DCT
3:19-cv-19345
Novartis Pharma Corp v. Macleods Pharma Ltd
Key Events
Complaint
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Novartis Pharmaceuticals Corporation (Delaware)
- Defendant: Macleods Pharmaceuticals Ltd. (India); Macleods Pharma USA, Inc. (Delaware)
- Plaintiff’s Counsel: McCarter & English, LLP
- Case Identification: 3:19-cv-19345, D.N.J., 10/25/2019
- Venue Allegations: Venue is alleged to be proper based on Defendant Macleods Pharma USA, Inc. having a regular and established place of business in the district, and Defendant Macleods Pharmaceuticals Ltd. being a foreign entity subject to suit in any judicial district.
- Core Dispute: Plaintiff alleges that Defendants' Abbreviated New Drug Application (ANDA) to market a generic version of the heart failure drug ENTRESTO® constitutes an act of infringement of three U.S. patents covering the drug's composition and methods of use.
- Technical Context: The technology concerns combination pharmaceutical therapies for cardiovascular diseases, specifically pairing an angiotensin receptor blocker (valsartan) with a neprilysin inhibitor (sacubitril) to achieve a dual mechanism of action.
- Key Procedural History: The complaint notes this action is a "backup suit" to a substantively identical case filed in the District of Delaware, filed to safeguard against potential jurisdictional or venue challenges. Novartis states it has sued twelve other groups of generic drug-makers in Delaware concerning their ANDAs for generic versions of ENTRESTO®.
Case Timeline
| Date | Event |
|---|---|
| 2002-01-17 | U.S. Patent No. 8,101,659 Priority Date |
| 2005-11-09 | U.S. Patent Nos. 8,877,938 & 9,388,134 Priority Date |
| 2012-01-24 | U.S. Patent No. 8,101,659 Issued |
| 2014-11-04 | U.S. Patent No. 8,877,938 Issued |
| 2016-07-12 | U.S. Patent No. 9,388,134 Issued |
| 2019-09-11 | Macleods sends Notice Letter to Novartis regarding ANDA filing |
| 2019-10-25 | 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 (’659 Patent)
The Invention Explained
- Problem Addressed: The patent’s background section describes the complex hormonal pathways, particularly the renin-angiotensin system, that contribute to hypertension and congestive heart failure. It notes that while existing therapies like ACE inhibitors are effective, there is a need for more efficacious combination therapies that can provide greater benefits, potentially with fewer side effects than simply combining different drug classes. (’659 Patent, col. 2:56-3:6).
- The Patented Solution: The invention is a pharmaceutical composition that combines two distinct active agents: valsartan, an angiotensin II (AT1) receptor antagonist, and a neprilysin (NEP) inhibitor. This combination is designed to simultaneously block the vasoconstrictive effects of angiotensin II while enhancing the beneficial vasodilating and diuretic effects of natriuretic peptides, which are normally broken down by the NEP enzyme. (’659 Patent, Abstract; col. 4:18-24). The patent suggests this dual-action approach provides a surprisingly greater therapeutic effect than either agent administered alone. (’659 Patent, col. 5:41-47).
- Technical Importance: This approach represented a new strategy for treating cardiovascular disease by simultaneously targeting two separate but related pathological pathways with a single combination product.
Key Claims at a Glance
- The complaint alleges infringement of one or more claims, including composition claims. (’659 Patent, Claim 1).
- Independent Claim 1 requires:
- A pharmaceutical composition comprising (i) the AT1-antagonist valsartan or a pharmaceutically acceptable salt thereof;
- (ii) a specific NEP inhibitor (sacubitril or its active metabolite/salt);
- (iii) a pharmaceutically acceptable carrier;
- wherein (i) and (ii) are administered in combination in about a 1:1 ratio.
- The complaint reserves the right to assert infringement of additional claims, which may include dependent claims. (Compl. ¶36).
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 (’938 Patent)
The Invention Explained
- Problem Addressed: The patent identifies essential hypertension as a polygenic disease that is often not adequately controlled by monotherapy. This creates a need for effective combination therapies that do not introduce deleterious side effects. (’938 Patent, col. 2:3-25).
- The Patented Solution: The invention moves beyond a simple combination of two drugs and discloses a novel "supramolecular complex"—a specific co-crystal containing valsartan, sacubitril, sodium cations, and water molecules—in a defined crystalline structure. (’938 Patent, Abstract; col. 6:21-44). This creates a single chemical entity with distinct physicochemical properties (e.g., stability, solubility, X-ray diffraction pattern) compared to a physical mixture of the individual components. (’938 Patent, col. 17:1-11).
- Technical Importance: The creation of a stable, dual-acting supramolecular complex provided a novel solid-state form that could offer advantages in manufacturing, formulation, and bioavailability over simple co-administration of the two active ingredients.
Key Claims at a Glance
- The complaint alleges infringement of one or more claims, including claims to the crystalline complex. (’938 Patent, Claim 1).
- Independent Claim 1 requires:
- Trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3'-methyl-2'-(pentanoyl{2"-(tetrazol-5-ylate)biphenyl-4'-ylmethyl}amino)butyrate] hemipentahydrate;
- in crystalline form.
- The complaint reserves the right to assert infringement of additional claims. (Compl. ¶37).
Multi-Patent Capsule: U.S. Patent No. 9,388,134 (’134 Patent)
- Patent Identification: 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: Continuing from the same family as the ’938 patent, this patent addresses the need for effective treatments for cardiovascular conditions like heart failure and hypertension. It claims a method of treating these conditions by administering a therapeutically effective amount of the specific sacubitril/valsartan trisodium hemipentahydrate complex described in the ’938 patent. (’134 Patent, Abstract; col. 21:50-58).
- Asserted Claims: The complaint asserts one or more claims, including method of treatment claims. Claim 1 is representative. (Compl. ¶26).
- Accused Features: The accused feature is the filing of the ANDA, which, if approved, would lead to the sale of a generic product specifically labeled for treating heart failure, thereby inducing infringement of the patented method. (Compl. ¶¶38, 39).
III. The Accused Instrumentality
- Product Identification: The "Macleods ANDA Products," which are the subject of ANDA No. 213728 submitted to the FDA. (Compl. ¶8). These products are generic versions of Novartis's ENTRESTO® (sacubitril/valsartan) tablets. (Compl. ¶1).
- Functionality and Market Context: The products are tablets formulated with sacubitril and valsartan in dosages of 24/26 mg, 49/51 mg, and 97/103 mg. (Compl. ¶1). The complaint alleges these products are intended for the same therapeutic use as ENTRESTO®, namely the treatment of heart failure. (Compl. ¶¶27, 38). The filing of the ANDA is an artificial act of infringement under the Hatch-Waxman Act, signifying Macleods' intent to market its generic product prior to the expiration of the patents-in-suit. (Compl. ¶9).
- No probative visual evidence provided in complaint.
IV. Analysis of Infringement Allegations
The complaint makes general allegations of infringement based on Defendants' ANDA filing, which seeks approval to market a generic version of ENTRESTO®.
’659 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| a pharmaceutical composition comprising (i) the AT1-antagonist valsartan or a pharmaceutically acceptable salt thereof; | The Macleods ANDA Products are alleged to be sacubitril/valsartan tablets. | ¶1, ¶36 | col. 16:20-22 |
| (ii) the NEP inhibitor... sacubitril... or a pharmaceutically acceptable salt thereof; | The Macleods ANDA Products are alleged to contain sacubitril. | ¶1, ¶22, ¶36 | col. 16:23-28 |
| (iii) a pharmaceutically acceptable carrier; | The Macleods ANDA Products are tablet formulations, which by definition contain pharmaceutically acceptable carriers. | ¶1 | col. 16:29-30 |
| wherein (i) and (ii) are administered in combination in about a 1:1 ratio. | The Macleods ANDA Products are alleged to be combination tablets where the active ingredients are administered in about a 1:1 ratio. | ¶22 | col. 16:31-34 |
’938 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| Trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3'-methyl-2'-(pentanoyl{2"-(tetrazol-5-ylate)biphenyl-4'-ylmethyl}amino)butyrate] hemipentahydrate | The Macleods ANDA Products are alleged to be generic versions of ENTRESTO®, which is this specific supramolecular complex. | ¶24, ¶37 | col. 31:40-46 |
| in crystalline form. | The complaint alleges that the Macleods ANDA Products will infringe the claim to the complex in its crystalline form. | ¶24, ¶37 | col. 31:47 |
Identified Points of Contention:
- Scope Questions: For the ’659 Patent, a potential point of dispute is the scope of the term "about a 1:1 ratio." The analysis will depend on whether the molar ratio of the active ingredients in the Macleods ANDA Products falls within the range permitted by this term, which is not explicitly defined in the patent.
- Technical Questions: For the ’938 Patent, the central infringement question is one of identity. Does the product described in Macleods' ANDA filing contain the specific "trisodium [...] hemipentahydrate" supramolecular complex in the same "crystalline form" as claimed? This raises an evidentiary question that will depend on a comparison of the analytical data for the defendants' proposed product with the data and definitions provided in the patent.
V. Key Claim Terms for Construction
The Term: "about a 1:1 ratio" (’659 Patent, Claim 1)
- Context and Importance: This term's construction is critical for determining infringement of the ’659 Patent. The defendant's product may not have an exact 1:1 molar ratio of the two active ingredients, and whether it infringes will depend on the degree of variance the court allows under the term "about." Practitioners may focus on this term because numerical ranges with modifiers like "about" are common subjects of claim construction disputes.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The patent uses the term "about" without providing an explicit numerical definition, which may support an argument that the term should be given its plain and ordinary meaning, connoting a reasonable degree of approximation. (’659 Patent, col. 16:34).
- Evidence for a Narrower Interpretation: A party could argue that the scope of "about" should be narrowed by the context of the invention as a whole. However, the specification of the ’659 Patent does not appear to provide specific embodiments or examples that would significantly limit the term's scope.
The Term: "crystalline form" (’938 Patent, Claim 1)
- Context and Importance: The patent protects a specific polymorphic form of the sacubitril/valsartan complex. Infringement of the ’938 Patent hinges on whether the defendant's proposed generic product is the same "crystalline form." If the defendant has created a different polymorph or an amorphous version, it may not infringe.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: Novartis may argue that the term "crystalline form" should be defined by the detailed characterization data provided in the patent, including the X-ray powder diffraction peaks and other data disclosed, and that any generic product exhibiting these characteristics infringes. (’938 Patent, col. 17:9-50).
- Evidence for a Narrower Interpretation: Macleods may argue that the term is strictly limited to the exact crystal structure disclosed. Any demonstrable difference in their product's analytical data (e.g., different XRPD peak locations or intensities) could be used to argue that their product is a different, non-infringing crystalline form.
VI. Other Allegations
- Indirect Infringement: The complaint alleges that upon approval, Macleods will induce and contribute to the infringement of the ’134 Patent. (Compl. ¶¶38, 39). Inducement is based on the allegation that the product's label will instruct physicians and patients to administer the drug for the treatment of heart failure, an infringing use. (Compl. ¶39). Contributory infringement is based on the allegation that the Macleods ANDA Products are especially made for this infringing use and are not suitable for substantial non-infringing use. (Compl. ¶39).
- Willful Infringement: The complaint does not explicitly allege "willful infringement." However, it alleges that Macleods was aware of the patents-in-suit when it filed its ANDA and knew the filing was an act of infringement. (Compl. ¶34). It also seeks a declaration that the case is "exceptional" under 35 U.S.C. § 285, which is the statutory basis for awarding enhanced damages and attorney's fees, the remedies for willful infringement. (Compl. ¶49).
VII. Analyst’s Conclusion: Key Questions for the Case
- A central issue will be one of pharmaceutical identity: does the generic product detailed in Macleods' ANDA constitute the same "trisodium [...] hemipentahydrate" complex in the specific "crystalline form" claimed in the ’938 patent, or has Macleods formulated a product with a different, non-infringing solid-state structure?
- A key legal question will be one of claim scope: can the term "about a 1:1 ratio" in the ’659 patent be construed to cover the precise molar ratio of the active ingredients in the Macleods ANDA Products, and what evidence will be required to establish the boundaries of that term?