DCT
1:18-cv-03632
Corcept Therap Inc v. Teva Pharma USA Inc
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Corcept Therapeutics, Inc. (Delaware)
- Defendant: Teva Pharmaceuticals USA, Inc. (Delaware) and Teva Pharmaceuticals Industries Ltd. (Israel)
- Plaintiff’s Counsel: SAUL EWING ARNSTEIN & LEHR LLP
- Case Identification: 1:18-cv-03632, D.N.J., 07/06/2018
- Venue Allegations: Plaintiff alleges venue is proper in the District of New Jersey based on Defendant Teva USA’s systematic and continuous contacts with the state, including maintaining facilities and employees, being registered as a business and drug manufacturer, and having previously litigated 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 300 mg mifepristone drug product constitutes an act of infringement of three patents covering methods of using and diagnosing with mifepristone.
- Technical Context: The technology relates to pharmaceutical methods for treating and diagnosing patients with Cushing's syndrome, a condition caused by prolonged exposure to high levels of cortisol.
- Key Procedural History: The litigation was initiated under the Hatch-Waxman Act following Defendant’s submission of an ANDA with a Paragraph IV certification, asserting that its generic product would not infringe Plaintiff’s patents or that the patents are invalid. Defendant provided notice of this certification to Plaintiff prior to the suit.
Case Timeline
| Date | Event |
|---|---|
| 2007-08-30 | '348 Patent Priority Date |
| 2014-12-30 | '348 Patent Issue Date |
| 2015-04-21 | '526 Patent Priority Date |
| 2015-08-13 | '495 Patent Priority Date |
| 2017-11-28 | '495 Patent Issue Date |
| 2018-01-31 | Teva's 1st Notice Letter sent re: '348 and '495 Patents |
| 2018-04-17 | '526 Patent Issue Date |
| 2018-05-14 | Teva's 2nd Notice Letter sent re: '526 Patent |
| 2018-07-06 | First Amended Complaint Filing Date |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 8,921,348 - "Optimizing mifepristone levels in plasma serum of patients suffering from mental disorders treatable with glucocorticoid receptor antagonists"
- Patent Identification: U.S. Patent No. 8,921,348, "Optimizing mifepristone levels in plasma serum of patients suffering from mental disorders treatable with glucocorticoid receptor antagonists," issued December 30, 2014. (Compl. ¶9).
The Invention Explained
- Problem Addressed: The patent’s background section states that administration of the same dose of mifepristone can produce "widely varying blood serum levels in different patients," which may result in some patients not receiving an effective dose ('348 Patent, col. 1:29-37).
- The Patented Solution: The invention proposes a method to personalize and optimize treatment by administering mifepristone, testing the patient's resulting blood serum levels to determine if they exceed a specific therapeutic threshold (1300 ng/mL), and then adjusting the dosage to ensure the patient’s blood levels remain in that efficacious range ('348 Patent, Abstract; col. 1:41-49).
- Technical Importance: This method provides a systematic approach to account for significant inter-patient pharmacokinetic variability, aiming to ensure more consistent therapeutic outcomes ('348 Patent, col. 1:50-62).
Key Claims at a Glance
- The complaint asserts infringement of one or more claims of the ’348 Patent (Compl. ¶39). Independent claim 1 is representative.
- Claim 1 recites a method with the following essential elements:
- Treating a patient with seven or more daily doses of mifepristone over a period of seven or more days.
- Testing the patient's serum levels to determine if the blood levels of mifepristone are greater than 1300 ng/mL.
- Adjusting the daily dose of the patient to achieve mifepristone blood levels greater than 1300 ng/mL.
(’348 Patent, col. 16:2-15).
U.S. Patent No. 9,829,495 - "Method for differentially diagnosing ACTH-dependent Cushing's Syndrome"
- Patent Identification: U.S. Patent No. 9,829,495, "Method for differentially diagnosing ACTH-dependent Cushing's Syndrome," issued November 28, 2017. (Compl. ¶10).
The Invention Explained
- Problem Addressed: The patent’s background section describes limitations with existing methods for distinguishing between two forms of ACTH-dependent Cushing's syndrome: Cushing's Disease (caused by a pituitary tumor) and ectopic ACTH syndrome (caused by a non-pituitary tumor). Existing diagnostic tests using agents like CRH or metyrapone are described as having issues with cost, availability, procedural complexity, and potential side effects (’495 Patent, col. 2:40-col. 3:17).
- The Patented Solution: The invention provides a diagnostic method that uses a glucocorticoid receptor antagonist (GRA) like mifepristone to stimulate ACTH production from the pituitary gland. By comparing the concentration of ACTH in blood sampled from the inferior petrosal sinus (near the pituitary) to blood from a peripheral vein, a ratio is calculated. A ratio greater than 3 is diagnostic of Cushing's Disease, helping to locate the source of the excess ACTH (’495 Patent, Abstract; col. 3:18-34).
- Technical Importance: This method offers an alternative diagnostic pathway that avoids the specific supply chain and safety concerns associated with the agents used in prior diagnostic protocols (’495 Patent, col. 7:51-col. 8:8).
Key Claims at a Glance
- The complaint asserts infringement of one or more claims of the ’495 Patent (Compl. ¶47). Independent claim 1 is representative.
- Claim 1 recites a method with the following essential elements:
- Selecting a patient with Cushing's syndrome and elevated ACTH levels.
- Administering a dose of a GRA sufficient to increase ACTH from the pituitary gland by at least two-fold.
- Waiting at least two hours.
- Obtaining an ACTH concentration ratio from inferior petrosal sinus and peripheral vein samples, where a ratio greater than 3 is diagnostic of Cushing’s disease.
(’495 Patent, col. 33:1-24).
U.S. Patent No. 9,943,526 - "Optimizing Mifepristone Levels for Cushing's Patients"
- Patent Identification: U.S. Patent No. 9,943,526, "Optimizing Mifepristone Levels for Cushing's Patients," issued April 17, 2018. (Compl. ¶11).
- Technology Synopsis: The patent asserts the surprising discovery that patients with Cushing's syndrome require a higher blood serum level of mifepristone for a therapeutic response (at least 1631 ng/mL) than patients with mental disorders (1300 ng/mL), despite the underlying mechanism involving the same glucocorticoid receptor (’526 Patent, col. 1:17-25). The patented solution is a method of treating Cushing's syndrome by administering mifepristone, testing the patient's blood levels, and adjusting the dose to achieve a level greater than 1631 ng/mL (’526 Patent, Abstract).
- Asserted Claims: The complaint asserts infringement of one or more claims of the ’526 Patent (Compl. ¶55). Claim 1 is the lead independent claim.
- Accused Features: The complaint alleges that Teva's proposed product instructions will cause prescribers to increase dosage based on clinical assessment and to consider measuring plasma levels to guide titration, which allegedly constitutes infringement of the claimed method (Compl. ¶58).
III. The Accused Instrumentality
Product Identification
The accused instrumentality is Defendant Teva's proposed generic 300 mg mifepristone drug product, which is the subject of Abbreviated New Drug Application (ANDA) No. 211436 filed with the FDA (Compl. ¶1).
Functionality and Market Context
The proposed product is a generic version of Plaintiff’s KORLYM® drug, which is FDA-approved to treat hyperglycemia secondary to hypercortisolism in adult patients with endogenous Cushing's syndrome (Compl. ¶12). Under 35 U.S.C. § 271(e)(2), the filing of the ANDA itself is the statutorily defined act of infringement giving rise to the suit (Compl. ¶39). The core of the infringement allegations is that the proposed labeling for Teva’s product will instruct physicians and patients to use the drug in a manner that practices the methods claimed in the patents-in-suit (Compl. ¶¶42, 50, 58).
No probative visual evidence provided in complaint.
IV. Analysis of Infringement Allegations
U.S. Patent No. 8,921,348 Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| treating the patient with seven or more daily doses of mifepristone over a period of seven or more days; | Teva's product is a generic version of KORLYM®, a mifepristone drug used for chronic treatment of Cushing's syndrome, which inherently involves daily dosing over extended periods. | ¶¶1, 12, 42 | col. 16:6-9 |
| testing the serum levels of the patient to determine whether the blood levels of mifepristone are greater than 1300 ng/mL; | Teva will allegedly instruct prescribers that "in the absence of improvements... prescribers should consider measuring a trough plasma KORLYM level to guide additional titration." | ¶42 | col. 16:10-12 |
| and adjusting the daily dose of the patient to achieve mifepristone blood levels greater than 1300 ng/mL. | Teva will allegedly instruct prescribers to "increase the dose of Teva's Proposed Products 'based on a clinical assessment of tolerability and degree of improvement in Cushing's syndrome manifestations.'" This is allegedly linked to achieving a therapeutic blood level. | ¶42 | col. 16:13-15 |
Identified Points of Contention
- Scope Questions: A central dispute may concern whether Teva’s alleged instruction to "consider measuring a trough plasma... level to guide additional titration" meets the claim limitation of "testing... to determine whether the blood levels... are greater than 1300 ng/mL." The claim requires a specific comparison against a numerical threshold, which may not be explicit in the alleged instruction.
- Technical Questions: The infringement theory hinges on inducement. A key question for the court will be whether the combination of alleged instructions in Teva’s proposed label would lead a prescriber to inevitably perform all steps of the claimed method, including adjusting the dose for the specific purpose of achieving the claimed blood concentration.
U.S. Patent No. 9,829,495 Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| ...method of concurrently treating Cushing's syndrome and differentially diagnosing... | Teva's product is for treating Cushing's syndrome, and the complaint alleges Teva will instruct prescribers to determine if a patient is a candidate for surgery, a determination that allegedly requires the patented differential diagnosis. | ¶¶12, 50 | col. 33:1-6 |
| administering a dose of glucocorticoid receptor antagonist (GRA)... | Teva's proposed product is mifepristone, which the '495 patent identifies as a GRA. | ¶1; '495 Patent, col. 2:39-43 | col. 33:10-14 |
| obtaining from the patient an ACTH concentration ratio wherein the ratio is derived from the ACTH concentrations in fluid obtained from either the left or right inferior petrosal venous sinus and from fluid obtained from a periphery venous sample; | The complaint alleges that Teva's instructions will cause prescribers to perform the claimed diagnostic method, which requires this specific, invasive sampling procedure. | ¶50 | col. 33:15-21 |
Identified Points of Contention
- Scope Questions: The complaint alleges that instructing a prescriber to "determine whether a patient with Cushing's syndrome is a candidate for surgery" constitutes inducement to perform the entire patented diagnostic method (Compl. ¶50). A point of contention will be whether such a general instruction can be equated with an instruction to perform the specific and invasive steps of the claimed method, particularly when alternative, non-infringing diagnostic methods may exist.
- Technical Questions: A key evidentiary question will be what specific language in Teva’s proposed label supports the allegation that it encourages the use of mifepristone not just for treatment, but for the specific diagnostic purpose outlined in the patent, including the inferior petrosal sinus sampling procedure.
V. Key Claim Terms for Construction
The Term: "adjusting the daily dose of the patient to achieve mifepristone blood levels greater than 1300 ng/mL" (’348 Patent, claim 1)
- Context and Importance: This term is critical because the infringement allegation rests on Teva’s proposed label instructing dose adjustment. Practitioners may focus on whether "to achieve" requires the adjustment to be made with the specific intent and purpose of reaching the 1300 ng/mL blood level, or if any adjustment that happens to result in that level infringes.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The plain language suggests a purpose or outcome of the adjustment step. One might argue that if the label guides a physician to titrate a dose until clinical efficacy is seen, and the patent teaches that efficacy correlates with this blood level, the adjustment is being made "to achieve" that level, even if indirectly.
- Evidence for a Narrower Interpretation: The specification repeatedly describes a direct feedback loop: "testing the serum levels... to determine whether the blood levels... are greater than 1300 ng/mL; and adjusting the daily dose... to achieve" that level (’348 Patent, col. 1:45-49). This suggests the testing result directly informs the adjustment, potentially narrowing the term to exclude adjustments based solely on "clinical assessment" without reference to a specific blood concentration target.
The Term: "differentially diagnosing" (’495 Patent, claim 1)
- Context and Importance: The theory of infringement for the ’495 patent depends on linking Teva's alleged instruction to assess a patient for surgery with the patented diagnostic method. The construction of "differentially diagnosing" will determine if the method is merely an option for surgeons or an essential step that Teva's label allegedly induces.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The patent abstract states the invention "provides for an improved method for differentially diagnosing ACTH-dependent Cushing's syndrome," framing it as a tool available to clinicians (’495 Patent, Abstract).
- Evidence for a Narrower Interpretation: The background section explicitly links the diagnosis to a specific clinical decision: "Correct differential diagnosis between the Cushing Disease and ectopic ACTH syndrome is important for endocrinologists to recommend transphenoidal surgery or appropriate imaging" (’495 Patent, col. 2:35-39). This language may support the argument that any instruction to consider surgery necessarily implicates the need for this type of differential diagnosis.
VI. Other Allegations
Indirect Infringement
The complaint's central theory is indirect infringement. It alleges that Teva, upon approval of its ANDA, will induce infringement by physicians who follow the instructions on the proposed product label (Compl. ¶¶42, 50, 58). Knowledge of the patents is alleged based on Teva’s Paragraph IV notice letters (Compl. ¶¶31-33, 34-36). The complaint also alleges contributory infringement, stating that Teva's product is "designed for a use that infringes" and "lacks a substantial non-infringing use" (Compl. ¶¶43, 51, 59).
Willful Infringement
The complaint does not contain an explicit allegation of willful infringement.
VII. Analyst’s Conclusion: Key Questions for the Case
- A core issue will be one of inducement by instruction: can instructions on a drug label to adjust dosage based on "clinical assessment" and to "consider measuring" plasma levels be found to actively encourage infringement of method claims that require testing against a specific numerical blood concentration and adjusting the dose to achieve that concentration?
- A second key question will be one of diagnostic necessity: does an alleged instruction to determine if a patient is a "candidate for surgery" induce infringement of a specific, complex diagnostic method patent, or can a defendant argue that its general instruction does not actively encourage the use of one particular patented method among other potential, non-infringing diagnostic options?
- The case may also turn on the question of substantial non-infringing use: can a generic drug for treating a specific condition have a substantial non-infringing use if, as the plaintiff alleges, the methods required for its safe and effective administration are covered by patents?