In re Entresto Sacubitril/Valsartan Patent Litig.

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In re Entresto Sacubitril/Valsartan Patent Litigation

MDL No. 20-2930-RGA

C.A. Nos. 19-1979-RGA, 19-2021-RGA, 19-2053-RGA

United States District Court, D. Delaware

July 7, 2023

Daniel M. Silver, Alexandra M. Joyce, McCARTER & ENGLISH, LLP Wilmington, DE; Nicholas N. Kallas, Christina Schwarz, Jared L. Stringham, Christopher E. Loh, Susanne L. Flanders Shannon Clark, Laura Fishwick, VENABLE LLP, New York, NY. Attorneys for Plaintiff.

Richard C. Weinblatt, Stamatios Stamoulis, STAMOULIS &amp WEINBLATT LLC, Wilmington, DE; Ronald M. Daignault, Richard Juang, DAIGNAULT IYER LLP, Mclean, VA. Attorneys for Defendants MSN Pharmaceuticals Inc., MSN Laboratories Private Limited, and MSN Life Sciences Private Limited

Daniel Taylor, Neal C. Belgam, SMITH, KATZENSTEIN & JENKINS LLP, Wilmington, DE; Dmitry V. Shelhoff, Kenneth S. Canfield, Edward D. Pergament, PERGAMENT & CEPEDA LLP, Florham Park, NJ. Attorneys for Defendants Hetero USA Inc., Hetero Labs Limited, Hetero Labs Limited Unit HI, Torrent Pharma Inc., and Torrent Pharmaceuticals Ltd.

April M. Ferraro, John M. Seaman, ABRAMS & BAYLISS LLP, Wilmington, DE; A. Neal Seth, Corey Weinstein, WILEY REIN LLP, Washington, DC. Attorneys for Defendants Macleods Pharmaceuticals Ltd. and Macleods Pharma USA, Inc.

TRIAL OPINION

ANDREWS, U.S. DISTRICT JUDGE

This case is part of the multi-district litigation of patent infringement claims regarding Entresto® (sacubitril/valsartan). Tn re Entresto (Sacubitril/Valsartan) Patent Litigation, C. A. No. 20-md-02930 (“In re Entresto''). Novartis brought this action against Defendants for infringement of U.S. Patent 8,877,938 (the “'938 Patent”), 9,388,134 (the “'134 Patent”), 8,101,659 (the “'659 Patent”) and 8,796,331 (the “'331 Patent”). Only the '659 Patent is at issue in this opinion.

The parties dispute whether claims 1-4 of the '659 Patent (collectively, “the asserted claims”) are invalid for obviousness, lack of written description, non-enablement, and indefmiteness. On September 12, 2022,1 held a three-day bench trial.^[1] (D.I. 595-597).^[2]

I have considered the parties' post-trial submissions (D.I 599, 600, 618, 619, 620). Having considered the documentary evidence and testimony, I make the following findings of fact and conclusions of law pursuant to Federal Rule of Civil Procedure 52(a).

I. BACKGROUND

Novartis is the holder of New Drug Application (“NDA”) No. 207620 for Entresto®, a tablet containing the active ingredients sacubitril^[3] and valsartan.^[4] (D.I. 521-1, Ex. 1 at 5-6). The FDA has approved Entresto® “to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction,” “for treatment of symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients aged one year and older,” and “to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure.” (Id.).

The '659 Patent is listed in the FDA's Orange Book for Entresto®. (Id. at 11). The '659 Patent's undisputed priority date is January 17, 2002. (Id. at 11). The patent generally relates to compositions of valsartan and sacubitril and the use of such compositions to treat hypertension and heart failure. Defendants submitted Abbreviated New Drug Application (“ANDAs”) for approval to market generic versions of Entresto®. (Id. at 7-11). Plaintiff initiated this lawsuit, asserting infringement of claims 1-4 of the '659 Patent (“the asserted claims”) against all Defendants. (Id. at 2, 11). Defendants stipulated to infringement of the asserted claims (id. at 1718), but Defendants assert that the claims are invalid.

II. ASSERTED CLAIMS

The claims at issue are claims 1-4 of the '659 Patent (“the asserted claims”). (D.I. 521-1, Ex. 1 at 11).

Claim 1 reads:

1. A pharmaceutical composition comprising:

(i) the AT 1-antagonist valsartan or a pharmaceutically acceptable salt thereof;

(ii) the NEP inhibitor N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoic acid ethyl ester or (2R,4S)-5-biphenyl-4-yl-4(3-carboxy-propionyl amino)-2-methyl-pentanoic acid or a pharmaceutically acceptable salt thereof; and

(iii) a pharmaceutically acceptable carrier;

wherein said (i) AT 1-antagonist valsartan or pharmaceutically acceptable salt thereof and said (ii) NEP inhibitor N-(3-carboxy- 1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoic acid ethyl ester or (2R,4S)- 5-biphenyl-4-yl-4(3-carboxy-propionyl amino)-2-methyl-pentanoic acid or pharmaceutically acceptable salt thereof, are administered in combination in about a 1:1 ratio.

(Id. at 11-12).

Claim 2 depends from claim 1 and reads:

2. The pharmaceutical composition of claim 1, wherein said (i) AT 1 -antagonist valsartan or a pharmaceutically acceptable salt thereof and said (ii) NEP inhibitor N-(3-carboxy-1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoic acid ethyl ester or (2R,4S)-5-biphenyl-4-yl-4(3-carboxy-propionyl amino)-2-methyl-pentanoic acid or pharmaceutically acceptable salt thereof are administered in amounts effective to treat hypertension or heart failure.

(Id. at 12).

Claim 3 depends from claim 1 and reads:

3. The pharmaceutical composition of claim 1 wherein (ii) said NEP inhibitor is N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoic acid ethyl ester.

(Id.).

Claim 4 depends from claim 3 and reads:

4. The pharmaceutical composition of claim 3 in the form of a capsule or tablet.

(Id.).

III. OBVIOUSNESS

A. Legal Standard

A patent claim is invalid as obvious under 35 U.S.C. § 103 “if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.” 35 U.S.C. § 103; see also KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 406-07 (2007). “As patents are presumed valid, a defendant bears the burden of proving invalidity by clear and convincing evidence.” Shire, LLC v. Amneal Pharms., LLC, 802 F.3d 1301,1306 (Fed. Cir. 2015) (citations omitted). “Under § 103, the scope and content of the prior art are to be determined; differences between the prior art and the claims at issue are to be ascertained; and the level of ordinary skill in the pertinent art resolved. Against this background, the obviousness or nonobviousness of the subject matter is determined.” KSR, 550 U.S. at 406 (internal citation and quotation marks omitted).

A court is required to consider secondary considerations, or objective indicia of nonobviousness, before reaching an obviousness determination, as a “check against hindsight bias.” See In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litig., 676 F.3d 1063, 1078-79 (Fed. Cir. 2012). “Such secondary considerations as commercial success, long felt but unsolved needs, failure of others, etc., might be utilized to give light to the circumstances surrounding the origin of the subject matter sought to be patented.” Graham v. John Deere Co. of Kansas City, 383 U.S. 1,17-18 (1966).

B. Findings of Fact

1. Level of Ordinary Skill in the Art

The parties dispute whether a person of ordinary skill in the art (“POSA”) would have knowledge and experience in solid-state chemistry. (See D.I. 599 at 5; D.I. 600 at 2-3; D.I. 618 at 35-38; D.I. 619 at 30-31; D.I. 620 at 11). The parties do not argue that the outcome of the obviousness analysis would change depending on whose position I adopt. Instead, the parties assert that their dispute is relevant to the enablement and written description analyses. (See, e.g., D.I. 619 at 30-31 (framing POSA definition as § 112 issue); D.I. 620 at 10 (same)). Accordingly, I discuss the parties' disagreement, and my conclusions, in that portion of this opinion. See infra Section IV.A.2.

Ultimately, I think that Plaintiffs definition of a POSA is the correct definition. I therefore conclude that a POSA with respect to the '659 Patent is “a medical doctor or Ph.D. in medicinal chemistry or a related field who is interested in developing new drugs for heart failure and hypertension, and would not have had experience, familiarity, or interest in solid-state chemistry.” (D.I. 619 at 30-31; Tr. at 47:17-23 (Dr. Fintel); Id. at 279:24-280:8 (Dr. Spinale); Id. at 399:821, 401:8-402:9 (Dr. Klibanov)).

2. Scope and Content of the Prior Art

a. Background

i. Heart Failure and Hypertension

Hypertension is “abnormally high arterial blood pressure”-a disease of the arteries. (Tr. at 281:4-10 (Dr. Spinale); JTX-133 at 308). Heart failure is a “condition in which the heart is unable to pump blood at an adequate rate or an adequate volume”-a disease of the heart muscle. (Tr. at 11-14 (Dr. Spinale); JTX-133 at 278). I agree with Plaintiff that, in 2002, a POSA understood these disease states to be distinct from each other. (D.I. 619 at 2; Tr. at 282:4-10 (Dr. Spinale)). Hypertension and heart failure were studied using different research methodologies (Tr. at 282:21-283:9 (Dr. Spinale)); entailed different goals and guidelines with respect to treatment (Id. at 284:6-10 (Dr. Spinale)); and were sometimes treated using drugs that ameliorate one condition, but not the other. (Id. at 283:22-284:5 (Dr. Spinale)).

I also agree with Defendants, however, that a POSA would also have understood that these disease states are related to each other in significant ways. (See D.I. 600 at 15). Hypertension is the most common clinical condition closely associated with and leading to heart failure. (Tr. at 50:19-51:8 (Dr. Fintel); JTX-211 at 1557). Over the decades prior to the...