Pfizer Inc. v. Mylan Pharmaceuticals Inc., 71 F.Supp.3d 458 (2014)
`
`71 F.Supp.3d 458
`United States District Court,
`D. Delaware.
`
`Pfizer Inc., Pharmacia & Upjohn Company, Pharmacia & Upjohn Company LLC, Sugen, Inc., C.P.,
`Pharmaceuticals International C.V., Pfizer Pharmaceuticals LLC, and PF Prism C.V., Plaintiffs,
`v.
`Mylan Pharmaceuticals Inc., Defendant.
`
`C.A.No. 10–528–GMS
`|
`Signed October 22, 2014
`
`Synopsis
`Background: Patentees brought action against competitor, alleging infringement of patents related to cancer treatment
`drugs that operated by blocking angiogenesis. Following bench trial, parties moved and cross-moved for judgment on
`partial findings with respect to issue of validity.
`
`Holdings: The District Court, Gregory M. Sleet, J., held that:
`
`[1] asserted claims were not obvious based on prior patent application disclosing approximately 1,200 drug combinations;
`
`[2] potential “lead compounds” proposed by competitor would not have been selected by one skilled in art;
`
`[3] even if competitor had identified appropriate “lead compound,” it failed to establish that modifications to yield
`claimed compound were obvious; and
`
`[4] even if competitor had established prima facie case of obviousness, secondary considerations weighed against finding
`of obviousness.
`
`Patentees' motion granted.
`
`Attorneys and Law Firms
`
`*462 Jack B. Blumenfeld, Maryellen Noreika, Morris, Nichols, Arsht & Tunnell, Wilmington, DE, Stanley E. Fisher,
`Pro Hac Vice, Thomas H.L. Selby, Pro Hac Vice, for Plaintiffs.
`
`Joshua A. Mack, Pro Hac Vice, Katherine Hasper, Pro Hac Vice, Katherine Van Gunst, Pro Hac Vice, Kirin K. Gill,
`Pro Hac Vice, Robert A. Delafield, II, Pro Hac Vice, Tung–On Kong, Pro Hac Vice, for Defendant.
`
`MEMORANDUM
`
`Gregory M. Sleet, UNITED STATES DISTRICT JUDGE
`
`I. INTRODUCTION
`
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`AstraZeneca Exhibit 2100
`Mylan v. AstraZeneca
`IPR2015-01340
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`Pfizer Inc. v. Mylan Pharmaceuticals Inc., 71 F.Supp.3d 458 (2014)
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`In this patent infringement action, plaintiffs Pfizer Inc., Pharmacia & Upjohn Company, Pharmacia & Upjohn
`Company LLC, Sugen, Inc., C.P. Pharmaceuticals International C.V., Pfizer Pharmaceuticals LLC, and PF Prism
`C.V. (collectively, “Pfizer”) allege that pharmaceutical products proposed by defendant Mylan Pharmaceuticals Inc.
`(“Mylan”) infringe the asserted claims of the patents-in-suit. (D.I.1.) The court held a four-day bench trial in this
`matter on November 26 through November 29, 2012. (D.I.148–151.) Presently before the court are the parties' post-trial
`proposed findings of fact and conclusions of law concerning the validity of the patents-in-suit, specifically whether the
`asserted claims are invalid as obvious under 35 U.S.C. § 103. (D.I.152, 153.)
`
`Pursuant to Federal Rule of Civil Procedure 52(a), and after having considered the entire record in this case and the
`applicable law, the court concludes that: (1) all asserted claims of the patents-in-suit are not invalid due to obviousness;
`and (2) Pfizer's Rule 52(c) motion is granted, and Mylan's Rule 52(c) motion is denied. These findings of fact and
`conclusions of law are set forth in further detail below.
`
`II. FINDINGS OF FACT 1
`
`A. The Parties
`
`1. Plaintiff Pfizer Inc. is a corporation organized and existing under the *463 laws of Delaware and has a place of
`business at 235 East 42nd Street, New York, New York 10017.
`
`2. Plaintiff Pharmacia & Upjohn Company was a Delaware corporation that was converted into a Delaware
`limited liability company and changed its name to Pharmacia & Upjohn Company LLC on August 14, 2004.
`Pharmacia & Upjohn Company LLC has offices located at 7000 Portage Road, Kalamazoo, Michigan 49001.
`
`3. Plaintiff Sugen, Inc. (“Sugen”) is a corporation organized under the laws of Delaware and has a place of
`business at 235 East 42nd Street, New York, New York 10017.
`
`4. Plaintiff C.P. Pharmaceuticals International C.V. (“CPPI CV”) is a limited partnership (commanditaire
`vennootschap ) organized under the laws of the Netherlands, having its registered seat in Rotterdam, the
`Netherlands, and registered at the trade register held by the Chamber of Commerce in Rotterdam, under
`number 24280998. CPPI CV is a wholly owned subsidiary of Pfizer Inc. and has a place of business at 235 East
`42nd Street, New York, New York 10017.
`
`5. Plaintiff PF PRISM C.V. (“PF PRISM CV”) is a limited partnership (commanditaire vennootschap ) organized
`under the laws of the Netherlands, and registered at the trade register held by the Chamber of Commerce in
`Rotterdam, the Netherlands, under number 51840456.
`
`6. Plaintiff Pfizer Pharmaceuticals LLC is a limited liability company organized under the laws of Delaware and
`has a place of business at Km 1.9, Road 689, Vega Baja, Puerto Rico 00693. Pfizer Pharmaceuticals LLC is a
`wholly-owned subsidiary of PF PRISM CV.
`
`7. The plaintiffs will collectively be referred to as “Pfizer.”
`
`8. Defendant Mylan Pharmaceuticals Inc. (“Mylan”) is a corporation organized and existing under the laws of
`West Virginia, and has a place of business located at 781 Chestnut Ridge Road, Morgantown, WV 26505.
`
`9. The court has subject matter jurisdiction, as well as personal jurisdiction over all parties.
`
`B. Background
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`Pfizer Inc. v. Mylan Pharmaceuticals Inc., 71 F.Supp.3d 458 (2014)
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`1. The idea of treating cancer by blocking angiogenesis, i.e., the formation of blood vessels, was first suggested in
`1971. The concept, however, was still unproven in October 2000, and the FDA had not approved any drug for this
`purpose.
`
`2. Of the many possible approaches to reduce angiogenesis, one branch of Sugen's research focused on using small
`molecules to inhibit receptor tyrosine kinases (“RTKs”) on the cell surface. Various RTKs bind to external
`growth factors that promote angiogenesis and tumor growth, such as VEGF (vascular endothelial growth
`factor), PDGF (platelet *464 derived growth factor), and FGF (fibroblast growth factor).
`
`3. Sugen's first compound to reach clinical studies was SU5416. It was the first small molecule shown to be effective
`in treating tumors by inhibiting angiogenesis. SU5416 was not orally bioavailable, meaning it could not be
`administered to a patient orally, and patients required frequent injections. SU5416 went all the way through
`FDA Phase III clinical trial but was never approved for market.
`
`4. Sugen synthesized SU11248—what came to known as sunitinib—as part of a research project aimed at
`attacking tumors directly, rather than through angiogenesis inhibition.
`
`5. Sunitinib has the following chemical structure:
`
`C. The Patents–in–Suit
`
`1. U.S. Patent Number 6,573,293 (“the ′293 patent”)—“Pyrrole Substituted 2–Indolinone Protein Kinase
`Inhibitors”—issued on June 3, 2003, to Sugen and Pharmacia & Upjohn Company, as assignees. Sugen is the current
`owner of the ′293 patent.
`
`2. U.S. Application Number 09/783,264 (“the ′264 application”), which issued as the ′293 patent, was filed on
`February 15, 2001 with the United States Patent and Trademark Office (“the PTO”).
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`Pfizer Inc. v. Mylan Pharmaceuticals Inc., 71 F.Supp.3d 458 (2014)
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`3. The expiration date of the ′293 patent is February 15, 2021.
`
`4. The ′293 patent lists ten inventors on its face: Peng Cho Tang, Todd A. Miller, Xiaoyuan Li, Li Sun, Chung
`Chen Wei, Shahrzad Shirazian, Congxin Liang, Tomas Vojkovsky, Asaad S. Nematalla, and Michael Hawley.
`
`5. The ′293 patent claims priority back to provisional applications filed on February 15, 2000, July 6, 2000, and
`October 27, 2000, as Provisional Application Numbers 60/182,710, 60/216,422, and 60/243,532, respectively.
`
`6. Pfizer is asserting infringement of claims 5 and 21 of the ′293 patent against Mylan. For purposes of this
`action, the priority date for asserted claims 5 and 21 is October 27, 2000.
`
`7. U.S. Patent Number 7,125,905 (“the ′905 patent”)—“Pyrrole Substituted 2–Indolinone Protein Kinase
`Inhibitors”—issued on October 24, 2006. *465 Sugen is the current owner of the ′905 patent.
`
`8. U.S. Application Number 11/028,477 (“the ′477 application”), which issued as the ′905 patent, was filed on
`January 4, 2005 with the PTO. The ′477 application is a continuation of Application Number 10/412,690, filed
`with the PTO on April 14, 2003, now abandoned, which is a division of the ′264 application.
`
`9. The expiration date of the ′905 patent is February 15, 2021.
`
`10. The ′905 patent lists ten inventors on its face: Peng Cho Tang, Todd A. Miller, Xiaoyuan Li, Li Sun, Chung
`Chen Wei, Shahrzad Shirazian, Congxin Liang, Tomas Vojkovsky, Asaad S. Nematalla, and Michael Hawley.
`
`11. The ′905 patent also claims priority back to provisional applications filed on February 15, 2000, July 6,
`2000, and October 27, 2000, as Provisional Application Numbers 60/182,710, 60/216,422, and 60/243,532,
`respectively.
`
`12. Pfizer is asserting infringement of claims 1 and 2 of the ′905 patent against Mylan. For purposes of this
`action, the priority date for asserted claims 1 and 2 is October 27, 2000.
`
`1. The Asserted Claims
`
`a. ′293 Patent, Claim 5
`
`1. Claim 5 of the ′293 Patent reads: The compound or salt of claim 1, wherein the compound is selected from the
`group consisting of:
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`or an L-malate salt thereof.
`
`2. Claim 21 of the ′293 Patent reads: A pharmaceutical composition, comprising a compound or salt of claim 5 and,
`a pharmaceutically acceptable carrier or excipient.
`
`b. ′293 Patent, Claim 21
`
`3. Claim 1 of the ′905 Patent reads: A compound that is the L-malate salt of 5–(5–fluoro–2–oxo–1,2–dihydroindol–
`3–ylidenemethyl)–2,4–dimethyl–1H–pyrrole–3–carboxylic acid (2–diethylaminoethyl)amide.
`
`c. ′905 Patent, Claim 1
`
`*466 d. ′905 Patent, Claim 2
`
`4. Claim 2 of the ′905 Patent reads: A pharmaceutical composition comprising the compound of claim 1 and a
`pharmaceutically acceptable carrier or excipient.
`
`D. Sutent® and Mylan's ANDA
`
`1. The ′293 and ′905 patents cover, inter alia, the compound sunitinib malate. Pfizer sells pharmaceutical capsules
`containing sunitinib malate under the trade name Sutent®, pursuant to a New Drug Application that has been
`approved by the United States Food and Drug Administration (“FDA”). Sutent® is indicated for the treatment
`of “advanced renal cell carcinoma,” “gastrointestinal stromal tumor after disease progression on or intolerance
`to imatinib mesylate,” and “progressive, well-differentiated pancreatic neuroendocrine tumors in patients with
`unresectable locally advanced or metastatic disease.” The FDA has approved Sutent® in 12.5 mg, 25 mg, 37.5 mg,
`and 50 mg dosage strengths.
`
`2. Mylan has submitted to the FDA Abbreviated New Drug Application (“ANDA”) No. 201–275, seeking
`approval to sell generic versions of drug products containing sunitinib malate in 12.5 mg, 25 mg, 37.5, and 50
`mg dosage strengths (“Mylan's ANDA Products”). ANDA No. 201–275 contains certifications pursuant to
`
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`Pfizer Inc. v. Mylan Pharmaceuticals Inc., 71 F.Supp.3d 458 (2014)
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`21 U.S.C. § 355(j)(2)(A)(vii)(IV) with respect to the ′293 and ′905 patents asserting that the ′293 and ′905
`patents are invalid, unenforceable, and/or will not be infringed by the manufacture, use, offer for sale, or sale
`of Mylan's ANDA products.
`
`3. Mylan has since stipulated that the manufacture, use, sale, offer for sale, or importation of Mylan's ANDA
`Products, as well as the active ingredient contained therein, infringes claims 5 and 21 of the ′293 Patent, and
`claims 1 and 2 of the ′905 Patent. 2
`
`III. DISCUSSION AND CONCLUSIONS OF LAW
`The court has subject matter jurisdiction over this matter pursuant to 28 U.S.C. §§ 1331, 1338, and 2201. Venue is proper
`in this court under 28 U.S.C. §§ 1391 and 1400(b). The only issue remaining is whether the asserted claims of the patents-
`in-suit are invalid due to obviousness. 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: (1) none of asserted
`claims of the patents-in-suit are invalid due to obviousness; and (2) Pfizer's Rule 52(c) motion is granted, and Mylan's
`Rule 52(c) motion is denied. The court's reasoning follows.
`
`A. Obviousness
`The defendants challenge the validity of each of the asserted claims, arguing that they are obvious in light of the prior
`art. The court finds, for the reasons that follow, that the defendants have failed to establish by clear and convincing
`evidence that the patents-in-suit are obvious.
`
`1. The Legal Standard
`
`[1] 35 U.S.C. § 103(a) provides that a patent may not be obtained “if the differences between the subject matter sought
`to be patented 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.” 35 U.S.C. § 103(a). *467 Obviousness is a question of law that is predicated on several factual
`inquires. See Richardson–Vicks v. Upjohn Co., 122 F.3d 1476, 1479 (Fed.Cir.1997). Specifically, 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, 86 S.Ct. 684, 15 L.Ed.2d
`545 (1966).
`
` [3] “A patent shall be presumed valid.” 35 U.S.C. § 282. A party seeking to challenge the validity of a patent based
`[2]
`on obviousness must demonstrate by “clear and convincing evidence” 3 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 Intern.
`Co. v. Teleflex, Inc., 550 U.S. 398, 421, 127 S.Ct. 1727, 167 L.Ed.2d 705 (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 nature of the problem, or the knowledge of a person having ordinary
`skill in the art, in order to find obviousness. See KSR, 550 U.S. at 415, 127 S.Ct. 1727. 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' in an obviousness determination.” Takeda Chem.
`Indus. v. Alphapharm Pty. Ltd., 492 F.3d 1350, 1356–57 (Fed.Cir.2007) (quoting KSR, 550 U.S. at 418, 127 S.Ct. 1727).
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` [5] “Obviousness does not require absolute predictability of success,” but rather, requires “a reasonable expectation
`[4]
`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 number 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.2008).
`
`2. The Level of Ordinary Skill in the Art
`
`A person of ordinary skill in the art with respect to the patents-in-suit would have: (1) the skills of a Ph.D.-educated
`medicinal chemist, with knowledge and experience regarding kinase targets and chemical scaffolds as they relate to
`anti-angiogenesis drugs; 4 or (2) the skills of a Ph.D. or *468 M.D. with experience in the fields of kinase inhibitor
`compounds and cancer treatment, with one to five years of post-doctoral experience in drug development. 5 The court
`concludes that the parties' definitions of a person of ordinary skill in the art do not differ in a meaningful way.
`
`3. The Scope and Content of the Prior Art and Differences Between the Claimed Subject Matter and the Prior Art
`
`Although there are four asserted claims in the patents-in-suit, the controlling question for each of the claims is whether
`synthesizing sunitinib malate would have been obvious to one skilled in the art as of the priority date. Mylan argues
`that the asserted claims are obvious for two reasons: (1) a nearly identical analog of sunitinib was disclosed in Patent
`Application WO 99/61422 (“the ′422 application”); and (2) the lead compounds available as of the priority date would
`have motivated one skilled in the art to derive the claimed sunitinib malate. The court addresses each of these arguments
`in turn.
`
`a. The ′422 Application
`
`[6] Mylan argues that the ′422 Application discloses a “generic preparation” for a “large number of potential
`oxindoles,” among which is a structurally similar analog of sunitinib: dimethyl sunitinib. 6 (D.I. 152 at 27–29; Tr.
`at 158–59 (Denny).) The difference between dimethyl sunitinib and sunitinib is simply that dimethyl sunitinib has
`a dimethylamine solubilizing group whereas the claimed compound has a diethylamine group. Although the ′422
`Application discloses approximately 1200 possible combinations, Mylan asserts that the ′422 Application instructs that
`each of the combinations will work, and therefore the “routine” steps of going from dimethyl sunitinib to sunitinib and
`finally to sunitinib malate were obvious. (D.I. 152 at 28–29.)
`
`Mylan relies on Merck & Co. v. Biocraft Laboratories, Inc. for this proposition. 874 F.2d 804 (Fed.Cir.1989). In Merck,
`the Federal Circuit distinguished between compounds that are merely “obvious to try”—which are not barred by § 103
`—versus compounds with an expectation of success, i.e., compounds that will work for their intended purpose. Id. at
`807. When a prior art reference lists a number of combinations, all of which should achieve the desired result, “routine”
`alterations or optimization will not preclude a finding of obviousness. Id. at 809.
`
`The court finds, however, that Mylan's reliance on Merck goes too far. In Merck, the prior art reference disclosed
`individual diuretic agents that could be co-administered to achieve the desired properties. Id. at 807. The Federal
`Circuit found the patent-in-suit obvious in light of the prior art reference because the patentee had merely followed the
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`instructions and optimized the dosage levels. Id. at 808–09. Similarly, in Mylan's other cited case, the claimed compound
`was simply a salt form of one of the compounds disclosed in the prior art, a step which was in fact suggested by the
`prior art reference. See Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1367 (Fed.Cir.2007) (“[T]he prior art provided not
`only the means of creating acid addition salts but also predicted the results, which Pfizer merely had to verify through
`routine testing.”) The court is not convinced that the steps needed to go from *469 dimethyl sunitinib ultimately to
`sunitinib malate constituted “routine optimization” on par with that in Merck or Pfizer. (D.I. 152 at 27–29.) Although
`Mylan states matter-of-factly that “the optimization of dimethyl to diethyl is even more routine and therefore obvious”
`than the steps taken in Merck and Pfizer, those cases involved little more than following clearly delineated steps outlined
`by the prior art. (Id. at 28.) Critical to the Federal Circuit's decision in Merck was the fact that “success [was] not
`dependent upon random variation of numerous parameters.” Merck, 874 F.2d at 807. The court finds that the process of
`going from dimethyl sunitinib to sunitinib to sunitinib malate would have required significant guesswork and variation
`of parameters to achieve the end result. The ′422 Application did not indicate that these steps would yield better
`angiogenesis inhibition, nor is the court convinced that the one skilled in the art would have found these “optimization”
`steps obvious without some data to support it. (Tr. at 227 (Denny).) The court recognizes that Merck predates KSR,
`and there is no requirement that the prior art offers an explicit teaching, suggestion, or motivation for the court to
`make an obviousness determination. See KSR, 550 U.S. at 415, 127 S.Ct. 1727. But given the sheer volume of possible
`combinations and the additional subsequent chemical alterations necessary to arrive at the claimed compound, the court
`cannot say that one skilled in the art would have had a reason to alter dimethyl sunitinib as Mylan suggests. Thus, the
`asserted claims are not obvious in light of the '422 Application. 7 See Takeda, 492 F.3d at 1356–57.
`
`b. Lead Compounds
`
`[7] Pfizer and Mylan both provide a list of “lead” compounds—compounds known in the art that would have served as
`logical “starting points[ ] for further development efforts.” See Otsuka Pharm. Co. v. Sandoz, Inc., 678 F.3d 1280, 1291
`(Fed.Cir.2012); see also Takeda, 492 F.3d at 1357–60. To establish a prima facie case of obviousness, Mylan must first
`establish that one skilled in the art would have selected a given lead compound. See Takeda, 492 F.3d at 1360; Eli Lilly
`& Co. v. Zenith Goldline Pharm., Inc., 471 F.3d 1369 (Fed.Cir.2006). If one skilled in the art would have chosen the lead,
`Mylan must then prove that modification of the lead compound to arrive at the claimed compound would have been
`obvious to one skilled in the art. Takeda, 492 F.3d at 1360–63.
`
`Pfizer argues that its proffered leads—Compounds 11f, 9a, and 9b; SU6668; PTK–787; ZD 4190; PD–74 and PD–85
`—take into account the entire state of the art, including compounds developed by other companies, and best illustrate
`trends in anti-angiogenesis research at the time. (D.I. 153 at 4–6; Tr. at 321–25 (Lydon).) Compounds 11f, 9a, and 9b
`were Sugen's “second-generation” oxindole compounds, developed on the heels of SU5416, which had gone to clinical
`trials with mixed success. (D.I. 153 at 4–5.) Sugen believed these second-generation compounds would overcome the
`shortcomings of SU5416; in particular, these second-generation compounds improved VEGFR potency and addressed
`solubility and oral bioavailability problems. (Id.) Based on Sugen's structural-activity relationship research, each of these
`compounds incorporated a propionic acid group on the pyrrole ring, which Sugen believed was “required” for potency.
`(Id.; JTX–113 at 7; Tr. at 648(Sun).)
`
`Pfizer next highlights SU6668 as a possible lead. (D.I. 153 at 5.) SU6668 was Sugen's second-generation clinical candidate.
`*470 Like Compounds 11f, 9a, and 9b, it incorporated a propionic acid group on the pyrrole ring and solved several
`of the problems that plagued SU5416: “The molecular modification of SU5416 provided significant improvements in
`pharmacokinetics, oral bioavailability, efficacy, preclinical safety, and pharmaceutical properties of SU6668.” (Id.; PTX–
`632 at 2; Tr. at 445–16 (Lyons) ( “[SU]5416 was an early first generation compound, at which, in the early '90s, was
`interesting, there is no doubt about that. However, [SU]6668 had already addressed multiple problems that that molecule
`had.”))
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`Finally, Pfizer provides several non-oxindole compounds that were developed by competitor companies to address
`angiogenesis in tumors. (D.I. 153 at 5–6.) PTK–7878 (developed by Novartis), ZD 4190 (developed by AstraZeneca), and
`PD–75 and PD–85 (developed by Parke–Davis) all showed notable improvements over SU5416. (Id.) Given the apparent
`success of these compounds, Pfizer argues that one skilled in the art would not have limited the scope of potential leads
`to only oxindole compounds.
`
`In contrast, Mylan proposes three possible lead compounds: SU5416, SU5408, and dimethyl sunitibin. As already noted,
`SU5416 was Sugen's first-generation compound and the first small molecule demonstrating RTK inhibition to reach
`clinical trials. (D.I. 152 at 8–9.) Mylan argues that Sugen itself had used SU5416 as a scaffold in developing other possible
`formulations, including SU6668, thus confirming its status as a lead compound, notwithstanding its oral bioavailability
`and metabolism concerns. (Id. at 10)
`
`Mylan also lists SU5408 as a possible lead compound. (Id. at 10.) SU5408 was another first-generation compound,
`structurally similar to both SU5416 and SU6668. It demonstrated strong VEGF potency, and its electronic-withdrawing
`ethyl ester group at C–4' position of the pyrrole ring would have helped reduce metabolism in the body. (Id. at 11.)
`Mylan argues that one skilled in the art would have recognized the promising base properties of SU5408 and would have
`modified it to achieve additional improvements. (Id.)
`
`Finally Mylan suggests one skilled in the part would have selected dimethyl sunitinib as a lead compound. (Id. at
`11–12.) As noted above, this compound is drawn from the ′422 Application, which provided a list of oxindoles and
`aldehydes that could be combined to create a possible RTK inhibitor. (Id.; Tr. at 158–59 (Denny).) The list provides
`for approximately 1200 distinct combinations. Mylan argues that dimethyl sunitinib would have been selected as a
`lead compound from among the various possible combinations contemplated by the ′422 Application because of the
`common core structure it shared with SU5416 and SU6668, and also because it would have addressed the metabolism
`and solubilization problems. (D.I. 152 at 12.)
`
`[8] Mylan bears the burden in proving that one skilled in the art would have considered its proposed lead compounds.
`See Bristol–Myers Squibb Co. v. Teva Pharm. USA, Inc., 923 F.Supp.2d 602, 654 (D.Del.2013). To avoid the possibility of
`hindsight bias, “the patent challenger must point to more than mere structural similarity as a reason to select a compound
`as a lead.” Id. (citing Daiichi Sankyo Co. v. Matrix Labs., Ltd., 619 F.3d 1346, 1354 (Fed.Cir.2010). Moreover, even if
`the compounds Mylan suggests are shown to be viable leads, Mylan must then establish that one skilled in the art would
`have found it obvious to modify the lead compounds to arrive ultimately at claimed compound: sunitinib malate. After
`considering the parties' submissions and the evidence on the record, the court is not *471 convinced that any of Mylan's
`proffered compounds would have constituted lead compounds as of the October 2000 priority date.
`
`i. SU5416
`
`[9] The court finds that, although SU5416 represented a breakthrough in anti-angiogenesis cancer treatment at the
`time it was first disclosed, as of the priority date in October 2000, one skilled in the art would have acknowledged
`its shortcomings and looked to more recent advances in the field. Sugen published its SU5416 data in 1998, but
`already by 1999 Sugen had published research on second-generation compounds that addressed SU5416's lack of oral
`bioavailability. By October 2000, SU6668 had also reached clinical trials and demonstrated improvements over SU5416
`in several respects. (Tr. at 383 (Lydon).) Sugen's publications disclosed that the presence of a propionic acid group was
`a necessary element for potency, and therefore taught away from SU5416, which lacked a propionic acid group. In
`considering lead compounds, one skilled in the art would not ignore these teachings and discount the improvements and
`progress that had been made in the field in favor of SU5416, simply because it was first. The art had advanced beyond
`SU5416 by October 2000. The court concludes one skilled in the art would not have chosen SU5416 as a lead compound.
`
` © 2016 Thomson Reuters. No claim to original U.S. Government Works.
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`Pfizer Inc. v. Mylan Pharmaceuticals Inc., 71 F.Supp.3d 458 (2014)
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`ii. SU5408
`
`[10] The court finds that SU5408 also would not have been selected by one skilled in the art as a lead compound.
`Mylan's choice of SU5408 as a lead compound appears largely the result of hindsight. SU5408, like SU5416, was one
`of Sugen's first-generation compounds. Although it demonstrated strong potency against VEGF in vitro, there is no in
`vivo data available for SU5408; indeed Mylan's expert Dr. Denny acknowledged that “[v]ery little work was done with
`SU5408.” (Tr. at 207 (Denny).) Mylan once again relies on a snapshot of the state of the art as it existed in 1998 when
`Sugen disclosed its first-generation compounds. (Tr. at 151 (Denny).) But as already stated, the field moved forward,
`and one skilled in the art would have kept pace with such progress in selecting lead compounds. Whereas SU5416 at least
`made it to clinical trials and yielded significant data, SU5408 never made it out of the lab. The data are very limited. One
`skilled in the art would not have had any particular motivation for selecting SU5408, especially in light of the second-
`generation compounds and their much more promising and complete data, which was widely available as of October
`2000.
`
`iii. Dimethyl Sunitinib
`
`[11] Finally Mylan argues that dimethyl sunitinib—a hypothetical compound listed as one of approximately 1200
`possible combinations in the ′422 Application—would have been a lead compound for one skilled in the art. The court
`finds that Mylan's choice of dimethyl sunitinib as a lead compound cannot be characterized by anything other than
`hindsight bias. The compound, which is referred to here as dimethyl sunitinib only for the sake of convenience, had
`no name, had no chemical structure, had never actually been synthesized, and of course had no data demonstrating its
`properties. The only hint that this compound could exist came from the ′422 Application's list of components, and there
`was nothing to suggest that this particular combination would yield promising results as a lead. (Tr. at 201–02 (Denny).)
`Dr. Denny's choice of dimethyl sunitinib as a lead was informed by a “logic chain.” (Id. at 202–03.) The court finds,
`however, that one skilled in the art would not have ignored actual, synthesized compounds *472 with actual data in
`favor of a hypothetical, never-created compound as a lead.
`
`In the previous discussion, the court explained that the claimed sunitinib malate is not obvious in light dimethyl sunitinib
`because more than routine optimization would have been needed to achieve the claimed compound. Similarly, the court
`now concludes that, under a lead compound analysis, one skilled in the art also would not have chosen dimethyl sunitinib
`as a lead compound. As quoted above, “the patent challenger must point to more than mere structural similarity as a
`reason to select a compound as a lead.” Bristol–Myers Squibb, 923 F.Supp.2d at 654. The court is not persuaded by Dr.
`Denny's “logic chain” rationale that resulted in selecting the almost identical structural analog of sunitinib malate. The
`court concludes that this post-hoc reconstruction of events is entirely informed by hindsight bias.
`
`iv. Modifying the Lead Compounds
`
`Even accepting Mylan's choices as lead compounds, the court finds that Mylan has not established by clear and
`convincing evidence that modifying the leads to yield sunitinib malate would have been obvious to one skilled in the
`art or that one skilled in the art would have had a reasonable expectation of success. See Daiichi Sankyo Co. v. Matrix
`Labs., Ltd., 619 F.3d 1346, 1352 (Fed.Cir.2010) (“Proof of obviousness based on structural similarity requires clear and
`convincing evidence that a medicinal chemist of ordinary skill would have been motivated to select and then to modify