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 to be proper because Novartis maintains regular and established places of business in the Northern District of California, specifically in San Carlos and Emeryville, and has committed acts of patent infringement within the district.
• Core Dispute: Plaintiffs allege that Defendant’s heart failure drug, Entresto®, infringes a patent related to the creation of pharmaceutical co-crystals with improved physical properties.
• Technical Context: The technology concerns the field of crystal engineering, which applies principles of molecular self-assembly to design and create novel solid forms of active pharmaceutical ingredients (APIs) intended to enhance properties such as solubility, stability, and bioavailability.
• Key Procedural History: The asserted patent is a continuation of an application filed in 2003, which itself claims priority to a 2002 provisional application. Subsequent to the filing of this complaint, an Inter Partes Review (IPR) was initiated against the patent (IPR2023-01347), which resulted in the patent owner disclaiming claim 16 of the patent.

Case Timeline

Date	Event
2002-03-01	'344 Patent Priority Date
2015-07-01	FDA Approval for Accused Product Entresto® (approx. date)
2020-04-28	'344 Patent Issue Date
2022-08-29	Complaint Filing Date
2023-08-28	Inter Partes Review (IPR2023-01347) Filed

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

• Patent Identification: U.S. Patent No. 10,633,344 ("the '344 Patent"), "Multiple-Component Solid Phases Containing at least One Active Pharmaceutical Ingredient," issued April 28, 2020. (Compl. ¶14).

The Invention Explained

• Problem Addressed: The patent's background section describes the significant challenge and "largely unmet goal" of predicting and controlling the crystal structure of pharmaceutical compounds ('344 Patent, col. 1:36-39, 2:17-20). The existence of multiple crystalline forms (polymorphs) for a single drug can lead to inconsistent physical properties, creating problems for manufacturing, stability, and bioavailability, which is a critical issue in the pharmaceutical industry (Compl. ¶24; ’344 Patent, col. 1:39-44).
• The Patented Solution: The invention provides a method of "crystal engineering" to rationally design new, stable, multiple-component solid phases (co-crystals). This is achieved by identifying an active pharmaceutical ingredient (API) and a "co-former" molecule that have complementary chemical functionalities. These functionalities are chosen to predictably form specific non-covalent bonds (supramolecular synthons), resulting in a new crystalline structure with potentially improved properties like solubility and dissolution rate (’344 Patent, Abstract; col. 3:7-28). The process is outlined in a flowchart in the patent's figures (’344 Patent, Fig. 24).
• Technical Importance: This approach provides a systematic way to modify the physical properties of known drug substances, potentially overcoming limitations of the original API and leading to more effective or reliable drug products (’344 Patent, col. 2:25-31).

Key Claims at a Glance

• The complaint asserts at least independent claim 10. (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 at least one active pharmaceutical ingredient (API) and at least one co-former.
  • The API must have a "first chemical functionality" (a carboxamide, carbonyl, or amine) that allows it to form "homosynthons" (bonds with itself) in its pure form.
  • The co-former must have a "second chemical functionality" that is complementary to the API's first functionality.
  • The co-former must be a solid at room temperature and pressure in its pure form.
  • The claimed 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 states infringement of "one or more claims," reserving the right to assert additional claims. (Compl. ¶13).

III. The Accused Instrumentality

Product Identification

• The accused products are Entresto® tablets in various dosage strengths, which combine the active ingredients sacubitril and valsartan. (Compl. ¶26).

Functionality and Market Context

• Entresto® is a prescription pharmaceutical composition indicated for use in patients with chronic heart failure to reduce the risk of cardiovascular death and hospitalization. (Compl. ¶28).
• The complaint alleges that Entresto® is a tablet formulation that includes a pharmaceutically acceptable carrier, such as microcrystalline cellulose. (Compl. ¶29).
• The core of the infringement allegation is that Entresto® contains "sacubitril-valsartan co-crystals" which are formed from supramolecular synthons, as described in scientific literature cited by the complaint. (Compl. ¶30).
• No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

'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...	Entresto® is a pharmaceutical composition, available in various dosage strengths, comprising a co-crystal and a carrier like microcrystalline cellulose.	¶28, ¶29	col. 24:2-5
...each supramolecular synthon formed from stoichiometric amounts of at least one active pharmaceutical ingredient (API) and at least one co-former...	Each synthon is formed from stoichiometric amounts of sacubitril (the API) and valsartan (the co-former).	¶31	col. 24:6-9
...the API has a first chemical functionality that permits formation of API homosynthons through non-covalent hydrogen bonding...	Sacubitril, the API, has a carboxamide functionality that permits the formation of API homosynthons.	¶32	col. 24:10-13
...the co-former has a second chemical functionality complimentary to the first chemical functionality via non-covalent hydrogen bonding...	Valsartan, the co-former, has a tetrazole functionality that is complimentary to sacubitril's carboxamide via non-covalent hydrogen bonding.	¶33, ¶35	col. 24:14-17
...said co-former is a solid at room temperature and atmospheric pressure when the co-former is in its pure form...	Valsartan is a solid at room temperature and atmospheric pressure in its pure form.	¶34	col. 24:18-20
...supramolecular synthons are formed via non-covalent hydrogen bonding between the first chemical functionality of the API and the second...	Supramolecular synthons are formed between sacubitril's carboxamide and valsartan's tetrazole via non-covalent hydrogen bonding.	¶35	col. 24:21-25
...the first chemical functionality is (i) a carboxamide, (ii) a carbonyl, or (iii) an amine.	The relevant functionality on the API, sacubitril, is a carboxamide.	¶32	col. 24:26-28

Identified Points of Contention

• Scope Questions: A central question for claim construction may be the definition of "co-former." The complaint alleges valsartan, an API, functions as the co-former. While the patent specification states that "co-crystal formers can be ... other drug molecules" (’344 Patent, col. 3:33-36), the claims consistently distinguish between the "API" and the "co-former," raising the question of whether one API can serve as the co-former for another within the scope of the claims.
• Technical Questions: The infringement theory rests on the specific chemical interactions within the Entresto® tablet. A key factual dispute will likely be whether the interaction between sacubitril's carboxamide group and valsartan's tetrazole group forms a "supramolecular synthon" via "non-covalent hydrogen bonding" that meets the claim requirements. The complaint's allegations for this point rely on an external scientific paper, the contents of which will be critical evidence. (Compl. ¶¶33, 35).

V. Key Claim Terms for Construction

• The Term: "co-former"

• Context and Importance: The definition of this term is critical to the infringement analysis because the accused product, Entresto®, is a combination of two distinct APIs, sacubitril and valsartan. The case depends on classifying valsartan as a "co-former" for the sacubitril "API." Practitioners may focus on this term because its construction will determine whether a combination of two APIs can infringe a claim that appears to frame the invention as one API plus a structurally complementary, but potentially non-active, partner.

• Intrinsic Evidence for Interpretation:

  • Evidence for a Broader Interpretation: The specification explicitly states, "The cocrystal formers can be, but are not limited to, solvent molecules, other drug molecules, GRAS compounds, or approved food additives." (’344 Patent, col. 3:33-36). This language directly supports the allegation that one API (valsartan) can be a co-former for another (sacubitril).
  • Evidence for a Narrower Interpretation: Throughout the claims, the patent consistently uses separate terms—"active pharmaceutical ingredient (API)" and "co-former"—which may suggest they are intended to be mutually exclusive categories for the purposes of the claims. A defendant could argue that the claim structure implies the co-former is a distinct entity added to modify the API, not another API itself.

• The Term: "supramolecular synthon"

• Context and Importance: This term describes the fundamental building block of the patented invention. Infringement requires proving that the accused product is constructed from these specific synthons. The dispute will likely focus on whether the alleged bond between sacubitril and valsartan meets the structural and functional definition of a synthon as defined by the patent.

• Intrinsic Evidence for Interpretation:

  • Evidence for a Broader Interpretation: The patent provides a broad definition: "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. 9:64-col. 10:3). This could be argued to cover a wide range of molecular interactions.
  • Evidence for a Narrower Interpretation: Claim 10 narrows this definition, requiring that the synthon be "formed via non-covalent hydrogen bonding between the first chemical functionality of the API and the second chemical functionality of the co-former." (’344 Patent, col. 24:21-25). A party could argue that this requires a specific and robust hydrogen bond, not merely an incidental interaction, and might point to the patent's specific illustrated examples (e.g., ’344 Patent, Fig. 2, 3) as context for the term's meaning.

VI. Other Allegations

• Indirect Infringement: The complaint does not plead a count for indirect infringement.
• Willful Infringement: The complaint does not plead a specific count for willful infringement. However, in the prayer for relief, Plaintiffs request a declaration that this is an "exceptional case" under 35 U.S.C. § 285, which could entitle them to attorneys' fees. (Compl. p. 9).

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

• A core issue will be one of definitional scope: Can the term "co-former", as defined in the context of the ’344 Patent, be construed to read on valsartan, which is itself an active pharmaceutical ingredient, or does the claim language require the "co-former" and "API" to be distinct classes of molecules?
• A key evidentiary question will be one of chemical structure and function: Does the interaction between the sacubitril and valsartan molecules in the accused Entresto® product create the specific "supramolecular synthon" defined by claim 10? This will likely require a detailed factual inquiry, supported by expert testimony and scientific evidence, into the existence and nature of the alleged non-covalent hydrogen bonds.