DCT
1:20-md-02930
In re: Entresto (Sacubitril/Valsartan) Patent Litigation
Key Events
Amended Complaint
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Novartis Pharmaceuticals Corporation (Delaware)
- Defendant: Lupin Atlantis Holdings, S.A. (Switzerland); Lupin Limited (India); Lupin Inc. (Delaware); Lupin Pharmaceuticals, Inc. (Delaware)
- Plaintiff’s Counsel: McCarter & English, LLP; Venable LLP
- Case Identification: Novartis Pharmaceuticals Corporation v. Lupin Atlantis Holdings, S.A., et al., 1:20-md-02930; 1:21-cv-00229, D. Del., 06/09/2021
- Venue Allegations: Plaintiff alleges venue is proper in the District of Delaware because Defendants Lupin Inc. and Lupin Pharmaceuticals, Inc. are incorporated in Delaware, and Defendants Lupin Atlantis Holdings and Lupin Limited are foreign entities that may be sued in any judicial district. The complaint also alleges that Defendant Lupin Atlantis Holdings has agreed to litigate this action in the District of Delaware.
- Core Dispute: Plaintiff alleges that Defendants' submission of an Abbreviated New Drug Application (ANDA) to the FDA for generic versions of Plaintiff's Entresto® (sacubitril/valsartan) tablets constitutes an act of infringement of four U.S. patents.
- Technical Context: The technology relates to pharmaceutical compositions and methods for treating cardiovascular diseases, such as hypertension and heart failure, by combining two different therapeutic agents.
- Key Procedural History: This amended complaint consolidates several prior actions between the parties concerning Defendants' ANDA No. 213808. The litigation was initiated in response to a series of notice letters sent by Defendants, beginning September 3, 2019, which certified that the patents-in-suit are invalid or will not be infringed by the proposed generic product.
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 |
| 2019-09-03 | Lupin Atlantis First Notice Letter Sent to Novartis |
| 2019-10-17 | Novartis Files First Complaint |
| 2020-02-12 | Lupin Atlantis Second Notice Letter Sent to Novartis |
| 2020-03-24 | Novartis Files Second Complaint |
| 2021-01-05 | Lupin Atlantis Third Notice Letter Sent to Novartis |
| 2021-02-18 | Novartis Files Third Complaint |
| 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," Issued January 24, 2012
The Invention Explained
- Problem Addressed: The patent's background describes the complex hormonal pathways involved in regulating blood pressure, specifically the renin-angiotensin system (which constricts blood vessels) and natriuretic peptides like ANF (which relax blood vessels and promote sodium excretion) (’659 Patent, col. 1:11-19; col. 2:10-24). The patent notes that while drugs targeting these systems individually exist, there remains a need for more effective combination therapies for conditions like hypertension and heart failure (’659 Patent, col. 3:1-6).
- The Patented Solution: The invention is a pharmaceutical composition that combines two active agents: valsartan, an angiotensin receptor blocker (ARB) that inhibits the vasoconstrictive effects of angiotensin II, and a neutral endopeptidase (NEP) inhibitor that prevents the breakdown of beneficial natriuretic peptides (’659 Patent, Abstract). By simultaneously blocking a harmful pathway and enhancing a beneficial one, the combination is intended to provide a more potent therapeutic effect than either agent alone (’659 Patent, col. 5:41-46).
- Technical Importance: This dual-mechanism approach represented a significant therapeutic strategy for managing complex cardiovascular diseases by addressing multiple pathophysiological pathways concurrently.
Key Claims at a Glance
- The complaint alleges infringement of claims 1-4 (Compl. ¶¶ 67, 68). Independent claim 1 is representative.
- Claim 1 Elements:
- A pharmaceutical composition comprising valsartan or a pharmaceutically acceptable salt thereof;
- and comprising the NEP inhibitor N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoic acid ethyl ester (sacubitril) or (2R,4S)-5-biphenyl-4-yl-4(3-carboxy-propionyl amino)-2-methyl-pentanoic acid (sacubitrilat) or a pharmaceutically acceptable salt thereof;
- and comprising a pharmaceutically acceptable carrier;
- wherein the valsartan and NEP inhibitor components are administered in combination in about a 1:1 ratio.
U.S. Patent No. 8,796,331 - "Methods of treatment and pharmaceutical composition," Issued August 5, 2014
The Invention Explained
- Problem Addressed: The ’331 Patent, which shares a specification with the ’659 Patent, addresses the same technical problem of providing improved treatments for hypertension and heart failure (’331 Patent, col. 1:19-3:12).
- The Patented Solution: Rather than claiming the composition itself, this patent claims a method of treating hypertension or heart failure by administering the combination of valsartan and a NEP inhibitor (’331 Patent, Abstract). The patent describes that the two components can be administered together in a single unit dose form or as two separate dosage forms (’331 Patent, col. 7:25-31).
- Technical Importance: This patent protects the therapeutic application of the combination therapy, covering the act of administering the two drug classes together for the specified indications.
Key Claims at a Glance
- The complaint alleges infringement of claims 1, 2, and 5-8 (Compl. ¶¶ 67, 68). Independent claim 1 is representative.
- Claim 1 Elements:
- 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) the AT 1-antagonist valsartan or a pharmaceutically acceptable salt thereof; and (ii) a NEP inhibitor or a pharmaceutically acceptable salt thereof;
- wherein (i) and (ii) are administered in one unit dose form or in two separate unit dose forms.
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," Issued November 4, 2014
- Technology Synopsis: The patent addresses the technical challenge of co-formulating valsartan and the NEP inhibitor sacubitril into a stable, solid dosage form (’938 Patent, col. 2:28-32). The patented solution is a novel supramolecular complex, specifically a crystalline solid comprising the anions of valsartan and sacubitril, along with sodium cations and water molecules (trisodium hemipentahydrate) (’938 Patent, Abstract; Fig. 1). This specific crystalline structure is asserted to provide advantageous physicochemical properties for pharmaceutical development.
- Asserted Claims: Claims 1-11 (Compl. ¶¶ 66, 68).
- Accused Features: The complaint alleges that Defendants' proposed generic sacubitril/valsartan tablets will be, or will contain, the specific crystalline complex claimed by the ’938 Patent (Compl. ¶ 72).
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," Issued July 12, 2016
- Technology Synopsis: The ’134 Patent is from the same family as the ’938 Patent and is directed to the same novel supramolecular complex of valsartan and sacubitril. Instead of claiming the compound itself, this patent claims a method of treating heart failure or hypertension by administering a therapeutically effective amount of that specific crystalline compound, sacubitril/valsartan trisodium hemipentahydrate (’134 Patent, Abstract).
- Asserted Claims: Claims 1-15 (Compl. ¶¶ 66, 68).
- Accused Features: The complaint alleges that the product labeling for Defendants' proposed generic drug will instruct medical professionals and patients to administer the tablets for the treatment of heart failure, thereby infringing the claimed method (Compl. ¶ 75).
III. The Accused Instrumentality
- Product Identification: Defendants' proposed generic sacubitril/valsartan tablets in 24 mg/26 mg, 49 mg/51 mg, and 97 mg/103 mg dosage strengths, for which approval is sought under ANDA No. 213808 (Compl. ¶¶ 1, 9).
- Functionality and Market Context: The accused products are generic versions of Novartis's branded drug, Entresto®, which is indicated for the treatment of heart failure (Compl. ¶¶ 1, 55). By filing an ANDA, Defendants are representing to the FDA that their proposed products are bioequivalent to Entresto® and have the same therapeutic use. The act of filing the ANDA to seek approval for commercial manufacture and sale prior to patent expiration is the statutory basis for this infringement action (Compl. ¶¶ 62-63).
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) the AT 1-antagonist valsartan or a pharmaceutically acceptable salt thereof; | Defendants' ANDA Products are tablets containing valsartan. | ¶9; ¶70 | col. 16:16-24 |
| (ii) the NEP inhibitor N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoic acid ethyl ester... | Defendants' ANDA Products are tablets containing sacubitril. | ¶9; ¶70 | col. 16:25-36 |
| and (iii) a pharmaceutically acceptable carrier; | As tablets intended for oral administration, the ANDA Products necessarily contain pharmaceutically acceptable carriers. | ¶9; ¶70 | col. 16:37-38 |
| wherein said (i) ... valsartan ... and said (ii) NEP inhibitor ... are administered in combination in about a 1:1 ratio. | The proposed dosage strengths (e.g., 24mg/26mg) correspond to approximately a 1:1 molar ratio of the active ingredients. | ¶9; ¶48; ¶70 | col. 16:47-50 |
’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 proposed labeling for the ANDA Products will instruct for use in the treatment of heart failure. | ¶55; ¶73 | col. 16:1-2 |
| comprising administering... a therapeutically effective amount of the combination of (i) ... valsartan ... and (ii) a NEP inhibitor... | The ANDA Products are combination tablets containing both valsartan and sacubitril, and their labeling will instruct for their administration. | ¶9; ¶73 | col. 16:3-9 |
| wherein (i) and (ii) are administered in one unit dose form or in two separate unit dose forms. | The ANDA Products are single tablets, which constitute administration in a "one unit dose form." | ¶9; ¶50 | col. 16:10-12 |
- Identified Points of Contention:
- Scope Questions: For the ’659 and ’331 patents, a potential point of dispute, though perhaps minor, could be the scope of the term "about a 1:1 ratio." A more significant issue for all patents will likely be validity, as is common in ANDA litigation where the accused product is intended to be bioequivalent to the patented product.
- Technical Questions: The central technical dispute for the ’938 and ’134 patents will concern the specific solid-state form of Defendants' active pharmaceutical ingredient. The key question is whether the generic product, as specified in the ANDA, uses the precise "trisodium hemipentahydrate" crystalline complex claimed in the patents, or if it uses a different crystalline form (polymorph) or an amorphous form that falls outside the claims' scope.
V. Key Claim Terms for Construction
- The Term: "crystalline form" (as recited in claim 1 of the ’938 patent via a specific chemical name for a crystalline solid)
- Context and Importance: The infringement analysis for the ’938 and ’134 patents will turn entirely on this feature. The patents claim a specific supramolecular complex with a defined crystalline structure. Practitioners may focus on this feature because if Defendants' ANDA specifies a different, non-infringing crystal form or an amorphous version of the drug substance, there would be no literal infringement of these patents.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The concept of "broader" interpretation is less applicable here, as the claim recites a specific chemical entity.
- Evidence for a Narrower Interpretation: The specification provides extensive, detailed characterization data that precisely defines the claimed crystalline solid. This includes X-ray powder diffraction patterns with specific peak locations, single-crystal X-ray analysis data, and detailed descriptions of the unit cell structure (’938 Patent, Fig. 1; col. 17:46-18:67). This data provides a narrow and specific definition of the claimed subject matter.
VI. Other Allegations
- Indirect Infringement: The complaint alleges that Defendants will induce and contribute to infringement of all four patents. For the method claims of the ’331 and ’134 patents, inducement is based on the allegation that Defendants' product labeling will instruct physicians and patients to administer the drug for the claimed therapeutic purpose (Compl. ¶¶ 73, 75, 84, 86). For all patents, contributory infringement is alleged on the basis that the accused products are especially made for an infringing use and are not suitable for a substantial non-infringing use (Compl. ¶¶ 71, 74, 76).
- Willful Infringement: While the complaint does not use the term "willful," it alleges that Defendants were aware of the patents-in-suit at the time of their ANDA filing and knew that the filing constituted an act of infringement (Compl. ¶ 64). This allegation of pre-suit knowledge could form the basis for a subsequent claim of willful infringement.
VII. Analyst’s Conclusion: Key Questions for the Case
- A central technical question will be one of polymorphism: does the generic product detailed in Lupin's ANDA contain the specific "trisodium hemipentahydrate" supramolecular complex claimed in the '938 and '134 patents, or does it utilize a different, non-infringing crystalline or amorphous form of the active ingredients? The outcome will depend on highly technical, fact-intensive evidence regarding the solid-state chemistry of the accused product.
- A core legal issue will be the validity of the asserted patents. As is typical in ANDA litigation where the accused product is designed to be bioequivalent, a primary defense strategy may involve challenging the patents on grounds of obviousness. This could raise the question of whether it was obvious to combine valsartan with a NEP inhibitor (’659 and ’331 patents) or to create the specific crystalline complex of the two molecules (’938 and ’134 patents).