Amgen Inc v. Apotex Inc

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Amgen Inc. (Delaware)
  • Defendant: Apotex Inc. (Canada)
  • Plaintiff’s Counsel: Gibbons P.C.
• Case Identification: 3:22-cv-03827, D.N.J., 06/14/2022
• Venue Allegations: Plaintiff alleges venue is proper because Defendant is a foreign company and has represented that it will not object to venue in the District of New Jersey for this matter.
• Core Dispute: Plaintiff alleges that Defendant’s filing of an Abbreviated New Drug Application (ANDA) to market a generic version of OTEZLA® (apremilast) constitutes an act of infringement of three U.S. patents related to the apremilast compound and methods of its use.
• Technical Context: The technology concerns apremilast, a small-molecule inhibitor of phosphodiesterase 4 (PDE4), used in oral tablets for treating inflammatory diseases such as psoriasis and psoriatic arthritis.
• Key Procedural History: The complaint notes extensive prior litigation against other ANDA filers (Sandoz, Zydus) involving two of the same patents-in-suit. In that case, U.S. Patent No. 7,427,638 was found not invalid and infringed, while specific claims of U.S. Patent No. 10,092,541 were found invalid as obvious. Those judgments are currently pending appeal at the U.S. Court of Appeals for the Federal Circuit. U.S. Patent No. 9,872,854 was asserted in the prior litigation, but the defendants settled before trial.

Case Timeline

Date	Event
2002-03-20	U.S. Patent No. 7,427,638 Priority Date
2008-09-23	U.S. Patent No. 7,427,638 Issue Date
2013-03-14	U.S. Patent No. 9,872,854 Priority Date
2014-03-21	FDA approves OTEZLA® New Drug Application (NDA)
2014-08-15	U.S. Patent No. 10,092,541 Priority Date
2018-01-23	U.S. Patent No. 9,872,854 Issue Date
2018-10-09	U.S. Patent No. 10,092,541 Issue Date
2021-06-14	Prior consolidated trial begins (Amgen v. Sandoz, et al.)
2021-09-20	Final Judgment issued in prior litigation
2021-11-18	Appeals in prior litigation consolidated at Federal Circuit
2022-05-06	Plaintiff receives Defendant’s ANDA Notice Letter
2022-06-14	Complaint Filed

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

U.S. Patent No. 7,427,638 - "(+)­-2-­[1-­(3-­Ethoxy-­4-­Methoxyphenyl)-­2-­Methylsulfonylethyl]-­4-­Acetylaminoisoindoline-­1,­3-­Dione: Methods of Using and Compositions Thereof," issued September 23, 2008

The Invention Explained

• Problem Addressed: The patent describes medical conditions associated with enhanced or unregulated production of Tumor Necrosis Factor alpha (TNF-α), a cytokine involved in inflammation. These conditions include inflammatory diseases like arthritis and psoriasis, as well as certain cancers. The background identifies phosphodiesterase 4 (PDE4) as a key enzyme in the inflammatory pathway, making it a target for therapeutic intervention ('638 Patent, col. 2:20-67).
• The Patented Solution: The invention is the specific stereomerically pure (+)-enantiomer of the apremilast compound. The patent discloses that isolating this specific optical isomer from its racemic mixture provides a compound with increased potency for inhibiting TNF-α and PDE4, suggesting potential for improved therapeutic benefit ('638 Patent, Abstract; col. 3:26-34).
• Technical Importance: The isolation of a single, more potent enantiomer of a drug can allow for more targeted therapy, potentially increasing efficacy while reducing the patient's exposure to less active or inactive isomers, which may contribute to side effects ('638 Patent, col. 3:26-28).

Key Claims at a Glance

• The complaint does not specify which claims are asserted but makes allegations consistent with infringement of composition claims (Compl. ¶55). Independent claim 1 is representative.
• Independent Claim 1:
  • A pharmaceutical composition comprising stereomerically pure (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, or a pharmaceutically acceptable salt, solvate or hydrate thereof; and
  • a pharmaceutically acceptable carrier, excipient or diluent.
• The complaint does not explicitly reserve the right to assert dependent claims.

U.S. Patent No. 9,872,854 - "Methods For the Treatment of Psoriatic Arthritis Using Apremilast," issued January 23, 2018

The Invention Explained

• Problem Addressed: The patent identifies psoriatic arthritis as a chronic inflammatory condition affecting the skin and joints, for which effective treatments are needed ('854 Patent, col. 2:21-50). A related patent notes that initial treatment with apremilast can be associated with gastrointestinal symptoms, an implicit problem addressed by a titration method ('541 Patent, col. 19:13-16).
• The Patented Solution: The patent claims a specific method for treating psoriatic arthritis by orally administering apremilast. The core of the invention is an "initial titration dosing schedule" where the dose is escalated over the first five days before reaching a final maintenance dose. This method is designed to manage the initiation of therapy ('854 Patent, Abstract; col. 3:3-30).
• Technical Importance: Dose titration schedules are a clinically important tool to improve a drug's tolerability, which can enhance patient compliance and the likelihood of achieving a therapeutic benefit, particularly for drugs with initial side effects.

Key Claims at a Glance

• The complaint alleges infringement of claims reciting methods of administering apremilast (Compl. ¶79). Independent claim 1 is representative.
• Independent Claim 1:
  • A method of treating a patient with psoriatic arthritis,
  • which comprises orally administering stereomerically pure (+)-apremilast in an initial titration dosing schedule consisting of specific escalating doses on days 1 through 5, and
  • administering a maintenance dose of 30 mg in the morning and 30 mg after noon on the sixth and every subsequent day.
• The complaint does not explicitly reserve the right to assert dependent claims.

U.S. Patent No. 10,092,541 - "Methods for the Treatment of Diseases Ameliorated by PDE4 Inhibition Using Dosage Titration of Apremilast," issued October 9, 2018

Technology Synopsis

The patent addresses the need for safe and effective methods of treating various inflammatory diseases ameliorated by PDE4 inhibition, such as psoriasis, ankylosing spondylitis, and Behçet's disease ('541 Patent, col. 1:12-18). The patented solution is a method of administering apremilast according to a specific, multi-day dose escalation schedule to reduce side effects associated with initial treatment ('541 Patent, col. 2:22-32, col. 19:13-16).

Asserted Claims

The complaint generally asserts claims that recite methods of administering apremilast (Compl. ¶101). Independent claim 1, directed to treating psoriasis, is representative.

Accused Features

The complaint alleges that Defendant will induce infringement by marketing its generic product with a label containing instructions for use that are substantially similar to the prescribing information for OTEZLA®, which follows the patented titration method (Compl. ¶105).

III. The Accused Instrumentality

Product Identification

The accused instrumentalities are Defendant’s generic apremilast tablets in 10 mg, 20 mg, and 30 mg dosage forms, for which Defendant has filed ANDA No. 217258 seeking FDA approval (Compl. ¶1, ¶43).

Functionality and Market Context

The accused products are oral tablets containing apremilast, a PDE4 inhibitor, as the active pharmaceutical ingredient (Compl. ¶43). They are intended to be therapeutic alternatives to Plaintiff's branded drug, OTEZLA®, for approved uses which include treating psoriatic arthritis and plaque psoriasis (Compl. ¶1, ¶18). The filing of the ANDA is an artificial act of infringement under the Hatch-Waxman Act, allowing for resolution of patent disputes before the generic product enters the market (Compl. ¶54). No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

'638 Patent Infringement Allegations

Claim Element (from Independent Claim 1)	Alleged Infringing Functionality	Complaint Citation	Patent Citation
a pharmaceutical composition comprising stereomerically pure (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione...	The accused ANDA products are alleged to be pharmaceutical compositions that contain (+)-apremilast as the active ingredient.	¶56	col. 3:9-25
a pharmaceutically acceptable carrier, excipient or diluent.	The accused ANDA products are tablets, which are solid dosage forms that necessarily contain carriers and excipients to form the tablet.	¶43	col. 7:4-8

• Identified Points of Contention:
  • Scope Questions: The complaint alleges that Apotex's Paragraph IV certification does not contend non-infringement (Compl. ¶62). If the accused product contains apremilast, factual infringement of the composition claims may not be a primary point of dispute. The case will likely focus on validity.
  • Legal Questions: The central issue for this patent may be the legal effect of the prior litigation, which found the patent not invalid and which is now on appeal (Compl. ¶37, ¶41). Questions of claim preclusion or issue preclusion may arise depending on the outcome of that appeal.

'854 Patent Infringement Allegations

Claim Element (from Independent Claim 1)	Alleged Infringing Functionality	Complaint Citation	Patent Citation
A method of treating a patient with psoriatic arthritis...	Defendant's proposed product label is alleged to contain instructions for using the product to treat psoriatic arthritis, similar to the approved uses for OTEZLA®.	¶18, ¶82	col. 2:54-58
which comprises orally administering... stereomerically pure (+)-...-dione in an initial titration dosing schedule consisting of... [days 1-5]	Defendant's proposed product label is alleged to instruct patients and physicians to follow a multi-day dose-escalation schedule that is substantially similar to the patented method.	¶82	col. 3:8-23
on the sixth and every subsequent day, administering to the patient 30 mg in the morning and 30 mg after noon...	Defendant's proposed product label is alleged to instruct patients to continue with a maintenance dose of 30 mg twice daily, consistent with the final step of the claimed method.	¶82	col. 3:24-30

• Identified Points of Contention:
  • Evidentiary Questions: The infringement theory is inducement, which hinges on the content of Defendant's proposed product label. A key question will be whether the instructions in that label direct users to perform all steps of the claimed method, thereby establishing the direct infringement necessary for a finding of inducement.
  • Legal Questions: As this patent was not tried to judgment in the prior litigation (Compl. ¶34), its validity is an open question. The analysis will likely focus on whether the claimed titration schedule for treating psoriatic arthritis would have been obvious to a person of ordinary skill in the art.

V. Key Claim Terms for Construction

For the '638 Patent

• The Term: "stereomerically pure"
• Context and Importance: This term is fundamental to the patent's claim of novelty over the prior art racemic mixture. The definition of the required level of purity will be central to determining both infringement and validity. Practitioners may focus on this term because the feasibility and necessity of achieving a specific purity level could be disputed.
• Intrinsic Evidence for Interpretation:
  • Evidence for a Broader Interpretation: The specification defines the term as meaning the compound "is substantially free of its other enantiomer" ('638 Patent, col. 6:15-18). The word "substantially" suggests that 100% purity is not required.
  • Evidence for a Narrower Interpretation: The specification provides a hierarchy of preferred purity levels, stating the compound "comprises greater than about 90% by weight of one stereoisomer," "more preferably greater than about 95%," and "most preferably greater than about 97%" ('638 Patent, col. 6:23-33). A party could argue these specific disclosures limit the term to a high degree of purity.

For the '854 Patent

• The Term: "after noon"
• Context and Importance: The method claims require a specific twice-daily dosing regimen, with the second dose occurring "after noon." The interpretation of this temporal limitation is necessary to assess infringement. Practitioners may focus on this term to determine if a variety of possible patient dosing behaviors would fall inside or outside the claim scope.
• Intrinsic Evidence for Interpretation:
  • Evidence for a Broader Interpretation: The plain and ordinary meaning of "after noon" is any time from 12:01 PM until midnight, giving the term a wide scope. The patent specification does not appear to provide a specific definition that would narrow this meaning ('854 Patent, col. 3:8-30).
  • Evidence for a Narrower Interpretation: A party might argue that in the context of pharmaceutical dosing, the term implies a standard twice-daily interval (e.g., approximately 12 hours between doses). If the "morning" dose is taken at 8 AM, this interpretation could suggest the "after noon" dose should be taken in the evening (e.g., around 8 PM), rather than at 1 PM. The prescribing information for OTEZLA® (referenced as Exhibit A) could be cited as extrinsic evidence of how a person of skill would understand this instruction in practice.

VI. Other Allegations

• Indirect Infringement: The complaint's primary theory for the '854 and '541 method patents is induced infringement. It alleges that Apotex, with knowledge of the patents, will market its product with a label and product insert that will intentionally encourage and instruct physicians and patients to perform the steps of the patented treatment methods (Compl. ¶82, ¶105).
• Willful Infringement: The complaint alleges that Apotex had actual notice of the patents-in-suit prior to filing its ANDA (Compl. ¶60, ¶83). It further alleges that Apotex's conduct in certifying the patents as invalid or not infringed in its Paragraph IV certification was done "without adequate justification," rendering the case "exceptional" under 35 U.S.C. § 285 (Compl. ¶63, ¶86, ¶106).

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

• A central legal question will be one of preclusion and precedent: to what extent will the findings from the prior Sandoz litigation—specifically, the validity of the '638 patent and the partial invalidity of the '541 patent—influence or control the outcome of this case, particularly with those findings currently under review by the Federal Circuit?
• A key evidentiary question will be one of induced infringement: does the specific language of Apotex’s proposed product label instruct a method of administration that meets every limitation of the asserted method claims in the '854 and '541 patents, thereby establishing the direct infringement and intent required for inducement?
• A core validity question will be one of obviousness: for the '854 patent, which was not previously litigated to judgment, will the claimed multi-day dose titration schedule for treating psoriatic arthritis be found to have been an obvious, conventional clinical practice to a person of ordinary skill in the art at the time of the invention?