Trials@uspto.gov Paper No.

8
571.272.7822 Entered: September 26, 2019

UNITED STATES PATENT AND TRADEMARK OFFICE

____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD

____________

SANDOZ INC.,
Petitioner,

v.

PHARMACYCLICS LLC,
Patent Owner.
____________

Case IPR2019-00865
Patent 9,795,604 B2
____________

Before SUSAN L. C. MITCHELL, JENNIFER MEYER CHAGNON, and

DAVID COTTA, Administrative Patent Judges.

COTTA, Administrative Patent Judge.

DECISION
Granting Institution of Inter Partes Review
35 U.S.C. § 314(a)
IPR2019-00865
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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
Institution of an inter partes review is authorized by statute only when
“the information presented in the petition . . . and any response . . . shows
that there is a reasonable likelihood that the petitioner would prevail with
respect to at least 1 of the claims challenged in the petition.” 35 U.S.C.
§ 314; see 37 C.F.R. §§ 42.4, 42.108. Upon considering the Petition, the
Preliminary Response, and the cited evidence, we conclude that Petitioner
has satisfied the burden under 35 U.S.C. § 314(a) to show that there is a
reasonable likelihood that it would prevail with respect to at least one of the
challenged claims.

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

                                                            
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.
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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.

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

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GVHD a therapeutically effective amount of a compound of the

structure:

thereby treating the chronic GVHD in the patient.

Ex. 1001, 77:41–68.

D. Prior Art and Asserted Grounds

Petitioner asserts that claims 1, 4, 6-10, 13, 15, 24, 28-31, 35, 39, 43-
46, 50-53, and 55 of the ’604 would have been unpatentable on the
following grounds:
Claims Challenged Statutory Basis Reference(s)
1, 4, 6–10, 13, 15, 24, § 102(a)(2) The ’085 publication3
28–31, 35, 39, 43–46,
50–53, and 55
1, 4, 6–10, 13, 15, 24, § 103(a) The ’085 publication
28–31, 35, 39, 43–46,
50–53, and 55

                                                            
3
Goldstein, US Patent Publication No. 2015/0140085 A1, published May
21, 2015 (Ex. 1002, “the ’085 publication”).
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Claims Challenged Statutory Basis Reference(s)

1, 4, 6–10, 13, 15, 24, § 103(a) The ’085 publication,
28–31, 35, 39, 43–46, Shimabukuro-Vornhagen,4
50–53, and 55 and Herman5
1, 4, 6–10, 13, 15, 24, § 103(a) The ’085 publication,
28–31, 35, 39, 43–46, Shimabukuro-Vornhagen,
50–53, and 55 and Uckun6
Petitioner submits the Declaration of Dr. James L. Ferrara (Ex. 1006)
in support of institution of inter partes review.

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
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

                                                            
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”).
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training, such as a fellowship in Hematology/Oncology as well as several

years’ experience specializing in transplantation.” Pet. 31; Ex. 1006 ¶¶ 52–
54. Petitioner also contends that the POSA would “preferably have had
some experience with pharmaceutical compositions for treating GVHD or
related conditions.” Pet. 31–32.
At this stage in the proceeding, Patent Owner does not challenge
Petitioner’s definition. Prelim. Resp. 19 (“For purposes of this Preliminary
Response, Patent Owner does not dispute Petitioner’s definition of a
POSA.”). Accordingly, for purposes of this Decision and based on the
present record, we accept Petitioner’s definition, as it is consistent with the
level of skill reflected in the asserted prior art references. See Okajima v.
Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001) (the prior art itself can
reflect the appropriate level of ordinary skill in the art).

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).” 37 C.F.R. § 42.100 (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.,

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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)).
For purposes of this decision, we need only construe the limitations in
claims 6, 7, 8, 29, 30, 31, 44, 45, 46, 51, 52, and 53 that recite particular
patient outcomes resulting from the administration of ibrutinib. The specific
claim limitations 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.”
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.”

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. 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 “relate back to and clarify what is required
by the [claim],” and “express[] the inventive discovery” of the claim.

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Prelim. Resp. 26. Based on the record currently before us, we find that
Petitioner has the better position.
The Federal Circuit has held that “[a] whereby clause in a method
claim is not given weight when it simply expresses the intended result of a
process step positively recited.” Minton v. Nat’l Ass’n of Sec. Dealers, Inc.,
336 F.3d 1373, 1381 (Fed. Cir. 2003). In Minton, the court was asked to
construe a claim reciting a method for trading securities that included the
language “whereby the security is traded efficiently between the first
[offering] individual and the second [replying] individual.” Id. at 1380. The
court found that “[t]he term ‘efficiently’ on its face does not inform the
mechanics of how the trade is executed” and was thus “a laudatory one
characterizing the result of the executing step.” Id. at 1381. Accordingly,
the court declined to give weight to the “traded efficiently” phrase in the
recited whereby clause. Id.
The limitations in claims 6, 7, 8, 29, 30, 31, 44, 45, 46, 51, 52, and 53
recite patient outcomes and, like the whereby clause at issue in Minton,
“simply express the intended result” of the recited method. Patent Owner
does not identify, and we do not find in the Specification, anything to
suggest that the recited result affects the steps preformed in connection with
the recited method. Put another way, the recited results do not affect the
manner in which ibrutinib is administered to treat cGVHD. Accordingly,
based on the record now before us, we do not accord these limitations
patentable weight.
Although Petitioner proposes several additional claim constructions
(Pet. 12–18), we determine that no explicit construction of any additional
claim term is necessary to determine whether to institute a trial in this case.

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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.
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. 35 U.S.C. § 314(a)

Before addressing the merits of the Petition, we consider Patent

Owner’s contention that we should exercise our discretion under 35 U.S.C.
§ 314(a) and deny institution. We have considered Patent Owner’s
arguments, but find them unpersuasive.
As discussed above, the ’604 patent was asserted in litigation in
district court. See supra p. 2–3. Patent Owner asserts that this litigation
(“the ANDA litigation”) involves “the same or substantially similar issues,
arguments, and evidence” as the present proceeding. Prelim Resp. 64.
According to Patent Owner, the District Court has already completed claim
construction, and trial in the ANDA litigation is scheduled to begin on
October 13, 2020. Id. Patent Owner argues that we should exercise our
discretion to deny institution because instituting a trial would be an
inefficient use of Board resources. Id. As support, Patent Owner cites E-
One, Inc., v. Oshkosh Corp., IPR2019-00161, Paper 16 at 5–9 (PTAB May
15, 2019) (“E-One”) and NHK Spring Co., v. Intri-plex Technologies, Inc.,
IPR2018-00752, Paper 8 at 19–20 (PTAB Sept. 12, 2018) (precedential)
(“NHK”), two Board decisions where the Board considered pending
litigations in exercising its discretion to deny institution. We are not
persuaded that we should exercise such discretion in this proceeding.

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The AIA explicitly contemplates that a party may choose to file an

inter partes review on a patent that is involved in concurrent litigation. See
35 U.S.C. § 315(b) (providing that a petitioner involved in concurrent
litigation may request inter partes review if the Petition is filed within one
year of being served a complaint alleging infringement of the patent).
Accordingly, the existence of concurrent litigation set to conclude more than
a year from the date of this decision, without more, does not persuade us to
exercise our discretion to deny institution.
We acknowledge Patent Owner’s argument that the ANDA litigation
and the present proceeding involve “the same or substantially similar
issues.” Prelim. Resp. 64. Trial in the ANDA litigation, however, is not
scheduled to begin until more than a year from the date of this decision, and
thus, the ANDA litigation will likely not be completed before our final
decision is due. In addition, although the District Court has completed claim
construction, the issues in this case do not appear to be fully resolved based
on resolution of claim construction arguments alone. See infra p. 6–9.7
These facts distinguish the present proceeding from E-One, where the
District Court had already “received briefing, heard oral argument, and
issued detailed decisions” on claim construction and on a motion for a
preliminary injunction, and where the issues in the Petition “essentially
duplicate[d]” these issues. E-One, Paper 16 at 7. In addition, the district
court in E-One, unlike the district court here, was scheduled to complete trial
in the parallel district court case “before a final decision would be due.” Id.
at 6.
                                                            
7
Patent Owner notes that Petitioner did not request that the District Court
construe any terms of the ’604 patent, suggesting that claim construction is
not likely to be dispositive in the district court proceeding. Prelim. Resp. 64.
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The facts in this case are also distinguishable from NHK. In NHK, the
Board denied institution under 35 U.S.C. § 325(d), finding the arguments
that the petitioner advanced in the petition were substantially similar to those
made by the Examiner during prosecution, before considering the “advanced
state of the district court proceeding” as an additional factor that weighed in
favor of denying the petition. NHK, Paper 8 at 20. Thus, the district court
timeline was merely one of many factors considered by the Board when
denying institution of the petition. Id. Here, Patent Owner does not contend
that the arguments advanced in the Petition are substantially similar to those
made during prosecution. In addition, the district court proceeding in NHK,
where trial was set to conclude six months before a final Board decision
would be due (id.), appears to have been substantially more advanced than
the district court proceeding is here. Here, Patent Owner has stated that trial
will begin on October 13, 2020, over two weeks after any final written
decision will be issued. Also, we will endeavor to issue a final written
decision as soon as practicable to assist the District Court with resolution of
the ANDA proceeding.
Accordingly, we decline to exercise our discretion under 35 U.S.C.
§ 314(a) on the basis that the issues duplicate those at issue in the pending
ANDA litigation.

III. 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. Prelim. Resp. 26–41. 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

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has demonstrated a reasonable likelihood of prevailing in showing that the

’085 publication anticipates at least claim 1 of the ’604 patent.
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, the “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,
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

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would have “at once envisaged that this disclosure pertains to both acute and
chronic GVHD.” Id. 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 claim 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
recited in claim 5, which depends from claim 1, and which recites amounts
corresponding to those disclosed in the ’085 publication. Id. at 14.
Based on the information presented at this stage of the proceeding,
Petitioner has shown sufficiently in the Petition that there is a reasonable
likelihood that it will prevail in showing the unpatentability of claim 1 over
the disclosure of the ’085 publication. We focus our further analysis on
Patent Owner’s arguments against institution in its Preliminary Response.
Patent Owner argues that the ’085 publication does not anticipate
claim 1 for three reasons. Prelim. Resp. 26–27. First, Patent Owner
contends that the ’085 publication fails to disclose treatment of chronic
GVHD. Id. at 38. Second, Patent Owner contends that Petitioner’s
anticipation arguments require picking and choosing among disclosures. Id.

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at 39–41. Third, Patent Owner contends that the ’085 publication is not
enabled. Id. at 27–34. We address each argument in turn.
With respect to Patent Owner’s argument that the ’085 publication
fails to disclose treatment of chronic GVHD, Patent Owner contends that
Petitioner improperly relies on the knowledge of the POSA to supply a
missing claim limitation. Prelim. Resp. 38. Patent Owner argues that unlike
the prior art in Kennametal and Wrigley, “the ’085 Publication does not
provide a narrow genus setting forth [the cGVHD limitation] from which a
single anticipatory species can be readily ascertained.” Id. We are not
persuaded.
As discussed above, the ’085 publication discloses treatment of
GVHD. However, the ’085 publication does not specify whether such
GVHD is chronic or acute. Petitioner provides evidence that there are two
types of GVHD, acute and chronic. Ex. 1006 ¶ 29 (cited at Pet. 7).
Accordingly, absent persuasive evidence to the contrary, 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 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. Accordingly, the current
record tends to suggest that a reasonable likelihood exists that the ’085
publication anticipates treatment of chronic GVHD.
We are not persuaded by Patent Owner’s argument that this result is
contrary to the case law. In Wrigley, the Federal Circuit explained that
where the “prior art reference . . . discloses a genus and the claim at issue

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recites a species of that genus . . . the issue of anticipation turns on whether

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.” 683 F.3d at
1361; see also Kennametal, 780 F.3d at 1381–1382 (holding that a prior art
reference disclosed five binding agents (one of which was ruthenium) and
three coating techniques (one of which was PVD) anticipated a claim drawn
to the specific combination of ruthenium and PVD). Here, the ’085
publication discloses a genus of two species – acute and chronic GVHD –
and the evidence tends to suggest that the POSA would at once envisage the
claimed species, chronic GVHD. Nidec Motor Corp. v. Zhongshan Board
Ocean Motor Co., 851 F.3d 1270 (Fed. Cir. 2017), cited by Patent Owner, is
not to the contrary. Nidec holds that anticipation does not permit one to “fill
in missing limitations simply because a skilled artisan would immediately
envision them.” 851 F.3d at 1274–1275. Here, the limitation of chronic
GVHD is not missing, but rather a member of a disclosed genus.
Patent Owner next argues that the ’085 publication does not anticipate
the claimed method because it requires too much picking and choosing from
different portions of the ’085 publication’s disclosure. Patent Owner
explains:
To construct this allegedly anticipatory embodiment, one would
have to pick: (1) the eighth out of nine aspects of the
disclosure, “treating cancer or an autoimmune disease,” (2) the
third out of six treatment embodiments, “heteroimmune
conditions or diseases,” (3) GVHD from among nine exemplary
choices, (4) combine that with a “therapeutically effective
amount” that is not specific to any one of the numerous recited
diseases and “will vary” depending on multiple factors,
including “the disease” chosen, and (5) choose treatment
instead of prevention, when the ’085 Publication defines
treatment to encompass both.

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Prelim. Resp. 40. We are not persuaded.

To arrive at the claimed method from the disclosure of the ’085
publication, the POSA would need to connect the disclosure of treating
GVHD (Ex. 1002 ¶ 98) with the disclosures of therapeutically effective
doses of ibrutinib (id. ¶¶ 30, 120). We do not view the connection between
these disclosures as being as attenuated as Patent Owner suggests. The ’085
publication discloses treating GVHD by “administering . . . a solid oral
dosage form disclosed herein” (id. ¶¶ 96, 98) and discloses solid oral dosage
forms having amounts of ibrutinib that overlap with doses encompassed by
claim 1. Id. ¶¶ 21, 30; Ex. 1001, 75:40–68, 76:7–10. In addition, the ’085
publication discloses “therapeutically effective amounts” of ibrutinib that
also overlap with doses encompassed by claim 1. Ex. 1002 ¶ 120.
Accordingly, based on the current record, the evidence tends to suggest that
it would not have required an inappropriate amount of “picking and
choosing” to select amounts of ibrutinib that were disclosed for “solid oral
dosage forms” and that were taught to be “therapeutically effective” when
following the teaching of the ’085 publication to treat GVHD with ibrutinib.
Patent Owner argues that the ’085 publication does not enable
treatment of cGVHD with ibrutinib because it would require undue
experimentation to practice the claimed invention. Patent Owner asserts that
cGVHD was “exceedingly difficult to treat, with numerous agents failing in
the clinic,” and that “cGVHD was poorly understood, and that its treatment
was extraordinarily difficult, unpredictable, and often based on trial and
error.” Prelim. Resp. 28. Patent Owner argues that “[i]nvestigation into
treatments for cGVHD was complicated by insufficiently predictive animal
models; confusion and debate about the basis of the disease; inappropriate

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diagnoses and application of disease response criteria; and conflicting and

inconclusive clinical trial data.” Id. at 29. 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 text of the ’085 Publication provides no guidance for
treating cGVHD. Instead, “graft versus host disease” is
generically identified among over 150 diseases listed as part of
the eighth aspect (of nine) of the disclosure. Ex. 1002 [0096]–
[0100]. The ’085 Publication provides no dose or doses of
ibrutinib as part of that eighth aspect for treating any particular
disease, let alone GVHD. Instead, Petitioner relies on a generic
definition of “therapeutically effective amount.” Pet., 37, 43
(citing Ex. 1002 [0030], [0120]). That disclosure, however, is
not tied to any particular disease, and makes clear that 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.” Ex. 1002 [0120]. In other
words, many factors must be considered to determine a
therapeutically effective amount for any particular disease, and
the ’085 Publication provides no guidance as to how one would
effectively treat GVHD (let alone cGVHD, which it does not
mention).
Prelim. Resp. 31. 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 discloses that these formulations may be used to treat a patient
“suffering from a heteroimmune condition or disease, e.g., graft versus host

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disease” (id. ¶ 98) by “administering to the patient . . . a solid oral dosage

form disclosed herein.” Id. ¶ 96.
We acknowledge Patent Owner’s argument that cGVHD is difficult to
treat, poorly understood, and lacking in predictive animal models. We
further acknowledge Patent Owner’s argument that numerous treatment
agents have failed in clinic. At this point in the proceeding, however, we are
not persuaded that the alleged failure to develop an effective treatment prior
to ibrutinib is sufficient to rebut the presumptively enabled teaching of the
’085 publication that ibrutinib can be used to treat GVHD.
We also acknowledge Patent Owner’s argument that the ’085
publication does not specifically disclose how to effectively treat cGVHD.
However, per claim 1, all that is required to treat cGVHD is to administer a
therapeutically effective dose of ibrutinib. The ’085 publication provides
general guidance – not specific to any one disease – on what constitutes a
therapeutically effective amount of ibrutinib. 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. 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

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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. At this stage in the proceeding, 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.
Accordingly, based on the information presented at this stage of the
proceeding, we conclude that Petitioner has shown sufficiently that there is a
reasonable likelihood that it will prevail in showing the unpatentability of
claim 1 over the disclosure of the ’085 publication. Having determined that
Petitioner has demonstrated a reasonable likelihood of success in proving
that at least claim 1 of the ’604 patent is unpatentable, we institute a review
as to all of challenged claims and all grounds contained in the Petition. See
SAS Inst., Inc. v. Iancu, 138 S. Ct. 1348, 1359–60 (2018); USPTO, Guidance
on the Impact of SAS on AIA Trial Proceedings (Apr. 26, 2018), available at
https://www.uspto.gov/patents-application-process/patent-trial-and-appeal-
board/trials/guidance-impact-sas-aia-trial.
We offer the following views on the remaining claims for the parties’
consideration, to the extent they wish to address them during the inter partes
review.

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Claims 4, 13, and 15

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.”
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 and refractory GVHD. Prelim. Resp. 38. Patent Owner argues
that unlike the prior art in Kennametal and Wrigley, “the ’085 Publication
does not provide a narrow genus setting forth [steroid dependent and/or
refractory patients] from which a single anticipatory species can be readily
ascertained.” Id. On this record, we tend to agree with Patent Owner.
While we recognize that it may well be the case that the POSA would
have started administering ibrutinib only if steroids were not being effective,
Petitioner does not identify any disclosure in the ’085 publication of using
steroids to treat GVHD. Nor does Petitioner identify any disclosure in the
’085 publication of whether ibrutinib is a first or second line treatment.
Accordingly, we tend to agree with the Patent Owner that Petitioner’s
anticipation argument with respect to claims 4, 13, and 15 improperly relies

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on the knowledge of the POSA to supply the limitations recited in these

claims.
Claims 6, 7, 8, 29, 31, 44, 45, 46, 51, 52, and 53
As discussed supra p. 6–9, the additional limitations in claims 6, 7, 8,
29, 30, 31, 44, 45, 46, 51, 52, and 53 recite patient outcomes that “simply
express the intended result” of the recited method. For the reasons discussed
supra, we do not accord the additional limitations recited in these claims
patentable weight. Accordingly, the patentability of these claims is likely
tied to the claims from which they depend.
Claim 108
Claim 10 depends from claim 1 and further requires that “the patient
had a hematopoietic cell transplantation.” 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.
Patent Owner argues that Petitioner improperly relies on the
knowledge of the POSA to supply the missing element of treating patients
having received a hematopoietic cell transplantation. Prelim. Resp. 38.
Patent Owner argues that unlike the prior art in Kennametal and Wrigley,
“the ’085 Publication does not provide a narrow genus setting forth [patients
having received a hematopoietic cell transplant] from which a single
anticipatory species can be readily ascertained.” Id. On this record, we do
not find this argument persuasive.

                                                            
8
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.
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At this point in the proceeding, the evidence tends to suggest 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 tend to 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 current record tends to support 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).” 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 argues that Petitioner improperly relies on the
knowledge of the POSA to supply the missing element of treating patients
having CLL. Prelim. Resp. 38. Patent Owner argues that unlike the prior art

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in Kennametal and Wrigley, “the ’085 Publication does not provide a narrow
genus setting forth [patients having CLL] from which a single anticipatory
species can be readily ascertained.” Id. On this record, we do not find this
argument persuasive.
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. At this point in the
proceeding, the evidence tends to suggest 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 current record tends to support that the ’085
publication anticipates claim 10.
Claims 24, 28, 35, 39, 43, 50, and 55
Dependent claims 24, 28, 35, 39, 43, and 50 recite administering “420
mg of [ibrutinib] . . . orally once per day.” Independent claim 55 recites
“administering . . . “about 420 mg/day of [ibrutinib].” As discussed in
connection with claim 1, the ’085 publication discloses treatment with
420 mg of ibrutinib. The ’085 publication also discloses oral pharmaceutical
formulations. Ex. 1002 ¶ 1. Accordingly, the current record tends to

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support that the ’085 publication anticipates claims 24, 28, 35, 39, 43, and
50.

IV. 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. Patent Owner opposes. Prelim. Resp. 41–49, 60–63. As
discussed above, in connection with Ground 1, we have determined that
Petitioner has shown sufficiently that there is a reasonable likelihood that it
will prevail in showing that claim 1 is anticipated by the ’085 publication.
We offer the following additional views on Ground 2 for the parties’
consideration, to the extent they wish to address them during the inter partes
review.
A. Analysis
Claim 1
Petitioner contends that “[t]o the extent the ’085 Publication fails to
anticipate chronic GVHD, this limitation would have been obvious when
combined with a POSA’s knowledge because a POSA would have readily
known that treating GVHD with ibrutinib would have encompassed treating
chronic GVHD.” Pet. 46. In addition, Petitioner contends that a POSA
“would have known that treatments for acute GVHD also work for chronic
GVHD, and vice versa” and that this, in combination with the disclosure of
the ’085 publication, would have motivated the POSA to administer
ibrutinib to patients having cGVHD. Id. at 47.
Patent Owner argues that Petitioner improperly relies on teachings of
treatment of acute GVHD to teach treating chronic GVHD. Patent Owner
presents evidence that “chronic GVHD is not simply a continuation of acute

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GVHD, and [] separate approaches will be required for its prevention and
management” (Ex. 2010, 4200) and that “the pathophysiology of CGVHD,
unlike that of acute GVHD, remains obscure, as do its effective prevention
and treatment.” Ex. 2003, 81. In addition, Patent Owner points to the
statement in a paper co-authored by Dr. Ferrara that “very few interventions
that decrease acute GVHD incidence have translated into decreased
incidence of chronic GVHD, suggesting that although acute GVHD is a risk
factor for chronic GVHD, the pathogenic mechanisms are likely to be
different; thus, requiring distinct strategies.” Ex. 2016, 6. Patent Owner
thus argues that Petitioner fails to establish that a POSA would have been
motivated to practice the claimed method to treat chronic GVHD. Prelim.
Resp. 44.
Based on the current record, we tend to agree with Petitioner that
claim 1 would have been obvious over the disclosure of the ’085 publication.
First, “anticipation is the epitome of obviousness,” Connell v. Sears,
Roebuck & Co., 722 F.2d 1542, 1548 (Fed. Cir. 1983), and, for the reasons
discussed above, we have concluded that Petitioner is likely to prevail in
establishing that the ’085 publication anticipates claim 1.
Second, we agree with the Petitioner that to the extent the ’085
publication does not anticipate treatment of chronic GVHD, it would have
been obvious to treat chronic GVHD based on the disclosure of treating a
genus of two possible disease states – chronic and acute.
Third, at this stage in the proceeding, the evidence tends to suggest
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.

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We acknowledge the evidence, discussed above, that chronic and acute

GVHD are separate diseases requiring distinct treatment strategies.
However, the current record tends to support the existence of multiple
treatments that apply to both acute and chronic GVHD, and thus provides
motivation to use treatments that work for acute GVHD to treat chronic
GVHD as well as a reasonable expectation of success in doing so. See, In re
O’Farrell, 853 F.2d 894, 903–04 (Fed. Cir. 1988) (“Obviousness does not
require absolute predictability of success. . . . For obviousness under § 103,
all that is required is a reasonable expectation of success.”). Accordingly,
the current record tends to support that the ’085 publication renders claim 1
obvious.
Claims 4, 13, and 15
Claims 4, 13, and 15 depends 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.”
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
with chronic GVHD would be warranted in situations where treatment
beyond steroids was necessary because either the chronic GVHD was

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getting worse after the steroids had been removed (as in claim 4) or the
steroids had not worked to treat the chronic GVHD.”).
Patent Owner argues that Petitioner “provides no support that
treatment of cGVHD with ibrutinib would be reasonably expected to
succeed for the particularly difficult subset of patients who had failed to
respond to standard steroid therapy.” Prelim. Resp. 45. Patent Owner
contends that these patients were particularly challenging to treat and
provides evidence that there was no second line therapy for cGVHD that had
gained acceptance. Id. at 46 (citing Ex. 2002, 13; Ex. 2004, 9).
As discussed in connection with claim 1, the current record tends to
suggest that it would have been obvious to administer ibrutinib to treat
cGVHD in view of the disclosure of the ’085 publication. At this point in
the proceeding, the evidence also tends to suggest that it would have been
obvious to treat patients for whom additional treatment beyond steroids
became necessary – i.e. patients with steroid dependent or refractory
cGVHD – using ibrutinib. See Ex. 1006 ¶ 108. We acknowledge that the
POSA would not have had absolute certainty that such treatment would be
effective, however that is not required. See In re O’Farrell, 853 F.2d at
903–04. Accordingly, the current record tends to support that the ’085
publication renders claims 4, 13, and 15 obvious.
Claims 6, 7, 8, 29, 31, 44, 45, 46, 51, 52, and 53
As discussed supra p. 6–9, the additional limitations in claims 6, 7, 8,
29, 30, 31, 44, 45, 46, 51, 52, and 53 recite patient outcomes that “simply
express the intended result” of the recited method. For the reasons discussed
supra, we do not accord the additional limitations recited in these claims

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patentable weight. Accordingly, the patentability of these claims is likely

tied to the claims from which they depend.
Claim 109
Claim 10 depends from claim 1 and further requires that “the patient
had a hematopoietic cell transplantation.” As discussed in connection with
Ground 1, Dr. Ferrara testifies that “GVHD is a potentially serious
complication of allogeneic hematopoietic stem cell transplantation, which is
commonly known as bone marrow transplantation.” Ex. 1006 ¶ 24.
Dr. Ferrara further testifies that it was “well known to a POSA at the
relevant time that virtually every patient with chronic GVHD previously had
a hematopoietic stem cell transplantation.” Id. ¶ 114.
Patent Owner argues that Petitioner “provides no evidence that a
POSA would have reasonably expected success in treating patients with
cGVHD also having [received a hematopoietic cell transplantation], as
opposed to the myriad of other conditions disclosed in the ’085 Publication.”
Prelim. Resp. 47. This argument is not persuasive because the prior art is
presumed to be enabled, and, for the reasons discussed above in connection
with Ground 1, the current record does not include persuasive evidence
rebutting this presumption. Antor, 689 F.3d at 1287–88; Amgen Inc., 314
F.3d at 1355.
Accordingly, the evidence tends to support Petitioner’s position that
“it would have been obvious to a POSA that administering ibrutinib to a
patient with chronic GVHD includes patients that had received a
hematopoietic cell transplantation.” Ex. 1006 ¶ 114.
                                                            
9
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.
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Claim 9
Claim 9 depends from claim 1 and further requires that “the patient
ha[ve] chronic lymphocytic leukemia (CLL).” As discussed in connection
with Ground 1, Dr. Ferrara testifies that contends that “hematopoietic stem
cell transplantation [discussed above in connection with claim 10] is used to
treat approximately a dozen diseases.” Id. ¶ 26. Dr. Ferrara further testifies
that it was “well known” that one such disease was CLL. Id. ¶ 112.
Patent Owner argues that Petitioner “provides no evidence that a
POSA would have reasonably expected success in treating patients with
cGVHD also having [CLL], as opposed to the myriad of other conditions
disclosed in the ’085 Publication.” Prelim. Resp. 47.10 This argument is not
persuasive because the prior art is presumed to be enabled, and, for the
reasons discussed above in connection with Ground 1, the current record
does not include persuasive evidence rebutting this presumption. Antor, 689
F.3d at 1287–88; Amgen Inc., 314 F.3d at 1355.
Accordingly, the evidence tends to support Petitioner’s position that it
would have been obvious that “patients in need of ibrutinib to treat chronic
GVHD would have included patients with CLL.” Ex. 1006, ¶ 112.
Claims 24, 28, 35, 39, 43, 50, and 55
Dependent claims 24, 28, 35, 39, 43, and 50 recite administering
“420 mg of [ibrutinib] . . . orally once per day.” Independent claim 55
recites “administering . . . about 420 mg/day of [ibrutinib].” As discussed in

                                                            
10
Claim 9 does not require that ibrutinib “treat” the chronic lymphocytic
leukemia. Rather claim 9 requires only that the patient have cGVHD and
have chronic cymphocytic leukemia. Thus, claim 9 would be met if the
patient were administered ibrutinib to treat the cGVHD even if it has no
other connection with treating chronic lymphocytic leukemia.
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connection with Ground 1, the ’085 publication discloses treatment with 420
mg of ibrutinib and also discloses oral formulations of ibrutinib.
Accordingly, the current record tends to support that the ’085 publication
renders claims 24, 28, 35, 39, 43, and 50 obvious.
B. Objective Indicia of Non-Obviousness
Patent Owner contends that objective evidence showing long-felt
need, failures of others, and industry praise further supports the non-
obviousness of the ’604 patent. Prelim. Resp. 60–63. Patent Owner argues
that, in the ANDA litigation, Petitioner was served with an interrogatory
response “setting forth objective indicia of nonobviousness” and that
“Petitioner’s failure to address this evidence supports denial” of the Petition.
Id. at 60.
Patent Owner’s argument that we should decline to institute because
Petitioner failed to address the objective indicia of non-obvious provided in
an interrogatory response served shortly before the filing of the Petition is
not persuasive at least because we have already determined that Petitioner
has satisfied the burden under 35 U.S.C. § 314(a) to show that there is a
reasonable likelihood that it would prevail in proving that claim 1 of the
’604 patent is anticipated by the ’085 publication. Because objective indicia
of non-obviousness have no applicability to anticipation, Petitioner’s failure
to address them does not warrant denial of institution on the ground of
anticipation. See Cohesive Techs., Inc. v. Waters Corp., 543 F.3d 1351,
1364 (Fed. Cir. 2008) (“[O]bviousness requires analysis of secondary
considerations of nonobviousness, while secondary considerations are not an
element of a claim of anticipation.”).

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In addition, we have reviewed Patent Owner’s interrogatory response,

as well as the evidence of objective indicia of non-obviousness described in
the Petition. Although there is some overlap, the interrogatory responses are
not coextensive with the evidence cited in the Preliminary Response.
Compare Prelim. Resp. 60–63, with Ex. 2042, 12–16, 20. In particular, we
note that the Preliminary Response includes evidence that was not cited in
the interrogatory response. We will consider Patent Owner’s evidence
regarding objective indicia of non-obviousness after the parties have had the
opportunity to fully develop the record during the inter partes review. See
Amneal Pharms., LLC v. Supernus Pharms., Inc., IPR2013-00368, Paper 8
at 12–13 (PTAB Dec. 17, 2013); Koios Pharms. LLC v. medac Gesellschaft
für klinische Spezialpräparate mbH, IPR2016-01370, Paper 13 at 35 (PTAB
Feb. 8, 2017).

V. 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 obvious claims 1, 4, 6–10,
13, 15, 24, 28–31, 35, 39, 43–46, 50–53, and 55 of the ’604 patent. Pet. 54–
62. Patent Owner opposes. Prelim. Resp. 49–57, 60–63. As discussed
above, in connection with Ground 1, we have determined that Petitioner has
shown sufficiently that there is a reasonable likelihood that it will prevail in
showing that at least claim 1 is anticipated by the ’085 publication. We offer
the following additional views on Ground 3 for the parties’ consideration, to
the extent they wish to address them during the inter partes review.

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A. Disclosures of the Asserted Prior Art

The ’085 Publication
The disclosure of the ’085 publication is discussed supra p. 12. 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 (e.g. non Hodgkin lymphoma (NHL) and B cell chronic lymphocytic
leukemia (B-CLL) . . . .” 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 further 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
stimuli provided by the microenvironment.” Ex. 1004, 6288. Herman

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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 . . . and TNF-α.” Id. at 6291.
B. Analysis
Claim 1
Petitioner contends that “[t]o the extent the Board finds that the ’085
Publication alone did not anticipate or render obvious administering
ibrutinib to treat chronic GVHD (because the ’085 Publication does not
explicitly recite the word ‘chronic’), claim 1 would have been obvious over
the ’085 Publication in view of Shimabukuro-Vornhagen and Herman.”
Pet. 54. Petitioner argues:
Based on the ’085 Publication’s disclosures (directed to
ibrutinib’s B-cell mechanism of action and use for GVHD) and
Shimabukuro-Vornhagen’s disclosures (that B-cell-inhibiting
drugs can treat chronic GVHD), a POSA would have been
motivated to combine these references and use ibrutinib to treat
chronic GVHD.
Id. at 56.
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 this
provides additional motivation to use ibrutinib to treat chronic GVHD by
teaching that “ibrutinib inhibits the production of these same inflammatory

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cytokines that were known to contribute to the cause of chronic GVHD.” Id.
(citing Ex. 1006 ¶ 125).
Patent Owner argues that the ’085 publication is directed to
formulations, Herman reports on the treatment of patients with CLL, and
Shimabukuro-Vornhagen does not mention or suggest ibrutinib. Prelim.
Resp. 50. According to Patent Owner, “a POSA would not have been
motivated to combine these disparate disclosures.” Id. Based on the current
record, we do not find this argument persuasive because the subject matters
disclosed – ibrutinib, CLL, and GVHD – overlap and are sufficiently related
that a skilled artisan would look to all three disclosures in seeking to develop
a treatment for cGVHD. See Ex. 1006 ¶¶ 119–126.
Patent Owner argues that the combination of references does not
provide a reasonable expectation of success because none of the cited art
includes preclinical or clinical data for ibrutinib, the prior art regarding the
role of B cells was equivocal, the role of B cells was poorly understood, and
rituximab was “fundamentally different” from ibrutinib. Prelim. Resp. 50–
52. We are not persuaded for the reasons discussed in connection with
Ground 1, in which we found on this record that Petitioner had established a
reasonable likelihood that Petitioner will prevail in showing that claim 1 was
anticipated by a subset of the art relied upon in connection with Ground 3.
Cf. In re Bush, 296 F.2d 491, 496 (CCPA 1961) (holding that the Board may
rely on fewer than all of the references relied on by the Examiner to affirm
an obviousness rejection).
In addition, although we acknowledge the arguments that “the
mechanisms by which B cells contribute to acute and chronic GVHD [we]re
only incompletely understood” (Prelim. Resp. 17) and that Shimabukuro-

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Vornhagen’s disclosure relates to rituximab, an antibody targeting CD20,

rather than ibrutinib, a small molecule inhibitor of BTK and ITK,
Shimabukuro-Vornhagen does suggest inhibiting B cells for treatment of
cGVHD. Ex. 1003, 4923. The evidence also suggests that ibrutinib was
known to inhibit the BTK enzyme in B cells and prevent B cells from
activating T cells. Ex. 1006 ¶ 120. The evidence thus tends to support that
the skilled artisan would have been motivated to treat cGVHD and would
have had a reasonable expectation of success in doing so as proposed by
Petitioner, particularly when Shimabukuro-Vornhagen’s disclosure is
considered together with the express suggestion in the ’085 publication to
treat GVHD with ibrutinib. Ex. 1002 ¶ 98; Ex. 1006 ¶ 122.
Similarly, we acknowledge the evidence cited by Patent Owner that
there was uncertainty as to whether cytokine levels correlated with cGVHD
severity. Prelim. Resp. 54; Ex. 1010, 4 (study noting “discrepancy” among
studies regarding the “correlation between cytokine levels and the severity
of cGVHD”). However, the current record tends to support Petitioner’s
position that it was known 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.” Ex. 1010, 169. Particularly when considered with the other
teachings in the art discussed above, the evidence tends to support that this
teaching would have provided additional motivation to use ibrutinib to treat
cGVHD and furthered the expectation that such treatment would be
successful. See Ex. 1006 ¶ 125. Accordingly, the current record tends to
support that claim 1 would have been obvious over the combination of the
’085 publication, Shimabukuro-Vornhagen, and Herman.

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Claims 4, 13, and 15

Petitioner contends that claims 4, 13, and 15 are rendered obvious for
the reasons discussed in connection with Ground 2. Pet. 59. In addition,
Petitioner points out that Shimabukuro-Vornhagen discloses that rituximab,
which, like ibrutinib, acts on B cells, was effective in treating steroid-
refractory cGVHD. Petitioner contends that this provides additional support
for the obviousness of claims 4, 13, and 15. Id. at 59–60.
Patent Owner argues that claims 4, 13, and 15 are non-obvious for the
reasons already discussed. Prelim. Resp. 55. In addition, Patent Owner
argues that the dissimilarities between rituximab and ibrutinib would have
dissuaded the POSA from forming a reasonable expectation of being able to
treat patients who had failed to respond to standard steroid therapy. Id.
For the reasons already discussed in connection with Ground 2, which
includes a subset of the art relied upon in connection with Ground 3, the
current record tends to suggest that claims 4, 13, and 15 would have been
obvious over the combination of the ’085 publication, Shimabukuro-
Vornhagen, and Herman. The current record also tends to suggest that
Shimabukuro-Vornhagen would have provided additional reason to treat
patients who failed to respond to standard steroid therapy with ibrutinib. See
Ex. 1006 ¶ 133.
Claims 6, 7, 8, 29, 31, 44, 45, 46, 51, 52, and 53
As discussed supra p. 6–9, the additional limitations in claims 6, 7, 8,
29, 30, 31, 44, 45, 46, 51, 52, and 53 recite patient outcomes that “simply
express the intended result” of the recited method. For the reasons discussed
supra, we do not accord the additional limitations recited in these claims

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patentable weight. Accordingly, the patentability of these claims is likely

tied to the claims from which they depend.
Claims 9 and 10
Petitioner contends that claim 9 is rendered obvious for the reasons
discussed in connection with Ground 2. Pet. 61. In addition, Petitioner
points out that Shimabukuro-Vornhagen discloses that “[a]llogeneic
hematopoietic stem cell transplantation is an established, potentially curative
treatment modality for malignant and nonmalignant diseases” and that
“[a]cute and chronic graft-versus-host diseases (GVHDs) are a major cause
of morbidity and mortality after allogeneic stem cell transplantation.”
Ex. 1003, 4919 (cited at Pet. 60–61). Petitioner contends that this disclosure
further supports the obviousness of claims 9 and 10.
Patent Owner contends that “nothing in Shimabukuro-Vornhagen (or
the other asserted references) supports using ibrutinib to treat patients with
cGVHD regardless of the underlying condition, let alone provides a
reasonable expectation of success.” Prelim. Resp. 56.
For the reasons already discussed in connection with Ground 2, which
includes a subset of the art relied upon in connection with Ground 3, the
current record tends to suggest that claims 9 and 10 would have been
obvious over the combination of the ’085 publication, Shimabukuro-
Vornhagen, and Herman. The current record also tends to suggest that
Shimabukuro-Vornhagen would have provided further support for
Petitioner’s contention that claims 9 and 10 would have been obvious. See
Ex. 1006 ¶ 136.

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Claims 24, 28, 35, 39, 43, 50, and 55

Dependent claims 24, 28, 35, 39, 43, and 50 recite administering “420
mg of [ibrutinib] . . . orally once per day.” Independent claim 55 recites
“administering . . . about 420 mg/day of [ibrutinib].” As discussed in
connection with claim 1, the ’085 publication discloses treatment with 420
mg of ibrutinib and discloses oral formulations of ibrutinib. Accordingly,
the current record tends to support that the ’085 publication renders claims
24, 28, 35, 39, 43, and 50 obvious.
C. Objective Indicia of Non-Obviousness
Patent Owner contends that objective evidence showing long-felt
need, failures of others, and industry praise further supports the non-
obviousness of the ’604 patent. Prelim. Resp. 60–63. We decline to address
Patent Owner’s proffered evidence regarding objective indicia of
non-obviousness at this stage of the proceeding for the reasons discussed in
connection with Ground 2.

VI. 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.
Patent Owner opposes. Prelim. Resp. 57–63. As discussed above, in
connection with Ground 1, we have determined that Petitioner has shown
sufficiently that there is a reasonable likelihood that it will prevail in
showing that claim 1 is anticipated by the ’085 publication. We offer the

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following additional views on Ground 4 for the parties’ consideration, to the

extent they wish to address them during the inter partes review.
A. Disclosures of the Asserted Prior Art
The ’085 Publication
The disclosure of the ’085 publication is discussed supra p. 12 and 32.
Shimabukuro-Vornhagen
The disclosure of Shimabukuro-Vornhagen is discussed supra p. 32.
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
BTK inhibitors may enhance their ability to attenuate the
severity of GVHD without increasing the risk of relapse post-
BMT in clinical settings.

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Id. at 1461. Uckun’s teaching involve mice with acute rather than chronic
GVHD. Ex. 1006 ¶ 148.
B. Analysis
Claim 1
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 argues that “both the ’085 Publication and Uckun
disclose and address ibrutinib as a BTK inhibitor, and they further disclose
using ibrutinib [disclosed in the ’085 publication] or a BTK inhibitor
[disclosed in Uckun] for treating GVHD.” Id. at 62–63. Petitioner
acknowledges that Uckun involved mice with acute GVHD (id. at 66) but
contends that Shimabukuro-Vornhagen teaches that “drugs useful for
treating acute GVHD are also useful for treating chronic GVHD, and vice
versa.” Id. at 63.
Patent Owner argues that Uckun relates to a different BTK inhibitor
that reversibly binds BTK while ibrutinib irreversibly binds BTK. Prelim.
Resp. 58. In addition, Patent Owner points out that Uckun’s BTK inhibitor
was known to inhibit protein kinases other than BTK. Id. Patent Owner
also argues that Uckun relates to prophylaxis rather than treatment and acute
rather than chronic GVHD. Id. Finally, Patent Owner contests Petitioner’s
argument that the POSA would understand that drugs useful to treat acute
GVHD would also be useful to treat chronic GVHD. We are not persuaded
for the reasons discussed in connection with Grounds 1, in which we found
on this record that Petitioner had established a reasonable likelihood that

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Petitioner will prevail in showing that claim 1 was anticipated by a subset of

the art relied upon in connection with Ground 4.
In addition, although we acknowledge Patent Owner’s argument that
Uckun relates to a reversible rather than an irreversible BTK binder, Patent
Owner has not persuasively explained how this teaching would have
countered the general teaching in Uckun that “the antileukemic activity of
BTK inhibitors may enhance their ability to attenuate the severity of GVHD
without increasing the risk of relapse post-BMT in clinical settings.”
Ex. 1005, 1461.
We also acknowledge Patent Owner’s argument that Uckun relates to
prophylaxis rather than treatment, but are not persuaded by this argument at
least because 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. We note that the definition of “treatment” in the ’085 publication
is in accord with how the ’604 patent defines treatment. Ex. 1001, 26:47–53
(“The terms ‘treat,’ ‘treating’ or ‘treatment,’ as used herein, include
lessening of severity of GVHD, delay in onset of GVHD, causing regression
of GVHD, relieving a condition caused by of GVHD, or stopping symptoms
which result from GVHD. The terms ‘treat,’ ‘treating’ or ‘treatment,’
include, but are not limited to, prophylactic and/or therapeutic treatments.”).
Finally, we acknowledge Patent Owner’s argument that the POSA
would not have understood that drugs useful to treat acute GVHD would
also be useful to treat chronic GVHD. We are not persuaded for the reasons
discussed supra p. 24–26.

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Particularly when considered with the other teachings in the art

discussed above, the evidence tends to support that the disclosures of
Shimabukuro-Vornhagen and Uckun would have provided additional
motivation to use ibrutinib to treat cGVHD and further confirm the
expectation that such treatment would be successful. Accordingly, the
current record tends to support that claim 1 would have been obvious over
the combination of the ’085 publication, Shimabukuro-Vornhagen, and
Uckun.
Remaining Claims
Petitioner does not identify any additional reasons why claims 4, 6-10,
13, 15, 24, 28-31, 35, 39, 43-46, 50-53, and 55 would have been obvious in
connection with this ground. Accordingly, we do not provide further
analysis of these claims.
C. Objective Indicia of Non-Obviousness
Patent Owner contends that objective evidence showing long-felt
need, failures of others, and industry praise further supports the non-
obviousness of the ’604 patent. We decline to address Patent Owner’s
proffered evidence regarding objective indicia of non-obviousness for the
reasons discussed in connection with Ground 2.

VII. CONCLUSION

For the foregoing reasons, we conclude that the information presented

in the Petition establishes a reasonable likelihood that Petitioner will prevail
in showing that at least claim 1 of the ’604 patent is unpatentable.
Accordingly, we institute an inter partes review of all challenged claims and
all grounds presented in the Petition.

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ORDER
In consideration of the foregoing, it is hereby:
ORDERED that pursuant to 35 U.S.C. § 314(a), an inter partes
review is instituted as to claims 1, 4, 6–10, 13, 15, 24, 28–31, 35, 39, 43–46,
50–53, and 55 of the ’604 Patent under 35 U.S.C. § 102 as anticipated by the
’085 publication;
FURTHER ORDERED that pursuant to 35 U.S.C. § 314(a), an inter
partes review is instituted as to claims 1, 4, 6–10, 13, 15, 24, 28–31, 35, 39,
43–46, 50–53, and 55 of the ’604 Patent under 35 U.S.C. § 103 as obvious
over the ’085 publication;
FURTHER ORDERED that pursuant to 35 U.S.C. § 314(a), an inter
partes review is instituted as to claims 1, 4, 6–10, 13, 15, 24, 28–31, 35, 39,
43–46, 50–53, and 55 of the ’604 Patent under 35 U.S.C. § 103 as obvious
over the combination of the ’085 publication, Shimabukuro-Vornhagen, and
Herman;
FURTHER ORDERED that pursuant to 35 U.S.C. § 314(a), an inter
partes review is instituted as to claims 1, 4, 6–10, 13, 15, 24, 28–31, 35, 39,
43–46, 50–53, and 55 of the ’604 Patent under 35 U.S.C. § 103 as obvious
over the ’085 publication, Shimabukuro-Vornhagen, and Uckun; and
FURTHER ORDERED that, pursuant to 35 U.S.C. § 314(c) and
37 C.F.R. § 42.4, notice is hereby given of the institution of a trial, which
will commence on the entry date of this Decision.

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PETITIONER:
Kirk Bradley
kirk.bradley@alston.com

Siraj Abhyankar
shri.abhyankar@alston.com

PATENT OWNER:
William Raich
william.raich@finnegan.com

Erin Sommers
erin.sommers@finnegan.com

Cora Holt
cora.holt@finnegan.com
Stefan Ochiana
stefan.ochiana@finnegan.com

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