DCT

3:18-cv-03592

Gilead Sciences Inc v. Natco Pharma Ltd

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 3:18-cv-03592, D.N.J., 03/14/2018
  • Venue Allegations: Plaintiffs allege venue is proper in the District of New Jersey because Defendants conduct business in the state, have regular and established places of business, and committed acts of infringement by filing Abbreviated New Drug Application (ANDA) No. 211373 with the intent to market the accused product in New Jersey.
  • Core Dispute: Plaintiff alleges that Defendants' filing of an ANDA to market a generic version of Gilead's Sovaldi® (sofosbuvir) tablets constitutes an act of infringement of six U.S. patents covering the compound, its crystalline forms, metabolites, and methods of use.
  • Technical Context: The technology relates to nucleoside analogue antiviral drugs, specifically sofosbuvir, which is a cornerstone therapy for the treatment of chronic Hepatitis C virus (HCV) infection.
  • Key Procedural History: This action was initiated under the Hatch-Waxman Act following Plaintiffs' receipt of a "Notice Letter" from Natco on February 8, 2018. This letter contained a Paragraph IV certification, asserting that the patents-in-suit are invalid, unenforceable, or will not be infringed by the proposed generic product. The complaint notes that the filing of this lawsuit within 45 days of receiving the Notice Letter triggers a statutory stay of up to 30 months on the FDA's approval of Natco's ANDA.

Case Timeline

Date Event
2003-05-30 Earliest Priority Date for ’572 and ’322 Patents
2008-09-30 U.S. Patent No. 7,429,572 Issues
2009-05-20 Earliest Priority Date for ’076, ’342, and ’217 Patents
2013-04-09 U.S. Patent No. 8,415,322 Issues
2013-12-23 Earliest Priority Date for ’568 Patent
2013-12-31 U.S. Patent No. 8,618,076 Issues
2015-12-08 U.S. Patent No. 9,206,217 Issues
2016-03-15 U.S. Patent No. 9,284,342 Issues
2016-05-17 U.S. Patent No. 9,340,568 Issues
2018-02-08 Plaintiff receives Notice Letter regarding ANDA No. 211373
2018-03-14 Complaint Filed

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

U.S. Patent No. 8,618,076 - “Nucleoside Phosphoramidates”

  • Issued: December 31, 2013.

The Invention Explained

  • Problem Addressed: The patent addresses the challenge of effectively delivering antiviral nucleoside analogues to target cells. Many such compounds are potent inhibitors of viral enzymes only after being converted (phosphorylated) inside a cell, but are poorly absorbed or prematurely metabolized when administered directly (’076 Patent, col. 1:49-58).
  • The Patented Solution: The invention is a specific phosphoramidate prodrug of a fluorinated nucleoside analogue. This chemical structure is designed to mask the charged phosphate group, facilitating the drug's passage across cell membranes. Once inside the cell, the masking groups are cleaved by cellular enzymes to release the active monophosphate form of the drug, bypassing the often inefficient first step of intracellular activation (’076 Patent, col. 2:4-21). The patent claims specific crystalline forms of this prodrug, which provide stability and formulation advantages.
  • Technical Importance: Prodrug strategies like phosphoramidates were critical for transforming potent but poorly bioavailable nucleoside analogues into viable oral medications for viral diseases like HCV and HIV (Compl. ¶5).

Key Claims at a Glance

  • The complaint asserts independent claim 1 (Compl. ¶¶ 49-50, 58-59).
  • Claim 1 is directed to:
    • A crystalline compound represented by a specific chemical formula (sofosbuvir).
    • Characterized by having X-ray powder diffraction (XRPD) 2θ-reflections (°) at about: 6.1, 8.2, 10.4, 12.7, 17.2, 17.7, 18.0, 18.8, 19.4, 19.8, 20.1, 20.8, 21.8, and 23.3.
  • The complaint reserves the right to assert other claims, including dependent claims (Compl. ¶49, fn. 1).

U.S. Patent No. 9,284,342 - “Nucleoside Phosphoramidates”

  • Issued: March 15, 2016.

The Invention Explained

  • Problem Addressed: Like the ’076 patent, this patent addresses the efficient intracellular delivery of antiviral nucleoside monophosphates (’342 Patent, col. 1:47-56). It further seeks to identify and claim specific, stable crystalline forms of the prodrug compound suitable for pharmaceutical formulation.
  • The Patented Solution: The invention claims a distinct crystalline form of the same phosphoramidate prodrug (sofosbuvir) described in the ’076 patent. This form is identified by a different, much smaller set of characteristic XRPD peaks, suggesting it is a different polymorph or crystal habit with unique physical properties compared to the form claimed in the ’076 patent (’342 Patent, col. 35:5-13).
  • Technical Importance: Identifying and patenting distinct polymorphs of a drug substance is a common and important practice in the pharmaceutical industry, as different crystalline forms can have significant differences in stability, solubility, and manufacturability (Compl. ¶¶ 70-71).

Key Claims at a Glance

  • The complaint asserts independent claim 1 (Compl. ¶¶ 70-71, 79-80).
  • Claim 1 is directed to:
    • A crystalline compound represented by a specific chemical formula (sofosbuvir).
    • Characterized by having XRPD 2θ-reflections (°) at about 6.1 and 12.7.
  • The complaint reserves the right to assert other claims (Compl. ¶70, fn. 3).

U.S. Patent No. 7,429,572 - "Modified Fluorinated Nucleoside Analogues"

  • Issued: September 30, 2008.
  • Technology Synopsis: The patent addresses the need for effective therapeutic agents against Flaviviridae infections, particularly HCV (’572 Patent, col. 1:39-44). The claimed solution is a class of (2'R)-2'-deoxy-2'-fluoro-2'-C-methyl nucleosides, which are chemical compounds designed to inhibit viral replication (’572 Patent, Abstract).
  • Asserted Claims: Claim 1 is asserted (Compl. ¶97).
  • Accused Features: The complaint alleges that the Natco ANDA Product contains, will metabolize into, or will be manufactured using a specific nucleoside or its salt that falls within the scope of claim 1 (Compl. ¶98). The accompanying chemical structure diagram depicts the active metabolite of sofosbuvir (Compl. ¶98).

U.S. Patent No. 8,415,322 - "Modified Fluorinated Nucleoside Analogues"

  • Issued: April 9, 2013.
  • Technology Synopsis: This patent is related to the ’572 patent and also addresses the need for anti-HCV therapies (’322 Patent, col. 1:39-44). The invention is a method of inhibiting HCV proliferation or treating an HCV infection by administering an effective amount of specific metabolites of sofosbuvir (’322 Patent, Abstract).
  • Asserted Claims: Claim 9 is asserted (Compl. ¶112).
  • Accused Features: The complaint alleges that the use of the Natco ANDA Product, in accordance with its label, will result in the formation of a metabolite compound that meets the limitations of the claimed method (Compl. ¶113). The complaint includes a chemical structure of the active triphosphate metabolite of sofosbuvir (Compl. ¶113).

U.S. Patent No. 9,206,217 - "Nucleoside Phosphoramidates"

  • Issued: December 8, 2015.
  • Technology Synopsis: This patent, like the ’076 and ’342 patents, relates to crystalline forms of the sofosbuvir prodrug (’217 Patent, col. 35:10-15). It claims different polymorphs defined by specific unit cell parameters and sets of XRPD peaks, distinguishing them from other known solid forms.
  • Asserted Claims: Claims 1 and 2 are asserted (Compl. ¶127).
  • Accused Features: The complaint alleges that Natco will manufacture a compound that is a monoclinic crystalline form of sofosbuvir having specific unit cell parameters (infringing claim 1) and specific XRPD reflections (infringing claim 2) (Compl. ¶¶ 128-129).

U.S. Patent No. 9,340,568 - "Solid Forms of an Antiviral Compound"

  • Issued: May 17, 2016.
  • Technology Synopsis: This patent relates to additional crystalline forms of sofosbuvir (’568 Patent, col. 1:16-19). The claims define these solid forms using different analytical techniques, including XRPD and solid-state nuclear magnetic resonance (SSNMR) spectroscopy, to characterize distinct polymorphs.
  • Asserted Claims: Claims 1, 3, 5, and 7 are asserted (Compl. ¶143).
  • Accused Features: The complaint alleges that Natco will manufacture a crystalline compound ("Compound I") that infringes claims 1, 3, 5, and 7 because it possesses the claimed XRPD and 13C SSNMR spectral peaks (Compl. ¶¶ 144-147).

III. The Accused Instrumentality

Product Identification

  • The "Natco ANDA Product," which is a proposed generic version of Gilead's Sovaldi® (sofosbuvir) 400 mg tablets, as described in ANDA No. 211373 filed with the FDA (Compl. ¶¶ 1-2, 35).

Functionality and Market Context

  • The Natco ANDA Product is alleged to contain the same active ingredient (sofosbuvir), dosage form, and strength as Sovaldi® and is intended for the same approved indication: the treatment of chronic HCV infection (Compl. ¶¶ 35, 40-41). Sovaldi® is described as a "groundbreaking" product, and the filing of an ANDA for a generic version suggests an intent to compete in the market for HCV treatments upon approval (Compl. ¶2). The complaint alleges, on information and belief, that the Natco product contains specific crystalline forms of sofosbuvir (Compl. ¶¶ 50, 71, 128, 144). The chemical structure diagram provided in the complaint depicts the (Sp) diastereomer of the sofosbuvir prodrug (Compl. ¶50).

IV. Analysis of Infringement Allegations

’8,618,076 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A crystalline compound represented by formula (Sp-4): The Natco ANDA Product allegedly contains a crystalline compound represented by the formula shown in the complaint, which is identical to formula (Sp-4). ¶50 col. 35:60-67
having XRPD 2θ-reflections (°) at about: 6.1, 8.2, 10.4, 12.7, 17.2, 17.7, 18.0, 18.8, 19.4, 19.8, 20.1, 20.8, 21.8, and 23.3. The Natco ANDA Product allegedly has XRPD 2θ-reflections at the same fourteen angular positions recited in the claim. ¶50 col. 36:1-6
  • Identified Points of Contention:
    • Scope Questions: The primary point of contention regarding infringement of the '076 Patent will likely be the interpretation of the term "about" as it modifies each of the fourteen recited XRPD peak positions. The dispute may center on whether the measured peak positions of the Natco ANDA Product, whatever they may be, are sufficiently close to the claimed values to fall within the scope of the claim.
    • Technical Questions: A key evidentiary question will be whether Natco's proposed product is, in fact, the specific crystalline polymorph claimed. The complaint alleges the presence of all fourteen characteristic peaks based on "information and belief" (Compl. ¶50). The case may turn on what evidence Gilead can produce from discovery to prove that the Natco product exhibits this specific XRPD pattern, as opposed to another known or unknown polymorph of sofosbuvir.

’9,284,342 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A crystalline compound represented by formula (Sp-4) The Natco ANDA Product allegedly contains a crystalline compound represented by the formula shown in the complaint, which is identical to formula (Sp-4). ¶71 col. 35:5-13
having XRPD 2θ-reflections (°) at about 6.1 and 12.7. The Natco ANDA Product allegedly has XRPD 2θ-reflections at the two specific angular positions recited in the claim. ¶71 col. 35:10-11
  • Identified Points of Contention:
    • Scope Questions: Compared to the '076 Patent, claim 1 of the ’342 Patent defines a crystalline form with far fewer characteristic peaks (two versus fourteen). This raises the question of whether this claim is broad enough to read on multiple polymorphs, and whether Natco's product possesses a form that meets this two-peak definition while potentially being distinguishable by other unlisted peaks.
    • Technical Questions: Similar to the '076 Patent, the infringement allegation rests on the factual assertion that the Natco product has peaks at "about: 6.1 and 12.7" (Compl. ¶71). The technical question will be what the actual XRPD data for Natco's product shows and how that data compares to the claimed values.

V. Key Claim Terms for Construction

  • The Term: "about"
  • Context and Importance: This term appears in the asserted claims of both the ’076 and ’342 patents, modifying the specific numerical values of the XRPD peak locations. The construction of "about" is critical because it defines the permissible range of deviation from the recited 2θ values. A broader interpretation would make it easier for Gilead to prove infringement, while a narrower interpretation would favor Natco. Practitioners may focus on this term because the entire infringement analysis for these composition claims could depend on whether the measured peaks of the accused product are "about" the claimed values.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The repeated use of "about" for every numerical value in the claims suggests the patentee intentionally included a degree of variability to account for minor experimental fluctuations inherent in XRPD measurements (’076 Patent, col. 36:1-6; ’342 Patent, col. 35:10-11).
    • Evidence for a Narrower Interpretation: The specifications of the patents provide specific examples with precise XRPD peak data without the "about" qualifier (’076 Patent, Table 1; ’342 Patent, Table 1). A party might argue that "about" should be construed narrowly to cover only the minor variations expected from instrumental error and not to expand the claim to cover distinctly different, albeit similar, crystalline forms.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges both induced and contributory infringement for all patents-in-suit. The theory of inducement is that Natco, with knowledge of the patents, will encourage and instruct patients and medical practitioners to administer the accused product according to its proposed package insert, causing direct infringement (Compl. ¶¶ 63, 84, 99, 114, 130, 148). The basis for contributory infringement is that the Natco product is especially made or adapted for infringing the patents and is not a staple article suitable for substantial non-infringing use (Compl. ¶¶ 65, 86, 101, 116, 132, 150).
  • Willful Infringement: The complaint alleges that Natco acted with full knowledge of at least the ’076 and ’342 patents, citing their listing in the FDA's Orange Book and Natco's own Notice Letter (Compl. ¶¶ 61, 82, 153). Gilead further alleges that Natco's Notice Letter does not contest infringement of numerous claims of the ’076 patent and fails to contest infringement of any claim of the ’342 patent, which may be presented as evidence that Natco knew or was willfully blind to the fact that its product would infringe (Compl. ¶¶ 62, 83). These allegations are based on alleged pre-suit knowledge.

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

  • A core issue will be one of definitional scope: how will the court construe the term "about" as applied to the analytical data (XRPD peaks) defining the claimed crystalline forms? The outcome of this construction will likely determine whether minor variations between the accused product and the patent's examples constitute infringement.
  • A key evidentiary question will be one of factual identity: what is the precise crystalline form of the proposed Natco ANDA Product? The complaint is based on "information and belief" prior to full discovery of the ANDA's contents, and the case will turn on whether Gilead can prove that Natco's product possesses the specific crystallographic and structural properties required by one or more of the asserted claims.
  • A third central question will relate to validity and inventiveness: Natco's Paragraph IV certification asserts the patents are invalid. The litigation will likely involve a significant dispute over whether the specific crystalline forms claimed in the various patents were obvious inventions in light of the prior art concerning sofosbuvir and pharmaceutical formulation generally.