UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF NEW JERSEY
`
`BOEHRINGER INGELHEIM
`PHARMACEUTICALS INC., BOEHRINGER
`INGELHEIM INTERNATIONAL GMBH,
`BOEHRINGER INGELHEIM CORPORATION,
`and BOEHRINGER INGELHEIM PHARMA
`GMBH & CO. KG,
`
`Plaintiffs,
`
`v.
`
`HEC PHARM CO., LTD., HEC PHARM USA,
`MYLAN PHARMACEUTICALS INC., MYLAN
`INC., MYLAN LABO RA TORIES LIMITED,
`ACCORD HEALTHCARE, INC., AUROBINDO
`PHARMA LIMITED, AUROBINDO PHARMA
`USA, INC., DR. REDDY'S LABORATORIES, ·
`LTD., DR. REDDY'S LABORATORIES, INC.,
`ZYDUS PHARMACEUTICALS USA, INC.,
`CADILA HEALTHCARE LTD., MSN
`LABORATORIES PRIVATE LIMITED, MSN
`PHARMACEUTICALS, INC., PRINSTON
`PHARMACEUTICAL INC., INV AGEN
`PHARMACEUTICALS INC., SUN
`_
`PHARMACEUTICAL INDUSTRIES LTD., SUN
`PHARMA GLOBAL FZE, and TEVA
`PHARMACEUTICALS USA, INC.,
`
`Defendants.
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`Civil Action No:
`15-cv-5982 (PGS)(TJB)
`
`MEMORANDUM
`
`RECEIVED
`
`OCT 2 5 2018
`
`AT 8:30--.~~M
`WILLIAM T. WALSH
`CLERK
`
`SHERIDAN, U.S.D.J.
`
`This is a consolidated a patent infringement action brought by Boehringer Ingelheim
`
`Pharmaceuticals Inc., Boehringer Ingelheim International GmbH, Boehringer Ingelheim
`
`Corporation, and Boehringer lngelheim Pharma GmbH & Co. KG (collectively, "Boehringer" or
`
`"Plaintiffs") against Mylan Pharmaceuticals Inc., Mylan Inc., and Mylan Laboratories Limited
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`("Mylan") and Aurobindo Pharma Limited and Aurobindo Phanna USA, Inc. ("Aurobindo) (all
`
`defendants collectively, "Defendants") 1 for filing an Abbreviated New Drug Application
`
`("ANDA") with the Food & Drug Administration ("FDA"), pursuant to 21 U.S.C. § 355(b)(2)
`
`(Hatch-Waxman Act), for approval to engage in the commercial manufacture, use or sale of a
`
`generic version of Tradjenta® and Jentadueto®. See 35 U.S.C. § 271 (Patent Act).
`
`Tradjenta® (linagliptin) and Jentadueto® (linagliptin + metformin) are used to manage
`
`type 2 diabetes. Boehringer listed several patents for both Tradjenta® and Jentadueto® in the
`
`Orange Book. These included U.S. Patent Nos. 8,178,541 ("'541 patent"), 8,673,927 ("'927
`
`patent) and 9,173,859 ("'859 patent"). These patents "generally describe methods to treat diabetes
`
`that involve the use of a compound known as linagliptin, alone or in combination with various
`
`other antidiabetic treatments [such as metformin]." (Tr. 480:20-24 (Accili)). While Aurobindo
`
`applied for an ANDA only with regards to Tradjenta®, Mylan applied for approval for both
`
`Tradjenta® and Jentadueto®. Defendants seek to start production of the generic products
`
`following expiration of Boehringer's U.S. Patent No. 7,407,955 ('955), U.S. Patent 8,119,648
`
`('648), and the '541 patent. Before the Court are claims 7, 9, 15, 17, 19, 25, and 26 of the '927
`
`patent, and claims 1, 14, 15, 20, and 21 of the '859 patent, (all collectively, the "Asserted Claims"
`
`of the patents-in-suit). Claims 14 and 15 of the '859 patent are collectively referred to herein as
`
`the "tablet claims," as they deal with the formation of the drug; and the remaining Asserted Claims
`
`are referred to as the "method claims," as they deal with the administration of the drug.
`
`Boehringer initiated this suit against Defendants alleging that Defendants' requests to
`
`market the generic version of Tradjenta® and Jentadueto® infringed upon Boehringer's rights
`
`granted under the '927 and '859 patents, because the proposed labels will induce physicians to
`
`1 Mylan and Aurobindo are the only remaining Defendants in this action.
`
`2
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`administer linagliptin in combination with metformin in a specific dosage ("Combination
`
`Therapy2").
`
`In response, Defendants argue that the asserted claims 7, 9, 15, 17, 19, 25, and 26 in the
`
`'927 patent and the asserted claims 1, 14, 15, 20, and 21 in the '859 patent are prima facie invalid
`
`for obviousness .. type double patenting, because these claims are a recitation of the claims found in
`
`the '541 patent. Defendants further argue that the asserted claims are prima facie invalid as
`
`obvious, as the asserted claims had been previously disclosed by prior art. At trial, Defendants,
`
`bearing the burden to invalidate the asserted claims of the '927a nd '859 patents, presented expert
`
`evidence to show that the asserted claims are invalid as noted above. The experts were Joshua
`
`Cohen, M.D., Domenico Accili, M.D., George M. Grass, Ph.D., David Blackbum, Ph.D., and
`
`Christian Wolf, Ph.D.
`
`In response, Boehringer defended the patents by arguing the '541 claims are patentably
`
`distinct. Further, Boehringer argues that the asserted claims are not invalid for obviousness as
`
`Defendants have failed to show that a person of ordinary skill in the art ("POSA") would have
`
`been directed to prior art, that a POSA would have been motivated to select specific dosages of
`
`linagliptin, and that a POSA would have been motivated to combine linagliptin and metformin.
`
`Additionally, Boehringer argues that secondary considerations support a non-obvious finding. In
`
`order to advance these positions, Boehringer relied on the following witnesses and experts:
`
`Michael G. Mark, Ph.D., M. James Lenhard, M.D., Y.W. Francis Lam, Ph.D., William L.
`
`Jorgensen, Ph.D., and Steven Schwartz, Ph.D.
`
`2 Dr. Accili, Defendant's expert, explained that "combination therapy is when you mix more than
`one drug for the purpose of treating diabetes." (Tr. 496:14 .. }9) (Accili)).
`
`3
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`At the end of the trial, the parties submitted proposed findings of fact and conclusions of
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`law, followed by reply papers.
`
`A. The Parties
`
`I
`
`Plaintiff Boehringer is a corporation organized and existing under the laws of the State of
`
`Delaware, having a principal place of business in Ridgefield, Connecticut. (Stip. of Facts, ECF
`
`No. 539-1at11). Plaintiff Boehringer Ingelheim International GmbH ("BIi") is a private limited
`
`liability company organized and existing under the laws of Germany, having a principal place of
`
`business in lngelheim, Germany. (Id.) Plaintiff Boehringer lngelheim Pharma GmbH & Co. KG
`
`("BIPKG") is a limited liability partnership organized and existing under the laws of Germany,
`
`having a principal place of business in lngelheim, Germany. (Id) Plaintiff Boehringer lngelheim
`
`Corporation ("BIC") is a corporation organized and existing under the laws of Nevada, having a
`
`principal place of business in Ridgefield, Connecticut. (Id.) BIPI, Bil, BIPKG and BIC are
`
`collectively referred to as "Plaintiffs" or "Boehringer."
`
`Defendant Mylan Pharmaceuticals Inc. ("Mylan Pharms") is a corporation organized and
`
`existing under the laws of the State of West Virginia, having a principal place of business in
`
`Morgantown, West Virginia. (Id) Defendant Mylan Inc. is a corporation organized and existing
`
`under the laws of the State of Pennsylvania, having a principal place of business in Canonsburg,
`
`Pennsylvania. (Id.) Defendant Mylan Laboratories Limited ("Mylan Labs") is a corporation
`
`organized and existing under the laws oflndia and has a principal place of business in Hyderabad,
`
`India. (Id.) Mylan Pharms, Mylan Inc., and Mylan Labs are collectively referred to hereinafter as
`
`"Mylan."
`
`Defendant Aurobindo Pharma Limited ("Aurobindo Ltd.") is a corporation organized and
`
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`existing under the laws oflndia, with a registered place of business in Andhra Pradesh, India. (Id.)
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`Defendant Aurobindo Pharma USA, Inc. ("Aurobindo USA") is a corporation organized and
`
`existing under the laws of the State of Delaware and has a principal place of business in Dayton,
`
`New Jersey.
`
`(Id.) Aurobindo Ltd. and Aurobindo USA are collectively referred to as
`
`"Aurobindo."
`
`B. The Drugs
`
`1. Tradjenta ®
`
`Boehringer holds an approved New Drug Application (No. 201280) ("NDA") for
`
`linagliptin, for oral use in 5mg dosages, which is marketed and sold under the trade name
`
`Tradjenta®. (Stip. Facts, ECF No. 539-1, at 135.) Tradjenta® was first approved by the FDA in
`
`2011, and contains 5mg of linagliptin as its active ingredient. (Id. at 11 36-37). Unagliptin is a
`
`Dipeptidyl peptidase-4 (DPP-IV) inhibitor, and is used to treat type 2 diabetes mellitus (hereinafter
`
`"type 2 diabetes"). (Id. at ,r 46). Linagliptin has the following chemical structure:
`
`Among others, Boehringer listed U.S. Patent Nos. '541, '927, and '859 in the FDA's
`
`Orange Book for Tradjenta ®· (Id. at ,r 57).
`
`2. Jentadueto ®
`
`Boehringer holds an approved NOA (No. 201281) for linagliptin and metformin
`
`hydrochloride tablets, for oral use in 2.Smg/500 mg, 2.Smg/850 mg, and 2.5/1000 mg dosages,
`
`which is marketed and sold under the trade name Jentadueto ®. (Id. at ,r 47). Jentadueto® was
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`first approved by the FDA in 2012, and contains 2.5 mg linagliptin/500 mg metfonnin
`
`hydrochloride, 2.5 mg linagliptin/850 mg metfonnin hydrochloride, or 2.5 mg linagliptinfl 000 mg
`
`metformin hydrochloride as its active ingredients. (Id at ,r 49). Jentadueto® is used to improve
`glycemic control in adults with type 2 diabetes. (Id at ,r 56).
`
`Among others, Boehringer listed patent Nos. '541, '927, and '859 in the FDA's Orange
`Book for Jentadueto®. (Id. at ,r 58).
`
`3. Aurobindo's Generic
`
`Aurobindo submitted ANDA No. 208415 to the FDA, identifying Tradjenta® and seeking
`approval to market linagliptin, for oral use, in 5 mg dosages. (Id. ,r 60). Aurobindo included in
`
`ANDA No. 208415 a Paragraph IV certification. (Def. 's Proposed Findings of Fact ("PFoF"),
`
`ECF No. 597 at ,r 129). Arbundo later submitted an amendment to ANDA No. 208415 which
`
`included paragraph IV certifications as to the '859 patent. (Id.)
`
`4. Mylan's Generic
`
`Mylan submitted ANDA No. 208431 to the FDA, identifying Tradjenta® and seeking
`
`approval to market linagliptin, for oral use, in 5 mg dosage (the "Mylan, Generic"). (Stip. Facts at
`
`,r 67.) Mylan also submitted ANDA No. 208430 to the FDA, identifying Jentadueto® and seeking
`
`approval to market linagliptin and metformin, for oral use, in 2.5 mg/500 mg, 2.5 mg/850 mg, and
`2.5 mg/1000 mg dosages (the "Mylan Generic Combination"). (Id at ,r 68.) Included with ANDA
`
`No. 20831 was a certification pursuant to 21 U.S.C. § 355G)(2)(A)(vii)(IV),
`
`-
`
`-
`
`- - - - - - ---
`
`(Id. at ,r 69.) Additionally, Mylan included in ANDA
`
`No. 208430 paragraph IV certifications
`
`- - -
`
`-~ - -
`
`-
`
`- - - - - -
`
`-
`
`-
`
`(Id. at ,r,r 69-70.)
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`5. Development of Tradjenta® and Jentadueto®
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`a. Linagliptin
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`Tradjenta® and Jentadueto® are two drugs used to manage type 2 diabetes. Diabetes is a
`
`chronic disease, and is characterized by elevated levels of glucose and blood sugar. (See Tr.
`
`287:15-16 (Lenhard); Tr. 485:7-8 (Accili)). Insulin is the hormone that regulates glucose sugar
`
`levels. (Tr. 485:22-25 (Accili)). Insulin resistance is the "cause of diabetes;" and an individual
`
`with insulin resistance has difficulty keeping their glucose levels within normal range. (Tr. 486: 1-
`
`2 (Accili)). Dr. Accili explained, "the liver makes glucose, for example, while we eat[;] the reason
`
`we don't go into low blood sugar when we do not eat is the liver takes up the function of making
`
`glucose. [If] this process in diabetes is uncontrolled, ... it makes [excessive] glucose." (Tr.
`
`489: 16-23) (Accili)).
`
`Diabetes causes both microvascular and macrovascular complications. Microvascular
`
`complications can occur when diabetes affects small blood vessel, which can cause damage to the
`
`eyes, heart, nerves, and kidneys. (Tr. 289:8-17 (Lenhard)). Macrovascular complications can
`
`occur when diabetes affects large blood vessels, and can cause heart attack, stroke, blood clots and
`
`blockages to the lower extremities. (Tr. 289:8-17 (Lenhard)). Renal impairment and impaired
`
`kidneys affect how specific drugs act in the body. Boehringer's expert Dr. Lenhard testified that
`
`"[m]any drugs are excreted from the body by way of the kidney after they serve their therapeutic
`
`use, they're filtered from the blood by the kidney ... if the kidney is functioning normally ... ,
`
`then the drug is excreted in its entirety." (Tr. 854:10-14 (Lenhard)). However, "[i]fthe kidney is
`
`impaired in some way, then the drug may not be cleared to the same extent[,] leading to a build(cid:173)
`
`up of the drug [in the body]." (Tr. 854:14-16 (Lenhard)). After excretion through the kidney,
`
`drugs then go through urinary excretion. (Tr. 854:20-22 (Lenhard)). Patients that experience renal
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`impairment are limited in which drugs they may take to treat their type 2 diabetes. (Pl.' s Findings
`
`of Fact ("PFoF"), ECF No. 594 at ,r 73). The following graphic displays the issues related to renal
`
`impairment and drug clearance:
`
`,
`,, ,
`~ Kidney Clearance', , ;',,, -_
`,_,,,,
`>
`,
`\
`i~'?(f~Jt~t~pz;;'.t,:~~efft:;;.,;.,.J. J{ ~::tl7~¥1\if~2ttf~~\\\f(;/;[P.:nr~~i~<\:4.A:tt f;~j; :f£f) :{;!t~1:~; :/·{ f._~: i/~,l,,
`
`- - - - -
`
`Drug
`
`Healthy Kidney
`
`Impaired Kidney
`
`(PDX-6.11 ).
`
`Drugs used to treat type 2 diabetes are cleared primarily through the kidney, thus, renal
`
`impairment is a primary concern for type 2 diabetes patients. For example,"[f]ollowing oral
`
`administration [of metformin, a first-line drug to treat type 2 diabetes], approximately 90% of the
`
`absorbed drug is eliminated via the renal route within the first 24 hours." (DTX-39.3). For this
`
`reason, metformin is "contraindicated in patients with: renal disease or renal dysfunction ... which
`
`may also result from conditions such as cardiovascular collapse (shock), acute myocardial
`
`infarction, and septicemia," and the prescribing label for metformin cautions against the use of
`
`metformin in renally impaired patients.
`
`(DTX-39.14.) Other DPP-IV inhibitors also clear
`
`primarily through the kidney: Sitagliptin (79% cleared through the kidney); Saxagliptin (24%,
`
`36% and 45% cleared through the kidney); Alogliptin (76% cleared through the kidney); and
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`Vildagliptin (85% cleared through the kidney). (PFoF, ECF No. 594 at ,r 806).
`
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`Dr. Accili testified that patients suffering from type 2 diabetes have their renal functions
`
`tested about once a year. (Tr. 1338:1-10) (Accili)). Dr. Accili explained: "So, in all these patients
`
`the main reason you test renal function is because of their diabetes, not because of the drug they're
`
`on ... [, but because] kidney disease ... [is an] important component of diabetes. And so most
`
`professional associations recommend that patients be tested yearly, so you have to do that as a
`
`baseline."
`
`(Tr. 1338:16-24) (Accili)). To test a renal function, physicians conduct a blood test
`
`that measures a patient's renal impairment. (Tr. 1339:12-16 (Accili)).
`
`The dosage of a drug affects renal excretion, depending on "how quickly the drug builds
`
`up in the bloodstream and ... whether there is a reason to threshold for renal excretion." (Tr.
`
`1345:21-23 (Accili)). Accordingly, patients with renal impairment require dose adjustments,
`
`which starts with giving a patient half the required dose of a drug. (Tr. 1337:6-12 (Accili)). The
`
`further the renal impairment progresses, the more the dose is adjusted; for example, if the starting
`
`dose is 100mg, a physician would cut the dose in half to 50mg, and then eventually reach 25mg of
`
`a drug. (Tr. 1337:19 to 23)(Accili)).
`
`Common therapies to treat type 2 diabetes included metformin, insulin sensitizers, insulin
`
`secretagogues, glucose absorption inhibitors, GLP-1 receptor agonists, and OPP-IV inhibitors.
`
`(Tr. 488:1 to 492:6 (Accili)). The American Diabetes Association ("ADA") publishes guidelines
`
`for the treatment of diabetes, and these guidelines recommend that patients be treated first with
`
`metformin monotherapy. (Tr. 291 :2-22 (Lenhard); see also Tr. 492:25 to 493:2 (Accili)). At trial,
`
`Dr. Accili explained that "metformin ... appeared in the British formulary in ... 1958, 60 years
`
`ago. However, there are reports even from the 1940s saying that it lowered glucose. Metfonnin
`
`is a plant extract essentially, so it's been around for a long time." (Tr. 493:7-11 (Accili)).
`
`Metfonnin was approved by the FDA in 1995. (Defs. PFoF, ECF No. 597, at 171). Accordingly,
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`Dr. Dugi opined that "[M]etformin was available commercially on the market for a long time with
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`an FDA approved label. Physicians knew how to use metformin." (Tr. 1458:13-1459:15) (Dugi)).
`
`After measuring a patients HbA 1 c, if it is shown that metformin treatment is not successful on its
`
`own, a physician would add a second drug to the treatment. 3 (Tr. 291 : 12-18) (Lenhard)). The
`
`ADA guidelines recommend comprising ''two drug therapy [with] metformin and life-style
`
`changes with one of several different drugs added to that." (Tr. 291 :23-292:2 (Lenhard)). For
`
`example, two drug therapy can include metfonnin and a DPP-IV inhibitor.
`
`(T2. 292:3-8)
`
`(Lenhard)).
`
`During the 1990s, Boehringer biologist Dr. Michael Mark determined "there [was] ... a
`
`high therapeutic need for novel treatments in diabetes, because none of the treatments at that point
`
`in time [were] able to reduce the progression of the disease."
`
`(Tr. 39:24 to 40:2 (Mark)).
`
`Accordingly, Boehringer focused on developing DPP-IV inhibitors as a potential treatment for
`
`type 2 diabetes. (Tr. 42:7-8) (Mark)). DPP-IV inhibitors work to allow Glucagon-like peptide-I
`
`("GLP-1 ") to function correctly. GLP-1 is a "very important hormone which ... [controls] the
`
`glucose levels of the human being, ... [and is] able to increase the insulin secretion." (Tr. 42:20-
`
`22 (Mark)). Dr. Mark explained that "[A]fter someone eats a meal, their blood glucose level goes
`
`up," and "then the body releases[] [GLP-1]." (Tr. 42:23-25 (Mark)). GLP-1 then "signal[s] ...
`
`the body to release insulin to address the higher glucose level," and "insulin is able to reduce
`
`glucose levels." (Tr. 43:3 to 5 (Mark)). In contrast, DPP-IV is the enzyme that inactivates GLP-
`
`1, thus making it unfunctional. (Tr! 43:8-9 (Mark)). DPP-IV inhibitors, like linagliptin, block this
`
`3 HbA 1 c is the measurement of glucose in the blood. (See Tr. 40: 12-20 (Mark)).
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`function of the DPP-IV enzyme, thus allowing "longer and higher [GLPl-] levels existing" in the
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`blood, which in turn allows "the body [to] secret[e] insulin." (Tr. 43:12-17) (Mark)).
`
`Boehringer first developed a proprietary assay to search for OPP-IV inhibitors, and after
`
`screening approximately 500,000 compounds, identified a "double digit" number of "hits." (Tr.
`
`47:6-22) (Mark)). The proprietary assay was then "adapted for[] high throughput screening" and
`
`using this, Boehringer screened approximately 500,000 compounds, comprising of "all the
`
`compounds which were existing in Boehringer[] at that point in time." (Tr. 45:8-24 (Mark).)
`
`Next, Boehringer began to structurally modify the hits in an attempt to identify "novel
`
`molecules ... with different features and different results." (Tr. 48:6-20 (Mark)). Boehringer
`
`estimates it synthesized approximately 1,500 molecules over a two year period. (Tr. 48:21 to 49-
`
`2 (Mark)). Based on in vivo and in vitro assays, Boehringer selected BI-1344 for development;
`
`however, in developing that compound, Boehringer discovered "negative safety signals, and ...
`
`had to discontinue the further development of BI-1344." (Tr. 50:13-25; 51:9-13 (Mark)).
`
`Thereafter, Boehringer identified BI-1356 (now known as linagliptin, (Tr. 51 :22-25 (Mark)), and
`
`conducted in vivo and in vitro assays, which did not exhibit the same negative.safety signals as BI-
`
`1344 during development. Linagliptin was ultimately approved by the FDA for use in treating
`
`patients with type 2 diabetes. (Tr. 54-21 to 55-3 (Mark)).
`
`After identifying linagliptin, Boehringer tested the compound ''in various animal models
`
`and in various species," and identified a dose range of one to three milligrams. (Tr. 55:9-19
`
`(Mark)). This dose range equates to between 50 and 200 milligrams in human dosages. (Tr. 55:9-
`
`19 (Mark)). Using this estimate, Boehringer conducted a human trial (in vivo) on non-type 2
`
`diabetic, healthy volunteers, to start with a dose of about 5 mg as a subtherapeutic dose, which is
`
`a dose "showing no efficacy ... meant as a safety measure to really start in the first human exposure
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`relatively low and safe." (Tr. 56: 14 to 57:2) (Mark)). Boehringer's expected therapeutic dose was
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`between 50 and 200mg per day. (Tr. 62:6-7) (Mark)). As a result of this clinical study, Boehringer
`
`determined that "there was a greater than 60% OPP-IV inhibition" after twenty-four hours with a
`
`5 mg dose. (Id. at 1 90). Additionally, Boehringer found that in the 2.5 and 5 mg doses, only a
`
`small amount was excreted via the kidney. (Pl.s' FoF, ECFNo. 594, at 1811; Tr.64:15-21 (Mark)).
`
`Linagliptin is instead "excreted through the intestine and the liver and not through the kidney[s]
`
`like the other OPP-IV inhibitors." (Tr. 902: 12-14 (Lenhard)). Thus, linagliptin's "renal excretion
`
`as percentage of dose oflinagliptin" increases at a higher dose and decreases at a lower dose. (Pl.s'
`
`PFoF, ECF No. 594, at 191).
`
`After the results of the first clinical study, Boehringer narrowed the dose range to 1, 2.5, 5
`
`and 10 mg, and conducted subsequent clinical studies, this time on individuals with type 2 diabetes.
`
`(Pl.s' FoF, ECF No. 594, at 11 92-94. These studies showed that linagliptin is "safe and well
`
`tolerated" in "oral doses of2.5, 5 and lOmg", and the "maximum inhibitory effect" approached the
`
`5 mg dose. (Id. at 1196-100). They also showed that "[r]enal excretion of [linagliptin] accounted
`
`for about 3% of the total clearance." (Pl.s' FoF, ECF No. 594, at 1 97). Because most type 2
`
`diabetic patients suffer from renal impainnent, "they have a reduced kidney function, and therefore
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`any compound which is eliminated via the kidney would additionally put [a] burden [on] the
`
`kidney which is malfunctioning in these patients" thus, the lower the amount to pass through the
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`kidney, the lower the burden on the kidney. (Tr. 65: 1-8; 74-20 (Mark)).
`
`Around this time, Boehringer began to investigate linagliptin' s effect on HbA 1 c. (Pl.s'
`
`FoF, ECF No. 594, at 1 99). If there is a significant reduction in a HbAlc value, there is an
`
`improvement in glycemic control. (Tr. 75:21-23 (Mark)). Dr. Mark explained, "HbAlc is the final
`
`marker which is needed for regulatory bodies, but it's also used for the doctor, to really see whether
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`there is a change in the glycemic control." (Tr. 74:22-24 (Mark)). Boehringer found a "a
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`statistically significant reduction of HbAlc," and proceeded to file the '927 and '859 patents,
`
`which have the earliest effective filing date of May 4, 2006. (Id. at 11 101-102). After filing the
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`'927 and '859 patents, Boehringer continued to perform clinical studies, which revealed the 5mg
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`dosage of linagliptin was "the most suitable dose to put forward and can be considered as the
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`therapeutic dose." (Tr. 76:21-25; 77:11-21 (Mark)). Based on the results of the clinical studies,
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`Boehringer submitted a New Drug Application, seeking approval for linagliptin for treating type
`
`2 diabetes at a 5mg dose. (Id.).
`
`b. The '541 Patent
`
`The '541 patent titled titled "8-[3-amino-piperidin-1-yl]-xanthines, the Preparation
`
`thereof and their Use as Pharmaceutical Compositions" was issued on May 15, 2012, and was filed
`
`as U.S. Patent No. 12/143,128 on June 20, 2008. (Stip. Facts, ECF No. 539-1, at 1128). The '541
`
`patent is a continuation of U.S. Application No. 10/639,036 (now the '955 patent), which was filed
`
`on August 12, 2003, and claims priority to U.S. Provisional Application Nos. 60/409,312 (filed on
`
`September 9, 2002), No. 60/461,752 (filed on April 10, 2003), German application nos. DE 102
`
`38 243.3 (filed August 21, 2002), and DE 103 12 353.9 (filed March 20, 2003). (Id) The '541
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`patent expires on August 12, 2024. (Id at 1 115). Boehringer is listed on the face of the '541
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`patent as the assignee. (Id at 1117).
`
`At issue in the present litigation are Patent Reference Claims 44 and 45 of the '541 patent.
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`Claim 44 of the '541 recites: "A pharmaceutical composition comprising l-[(4-methyl-quinazolin-
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`2-yl)methyl]-3-methyl-7-(2-butyn-l-yl)-8-(3-(R)-amino-pfperidin-l-yl)-xanthine
`
`[hereinafter
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`"linagliptin"] and metformin." (Id. at 1 126). Claim 45 of the '541 patent recites: "A method of
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`treating type II diabetes mellitus comprising administering to a patient in need thereof a
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`pharmaceutically effective amount of [linagliptin] and metformin. 11 (Id. at 1 127).
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`c. The Asserted Patents
`
`i. The '927Patent
`
`The '927 patent, titled "Uses of DPP-IV Inhibitors," was issued on March 18, 2014, from
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`Application No. 12/946, 193 ("the '193 application"), which was filed on November 15, 2010. (Id.
`
`at~ 128). The '193 application is a continuation of U.S. Application No. 11/744,703 ("the '703
`
`application"), filed May 4, 2007 (now U.S. Patent No. 8,232,281). (Id) The '703 application
`
`claims priority to European Patent Application No. EP 06009203 (filed May 4, 2006). (Id) The
`
`'927 patent expires on May 4, 2027. (Id. at 1129). Boehringer is listed on face of the '927 patent
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`as the assignee. (Id at, 131 ). Boehringer claims Defendants have infringed claims 7, 9, 15, 17,
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`19, 25 and 26 of the '927 patent.
`
`The '927 patent describes "the use of selected DPP-IV inhibitors for the treatment of
`
`physiological functional disorders and for reducing the risk of the occurrence of such functional
`
`disorders in at-risk patient groups. In addition, the use of above-mentioned DPP-IV inhibitors in
`
`conjunction with other active substances is described, by means of which improved treatment
`
`outcomes can be achieved. 11 (JTX-1.2).
`
`Claim 7 of the '927 patent recites: "The method according to claim I, wherein [linagliptin]
`
`is administered in an oral dosage of 2.5 mg or 5 mg." (Id. at~ 132).
`
`Claim 9 of the '927 patent recites: "The method according to claim 1, wherein [linagliptin]
`
`is administered in an oral daily dose of 5 mg." (Id. at 1133).
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`Claim 15 of the '927 patent recites: "The method according to claim 10, wherein
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`[linagliptin] is administered in an oral dosage of 2.5 mg or 5 mg." (Id. at 1 134).
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`Claim 17 of the '927 patent recites: "The method according to claim 10, wherein
`[linagliptin] is administered in an oral daily dose of 5 mg." (Id at ,r 135).
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`Claim 19 of the '927 patent recites: "A method of treating type II diabetes mellitus
`
`comprising administering to a patient in need thereof a pharmaceutically effective oral amount of
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`[linagliptin] which is an oral daily dose of 5 mg, and a pharmaceutically effective amount of
`metformin." (Id. at ,r 136).
`
`Claim 25 of the '927 patent recites: "The method according to claim 20, wherein
`
`th[linagliptin] is administered in an oral dosage of 2.5 mg or 5 mg." (Id at ,r 136).
`
`Claim 26 of the '927 patent recites: "The method according to claim 20, wherein the
`[linagliptin] is administered in an oral daily dose of 5 mg." (Id at ,r 138).
`
`ii. The '859 Patent
`
`Patent '859, titled "Uses of OPP IV Inhibitors," was issued on November 3, 2015. (Id. at
`,r 141). The '859 patent results from U.S. Patent Application No. 14/161,007 ("the '007
`
`application"), which was published as U.S. Patent Application Publication No. 2014/0135348 A 1
`
`("the '348 Publication") on May 15, 2014. (Id.) The '007 application was filed on January 22,
`
`2014, and is a continuation of U.S. Patent Application No. 12/946, 193, filed on November 15,
`
`2010, now the '927, which is a continuation of U.S. Patent Application No. 11/744~703 ("the '703
`
`application"), filed on May 4, 2007, now U.S. Patent No. 8,232,281. (Id) The '703 application
`
`claims priority to European Patent Application No. EP 06009203, filed May 4, 2006. (Id.) The
`
`'859patent expires on May 4, 2027. (Id.) Boehringer is listed on face of the '859 patent as the
`assignee. (Id. at ,r 144). Boehringer claims Defendants have infringed claims 1, 14, 15, 20, and
`
`21 of the '859 patent.
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`The '859 patent describes "the use of selected DPP-IV inhibitors for the treatment of
`
`physiological functional disorders and for reducing the risk of the occurrence of such functional
`
`disorders in at-risk patient groups. In addition, the use of above-mentioned DPP-IV inhibitors in
`
`conjunction with other active substances is described, by means of which improved treatment
`
`outcomes can be achieved." (JTX-2.13).
`
`Claim 1 of the '859 patent recites:
`
`A method of treating type 2 diabetes comprising administering to a patient in need
`thereof (a) [linagliptin], or a therapeutically active salt thereof, in an oral dosage of
`2.5 mg or 5 mg, and (b) metformin wherein the dose of metformin is 100 mg to 500
`mg or 200 mg to 850 mg (1-3 times a day), or 300 mg to 1000 mg once or twice a
`day, or as delayed-release metformin in a dose of 500 mg to 1000 mg once or twice
`a day, or 500 mg to 2000 mg once a day, or wherein the dose of metformin is 500
`mg, 850 mg or I 000 mg as a single dose with a total daily dose of metformin of
`500-2850 mg, or 500 mg, 1000 mg, 1500 mg or 2000 mg metformin in delayed
`release form, or wherein the dose of metformin is 500 mg to 1000 mg.
`
`(Id. at 1 145).
`
`Claim 14 of the '859 patent recites: "An oral tablet formulation comprising
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`[linagliptin] in an amount of 2.5 mg or 5 mg optionally in combination with metformin,
`
`and a pharmaceutically acceptable carrier or diluent." (Id. at 1 146).
`
`Claim 15 of the '859 patent recites: "The oral tablet according to claim 14, containing 500
`
`mg to 1000 mg metformin." (Id. at 1 14 7).
`
`Claim 20 of the '859 patent recites: "A method of treating type 2 diabetes comprising
`
`administering to a patient in need thereof the oral tablet of claim 14, wherein the daily oral amount
`
`of [linagliptin] administered to said patient is Smg." (Id. at 1 148).
`
`Claim 21 of the '859 patent recites: "The method according to claim 5, wherein [linagliptin]
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`in a dosage of 2.5 mg is administered twice daily." (Id. at 1149).
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`C. The Specific Allegations
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`The parties have previously stipulated that Mylan's submission of ANDA No. 208431
`
`infringed claims 14 and 20 of the '859 patent pursuant to 35 U.S.C. § 27l(e)(2)(A). Boehringer
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`further contends that the submission of Mylan's ANDA No. 208430 to market a generic version
`
`of Jentadueto® infringed the asserted claims of the '927 and '859 patent, specifically infringing
`
`upon claims 7, 9, 15, 17, 19, 25, and 26 of the '927 patent and claims l, 14, 15, 20, and 21 of the
`
`'859 Patent. Boehringer also contends that the submission of Mylan's ANDA No. 208431 to
`
`market a generic version of Tradjenta®, a linagliptin product with standard doses of metfonnin,
`
`infringed the asserted claims of the '927 and '859 patent. Specifically, Boehringer argues that
`
`Mylan infringed upon claims 7, 9, 15, 17, 19, 25, and 26 of the '927 patent, and claim 1 of the '859
`
`patent. Additionally, Boehringer argues that Mylan's proposed labels, described in ANDA No.
`
`208431, promote, recommend, and encourage the administration of standard commercial doses of
`
`metformin with a 5mg oral dose of linagliptin to treat patients with type 2 diabetes. Boehringer
`
`contends that, pursuant to 35 U.S.C. § 271(b), this proposed label induces infringement of claims
`
`7, 9, 15, 17, 19, 25, and 26 of the '927 patent and claim 1 of the '859 patent, and will induce
`
`physicians to administer the Claimed Combination Therapy.
`
`Regarding Aurobindo, the parties have previously stipulated that Aurobindo's submission
`
`of ANDA No. 208415 infringed claims 14 and 20 of the '859 patent. Boehringer further argues
`
`the administration of linagliptin with the standard commercial doses of metfonnin, described in
`
`ANDA No. 208415, infringed upon claim 1 of the '859 patent. Additionally, Boehringer argues
`
`that Aurobindo's proposed labels, described in ANDA No. 208415, promote, recommend and
`
`encourage the administration of standard commercial doses of metformin with a 5mg oral dose of
`
`linaglipt