Case 1:19-cv-00101-IMK Document 204 Filed 10/26/22 Page 1 of 120 PageID #: 11848
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE NORTHERN DISTRICT OF WEST VIRGINIA
`
`MERCK SHARP & DOHME LLC,
`
`
`
`
`Plaintiff,
`
`v.
`
`
`
`
`
`
`
`
`
`
`
`MYLAN PHARMACEUTICALS INC.,
`
`
`
`
`Defendant.
`
`
`
`
`
`
` CIVIL ACTION NO. 1:19CV101
`
` (Judge Keeley)
`
`**SEALED**
`MEMORANDUM OPINION AND ORDER FOLLOWING BENCH TRIAL
`I.
`INTRODUCTION
`In this patent infringement action, the plaintiff, Merck
`Sharp & Dohme LLC (“Merck”), and the defendant, Mylan
`Pharmaceuticals Inc. (“Mylan”),1 dispute whether Mylan has
`infringed claim 3 of Merck’s U.S. Patent No. 7,326,708 (“the ’708
`patent”) and claim 1 of Merck’s U.S. Patent No. 8,414,921 (“the
`’921 patent”). They also dispute whether claims 1, 2, 3, and 19 of
`’708 patent are valid and enforceable.
`The ’708 patent and the ’921 patent (“the patents-in-suit”)
`are associated with Januvia® and Janumet®, Merck’s New Drug
`Application (“NDA”) products approved by the Food and Drug
`Administration (“FDA”) and directed to the dihydrogenphosphate
`
`
`1 Although Merck originally included Mylan Inc. as a defendant in this
`action, the parties previously stipulated to its dismissal from this
`civil action (Dkt. No. 43).
`
`
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE NORTHERN DISTRICT OF WEST VIRGINIA
`
`MERCK SHARP & DOHME LLC,
`
`
`
`
`Plaintiff,
`
`v.
`
`
`
`
`
`
`
`
`
`
`
`MYLAN PHARMACEUTICALS INC.,
`
`
`
`
`Defendant.
`
`
`
`
`
`
` CIVIL ACTION NO. 1:19CV101
`
` (Judge Keeley)
`
`**SEALED**
`MEMORANDUM OPINION AND ORDER FOLLOWING BENCH TRIAL
`I.
`INTRODUCTION
`In this patent infringement action, the plaintiff, Merck
`Sharp & Dohme LLC (“Merck”), and the defendant, Mylan
`Pharmaceuticals Inc. (“Mylan”),1 dispute whether Mylan has
`infringed claim 3 of Merck’s U.S. Patent No. 7,326,708 (“the ’708
`patent”) and claim 1 of Merck’s U.S. Patent No. 8,414,921 (“the
`’921 patent”). They also dispute whether claims 1, 2, 3, and 19 of
`’708 patent are valid and enforceable.
`The ’708 patent and the ’921 patent (“the patents-in-suit”)
`are associated with Januvia® and Janumet®, Merck’s New Drug
`Application (“NDA”) products approved by the Food and Drug
`Administration (“FDA”) and directed to the dihydrogenphosphate
`
`
`1 Although Merck originally included Mylan Inc. as a defendant in this
`action, the parties previously stipulated to its dismissal from this
`civil action (Dkt. No. 43).
`
`
`
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`salt of the compound known as sitagliptin for the treatment of
`type 2 diabetes. Mylan seeks to market two Abbreviated New Drug
`Applications products (“the ANDA products”) that are the
`bioequivalent to Januvia® and Janumet® prior to the expiration of
`the patents-in-suit.
`The Drug Price Competition and Patent Term Restoration Act of
`1984, Pub. L. No. 98-417, 98 Stat. 1585 (otherwise known as the
`“Hatch-Waxman Act”), seeks to encourage “pioneering research and
`development of new drugs,” as well as the “production of low-cost,
`generic copies of those drugs.” Eli Lilly & Co. v. Teva Pharm.
`USA, Inc., 557 F.3d 1346, 1348 (Fed. Cir. 2009). To that end, a
`manufacturer may obtain FDA approval to market a generic drug by
`making a certification regarding patents listed in the FDA’s
`Approved Drug Products with Therapeutic Equivalence Evaluations
`(“the Orange Book”) as covering the NDA drug, and certifying that
`those patents are “invalid or will not be infringed by the
`manufacture, use, or sale of the new generic drug for which the
`ANDA is submitted” (“paragraph IV certification”). Id. (citing 21
`U.S.C. § 355(j)(2)(A)(vii)(IV)). Following an applicant’s
`paragraph IV certification, a patentee may sue the applicant for
`patent infringement within 45 days, thus delaying FDA approval of
`the ANDA. Id. (citing 21 U.S.C. § 355(j)(5)(B)(iii)).
`
`
`
`2
`
`
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`MEMORANDUM OPINION AND ORDER FOLLOWING BENCH TRIAL
`
`In this case, where Merck has sued Mylan under the Hatch-
`Waxman Act for infringement of the patents-in-suit, the Court is
`tasked with deciding the following: (1) do Mylan’s ANDA products
`infringe claim 3 of the ’708 patent or claim 1 of the ’921 patent;
`(2) are claims 1, 2, 3, and 19 of the ’708 patent invalid under
`the judicially created obviousness-type double patenting doctrine;
`and (3) are claims 1, 2, 3, and 19 of the ’708 patent invalid under
`35 U.S.C. § 112 for lack of written description or enablement.
`Following a five-day bench trial, the parties submitted their
`memoranda of law, and the case is ripe for the Court’s decision.
`II. BACKGROUND
`The Parties, Jurisdiction, and Venue
`Merck Sharp & Dohme Corporation, a corporation organized
`under the laws of the State of New Jersey, with its principal place
`of business at One Merck Drive, Whitehouse Station, New Jersey
`08889, commenced this action on May 2, 2019 (Dkt. No. 123 at 1).
`Due to a later transfer of ownership, however, the Court granted
`Merck’s unopposed motion to substitute Merck Sharp & Dohme, LLC as
`the plaintiff in this civil action (Dkt. No. 190).2 Merck Sharp &
`Dohme LLC is organized under the laws of the State of New Jersey,
`
`A.
`
`
`2 Effective May 1, 2022, Merck Sharp & Dohme Corporation merged into
`Merck Sharp & Dohme, LLC, with the latter emerging as the surviving
`entity (Dkt. No. 189).
`
`
`
`3
`
`
`
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`MEMORANDUM OPINION AND ORDER FOLLOWING BENCH TRIAL
`with its principal place of business at 126 East Lincoln Avenue,
`P.O. Box 20000, Rahway, New Jersey 07065. Id. at 6. Mylan is a
`company organized under the laws of the State of West Virginia
`with its principal place of business at 781 Chestnut Ridge Road,
`Morgantown, West Virginia 26505. Id. The Court has subject matter
`and personal jurisdiction, and venue in this District is proper.
`B.
`Factual and Procedural Background
`The Court begins its analysis with a review of the chemical
`compound known as sitagliptin, how and why pharmaceutical salts
`are formed, Merck’s synthesis and development of the
`dihydrogenphosphate salt of sitagliptin, the asserted claims of
`the patents-in-suit, other relevant patents and patent
`applications, and the parties’ prior art references.
`1.
`Sitagliptin
`The patents-in-suit relate to the basic compound known as
`“sitagliptin,”
`4-oxo-4-[3-trifluorom-ethyl)-5,6-dihyrdo[1,2,4]
`triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-
`2-amine, belonging to a class of compounds that act as dipeptidyl
`peptidase-IV (“DPP-IV”) inhibitors (Dkt. No. 123 at 2; JTX
`001.0001; JTX 002.0002; Trial Trans. 55:5-11, 309:7-9 (Buckton)).
`DPP-IV is an enzyme produced by the human body to raise glucose,
`or blood sugar (Trial Trans. 55:5-11). Sitagliptin inhibits
`production of the DPP-IV enzyme to improve glycemic control in
`4
`
`
`
`
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`adults with type 2 diabetes (Dkt. No. 123 at 2; Trial Trans. 268:9-
`13). Sitagliptin has one chiral center, or one carbon atom around
`which the molecule can orient itself (Trial Trans. 281:7-16
`(Buckton); 535:21-23 (Shupe); 689:2-5 (Cockcroft)). Because it has
`one chiral center, sitagliptin has two isomers, or configurations,
`the (R)-configuration and the (S)-configuration. Id.
`2.
`Salt Formation
`The patents-in-suit relate to a particular salt form of
`sitagliptin synthesized by Merck. Pharmaceutical salts are formed
`by reacting an active compound with a counterpart acid or base.
`When a basic compound is combined with a counterpart acid, a salt
`forms when the acid donates a hydrogen ion to the base. Id. at
`9:22-10:5. If the acid used in this reaction is polyprotic, or
`capable of donating multiple hydrogen ions, salts in different
`ratios or stoichiometries may form. Id. at 820:7-24 (Myerson).
`But whether a salt will form is highly unpredictable (Trial
`Trans. 837:22-838:17, 840:4-841:3, 883:17-884:9 (Myerson); Dkt.
`No. 104-1 at 55, 58). Also unpredictable are what pharmaceutical
`properties any resulting salt might display (Trial Trans. 110:13-
`15 (Hansen); 344:18-22 (Buckton); 927:16-22 (Myerson); 740:3-6
`(Wenslow)).
`After selecting a chemical compound for development,
`pharmaceutical manufacturers may create one or more salt forms of
`5
`
`
`
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`the compound in the hope that one such salt will possess
`pharmaceutical properties suitable for manufacturing, such as
`increased solubility, increased stability, and block-like
`morphology. Id. at 92:3-6 (Hansen); 287:10-19 (Buckton); 743:5-11
`(Wenslow). To find salt forms of a basic compound, the manufacturer
`conducts a “salt screen” in which it pairs various acids and
`solvents with the single basic compound to determine whether a
`resulting salt, if any, possesses better pharmaceutical properties
`than the free form of the basic compound. Id. at 109:20-110:6,
`113:5-14 (Hansen); 293:14-19 (Buckton); 951:11-15 (Myerson).
`3.
`Merck’s Development of the Dihydrogenphosphate Salt of
`Sitagliptin
`In 2001, Merck set out to market the first DPP-IV inhibitor
`for the treatment of type 2 diabetes. Id. at 94:17-23 (Hansen).
`While several DPP-IV inhibitors were known in the literature, none
`had been approved by the FDA to treat non-insulin dependent
`diabetes. Id. at 94:17-18 (Hansen); 757:18-23, 773:4-7
`(MacMillan)). Merck classified two lead compounds for development
`in its DPP-IV project, L221869 and L224715. Id. at 95:8-13
`(Hansen). Compound L224715 is now known as sitagliptin. Id. at
`95:24-25 (Hansen).3
`
`
`3 Merck first synthesized the sitagliptin free base compound in early
`2001. Id. at 96:11-13 (Hansen).
`
`
`
`6
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`To begin, Dr. Leigh Schulz conducted a preliminary assessment
`of the pharmaceutical properties of sitagliptin free base. Id. at
`98:18-21, 99:7-25 (Hansen). According to that assessment,
`sitagliptin
`presented
`several
`hurdles
`to
`pharmaceutical
`development. Id. at 102:2-14, 103:10-104:4, 104:15-105:11
`(Hansen). Although it had “great” solubility, it also had needle-
`like morphology (which is not preferred for the production of
`pharmaceutical tablets) and exhibited degradation and deamination
`(indicating instability in both solution and bulk powder). Id. As
`a consequence, Merck prioritized finding a salt form of sitagliptin
`in the hope that it would exhibit superior properties. Id. at
`106:20-107:7 (Hansen).
`Next, Vicky Vydra conducted a salt screen by reacting the
`sitagliptin free base with eleven different acids in a variety of
`solutions to determine if any salts would form. Id. at 110:16-25,
`114:1-3, 115:10-11 (Hansen); 715:7-8 (Vydra). If a salt formed,
`she used x-ray powder diffraction (“XRPD”) to characterize the
`salt as either crystalline or amorphous.4 Id. at 115:3-11 (Hansen);
`721:19-23 (Vydra).
`
`
`4 In a crystalline salt, the molecules are arranged in a repeating pattern
`that does not exist in an amorphous salt (Trial. Trans. 114:9-11
`(Hansen); 277:7-10 (Buckton)).
`
`
`
`7
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`During Vydra’s salt screen, a salt was produced from the
`reaction of sitagliptin with five acids, including phosphoric
`acid, sulfuric acid, tartaric acid, benzene sulphonic acid, and
`toluene sulphonic acid. Id. at 115:5-9 (Hansen); 722:5-14 (Vydra).
`Vydra included hydrochloric acid in this screen, but despite the
`fact that another Merck employee had previously formed a
`hydrochloride (“HCL”) salt of sitagliptin, no salt formed. Id. at
`108:4-14, 114:15-115:4 (Hansen).
`Thereafter, Dr. Karl Hansen performed “scaleup reactions” in
`which he generated larger quantities of the known sitagliptin salts
`to determine their viability for further development. Id. at 116:8-
`17 (Hansen). He replicated the phosphate salt of sitagliptin but
`because it appeared to be amorphous, he prioritized other salts.
`Id. at 117:4-19 (Hansen). After recommending the besylate and
`tartrate salts for further development, he returned to the
`phosphate salt. Id. at 122:10-17 (Hansen).
`Following “a number of trial and error” experiments, Dr.
`Hansen synthesized a crystalline phosphate salt of sitagliptin,
`the dihydrogenphosphate (“DHP”) salt, which he also recommended
`for development. Id. at 122:10-17 (Hansen). Because phosphoric
`acid can donate up to three protons and sitagliptin can receive up
`to two protons, salts from this reaction may form in different
`stoichiometries. Id. at 820:8-9, 821:11-13, 821:17-20, 879:4-7
`8
`
`
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`(Myerson); 157:11-13 (Hansen). In the DHP salt of sitagliptin
`formed by Dr. Hansen, phosphoric acid and sitagliptin exist in a
`1-to-1 ratio (Dkt. No. 104-1 at 3). Later, Dr. Hansen also
`synthesized an HCL salt of sitagliptin after “a lot of
`experimentation” but he did not recommend it for development due
`to its instability and needle-like morphology (Trial Trans.
`116:25-117:3, 128:12-24 (Hansen)).
`These salts recommended by Dr. Hansen were referred back to
`Dr. Schulz to undergo a preliminary assessment. Id. at 118:20-
`119:1 (Hansen). Her assessment allowed Merck’s DPP-IV team to
`compare the pharmaceutical properties of each salt. Ultimately,
`that comparison established that the DHP salt was superior to the
`besylate and tartrate salts because it had good solubility, was
`the most stable, and eliminated several of the hurdles the other
`salts presented. Id. at 118:20-119:1, 120:11-22 (Hansen). And,
`unlike the besylate and tartrate salts, the DHP salt showed no
`signs of degradation in a bulk powder. Id. at 120:25-122:8, 124:13-
`126:5 (Hansen). It also presented the lowest risk of liquifying at
`a higher humidity; appeared to only have one polymorph, or distinct
`crystalline structure; and exhibited a “flake-like” morphology,
`rather than the “needles and rods” morphology known to inhibit
`production. Id. Surprised to discover this unique set of favorable
`
`
`
`9
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`properties,5 the members of Merck’s DPP-IV team selected the DHP
`salt for continued development. Id. at 129:2-5 (Hansen).
`Initially, the DPP-IV team believed the DHP salt existed in
`one form only, an anhydrous crystalline polymorph that did not
`contain water in the crystal lattice. Id. at 126:7-10; 129:10-13
`(Hansen); 278:23-25 (Buckton). But later the team discovered
`several other anhydrous forms, id., and in April 2003 Stephen Cypes
`unexpectedly synthesized a hydrated form of the DHP salt. Id. at
`129:18-130:1 (Hansen). Before this, Merck’s DPP-IV team had
`believed no hydrated DHP salt could exist.6 Id. at 132:18-133:10
`(Hansen).
`Merck’s DPP-IV team then determined that the newly
`discovered, crystalline monohydrate7 form of the DHP salt possessed
`exceptional pharmaceutical properties, superior even to the
`properties of its anhydrous forms. Id. Its morphology was more
`
`
`5 In an email to other members of the DPP-IV team discussing the
`properties of DHP salt of sitagliptin, Ivan Santos, the head of Merck’s
`physical measurements team stated: “I too recommend the phosphate salt.
`Given the data we have to date, we have a simple solid-state system,
`good solubility and stability, a workable morphology. This is incredible.
`Not often do we see these.” (PTX 082.0001; Trial Trans. 126:19-22
`(Hansen)).
`6 Prior to Cypes’s synthesis of the crystalline monohydrate, Dr. Hansen
`had unsuccessfully attempted to create a hydrated form of the DHP salt.
`Id. at 132:18-25, 133:10. Determining whether hydrated forms of the salt
`could be synthesized was important to Merck because hydrated salt forms
`could have presented additional hurdles its development program. Id.
`7 In the crystalline monohydrate form, water and the DHP salt exist in
`a 1-to-1 ratio in the crystal lattice.
`10
`
`
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`suitable to manufacturing and it had only one polymorph. Id. at
`133:12-134:22 (Hansen). Notably, as of 2021, the crystalline
`monohydrate remains the only known hydrate of the DHP salt of
`sitagliptin. Id. at 134:23-135:1 (Hansen).
`Based on all this, Merck’s DPP-IV team chose to commercialize
`the crystalline monohydrate form of the DHP salt of sitagliptin.
`Id. at 136:12-14, 147:17-148:10 (Hansen). After clinical studies
`indicated that it could be effective in the treatment of diabetes,
`this salt became the active ingredient in the first FDA approved
`DPP-IV inhibitor to treat diabetes, Merck’s Januvia® product. Id.
`at 97:15-98:5 (Hansen). It also became the active ingredient in
`Merck’s Janumet® product, which combines sitagliptin with
`metformin to treat diabetes and hypertension. Id. at 180:23-181:1
`(Alani).
`4. The Asserted Claims
`The ’708 patent covers the 1-to-1 DHP salt of sitagliptin and
`methods of use. The ’921 patent describes pharmaceutical
`compositions of the 1-to-1 DHP salt of sitagliptin in combination
`with metformin.
`a.
`The ’708 Patent
`The ’708 patent, filed on June 23, 2004, is titled “Phosphoric
`Acid Salt of a Dipeptidyl Peptidase-IV Inhibitor” (JTX 001.0001).
`It lists Stephen Cypes, Alex Chen, Russell Ferlita, Karl Hansen,
`11
`
`
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`Ivan Lee, Vicky Vydra, and Robert Wenslow, Jr. as inventors and
`Merck as the assignee. Id. Issued on February 5, 2008, the patent,
`with pediatric exclusivity, expires on March 24, 20278 (Dkt. No.
`123 at 2-3). The asserted claims are as follows:
`1.
`A
`dihydrogenphosphate
`salt
`of
`4-oxo-4-[3-
`trifluorom-ethyl)-5,6-dihyrdo [1,2,4]triazolo[4,3-
`a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)
`butan-2-amine of structural formula I:
`
`
`
`or a hydrate thereof.
`The salt of claim 1 of structural formula II having
`the (R)-configuration at the chiral center marked
`with an *
`
`2.
`
`3.
`
`
`The salt of claim 1 of structural formula III having
`the (S)-configuration at the chiral center marked
`with an *
`
`
`8 Without pediatric exclusivity, the ’708 patent expires on November 24,
`2026 (Dkt. No. 123 at 3).
`
`
`
`12
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`
`
`19. A method for the treatment of type 2 diabetes
`comprising administering to a patient in need of
`such treatment a therapeutically effective amount
`of the salt according to claim 2 or a hydrate
`thereof.
`JTX 001.0014-15. Claims 4 through 16 of the ’708 patent, no longer
`at issue in this case,9 relate to the crystalline monohydrate form
`of the 1-to-1 DHP salt of sitagliptin. Id. Merck alleges that
`Mylan’s ANDA products will infringe claim 3 of the ‘708 patent.
`Mylan alleges that claims 1, 2, 3, and 19 of the ‘708 patent are
`invalid and unenforceable.
`b.
`The ’921 Patent
`The ’921 patent, filed on December 16, 2005, is titled
`“Pharmaceutical Compositions of Combinations of Dipeptidyl
`Peptidase-4 Inhibitors with Metformin” (Dkt. No. 123 at 3-4; JTX
`002.0001). It lists Ashkan Kamali, Laman Alani, Kyle Fliszar,
`Soumojeet Ghosh, and Monica Tijerina as inventors and Merck as the
`assignee (JTX 002.0001). Issued on April 13, 2013, the patent,
`
`
`9 Prior to trial, Merck withdrew its allegation that Mylan’s ANDA products
`infringe claims 4-16 of the ’708 patent (Dkt. No. 152).
`13
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`with pediatric exclusivity, expires on January 21, 2029 (Dkt. No.
`123 at 4).10 The following claim is asserted:
`1.
`A pharmaceutical composition comprising:
`(a) about 3 to 20% by weight of sitagliptin, or a
`pharmaceutically acceptable salt thereof;
`(b) about 25 to 94% by weight of metformin
`hydrochloride;
`(c) about 0.1 to 10% by weight of a lubricant;
`(d) about 0 to 35% by weight of a binding agent;
`(e) about 0.5 to 1% by weight of a surfactant; and
`(f) about 5 to 15% by weight of a diluent.
`(JTX 002.0007). Merck alleges that Mylan’s ANDA products will
`infringe each element of this claim.
`5. Claim Construction
`On August 8, 2019, the United States Judicial Panel on
`Multidistrict Litigation granted Merck’s request to centralize
`pretrial proceedings in this case with Merck’s thirteen other
`lawsuits against generic manufacturers related to its Januvia® and
`Janumet® products then pending in the District of Delaware (Dkt.
`No. 49). In that litigation, Judge Richard Andrews construed
`several terms in the claims at issue before this Court. See
`generally, In re Sitagliptin Phosphate ('708 & '921) Pat. Litig.,
`2020 WL 6743022, at *3 (D. Del. Nov. 17, 2020).11
`
`
`10 Without pediatric exclusivity, the ’921 patent expires on July 21,
`2028 (Dkt. No. 123 at 4).
`11 Because Mylan had instigated an inter partes review of the ’708 patent,
`it did not propose constructions of the disputed terms or join in the
`other defendants’ proposed constructions. In re Sitagliptin, 2020 WL
`6743022 at n.1.
`
`
`
`14
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`MERCK SHARPE & DOHME LLC V. MYLAN PHARM. INC
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`MEMORANDUM OPINION AND ORDER FOLLOWING BENCH TRIAL
`As proposed by Merck, Judge Andrews construed the term “the
`salt of claim 1 [or 2]” in claims 2 and 3 of the ’708 patent to
`include hydrates of the molecules described. Id. at *4. He
`construed the term “crystalline monohydrate” used in claims 4 and
`24 of the ’708 patent as “a repeating unit cell incorporating a
`1:1 ratio of water to a dihydrogenphosphate salt of sitagliptin.”
`Id. at *3. He also construed the term “surfactant” in claim 1 of
`the ’921 patent as a “surfactant that works as a wetting agent to
`increase the dissolution of sitagliptin.” Id. at *8, *11.
`Judge Andrews rejected the generics’ suggestion to limit the
`term “sitagliptin” in claim 1 of the ’921 patent to “the
`dihydrogenphosphate salt of sitagliptin in the form of a
`monohydrate.” Id. at *11-12. He was unpersuaded that Merck had
`thus limited the scope of the term during prosecution where it
`cited to the unexpected results of the specific crystalline
`monohydrate form of the DHP salt. Id. He found that this single
`comment in the prosecution history did not “rise to the level of
`clear and unmistakable disavowal.” Id. at *12.
`6. Related Patents and Applications
`a.
`U.S. Patent Number 6,699,871
`U.S. Patent Number 6,699,871 (“the ’871 patent”), filed on
`July 5, 2002, is titled “Beta-Amino Heterocyclic Dipeptidyl
`Peptidase Inhibitors for the Treatment or Prevention of Diabetes”
`15
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`
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`MEMORANDUM OPINION AND ORDER FOLLOWING BENCH TRIAL
`(DTX 2054.0001). It lists Scott Edmonson, Michael Fisher, Dooseop
`Kim, Malcolm Maccoss, Emma Parmee, Anne Weber, and Jinyou Xu as
`inventors and Merck as the assignee. Id. Issued on March 2, 2004,
`with pediatric exclusivity, the patent expires on January 26, 2023
`(Dkt. No. 123 at 9-10).12
`The ’871 patent is directed to DPP-IV inhibitors “which are
`useful in the treatment or prevention of diseases in which the
`[DPP-IV] enzyme is involved, such as diabetes and particularly
`type 2 diabetes” (DTX 2054.0001). It is also directed to
`“pharmaceutical compositions comprising of these compounds and the
`use of these compounds and compositions in the prevention or
`treatment of such diseases.” Id. This patent discloses thirty-
`three (33) DPP-IV inhibiting compounds, including sitagliptin. Id.
`at .0019-21.
`Claims 17 and 20 of the ’871 patent are relevant to the issues
`in this case. Claim 17 depicts the sitagliptin compound in its
`(R)-configuration “or a pharmaceutically acceptable salt thereof.”
`Id. at .0022. Claim 20 covers “[a] pharmaceutical composition which
`comprises an inert carrier and a compound of claim 17.” Id.
`The ’871 patent specification defines “pharmaceutically
`acceptable salts” as those “prepared from pharmaceutically
`
`
`12 Without pediatric exclusivity, the ’871 patent expires on July 26,
`2022 (Dkt. No. 123 at 10).
`
`
`
`16
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`acceptable non-toxic bases or acids including inorganic or organic
`bases and inorganic or organic acids.” Id. at .0004. The
`specification also states that “[w]hen the compound of the present
`invention is basic, salts may be prepared from pharmaceutically
`acceptable non-toxic acids, including inorganic and organic
`acids.” Id. It then provides a list of twenty-six (26) acceptable
`acids and a list of eight (8) preferred acids, both of which
`include phosphoric acid. Id. at .0004-05.
`The specification also provides that each of the claimed
`compounds has one chiral center that can produce two isomers “and
`it is intended that all of the possible optical isomers . . . are
`included within the ambit of this invention.” Id. at .0004. Example
`7 of the ’871 patent depicts an HCL salt of sitagliptin, id. at
`.0018, but the ’871 patent does not describe or exemplify any
`phosphate salt of sitagliptin, or any other compound.
`b.
`W/O 03/004498
`W/O 03/004498 (“WO ’498”) is an international patent
`application filed by Merck prior to the patents-at-issue and is
`directed to DPP-IV inhibitors “which are useful in the treatment
`or prevention of diseases in which the [DPP-IV] enzyme is involved,
`such as diabetes and particularly type 2 diabetes” (DTX 036.0004).
`The specifications of the ’871 patent and WO ‘498 are substantively
`identical (Trial Trans. 327:25-328:2 (Buckton)).
`17
`
`
`
`
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`Case 1:19-cv-00101-IMK Document 204 Filed 10/26/22 Page 18 of 120 PageID #: 11865
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`MEMORANDUM OPINION AND ORDER FOLLOWING BENCH TRIAL
`c.
`Patent Application Publication No. 2006/0287528
`
`Patent Application Publication No. 2006/0287528 (“the ’528
`publication”), filed on September 3, 2003, is titled “Novel
`Crystalline Forms of a Phosphoric Acid Salt of a Dipeptidyl
`Peptidase Inhibitor” and lists Robert Wenslow, Joseph Armstrong
`III, Alex Chen, Stephen Cypes, Russell Ferlita, Karl Hansen,
`Christopher Lindemann, and Evangelia Spartalis as inventors (DTX
`2198.0001). On March 18, 2008, the USPTO issued a Notice of
`Abandonment of the ’528 publication (Dkt. No. 123 at 9-11).
`d.
`Common Ownership
`Each inventor of the ’708 patent, the ’871 patent, and WO
`’498 assigned their inventions, patent applications, and patents
`to Merck. Id. at 17. Thus, the subject matter of the ’708 patent,
`the ’871 patent, and WO ’498 were commonly owned by Merck at the
`time of the inventions claimed in the ’708 patent. Id.
`7. Inter Partes Review
`On May 7, 2021, the United States Patent Trial and Appeal
`Board (“PTAB”) adjudicated Mylan’s petition for inter partes
`review of claims 1, 2, 3, 4, 19, 21, 22, and 23 of the ’708 patent
`(Dkt. No. 104-1). In this proceeding, Mylan raised anticipation
`and obviousness challenges to the asserted claims pursuant to 35
`U.S.C. § 102 and § 103, respectively. Id. at 4-5.
`
`
`
`18
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`Case 1:19-cv-00101-IMK Document 204 Filed 10/26/22 Page 19 of 120 PageID #: 11866
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`MEMORANDUM OPINION AND ORDER FOLLOWING BENCH TRIAL
`The PTAB concluded that WO ’498 did not expressly or
`inherently disclose the 1-to-1 DHP salt of sitagliptin used in
`Merck’s Januvia® and Janumet® products. Id. at 41. And because no
`other prior art disclosed that phosphoric acid and sitagliptin
`could form non-1-to-1 salts, the PTAB concluded that Mylan’s
`anticipation challenges based on WO ’498 and the ’871 patent
`failed. Id. at 41-43.
`And because Merck had reduced to practice the subject matter
`of claims 1, 2, 17, 19, 21, 22, and 23 before WO ’498 was published,
`and given that both the ’708 patent and WO ’498 were commonly owned
`by Merck, the PTAB concluded that WO ’498 could not be used as a
`prior art reference under § 102(a). Id. at 69. As to claims 3 and
`4 of the ’708 patent that remained subject to Mylan’s obviousness
`challenge, the PTAB determined that neither of these claims was
`obvious in view of the prior art. Id.
`8. Mylan’s Accused ANDA Products
`Mylan submitted ANDA No. 202473 to the FDA seeking approval
`to manufacture a generic version of Merck’s Januvia® product prior
`to the expiration of the ’708 patent (Dkt. No. 123 at 11). It also
`submitted ANDA No. 202478 to the FDA seeking approval to
`manufacture a generic version of Merck’s Janumet® product prior to
`the expiration of the patents-in-suit. Id.
`
`
`
`19
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`Case 1:19-cv-00101-IMK Document 204 Filed 10/26/22 Page 20 of 120 PageID #: 11867
`
`MERCK SHARPE & DOHME LLC V. MYLAN PHARM.
`
`INC
`
`1:19CV101
`
`* * SEALED **
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`MEMORANDUM OPINION AND ORDER FOLLOWING BENCH TRIAL
`
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`Case 1:19-cv-00101-IMK Document 204 Filed 10/26/22 Page 21 of 120 PageID #: 11868
`MERCK SHARPE & DOHME LLC V. MYLAN PHARM. INC
`1:19CV101
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`**SEALED**
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`MEMORANDUM OPINION AND ORDER FOLLOWING BENCH TRIAL
`
`
`
`
`9. Prior Art
`Berge
`a.
`Berge, a journal article published in 1977, teaches that salt
`formation is crucial to the pharmaceutical industry because it
`alters the properties of a new drug entity and allows the most
`suitable form of the drug to be developed (DTX 006.0004-05). But
`Berge warns that choosing the most suitable salt form is a “very
`difficult task, since each imparts unique properties to the parent
`compound” and there are numerous available salt forms. Id. at
`.0001-02. Further, salt formation is highly unpredictable and
`“there is no reliable way of predicting the influence of a
`particular salt species on the behavior of the parent compound.”
`Id. at .0001.
`Various salt forms of the same compound have different
`physical, chemical, and thermodynamic properties. Id. at .0001-
`02. Due to this unpredictability, “[s]alt-forming agents are often
`chosen empirically. Of the many salts synthesized, the preferred
`form is selected by pharmaceutical chemists primarily on a
`practical basis: cost of raw materials, ease of crystallization,
`and percent yield. Other basic considerations include stability,
`
`
`
`21
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`Case 1:19-cv-00101-IMK Document 204 Filed 10/26/22 Page 22 of 120 PageID #: 11869
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`MEMORANDUM OPINION AND ORDER FOLLOWING BENCH TRIAL
`hygroscopicity, and flowability of the resulting bulk drug.” Id.
`at .0001.
`Berge also discloses a list of FDA approved salts of basic
`drugs. Chloric, hydrochloric, and dihydrochloric acids were the
`most frequently used acids, appearing in 47.66% of the salts of
`basic drugs. Id. at .0004. Phosphoric and diphosphoric acids were
`the fourth most frequently used acids, found in 3.16% of the salts
`of basic drugs. Id.
`b.
`Gould
`Gould, a journal article published in 1986, discusses salt
`selection for basic drugs and describes the ideal salt as
`“chemically stable, non-hygroscopic, not [the] cause [of]
`processing problems, and . . . quick[] [dissolving] from solid
`dosage forms” (DTX 012.0005). It also teaches that, based on its
`availability and pharmaceutical properties, hydrochloride salts
`are “by far the most frequent (~40%) choice” of all the available
`acids. Id. at .0005.
`According to Gould, “there is clear precedent, and an
`overwhelming argument on many grounds to immediately process to
`the hydrochloride salt and evaluate other forms only if problems
`with the hydrochloride emerge.” Id. Such problems may include a
`reduced dis
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