DCT
1:19-cv-00622
Lipocine Inc v. Clarus Therap Inc
Key Events
Complaint
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Lipocine Inc. (Delaware)
- Defendant: Clarus Therapeutics, Inc. (Delaware)
- Plaintiff’s Counsel: Fish & Richardson P.C.
- Case Identification: 1:19-cv-00622, D. Del., 04/02/2019
- Venue Allegations: Venue is alleged to be proper as both parties are Delaware corporations. Personal jurisdiction is also asserted based on Defendant's intent to market and sell its product in Delaware and its prior litigation activity in the district.
- Core Dispute: Plaintiff alleges that Defendant’s oral testosterone pharmaceutical product, JATENZO®, will infringe six patents related to testosterone undecanoate compositions and methods for administering testosterone replacement therapy.
- Technical Context: The case concerns oral formulations for testosterone replacement therapy, a market where achieving consistent and safe therapeutic blood levels via oral administration presents significant pharmacological challenges.
- Key Procedural History: The complaint notes that the parties have a prior litigation history in the District of Delaware. It also details the FDA regulatory history for the accused JATENZO® product, including an initial rejection, a new Phase 3 clinical investigation, and eventual FDA approval on March 27, 2019.
Case Timeline
| Date | Event |
|---|---|
| 1999-11-23 | Priority Date for ’463 and ’988 Patents |
| 2003-05-27 | Issue Date for U.S. Patent No. 6,569,463 |
| 2005-08-02 | Issue Date for U.S. Patent No. 6,923,988 |
| 2010-11-30 | Priority Date for ’858, ’057, ’690, and ’390 Patents |
| 2014-01-03 | Defendant Clarus files New Drug Application (NDA) for JATENZO® |
| 2015-05-19 | Issue Date for U.S. Patent No. 9,034,858 |
| 2015-08-27 | Plaintiff Lipocine files NDA for its TLANDO™ product |
| 2015-12-08 | Issue Date for U.S. Patent No. 9,205,057 |
| 2016-11-01 | Issue Date for U.S. Patent No. 9,480,690 |
| 2017-06-26 | Defendant Clarus resubmits NDA for JATENZO® |
| 2017-09-12 | Issue Date for U.S. Patent No. 9,757,390 |
| 2018-05-08 | FDA rejects Plaintiff Lipocine's NDA for TLANDO™ |
| 2019-03-27 | Defendant Clarus receives FDA approval for JATENZO® |
| 2019-04-02 | Complaint Filing Date |
| End of 2019 | Defendant's announced intention to launch JATENZO® |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 9,034,858 - "High-Strength Testosterone Undecanoate Compositions"
Issued May 19, 2015
The Invention Explained
- Problem Addressed: The patent addresses the challenge of providing a stable and effective serum concentration of testosterone for hypogonadal males through oral administration (Compl. ¶15; ’858 Patent, col. 2:11-16). Conventional oral delivery of testosterone is difficult due to poor bioavailability and first-pass metabolism.
- The Patented Solution: The invention is a method of treatment involving a specific dosing and titration protocol. It begins with an initial oral regimen of a testosterone undecanoate composition at a specified weight percentage and daily dose, administered with a meal. Next, a "dose titration metric" is determined by measuring the patient's serum testosterone concentration at a specific time window post-dose. Based on this metric, a maintenance regimen is established, with the daily dose adjusted within a defined percentage (±40%) of the initial dose to achieve a target serum testosterone concentration (Compl. ¶16; ’858 Patent, Abstract). The method aims to achieve specific pharmacokinetic outcomes, such as a ratio of the maximum serum concentration (Cmax) to the average concentration (Cave) of 2.7 or less (Compl. ¶16).
- Technical Importance: This titration method offers a personalized approach to oral testosterone therapy, aiming to overcome patient-to-patient variability and achieve consistent therapeutic levels that mimic natural testosterone patterns more closely than a fixed-dose regimen might allow.
Key Claims at a Glance
- The complaint asserts independent claims 1 and 20 (Compl. ¶¶ 16-17).
- The essential elements of independent claim 1 include:
- Orally administering an initial regimen of a testosterone undecanoate composition twice a day with a meal, with the composition having a specified weight percentage (14-35 wt %) and providing a specified daily dose (360-480 mg).
- Determining a dose titration metric based on a serum testosterone measurement taken 1 to 8 hours after a single dose at steady state.
- Orally administering a maintenance regimen twice a day with a meal, with the daily dose adjusted within ±40% of the initial dose based on the determined titration metric.
- Wherein the composition provides a ratio of Cmax to Cave of 2.7 or less or a specified dose-normalized Cave.
U.S. Patent No. 9,205,057 - "High-Strength Testosterone Undecanoate Compositions"
Issued December 8, 2015
The Invention Explained
- Problem Addressed: The patent is directed to methods for testosterone replacement therapy in males with a deficiency of endogenous testosterone, aiming to provide a serum testosterone level within the normal physiological range (Compl. ¶19; ’057 Patent, col. 2:14-19).
- The Patented Solution: The invention is a method of treatment that, similar to the ’858 Patent, involves an initial daily dosing regimen, a step of determining the patient's serum testosterone level 1-8 hours post-dose, and a subsequent maintenance regimen with a dose adjusted within ±40% of the initial dose. The method's stated goal is to provide a serum testosterone Cave in the range of about 300-1100 ng/dL (Compl. ¶¶ 19-20; ’057 Patent, Abstract).
- Technical Importance: The method provides a structured protocol for physicians to tailor oral testosterone undecanoate therapy to individual patient needs to achieve and maintain therapeutic serum concentrations.
Key Claims at a Glance
- The complaint asserts independent claims 1, 11, and 20 (Compl. ¶¶ 20-21).
- The essential elements of independent claim 1 include:
- Orally administering a daily dosing regimen of a pharmaceutical composition (14-35 wt % testosterone undecanoate and a carrier) that provides from about 360 mg to 480 mg of testosterone undecanoate per day.
- Determining the serum level of testosterone 1-8 hours after single dose administration at steady state.
- Orally administering a maintenance daily dosing regimen that provides a dose within ±40% of the initial 360-480 mg range, based on the determined serum testosterone level.
- The method provides a serum testosterone Cave in the male in the range of from about 300-1100 ng/dL.
U.S. Patent No. 9,480,690 - "High-Strength Testosterone Undecanoate Compositions"
Issued November 1, 2016
- Technology Synopsis: This patent discloses a method for testosterone replacement therapy similar to the ’057 Patent. Its claims add a specific requirement for the composition's formulation, namely that the carrier for the testosterone undecanoate comprises a fatty acid and a polyoxyethylene hydrogenated vegetable oil (Compl. ¶¶ 23-24).
- Asserted Claims: Independent claims 1, 11, and 20 (Compl. ¶¶ 24-25).
- Accused Features: The complaint alleges that JATENZO® infringes because its formulation includes oleic acid (a fatty acid) and Cremophor RH 40 (polyoxyl 40 hydrogenated castor oil, a type of polyoxyethylene hydrogenated vegetable oil) (Compl. ¶¶ 59, 62).
U.S. Patent No. 9,757,390 - "High-Strength Testosterone Undecanoate Compositions"
Issued September 12, 2017
- Technology Synopsis: This patent discloses a method for testosterone replacement therapy similar to the other method patents. Its claims specify a particular daily dose of "about 450 mg or about 480 mg of testosterone undecanoate" for the initial and maintenance regimens (Compl. ¶¶ 27-28).
- Asserted Claims: Independent claims 1, 13, and 24 (Compl. ¶¶ 28-29).
- Accused Features: The complaint alleges infringement based on the recommended starting daily dose for JATENZO®, which is 474 mg (237 mg taken twice daily) (Compl. ¶50).
U.S. Patent No. 6,569,463 - "Solid Carriers for Improved Delivery of Hydrophobic Active Ingredients in Pharmaceutical Compositions"
Issued May 27, 2003
- Technology Synopsis: This patent discloses a pharmaceutical composition, not a method. The claimed invention is a composition in the form of a solid carrier comprising an admixture of a hydrophobic active ingredient (like testosterone), a hydrophilic surfactant to solubilize it, and a lipophilic additive (Compl. ¶31-32).
- Asserted Claims: Claim 29 (Compl. ¶32).
- Accused Features: JATENZO® is alleged to be a "solid carrier (e.g., gelatin capsule)" containing testosterone undecanoate (hydrophobic active ingredient), Cremophor RH 40 (hydrophilic surfactant), and lipophilic additives such as oleic acid and borage seed oil (Compl. ¶63).
U.S. Patent No. 6,923,988 - "Solid Carriers for Improved Delivery of Active Ingredients in Pharmaceutical Compositions"
Issued August 2, 2005
- Technology Synopsis: This patent discloses a pharmaceutical composition in the form of a solid carrier. It requires an admixture of a pharmaceutical active ingredient selected from a long list (which includes sex hormones), an "effective solubilizing amount" of a hydrophilic surfactant, and an optional additive. A key feature is that the hydrophilic surfactant solidifies at ambient room temperature (Compl. ¶¶ 34-35).
- Asserted Claims: Claim 1 (Compl. ¶35).
- Accused Features: The complaint alleges JATENZO® infringes because its formulation contains testosterone (a sex hormone), and its hydrophilic surfactant, Cremophor RH 40, "solidifies at ambient room temperature" (Compl. ¶¶ 62, 199-201).
III. The Accused Instrumentality
Product Identification
- JATENZO®, an oral testosterone undecanoate pharmaceutical product (Compl. ¶1).
Functionality and Market Context
- JATENZO® is provided as gelatin capsules in 158 mg, 198 mg, and 237 mg strengths for twice-daily administration with food (Compl. ¶¶ 46, 48, 51). The product's approved label recommends a starting dose of 237 mg twice daily (totaling 474 mg) (Compl. ¶50). The label directs physicians to adjust this dose based on a serum testosterone measurement taken 6 hours after the morning dose, using a provided table to guide adjustments (Compl. ¶¶ 52-53). The complaint alleges that JATENZO®'s inactive ingredients include oleic acid and polyoxyl 40 hydrogenated castor oil (Cremophor RH 40) (Compl. ¶59). The product is a direct competitor to Plaintiff's own product candidate and received FDA approval on March 27, 2019, with a commercial launch planned for late 2019 (Compl. ¶¶ 6, 42-43).
IV. Analysis of Infringement Allegations
No probative visual evidence provided in complaint.
'858 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| orally administering to the male subject twice a day with a meal an initial regimen including a daily dose of a testosterone undecanoate-containing composition, wherein the testosterone undecanoate comprises about 14 wt % to about 35 wt %...and wherein the daily dose provides about 360 mg to about 480 mg of testosterone undecanoate | The JATENZO® label recommends a starting dose of 237 mg taken twice daily (totaling 474 mg) with food. The wt % is alleged to be between 14% and 35%. | ¶47, ¶50, ¶51 | col. 25:39-49 |
| determining a dose titration metric based on a measurement of serum testosterone concentration for the male subject...from 1 to 8 hours after single dose administration...at steady state | The JATENZO® label instructs that serum testosterone concentration is to be measured 6 hours after the morning dose to ensure proper dose adjustment. | ¶52 | col. 25:50-57 |
| orally administering to the male subject twice a day with a meal a maintenance regimen...wherein the maintenance regimen provides a daily dose of testosterone undecanoate within ±40% of the amount of testosterone undecanoate of the initial regimen daily dose to the subject based on the titration metric | The JATENZO® label provides a table with recommended dose adjustments based on the measured serum testosterone, which allegedly constitutes a variance within ±40% of the initial amount. | ¶53 | col. 25:58-67 |
| wherein the testosterone undecanoate-containing composition provides upon single dose administration a ratio of serum testosterone Cmax to Cave of 2.7 or less | The pharmacokinetic parameters of JATENZO® are alleged to result in a ratio of serum Cmax to Cave of approximately 2.5. | ¶58 | col. 26:5-8 |
Identified Points of Contention
- Scope Questions: A central question for the method claims will be whether the prescribing of JATENZO® by physicians in accordance with its FDA-approved label constitutes infringement. Plaintiff's case relies on a theory of indirect infringement, where Defendant is alleged to induce physicians and patients to perform the patented steps.
- Technical Questions: A factual question may arise as to whether JATENZO®'s real-world pharmacokinetic performance consistently achieves the specific Cmax-to-Cave ratio of 2.7 or less as required by claim 1 of the ’858 Patent. The complaint relies on information from the product label, but actual clinical performance could be a point of dispute.
'057 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| (a) Orally administering to said male a daily dosing regimen of a pharmaceutical composition...that provides from about 360 mg to about 480 mg of testosterone undecanoate to said male per day | The JATENZO® label recommends a starting daily dose of 474 mg. | ¶50 | col. 25:40-46 |
| (b) Determining the serum level of testosterone of said male during the daily dosing regimen at from 1-8 hours after single dose administration...at steady state | The JATENZO® label instructs that serum testosterone concentration is to be measured 6 hours after the morning dose. | ¶52 | col. 25:47-51 |
| (c) Orally administering a maintenance daily dosing regimen...that provides within plus or minus 40% of from about 360 mg to about 480 mg of testosterone undecanoate to said male based on the serum testosterone level determined in step (b) | The JATENZO® label provides for dose adjustments that are alleged to be within ±40% of the initial dose range. | ¶53 | col. 25:52-59 |
| to provide a serum testosterone Cave in said male in the range of from about 300-1100 ng/dL | The JATENZO® label instructs that dosing should be adjusted to achieve a serum testosterone concentration between 425 ng/dL to 970 ng/dL, which is within the claimed range. | ¶57 | col. 25:60-62 |
Identified Points of Contention
- Scope Questions: Similar to the ’858 Patent, the infringement allegation rests on the instructions provided with the JATENZO® product, raising the question of whether selling the product induces performance of the claimed method.
- Technical Questions: The complaint does not provide sufficient detail for analysis of whether JATENZO®'s carrier meets the specific limitations of independent claims 11 and 20 of the ’057 Patent, which require specific carrier components and dissolution properties. This may require discovery and expert testimony.
V. Key Claim Terms for Construction
The Term: "dose titration metric" (’858 Patent, claim 1)
Context and Importance
This term is the lynchpin of the titration method claimed in the ’858 patent. The infringement analysis depends on whether the process described on the JATENZO® label—measuring serum testosterone at 6 hours and using a table to adjust the dose—constitutes a "dose titration metric." Practitioners may focus on this term because its construction will determine if a specific set of label instructions meets the claim limitation.
Intrinsic Evidence for Interpretation
- Evidence for a Broader Interpretation: The patent specification may describe the "dose titration metric" in general terms, potentially encompassing any systematic rule or parameter derived from a serum measurement used to guide dosing adjustments, which could support Plaintiff's theory.
- Evidence for a Narrower Interpretation: The specification may define the "dose titration metric" by referencing specific formulas or calculations in its examples. Defendant could argue the term is limited to these specific embodiments, potentially excluding the simple table-based adjustment on the JATENZO® label.
The Term: "solid carrier" (’463 and ’988 Patents, claims 29 and 1)
Context and Importance
The composition patents are directed to a "pharmaceutical composition in the form of a solid carrier comprising an admixture of..." various components. The physical nature of the "carrier" is critical. Plaintiff's infringement theory appears to be that the entire JATENZO® formulation inside the gelatin capsule is the "solid carrier." A dispute may arise over whether this interpretation is correct or if the term has a more limited meaning.
Intrinsic Evidence for Interpretation
- Evidence for a Broader Interpretation: The specification of the ’463 and ’988 patents may use "solid carrier" to refer broadly to the entire solid dosage form, including all active and inactive ingredients formulated to be solid at room temperature.
- Evidence for a Narrower Interpretation: The patents may distinguish between the "carrier" and the "active ingredient," suggesting the carrier is only the excipient matrix. Defendant may argue that in the context of a capsule, the carrier is the capsule shell itself, not the liquid or semi-solid admixture contained within, which could challenge the infringement allegation.
VI. Other Allegations
- Indirect Infringement: The complaint's primary allegations for the four method patents (’858, ’057, ’690, ’390) are for indirect infringement. Inducement is alleged based on Defendant's intent to market JATENZO® with a label and instructions that actively encourage and direct physicians and patients to perform the steps of the patented methods (Compl. ¶¶ 85, 110, 135, 160). Contributory infringement is alleged on the basis that JATENZO® is especially adapted for an infringing use and has no substantial non-infringing uses (Compl. ¶¶ 89-90, 114-115, 139-140, 164-165).
- Willful Infringement: The complaint alleges that Defendant had actual knowledge of the asserted patents no later than their issue dates and proceeded with its commercialization plans despite this knowledge (Compl. ¶¶ 79-81, 104-106). This forms the basis for the request for a finding of willful infringement and enhanced damages.
VII. Analyst’s Conclusion: Key Questions for the Case
- A core issue will be one of induced infringement: will the act of selling JATENZO® with its FDA-approved label, which instructs physicians and patients on a specific dosing and monitoring protocol, be found to actively induce the performance of the patented methods? This will require a step-by-step comparison of the label's instructions to the elements of the asserted method claims.
- A second central issue will be one of claim construction: can the term "solid carrier," as used in the ’463 and ’988 composition patents, be construed to read on the semi-solid admixture of active and inactive ingredients found within the JATENZO® gelatin capsule, as the complaint alleges?
- A key evidentiary question will be one of pharmacokinetic equivalence: does the JATENZO® product, when used by patients, actually and consistently produce the specific pharmacokinetic outcomes (e.g., Cmax/Cave ratio ≤ 2.7) required by certain claims, or is there a material difference between the product label's data and real-world performance?