Case: 21-2270 Document: 59 Page: 1 Filed: 11/15/2022
NOTE: This disposition is nonprecedential.
United States Court of Appeals
for the Federal Circuit
______________________
PHARMACYCLICS LLC, JANSSEN BIOTECH, INC.,
Plaintiffs-Appellees
v.
ALVOGEN, INC., NATCO PHARMA LIMITED,
Defendants-Appellants
______________________
2021-2270
______________________
Appeal from the United States District Court for the
District of Delaware in No. 1:19-cv-00434-CFC-CJB, Chief
Judge Colm F. Connolly.
______________________
Decided: November 15, 2022
______________________
CHRISTOPHER NEIL SIPES, Covington & Burling LLP,
Washington, DC, argued for all plaintiffs-appellees. Plain-
tiff-appellee Pharmacyclics LLC also represented by ERICA
NICOLE ANDERSEN, BRIANNE BHARKHDA.
IRENA ROYZMAN, Kramer Levin Naftalis & Frankel
LLP, New York, NY, for plaintiff-appellee Janssen Biotech,
Inc. Also represented by CHRISTINE WILLGOOS; HANNAH
YUNKYUNG LEE, DANIEL DAVID WILLIAMS, Redwood Shores,
CA.
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2 PHARMACYCLICS LLC v. ALVOGEN, INC.
SIEGMUND Y. GUTMAN, Proskauer Rose LLP, Los Ange-
les, CA, argued for defendants-appellants. Also repre-
sented by DAVID M. HANNA; JOHN E. ROBERTS, Boston, MA.
______________________
Before CHEN, BRYSON, and HUGHES, Circuit Judges.
BRYSON, Circuit Judge.
Appellees Pharmacyclics LLC and Janssen Biotech,
Inc., (collectively, “Pharmacyclics”) own several patents re-
lated to the compound ibrutinib, which is the active ingre-
dient in Pharmacyclics’ branded drug Imbruvica. Ibrutinib
is one of a genus of compounds, known as “BTK inhibitors,”
that block the protein Bruton’s tyrosine kinase (“BTK”).
Imbruvica is used to treat a cancer of the immune system
known as mantle cell lymphoma (“MCL”), including the
“relapsed” or “refractory” type of MCL (“R/R MCL”). 1
In November 2018, appellants Alvogen, Inc., and Natco
Pharma Limited (collectively, “Alvogen”) filed an abbrevi-
ated new drug application (“ANDA”) to market a generic
version of Imbruvica. Pursuant to procedures set forth in
the Hatch-Waxman Act, Pharmacyclics then brought this
lawsuit charging Alvogen with infringement of a number
of Pharmacyclics’ patents relating to ibrutinib. The district
court held a bench trial and determined that all of the as-
serted claims were infringed and not invalid. We affirm.
I
A
Pharmacyclics originally asserted dozens of claims
across 17 patents, but by the time of trial, it had reduced
the number of asserted claims to five: claim 10 of U.S.
1 R/R MCL is MCL that occurs in patients who have
already received at least one prior therapy for MCL.
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PHARMACYCLICS LLC v. ALVOGEN, INC. 3
Patent No. 8,008,309 (“the ’309 patent”), claim 2 of U.S. Pa-
tent No. 8,754,090 (“the ’090 patent”), claim 5 of U.S. Pa-
tent No. 9,725,455 (“the ’455 patent”), and claims 30 and
37 of
U.S. Patent No. 9,655,857 (“the ’857 patent”).
Claim 10 of the ’309 patent recites the ibrutinib com-
pound:
10. The compound of claim 1 [which claims a genus
of BTK inhibitor compounds] having the formula 1-
((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyra-
zolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-
1-one.
’309 patent, claim 10.
Claim 2 of the ’090 patent, which depends from claim 1
of that patent, recites a method of treating MCL using ib-
rutinib at an oral dose of about 560 mg:
1. A method for treating mantle cell lymphoma in
an individual who has already received at least one
prior therapy for mantle cell lymphoma comprising
administering to the individual once per day be-
tween about 420 mg to about 840 mg of an oral dose
of an inhibitor of Bruton’s tyrosine kinase (Btk)
having the structure:
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4 PHARMACYCLICS LLC v. ALVOGEN, INC.
2. The method of claim 1, wherein the once per
day oral dose is about 560 mg.
’090 patent, claims 1–2.
Claim 5 of the ’455 patent, which depends from claim 1
of that patent, recites a crystalline form of ibrutinib:
1. A crystalline form A of [ibrutinib] that has an
X-ray powder diffraction (XRPD) pattern compris-
ing 2-Theta peaks at 5.7±0.1º, 18.9±0.1º, and
21.3±0.1º.
5. The crystalline form of claim 1, wherein the X-
ray powder diffraction (XRPD) pattern further
comprises 2-Theta peaks at 13.6±0.1º, 16.1±0.1º,
and 21.6±0.1º.
’455 patent, claims 1, 5.
Claims 30 and 37 of the ’857 patent recite tablet formu-
lations for ibrutinib:
30. The high-load solid tablet formulation of claim
1 [which recites a genus tablet formulation for ib-
rutinib], consisting essentially of:
a) about 70% w/w of ibrutinib,
b) about 14% w/w of lactose monohydrate,
c) about 5% w/w of microcrystalline cellu-
lose,
d) about 2% w/w of polyvinylpyrrolidone,
e) about 7% w/w of croscarmellose sodium,
f) about 1% w/w of sodium lauryl sulfate,
g) about 0.5% w/w of colloidal silicon diox-
ide, and
h) about 0.5% w/w of magnesium stearate.
37. The solid tablet formation of claim 27 [which
recites a genus tablet formulation for ibrutinib in
an amount of about 70 mg to about 840 mg] consist-
ing essentially of
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PHARMACYCLICS LLC v. ALVOGEN, INC. 5
a) about 69% w/w to about 71% w/w of ib-
rutinib,
b) about 13% w/w to about 15% w/w of lac-
tose monohydrate,
c) about 2% w/w to about 5% w/w of micro-
crystalline cellulose,
d) about 1% w/w to about 3% w/w of polyvi-
nylpyrrolidone,
e) about 6% w/w to about 8% w/w of croscar-
mellose sodium,
f) about 1% w/w to about 4% w/w of sodium
lauryl sulfate,
g) about 0.4% w/w to about 0.6% w/w of col-
loidal silicon dioxide, and
h) about 0.4% w/w to about 0.6% w/w of
magnesium stearate.
’857 patent, claims 30, 37.
B
At trial, Alvogen stipulated that it infringed the as-
serted claims of the ’309, ’090, and ’455 patents, and the
district court found that Alvogen infringed the asserted
claims of the ’857 patent. Pharmacyclics LLC v. Alvogen
Pine Brook LLC,
556 F. Supp. 3d 377, 385–86 (D. Del.
2021). Alvogen alleged that each of the asserted claims is
invalid, based on various theories. The district court re-
jected each of those theories and held that none of the
claims had been proved invalid by clear and convincing ev-
idence. See
id. at 424.
1
Alvogen argued that claim 10 of the ’309 patent (the
compound claim) was anticipated by an article referred to
as “Pan.” The parties did not dispute that the Pan article
describes ibrutinib, but Pharmacyclics argued that the in-
vention of claim 10 of the ’309 patent pre-dated the publi-
cation of Pan.
Id. at 390.
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6 PHARMACYCLICS LLC v. ALVOGEN, INC.
The Pan article was published on December 12, 2006,
and the application for the ’309 patent was filed on Decem-
ber 28, 2006.
Id. However, Pharmacyclics argued that the
date of invention of claim 10 was the date that one of two
provisional patent applications was filed: either September
22, 2006, or October 6, 2006. 2
Id. Alvogen argued that the
provisional applications did not establish priority because
they did not satisfy the written description and enablement
requirements of
35 U.S.C. § 112 with respect to the ibru-
tinib compound.
Id. at 390–91. Therefore, Alvogen argued,
the Pan article anticipated claim 10 of the ’309 patent.
Id.
The provisional applications disclosed ibrutinib and
noted that the synthesis of ibrutinib “was accomplished us-
ing a procedure analogous to that described for” another
compound, referred to as “[C]ompound 4.” See J.A. 18001–
02. The procedure described for Compound 4 begins with
another compound, “[I]ntermediate 2.” J.A. 16611, 18001.
Alvogen argued that because the provisional applications
did not disclose how to synthesize Intermediate 2, Com-
pound 4 (and, by extension, ibrutinib) had not been ena-
bled. Pharmacyclics, 556 F. Supp. 3d at 393.
The district court found that “the disclosure of the
structure of Intermediate 2 in the Compound 4 Scheme
would have enabled a skilled artisan to synthesize Inter-
mediate 2.” Id. at 394. The court based that finding on two
considerations. First, the court observed that “[t]he provi-
sional applications have a bracketed citation to the World
Intellectual Property Organization patent WO 2001019829
[“WO ’829”] immediately after they mention Intermediate
2.” Id. at 393. The court found that “[a]n artisan of ordi-
nary skill would have understood that the inventors cited
[WO ’829] to explain how to synthesize Intermediate 2.” Id.
2 Those applications are U.S. Provisional Patent Ap-
plication Nos. 60/826,720 and 60/828,590.
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PHARMACYCLICS LLC v. ALVOGEN, INC. 7
Second, and in the alternative, the district court found
that “an artisan of ordinary skill could also have synthe-
sized Intermediate 2 without the teachings of [WO ’829]
based on the structure of Intermediate 2 disclosed in the
diagram of the Compound 4 Scheme.” Id. In so finding,
the court relied on testimony from Pharmacyclics’ expert,
Dr. Paul Reider, who testified that “his undergraduate stu-
dents—whose abilities would fall below that of [an artisan
of ordinary skill]—would have been able to synthesize In-
termediate 2 . . . by working backwards from its structure
to known starting compounds.” Id. at 393–94.
Based on those findings, the district court concluded
that the provisional applications contained adequate writ-
ten description support for and sufficiently enabled claim
10 of the ’309 patent. Id. at 398. Accordingly, the court
concluded that claim 10 of the ’309 patent was entitled to
an invention date of September 22, 2006, and was not an-
ticipated by the Pan article. Id.
2
Alvogen argued that claim 2 of the ’090 patent (the
method-of-treatment claim) was not adequately described
or enabled, was obvious in view of four prior art references,
and was invalid for obviousness-type double patenting. Id.
at 398.
As for written description, the district court found that
“ibrutinib is the only BTK inhibitor identified by name in
the Summary of the Invention and is the only BTK [inhib-
itor] identified for the treatment of R/R MCL.” Id. at 401.
For those reasons, the court found that a skilled artisan
would have recognized ibrutinib as “the inventor’s pre-
ferred BTK inhibitor for treating R/R MCL.” Id. The court
then referred to “Example 13” in the written description,
which discloses a protocol for a Phase II clinical trial in-
volving the use of BTK inhibitors at a dose of 560 mg per
day to treat R/R MCL. Id. (citing ’090 patent, col. 141, line
58, through col. 142, line 27). The court found that
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8 PHARMACYCLICS LLC v. ALVOGEN, INC.
“[a]lthough Example 13 does not explicitly identify a spe-
cific BTK inhibitor to use,” a skilled artisan “would under-
stand to use the inventor’s preferred BTK inhibitor (i.e.,
ibrutinib) in the Phase II protocol described in Example
13.” Id. The court therefore concluded that Alvogen had
not shown that claim 2 of the ’090 patent was not ade-
quately described. Id. at 407.
Alvogen’s arguments on enablement largely mirrored
its arguments on written description. The district court
concluded that claim 2 had been enabled because “an arti-
san of ordinary skill would be able to follow the protocol of
Example 13 using ibrutinib and thus practice the method
described in claim 2.” Id. at 406.
On the issue of obviousness, Alvogen proposed a com-
bination of four prior art references: U.S. Patent Publica-
tion No. 2008/0076921 (“the ’921 publication”);
U.S. Patent
No. 8,952,015 (“the ’015 patent”); an article referred to as
“Pollyea”; and a December 2009 press release.
Id. at 401–
02. Alvogen also sought to rely on another reference, “Ad-
vani,” but the district court determined that Advani could
not be considered part of Alvogen’s obviousness combina-
tion and would instead be treated as background art.
Id.
at 402–03 n.7.
The ’015 patent discloses ibrutinib by its chemical
name, and it also discloses dozens of other compounds ei-
ther by name or by structure. 3 ’015 patent, col. 4, ll. 1–26;
id. at col. 36, line 30 through col. 51, line 37. The written
description of the ’015 patent discloses a general dose range
of “0.02–5000 mg per day” or “about 1–1500 mg per day” to
3 As the district court observed, the ’921 publication
and the ’015 patent “share essentially the same written de-
scription and differ only in their claims.” Pharmacyclics,
556 F. Supp. 3d at 401. Allusions to the ’015 patent in this
opinion therefore apply to both references.
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PHARMACYCLICS LLC v. ALVOGEN, INC. 9
treat a variety of conditions. Id. at col. 84, ll. 31–34. It
adds that a “therapeutically effective amount[] may be de-
termined by routine experimentation, including but not
limited to a dose escalation clinical trial.” Id. at col. 21, ll.
49–52. The ’015 patent, however, does not specifically dis-
close using ibrutinib to treat R/R MCL. Pharmacyclics, 556
F. Supp. 3d at 401.
The Pollyea article reported the interim results of a
Phase I dose escalation study of ibrutinib. The article dis-
closed dosing based on the patient’s weight rather than us-
ing a fixed dose of about 560 mg per day. J.A. 16671. It
further disclosed that none of the seven patients involved
in the trial had exhibited complete or partial responses to
treatment. See J.A. 16672. The December 2009 press re-
lease disclosed subsequent interim results for the Pollyea
study and reported that two patients who suffered from
had R/R MCL exhibited a partial response to the treat-
ment. See J.A. 15041, 16451.
The district court found that a skilled artisan would not
have been motivated to combine Alvogen’s references to
treat R/R MCL with a once-daily dose of about 560 mg of
ibrutinib, for three reasons. First, the district court found
that a skilled artisan would not have interpreted the re-
sults of the study disclosed in Pollyea “as showing that ib-
rutinib could be used as a treatment for R/R MCL,” given
the “unpredictable nature of oncology” and that only two
R/R MCL patients in the study had exhibited any response
to the treatment. Pharmacyclics, 556 F. Supp. 3d at 403.
Second, the court found that none of the references, alone
or in combination, would have motivated a skilled artisan
to use a once-daily dose of about 560 mg. Id. That was
because “[t]he only references that mention R/R
MCL . . . disclose a weight-based dosing regimen,” and the
evidence did not suggest that conventional methods of de-
termining an effective dose “would lead to a dose of about
560 mg.” Id. Third, the court found that “safety concerns
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10 PHARMACYCLICS LLC v. ALVOGEN, INC.
about ibrutinib would have discouraged an artisan of ordi-
nary skill from treating R/R MCL with ibrutinib.” Id.
For similar reasons, the district court found that a
skilled artisan would not have had a reasonable expecta-
tion of success in treating R/R MCL with a daily dose of
about 560 mg of ibrutinib. Id. at 404. The court also found
that six secondary considerations favored nonobviousness:
a long-felt but unmet need, the failure of others, skepti-
cism, unexpected results, praise, and commercial success.
Id. at 404–06. The court therefore concluded that claim 2
of the ’090 patent would not have been obvious because of
the lack of a motivation to combine the references, the lack
of a reasonable expectation of success, and the secondary
considerations of nonobviousness. Id. at 407.
On the issue of obviousness-type double patenting, Al-
vogen argued that it was entitled to a presumption of obvi-
ousness because claim 20 of the ’015 patent recites the
administration of a “therapeutically effective amount” of
ibrutinib, which the specification of that patent identified
as falling within the range of 1 mg to 1500 mg. Id. at 407.
The dosage recited in claim 2 of the ’090 patent, about 560
mg, would fall within that range. Id.
The district court rejected Alvogen’s presumption-of-
obviousness argument for four reasons. First, the court
noted that there were other differences, besides the dosage
amount, between claim 20 of the ’015 patent and claim 2 of
the ’090 patent. Id. at 408 (citing Tris Pharma, Inc. v. Ac-
tavis Labs. FL, Inc.,
503 F. Supp. 3d 183, 203 (D. Del.
2020)). Second, the court pointed out that the breadth of
the ranges in the written description of the ’015 patent
weighed against applying the presumption of obviousness.
Id. Third, the court restated its earlier finding that “rou-
tine experimentation would not have resulted in a dose
amount of 560 mg.”
Id. at 409. And fourth, the court found
that the evidence presented by Pharmacyclics at trial
“would have rebutted any presumption of obviousness.”
Id.
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PHARMACYCLICS LLC v. ALVOGEN, INC. 11
3
Alvogen argued that claim 5 of the ’455 patent (the
crystalline form claim) was inherently anticipated by the
clinical study disclosed in the Pollyea article and another
reference, “Fowler,” which disclosed updated results for the
same study.
Id. at 413. Alvogen also argued that the claim
was obvious in view of a combination of four references.
Id.
at 412.
The written description of the ’455 patent indicates
that ibrutinib exists in multiple crystalline forms and in an
amorphous form. ’455 patent, col. 10, ll. 17–50. Claim 5 of
the ’455 patent recites one of those forms, “Form A,” which
is “the most stable form of ibrutinib currently known.”
Pharmacyclics, 556 F. Supp. 3d at 410.
On the issue of inherent anticipation, the study dis-
closed in the Pollyea and Fowler references used a BTK in-
hibitor known as PCI-32765. J.A. 16466, 16671. The
district court found that PCI-32765 refers to ibrutinib gen-
erally, and not to any specific form of ibrutinib. Pharma-
cyclics, 556 F. Supp. 3d at 410. But the evidence presented
at trial showed that every lot of PCI-32765 used in the
study was Form A of ibrutinib. See Appellants’ Br. 34–35.
The district court concluded that Alvogen had not
proved that the study disclosed in Pollyea and Fowler
“could only be conducted with crystalline Form A of ibru-
tinib.” Pharmacyclics, 556 F. Supp. 3d at 414. The court
added that “a skilled artisan, reviewing Pollyea or Fowler,
would not have necessarily recognized that Pollyea’s or
Fowler’s authors used crystalline Form A for their reported
clinical study.” Id. (citing Endo Pharms. Sols., Inc. v. Cus-
topharm Inc.,
894 F.3d 1374, 1382 (Fed. Cir. 2018))
(cleaned up). Accordingly, the court determined that claim
5 of the ’455 patent was not inherently anticipated by the
study disclosed in Pollyea and Fowler. See
id.
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12 PHARMACYCLICS LLC v. ALVOGEN, INC.
On the issue of obviousness, Alvogen argued that claim
5 of the ’455 patent would have been obvious in view of the
following four references: an article referred to as “Ho-
nigberg”;
U.S. Patent No. 7,514,444 (“the ’444 patent”); and
two general references addressing polymorphism, “Miller”
and “Bauer.” 4
Id. at 410–11.
The Honigberg reference discloses the chemical struc-
ture of ibrutinib and notes that ibrutinib had “shown prom-
ising clinical activity” as a “potent, selective and
irreversible [BTK] inhibitor.” J.A. 16472. Similarly, the
’444 patent discloses the chemical name and structure of
ibrutinib, along with other compounds, as well as a method
for synthesizing ibrutinib. ’444 patent, col. 4, ll. 4–6;
id. at
col. 97, ll. 1–35. The patent further states that the dis-
closed compounds “may be in various forms,” including
crystalline forms, but does not assert that any crystalline
forms of ibrutinib actually exist.
Id. at col. 60, ll. 38–49.
The Miller and Bauer references are general references
on polymorphism. Neither mentions ibrutinib or teaches
how to make a crystalline form of ibrutinib. See generally
J.A. 17837–93 (Miller); J.A. 17401–09 (Bauer). Miller
“gives a general introduction to crystal forms, crystal sta-
bility, crystallization, and polymorph screening.” Pharma-
cyclics, 556 F. Supp. 3d at 411. Bauer teaches that
“crystalline solids are usually highly stable” but that the
polymorphs of a particular drug that will form under cer-
tain conditions “cannot be predicted.” Id. (citing J.A.
17402).
The district court found that a skilled artisan “would
have been motivated to develop a crystalline form of
4 “Polymorphism” refers to a compound having more
than one crystalline form. Pharmacyclics, 556 F. Supp. 3d
at 409. The crystalline forms of such a compound are re-
ferred to as “polymorphs.” Id.
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PHARMACYCLICS LLC v. ALVOGEN, INC. 13
ibrutinib” based on the four references identified by Al-
vogen, but that none of those references “would have moti-
vated an artisan to develop a crystalline form of ibrutinib
with the claimed 2-Theta peaks,” i.e., Form A. Id. at 412.
That was because none of the references disclosed such a
crystalline form or “suggested that [Form A] would be more
desirable than any other crystalline form.” Id.
The district court similarly found that a skilled artisan
“could not reasonably have expected to make a crystalline
form of ibrutinib with the six claimed 2-Theta peaks.” Id.
The court based that finding on the fact that “discovering
new crystalline forms is challenging and unpredictable,”
and that the prior art did not teach which of “numerous
variables in the crystallization process” would have been
“key to crystallizing ibrutinib.” Id. The court also found
that two secondary considerations weighed in favor of non-
obviousness: unexpected benefits and copying. Id. at 412–
13.
In view of its findings regarding the motivation to com-
bine, the reasonable expectation of success, and the second-
ary considerations, the court concluded that claim 5 of the
’455 patent would not have been obvious. Id. at 414.
4
Alvogen argued that claims 30 and 37 of the ’857 patent
(the tablet formulation claims) were invalid for lack of ad-
equate written description and obviousness. Id.
The district court observed that the written description
of the ’857 patent “recites verbatim the formulations
claimed in claims 30 and 37.” Id. at 415 (citing ’857 patent,
col. 43, line 47 through col. 44, line 6). Second, the court
noted that the specification discloses an ibrutinib tablet
formulation, BK21A, which satisfies the limitations of
claims 30 and 37. Id. at 416 (citing ’857 patent at Table
1F). Third, the court noted that the specification describes
experiments conducted using the BK21A formulation at
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14 PHARMACYCLICS LLC v. ALVOGEN, INC.
doses of 140 mg and 560 mg. Id. (citing ’857 patent at Ta-
bles 7, 8). In view of those disclosures, the court found that
a skilled artisan could have scaled the formulations dis-
closed in the ’857 patent “to make a tablet with the full
range of claimed ibrutinib amounts.” Id. Accordingly, the
court concluded that claims 30 and 37 were not invalid for
lack of adequate written description. Id. at 424.
On the issue of obviousness, the district court con-
cluded that claims 30 and 37 would not have been obvious
in view of Alvogen’s proposed combination of references.
Id. at 423–24. That ruling is not at issue in this appeal.
II
Alvogen challenges several of the district court’s deter-
minations. First, Alvogen argues that the court erred in
rejecting Alvogen’s written description and obviousness
challenges to claim 2 of the ’090 patent. Second, Alvogen
argues that the court erred in concluding that claim 5 of
the ’455 patent was neither inherently anticipated nor ob-
vious. Third, Alvogen argues that the court erred in reject-
ing Alvogen’s written description challenges to claims 30
and 37 of the ’857 patent. Fourth, Alvogen argues that the
court erred in concluding that claim 10 of the ’309 patent
was not anticipated by the Pan reference. We reject each
of Alvogen’s arguments.
On appeal from a bench trial, we review the district
court’s legal conclusions de novo and the district court’s fac-
tual findings for clear error. UCB, Inc. v. Watson Lab’ys
Inc.,
927 F.3d 1272, 1286 (Fed. Cir. 2019). The clear error
standard requires courts to affirm the finding below unless
we have a “definite and firm conviction that a mistake has
been made.” Biogen Int’l GMBH v. Mylan Pharms. Inc.,
18
F.4th 1333, 1341 (Fed. Cir. 2021) (citation omitted). Antic-
ipation and written description are issues of fact. Id.; UCB,
927 F.3d at 1286. We review the legal conclusion of obvi-
ousness de novo and any underlying factual findings for
clear error. UCB, 927 F.3d at 1286.
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PHARMACYCLICS LLC v. ALVOGEN, INC. 15
A
Alvogen first argues that the district court erred in de-
termining that claim 2 of the ’090 patent contained ade-
quate written description support, was enabled, and would
not have been obvious.
1
The specification of the ’090 patent discloses two clini-
cal trial protocols relating to treating R/R MCL with a BTK
inhibitor. One protocol, “Example 7,” discloses treating
R/R MCL using a genus of BTK inhibitors dosed based on
a patient’s weight. ’090 patent, col. 133, ll. 42–55. The
other, “Example 13,” discloses treating R/R MCL using a
broader genus of BTK inhibitors at a dose of 560 mg per
day. Id. at col. 141, line 58 through col. 142, line 7. The
summary of the invention section of the ’090 patent further
discloses treating R/R MCL with ibrutinib. Id. at col. 4, ll.
59–67. Alvogen argues that the district court “cherry-
pick[ed]” those aspects of the specification in finding that
there was written description support for claim 2. Appel-
lants’ Br. 16.
The written description requirement is satisfied if the
specification conveys with reasonable clarity to those
skilled in the art that the inventor was in possession of the
claimed invention. Biogen, 18 F.4th at 1341–42. When a
specification discloses its subject matter in terms of a broad
genus, we have required that the specification “provide suf-
ficient ‘blaze marks’ to guide a reader through the forest of
disclosed possibilities” toward the claimed invention. No-
vozymes A/S v. DuPont Nutrition Biosciences APS,
723
F.3d 1336, 1346 (Fed. Cir. 2013) (quoting In re Ruschig,
379
F.2d 990, 994–95 (C.C.P.A. 1967)).
Alvogen argues that the specification of the ’090 patent
did not contain sufficient blaze marks, because a skilled ar-
tisan would not have understood ibrutinib to be the inven-
tor’s preferred BTK inhibitor. As the district court
Case: 21-2270 Document: 59 Page: 16 Filed: 11/15/2022
16 PHARMACYCLICS LLC v. ALVOGEN, INC.
observed, however, “ibrutinib is the only BTK inhibitor
identified by name in the Summary of the Invention and is
the only BTK [inhibitor] identified for the treatment of R/R
MCL” in the ’090 patent. Pharmacyclics, 556 F. Supp. 3d
at 401. In view of those disclosures, we hold that it was not
clearly erroneous for the district court to find that the ’090
patent demonstrated that ibrutinib was the inventor’s pre-
ferred BTK inhibitor.
Alvogen also argues that the protocol disclosed in Ex-
ample 13, which describes treating R/R MCL with a genus
of BTK inhibitors at a dose of 560 mg per day, does not de-
scribe the full claimed scope of “about 560 mg.” That argu-
ment is unpersuasive in view of the fact that the summary
of the invention explicitly discloses one possible dosage of
ibrutinib to be “about 560 mg/day.” ’090 patent, col. 5, ll.
8–11.
This case is unlike our recent decision in Biogen, in
which we upheld a district court’s ruling that a method-of-
treatment claim lacked adequate written description sup-
port. Biogen, 18 F.4th at 1342–45. In that case, the
claimed dosage of 480 mg was “listed only once in the entire
specification,” and it appeared “at the end of one range
among a series of ranges.” Id. at 1343. By contrast, the
dosage of “about 560 mg/day” recited in claim 2 of the ’090
patent is expressly recited by itself (rather than as part of
a range) in the specification, and a 560 mg daily dose ap-
pears again in the specification’s discussion of Example 13.
Moreover, our standard of review is significant; in Biogen,
we held that the district court did not clearly err when it
found that the claim lacked written description support. 18
F.4th at 1346. In this case, the court found the opposite:
that claim 2 was adequately described by the specification.
Viewing the written description of the ’090 patent in its
entirety, we hold that the district court did not clearly err
in finding that claim 2 of the ’090 was adequately sup-
ported by the written description.
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PHARMACYCLICS LLC v. ALVOGEN, INC. 17
2
Alvogen’s argument on the issue of enablement is sim-
ilar to its argument on written description. Specifically,
Alvogen argues that the specification does not teach a
skilled artisan how to practice claim 2 without undue ex-
perimentation.
The crux of Alvogen’s argument is that Example 13 dis-
closes a dose of exactly 560 mg per day, rather than the full
claimed scope of “about” 560 mg per day. However, the
summary of the invention explicitly discloses a dose of
“about 560 mg/day.” ’090 patent, col. 5, ll. 8–11. With re-
spect to enablement, the district court concluded that a
skilled artisan “would be able to follow the protocol of Ex-
ample 13 using ibrutinib and thus practice the method de-
scribed in claim 2.” Pharmacyclics, 556 F. Supp. 3d at 406.
We discern no error in that conclusion.
3
As to the obviousness of claim 2 of the ’090 patent, Al-
vogen first challenges the district court’s finding that a
skilled artisan would not have been motivated to treat R/R
MCL with ibrutinib. Alvogen argues that “when claim 20
of the ’015 patent discloses treating MCL with ibrutinib,”
it necessarily discloses the treatment of R/R MCL. Appel-
lant’s Br. 23. That argument runs headlong into the dis-
trict court’s factual finding that “a disclosure of treating
MCL with a drug” would not be interpreted by a skilled ar-
tisan “as evidence that the drug would be effective at treat-
ing R/R MCL.” Pharmacyclics, 556 F. Supp. 3d at 403 n.8.
Alvogen also argues that the district court improperly
discounted the disclosure in the December 2009 press re-
lease that two R/R MCL patients had exhibited a partial
response to ibrutinib. But given the small sample size, we
are not persuaded that the district court clearly erred in
finding that a skilled artisan “would not interpret th[o]se
results as showing that ibrutinib could be used as a
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18 PHARMACYCLICS LLC v. ALVOGEN, INC.
treatment for R/R MCL,” particularly in view of the fact
that “less than five percent of oncology drugs that enter a
Phase I trial ultimately receive FDA approval.” Id. at 403. 5
Alvogen also argues that the district court failed to
properly account for the admission in the ’015 patent that
a “therapeutically effective amount” of ibrutinib could be
determined using “routine experimentation.” See ’015 pa-
tent, col. 21, ll. 49–52. The district court found, however,
that a “typical 3+3 dose escalation study . . . would have
reached the [maximum tolerated dose] as the dosage,”
which for ibrutinib is “above 560 mg.” Pharmacyclics, 556
F. Supp. 3d at 403. The district court further found that
“[t]o reach the claimed dose of about 560 mg, an artisan
would need to conduct a study using pharmacodynamic
endpoints,” which Alvogen’s combination of references did
not disclose. Id. Although Alvogen suggests that “other
routine methods could achieve the same claimed dose,” it
offers no evidence of what such a routine method would be.
See Appellants’ Br. 28. We discern no error in the district
court’s findings on that issue, and we therefore hold that
the district court did not clearly err in determining that the
prior art would not have motivated a skilled artisan to use
a dose of about 560 mg per day.
5 Relatedly, Alvogen argues that the district court
erred by failing to require a demonstration of efficacy for
purposes of written description and enablement but “im-
posing an efficacy requirement for obviousness.” Appel-
lants’ Br. 27. The court imposed no such requirement for
obviousness. Alvogen argued to the district court that a
skilled artisan would be motivated to combine Pollyea and
the press release with the ’015 patent because the data
from the Pollyea study “show[ed] that ibrutinib is effica-
cious in treating R/R MCL.” J.A. 12350. The court merely
rejected that argument, and it did not err in doing so.
Case: 21-2270 Document: 59 Page: 19 Filed: 11/15/2022
PHARMACYCLICS LLC v. ALVOGEN, INC. 19
Further as to the motivation to combine, Alvogen ar-
gues that the district court erred in relying on the testi-
mony of Dr. Reider regarding safety concerns involving
ibrutinib. According to Alvogen, Dr. Reider’s testimony fo-
cuses on safety concerns as of 2006, whereas the obvious-
ness of claim 2 should be measured from 2010. Alvogen
ignores that the district court also relied on testimony from
another expert, Dr. Simon Rule, in finding that “[a]n arti-
san of ordinary skill would not have considered irreversible
BTK inhibitors or molecules with a Michael acceptor
[which were considered to be dangerous] to be promising
drug classes in June 2010.” Id. at 399 (citing J.A. 15002,
15050). Alvogen’s only evidence that a skilled artisan
would have considered ibrutinib to be safe as of 2010 is the
set of references relating to the clinical trial described in
Pollyea. See Appellants’ Br. 28–29. We do not find that
those references demonstrate that the district court clearly
erred in finding that safety concerns weighed against a mo-
tivation to combine.
Alvogen next argues that the district court erred in not
applying the presumption of obviousness that Alvogen ar-
gues was created by claim 20 of the ’015 patent. We reject
that argument for two reasons.
First, a presumption of obviousness may be invoked
“when the only difference from the prior art is a difference
in the range or value of a particular variable.” In re Kumar,
418 F.3d 1361, 1366 (Fed. Cir. 2005). In this case, however,
there are additional differences between the prior art and
claim 2 of the ’090 patent. For example, the district court
found that the prior art did not disclose that ibrutinib was
effective at treating R/R MCL in particular. Pharmacy-
clics, 556 F. Supp. 3d at 403 & n.8. That finding was not
clearly erroneous.
Second, the district court found that Pharmacyclics
nevertheless “would have rebutted any presumption of
Case: 21-2270 Document: 59 Page: 20 Filed: 11/15/2022
20 PHARMACYCLICS LLC v. ALVOGEN, INC.
obviousness.” Id. at 409. Alvogen has not persuaded us
that the court clearly erred in making that finding.
Regarding the secondary considerations cited by the
district court, we need not reach that issue because the
court’s findings regarding the motivation to combine and
reasonable expectation of success are “fatal to Alvogen’s ob-
viousness theory.” Id. at 407. We hold that the court did
not err in concluding that claim 2 of the ’090 patent would
not have been obvious, and we therefore affirm the court’s
judgment with respect to that claim.
B
Alvogen next argues that the district court erred in de-
termining that claim 5 of the ’455 patent was not inher-
ently anticipated and would not have been obvious.
1
In Alvogen’s view, the fact that Form A was the only
form of ibrutinib actually used in the clinical study dis-
closed in Pollyea and Fowler was sufficient to inherently
anticipate claim 5 of the ’455 patent, even if another form
of ibrutinib could have been used in the clinical study.
In support of its argument, Alvogen relies upon our de-
cision in Abbott Laboratories v. Geneva Pharmaceuticals,
Inc.,
182 F.3d 1315 (Fed. Cir. 1999). In that case, we held
that the sale of a compound, which was later determined to
be in the same form as that recited in the asserted claim,
triggered the on-sale bar even though “at the time of the
sales, the parties to the . . . transactions did not know the
identity of the particular crystalline form with which they
were dealing.”
Id. at 1317–18. As the Abbott court noted,
however, the key question with respect to the on-sale bar
is what the product that was sold actually embodied. See
id. at 1319. Once it became clear that the sold product con-
tained the same components that were listed in the claims,
that was enough to support a finding of invalidity. See
id.
When determining whether a claim is inherently
Case: 21-2270 Document: 59 Page: 21 Filed: 11/15/2022
PHARMACYCLICS LLC v. ALVOGEN, INC. 21
anticipated by a prior art publication, however, the ques-
tion is different: The question is what is “necessarily” in-
herent in the anticipating reference. Schering Corp. v.
Geneva Pharms.,
339 F.3d 1373, 1377 (Fed. Cir. 2003).
Our decision in Endo Pharmaceuticals, a case on which
the district court relied, is closely analogous to this case.
In Endo, the defendant relied on prior art publications that
reported on a clinical study for testosterone therapy deliv-
ered by injection. Endo, 894 F.3d at 1376. The claim at
issue required a specific “vehicle formulation” for the injec-
tion, and it was later revealed that the vehicle formulation
used in the clinical study was the same as that recited in
the claim. Id. at 1381. The Endo court noted that there
was no evidence “that only one vehicle formulation—the
claimed vehicle formulation” could be used to achieve the
results of the clinical study disclosed in the publications.
The court therefore found no error in the trial court’s find-
ing that the claimed vehicle formulation was not inherent
in the prior art. Id. at 1381–83.
In this case, the district court likewise found no evi-
dence that only Form A could have been used to achieve the
results of the clinical study disclosed in Pollyea and Fowler.
To the contrary, the court found that “a Phase I dose esca-
lation study could be performed with amorphous ibrutinib
or one of its metastable polymorphs,” and therefore that
“Form A was not necessarily present in Pollyea or Fowler.”
Pharmacyclics, 556 F. Supp. at 414. The court’s findings
on that score were not clearly erroneous, and in light of
Endo, those findings dictate rejection of Alvogen’s inherent
anticipation argument.
2
On the issue of obviousness, the district court found
that a skilled artisan would not have been motivated to
combine Honigberg, the ’444 patent, Miller, and Bauer to
make Form A of ibrutinib, and would not have had a rea-
sonable expectation of success in doing so. Alvogen
Case: 21-2270 Document: 59 Page: 22 Filed: 11/15/2022
22 PHARMACYCLICS LLC v. ALVOGEN, INC.
challenges those findings as well as the court’s findings re-
garding the secondary considerations of nonobviousness.
Neither party disputes the district court’s finding that
“an artisan of ordinary skill would have been motivated to
develop a crystalline form of ibrutinib.” See id. at 412. Al-
vogen argues, however, that the court should have found
that a skilled artisan would have been motivated to develop
the most stable form of ibrutinib, which is now known to be
Form A, and that the skilled artisan would have had a rea-
sonable expectation of successfully developing Form A.
In support of those arguments, Alvogen cites the expert
opinion of Dr. Jennifer Swift, who testified that a skilled
artisan would have inevitably developed Form A upon per-
forming a routine polymorph screen. J.A. 14166. Alvogen
adds that the Miller reference “demonstrates that a [skilled
artisan] would have designed a routine polymorph screen
to discover the most stable form as soon as possible in the
screen.” Appellants’ Br. 44 (citing J.A. 17862).
Relying on contrary testimony, the district court found
that “[d]iscovering new crystalline forms is challenging and
unpredictable.” Pharmacyclics, 556 F. Supp. 3d at 410.
For example, Dr. Allan Myerson, Pharmacyclics’ expert,
testified that a skilled artisan would not “have been able to
predict in advance whether a new compound would form
polymorphs,” and that polymorphs can be discovered out-
side the context of a polymorph screen. J.A. 15326–27. Dr.
Myerson added that “we also can’t predict in advance the
physical properties that a crystalline form will have.” J.A.
15418. Dr. John Steed, the expert for one of Alvogen’s co-
defendants, testified similarly. See J.A. 14325–28. In view
of the testimony of Drs. Myerson and Steed, the district
court’s finding of no reasonable expectation of success can-
not be deemed clearly erroneous.
We disagree with Alvogen’s contention that the district
court’s findings required a skilled artisan to “predict[]”
what conditions would result in the production of Form A
Case: 21-2270 Document: 59 Page: 23 Filed: 11/15/2022
PHARMACYCLICS LLC v. ALVOGEN, INC. 23
of ibrutinib. Appellants’ Br. 47. Rather, the court found
that, given the lack of teaching in the art regarding crys-
talline forms of ibrutinib and the expert testimony that pol-
ymorph screening can produce unpredictable results, a
skilled artisan would not have reasonably expected success
in producing Form A of ibrutinib. That finding was not
clearly erroneous. See Grunenthal GMBH v. Alkem Lab’ys
Ltd.,
919 F.3d 1333, 1344 (Fed. Cir. 2019) (upholding a dis-
trict court’s finding that a skilled artisan would not have
expected success in producing a particular crystalline form
of a compound when a skilled artisan would not have had
“reason to know[] how the multiple variables involved in
conducting a polymorph screen would affect the recrystal-
lization” of the compound).
Because we hold that the district court did not err in
finding that a skilled artisan would not have been moti-
vated to combine the prior art to create Form A and would
not have had a reasonable expectation of success in doing
so, we need not reach Alvogen’s arguments regarding the
secondary considerations of nonobviousness. We affirm the
district court’s determination that claim 5 of the ’455 pa-
tent is neither inherently anticipated nor obvious.
C
Alvogen next argues that the district court erred in
finding that claims 30 and 37 of the ’857 patent were ade-
quately supported by the written description.
Alvogen points to BK21A, a formulation that is dis-
closed in the specification and that embodiesis one species
of the ranges recited in claims 30 and 37. See ’857 patent,
col. 89, ll. 43–54. Alvogen argues that possession of that
one species is not sufficient to demonstrate possession of
the broader ranges recited in claims 30 and 37.
The problem for Alvogen, however, is that the precise
ranges recited in the claims are found in formulations dis-
closed in the specification.
Id. at col. 43, line 64, through
Case: 21-2270 Document: 59 Page: 24 Filed: 11/15/2022
24 PHARMACYCLICS LLC v. ALVOGEN, INC.
col. 44, line 6 (claim 30);
id. at col. 43, ll. 47–63 (claim 37).
The specification also discloses that the dosage of ibrutinib
can range from “about 35 mg to about 840 mg per tablet.”
Id. at col. 45, ll. 32–34. Because the written description
describes the ingredient amounts “by their respective
weight concentrations,” and because the written descrip-
tion describes experiments conducted using BK21A at two
different doses of ibrutinib, the district court found that the
written description “would have conveyed to [a skilled ar-
tisan] that the inventor had possession of the claimed sub-
ject matter.” Pharmacyclics, 556 F. Supp. 3d at 416. That
finding is not clearly erroneous, and we therefore affirm
the district court’s judgment with respect to claims 30 and
37 of the ’857 patent. 6
D
Alvogen’s final challenge is to the district court’s find-
ing that the Pan reference did not anticipate claim 10 of
the ’309 patent. Alvogen argues that a skilled artisan could
not have synthesized Intermediate 2 without undue exper-
imentation, and that the court failed to apply the proper
legal standard for incorporation of a document by refer-
ence.
On the first point, Alvogen argues that it was error for
the district court to rely upon the testimony of Dr. Reider
in finding that the provisional applications enabled
6 We reject Alvogen’s argument that the district
court “read into the specification [the] supposed knowledge
of a [skilled artisan]” that the amounts disclosed with re-
spect to BK21A could be scaled. Appellants’ Br. 55. The
use of weight concentrations in describing BK21A and in
claims 30 and 37, along with the use of two different doses
of the BK21A tablet, are sufficient to convey that the tablet
formulation can be scaled without importing any extrane-
ous knowledge of a skilled artisan.
Case: 21-2270 Document: 59 Page: 25 Filed: 11/15/2022
PHARMACYCLICS LLC v. ALVOGEN, INC. 25
Intermediate 2. Specifically, Alvogen argues that Dr.
Reider’s testimony that his undergraduate students could
synthesize intermediate 2 did not establish that they could
do so “without undue experimentation.” Appellants’ Br.
60–62. Alvogen also points to our holding in Genentech,
Inc. v. Novo Nordisk A/S that “the specification, not the
knowledge of one skilled in the art, . . . must supply the
novel aspects of an invention in order to constitute ade-
quate enablement.”
108 F.3d 1361, 1366 (Fed. Cir. 1997).
We hold that it was not error for the district court to
rely on the testimony of Dr. Reider. Although Dr. Reider
did not explicitly state that his students could have synthe-
sized ibrutinib without undue experimentation, his testi-
mony clearly conveyed that was the case. See J.A. 15108–
10. Moreover, it is clear that Intermediate 2 was not novel
because it was disclosed in the WO ’829 publication. Phar-
macyclics, 556 F. Supp. 3d at 398. The district court there-
fore did not run afoul of our holding in Genentech, because
Intermediate 2 was not a “novel aspect[]” of claim 10 of the
’309 patent. See Genentech,
108 F.3d at 1366.
On the second point, Alvogen argues that the district
court erred in determining that the provisional applica-
tions had incorporated the WO ’829 publication by refer-
ence. That argument is not dispositive, because the court
properly found that “a skilled artisan could have synthe-
sized Intermediate 2 and thus ibrutinib” without reference
to WO ’829. Pharmacyclics, 556 F. Supp. 3d at 397–98. In
any event, formal incorporation by reference is not neces-
sary if the material being incorporated is background art.
See, e.g., Falko-Gunter Falkner v. Inglis,
448 F.3d 1357,
1365 (Fed. Cir. 2006) (holding that information readily ac-
cessible in journals need not be incorporated by reference
in order to enable the patent claims at issue). Accordingly,
we find Alvogen’s argument as to incorporation by refer-
ence to be unpersuasive. We therefore affirm the district
court’s ruling that claim 10 of the ’309 patent is not antici-
pated by the Pan article.
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26 PHARMACYCLICS LLC v. ALVOGEN, INC.
*****
Finding no reversible error in any of the rulings of the
district court challenged on appeal, we uphold the judg-
ment of the district court.
AFFIRMED
