grade botulinum neurotoxin type A (BoNT/A), a potent biological agent widely used in therapeutic and cosmetic treatments, and methods for ensuring its stability and purity without using animal-derived products.
  • Key Procedural History: The complaint details Defendants' pursuit of FDA approval for their accused product, including the filing of a Biologics License Application (BLA), an FDA inspection that resulted in a Form 483 identifying manufacturing deficiencies, and the subsequent issuance of a Complete Response Letter (CRL) indicating the BLA was not ready for approval. Plaintiff leverages these events to argue for the existence of an immediate and substantial controversy supporting a declaratory judgment of future infringement upon expected FDA approval.

Case Timeline

Date Event
2001-06-15 Priority Date for ’567 Patent
2003-08-29 Priority Date for ’740 and ’828 Patents
2005-10-06 Priority Date for ’625 and ’878 Patents
2008-02-19 ’567 Patent Issued
2008-04-08 ’740 Patent Issued
2010-07-13 Priority Date for ’786 Patent
2013-04-02 ’828 Patent Issued
2019-11-01 Revance files BLA for DaxibotulinumtoxinA for Injection (approx. date)
2020-02-05 FDA accepts Revance's BLA
2020-11-24 FDA defers decision on Revance’s BLA
2021-06-15 ’625 Patent Issued
2021-07-02 FDA issues Form 483 to Revance regarding manufacturing facility
2021-09-21 ’786 Patent Issued
2021-10-15 FDA issues Complete Response Letter for Revance’s BLA
2021-10-19 ’878 Patent Issued
2021-11-24 Complaint Filed

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

U.S. Patent No. 11,033,625 - “Method for Stabilizing a Toxin”

  • Issued: June 15, 2021 (the ’625 Patent)

The Invention Explained

  • Problem Addressed: The patent’s background describes the difficulty in creating stable pharmaceutical formulations for large, fragile proteins like botulinum toxin, particularly at the low concentrations used in final products. (Compl. ¶23; ’625 Patent, col. 1:55-2:13). Historically, animal-derived proteins like human serum albumin were used as stabilizers, but these carry risks of transmitting pathogens. (Compl. ¶23; ’625 Patent, col. 2:50-59).
  • The Patented Solution: The invention is a powdered pharmaceutical composition that stabilizes the toxin without using any animal proteins. (’625 Patent, Abstract). It achieves this stability through a specific combination of excipients: a surfactant, a disaccharide such as sucrose or trehalose, and a buffer that maintains a specific pH range upon reconstitution, ensuring the toxin retains its potency during storage. (’625 Patent, col. 73:38-54).
  • Technical Importance: This approach provides a way to formulate botulinum toxin products that are stable and effective while avoiding the safety risks associated with animal-derived components. (Compl. ¶23).

Key Claims at a Glance

  • The complaint asserts at least claim 1. (Compl. ¶84).
  • Claim 1 of the ’625 Patent requires:
    • A powder pharmaceutical composition, comprising:
    • a botulinum toxin, wherein the botulinum toxin is a type A serotype;
    • a surfactant;
    • at least one disaccharide selected from the group consisting of sucrose and trehalose; and
    • a buffer sufficient to maintain a pH of from about 5 to about 7.3 upon reconstitution with sterile normal saline or water;
    • wherein the composition is suitable for intramuscular or subcutaneous injection following reconstitution;
    • wherein the composition is animal protein free; and
    • wherein the composition retains at least about 75% of the theoretical maximum potency of the botulinum toxin following storage as a powder for three months at below freezing temperature.

U.S. Patent No. 11,147,878 - “Animal Protein-Free Pharmaceutical Compositions”

  • Issued: October 19, 2021 (the ’878 Patent)

The Invention Explained

  • Problem Addressed: Similar to the ’625 Patent, the invention addresses the challenge of creating stable pharmaceutical formulations of botulinum toxin without using animal-derived proteins. (Compl. ¶23; ’878 Patent, col. 1:55-2:55).
  • The Patented Solution: The ’878 Patent claims a method of stabilizing the neurotoxin. The method involves two main steps: (a) "compounding" an aqueous carrier with the toxin and specific non-animal derived excipients (a surfactant and a disaccharide), and (b) "lyophilizing or vacuum-drying" the mixture to create a stable powder. (’878 Patent, col. 71:36-41). The resulting powder is defined by functional properties, including being animal protein free and retaining at least 50% potency upon reconstitution. (’878 Patent, col. 71:42-59).
  • Technical Importance: This patent protects the manufacturing process used to create the animal-protein-free botulinum toxin formulation, complementing patents that claim the composition itself. (Compl. ¶23).

Key Claims at a Glance

  • The complaint asserts at least claim 1. (Compl. ¶97).
  • Claim 1 of the ’878 Patent requires:
    • An animal protein free method to stabilize a serotype A...neurotoxin, comprising:
    • (a) compounding an aqueous carrier with two or more non-animal derived non-protein excipients and a...neurotoxin to form a compounded formulation; and
    • (b) lyophilizing or vacuum-drying the compounded formulation to provide a stable powdered formulation;
    • wherein the excipients comprise (i) a surfactant and (ii) a disaccharide (trehalose or sucrose);
    • wherein the formulation retains at least about 50% potency after reconstitution;
    • wherein the formulation has a pH from about 5 to 7.3 after reconstitution;
    • wherein the formulation is suitable for intramuscular or subcutaneous administration; and
    • wherein the formulation is animal protein free and polysaccharide free.

U.S. Patent No. 7,354,740 - “Animal Product Free System and Process for Purifying a Botulinum Toxin”

  • Issued: April 8, 2008 (the ’740 Patent)
  • Technology Synopsis: The patent claims an animal-protein-free process for purifying botulinum toxin from a fermentation culture. The process utilizes a specific two-step chromatography sequence: first, capturing the toxin on a hydrophobic interaction chromatography (HIC) column, and second, further purifying the eluent from the HIC column on an ion exchange column. (Compl. ¶¶32, 35).
  • Asserted Claims: Claim 1. (Compl. ¶110).
  • Accused Features: The complaint alleges that Defendants' manufacturing process for their botulinum toxin product infringes the ’740 Patent. (Compl. ¶¶55, 110). It alleges, based on a Revance-owned patent, that the accused process involves HIC followed by anion exchange chromatography, mapping to the claimed steps. (Compl. ¶57).

U.S. Patent No. 8,409,828 - “Animal Product Free System and Process for Purifying a Botulinum Toxin”

  • Issued: April 2, 2013 (the ’828 Patent)
  • Technology Synopsis: The patent claims a broader animal-product-free process for purifying botulinum toxin than the ’740 patent. It requires passing a fermentation culture over two chromatography columns that utilize two different separation mechanisms selected from a group including ion exchange, hydrophobic interaction, gel filtration, and mixed mode mechanisms. (Compl. ¶¶36, 39).
  • Asserted Claims: Claim 1. (Compl. ¶123).
  • Accused Features: The complaint alleges infringement by Defendants' manufacturing process. (Compl. ¶123). The allegations point to Defendants' use of HIC and ion exchange chromatography, which constitute two different separation mechanisms from the claimed group. (Compl. ¶57).

U.S. Patent No. 11,124,786 - “Process and System for Obtaining Botulinum Neurotoxin”

  • Issued: September 21, 2021 (the ’786 Patent)
  • Technology Synopsis: The patent claims a substantially animal-product-free process specifically for purifying dissociated, approximately 150 kDa BoNT/A. The process requires a specific sequence of anion exchange chromatography (AEX) followed by cation exchange chromatography (CEX), with particular buffer and salt eluting steps. (Compl. ¶¶40, 43).
  • Asserted Claims: Claim 1. (Compl. ¶136).
  • Accused Features: The complaint accuses Defendants' manufacturing process of infringement. (Compl. ¶136). It alleges, based on a Revance-owned patent, that the accused process uses an HIC column, followed by an anion exchange column, and then a cation exchange column, which appears to align with the claimed AEX and CEX steps. (Compl. ¶57).

U.S. Patent No. 7,332,567 - “FRET Protease Assays for Clostridial Toxins”

  • Issued: February 19, 2008 (the ’567 Patent)
  • Technology Synopsis: The patent claims a substrate for use in a potency assay for botulinum toxin serotype A (BoNT/A). The substrate is designed for a Fluorescence Resonance Energy Transfer (FRET) assay and comprises a donor fluorophore, an acceptor fluorophore, and a BoNT/A recognition sequence with a cleavage site between the two fluorophores. When the toxin cleaves the substrate, the fluorophores are separated, causing a detectable change in resonance energy transfer. (Compl. ¶¶44, 47).
  • Asserted Claims: Claim 1. (Compl. ¶149).
  • Accused Features: The complaint alleges that Defendants use an infringing BoNT/A substrate in their cell-based potency assay for product release and stability testing. (Compl. ¶¶60, 149). The accused assay is alleged to use a recombinant protein with two distinct fluorescent proteins (fluorophores) that is cleaved in the presence of the toxin, with potency measured by assessing the emission ratio of the fluorophores, a method consistent with the claimed FRET substrate technology. (Compl. ¶61).

III. The Accused Instrumentality

Product Identification

The accused instrumentalities are the product “DaxibotulinumtoxinA for Injection” (also referred to as “DAXI”), its associated manufacturing process, and the BoNT/A substrate used in its potency assay. (Compl. ¶¶48, 55, 60).

Functionality and Market Context

  • DaxibotulinumtoxinA for Injection is a botulinum toxin product intended for aesthetic and therapeutic uses that would directly compete with Plaintiff’s BOTOX® and BOTOX® Cosmetic products. (Compl. ¶48). The formulation is supplied as a lyophilized powder that is reconstituted for injection. (Compl. ¶52). The complaint alleges the formulation includes 150 kDa BoNT/A, a peptide, a sugar, a surfactant (polysorbate-20), and buffers, and that it is "entirely free of animal and human-derived materials." (Compl. ¶¶50, 51, 55).
  • The manufacturing process is alleged to be an animal-product-free process that utilizes multi-step chromatography. (Compl. ¶¶55, 57). The potency assay is a cell-based assay used for release and stability testing that employs a FRET-based substrate to measure the toxin's activity. (Compl. ¶¶60, 61). Defendants have allegedly stockpiled commercial batches of the product in preparation for an "imminent" launch upon FDA approval. (Compl. ¶¶76-78).

No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

’625 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A powder pharmaceutical composition... DaxibotulinumtoxinA for Injection is supplied as a lyophilized powder. ¶52 col. 73:38
comprising: a botulinum toxin, wherein the botulinum toxin is a type A serotype; The formulation includes 150 kDa BoNT/A. ¶50 col. 73:39-40
a surfactant; The formulation includes a surfactant (polysorbate-20). ¶50 col. 73:41
at least one disaccharide selected from the group consisting of sucrose and trehalose; and The formulation includes a sugar. ¶50 col. 73:42-44
a buffer sufficient to maintain a pH of from about 5 to about 7.3 upon reconstitution... The formulation includes buffers. ¶50 col. 73:45-47
wherein the composition is animal protein free, and The product "does not contain human or animal-based components." ¶51 col. 73:51
wherein the composition retains at least about 75% of the theoretical maximum potency...following storage as a powder for three months at below freezing temperature. On information and belief, the formulation retains at least about 75% of the theoretical maximum potency of the toxin following storage as a powder for three months at below-freezing temperature. ¶54 col. 73:52-54

Identified Points of Contention

  • Scope Questions: A central question may be the scope of "animal protein free." The accused product contains a peptide ("RTP004") (Compl. ¶50). The case may turn on whether this peptide falls within the patent’s definition of an animal-derived protein, which the patent specification suggests excludes recombinantly produced proteins ('625 Patent, col. 8:1-24). Another question concerns the "disaccharide" element; the complaint alleges a "sugar," which will require factual discovery to determine if it is a sucrose or trehalose as claimed.
  • Technical Questions: The primary technical question will be evidentiary. What evidence supports the complaint’s "information and belief" allegation that the accused product meets the 75% potency retention requirement after three months of storage? This is a functional limitation that requires empirical testing for verification.

’878 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
An animal protein free method to stabilize a serotype A...neurotoxin, comprising: Revance's manufacturing process is "entirely free of animal and human-derived materials." ¶55 col. 71:36-37
(a) compounding an aqueous carrier with two or more non-animal derived non-protein excipients... The accused formulation contains multiple non-animal derived components, including a sugar, a surfactant, and buffers. ¶50 col. 71:38-41
(b) lyophilizing or vacuum-drying the compounded formulation... DaxibotulinumtoxinA for Injection is supplied as a lyophilized powder. ¶52 col. 71:42-43
wherein: the two or more...excipients comprise (i) a surfactant and (ii) a disaccharide selected from...trehalose and sucrose; The accused formulation includes a surfactant (polysorbate-20) and a sugar. ¶50 col. 71:45-48
the powdered formulation is animal protein free and polysaccharide free. The accused formulation is alleged to not contain animal-based components. ¶51 col. 71:57-59

Identified Points of Contention

  • Scope Questions: A key question will be the scope of "polysaccharide free." The complaint alleges the accused product contains "a sugar" (Compl. ¶50). Infringement will depend on whether this sugar is a disaccharide (as required by another limitation and not a polysaccharide) or if it contains any polysaccharides, which would place it outside the claim scope.
  • Technical Questions: The complaint does not provide direct evidence of Defendants' manufacturing steps. Infringement of this method claim will depend entirely on evidence obtained during discovery to confirm that the alleged "compounding" and "lyophilizing" steps are actually performed as claimed and that the resulting product meets the 50% potency retention requirement.

V. Key Claim Terms for Construction

The Term: "animal protein free"

  • Appears In: Asserted claims of ’625 and ’878 Patents
  • Context and Importance: This term is critical because the central premise of the inventions is stabilization without animal-derived products. The accused product is alleged to be "animal-based component" free (Compl. ¶51), but also contains a "peptide" (Compl. ¶50). Practitioners may focus on this term because its construction will determine whether the presence of this specific peptide removes the accused product from the scope of the claims.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The term itself, given its plain meaning, could be argued to encompass any substance derived from an animal, regardless of its production method.
    • Evidence for a Narrower Interpretation: The specification of the ’625 Patent explicitly defines the term as referring to "the absence of blood-derived, blood-pooled and other animal-derived products or compounds" and clarifies that "an animal protein recombinantly produced from a microorganism is excluded from the term 'animal-derived product or compound'." (’625 Patent, col. 8:1-24). This language may support an interpretation that excludes certain types of peptides, potentially including the one in the accused product.

The Term: "retains at least about 75% of the theoretical maximum potency"

  • Appears In: ’625 Patent, claim 1
  • Context and Importance: This functional limitation defines the stability of the claimed composition. Infringement hinges on whether the accused product actually performs to this standard. Practitioners may focus on this term because the method for measuring "potency" and establishing the "theoretical maximum" is not defined in the claim, leaving it open to disputes over testing methodology and interpretation of results.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The patent does not specify a particular assay for measuring potency, which could support using any of a number of scientifically reasonable methods known at the time.
    • Evidence for a Narrower Interpretation: The specification discusses potency in the context of biological activity and may reference specific assays, such as mouse bioassays ('625 Patent, col. 37:5-14), which could be used to argue for a narrower, more specific method of measurement.

VI. Other Allegations

The complaint does not contain formal counts for indirect or willful infringement.

  • Indirect Infringement: The complaint alleges that Defendant Revance "directs and controls" the manufacturing efforts of Defendant ABPS, which may lay the groundwork for a theory of vicarious or joint liability for infringement by manufacture. (Compl. ¶59).
  • Willful Infringement: The complaint does not plead willfulness or allege that Defendants had pre-suit knowledge of the asserted patents.

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

  • A core issue will be one of definitional scope: can the term "animal protein free," as defined and used in the patents, be construed to read on a formulation that contains a peptide? The outcome will likely depend on claim construction informed by the patent’s explicit definition and factual discovery into the nature and origin of the peptide in the accused product.
  • A second central issue will be one of process-to-claim mapping: what are the actual steps of Defendants’ multi-stage chromatography process, and do they align with the specific sequences and separation mechanisms required by the asserted process patents (’740, ’828, and ’786)? The complaint’s reliance on a third-party patent as evidence of the accused process suggests this will be a heavily contested, discovery-dependent issue.
  • A key evidentiary question will be one of functional performance: does the accused product actually meet the quantitative stability requirements of the asserted claims, such as retaining at least 75% potency after three months of storage? As this is alleged only on "information and belief," it will require empirical evidence and potentially lead to disputes over testing protocols and what constitutes "potency."