DCT

1:16-cv-00188

Salix Pharma Ltd v. Actavis Laboratories FL Inc

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Key Events
Amended Complaint

I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:16-cv-00188, D. Del., 06/14/2016
  • Venue Allegations: Plaintiffs allege venue is proper because Defendant distributes and sells pharmaceutical products in Delaware and has previously submitted to the jurisdiction of the court in other actions.
  • Core Dispute: Plaintiffs allege that Defendant’s filing of an Abbreviated New Drug Application (ANDA) to market a generic version of Plaintiffs’ 550 mg rifaximin tablets (Xifaxan®) constitutes an act of infringement of twenty-three U.S. patents.
  • Technical Context: The dispute centers on rifaximin, a non-systemic antibiotic used to treat hepatic encephalopathy (HE) and irritable bowel syndrome with diarrhea (IBS-D), with the patents-in-suit covering methods of use and specific crystalline forms (polymorphs) of the drug.
  • Key Procedural History: The action was triggered by a Paragraph IV certification in Defendant’s ANDA No. 208959, communicated to Plaintiffs via a notice letter dated February 11, 2016. The patents-in-suit are listed in the U.S. Food and Drug Administration's "Orange Book" as covering the Xifaxan® product, which provides the statutory basis for this Hatch-Waxman litigation.

Case Timeline

Date Event
1999-08-11 '053', '857', '240', '608', '799', '569', '573', '017', '252', and '398' Patents - Earliest Priority Date
2003-11-07 '620', '199', '206', '542', '275', '644', '781', '196', '949', '904', '452', '231', and '968' Patents - Earliest Priority Date
2004-05-25 FDA approved Xifaxan® 200 mg tablets (NDA No. 021361)
2005-03-01 U.S. Patent No. 6,861,053 Issued
2006-05-16 U.S. Patent No. 7,045,620 Issued
2008-11-18 U.S. Patent No. 7,452,857 Issued
2009-10-20 U.S. Patent No. 7,605,240 Issued
2009-11-03 U.S. Patent No. 7,612,199 Issued
2010-03-24 FDA approved Xifaxan® 550 mg tablets (NDA No. 022554)
2010-05-18 U.S. Patent No. 7,718,608 Issued
2011-03-08 U.S. Patent No. 7,902,206 Issued
2011-03-15 U.S. Patent No. 7,906,542 Issued
2011-03-29 U.S. Patent No. 7,915,275 Issued
2011-05-03 U.S. Patent No. 7,935,799 Issued
2012-04-17 U.S. Patent No. 8,158,644 Issued
2012-04-17 U.S. Patent No. 8,158,781 Issued
2012-06-05 U.S. Patent No. 8,193,196 Issued
2012-11-13 U.S. Patent No. 8,309,569 Issued
2013-08-27 U.S. Patent No. 8,518,949 Issued
2014-02-04 U.S. Patent No. 8,642,573 Issued
2014-06-03 U.S. Patent No. 8,741,904 Issued
2014-09-09 U.S. Patent No. 8,829,017 Issued
2014-09-16 U.S. Patent No. 8,835,452 Issued
2014-10-07 U.S. Patent No. 8,853,231 Issued
2015-02-03 U.S. Patent No. 8,946,252 Issued
2015-03-03 U.S. Patent No. 8,969,398 Issued
2016-02-11 Actavis sends Notice Letter regarding ANDA No. 208959
2016-03-01 U.S. Patent No. 9,271,968 Issued
2016-06-14 Complaint Filed

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

U.S. Patent No. 6,861,053 - "Methods of diagnosing or treating irritable bowel syndrome and other disorders caused by small intestinal bacterial overgrowth", issued March 1, 2005

The Invention Explained

  • Problem Addressed: The patent addresses the challenge that irritable bowel syndrome (IBS) is a widespread gastrointestinal disorder with a variety of symptoms but no fully accepted underlying cause, making treatment difficult and often directed only at symptoms rather than a root cause (’053 Patent, col. 1:22-44).
  • The Patented Solution: The invention proposes that a condition known as small intestinal bacterial overgrowth (SIBO) is a direct cause of IBS and other related disorders (’053 Patent, col. 2:23-28). The patented solution is a method that involves first diagnosing the presence of SIBO in a patient and then treating the patient by "at least partially eradicating" the bacterial overgrowth, such as through the administration of antimicrobial agents (’053 Patent, Abstract).
  • Technical Importance: This approach provided a potential paradigm shift in gastroenterology, reframing IBS not just as a functional disorder to be managed symptomatically, but as a condition with a treatable, underlying bacterial cause (’053 Patent, col. 2:23-28).

Key Claims at a Glance

The complaint does not identify specific claims, but asserts infringement of claims covering "methods of treating irritable bowel syndrome with rifaximin" (Compl. ¶52). Independent claim 18 is representative of this technology.

  • A method of treating irritable bowel syndrome, comprising:
    • at least partially eradicating a small intestinal bacterial overgrowth condition
    • in a human subject having irritable bowel syndrome.
  • The complaint does not explicitly reserve the right to assert dependent claims for this patent.

U.S. Patent No. 7,045,620 - "Polymorphous forms of rifaximin, processes for their production and use thereof in medicinal preparations", issued May 16, 2006

The Invention Explained

  • Problem Addressed: The patent identifies a lack of standardization in the production of rifaximin, noting that different manufacturing batches can result in different crystalline structures, or polymorphs, which in turn can alter the drug's pharmacological properties like bioavailability and stability (’620 Patent, col. 1:5-14).
  • The Patented Solution: The invention identifies, characterizes, and claims three distinct polymorphous forms of rifaximin, designated α (alpha), β (beta), and γ (gamma), each defined by unique X-ray powder diffraction patterns (’620 Patent, col. 1:39-44, FIGS. 1-3). It also discloses specific crystallization and drying processes that allow for the consistent production of these desired forms by controlling variables like solvent composition, temperature, and water content (’620 Patent, col. 1:30-38).
  • Technical Importance: By defining and controlling the specific crystalline forms of rifaximin, the invention enables consistent, large-scale manufacturing of a drug product with predictable and reliable pharmacologic properties, a critical requirement for regulatory approval and therapeutic consistency (’620 Patent, col. 2:50-59).

Key Claims at a Glance

The complaint asserts infringement of claims covering "crystalline forms of rifaximin" (Compl. ¶65). Independent claim 1 is representative of this technology.

  • Rifaximin in a polymorphous form α, characterized in that it shows a powder X-ray diffractogram with peaks at values of the diffraction angles 2θ of:
    • 6.6°; 7.4°; 7.9°; 8.8°; 10.5°; 11.1°; 11.8°; 12.9°; 17.6°; 18.5°; 19.7°; 21.0°; 21.4°; 22.1°.
  • The complaint does not explicitly reserve the right to assert dependent claims for this patent.

Multi-Patent Capsule: U.S. Patent No. 7,452,857

  • Patent Identification: U.S. Patent No. 7,452,857, "Methods of treating irritable bowel syndrome and other disorders caused by small intestinal bacterial overgrowth," issued November 18, 2008.
  • Technology Synopsis: This patent is related to the '053 Patent and further claims methods for treating IBS and other disorders by administering rifaximin to a subject to eradicate an underlying SIBO condition. It specifies particular dosing regimens for rifaximin.
  • Asserted Claims: The complaint asserts infringement of claims covering "methods of treating irritable bowel syndrome with rifaximin" (Compl. ¶72).
  • Accused Features: The accused feature is the intended use of Actavis's generic rifaximin product to treat IBS-D, which Plaintiffs allege will directly infringe the patented method (Compl. ¶74).

Multi-Patent Capsule: U.S. Patent No. 7,605,240

  • Patent Identification: U.S. Patent No. 7,605,240, "Methods of treating diarrhea and bloating caused by small intestinal bacterial overgrowth," issued October 20, 2009.
  • Technology Synopsis: This patent is also related to the '053 Patent and claims methods of treating specific symptoms of SIBO, namely bloating and diarrhea, by administering rifaximin. It provides further support for the link between SIBO and common gastrointestinal symptoms.
  • Asserted Claims: The complaint asserts infringement of claims covering "methods of treating bloating with rifaximin" (Compl. ¶85).
  • Accused Features: The accused feature is the intended use of Actavis's generic rifaximin product to relieve symptoms of IBS-D, which includes diarrhea and bloating, thereby allegedly infringing the patented method (Compl. ¶87).

Analyst Note: The complaint asserts 19 additional patents. These patents largely fall into two categories: (1) further method-of-use patents related to the '053 patent, claiming treatments for various gastrointestinal conditions (e.g., traveler's diarrhea, hepatic encephalopathy) with specific rifaximin dosing regimens; and (2) further composition-of-matter patents related to the '620 patent, claiming different polymorphic forms of rifaximin (e.g., forms δ and ε) or pharmaceutical compositions containing them. The infringement allegations for these additional patents follow the same patterns described for the '053 and '620 patents, respectively.

III. The Accused Instrumentality

Product Identification

The accused instrumentality is "Actavis' Generic Product," identified as 550 mg rifaximin tablets for which Actavis submitted ANDA No. 208959 to the FDA for approval (Compl. ¶43).

Functionality and Market Context

The complaint alleges that Actavis's ANDA seeks approval to manufacture and sell its generic product for the same indications as the branded Xifaxan® 550 mg tablets (Compl. ¶44). These indications are the "reduction in risk of overt hepatic encephalopathy (HE) recurrence in adults and treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults" (Compl. ¶45). The filing of the ANDA itself, seeking to market a generic version prior to the expiration of the Orange Book-listed patents, forms the statutory basis for the infringement action under 35 U.S.C. § 271(e)(2)(A) (Compl. ¶51).

IV. Analysis of Infringement Allegations

No probative visual evidence provided in complaint.

6,861,053 Patent Infringement Allegations

Claim Element (from Independent Claim 18) Alleged Infringing Functionality Complaint Citation Patent Citation
A method of treating irritable bowel syndrome, comprising: Actavis's Generic Product will be prescribed and administered to patients to relieve the signs and symptoms of irritable bowel syndrome with diarrhea (IBS-D). ¶54 col. 2:23-25
at least partially eradicating a small intestinal bacterial overgrowth condition The accused product contains the antibiotic rifaximin, which eradicates intestinal bacteria. The administration of the product for its intended uses is alleged to constitute the direct infringement of this claimed step. ¶54 col. 2:26-28
in a human subject having irritable bowel syndrome. Actavis's ANDA seeks approval for an indication to treat IBS-D in adults. ¶45 col. 2:23-25

7,045,620 Patent Infringement Allegations

The complaint does not provide sufficient detail for a limitation-by-limitation analysis of the accused product's physical characteristics. The infringement theory is based on the allegation that the product Actavis seeks to market is, or contains, the claimed polymorphous form of rifaximin.

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
Rifaximin in a polymorphous form α, characterized in that it shows a powder X-ray diffractogram with peaks at values of the diffraction angles 2θ of 6.6°; 7.4°; 7.9°; 8.8°; 10.5°; 11.1°; 11.8°; 12.9°; 17.6°; 18.5°; 19.7°; 21.0°; 21.4°; 22.1°. The complaint alleges that Actavis's manufacture, use, or sale of its Generic Product will infringe one or more claims of the '620 patent. This implies an allegation that the rifaximin active ingredient in the generic product exhibits the crystalline structure of polymorphous form α. ¶64, ¶66 col. 5:2-9

Identified Points of Contention

  • Scope Questions: For the '053 Patent, a central question may be whether administering an antibiotic for the FDA-approved indication of "IBS-D" inherently constitutes "eradicating a small intestinal bacterial overgrowth condition" as required by the claim. The dispute may focus on whether the label's instruction for IBS-D treatment necessarily directs infringement of a method for treating SIBO.
  • Technical Questions: For the '620 Patent, the primary dispute will likely be factual: does the rifaximin in Actavis's generic product actually exist in the specific polymorphous form α, as defined by the claimed X-ray diffraction peaks? The complaint does not present evidence on this point, which suggests this will be a central subject of discovery and expert testimony.

V. Key Claim Terms for Construction

’053 Patent

  • The Term: "small intestinal bacterial overgrowth condition"
  • Context and Importance: The definition of this term is critical because infringement of the method claim requires that the accused act (administering rifaximin for IBS-D) actually treats this specific "condition." Practitioners may focus on this term to determine if the general antibacterial effect of rifaximin in an IBS-D patient meets the specific definition of treating SIBO as understood in the patent.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The patent abstract broadly links IBS itself with SIBO, suggesting any effective treatment for IBS via antibacterial action could be construed as treating a SIBO condition (’053 Patent, Abstract).
    • Evidence for a Narrower Interpretation: The specification provides a specific clinical definition, stating that SIBO "is defined as greater than 10⁵ CFU/mL small intestinal effluent" (’053 Patent, col. 11:27-29). A defendant may argue this quantitative threshold must be met and diagnosed for the "condition" to exist.

’620 Patent

  • The Term: "about" (as used in "peaks at values of the diffraction angles 2θ of about 6.6°")
  • Context and Importance: The scope of "about" is central to determining literal infringement. Because X-ray diffraction measurements have inherent variability, the breadth of this term will define whether minor deviations in the peak locations of the accused product fall within or outside the claim scope.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The term "about" is used consistently in the claims, suggesting the patentee intended to claim a degree of instrumental and experimental variability beyond the precise numbers listed (’620 Patent, col. 8:3-9).
    • Evidence for a Narrower Interpretation: While the '620 Patent itself does not provide a specific numerical range for "about," other patents in the same family and cited in the complaint do. For example, U.S. Patent No. 9,271,968 (a related patent) claims peaks "at about 5.7°±0.2" (Compl. ¶289a). Plaintiffs may argue this demonstrates a clear understanding of experimental tolerance, while a defendant may argue the absence of such explicit ranges in the '620 Patent implies a narrower scope was intended for that specific patent.

VI. Other Allegations

Indirect Infringement

The complaint alleges induced infringement for the method patents (e.g., '053, '857). The factual basis alleged is that Actavis, with knowledge of the patents from their Orange Book listing and the notice letter, will create a product label that instructs physicians and patients to use the generic drug for the patented methods (e.g., treating IBS-D), thereby intentionally encouraging direct infringement (Compl. ¶56, ¶60). Contributory infringement is alleged on the basis that the generic product is not a staple article of commerce suitable for substantial non-infringing use (Compl. ¶57).

Willful Infringement

Willfulness is alleged based on Actavis’s pre-suit knowledge of the patents-in-suit via their listing in the FDA’s Orange Book and the receipt of the notice letter (Compl. ¶60). The complaint further alleges that Actavis’s stated opinions on non-infringement and invalidity are "devoid of an objective good faith basis," characterizing the case as "exceptional" (Compl. ¶61).

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

  • A core issue will be one of infringement linkage: for the method patents, can Plaintiffs establish that administering rifaximin for the FDA-approved indication of IBS-D necessarily results in the "eradicating [of] a small intestinal bacterial overgrowth condition" as claimed in the patents, or is there a disconnect between the labeled indication and the patented method?
  • A key evidentiary question will be one of physical identity: for the composition patents, does the rifaximin in Actavis's proposed generic product meet the specific structural requirements of the claimed polymorphous forms, as defined by precise X-ray powder diffraction data?
  • The outcome may also turn on a question of definitional scope during claim construction: how broadly will the court construe the term "about" as it applies to the numerical peaks defining the patented crystalline structures, and what clinical criteria define the existence of a "small intestinal bacterial overgrowth condition"?