Sun Pharmaceutical Industries, Inc. v. Incyte Corporation

Case: 19-2011 Document: 117 Page: 1 Filed: 08/22/2023

NOTE: This disposition is nonprecedential.

United States Court of Appeals for the Federal Circuit ______________________

SUN PHARMACEUTICAL INDUSTRIES, INC., F/D/B/A CONCERT PHARMACEUTICALS, INC. Appellant

v.

INCYTE CORPORATION, Appellee

KATHERINE K. VIDAL, UNDER SECRETARY OF COMMERCE FOR INTELLECTUAL PROPERTY AND DIRECTOR OFTHE UNITED STATES PATENT AND TRADEMARK OFFICE, Intervenor ______________________

2019-2011 ______________________

Appeal from the United States Patent and Trademark Office, Patent Trial and Appeal Board in No. IPR2017- 01256. ______________________

Decided: August 22, 2023 ______________________

WILLIAM M. JAY, Goodwin Procter LLP, Washington, DC, argued for appellant. Also represented by GERARD JUSTIN CEDRONE, EMILY L. RAPALINO, DARYL L. WIESEN,

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DAVID ZIMMER, Boston, MA.

MARK J. FELDSTEIN, Finnegan, Henderson, Farabow, Garrett & Dunner, LLP, Washington, DC, argued for ap- pellee. Also represented by DREW CHRISTIE, C. COLLETTE CORSER, JASON LEE ROMRELL; J. DEREK MCCORQUINDALE, Reston, VA; TRENTON A. WARD, Atlanta, GA.

ROBERT MCBRIDE, Office of the Solicitor, United States Patent and Trademark Office, Alexandria, VA, for interve- nor. Also represented by THOMAS W. KRAUSE, FARHEENA YASMEEN RASHEED; SCOTT R. MCINTOSH, MELISSA N. PATTERSON, Civil Division, Appellate Staff, United Depart- ment of Justice, Washington, DC.

JOHN C. KAPPOS, O'Melveny & Myers LLP, Dallas, TX, for amicus curiae Bald Girls Do Lunch. Also represented by CAITLIN P. HOGAN, New York, NY. ______________________

Before HUGHES, LINN, and STARK, Circuit Judges. STARK, Circuit Judge. Sun Pharmaceutical Industries, Inc. (“Sun”) 1 appeals the Final Written Decision of the Patent and Trial Appeal Board (“Board”) in an inter partes review (“IPR”) in which Petitioner, Incyte Corporation (“Incyte”), challenged all claims of Sun’s U.S. Patent No. 9,249,149 (“’149 patent”). The Board concluded that the claims were invalid as obvi- ous. Sun sought review by the Director of the Patent and Trademark Office, which was denied, and then timely filed an appeal to this court. We have jurisdiction pursuant to

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28 U.S.C. § 1295(a)(4) and 35 U.S.C. §§ 141(c) and 319. We affirm. I A The ’149 patent, entitled “Deuterated Derivatives of Ruxolitinib,” “relates to novel heteroaryl-substituted pyr- rolo[2,3-d]pyrimidines, and pharmaceutically acceptable salts thereof,” including the compounds and their use “in methods of treating diseases and conditions that are bene- ficially treated by administering an inhibitor of Janus-as- sociated kinase with selectivity for subtypes 1 and 2 (JAK¹/JAK²).” ’149 patent 3:25-32. Ruxolitinib is a known JAK1/JAK2 inhibitor and is “currently approved for the treatment of patients with intermediate or high-risk myelofibrosis.” Id. at 2:53-67. Common adverse reactions associated with ruxolitinib include thrombocytopenia, ane- mia, bruising, dizziness, and headache. Id. at 3:15-18. Deuteration involves replacing one or more hydrogen atoms of a drug with deuterium, an isotope of hydrogen, “to slow” the “CYP-mediated metabolism” (i.e., cytochrome P450 enzyme) “of a drug or to reduce the formation of un- desirable metabolites.” Id. at 2:7-10. The bonds formed between deuterium and carbon are stronger than carbon- hydrogen bonds; this stronger bond “can positively impact the ADME [absorption, distribution, metabolism, and/or excretion] properties of a drug, creating the potential for improved drug efficacy, safety, and/or tolerability” without “affect[ing] the biochemical potency and selectivity of the drug as compared to the original chemical entity that con- tains only hydrogen.” Id. at 2:12-20. These measures of how a human body processes a drug, ADME, are also re- ferred to as the drug’s pharmacokinetic properties. J.A. 8225-46.

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The ’149 patent has two independent claims, 1 and 9. Claim 1 claims deuterated variations of Formula A and is reproduced below: 1. A compound of Formula A:

or a pharmaceutically acceptable salt thereof, wherein: Y1 is hydrogen; each Y2 is selected from hydrogen and deuterium, and each Y2 is the same; each Y³ is selected from hydrogen and deuterium, and each Y3 is the same; Y4 is selected from hydrogen and deuterium; each Y5 is the same and is selected from hydrogen and deuterium; and Y6, Y7, Y8, Y9, and Y¹⁰ are each independently se- lected from hydrogen and deuterium; provided that: each Y2 is deuterium; or

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each Y3 is deuterium; or each Y2 and each Y3 is deuterium. Id. at 36:17-53. The IPR focused primarily on three compounds, pic- tured below, all of which are within the scope of claim 7, which depends from claim 1: an “octo-deuterated” rux- olitinib analog, in which every Y2 and Y3 hydrogen is deu- terated,

and two “tetra-deuterated” ruxolitinib analogs,

in which either Y2 hydrogens or Y3 hydrogens are deuter- ated. Id. at 36:66-40. Sun named the octo-deuterated analog with a high iso- topic purity CTP-543. Sun contends that CTP-543 has the potential to be a desirable treatment for alopecia areata. The FDA has given “Fast Track” and “Breakthrough Ther- apy” designations to CTP-543, which means the FDA will

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expedite its review of CTP-543 as a new drug. See, e.g., J.A. 10102. B In its IPR petition, Incyte presented two obviousness grounds, but the Board only considered one: the combina- tion of Rodgers, Shilling, and the Concert Backgrounder. 2 We summarize these prior art references below. Rodgers is a U.S. patent directed to “heteroaryl substi- tuted pyrrolo[2,3,-b]pyridines and heteroaryl substituted pyrrolo[2,3-b]pyrmidines that modulate the activity of Ja- nus kinases.” J.A. 1747. Rodgers’ claimed compounds all depend on “Formula I,” reproduced below, and include rux- olitinib. J.A. 1749, 1933.

Shilling discloses a study of the “metabolism, excretion, and pharmacokinetics” of ruxolitinib and teaches that rux- olitinib is a “potent, selective inhibitor” of JAK1/JAK2. J.A. 1729. It adds that ruxolitinib was the “first

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investigational drug of its class in phase III studies for the treatment of myelofibrosis.” Id. Importantly, Shilling also identifies ruxolitinib’s metabolic “hotspots,” which are the sites on a compound where oxidative metabolism occurs during in vivo metabolism. J.A. 154, 1734. The study iden- tifies that the majority of ruxolitinib’s metabolism occurs on its cyclopentyl ring at its four methylene carbons (the Y2 and Y3 positions in Formulas A and I of the ’149 patent and the positions that are deuterated in octo-deuterated and tetra-deuterated ruxolitinib). See J.A. 1736. The Concert Backgrounder is a marketing publication issued by the original owner of the ’149 patent, Concert. It teaches that deuteration of compounds provides the poten- tial for improved safety, better tolerability, and enhanced efficacy. J.A. 1739 (“[S]ince deuterium is heavier than hy- drogen, it forms significantly stronger bonds with carbon resulting in differentiated ADME (Adsorption, Distribu- tion, Metabolism and Excretion). . . . [Hence,] [d]euterium substitution has the potential to create NCEs [new chemi- cal entities] with improved safety, tolerability and effi- cacy.”). The Concert Backgrounder observes that “the magnitude and nature of the deuterium benefit cannot be predicted a priori,” so it is necessary to first “test multiple compounds in a range of assays to identify those that are differentiated.” J.A. 1740. It further emphasizes, however, that “[d]euteration provides novel agents with the poten- tial for . . . [i]mproved safety[,] . . . [b]etter tolerability[,] . . . [and] [e]nhanced efficacy,” adding that Concert “is deploy- ing its product technology platform to rapidly assemble a pipeline of valuable new deuterated drugs.” J.A. 1740, 1743 (emphasis omitted). II “Obviousness under 35 U.S.C. § 103 is a mixed ques- tion of law and fact. We review the Board’s ultimate obvi- ousness determination de novo and underlying fact-

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findings for substantial evidence.” Hologic, Inc. v. Smith & Nephew, Inc., 884 F.3d 1357, 1361 (Fed. Cir. 2018). “A claimed invention is unpatentable if the differences be- tween the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious to one of ordinary skill in the relevant art.” Intercontinen- tal Great Brands LLC v. Kellogg N. Am. Co., 869 F.3d 1336, 1343 (Fed. Cir. 2017) (internal quotation marks omitted). The presence or absence of a motivation to combine prior art references, and a reasonable expectation of success in doing so, are questions of fact. See Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1366 (Fed. Cir. 2016). In an IPR, it is the petitioner’s burden to prove, by a preponderance of the evidence, that a person of ordinary skill in the art would have been motivated to combine the prior art references the petitioner is relying on in its obvi- ousness grounds. See 35 U.S.C. § 316(e) (“In an inter partes review instituted under this chapter, the petitioner shall have the burden of proving a proposition of unpatent- ability by a preponderance of the evidence.”). 3 Motivation

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SUN PHARMACEUTICAL INDUSTRIES, INC. v. 15 INCYTE CORPORATION

patented invention, and that others tried but failed to sat- isfy that demand.” Id. (internal quotation marks omitted). Assuming, without deciding, that the need for an effective and safe alopecia areata treatment existed, the Board had substantial evidence for its finding that CTP-543 had not actually satisfied this long-felt need, but only had the “po- tential” and “likelihood” to do so. J.A. 36-37; see also J.A. 9385-86 (Dr. Mackay-Wiggin Decl.). While we agree with Sun (and amicus Bald Girls Do Lunch) that FDA approval is not a prerequisite to showing that a long-felt need has been met, and FDA’s designation of CTP-543 for “Break- through Therapy” and “Fast-Track” approval are probative of nonobviousness, here Sun expressly framed its objective indicia argument as “CTP-543 satisfies the long-felt need for an FDA-approved, evidence-based alopecia areata treatment,” J.A. 465 (emphasis added), and the Board rea- sonably found that CTP-543 had not met this need because it lacked FDA approval, see J.A. 1366. 5 Thus, substantial evidence supports the Board’s conclusion that Sun did not prove that CTP-543 has satisfied this long-felt need. III We have considered Sun’s remaining arguments and find them unpersuasive. For the foregoing reasons, we af- firm. AFFIRMED

5 Evidence provided by the amicus, Bald Girls Do Lunch, but not otherwise in the record cannot be consid- ered on appeal. See In re Watts, 354 F.3d 1362, 1367 (Fed. Cir. 2004).

Footnotes

[1] The original appellant was Concert Pharmaceuti- cals, Inc. (“Concert”), which merged with Sun on March 31, 2023. We granted Sun’s motion to replace Concert as the appellant on April 26, 2023.

[2] U.S. Patent No. 7,598,257 (“Rodgers”) (J.A. 1744- 933); Adam D. Shilling et al., Metabolism, Excretion, and Pharmacokinetics of [14C]INCB018424, a Selective Janus Tyrosine Kinase 1/2 Inhibitor, in Humans, 38 Drug Metab- olism & Disposition 2023 (2010) (“Shilling”) (J.A. 1729-37); Concert Pharmaceuticals, Inc., Precision Deuterium Chemistry Backgrounder (2007) (“Concert Backgrounder”) (J.A. 1738-43).

[3] The parties disagree as to whether our case law limits the reasonable expectation of success inquiry to only those properties that are actually claimed in the patent be- ing challenged. Compare, e.g., Appellee Resp. Br. at 51 (“Although an unclaimed property may be relevant to the motivation-to-combine inquiry where it is the reason prof- fered for the motivation, unclaimed properties are ‘of no moment’ to the separate ‘reasonable expectation of success’ inquiry directed to ‘success in meeting the claims.’”) (inter- nal emphasis omitted; quoting Intelligent BioSystems, 821 F.3d at 1367-68), with Appellant Reply Br. at 18-19 (re- sponding “that has never been this Court’s approach to compound patents” and citing Takeda Chem. Indus., Ltd. SUN PHARMACEUTICAL INDUSTRIES, INC. v. 9 INCYTE CORPORATION to combine “need not be [based on] an explicit teaching that the claimed compound will have a particular utility; it is sufficient to show that the claimed and prior art com- pounds possess a sufficiently close relationship to create an expectation, in light of the totality of the prior art, that the new compound will have similar properties to the old.” Aventis Pharma Deutschland GmbH v. Lupin, Ltd., 499 F.3d 1293, 1301 (Fed. Cir. 2007) (internal quotation marks and alterations omitted). “[T]he greater the structural sim- ilarity between the compounds, the greater the motivation to combine and reasonable expectation of success.” Anacor Pharms. Inc. v. Iancu, 889 F.3d 1372, 1385 (Fed. Cir. 2018). In evaluating an obviousness claim, we also consider, where present, the objective indicia of nonobviousness. See Apple Inc. v. Samsung Elecs. Co., 839 F.3d 1034, 1048 (Fed. Cir. 2016). These can include “commercial success enjoyed by devices practicing the patented invention, industry praise for the patented invention, copying by others, and the existence of a long-felt but unsatisfied need for the in- vention.” Id. at 1052. A patentee’s evidence of objective indicia can rebut a petitioner’s prima facie showing of ob- viousness. See WMS Gaming, Inc. v. Int’l Game Tech., 184 F.3d 1339, 1359 (Fed. Cir. 1999). A For new chemical compounds, we apply a two-step test for determining obviousness. “First, the court determines v. Alphapharm Pty., Ltd., 492 F.3d 1350 (Fed. Cir. 2007)). This case does not call on us to resolve this dispute. In- stead, we conclude that the Board had substantial evidence to support its conclusion of obviousness even assuming (without deciding) that a skilled artisan would have needed to have reasonably expected success in obtaining the bene- ficial (though possibly unclaimed) properties Sun posits for it claimed compounds.

[10] SUN PHARMACEUTICAL INDUSTRIES, INC. v. INCYTE CORPORATION whether a chemist of ordinary skill would have selected the asserted prior art compounds as lead compounds, or start- ing points, for further development efforts.” Otsuka Pharm. Co. v. Sandoz, Inc., 678 F.3d 1280, 1291 (Fed. Cir. 2012). “The second inquiry in the analysis is whether the prior art would have supplied one of ordinary skill in the art with a reason or motivation to modify a lead compound to make the claimed compound with a reasonable expecta- tion of success.” Id. at 1292. The parties do not dispute that a person of ordinary skill would have selected ruxolitinib as the lead compound. Rather, Sun argues that the Board erred, in three respects, in connection with the second portion of this test. Specifi- cally, Sun contends the Board failed to (1) ask whether a person of ordinary skill would have been motivated to deu- terate ruxolitinib to alter its pharmacokinetic properties, (2) determine whether the skilled artisan would have been motivated to make the specific molecular modifications claimed in the ’149 patent, and (3) consider whether the person of ordinary skill would have reasonably expected success in modifying ruxolitinib. We review each of these arguments in turn. 1 Sun asks us to reject the Board’s finding of obviousness because the Board purportedly failed to consider whether a person of ordinary skill would have been motivated to deuterate ruxolitinib to modify its pharmacokinetic prop- erties, including its ADME. We conclude that the Board had substantial evidence, including the testimony of In- cyte’s expert, Dr. Guengerich, to find that the combined teachings of Shilling, Rodgers, and the Concert Back- grounder would have provided a skilled artisan with moti- vation to deuterate ruxolitinib, at its metabolic hotspots, in order “to achieve the potential benefits that the Concert Backgrounder disclosed, e.g., improved safety, tolerability, SUN PHARMACEUTICAL INDUSTRIES, INC. v. 11 INCYTE CORPORATION and efficacy.” J.A. 23-24; see also J.A. 1472-87 (Dr. Guengerich testifying to deuteration’s effect on compound’s ADME, including improved safety, tolerability, and effi- cacy), J.A. 1491-92 (Dr. Guengerich stating that Concert Backgrounder teaches deuteration has “substantially re- duced R&D risk, time and expense”). The close structural similarity between prior art ruxolitinib and the deuterated ruxolitinib analogs of the ’149 patent is undisputed and was reasonably found by the Board to have motivated a skilled artisan to modify ruxolitinib to retain its potency and selectivity, but improve the pharmacokinetic proper- ties identified in the Backgrounder. This conclusion is fur- ther supported by Sun’s own expert, Dr. Harbeson, J.A. 6016, and Concert’s chief executive officer, who added “we’ve never seen any biologically relevant differences in target selectivity or potency of a drug when we deuterate it,” J.A. 2406; see also J.A. 2919 (“The attraction of specific deuterium substitution as a parameter in drug design is based on the facts that not only is the replacement of one or a few hydrogens in a drug molecule by deuterium the smallest structural change that can be made but also such a change will have negligible steric consequences or influ- ence on physicochemical properties . . . .”). 2 Sun argues that the Board erred in failing to ask whether a person of ordinary skill would have pursued the specific modifications claimed in the ’149 patent, particu- larly those that would have resulted in the tetra- and octo- deuterated analogs of ruxolitinib. But the combination of the Concert Backgrounder, Shilling, and Dr. Guengerich’s declaration provides substantial evidence for the Board’s finding that a person of ordinary skill would have been mo- tivated to modify ruxolitinib at its metabolic hotspots on its cyclopentyl ring. J.A. 23-24; see also J.A. 1736 (Shilling identifying ruxolitinib’s metabolic hotspots as four meth- ylene carbons on its cyclopentyl ring); J.A. 1739-42

[12] SUN PHARMACEUTICAL INDUSTRIES, INC. v. INCYTE CORPORATION (Concert Backgrounder teaching that “[m]etabolic ‘hotspots’” are deuterated to improve compound’s efficacy, safety, and tolerability). Dr. Guengerich testified that a skilled artisan “would have deuterated at the site corre- sponding to Y2 and/or Y3 in Formula A or Formula I . . . at every Y2 and/or every Y3,” meaning that the “most reason- able deuterated analogs” would be the tetra- and octo-deu- terated analogs of dependent claim 7. J.A. 1500-02 (emphasis omitted). Hence, there is substantial evidence that an ordinarily skilled artisan would have been moti- vated to make the specific modifications necessary to mod- ify ruxolitinib to its deuterated analogs. 3 Sun argues that, in finding Incyte had proven a reason- able expectation of success, the Board erred by ignoring the unpredictable effects of deuterating ruxolitinib and by not considering how that unpredictability would have deterred a skilled artisan. “The reasonable expectation of success requirement refers to the likelihood of success in combining references to meet the limitations of the claimed invention. . . . [O]ne must have . . . a reasonable expectation of achiev- ing what is claimed in the patent-at-issue.” Intelligent Bio- Sys., 821 F.3d at 1367. The Board had substantial evidence to conclude that a person of ordinary skill would have had a reasonable ex- pectation that she could succeed in modifying ruxolitinib to arrive at its tetra- and octo-deuterated analogs, which she would expect to display “superior ADME properties.” J.A. 32; see also J.A. 1491-92, 1495-96 (Dr. Guengerich Decl.). Dr. Guengerich opined that a person of ordinary skill would have viewed the deuteration strategy as predictable, would have been able to synthesize the claimed compounds of the ’149 patent, and would also have expected the resulting compounds to demonstrate metabolic stability. J.A. 1503- 22. The Board acknowledged that the Concert SUN PHARMACEUTICAL INDUSTRIES, INC. v. 13 INCYTE CORPORATION Backgrounder discloses that the “magnitude and nature of the deuterium benefit cannot be predicted a priori,” J.A. 14, 31, 1740, but found, nonetheless, that an ordinarily skilled artisan would have reasonably expected – based on the overall teachings of the Backgrounder and the opinions of Dr. Guengerich – that deuterium modification could “re- sult[] in differentiated ADME,” including potential “[r]educed Cmax-driven side effects” and “[i]mproved effi- cacy, convenience and compliance,” J.A. 1739; see also J.A. 1491-92 (Dr. Guengerich explaining that deuteration “sub- stantially reduce[s] R&D risk, time, and expense,” notwith- standing lack of a priori predictability). “[O]bviousness cannot be avoided simply by a showing of some degree of unpredictability in the art so long as there was a reasona- ble probability of success.” Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364 (Fed. Cir. 2007). Thus, the Board had substantial evidence to support its findings that a person of ordinary skill in the art would have been motivated to modify ruxolitinib to create the ’149 patent’s deuterated analogs to alter its pharmacokinetic properties and would have reasonably expected that such modifications would lead to the beneficial changes sug- gested by the Concert Backgrounder. B Sun further argues the Board erred in its evaluation of two objective indicia of nonobviousness: unexpected results and long-felt need. We disagree. Nothing about Sun’s ob- jective indicia evidence rebuts Incyte’s prima facie showing of obviousness. 4 4 Incyte argues that none of Sun’s objective indicia evidence is probative of nonobviousness because it all re- lates solely to CTP-543, which is a single embodiment and

[14] SUN PHARMACEUTICAL INDUSTRIES, INC. v. INCYTE CORPORATION Sun argues that CTP-543, the highly pure octo-deuter- ated embodiment of claim 7 of its ’149 patent, displays two unexpected results: (1) a flatter pharmacokinetic curve, which increases the time of the drug in the therapeutic window, and (2) a greater relative increase in half-life for patients who metabolized ruxolitinib most quickly. The record contains substantial evidence to support the Board’s contrary finding that CTP-543’s results were “an increase in the same clinical activity observed with ruxolitinib, and therefore represent merely a difference in degree and not in kind.” J.A. 35; see Bristol-Myers Squibb Co. v. Teva Pharms. USA Inc., 752 F.3d 967, 977 (Fed. Cir. 2014) (“While a ‘marked superiority’ in an expected property may be enough in some circumstances to render a compound pa- tentable, a ‘mere difference in degree’ is insufficient.”). That is, the Board reasonably concluded that CTP-543’s in- creased time in the therapeutic window and increased clin- ical response at a given dose were differences in degree that did not indicate a marked superiority in these properties. See J.A. 6636-37, 6745-55 (Incyte’s experts testifying that therapeutic differences between CTP-543 and ruxolitinib were not “clinically meaningful” or “clinically impactful”). “The existence of a long-felt but unsolved need that is met by the claimed invention is further objective evidence of non-obviousness.” Millennium Pharms., Inc. v. Sandoz Inc., 862 F.3d 1356, 1369 (Fed. Cir. 2017). “Evidence of a long-felt need is particularly probative of obviousness when it demonstrates both that a demand existed for the not commensurate with the scope of any claim of the ’149 patent. It is sufficient for our purposes, as it was for the Board, see J.A. 35, to assume without deciding that Sun has met its burden to show that CTP-543 is representative of all embodiments within the scope of a challenged claim, as Sun’s evidence lacks significant probative value for other reasons that we explain.