Regents Of University Of Michigan v. Novartis Pharma Corp

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: The Regents of the University of Michigan (Michigan) and The University of South Florida Board of Trustees (Florida)
  • Defendant: Novartis Pharmaceuticals Corporation (Delaware)
  • Plaintiff's Counsel: Fish & Richardson P.C.
• Case Identification: 3:22-cv-04913, N.D. Cal., 08/29/2022
• Venue Allegations: Venue is alleged based on Defendant Novartis maintaining regular and established places of business at its San Carlos and Emeryville, California campuses, and because it has allegedly committed acts of patent infringement within the district.
• Core Dispute: Plaintiff alleges that Defendant's heart failure drug Entresto® infringes a patent related to the formation of pharmaceutical co-crystals with improved physical properties.
• Technical Context: The technology involves crystal engineering, a field of supramolecular chemistry used to design and synthesize solid-state structures, to improve characteristics of active pharmaceutical ingredients (APIs) such as solubility, stability, and bioavailability.
• Key Procedural History: The asserted patent is a continuation of a 2003 application that claims priority to a 2002 provisional application. Subsequent to the filing of this complaint, an Inter Partes Review (IPR) was instituted against the patent, which resulted in a certificate disclaiming claim 16. This proceeding does not directly impact the asserted claim 10 but indicates post-filing validity challenges.

Case Timeline

Date	Event
2002-03-01	'344 Patent Priority Date
2015-07	Entresto® FDA Approval
2020-04-28	'344 Patent Issue Date
2022-08-29	Complaint Filing Date
2023-08-28	IPR2023-01347 Filing Date
2025-06-05	IPR Certificate Issuing Disclaimer of Claim 16

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

U.S. Patent No. 10,633,344 - "Multiple-Component Solid Phases Containing at least One Active Pharmaceutical Ingredient"

• Patent Identification: U.S. Patent No. 10,633,344, "Multiple-Component Solid Phases Containing at least One Active Pharmaceutical Ingredient," issued April 28, 2020.

The Invention Explained

• Problem Addressed: The patent background describes the difficulty in creating predictable crystal structures for pharmaceutical compounds and the challenge of overcoming undesirable properties of APIs, such as poor solubility, dissolution rates, stability, and bioavailability, which can limit a drug's effectiveness '344 Patent, col. 2:28-36 Compl. ¶24
• The Patented Solution: The invention provides a method for designing new multi-component solid phases, or "co-crystals," by applying the principles of crystal engineering '344 Patent, col. 3:6-11 The process involves identifying an API and a "co-crystal former" that have complementary chemical functionalities capable of forming predictable non-covalent bonds, known as "supramolecular synthons" '344 Patent, abstract This creates a new crystalline structure with potentially improved physical and chemical properties compared to the original API alone '344 Patent, col. 3:25-28
• Technical Importance: This methodology provides a systematic approach to improve the physical characteristics of known drug compounds without chemically altering the API itself, offering a pathway to enhance drug performance and create new, patentable solid forms of existing medicines Compl. ¶24

Key Claims at a Glance

• The complaint asserts at least independent claim 10 '344 Patent, col. 24:4-32 Compl. ¶27
• The essential elements of independent claim 10 are:
  • A pharmaceutical composition with a carrier and a therapeutically effective amount of a co-crystal.
  • The co-crystal comprises "supramolecular synthons" formed from stoichiometric amounts of an active pharmaceutical ingredient (API) and a co-former.
  • Each supramolecular synthon comprises an "API homosynthon" formed via non-covalent hydrogen bonding.
  • The API has a "first chemical functionality" that permits the formation of these API homosynthons.
  • The co-former has a "second chemical functionality" that is complementary to the API's first functionality.
  • The co-former is a solid at room temperature and pressure.
  • The supramolecular synthons are formed by non-covalent hydrogen bonding between the first functionality of the API and the second functionality of the co-former.
• The complaint notes infringement of "one or more claims" of the patent, reserving the right to assert others Compl. ¶13

III. The Accused Instrumentality

Product Identification

• The accused products are Entresto® tablets in various dosage strengths Compl. ¶¶19-21

Functionality and Market Context

• Entresto® is a prescription medication indicated to reduce the risk of cardiovascular death and hospitalization for heart failure Compl. ¶28
• The complaint alleges that Entresto® is a co-crystal drug that contains sacubitril (the alleged API) and valsartan (the alleged co-former) Compl. ¶¶30-31
• The complaint alleges Novartis markets and distributes Entresto® globally, including throughout the United States, following its FDA approval in July 2015 Compl. ¶9 Compl. ¶10

IV. Analysis of Infringement Allegations

No probative visual evidence provided in complaint.

'344 Patent Infringement Allegations

Claim Element (from Independent Claim 10)	Alleged Infringing Functionality	Complaint Citation	Patent Citation
A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a co-crystal comprising supramolecular synthons,	Each dosage strength of Entresto® is a tablet comprising a carrier (e.g., microcrystalline cellulose) and contains a therapeutically effective amount of a co-crystal with sacubitril-valsartan supramolecular synthons.	¶29; ¶30	col. 10:8-15
each supramolecular synthon formed from stoichiometric amounts of at least one active pharmaceutical ingredient (API) and at least one co-former,	Each supramolecular synthon in Entresto® is allegedly formed from stoichiometric amounts of sacubitril (API) and valsartan (co-former).	¶31	col. 24:8-13
and each supramolecular synthon comprising an API homosynthon formed via non-covalent hydrogen bonding,	The API, sacubitril, has a first chemical functionality (a carboxamide) that permits the formation of API homosynthons through non-covalent hydrogen bonding.	¶32	col. 24:14-19
wherein the API has a first chemical functionality that permits formation of API homosynthons through non-covalent hydrogen bonding when the API is in its pure form,	Sacubitril has a carboxamide functionality that permits formation of homosynthons.	¶32	col. 24:16-19
wherein the co-former has a second chemical functionality complimentary to the first chemical functionality via non-covalent hydrogen bonding,	The co-former, valsartan, has a tetrazole functionality that is complementary to sacubitril's carboxamide functionality via non-covalent hydrogen bonding.	¶33	col. 24:20-23
wherein said co-former is a solid at room temperature and atmospheric pressure when the co-former is in its pure form,	The co-former, valsartan, is a solid at room temperature and atmospheric pressure in its pure form.	¶34	col. 24:24-27
and wherein supramolecular synthons are formed via non-covalent hydrogen bonding between the first chemical functionality of the API and the second chemical functionality of the co-former.	Supramolecular synthons are allegedly formed between the carboxamide of sacubitril and the tetrazole of valsartan via non-covalent hydrogen bonding.	¶35	col. 24:28-32

Identified Points of Contention

• Scope Questions: Claim 10 requires that the resulting supramolecular synthon "compris[es] an API homosynthon." The complaint alleges that the API (sacubitril) merely "permits formation of API homosynthons" Compl. ¶32 This raises the question of whether the claim requires the physical presence of an API-to-API homosynthon bond within the final co-crystal, or if it is sufficient that the API is merely capable of forming one on its own.
• Technical Questions: The infringement allegations rely on assertions about specific chemical functionalities (carboxamide, tetrazole) and the non-covalent hydrogen bonds between them Compl. ¶33 Compl. ¶35 A point of contention may be what factual evidence exists to prove that the sacubitril and valsartan molecules in Entresto® are arranged and bonded in the precise manner required to meet these claim limitations.

V. Key Claim Terms for Construction

• The Term: "API homosynthon"

• Context and Importance: This term is critical because Claim 10 requires the final supramolecular synthon to "compris[e]" an API homosynthon. The interpretation of this phrase will determine whether the claim is infringed if the API-to-API bond is disrupted and replaced by an API-to-co-former bond, as is common in co-crystal formation.

• Intrinsic Evidence for Interpretation:

  • Evidence for a Broader Interpretation: Plaintiffs may argue that "comprising" should be read to mean that the API molecule, which is a component of the homosynthon, is present in the final structure. The specification's general goal is to create new phases, and a construction that excludes the most common co-crystal structures (where homosynthons are broken) could be argued to render the patent ineffective.
  • Evidence for a Narrower Interpretation: The patent specification discusses a method for identifying co-crystal formers by selecting functionalities capable of "disrupting non-covalent bonding within the supramolecular synthon formed by the API" '344 Patent, col. 4:22-25 This language may support an interpretation that the original API homosynthon is broken and replaced, not "comprised" in the final co-crystal, thus narrowing the claim's scope.

• The Term: "supramolecular synthon"

• Context and Importance: As the fundamental building block of the invention, the definition of this term dictates what types of non-covalent interactions fall within the patent's scope. Practitioners may focus on this term to dispute whether the alleged interactions in Entresto® qualify as the structured, designed "synthon" envisioned by the patent.

• Intrinsic Evidence for Interpretation:

  • Evidence for a Broader Interpretation: The patent defines the term broadly as "the sum of the components of a multi-component non-covalent interaction, wherein the non-covalent interaction contributes to the formation of a discrete supramolecular entity or polymeric structure" '344 Patent, col. 9:66-10:4 This suggests any qualifying non-covalent assembly could be a synthon.
  • Evidence for a Narrower Interpretation: The specification heavily emphasizes "crystal engineering" and rational design based on robust, predictable interactions like the carboxylic acid-pyridine synthon '344 Patent, Fig. 2 '344 Patent, col. 3:6-11 A defendant may argue that the term should be limited to these well-defined, directional, and predictable synthons, not just any observed intermolecular interaction.

VI. Other Allegations

The complaint does not contain specific counts for indirect or willful infringement. It alleges direct infringement under 35 U.S.C. § 271(a) Compl. ¶26 and includes a prayer for an exceptional case finding under 35 U.S.C. § 285 Compl., p. 9, prayer 3

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

• A core issue will be one of definitional scope: can the claim limitation requiring a supramolecular synthon "comprising an API homosynthon" be met if the co-crystal is formed by disrupting the API's homosynthon and replacing it with a heterosynthon (API-to-co-former bond)? The case may turn on whether "comprising" requires the physical presence of the homosynthon bond in the final structure.
• A key evidentiary question will be one of technical proof: assuming a favorable claim construction for the Plaintiff, does the evidence, including external scientific literature referenced by the complaint, factually demonstrate that the sacubitril and valsartan components of Entresto® form the specific supramolecular structure-including the complementary functionalities and non-covalent hydrogen bonding-recited in claim 10?