Pfizer Inc. et al v. Mylan Inc. et al
MEMORANDUM. Signed by Judge Gregory M. Sleet on 10/22/2014. (mdb)
IN THE UNITED STATES DISTRICT COURT
FOR THE DISTRICT OF DELAWARE
PFIZER INC., PHARMACIA & UPJOHN
COMPANY, PHARMACIA & UP JOHN
COMPANY LLC, SUGEN, INC., C.P..
C.V., PFIZER PHARMACEUTICALS LLC,
and PF PRISM C.V.,
MYLAN PHARMACEUTICALS INC.,
C.A. No. 10-528-GMS
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 ofthe
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 oflaw are set
forth in further detail below.
FINDINGS OF FACT 1
1. Plaintiff Pfizer Inc. is a corporation organized and existing under the laws of Delaware
and has a place of business at 23 5 East 42nd Street, New York, New York 1001 7.
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 ofbusiness 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
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 ofPF PRISM CV.
7. The plaintiffs will collectively be referred to as "Pfizer."
Prior to trial, the parties submitted an exhibit of uncontested facts in conjunction with their Pretrial Order.
(D.I. 138, Ex. 1.) The court takes most of its findings of fact from the parties' uncontested facts. The court has also
reordered and renumbered some paragraphs, corrected some formatting errors, and 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 Part III this opinion ("Discussion and Conclusions of Law"), preceded by the phrase "the court finds" or
"the court concludes."
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.
I. 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 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:
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 ofthe '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").
3. The expiration date ofthe '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. 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
601182,710, 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 ofthis action, the priority date for asserted claims 1 and 2 is October 27, 2000.
1. The Asserted Claims
'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:
or an L-malate salt thereof.
'293 Patent, Claim 21
2. Claim 21 of the '293 Patent reads: A pharmaceutical composition, compnsmg a
compound or salt of claim 5 and, a pharmaceutically acceptable carrier or excipient.
'905 Patent, Claim 1
3. Claim 1 of the '905 Patent reads: A compound that is the L-malate salt of 5-(5-fluoro-2oxo-1 ,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid (2diethylaminoethyl)amide.
'905 Patent, Claim 2
4. Claim 2 of the '905 Patent reads: A pharmaceutical composition compnsmg the
compound of claim 1 and a pharmaceutically acceptable carrier or excipient.
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
2. Mylan has submitted to the FDA Abbreviated New Drug Application ("ANDA'') No. 201275, 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 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 ofMylan'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 ofthe '293 Patent, and claims 1 and 2 ofthe '905 Patent. 2
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.
(D.I. 106, 107.)
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
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).
Obviousness is a question of law that is predicated on several factual inquires. See RichardsonVicks 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 (1966).
"A patent shall be presumed valid." 35 U.S.C. § 282. A party seeking to challenge the
validity of a patent based 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. Telejlex, 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
"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)).
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. 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 Chern. Indus. v. Alphapharm Pty. Ltd., 492 F.3d 1350, 1356-57 (Fed.
Cir. 2007) (quotingKRS, 550 U.S. at 418).
"Obviousness does not require absolute predictability of success," but rather, requires "a
reasonable expectation of success." See Medichem, S.A. v. Rolado, S.L., 437 F.3d 1157, 1165
(Fed. Cir. 2006) (quoting In re 0 '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
Pfizer's identification of a person of ordinary skill in the art is derived from Drs. Lydon and Denny.
(D.I. 153 at 3 (citing Tr. 306:19-307:13 (Lydon); Tr. 77:22-78:8 (Denny).)
Ph.D. or 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 tum.
a. The '422 Application
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
Mylan's description of a personal of ordinary skill in the art is found in DTX-102 L
Pfizer refers to this compound as the "Hypothetical '422 Compound," whereas Mylan uses the shorthand
"dimethyl sunitinib." The court adopts Mylan's phraseology for convenience only.
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. !d. 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. !d. 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. !d. 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 instructions and optimized
the dosage levels. !d. 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 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. (!d. 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. 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
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 Goldfine 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.
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
To remain consistent with the parties' briefing, the court also discusses the '422 Application and dimethyl
sunitinib below, in the context of lead 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 "secondgeneration" 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.
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.
Like Compounds 11 f, 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 SU 5416 provided significant improvements in pharmacokinetics,
oral bioavailability, efficacy, preclinical safety, and pharmaceutical properties of SU6668." (!d.;
PTX-632 at 2; Tr. at 445-46 (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."))
Finally, Pfizer provides several non-oxindole compounds that were developed by
competitor companies to address angiogenesis in tumors.
(D.I. 153 at 5-6.)
(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. (Jd. 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. (ld. 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
(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.)
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 convinced that any of
Mylan's proffered compounds would have constituted lead compounds as of the October 2000
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.
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 ofthe state ofthe 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.
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." (!d. at 202-03.) The court
finds, however, that one skilled in the art would not have ignored actual, synthesized compounds
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.
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,
13 52 (Fed. Cir. 201 0) ("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 a prior art compound (e.g., a lead compound) to arrive at a claimed
compound with a reasonable expectation that the new compound would have similar or improved
properties compared with the old." (emphasis added)).
To obtain sunitinib from dimethyl sunitinib, one skilled in the art only would have had to
replace the dimethylamine solubilizing group with a diethylamine group.
The court is not
convinced, however, that even this single modification would have been obvious. Dr. Denny's
testimony confirmed that a diethylamine group was similarly susceptible to the problem of
dealkylation as a dimethylene group. (Tr. at 258 (Denny).) And Pfizer's expert Dr. Stafford
testified that one skilled in art-if faced with a dealkyation problem (referred to as
"demethylation" in his testimony)-would not have turned to a diethylamine group for the
solution. (Tr. at 538-39 (Stafford).) Rather, several other structural changes, such as creating a
cyclic version, would have been appealing next steps. (!d. at 539.) The court is not convinced
that one skilled in the art-assuming dealkylation were recognized as a problem at all-would
have expected the addition of diethylamine to solve the apparent problem.
As for SU5416 and SU5408, both require several sequential modifications to arrive at
sunitinib. The modification chain is largely the same for both except than one additional step is
needed initially to modify SU5416 to create SU5048. This first step requires adding an electronwithdrawing ester to the pyrrole ring of SU5416. Dr. Denny argues that one skilled in the art
would have found it obvious to lower the electron density of the pyrrole ring (by introducing an
electron-withdrawing group) in order to improve activity and reduce metabolism. (Tr. at 164
(Denny).) The court disagrees with this conclusion.
First, the statement is contrary to the
Sugen's explicit teachings that propionic acid, an electron-donating group, was "required" for
high potency. (JTX 113 at 7.) One skilled in the art would not discount data published by the
very researchers working with SU5416. Second, one skilled in the art would not have modified a
relatively successful compound like SU5416 simply to recreate SU5408, a compound that had
already been tested and essentially ignored by Sugen as a candidate. Mylan fails to show this first
modification ofSU5416 would have been obvious.
In addition, the court finds Mylan also fails to show that the remaining modifications from
SU5408 to sunitinib would have been obvious. Dr. Denny maintains that one skilled in the art
would have replaced the C-5 hydrogen with fluorine to reduce metabolism of the oxindole. (Tr.
at 174-75 (Denny).) But both Dr. Denny and Dr. Stafford testified that there were no data
available for any oxindole compound with fluorine at the C-5 position. (Tr. 254-55 (Denny); Tr.
at 510 (Stafford).) Moreover, it is not clear that metabolism at the C-5 position presented a major
problem that required a substitution; after all, in its next clinical candidate, SU6668, Sugen made
no substitution to the C-5 position. (Tr. at 503-504 (Stafford).) Even assuming that metabolism
was a problem to be addressed, the court is not convinced that choosing fluorine to do so would
have been an obvious modification to one skilled in the art, as opposed to any other blocking
group placed at the C-5 position. (!d. at 556-57.) Mylan only points to the dimethyl sunitinib to
support its assertion that a fluorine at the C-5 position would have been an obvious modification;
the court is not persuaded that this hypothetical compound in the '422 Application that had never
been synthesized is sufficient to render the modification obvious.
Mylan next argues that replacing the ester at the C-4' position with an amide would have
been obvious in order to increase stability because of the potential for ester hydrolysis in the
bloodstream and liver. (Tr. 153-54 (Denny).) In the context of SU5416, this would require
substituting the ester that had just been added in the previous step with an amide, an exercise that
defies logic. But even in the SU5408 scenario, the court is not convinced that such a substitution
would have been obvious. Mariy successful drugs have esters, and it would be very difficult to
predict whether ester hydrolysis would pose a problem for any particular compound without test
data. (Tr. at 482-83 (Stafford).) As noted above, there was no in vivo data for SU5408 to prompt
one skilled in the art to worry about ester hydrolysis.
Mylan next contends that after substituting the amide, one skilled in the art would have
appended an additional solubilizing group to the C-4' amide in order improve solubility. (Tr. at
167 (Denny).) Dr. Denny testified that a diethylamine would have been the obvious choice
because amides were generally preferred over acid solubilizing groups and diethylamine groups
were commonly used for this purpose. (!d. at 165-67, 171.) But again, Mylan fails to establish
that one skilled in the art would have assumed there to be a solubility problem in the first place.
Dr. Stafford's testimony reveals that theoretical solubility of the unmodified compound would
have fallen within the acceptable range. (Tr. at 490-91 (Stafford).) The court finds that, without
data demonstrating a solubility concern, one skilled in the art would have had no reason (and
therefore it was not obvious) to add a solubilizing amide. See Takeda, 492 F.3d at 1356-57.
Moreover, even if one skilled in the art were motivated to address solubility, the court finds that
the natural choice would have been to use propionic acid, as taught by Sugen's publications. Dr.
Denny acknowledged that acid solubilizing agents could be equally if not more effective than
base agents in some cases. (Tr. at 249 (Denny).) The court is not convinced that that one skilled
in the art would have found it obvious to select this particular amide side chain as opposed to any
of the other possibilities, especially when the art pointed towards propionic acid.
For attaching the diethylamine solubilizing side chain to the C-4' amide, Mylan argues a
two-carbon linker would have been used because it was the minimal stable linker length between
the two nitrogens, and it was the most conservative change. (Tr. at 174 (Denny).) But Dr. Denny
also testified that the length of the carbon linkage could affect the potency of the compound. (!d.
at 248.) One skilled in the art would not have arbitrarily chosen a two-carbon chain because it
was the most conservative. Rather, one skilled in the art would have looked to test data to
determine the optimal linker length to maximize activity. The court finds that, without any data,
there was no reason for one skilled in the art to assume two carbons was the obvious length for
the linkage, and there was no way of having a reasonable expectation of success. 8
The last required modification for each of Mylan's proposed lead compounds-SU5416,
SU5408, and dimethyl sunitinib--is to create the malate salt form of sunitinib. The court finds
that one skilled in the art would not have found this particular salt form obvious. Assuming one
skilled in the art would have been motivated to try a sunitinib salt, there is no explanation for why
one skilled in the art would have found malate to be an obvious choice. Dr. Denny testified that
in his salt selection experience, he would limit tests to three or four options, and never had he
selected malate. (Tr. at 261 (Denny).) He confirmed that malate is one of the rarest salts in
pharmaceutical compounds. (!d.) Despite this testimony, Mylan asserts that selecting malate
would have been the result of routine optimization. The court finds that Mylan misinterprets the
case law on this topic. As discussed briefly in the previous section, Mylan's reliance on Pfizer is
misplaced. 480 F.3d 1348. In Pfizer, the Federal Circuit held that the patentee's creation of an
acid salt was obvious because it was the result of"routine testing." !d. at 1367. But the court was
careful to emphasize that its holding was based on the ''particularized facts of this case" because
the prior art had specifically "predicted the results." !d. (emphasis in original). Here, unlike in
Pfizer, there was nothing in the prior art to suggest to one skilled in the art that malate was one of
a limited subset of salts to choose, or even that a salt form of sunitinib would be beneficial. 9
Pfizer additionally argues that one skilled in the art would not have retained the methyl side groups at the
C-3' and C-5' position because the prior art taught away from this configuration. The court does not consider
retention of lead compound attributes to be a "modification" as contemplated by case law. The court, therefore, does
not discuss this as a necessary modification.
The court once again recognizes that an obviousness determination does not require an explicit motivation
in the art. See Daiichi Sankyo Co., 619 F.3d at 1352. But because the Federal Circuit's decision in Pfizer was
Indeed, malate did not appear on the most current FDA list of approved salt forms. (PTX-328 at
3; Tr. at 263 (Denny).) Despite the inherent unpredictability of acid salts-acknowledged by both
parties' experts (Tr. at 264 (Denny); Tr. at 681 (Myerson))-Mylan nonetheless argues that
testing essentially all possibilities would have been done as a matter of course. (Tr. at 177-78
(Denny).) The court disagrees and finds that one skilled in the art would not have found the
malate salt modification obvious. See Sanofi-Synthelabo v. Apotex, Inc., 550 F.3d 1075 (Fed. Cir.
2008) (upholding the district court's finding of non-obviousness where there were a "wide range
of possible outcomes" and a "relative unlikelihood" that the desired results would be obtained).
The court has already explained that Mylan's choice of lead compound would not have
been selected by one skilled in the art. Nonetheless, the court also concludes that the requisite
modifications needed to go from the lead compounds to sunitinib malate would not have been
obvious to one skilled in the art.
4. Secondary Considerations
Pfizer contends that Mylan has failed to make a prima facie showing of obviousness under
§ 103, or, in the alternative, that the secondary considerations of non-obviousness rebut Mylan's
primafacie showing. See Graham, 383 U.S. at 17-18. The court has found that Mylan failed to
establish a prima facie case of obviousness. Assuming Mylan had satisfied its initial burden,
however, the court finds that Pfizer's secondary considerations-unexpected properties, long-felt
need, failure of others, commercial success, skepticism, and acceptance and praise-support a
determination of non-obviousness.
a. Unexpected Properties
heavily influenced by the prior art's explicit teachings, the court finds this to be a critical distinction. See Pfizer,
480 F.3d at 1367.
The court agrees that the claimed compounds, including sunitinib, possessed unexpected
properties, thus weighing in favor of a non-obviousness finding. First, the activity of sunitinib
compared with the previous clinical candidates, SU5416 and SU6668, was "certainly much more
potent" against each of the target RTKs in vitro. (Tr. at 267 (Denny); Tr. at 542 (Stafford).)
Considering that sunitinib was synthesized with entirely different goals in mind, the court finds its
significant activity to be unexpected. (Tr. at 667-670 (Sun).)
Moreover, the malate salt form of sunitinib solved several manufacturing problems that
posed a major barrier to bringing sunitinib to market. (Tr. at 695 (Myerson).) Malate was not
among the initial screen of salts. (Id at 691-92.) None of the salts from this screen were
selected. (Id at 691.) Researchers, however, discovered that the freebase sunitinib possessed
"terrible filtration and drying properties," which persuaded them to do an additional salt screen.
(Id at 692.) For this second screen, malate was chosen "just for kicks," and it turned out that
sunitinib malate had superior properties across the board compared to other salts; such properties
made it possible to commercialize sunitinib. (Id at 695-96.) The court finds that one skilled in
the art would not have expected sunitinib malate to outperform the other salts in all categories.
Long-Felt Need and Failure of Others
The court also agrees that sunitinib malate satisfied a long-felt need in the market for
treatments for renal cell carcinoma ("RCC") and pancreatic neuroendocrine tumors ("PNET").
See Procter & Gamble Co. v. Teva Pharm. USA, Inc., 566 F.3d 989 (Fed. Cir. 2009). This need
was caused largely by frequent failures of others to develop an effective treatment for these
cancers. (Tr. at 724 (Bukowski) ("[l]f you want to show a new drug to fail, test it in kidney
cancer.")) There is no question that others, including Sugent, had tried to address the question of
anti-angiogenesis and failed. (Tr. at 544 (Stafford).) The evidence demonstrated that sunitinib
malate provided greatly improved clinical outcomes for RCC patients, and represented a "huge
paradigm shift" for the treatment of PNET. (PTX-524 at 1; Tr. at 742-43 (Bukowski); (Tr. at
790-93 (Kulke)). The court finds that, even with the competing drugs available, sunitinib malate
satisfied a long-felt need in the treatment of these cancers. (Tr. at 721-24; 730 (Bukowski).)
Mylan makes a false distinction between properties identified in the claims versus the
specification. (D.I. 152 at 39.) The patents-in-suit need not specifically identify RCC and PNET
in the claims for the purposes of evaluating long-felt need. See In re Papesch, 315 F .2d 381, 391
(C.C.P.A 1963) ("From the standpoint of patent law, a compound and all of its properties are
inseparable; they are one and the same thing.") Mylan's reliance on Therasense, which did not
discuss chemical compound claims, is inapposite. See Therasense, Inc. v. Becton, Dickinson &
Co., 593 F.3d 1325 (Fed. Cir. 2010).
c. Commercial Success
Pfizer and Mylan presented competing experts who testified as to whether Sutent®,
Pfizer's brand-name embodiment of sunitinib malate, has been a commercial success. The court
finds that Sutent® has indeed been a commercial success.
The court notes initially that any
success Sutent® has had-whatever it may be-is attributable to the active, claimed compound,
sunitinib malate, and not marketing. See Demaco Corp. v. F. Von Langsdorff Licensing Ltd.,
851 F.2d 1387, 1392-93 (Fed. Cir. 1988) ("A prima facie case of nexus is generally made out
when the patentee shows both that there is commercial success, and that the thing (product or
method) that is commercially successful is the invention disclosed and claimed in the patent.")
Mylan has not rebutted this presumption.
Although the parties presented directly opposing evidence, the court finds Pfizer's
testimony was the more compelling. Sutent® remains the dominant drug for RCC treatment,
maintaining nearly fifty percent of the market six years after its launch, with almost twice as
much market share as the nearest competitor. 10 (PTX-620.) Sutent® is Pfizer's largest revenue
generator among its oncology drugs. (Tr. at 813 (Robertson).) Revenues have exceeded expenses
each year Sutent® has been on the market. (!d.) Moreover, on average, drugs in the industry tend
to take fifteen or sixteen years to break even and recoup the investment; Sutent® is on pace to
break even within ten years. (!d. at 872- 73.) Mylan presented evidence that Sutent® failed to
meet Pfizer's own internal projections and failed to obtain FDA approval for several indications.
(!d. at 832-33; 836-38.) While it considers these as factors, in the larger picture, the court still
finds that Sutent® has been a commercial success. The fact that competitors have entered the
market and diminished Sutent®' s overall share does not change the court's conclusion.
d. Skepticism and Praise
Evidence of both initial skepticism and subsequent acceptance and praise after patenting
are probative factors for evaluating non-obviousness. See Kinetic Concepts, Inc. v. Smith &
Nephew, Inc., 688 F.3d 1342, 1367-68 (Fed. Cir. 2012). In this case, the court finds these factors
also weigh toward a finding of non-obviousness. Several prior failed attempts at creating an
effective anti-angiogenesis drug created a general sense of skepticism as to whether the concept
could work in practice. See OS! Pharm., Inc. v. My/an Pharm. Inc., 858 F. Supp. 2d 341 (D. Del.
2012) (noting the "almost insurmountable failure rate for new drug candidates" in evaluating
Moreover, Pfizer has presented convincing evidence that Sutent® was a
breakthrough in the industry, widely praised by researchers and doctors. (PTX-524; PTX-505;
Tr. at 746-47 (Bukowski); Tr. at 791 (Kulke).)
"Substantial industry praise" is compelling
evidence ofnon-obviousness. See Crocs., Inc. v. fTC, 598 F.3d 1294, 1311 (Fed. Cir. 2010).
The data only went through 20 II.
In sum, Mylan has failed to present a prima facie case that the asserted claims of the
patents-in-suit are invalid as obvious. Moreover, even assuming a prima facie case had been
made, the court finds that the secondary, objective indicia point towards a finding of nonobviousness. The asserted claims are not invalid as obvious.
For the reasons stated above, the court concludes that: (1) none of the asserted claims of
the patents-in-suit are invalid due to obviousness; (2) Pfizer's Rule 52(c) motion is granted, and
Mylan's Rule 52(c) motion is denied. 11
Dated: October 1-);.2014
As noted, all parties submitted Proposed Findings of Fact and Conclusions of Law, requesting that the
court find in its favor on the issue of obviousness. For the reasons stated above and based on the court's findings, the
court grants Pfizer's Rule 52(c) motion and denies Mylan's motion.
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