Millennium Pharma Inc v. Qilu Pharmaceutical Co Ltd

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Millennium Pharmaceuticals, Inc. (Delaware)
  • Defendant: Qilu Pharmaceutical Co., Ltd. (China) and Qilu Pharma Inc. (Pennsylvania)
  • Plaintiff’s Counsel: Morris, Nichols, Arsht & Tunnell LLP; Wilmer Cutler Pickering Hale and Dorr LLP
• Case Identification: 1:17-cv-01830, D. Del., 12/20/2017
• Venue Allegations: Plaintiff alleges that Defendants have consented to venue and personal jurisdiction for the purpose of this action. It further alleges that Defendants have systematic and continuous contacts with Delaware and have previously taken advantage of the court's jurisdiction by filing counterclaims in other litigation.
• Core Dispute: Plaintiff alleges that Defendants' filing of an Abbreviated New Drug Application (ANDA) for a generic version of the cancer drug VELCADE® constitutes an act of infringement of two patents related to stable formulations of boronic acid compounds.
• Technical Context: The technology concerns methods for stabilizing boronic acid-based pharmaceutical compounds, such as the proteasome inhibitor bortezomib, by creating lyophilized (freeze-dried) boronate esters, which improves shelf-life and suitability for injection.
• Key Procedural History: This action was initiated under the Hatch-Waxman Act following Plaintiff's receipt of a Notice Letter regarding Defendants' ANDA No. 210824, which included a Paragraph IV certification challenging the patents-in-suit as invalid. The complaint notes that the patents-in-suit are listed in the FDA's "Orange Book" for VELCADE® and were the subject of prior litigation against another generic manufacturer. Plaintiff Millennium is the exclusive licensee of the patents-in-suit, which are owned by the U.S. government.

Case Timeline

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

U.S. Patent No. 6,713,446 - “Formulation of Boronic Acid Compounds”

The Invention Explained

• Problem Addressed: The patent's background section describes that boronic acid compounds, while pharmaceutically useful, are often difficult to obtain in pure form and are unstable. They can readily form anhydrides ("boroxines") or oxidize when exposed to air, which complicates their characterization and limits their pharmaceutical shelf life (ʼ446 Patent, col. 2:51-62).
• The Patented Solution: The invention addresses this stability issue by lyophilizing (freeze-drying) an aqueous mixture of a boronic acid compound and a stabilizing agent, specifically a compound with at least two hydroxyl groups, such as the sugar alcohol mannitol (ʼ446 Patent, col. 2:7-14). This process forms a stable, solid boronate ester adduct that, upon reconstitution with an aqueous solvent, readily releases the active boronic acid compound for administration (ʼ446 Patent, col. 13:6-14).
• Technical Importance: This formulation strategy provides a practical method for creating a stable, solid, and pharmaceutically acceptable version of an otherwise unstable class of drug compounds, making them viable for commercial distribution and clinical use (ʼ446 Patent, col. 2:62-68).

Key Claims at a Glance

• The complaint asserts infringement of at least independent claim 1 and dependent claim 20, among others (Compl. ¶¶30, 43).
• Independent Claim 1 requires, in essence:
  • A compound of a specific chemical formula representing a peptide boronate ester.
  • Wherein two oxygen atoms of the boronate ester group (Z¹ and Z²) together form a moiety derived from a sugar.
• The complaint reserves the right to assert additional claims (Compl. ¶43).

U.S. Patent No. 6,958,319 - “Formulation of Boronic Acid Compounds”

The Invention Explained

• Problem Addressed: As a continuation of the application that led to the ’446 Patent, the ’319 Patent addresses the same technical challenge: the inherent instability of boronic acid compounds, which limits their utility as pharmaceutical agents (’319 Patent, col. 2:55-65).
• The Patented Solution: The patented solution is materially the same as in the ’446 patent, involving the creation of stable compositions by lyophilizing a boronic acid compound with a sugar or other dihydroxy compound to form a boronate ester (’319 Patent, Abstract; col. 2:9-17). The claims in this patent are directed specifically to the "lyophilized compound."
• Technical Importance: The invention provides a stable, lyophilized powder formulation that enhances the shelf life of boronic acid drugs and allows for convenient reconstitution before administration (’319 Patent, col. 3:1-5).

Key Claims at a Glance

• The complaint asserts infringement of at least independent claim 14 and dependent claim 26, among others (Compl. ¶¶31, 52).
• Independent Claim 14 requires, in essence:
  • A lyophilized compound of a specific chemical formula representing a peptide boronate ester.
  • Wherein two oxygen atoms of the boronate ester group (Z¹ and Z²) together form a moiety derived from a sugar.
• The complaint reserves the right to assert additional claims (Compl. ¶52).

III. The Accused Instrumentality

Product Identification

The accused instrumentality is Defendants' proposed generic drug product for which they submitted Abbreviated New Drug Application (ANDA) No. 210824 to the FDA (Compl. ¶1).

Functionality and Market Context

The complaint alleges that the Defendants' ANDA Product is a generic version of VELCADE® (bortezomib) for injection, 3.5 mg/vial (Compl. ¶32). The product is described as the "lyophilized mannitol ester of bortezomib" (Compl. ¶¶30, 45). Bortezomib is a proteasome inhibitor used for treating multiple myeloma and mantle cell lymphoma (Compl. ¶27). The filing of the ANDA is an artificial act of infringement under 35 U.S.C. § 271(e)(2)(A), signaling Defendants' intent to market a generic competitor to Plaintiff's branded drug upon FDA approval (Compl. ¶36).

IV. Analysis of Infringement Allegations

No probative visual evidence provided in complaint.

The complaint alleges that Defendants' Notice Letter did not contest infringement of the asserted claims, but instead asserted that the claims are invalid (Compl. ¶¶34-35). The infringement theory is therefore based on the premise that the ANDA product is what it purports to be: a generic equivalent of VELCADE®.

’446 Patent Infringement Allegations

’319 Patent Infringement Allegations

Identified Points of Contention

• Factual Confirmation: While the complaint alleges infringement is not contested, a primary question for discovery will be confirming the exact chemical composition and manufacturing process of the Defendants' ANDA product. Will discovery confirm that the ANDA product is, in fact, a lyophilized mannitol ester of bortezomib as alleged, or will any structural, isomeric, or process differences emerge that could form a basis for a non-infringement defense?
• Scope Questions: The central dispute, as framed by the complaint, is not infringement but validity (Compl. ¶¶34, 35). Therefore, the primary legal questions will concern whether the claimed inventions are invalid as anticipated or obvious in light of the prior art.

V. Key Claim Terms for Construction

While the complaint suggests infringement is not contested, the construction of key terms will be critical for the anticipated validity challenge.

"a moiety derived from a sugar" (’446 Patent, cl. 1; ’319 Patent, cl. 14)

• Context and Importance: This term defines the stabilizing agent that forms the boronate ester with the active drug. The scope of "sugar" is central to the obviousness analysis, as it determines what universe of potential stabilizing agents the prior art would have suggested to a person of ordinary skill.
• Intrinsic Evidence for a Broader Interpretation: The specification provides a broad definition, stating the sugar can be a "monosaccharide or disaccharide" and provides a non-limiting list including "glucose, sucrose, fructose, trehalose, xylitol, mannitol, and sorbitol" (’446 Patent, col. 6:41-44).
• Intrinsic Evidence for a Narrower Interpretation: A party challenging the patent might argue the term's scope should be informed by the preferred embodiments, which consistently highlight D-mannitol, particularly in the working examples (’446 Patent, col. 7:42-44; col. 13-14, Examples 1-3).

"lyophilized compound" (’319 Patent, cl. 14)

• Context and Importance: This term appears in the preamble of the independent claims of the ’319 Patent, making it a potential limitation on their scope. Its construction is important for determining whether prior art methods of simply mixing or co-precipitating compounds would anticipate or render the claims obvious.
• Intrinsic Evidence for a Broader Interpretation: The patent describes lyophilization in general terms as a process to obtain a "solid material... by lyophilization of an aqueous mixture" (’446 Patent, col. 3:45-48, incorporated by reference into the ’319 Patent).
• Intrinsic Evidence for a Narrower Interpretation: Practitioners may focus on the detailed, multi-step lyophilization cycles described in the patent's examples, which involve specific temperature, pressure, and time parameters, to argue that the term requires more than simple freeze-drying (’446 Patent, col. 14:15-33).

VI. Other Allegations

Indirect Infringement

The complaint alleges both induced and contributory infringement. Inducement is based on the allegation that Defendants' proposed product labeling will instruct medical professionals and patients to reconstitute and administer the drug in a manner that infringes method claims of the patents (Compl. ¶¶45, 54). Contributory infringement is based on the allegation that the ANDA product is specially made for infringement and has no substantial non-infringing use (Compl. ¶¶46, 55).

Willful Infringement

The complaint alleges that Defendants had pre-suit knowledge of the patents-in-suit. This allegation is based on the patents' listing in the FDA Orange Book, prior litigation against other generic manufacturers involving the same patents, and Defendants' own Notice Letter acknowledging the patents. The complaint asserts Defendants acted "without a reasonable basis" for their actions and/or were willfully blind to the infringement (Compl. ¶¶44, 47, 53, 56).

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

• A core issue will be patent validity: Given that the complaint portrays infringement as uncontested, the case will likely center on whether Defendants can prove by clear and convincing evidence that the asserted claims are invalid, presumably on grounds of obviousness based on prior art knowledge of boronic acid chemistry and pharmaceutical formulation techniques.
• A key secondary issue will be willfulness: Should the patents be found not invalid and infringed, a central question will be whether Defendants' awareness of the patents through the Orange Book, prior litigation, and their own Paragraph IV certification constitutes the type of egregious conduct required for an enhancement of damages under 35 U.S.C. § 284.