Case 1:14-cv-00664-GMS Document 383 Filed 02/02/17 Page 1 of 18 PageID #: 3283
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`ASTRAZENECA AB,
`
`Plaintiff,
`
`v.
`
`AUROBINDO PHARMA LTD., et al.
`
`Defendants.
`
`)
`)
`)
`)
`)
`)
`)
`)
`)
`)
`
`C.A. No. 14-664-GMS
`(CONSOLIDATED)
`
`I.
`
`INTRODUCTION
`
`MEMORANDUM
`
`In this consolidated patent infringement action, plaintiff AstraZeneca alleges that
`
`pharmaceutical products proposed by defendants Aurobindo Pharma Ltd., Aurobindo Pharma
`
`U.S.A., Wockhardt Bio AG, Wochardt USA LLC, Amneal Pharmaceuticals LLC, Sun
`
`Pharmaceutical Industries Ltd., Sun Pharmaceutical Industries Ltd., Sun Pharma Global FZE,
`
`Mylan Pharmaceuticals Inc., Watson Laboratories, Inc., and Actavis Laboratories FL, Inc.
`
`(collectively "Aurobindo") infringe the asserted claims of U.S. Reissue Patent No. RE44,186
`
`("RE'186 patent" or "the patent-in-suit"). 1 The court held a three-day bench trial on September
`
`19, 2016 through September 21, 2016. (D.I. 369-371.) Presently before the court are the parties'
`
`proposed finding of fact and conclusions of law concerning the validity of the RE'186 patent,
`
`specifically whether the asserted claims are invalid as obvious under 35 U.S.C. § 103. (D.I. 373,
`
`374, 375.)
`
`1 AstraZeneca asserts claims 25 and 26 of the RE'186 patent. Two additional patents were originally at
`issue: U.S. Patent No.7,951,400 ("'400 patent") and U.S. Patent No. 8,628,799 ('"799 patent"). Following
`stipulations dismissing all claims concerning the '400 patent and '799 patent, the court dismissed these cases from
`the consolidated action: Civil Action Nos. 14-cv-665, 14-cv-666, 14-cv-695, 14-cv-698, and 14-cv-845.
`
`1
`
`

`

`Case 1:14-cv-00664-GMS Document 383 Filed 02/02/17 Page 2 of 18 PageID #: 3284
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`Pursuant to Federal Rule of Civil Procedure 52(a), having considered the entire record in
`
`this case and the applicable law, the court concludes that the asserted claims of the RE'186 patent
`
`are not invalid due to obviousness. These findings of fact and conclusions of law are set forth in
`
`further detail below.
`
`II.
`
`Findings of Fact2
`
`A.
`
`The Parties
`
`Plaintiff AstraZeneca is a company operating and existing under the laws of Sweden, with
`1.
`its principal place of business at S-151 85 S6dertalje, Sweden.
`
`Plaintiff's subsidiary, AstraZeneca Pharmaceutfoals LP, is a limited partnership operating
`2.
`and existing under the laws of Delaware, with its principal place of business at 1800 Concord Pike,
`Wilmington, Delaware 19803.
`
`Wockhardt Bio AG. is a corporation organized and existing under the laws of Switzerland,
`3.
`having a principal place of business at Grafenauweg 6, 6300 Zug, Switzerland.
`
`Wockhardt USA LLC is a limited liability company, existing under the laws of the State
`4.
`of Delaware and having a principal place of business at 20 Waterview Boulevard, Parsippany,
`New Jersey 07054.
`
`5.
`
`Wockhardt USA LLC is an indirect subsidiary ofWockhardt Bio AG.
`
`Aurobindo Pharma Ltd. is a corporation organized and existing under the laws of India,
`6.
`having a principal place of business of Plot #2, Maitri Vihar, Ameerpet, Hyderabad - 500038,
`Andhra Pradesh, India.
`
`Aurobindo Pharma U.S.A., Inc. is a corporation organized and existing under the laws of
`7.
`the State of Delaware, having its principal place of business at 6 Wheeling Road, Dayton, New
`Jersey 08810.
`
`8.
`
`Aurobindo Pharma U.S.A., Inc. is a wholly owned subsidiary of Aurobindo Pharma Ltd.
`
`2 Prior to trial, the parties submitted an exhibit of uncontested facts in conjunction with their Pretrial Order.
`(D.I. 338, Ex. A) The court takes most of its findings of fact from the parties' uncontested facts. Where necessary,
`the court has overruled objections to the inclusion of these facts. The court has also reordered and renumbered some
`paragraphs, corrected some spelling and formatting errors, iµid made minor edits for the purpose of concision and
`clarity that it does not believe alters the meaning of the paragraphs from the Pretrial Order. Otherwise, any differences
`between this section and the parties' statement of uncontested facts are unintentional. The court's findings of fact
`with respect to matters that were the subject of dispute between the parties are included in the Discussion and
`Conclusions of Law section of this opinion, preceded by the phrase "the court finds" or "the court concludes."
`
`2
`
`

`

`Case 1:14-cv-00664-GMS Document 383 Filed 02/02/17 Page 3 of 18 PageID #: 3285
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`Amneal Pharmaceuticals LLC is a limited liability company, existing under the laws of the
`9.
`State of Delaware and having a principal place ofbusiness at 400 Crossing Boulevard, Third Floor,
`Bridgewater, New Jersey 08807.
`
`Sun Pharmaceutical industries Ltd. is a company organized and existing under the laws of
`10.
`India, having a principal place of business at Acme Plaza, Andheri-Kurla Rd., Andheri (E),
`Mumbai-400 059, India.
`
`Sun Pharma Global FZE is a company organized and existing under the laws of the United
`11.
`Arab Emirates, having a principal place of business at Executive Suite #43, Block Y, SAIF Zone,
`P.O. Box 122304, Sharjah, United Arab Emirates.
`
`Sun Pharma Global FZE is a wholly-owned subsidiary of Sun Pharma Global Inc., a
`12.
`corporation organized and existing under the laws of the British Virgin Islands, which in turn is a
`wholly-owned subsidiary of Sun Pharmaceutical Industries Ltd.
`
`13. Mylan Pharmaceuticals Inc. is a corporation organized and existing under the laws of West
`Virginia, having a principal place of business at 781 Chestnut Ridge Road, Morgantown, West
`Virginia 26505.
`
`14. Watson Laboratories, Inc. is a corporation organized and existing under the laws of
`Nevada, having a principal place of business at Morris Corporate Center III, 400 Interpace
`Parkway, Parsippany, New Jersey 07054.
`
`Actavis Laboratories FL, Inc. (f/k/a Watson Laboratories, Inc. - Florida) is a corporation
`15.
`organized and existing under the laws of Florida, having a principal place of business at 4955
`Orange Drive, Davie, Florida 33314.
`
`16.
`
`The court has subject matter jurisdiction and personal jurisdiction over all parties.
`
`B.
`
`Background
`
`These consolidated actions arise out of Defendants' submission of several Abbreviated
`1.
`New Drug Applications ("AND As") under§ 505G) of the Federal Food, Drug and Cosmetic Act
`to the United States Food and Drug Administration ("FDA"), seeking approval to market and sell
`generic saxagliptin pharmaceutical drug products prior to the expiration of AstraZeneca' s RE' 186
`patent.
`
`Saxagliptin is chemical compound that is an FDA-approved DPP4 inhibitor that has been
`2.
`used to treat type 2 diabetes. Saxagliptin has the following chemical structure:
`
`3
`
`

`

`Case 1:14-cv-00664-GMS Document 383 Filed 02/02/17 Page 4 of 18 PageID #: 3286
`
`3-Hydroxy- HO
`Quaternary carbon _
`
`___,___,_
`
`-
`
`cis-4,5-cyclopropyl
`
`Primary amine -
`
`H2N
`
`O
`
`CN -cyano (or "nifrile")
`
`Saxagliptin's structure includes a cis-4,5-cyclopropyl group fused to a cyanopyrrolidine
`3.
`ring. The resulting cis-4,5-cyclopropyl-cyanopyrrolidine moiety represents the Pl group.
`Saxagliptin also contains a 3-hydroxyadamantyl group that is C-linked through a quartemary
`carbon (a carbon with four non-hydrogen groups attached to it) to the peptide backbone, resulting
`in primary amine. The C-linked 3-hydroxyadamantyl glycine moiety represents the P2 group.
`
`AstraZeneca is the holder of New Drug Application ("NDA") No. 022350, by which the
`4.
`FDA granted approval for the marketing and sale of 2.5 mg and 5 mg strength saxagliptin
`hydrochloride tablets as an adjunct to diet and exercise to improve glycemic control in adults with
`type 2 diabetes mellitus in multiple clinical settings.
`
`AstraZeneca markets 2.5 mg and 5 mg strength saxagliptin hydrochloride tablets in the
`5.
`United States, through its Ilelaware subsidiary AstraZeneca Pharmaceuticals LP, under the trade
`name "Onglyza®."
`
`Pursuant to 21 U.S.C. § 355 and attendant FDA regulations, the RE'186 patent is listed in
`6.
`the FDA publication "Approved Drug Products with Therapeutic Equivalence Evaluations" (the
`"Orange Book") with respect to Onglyza®.
`
`The Orange Book includes 2.5 mg and 5 mg strength Onglyza® together with the RE'l86
`
`7.
`patent.
`
`AstraZeneca is the holder of NDA No. 200678, by which the FDA granted approval for
`8.
`the marketing and sale of 5 mg/500 mg, 5 mg/l 000 mg, and 2.5 mg/l 000 mg strength saxagliptin
`hydrochloride and metformin hydrochloride extended release tablets as an adjunct to diet and
`exercise to improve glycemiC control in adults with type 2 diabetes mellitus when treatment with
`both saxagliptin and metformin is appropriate.
`
`AstraZeneca markets 5 mg/500 mg, 5 mg/1000 mg, and 2.5 mg/1000 mg strength
`9.
`saxagliptin hydrochloride and metformin hydrochloride extended release tablets in the United
`States, through its Delaware subsidiary AstraZeneca Pharmaceuticals LP, under the trade name
`"KombiglyzeTM XR."
`
`Pursuant to 21 U.S.C. § 355 and attendant FDA regulations, the RE'186 patent is listed in
`10.
`the Orange Book with respect to Kombiglyze TM XR.
`
`The Orange Book includes 5 mg/500 mg, 5 mg/1000 mg, and 2.5 mg/l 000 mg strength
`11.
`KombiglyzeTM XR together with the RE'186 patent.
`
`4
`
`

`

`Case 1:14-cv-00664-GMS Document 383 Filed 02/02/17 Page 5 of 18 PageID #: 3287
`
`C.
`
`The Patent-in-Suit
`
`U.S. Reissue Patent Number RE44, 186 (''the RE'186 patent"), issued on April 30, 2013,
`1.
`and is entitled "Cyclopropyl-fused pyrrodlidine-based inhibitors of dipeptidyl peptidase IV and
`method." The R.8'186 patent names Jeffrey A. Rohl, Richard B. Slusky, David J. Augeri, David
`R. Magnin, Lawrence G. Hamann, and David A. Betebenner as inventors.
`
`2.
`
`AstraZeneca is the assignee of the RE'186 patent.
`
`AstraZeneca is the owner by assignment of the RE' 186 patent. AstraZeneca has standing
`3.
`to bring suit on the RE' 186 patent.
`
`U.S. Application No. 13/308,658 ("the '658 Application"), which issued as the RE'186
`4.
`patent, was filed with the United States Patent and Trademark Office ("PTO") on December 1,
`2011.
`
`The RE'186 patent is a reissue of U.S. Patent No. 6,395,767 ("the '767 patent"), which
`5.
`originally issued on May 28, 2002.
`
`The '767 patent was filed on February 16, 2001 and claims priority to provisional
`·6.
`application 60/188,155 ("the '155 application) filed on March 10, 2000.
`
`1) The Asserted Claims
`
`AstraZeneca has asserted infringement of claims 25 and 26 of the RE' 186 patent against
`7.
`each defendant.
`
`i. RE'186 Patent, Claim 25
`
`8.
`
`Claim 25 of the RE'186 patent reads: A compound that is
`
`HO
`
`N~
`
`O NC
`
`or a pharmaceutically acceptable salt thereof
`
`ii. RE'186 Patent, Claim 26
`
`Claim 26 of the RE'186 patent reads: The compound as defined in claim 25, wherein the
`9.
`pharmaceutically acceptable salt is the hydrochloride salt.
`
`10.
`
`Claim 26 is directed to the single compound saxagliptin hydrochloride salt.
`
`5
`
`

`

`Case 1:14-cv-00664-GMS Document 383 Filed 02/02/17 Page 6 of 18 PageID #: 3288
`
`D.
`
`Procedural History
`
`On May 23, 2014, AstraZeneca filed suit against Aurobindo asserting infringement of the
`1.
`RE'186 patent. (Civil Action No. 1:14-cv-1469-GMS (D.I. 1).)
`
`In a Complaint dated May 23, 2014, AstraZeneca filed suit against Wockhardt asserting
`2.
`infringement of the RE'186 patent and the '400 patent. (Civil Action No. 1:14-cv-667-GMS (D.I.
`1).
`
`In a Complaint dated August 15, 2014, AstraZeneca filed suits_against Watson, Actavis,
`3.
`Inc., and Actavis LLC asserting infringement of the RE'186 patent and the '400 patent. (Civil
`Action No. 1:14-cv-1051-GMS (D.I. 1).)
`
`In a Complaint dated June 2, 2014, AstraZeneca filed suifagainst Suri Pharma asserting
`4.
`infringement of the RE'186 patent and the '400 patent. (Civil Action No. 1:14-cv-694-GMS (D.I.
`1).)
`
`In a Complaint dated June 2, 2014, AstraZeneca filed suit against Mylan asserting
`5.
`infringement of the RE' 186 patent and the '400 patent. (Civil Action No. 1 :14-cv-696-GMS (D.I.
`1).)
`
`In a Complaint dated June 2, 2014, AstraZeneca filed suit against Amneal asserting
`6.
`infringement of the RE'186 patent and the '400 patent. (Civil Action No. 1:14-cv-697-GMS (D.I.
`1).)
`
`In a Complaint dated October 31, 2014, AstraZeneca filed suit againstActavis Laboratories
`7.
`FL, Inc., Actavis, Inc., and Actavis LLC asserting infringement of RE'186 patent and the '799
`patent. (Civil Action No. 1 :14-cv-1356-GMS (D.I. 1).)
`
`The Plaintiff's patent infringement claims against Aurobindo, Amneal, Wockhardt, Sun
`8.
`Pharma, Mylan, Watson, and Actavis were consolidated under Civil Action No. 14-664 on October
`8, 2014.
`
`On October 8, 2014, the court consolidated Civil Action Nos. 14-cv-664, 14-cv-665, 14-
`9.
`cv-666, 14-cv-667, 14-cv-694, 14-cv-695, 14-cv-696, 14-cv-697, 14-cv-698, 14-cv-845, and 14-
`cv-1051.3 (Civil Action No. 1:14-cv-664-GMS (D.I. 23).)
`
`On November 17, 2014, AstraZeneca, Actavis Laboratories FL, Inc., Watson, Actavis, Inc.
`10.
`and Actavis LLC jointly filed a Stipulated Order to Consolidate Civil Action No. 14-cv-1356 with
`
`3 The consolidated action originally involved the RE' 186 patent, U.S. Patent No. 7 ,951,400 ('" 400 patent"),
`and/or U.S. Patent No. 8,628, 799 ("'799 patent"). Following stipulations dismissing all claims concerning the '400
`and '799 patents (formulation patents), Civil Action Nos. 14-cv-665, 14-cv-666, 14-cv-695, 14-cv-698, and 14-cv-
`845 were dismissed from the consolidated action.
`
`6
`
`

`

`Case 1:14-cv-00664-GMS Document 383 Filed 02/02/17 Page 7 of 18 PageID #: 3289
`
`Consolidated Civil Action No. 14-cv-664, (Civil Action No. 1:14-cv-1356-GMS (D.I. 7)), which
`the court granted on November 19, 2014. (D.I. 8.)
`
`On January 23, 2015, AstraZeneca and Aurobindo jointly filed a Stipulated Order to
`11.
`Consolidate Civil Action No. 14-cv-1469 with Consolidated Civil Action No. 14-cv-664 (Civil
`Action No. 1 :14-cv-1469-GMS, D.I. 12), which the court granted on January 27, 2015. (D.I. 13.)
`
`On January 27, 2015, AstraZeneca, Watson, Actavis, Inc., and Actavis LLC jointly filed a
`12.
`Stipulated Order of Dismissal to dismiss Watson Laboratories Inc., Actavis, Inc., and Acta vis LLC
`without prejudice from Civil Action No. 1:14-cv-1051. The court granted the Stipulation on
`January 27, 2015. (D.I. 19.)
`
`On January 27, 2015, AstraZeneca, Actavis Laboratories FL, Inc., Watson, Actavis, Inc.,
`13.
`and Actavis LLC jointly filed a Stipulated Order of Dismissal to dismiss Watson Laboratories Inc.,
`Actavis, Inc., and Actavis LLC without prejudice froin Civil Action No. 1:14~cv-1356. The court
`granted the Stipulation on January 27, 2015. (D.I. 10.)
`
`The court held a three-day bench trial in this matter on September 19 through September
`14.
`21, 2016. (D.I. 369-371.) Aurobindo stipulated to infringement of all asserted claims. Thus, the
`sole issue is Aurobindo's obviousness defense with respect to the RE'186 patent.
`
`III. Discussion and Conclusions of Law
`
`These consolidated cases arise under the patent laws of the United States, 35 U.S.C. §§
`
`1331, 1338, 2201, and 2202. Venue is proper in this court under 28 U.S.C. 1391(b) and (c), and
`
`1400(b). The defendants challenge the validity of the RE'186 patent as obvious in light of the
`
`prior art. After having considered the entire record in this case, the substantial evidence in the
`
`record, the parties' post-trial submissions, and the applicable law, the court concludes that the
`
`defendants have failed to establish by clear and convincing evidence that the asserted claims of the
`
`RE'186 patent would have been obvious to a person of ordinary skill in the art as of the February
`
`16, 2001 filing date. The asserted claims of the RE'186 patent are valid under 35 U.S.C. § 103.
`
`Aurobindo's Rule 52(c) motion is denied and AstraZeneca's Rule 52(c) motion is granted. The
`
`court's reasoning follows.
`
`7
`
`

`

`Case 1:14-cv-00664-GMS Document 383 Filed 02/02/17 Page 8 of 18 PageID #: 3290
`
`A.
`
`Obviousness
`
`1) The Legal Standard
`
`A patent may not be obtained "if the differences between the claimed invention and the
`
`prior art are such that the subject matter as a whole would have been obvious to a person having
`
`ordinary skill in the art" ("POSA"). 35 U.S.C. § 103(a). Obviousness is a question oflaw that is
`
`predicated on several factual inquires. See Richardson-Vicks v. Upjohn Co., 122 F.3d 1476, 1479
`
`(Fed. Cir. 1997). The trier of fact is directed to assess four considerations: (1) the scope and
`
`content of the prior art; (2) the level of ordinary skill in the art; (3) the differences between the
`
`claimed subject matter and the prior art; and ( 4) secondary considerations of non-obviousness,
`
`such as commercial success, long-felt but unsolved need, failure of others, acquiescence of others
`
`in the industry that the patent is valid, and unexpected results. See Graham v. John Deere Co.,
`
`383 U.S. 1, 17-18 (1966).
`
`"A patent shall be presumed valid." 35 U.S.C. § 282(a). A party seeking to challenge the
`
`validity of a patent based on obviousness must demonstrate by clear and convincing evidence4 that
`
`the invention described in the patent would have been obvious to a person of ordinary skill in the
`
`art at the time the invention was made. Importantly, in determining what would have been obvious
`
`to one of ordinary skill in the art, the use of hindsight is not permitted. See KSR Int 'l Co. v.
`
`Teleflex, Inc., 550 U.S. 398, 421 (2007) (cautioning the trier of fact against "the distortion caused
`
`by hindsight bias" and "arguments reliant upon ex post reasoning" in determining obviousness).
`
`In KSR, the Supreme Court rejected the rigid application of the principle that there should be an
`
`explicit teaching, suggestion, or motivation in the prior art, the "TSM test," in order to find
`
`4 "Clear and convincing evidence is evidence that places in the fact finder 'an abiding conviction that the
`truth of[the] factual contentions are 'highly probable."' Alza Corp. v. Andrx Pharms., LLC, 607 F. Supp. 2d 614, 631
`(D. Del. 2009) (quoting Colorado v. New Mexico, 467 U.S. 310, 316 (1984)).
`
`8
`
`

`

`Case 1:14-cv-00664-GMS Document 383 Filed 02/02/17 Page 9 of 18 PageID #: 3291
`
`obviousness. See id. at 415. The KSR Court acknowledged, however, the importance of
`
`identifying "a reason that would have prompted a person of ordinary skill in the relevant field to
`
`combine the elements in the way the claimed new invention does." Id. at 418.
`
`"Obviousness does not require absolute predictability of success," but rather, requires "a
`
`reasonable expectation of success." See Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1165
`
`(Fed. Cir. 2006) (quoting In re O'Farrell, 853 F.2d 894, 903-04 (Fed. Cir. 1988)). To this end,
`
`obviousness "cannot be avoided simply by a showing of some degree of unpredictability in the art
`
`so long as there was a reasonable probability of success." Pfizer, Inc. v. Apotex, Inc., 480.F.3d
`
`1348, 1364 (Fed. Cir. 2007). Moreover, while the Federal Circuit has noted that pharmaceuticals
`
`can be an "unpredictable art" to the extent that results may be unexpected, it also recognizes that,
`
`per KSR, evidence of a "finite nun;iber of identified, predictable solutions" or alternatives "might
`
`support an inference of obviousness." See Eisai Co. Ltd. v. Dr. Reddy 's Labs. Ltd., 533 F.3d 1353,
`
`1359 (Fed. Cir. 200).
`
`2) Level of Ordinary Skill in the Art
`
`The court must first determine the level of ordinary skill in the art at the time of the filing
`
`of the RE' 186 patent. The parties agree that a person of ordinary skill in the art relevant to the
`
`RE' 186 patent is a medicinal chemist with (1) a Ph.D. in chemistry and several years of practical
`
`experience working with pharmaceutical chemical compounds for potential and eventual clinical
`
`use in patients; or (2) a Bachelor's or Master's degree in chemistry with significantly more
`
`experience.5 The court concludes that the parties' definitions of ordinary skill in the art do not
`
`differ in a meaningful way. 6
`
`5 The defendants' description of a person of ordinary skill in the art is derived from Dr. Powers' testimony.
`(Tr. 88:2-10 (Powers).) The plaintiffs identification ofa person ofordinary skill in the art is derived from Dr. Weber's
`testimony. (Tr. 203:19-204:9 (Weber).)
`6 Dr. Weber disagreed with Dr. Powers' definition of a POSA, because he omitted the "fundamental"
`qualification captured in the last sentence of her definition: familiarity with the spectrum of properties needed for a
`
`9
`
`

`

`Case 1:14-cv-00664-GMS Document 383 Filed 02/02/17 Page 10 of 18 PageID #: 3292
`
`3) The Scope and Content of the Prior Art and Differences Between the
`Claimed Subject Matter and the Prior Art
`
`The court will consider whether Aurobindo has established a prima facie case of
`
`obviousness in light of the evidence adduced at trial. To establish a prima facie case of
`
`obviousness in cases involving new chemical compounds, the accused infringer must identify a
`
`known "lead" compound, a reason for selecting that compound, and "some reason that would have
`
`led a chemist to modify a known compound" in a way that leads to the claimed invention. Bristol- .
`
`Myers Squibb Co. v. Teva Pharm. USA, Inc., 752 E3d 967, 973 (Fed. Cir. 2014). Aurobindo
`
`argues that the asserted claims were obvious for three reasons: (1) a person of ordinary skill in the
`
`art would have been motivated to select vildagliptin7 as a lead compound; (2) a person of ordinary
`
`skill in the art would have been motivated to move the hydroxyadmantyl group; and (3) a person
`
`of ordinary skill in the art would have added a cyclopropyl ring. The court addresses each of these
`
`arguments in turn.
`
`i. Selection of Vildagliptin as a Lead Compound
`
`To establish a prima facie case of obviousness, Aurobindo must first establish that the
`
`POSA would have selected a given lead compound. See Takeda, 492 F.3d 1350, 1360 (Fed. Cir.
`
`2007); Eli Lilly & Co. v. Zenith Goldfine Pharm., Inc., 471 F.3d 1369, 1379 (Fed Cir. 2006).
`
`Aurobindo argues that a POSA would have been motivated to select vildagliptin as a lead
`
`compound. (D.I. 374 at 10-12.) Aurobindo relies on the testimony of Dr. Powers and contends
`
`that vildagliptin was a likely lead compound because it demonstrated good potency, a favorable
`
`class history, and efficacy in biological data. (Id. at 11.) Aurobindo maintains, given the literature
`
`successful drug, the potential difficulties in obtaining them, and potential effects of pharmaceutics in the body. Dr.
`Weber underscored that Dr. Powers has no relevant experience in the field of reversible DPP-4 inhibitors, has not
`published in the field, and has no experience with human clinical trials. AstraZeneca contends that Dr. Power is not
`a POSA At trial, the court recognized Dr. Powers as a POSA.
`7 AstraZeneca refers to this compound by Villhauer-063 Ex. 1, but the court will refer to it as "vildagliptin"
`for convenience, unless it is necessary to distinguish among prior art Villhauer compounds.
`
`10
`
`

`

`Case 1:14-cv-00664-GMS Document 383 Filed 02/02/17 Page 11 of 18 PageID #: 3293
`
`on potent and stable DPP4 inhibitors, a POSA would have recognized that vildagliptin structurally
`
`met the criteria of a lead compound. (Id.) Aurobindo contends in vitro tests showed good potency
`
`in human plasma. (Id.) Particularly, Aurobindo notes that of the three compounds with reported
`
`potency data as of the priority date, vildagliptin showed at least two-fold greater potency. (Id. at
`
`11-12.)
`
`i ~NTIN~
`
`HO
`
`. H
`
`Vildagliptin
`
`I
`0
`
`.
`
`"'H
`
`c
`111
`N
`
`In contrast, AstraZeneca argues that there is no reason, absent the use of hindsight, that the
`
`POSA would have selected vildagliptin as a lead compound. (D.I. 373 at 10 Tr. 199:7-18, 209:6-
`
`20, 225:5-24 (Weber).) AstraZeneca relies on Dr. Weber's testimony noting that vildagliptin was
`
`not the natural choice for further development in light of data on two more advanced compounds
`
`that had already entered the clinic: Probiodrug's compound P32/98 and Novartis' compound NVP-
`
`DPP728. (Tr. 199:7-18, 209:6-20, 225:5-24 (Weber).) According to Dr. Weber, P32/98 and NVP-
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`DPP728 were the only two compounds that had advanced into the clinic. (Tr. 208:22-209:20
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`(Weber).) Dr. Weber further testified that in vivo data trumps in vitro data, but the ultimate data
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`is human data. (Tr. 209:6-17 (Weber).) In addition, AstraZeneca argues there was no reason to
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`choose vildagliptin (Villhauer-063 Ex. 1) over other prior art Villhauer compounds. (D.I. 373 at
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`10.)
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`The court agrees that Aurobindo fails to demonstrate that a POSA would have selected
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`vildagliptin as a lead compound. Lead compound analysis "requires the challenger to demonstrate
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`... that one of ordinary skill in the art would have had a reason to select a proposed lead compound
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`11
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`or compounds over other compounds in the prior art." Daiichi Sankyo Co. v. Matrix Labs., Ltd,
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`619 F.3d 1346, 1354 (Fed. Cir. 2010). In the court's view, Aurobindo's lead compound analysis
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`is flawed because their expert narrowly focused on potency. The plaintiffs expert Dr. Weber
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`testified that a POSA would have considered other pharmacokinetic and pharmacodynamics
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`properties involved in what determines the final dose of a compound, not simply potency. (Tr.
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`214:8-215:8 (Weber).)
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`Furthermore, the court finds that a POSA would not have ignored the human clinical data
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`of compound P32/98 and compound NVP-DPP728 in favor of limited in vivo rat data. This
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`specific error reveals the taint of hindsight bias in Dr. Powers' analysis of the prior art. Dr. Powers
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`admitted that NVP-DPP728 was a "perfectly reasonable lead compound", Tr. 97:6- 16 (Powers),
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`and that, in forming his opinion, he did not consider that NVP-DPP728 had actually been shown.
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`to be effective in humans. (Tr. 143:6-10 (Powers); Tr. 339:4-11 (Weber).) The experts agree that
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`instability due to a cyclization was a serious problem for DPP4 inhibitors in 2000. (Tr. 112:14 -
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`113:7 (Powers); Tr. 212:17-22 (Weber).) Because a POSA would have recognized that P32/98 .
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`did not suffer from the chemical instability problem in the art, Tr. 211:13-21 (Weber), the court·
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`finds that P32/98 would have also been a natural lead.
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`The court also considers it important that prior art references included later Novartis
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`compounds that were just as potent and that also incorporated Ashworth II's "optimum" Pl group.
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`(Tr. 141:11-142:4 (Powers); PTX-2066 at 3; JTX-126 at 2-3.) Aurobindo has not shown why one
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`skilled in th~ art would have ignored the more recent advances of the compound in making a lead
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`compound selection. The court is not persuaded by the biological data-insulin response in an
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`animal model- because several compounds in the Villhauer patents had better insulin response
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`in the in vivo rat assay than Villhauer-063 Ex. 1. (JTX-49 at 4, PDX-223.)
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`Case 1:14-cv-00664-GMS Document 383 Filed 02/02/17 Page 13 of 18 PageID #: 3295
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`Dr. Powers' approach to the lead compound analysis fatally undermines his credibility. Dr.
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`Powers did not perform an analysis of the art as a whole. (D.I. 373 at 7.) Instead, Dr. Powers
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`initially looked at the chemical structure of saxagliptin. Then, with that structure in mind, Dr.
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`Powers looked to a selection of prior art handpicked by Aurobindo's counsel in order to select the
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`compound for his obviousness analysis. (Tr. 122:9-123:6 (Powers).) This is evidence of classic
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`hindsight bias. Based on the Dr. Weber's testimony, the court concludes that a POSA would have
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`considered P32/98 and NVP-DPP728 in addition to several other lead compounds.
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`ii. First Modification of Vildagliptin
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`Even accepting Aurobindo's selection as lead compound, the court finds that Aurobindo
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`has not established by clear and convincing evidence that modifying the lead to yield saxagliptin
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`would have been obvious to a POSA. See Daiichi at1352 ("ProQf of obviousness based on
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`structural similarity requires clear and convincing evidence that a medicinal chemist of ordinary
`
`skill would have been motivated to select and then to modify a prior art compound (e.g., a lead
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`compound) to arrive at a claimed compound with a reasonable expectation that the new compound
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`would have similar or improved properties compared with the old."). ·
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`Aurobindo argues the POSA would have moved the hydroxyadamantyl group from the
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`nitrogen of the glycine to the alpha-carbon of the glycine in order to improve potency. Dr. Powers
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`testified that a person of ordinary skill would have been motivated to do so because the prior art
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`taught that DPP4 preferred bulky groups, with a free amino group, at its P2-substrate binding
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`pocket. (Tr. 79:13-14 (Powers).) According to Aurobindo, a POSA would have been motivated
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`to make this modification for three reasons directed to increasing the potency of the molecule: (1)
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`primary amines more closely resemble the natural substrates for DPP4, (2) beta-branching was
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`known to increase potency, and (3) primary amines were generally more potent than secondary
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`ammes. (D.I. 374 at 14.) Specifically, Aurobindo relies on the teachings of Mentlein (JTX-57)
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`and Ashworth I (JTX-50). Mentlein disclosed that natural substrates of DPP4 enzymes are
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`peptides with primary amines at N-terminus. (JTX-57 at 5.) Ashworth I taught that the most
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`potent, reversible DPP4 inhibitors were primary amines. (JTX-53 at 4-5.)
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`AstraZeneca responds that there was no such motivation and no reasonable expectation of
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`success in making this modification. (D.I. 373 at 14-16.) Dr. Weber testified that the prior art
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`taught away from eliminating N-linkage from vildagliptin because it would have been a step
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`backwards to abandon what was perceived to be the stabilizing feature of the compound. (D.I.
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`373 at 35; Tr. 223:9-12, Tr. 262:5-12 (Weber).) Dr. Weber maintains that one skilled in the art
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`would have been dissuaded from making Dr. Powers' proposed change, because it was recognized
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`that the Novartis N-linked compounds ~lready had good potency and stability. (Tr. 267:6-14
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`(Weber).)
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`The court finds that Dr. Powers failed to show a motivation to move the hydroxadamantyl
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`group of his lead compound with any reasonable expectation of success. See Medichem, S.A. v.
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`Rolablo, S.L., 437 F.3d 1157, 1165 (Fed. Cir. 2006) (When prior art "suggest that the line of
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`development flowing from the reference's disclosure is unlikely to be productive of the result
`
`sought by the applicant the piece of prior art is said to 'teach away' from the claimed invention.).
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`The limited structural information on moving from N-linkage to C-linkage, the existence of
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`sufficiently potent compounds, and the inconsistency with an established solution to the stability
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`problem in the field all demonstrate that Dr. Weber is the more credible of the experts on the
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`proposition. Consequently, the court concludes this proposed modification would not have been
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`obvious.
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`Case 1:14-cv-00664-GMS Document 383 Filed 02/02/17 Page 15 of 18 PageID #: 3297
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`ill. Second Modification of Vildagliptin
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`Next, Aurobindo argues that a POSA would have expected to counteract the potential loss
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`of stability that results from modifying vildagliptin to improve potency by creating a primary
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`amine. (Tr. 110:117-111:18 (Powers); D.I. 374 at 16.) Aurobindo claims a POSA would have
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`tried the simplest modification to cause rigidity and strain to the compound-adding a 4,5
`
`cyclopropyl ring-in order to address the stability problem. (D.I. 374 at 16.) Aurobindo reasons
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`that a POSA would have been aware of and used the known method of synthesis provided by the
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`Hanessian 1998 reference in order to make the 4,5 cyclopropyl modification. (D.I. 374 at 17; JTX-
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`51.) Aurobindo also argues that selection of the point of attachment for the cyclopropyl ring would
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`have been straightforward for a POSA.
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`Auropindo's analysis is flawed. First, Dr. Powers failed to explain why a POSA would
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`introduce the problem of instability into a DPP4 inhibitor by moving from N-linkage to C-linkage
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`and then adding a cyclopropyl group to solve the newly created stability problem. The
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`combination of "several sequential modifications" is not obvious where there is no reason in the
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`prior art to make the subsequ