DCT
1:22-cv-01420
Servier Pharma LLC v. Alembic Pharma Ltd
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Servier Pharmaceuticals LLC (Delaware)
- Defendant: Alembic Pharmaceuticals Limited (India)
- Plaintiff’s Counsel: Morris, Nichols, Arsht & Tunnell LLP
- Case Identification: 1:22-cv-01420, D. Del., 10/26/2022
- Venue Allegations: Venue is alleged to be proper in the District of Delaware because the defendant is a corporation organized under the laws of a foreign country and is subject to personal jurisdiction in the district.
- Core Dispute: Plaintiff alleges that Defendant's filing of an Abbreviated New Drug Application (ANDA) to market a generic version of Plaintiff's cancer drug TIBSOVO® (ivosidenib) constitutes an act of infringement of four U.S. patents related to the drug's crystalline form, formulation, and method of use.
- Technical Context: The patents-in-suit cover specific pharmaceutical compositions and therapeutic methods for ivosidenib, an inhibitor of the mutant isocitrate dehydrogenase 1 (IDH1) enzyme used in the treatment of certain cancers.
- Key Procedural History: This action was initiated under the Hatch-Waxman Act following Defendant's submission of ANDA No. 217768 to the FDA. The Defendant’s ANDA included a "Paragraph IV Certification" alleging that the patents-in-suit are invalid, unenforceable, and/or will not be infringed by its proposed generic product.
Case Timeline
| Date | Event |
|---|---|
| 2014-03-14 | Priority Date for ’595, ’184, and ’490 Patents |
| 2018-05-15 | U.S. Patent No. 9,968,595 Issues |
| 2018-06-08 | Priority Date for ’788 Patent |
| 2019-10-22 | U.S. Patent No. 10,449,184 Issues |
| 2020-10-13 | U.S. Patent No. 10,799,490 Issues |
| 2021-04-20 | U.S. Patent No. 10,980,788 Issues |
| 2022-09-14 | Date of Defendant's Notice Letter regarding ANDA filing |
| 2022-10-26 | Complaint Filing Date |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 9,968,595 - Pharmaceutical compositions of therapeutically active compounds
The Invention Explained
- Problem Addressed: The patent describes that mutations in the isocitrate dehydrogenase 1 (IDH1) enzyme can lead to the production of R(-)-2-hydroxyglutarate (2HG), a metabolite believed to contribute to the formation and progression of cancer (’595 Patent, col. 2:56-64). The background notes a need for pharmaceutical compositions of IDH1 inhibitors that possess properties suitable for large-scale manufacturing and formulation (’595 Patent, col. 2:10-15).
- The Patented Solution: The patent discloses specific crystalline forms of (S)-N-((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide, also known as ivosidenib. These specific solid-state forms are characterized by distinct X-ray powder diffraction (XRPD) patterns, which provide stability and consistency critical for drug product manufacturing (’595 Patent, col. 14:1-67).
- Technical Importance: The specific crystalline form of an active pharmaceutical ingredient is critical as it can affect key drug properties such as stability, dissolution rate, and bioavailability, thereby influencing the drug's safety and efficacy.
Key Claims at a Glance
- The complaint asserts independent claim 1 and dependent claim 4 (Compl. ¶27).
- Independent Claim 1 requires:
- A crystalline form of the compound ivosidenib.
- Characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ angles (±0.2°) of 8.6°, 15.6°, 18.5°, and 21.6°.
U.S. Patent No. 10,449,184 - Pharmaceutical compositions of therapeutically active compounds
The Invention Explained
- Problem Addressed: The patent addresses the same underlying technical problem as the ’595 Patent: the need for effective, manufacturable compositions of IDH1 inhibitors for treating certain cancers, including advanced hematologic malignancies (’184 Patent, col. 2:10-20).
- The Patented Solution: The invention provides a pharmaceutical composition in the form of a "solid dispersion." This formulation combines the active compound (ivosidenib) with a polymer, which can enhance the solubility and improve the systemic exposure of the drug when administered orally compared to its neat crystalline form (’184 Patent, col. 16:11-34).
- Technical Importance: Solid dispersions are a key formulation technology for improving the oral bioavailability of poorly water-soluble drugs, enabling them to be effective as oral medications.
Key Claims at a Glance
- The complaint asserts independent claim 1 (Compl. ¶34).
- Independent Claim 1 requires:
- A pharmaceutical composition for oral administration.
- Comprising a solid dispersion.
- The solid dispersion comprises between 25-75% w/w of the compound ivosidenib (or a salt thereof) and a polymer.
- The polymer is selected from a specific group including HPMCAS, PVAP, HPMC, and HPMCP.
- The composition optionally includes one or more pharmaceutically acceptable carriers.
U.S. Patent No. 10,799,490 - Pharmaceutical compositions of therapeutically active compounds
- Technology Synopsis: This patent, part of the same family as the ’184 Patent, is also directed to solid dispersion formulations of ivosidenib. The claims specifically require the use of a "cellulosic polymer" in the solid dispersion to improve the drug's pharmaceutical properties (’490 Patent, col. 2:51-54).
- Asserted Claims: The complaint asserts at least independent claim 1 (Compl. ¶41).
- Accused Features: The complaint alleges that the presence and use of a composition comprising ivosidenib in the Proposed ANDA Product infringes this patent (Compl. ¶41).
U.S. Patent No. 10,980,788 - Therapy for treating malignancies
- Technology Synopsis: This patent claims a method of treating malignancies characterized by an IDH1 mutation. The method requires administering a specific daily oral dose of ivosidenib to a subject who has not ingested a high-fat meal, thereby addressing a negative food effect on the drug's bioavailability (’788 Patent, col. 2:1-20).
- Asserted Claims: The complaint asserts at least independent claim 1 (Compl. ¶48).
- Accused Features: The complaint alleges infringement will occur through the use of the Proposed ANDA Product, as will be instructed by the product's labeling (Compl. ¶48, 50).
III. The Accused Instrumentality
Product Identification
- Defendant’s "Proposed ANDA Product," which is a generic version of TIBSOVO® (ivosidenib tablets) 250 mg tablets (Compl. ¶1).
Functionality and Market Context
- The accused product is a tablet for oral administration containing ivosidenib as the active pharmaceutical ingredient (Compl. ¶21). It is intended for the treatment of newly-diagnosed or relapsed/refractory acute myeloid leukemia and cholangiocarcinoma (Compl. ¶16).
- The complaint alleges that the Defendant's ANDA filing contains data demonstrating the bioequivalence of the Proposed ANDA Product to the innovator drug, TIBSOVO® (Compl. ¶22). Alembic seeks FDA approval to commercially manufacture and sell this product in the United States prior to the expiration of the patents-in-suit (Compl. ¶19).
IV. Analysis of Infringement Allegations
No probative visual evidence provided in complaint.
U.S. Patent No. 9,968,595
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A crystalline form of (S)-N-((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide... | The Proposed ANDA Product contains the active ingredient ivosidenib. | ¶21 | col. 14:1-12 |
| ...characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ angles (±0.2°) 8.6°, 15.6°, 18.5°, and 21.6°. | The complaint alleges the Proposed ANDA Product contains an ivosidenib crystalline form "as covered by" at least claim 1. | ¶27 | col. 14:34-39 |
- Identified Points of Contention:
- Evidentiary Question: A primary point of contention will be factual: does the ivosidenib in Alembic's product exist in the specific crystalline form defined by the claimed XRPD peaks? The complaint makes a conclusory allegation but does not provide specific test data for the accused product.
- Scope Questions: The complaint alleges infringement "either literally or under the doctrine of equivalents" (Compl. ¶27). This raises the question of whether Alembic's product, if not literally infringing, contains a crystalline form that is equivalent to the one claimed.
U.S. Patent No. 10,449,184
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A pharmaceutical composition for oral administration... | The Proposed ANDA Product is a tablet intended for oral administration. | ¶1 | col. 18:49-50 |
| ...comprising (a) a solid dispersion comprising between 25-75% w/w of ... [ivosidenib] ... and a polymer selected from hydroxypropylmethylcellulose acetate succinate (HPMCAS), polyvinyl acetate phthalate (PVAP), hydroxypropylmethylcellulose (HPMC) and hydroxypropylmethylcellulose phthalate (HPMCP)... | The complaint alleges the Proposed ANDA Product is a "composition comprising ivosidenib as covered by" at least claim 1. | ¶34 | col. 16:11-21 |
- Identified Points of Contention:
- Technical Questions: A key question will be whether Alembic's formulation technically constitutes a "solid dispersion" as that term is used in the patent. Further, does the formulation contain one of the specifically recited polymers, and is the ivosidenib present within the claimed 25-75% weight/weight range? The complaint does not provide these formulation details.
V. Key Claim Terms for Construction
"crystalline form" (’595 Patent)
- Context and Importance: The infringement allegation for the ’595 Patent hinges entirely on the specific solid-state structure of the ivosidenib in the accused product. The definition of what constitutes this specific "crystalline form," particularly in view of the provided XRPD peaks, will be central to determining literal infringement.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The claims use the open-ended term "comprising" with respect to the list of XRPD peaks, which may suggest that the presence of other, unlisted peaks does not defeat infringement as long as the required peaks are present (’595 Patent, col. 14:36).
- Evidence for a Narrower Interpretation: The specification provides detailed characterization data for two distinct polymorphs, Form 1 and Form 2 (’595 Patent, col. 14-15). A defendant may argue that the term "crystalline form" should be construed as being limited to the specifically disclosed and characterized polymorphs, particularly Form 1, which corresponds to the peaks in claim 1.
"solid dispersion" (’184 Patent)
- Context and Importance: This term defines the core technological basis of the ’184 Patent's composition claims. Whether Alembic's tablet formulation meets this definition will be a dispositive issue for infringement of this patent. Practitioners may focus on this term because the physical state of a drug and its interaction with polymers can be complex and subject to multiple interpretations.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The patent provides a general definition, stating solid dispersions can enhance solubility and provide improved exposure upon oral dosing (’184 Patent, col. 16:26-34). This functional language could support a broader reading covering various formulations that achieve this result.
- Evidence for a Narrower Interpretation: The specification describes specific methods for preparing solid dispersions, such as spray-drying, and lists specific polymers (’184 Patent, col. 21:7-9; col. 18:31-44). A defendant may argue these specific disclosures limit the term to formulations made by similar processes or containing similar polymer interactions, rather than any simple mixture of drug and polymer.
VI. Other Allegations
- Indirect Infringement: The complaint alleges induced infringement for all patents-in-suit. The basis is the allegation that Alembic's proposed product labeling will instruct healthcare providers and patients to administer the drug for its approved indications, which will directly infringe the asserted claims (Compl. ¶29-31, 36-38, 43-45, 50-52). This is particularly relevant for the ’788 method of treatment patent.
- Willful Infringement: While the complaint does not use the term "willful," it alleges that Alembic was aware of the patents-in-suit when it submitted its ANDA with a Paragraph IV certification (Compl. ¶20). The prayer for relief requests a declaration that the case is "exceptional" under 35 U.S.C. § 285, which is the statutory basis for awarding enhanced damages and attorneys' fees, often predicated on a finding of willfulness (Compl. p. 11, ¶e).
VII. Analyst’s Conclusion: Key Questions for the Case
- A core issue will be one of evidentiary proof: does the physical and chemical composition of Alembic’s proposed generic product—specifically its crystalline structure, excipients, and concentration of active ingredient—fall within the precise boundaries of the asserted claims? The complaint's general allegations will require substantiation through discovery and expert technical analysis.
- A second central question, particularly for the ’788 method patent, will be one of inducement: will the language of Alembic’s proposed product label be found to actively encourage or instruct physicians and patients to administer the drug in a manner that directly infringes the patented method, specifically by avoiding high-fat meals?