UNITED STATES PATENT AND TRADEMARK OFFICE

_________________________

BEFORE THE PATENT TRIAL AND APPEAL BOARD _________________________

INCYTE CORPORATION, PETITIONER

V. CONCERT PHARMACEUTICALS, INC.,

PATENT OWNER ______________________

CASE IPR2017-01256 PATENT NO. 9,249,149

_________________________

PETITIONER’S REPLY TO PATENT OWNER’S RESPONSE

IPR2017-01256 PATENT NO. 9,249,149

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TABLE OF CONTENTS Page

I. Introduction ...................................................................................................... 1

II. Concert’s Alleged Secondary Indicia Are Insufficient ................................... 2

A. Concert’s Secondary Indicia Are Not Commensurate in Scope ........... 2

B. No Long-Felt Need Fulfilled by CTP-543 ............................................ 3

C. Concert’s Results Would Have Been Expected .................................... 5

1. Expected Effects of Reduced P450 Metabolism ........................ 5

2. Concert’s “Therapeutic Window” Is Expected and Insignificant ................................................................................ 8

3. Known Effect on Rapid Metabolizers ...................................... 10

III. Motivation and Reasonable Expectation of Success ..................................... 12

A. Similar Efficacy Would Have Been Expected .................................... 12

B. Improved Metabolic Properties Would Have Been Expected ............ 15

1. Ruxolitinib Was an Ideal Candidate for Deuteration ............... 15

2. Expectation of Improved Metabolic Stability ........................... 16

a. KIE Magnitude Can Be Predicted .................................. 18

b. Enzymatic Pathway Details are Academic ..................... 18

c. Metabolic Switching Would Not Eliminate KIE ........... 20

d. Concert’s Inapt In Vitro Comparison ............................. 20

e. In Vivo KIE Reasonably Expected ................................. 21

IV. The Concert Backgrounder and Jakafi® Label Are Printed Publications .................................................................................................... 23

A. The Concert Backgrounder ................................................................. 23

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B. The Jakafi® Label ................................................................................ 28

V. Conclusion ..................................................................................................... 28

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TABLE OF AUTHORITIES

Page(s)

Federal Cases

Allergan, Inc. v. Sandoz Inc., 726 F.3d 1286 (Fed. Cir. 2013) .................................................................... 15, 18

Ariosa Diagnostics v. Verinata Health, Inc., 805 F.3d 1359 (Fed. Cir. 2015) .......................................................................... 28

Bayer Schering Pharma AG v. Barr Laboratories Inc., 575 F. 3d 1341 (Fed. Cir. 2009) ......................................................................... 14

Blue Calypso, LLC v. Groupon, Inc., 815 F.3d 1331 (Fed. Cir. 2016) .............................................................. 24, 26, 27

Bristol-Myers Squibb Co. v. Teva Pharm. USA, Inc., 752 F.3d 967 (Fed. Cir. 2014) .............................................................................. 9

Bruckelmyer v. Ground Heaters, Inc., 445 F.3d 1374 (Fed. Cir. 2006) .......................................................................... 27

Butamax™ Advanced Biofuels LLC, Petitioner, IPR2013-00214, Paper 46, 24 (Sept. 23, 2014) .................................................... 4

Cornell Univ. v. Hewlett-Packard Co., No. 01-cv-1974, 2008 U.S. Dist. Lexis 39343 (N.D.N.Y May 14, 2008) ....................................................................................................... 25, 26, 27

Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293 (Fed. Cir. 2005) .......................................................................... 28

Eastman Kodak Co. v. CTP Innovations, LLC, IPR2014-00789, Paper 34, 19 (PTAB Nov. 25, 2015) ....................................... 26

Eli Lilly & Co. v. Zenith Goldline, 471 F.3d 1369 (Fed. Cir. 2006) ............................................................................ 8

Galderma Labs., L.P. v. Tolmar, Inc., 737 F.3d 731 (Fed. Cir. 2013) ........................................................................ 9, 13

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GoPro, Inc. v. Contour IP Holding LLC, 898 F.3d 1170 (Fed. Cir. 2018) .......................................................................... 24

In re Grasselli, 713 F.2d 731 (Fed. Cir. 1983) .............................................................................. 2

Healthcare Inc. v. Daiichi Sankyo Co., Ltd., IPR2015-00864, Paper 104 (PTAB September 12, 2016) ................................... 9

Intel Corp. v. R2 Semiconductor, Inc., IPR2017-00707, Paper 81 ................................................................................... 28

Jazz Pharm. Inc. v. Amneal Pharm., LLC, 895 F.3d 1347 (Fed. Cir. 2018) .......................................................................... 26

KSR Int’l Co. v Teleflex Inc., 550 U.S. 398 ....................................................................................................... 14

In re Lister, 583 F.3d 1307 (Fed. Cir. 2009) .......................................................................... 24

Medtronic, Inc. v. AGA Med. Corp., 618 F. Supp. 2d 1191 (N.D. Cal. 2009) .............................................................. 24

In re Mouttet, 686 F.3d 1322 (Fed. Cir. 2012) .......................................................................... 14

Nat’l Steel Car, Ltd. v. Canadian Pacific Ry., Ltd., 357 F.3d 1319 (Fed. Cir. 2004) .......................................................................... 28

Orthopedic Equipment Co., Inc. v. U.S., 702 F.2d 1005 (Fed. Cir. 1983) ............................................................................ 4

Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348 (Fed. Cir. 2007) ...................................................................... 7, 19

Taiwan Semiconductor Mfg. Co. v. Godo Kaisha Ip Bridge 1, IPR2016-01246, Paper 49 (PTAB Jan. 3, 2018) ................................................ 28

Rules

Fed. R. Evid. 801(d)(2) ............................................................................................ 16

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I. Introduction

In the context of this IPR involving deuterated-ruxolitinib, Concert has

admitted: “[T]he expectation is that a deuterated drug will have similar

pharmacodynamic properties as the protio drug[.]” Paper 27, 55. This is confirmed

by the art as a whole and Concert’s declarants. Ex. 1008, 49-50; Ex. 1010, 4; Ex.

1027, 5; Ex. 1039, 1; Ex. 1041, 4-5; Ex. 1089, 97:4-18; Ex. 2048, ¶¶25, 38.

Concert’s counter arguments of non-obviousness, moreover, improperly rely on

unclaimed properties and hypotheticals inapplicable to an expectation of success for

the “claimed invention”—deuterated molecules independent of any use.

Tellingly, Concert’s purported “unexpected” results are, in fact, expected.

They also lack clinical importance and are not remotely commensurate with the

scope of the claims. Worse still, Concert mispresents a half-life trend as “unexpected”

for P450 metabolism; Concert’s declarant saw the same trend in the only FDA

approved deuterated drug and admitted the trend exists in Concert’s own data for

another drug. Nor was there any long-felt need for the treatment of alopecia areata

(“AA”), because, in fact, treatment using ruxolitinib and other Janus Kinase (“JAK”)

inhibitors had previously been taught in the prior art.

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II. Concert’s Alleged Secondary Indicia Are Insufficient

Concert contends its claims are supported by “unexpected results” and

“satisfaction of a long-felt need.” Paper 27, 67-71. However, no secondary evidence

supports patentability of the challenged claims.

A. Concert’s Secondary Indicia Are Not Commensurate in Scope

Abandoning the alleged secondary indicia on which it relied during

prosecution (Paper 8, 26-27), Concert now relies solely on one clinical batch of CTP-

543.1 Exhibit 2090, ¶9.

(Ex. 2071, ¶10), is not even remotely probative for the ’149 patent’s much

broader claims because “objective evidence of non-obviousness must be

commensurate in scope with the claims which the evidence is offered to support.” 2

In re Grasselli, 713 F.2d 731, 743 (Fed. Cir. 1983).

1 “Compound 111” refers to the octa-deuterated molecule in claim 7 where each

“D” is a deuterium atom. See Ex. 1001, col. 37:28-40. It is referred to as “octa-

deuterated ruxolitinib” in the Petition (Paper 1, 8) and as CTP-543 by Concert. Ex.

2001, ¶4.

2 Concert does not argue secondary indicia differently for any claim; accordingly,

they should stand or fall with claim 1. Paper 27, 67-70.

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First, even without accounting for isotopic purity and isotopologues, claim 1

covers hundreds of molecules, and no claim covers less than three. Ex. 1103, ¶¶13-

16. None is limited to Compound 111. Id. Claims 3, 4, 11, and 12 do not even

cover Compound 111. Id. Results from CTP-543 are thus not probative for any

claim because Concert has repeatedly argued that clinical effects of deuteration are

unpredictable on a species-by-species level. (E.g., Paper 27, 50 n.12; Ex. 2002, ¶75).

Second, no claim limits the deuterium isotopic enrichment narrower than the

patent’s default of “at least 45%.” Ex. 1001 3:65-4:3; Paper 1, 24-26; Paper 27, 39.

Ex. 2075, 2. Dr. Baillie admitted that deuterium

incorporation levels affect properties; thus conceding that the results from the single

CTP-543 batch are not probative of non-obviousness of the much broader claims.

Ex. 1087, 82:17-83:25; Ex. 1103, ¶¶75-77, Ex. 2071, ¶10.

B. No Long-Felt Need Fulfilled by CTP-543

Concert improperly argues that “CTP-543 Satisfies the Long-Felt Need for an

FDA-Approved, Evidence-Based Alopecia Areata Treatment.” Paper 27, 38-39, 70-

71. Concert has not met this alleged need. CTP-543 is not “FDA-approved” for

anything, let alone AA.

Moreover, by legal standards, there was no need for FDA approved AA

treatment, as the full technical solution of using JAK inhibitors to treat AA was

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already taught. By June of 2012, treatment of alopecia areata (“AA”) with a JAK

inhibitor—including previously FDA approved ruxolitinib—had already been

taught. Ex. 1014, 3-4, 54, 75; Ex. 1086, 2-3; Ex. 1090, 56:9-58:14, 60:14-64:11,

70:21-71:2; Ex. 1117, ¶¶18-26. This technical solution available prior to the ’149

patent fully met any need, as the availability of a commercial solution is irrelevant.

Orthopedic Equipment Co., Inc. v. U.S., 702 F.2d 1005, 1013 (Fed. Cir. 1983)

(“[T]he fact that the two disclosed apparatus would not be combined by businessmen

for economic reasons is not the same as saying that it could not be done because

skilled persons in the art felt that there was some technological incompatibility that

prevented their combination. Only the latter fact is telling on the issue of

nonobviousness.”); Butamax™ Advanced Biofuels LLC, Petitioner, IPR2013-00214,

Paper 46, 24 (Sept. 23, 2014) (“[C]ommercial viability does not control the

obviousness determination[.]”)

Concert asserts it “is developing CTP-543 as a first-in-class treatment” 3 for

AA. Paper 27, 70. Not so; multiple JAK inhibitors are being developed for AA and

treatment guidelines are already in place. Ex. 1133, 1; Ex. 1134, 1; Ex. 1117, ¶¶28-

29. Tofacitinib, a JAK inhibitors, is routinely used in clinical practice for the

treatment of AA. Ex. 1117, ¶¶26-27. Concert’s arguments (Paper 27, 9-10) relying

3 Unless indicated otherwise, bold italic emphasis is added.

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on JAK inhibitor side-effect profile in cancer patients is also inapplicable to AA

patients. Ex. 1117, ¶¶32-33, 36, 42.

C. Concert’s Results Would Have Been Expected

1. Expected Effects of Reduced P450 Metabolism

Even if assumed relevant, Concert’s alleged increased Area Under the Curve

(“AUC”) and elimination t1/2 results are the expected result of inhibiting P450

metabolism (decreasing clearance). Paper 27, 31-34. It is textbook science that, as

shown below in Rowland Fig. 4-6, “[a] twofold reduction in clearance increases the

[AUC] (colored line, top graph) twofold… The terminal slope reflects the increased

elimination half-life.” Ex. 2013, 40-41, Fig. 4-6; see also Ex. 1070, 9-10, Fig. 4-6;

Ex. 1087, 5:16-6:13, 11:4-7.

Figure 1. Ex. 2013, 41 Fig.4-6 (colorized)

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Even assuming Concert is correct, picking from one of two possible results—heads

or tails—is not unexpected. Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364 (Fed.

Cir. 2007) (rejecting “a rule of law equating unpredictability to patentability . . .

[where the] properties of each [compound] must be verified through testing”).

Furthermore, (A) the “tolerability/efficacy” panel above shows the expected

effect of deuterium on systemic metabolism and (B) the “bioavailability/efficacy”

panel shows the expected effect on pre-systemic (“first-pass”) metabolism.4 Ex.

1077, 1; Ex. 1088, 62:20-68:7. For ruxolitinib, (A) was expected based on its

published metabolic properties: when its P450-mediated clearance was reduced by

half with a metabolic inhibitor, AUC and t1/2 increased proportionally—just as

expected. Ex. 1071, 6; Ex. 1087, 5:16-6:13, 9:20-10:13, 14:1-20:5; Ex. 2013, 41-

42; Ex. 2047, 45:21-47:2. The literature also showed essentially no first pass (pre-

systemic) metabolism for ruxolitinib, meaning that (B) was not an option. Ex. 1005,

1; Ex. 1088, 33:14-36:11; Ex. 2012, 1.

4 These are neither “mutually exclusive” nor “opposite.” Paper 27, 21; Ex. 2057,

¶19. Rather, contradicting his declaration, Dr. Ortiz de Montellano admitted it “is

possible you would have a mixture of the two.” Ex. 1088, 67:5-14.

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2. Concert’s “Therapeutic Window” Is Expected and Insignificant

Concert alleges, “CTP-543 has the potential to demonstrate an unexpected

clinical benefit by maintaining safe and effective drug levels for a longer period,”

by reliance on a concocted “therapeutic window.” Paper 27, 68; see also id. 34-36;

Ex. 2002, ¶44. Concert is wrong again.

First, it is 100% predictable that mathematically increasing the ruxolitinib

dose to a hypothetical 27 mg (as Concert does to match the longer half-life of CTP-

543) will increase its Cmax. Ex. 1087, 28:23-30:14; Ex. 1129, ¶¶37-39; Ex. 2001,

¶12 n.1; Ex. 2012, 6. Concert’s alleged potential for increased “Cmax-related side

effects” (Paper 27, 36) is a direct artifact of Concert mathematically increasing the

ruxolitinib dose to 27 mg. Ex. 1129, ¶¶37-39.

Moreover, Concert’s comparison of 16 mg CTP-543 and 27 mg ruxolitinib is

artificial and exaggerated. Elsewhere, Concert inconsistently represented that 16

mgs of CTP-543 twice-daily (“BID”) is “comparable to … the 20 mg BID ruxolitinib

dose shown to be effective at inducing hair regrowth in patients with moderate to

severe alopecia.” Ex. 1136, ¶116. Compared to 27 mg, 20 mg ruxolitinib would

necessarily have lower Cmax related side effects. Ex. 2001, ¶12 n.1; Ex. 2012, 6.

Second, to be probative of non-obviousness, differences must have been

“unexpected and significant.” Eli Lilly & Co. v. Zenith Goldline, 471 F.3d 1369,

1378 (Fed. Cir. 2006). At best, Concert’s 0.4 hr. longer half-life (Ex. 2002, ¶51) is

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an insignificant difference in degree. Galderma Labs., L.P. v. Tolmar, Inc., 737 F.3d

731, 739 (Fed. Cir. 2013); Bristol-Myers Squibb Co. v. Teva Pharm. USA, Inc., 752

F.3d 967, 977 (Fed. Cir. 2014); Accord Healthcare Inc. v. Daiichi Sankyo Co., Ltd.,

IPR2015-00864, Paper 104, 29-30 (PTAB September 12, 2016); Ex. 1014, ¶[0289];

Ex. 1117, ¶¶47, 49-50; Ex. 1129, ¶¶40, 46-48.

Concert’s alleged benefit of “maintaining safe and effective drug levels for a

longer period,” i.e., from 12.7 hours to 14.9 hours, is also a matter of degree without

clinical relevance. Paper 27, 68; Ex. 1117, ¶¶47, 49-50; Ex. 1129, ¶¶44-45, 49. In

practice, ruxolitinib and CTP-543 must be administered twice-daily. Ex. 1004, 1;

Ex. 1014, ¶[0289]; Ex. 2048, ¶33. With the second dose administered at 12 hours,

neither drug will dip below Concert’s “effective drug levels.” Paper 27, 68; see also

id. 30-31, 36; Ex. 1087, 39:12-24, 42:11-43:17, 51:4-10, 53:10-17; Ex. 1129, ¶¶44-

45, 49.

In fact, 15 mg ruxolitinib BID was reported to have a steady state Cmin

(“trough”) above 50 nM and a steady state Cmax 649 nM. Ex. 1072; Ex. 2012, 8

(Table 5), 9 (Fig. 4); Ex. 1087, 44:21-48:9. As shown in blue below, this range is

fully within Concert’s therapeutic window.

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Third, Concert’s argument that CTP-543 would have lower Cmax side effects

rests on the improper assertion that “[i]mportantly, there was no statistically

significant change in Cmax.” Paper 27, 33. In fact, the reported 16 mg CTP-543 Cmax

was greater than the dose-normalized 16 mg ruxolitinib. Ex. 1087, 24:23-25:2,

53:23-54:5; Ex. 2001, ¶12, Table 3. And nothing can be inferred here from the

absence of statistical significance. Ex. 1129, ¶¶18-21, 41-43 (citing Exs. 1131, 2057,

2071.)

3. Known Effect on Rapid Metabolizers

Concert characterizes a relatively greater increase in half-life for fast

ruxolitinib metabolizers as unexpected by wrongly asserting that “Concert’s

Figure 3. Annotated Figure 3a (Ex. 2071, ¶¶5-6)

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declarants are not aware of another example where a comparison of a CYP450-

metabolized deuterated drug to a non-deuterated drug showed an inverse relationship

between the magnitude of half-life improvement and the half-life for the non-

deuterated drug.” Paper 27, 37. Directly contradicting Concert, Concert’s declarant

Dr. Harbeson admitted he was “aware of a similar occurrence, which is the case

of deutero tetrabenazine in -- which is metabolized by CYP2D6.”5 Ex. 1089, 70:4-

71:15; see also Ex. 1129 ¶¶17-22, 24. Deuterotetrabenazine is marketed as

AustedoTM, the only FDA-approved deuterated drug to date. Ex. 1137, 1.

• venlafaxine inhibited with ketoconazole (Figure 4). Ex. 1129, ¶33; Ex.

1132, 5.

•

5 CYP450-2D6 is a CYP enzyme. Ex. 2061, 19.

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55). Indeed, “[r]eplacement of one or a few hydrogens in a drug molecule by

deuterium is the smallest structural change that can be made.” Ex. 1041, 4-5.

Concert admits that “the expectation is that a deuterated drug will have similar

pharmacodynamic properties as the protio drug.” Paper 27, 55; see also Ex. 1002,

¶55; Ex. 1008, 51-52 (“in most respects the deuterated compound is quite similar to

the all-hydrogen compound”) Ex. 1013, 3,5; Ex. 1089, 97:4-18. Dr. Harbeson even

admits that for “any deuterated analog of ruxolitinib we would presume to retain the

same intrinsic biology and pharmacology” as ruxolitinib. Ex. 1089, 97:4-18.

Concert’s “long-felt need” argument (Paper 27, 38, 70) also depends on this

expectation; Concert relies on ruxolitinib’s demonstrated efficacy against AA to

infer similar efficacy from CTP-543. Paper 27, 71; Ex. 2048, ¶¶10, 25, 29, 37-38,

40-41.

Concert inconsistently asserts that a POSA would have been “affirmatively

motivated not to attempt ADME modification” because “ruxolitinib had dose

limiting toxic side effects that could be exacerbated by slowing its metabolism.”

Paper 27, 47. The Federal Circuit, on nearly identical facts, rejected this very

argument. Galderma Labs., L.P. v. Tolmar, Inc., 737 F.3d 731, 738–39 (Fed. Cir.

2013) (dose-dependent side effects did not teach away from increased dose).

Moreover, Concert ignores that when metabolism is reduced, a POSA could

have simply lowered the dose to reduce side effects. Ex. 1087, 20:20-21:21, 22:19-

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23, 42:11-19; Ex. 1088, 64:18-66:15. Indeed, dose adjustment is a fundamental

concept; specifically taught in “The Bible of PK and PD.” Ex. 1087, 40:3-41:8; Ex.

2032, 32, 37-41; Ex. 2013, 53-83, 395-424. Concert also ignores that the Jakafi™

label warning “against administering the drug with strong metabolic inhibitors,”

applies only to a specific subset of sick patients. Paper 27, 10; Ex. 1004, 4. For all

other patients, the label teaches dose reduction when metabolism is inhibited (Ex.

1004, 4, 8-9), just as one would do for a deuterated drug. Ex. 1087, 20:20-21:21,

42:11-19; Ex. 1088, 64:18-66:15.

Concert further contends a POSA would have used extended release dosage

forms to delay ruxolitinib’s metabolism instead of “expensive” deuteration. Paper

27, 49; Ex. 1088, 57:19-59:6 (admitting motivation for extended release ruxolitinib

for AA). But extended release does not teach away from deuteration. Bayer

Schering Pharma AG v. Barr Laboratories Inc., 575 F. 3d 1341, 1350 (Fed. Cir.

2009) (where selection of one of two potential pharmaceutical formulation options

“led to the result anticipated . . . the invention would have been obvious” (citing KSR

Int’l Co. v Teleflex Inc., 550 U.S. 398, 421); In re Mouttet, 686 F.3d 1322, 1334 (Fed.

Cir. 2012). Instead, the motivation for extended release ruxolitinib applies equally

to deuteration, as both are used to reduce dose and dosing frequency. Paper 27, 49;

Ex. 2056, 3-4.

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B. Improved Metabolic Properties Would Have Been Expected

Concert next improperly contends that there must be a “reasonable

expectation that the pharmacokinetics of deuterated ruxolitinib would be positively

differentiated from those of ruxolitinib.” Paper 27, 4. Concert further adds that there

needs to have been a reasonable expectation of “achieving an in vivo KIE,” and that

“deuterating ruxolitinib would result in a safe and efficacious new drug.” Paper 27,

65-67. These arguments are misdirected as the ’149 patent does not claim any in

vivo, efficacy, safety, or pharmacokinetic parameters. Ex. 1001, 34:53–35:20.

Allergan, Inc. v. Sandoz Inc., 726 F.3d 1286, 1292 (Fed. Cir. 2013) (“the person of

ordinary skill need only have a reasonable expectation of success of developing the

claimed invention”). Concert’s requirement for in vivo properties is also inconsistent

with its exclusive reliance during prosecution on in vitro data to demonstrate

successful deuteration. Ex. 1009, 282-288.

Nevertheless, while unnecessary, the motivation and reasonable expectation

of such improved properties, for both tetra and octo-deuterated ruxolitinib, has also

been shown.

1. Ruxolitinib Was an Ideal Candidate for Deuteration

Contrary to what Concert now argues, the art is replete with references—

including references from Concert that are admissions under F.R.E. 801(d)(2)—

explaining the motivation for using deuterium “to lower efficacious doses and /or

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reduced frequency of administration.” Ex. 1076, 521; Ex. 1077, 1; Ex. 1078, 14; Ex.

1006, 3; Ex. 1047, 3. As Dr. Mackay-Wiggan confirmed, there are “significant

clinical benefits” to improved metabolic stability. Ex. 2048, ¶¶38-39; Ex. 1090,

87:24-91:7; see also Ex. 1088, 54:20-55:15, Ex. 2047, 93:17-94:6. From the

POSA’s perspective, Concert’s selection of ruxolitinib for deuteration would have

been obvious, as it was recognized that “[t]he easiest way to find a drug is to start

with one.” Ex. 1013, 5; Ex. 1002, ¶58, Paper 1, 15-16; Ex. 1041, 4-5. In June of

2012 ruxolitinib was just such a starting point.

Ruxolitinib was known to be highly potent against and selective for JAK1/2,

was the only FDA approved treatment for myelofibrosis, and was taught for a range

of other diseases, including AA. Paper 1, 23-24, 30-31; Ex. 1001, 2:66-3:21; Ex.

1014, 75, 86, 91-93; Ex. 1089, 6:22-25; Ex. 1013, 5. As explained below, a “larger”

KIE would have been expected due to ruxolitinib’s aliphatic oxidation (Ex. 1002,

¶55; Ex. 1087, 64:1-10; Ex. 2047, 189:20-190:9; Ex. 1005, 5-6; Ex. 1031, 1; Ex.

1039, 1; Ex. 2043, 3; 2063, 2) and the absence of masking effects meant the KIE

would be expected in vivo. Paper 1, 33-34; Ex. 1002, ¶30; Ex. 1088, 19:14-21:7; Ex.

2047, 95:15-96:4, 96:12-98:3, 108:6-109:13, 238:9-241:8.

2. Expectation of Improved Metabolic Stability

Concert goes to great lengths to obscure the expected effects of deuterium by

focusing on unclaimed and distinguishable metabolic considerations. Paper 27, 12-

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16, 23-30, 58-65. One need not digress into these allegedly complicating factors but

rather focus on the extensive precedent for expecting a KIE that established a

reasonable expectation of success.

The exhibits of record in this IPR report the effect of deuterium in 184 unique

deuterated compounds. Ex. 1103, ¶99. Of these, as shown in Figure 5 below, 145

(79%) showed a KIE; 23 (12%) were reported to be unchanged; 16 (9%) reported an

increased rate of metabolism versus the hydrogen counterpart. Id.

Concert misrepresents the scientific precedent, contending, for example, that

there are only a “handful of instances where Dr. Guengerich has observed a KIE.”

Paper 27, 60. In truth, Dr. Guengerich had published the effect of deuterium on 33

unique deuterated compounds as of June 2012; of these, he observed a KIE in 31—

Figure 5. Effect of Deuterium

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94%. Ex. 1103, ¶100. As reflected in Figure 5 above, Dr. Guengerich’s results are

not an anomaly. Ex. 1103, ¶101.

In any event, while Concert’s reliance on unclaimed metabolic properties has

no bearing on the likelihood of success of “the claimed invention,” each of Concert’s

assertions is misplaced and erroneous. Allergan, 726 F.3d at 1292 (Fed. Cir. 2013)

a. KIE Magnitude Can Be Predicted

Concert improperly argues that the “magnitude” and “clinical effects” of

deuteration cannot be predicted. E.g., Paper 27, 21. However, a KIE (aka DV) of 1-

10 can be predicted, especially for alkyl hydroxylation (as in ruxolitinib).6 Ex. 2047,

44:3-18, 61:21-63:2, 189:12-191:2. Regardless, “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, 480 F.3d at 1364.

b. Enzymatic Pathway Details are Academic

Concert next conflates whether a KIE will be expected with the academic

question of why a KIE is observed. Paper 27, 12-18. In fact, in every scenario

described by Drs. Guengerich, Ortiz de Montellano, and Baillie, deuteration is

expected to inhibit metabolism.

6 A value greater than 1 means that the deuterated compound is more metabolically

stable. Ex. 2047, 155:13-21, Paper 27, 12-13; Ex. 1041, 4-5.

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For example, Dr. Ortiz de Montellano asserts that the C-H bond breaking in

P450 metabolism is not generally the rate-limiting step, but admits that the increased

C-D bond strength results in “shunting the reaction to the branched pathway

immediately before C-H bond breaking.” Ex. 2057, ¶¶33, 36. Whether the C-D

bond breaking is directly rate-limiting or causes “shunting,” a KIE will result

because both “will inhibit overall metabolism.” 7 Id; Ex. 1088, 11:15-22. His

“disagreement” regarding the explanation for the KIE is purely academic, as the

observed effect—slowed metabolism—is the same, independent of the explanation.

Ex. 2057, ¶36; Ex. 1088, 14:9-19, 15:15-19; see also Ex. 2047, 43:20-44:18.

Concert also mischaracterizes Exhibit 1035 (Paper 27, 62-63), where the

unpredictable “behavior of the system” actually references how the enzyme interacts

with the substrate, not whether a KIE exists. Ex. 1035, 1. In fact, a KIE—upon

which use of deuterium to study reaction mechanisms is predicated— is clearly

assumed and is reported for all compounds examined in the paper. Id; Ex. 1041, 4-

5; Ex. 1039, 1.

7 “Unmasking” is synonymous with “increasing” the observed KIE. Ex.

1088,15:15-19.

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c. Metabolic Switching Would Not Eliminate KIE

Concert contends metabolic switching can “contribute[] to the

unpredictability of deuteration” due to (1) increased formation of “toxic metabolites”

and (2) “masking of the KIE in vitro.” Paper 27, 16-17. But no metabolites of

ruxolitinib had been identified as toxic to be increased. See Ex. 1004, 13-14; Ex.

1005, 6-8; Ex. 1071, 815-816; Ex. 1008, 50 (no “reports of deuteration resulting in

the formation of unique metabolites that were not also observed for the all-hydrogen

analog”). While metabolic switching for ruxolitinib might reduce KIE, “some effect”

would still have been expected. Ex. 1087, 54:22-55:11, 56:20-57:17, 57:20-58:3.

Even when metabolic switching increased a minor product from 5% to 45% in

Concert’s principal example, an “overall kinetic isotope effect of about 1.2 or 1.25”

was still observed. Ex. 2047, 124:16-22; 1033, 4; Paper 27, 16-18, 64.

d. Concert’s Inapt In Vitro Comparison

Concert identifies iloperidone and maraviroc as examples of deuterium

negatively impacting metabolism. These counter-examples represent exceedingly

rare exceptions—less than nine percent of the art shows deuterium increasing

metabolism. Supra, Figure 5; Ex. 1103, ¶99; see also Ex. 2047, 48:13-21. Moreover,

iloperidone and maraviroc (Paper 27, 24-25, 27-29) are both readily distinguished

from ruxolitinib, where its “metabolic hotspots” were conclusively identified,

accounted for the majority of metabolism, and were all subject to aliphatic oxidation

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via P450. Ex. 1005, 6-7; Ex. 2012, 1, Ex. 1004, 8-9; supra §III(B)(2) (KIE in 79%

of deuterated compounds). Neither iloperidone nor maraviroc shares these

characteristics, and in both, Concert mistakes the “major” paths of metabolism.

Contrary to Concert’s assertion (Paper 27, 24), the metabolism of iloperidone

is dominated by reduction of an oxygen via a collection of unidentified “cytosolic

and microsomal enzymes.” Ex. 2020, 2, 5-6; Ex. 1087, 66:19-22. For maraviroc,

Concert relies on routes representing 10% and 7% of metabolism, minor pathways

compared with 74% at ruxolitinib’s cyclopentyl ring. Ex. 2022, 3; Ex. 1005, 4.

e. In Vivo KIE Reasonably Expected

Concert is mistaken (Paper 27, 18, 65) that slowing in vivo metabolism would

not have been reasonably expected for deuterated-ruxolitinib. Supra §III(B)(1); Ex.

2047, 45:21-47:2, 138:11-21. Even Concert’s alleged “affirmative motivation” to

not deuterate ruxolitinib for risk of extended side effects presupposes an expected

slowing of in vivo metabolism. Paper 27, 46-47.

Concert’s contentions that Dr. Guengerich did not address the expected in vivo

benefit of deuterated ruxolitinib (Paper 27, 20-21) are also wrong. E.g., Ex. 1002,

¶50. Dr. Guengerich extensively addressed the effect of deuterium substitution on

ruxolitinib metabolism; the “in vivo KIE” he addresses is, by definition, a change in

metabolism caused by deuterium. E.g., Ex. 1002, ¶¶43-53; 71-82, 94-95, 102; cf.

Paper 27, 12-13.

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Without addressing the extensive literature on ruxolitinib, Concert asserts that

obtaining a KIE in vivo was not assured as the “KIE can be masked by competing

biological effects.” Paper 27, 18-23; Ex. 2057, ¶¶19-22. As Dr. Ortiz de Montellano

admitted, none of the examples Concert provides is specific or applicable to

ruxolitinib. Ex. 1088, 25:15-26:10; 28:20-30:8, 32:10-19, 40:22-41:8, 43:1-8,

52:17-54:10, 69:16-72:1; Ex. 2047, 97:8-98:3, 100:14-101:16; compare Ex. 1074,

632 with Ex. 2047, 100:14-101:3, Ex. 2012, 10 (blood flow not masking); compare

Ex. Paper 27, 18-19 with Ex. 1071, 809-10, Ex. 1004, 8-9 (no other enzymatic

pathways); compare Ex. Paper 27, 18 with Ex. 2047, 64:7-65:9, 96:12-97:7 Ex. 2012,

2 (competing biological processes “negligible”).

Concert identifies four examples for unpredictability in vivo. Paper 27, 25,

29. None undermines the reasonable expectation of success for an in vivo KIE for

ruxolitinib.

• Atazanavir: while Concert’s confidential, unpublished data (Ex. 2019)

could not have informed the expectations of a POSA,

Ex. 2001, ¶17.

• Tramadol: subject to in vivo “masking” effects not relevant to

ruxolitinib. Paper 27, 18-19; Ex.s 1074, 1; Ex. 1138, 2 (showing 30%

of dose eliminated via renal clearance and metabolism via conjugative

enzymes).

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• Tolbutamide: 1.19 in vivo KIE directly in line with 1.16 in vitro KIE.

See Ex. 2077, 9; Ex. 2068, 2-3.

• Nerispiridine: “metabolized principally by N-dealkylation,” has no

bearing on the predictability of aliphatic oxidation in ruxolitinib, but

still showed a 1.09 in vivo KIE. Ex. 2078, 2, 7-8.

While Concert denigrates these last two as not having a “meaningful KIE[]”

(Paper 27, 30), regardless of magnitude they are consistent with the expected in vivo

effect of deuteration, and closely bracket the 1.14 KIE of CTP-543 that is allegedly

“clinically superior” to ruxolitinib. Ex. 2001, 12; Paper 27, 31.

IV. The Concert Backgrounder and Jakafi® Label Are Printed Publications

A. The Concert Backgrounder

The Concert Backgrounder is printed publication prior art—the inquiry for

which is interpreted “broadly” and “find[s] that even relatively obscure documents

qualify as prior art so long as the relevant public has a means of accessing them.”

GoPro, Inc. v. Contour IP Holding LLC, 898 F.3d 1170, 1174 (Fed. Cir. 2018).

Concert’s arguments that the Concert Backgrounder is not a printed publication

focus on “indexing” (Paper 27, 42-45). But indexing is not a “necessary condition

for a reference to be publicly accessible.” In re Lister, 583 F.3d 1307, 1312 (Fed.

Cir. 2009). Instead, public accessibility is established where, as here, the reference

was disseminated and accessed by a POSA. Blue Calypso, LLC v. Groupon, Inc.,

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815 F.3d 1331, 1349-51 (Fed. Cir. 2016) (actual reading or dissemination evidences

public availability); Medtronic, Inc. v. AGA Med. Corp., 618 F. Supp. 2d 1191, 1193

(N.D. Cal. 2009) (citation of reference in two articles was evidence of public

accessibility); Cornell Univ. v. Hewlett-Packard Co., No. 01-cv-1974, 2008 U.S.

Dist. Lexis 39343, at *16-25 (N.D.N.Y May 14, 2008) (a thesis cited in another

publication publicly accessible despite its lack of indexing).

The Concert Backgrounder’s accessibility is evidenced by the fact it was

actually disseminated to and accessed by multiple POSAs: the Buteau8 law review

article (Ex. 1018, 45 n.268), two International Search Reports (Ex. 1021, 3; Ex. 1048,

3-4),9 a European Search Report (Ex. 1064, 2,5), and an International Searching

8 Ms. Buteau meets the parties’ POSA definitions. Compare. Ex. 1018, 1 with

Paper 27, 39-40 and Paper 1, 9.

9 Concert asserts that because there is a one-day difference in the dates the

WebCite® database (Ex. 1016) and Exhibit 1021 were reported as cached, Incyte

has failed to establish that the Concert Backgrounder cited in these exhibits are

identical. Paper 27, 45, n.9. However, the URL recited in Exhibit 1021 is identical

to the other exhibits citing to the archived WebCite® document, demonstrating the

two documents are the same. Cf. Exs. 1018, 1048, 1063, 1064, with Ex. 1021, 3.

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Authority written opinion (Ex. 1063, 3).10 Concert confirms the authenticity of this

document as Concert-drafted, thereby affirming its non-hearsay status (E.g., Ex.

1139, 4-6), and further admits to having received Ex. 1006 from “an examiner in a

European Search Report of a counterpart application” and then disseminating it to

the USPTO (id. at 7; see also Ex. 1047; Ex. 1050).

Each of these documented disseminations occurred prior to the priority date

in issue, and identify the same URL, http://www.webcitation.org/5e81SGCnl, a

precise citation to “guid[e] those of skill in the field” to locate Backgrounder.

Cornell, 2008 U.S. Dist. Lexis 39343, at *21; see also Jazz Pharm. Inc. v. Amneal

Pharm., LLC, 895 F.3d 1347, 1357 (Fed. Cir. 2018) (online availability evidences

public accessibility); Ex. 1051, ¶3.

Moreover, as a “published article with an express citation to” the

Backgrounder, the Buteau article further supports a finding of public accessibility.

Blue Calypso, 815 at 1350. Indeed, the Buteau article was relied upon in a

deuterium-related scientific article published in 2011 (Ex. 1140, n.10), by Concert

during prosecution of other prior art patents (e.g., Ex. 1141, 2; Ex. 1142, 2), and by

10 See Eastman Kodak Co. v. CTP Innovations, LLC, IPR2014-00789, Paper 34, 19

(PTAB Nov. 25, 2015) (reply evidence rebuts a public availability argument), aff’d

by 671 F. App’x 801 (Fed. Cir. 2016).

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several patent examiners (Ex. 1021, 3; Ex. 1048, 4; Ex. 1063, 3). Cornell, 2008 U.S.

Dist. Lexis 39343, at *21-22 (“The question of whether a reference was

‘meaningfully catalogued or indexed’ falls to the side when a ‘research aid’ enables

one of skill in the art to locate the sought-after reference.”) (citing Bruckelmyer v.

Ground Heaters, Inc., 445 F.3d 1374, 1379 (Fed. Cir. 2006))

Concert’s cited cases support Backgrounder’s being a printed publication.

Blue Calypso recognized that, public accessibility can be demonstrated by showing

that the reference was found by a POSA or “a published article with an express

citation to the potentially invalidating reference” 815 F.3d at 1349-50. SRI is readily

distinguishable because there was “no intent to publicize” the reference. 511 F.3d

1186, 1198 (Fed. Cir. 2008). In Adobe, the Petitioner failed to “introduce[] any

evidence that [the reference] was actually disseminated to any skilled artisans prior

to the earliest effective filing date.” IPR2018-00418, Paper 7, 12 (PTAB June 21,

2018).

Even if this Board finds that Backgrounder is not a printed publication, the

reference should still be considered as it provides motivation reflective of the

understanding of a POSA. See, e.g., Ex. 1002, ¶¶ 75-77, 82; Ex. 1089, 89:4-90:14;

Ex. 1008, 49, 52; Ex. 1010, 4, 6; Ex. 1076, 521; Ex. 1077, 1; Ex. 1078. Concert’s

distribution of this document (Paper 8, 33; Ex. 1139, 5-6), further evidences that this

general motivation was known. As a source of motivation, Backgrounder need not

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meet the printed publication standard. Cross Med. Prods., Inc. v. Medtronic Sofamor

Danek, Inc., 424 F.3d 1293, 1322 (Fed. Cir. 2005); Nat’l Steel Car, Ltd. v. Canadian

Pacific Ry., Ltd., 357 F.3d 1319, 1337–38 (Fed. Cir. 2004); Taiwan Semiconductor

Mfg. Co. v. Godo Kaisha Ip Bridge 1, IPR2016-01246, Paper 49, 65-67 (PTAB Jan.

3, 2018).

Moreover, Concert recognizes that for motivation the Petition relied on the

expectation, based on background reference Ex. 1013, “that deuterated drugs have

‘selectivity and potency comparable to their hydrogen analogs.’” Paper 27, 56

(quoting (Paper 1, 30-31; Ex. 1002, ¶55)); see also Paper 27, 51 (“the sole basis for

such a motivation derived from the Federal Circuit’s cases finding that motivation

to produce a claimed compound can be based on structural similarity to a prior art

compound”). Backgrounder (Ex. 1006) provides “additional reason or motivation,”

but is not relied on to teach or suggest any claim element. Paper 1, 31; Ex. 1002,

¶55. Since motivation is supported by the documented understanding of a POSA,

Backgrounder is not critical to a finding of obviousness. Ariosa Diagnostics v.

Verinata Health, Inc., 805 F.3d 1359, 1365 (Fed. Cir. 2015) (“Exhibit 1010 had to

be considered [as evidence of POSA’s understanding] by the Board even though it

was not one of the three pieces of prior art presented as the basis for obviousness”);

Intel Corp. v. R2 Semiconductor, Inc., IPR2017-00707, Paper 81, 32 n.19, 81-82

(PTAB. July 31, 2018).

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B. The Jakafi® Label

In November 2011, the FDA approved ruxolitinib and the Jakafi® Label

disclosed in Exhibit 1004. Ex. 1004; Ex. 1042; Ex. 1043; Ex. 1051, ¶ 2; Ex. 1052.

One month later, ruxolitinib and Jakafi® were included in the December 2011

Edition of the Orange Book. Ex. 1049, 11.

At this time, Incyte also began marketing and promoting its product, as

evidenced by archived versions of incyte.com and jakafi.com (Ex. 1044; Ex. 1045),

Incyte’s 2011 Form 10-K (Ex. 1060, 7), and Incyte’s 2011 Annual Report (Ex. 1059).

The labels available on incyte.com as of November 19, 2011 and on jakafi.com as

of November 17, 2011 (Ex. 1046; see also Ex. 1058), are the same as Exhibit 1004.

Ex. 1051 ¶ 2; see also Ex. 1143.

The label’s public availability is further supported by Dr. Guengerich’s

observation that, as of the priority date, ruxolitinib was “a well-established,

pharmaceutical drug” that had been recognized by POSAs as being active against

indications besides just those that had received FDA approval. Ex. 1002 ¶ 63-64.

V. Conclusion

Petitioner respectfully requests the Board hold the claims unpatentable.

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Date: September 10, 2018 Respectfully submitted,

/Thomas L. Irving/ Thomas L. Irving, Reg. No. 28,619 Finnegan, Henderson, Farabow,

Garrett & Dunner, LLP Counsel for Petitioner Incyte

Corporation

IPR2017-01256 PATENT NO. 9,249,149

CERTIFICATE OF COMPLIANCE

The undersigned certifies that a copy of the foregoing Petitioner’s Reply to

Patent Owner’s Response contains 5,586 words, excluding those portions

identified in 37 C.F.R. § 42.24(a), as measured by the word-processing system used

to prepare this paper.

Dated: September 10, 2018 By: /Thomas L. Irving/

IPR2017-01256 PATENT NO. 9,249,149

CERTIFICATE OF SERVICE

The undersigned hereby certifies that a copy of the foregoing Petitioner’s

Reply to Patent Owner’s Response was served electronically via email on

September 10, 2018, in its entirety on the following:

Cynthia Lambert Hardman Goodwin Procter LLP The New York Times Building 620 Eighth Avenue New York, NY 10018-1405 Email: chardman@goodwinlaw.com

Marta E. Delsignore Goodwin Procter LLP The New York Times Building 620 Eighth Avenue New York, NY 10018-1405 Email: mdelsignore@goodwinlaw.com Daryl L. Wiesen Sarah J. Fischer Emily L. Rapalino Goodwin Procter LLP 100 Northern Avenue Boston, MA 02210 Email: dwiesen@goodwinlaw.com Email: sfischer@goodwinlaw.com Email: erapalino@goodwinlaw.com

Dated: September 10, 2018 By: /William Esper/

William Esper Legal Assistant FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER, L.L.P.