DCT

3:19-cv-18566

Salix Pharma Ltd v. Sandoz Inc

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Key Events
Complaint

I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 3:19-cv-18566, D.N.J., 09/30/2019
  • Venue Allegations: Venue is alleged to be proper in the District of New Jersey because Defendant Sandoz has committed acts of infringement in New Jersey and maintains a regular and established place of business in the state, including offices and laboratories.
  • Core Dispute: Plaintiffs allege that Defendant’s filing of an Abbreviated New Drug Application (ANDA) to market a generic version of Plaintiffs' Xifaxan® (rifaximin) 550 mg tablets constitutes infringement of fourteen patents related to specific crystalline forms (polymorphs) of rifaximin, pharmaceutical compositions containing them, and methods of their use.
  • Technical Context: The patents relate to the control of polymorphism in the antibiotic rifaximin, a critical factor for ensuring consistent drug solubility and bioavailability for treating gastrointestinal disorders like irritable bowel syndrome and hepatic encephalopathy.
  • Key Procedural History: This action was initiated under the Hatch-Waxman Act following Defendant Sandoz’s submission of ANDA No. 213713 to the FDA and its subsequent issuance of a Paragraph IV certification notice letter to Plaintiffs, asserting that the patents-in-suit are invalid, unenforceable, and/or not infringed by its proposed generic product.

Case Timeline

Date Event
2003-11-07 Earliest Priority Date for ’620, ’199, ’206, ’542, ’275, ’644, ’781, ’452, ’231 Patents
2004-05-25 FDA approval of Xifaxan® 200 mg tablets
2005-03-03 Earliest Priority Date for ’196, ’949, ’904, ’968 Patents
2006-05-16 ’620 Patent Issued
2008-02-26 Earliest Priority Date for ’569 Patent
2009-11-03 ’199 Patent Issued
2010-03-24 FDA approval of Xifaxan® 550 mg tablets
2011-03-08 ’206 Patent Issued
2011-03-15 ’542 Patent Issued
2011-03-29 ’275 Patent Issued
2012-04-17 ’644 Patent Issued
2012-04-17 ’781 Patent Issued
2012-06-05 ’196 Patent Issued
2012-11-13 ’569 Patent Issued
2013-08-27 ’949 Patent Issued
2014-06-03 ’904 Patent Issued
2014-09-16 ’452 Patent Issued
2014-10-07 ’231 Patent Issued
2016-03-01 ’968 Patent Issued
2019-09-04 Sandoz Notice of Paragraph IV Certification sent
2019-09-30 Complaint Filed

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

U.S. Patent No. 7,045,620 - Polymorphous forms of rifaximin, processes for their production and use thereof in medicinal preparations

The Invention Explained

  • Problem Addressed: The patent’s background section notes that prior art methods for producing the antibiotic rifaximin were generic and did not control for or even recognize the existence of different crystalline forms, or polymorphs (’620 Patent, col. 1:14-24). This lack of control could lead to different production batches having inconsistent pharmacological properties, such as dissolution profiles and bioavailability, a significant issue for drug manufacturing and patient safety (’620 Patent, col. 2:5-13).
  • The Patented Solution: The invention discloses the discovery of specific polymorphous forms of rifaximin, named α, β, and γ, and describes processes to reliably produce them (’620 Patent, Abstract). The solution hinges on controlling specific parameters during crystallization and drying, particularly the presence of water in the solvent, the temperature, and the final water content of the product, which determines which polymorph is formed (’620 Patent, col. 2:32-39). The different crystal structures are characterized by distinct powder X-ray diffraction patterns, illustrated in Figures 1-3 of the patent.
  • Technical Importance: Standardizing the production of a specific, homogeneous polymorph is critical for ensuring consistent quality, safety, and efficacy in a pharmaceutical product marketed for human use (’620 Patent, col. 1:46-58).

Key Claims at a Glance

  • The complaint does not specify which claims are asserted but makes general allegations of infringement of the patent (Compl. ¶¶ 45-46). Representative independent claims include Claims 1, 3, 5, and 6.
  • Claim 1 (representative product claim):
    • A purified rifaximin α, a polymorph of the antibiotic rifaximin
    • wherein said rifaximin α has a water content of 3% or less
    • and produces a powder X-ray diffractogram showing peaks at specified 2θ angle values (6.6°; 7.4°; 7.9°; etc.).
  • The complaint generally alleges infringement of "one or more claims" of the ’620 patent (Compl. ¶46).

U.S. Patent No. 7,612,199 - Polymorphic forms α, β, and γ of Rifaximin

The Invention Explained

  • Problem Addressed: As a continuation of the family that includes the ’620 patent, this patent addresses the same technical problem: the need for standardized manufacturing processes to produce specific, well-defined polymorphous forms of rifaximin to ensure consistent pharmacological properties (’199 Patent, col. 2:3-21).
  • The Patented Solution: The patent claims specific polymorphic forms α, β, and γ of rifaximin, defined by their characteristic powder X-ray diffraction patterns and water content (’199 Patent, col. 3:13-col. 4:67). The solution, as described in the specification, relies on controlling crystallization and drying conditions, such as solvent composition, temperature, and duration, to selectively produce the desired polymorph (’199 Patent, col. 4:1-12).
  • Technical Importance: The ability to isolate and claim distinct polymorphs with defined characteristics provides a basis for developing drug products with predictable and reproducible performance, a key requirement for regulatory approval and commercialization (’199 Patent, col. 1:50-62).

Key Claims at a Glance

  • The complaint does not specify which claims are asserted (Compl. ¶¶ 52-53). Representative independent claims include Claims 1, 4, and 6.
  • Claim 1 (representative product claim):
    • Rifaximin in polymorphic form α
    • wherein the rifaximin has x-ray powder diffraction pattern peaks at about 7.4°; 19.7°; 21.0° and 22.1° 2-θ
    • and wherein the rifaximin has a water content of less than 4.5%.
  • The complaint generally alleges infringement of "one or more claims" of the ’199 patent (Compl. ¶53).

U.S. Patent No. 7,902,206 - Polymorphic forms a, ß and y of rifaximin

  • Technology Synopsis: This patent, related to the ’620 and ’199 patents, further claims crystalline forms of rifaximin, processes for preparing them, and pharmaceutical compositions comprising them. The technology centers on controlling polymorphism through specific manufacturing conditions to achieve desired therapeutic profiles.
  • Asserted Claims: The complaint asserts infringement of one or more unspecified claims (Compl. ¶¶ 59-60).
  • Accused Features: The accused feature is Sandoz's proposed generic rifaximin tablet, which allegedly comprises the claimed crystalline forms of rifaximin (Compl. ¶¶ 58-60).

U.S. Patent No. 7,906,542 - Pharmaceutical compositions comprising polymorphic forms a, ß, and y of rifaximin

  • Technology Synopsis: This patent claims pharmaceutical compositions containing the rifaximin polymorphs α, β, and γ. The invention relates to formulating these specific crystalline forms into stable and effective dosage forms for treating bacterial infections.
  • Asserted Claims: The complaint asserts infringement of one or more unspecified claims (Compl. ¶¶ 66-67).
  • Accused Features: Sandoz's ANDA product is accused of being a pharmaceutical composition that contains the claimed rifaximin polymorphs (Compl. ¶¶ 65-67).

U.S. Patent No. 7,915,275 - Use of polymorphic forms of rifaximin for medical preparations

  • Technology Synopsis: This patent claims methods of treating bacterial infections and bowel-related disorders by administering the specified crystalline forms of rifaximin. The invention is directed to the therapeutic application of these specific polymorphs.
  • Asserted Claims: The complaint asserts infringement of one or more unspecified claims (Compl. ¶¶ 73-74).
  • Accused Features: The accused act is Sandoz seeking approval for its ANDA product for an indication (IBS-D) that allegedly practices the claimed methods of treatment (Compl. ¶¶ 39, 75).

U.S. Patent No. 8,158,644 - Pharmaceutical compositions comprising polymorphic forms α, β, and γ of rifaximin

  • Technology Synopsis: This patent claims solid pharmaceutical compositions containing rifaximin polymorphs. It is part of the same family as the '542 patent and covers formulations designed to deliver the specific crystalline forms of the drug.
  • Asserted Claims: The complaint asserts infringement of one or more unspecified claims (Compl. ¶¶ 84-85).
  • Accused Features: The accused feature is Sandoz's proposed generic rifaximin tablet, which is alleged to be a composition containing the claimed polymorphs (Compl. ¶¶ 83, 85).

U.S. Patent No. 8,158,781 - Polymorphic forms a, ß and y of rifaximin

  • Technology Synopsis: This patent, related to the ’620 patent family, claims the specific rifaximin polymorphs α, β, and γ, defined by their distinct crystallographic properties. The technology focuses on the solid-state chemistry of the active pharmaceutical ingredient.
  • Asserted Claims: The complaint asserts infringement of one or more unspecified claims (Compl. ¶¶ 91-92).
  • Accused Features: The active pharmaceutical ingredient in Sandoz's ANDA product is alleged to be one of the claimed crystalline forms of rifaximin (Compl. ¶¶ 90, 92).

U.S. Patent No. 8,193,196 - Polymorphous forms of rifaximin, processes for their production and use thereof in the medicinal preparations

  • Technology Synopsis: This patent claims rifaximin polymorphs, compositions containing them, and methods of treating gastrointestinal bacterial activity. The invention covers the specific solid forms of the drug, its formulation, and its therapeutic use.
  • Asserted Claims: The complaint asserts infringement of one or more unspecified claims (Compl. ¶¶ 98-100).
  • Accused Features: Sandoz's ANDA product and its proposed use for treating IBS-D are alleged to infringe the patent's claims to compositions and methods of treatment (Compl. ¶¶ 97, 100).

U.S. Patent No. 8,309,569 - Methods for treating diarrhea-associated irritable bowel syndrome

  • Technology Synopsis: This patent is directed specifically to methods of treating diarrhea-associated irritable bowel syndrome (IBS-D) by administering rifaximin. The invention lies in the specific application of the drug to this condition.
  • Asserted Claims: The complaint asserts infringement of one or more unspecified claims (Compl. ¶¶ 111-112).
  • Accused Features: Sandoz is accused of infringement by seeking FDA approval for its ANDA product for the explicit indication of treating IBS-D, which Plaintiffs allege is covered by the patent's method claims (Compl. ¶¶ 39, 113).

U.S. Patent No. 8,518,949 - Polymorphous forms of rifaximin, processes for their production and use thereof in the medicinal preparations

  • Technology Synopsis: This patent, related to the ’196 patent, claims solid pharmaceutical compositions containing specific crystalline forms of rifaximin. The technology is focused on the formulation of these particular polymorphs into drug products.
  • Asserted Claims: The complaint asserts infringement of one or more unspecified claims (Compl. ¶¶ 124-125).
  • Accused Features: Sandoz's proposed generic rifaximin tablet is alleged to be a composition that infringes the patent's claims (Compl. ¶¶ 123, 125).

U.S. Patent No. 8,741,904 - Polymorphous forms of rifaximin, processes for their production and use thereof in the medicinal preparations

  • Technology Synopsis: This patent claims crystalline forms of rifaximin, methods of treating bacterial activity in the gastrointestinal tract, and medicinal preparations containing them. The patent covers the active ingredient itself, its therapeutic use, and its formulation.
  • Asserted Claims: The complaint asserts infringement of one or more unspecified claims (Compl. ¶¶ 131-132).
  • Accused Features: The infringement allegation targets both the composition of Sandoz's ANDA product and its intended use for treating IBS-D (Compl. ¶¶ 130, 133).

U.S. Patent No. 8,835,452 - Polymorphic forms α, β and γ of rifaximin

  • Technology Synopsis: This patent, part of the ’620 family, claims the specific crystalline forms of rifaximin and pharmaceutical compositions containing them. The technology relates to the solid-state chemistry of the active ingredient and its formulation.
  • Asserted Claims: The complaint asserts infringement of one or more unspecified claims (Compl. ¶¶ 144-145).
  • Accused Features: Sandoz's generic rifaximin tablet is alleged to contain the patented crystalline forms (Compl. ¶¶ 143, 145).

U.S. Patent No. 8,853,231 - Pharmaceutical compositions comprising polymorphic forms α, β, and γ of rifaximin

  • Technology Synopsis: This patent claims pharmaceutical compositions containing the specified rifaximin polymorphs. The invention focuses on the formulation of these distinct crystalline forms into dosage forms.
  • Asserted Claims: The complaint asserts infringement of one or more unspecified claims (Compl. ¶¶ 151-152).
  • Accused Features: Sandoz's ANDA product is alleged to be a pharmaceutical composition that infringes the patent's claims (Compl. ¶¶ 150, 152).

U.S. Patent No. 9,271,968 - Polymorphous forms of rifaximin, processes for their production and use thereof in the medicinal preparations

  • Technology Synopsis: This patent claims pharmaceutical compositions comprising crystalline forms of rifaximin. The invention relates to the formulation of specific, defined polymorphs of the active pharmaceutical ingredient.
  • Asserted Claims: The complaint asserts infringement of one or more unspecified claims (Compl. ¶¶ 158-159).
  • Accused Features: The accused feature is Sandoz's proposed generic rifaximin tablet, which allegedly falls within the scope of the patent's composition claims (Compl. ¶¶ 157, 159).

III. The Accused Instrumentality

  • Product Identification: The accused instrumentality is Sandoz’s Abbreviated New Drug Application ("ANDA") No. 213713 product, which is a generic version of rifaximin 550 mg tablets (Compl. ¶¶ 12, 38).
  • Functionality and Market Context: The complaint alleges that Sandoz’s ANDA seeks approval to manufacture, use, and sell a generic version of Plaintiffs’ Xifaxan® 550 mg tablets (Compl. ¶ 38). The product is intended for the indication of "treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults" (Compl. ¶ 39). The filing of the ANDA itself constitutes a statutory act of infringement under 35 U.S.C. § 271(e)(2)(A) (Compl. ¶ 44). If approved, Sandoz’s product would compete directly with Plaintiffs' branded Xifaxan® product (Compl. ¶ 38). No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint does not provide claim charts or detailed element-by-element infringement allegations for any of the asserted patents. Instead, it relies on general allegations typical of an initial ANDA complaint.

For the patents claiming crystalline forms of rifaximin (e.g., the ’620 and ’199 patents), the core infringement theory is that the rifaximin active pharmaceutical ingredient in Sandoz's ANDA product will be one or more of the patented polymorphous forms (Compl. ¶¶ 45-46, 52-53). For the patents claiming pharmaceutical compositions (e.g., the ’542 patent), the allegation is that Sandoz's final tablet formulation will contain these patented polymorphs (Compl. ¶¶ 66-67). For the patents claiming methods of use (e.g., the ’275 and ’569 patents), the allegation is that Sandoz will induce and contribute to infringement by seeking FDA approval to label and market its generic product for the patented therapeutic indications, such as IBS-D (Compl. ¶¶ 75, 113).

  • Identified Points of Contention:
    • Factual Questions: A primary point of contention will be a factual dispute over the solid-state characterization of Sandoz's generic product. The case will likely require extensive discovery and expert analysis, using techniques like X-ray powder diffraction (XRPD), to determine if the crystalline structure and water content of the rifaximin in Sandoz's product meet the specific limitations of the asserted product and composition claims.
    • Scope Questions: The interpretation of claim terms defining the polymorphs will be critical. For example, for claims that define a polymorph by a set of characteristic XRPD peaks "at about" certain angles (e.g., ’199 Patent, Claim 1), a central question for claim construction will be the permissible range of variability denoted by the term "about."

V. Key Claim Terms for Construction

  • The Term: "produces a powder X-ray diffractogram showing peaks at values of the diffraction angles 2θ of [specific values]°" (language from ’620 Patent, Claim 1) and "has x-ray powder diffraction pattern peaks at about [specific values]° 2-θ" (language from ’199 Patent, Claim 1).
  • Context and Importance: The definition of the polymorphs in the patents-in-suit is primarily based on lists of characteristic peaks from powder X-ray diffraction analysis. The infringement determination will depend entirely on whether the XRPD pattern of Sandoz's product matches the claimed patterns. Practitioners may focus on whether the claimed peaks are merely illustrative or strictly define the metes and bounds of the invention, and what degree of instrumental or experimental variance is permitted by the claim language.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The use of the term "about" in the claims of the ’199 patent explicitly suggests that the peak values are not meant to be exact, allowing for some experimental variability (’199 Patent, Claim 1). The specification of the ’620 patent describes the specific instrument and conditions used to generate the disclosed diffractograms, which could be argued to imply that results may vary slightly on different equipment without changing the fundamental crystalline form (’620 Patent, col. 6:11-20).
    • Evidence for a Narrower Interpretation: The patents distinguish the different polymorphs (α, β, and γ) from each other based on their unique sets of XRPD peaks, as shown in Figures 1-3 (’620 Patent, Figs. 1-3). This suggests that the listed peaks are essential, defining features. A party could argue that the absence of a recited peak or the presence of a significant unrecited peak in an accused product’s diffractogram indicates a different, non-infringing crystalline form.

VI. Other Allegations

  • Indirect Infringement: For the asserted method-of-use patents, the complaint alleges that Sandoz will induce infringement by seeking approval for a label that instructs physicians and patients to administer the ANDA product for the patented indications, such as treating IBS-D (Compl. ¶¶ 75-77, 100-102, 113-115, 133-135). The complaint also alleges contributory infringement, stating the ANDA product is not a staple article of commerce suitable for substantial non-infringing use (Compl. ¶¶ 78, 103, 116, 136).
  • Willful Infringement: The complaint alleges that Sandoz was aware of the existence of the patents-in-suit, as demonstrated by their listing in the FDA’s Orange Book and Sandoz’s own reference to the patents in its Paragraph IV notice letter (e.g., Compl. ¶ 47, 54). The complaint further alleges that Sandoz's positions on non-infringement and invalidity are devoid of an objective good faith basis and that the case is "exceptional" (e.g., Compl. ¶ 48, 55).

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

  • A central evidentiary question will be one of polymorphic identity: Through discovery and expert analysis, what are the actual crystallographic properties (e.g., XRPD pattern) and water content of the rifaximin active ingredient in the final dosage form of Sandoz’s ANDA product, and do these properties fall within the scope of the asserted claims?
  • A key legal question will be one of definitional scope: During claim construction, how broadly will the court interpret the terms defining the polymorphs, particularly the recitation of specific XRPD peaks? The outcome will determine whether minor variations in an accused product's crystal structure are sufficient to avoid infringement.
  • For the method-of-use patents, a core issue will be whether Sandoz's proposed label will actively encourage, recommend, or promote an infringing use, and whether any substantial non-infringing uses for the product exist that would defeat claims of inducement or contributory infringement.