ANTECIP BIOVENTURES II LLC

Patent Trials and Appeals Board

Dec 22, 2020

PGR2018-00092 (P.T.A.B. Dec. 22, 2020)

Trials@uspto.gov Paper 31
Tel: 571-272-7822 Entered: December 22, 2020

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

GRÜNENTHAL GMBH,
Petitioner,

v.

ANTECIP BIOVENTURES II LLC,
Patent Owner.
____________

PGR2018-00092
Patent 9,820,999 B2
____________

Before GRACE KARAFFA OBERMANN, SHERIDAN K. SNEDDEN,
and CHRISTOPHER M. KAISER, Administrative Patent Judges.

SNEDDEN, Administrative Patent Judge.

JUDGMENT
Final Written Decision
Determining All Challenged Claims Unpatentable
35 U.S.C. § 328(a)

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I. INTRODUCTION
We issue this revised Final Written Decision after our decision to
grant Petitioner’s Request for Rehearing (Paper 29) and vacate our original
Final Written Decision (Paper 25).
This Final Written Decision is issued pursuant to 35 U.S.C. § 328(a)
and 37 C.F.R. § 42.73. Petitioner bears the burden of proving
unpatentability of the challenged claims, and that burden of persuasion never
shifts to Patent Owner. Dynamic Drinkware, LLC v. Nat’l Graphics, Inc.,
800 F.3d 1375, 1378 (Fed. Cir. 2015). The evidentiary standard is a
preponderance of the evidence. See 35 U.S.C. § 326(e) (2012); 37 C.F.R.
§ 42.1(d) (2018).
For the reasons that follow, we determine that Petitioner has
established by a preponderance of the evidence that claims 1–30 of U.S.
Patent No. 9,820,999 B2 (Ex. 1001, “the ’999 patent”) are unpatentable.
A. Procedural Background
Petitioner filed a Petition requesting inter partes review of claims 1–
30 (“the challenged claims”) of the ’999 patent. Paper 2 (“Pet.”). Patent
Owner did not file a Patent Owner Preliminary Response. Upon
consideration of the information presented in the Petition, we instituted an
inter partes review of claims 1–30 of the ’999 patent on each ground of
unpatentability set forth in the Petition. See infra Section I.E.
Subsequently, Patent Owner filed a Patent Owner Response
(Paper 10; “PO Resp.”), Petitioner filed a Reply (Paper 11; “Reply”), and
Patent Owner filed a Sur-Reply (Paper 18; “Sur-Reply”).
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The Petition is supported by the Declaration of Lawrence Poree,
M.D., Ph.D. Ex. 1003. In its Reply, Petitioner relies on the Declaration of
Dr. Philip Robinson, MBChB, PhD, FRACP (Ex. 1044).
Oral argument was conducted on November 21, 2019. A transcript is
entered as Paper 23 (“Tr.”).
Petitioner timely filed a Request for Rehearing (Paper 26, “Req.
Reh’g.”) requesting rehearing of our original Final Written Decision (Paper
25). We granted Petitioner’s request for rehearing and vacated our original
Final Written Decision. Paper 29.
In this revised, corrected Final Written Decision, we address all
arguments and evidence set forth in the Papers to the extent necessary to
resolve the dispute between the parties.
B. The ’999 Patent (Ex. 1001)
The ’999 patent is titled “Neridronic Acid for Treating Complex
Regional Pain Syndrome.” Ex. 1001, [54]. The specification of the ’999
patent describes “[o]steoclast inhibitors, such as neridronic acid, in an acid
or salt form” for treating or alleviating “pain or related conditions, such as
complex regional pain syndrome” (“CRPS”). Id., [57]. Two
bisphosphonates specifically discussed in the specification are zoledronic
acid and neridronic acid. See Ex. 1001, Figs. 1–16, 2:64–4:3 (figures and
descriptions of figures, all pertaining to a method that employs zoledronic
acid); see also id. at 2:50–60, 4:8 (identifying both zoledronic acid and
neridronic acid as useful for treating CRPS triggered by bone fracture).
The ’999 patent specification discusses a method of administering
bisphosphonates—and, in particular, zolendronic acid or neridronic acid—
for treating “bone fractures or to enhance the healing of bone fractures” in “a
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human being that is treated for CRPS, suffered from a precipitating injury
such as a bone fracture.” Id. at 8:27–37. The specification, moreover, states
that “[a]n oral dosage form of bisphosphonate such as zoledronic acid may
be used to treat, or provide relief of, any type of pain including, but not
limited to,” for example, CRPS. Id. at 7:43–52. The specification identifies
“bisphosphonate” compounds generally, and neridronic acid in particular, as
useful for mitigating “pain associated” with, for example, “vertebral crush
fractures” in a human being. Ex. 1001, 7:66–8:19, 8:64–67, 15:25–37, 91:5–
7 (Embodiment 282), 93:50–94:5–32 (Embodiments 314–318).
Example 3 relates to “[t]he effect of orally administered zoledronic
acid” in a “rat tibia fracture model of” CRPS. Id. at 51:28–30. Example 3
reports that zoledronic acid mitigates pain associated with CRPS, where that
condition is induced in “rats by fracturing the right distal tibias of the
animals.” Id. at 51:30–31. Example 3 discusses pain assessment methods
and pain reduction achieved in the rat tibia fracture model when zoledronic
acid is selected as the bisphosphonate. Id. at 51:47–52:11. In addition,
Example 3 explains that “[t]his animal model has been shown to replicate
the inciting trauma” (for example, a bone “fracture”) that is “observed in
human CRPS patients.” Id. at 51:33–38.
The ’999 patent includes no working example using neridronic acid as
the bisphosphonate. The general disclosure provides dosing information
pertaining to neridronic acid when that compound is selected for use in the
claimed method. See, e.g., id. at 26:30–43.
C. Illustrative Claim
Claim 1, the only independent challenged claim, is illustrative and
reproduced below:
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1. A method of treating pain associated with complex regional
pain syndrome (CRPS) comprising selecting a human being
having CRPS triggered by bone fracture and administering
neridronic acid or a pharmaceutically acceptable salt thereof to
the human being, wherein the treatment is effective in reducing
pain.
Ex. 1001, 106:25–30 (emphasis added).
The other challenged claims (namely, claims 2–30) depend directly or
indirectly from claim 1 and specify additional limitations that pertain to the
type of CRPS, the form of neridronic acid, the method of administration, the
age of the treated human being, baseline pain intensity, and dosing regimens.
See id. at 106:31–107:26.
D. Asserted Prior Art
The Petition identifies the following references as prior art in the
grounds of unpatentability:
(1) M. Varenna et al., Treatment of complex regional pain syndrome
type I with neridronate: a randomized, double-blind, placebo-controlled
study, RHEUMATOLOGY 52:534–42 (NOV. 2012) (Ex. 1005,
“Varenna 2012”);

(2) M. Varenna et al., Predictors of responsiveness to bisphosphonate
treatment in patients with complex regional pain syndrome type I: A
retrospective chart analysis, PAIN MED. 18:1131–38 (2017) (Ex. 1015,
“Varenna 2016”);

(3) Manara et al., SAT0524 Predictors of a Clinical Response to
Bisphosphonates Treatment in Patients with Complex Regional Pain
Syndrome Type I, ANNALS OF THE RHEUMATIC DISEASES, 73 (Suppl. 2)
(2014) (Ex. 1037, “Manara”);

(4) S. Bruehl, “How common is complex regional pain syndrome-
Type I?,” PAIN 129:1–2 (2007) (Ex. 1006, “Bruehl”);

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(5) D. Gatti et al., Neridronic acid for the treatment of bone
metabolic diseases, EXPERT OP. ON DRUG METABOLISM & TOXICOLOGY
5(10): 1305–11 (Sept. 2009) (Ex. 1007, “Gatti”);

(6) G. La Montagna et al., Successful neridronate therapy in transient
osteoporosis of the hip, CLIN. RHEUMATOL. 24: 67–69 (Aug. 2004) (Ex.
1008, “La Montagna”);

(7) D. Manicourt et al., Role of alendronate in therapy for
posttraumatic complex regional pain syndrome type I of the lower extremity,
ARTHRITIS & RHEUMATISM 50(11): 3690–97 (Nov. 2004) (Ex. 1009,
“Manicourt”);

(8) M. Muratore et al., Il neridronato nel trattamento
dell’algodistrofia simpatica riflessa dell’anca: confronto in aperto con il
clodronato, PROGRESSI IN RHEUMATOLOGIA, ABSTRACT BOOK VII
CONGRESSO NAZIONALE COLLEGIO DEI REUMATOLOGI OSPEDALIERI 5
(Suppl. 1): 89 (April 16–18, 2004) (certified English translation) (Ex. 1010,
“Muratore”); and

(9) Schwarzer & Maier, Complex regional pain syndrome, in GUIDE
TO PAIN MANAGEMENT IN LOW-RESOURCE SETTINGS 249–254 (Kopf & Patel
eds. 2010) (Ex. 1020, “Schwarzer”).

E. Asserted Grounds of Unpatentability
We instituted review of claims 1–30 of the ’999 patent as follows.
Paper 7.
Claims 35 U.S.C. §1 Reference(s)/Basis
1–4, 9, 10, 12, 14, 16–
18, 23–25, 27–29 102(a) Varenna 2012

1 The Leahy-Smith America Invents Act (“AIA”), Pub. L. No. 112-29, 125
Stat. 284, 287–88 (2011), amended 35 U.S.C. §§ 102 and 103. Because the
’514 patent was filed before March 16, 2013 (the effective date of the
relevant amendment), the pre-AIA version of § 103 applies.
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Claims 35 U.S.C. §1 Reference(s)/Basis
1–4, 9, 10, 12, 14, 16–
18, 23–25, 27–28 102(a) Varenna 2016
1–4, 9, 10, 12, 14, 16–
18, 24–25, 27–28 102(a) Manara
1–4, 9–20, 22–29 103(a)
Varenna 2012, Varenna 2016,
Manara, Bruehl
Gatti, La Montagna,
Muratore
5–8, 21 103(a) Varenna 2012, Varenna 2016, Manara, and Manicourt
30 103(a)
Varenna 2012, Varenna 2016
Manara, Schwarzer, Bruehl,
Gatti, La Montagna, Muratore
1–30 112(a), Enablement

II. ANALYSIS
A. Level of Ordinary Skill in the Art
We consider the grounds of unpatentability in view of the
understanding of a person of ordinary skill in the art (“POSA”) at the time of
the invention. Petitioner argues that an ordinarily skilled artisan would have
had “an M.D. or a Ph.D. in a pain-medicine-relevant discipline, such as
clinical health psychology or neuroscience, and at least 3–5 years of
experience in the treatment of CRPS or related chronic pain conditions, or in
the study of CRPS or related types of chronic pain.” Pet. 13–14 (citing
Ex. 1003 ¶ 20).
Patent Owner disputes Petitioner’s definition for a person of ordinary
skill in the art. PO Resp. 2. Patent Owner contends that the “claims are
directed to methods of treating pain associated with CRPS using a
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medication, i.e. neridronic acid,” and as such, “a POSA would have an M.D.
or a Ph.D. in a discipline related to the interaction of drugs with a human
body, such as biology, pharmacology, etc., and experience in supervising,
carrying out, or collaborating in animal or human testing, including off-label
treatment of patients related to drug development in the pain area.” Id. at 2–
3.
Having considered the parties’ positions and evidence of record,
summarized above, we agree with Patent Owner that the claims are limited
to methods of treating pain associated with CRPS and agree that the
definition of a person of ordinary skill in the art should likewise include
those persons having the relevant education and sufficient clinical expertise
in treating patients with pain associated with CRPS. That said, we discern
no material differences between the parties’ respective definitions that would
alter the outcome of our decision based on our acceptance of one over the
other.
We further note that prior art may also demonstrate the level of skill
in the art at the time of the invention. See Okajima v. Bourdeau, 261 F.3d
1350, 1355 (Fed. Cir. 2001) (explaining that specific findings regarding
ordinary skill level are not required “where the prior art itself reflects an
appropriate level and a need for testimony is not shown”) (quoting Litton
Indus. Prods., Inc. v. Solid State Sys. Corp., 755 F.2d 158, 163 (Fed. Cir.
1985)).
B. Claim Construction
For petitions filed before November 13, 2018, we interpret the claims
of an unexpired patent that will not expire before issuance of a final written
decision using the broadest reasonable interpretation in light of the
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specification. See 37 C.F.R. § 42.100(b) (2018)2; Cuozzo Speed Techs., LLC
v. Lee, 136 S. Ct. 2131, 2144–46 (2016). Under the broadest reasonable
construction standard, claim terms are presumed to have their ordinary and
customary meaning, as would be understood by one of ordinary skill in the
art in the context of the entire disclosure. In re Translogic Tech., Inc.,
504 F.3d 1249, 1257 (Fed. Cir. 2007). Only terms that are in controversy
need to be construed, and then only to the extent necessary to resolve the
controversy. Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803
(Fed. Cir. 1999).
Petitioner proposes claim constructions for the claim terms set forth in
the table below. Pet. 14–18.
Term Claims Petitioner’s Proposed Construction
“A method of treating
pain associated with
complex regional pain
syndrome (CRPS)
comprising selecting a
human being having
CRPS”
1–30 Requires that neridronic acid be
administered to a human being having
CRPS for the purpose of diagnosing,
curing, mitigating, or preventing pain
associated with CRPS, or for activity
that otherwise affects the structure or
any function of the body in a human
being with CRPS.
“triggered by bone
fracture”
1–30 Synonymous with fracture as a
“precipitating event” or “predisposing
event,” i.e., a bone fracture causes or
contributes to the occurrence or onset of
CRPS.

2 An amendment to this rule does not apply here, because the Petition
was filed before November 13, 2018. See Changes to the Claim
Construction Standard for Interpreting Claims in Trial Proceedings Before
the Patent Trial and Appeal Board, 83 Fed. Reg. 51,340 (Oct. 11, 2018)
(amending 37 C.F.R. § 42.200(b) effective November 13, 2018) (now
codified at 37 C.F.R. § 42.100(b) (2019)).
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“wherein the treatment
is effective in
reducing pain”
1–30 The treatment actually results in an
observed and/or measured reduction in
pain in a patient.

We have considered Petitioner’s claim constructions and adopt
Petitioner’s undisputed construction for the terms “triggered by bone
fracture” and “wherein the treatment is effective in reducing pain.”
Petitioner’s construction of those terms aligns with the plain words of the
claim, finds support in the uncontroverted testimony of Dr. Poree, and is not
contested by Patent Owner. Pet. 14–15; Ex. 1003 ¶¶ 35–41; see PO
Resp. 3–4 (Patent Owner, nowhere opposing that construction).
Patent Owner disputes Petitioner’s construction for “[a] method of
treating pain associated with complex regional pain syndrome (CRPS)
comprising selecting a human being having CRPS” in claim 1 of the ’999
patent. PO Resp. 3–4. Patent Owner first notes that the term “comprising”
transitions from the preamble “[a] method of treating pain associated with
complex regional pain syndrome (CRPS)” to the body of the claim, which
begins with the verb “selecting.” Next, Patent Owner contends that the first
element in the body of the claims is “selecting a human being having CRPS
triggered by a bone fracture,” and that Petitioner’s proposed construction
reads the term “selecting” out of the claim. Id.
We agree with Patent Owner the term “selecting” appears in the body
of the claim and that “selecting a human being having CRPS triggered by
bone fracture” is a required element of the claims. To the extent further
discussion of the meaning of this term is necessary to our decision, we
provide that discussion below in our analysis of the asserted grounds of
unpatentability.
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We determine that no express construction of any other claim term is
necessary to determine whether Petitioner has shown by a preponderance of
the evidence that the claims are unpatentable in this case.
C. Effective Filing Date of the ’999 Patent
We next resolve the effective filing date of the ’999 patent. When
discussing the prior art status of Varenna 2012, Petitioner indicates that the
effective filing date of the ’999 patent is “May 14, 2013—the filing date of
U.S. Patent Application No. 13/894,274” (“the ’274 application”). Pet. 32;
see Ex. 1001, [63] (identifying the ’274 application as a priority document).
Elsewhere in the Petition, however, Petitioner repeatedly asserts that the
earliest possible effective filing date is December 7, 2016—that is, the filing
date of Provisional Application No. 62/431,287 (“the ’287 application”),
which is the third-filed of three provisional applications identified on the
face of the ’999 patent. Pet. 9, 11–12, 16, 20, 24 n.1, 45–46; see Ex. 1001,
[60] (claiming priority through three provisional applications, including the
’287 application). For reasons explained below, we find that the effective
filing date of the ’999 patent is May 14, 2013, the filing date of the ’274
application. See Ex. 1001, [63] (identifying chain of priority from May 14,
2013, the filing date of the ’274 application).
Petitioner acknowledges that the ’999 patent claims the benefit of
priority not only from the filing date of the ’274 application, but also from
the filing date of Provisional Application No. 61/646,538 (“the ’538
application”), which is the first-filed provisional application identified on the
face of the ’999 patent. Pet. 32; see Ex. 1001, [60] (identifying the ’538
application, filed May 14, 2012); see id. at [63] (claiming priority also
through the ’247 application, filed May 14, 2013). The ’538 application was
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filed on May 14, 2012. Petitioner argues that the disclosure of the ’538
application, however, does not support the challenged claims because that
application nowhere refers to the claim 1 limitation that requires “bone
fracture as a triggering event for CRPS.” Id.3
We find that Petitioner shows sufficiently that the disclosure of
the ’538 application does not support the claims of the ’999 patent. See
Pet. 20–24 (and evidence cited therein). Petitioner’s information on that
point is not challenged. On this record, we agree with Petitioner that
the ’538 application nowhere mentions any triggering events for CRPS and,
further, that a person of ordinary skill in the art “would not have understood
that administering neridronic acid to treat CRPS specifically triggered by
bone fracture was an aspect of the alleged invention.” Pet. 20; Ex. 1003 ¶ 45
(Dr. Poree’s assertion that “[t]he terms ‘bone,’ ‘fracture,’ and ‘triggered’ do
not appear anywhere in the [’538] application”), ¶ 46 (Dr. Poree’s further
assertion that “[n]othing in the ’538 application suggests that the patentee
was in possession of a method of treating pain associated with CRPS

3 Elsewhere in the Petition, Petitioner asserts that the ’999 patent claims are
not entitled to the benefit of the filing date of the second-filed Provisional
Application No. 62/378,140 (“the ’140 application”), which was filed on
August 22, 2016. Pet. 29. We agree with Petitioner that the ’140
application “does not even mention neridronic acid at all.” Id.; see generally
Ex. 1029, 9–35 (the ’140 application). We disagree with Petitioner’s further
contention, however, that the ’140 application does not support the
limitation that requires bone fracture as a triggering event for CRPS.
Pet. 46. In that regard, the ’140 application discloses “[t]he therapeutic
efficacy of bisphosphonate treatment in the rat CRPS fracture model”—
including data pertaining to a rat tibia fracture study, which demonstrates
“that bisphosphonate therapy inhibits pain . . . in the rat fracture model
of CRPS.” Ex. 1029, 9, 11, 23.
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triggered by bone fracture” or “that this was even an aspect of the alleged
invention”); see Ex. 1016, 4–6 (disclosure from the ’538 application,
nowhere mentioning bone fracture as a triggering event for CRPS).
Petitioner does not show adequately, however, that the ’999 patent is
not entitled to claim the benefit of the filing date of the ’274 application,
which was filed on May 14, 2013. Ex. 1001, [63] (the ’999 patent,
identifying the ‘274 application as a priority document); see, e.g., Pet. 9, 11–
12, 16, 20, 24 n.1, 45–46 (Petitioner, asserting that the earliest possible
effective priority date is December 7, 2016, but failing to account adequately
for the claim of priority that derives from the filing date of the ’274
application). On that point, Petitioner argues only that the ’274 application
contains no “additional information about how to treat CRPS with
neridronate other than the limited information in the ’999 patent
specification.” Pet. 29. Significantly, however, the ’274 application
identifies “neridronate or neridronic acid” as “another bisphosphonate” that
“may also be useful to treat complex regional pain syndrome” and “acute
vertebral crush fracture.” Ex. 1024 ¶¶ 23, 37, claim 79. The ’274
application expressly defines “[t]he term ‘treating’ or ‘treatment’” to
“broadly include any kind of treatment activity, including . . . mitigation or
prevention of disease in man . . . or any activity that otherwise affects the
structure or any function of the body of man.” Id. ¶ 24. The ’274
application also discloses data, in Example 3, which specifically addresses
the efficacy of administering a bisphosphonate compound, and reports the
results of a rat tibia fracture model study, which includes pain assessments
performed on rats having CRPS triggered by bone fractures. Id. ¶¶ 97–101.
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On this record, we reject Petitioner’s contention that the ’274
application fails to support the limitation of claim 1 that requires the
effective treatment of pain associated with CRPS triggered by bone fracture.
Pet. 32. Accordingly, we assign the ’999 patent an effective filing date of
May 14, 2013—the date of filing of the ’274 application. Ex. 1001, [63].
D. Varenna 2012 is a Prior Art Printed Publication
Inter partes review may be requested only “on a ground that could be
raised under section 102 or 103 and only on the basis of prior art consisting
of patents or printed publications.” 35 U.S.C. 311(b). There is no
presumption in favor of finding that a reference is a printed publication.
Hulu, LLC v. Sound View Innovations, LLC, IPR2018-01039, Paper 29 at
12–14 (PTAB Dec. 20, 2019) (precedential). To qualify as a “printed
publication” within the meaning of § 102, a reference “must have been
sufficiently accessible to the public interested in the art” before the critical
date. In re Cronyn, 890 F.2d 1158, 1160 (Fed. Cir. 1989). Whether a
reference is publicly accessible is determined on a case-by-case basis based
on the “facts and circumstances surrounding the reference’s disclosure to
members of the public.” In re Lister, 583 F.3d 1307, 1311 (Fed. Cir. 2009).
A reference is considered publicly accessible if it was disseminated or
otherwise made available to the extent that persons interested and ordinarily
skilled in the subject matter or art, exercising reasonable diligence, can
locate it. Id.; see also Acceleration Bay, LLC v. Activision Blizzard Inc., 908
F.3d 765, 772 (Fed. Cir. 2018) (“A reference is considered publicly
accessible if it was ‘disseminated or otherwise made available to the extent
that persons interested and ordinarily skilled in the subject matter or art,
exercising reasonable diligence, can locate it.’”).
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In the present case, Patent Owner argues that Petitioner cites to no
evidence to support its contention that Varenna 2012 was publicly accessible
before the effective filing date of the invention and therefore prior art to the
’999 patent. PO Resp. 4–13. Patent Owner contends that the only evidence
entered in support of the Petition is Ex. 1005, “a .pdf file downloaded from
the Internet on December 6, 2017.” PO Resp. 4–5; Ex. 1005. Patent Owner
contends that “[s]omething downloaded from the Internet on December 6,
2017, is obviously not prior art to something having a priority date of May
14, 2013, such as the ’999 patent.” Id. at 5; Sur-Reply 6–7. Patent Owner
further contends that a copyright notice standing alone does not constitute
evidence demonstrating that Varenna 2012 was in fact publicly accessible
before the priority date of May 14, 2013. PO Resp. 5–6; Sur-Reply 12–13.
In its Reply, Petitioner contends that it has provided sufficient
evidence demonstrating that Varenna 2012 is a prior art printed publication
to the ’999 patent. Reply 5–11. Specifically, Petitioner argues that
Varenna 2012 was plainly published, i.e. made publicly
available, before [earliest possible priority date of May 14,
2013]. At the top of the first page, Varenna 2012 expressly states
that it is an article from the journal Rheumatology published on
November 30, 2012. Ex. 1005 at 534. Moreover, the copyright
line at the bottom of the first page reads: “© The Author 2012.
Published by Oxford University Press on behalf of the British
Society for Rheumatology. All rights reserved. For Permissions,
please email: journals.permissions@oup.com.” Id. This
indicates that Varenna 2012 was published in 2012 by a well-
known and reputable publisher.
Id. at 5. In its Reply, Petitioner additionally relies on the Declaration of Dr.
Philip Robinson, who testifies that he accessed, reviewed, and posted about
Varenna 2012 on the social media site Twitter in February 2013, which is
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before the May 14, 2013 priority date of the ’999 patent. Ex. 1044;
Reply 11.
We have considered the parties’ positions, summarized above, and
find Petitioner to have the better position. In reaching our determination, we
weigh the totality of the evidence currently in the record to resolve the
dispute between the parties of whether Varenna 2012 is a prior art printed
publication. On one hand, we weigh the evidence supporting Petitioner’s
position that Varenna 2012 was published and made available to the
interested scientific community via the journal Rheumatology prior to the
priority date of the ’999 patent, summarized above. Reply 7–11; Ex. 1005
(indicia on the face of the document); Ex. 1044. To that point, we are
persuaded that the information pertaining to the publication of Varenna 2012
on the face of the document is sufficient to establish Varenna 2012 as a
printed publication. See, e.g., Telefonaktiebolaget LM Ericsson v. TCL
Corp., 941 F.3d 1341, 1344, 1347 (Fed. Cir. 2019) (holding that “the date on
the face of the journal” was part of the substantial evidence supporting
PTAB’s finding that a journal article was prior art); Hulu, at 17–20 (“[T]he
indicia on the face of a reference, such as printed dates and stamps, are
considered as part of the totality of the evidence.”).
In particular, Varenna 2012 bears several hallmarks suggesting it was
published in 2012 as part of a regularly distributed medical journal. These
hallmarks include the name of the journal (“Rheumatology”); citation
information reflecting the date, the volume number, and the pertinent page
numbers of the journal (“2013; 52:534–542”); the dates the article was
available to the public (“Advance Access publication 30 November 2012”);
a link to the website of the journal (“www.rheumatology.oxfordjournals
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.org”); the publisher of the journal (“© The Author 2012. Published by
Oxford University Press on behalf of the British Society for
Rheumatology”); and where readers interested in learning more about the
topic of Varenna 2012 can make inquiries (“Correspondence to: Silvano
Adami, Rheumatology Unit, Policlinico GB Rossi, Piazzale Scuro, 37121
Verona, Italy”). Ex. 1005.
On the other hand, we consider the lack of evidence supporting Patent
Owner’s position that Varenna 2012 is not a printed publication. In this
regard, we note that Patent Owner provides no evidence to counter the
indicia on the face of Varenna 2012 or the testimony of Dr. Philip Robinson.
PO Resp. 4–13; Sur-Reply 5–13. Indeed, Patent Owner does not even
contest that Oxford University Press is a known publisher or that
Rheumatology is an established journal. Tr. 30:13–21. Rather, Patent
Owner’s position is that Petitioner has failed to meet its burden of
establishing Varenna 2012 as a prior art printed publication—that is, the
indicia of publication on the face of the document are insufficient to
establish the Varenna 2012 as a prior art printed publication. PO Resp. 8–
10.
We also consider Patent Owner’s attorney argument in response to the
declaration evidence of Dr. Robinson, that
This testimony does not show accessibility by interested POSAs.
The declarant does not say, for example, whether he “accessed
[and] reviewed” Varenna 2012 after a reasonably diligent search,
or whether someone simply directed him to it. Nor does the
declarant provide any information that would allow a conclusion
that his mere possession of Varenna 2012 can be extrapolated to
legally significant accessibility by interested POSAs at large.
The declarant likewise says nothing about his Twitter following,
that is, about whether some or all of his followers qualify as
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POSAs. Further diluting things, the declarant also attaches two
versions of Varenna 2012 he purports are the same as they were
on February 3, 2013, but that testimony defies belief. It would
require a photographic and infallible memory of things seen and
read over six years ago. At best it shows merely that the two
articles may or may not be similar or identical to something the
declarant saw or thinks he saw six years ago. Hyperlinks on the
Internet are not static, so retrieving an article from a URL today
does nothing to prove that article was there yesterday, or what it
looked like yesterday. This evidence fails to establish the public
accessibility of Varenna 2012 to the level the law requires.
Sur-Reply 23. It is well established that such bare attorney arguments
cannot take the place of objective evidence and, thus, we accord them little
evidentiary weight. In re Payne, 606 F.2d 303, 315 (CCPA 1979); In re
Pearson, 494 F.2d 1399, 1405 (CCPA 1974) (“Attorney’s argument in a
brief cannot take the place of evidence”). That bare attorney argument does
not outweigh the objective proof advanced by Dr. Robinson showing that he
accessed, reviewed, and posted about Varenna 2012 on the social media site
Twitter in February 2013, which is before the May 14, 2013 priority date of
the ’999 patent. See Ex. 1044 ¶¶ 5–7 (directing us to Exhibits A, B, and C,
which tend to establish the veracity of Dr. Robinson’s testimony on point).4

4 Patent Owner moved to strike Dr. Robinson’s Declaration and related
portions of Petitioner’s Reply, which we denied. Papers 11 and 24. Even if
we set aside Dr. Robinson’s Declaration, however, we are persuaded that the
indicia of publication on the face of Varenna 2012 are sufficient to establish
that Varenna 2012 was “sufficiently accessible to the public interested in the
art” and “disseminated or otherwise made available” to the interested public
before the critical date, and consequently, a printed publication. Blue
Calypso, LLC v. Groupon, Inc., 815 F.3d 1331, 1348 (Fed. Cir. 2016).
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Having considered the parties’ positions and evidence of record,
summarized above, we determine the totality of the evidence—the indicia of
publication on the face of the document and testimony of Dr. Robinson—
supports a finding that Varenna 2012 was publicly available as of November
30, 2012, the “Advance Access” publication date on the face of the journal.
We further credit the testimony of Dr. Robinson and are not persuaded by
Patent Owner’s bare attorney argument to the contrary. Attorney argument
cannot take the place of evidence lacking in the record. In re Pearson, 494
F.2d at 1405.
In view of the above, we determine that Varenna 2012 qualifies as a
prior art printed publication to the ’999 patent.
E. The Asserted Grounds of Unpatentability
In this section, we address in turn the following grounds of
unpatentability advanced in the Petition: (1) anticipation; (2) obviousness;
and (3) lack of enablement. Pet. 8–9.
1. The Grounds Based on Anticipation
Petitioner asserts three anticipation grounds against claims 1–4, 9, 10,
12, 14, 16–18, 23–25, and 27–29 based on, respectively, the disclosures of
Varenna 2012, Varenna 2016, and Manara. Pet. 8. We address the three
anticipation grounds in turn below.
a. Anticipation by Varenna 2012
Petitioner asserts that claims 1–4, 9, 10, 12, 14, 16–18, 23–25, and
27–29 are anticipated by Varenna 2012. Pet. 31–44. We first address
independent claim 1, then turn to the dependent challenged claims.
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(i) Claim 1
The parties do not dispute that Varenna 2012 discloses administration
of neridronic acid to human beings having CRPS as recited in claim 1.
Pet. 33–34; Ex. 1003 ¶ 87; PO Resp. 14–20. The dispute between the parties
is whether Varenna 2012 expressly or inherently discloses the recited
elements of 1) “selecting a human being having CRPS triggered by bone
fracture” and 2) “wherein the treatment is effective in reducing pain” in
patients with CRPS triggered by bone fracture. PO Resp. 14; Pet. 31–37
(information directed to anticipation of claim 1 by Varenna 2012); Ex. 1001,
106:25–30 (claim 1). For the reasons that follow, we determine that
Varenna 2012 discloses each of the disputed elements of claim 1 and that
Varenna 2012 anticipates claim 1.
(a) “selecting a human being having CRPS
triggered by bone fracture”
With regard to the element of “selecting a human being having CRPS
triggered by bone fracture,” Petitioner contends that “this limitation should
be construed as requiring the human being treated to have CRPS wherein a
bone fracture caused or contributed to the occurrence or onset of CRPS, and
is synonymous with bone fracture as a precipitating or predisposing event.”
Pet. 34. On this point, Petitioner contends that Varenna 2012
discloses that 11 of the 41 patients enrolled in the neridronate
arm of the study (26.8%) had fracture as a precipitating event for
CRPS. Ex. 1005 at 536, Table 1; Ex. 1003 ¶ 89. Of the 41
patients enrolled in the placebo arm, 17 had fracture as a
precipitating event for CRPS (41.4%). Ex. 1005 at 536, Table 1;
Ex. 1003 ¶ 89. After the double-blind phase of the study
concluded, the patients that had been on placebo were given
neridronate following the same regimen (four 100-mg infusions
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over 10 days) as in the double-blind phase. Ex. 1005 at 535; Ex.
1003 ¶ 90.
Pet. 34–35 (citing Ex. 1005, 534, 535; Ex. 1003 ¶¶ 87–90).
Petitioner further relies on Dr. Poree’s declaration, wherein Dr. Poree
specifically opines that the limitation “comprising selecting a human being
having CRPS triggered by bone fracture” is disclosed in Varenna 2012.
Ex. 1003 ¶¶ 86–90. Dr. Poree explains that “[t]his limitation requires the
human being treated to have CRPS wherein a bone fracture caused or
contributed to the occurrence or onset of CRPS, and has the same meaning
as bone fracture as a precipitating or predisposing event for CRPS.” Id. at
¶ 86. Thus, according to Petitioner, “Varenna 2012 discloses selecting and
treating a human being having CRPS triggered by bone fracture as required
by claim 1.” Pet. 35 (citing Ex. 1003 ¶ 87).
Patent Owner contends that Varenna 2012 does not expressly disclose
the claim requirement for “selecting a human being having CRPS triggered
by bone fracture.” PO Resp. 14. In short, Patent Owner argues that the
study reported by Varenna 2012 did not select patients on the basis of having
CRPS triggered by bone fracture, the study only happened to include such
patients. PO Resp. 14–20; Sur-Reply 14–17. Specifically, Patent Owner
contends that
Varenna 2012 does not disclose deliberately selecting
humans suffering from CRPS because their CRPS was caused by
bone fracture. “Selecting” requires deliberation. It is not enough
to simply apply the claimed method to people who happen to
have CRPS that happens to have been caused by bone fracture;
the selection must have been deliberately made based on those
criteria. Varenna 2012 does not disclose “selecting” in this way.
Sur-Reply 14 (emphasis omitted).
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To support its position, Patent Owner directs our attention to the
section of Varenna 2012 that provides detail on the methods and criteria
used to select patients for the study. Id. at 14–15 (citing Ex. 1005, 535).
With reference to that section of Varenna 2012, Patent Owner contends that
Varenna 2012 used at least 15 criteria to select patients for the study,
however, “CRPS triggered by bone fracture” is not among the criteria used.
Id. at 14–15 (citing Ex. 1005, 535). Specifically, Patent Owner contends
that Varenna 2012
contains at least 15 examples of “to choose from a number or
group: pick out.” These are at least: 1) patients fulfilled the
Budapest criteria, 2) patients had involvement of hands or feet,
3) patients had an age of at least 18 years, 4) patients had disease
duration no longer than 4 months, 5) patients had a VAS of at
least 50 mm, 6) patients had abnormal uptake of the bone seeking
agent in three-phase bone scintigraphy in both early and late
phases, 6)[sic] female patients of childbearing age had a negative
pregnancy test, 7) patients had no hepatic disease, 8) patients had
no renal disease, 9) patients had no endocrine disease,
10) patients had no haematological disease, 11) patients had no
cardiac disease, 12) patients had no pulmonary disease,
13) patients had no neurological disease, 14) patients had no
routine laboratory abnormalities, and 15) patients had no prior
treatment with bisphosphonates. Thus, Varenna 2012 did a great
deal of selecting, but none that had to do with “selecting a human
being having CRPS triggered by bone fracture.”
Id. at 15 (emphasis omitted).
Patent Owner contends that Dr. Poree’s declaration does not provide
factual support for Petitioner’s assertion that Varenna 2012 discloses
selecting patients on the basis of having CRPS triggered by fracture. Id.
at 17 (citing Ex. 1003 ¶ 87). In particular, Patent Owner contends that
Dr. Poree makes no express statement supporting Petitioner’s notion that
Varenna 2012 discloses selecting patients having CRPS triggered by
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fracture. Id. Thus, according to Patent Owner, Petitioner has “offered
absolutely no evidence that Varenna 2012 discloses selecting a human being
having CRPS triggered by bone fracture, either expressly or inherently.” Id.;
Ex. 1003 ¶¶ 86–90.
Patent Owner further contends that
[t]he only place where Varenna 2012 even mentions bone
fracture is in Table 1, and Varenna 2012 makes it clear that
patients were not selected for fracture as a precipitating event
because assignment to neridronic acid treatment was random.
Varenna 2012 states that “[a] centrally computer-generated table
of random numbers was used for the treatment assignment.
Patients were treated with either neridronate . . . or placebo with
an identical appearance in a 1:1 ratio . . . Neither patients nor
investigators knew whether the assignment would be the placebo
or the neridronate group.” (Ex. 1005 at 535 (emphasis added).)
Therefore, the element “selecting a human being having CRPS
triggered by bone fracture” is not expressly or inherently found
in Varenna 2012, and claims 1–30 are not anticipated by the
reference.
PO Resp. 14–15.
Thus, according to Patent Owner, Varenna 2012 does not in fact
disclose deliberate “selecting” based on CRPS having been caused by bone
fracture. PO Resp. 14–20; Sur-Reply 14–17. “Rather, the Petition simply
addresses the clause as if the word ‘selecting’ has no effect at all upon its
meaning.” Sur-Reply 16 (citing Pet. 34–35).
Having considered the parties’ positions and evidence of record,
summarized above, we determine that Varenna 2012 inherently discloses the
required element of selecting a human being having CRPS triggered by bone
fracture. Varenna discloses that a subset of the patients included in the
human clinical study experienced bone “fracture” as a “[p]recipitating
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event” for CRPS. Ex. 1005, 536 (Table 1). Additionally, Varenna 2012
shows that the data collected was analyzed on the basis of precipitating
events—that is, predisposing factors were among the variables analyzed.
Ex. 1005, 536. Those precipitating events include fracture, trauma, and
surgery. Id. at 536 (Table 1). While Varenna 2012 does not expressly
disclose that those patients were selected because they have CRPS triggered
by bone fracture, the study was designed to assess predisposing factors as a
distinct variable in order “to assess the potential influence of baseline
variables on treatment effect.” Id. at 536 (“Multivariate regression analysis
was performed to assess the potential influence of baseline variables on
treatment effect [site of disease: (upper/lower limb), disease duration and
precipitating event (none/trauma, surgery)].”).
Additionally, Dr. Poree testifies that Varenna 2012 shows that patients
having fracture-induced CRPS were selected for inclusion in the neridronate
treatment study. Ex. 1003 ¶ 89. More specifically, he testifies that 11 of the
41 patients included in the neridronate arm and 17 of 41 patients included in
the placebo arm had fracture-induced CRPS. Id. at ¶¶ 88–90. We see no
meaningful distinction between including a patient in a study, which
involves treating that patient with neridronate, and selecting a patient for
treatment with neridronate. Thus, in our view, the 11 patients included in
the neridronate arm of the study were, in essence, selected for treatment with
neridronate. Further, as Dr. Poree testifies, all of the patients in the placebo
arm, including the 17 fracture-induced CRPS patients, who had initially
been given placebo were then put into the open-extension phase of the study,
in which they were given neridronate using the same regimen given to those
patients initially in the treatment group. Id. at ¶ 90. In other words, those 17
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fracture-induced CRPS patients were included in the open-extension phase
of the study (and, thereby, were selected for treatment with neridronate).
When we consider Dr. Poree’s testimony with the results disclosed by
Varenna 2012, we are persuaded that the totality of the evidence shows that
Varenna 2012 discloses that CPRS triggered by bone fracture was among the
criteria used to select patients and to determine treatment outcomes. That is,
selecting a patient having CRPS triggered by bone fracture is inherent to the
study design as evidence by the presentation of the results and statistical
analysis based on predisposing factors in Varenna 2012.
(b) “wherein the treatment is effective in
reducing pain”
With regard to the element of “wherein the treatment is effective in
reducing pain,” we are not persuaded by Patent Owner’s argument that
Varenna 2012 does not disclose that neridronic acid is effective in reducing
pain in human patients having CRPS triggered by bone fracture. PO
Resp. 14–16; Sur-Reply 17–22. Rather, we are persuaded that Petitioner
advances information that sufficiently supports that factual contention.
Pet. 36–37 (citing Ex. 1005, 534–538, Table 1; Ex. 1003 ¶¶ 95–100). In
particular, we note that Varenna 2012 reports “the efficacy of the amino-
bisphosphonate neridronate in patients with” CRPS, including “clinically
relevant and persistent benefits” associated with the administration of
neridronate. Id. at 33 (citing Ex. 1005 at 534; Ex. 1003 ¶¶ 83–84).
Significantly, Varenna expressly teaches that neridronate effectively
mitigates pain associated with CRPS in patients presenting with “bone
fracture” as “a predisposing event for” that condition. Ex. 1001, 84:61–62;
see Pet. 34–35 (citing, for example, Ex. 1005, 535–36, 538–39, Table 1; Ex.
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1003 ¶¶ 87–90). Of particular significance is Varenna’s identification of a
subset of patients in a human clinical study that experienced bone “fracture”
as a “[p]recipitating event” for CRPS. Ex. 1005, 536 (Table 1). Varenna
reports that, in that subset of patients, the administration of neridronate
effectively mitigated pain. Pet. 32–33, 37–39 (and evidence cited therein);
Ex. 1005, 534, 536; Ex. 1003 ¶¶ 95–100.
Further to that point, we agree with Petitioner that Varenna 2012
discloses that “the particular type of precipitating event did not influence
outcomes in the study, indicating that patients with all types of precipitating
events, including fractures, benefited from the neridronate treatment.”
Pet. 37, 63 (citing Ex. 1003 ¶¶ 100, 234); see Ex. 1005, 538 (Varenna 2012,
explaining, “[i]n multivariate regression analysis,” no “baseline variables
except treatment assignment” “appeared to influence outcome measures”).
Here, we credit Dr. Poree’s testimony on that point. Specifically, Dr. Poree
states in his declaration that:
A “[m]ultivariate regression analysis was performed to assess the
potential influence of baseline variables on treatment effect [site
of disease: (upper/lower limb), disease duration and precipitating
event (none/trauma, surgery)].” Exhibit 1005, Varenna 2012 at
536. In the multivariate regression analysis, baseline variables
other than treatment assignment did not appear to influence
outcome measures.
Ex. 1003 ¶ 99 (emphasis added).
Several other facts confirm our above analysis. Varenna informs,
“[i]n patients with acute CRPS-I,” the intravenous administration of
neridronate is “associated with clinically relevant and persistent benefits.”
Ex. 1005, 534; see Pet. 36–39 (and evidence cited therein). Varenna reports
results that provide “conclusive evidence that the use of bisphosphonates . . .
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is the treatment of choice for CRPS-I.” Ex. 1005, 534. CRPS was known in
the prior art as “a severely debilitating pain syndrome that sometimes
develops after trauma such as a bone fracture.” Pet. 1. Varenna discloses
with anticipatory specificity the mitigation of pain in patients suffering from
CRPS (including those in which that pain syndrome was triggered by bone
fracture) by treatment with neridronate. Pet. 33–34, 36–37; Ex. 1005, 534,
536; Ex. 1003 ¶¶ 95–100. In addition, these facts are similar to Montgomery
where the drug ramipril was administered to patients in need of stroke
prevention and our reviewing court found that “efficacy is inherent in
carrying out the claim steps.” In re Montgomery, 677 F.3d 1375, 1381 (Fed.
Cir. 2012).
Accordingly, we determine, on this record, Petitioner shows
sufficiently that pain was mitigated effectively in those patients by
administration of neridronate. Pet. 33–34, 36–37 (and evidence cited
therein).
(ii) Dependent Claims
Our analysis pertaining to claim 1 applies with equal force to
dependent claims 2–4, 9, 10, 12, 14, 16–18, 23–25, and 27–29, each of
which depends directly or indirectly from claim 1.
Petitioner contends that Varenna 2012 anticipates the subject matter
of dependent claims 2–4, 9, 10, 12, 14, 16–18, 23–25, and 27–29. Pet. 39–
46. To support its position, Petitioner provides a detailed discussion
explaining how each claim limitation is disclosed in Varenna 2012. Id.
Patent Owner raises no new argument directed to any of those
dependent claims. PO Resp. 14–20; Sur-Reply 14–22. Instead, Patent
Owner relies on argument presented in the context of claim 1. Id.
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Having considered the parties’ positions and evidence of record, we
are persuaded by Petitioner that Varenna 2012 discloses each element of
claims 2–4, 9, 10, 12, 14, 16–18, 23–25, and 27–29 for the reasons set forth
in the Petition. See Pet. 39–46 (including substantial evidence cited therein).
Accordingly, we determine that Varenna 2012 anticipates dependent claims
2–4, 9, 10, 12, 14, 16–18, 23–25, and 27–29.
b. Anticipation by Varenna 2016
Petitioner asserts that claims 1–4, 9, 10, 12, 14, 16–18, 23–25, and 27,
28 are anticipated by Varenna 2016. For reasons explained above, on this
record, we find that the effective filing date of the ’999 patent is May 14,
2013. Petitioner asserts that, “[a]lthough the issue of the journal” in which
the reference appears “is dated June 2017, Varenna 2016 was first published
on September 20, 2016.” Pet. 45 (citing Ex. 1003 ¶ 133). Even if we accept
that contention, Varenna 2016 does not qualify as prior art against the ’999
patent claims, because the reference was published after the effective filing
date of the patent. Accordingly, on this record, we find that Petitioner has
not shown that any challenged claim is anticipated by Varenna 2016.
c. Anticipation by Manara
Petitioner asserts that claims 1–4, 9, 10, 12, 14, 16–18, 24–25, and 27,
28 are anticipated by Manara. For reasons explained above, on this record,
we find that the effective filing date of the ’999 patent is May 14, 2013.
Petitioner asserts that Manara was first published in June of 2014. Pet. 55–
56. Even if we accept that contention, Manara does not qualify as prior art
against the ’999 patent claims, because the reference was published after the
effective filing date of the patent. Accordingly, on this record, we find that
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Petitioner has not shown that any challenged claim is more likely than not
anticipated by Manara.
2. The Grounds Based on Obviousness
a. Obviousness Grounds Relying on Varenna 2016 and
Manara
Petitioner asserts a plurality of alternative obviousness grounds that
depend on the contention that Varenna 2016 and Manara constitute prior art.
Pet. 8, 62–79 (and evidence cited therein). For reasons explained above, we
find that Petitioner fails to show sufficiently that those references are prior
art against the ’999 patent claims. See supra. Accordingly, for that reason,
we find also that Petitioner fails to show that it is more likely than not that
any challenged claim is unpatentable based on the obviousness grounds
relying on Varenna 2016 and/or Manara. See Pet. 62–79 (obviousness
grounds).
b. Obviousness Grounds Relying on Varenna 2012
It is axiomatic patent law that a disclosure that anticipates under
35 U.S.C. § 102 also may render the claim unpatentable under 35 U.S.C.
§ 103, because anticipation is the epitome of obviousness. See In re
McDaniel, 293 F.3d 1379, 1385 (Fed.Cir.2002) (“It is well settled that
‘anticipation is the epitome of obviousness.’”) (quoting Connell v. Sears,
Roebuck & Co., 722 F.2d 1542, 1548 (Fed.Cir.1983)). In that regard, the
Board is allowed to rely on findings regarding whether a reference
anticipates a limitation in its obviousness analysis. See Wasica Fin. GmbH
v. Cont’l Auto. Sys., Inc., 853 F.3d 1272, 1278 (Fed. Cir. 2017) (stating
approvingly in a footnote that the “Board noted that Oselin rendered [the
challenged claims] obvious by virtue of its anticipation of them.”).
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Petitioner contends that claims 1–4, 9, 10, 12, 14, 16–18, 23–25, and
27–29 are anticipated by Varenna 2012. Petitioner also relies on
Varenna 2012 to assert three alternative obviousness grounds of
unpatentability that, taken together, challenge the patentability of claims 1–
30 of the ’999 patent. Pet. 62–79. Thus, Petitioner relies on Varenna 2012
to argue separately that claims 1–4, 9, 10, 12, 14, 16–18, 23–25, and 27–29
would have been obvious. We rely on our anticipation findings above to
determine that determining that Varenna 2012 renders obvious claims 1–4,
9, 10, 12, 14, 16–18, 23–25, and 27–29.
We address below Petitioner’s obviousness challenges to claims 5–8,
11, 13, 15, 19–22, 26, and 30 of the ’999 patent to the extent those grounds
rely on Varenna 2012.
(i) Obviousness of claims 11, 13, 15, 19–20, 22, 26,
and 30 over the combination of Varenna 2012,
Bruehl, Gatti, La Montagna, and Muratore
Dependent claims 11, 13, 15, 19–20, 22, and 26 all recite limitations
that relate to specific neridronic acid dosing amounts, frequencies, and/or
durations for the treatment of pain associated with CRPS triggered by bone
fracture. Claims 11, 13, 15, 19–20, 22, and 26 are reproduced below
(parenthetical text added):
11. The method of claim 9 [(reciting parenteral
administration)], wherein a total of about 5 mg to about 200 mg
of the neridronic acid is administered within one month.

13. The method of claim 9 [(reciting parenteral
administration)], wherein a total of about 100 mg to about 300
mg of the neridronic acid is administered within one month.

15. The method of claim 1, wherein a total of about 100 mg
to about 300 mg of the neridronic acid is administered.
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19. The method of claim 4 [(reciting intravenous
administration)], wherein each dose contains about 50 mg to
about 65 mg of the neridronic acid.

20. The method of claim 19, wherein the neridronic acid is
administered about every three days.

22. The method of claim 3 (reciting salt form of neridronic
acid), wherein each dose contains an equivalent of about 50 mg
to about 60 mg of the neridronic acid in an acid form.

26. The method of claim 1, wherein the neridronic acid is
administered weekly for about four to about six weeks.
Ex. 1001, 106:50–107:25.
Petitioner acknowledges that “Varenna 2012 does not expressly
disclose the additional limitations of these claims because in its clinical
study, a total of 400 mg neridronate was administered within one month over
a period of ten days.” Pet. 71 (citing Ex. 1003 ¶ 256). For the claim
elements related to neridronic acid dosing amounts, frequencies, and/or
durations, Petitioner relies on Gatti, La Montagna, and Muratore.
Specifically, Petitioner contends that
Gatti, Muratore, and La Montagna confirm to a POSA that
neridronic acid can be used to treat patients with CRPS. La
Montagna further teaches that patients with transient
osteoporosis of the hip, which is associated with fracture, can be
successfully treated with neridronic acid.
Pet. 67. Petitioner contends that “it would have been obvious, routine, and
within the skill of a POSA to determine the dosing regimen of neridronic
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acid to administer for treatment of pain associated with CRPS triggered by
fracture for a particular patient.” Id. 71 (citing Ex. 1003 ¶ 257).5
We now turn to the disclosures of Gatti, Muratore, and La Montagna
and to the relevance of each of these references to claims 11, 13, 15, 19–20,
22, and 26. Gatti6 reports that “[i]ntravenous high doses of bisphosphonates
are increasingly used for the treatment of reflex sympathetic dystrophy
syndrome or algodystrophy.”7 Ex. 1007, 1308. According to Gatti, “the
most effective dose is 100 mg diluted in 250 ml of saline solution given
intravenously over 4 days,” and, “[w]ith this treatment regimen, the
proportion of patients experiencing rapid (in 7 – 12 days) > 70%
symptomatic improvements is close to 80%.” Id. at 1308. Because of these
“preliminary observations,” Gatti reports that “the first formal registrative
randomized double-blind clinical trial comparing 400 mg neridronic acid to
placebo in patients with foot or forearm algodystrophy syndrome has been
designed and is underway.” Id. Accordingly, we find that Gatti discloses
intravenous administration of 100 mg neridronate administered within 4
days. That dosage regimen falls within the scope of claim 11 (about 5–200
mg of neridronic acid within one month), claim 13 (about 100–300 mg of

5 We find that Dr. Poree’s testimony is conclusory and largely parrots the
attorney argument in the Petition. Ex. 1003 ¶¶ 256–257.
6 Gatti originally was written in Italian, but we refer to the English
translation Petitioner submitted.
7 According to Petitioner, “CRPS is also referred to as algodystrophy or
reflex sympathetic dystrophy syndrome.” Pet. 65, n.5 (citing Ex. 1007,
1308; Ex. 1003 ¶ 243).
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neridronic acid within one month), and claim 15 (total of about 100–300 mg
of neridronic acid).
Muratore reports the results of a comparison of neridronate and
clodronate “in the treatment of reflex sympathetic hip algodystrophy.”
Ex. 1010, 89, 90. The purpose of the study was “[t]o evaluate the
therapeutic efficacy of Neridronate.” Id. One group of patients in the study
“was administered neridronate 100 mg, intravenously diluted in 250 cc of
saline solution every 4 days 4 times.” Id. Both neridronate and clodronate
“demonstrated being efficacious in the treatment of Reflex Sympathetic
Algodystrophy but the speed of improvement of pain symptoms with
recovery of functional/motor capability . . . was demonstrated to be
statistically more significant in patients treated with Neridronate.”
Ex. 1007, 89. Accordingly, we find that Muratore discloses intravenous
administration of 100 mg neridronate every 4 days 4 times, or 400 mg
neridronate administered intravenously within about 2 weeks. We find
Muratore’s teaching of administering neridronate every 4 days to be
particularly relevant to element of claim 20 (about every three days).
La Montagna reports a case study of a patient with “an uncommon
case of bilateral transient osteoporosis of the hip (TOH)” who was
“successfully treated” with 25 mg/month neridronate sodium for 6 months.
Ex. 1008, 67–68. TOH “is a rare clinical syndrome characterized by
transient osteopenia, rapidly or gradually increasing pain, and disability
without deformity.” Id. at 67.
Petitioner contends that the recited doses would have been obvious
because “[t]he doses recited in claims 11, 13, 15, 19, and 22 are lower than
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the 400 mg total neridronic acid that was administered in the study reported
in Varenna 2012.” Pet. 71. Petitioner further contends that
A POSA would be motivated to use the lowest dose that provides
efficacy in a particular patient due to safety and side effect
concerns. Ex. 1003 ¶ 259. For example, in La Montagna, a dose
of only 25 mg per month [of neridronate sodium] for six months
was effective for treating transient osteoporosis of the hip, a type
of CRPS. Ex. 1008 at 67–68; Ex. 1003 ¶ 260. And, according
to Varenna 2012, although the 400 mg neridronate dose had the
best results, some degree of efficacy in certain patients was
previously observed with smaller doses of 200 and 300 mg i.v.
neridronate. Ex. 1005 at 540; Ex. 1003 ¶ 260.
Id. at 71–72.
Petitioner further contends that the ’999 patent specification 1) “lists
dozens of different dosage ranges and states that any suitable amount of a
bisphosphonate may be used;” 2) “attaches no criticality to any particular
dosing regimen for any condition;” and 3) “does not suggest any critical
dosing regimen for treating pain associated with CRPS triggered by
fracture.” Id. at 73. Thus, according to Petitioner, “it would have been
within the level of ordinary skill in the art to determine the optimal dosing
regimen of neridronic acid to use as claimed in challenged claims 11, 13, 15,
19–20, 22, and 26.” Id. at 73–74. Petitioner further contends that “routine
determination of the appropriate dose of a known drug is not inventive” and,
more specifically, that “mere differences in concentration, proportions, or
degree will not support the patentability of subject matter encompassed by
the prior art unless there is evidence indicating such concentration,
proportion, or degree is critical.” Id. at 72–73 (citing In re Williams, 17
C.C.P.A. 718, 722 (C.C.P.A. 1929); In re Hoeschele, 406 F.2d 1403, 1406
(C.C.P.A. 1969); Merck & Co., Inc. v. Biocraft Labs., Inc., 874 F.2d 804,
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809 (Fed. Cir. 1989) (describing “routine procedures” used to determine
appropriate dose of drugs and finding that “experimentation needed to arrive
at the claimed dosages was nothing more than routine”)); see also Eli Lilly
and Co. v. Actavis Elizabeth LLC, 435 Fed. Appx. 917, 922 (Fed. Cir. 2011)
(“The optimum dose for each patient, as always, must be set by the
physician in charge of the case, taking into account the patient’s size, other
medications which the patient requires, severity of the disorder and all of the
other circumstances of the patient.”).
Patent Owner presents no additional arguments regarding the
obviousness challenge to these claims, except for the previously-discussed
arguments addressed to claim 1. See generally PO Resp. and PO Sur-Reply.
Based on our review of Petitioner’s unopposed argument and
evidence, summarized above, which we adopt as our own findings, we
conclude that the claimed neridronic acid dosing amounts, frequencies,
and/or durations to be encompassed by or substantially similar to the
treatment ranges and conditions disclosed in Varenna 2012, Gatti, La
Montagna, and Muratore. That is, the combination of Varenna 2012, Gatti,
La Montagna, and Muratore teaches or suggests general dosing regimens for
neridronic acid for the treatment of CRPS or similar conditions and that a
person of ordinary skill in the art would have reasonably expected the
claimed dosing parameters to be achieved with routine optimization.
Accordingly, we determine Petitioner has proven by a preponderance of
evidence that claims 5–8 and 21 would have been obvious over the
combination of Varenna 2012, Gatti, La Montagna, and Muratore.
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(ii) Obviousness of claims 5–8 and 21 over the
combination of Varenna 2012 and Manicourt
Claims 5–8 and 21 require oral administration of neridronic acid.
Petitioner acknowledges that Varenna 2012 does not expressly disclose oral
administration of neridronic acid. Pet. 74. Petitioner contends, however,
that “it would have been obvious to a POSA to orally administer neridronic
acid for the treatment of pain associated with CRPS triggered by fracture
based upon the combination of Varenna 2012 . . . with Manicourt.” Id.
Manicourt reports the results of a clinical study designed “[t]o
evaluate the effects of the antiresorptive agent alendronate8 at a daily oral
dose of 40 mg in patients with posttraumatic complex regional pain
syndrome type I (CRPS I) of the lower extremity.” Ex. 1009, Abstr. The
patients in the study exhibited various clinical characteristics of CRPS,
including severe spontaneous pain, allodynia and hyperalgesia of the
diseased area, and skin swelling and discoloration. Id. at 3691. The
treatment group received daily doses of tablets containing 40 mg alendronate
sodium for 8 weeks. Id. at 3691–92. Manicourt reports that “oral
alendronate taken at a daily dose of 40 mg was well tolerated and appeared
to be a very effective tool in the management of CRPS I.” Id. at 3696.
Petitioner contends that a person of ordinary skill in the art would
have had motivation to combine Varenna 2012 with Manicourt because
As of at least 2012, the use of oral bisphosphonates would have
been well-known to a POSA. Multiple bisphosphonates were
marketed and prescribed orally, including Fosamax®
(alendronate sodium) Tablets and Oral Solution, and Boniva®

8 Alendronate is another bisphosphonate compound, like neridronic acid.
Ex. 1003 ¶ 265; Ex. 1001, 4:6–13.
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(ibandronate sodium) Tablets. Ex. 1018 at 1, 3; Ex. 1019 at 1–
2; Ex. 1003 ¶ 272. Therefore, a POSA reading Varenna 2012 . . .
would have been motivated to look to other prior art examples of
orally administered bisphosphonates, like Manicourt. Ex. 1003
¶ 272. A POSA would have been motivated to combine the
disclosures of Varenna 2012 . . . with Manicourt to administer
neridronic acid in an oral formulation because all of these
references concern clinical trials investigating the use of
bisphosphonates to treat CRPS, and both included patients with
fracture as a predisposing or triggering event. Id. ¶ 271.
Manicourt teaches a POSA that a pharmaceutically acceptable
oral formulation of alendronate, one which was “well tolerated”
and “effective,” was possible. Therefore a POSA would have
been motivated to administer neridronic acid orally. Id. ¶ 272.
Pet. 75–76.
Patent Owner presents no additional arguments regarding the
obviousness challenge to these claims, except for the previously-discussed
arguments addressed to claim 1. See generally PO Resp. and PO Sur-Reply.
Based on our review of Petitioner’s argument and evidence,
summarized above, which we adopt as our own findings, we conclude that
Petitioner has proven by a preponderance of evidence that claims 5–8 and 21
would have been obvious over the combination of Varenna 2012 and
Manicourt.
(iii) Obviousness of claim 30 over the combination of
Varenna 2012, Schwarzer, Bruehl, Gatti, La
Montagna, and Muratore
Claim 30 depends from claim 1 and further requires that the CRPS be
CRPS type II. Petitioner acknowledges that Varenna 2012 does not
expressly disclose treating CRPS type II, but contends that “it would have
been obvious to a POSA to administer neridronic acid for the treatment of
pain associated with CRPS type II wherein bone fracture is a predisposing or
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triggering event.” Pet. 77. Citing Schwarzer, Petitioner contends that it was
known that “there are no clinical differences between CRPS type I and type
II; expect for the nerve damage,” and therefore “would have understood that
the treatment options available for CRPS could be used in either type of
CRPS.” Id. at 77–78. In particular, Petitioner directs our attention to
Schwarzer and contends that
Schwarzer notes that two types of CRPS are recognized, CRPS
type I without nerve injury, and CRPS type II which is associated
with major nerve injury. Ex. 1020 at 249; Ex. 1003 ¶280.
However, the authors drop this distinction soon after making it:
in describing the treatment options, clinical symptoms,
diagnostic criteria, main characteristics, incidence, and prognosis
of the disease, Schwarzer refers to CRPS generally,
encompassing both CRPS I and CRPS II. Ex. 1003 ¶282; see
generally Ex. 1020.
Id.
Patent Owner presents no additional arguments regarding the
obviousness challenge to claim 30, except for the previously-discussed
arguments addressed to claim 1. See generally PO Resp. and PO Sur-Reply.
Having considered the parties’ positions and evidence of record,
summarized above, we find the preponderance of evidence of record to
support Petitioner’s position that a person of ordinary skill in the art would
have understood that the treatment options available for CRPS could be used
in either type I or type II of CRPS. Accordingly, for the reasons discussed
above, Petitioner has shown by a preponderance of the evidence that claim
30 of the ’999 patent would have been obvious over the combination of
Varenna 2012, Schwarzer, Bruehl, Gatti, La Montagna, and Muratore.
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3. The Ground Based on Lack of Enablement
We next address Petitioner’s assertion that the ’999 patent
specification fails to enable the claimed invention. Pet. 25–30. We evaluate
enablement by considering whether the patent disclosure, at the time of
filing,9 would have enabled a person of ordinary skill in art to make and use
the subject matter of the claims. In re Wands, 858 F.2d 731, 737 (Fed. Cir.
1988). The touchstone of enablement is whether undue experimentation
would have been required to practice the claimed invention. Id.
At the outset, we note that Petitioner has established that Varenna
2012 anticipates many of the challenged claims, including independent
claim 1. See supra. That circumstance appears inconsistent with
Petitioner’s further view that the degree of detail and guidance provided in
the specification is inadequate in view of the state of the prior art as revealed
by the disclosure of Varenna 2012. Pet. 26–29. Significantly, on that point,
Petitioner admits that “methods of treating pain associated with CRPS with
neridronic acid—including pain associated with CRPS triggered by
fracture—were known in the prior art.” Id. at 30.
Having considered Varenna 2012 and Petitioner’s arguments and
evidence related to Varenna 2012, we find that the disclosure of Varenna
2012 would have informed an ordinary artisan, well before the critical date,
exactly how to administer neridronic acid to humans having CRPS triggered
by bone fracture with an expectation of mitigating pain associated with that

9 We follow Petitioner’s convention of referring to the ’999 patent
specification, rather than any priority application, when discussing the
ground based on lack of enablement. Pet. 26–28.
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condition. Ex. 1005, 534 (Abstract), 535 (study design), 536 (Table 1 and
results and efficacy data), 538 (Table 2 and discussion of improvement in
pain symptoms upon treatment with neridronate). That finding is fully
consistent with views formed by the Examiner during patent prosecution.
Ex. 1022, 454 (“[T]he dosage forms and the herein claimed routes of
administration and the dosing regimens are all well-known according to the
teachings of the cited prior art. The dosage of neridronic acid taught in the
prior art encompasses the herein claimed dosage.”). On that point, we
observe that Varenna 2012—which is cited on the face of the ’999 patent
(Ex. 1001 (56))—was among the prior art references before the Examiner.
The information advanced in the Petition does not account adequately
for the fact that Varenna 2012 establishes a level of ordinary skill in the art
that makes reasonable the degree of detail set forth in the specification.
Pet. 26–29. “The specification need not disclose what is well known in the
art.” In re Buchner, 929 F.2d 660, 661 (Fed. Cir. 1991). On this record, the
Petition does not advance information from which we reasonably can find
that any experimentation, much less undue experimentation, would have
been necessary to enable the claimed invention. Pet. 26–29. Here, we take
account of both the disclosures set forth within the specification and the
general knowledge of an ordinarily skilled artisan as demonstrated by
Varenna 2012. See, e.g., Ex. 1001, 2:59–60, 4:7–13, 7:38–8:38, 26:30–43,
33:26–57, 42:7–46:59, 51:24–52:61, 71:38–42, 72:12–15 (patent
disclosures); Ex. 1005 (Varenna 2012). The state of the prior art informs our
decision that the specification includes details and guidance that, under the
particular facts and circumstances of this case, sufficiently enable the claims.
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An enabling disclosure need not disclose any working examples or
demonstrate that the claimed invention was actually reduced to practice at
the time of filing. Alcon Research Ltd. v. Barr Labs, Inc., 745 F.3d 1180,
1190 (Fed. Cir. 2014)). Where there is no need for an actual reduction to
practice, we are not persuaded that the failure to include a working example,
specific to neridronic acid, supports a conclusion that undue experimentation
would have been necessary to make and use the claimed invention. See
Pet. 28–29 (arguing that the failure to include a working example directed to
neridronic acid, in particular, supports a finding of lack of enablement).
In reaching our conclusions on the ground based on enablement, we
take notice that “a considerable amount of [routine] experimentation” is
permitted without rising to the level of undue experimentation under a
correct enablement analysis. PPG Indus. v. Guardian Indus. Corp., 75 F.3d
1558, 1564 (Fed. Cir. 1996). Petitioner does not address, much less explain
adequately, how or why any required experimentation would have risen
above the routine, given the state of the art as exemplified by the disclosure
of Varenna 2012. Pet. 26–30.
In view of the above, we determine that Petitioner has failed to
demonstrate that any challenged claim is unpatentable for lack of an
enabling disclosure.
III. CONCLUSION
In summary, we make the following conclusions.10

10 Should Patent Owner wish to pursue amendment of the challenged
claims in a reissue or reexamination proceeding subsequent to the
issuance of this decision, we draw Patent Owner’s attention to the April
2019 Notice Regarding Options for Amendments by Patent Owner
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Claims 35 U.S.C. §
Reference(s)/
Basis
Claims
Shown
Unpatentable
Claims Not
Shown
Unpatentable
1–4, 9, 10,
12, 14, 16–
18, 23–25,
27–29
102(a) Varenna 2012
1–4, 9, 10, 12,
14, 16–18,
23–25, 27–29

1–4, 9, 10,
12, 14, 16–
18, 23–25,
27, 28
102(a) Varenna 2016
1–4, 9, 10, 12,
14, 16–18,
23–25, 27, 28
1–4, 9, 10,
12, 14, 16–
18, 24–25,
27, 28
102(a) Manara
1–4, 9, 10, 12,
14, 16–18,
24–25, 27,28
1–4, 9–20,
22–29 103(a)
Varenna 2012,
Varenna 2016,
Manara,
Bruehl
Gatti, La
Montagna,
Muratore
1–4, 9–20,
22–29
5–8, 21 103(a)
Varenna 2012,
Varenna 2016,
Manara,
Manicourt
5–8, 21

Through Reissue or Reexamination During a Pending AIA Trial
Proceeding. See 84 Fed. Reg. 16,654 (Apr. 22, 2019). If Patent Owner
chooses to file a reissue application or a request for reexamination of the
challenged patent, we remind Patent Owner of its continuing obligation to
notify the Board of any such related matters in updated mandatory
notices. See 37 C.F.R. § 42.8(a)(3), (b)(2)
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Claims 35 U.S.C. §
Reference(s)/
Basis
Claims
Shown
Unpatentable
Claims Not
Shown
Unpatentable
30 103(a)
Varenna 2012,
Varenna 2016
Manara,
Schwarzer,
Bruehl,
Gatti, La
Montagna,
Muratore
30
1–30 112(a) 1–30
Overall
Outcome 1–30

IV. ORDER
Accordingly, it is
ORDERED that claims 1–30 of the ’999 patent are unpatentable; and
FURTHER ORDERED that, because this is a Final Written Decision,
parties to the proceeding seeking judicial review of the decision must
comply with the notice and service requirements of 37 C.F.R. § 90.2.

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FOR PETITIONER:
Daniel Minion
Bruce Haas
VENABLE LLP
dminion@venable.com
bchaas@venable.com

FOR PATENT OWNER:
Brent Johnson
Parrish Freeman
MASCHOFF BRENNAN
bjohnson@mabr.com
pfreeman@mabr.com