DCT
1:19-cv-02252
Millennium Pharma Inc v. Fresenius Kabi USA LLC
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Millennium Pharmaceuticals, Inc. (Delaware)
- Defendant: Fresenius Kabi USA, LLC (Delaware) and Fresenius Kabi AG (Germany)
- Plaintiff’s Counsel: Morris, Nichols, Arsht & Tunnell LLP; Wilmer Cutler Pickering Hale and Dorr LLP
- Case Identification: 1:19-cv-02252, D. Del., 12/10/2019
- Venue Allegations: Venue is asserted based on Fresenius Kabi USA, LLC being a Delaware limited liability company and Fresenius Kabi AG being a foreign corporation not resident in the United States.
- Core Dispute: Plaintiff alleges that Defendants' submission of an Abbreviated New Drug Application (ANDA) to the FDA for a generic version of the cancer drug VELCADE® constitutes an act of infringement of two patents related to stable, lyophilized formulations of boronic acid compounds.
- Technical Context: The technology concerns pharmaceutical formulations designed to improve the stability and shelf-life of peptide boronic acids, which are a class of proteasome inhibitors used in oncology.
- Key Procedural History: This action arises under the Hatch-Waxman Act, triggered by Defendants' submission of ANDA No. 209659 with a Paragraph IV certification, asserting the patents-in-suit are invalid or not infringed. The complaint notes that Plaintiff Millennium is an exclusive licensee of the patents-in-suit, which are listed in the FDA's Orange Book for VELCADE®. The complaint alleges a history of prior litigation between the parties involving the same patents and states that in a pre-suit Notice Letter, Defendants did not contest infringement of numerous claims but instead asserted invalidity.
Case Timeline
| Date | Event |
|---|---|
| 2001-01-25 | Priority Date for ’446 and ’319 Patents |
| 2002-12-02 | Millennium obtains exclusive license to patents |
| 2003-01-01 | VELCADE® (bortezomib) first approved by FDA |
| 2004-03-30 | U.S. Patent No. 6,713,446 Issues |
| 2005-10-25 | U.S. Patent No. 6,958,319 Issues |
| 2019-10-28 | Defendants send Paragraph IV Notice Letter |
| 2019-12-10 | Complaint Filed |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 6,713,446 - Formulation of Boronic Acid Compounds (Issued Mar. 30, 2004)
The Invention Explained
- Problem Addressed: The patent addresses the inherent instability of peptide boronic acids, a class of pharmaceutically useful compounds. These compounds are difficult to purify and tend to degrade, readily forming anhydrides (boroxines) or oxidizing in the presence of air, which complicates their formulation and limits their shelf-life ( Compl. ¶27; ’446 Patent, col. 2:50-62).
- The Patented Solution: The invention stabilizes the boronic acid compound by lyophilizing (freeze-drying) it in the presence of a bulking agent with at least two hydroxyl groups, such as the sugar alcohol mannitol. This process is described as forming a stable boronate ester, which protects the active drug. Upon reconstitution with an aqueous solvent (e.g., saline), the ester bond is designed to quickly hydrolyze, releasing the active boronic acid compound for administration (’446 Patent, Abstract; col. 2:8-14).
- Technical Importance: This formulation strategy provided a method to create a stable, solid, injectable dosage form for a chemically sensitive but therapeutically valuable class of drugs, enabling their practical development and commercialization (’446 Patent, col. 2:63-65).
Key Claims at a Glance
- The complaint asserts infringement of multiple claims, including independent claim 11 (Compl. ¶¶34, 43).
- Independent Claim 11 recites the following essential elements:
- A lyophilized compound of formula (1)
- Wherein specific chemical moieties (P, R, A, R¹, R², R³) define a peptide boronic acid structure
- Wherein Z¹ and Z² together form a moiety derived from a sugar, with oxygen atoms bonded to the boron atom
- And wherein the sugar is mannitol
- The complaint also reserves the right to assert numerous other claims, including dependent and method claims (Compl. ¶43).
U.S. Patent No. 6,958,319 - Formulation of Boronic Acid Compounds (Issued Oct. 25, 2005)
The Invention Explained
- Problem Addressed: The ’319 Patent, a continuation of the application leading to the ’446 Patent, addresses the same technical problem of the chemical instability of peptide boronic acids (’319 Patent, col. 2:55-63).
- The Patented Solution: The patented solution is identical to that of the ’446 Patent: forming a stable, lyophilized boronate ester by combining the boronic acid compound with a multi-hydroxyl compound, such as a sugar, which readily releases the active ingredient upon reconstitution (’319 Patent, Abstract; col. 2:9-16).
- Technical Importance: This patent extends the protection for the core formulation technology that enables the commercial use of drugs like bortezomib.
Key Claims at a Glance
- The complaint asserts infringement of multiple claims, including independent claim 14 (Compl. ¶¶35, 52).
- Independent Claim 14 recites the following essential elements:
- A lyophilized compound of formula (1)
- Wherein specific chemical moieties (P, R, A, R¹, R², R³) define a peptide boronic acid structure
- Wherein Z¹ and Z² together form a moiety derived from a sugar, with oxygen atoms bonded to the boron atom
- The complaint also reserves the right to assert numerous other claims, including dependent claims that further specify the compound, such as claim 26 which is explicitly mentioned in the complaint body (Compl. ¶¶31, 52).
III. The Accused Instrumentality
Product Identification
- The accused instrumentality is Defendants' generic bortezomib for injection, 3.5 mg/vial, as described in Abbreviated New Drug Application (ANDA) No. 209659 ("Defendants' ANDA Product") (Compl. ¶32).
Functionality and Market Context
- The complaint alleges that the ANDA Product is a generic version of Millennium's VELCADE®, which is a proteasome inhibitor approved for treating multiple myeloma and mantle cell lymphoma (Compl. ¶27). The product is described as the "lyophilized mannitol ester of bortezomib" (Compl. ¶30). As an ANDA product, it is intended to be a bioequivalent substitute for the brand-name drug, sold at a lower price after receiving FDA approval, thereby directly competing with the Plaintiff's product (Compl. ¶1).
IV. Analysis of Infringement Allegations
No probative visual evidence provided in complaint.
’446 Patent Infringement Allegations
| Claim Element (from Independent Claim 11) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A lyophilized compound of formula (1)... | The Defendants' ANDA Product is alleged to be a lyophilized formulation containing bortezomib. | ¶32, ¶45 | col. 3:41-43 |
| wherein P is... an amino-group protecting moiety... | The bortezomib in the ANDA product is N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid, where the (2-pyrazine)carbonyl group serves as the amino-group protecting moiety. | ¶30 | col. 8:55-57 |
| wherein Z¹ and Z² together form a moiety derived from a sugar... wherein the sugar is mannitol. | The ANDA Product is alleged to be a "lyophilized mannitol ester of bortezomib," meaning it is a compound formed from the reaction of bortezomib with mannitol, which is the specified sugar. | ¶30, ¶45 | col. 4:40-44 |
’319 Patent Infringement Allegations
| Claim Element (from Independent Claim 14) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A lyophilized compound of the formula (1)... | The Defendants' ANDA Product is alleged to be a lyophilized formulation containing bortezomib. | ¶32, ¶54 | col. 3:45-47 |
| wherein P is... an amino-group protecting moiety... | The bortezomib in the ANDA product is N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid, where the (2-pyrazine)carbonyl group serves as the amino-group protecting moiety. | ¶30, ¶54 | col. 9:5-6 |
| wherein Z¹ and Z² together form a moiety derived from a sugar... | The ANDA Product is alleged to be a "lyophilized mannitol ester of bortezomib," meaning it is a compound formed from the reaction of bortezomib with mannitol, a sugar. | ¶30, ¶54 | col. 6:40-44 |
- Identified Points of Contention:
- Infringement vs. Validity: The complaint alleges that in their pre-suit notice, Defendants did not contest infringement of many asserted claims but instead focused on invalidity (Compl. ¶¶34-35). This suggests the primary legal battleground may not be over claim interpretation or factual infringement, but rather over whether the patent claims are valid in the first place.
- Technical Questions: A latent technical question for the court is whether the chemical species in the Defendants' ANDA product is, in fact, the specific covalently-bonded boronate ester of formula (1) as claimed, or if it exists as a different entity, such as a non-covalent complex or a simple physical mixture of bortezomib and mannitol. The infringement allegation rests on the product being a "mannitol ester," which will need to be confirmed through discovery and expert analysis.
V. Key Claim Terms for Construction
While the complaint suggests infringement may not be the central dispute, the construction of certain terms remains fundamental to the scope of the asserted claims.
The Term: "lyophilized compound"
Context and Importance: This term appears in the preamble of the key independent claims (e.g., ’446 Patent, cl. 11; ’319 Patent, cl. 14). Its construction determines whether the claims cover a specific chemical entity formed during lyophilization or merely a mixture of ingredients that has undergone a freeze-drying process. Practitioners may focus on this term because it distinguishes between claiming a process outcome versus a novel composition of matter.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The patents' general description refers to lyophilizing a "mixture" comprising the boronic acid and the sugar (’446 Patent, col. 2:8-14), which could suggest the claim covers the resulting solid product of that process, regardless of the precise bonding.
- Evidence for a Narrower Interpretation: The claim preamble recites "A lyophilized compound," not a "lyophilized composition." Furthermore, the patent describes using mass spectrometry to identify a "covalent boronate ester adduct" between bortezomib and mannitol in the lyophilized product, supporting the interpretation that a specific new chemical compound is formed and claimed (’446 Patent, col. 13:54-61).
The Term: "moiety derived from a sugar"
Context and Importance: This term defines the nature of the stabilizing agent (e.g., mannitol) and its chemical relationship with the boronic acid. The interpretation clarifies whether a specific covalent bond is required.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The phrase "derived from" could be argued to be broad, not strictly limited to a specific chemical reaction product.
- Evidence for a Narrower Interpretation: The patent consistently refers to the invention as forming a "boronate ester" and depicts a specific chemical structure (Formula 1) where two oxygen atoms from the sugar form covalent bonds with the boron atom. This suggests the "moiety" is what remains of the sugar molecule after it has undergone esterification (’446 Patent, col. 4:45-50; col. 6:33-35).
VI. Other Allegations
- Indirect Infringement: The complaint alleges that Defendants' proposed product labeling will instruct medical professionals on how to reconstitute and administer the ANDA Product. This act of reconstitution is alleged to induce infringement of method claims covering the preparation of the drug for administration (Compl. ¶¶45, 54). It also alleges the ANDA product is specially made for this infringing use and has no substantial non-infringing use, supporting a claim for contributory infringement (Compl. ¶¶46, 55).
- Willful Infringement: The willfulness allegation is based on Defendants' alleged knowledge of the patents-in-suit. The complaint cites the patents' listing in the FDA Orange Book, a history of prior patent litigation between Millennium and Fresenius over the same patents, and Defendants' own Paragraph IV notice letter as evidence of pre-suit knowledge (Compl. ¶¶44, 53).
VII. Analyst’s Conclusion: Key Questions for the Case
- A central issue appears to be one of patent validity: as the complaint alleges Defendants do not contest infringement for many claims, the case will likely focus on whether Defendants can prove by clear and convincing evidence that the claims covering a lyophilized bortezomib-mannitol formulation are invalid, for example, as being obvious in light of prior pharmaceutical formulation techniques.
- A key secondary issue will be willfulness: given the alleged history of prior litigation between the parties over the same patents, a core question for the court will be whether Defendants' decision to file an ANDA was objectively reckless or based on a reasonable, good-faith belief that the patents were invalid, which will determine potential liability for enhanced damages.
- Finally, a latent evidentiary question is one of chemical identity: should infringement become a contested issue, the case may turn on whether discovery reveals the Defendants' ANDA product to be the specific, covalently-bonded "mannitol ester" compound required by the claims, or a different physical or chemical entity that falls outside their scope.