Case 3:17-cv-05319-FLW-DEA Document 243 Filed 03/22/21 Page 1 of 63 PageID: 12125
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`*NOT FOR PUBLICATION*
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`UNITED STATES DISTRICT COURT
`DISTRICT OF NEW JERSEY
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`MITSUBISHI TANABE PHARMA
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`CORPORATION, JANSSEN
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`PHARMACEUTICALS, INC., JANSSEN
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`PHARAMCEUTICA NV, JANSSEN
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`: Civil Action No. 17-5319 (FLW) (DEA)
`RESEARCH AND DEVELOPMENT, LLC,
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`and CILAG GMBH INTERNATIONAL,
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`Plaintiffs,
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`v.
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`SANDOZ, INC., et al.,
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`Defendants.
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`WOLFSON, Chief Judge:
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` OPINION
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`This consolidated action was filed by Plaintiffs, Mitsubishi Tanabe Pharma Corp.
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`(“MTPC”), Janssen Pharmaceuticals, Inc. (“JPI”), Janssen Pharmaceutica NV (“JNV”), Janssen
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`Research and Development, LLC (“JRD”), and Cilag GmbH International (“Cilag”)1 (collectively,
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`“Plaintiffs”) against Defendant Zydus Pharmaceuticals (U.S.A.) Inc. (“Zydus” or “Defendant”) for
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`patent infringement in violation of section 271(e)(2) of Title 35 of the United States Code. In
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`response, Zydus has filed a counterclaim seeking a declaratory judgment against Plaintiffs that the
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`patents-in-suit are invalid.
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`Defendant is alleged to infringe the following claims of the corresponding United States
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`Patents held by Plaintiffs: (1) claims 12 and 20 of United States Patent Number 7,943,788 (“the
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`’788 Patent”); (2) claim 22 of United States Patent Number 8,222,219 (“the ’219 Patent”); and (3)
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`1
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`The Court refers to JPI, JNV, JRD, and Cilag, collectively, as “Janssen.”
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`claim 26 of United States Patent Number 8,785,403 (“the ’403 Patent”) (collectively, the “asserted
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`claims”).2 The patents-in-suit relate to the pharmaceutical composition and method of treatment
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`encompassed by the drugs “Invokana” and “Invokamet” (together “the Invokana Products”),
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`which are used to treat type 2 diabetes. Plaintiffs’ infringement claims are based on Zydus’s filing
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`of Abbreviated New Drug Applications (“ANDA”) with the Food and Drug Administration
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`(“FDA”) seeking approval to commercially manufacture and market generic versions of the
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`Invokana Products prior to the expiration of the patents-in-suit.3 Zydus has stipulated that its
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`submission of the ANDAs and any commercial manufacture, use, offer for sale, sale, or
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`importation of the ANDA products before expiration of the patents-in-suit would infringe the
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`asserted claims. As its defense, Zydus contends that (1) the asserted claims of patents-in-suit are
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`invalid as obvious; and (2) claims 12 and 20 of the ’788 Patent are invalid under the doctrine of
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`obviousness-type double patenting.
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`The Court conducted a six-day bench trial,4 during which numerous experts testified as to
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`the issues of obviousness and obviousness-type double patenting. In accordance with Federal Rule
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`of Civil Procedure 52(a), the Court sets forth herein its findings of facts and conclusions of law.
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`After consideration of all the evidence, the Court finds that the patents-in-suit are not invalid as
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`obvious and that claims 12 and 20 of the ’788 Patent are not invalid under the doctrine of
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`2
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`The Court refers to the ’788, ’219, and ’403 Patents, collectively, as the “patents-in-suit.”
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` 3
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`Zydus has agreed not to launch the products within the scope of the ANDAs at issue, i.e.,
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`the generic equivalents of Invokana and Invokamet, until four months after the parties submitted
`their Proposed Findings of Fact and Conclusions of Law. (ECF No. 206.) The parties submitted
`their Proposed Findings of Fact and Conclusions of Law on November 23, 2020. (See Zydus
`Proposed Findings of Fact and Conclusions of Law (“DFOF”), ECF No. 221; Plaintiffs’ Proposed
`Findings of Fact and Conclusions of Law (“PFOF”), ECF No. 220.)
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`In light of the ongoing COVID-19 pandemic, the bench trial was held remotely via Zoom.
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`2
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`obviousness-type double patenting. Based on Zydus’s concession, the Court further concludes
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`that the filed ANDAs infringe upon the patents-in-suit.
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`I. OVERVIEW
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`A. Parties
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`MTPC is the lawful assignee of the patents-in-suit. (Pretrial Order, Stipulation of Facts
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`(“SOF”) ¶ 1, ECF No. 144.) JPI, JRD, and Cilag are the exclusive licensees of the patents-in-suit,
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`and JNV is an exclusive sublicensee of the patents-in-suit. (Id. ¶ 8.) JPI holds approved New
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`Drug Application (“NDA”) No. 204042 for canagliflozin tablets, which are prescribed and sold as
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`Invokana, and approved NDA No. 204353 for canagliflozin and metformin hydrochloride tablets,
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`which are prescribed and sold as Invokamet. (Id. ¶ 9.) Canagliflozin is in a class of compounds
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`known as SGLT-2 inhibitors which are used in the treatment of type 2 diabetes.
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`Zydus is a manufacturer and distributor of generic drugs. Zydus filed ANDA Nos. 210541
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`and 210542 with the FDA, seeking approval to commercially manufacture and market generic
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`versions of the Invokana Products prior to the expiration of the patents-in-suit. (Id. ¶ 14.)
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`B. The Patents-in-Suit
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`1. The ’788 Patent
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`The ’788 Patent was issued by the United States Patent and Trademark Office (“USPTO”)
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`on May 17, 2011, and is entitled “Glucopyranoside Compound.” (Id. ¶ 22; DTX-001.) The ’788
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`Patent lists Sumihiro Nomura, Eiji Kawanishi, and Kiichiro Ueta as the named inventors. (SOF ¶
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`23.) The ’788 Patent was issued in connection with U.S. Patent Application No. 11/045,446 (the
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`“’446 application”), which was filed on January 31, 2005, and was a continuation of International
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`Application No. PCT/JP2004/011312, which was filed on July 30, 2004. (Id. ¶¶ 24–25.) Asserted
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`claims 12 and 20 of the ’788 Patent are directed to the compound now known as canagliflozin.
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`(Id. ¶¶ 26–27.) Specifically, claim 12 recites “1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluoro-
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`phenyl)-2-thienylmethyl]benzene,” which is the chemical name for canagliflozin. (Id. ¶ 26.)
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`Claim 20 of the ’788 Patent recites “[a] compound having the following structure,” and depicts the
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`chemical structure of canagliflozin:
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`(DTX-001, at 224:40-55.)
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`2. The ’219 Patent
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`The ’219 Patent was issued by the USPTO on July 17, 2012, and is titled “Glucopyranoside
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`Compound.” (SOF ¶ 28; DTX-002.) Like the ’788 Patent, the listed inventors of the ’219 Patent
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`are Drs. Nomura, Kawanishi, and Ueta. (Id. ¶ 29.) The ’219 Patent was issued in connection with
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`U.S. Patent Application No. 13/174,814 (“the ’814 application”), which was filed on July 1, 2011.
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`(Id. ¶ 30.) The ’814 application was filed as a division of U.S. Patent Application No. 13/005,757
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`(“the ’757 application”), which was filed on January 13, 2011. (Id. ¶ 31.) The ’757 application
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`was filed as a division of the ’446 application, which was issued as the ’788 Patent. (Id.) Asserted
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`claim 22 of the ’219 Patent is directed to a method of treating or delaying the progression or onset
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`of type 2 diabetes with the compound of the following structure, which is now known as
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`canagliflozin:
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`(SOF ¶ 32; DTX-002, at 220:43-46.)
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`3. The ’403 Patent
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`The ’403 patent is titled “Glucopyranoside Compound” and was issued by the USPTO on
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`July 22, 2014. (SF ¶ 33; DTX-003.) The ’403 Patent lists Drs. Nomura, Kawanishi, and Ueta as
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`the inventors. (SF ¶ 34.) The ’403 Patent was issued in connection with U.S. Patent Application
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`No. 13/494,602 (the “’602 application”), which was filed on June 12, 2012. (Id. ¶ 35.) The ’602
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`application was a continuation of the ’814 application. (Id. ¶ 36.) Asserted claim 26 of the ’403
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`Patent is directed to a pharmaceutical composition comprising a biguanide compound and the
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`compound of the following structure, which is now known as canagliflozin:
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`(SOF ¶ 37; DTX-003, at 221:25–26.)
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`C. The Invokana Products
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`Invokana, with canagliflozin as its active ingredient, was approved for use by the FDA in
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`March 2013. (PTX-1086.) It was the first SGLT5 inhibitor to be approved in the United States.6
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`(Williams Tr., at 1055:23–25.)7 Invokamet was approved for use by the FDA in August 2014, and
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`combines canagliflozin with metformin. (Brennan Dep. Tr., at 71:2–3; PTX-1085.) The Invokana
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`Products act by inhibiting SGLT2 in the kidneys and suppressing glucose reabsorption. (See
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`Bannister Demonstrative, at 7.) This leads to glucose being excreted in the urine in greater
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`amounts, reducing blood glucose levels. (PTX-1086, at 7.) The Invokana Products also have the
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`ability to inhibit SGLT1 and reduce the uptake of glucose from the gut. (Gavin Tr., at 757:–21.)
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`Clinical data has demonstrated that Invokana significantly reduces A1C, fasting plasma
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`glucose levels, body weight, and systolic blood pressure in diabetic patients and that it is generally
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`well tolerated. (Id. at 746:3–23; PTX-1086, at 9–14.) The Invokana Products are currently
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`indicated: (1) as an adjunct to diet and exercise to improve glycemic control in adults with type 2
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`diabetes; (2) to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes
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`mellitus and established cardiovascular disease; and (3) to reduce the risk of end-stage kidney
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`disease, doubling of serum creatinine, cardiovascular death, and hospitalization for heart failure in
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`adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria. (Gavin Tr., at
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`5
`SGLT refers to a sodium glucose transporter. (Bannister Tr., at 112:19–22.) SGLTs are
`present in the kidneys, which filter blood for the human body. (Id. at 112:23–24.) Waste filtered
`by the kidneys is generally shunted to the bladder and excreted in urine. (Id. at 112:25–113:3.)
`However, SGLTs reabsorb—or transport—glucose initially filtered by the kidney back into the
`blood. (Id. at 113:8–25.) There are two types of SGLTs—SGLT1 and SGLT2. SGLT2s are only
`present in the kidneys, while SGLT1s are responsible for shunting glucose in other parts of the
`body, including the gut and heart. (Id. at 114:17–22.)
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` 6
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`The FDA has since approved three additional SGLT inhibitors for use. In 2014, the FDA
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`approved both dapagliflozin, marketed as Farxiga, and empagliflozin, marketed as Jardiance.
`(Williams Tr., at 1056:6–14.) In 2017, the FDA approved ertugliflozin. (Id. at 1056:14–16.)
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` 7
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`For ease of reference, the Court refers to the trial transcripts by the name of the expert
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`testifying during that portion of the transcript.
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`743:10–19; PTX-1086, at 1; PTX-1085, at 1.)
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`D. Procedural History
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`On July 20, 2017, Plaintiffs filed the instant patent infringement action against Zydus
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`arising from Zydus’s filing of ANDA Nos. 210541 and 210542.8 (SOF ¶ 14; ECF No. 1.) Zydus
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`has stipulated that its submission of ANDA Nos. 210541 and 210542 to the FDA and any
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`commercial manufacture, use, offer for sale, sale, or importation of Zydus’s ANDA Products
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`before the expiration of the patents-in-suit would infringe on the asserted claims, to the extent they
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`are not found invalid. (SOF ¶ 17; ECF No. 100, at 2–3.) Rather, Zydus maintains that the patents-
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`in-suit are invalid as obvious. As such, the sole issues presented at trial were (1) whether the
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`patents-in-suit are invalid as obvious and (2) whether claims 12 and 20 of the ’788 Patent are
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`invalid for obviousness-type double patenting.
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`The Court held a six-day bench trial on September 24, 25, and 30; October 1 and 2; and
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`November 5, 2020. At trial, Defendant presented four expert witnesses: Thomas T. Bannister,
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`Ph.D.; DeForest McDuff, Ph.D.; Jonathan S. Williams, M.D., M.M.Sc.; and James T. Carmichael,
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`Esq. Dr. Bannister was accepted without objection as an expert in molecular medicine and
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`chemistry, drug discovery, and medicinal chemistry. (Bannister Tr., at 106:9–12, 107:18–22.) Dr.
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`McDuff was accepted without objection as an expert in economics and commercial success.
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`(McDuff Tr., at 406:1–3.) Dr. Williams was accepted without objection as an expert in the field
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`8
`This consolidated matter initially included as defendants Sandoz, Inc. (“Sandoz”), InvaGen
`Pharmaceuticals, Inc. (“InvaGen”), Aurobindo Pharma USA Inc. (“Aurobindo”), and Prinston
`Pharmaceutical Inc. (“Prinston”). The Court entered Consent Judgments of infringement with
`permanent injunctions lasting through patent expiration with respect to InvaGen, Prinston, and
`Aurobindo. (See ECF Nos. 99, 102, 172.) Sandoz was dismissed from this matter pursuant to a
`stipulation between Plaintiffs and Sandoz after Sandoz abandoned its last-remaining defense. (See
`ECF No. 129.) Sandoz, however, continues to challenge other patents covering the Invokana
`Products in a separate matter also proceeding in this District.
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`of clinical management and development of type 2 diabetes. (Williams Tr., at 1036:21–1037:24.)
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`Mr. Carmichael was accepted as an expert in USPTO procedure. (Carmichael Tr., at 1274:19–
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`1280:21.)
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`Plaintiff also presented four expert witnesses: Stephen G. Davies, Ph.D.; Raymond Sims;
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`James R. Gavin III, M.D.; and Robert Stoll, Esq. Dr. Davies was accepted as an expert in
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`medicinal chemistry. (Davies Tr., at 502:22–503:14.) Mr. Sims was accepted as an expert in
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`intellectual property research and analysis regarding whether a patented product is a commercial
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`success. (Sims Tr., at 935:14–23.) Dr. Gavin was accepted as an expert in the field of clinical
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`management and development of type 2 diabetes treatment. (Gavin Tr., at 728:16–729:15.) Mr.
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`Stoll was accepted as an expert in USPTO procedures, practices, and policy. (Stoll Tr., at 1194:21–
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`1196:1.) Plaintiffs also presented testimony from Dr. Kawanishi, who is identified as the inventor
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`of canagliflozin. (Kawanishi Tr., at 893:17–25.)
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`During trial, the Court denied Plaintiffs’ motion for judgment as a matter of law pursuant
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`to Federal Rule of Civil Procedure 52(c). (Trial Tr., at 432:2–3.) Limited closing arguments were
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`presented on December 22, 2020.
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`II. OBVIOUSNESS
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`A. Findings of Fact
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`Because the question of obviousness is a factual question that is guided by legal principles,
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`I make certain factual findings before setting forth my conclusions of law, infra. As such, this
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`section contains the relevant factual background necessary for the Court to conduct its obviousness
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`analysis. To the extent any finding of fact below is a conclusion of law, it is also adopted as a
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`conclusion of law.
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`1. Medicinal Chemistry & Drug Discovery
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`Medicinal chemistry is a multidisciplinary approach which uses molecular biology,
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`biochemistry, pharmacology, medicine, analytical chemistry, and organic chemistry to identify
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`organic compounds that may treat diseases in humans. (Davies Tr., at 502:3–10.) In other words,
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`the study of medicinal chemistry seeks “to understand how drug substances work.” (Bannister Tr.,
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`at 112:9–11.) In that connection, the drug discovery process “is a data-driven, iterative process,”
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`that typically involves: (1) analyzing biological targets and known compounds in the prior art for
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`a particular disease area; (2) selecting lead compounds for improvement based on known data; (3)
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`identifying assays that can verify whether the compounds being developed have the desired effect;
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`(4) identifying one portion of each selected compound to modify; (5) synthesizing, testing, and
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`analyzing each modification to the selected lead compounds; (6) identifying a potentially
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`promising compound for further biological development based on the testing results; (7)
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`conducting further studies on that promising compound; and (8) advancing that compound to
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`clinical development, if appropriate. (Davies Tr., at 511:4–514:9.)
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`The second step of that process, the selection of a lead compound, involves a discrete
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`number of biological targets and their corresponding compounds because of limited time and
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`resources. (Id. at 512:4–7, 650:15–24.) Once a lead compound is selected, the medicinal chemist
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`investigates the effect of various structural modifications upon biological activity, usually through
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`a lengthy, iterative, and labor-intensive program with the goal of finding an improved candidate
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`molecule for further evaluation. (Id. at 512:4–513:18; Bannister Tr., at 313:21–315:8 (agreeing
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`that “drug compound discovery is a highly iterative process” in which a medicinal chemist would
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`“try [to] improve [a] starting compound”).) The drug development process is “lengthy” because,
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`inter alia, it is necessary to make modifications to one portion of the compound at a time to
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`determine if the change was helpful, harmful, or neutral. (Davies Tr., at 512:4–10, 514:14–21;
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`Bannister Tr., at 314:23–315:18 (agreeing that “the goal of a medicinal chemist would be to try
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`[to] improve [a] starting compound” by changing “one area of the molecule at a time”).)
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`Bioisosterism, a relevant principle of medicinal chemistry, is the observation that, in certain
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`cases, “one group of atoms take[s] the place of another group of atoms in a biologically active
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`molecule [resulting in] roughly the same biological activity.” (Bannister Tr., at 181:3–10; Davies
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`Tr., at 655:19–25 (explaining that bioisosterism is a concept that permits you to “swap groups
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`around in order to keep biological activity and change the other properties”).) In other words,
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`bioisosterism is the “idea that one substructure can be swapped out for another.” (Bannister Tr.,
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`at 181:12–14.) The “two different collections of atoms [that can be swapped] are called
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`bioisosteres.” (Id. at 181:11–12.)
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`2. Type 2 Diabetes and its Treatment History
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`Diabetes mellitus, commonly referred to as “diabetes,” is “a very complex and progressive
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`metabolic disease.” (Gavin Tr.,731:10.) There are four types of diabetes, the most common of
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`which is type 2 diabetes. (Id. 731:11–12.) Type 2 diabetes is characterized by a state of insulin
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`insensitivity and resistance. (Williams Tr., at 1040:25–1041:9.) While a person with type 2
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`diabetes may be able to produce a reduced amount of insulin, he or she will, over time, experience
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`resistance to insulin’s blood sugar-lowering action and/or inadequate functioning of β cells.9
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`Doctors diagnose type 2 diabetes through a variety of tests, including measuring blood
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`sugar under certain conditions, such as fasting, or monitoring glycemic control “A1C” test. (Gavin
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`Tr., at 732:17–25; Williams Tr., at 1044:9–13.) A1C is a measurement of the average blood
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`glucose level in a patient over the previous few months. (Gavin Tr., at 732:12–736:3.)
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`β cells are responsible for the production and release of insulin. (Gavin Tr., at 731:10–17.)
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`Once diagnosed, type 2 diabetes is generally treated in a stepwise manner. (Gavin Tr., at
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`736:9–19.) Typically, the initial recommendation is to incorporate diet and exercise into the
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`patient’s daily lifestyle. (Id.) Then, if necessary, a drug would be administered to control the
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`patient’s glucose levels. (Id.) A healthcare provider would introduce one drug at a time, beginning
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`with metformin and then including additional agents, as necessary. (See id. at 736:9–737:16.) In
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`the 2003 time-period, the most commonly used type 2 diabetes drugs included biguanides,
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`sulfonylureas, α-glucosidase inhibitors, thiazolidinediones (“TZDs”), and meglitinides. (PTX-
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`176, at 48–51.) However, the FDA-approved compounds in these classes of drugs each had certain
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`shortcomings, including administration difficulties, weight gain, hypoglycemia, gastrointestinal
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`side effects, negative psychological impact, and/or efficacy issues. (See id.) Accordingly, in 2003,
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`additional tools were required to adequately manage type 2 diabetes and its complications. (See
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`id.)
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`3. The POSA and the Problem to be Solved
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`The parties agree that the person of ordinary skill in the art (the “POSA”) in this case would
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`have had a graduate degree in medicinal chemistry, pharmacology, and/or a related field, with
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`experience in the development of pharmaceutical compositions and an awareness of the
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`antidiabetic drug field. (Bannister Tr., at 163:11–22; Davies Tr., at 516:17–21.) Additionally, a
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`POSA would have had a “relatively low” level of creativity and would have had access to
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`individuals having skills in chemistry and pharmacology, and would collaborate with them, as
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`necessary. (See Bannister Tr., at 101:2224, 334:16–335:18; Davies Tr., at 502:510.)
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`Dr. Bannister and Dr. Davies further agreed that a POSA in this case would be “looking to
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`positively alter the options for treating diabetes.” (See Bannister Tr., at 280:11–14; Davies Tr., at
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`518:1–4 (explaining that the problem facing a POSA was “[t]o find an improved treatment, a better
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`drug, for the treatment of type 2 diabetes).)
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`4. Prior Art References
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`For the purpose of determining whether the patents-in-suit are obvious, the Court finds that
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`the date of invention of the patents-in-suit occurred no later than October 29, 2003. (Kawanishi
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`Tr., at 861:16–23.) October 29, 2003 is, therefore, the relevant date for determining the scope of
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`prior art under 35 U.S.C. §§ 102(a), (e).10 July 30, 2004, the earliest effective filing date for the
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`patents-in-suit, is the relevant date for determining the scope of prior art under § 102(b).11 In other
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`words, references filed prior to July 30, 2003 may be considered prior art. See §§ 102(a), (b), (e).
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`In this section, the Court discusses the key prior art references in this matter.
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`a) T-1095
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`In the 1990s, Tanabe Seiyaku (“Tanabe”), MTPC’s predecessor, developed an analog of
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`10
`Because the patents-in-suit stem from patent applications that were filed before March 16,
`2013, i.e., before the passage of the Leahy-Smith America Invents Act (“AIA”), the Court refers
`to the pre-AIA version of 35 U.S.C. § 102. Pre-AIA section 102(a) provided that “[a] person shall
`be entitled to a patent unless the invention was known or used by others in this country, or patented
`or described in a printed publication in this or a foreign country, before the invention thereof by
`the applicant for patent.” 35 U.S.C. § 102(a) (2002). Pre-AIA section 102(e) provided that a
`person was not entitled to a patent if “the invention was described in (1) an application for a patent
`. . . by another filed in the United States before the invention by the applicant for a patent or (2) a
`patent granted on an application by another filed in the United States before the invention by the
`applicant for patent.” Id. § 102(e).
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`11
`Pre-AIA section 102(b) provided that a person was not entitled to a patent if “the invention
`was patented or described in a printed publication in this or a foreign country or in a public use or
`on sale in this country, more than one year prior to the date of the application for patent in the
`United States.” 35 U.S.C. § 102(b) (2002).
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`12
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`Case 3:17-cv-05319-FLW-DEA Document 243 Filed 03/22/21 Page 13 of 63 PageID: 12137
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`phlorizin,12 known as T-1095, a potential anti-diabetic agent.13 (Bannister Tr., at 125:23–26.) T-
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`1095 is an O-glucoside, meaning that glucose is “attached through an oxygen atom to the rest of
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`the molecule.” (Id. at 126:3–18; see also Bannister Demonstrative, at 16.) According to Dr.
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`Bannister, T-1095 was a “much improved phlorizin analog” because it remained metabolically
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`stable. (See Bannister Tr., at 130:5–131:5.) As T-1095 was shown to be absorbed through the
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`stomach, it could be given to animals orally. (Id. at 131:15–17.) Accordingly, “it actually became
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`a clinical compound to be tested in humans and potentially be developed as a drug.” (Id. at 131:17–
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`19.)
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`Dr. Davies specifically observed that the T-1095 references highlighted two compounds:
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`T-1095 and T-1095A. (Davies Tr., at 538:19–22.) Dr. Davies explained that:
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`T-1095 is a prodrug for T-1095A. A prodrug is a derivative of a
`drug that is converted in the body to the drug itself. So where you
`have a compound that has good biological pharmaceutical activity
`but doesn’t have, for example, good absorption profile, you can
`form what is called a prodrug. You can attach, temporarily, a group
`to that drug molecule that improves the, in this case, the absorption.
`But the body is able to, using its enzymes, take off that extra unit
`you put on, that temporary group you put on, to release the drug
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`
`12
`Phlorizin is a natural compound that was shown to lower blood glucose in the 1930s. (See
`Bannister Tr., at 115:23–116:3.) Phlorizin, however, had certain limitations for use as an
`antidiabetic agent. (Id. at 118:14–17.) Notably, it needed to be injected into the blood, rather than
`be orally ingested, to have biological effect, and it was known to be metabolically unstable. (Id.
`at 118:14–120:15.)
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`13
`Tanabe’s findings with respect to T-1095 are set forth in several publications, including
`Akira Oku, et al., Antidiabetic effect of T-1095, an inhibitor of Na+-glucose cotransporter in
`neonatally streptozotocin-treated rats, 391 Eur. J. Pharmacol. 183 (2000); Akira Oku, et al., T-
`1095, an Inhibitor of Renal Na+-Glucose Cotransporters, May Provide a Novel Approach to
`Treating Diabetes, 48 Diabetes 1794 (1999); Kenji Tsujihara, et al., Na+-Glucose Cotransporter
`(SGLT) Inhibitors as Antidiabetic Agents. 4. Synthesis and Pharmacological Properties of 4’-
`Dehydroxyphlorizin Derivatives Substituted on the B Ring, 42 J. Med. Chem. 5311 (1999); and
`Kenji Tsujihara et al., Na+-Glucose Cotransporter Inhibitors as Antidiabetics. I. Synthesis and
`Pharmacological Properties of 4’Dehydroxyphlorizin Derivatives Based on a New Concept, 44
`Chem. Pharm. Bull. 1174 (1996). The Court refers to these publications, collectively, as the “T-
`1095 references.”
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`13
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`Case 3:17-cv-05319-FLW-DEA Document 243 Filed 03/22/21 Page 14 of 63 PageID: 12138
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`inside the body.
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`So in this case it shows the prodrug and the actual compound
`through oral administration. . . . It shows that they both induce
`urinary glucose excretion, and the prodrug increases it over the
`parent drug. So 1095 is better than 1095A, but the actual active
`species is the same.
`
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`(Id. at 538:22–539:12.) Tanabe, therefore, selected T-1095, the prodrug, “as a promising
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`[candidate] for the treatment of diabetes.” (Id. at 539:19–20; PTX-122, at 5314.) Indeed, as Dr.
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`Davies observed, “[Tanabe] scientists had demonstrated that . . . long term treatment with T-1095
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`restored deterioration of diabetic states.” (Id. at 633:2–6.) Further, “T-1095A had been selected
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`for further evaluation and as a potential anti-diabetic agent and was expected to be used as therapy
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`for patients with type 2 diabetes.” (Id. at 636:3–12.)
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`b) Link
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`The Link reference14 was published in 2000 and explored whether phlorizin can be made
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`more stable by transforming it from an O-glucoside, a glucose with an oxygen linker, to a C-
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`glucoside, a glucose with a carbon linker. (See Bannister Tr., at 132:9–133:8.) Link found,
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`however, the C-glucosides were weaker than O-glucosides in terms of efficacy. (Davies Tr., at
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`545:14–16; see also Bannister Tr., at 133:21–134:1.) Accordingly, the Link authors concluded
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`that the O-glucoside linkage was important to SGLT-inhibition activity. (Davies Tr., at 545:3–
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`12.)
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`While the parties agree that the Link reference demonstrates that O-glucosides were more
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`effective compounds, there is some disagreement as to whether Link demonstrates that C-
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`glucosides are more metabolically stable than O-glucosides. Dr. Bannister testified that Link
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`14
`Link & Sorensen, A method for preparing C-glycosides related to phlorizin, 41
`Tetrahedron Letts 9213 (2000).
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`14
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`Case 3:17-cv-05319-FLW-DEA Document 243 Filed 03/22/21 Page 15 of 63 PageID: 12139
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`demonstrated that C-glucosides were more stable because replacing an oxygen bond with a carbon
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`bond, generally, makes the molecule more stable. (Bannister Tr., Vol. 1., at 133:12–20.) However,
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`Dr. Bannister admitted that Link only “made what [are] presumably stable compounds” and that
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`Link “doesn’t describe the stability.” (Id. at 136:16–18.) In that regard, Dr. Davies explained that
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`“[t]here are many instances where replacing a CO bond with a CC bond will improve stability . . .
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`it’s not a given. It depends on what carbon bond you’ve made and where – where in the body
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`you’re putting the drug.” (Davies Tr., at 662:14–17.) As such, the Court finds that the Link
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`reference demonstrates only that O-glucosides were more effective at inhibiting SGLT activity.
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`The Link reference would not, however, have taught a POSA that C-glucosides are more stable
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`than O-glucosides as Link made no specific findings with respect to stability.
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`c) US ’674
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`In 2001, U.S. Patent Application Publication No. 2001/0041674 (“US ’674”) disclosed that
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`C-glucosides are metabolically stable and could have “potent anti-diabetic activities.” (DTX-172,
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`at 1 ¶ 14.) US ’674 recognized that O-glucosides are subject to glucosidases when administered
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`orally. (Id. at 1 ¶ 8.) Thus, US ’674 posited that C-glucosides could “overcome the stability
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`against glycosidases” and further observed that “it is not reported that C-glycosides [have] strong
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`SGLT [inhibition], so far.” (Id. at 1 ¶ 10.)
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`US ’674 confirmed the findings of Link—that replacing the oxygen with a carbon atom
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`does not produce a potent compound. (See Bannister Tr., at 141:22–142:3.) The compound
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`disclosed in US ’674 instead omitted a “spacer” in the carbon bond between the glucose and the
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`A ring for a direct carbon-to-carbon bond, which permitted the compound to remain “biologically
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`active.” (Id. at 141:22–142:23.) The potency of the compounds disclosed in US ’674 was
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`supported with biological data showing an increase in “the amount of glucose that was going out
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`in the urine which necessarily means it decreases the amount of glucose in the blood.” (Id. at
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`138:21–139:4.) However, as Dr. Davies highlighted, the biological activity reported in US ’674
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`was based only on administration by intraperitoneal injection, not oral administration. (Davies
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`Tr., at 669:1–670:80.)
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`d) The BMS Patents
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`i. The ’126 Patent
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`On July 2, 2002, US Patent No. 6,414,126 (“the ’126 Patent”) was issued to Ellsworth, et
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`al., and assigned to the Bristol Myers Squibb Company (“BMS”). (DTX-084.) The ’126 Patent
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`describes a family of C-glucoside compounds, which maintained the direct carbon link set forth in
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`US ’674, but modified the B and C rings of the molecule to attempt to formulate C-glucosides with
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`greater potency. (See Bannister Tr., at 144:4–19.) Specifically, the ’126 Patent states that “[t]he
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`present invention relates to C-aryl glucosides which are inhibitors of sodium dependent glucose
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`transporters found in the intestine and kidney (SGLT2) and to a method for treating diabetes,
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`especially type II diabetes.” (DTX-084 at 1.) The ’126 Patent disclosed approximately 80
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`examples of C-glucosides and made “some broad claims about what different variables can be on
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`different rings.” (Bannister Tr., Vol.1, at 144:20–145:4.) The ’126 Patent further provides a
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`detailed description of a cell-based SGLT-2 inhibition assay. (DTX-084, at 35–36