DCT

1:19-cv-02053

Novartis Pharma Corp v. MSN Pharma Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:19-cv-02053, D. Del., 06/09/2021
  • Venue Allegations: Plaintiff alleges that venue is proper in the District of Delaware because several defendants are incorporated in Delaware, and the remaining foreign defendants may be sued in any judicial district. The complaint further notes that all defendants have agreed to litigate these patent actions in the District of Delaware and not to challenge personal jurisdiction or venue.
  • Core Dispute: Plaintiff alleges that Defendants' submission of Abbreviated New Drug Applications (ANDAs) to the FDA, seeking approval to market generic versions of Plaintiff's heart failure drug ENTRESTO®, constitutes an act of infringement of four patents covering the drug's composition and methods of use.
  • Technical Context: The technology relates to pharmaceutical compositions for treating cardiovascular conditions, specifically combining an angiotensin receptor blocker (valsartan) with a neprilysin (NEP) inhibitor (sacubitril) to achieve a dual mechanism of action.
  • Key Procedural History: This action arises under the Hatch-Waxman Act, triggered by notice letters sent by each defendant group to Novartis in September 2019, informing Novartis of their respective ANDA filings which included Paragraph IV certifications challenging the patents-in-suit.

Case Timeline

Date Event
2002-01-17 Earliest Priority Date for ’659 and ’331 Patents
2005-11-09 Earliest Priority Date for ’938 and ’134 Patents
2012-01-24 ’659 Patent Issued
2014-08-05 ’331 Patent Issued
2014-11-04 ’938 Patent Issued
2016-07-12 ’134 Patent Issued
2019-09-16 Novugen sends Notice Letter regarding its ANDA filing
2019-09-17 MSN sends Notice Letter regarding its ANDA filing
2019-09-18 Dr. Reddy's, Hetero, and Zydus send Notice Letters regarding their ANDA filings
2021-06-09 Amended Complaint Filed

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

U.S. Patent No. 8,101,659 - "Methods of treatment and pharmaceutical composition"

The Invention Explained

  • Problem Addressed: The patent's background describes the complex hormonal cascade known as the renin-angiotensin system (RAS) and its role in the pathophysiology of hypertension and other cardiovascular diseases (Compl. ¶98; ’659 Patent, col. 1:11-30). Existing treatments targeting this system, such as ACE inhibitors, had limitations and did not address other relevant biological pathways like those involving atrial natriuretic peptides (ANPs), which have beneficial vasodilator and diuretic effects (’659 Patent, col. 1:45-2:4).
  • The Patented Solution: The invention is a pharmaceutical composition that combines two active agents: (1) valsartan, an angiotensin II (Ang II) antagonist that blocks the harmful effects of the RAS, and (2) a neutral endopeptidase (NEP) inhibitor that prevents the breakdown of beneficial ANPs (’659 Patent, Abstract). By simultaneously blocking the RAS and potentiating the ANP system, the composition is designed to provide a more effective treatment for conditions like hypertension and heart failure than either agent alone (’659 Patent, col. 5:41-49).
  • Technical Importance: This dual-mechanism approach represented a therapeutic strategy that could address multiple pathological pathways of heart failure and hypertension concurrently. (Compl. ¶98-99).

Key Claims at a Glance

  • The complaint alleges infringement of one or more claims, with specific reference to claims 1-4 against at least one defendant (Compl. ¶115). Independent claim 1 is central.
  • Claim 1 of the ’659 Patent recites:
    • A pharmaceutical composition comprising (i) valsartan or a pharmaceutically acceptable salt thereof;
    • (ii) the NEP inhibitor N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoic acid ethyl ester (the prodrug of sacubitrilat) or a pharmaceutically acceptable salt thereof;
    • (iii) a pharmaceutically acceptable carrier;
    • wherein (i) and (ii) are administered in combination in about a 1:1 ratio.
  • The complaint does not explicitly reserve the right to assert dependent claims but alleges infringement of "one or more claims" (Compl. ¶114).

U.S. Patent No. 8,796,331 - "Methods of treatment and pharmaceutical composition"

The Invention Explained

  • Problem Addressed: The patent addresses the same technical problem as its parent ’659 Patent: the need for improved treatments for cardiovascular conditions like hypertension and heart failure by targeting multiple physiological pathways (Compl. ¶100; ’331 Patent, col. 1:9-29).
  • The Patented Solution: The patent claims a method of treating these conditions by administering the combination of valsartan and a NEP inhibitor (’331 Patent, Abstract). The key inventive concept is the therapeutic application of the composition, specifying that the two active agents can be administered either together in a single unit dose form (like a combination pill) or as two separate unit dose forms (’331 Patent, col. 10:28-32).
  • Technical Importance: This patent provides protection for the specific therapeutic use of the dual-action combination, a critical aspect of protecting a pharmaceutical product in the market. (Compl. ¶101).

Key Claims at a Glance

  • The complaint alleges infringement of one or more claims, with specific reference to claims 1, 2, and 4-8 against at least one defendant (Compl. ¶115). Independent claim 1 is central.
  • Claim 1 of the ’331 Patent recites:
    • A method for the treatment of hypertension or heart failure,
    • comprising administering to a patient in need thereof a therapeutically effective amount of the combination of (i) valsartan or a pharmaceutically acceptable salt thereof; and
    • (ii) the NEP inhibitor N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoic acid ethyl ester or a pharmaceutically acceptable salt thereof;
    • wherein (i) and (ii) are administered in one unit dose form or in two separate unit dose forms.
  • The complaint does not explicitly reserve the right to assert dependent claims but alleges infringement of "one or more claims" (Compl. ¶114).

U.S. Patent No. 8,877,938 - "Compounds containing S-N-valeryl-N-{[2'-(1H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine and (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester moieties and cations"

  • Technology Synopsis: This patent addresses the challenge of creating a stable, solid dosage form of the sacubitril and valsartan combination. It claims a specific supramolecular complex where the two active ingredients are combined with sodium cations and water molecules to form a distinct crystalline structure, described as a "trisodium...hemipentahydrate complex" (Compl. ¶103; ’938 Patent, Abstract).
  • Asserted Claims: The complaint alleges infringement of "one or more claims" (Compl. ¶119).
  • Accused Features: The defendants' ANDA products, which are generic versions of sacubitril/valsartan tablets, are alleged to infringe (Compl. ¶119).

U.S. Patent No. 9,388,134 - "Compounds containing S-N-valeryl-N-{[2'-(1H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine and (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester moieties and cations"

  • Technology Synopsis: This patent is a method-of-use patent related to the ’938 Patent. It claims a method for treating heart failure or hypertension by administering a therapeutically effective amount of the specific sacubitril/valsartan trisodium hemipentahydrate complex claimed in the ’938 Patent (Compl. ¶105; ’134 Patent, Abstract).
  • Asserted Claims: The complaint alleges infringement of "one or more claims" (Compl. ¶122).
  • Accused Features: The proposed use of the defendants' generic sacubitril/valsartan tablets, as will be described in their product labeling, is alleged to infringe (Compl. ¶122).

III. The Accused Instrumentality

Product Identification

The accused instrumentalities are the generic sacubitril/valsartan tablets for which the defendant groups have each filed an ANDA with the FDA (Compl. ¶7, 21, 36, 47, 56). These products are referred to in the complaint as, for example, the "Dr. Reddy's ANDA Products" (Compl. ¶7).

Functionality and Market Context

The defendants' products are designed to be generic equivalents of Novartis's branded drug, ENTRESTO®, available in dosages such as 24 mg/26 mg, 49 mg/51 mg, and 97 mg/103 mg (sacubitril/valsartan) (Compl. ¶1, 7). Upon FDA approval, these generic products would be marketed for the same indications as ENTRESTO®, which include reducing the risk of cardiovascular death and hospitalization for heart failure (Compl. ¶106). The filing of the ANDAs represents a direct commercial challenge to Novartis's market for ENTRESTO® (Compl. ¶8).

No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

’659 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A pharmaceutical composition comprising (i) valsartan or a pharmaceutically acceptable salt thereof; Defendants' ANDA products are sacubitril/valsartan tablets. ¶7 col. 10:1-10
(ii) the NEP inhibitor N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoic acid ethyl ester... or a pharmaceutically acceptable salt thereof; Defendants' ANDA products contain sacubitril, which is the specified NEP inhibitor. ¶7 col. 10:1-10
and (iii) a pharmaceutically acceptable carrier; The ANDA products are tablets which, by definition, contain pharmaceutically acceptable carriers. The complaint also alleges the product labels will instruct preparation of an aqueous oral suspension containing a carrier. ¶117 col. 10:1-10
wherein said (i)... and said (ii)... are administered in combination in about a 1:1 ratio. The product label for the ANDA products will allegedly instruct for administration in combination at about a 1:1 ratio. The approved dosage strengths are consistent with this ratio. ¶117 col. 10:12-14

’331 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method for the treatment of hypertension or heart failure, The defendants' proposed product labeling will contain instructions for using the ANDA products to treat heart failure. ¶120 col. 10:28-29
comprising administering to a patient in need thereof a therapeutically effective amount of the combination of (i) valsartan... and (ii) the NEP inhibitor...; The defendants' product labels will instruct physicians and patients to administer the tablets, which contain the claimed combination of active ingredients. ¶120 col. 10:29-41
wherein (i) and (ii) are administered in one unit dose form or in two separate unit dose forms. The accused products are tablets, which constitute a "one unit dose form" containing both active ingredients. ¶7 col. 10:42-44

Identified Points of Contention

  • Scope Questions: A central question may be the interpretation of "about a 1:1 ratio" in the ’659 Patent. The parties may dispute how much deviation from a precise 1:1 molar ratio is permitted by the term "about." Additionally, for the ’938 and ’134 patents, a key dispute may arise over whether the specific crystalline form of the complex in the defendants' ANDA products is identical to the "trisodium...hemipentahydrate complex" claimed, or if it constitutes a different, non-infringing polymorph.
  • Technical Questions: The complaint alleges infringement based on the contents of the defendants' ANDA filings. The ultimate technical question will be whether the chemical composition and physical form of the proposed generic products, as described in their ANDAs, meet every limitation of the asserted claims.

V. Key Claim Terms for Construction

"about a 1:1 ratio" (’659 Patent, Claim 1)

  • Context and Importance: This term is critical because it defines the required proportional relationship between the two active ingredients in the claimed composition. The scope of "about" will determine whether a generic product with a molar ratio that is close, but not exactly 1:1, infringes the claim. Practitioners may focus on this term to argue for or against infringement based on the precise formulation specified in an ANDA.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The use of the word "about" itself suggests the patentee did not intend to be limited to a precise ratio. The specification does not appear to provide an explicit numerical definition for "about," which may support an interpretation that includes functionally equivalent ratios that achieve the invention's purpose.
    • Evidence for a Narrower Interpretation: The specification of the ’659 patent does not appear to describe embodiments or examples with ratios other than 1:1. A defendant may argue that in the absence of such examples, the term "about" should be construed narrowly to cover only minor, insignificant variations from a 1:1 ratio.

"sacubitril/valsartan trisodium hemipentahydrate complex in crystalline form" (’938 Patent, Claim 10)

  • Context and Importance: This term defines the specific, solid-state chemical entity protected by the patent. In pharmaceutical cases, infringement can turn on whether an accused generic product contains the exact same crystalline form (polymorph) as the one claimed. The definition of this complex—including its stoichiometry of sodium and water—is central to the infringement analysis for the ’938 and ’134 patents.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: A plaintiff might argue that the term should be construed to cover any crystalline form that is bioequivalent and shares the essential structural characteristics identified in the patent, even with minor variations in diffraction patterns or other metrics.
    • Evidence for a Narrower Interpretation: The ’938 patent provides specific characterization data, such as X-ray powder diffraction patterns and single crystal X-ray analysis, for the claimed complex (’938 Patent, col. 17:6-50, FIG. 1). A defendant may argue that the claim is strictly limited to a crystalline form that matches this detailed "fingerprint" and that any alternative polymorph, even if chemically similar, falls outside the claim scope.

VI. Other Allegations

Indirect Infringement

The complaint alleges both induced and contributory infringement. The inducement theory is based on allegations that the defendants' product labels and instructions will actively encourage and instruct physicians and patients to administer the generic drugs in a manner that directly infringes the method claims of the ’331 and ’134 patents (Compl. ¶120, 122). The contributory infringement theory is based on allegations that the defendants' products are especially made for and have no substantial non-infringing use other than the patented methods (Compl. ¶121, 123).

Willful Infringement

The complaint does not contain a separate count for willful infringement, but it lays the factual groundwork for such a claim. It alleges that the defendants were aware of the patents-in-suit at the time they filed their ANDAs, and that the filing itself was an act of infringement (Compl. ¶113, 131, 148, 166, 184). This alleged pre-suit knowledge could be used to support a later claim for enhanced damages if infringement is found.

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

This ANDA litigation will likely center on two main areas of dispute, one definitional and one structural, which will determine whether the defendants' proposed generic products infringe.

  • A core issue will be one of definitional scope: How broadly will the court construe the term "about a 1:1 ratio" from the ’659 patent? The answer will dictate whether minor variations in the molar quantities of the active ingredients in the defendants' ANDA products are sufficient to avoid infringement of the foundational composition patent.
  • A key question will be one of structural identity: Do the defendants' proposed products contain the specific "trisodium hemipentahydrate complex in crystalline form" as claimed in the ’938 patent and used in the method of the ’134 patent? The case may involve a technical, fact-intensive comparison of the crystallographic data of the defendants' products against the precise form defined and characterized in the patent specifications.