Pharmacyclics LLC

Patent Trials and Appeals Board

Sep 24, 2020

IPR2019-00865 (P.T.A.B. Sep. 24, 2020)

Trials@uspto.gov Paper 29
571-272-7822 Entered: September 24, 2020

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

SANDOZ INC.,
Petitioner,
v.
PHARMACYCLICS LLC,
Patent Owner.
____________

IPR2019-00865
Patent 9,795,604 B2
____________

Before SHERIDAN K. SNEDDEN, SUSAN L. C. MITCHELL, and
DAVID COTTA, Administrative Patent Judges.

COTTA, Administrative Patent Judge.

FINAL WRITTEN DECISION
Determining Some Challenged Claims Unpatentable
Denying in Part and Dismissing in Part Motion to Strike
35 U.S.C. § 318(a); 37 C.F.R. § 42.5; 37 C.F.R. § 42.20

IPR2019-00865
Patent 9,795,604 B2

2
I. INTRODUCTION
Sandoz Inc. (“Petitioner”) filed a Petition requesting an inter partes
review of claims 1, 4, 6–10, 13, 15, 24, 28–31, 35, 39, 43–46, 50–53, and 55
of U.S. Patent No. 9,795,604 B2 (Ex. 1001, “the ’604 patent”).1 Paper 2
(“Pet.”). Pharmacyclics LLC (“Patent Owner”) filed a Preliminary
Response to the Petition. Paper 6 (Prelim. Resp.).2 We determined, based
on the information presented in the Petition and Preliminary Response, that
there was a reasonable likelihood that Petitioner would prevail in showing
that at least one of the challenged claims was unpatentable over the cited art.
Pursuant to 35 U.S.C. § 314, the Board instituted trial on September 26,
2019. Paper 8 (“Institution Decision” or “Inst. Dec.”).
Patent Owner filed a Response to the Petition (Paper 13, “PO Resp.”),
Petitioner filed a Reply to Patent Owners’ Response (Paper 17, “Reply”),
and Patent Owner filed a Sur-Reply (Paper 24, “Sur-Reply”). With our prior
authorization, Patent Owner filed a Motion to Strike Improper Reply
Arguments (Paper 25, “Mot.”), Petitioner filed an Opposition to Patent
Owner’s Motion to Strike (Paper 26, “Mot. Opp.”), and Patent Owner filed a
Reply in Support of its Motion to Strike (Paper 27, “Mot. Reply”).
On March 21, 2019, the parties presented arguments at an oral
hearing. The transcript of the hearing has been entered into the record.
Paper 28 (“Tr.”).
We have jurisdiction under 35 U.S.C. § 6. We issue this Final Written
Decision pursuant to 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73. Based on

1 Petitioner identifies Sandoz Inc. and Lek Pharmaceuticals D.D. as the real
parties in interest. Pet. 2.
2 Patent Owner identifies Pharmacyclics LLC, AbbVie Inc, and Janssen
Biotech, Inc. as the real parties in interest. Paper 4, 1.
IPR2019-00865
Patent 9,795,604 B2

3
the record before us, we conclude that Petitioner has demonstrated, by a
preponderance of the evidence, that claims 1, 6–10, 24, 35, 39, and 55 of the
’604 patent are unpatentable, but that Petitioner has not demonstrated, by a
preponderance of the evidence, that claims 4, 13, 15, 28–31, 43–46 and 50–
53 are unpatentable. We deny in part and dismiss in part Patent Owners’
Motion to Strike.
A. Related Proceedings
Petitioner and Patent Owner represent that the ’604 patent was
asserted in Pharmacyclics LLC v. Zydus Worldwide DMCC, Civ. No. 1:18-
cv-00275-CFC (D. Del.), which has been consolidated with Pharmacyclics
LLC v. Fresenius Kabi USA, LLC, 1:18-cv-00192-CFC (D. Del). Pet. 2;
Paper 4, 1. Petitioner and Patent Owner also represent that U.S. Patent
Application No. 15/586,058, filed May 3, 2017, is related to the ’604 patent.
Pet. 2; Paper 4, 1.
B. The ’604 Patent (Ex. 1001)
The ’604 patent issued October 24, 2017, identifying John C. Byrd,
Jason A. Dubovsky, Natarajan Muthusamy, Amy Jo Johnson, and David
Miklos as inventors. Ex. 1001, at codes (45), (72). The patent teaches:
Chronic graft versus host disease (cGVHD) is the most
common long-term complication following allogeneic stem cell
transplant (SCT), affecting 30-70% of patients who survive
beyond the first 100 days. cGVHD and its associated immune
deficiency have been identified as a leading cause of
non-relapse mortality (NRM) in allogeneic SCT survivors.
Id. at 1:29–36. The ’604 patent discloses “methods for treating and
preventing graft versus host disease using . . . an ACK inhibitor such as
ibrutinib.” Id. at Abstract.
IPR2019-00865
Patent 9,795,604 B2

4
C. Challenged Claims
Petitioner challenges claims 1, 4, 6–10, 13, 15, 24, 28–31, 35, 39, 43–
46, 50–53, and 55 of the ’604 patent. Claim 1 is representative and is
reproduced below:
1. A method of treating chronic graft versus host disease
(GVHD) comprising administering to a patient having chronic
GVHD a therapeutically effective amount of a compound of the
structure:

thereby treating the chronic GVHD in the patient.

Ex. 1001, 75:41–68.
D. Prior Art and Asserted Grounds
We instituted trial based on each challenge to the patentability of the
’604 patent presented in the Petition. The Petition challenged the
patentability of claims 1, 4, 6–10, 13, 15, 24, 28–31, 35, 39, 43–46, 50–53,
and 55 of the ’604 patent on the following grounds:
IPR2019-00865
Patent 9,795,604 B2

5
Claims Challenged 35 U.S.C. § Reference(s)/Basis
1, 4, 6–10, 13, 15, 24,
28–31, 35, 39, 43–46,
50–53, 55
102 The ’085 publication3
1, 4, 6–10, 13, 15, 24,
28–31, 35, 39, 43–46,
50–53, 55
103 The ’085 publication
1, 4, 6–10, 13, 15, 24,
28–31, 35, 39, 43–46,
50–53, 55
103 The ’085 publication,
Shimabukuro-Vornhagen,4
Herman5
1, 4, 6–10, 13, 15, 24,
28–31, 35, 39, 43–46,
50–53, 55
103 The ’085 publication,
Shimabukuro-Vornhagen,
Uckun6
Pet. 30–31.
Petitioner submits the Declaration of Dr. James L. Ferrara (Ex. 1006)
in support of the Petition. Patent Owner submits the Declaration of Dr. John
Koreth (Ex. 2055) in support of its Response to the Petition.
E. Person of Ordinary Skill in the Art
Factual indicators of the level of ordinary skill in the art include “the
various prior art approaches employed, the types of problems encountered in

3 Goldstein, US Patent Publication No. 2015/0140085 A1, published May
21, 2015 (Ex. 1002, “the ’085 publication”).
4 Shimabukuro-Vornhagen, et al., The Role of B Cells in the Pathogenesis of
Graft-Versus-Host Disease, 114(24) BLOOD 4919–4927 (2009) (Ex. 1003,
“Shimabukuro-Vornhagen”).
5 Herman, et al., Bruton Tyrosine Kinase Represents a Promising
Therapeutic Target for Treatment of Chronic Lymphocytic Leukemia and is
Effectively Targeted by PCI-32765, 117(23) BLOOD 6287–6296 (2011)
(Ex. 1004, “Herman”).
6 Uckun, et al., Bruton’s Tyrosine Kinase as a Molecular Target in
Treatment of Leukemias and Lymphomas as well as Inflammatory Disorders
and Autoimmunity, 20(11) EXPERT OPIN. THER. PATENTS 1457–1470 (2010)
(Ex. 1005, “Uckun”).
IPR2019-00865
Patent 9,795,604 B2

6
the art, the rapidity with which innovations are made, the sophistication of
the technology involved, and the educational background of those actively
working in the field.” Jacobson Bros., Inc. v. U.S., 512 F.2d 1065, 1071
(Ct. Cl. 1975); see also Orthopedic Equip. Co., v. U.S., 702 F.2d 1005, 1011
(Fed. Cir. 1983) (quoting with approval Jacobson Bros.).
Petitioner contends that the person of ordinary skill “would have had
an advanced degree in the field of medicine with additional, specialized
training, such as a fellowship in Hematology/Oncology as well as several
years’ experience specializing in transplantation.” Pet. 31; Ex. 1006 ¶¶ 53.
Petitioner also contends that the POSA would “preferably have had some
experience with pharmaceutical compositions for treating GVHD or related
conditions.” Pet. 31–32.
In our Institution Decision, we accepted Petitioner’s definition of the
POSA. Inst. Dec. 5–6. Patent Owner does not challenge the definition set
forth by Petitioner and adopted in our Institution Decision. See generally
PO Resp, Sur-Reply. The fully developed trial record supports that this
definition is consistent with the level of skill reflected in asserted prior art
references and in the ’604 patent. Accordingly, in this decision, we apply
Petitioner’s definition of the POSA.
F. Claim Construction
We construe claims “using the same claim construction standard that
would be used to construe the claim in a civil action under 35 U.S.C.
[§] 282(b).” See Changes to the Claim Construction Standard for
Interpreting Claims in Trial Proceedings Before the Patent Trial and Appeal
Board, 83 Fed. Reg. 51,340, 51,340, 51,358 (Oct. 11, 2018) (amending
37 C.F.R. § 42.100(b) effective November 13, 2018) (now codified at 37
IPR2019-00865
Patent 9,795,604 B2

7
C.F.R. § 42.100(b) (2019)). Therefore, we construe the challenged claims
under the framework set forth in Phillips v. AWH Corp., 415 F.3d 1303,
1312–19 (Fed. Cir. 2005) (en banc). Under this framework, claim terms are
given their ordinary and customary meaning, as would have been understood
by a person of ordinary skill in the art, at the time of the invention, in light of
the language of the claims, the specification, and the prosecution history of
record. Id. Only those terms that are in controversy need be construed, and
only to the extent necessary to resolve the controversy. See Nidec Motor
Corp. v. Zhongshan Broad Ocean Motor Co., 868 F.3d 1013, 1017 (Fed.
Cir. 2017) (citing Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795,
803 (Fed. Cir. 1999)).
Patent Owner requests that we construe what it terms “efficacy
limitations” in claims 6, 7, 8, 29, 30, 31, 44, 45, 46, 51, 52, 53, and 55.
PO Resp. 5–16. These limitations recite particular patient outcomes
resulting from the administration of ibrutinib in dependent claims 6, 7, 8, 29,
30, 31, 44, 45, 46, 51, 52, and 53. The particular patient outcomes recited in
these dependent claims are summarized in the Table below.
Dependent Claims Text of limitations
6, 29, 44, 51 “wherein, following administration
of the compound, the patient
achieves partial response (PR),
wherein the PR is an objective
response in one involved organ in
the patient with no evidence of
progression elsewhere and no
requirements for additional systemic
therapy.”
IPR2019-00865
Patent 9,795,604 B2

8
Dependent Claims Text of limitations
7, 30, 45, 52 “wherein, following administration
of the compound, the patient
achieves complete response (CR),
wherein the CR is a complete
restoration of symptoms attributable
to GVHD.”
8, 31, 46, 53 “wherein, following administration
of the compound, the severity of the
GVHD is reduced.”

Patent Owner also requests that we construe the terms “method of treating,”
which is recited in claims 1 and 55, and the limitation “thereby treating the
chronic GVHD in the patient,” which is recited in claim 1. PO Resp. 6.
In its Petition and in its Reply, Petitioner argues that these claim
limitations merely state the result of performing the method set forth in the
claim and add nothing to the patentability or substance of the claim. Pet. 40;
Pet. Reply 2. Accordingly, Petitioner contends that these limitations are not
entitled to patentable weight. Id. Patent Owner contends that the recited
patient outcomes should be given patentable weight because they “are
material to patentability and express the inventive aspect of the claimed
invention.” PO Resp. 6.
Although the parties dispute the proper claim construction of these
claim terms, we determine that no explicit construction of these terms is
necessary to resolve this dispute because, as discussed infra 11–12 and 27–
30, we find that these limitations are inherently present in the cited art. See
Nidec, 868 F.3d at 1017 (“[W]e need only construe terms ‘that are in
controversy, and only to the extent necessary to resolve the controversy’”
(quoting Vivid Techs., 200 F.3d at 803)); Wellman, Inc. v. Eastman Chem.
IPR2019-00865
Patent 9,795,604 B2

9
Co., 642 F.3d 1355, 1361 (Fed. Cir. 2011) (“[C]laim terms need only be
construed ‘to the extent necessary to resolve the controversy’”).
II. GROUND 1: ANTICIPATION BY THE ’085 PUBLICATION
Petitioner asserts that the ’085 publication anticipates claims 1, 4, 6–
10, 13, 15, 24, 28–31, 35, 39, 43–46, 50–53, and 55 of the ’604 patent.
Pet. 34–44. Patent Owner opposes. PO Resp. 16–21, 53–56. We have
reviewed Petitioner’s and Patent Owner’s assertions, as well as the evidence
of record, and, for the reasons discussed below, we conclude that Petitioner
has demonstrated by a preponderance of the evidence, that claims 1, 6–10,
24, 35, 39, and 55 of the ’604 patent are anticipated by the ’085 publication,
but that Petitioner has not demonstrated, by a preponderance of the evidence,
that claims 4, 13, 15, 28–31, 43–46 and 50–53 are anticipated by the ’085
publication.
A. Disclosures of the Asserted Prior Art
The ’085 Publication
The ’085 publication discloses “[o]ral pharmaceutical formulations of
ibrutinib . . . and use of these formulations for the treatment of diseases
treatable by ibrutinib such as . . . autoimmune diseases.” Ex. 1002, Abstract.
Among the autoimmune diseases disclosed as treatable using the oral
pharmaceutical formulations of the ’085 publication is graft versus host
disease. Id. ¶ 98 (“In another embodiment of this aspect, the patient in need
is suffering from a heteroimmune condition or disease, e.g., graft versus host
disease.”). According to the ’085 publication, “[t]he therapeutically
effective amount of ibrutinib . . . can be from about 20 mg per day to about
450 mg/day, or 20 mg/day to about 420 mg/day; or about 20 mg/day or 30
mg/day to about 300 or 350 mg/day; or about 30 or 50 mg/day to about 200,
IPR2019-00865
Patent 9,795,604 B2

10
or 220 or 250 mg/day; or about 30 or 50 mg/day to about 100 or 150 mg/day
and can be administered in single or multiple doses.” Id. ¶ 30.
B. Analysis
Claim 1
Petitioner contends that the ’085 publication discloses all of the
limitations of claim 1. Petitioner acknowledges that the ’085 publication
discloses treating graft versus host disease rather than chronic graft versus
host disease, as claimed. Pet. 35. However, Petitioner contends that there
are only two types of graft versus host disease – chronic and acute. Id.
Supported by the testimony of Dr. Ferrara, Petitioner asserts that a POSA
would have “at once envisaged that this disclosure pertains to both acute and
chronic GVHD.” Id. (citing Ex. 1006 ¶ 77). Petitioner thus contends that
the ’085 publication anticipates treatment of chronic GVHD. Id. Petitioner
cites Wm. Wrigley Jr. Co. v. Cadbury Adams USA LLC, 683 F.3d 1356,
1361 (Fed. Cir. 2012) and Kennametal, Inc. v. Ingersoll Cutting Tool Co.,
780 F.3d 1376, 1381 (Fed. Cir. 2015) as supporting the proposition that a
species within a genus is anticipated where the genus was of “such a defined
and limited class that one of ordinary skill in the art could ‘at once envisage’
each member of the genus.” Pet. 35.
With respect to the requirement of claim 1 for “administering . . . a
therapeutically effective amount,” Petitioner points to the disclosure in the
’085 publication of “therapeutically effective” amounts of ibrutinib.
Pet. 36–37 (citing Ex. 1002 ¶¶ 30, 120). Petitioner argues that the term
“therapeutically effective amount” in claim 1 must encompass the amounts
IPR2019-00865
Patent 9,795,604 B2

11
recited in claim 5, which depends from claim 1, and which recites amounts
corresponding to those disclosed in the ’085 publication. Id. at 14.
With respect to the “thereby treating the chronic GVHD in the
patient” recitation in claim 1, Petitioner argues that to the extent it is
limiting, the ‘085 publication discloses it both expressly and inherently. Id.
at 37.
Based on the arguments and evidence presented during this review,
we find that Petitioner has shown by a preponderance of the evidence that
the ’085 publication discloses each and every limitation of claim 1 of the
’085 publication. As discussed above, the ’085 publication discloses
treatment of GVHD. See supra p. 9. Although, the ’085 publication does
not specify whether such GVHD is chronic or acute, Petitioner provides
evidence that there are only two types of GVHD, acute and chronic.
Ex. 1006 ¶ 29 (cited at Pet. 7). Accordingly, we understand the ’085
publication’s reference to GVHD to disclose a genus comprised of acute and
chronic GVHD. Petitioner offers the testimony of Dr. Ferrara, which we
credit as supported by the record, that the POSA, “upon seeing the ’085
Publication’s disclosure directed to treating ‘graft versus host disease,’ . . .
would have immediately understood and envisioned that the ’085
Publication’s disclosure of treating GVHD includes specifically chronic
GVHD.” Id. ¶ 77. The trial record thus supports that the POSA would have
understood the ’085 publication to disclose treatment of chronic GVHD.
The trial record also supports that the ’085 publication discloses
administration of a therapeutically effective amount of ibrutinib.
Ex. 1002 ¶¶ 30, 120; Ex. 1006 ¶¶ 78–82. And, to the extent the recitation
“thereby treating the chronic GVHD in the patient” is considered to limit
IPR2019-00865
Patent 9,795,604 B2

12
claim 1, the ’085 publication discloses such treatment (Ex. 1002 ¶¶ 94, 98,
117–120) and the trial record supports that administration of a
“therapeutically effective amount” of ibrutinib will inherently “treat”
cGVHD (Ex. 1006 ¶ 83; see also, Ex. 1001, 26:47–53 (’604 patent defining
the term “treating” broadly)).
Patent Owner no longer disputes that the ’085 publication teaches
treatment of cGVHD, but instead argues that the ’085 publication does not
anticipate the ’604 patent because it does not enable treatment of cGVHD
with ibrutinib. PO Resp. 53–56.7 More specifically, Patent Owner argues
that the ’085 publication does not enable treatment of cGVHD “because of
its lack of guidance and working examples in an exceedingly unpredictable
field.” PO Resp. 53. According to Patent Owner, cGVHD was “poorly
understood” and “widely recognized as an unpredictable disease that was
exceedingly difficult to treat.” Id. Research on cGVHD was hampered by
the absence of “adequate animal models or reliable biomarkers” and “the
field was inundated with unreliable studies.” Id. Patent Owner contends
that, as a result, “the prior art recognized that the ‘trial-and-error system’
was the ‘only way’ to identify drugs effective for cGVHD.” Id. at 53–54.

7 In its Preliminary Response, Patent Owner also argued that the ’085
publication did not anticipate claim 1 because it did not disclose treatment of
chronic GVHD and because Petitioner’s anticipation arguments required
picking and choosing among disclosures. Prelim. Resp. 38–41. These
arguments are waived because Patent Owner did not pursue them in its post-
institution briefing. See Paper 9, 7 (“Patent Owner is cautioned that any
arguments for patentability not raised in the response may be deemed
waived.”). Even if we were to consider these arguments, we would find
them unpersuasive for the reasons set forth in our Institution Decision at 14–
16.

IPR2019-00865
Patent 9,795,604 B2

13
Against this backdrop, Patent Owner contends that the ’085 publication
provides insufficient guidance to enable the POSA to practice the claimed
invention. Id. at 31. Patent Owner explains:
[T]he ’085 Publication contains no in vitro, preclinical, or
clinical data indicating that ibrutinib could treat cGVHD, which
it fails even to mention. EX2055, ¶¶124–130. The ’085
Publication is devoid of working examples for treating any
disease. See generally EX1002. Instead, each of the six
examples (five of which are prophetic) relates to formulations
untethered to treating any particular disease. Supra § VI.A.1.
The text of the ’085 Publication likewise provides no guidance
for treating cGVHD. Instead, “graft versus host disease” is
generically identified among over 150 diseases. EX1002,
[0096]–[0100]. Although the ’085 Publication provides
generalized disclosures about “therapeutically effective
amounts,” that disclosure does not specify any particular
disease and is taught to “vary depending on the compound, the
disease and its severity[,] and the age, weight, etc. of the
mammal to be treated.” Supra § VI.A.1; EX1002, [0030],
[0120]. In other words, while teaching that many factors must
be considered to determine a “therapeutically effective amount”
for a particular disease, the ’085 Publication provides no
guidance as to how one would effectively treat cGVHD,
especially against the backdrop of unpredictability in this field.
EX2055, ¶¶121–122.
PO Resp. 54–55. We are not persuaded.
Prior art publications and patents are presumed to be enabled. In re
Antor Media Corp., 689 F.3d 1282, 1287–88 (Fed. Cir. 2012); Amgen Inc. v.
Hoechst Marion Roussel, Inc., 314 F.3d 1313, 1355 (Fed. Cir. 2003). Here,
the ’085 publication discloses “[o]ral pharmaceutical formulations of
ibrutinib and/or a pharmaceutically acceptable salt thereof.” Ex. 1002,
Abstract. It also discloses that these formulations may be used to treat a
patient “suffering from a heteroimmune condition or disease, e.g., graft
IPR2019-00865
Patent 9,795,604 B2

14
versus host disease” (id. ¶ 98) by “administering to the patient . . . a solid
oral dosage form disclosed herein.” Id. ¶ 96.
We acknowledge Patent Owner’s argument that the ’085 publication
does not include instructions specific to cGVHD. However, per claim 1, all
that is required to treat cGVHD is to administer a therapeutically effective
dose of ibrutinib, which the ’085 publication teaches. Ex. 1001, 75:40–67
(claim 1); see also, Tr. 37–38 (MR. RAICH: “. . . The ’085 Publication as I
mentioned earlier, has no guidance whatsoever in terms of how to treat the
disease . . . . JUDGE COTTA: What guidance is needed beyond just
identifying a dose? MR. RAICH: I would say a dose and a dosing regimen
would be an appropriate thing to provide in terms of how to actually treat the
disease.”).
The ’085 publication provides general guidance – not specific to any
one disease – on administering therapeutically effective doses of ibrutinib
and on the frequency with which those doses should be administered. In
describing one of the disclosed solid oral dosage forms, it states:
The therapeutically effective amount of ibrutinib and/or a
pharmaceutically acceptable salt thereof when administered into
the intestine by bypassing the stomach can be from about 20 mg
per day to about 450 mg/day, or 20 mg/day to about 420
mg/day; or about 20 mg/day or 30 mg/day to about 300 or 350
mg/day; or about 30 or 50 mg/day to about 200, or 220 or 250
mg/day; or about 30 or 50 mg/day to about 100 or 150 mg/day
and can be administered in single or multiple doses.
Ex. 1002 ¶ 30; see also, id. ¶26. Similarly, in defining the term
“therapeutically effective amount,” the ’085 publication teaches:
The “therapeutically effective amount” will vary depending on
the compound, the disease and its severity and the age, weight,
etc., of the mammal to be treated. The therapeutically effective
amount of ibrutinib and/or a pharmaceutically acceptable salt
IPR2019-00865
Patent 9,795,604 B2

15
thereof when administered in the intestine can be from about 20
mg per day to about 450 mg/day, or any permu[t]ations and
combinations thereof. Such as 20 mg/day to about 420 mg/day;
or about 20 mg/day or 30 mg/day to about 300 or 350 mg/day;
or about 30 or 50 mg/day to about 200, or 220 or 250 mg/day;
or about 30 or 50 mg/day to about 100 or 150 mg/day and can
be administered in single or multiple doses.
Id. ¶ 120. The doses described in the ’085 publication correlate with those
identified as “therapeutically effective” in the ’604 patent. Compare id.
¶¶ 30, 120 with Ex. 1001, 76:7–10 (claim 5).
Patent Owner, through the testimony of Dr. Koreth, observes that the
’085 publication provides “no dose or doses of ibrutinib as part of [the]
eighth aspect for treating any particular disease, including GVHD.”
Ex. 2055 ¶ 125. Dr. Koreth also testifies the ’085 publication’s disclosure of
a “therapeutically effective amount” of ibrutinib “is insufficient to provide
any information about a therapeutically effective dose of ibrutinib to treat
cGVHD, especially as the prior art does not disclose any ibrutinib dose for
the treatment of patients with cGVHD.” Id. ¶ 126. We do not find this
persuasive.
We find that the POSA would readily have connected the disclosure
in the ’085 publication that in an “eighth aspect of the present disclosure”
ibrutinib can be used to treat GVHD with the disclosure of dosages of
ibrutinib provided in elsewhere in the ’085 publication. In this regard, we
note that the “eighth aspect” is directed to treating an autoimmune disease,
including GCHD, by “administering . . . a solid oral dosage form disclosed
herein,” and the “solid oral dosage form[s] disclosed” in the ’085 publication
specify doses of ibrutinib and frequency of administration. See, e.g., Ex.
1002, ¶¶ 26 (identifying ranges of dosages for a “forth aspect” of the present
disclosure, which aspect was previously described as providing a “solid oral
IPR2019-00865
Patent 9,795,604 B2

16
dosage” form); 30 (same), 96 (disclosing treatment of autoimmune disease
by administering “a solid oral dosage form disclosed herein” as an eighth
aspect of the present disclosure), 98 (specifying that the autoimmune disease
is graft versus host disease). We are persuaded that the POSA would have
understood the “solid oral dosage form disclosed herein” (id. ¶ 96) to
include the solid oral dosage forms disclosed the “forth aspect” of the
disclosure of the ’085 patent (id. ¶¶ 26, 30), particularly as those doses are
consistent with the doses described as being therapeutically effective (id. ¶
120). KSR Intern. Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007) (“A person
of ordinary skill is also a person of ordinary creativity, not an automaton.”).
For similar reasons, we are not persuaded that, as Dr. Koreth seems to
suggest, a POSA would have required a statement specific to ibrutinib in
order to connect the teaching of the ’085 patent to treat GVHD with the
disclosure of therapeutically effective amounts of ibrutinib. Ex. 2055 ¶ 126;
Ex. 1002 ¶¶ 98, 120; see also Ex. 1006 ¶¶ 96–101 (Dr. Ferrara testimony on
what the POSA would have understood from the disclosure of the ’085
publication regarding dosing). Rather, we find that a POSA would naturally
have connected the teaching of treating GVHD with the disclosed
therapeutically effective amounts of ibrutinib.
In sum, the record does not support a conclusion that a POSA,
provided with both information regarding therapeutically effective amounts
of ibrutinib and the teaching that ibrutinib can be used to treat GVHD,
would have required undue experimentation to carry out the claimed method
by selecting a patient appropriate ibrutinib dosage based on age, weight, and
other disclosed parameters. Indeed, it is not clear that the POSA would have
required any experimentation, much less undue experimentation, as all that
IPR2019-00865
Patent 9,795,604 B2

17
is required to carry out the claimed method is to do what the ’085
publication suggests – administer a therapeutically effective amount of
ibrutinib.
We acknowledge Patent Owner’s argument that cGVHD is a poorly
understood, unpredictable disease, and that the prior art relied on trial-and-
error to identify drugs effective for cGVHD. However, we are not
persuaded that these difficulties, and the other difficulties identified by
Patent Owner in its briefing (see PO Resp. 53–56), are sufficient to rebut the
presumptively enabled teaching of the ’085 publication that ibrutinib can be
used to treat GVHD. In this regard, we are guided by our reviewing court’s
decision in Rasmussen v. SmithKline Beecham Corp. 413 F.3d 1318 (Fed.
Cir. 2005). The issue in Rasmussen was whether the disclosure of a prior art
reference, EP ’383, enabled the use of finasteride to treat prostate cancer so
as to anticipate the patent at issue. Id. at 1325–1326. The Board made
several findings akin to those argued by Patent Owner here. Specifically, it
found:
(1) that in light of the state of the art at the time of the
publication of EP ‘383 in 1988, there was no reasonable
scientific basis for a person of ordinary skill in the art to
conclude that the claimed method would be effective in treating
prostate cancer, and (2) that given the lack of proof provided in
the publication itself, a person of ordinary skill in the art as of
the publication date of EP ‘383 would not have believed that
the method described in EP ‘383 would be effective.
Id. at 1326. Our reviewing court found that these findings were “insufficient
to support the Board’s conclusion that EP ’383 is not an enabling reference
for purposes of anticipation.” Id; see also, Bristol-Myers Squibb v. Ben
Venue Laboratories, Inc., 246 F.3d 1368, 1370, 1378 (Fed. Cir. 2001)
(finding that prior art reference anticipated a claim directed to a “method for
IPR2019-00865
Patent 9,795,604 B2

18
reducing hematologic toxicity in a cancer patient undergoing [t]axol
treatment comprising parenterally administering to said patient an
antineoplastically affective amount of . . . taxol” even though the reference
showed that carrying out the method lacked efficacy).
Patent Owner relies on Impax Laboratories, Inc. v. Aventis
Pharmaceuticals, Inc., 545 F.3d 1312 (Fed. Cir. 2008) to support its
argument that the ’085 publication does not enable the method it discloses.
PO Resp. 55–56. Impax, however, is readily distinguishable. In Impax, our
reviewing court found that a prior art reference did not enable the use of
riluzole to treat ALS where: 1) “nothing in [the prior art reference] would
direct one skilled in the art to recognize that riluzole could be used to treat
ALS,” 2) the “dosage guidelines [were] broad and not specific to any of the
hundreds of formula I compounds of the claimed invention or to any of the
listed diseases,” and 3) the prior art reference “tie[d] the dosing information
to ‘the compounds of the invention’ and specifically exclude[d] riluzole
from the invention.” Id. at 1315. Here, the ’085 publication specifically
teaches that ibrutinib can be used to treat GVHD (Ex. 1002 ¶ 98), and limits
its disclosure to one compound, ibrutinib, rather than the hundreds of
compounds encompassed by the disclosure in Impax. Moreover, there is
nothing in the ’085 publication remotely equivalent to Impax’s specific
exclusion of riluzole from the invention. We acknowledge that the dosage
guidelines in the ’085 publication are, like those in Impax, not specific to
any one disease. However, they are specific to ibrutinib and, as discussed
above, we find that the POSA would have connected the dosage guidelines
with the teaching that ibrutinib could be used to treat GVHD.
IPR2019-00865
Patent 9,795,604 B2

19
Accordingly, because the ’085 publication discloses all of the
elements in the method of claim 1, and because Patent Owner has not
rebutted the presumption that the ’085 publication is enabled, we find that
the preponderance of the evidence supports that the ’085 publication
anticipates claim 1 of the ’865 patent.

Claims 4, 13, 15, 28–31, 43–46, and 50–53
Claims 4, 13, and 15 depend from claim 1 and provide additional
limitations concerning the patients to whom ibrutinib is administered.
Claim 4 specifies that “the patient has steroid-dependent/refractory chronic
GVHD.” Claim 13 specifies that “the chronic GVHD is steroid resistant
GVHD.” And claim 15 specifies that “the chronic GVHD is refractory
GVHD.” Claims 28–31, 43–46, and 50–53 each depend from one of claims
4, 13, and 15.
Petitioner contends that the ’085 publication anticipates treatment of
such patients because a POSA “would have known that post-steroid
treatments – including administering ibrutinib – were started only if steroids
were not being effective.” Pet. 38–39 (citing Ex. 1006 ¶ 86).
Patent Owner argues that Petitioner improperly relies on the
knowledge of the POSA to supply the missing elements of treating steroid-
dependent/refractory, steroid-resistant, and refractory cGVHD. PO Resp.
21. Patent Owner contends that “nothing in the ’085 Publication discloses
whether ibrutinib would be used before, after, or during steroid therapy” nor
does it “recognize any of the many variations, in terms of patient subset and
disease classification, that identifies the claimed treatment in steroid
IPR2019-00865
Patent 9,795,604 B2

20
resistant/refractory patients.” Id. (citing Ex. 2055 ¶¶ 135–137). We agree
with Patent Owner.
The Petition does not identify any disclosure in the ’085 publication
of using steroids to treat GVHD. Nor does the Petition identify any
disclosure in the ’085 publication of whether ibrutinib is a first or second
line treatment, instead relying impermissibly on the knowledge of the POSA
to supply the limitations recited in these claims. Pet. 38–39. Accordingly,
the Petition does not establish by a preponderance of the evidence that the
’085 publication anticipates claims 4, 13, and 15. Nidec Motor Corporation
v. Zhongshan Broad Ocean Motor Co. Ltd., 851 F.3d 1270, 1274–75 (Fed.
Cir. 2017) (“Kennametal does not permit the Board to fill in missing
limitations simply because a skilled artisan would immediately envision
them.”).
In addition, beyond Petitioner’s improper reliance on the knowledge
of the POSA, we are not persuaded as a factual matter that a POSA would
have looked at the bald disclosure in the ’085 publication of treatment of
GVHD with ibrutinib and immediately envisioned from that disclosure that
ibrutinib would be used as a second line treatment and in instances where
treatments with steroids had failed. See Ex. 1006 ¶ 86 (Ferrara testimony to
this effect). While we recognize that steroids were generally accepted as a
first line treatment, the record supports a desire to find new first line
treatments. Ex. 2019, 5074 (“Long-term glucocorticoid treatment causes
numerous complications, including infections, myopathy, avascular necrosis,
osteoporosis, glucose intolerance, hypertension, growth retardation in
children, weight gain, changes in body habitus, cutaneous atrophy and striae,
cataracts, emotional lability, and interference with sleep. Development of
IPR2019-00865
Patent 9,795,604 B2

21
less toxic treatments that could reduce the dose or duration of glucocorticoid
administration or improve disease control would be of enormous benefit for
patients with chronic GVHD.”); Ex. 1006 ¶ 33 (Ferrara testimony: “While
steroids are the primary treatment for chronic GVHD, they are often
ineffective.”). Indeed, the evidence supports that those of skill in the art
continued to investigate and use drugs as first line treatments even though
steroids were generally accepted in that role. Ex. 2019, abstract
(investigating whether “the addition of mycophenolcate mofetil (MMF)
improves the efficacy of initial systemic treatment of chronic graft-versus-
host disease”); Ex. 2001, 49 ( “A combination regimen of ciclosporin [a
calcineurin inhibitor] and prednisolone may have a steroid-sparing effect and
reduce the incidence of steroid-associated complications.”); Ex. 2055 ¶ 33
(Dr. Koreth testimony: “It was not uncommon for calcineurin inhibitors
(cyclosporine tacrolimus) to be used in combination with corticosteroids as a
first line treatment approach”).
In addition, steroid-dependent/refractory, steroid-resistant, and
refractory cGVHD patients were recognized as “particularly difficult to
treat.” Ex. 2055 ¶ 137; id ¶ 38 (Dr. Koreth’s well supported testimony
summarizing the prior art as recognizing “steroid-dependent/refractory,
steroid-resistant, or refractory cGVHD patients were very hard to treat.”); id.
¶¶ 35–37 (discussing unsuccessful attempts to treat such patients); id.
¶¶ 174–180 (discussing safety concerns for drugs, like ibrutinib, that target
B and T cells when administered to steroid-dependent/ refractory, steroid-
resistant, or refractory cGVHD patients); Ex. 2056, 124:7–11 (Dr. Ferrara
testimony: “So in that sense, a patient with chronic GvHD, particularly one
who is being treated for chronic GvHD [i.e. treated with steroids], has an
IPR2019-00865
Patent 9,795,604 B2

22
immune system that is less than that of a newborn baby. Less effective or
less protective than that of a newborn baby.”); Ex. 2059, 207 (stating that
“[t]here are major challenges to developing therapy for cortico-steroid-
resistant cGVHD” and identifying some of these challenges). In view of
these difficulties, it is difficult to credit Dr. Ferrara’s testimony that the
POSA would look at the disclosure of treating GVHD in the ’085
publication and immediately envision that it discloses treatment of these
challenging patients. Ex. 1006 ¶ 86 (Dr. Ferrara testimony on this issue);
Ex. 2055 ¶¶ 133–138 (Dr. Koreth testimony on the scope of what is
encompassed by “GVHD” and the difficulties in treating the claimed patient
population).
For these additional reasons, the Petition does not establish by a
preponderance of the evidence that the ’085 publication anticipates claims 4,
13, and 15.
In its Reply, Petitioner cites to Dr. Ferrara’s testimony in his
deposition that the drugs listed in paragraph 124 of the ’085 publication are
“all steroids that we use to treat Graft-versus-host disease.” Reply 9.8
Petitioner then points to the disclosure in the ’085 publication that “other
drug(s) may be administered . . . contemporaneously or sequentially with a
compound of the present disclosure” (Ex. 1002 ¶ 121) and argues that this

8 Contrary to the statement in Petitioner’s Reply, not all of the drugs listed in
paragraph 124 are steroids. Paragraph 124 also includes: “non-steroidal
anti-inflammatory drugs,” “immunosuppressants,” “Cox-2-specific
inhibitors,” “TNF-alpha binding proteins,” “allergy vaccines,”
“antihistamines,” “antileukotrienes,” “beta-agonists,” “anticholinergics,” and
a host of other drugs. Ex. 1002 ¶ 124. This is consistent with Dr. Ferrara’s
deposition testimony, which appears to identify only the glucocorticoids
specifically listed in paragraph 124 as “steroids that we use to treat Graft-
versus-host disease.” Ex. 2056, 210:25–212:7.
IPR2019-00865
Patent 9,795,604 B2

23
teaches that “ibrutinib was disclosed as being given sequentially with
steroids, such as when steroids are ineffective” (Pet. Reply 10). Patent
Owner moves to strike this on the basis that it presents new argument. Mot.
1. We agree that Petitioner has presented a new argument, and do not
consider it for that reason. We address Patent Owner’s motion to strike
infra. p. 65–66.
The Petition relied on the theory, shown through the knowledge of the
POSA rather than a disclosure in the ’085 patent, that the POSA would have
at once envisaged administration of ibrutinib to the claimed patient
populations. Pet. 38–39 (“[A] POSA would have known that steroids are
universally given as first-line treatment . . . . A POSA likewise would have
known that post-steroid treatments—including administering ibrutinib—
were started only if steroids were not being effective.”); see also, Ex. 1006
¶¶ 32, 86 (Dr. Ferrara’s testimony, cited in the Petition). Neither the Petition
nor Dr. Ferrara’s declaration make any reference to paragraphs 121 or 124 or
otherwise suggest that the ’085 publication expressly teaches treatment of
these patients. In contrast, Petitioner’s Reply now contends for the first time
that the ’085 publication itself teaches treatment of steroid-dependent/
refractory, steroid-resistant, and refractory patients by teaching sequential
combination therapy with ibrutinib and steroids. Pet. Reply 9–10 (citing Ex.
1002 ¶¶ 121, 124).
There is some overlap between the arguments in the Petition and those
in the Reply because, as discussed infra, Petitioner’s new anticipation
argument still relies on the knowledge of the POSA to infer administration
to the relevant patient population. Nonetheless, the difference between
Petitioner’s arguments is significant and the timing of Petitioner’s change in
IPR2019-00865
Patent 9,795,604 B2

24
theories leaves us with an incomplete record.9 See Ariosa Diagnostics v.
Verinata Health, Inc., 805 F.3d 1359, 1376–68 (Fed. Cir. 2015) (finding that
the Board did not err in declining to consider “previously unidentified
portions of a prior art reference” where the petition “point[ed] to a generic
statement in [the reference] that any sequencing method can be used” and
petitioner did not identify “specific embodiments of [the reference]” that use
a particular sequencing method until filing a reply).
Our rules require that a Petition must identify “[t]he supporting
evidence relied upon to support the challenge and the relevance of the
evidence to the challenge raised, including identifying specific portions of
the evidence that support the challenge.” 37 C.F.R. § 42.104(b)(5). Our
rules also provide that we “may exclude or give no weight to the evidence
where a party has failed to state its relevance or to identify specific portions
of the evidence that support the challenge” in the Petition. Id.
The portion of the ’085 publication cited by Petitioner in its Reply
was not identified in the Petition. Pet. 38–39. Petitioner contends that it is
entitled to rely on the previously uncited portions of the ’085 publication
because Patent Owner stated in its Response: “[i]t is undisputed that the
steroid-resistant/refractory limitations are not disclosed in the ’085
Publication.” Mtn. Opp. 1 (citing PO Resp. 20). Petitioner argues that
“[r]eplies are a vehicle for responding to arguments raised in a
corresponding patent owner response.” Id. at 2 (citing Unified Patents v.

9 For example, the record does not include evidence from Patent Owner on
the nature of the drugs recited in paragraph 124 of the ’085 publication or on
how the POSA would interpret the disclosure of sequential combination
therapy in paragraph 121 of the ’085 publication.
IPR2019-00865
Patent 9,795,604 B2

25
Intellectual Ventures, IPR2016-01643, Paper 51 at 50 (PTAB Mar. 26,
2018)). We are not persuaded.
While we agree that replies are a vehicle for responding to arguments,
they are not a vehicle for introducing new theories of unpatentability. See,
e.g., Juniper Networks v. Chrimar Sys., IPR2016-01391, Paper 66 at 77
(PTAB Dec. 20, 2017) (cited by Petitioner at Mot. Opp. 2) (“Thus, the
portions of Petitioner’s Reply that address Bob Smith terminations and
common mode chokes are a proper response to an argument raised by Patent
Owner in the Response, not a new theory of unpatentability.”).
Here, Petitioner’s reliance on the ’085 publication’s disclosure of
sequential combination therapy is a new theory of unpatentability, not a
proper response to Patent Owner’s argument. Indeed, it is difficult to
characterize the statement that Petitioner purports to respond to as an
argument at all. Rather, the statement at issue – “[i]t is undisputed that the
steroid-resistant/refractory limitations are not disclosed in the ’085
Publication” – is more aptly characterized as describing Petitioner’s position
than as setting forth an argument that justifies responsive evidence. While
Petitioner is certainly entitled to correct mischaracterizations of its position,
it is not entitled to advance a new theory of unpatentability simply to counter
Patent Owner’s statement that it was not advancing that theory.
Accordingly, we exclude Petitioner’s new argument from consideration.
Even if we were to consider Petitioner’s new argument, we would not
find it persuasive for two reasons. First, the ’085 publication discloses a
long list of drugs that can be used in combination with ibrutinib to treat auto-
immune diseases (Ex. 1002 ¶ 124) and a long list of autoimmune diseases
(id. ¶ 98). Arriving at the use of steroids in combination with ibrutinib to
IPR2019-00865
Patent 9,795,604 B2

26
treat patients with GVHD – the first analytical step in Petitioner’s new
anticipation theory – requires too much picking and choosing among
therapies and diseases. In re Arkley, 455 F.2d 586, 587–588 (CCPA 1972)
(In order for a reference to anticipate a claim, it must “clearly and
unequivocally disclose the claimed [method] or direct those skilled in the art
to the [product] without any need for picking, choosing, and combining
various disclosures not directly related to each other by the teachings of the
cited reference.”).
Second, claims 4, 13, and 15 require treating steroid-
dependent/refractory, steroid-resistant, or refractory cGVHD patients. Dr.
Ferrara testifies that in such patients, ibrutinib is administered “when
steroids are not effectively treating the GVHD.” Ex. 1006 ¶ 86. The ’085
publication states:
The compounds of the present disclosure may be used in
combination with one or more other drugs in the treatment of
diseases or conditions for which compounds of the present
disclosure or the other drugs may have utility, where the
combination of the drugs together are safer or more effective
than either drug alone. Such other drug(s) may be
administered . . . contemporaneously or sequentially with a
compound of the present invention.
Ex. 1002 ¶ 121 (emphasis added). This disclosure is not the same as
disclosing the use of ibruinib “when steroids are not effectively treating the
GVHD,” i.e, when the patient has steroid-dependent/refractory, steroid-
resistant, or refractory cGVHD. Ex. 1006 ¶ 86. To arrive at the method of
claims 4, 13, and 15 from the disclosure of combination therapy in the ’085
publication, Petitioner must draw on the knowledge of the POSA to infer a
specific patient population and to infer a sequence of administration in
IPR2019-00865
Patent 9,795,604 B2

27
which ibrutinib is administered after treatment with steroids.10 This is not
permissible. Connell v. Sears, Roebuck & Co., 722 F.2d 1542, 1548–49
(Fed. Cir. 1983) (rejecting argument that anticipation may be shown where
the “general aspects” of a reference are the same as recited in a claim and
“the differences in minor matters is only such as would suggest itself to one
of ordinary skill in the art”).
Accordingly, even if we were to consider Petitioner’s new anticipation
theory, we would find that Petitioner has not established, by a preponderance
of the evidence, that the ’085 publication anticipates claims 4, 13, and 15.
Claims 28–31, 43–46, and 50–53 each depend from one of claims 4,
13, and 15. Because the preponderance of the evidence does not support that
the ’085 publication anticipates claims 4, 13, and 15, it necessarily also does
not support that the ’085 publication anticipates dependent claims 28–31,
43–46, and 50–53.
Claims 6–8
Claims 6–8 recite patient outcomes, including that the patient achieves
a “partial response” (claim 6), that the patient achieves a “complete
response” (claim 7), and that the “the severity of the GVHD is reduced”
(claim 8).11 Petitioner argues that the additional limitations in claims 6–8,
recite patient outcomes that simply express the intended result of the recited
method, and thus the additional limitations recited in these claims are not

10 Manifestly, a patient must first have been administered steroids in order to
have become steroid-dependent/refractory, steroid-resistant, or refractory.
11 Claims 29–31, 44–46, and 51–53 each also recite one of these three
possible outcomes. We do not discuss them here because they depend from
claims 4, 13, and 15 and, as discussed above, we have determined that a
preponderance of the evidence does support that the ’085 publication
anticipates claims 4, 13, and 15.
IPR2019-00865
Patent 9,795,604 B2

28
entitled to patentable weight. Pet. 40. In addition, Petitioner argues that
even if these limitations are given patentable weight, the “patient outcomes
recited in these dependent claims are an inherent and necessary effect of
administering a therapeutically effective amount of ibrutinib to a patient
with chronic GVHD.” Id.; see also, Ex. 1006 ¶ 88.
Patent Owner contends that these limitations are “efficacy limitations”
that must be given patentable weight. PO Resp. 5–16. Patent Owner also
disputes Petitioner’s contention that the efficacy limitations are inherent in
the administration of a therapeutically effective amount of ibrutinib because
some patients show no response, some patients achieve a partial response,
and some patients achieve a complete response. Id. at 13.
We do not resolve the claim construction issue of whether these
limitations should be given patentable weight because we find that even if
the limitations recited in claims 6–8 were given patentable weight, they
would have been inherent in the administration of a therapeutically effective
amount of ibrutinib. We recognize that the administration of a
therapeutically effective amount of ibrutinib will not, in all patients, result in
any one of the three potential outcomes recited in claims 6–8. Ex. 2055
¶ 142. However, on the facts of this case, the potential for different
outcomes does not preclude a finding of anticipation, as reflected in our
reviewing court’s decision in King Pharmaceuticals Inc., v. Eon Labs, Inc.,
616 F.3d. 1267 (Fed. Cir. 2010).
The patent claim at issue in King was drawn to a “method of
increasing the bioavailability of metaxalone” by administering “a
therapeutically effective amount of metaxalone in a pharmaceutical
composition with food.” Id. at 1274. On appeal, patentee argued that
IPR2019-00865
Patent 9,795,604 B2

29
defendant had not established inherent anticipation because it had not
provided any evidence or expert testimony that the prior art would
necessarily result in an increase in metaxalone’s bioavailability. Id. In
contrast, patentee had provided expert testimony that “taking metaxalone
with food would not inherently . . . increase[e] the bioavailability of
metaxalone.” Id. at 1275. Our reviewing court nevertheless found the
challenged claim anticipated because “[a]s taught by the [challenged] patent,
the only steps required to increase metaxalone’s bioavailability [were] (1)
ingesting metaxalone (2) with food” and because “[t]hese steps [were]
undeniably disclosed by the prior art.” Id. at 1276. The court explained:
To anticipate, the prior art need only meet the inherently
disclosed limitation to the extent the patented method does. See
Hewlett–Packard Co. v. Mustek Systems, Inc., 340 F.3d 1314,
1326 (Fed. Cir. 2003) (“[A] prior art product that sometimes,
but not always, embodies a claimed method nonetheless teaches
that aspect of the invention.”). Because the [challenged] patent
discloses no more than taking metaxalone with food, to the
extent such a method increases the bioavailability of
metaxalone, the identical prior art method does as well. As the
district court aptly stated, “to inherently anticipate, the prior art
need only give the same results as the patent, not better.” King
Pharms., Inc., 593 F.Supp.2d at 509.
Id.
Here the only step required to achieve the claimed patient outcome is
to administer a therapeutically effective amount of ibrutinib. As discussed
above, the ’085 publication discloses performing this same method step.
Patent Owner does not identify, and we do not find, that the ’865 patent
identifies any different or additional steps that must be performed in order to
obtain a particular one of the three recited outcomes. That performing the
step of administering ibrutinib may achieve the claimed patient outcomes in
IPR2019-00865
Patent 9,795,604 B2

30
some patients but not in others does not prevent a finding of anticipation
because, under King, “the prior art need only meet the inherently disclosed
limitation to the extent the patented method does.” Id. Because there are no
differences between the claimed step and the step disclosed in the prior art,
we find that the ’085 publication inherently discloses the patient outcomes
recited in claims 6–8.

Claim 1012
Claim 10 depends from claim 1 and further requires that “the patient
had a hematopoietic cell transplantation.” Ex. 1001, 76:42–32. Petitioner
presents the testimony of Dr. Ferrara that “GVHD is a potentially serious
complication of allogeneic hematopoietic stem cell transplantation, which is
commonly known as bone marrow transplantation.” Ex. 1006 ¶ 24. Thus,
according to Petitioner, having a hematopoietic cell transplantation is a
“prerequisite” to developing GVHD. Pet. 42. Patent Owner does not
separately argue the patentability of claim 10. See generally, PO Resp.13

12 We address claim 10 before addressing claim 9 because our discussion of
the evidence with respect to claim 9 builds on our discussion of the evidence
with respect to claim 10.
13 In its Preliminary Response, Patent Owner argued that Petitioner
improperly relied on the knowledge of the POSA to supply the missing
element of treating patients having received a hematopoietic cell
transplantation. Prelim. Resp. 38. This argument is waived because Patent
Owner did not pursue it in its post-institution briefing. See Paper 9, 7
(“Patent Owner is cautioned that any arguments for patentability not raised
in the response may be deemed waived.”) Even if we were to consider this
argument, we would find it unpersuasive for the reasons set forth in our
Institution Decision. Inst. Dec. 21–22.

IPR2019-00865
Patent 9,795,604 B2

31
We agree with Petitioner that the ’085 publication anticipates claim
10. The evidence of record supports that cGVHD is a complication of
allogeneic hematopoietic stem cell transplantation and that “virtually all
chronic GVHD patients have had a hematopoietic cell transplantation.” See
Ex. 1006 ¶¶ 24, 94. For this reason, we agree with Petitioner that the POSA
would have immediately understood the disclosure of the ’085 publication of
treating patients with GVHD to refer to treating patients who had received a
hematopoietic cell transplant and developed GVHD as a complication of that
transplant. Accordingly, the preponderance of the evidence supports that the
’085 publication anticipates claim 10.
Claim 9
Claim 9 depends from claim 1 and further requires that “the patient
ha[ve] chronic lymphocytic leukemia (CLL).” Ex. 1001, 76:40–41.
Dr. Ferrara testifies that “hematopoietic stem cell transplantation [discussed
above in connection with claim 10] is used to treat approximately a dozen
diseases” including, chronic lymphocytic leukemia. Ex. 1006 ¶ 26.
Petitioner contends that the ’085 publication anticipates claim 9
because it discloses the use of ibrutinib to treat chronic lymphocytic
leukemia. Pet. 41 (citing Ex. 1002 ¶¶ 4, 5, 97); Ex. 1006 ¶ 90 (discussing
same). Thus, according to Petitioner, “upon reading the ’085 Publication’s
disclosure, a POSA would have at once envisaged that in order to develop
chronic GVHD the patient had one of approximately a dozen diseases,
including CLL.” Pet. 41–42 (citing Ex. 1002 ¶¶ 90–92). Patent Owner does
IPR2019-00865
Patent 9,795,604 B2

32
not argue the patentability of claim 9 based on the patient having CLL. See
generally, PO Resp.14
We agree with Petitioner that the ’085 publication anticipates claim 9.
In order to anticipate claim 9, the ’085 publication must disclose treatment
of a patient with CLL and with cGVHD. The ’085 publication discloses
treatment both of CLL and of GVHD; however, these two diseases are
disclosed as two among many diseases that may be treated using ibrutinib.
See, e.g., Ex. 1002 ¶¶ 96–101. Accordingly, anticipation turns on “‘whether
the number of categories and components’ disclosed in [the ’085
publication] is so large that the combination of [treating a patient with both
CLL and cGVHD] ‘would not be immediately apparent to one of ordinary
skill in the art.’” Kennametal, 780 F.3d at 1382. The evidence of record
supports that given the medical connection between CLL and cGVHD (see
Ex. 1006 ¶ 92), it would have been immediately apparent to the POSA to
treat a patient having both CLL and cGVHD. Accordingly, the
preponderance of the evidence supports that the ’085 publication anticipates
claim 10.

14 In its Preliminary Response, Patent Owner argued that Petitioner
improperly relied on the knowledge of the POSA to supply the missing
element of treating patients having CLL. Prelim. Resp. 38. This argument
is waived because Patent Owner did not pursue it in its post-institution
briefing. See Paper 9, 7 (“Patent Owner is cautioned that any arguments for
patentability not raised in the response may be deemed waived.”) Even if
we were to consider this argument, we would find it unpersuasive for the
reasons set forth in our Institution Decision. Inst. Dec. 22–23.

IPR2019-00865
Patent 9,795,604 B2

33
Claims 24, 35, 39, and 55
Dependent claims 24, 35, and 39 recite administering “about 420 mg
of [ibrutinib] . . . orally once per day.”15 Independent claim 55 recites
“administering . . . about 420 mg/day of [ibrutinib].” Petitioner contends
that the ’085 publication “repeatedly discloses administering ibrutinib to a
patient in an oral dosage of 420 mg/day.” Pet. 43 (citing Ex. 1002 ¶¶ 30,
120). According to Petitioner, the ’085 publication “discloses use of
ibrutinib at 420 mg/day in Phase II clinical trials [for treatment of chronic
lymphocytic leukemia], meaning ibrutinib had already been used safely at
that dosage in earlier, Phase I safety trials.” Id. at 44 (citing Ex. 1002 ¶¶ 4, 5
and Ex. 1006 ¶¶ 96–101). Petitioner also contends that the ’085 publication
discloses that “ibrutinib can be administered orally once per day” and “can
be administered in single or multiple doses” per day. Id. (citing Ex. 1002
¶¶ 30, 93, 94, 120, and claim 20).
Patent Owner argues that the ’085 publication “lists a huge number of
diseases and a wide variety of potential doses, explaining that the dose will
vary depending on the disease and its severity, and the age, weight, and
other characteristics of the mammal to be treated.” PO Resp. 51. Patent
Owner further argues that “Petitioner makes no showing as to why a POSA
would have selected, from the thousands of potential embodiments in the
’085 Publication, the particular claimed dose, administration regimen,

15 Claims 28, 43, and 50, each also recite administering “about 420 mg of
[ibrutinib] . . . orally once per day.” We do not discuss them here because
they depend from claims 4, 13, and 15 and, as discussed above, we have
determined that a preponderance of the evidence does support that the ’085
publication anticipates claims 4, 13, and 15.
IPR2019-00865
Patent 9,795,604 B2

34
disease, and patient subpopulations, with a reasonable expectation of
therapeutic efficacy.” Id.16
For the reasons discussed in connection with claim 1, we find that the
POSA would reasonably have connected the disclosure in the ’085
publication that in an “eighth aspect of the present disclosure” ibrutinib can
be used to treat GVHD with the dosages of ibrutinib provided in elsewhere
in the disclosure. See supra p. 14–17. The dosages disclosed in the ’085
publication include a dose of 425 mg and ranges encompassing the claimed
420 mg/day. Ex. 1002 ¶¶ 30, 120. Moreover, Patent Owner has not argued
or identified evidence to support that the claimed dosing of 420 mg/day is
critical (see generally, PO Resp. 50–52) and, in fact, the ’604 patent
identifies doses ranging from 40 mg/day to 840 mg/day as “therapeutically
effective” (Ex. 1001, 76:7–10 (claim 5)). While we recognize the potential
that a particular dose may be critical, in the absence of supporting evidence,
we will not speculate as to whether the claimed dose meets the criteria for
establishing criticality. Accordingly, we find that the ’085 publication
anticipates claims 24, 35, 39, and 55. Ex. 1002 ¶¶ 30, 120. See
ClearValue, Inc. v. Pearl River Polymers, Inc., 668 F.3d 1340, 1345 (Fed.
Cir. 2012) (finding that disclosure of a range of raw alkalinity of less than
150 ppm anticipated a claim requiring 50 ppm where there was “no
allegation of criticality or any evidence demonstrating any difference across
the range”).

16 On the cited pages, Patent Owner also makes arguments relating to
obviousness for these claims. We do not address these argument here as this
discussion is focused on anticipation.
IPR2019-00865
Patent 9,795,604 B2

35
III. GROUND 2: OBVIOUSNESS OVER THE ’085 PUBLICATION
Petitioner asserts that the ’085 publication renders claims 1, 4, 6–10,
13, 15, 24, 28–31, 35, 39, 43–46, 50–53, and 55 of the ’604 patent obvious.
Pet. 44–53. We limit our discussion to whether the ’085 publication would
have rendered claims 4, 13, 15, 28–31, 43–46 and 50–53 obvious because
we have already determined that a preponderance of the evidence supports
that the ’085 publication anticipates claims 1, 6–10, 24, 35, 39, and 55. We
have reviewed Petitioner’s and Patent Owner’s assertions, as well as the
evidence of record, and, for the reasons discussed below, we conclude that
Petitioner has not demonstrated, by a preponderance of the evidence, that
claims 4, 13, 15, 28–31, 43–46 and 50–53 would have been obvious over the
’085 publication.
A. Factual Background
The evidence supports that a POSA would have viewed cGVHD as a
“complex and poorly understood” disease. Ex. 2059, abstract; Ex. 2003, 80
(“the biology of CGVHD has not been determined”); id. at 81 (“the
pathophysiology of CGVHD, unlike that of acute GVHD, remains
obscure”); Ex. 2006 (“Chronic GVHD was recognized as a complication of
allogeneic hematopoietic cell transplantation more than 30 years ago, but
progress has been slowed by the limited insight into the pathogenesis of the
disease and the mechanisms that lead to development of immunological
tolerance.”); Ex. 2054, 2 (article coauthored by Dr. Ferrara noting a “lack of
significant understanding of the immunobiology of chronic GVHD when
compared with acute GVHD”); Ex. 2007, 1556 (article coauthored by Dr.
Ferrara stating “[b]y contrast with acute GVHD, the pathophysiology of
chronic GVHD remains poorly understood”); Ex. 2059, 204 (“cGVHD is a
IPR2019-00865
Patent 9,795,604 B2

36
multiorgan alloimmune and autoimmune disorder characterized by immune
dysregulation, immune deficiency, impaired end-organ function and
decreased survival. Although these features of cGVHD were noted > 30
years ago there has been little progress sorting out the precise
mechanism(s).”).
The POSA would have attributed the lack of understanding of
cGVHD in part to the absence of predictive models and standardized criteria
for measurement. Ex. 2003, 80 (teaching that “defining the pathophysiology
of CGVHD has been complicated by the absence of animal models that
accurately recapitulate the disease or its clinical setting”); Ex. 2054, 2
(article coauthored by Dr. Ferrara stating that the “paucity of appropriate
mouse models for chronic GVHD has resulted in a lack of significant
understanding of the immunobiology of chronic GVHD when compared
with acute GVHD”); Ex. 2056, 73–74 (Dr. Ferrara’s testimony agreeing that
“the lack of standardized criteria for quantitative measurement of therapeutic
response in clinical trials poses a major obstacle for the development of new
agents in chronic Graft-versus-host disease”); Ex. 2048, abstract (“The lack
of standardized criteria for quantitative measurement of therapeutic response
in clinical trials poses a major obstacle for the development of new agents in
chronic graft-versus-host disease.”).
Not surprisingly, given the poor understanding of the disease, the
evidence supports that the POSA would have understood that treating
patients with cGVHD was very difficult. Ex. 2045, 2 (article by Dr. Ferrara
teaching that treating patients with advanced cGVHD “is one of the most
challenging scenarios, not only in transplant medicine, but in all of
medicine”). As Dr. Ferrara explained in his deposition, cGVHD patients are
IPR2019-00865
Patent 9,795,604 B2

37
“often on 15 or 20 medications a day” and, as a result, treating them is “has
now become a sort of three-dimensional chess game as opposed to the
largely two-dimensional chess game that acute Graft-versus-host disease
treatment is, because you’ve got a much firmer baseline . . . [and] better
animal models.” Ex. 2056, 92:9–15.
More importantly for purposes of obviousness, the evidence supports
that a POSA would have viewed treating patients with cGVHD as highly
unpredictable and relied on trial and error to identify drugs for treating
individual patients. Ex. 2007, 1556 (article coauthored by Dr. Ferrara
stating “[t]he response of chronic GVHD to treatment is unpredictable, and
mixed responses in different organs can take place in the same patient”); Ex.
2050, 2 (“Although different treatment options are available for salvage
therapy of steroid refractory cGVHD, the ‘trial-and error system’ remains to
date the only way to identify the drug or drug combination effective in an
individual patient.”); Ex. 2059, 207 (“cGVHD is complex and there are no
convincing surrogate in-vitro or in-vivo parameters to predict benefit.”).
A POSA would have viewed steroid-dependent/refractory, steroid-
resistant, and refractory patients as particularly difficult to treat. Ex. 2055
¶ 38 (Dr. Koreth’s well supported testimony summarizing the prior art as
recognizing that “steroid-dependent/refractory, steroid-resistant, or
refractory cGVHD patients were very hard to treat.”); id. ¶¶ 35–37
(discussing unsuccessful attempts to treat such patients); id. ¶¶ 174–180
(discussing safety concerns for drugs, like ibrutinib, that target B and T cells
when administered to steroid-dependent/ refractory, steroid-resistant, or
refractory cGVHD patients); Ex. 2056, 124:7–11 (Dr. Ferrara testimony:
“[A] patient with chronic GvHD, particularly one who is being treated for
IPR2019-00865
Patent 9,795,604 B2

38
chronic GvHD [i.e. treated with steroids], has an immune system that is less
than that of a newborn baby. Less effective or less protective than that of a
newborn baby.”); Ex. 2059, 207 (stating that “[t]here are major challenges to
developing therapy for cortico-steroid-resistant cGVHD” and identifying
some of these challenges).
Given the poor understanding of cGVHD, the lack of animal models
and standardized measurement criteria, and the unpredictability in the field,
it is not surprising that many potential treatments have proven unsuccessful.
Ex. 2045, 2 (article by Dr. Ferrara stating “[d]espite dozens of trials, nothing
has ever worked, in part because we have not had good drugs, and in part
because the trials are difficult to perform.”); Ex. 2055 ¶ 147 (Dr. Koreth
testimony regarding the “litany of treatment failures for cGVHD patients
known in the art”); id. ¶¶ 43–51, 221–225 (discussing specific failed
treatments for cGVHD); Ex. 2046, 1 (article reporting that “very smart
senior VP of a pharma company” told Dr. Ferrara that “GVHD is where new
drugs go to die”); Ex. 2059, 203 (“There has been little progress over the
past 30 years in preventing and/or treating cGVHD.”); id. at 204–205
(teaching that “[t]here is no standard next therapy” after treatment with
steroids and noting that “recommended interventions include about 40 drugs,
all studied in poorly standardized, phase-2 trials or reported in retrospective
case analyses”); Ex. 2056, 222:13–223:13 (Dr. Ferrara testimony explaining
that “between 20 and 30 compounds” have been tested for treatment of
cGVHD and “even more compounds have been tried but not reported on”).
In view of these failures, the POSA would have viewed potential new
treatments with some degree of skepticism. See e.g., Ex. 2006, 158 (“The
contrast with results of the prospective phase III trial testing MMF for initial
IPR2019-00865
Patent 9,795,604 B2

39
treatment of chronic GVHD raises a general concern that other previously
tested agents also do not provide as much benefit [for treating cGVHD] as
suggested in the reports.”)
We view Petitioner’s evidence and argument as to why the POSA
would reasonably have expected to be able to treat the patient populations
identified in claims 4, 13, and 15 against the above discussed factual
backdrop.

B. Disclosures of the Asserted Prior Art
The ’085 Publication
The disclosure of the ’085 publication is discussed supra p. 9–10.

C. Analysis
Claims 4, 13, and 15 depend from claim 1 and provide additional
limitations concerning the patient to whom ibrutinib is administered.
Claim 4 specifies that “the patient has steroid-dependent/refractory chronic
GVHD.” Claim 13 specifies that “the chronic GVHD is steroid resistant
GVHD.” And claim 15 specifies that “the chronic GVHD is refractory
GVHD.” Claims 28–31, 43–46, and 50–53 each depend from one of claims
4, 13, and 15.
Petitioner, supported by Dr. Ferrara, contends that “a POSA would
have known, and it would have been obvious, that additional treatments for
chronic GVHD, including specifically administering ibrutinib, would have
been employed where steroid treatment was not effective for treating chronic
GVHD.” Pet. 49; see also Ex. 1006 ¶ 108 (Dr. Ferrara testifying that “it
would have been obvious to a POSA that administering ibrutinib to a patient
IPR2019-00865
Patent 9,795,604 B2

40
with chronic GVHD would be warranted in situations where treatment
beyond steroids was necessary because either the chronic GVHD was
getting worse after the steroids had been removed (as in claim 4) or the
steroids had not worked to treat the chronic GVHD (as in claims 4, 13, and
15).”).
Patent Owner argues, inter alia, that Petitioner has not met its burden
to establish that a POSA would reasonably have expected ibrutinib to
successfully treat steroid-resistant, steroid-dependent and refractory patients.
PO Resp. 24–28. Patent Owner points out that “steroid-resistant/refractory
patients were especially difficult to treat since prior steroid administration
results in an immunocompromised, heterogeneous, and vulnerable patient
population.” Id. at 27. Patent Owner argues that the ’085 publication lacks
data showing that ibrutinib can be used to treat cGVHD and that a POSA
“would have read this deficient disclosure against the litany of failures for
treating steroid-resistant and refractory patients.” Id. at 26, 27. We agree
with Patent Owner that the record does not support that the POSA would
reasonably have expected, based on the ’085 publication, that ibrutinib could
be used to successfully treat steroid-resistant, steroid-dependent and
refractory cGVHD patients.
Petitioner’s position on why the POSA would have expected success
in administering ibrutinib to cGVHD patients in the claimed patient
populations appears be, essentially, that the POSA would have expected
administration of ibrutinib to be successful because the ’085 publication
teaches to administer ibrutinib to treat chronic GVHD. Pet. 48 (“In fact, as
explained by Dr. Ferrara, a POSA would have understood the disclosure of
‘graph versus host disease’ in the ’085 Publication to concern chronic
IPR2019-00865
Patent 9,795,604 B2

41
GVHD in particular. Accordingly, a POSA would have reasonably expected
that administering ibrutinib to patients with chronic GVHD would
successfully treat the disease, rendering claim 1 obvious.”) (internal citation
omitted); id. at 49 (“A POSA would have known, and it would have been
obvious, that additional treatments for chronic GVHD, including specifically
administering ibrutinib, would have been employed where steroid treatment
was not effective for treating GVHD.”); see also, Ex. 1006 ¶¶ 106–108 (Dr.
Ferrara testimony to the same effect). We do not find this persuasive.
In the absence of data showing ibrutinib to be effective in treating
steroid-dependent/refractory, steroid-resistant, and/or refractory cGVHD
patients, we do not find the bald teaching that ibrutinib can be used to treat
the genus GVHD to be sufficient to provide the POSA with a reasonable
expectation of success. Simply put, the factual background described above
– reflecting a poor understanding of cGVHD, an absence of predictive
models and standardized measurement criteria, a multitude of unsuccessful
treatments, unpredictability with respect to treatments, and trial and error
testing – outweighs the unsupported teaching of the ’085 publication,
particularly when applied to the difficult-to-treat patient subpopulations
recited in claims 4, 13, and 15; see Ex. 1030, 149:14–150:7 (Dr. Koreth
testimony that POSA would expect cGVHD treatments to fail). We find that
even considering the disclosure in the ’085 publication that ibrutinib can be
used to treat the genus GVHD, the POSA would not reasonably have
expected success in doing so with respect to the patient subpopulations
recited in claims 4, 13, and 15.
Accordingly, we find that Petitioner has not established, by a
preponderance of the evidence, that claims 4, 13, and 15 would have been
IPR2019-00865
Patent 9,795,604 B2

42
obvious in view of the ’085 publication.17 Claims 28–31, 43–46, and 50–53
each depend from one of claims 4, 13, and 15. Because the preponderance
of the evidence does not support that the ’085 publication renders claims 4,
13, and 15 obvious, it necessarily also does not support that the ’085
publication renders dependent claims 28–31, 43–46, and 50–53 obvious.
IV. GROUND 3: OBVIOUSNESS OVER THE COMBINATION OF
THE ’085 PUBLICATION, SHIMABUKURO-VORNHAGEN, AND
HERMAN
Petitioner asserts that the combination of the ’085 publication,
Shimabukuro-Vornhagen, and Herman renders claims 1, 4, 6–10, 13, 15, 24,
28–31, 35, 39, 43–46, 50–53, and 55 of the ’604 patent obvious. Pet. 54–62.
We limit our discussion to whether the ’085 publication, Shimabukuro-
Vornhagen, and Herman would have rendered claims 4, 13, 15, 28–31, 43–
46 and 50–53 obvious because we have already determined that a
preponderance of the evidence supports that the ’085 publication anticipates
claims 1, 6–10, 24, 35, 39, and 55. We have reviewed Petitioner’s and
Patent Owner’s assertions, as well as the evidence of record, and, for the
reasons discussed below, we conclude that Petitioner has not demonstrated,
by a preponderance of the evidence, that claims 4, 13, 15, 28–31, 43–46 and
50–53 would have been obvious over the combination of the ’085
publication, Shimabukuro-Vornhagen, and Herman.

17 Patent Owner included extensive discussion of objective indicia of non-
obviousness. PO Resp. 57–65. We have determined that it is not necessary
to address this evidence in detail because it can only benefit the Patent
Owner and we have already determined that the evidence does not support a
finding that claims 4, 13, 15, 28–31, 43–46, and 50–53 would have been
obvious over the ’085 publication.
IPR2019-00865
Patent 9,795,604 B2

43
The factual background discussed above with respect to Ground 2 (see
supra p. 35–39.) applies equally with respect to Ground 3. The following
additional considerations apply to our discussion of ground 3.
A. Disclosures of the Asserted Prior Art
The ’085 Publication
The disclosure of the ’085 publication is discussed supra p. 9–10. In
addition to the disclosures of the ’085 publication already discussed, the
’085 publication also discloses that “[i]brutinib is an orally available drug
that targets Bruton’s tyrosine kinase (BTK)” and serves as an “irreversible
small molecule BTK inhibitor.” Ex. 1002 ¶ 4. The ’085 publication further
discloses that the “development of drugs which inhibit BTK can have
therapeutic significance in the treatment of both B cell-related hematological
cancers . . . and autoimmune diseases.” Id. ¶ 2.
Shimabukuro-Vornhagen
Shimabukuro-Vornhagen discloses that “[s]everal independent lines
of evidence clearly demonstrate that B cells are involved in the pathogenesis
of chronic GVHD.” Ex. 1003, 4922. The reference also discloses that “[t]he
incidental clinical observation that treatment of immune thrombocytopenia
in a patient with chronic GVHD with rituximab led to improvement of some
manifestations of chronic GVHD . . . raised the question whether the
depletion of B cells could be used to treat chronic GVHD.” Id. at 4923.
Shimabukuro-Vornhagen concludes that “B-cell depletion may . . . be a
promising approach for the treatment of chronic GVHD.” Id.
Herman
Herman discloses that ibrutinib “promotes apoptosis, inhibits
proliferation, and also prevents CLL cells from responding to survival
IPR2019-00865
Patent 9,795,604 B2

44
stimuli provided by the microenvironment.” Ex. 1004, 6288. Herman
concludes that “these studies provide significant support for the development
of [ibrutinib] as a therapeutic agent for the treatment of CLL and related
diseases.” Id. Herman also discloses that ibrutinib “can inhibit production
of inflammatory cytokines such as IL-6, IL-10, and TNF-α.” Id. at 6291.

D. Analysis
As discussed above, claims 4, 13, and 15 depend from claim 1 and
provide additional limitations concerning the patient to whom ibrutinib is
administered. Claim 4 specifies that “the patient has steroid-dependent/
refractory chronic GVHD.” Claim 13 specifies that “the chronic GVHD is
steroid resistant GVHD.” And claim 15 specifies that “the chronic GVHD is
refractory GVHD.” Claims 28–31, 43–46, and 50–53 each depend from one
of claims 4, 13, and 15.
Petitioner argues that “[t]he ’085 publication teaches administering
ibrutinib to treat a number of conditions in which B cells play a key role,
including ‘graft versus host disease.’” Pet. 55. According to Petitioner, the
’085 publication teaches that ibrutinib targets Bruton’s tyrosine kinase
(BTK), an enzyme in B cells, “thus preventing B cells from activating
downstream T cells.” Id. Petitioner also argues that Shimabukuro-
Vornhagen teaches that “B cells are involved in the pathogenesis of chronic
GVHD” and that drugs that “inhibited or depleted (i.e. killed) B cells and
prevented their activation of downstream T cells successfully treated chronic
GVHD.” Id. As to the expectation of success, Petitioner concludes:
“considering that ibrutinib was a known BTK inhibitor (i.e. a drug that
works on B cells) in light of Shimabukuro-Vornhagen’s disclosures that B-
IPR2019-00865
Patent 9,795,604 B2

45
cell inhibiting drugs treat chronic GVHD, a POSA would have reasonably
expected that ibrutinib would treat chronic GVHD.” Id. at 58.
Petitioner also argues that it was “well known that inflammatory
cytokines are produced in an abnormal fashion in patients with chronic
GVHD.” Id. at 57 (citing Ex. 1010, 169 (disclosing that “[c]ytokines play a
key role in pathogenesis of chronic Graft versus Host Disease (cGVHD) and
various studies have shown abberant [sic] production of cytokines by
immune cells from GVHD patients.”)). Petitioner contends that Herman
provides additional motivation to use ibrutinib to treat chronic GVHD by
teaching that “ibrutinib inhibits the production of [the] same inflammatory
cytokines that were known to contribute to the cause of chronic GVHD.” Id.
(citing Ex. 1006 ¶ 125). Petitioner contends that the knowledge that
ibrutinib inhibits inflammatory cytokines would provide an “additional
reason” why “a POSA would have had a reasonable expectation of success
in using ibrutinib to treat chronic GVHD.” Id. at 58–59.
Patent Owner argues, inter alia, that a POSA would not reasonably
have expected success in treating the recited patient population in view of
the combined disclosures of the ’085 publication, Shimabukuro-Vornhagen,
and Herman. PO Resp. 31–43. With respect to Shimabukuro-Vornhagen,
Patent Owner contends that a POSA, aware of all of the pertinent art, would
have been skeptical of Shimabukuro-Vornhagen’s “small, uncontrolled, non-
standardized” study. PO Sur-reply 19. Patent Owner also argues that
Shimabukuro-Vornhagen’s teachings are based on rituximab, a drug that
“target[s] different molecules, expressed in different cells, that exert[s its]
influence through [a] different molecular pathway[], and ha[s] different
effects on B cells” than ibrutinib.” Id.
IPR2019-00865
Patent 9,795,604 B2

46
With respect to Herman, Patent Owner contends that Petitioner
ignores: “(1) ibrutinib’s reported inhibition of IL-10, which multiple
references (including those from Petitioner’s expert) characterized as a
beneficial anti-inflammatory cytokine that could be used to prevent GVHD;
(2) the uncertain relationship between cytokine levels and cGVHD; and (3)
the understanding that many drugs targeting TNFα or IL-6R were not
recommended for treating cGVHD.” Id. at 19–20. We agree with Patent
Owner that the evidence of record does not support a reasonable expectation
of success.
Our analysis first considers the contribution of Shimabukuro-
Vornhagen to a reasonable expectation of success. More particularly, it
considers Shimabukuro-Vornhagen’s teaching, based on rituximab, that B–
cell depletion may be a promising approach for treating cGVHD, and it
considers whether the POSA would expect that teaching to carry over to
ibrutinib. It also considers the import of Shimabukuro-Vornhagen’s
teaching that B cells are involved in the pathogenesis of cGVHD. After
evaluating the contribution of Shimabukuro-Vornhagen, our analysis
considers the contribution of Herman and whether the knowledge that
ibrutinib inhibits the cytokines IL-6, IL-10, and TNF-α contributes to a
reasonable expectation of success. We then consider the teaching of the
’085 publication that ibrutinib can be used to treat GVHD and, more
generally that BTK inhibitors can be used to treat autoimmune diseases.
Finally, we consider all of the evidence together and reach a conclusion as to
whether the cited art supports that the POSA would reasonably have
expected success in treating cGVHD patients having steroid-
dependent/refractory, steroid- resistant and/or refractory cGVHD using
IPR2019-00865
Patent 9,795,604 B2

47
ibrutinib. We conclude that the cited art does not support a reasonable
expectation of success.
1. Contribution of Shimabukuro-Vornhagen to a reasonable
expectation of success
Shimabukuro-Vornhagen states that “B-cell depletion may . . . be a
promising approach for the treatment of chronic GVHD, particularly steroid
refractory skin disease.” Ex. 1003, 4923. As discussed above, in the absence
of data showing a drug to be effective in treating steroid-dependent/
refractory, steroid-resistant, and/or refractory cGVHD patients, a POSA
would not find a bald teaching that a drug can be used to treat cGVHD to be
sufficient to provide a reasonable expectation of success. See supra p. 35–
42. Patent Owner argues that Shimabukuro-Vornhagen lacks in vitro,
preclinical, or clinical data. PO Resp. 30–31. Shimabukuro-Vornhagen,
however, is not completely devoid of supporting data.
Shimabukuro-Vornhagen’s statement that B-cell depletion may be a
“promising approach” is a conclusion drawn largely from analysis of eight
“case series and small clinical trials” studying the effectiveness of rituximab.
Ex. 1003, 4923. Shimabukuro-Vornhagen’s statement that targeting B cells
with rituximab was “promising” thus has some evidentiary grounding.
Nonetheless, Shimabukuro-Vornhagen recognized the limitations of its data,
concluding that “[f]ormal proof in the form of a prospective, randomized
clinical trial with long-term follow up will still be required.” Id. at 4924.
Shimabukuro-Vornhagen’s conclusions are largely consistent with a
meta-analysis, cited by Patent Owner (PO Resp. 39–40), analyzing much the
same studies that Shimabukuro-Vornhagen analyzed.18 The meta-analysis

18 Shimabukuro-Vornhagen analyzed eight rituximab studies. Ex. 1003,
4923 (see particularly Table 1, listing studies). The meta-analysis analyzes
IPR2019-00865
Patent 9,795,604 B2

48
found that the studies “suggest that rituximab is effective in treating
cutaneous cGVHD” and noted that “steroid-refractory cGVHD demonstrates
that the skin is the most responsive organ.” Ex. 2052, 1009. Nonetheless,
the meta-analysis found that the studies had several significant limitations,
including the “absence of randomized trials,” a “very small number of
patients,” “poor methodological quality,” and “lack of a homogeneous
response criteria among studies.” Id. at 1011. The meta-analysis concluded
“[i]t is important to understand that the totality of the evidence generated
through this systemic review demonstrates the gaps in the existing evidence
base related to the efficacy of rituximab in treating patients with steroid-
refractory cGVHD.” Id. at 1012. Thus looking at Shimabukuro-Vornhagen
alone, or at Shimabukuro-Vornhagen together with the meta-analysis, the
statement that “B cell depletion may . . . be a promising approach” provides
some support for the proposition that a POSA would expect that rituximab
might work for treating cGVHD patients, particularly those with steroid
refractory skin disease.
The art, however, is not limited to just Shimabukuro-Vornhagen and
the meta-analysis. In particular, the art includes George, a prior-art study
conducted subsequent to Shimabukuro-Vornhagen, in which the authors
“retrospectively reviewed the medical records of patients with steroid-
refractory cutaneous cGVHD” who had been “treated with rituximab
375 mg/m2 weekly for three to four doses.” Ex. 2053, 737. The authors
identified nine patients with steroid-refractory cutaneous cGVHD. Id. The
authors noted that the above discussed meta-analysis had suggested that

seven of these studies, omitting to consider a seven-patient study by
Teshima et al. Ex. 2052, 1009.
IPR2019-00865
Patent 9,795,604 B2

49
rituximab might be effective in treating such patients, but found that “[n]one
of our patients achieved a complete or partial response.” Id; see also
Ex. 2056, 146:2–147:23 (Dr. Ferrara testimony confirming same). This
result diminishes the modest expectation created by the data reported in
Shimabukuro-Vornhagen that rituximab would be effective in treating
cGVHD in the claimed patient sub-populations.
We turn now to whether the POSA would have reasonably have
expected Shimabukuro-Vornhagen’s teachings with respect to the use of
rituximab to translate to ibrutinib.
Rituximab is a “genetically engineered chimeric murine/human
monoclonal antibody.” Ex 2061, 1. Ibrutinib, in contrast, is a “small
molecule inhibitor of BTK.” Ex. 2036, 27. The two molecules also have
different mechanisms of action. Rituximab binds to an antigen on the
surface of B cells, causing their “rapid and selective depletion.” Ex. 2055
¶ 170. Ibrutinib “was understood not to deplete B cells and to bind an
entirely different target [BTK] located within the cytoplasm of B cells,” this
“inhibit[s] activation of B cells, thereby arresting B cells in an unstimulated
state.” Id. ¶ 171. “Ibrutinib also directly targets T cells by covalently
binding to ITK, a kinase in the T cell signaling pathway.” Id. ¶ 172.
“[U]nlike rituximab’s target (CD20), ibrutinib’s targets (BTK and ITK) are
also expressed in many other cell types, including T cells, monocytes,
macrophages, and mast cells.” Id.
Dr. Koreth opines that these difference “matter in a clinical context”
as evidenced by ability of ibrutinib to treat a patient for cGVHD after
rituximab had failed. Id. ¶ 173. Dr. Ferrara acknowledges differences
between the two drugs (Ex. 2056, 131:6–132:23 (Dr. Ferrara deposition
IPR2019-00865
Patent 9,795,604 B2

50
testimony)),19 but finds a reasonable expectation of success based on the fact
that both drugs prevent the activation of downstream T cells that mediate
chronic GVHD (Ex. 1006 ¶ 128). We credit Dr. Koreth’s well-supported,
detailed, and specific testimony (Ex. 2055 ¶¶ 168–173) over Dr. Ferrara’s
more generalized, bird’s-eye view testimony (Ex. 1006 ¶ 128). We find that
the differences between ibrutinib and rituximab would have left the POSA
with some reservations as to whether the two drugs would be similarly
efficacious in treating an unpredictable disease like cGVHD, particularly as
relates to the claimed patient populations.
Having considered Shimabukuro-Vornhagen’s rituximab based
teachings, we now consider its teaching that “several independent lines of
evidence clearly demonstrate that B cells are involved in the pathogenesis of
chronic GVHD.” Ex. 1003, 4922. Petitioner relies on the knowledge that
B cells are involved in cGVHD as support for its obviousness position.
Pet. 55, 58. Patent Owner contends “the role of B cells in cGVHD
pathogenesis was complex and poorly understood.” PO Resp. 31 (emphasis
omitted).
The evidence supports that a POSA would have known that B cells
are involved in the pathogenesis of cGVHD. Ex. 1003 at 4922 (“Several
independent lines of evidence clearly demonstrate that B cells are involved
in the pathogenesis of chronic GVHD.”); Ex. 2055 ¶ 26 (Dr. Koreth’s
testimony that the prior art reports that “T cells and B cells appear to be
involved in cGVHD pathogenesis”). However, the evidence is inconclusive
as to how B cells are “involved.” Shimabukuro-Vornhagen itself teaches

19 Dr. Ferrara also testified in his deposition that he did not know whether
ibrutinib was known, as of October 2013, to inhibit ITK. Ex. 2055, 171:21–
172:3.
IPR2019-00865
Patent 9,795,604 B2

51
that it was not clear whether B-cells were causing cGVHD or merely a
marker of the disease. Id. at 4922–23 (“Whether the occurrence of
antibodies in GVHD represents a bystander effect caused by polyclonal B-
cell activation remains unknown. In fact, to date a direct involvement of
autoantibodies in GVHD pathology has not been conclusively
demonstrated.”); id. at 4923 (teaching that “no direct evidence for the causal
relationship of autoantibodies or alloantibodies and the pathogenesis of
organ manifestations of chronic GVHD in humans exist.”); id. at 4919 (“The
mechanisms by which B cells contribute to acute and chronic GVHD
currently are only incompletely understood.”); Ex. 2055 ¶ 163 (Dr. Koreth
testimony: “[T]he mechanisms by which B cells interact with T cells, and
the resulting effect (if any) on cGVHD pathogenesis, were complex and far
from understood in 2013.”). Accordingly, the record supports, at best, a
weak expectation that drugs that target B cells would be effective in treating
the claimed patient populations based on mechanism of action.
Petitioner cites to several statements by Dr. Koreth to counter the
evidence that the role of B cells was “only incompletely understood.” Pet.
Reply 19. For example, Petitioner cites Dr. Koreth’s statement that “T cells
and B cells appear to be involved in cGVHD pathogenesis” and his
deposition testimony that there was “there was a growing sense that B-cells
deserved looking at and may indeed . . . have a role to play in the
pathogenesis or the development of chronic GVHD.” Id. (citing Ex.
2055 ¶ 26 and Ex. 1030, 59:17–60:5). However these statements are
consistent with and cumulative of what is taught in Shimabukuro-
Vornhagen, particularly as Dr. Koreth does not indicate in his deposition that
IPR2019-00865
Patent 9,795,604 B2

52
the role B cells play in the pathogenesis of cGVHD was causative or even
that the specific role was known.
Petitioner also cites Dr. Koreth’s testimony that “‘cGVHD clinical
trial candidates targeted B cells’ before 2013.” Id. (citing Ex. 2055 ¶ 46 and
Ex. 1030, 58:13–20). However, Dr. Koreth subsequently explains that these
trials did not result in successful treatments, diminishing the import of the
teaching that “clinical trial candidates targeted B cells.” Ex. 2055 ¶¶ 46–47.
Patent Owner cites several examples of drugs that were known to deplete B
and T cells and that do not provide effective treatments for cGVHD,
including include alemtuzumab, MMF, and azathioprine. PO Resp. 37
(citing evidence including e.g, Ex. 2050, Table 4, 9 (addressing
alemtuzumab); Ex. 2019, abstract (addressing MMF); Ex. 2057, abstract
(addressing azathioprine); and Ex. 2064, 1617 (also addressing
azathioprine)); see also, Ex. 2055 ¶ 175–179 (Dr. Koreth’s testimony
discussing these drugs); Ex. 2015, 2657, 2661 (teaching that ABX-CBL, a
monoclonal antibody that depletes T cells and B cells, demonstrated “no
clinically or statistically significant advantage in regard to treatment
response using ABX-CBL compared with ATG [antithyomocyte globulin],
and survival was sufficiently unfavorable on ABX-CBL that one can rule out
even moderate improvement relative to ATG.”). Awareness of these
unsuccessful treatments would, to some extent, have diminished the weak
expectation that because B cells were known to be involved in the
pathogenesis of cGVHD, drugs that target B cells could be used to
successfully treat steroid-dependent/refractory, steroid-resistant, and
refractory cGVHD patients.

IPR2019-00865
Patent 9,795,604 B2

53
2. Contribution of Herman to a reasonable expectation of
success
Herman discloses that ibrutinib “can inhibit production of
inflammatory cytokines such as IL-6, IL-10, and TNF-α.” Ex. 1004, 6291.
Petitioner contends that this teaching contributes to a reasonable expectation
of success because it was well known the production of inflammatory
cytokines contributes to the causing cGVHD. Pet. 56–57. We find that the
teachings of Herman do not meaningfully contribute to an expectation that
ibrutinib could be used to successfully treat patients steroid-
dependent/refractory, steroid-resistant, and refractory cGVHD patients.
Patent Owner contends that “[t]he role of cytokines . . . was poorly
understood: while some studies showed correlation of cytokine levels with
cGVHD severity, others did not.” PO Resp. 41. The evidence supports
Patent Owner’s position. Compare Ex. 1010, 172 (“In this study we have
shown that patients who underwent BMT [bone marrow transplant] and
subsequently developed cGVHD produce high or even extremely high levels
of inflammatory cytokines as IL-β, IL-6, TNFα. Moreover, we found a good
correlation between the severity of GVHD and the elevated cytokine
levels.”); with Ex. 2068, 336 (“Chronic GVHD has been observed in
experimental models where acute GVHD is prevented with anti-TNF-α,
suggesting that early release of TNF-α and conditioning-related tissue
damage accelerate and amplify acute GVHD but are not relevant to the
induction of chronic GVHD.”); and id. at 337 (“These results would suggest
that the proinflammatory cascade (IFNγ  TNF-α) does not operate during
the pathophysiology of chronic GVHD, but further studies are needed.”); Ex.
2055 ¶ 190 (Dr. Koreth testimony: “some studies showed correlation of
cytokine levels with cGVHD severity, while others did not”). In view of the
IPR2019-00865
Patent 9,795,604 B2

54
uncertainty regarding the correlation of cytokines and cGVHD severity,
Herman’s teaching that ibrutinib inhibits cytokines does little to support a
reasonable expectation of success.
Moreover, Herman teaches that one of the cytokines inhibited by
ibrutinib is IL-10. Ex, 1004, 6291. The evidence supports that the POSA
would have some concern that inhibiting IL-10 would be counterproductive
in cGVHD patients because IL-10 was thought to be involved in suppressing
immune responses. Ex. 2055 ¶¶ 164, 193 (Dr. Koreth’s well-supported
testimony that “numerous prior-art references . . . characterize IL-10 as an
anti-inflammatory cytokine that could be used to prevent GVHD”);
Ex. 2054, 8 (“IL-10 plays a key role in suppressing immune responses”); Ex.
1003, 4920 (“Regulatory B cells induce tolerance not only by acting as
tolerogenic APCs, but also by producing well-known immunomodulatory
cytokines, foremost IL-10 and TGF-β, which can suppress T-cell
responses.”). According to Dr. Koreth the teaching that ibrutinib inhibits
IL–10 would have deterred one from using ibrutinib to treat cGVHD.
Dr. Koreth concludes that “Herman counsels against the use of ibrutinib, a
compound known to inhibit a beneficial cytokine, to treat cGVHD, further
supporting the lack of any reasonable expectation of success to achieve the
claimed invention.” Ex. 2055 ¶ 193. We credit this well-supported,
unrebutted testimony.
3. Contribution of the ’085 publication to a reasonable
expectation of success
The ’085 publication discloses “[t]he development of drugs which
inhibit BTK can have therapeutic significance in the treatment of both
B cell-related hematological cancers . . . and autoimmune diseases.”
Ex. 1002 ¶ 2. The 085 publication also teaches that ibrutinib is a BTK
IPR2019-00865
Patent 9,795,604 B2

55
inhibitor (id. ¶ 4) and discloses “[o]ral pharmaceutical formulations of
ibrutinib . . . and use of these formulations for the treatment of diseases
treatable by ibrutinib such as . . . autoimmune diseases” (id., abstract).
Among the autoimmune diseases disclosed as treatable using the oral
pharmaceutical formulations of the ’085 publication is graft versus host
disease. Id. ¶ 98.
We find that the teaching of the ’085 publication regarding treatment
of B cell related conditions does not meaningfully add to expectation of
success fostered by Shimabukuro-Vornhagen’s similar teaching that “B-cell
depletion may . . . be a promising approach for the treatment of chronic
GVHD,” discussed supra p. 47–50. We also find that the ’085 publication’s
teaching that ibrutinib can be used to treat GVHD does not meaningfully
advance the expectation of success in the absence of supporting data, as
discussed supra p. 35–42.
4. Conclusion regarding the reasonable expectation of success
based on the combined teachings of the ’085 publication,
Shimabukuro-Vornhagen, and Herman
Our analysis of obviousness must take account of the factual
background discussed above with respect to Ground 2, which reflects a poor
understanding of cGVHD, an absence of predictive models and standardized
measurement criteria, a multitude of unsuccessful treatments,
unpredictability with respect to treatments, a dependence on trial and error
testing, and an understanding that the claimed patient population was
particularly difficult to treat. Starting from this background, a POSA would
have been skeptical that any proposed treatments of steroid-
dependent/refractory, steroid-resistant and/or refractory cGVHD patients
would be successful.
IPR2019-00865
Patent 9,795,604 B2

56
Here, the evidence identified by Petitioner in connection with
Ground 3, when considered against this background, is not sufficient to
support a reasonable expectation of success. To summarize, Shimabukuro-
Vornhagen supports a modest expectation that rituximab would be effective
in treating the claimed patient population, but as applied to ibrutinib this
modest expectation would have been diminished by reservations about
whether results obtained using rituximab would extend to ibrutinib.
Shimabukuro-Vornhagen also supports, at best, a weak expectation that
drugs that target B cells would be effective in treating the claimed patient
populations based on mechanism of action, but this expectation is
diminished by evidence that drugs that target B and T cells (as well as a host
of other drug candidates (see supra p. 38–39) had not been successful.
Herman’s teaching that ibrutinib inhibits cytokines does little to support a
reasonable expectation of success, instead suggesting that ibrutinib may be
detrimental because it targets the beneficial cytokine IL-10. Finally, the
teaching of the ’085 publication regarding B cells does not meaningfully add
to the expectations fostered by Shimabukuro-Vornhagen similar teaching
regarding B cell depletion and the teaching of the ’085 publication that
ibrutinib can be used to treat GVHD does not meaningfully advance an
expectation of success in the absence of supporting data.
Considering all of the evidence and the arguments of record with
respect to Ground 3, we find that Petitioner has not established by a
preponderance of the evidence that a POSA would reasonably have expected
ibrutinib to be successful in treating steroid-dependent/refractory, steroid-
IPR2019-00865
Patent 9,795,604 B2

57
resistant and/or refractory cGVHD patients.20 Accordingly, we find that
Petitioner has not established, by a preponderance of the evidence, that the
combination of the ’085 publication, Shimabukuro-Vornhagen, and Herman
would have rendered claims 4, 13, 15, 28–31, 43–46 and 50–53 obvious.
V. GROUND 4: OBVIOUSNESS OVER THE COMBINATION
OF THE ’085 PUBLICATION, SHIMABUKURO-VORNHAGEN,
AND UCKUN
Petitioner asserts that the combination of the ’085 publication,
Shimabukuro-Vornhagen, and Uckun renders claims 1, 4, 6–10, 13, 15, 24,
28–31, 35, 39, 43–46, 50–53, and 55 of the ’604 patent obvious. Pet. 62–66.
We limit our discussion to whether the ’085 publication, Shimabukuro-
Vornhagen, and Uckun would have rendered claims 4, 13, 15, 28–31, 43–46
and 50–53 obvious because we have already determined that a
preponderance of the evidence supports that the ’085 publication anticipates
claims 1, 6–10, 24, 35, 39, and 55. We have reviewed Petitioner’s and
Patent Owner’s assertions, as well as the evidence of record, and, for the
reasons discussed below, we conclude that Petitioner has not demonstrated,
by a preponderance of the evidence, that claims 4, 13, 15, 28–31, 43–46 and
50–53 would have been obvious over the combination of the ’085
publication, Shimabukuro-Vornhagen, and Herman.

20 Patent Owner included extensive discussion of objective indicia of non-
obviousness. PO Resp. 57–65. We have determined that it is not necessary
to address this evidence in detail because it can only benefit the Patent
Owner and we have already determined that the evidence does not support a
finding that claims 4, 13, 15, 28–31, 43–46, and 50–53 would have been
obvious over the ’085 publication, Shimabukuro-Vornhagen, and Herman.
IPR2019-00865
Patent 9,795,604 B2

58
The factual background discussed above with respect to Ground 2 (see
supra. p. 35–39) applies equally with respect to Ground 4. The following
additional considerations apply to our discussion of ground 4.
A. Disclosures of the Asserted Prior Art
The ’085 Publication
The disclosure of the ’085 publication is discussed supra p. 9–10 and
43.
Shimabukuro-Vornhagen
The disclosure of Shimabukuro-Vornhagen is discussed supra p. 43.
In addition to the disclosures of Shimabukuro-Vornhagen already discussed,
Shimabukuro-Vornhagen discloses that several treatments useful for treating
acute GVHD are also useful for treating chronic GVHD, including
glucocorticoids, rituximab, statins, and ECP. Ex. 1003, 4919, 4921–22,
4924.
Uckun
Uckun discloses that “the covalent inhibitor PCI-32765 [ibrutinib]
(Pharmacyclics) was developed as a selective and irreversible inhibitor of
BTK targeting the Cysteine-481 residue in the active site.” Ex. 1005, 1464.
Uckun further discloses that ibrutinib is a “potent nanomolar inhibitor of
BTK.” Id. Uckun also discloses:
Recent studies in a mouse BMT model demonstrated that the
addition of a BTK inhibitor to the GVHD prophylaxis regimens
significantly improves the survival outcome of allogeneic
BMT. Notably, > 70% of BMT recipients treated with a BTK
inhibitor-containing combination regimen remained alive
throughout the 80-day observation period. Therefore,
incorporation of BTK inhibitors in clinical GVHD prophylaxis
regimens may improve the outcome by reducing the incidence
of severe GVHD. We propose that the antileukemic activity of
IPR2019-00865
Patent 9,795,604 B2

59
BTK inhibitors may enhance their ability to attenuate the
severity of GVHD without increasing the risk of relapse post-
BMT in clinical settings.
Id. at 1461. Uckun’s teaching involves mice with acute rather than chronic
GVHD. Ex. 1006 ¶ 148.
B. Analysis
As discussed above, claims 4, 13, and 15 depend from claim 1 and
provide additional limitations concerning the patient to whom ibrutinib is
administered. Claim 4 specifies that “the patient has steroid-
dependent/refractory chronic GVHD.” Claim 13 specifies that “the chronic
GVHD is steroid resistant GVHD.” And claim 15 specifies that “the chronic
GVHD is refractory GVHD.” Claims 28–31, 43–46, and 50–53 each depend
from one of claims 4, 13, and 15.
Petitioner contends that “to the extent the Board finds that the ’085
Publication alone did not anticipate or render obvious administering
ibrutinib to treat chronic GVHD, that limitation would have been obvious
over the ’085 Publication in view of Shimabukuro-Vornhagen and Uckun.”
Pet. 62. Petitioner contends that: 1) the ’085 publication “discloses
administering therapeutically effective amounts of ibrutinib to treat GVHD,”
2) Uckun discloses that ibrutinib is a “potent” BTK inhibitor and that “BTK
inhibitors had been shown to treat acute GVHD in mice,” and 3)
Shimabukuro-Vornhagen teaches that “drugs that work for acute GVHD
commonly work for chronic GVHD and vice versa.” Id. at 65. Thus,
according to Petitioner, “when these three references are combined, a POSA
would have had a reasonable expectation that administering ibrutinib, at the
IPR2019-00865
Patent 9,795,604 B2

60
doses disclosed in the ’085 Publication, would have treated a patient’s
chronic GVHD.”21 Id.
Patent Owner argues:
Uckun’s disclosure of a different BTK inhibitor used for prophylaxis
in a mouse model of acute GVHD cannot establish a reasonable
expectation of success for the asserted combination because: (1)
results from mouse models failed to translate to clinical cGVHD in
humans; (2) aGVHD cannot be conflated with cGVHD, and
prophylaxis cannot be conflated with treatment; (3) LFM-A13 had not
been shown to treat aGVHD or cGVHD in mouse models or in the
clinic; (4) the cited LFM-A13 mouse study does not establish efficacy
with BTK inhibitors, even for prophylaxis; and (5) even if LFM-A13
had activity in GVHD, its simultaneous inhibition of other protein
kinases obfuscates any potential connection to BTK inhibition.
EX2055, ¶197.
PO. Resp. 44. We agree with Patent Owner that the record does not support
that the POSA would reasonably have expected, based on the ’085
publication, Shimabukuro-Vornhagen, and Uckun, that ibrutinib could be
used to successfully treat steroid-resistant, steroid-dependent and refractory
cGVHD patients.

1. Contribution of Uckun and Shimabukuro-Vornhagen to a
reasonable expectation of success
Uckun discloses that “[r]ecent studies in a mouse BMT model
demonstrated that the addition of a BTK inhibitor to the GVHD prophylaxis
regimens significantly improves the survival outcome of allogeneic BMT.”
Ex. 1005, 1461. For the reasons discussed below, we find that the record
does not support that this teaching would have contributed significantly to

21 Petitioner does not specifically address the patient populations recited in
claims 4, 13, and 15 as they relate to the combined teachings of the ’085
publication, Shimabukuro-Vornhagen, and Uckun in the Petition.
IPR2019-00865
Patent 9,795,604 B2

61
the expectation of a POSA that administering ibrutinib would successfully
treat patients with steroid-dependent/refractory, steroid-resistant, or
refractory cGVHD.
First, the evidence supports that mouse models were generally not
accepted as supporting treatment of cGVHD in humans. Ex. 2003, abstract
(“no animal model fully replicates all of the features of CGVHD in
humans”); id. at 84–85 (discussing mouse model noting, “the relevance of
this model for human CGVHD is questionable”); Ex. 2056, 92:21–95:21
(Dr. Ferrara’s deposition testimony discussing deficiencies of animal models
with respect to cGVHD); Ex. 2008, 859 (“Because models of CGVHD do
not replicate human disease and the models of AGVHD, it is difficult to
determine whether these results can be applicable to clinical GVHD
prevention and treatment.”); Ex. 2066 ¶ 206 (Dr. Koreth testimony that “it
was widely acknowledged by researchers, including Dr. Ferrara, that extant
mouse models correlated poorly to clinical manifestations of cGVHD in
patients”).
Second, the evidence supports that success in preventing cGVHD may
not extend to success in treating cGVHD.22 Ex. 2059, 207 (“Disparate
results of intervention to prevent and/or treat aGVHD or cGVHD are

22 The parties agree that “treatment” as recited in the claims excludes
prophylaxis. Pet. 16 n 2; see also, PO Resp. 15. We note that the ’085
publication discloses the use of a BTK inhibitor – ibrutinib – to treat GVHD
and defines “treatment” to include “arresting or reducing the development of
the disease or its clinical symptoms” or “causing regression of the disease or
its clinical symptoms.” Ex. 1002 ¶¶ 98, 116–119. However, as discussed
above, the ’085 publication lacks data to support this teaching. Accordingly,
in Ground 4, Petitioner relies on Uckun as providing supporting data.
Uckun does not define prophylaxis to include treatment.
IPR2019-00865
Patent 9,795,604 B2

62
common.”); Ex. 2004, 254–259 (distinguishing approaches for prophylaxis
and treatment); Ex. 2055, ¶205.23
Third, we agree with Petitioner that Shimabukuro-Vornhagen supports
that many treatments were used to treat both acute GVHD and chronic
GVHD, including steroids, rituximab, statins, and extracorporeal
photopheresis (“ECP”). See Ex. 1006 ¶ 32; Ex. 1003, 4919, 4921–22, 4924.
Nonetheless, the evidence also supports that drugs that were used for acute
GVHD were known to fail when used for chronic GVHD. Ex. 2010, 1
(“While there are some lessons that can be translated from basic and clinical
studies of acute GVHD, several lines of evidence suggest chronic GVHD is
not simply a continuation of acute GVHD, and that separate approaches will
be required for its prevention and management”); Ex. 2008, 854
(“[A]lthough AGVHD and CGVHD are similar in some respects, it seems
likely that the two diseases have different initiation requirements and
pathogenic mechanisms. More importantly from the experimental view, it is
not obvious whether findings based on the AGVHD models apply to
CGVHD syndrome.”); Ex. 2055 ¶ 205 (Dr. Koreth’s testimony regarding
extension of aGVHD treatments to cGVHD).
Fourth, Uckun teaches that “incorporation of BTK inhibitors in
clinical GVHD prophylaxis regimens may improve the outcome by
reducing the incidence of sever GVHD.” Ex. 1005, 1461 (emphasis added).
This statement is a conclusion drawn directly from the preceding sentence,

23 During prosecution, the Examiner recognized the distinction between
treating and preventing GVHD. Ex. 1021, 7 (rejecting then pending claims
as lacking written description support because the specification “while being
enabling for only a treatment method . . . does not reasonably provide
enablement for a method of preventing ‘the occurrence of graft versus host
disease”).
IPR2019-00865
Patent 9,795,604 B2

63
which states: “Notably, > 70% of BMT recipients treated with a BTK
inhibitor-containing combination regimen remained alive throughout the
80-day observation period.” Id. (emphasis added). Thus, Uckun’s teaching
is not that a BTK inhibitor by itself is beneficial, but rather that a BTK
inhibitor is beneficial when added to a combination prophylaxis regimen.
Indeed, the data on which Uckun relies shows that treatment with the BTK
inhibitor LFM-A13 had a limited effect, with only 2% of the treated animals
surviving 80 days. Ex. 1012, 824; Ex. 2055 ¶ 200 (Dr. Koreth discussing
same). By comparison, 73% of mice treated with both the BTK inhibitor
and a Janus kinase 3 (“JK3”) inhibitor survived 80 days. Ex. 1012, 824. We
recognize, that claims 4, 13, and 15 are “comprising” claims, and do thus not
preclude the addition of another treatment agent. But Petitioner’s
obviousness theory is predicated only on using a BTK inhibitor, making no
mention of combination therapy or, more specifically, of JK3 inhibitors.
Pet. 62–66.
2. Contribution of the ’085 publication to a reasonable
expectation of success
As discussed above in connection with Grounds 2 and 3, the teaching
of the ’085 publication that ibrutinib can be used to treat GVHD does not
meaningfully advance an expectation of success in the absence of supporting
data. See supra p. 39–42 and 54–55.

3. Conclusion regarding the reasonable expectation of success
based on the combined teachings of the ’085 publication,
Shimabukuro-Vornhagen, and Uckun
Our analysis of obviousness must take account of the factual
background discussed above with respect to Ground 2, which reflects a poor
understanding of cGVHD, an absence of predictive models and standardized
IPR2019-00865
Patent 9,795,604 B2

64
measurement criteria, a multitude of unsuccessful treatments,
unpredictability with respect to treatments, a dependence on trial and error
testing, and an understanding that the claimed patient population was
particularly difficult to treat. Starting from this background, a POSA would
have been skeptical that any proposed treatments of steroid-
dependent/refractory, steroid-resistant and/or refractory cGVHD patients
would be successful.
Here, the evidence identified by Petitioner in connection with
Ground 4, when considered against this background, is not sufficient to
support a reasonable expectation of success. To summarize, finding support
for the obviousness of the claimed method in Uckun’s disclosure requires
the POSA to: extend mouse models to human patients; extend teachings on
prevention to treatment; extend teachings on acute GVHD to the specifically
claimed population of cGVHD patients; and, based on the obviousness
theory set forth by Petitioner, extend teachings on combination therapy using
a BTK inhibitor to administration of BTK alone, or at least without a JK3
inhibitor. Considering all of the evidence together, we find that the teaching
in Uckun regarding the use of BTK in prophylaxis regimens is too
attenuated from treatment of patients with steroid-dependent/refractory,
steroid-resistant, or refractory cGVHD to meaningful contribute to a
reasonable expectation of success.
The other references cited in Ground 4 also do not support an
expectation of success. Petitioner relied on Shimabukuro-Vornhagen in
Ground 4 only for the teaching that drugs that treat acute GVHD have also
been used to treat chronic GVHD. This teaching was discussed above. The
teaching of the ’085 publication that ibrutinib can be used to treat GVHD
IPR2019-00865
Patent 9,795,604 B2

65
does not meaningfully advance an expectation of success in the absence of
supporting data for the reasons discussed above. See supra p. 39–42 and
54–55.
Considering all of the evidence and the arguments of record with
respect to Ground 4, we find that Petitioner has not established by a
preponderance of the evidence that a POSA would reasonably have expected
ibrutinib to be successful in treating steroid-dependent/refractory, steroid-
resistant and/or refractory cGVHD patients.24 Accordingly, we find that
Petitioner has not established the combination of the ’085 publication,
Shimabukuro-Vornhagen, and Uckun would have rendered claims 4, 13, 15,
28–31, 43–46 and 50–53 obvious.
VI. PATENT OWNER’S MOTION TO STRIKE
Patent Owner moves to strike two arguments made in Petitioner’s
Reply on the basis that they present new arguments. Mot. 1. First, Patent
Owner requests that we strike Petitioner’s argument that the ’085 publication
expressly discloses administration of ibrutinib to the patient populations
recited in claims 4, 13, and 15. Id. at 1–3 (identifying the briefing at Pet.
Reply 9–10). Second, Patent Owner requests that we strike Petitioner’s
argument that the ’085 publication expressly discloses the efficacy
limitations recited in claims 6–8, 29–31, 44–46, and 51–53. Id. at 3
(identifying the briefing at Pet. Reply 10–11).

24 Patent Owner included extensive discussion of objective indicia of non-
obviousness. PO Resp. 57–65. We have determined that it is not necessary
to address this evidence in detail because it can only benefit the Patent
Owner and we have already determined that the evidence does not support a
finding that claims 4, 13, 15, 28–31, 43–46, and 50–53 would have been
obvious over the ’085 publication, Shimabukuro-Vornhagen, and Uckun.
IPR2019-00865
Patent 9,795,604 B2

66
We addressed Petitioner’s argument that the ’085 publication
expressly discloses administration of ibrutinib to the claimed patient
populations in the context of our discussion of Ground 1, concluding both
that Petitioner’s argument was new, and thus should not be considered, and
also that it lacked merit. See supra p. 22–27. We discern no need to take
the additional step of striking this portion of Petitioner’s Reply brief. See
Trial Practice Guide August 2018 update, 17–18 (“In most cases, the Board
is capable of identifying new issues or belatedly presented evidence when
weighing the evidence at the close of trial, and disregarding any new issues
or belatedly presented evidence that exceeds the proper scope of reply or
sur-reply. As such, striking the entirety or a portion of a party’s brief is an
exceptional remedy that the Board expects will be granted rarely.”).
Accordingly, we deny Patent Owner’s motion to strike this portion of
Petitioner’s briefing.
We did not consider Petitioner’s argument that the ’085 publication
expressly discloses the efficacy limitations recited in certain of the
challenged claims because we found that these limitations were inherently
disclosed. Accordingly, we dismiss this portion of Patent Owner’s Motion
to Strike as moot.
VII. CONSTITUTIONAL CHALLENGE
Patent Owner states: “Given Arthrex, Inc. v. Smith & Nephew Inc.,
941 F.3d 1320 (Fed. Cir. 2019) and subsequent Federal Circuit authority,
Patent Owner challenges the constitutionality of this proceeding and
authority of the panel to adjudicate this dispute.” PO. Resp. 66.
We decline to consider Patent Owner’s constitutional challenge as the
issue has been addressed by the Federal Circuit in Arthrex. See Arthrex, 941
IPR2019-00865
Patent 9,795,604 B2

67
F.3d at 1337 (“This as-applied severance . . . cures the constitutional
violation . . . .”).
VIII. CONCLUSION25
Claims

35
U.S.C.
§
Reference(s)/Basis
Claims
Shown
Unpatentable
Claims
Not Shown
Unpatentable
1, 4, 6–10,
13, 15, 24,
28–31, 35,
39, 43–46,
50–53, 55
102 ’085 publication 1, 6–10, 24, 35, 39, 55
4, 13, 15, 28–
31, 43–46,
50–53
1, 4, 6–10,
13, 15, 24,
28–31, 35,
39, 43–46,
50–53, 55
10326 ’085 publication
4, 13, 15, 28–
31, 43–46,
50–53
1, 4, 6–10,
13, 15, 24,
28–31, 35,
39, 43–46,
50–53, 55
103
‘085 publication,
Shimabukuro-
Vornhagen,
Herman

4, 13, 15, 28–
31, 43–46,
50–53
1, 4, 6–10, 103 ‘085 publication, 4, 13, 15, 28–

25 Should Patent Owner wish to pursue amendment of the challenged claims
in a reissue or reexamination proceeding subsequent to the issuance of this
decision, we draw Patent Owner’s attention to the April 2019 Notice
Regarding Options for Amendments by Patent Owner Through Reissue or
Reexamination During a Pending AIA Trial Proceeding. See 84 Fed. Reg.
16,654 (Apr. 22, 2019). If Patent Owner chooses to file a reissue application
or a request for reexamination of the challenged patent, we remind Patent
Owner of its continuing obligation to notify the Board of any such related
matters in updated mandatory notices. See 37 C.F.R. § 42.8(a)(3), (b)(2).
26 We limited our analysis of Petitioner’s three obviousness grounds to
whether the cited art rendered claims 4, 13, 15, 28–31, 43–46 and 50–53
obvious because we had already determined that a preponderance of the
evidence supported that the ’085 publication anticipated claims 1, 6–10, 24,
35, 39, and 55.
IPR2019-00865
Patent 9,795,604 B2

68
Claims

35
U.S.C.
§
Reference(s)/Basis
Claims
Shown
Unpatentable
Claims
Not Shown
Unpatentable
13, 15, 24,
28–31, 35,
39, 43–46,
50–53, 55
Shimabukuro-
Vornhagen, Uckun
31, 43–46,
50–53
Overall
Outcome
1, 6–10, 24,
35, 39, 55
4, 13, 15, 28–
31, 43–46,
50–53
ORDER
In consideration of the foregoing, it is hereby:
ORDERED that Petitioner has shown by a preponderance of the
evidence that claims 1, 6–10, 24, 35, 39, and 55 of the ’604 patent are
unpatentable;
FURTHER ORDERED that Petitioner has not proven by a
preponderance of the evidence that claims 4, 13, 15, 28–31, 43–46, 50–53
are unpatenable;
FURTHER ORDERED that Patent Owner’s motion to strike is denied
in part and dismissed in part;
FURTHER ORDERED that, because this is a Final Written Decision,
parties to this proceeding seeking judicial review of our decision must
comply with the notice and service requirements of 37 C.F.R. § 90.2.

IPR2019-00865
Patent 9,795,604 B2

69
PETITIONER:
Kirk T. Bradley
Siraj M. Abhyankar
ALSTON & BIRD LLP
kirk.bradley@alston.com
shri.abhyankar@alston.com

PATENT OWNER:

William B. Raich
Erin M. Sommers
Cora R. Holt
Stefan O. Ochiana
FINNEGAN, HENDERSON, FARABOW,
GARRETT & DUNNER, LLP
william.raich@finnegan.com
erin.sommers@finnegan.com
cora.holt@finnegan.com
stefan.ochiana@finnegan.com