DCT

1:18-cv-00085

Hikma Pharma USA Inc v. Granules Pharma Inc

I. Executive Summary and Procedural Information

Parties & Counsel:
- Plaintiff: West-Ward Pharmaceuticals Corp. (Delaware) and Hikma Pharmaceuticals LLC (Jordan)
- Defendant: Granules Pharmaceuticals, Inc., USA (Delaware)
- Plaintiff’s Counsel: Winston & Strawn LLP
Case Identification: 1:18-cv-00085, D. Del., 01/12/2018
Venue Allegations: Venue is alleged to be proper in the District of Delaware based on Defendant's incorporation in the state.
Core Dispute: Plaintiffs allege that Defendant’s Abbreviated New Drug Application (ANDA) to market a generic version of the gout medication Mitigare® (colchicine) constitutes an act of infringement of five patents related to methods of safely co-administering colchicine with other drugs.
Technical Context: The patents address the safe administration of colchicine, a drug with a narrow therapeutic window, when used concurrently with other medications that inhibit specific metabolic pathways (CYP3A4 or P-glycoprotein).
Key Procedural History: This action was filed under the Hatch-Waxman Act following Plaintiffs' receipt of a Paragraph IV certification notice from Defendant. In its notice, Defendant stated its belief that Plaintiffs' patents, which are listed in the FDA's "Orange Book" for the drug Mitigare®, are invalid, unenforceable, or will not be infringed by its proposed generic product.

Case Timeline

Date	Event
2013-08-20	Earliest Priority Date for all Patents-in-Suit
2015-01-06	U.S. Patent No. 8,927,607 Issues
2016-07-26	U.S. Patent No. 9,399,036 Issues
2017-01-31	U.S. Patent No. 9,555,029 Issues
2017-06-13	U.S. Patent No. 9,675,613 Issues
2017-10-17	U.S. Patent No. 9,789,108 Issues
2017-11-28	Date of Defendant's ANDA Notice Letter
2018-01-12	Complaint Filing Date

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

U.S. Patent No. 8,927,607 - Methods of Colchicine Administration

The Invention Explained

Problem Addressed: The patent describes that colchicine, a drug for treating gout, has a narrow margin of safety and can become toxic if its concentration in the blood increases unexpectedly (Compl. ¶18; ’607 Patent, col. 2:6-13). This risk is heightened when co-administered with other drugs that inhibit the two primary physiological pathways responsible for clearing colchicine from the body: the CYP3A4 metabolic enzyme and the P-glycoprotein (P-gp) efflux pump (’607 Patent, col. 2:20-38). The prior medical consensus was that any drug inhibiting either pathway required a reduction in the colchicine dose, which could compromise its therapeutic effectiveness (’607 Patent, col. 2:47-53).
The Patented Solution: The invention is based on the discovery that colchicine can be safely co-administered at its normal therapeutic dose with drugs that inhibit only one of these two pathways, but not both (’607 Patent, col. 3:26-33). The patent claims methods of treating inflammatory disorders by administering a standard maintenance dose of colchicine along with a second drug that is a "single inhibitor" (i.e., it inhibits CYP3A4 or P-gp, but not both) "without dose reduction" (’607 Patent, col. 10:51-64).
Technical Importance: This method allows patients suffering from gout and other co-morbid conditions to continue taking their required medications without the risk of colchicine toxicity or the loss of efficacy that would result from a precautionary dose reduction (’607 Patent, col. 3:12-24).

Key Claims at a Glance

The complaint does not identify specific claims, but the patents-in-suit contain method claims that cover the alleged infringement. Claim 1 of the ’607 Patent is an independent method claim.
Claim 1 of the ’607 Patent includes the following essential elements:
- A method of treating a patient for an inflammatory disorder selected from chronic gout, familial Mediterranean fever, or Behçet's disease;
- The method involves administering colchicine while concomitantly administering a second drug that is an inhibitor of CYP3A4 but is not an inhibitor of P-gp;
- The second drug is specified as voriconazole, fluconazole, or cimetidine;
- The method requires administering a fixed maintenance dose of colchicine (from 0.6 to 1.2 mg/day) "without dose reduction."
The complaint alleges infringement of "one or more claims" of the patent, which may include dependent claims (Compl. ¶27).

U.S. Patent No. 9,399,036 - Methods of Colchicine Administration

The Invention Explained

Problem Addressed: The ’036 Patent addresses the same technical problem as the ’607 Patent: the risk of drug-drug interactions increasing colchicine to toxic levels in patients, and the consequent prior art practice of reducing colchicine dosage even when it might not be necessary (’036 Patent, col. 2:20-53).
The Patented Solution: The solution is also the same: methods of co-administering a standard dose of colchicine with a second drug that inhibits only the CYP3A4 pathway or only the P-gp pathway, but not both, thereby avoiding toxicity without requiring a dose reduction (’036 Patent, Abstract; col. 3:42-53).
Technical Importance: As with the ’607 Patent, this approach is presented as enabling safer and more effective long-term treatment for patients with gout and other conditions who also require medication for co-morbidities (’036 Patent, col. 3:18-33).

Key Claims at a Glance

The complaint does not identify specific claims. Claim 1 of the ’036 Patent is an independent method claim.
Claim 1 of the ’036 Patent includes the following essential elements:
- A method of administering colchicine to a patient while concomitantly administering a second drug that is a CYP3A4 inhibitor but not a P-gp inhibitor;
- The second drug is specified as voriconazole, fluconazole, or cimetidine;
- The method comprises administering a therapeutic fixed maintenance dose of colchicine (from 0.6 to 1.2 mg/day) "without dose reduction."
The complaint alleges infringement of "one or more claims" of the patent (Compl. ¶36).

Multi-Patent Capsule: U.S. Patent No. 9,555,029

Patent Identification: U.S. Patent No. 9,555,029, titled Methods of Colchicine Administration, issued January 31, 2017.
Technology Synopsis: This patent claims the other side of the core invention, disclosing a method of treating inflammatory disorders by co-administering colchicine with a second drug that is an inhibitor of P-gp but is not an inhibitor of CYP3A4 (’029 Patent, Abstract). The patent identifies propafenone as such a drug (’029 Patent, col. 12:5-8).
Asserted Claims: The complaint asserts "one or more claims" of the patent (Compl. ¶45). Claim 1 is independent.
Accused Features: The accused infringement is the filing of an ANDA for a generic colchicine product whose intended use is alleged to be covered by the patent's method claims (Compl. ¶¶ 45-46).

Multi-Patent Capsule: U.S. Patent No. 9,675,613

Patent Identification: U.S. Patent No. 9,675,613, titled Methods of Colchicine Administration, issued June 13, 2017.
Technology Synopsis: This patent is also directed to methods of preventing gout flares by administering colchicine with a second drug that inhibits P-gp but not CYP3A4, specifically identifying propafenone (’613 Patent, Abstract; col. 28:7-16).
Asserted Claims: The complaint asserts "one or more claims" of the patent (Compl. ¶54). Claim 1 is independent.
Accused Features: The accused infringement is the filing of an ANDA for a generic colchicine product whose intended use is alleged to be covered by the patent's method claims (Compl. ¶¶ 54-55).

Multi-Patent Capsule: U.S. Patent No. 9,789,108

Patent Identification: U.S. Patent No. 9,789,108, titled Methods of Colchicine Administration, issued October 17, 2017.
Technology Synopsis: This patent returns to the subject matter of the ’607 and ’036 patents, claiming methods of administering colchicine with a second drug that inhibits CYP3A4 but not P-gp, such as voriconazole, fluconazole, or cimetidine (’108 Patent, Abstract; col. 26:15-24).
Asserted Claims: The complaint asserts "one or more claims" of the patent (Compl. ¶63). Claim 1 is independent.
Accused Features: The accused infringement is the filing of an ANDA for a generic colchicine product whose intended use is alleged to be covered by the patent's method claims (Compl. ¶¶ 63-64).

III. The Accused Instrumentality

Product Identification

The accused instrumentality is Defendant's proposed generic colchicine 0.6 mg capsule product, which is the subject of ANDA No. 210757 ("Granules' ANDA Product") (Compl. ¶20).

Functionality and Market Context

The complaint alleges that Granules' ANDA Product is a generic version of Plaintiffs' Mitigare® product (Compl. ¶20). Mitigare® is indicated for the prophylaxis of gout (Compl. ¶18). The act of infringement alleged under the Hatch-Waxman Act is the submission of the ANDA itself, which seeks FDA approval to market this generic drug for a patented use prior to the expiration of the patents-in-suit (Compl. ¶28). The complaint alleges that the "use of Granules' ANDA Product is covered by one or more claims" of the asserted patents (Compl. ¶23). No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint does not provide a claim chart or a detailed, element-by-element infringement analysis. The infringement allegation is a statutory one under 35 U.S.C. § 271(e)(2), where the filing of an ANDA for a drug claimed in a patent or for a use claimed in a patent is an act of infringement. The core theory is that Defendant's proposed product, if approved and marketed with its proposed label, would be used by patients and physicians in a manner that infringes the asserted method claims.

’607 Patent Infringement Allegations

Claim Element (from Independent Claim 1)	Alleged Infringing Functionality	Complaint Citation	Patent Citation
A method of treating a patient for an inflammatory disorder, wherein the inflammatory disorder is chronic gout...	Defendant seeks approval via its ANDA to market a generic version of Mitigare®, a colchicine capsule indicated for the prophylaxis of gout.	¶¶18, 20, 27	col. 2:13-16
with colchicine while concomitantly administering a second drug that is an inhibitor of the cytochrome P450 3A4 isoenzyme (CYP3A4) but is not an inhibitor of P-glycoprotein 1 (P-gp)...	The complaint alleges that the intended use of the ANDA product is covered by the claims, which suggests the proposed label contemplates or instructs co-administration with such drugs.	¶¶23, 27-28	col. 10:52-57
administering to the patient...a therapeutically effective fixed maintenance dose of colchicine in an amount of from about 0.6 to about 1.2 mg/day...without dose reduction.	Defendant's ANDA is for a 0.6 mg colchicine capsule. The allegation suggests the proposed product label will instruct or permit administration of this dose without reduction when co-administered with a specified single inhibitor.	¶20	col. 10:58-64

Identified Points of Contention

Scope Questions: A primary question will be whether Defendant's proposed product label will induce infringement. For infringement to occur, the label would need to instruct or encourage physicians and patients to co-administer the generic colchicine with a CYP3A4 inhibitor (like fluconazole) without reducing the colchicine dose. The complaint does not contain the proposed label, so the basis for this allegation is not yet detailed.
Technical Questions: A key dispute may arise from Defendant's Paragraph IV certification, which asserts non-infringement and/or invalidity (Compl. ¶22). This raises the question of what specific technical or legal arguments Defendant will advance to argue that its proposed product or its use falls outside the claim scope, or that the claims themselves are invalid over the prior art.

V. Key Claim Terms for Construction

The Term: "without dose reduction"
Context and Importance: This phrase is central to the inventive concept, as the patents distinguish themselves from prior art that allegedly required dose reductions when co-administering colchicine with any CYP3A4 or P-gp inhibitor. The infringement analysis may turn on whether Defendant's proposed label instructs a dose reduction in the circumstances described by the claims. If it does, Defendant may argue non-infringement.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The specification repeatedly contrasts the invention with prior art that required dose reductions of "33-75%" (’607 Patent, col. 2:56-59). The plain meaning of "without dose reduction" could therefore be interpreted broadly as administering the standard therapeutic dose (e.g., 0.6 mg/day) rather than a lowered one.
- Evidence for a Narrower Interpretation: The phrase is defined relative to the "fixed maintenance dose" recited in the claims (’607 Patent, col. 10:62-64). An argument could be made that its meaning is tied to the specific pharmacokinetic outcomes detailed in the patent's clinical trial examples, potentially limiting its scope to scenarios producing those specific results.
The Term: "an inhibitor of [CYP3A4] but is not an inhibitor for [P-gp]"
Context and Importance: The classification of the second, co-administered drug as a "single inhibitor" is a critical claim limitation. Practitioners may focus on this term because a drug's inhibitory effects on these pathways can be a matter of degree. A dispute could arise if a co-administered drug has some minor, clinically insignificant effect on the second pathway.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The specification explicitly incorporates the FDA's definitions for classifying drugs as strong, moderate, or weak inhibitors of CYP3A4, and as inhibitors or non-inhibitors of P-gp, based on quantitative effects on substrate drug exposure (AUC) (’607 Patent, col. 8:51 - col. 9:11). This suggests the terms are meant to be understood according to these established, objective criteria.
- Evidence for a Narrower Interpretation: The claims in several of the patents recite specific exemplary drugs (e.g., "wherein the second drug is voriconazole, fluconazole or cimetidine") (’607 Patent, cl. 1). A defendant might argue that the scope of the "single inhibitor" term should be construed in light of the specific properties of these enumerated compounds.

VI. Other Allegations

Indirect Infringement: The complaint alleges that Defendant will actively induce infringement upon approval of its ANDA (Compl. ¶¶ 31, 40, 49, 58, 67). This allegation is prospective and appears to be based on the theory that Defendant's product labeling will instruct medical professionals and patients to use the generic drug in a manner that directly infringes the asserted method claims.
Willful Infringement: The complaint does not use the word "willful," but it alleges that Defendant had knowledge of the patents-in-suit when it submitted its ANDA (Compl. ¶24). This allegation of pre-suit knowledge could form the basis for a later claim of willful infringement.

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

A core issue will be one of induced infringement: will the contents of the proposed label for Defendant’s generic colchicine product instruct or encourage physicians to prescribe it for co-administration with the specific "single inhibitors" recited in the claims without a dose reduction? The outcome may depend heavily on the specific language, warnings, and dosage instructions in Defendant's proposed labeling, which is not included in the complaint.
A second key issue, raised by Defendant's Paragraph IV certification, will be one of patent validity: can the patented methods—which are based on the discovery that "single inhibitors" do not necessitate a colchicine dose adjustment—withstand an obviousness challenge, particularly in light of prior art knowledge regarding the distinct roles of the CYP3A4 and P-gp pathways in drug metabolism?