Quest Diagnostics Investments LLC

Patent Trials and Appeals Board

Sep 1, 2020

IPR2019-00738 (P.T.A.B. Sep. 1, 2020)

Trials@uspto.gov Paper No. 36
571-272-7822 Date: September 1, 2020

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

LABORATORY CORPORATION OF AMERICA HOLDINGS,
Petitioner,
v.
QUEST DIAGNOSTICS INVESTMENTS LLC,
Patent Owner.
____________

IPR2019-00738
Patent No. US 8,409,862 B2
____________

Before ULRIKE W. JENKS, SUSAN L. C. MITCHELL, and
ROBERT A. POLLOCK, Administrative Patent Judges.

JENKS, Administrative Patent Judge.

FINAL WRITTEN DECISION
35 U.S.C. § 318(a) and 37 C.F.R. § 42.73

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I. INTRODUCTION
Laboratory Corporation of America Holdings (“Petitioner”) filed a
Petition requesting inter partes review of claims 1, 2, and 4–14 (“the
challenged claims”) of U.S. Patent No. US 8,409,862 B2 (Ex. 1001, “the
’862 patent”). Paper 1 (“Pet.”). Quest Diagnostics Investments LLC (“Patent
Owner”) filed a Patent Owner’s Preliminary Response. Paper 7 (“Prelim.
Resp.”). With our authorization, Petitioner filed a Reply to the Preliminary
Response (Paper 10), and Patent Owner filed a Sur-reply (Paper 12). On
September 4, 2019, we instituted an inter partes review of claims 1, 2, and
4–14 of the ’862 patent. Paper 14 (“Dec. Inst.”), 31.
Patent Owner filed a Response to the Petition. Paper 20 (“PO Resp.”).
Petitioner filed a Reply. Paper 27 (“Pet. Reply”). Patent Owner filed a Sur-
reply (Paper 29, “PO Sur-reply”).
An oral hearing was held on June 3, 2020, a transcript of which has
been entered in the record. Paper 35 (“Tr.”).
Pursuant to 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73, we issue this
Final Written Decision. Having considered the record before us, we
determine that Petitioner has shown by a preponderance of the evidence that
claims 1, 2, and 4–14 of the ’862 patent are unpatentable. See 35 U.S.C.
§ 316(e) (2018).
A. Related Proceedings
The parties identify the following matter in which the ’862 patent has
been asserted: Quest Diagnostics Investments LLC v. Laboratory Corp. of
America Holdings, No. 1:18-CV-01436-UNA (D. Del. Sept. 17, 2018).
Pet. 1; Paper 5, 1.
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B. The ’862 Patent (Ex. 1001)
The ’862 patent is titled “Determination of Testosterone by Mass
Spectrometry.” Ex. 1001, code (54). The ’862 patent issued from
Application No. 12/946,785 (“the ’785 application”), filed November 15,
2010, which ultimately claims the benefit of U.S. Provisional Application
No. 60/501,255, filed Sept. 8, 2003. Id. at code (60).
The ’862 patent explains that “[t]estosterone levels are much lower in
females compared to males. . . . The clinical manifestations of excess
testosterone in females include infertility, hirsutism, amenorrhea, and
obesity.” Id. 1:49–56. The ’862 patent explains that “[t]estosterone strongly
binds to plasma proteins such as sex hormone-binding globulin (SHBG) or
testosterone-estradiolbinding globulin (TEBG). Testosterone also binds with
low affinity to CBG (cortisol-binding globulins) and albumin. Less than
2.5% of testosterone circulates unbound to plasma proteins.” Id. 1:60–65.
The ’862 patent exemplifies sample preparation from serum prior to
detection of testosterone by ionization mass spectrometry. Id. 12:10–45
(Example 1), see also 16:15−21 (“Female samples were run on both RIA
and HTLC/MS/MS Testosterone assays”). According to the Specification,
[t]he terms “mass spectrometry” or “MS” . . . refer to
methods of filtering, detecting, and measuring ions based on
their mass-to-charge ratio, or “m/z.” In general, one or more
molecules of interest are ionized, and the ions are subsequently
introduced into a mass spectrographic instrument where, due to
a combination of magnetic and electric fields, the ions follow a
path in space that is dependent upon mass (“m”) and charge
(“z”).
Id. at 6:27–35.
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The ’862 patent describes that samples containing testosterone should
be purified prior to ionization, citing numerous methods for purifying
testosterone such as high performance liquid chromatography (HPLC), thin
layer chromatography (TLC), and high turbulence liquid chromatography
(HTLC) among others. See id. 3:7–44. “[P]urification refers to a procedure
that enriches the amount of one or more analytes of interest [such as
testosterone] relative to one or more other components of the sample.” Id.
3:50–54. Any of the known purification methods can be used alone or in
combination. Id. 3:17–18. The ’862 patent explains that liquid
chromatography (LC) and high-performance liquid chromatography (HPLC)
require a significant amount of sample preparation prior to the separation
and subsequent analysis with a mass spectrometer (MS). Id. 6:8–14.
The ’862 patent describes methods for determining the presence or
amount of testosterone in a test sample by ionizing the testosterone present
in a sample so it is detectable by a mass spectrometer. Ex. 1001, code (57).
“[T]he testosterone ions detectable in a mass spectrometer include ions with
a mass/charge ratio (m/z) of 289.1±0.5, 109.2±0.5, and/or 96.9±0.5, the
latter two being fragments of the larger ion.” Id. 2:36–39. The preferred
internal testosterone standard is 2,2,4,6,6-d5-testosterone having a
mass/charge ratio (m/z) of 294.1±0.5, 113.2±0.5 and/or 99.9±0.5. Id.
2:42−49. The ’862 patent acknowledges that numerous ionization methods
are known and available. Id. 3:59–67, 7:19–34.
The mass spectrometer typically provides the user with an ion
scan; that is, the relative abundance of each m/z over a given
range (e.g., 100 to 900). The results of an analyte assay, that is,
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a mass spectrum, can be related to the amount of the analyte in
the original sample by numerous methods known in the art.
Id. 4:19–24. The ’862 patent explains that “one can quantitate the amount of
testosterone in a sample by comparing the summed daughter ion signal of
the unknown sample with a standard curve of summed daughter ion signals
for known amounts of testosterone.” Id. 3:2–6.
C. Illustrative Claim
Claim 1, the sole independent claim under consideration in the present
proceeding involving ’862 patent is illustrative and reproduced below:
1. A method for determining the amount of testosterone
in a sample when taken from a female human, comprising:
(a) purifying testosterone from a sample from a female
human, wherein said purifying comprises extracting
testosterone from said sample;
(b) ionizing said purified testosterone to produce one or
more testosterone ions detectable by a mass spectrometer; and
(c) detecting the amount of one or more of the
testosterone ion(s) by a mass spectrometer, wherein the amount
of one or more of the testosterone ion(s) is related to the
amount of testosterone in the sample;
wherein said testosterone is not derivatized prior to mass
spectrometry, and
wherein the method is capable of detecting testosterone
at concentrations of less than 10 ng/dL in the sample.
Ex. 1001, 19:50–65.
D. Prior art
Petitioner relies upon the following prior art (Pet. 11, 19−63):
Reference Patent / Publication Exhibit No.
S.D. Clarke
et al.
(“Clarke”)
Determination of Suppressed Testosterone
Levels in Human Serum by LC-MS/MS,
Proceedings of the 49th ASMS Conference
on Mass Spectrometry and Allied Topics,
1003
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Reference Patent / Publication Exhibit No.
Chicago, Illinois, May 27–31, 2001
R. Draisci et
al.
(“Draisci”)
Quantitation of anabolic hormones and
their metabolites in bovine serum and
urine by liquid chromatography-tandem
mass spectrometry, 870 J.
Chromatography A, 511–22 (2000)
1004
Robert L.
Fitzgerald &
David A.
Herold
(“Fitzgerald”)
Serum total testosterone: immunoassay
compared with negative chemical
ionization gas chromatography-mass
spectrometry, 42 Clin. Chem. 749–55
(1996)
1005
Petitioner also relies upon the Declaration of Robert L. Fitzgerald,
Ph.D. (Ex. 1002) to support its contentions. Patent Owner relies upon the
Declaration of Dr. Patrick Sluss Ph.D. (Ex. 2013) to support its opposition to
the Petition.
E. The Instituted Grounds of Unpatentability
Petitioner challenges the patentability of claims 1, 2, and 4–14 of the
’865 patent on the following grounds (Pet. 19–63):
Claim(s) Challenged Basis1 Reference(s)
1, 2, 5–7, 10–14 § 102(b) Clarke
8, 9 § 103(a) Clarke
4 § 103(a) Clarke and Fitzgerald
1, 2, 4–14 § 103(a) Draisci and Clarke

1 We apply pre-AIA 35 U.S.C. § 103 because the effective filing date of the
ʼ862 patent precedes the March 16, 2013, effective date for changes to
35 U.S.C. § 103. See MPEP § 2159 (Rev. 08.2017).
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II. ANALYSIS
A. Person of Ordinary Skill in the Art
The level of skill in the art is a factual determination that provides a
primary guarantee of objectivity in an obviousness analysis. Al–Site Corp. v.
VSI Int’l Inc., 174 F.3d 1308, 1324 (Fed. Cir. 1999) (citing Graham v. John
Deere Co., 383 U.S. 1, 17–18 (1966); Ryko Mfg. Co. v. Nu–Star, Inc., 950
F.2d 714, 718 (Fed. Cir. 1991)). In determining the level of skill in the art,
we consider the type of problems encountered in the art, the prior art
solutions to those problems, the rapidity with which innovations are made,
the sophistication of the technology, and the educational level of active
workers in the field. Custom Accessories, Inc. v. Jeffrey-Allan Indus., Inc.,
807 F.2d 955, 962 (Fed. Cir. 1986).
Petitioner asserts that a person of ordinary skill in the art (POSITA)
would have had at least a Masters or Ph.D degree in chemistry, or a related
field with several years of experience with various extraction methods, mass
spectrometry, and high performance liquid chromatography (HPLC),
including the use of such methods for determining levels of analytes in
biological samples. Pet. 18–19 (citing Ex. 1002 ¶ 12).
Patent Owner asserts that a person of ordinary skill in the art would
have “a bachelor’s degree in chemistry, medicinal chemistry, biochemistry,
pharmaceutics, or a related discipline and at least three to four years of
experience using chromatography to perform analytical assays to
characterize organic and/or biological materials.” PO Resp. 14. Alternately,
Patent Owner asserts that a person of ordinary skill in the art would have “an
advanced degree in these same fields and a lesser amount of experience.” Id.
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Based on the record as a whole, we find that Patent Owner’s
description more appropriately encompasses the broad education that the
person of ordinary skill in the relevant art may possess. Thus, we adopt that
description of the POSITA. We note, however, that neither party asserts
specifically that the ultimate conclusion of obviousness turns on the
adoption of a particular level of ordinary skill. We further note that the prior
art itself demonstrates the level of skill in the art at the time of the invention
and supports the breadth of Patent Owner’s description of a POSITA. 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
In an inter partes review based on a petition filed after November 13,
2018, such as the present Petition, the Board interprets a claim term by
applying “the standard used in federal courts, in other words, the claim
construction standard that would be used to construe the claim in a civil
action under 35 U.S.C. [§] 282(b), which is articulated in Phillips.”2 83 Fed.
Reg. 51,340, 51,343. Under that standard, the words of a claim “are
generally given their ordinary and customary meaning,” which is “the

2 See Changes to the Claim Construction Standard for Interpreting Claims in
Trial Proceedings Before the Patent Trial and Appeal Board, 83 Fed. Reg.
51,340, 51,340, 51,344 (Oct. 11, 2018) (amending 37 C.F.R. § 42.100(b)
effective November 13, 2018) (now codified at 37 C.F.R. § 42.100(b)
(2019)).
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meaning that the term would have to a person of ordinary skill in the art in
question at the time of the invention, i.e., as of the effective filing date of the
patent application.” Phillips v. AWH Corp., 415 F.3d 1303, 1312–13 (Fed.
Cir. 2005) (en banc) (citations omitted). Any special definitions for claim
terms must be set forth with reasonable clarity, deliberateness, and precision.
In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994).
Neither party requests construction of any terms. See generally Pet.;
PO Resp. 15. In a related litigation involving the ’862 patent, the district
court addressed several terms in dispute in that litigation. See Ex. 1036, 2.
We address one of the district court’s claim constructions below. In addition,
we address construction of the term “from a human female.”
1. “from a female human”
Patent Owner emphasizes that the phrase ‘“purifying testosterone
from a sample from a female human,’ from claim 1(a), requires a sample
from a female human.” PO Resp. 15. Petitioner agrees that the claim
requires a sample from a human female. See Tr. 6:10–11. We determine that
the plain and ordinary reading of the limitation recited in claim 1(a) is that
the sample to be purified is sourced from a human female.
2. “less than 10 ng/dL”
Claim 1 recites, “wherein the method is capable of detecting
testosterone at concentrations of less than 10 ng/dL in the sample.”
Patent Owner asserts that the claimed method requires quantifying
testosterone in a female human sample at the recited (below 10 ng/ ml) level.
see PO Resp. 21 (asserting that “not a single female human sample [in
Clarke] proves the purportedly anticipatory method” because the samples
tested in Clarke were not quantified). Petitioner disagrees, contending that
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“[t]he claims merely require the methods are capable of detecting
testosterone at certain concentrations, without limiting sample or injection
volumes or requiring high-throughput analysis.” Pet. Reply 3, 15 (“The
claims merely require the methods are capable of detecting testosterone at
certain concentrations, without limiting sample or injection volumes or
requiring high-throughput analysis.”).
In the related district court litigation involving the ’862 patent, the
court addressed the limitation “wherein the method is capable of detecting
testosterone at concentrations of less than 10 ng/dL [, 5 ng/dL, or 1 ng/dL] in
the sample,” of claims 1, 8, and 9, respectively, but did not address whether
the sample derived “from a human female” needs to actually be measured
below the detection level recited in the claim in order to meet the limitation.
See Ex. 1036, 2 (alteration in original).
We agree with Petitioner, that the claim does not require measuring
testosterone in a female sample below the recited detection limit, but need
only be “capable” of such measurement.3 See Pet. Reply 3–4. As the district
court also held, all that is required by the claim is that the method is able to
detect testosterone below said limitation. See Ex. 1036, 2 (the limitation
“shall be given its plain and ordinary meaning, which is ‘the method is able
to detect testosterone at concentrations below 10 ng/dL [or 5 ng/dL or
1 ng/dL] in the sample’”); see Ex. 1035, 138:18–20 (testimony of Patent
Owner’s expert, Dr. Sluss, that “the claims don’t indicate a limit of
quantitation. They are talking about limit of detection.”); Tr. 31:9–11 (Patent

3 Normal serum testosterone levels in human females range from 0.15 to
0.7 ng/ml (i.e. 15 to 70 ng/dL). Ex. 1003, 1.
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Owner’s counsel, stating: “[T]he method has to be capable of detecting
these levels of testosterone in a sample taken from a female human. There’s
no requirement that the measurement actually be done in a female human.”).
The ’862 patent describes the construction of standard curves encompassing
low concentrations of testosterone standards in the range of 0.25–2.5 ng/dL.
See Ex. 1001, 4:24–35; 15:15–45. The ’862 patent describes that the lower
limit of quantification is “the point where measurements become
quantitatively meaningful and concentration where CV of the replicates is
less than 20%.” Id. 15:18–20. In contrast the limit of detection is the ’862
patent is described as the mean counts per second of the zero standard plus
three standard deviations. Id. 14:63–65. In other words, limit of detection is
the lowest counts measured that can be distinguished from the zero standard.
Based on these disclosures, we determine that the record supports the
position that the plain reading of the claim limitation “below 10 ng/dL”
describes detecting testosterone above the zero standard but below the
recited level.
Upon review of the record, we agree with and adopt the district
court’s claim construction and determine that the plain and ordinary reading
of the limitation “the method is capable of detecting testosterone at
concentrations of less than 10 ng/dL [, 5 ng/dL, or 1 ng/dL] in the sample” is
that the method is able to detect testosterone below 10 ng/dL4 as recited in
the claim.

4 We note that dependent claims 8 and 9 recite a method for detecting
testosterone at a concentration of less than 5 ng/dL and 1 ng/dL respectively.
We determine that these claims similarly require that the method need only
be able to detect testosterone below 5 ng/dL and 1 ng/dL.
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In view of our analysis, we determine that construction of other claim
terms is not necessary for purpose of this Decision. See Vivid Techs., Inc. v.
Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999) (only terms that
are in controversy need to be construed, and only to the extent necessary to
resolve the controversy).
C. Principles of Law
In an inter partes review, the burden of persuasion is on the petitioner
to prove “unpatentability by a preponderance of the evidence,” 35 U.S.C.
§ 316(e), and that burden never shifts to the patentee. Dynamic Drinkware,
LLC v. National Graphics, Inc., 800 F.3d 1375, 1378 (Fed. Cir. 2015).
To establish anticipation under 35 U.S.C. § 102(b), “all of the
elements and limitations of the claim must be shown in a single prior
reference, arranged as in the claim.” Karsten Mfg. Corp. v. Cleveland Golf
Co., 242 F.3d 1376, 1383 (Fed. Cir. 2001). When evaluating a single prior
art reference in the context of anticipation, the reference must be
“considered together with the knowledge of one of ordinary skill in the
pertinent art.” In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994) (quoting
In re Samour, 571 F.2d 559, 562 (CCPA 1978)). “‘[T]he dispositive
question regarding anticipation [i]s whether one skilled in the art would
reasonably understand or infer from the [prior art reference’s] teaching’ that
every claim element was disclosed in that single reference.” Dayco Prods.,
Inc. v. Total Containment, Inc., 329 F.3d 1358, 1368 (Fed. Cir. 2003)
(second and third alterations in original) (quoting In re Baxter Travenol
Labs., 952 F.2d 388, 390 (Fed. Cir. 1991)).
A patent claim is unpatentable under 35 U.S.C. § 103(a) if the
differences between the claimed subject matter and the prior art are such that
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the subject matter, as a whole, would have been obvious at the time the
invention was made to a person having ordinary skill in the art to which said
subject matter pertains. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406
(2007). The question of obviousness is resolved on the basis of underlying
factual determinations, including: (1) the scope and content of the prior art;
(2) any differences between the claimed subject matter and the prior art; (3)
the level of skill in the art; and (4) objective evidence of nonobviousness.
Graham v. John Deere Co. of Kansas City, 383 U.S. 1, 17–18 (1966).
“[A] patent composed of several elements is not proved obvious
merely by demonstrating that each of its elements was, independently,
known in the prior art.” KSR, 550 U.S. at 418. “[I]t can be important to
identify a reason that would have prompted a person of ordinary skill in the
relevant field to combine elements in the way the claimed new invention
does.” Id. Accordingly, a party who petitions the Board for a determination
of unpatentability based on obviousness must show that “a skilled artisan
would have been motivated to combine the teachings of the prior art
references to achieve the claimed invention, and that the skilled artisan
would have had a reasonable expectation of success in doing so.” In re
Magnum Oil Tools Int’l, Ltd., 829 F.3d 1364, 1381 (Fed. Cir. 2016)
(citations omitted).
We analyze the instituted grounds of unpatentability in accordance
with the above-stated principles.
D. Ground 1: Anticipation based on Clarke
Petitioner asserts that claims 1, 2, 5–7, and 10–14 are unpatentable as
anticipated by Clarke. Pet. 19–33. Patent Owner disagrees. PO Resp. 16–37.
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1. Overview of Clarke
Clarke is titled “Determination of Suppressed Testosterone Levels in
Human Serum by LC-MS/MS” and relates to an experimental protocol for
determining testosterone levels in serum. Ex. 1003, 1. Clarke’s method
allows for monitoring testosterone levels from a patient serum sample and
shows “a lower limit of quantification of 50 pg/mL,” which is equivalent to
5 ng/dL.5 Id.; see also id. at 2 (“The lower limit of quantification (LLOQ), as
defined by the lowest QC [(quality control)] at which accuracy was within
80-120% of nominal and precision was better than ±20%, was 50 pg/mL”).
Clarke discloses that the normal range for testosterone in serum in males is
3.5 to 10.8 ng/ml, while the normal range for females is 0.15 to 0.7 ng/ml.
Id. at 1.6
Clarke’s experimental method contains three steps: (1) sample
preparation step using solid phase extraction (SPE) cartridges (e.g. Isolute
Array C18 100 mg/ 2 ml (96 well format)); (2) high pressure liquid
chromatography (HPLC) step using a Genesis C18 column; and (3) mass
spectrometry detection and quantification by monitoring ions at 289.2 →
97.1 (testosterone), and 292.2 → 97.1 (D3-testosterone). Id.
Clarke discloses that one of the issues with determining testosterone
levels in serum “is obtaining suitable ‘blank’ serum” needed for testing and
quantification. Id. Clarke describes three approaches for obtaining a “blank”

5 The formula for converting pg/ml → ng/DL is: pg/ml X (1 ng/1000 pg) X
(100 mL/1 dL) = ng/dL. See Ex. 1002 ¶ 36 fn 2. Thus, 50 pg/ml is equal to
5 ng/dL. Id.
6 The formula for converting ng/ml → ng/dL is: ng/ml X (100 mL/1 dL).
Accordingly, Clarke discloses that the normal ranges for testosterone in
serum is 350 to 1,080 ng/dL in males and 15 to 70 ng/dL in females.
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serum: (1) use of a surrogate matrix (i.e. equine (gelding) serum), (2)
removal of testosterone from serum using a specific testosterone antibody,
and (3) using charcoal stripped plasma. Id. Clarke’s experimental protocol
opted to use equine (gelding) serum as a blank and relied on “stable
isotopically labelled testosterone for preparation of calibration and quality
control standards, quantifying the samples against the calibration line for the
isotopically labelled testosterone.” Id. Clarke discloses using control human
serum containing endogenous levels of testosterone as the “low QC level”
control. Id. Clarke also discloses comparing calibration lines made with
gelding serum, as well as human female serum. Id. at 2.
2. Analysis
We agree with Petitioner and find that Clarke teaches each of the
elements of claims 1, 2, 5–7, and 10–14 for the reasons set forth in the
Petition and the declaration of Dr. Fitzgerald. Pet. 19–33; Ex. 1002 ¶¶ 45–
56. Patent Owner opposes. PO Resp. 16–37. Specifically, Patent Owner
contends that Clarke (a) is not a printed publication (b) does not anticipate
the claims (c) is not enabled, and (d) is not peer reviewed. PO Resp. 16–37.
We address Patent Owner’s contention below.
(a) Printed publication
Each asserted ground of unpatentability relies on the Clarke reference.
Pet. 11. Clarke is an abstract disclosed on a compact disk (CD) which is a
compellation of the Proceedings of the 49th ASMS Conference on Mass
Spectrometry and Allied Topics. Ex. 1003. Petitioner relies on declarations
from Ms. Waters, a librarian at the University of Wisconsin-Madison library
system, to establish the availability of the Clarke abstract. Pet. 13, n1 (citing
Ex. 1017). Pet. Reply 5 (citing Ex. 1017 and Ex. 1030). In the initial
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declaration Ms. Waters avers to the standard operating procedures for adding
materials to the library system. Ex. 1017.7 In response to Patent Owner’s
Reply, Petitioner submitted the Supplemental Watters Declaration to clarify
issues with the bar code numbering on the CD in the library system, and to
the ability to search the CD. See Ex. 1030.8 Petitioner relies on these two
Watters Declarations to establish that the Clarke abstract is a printed
publication that was publically available more than one year before the
earliest priority date of the ’862 patent and, thus, available as prior art under
§102(b). Pet. 13, n1 (citing Ex. 1017); see Pet. Reply 4–6 (citing Ex. 1030).
In addition, Petitioner relies on the American Society for Mass Spectrometry
(ASMS) website to show that the abstracts were searchable. Pet. Reply
(citing Ex. 1029; Ex. 1032); Tr. 9:9–10 (“We’re relying on the catalogued
CD. And we used the distribution to members as well as libraries to show
that one with skill in the art would have been aware of the proceedings.”).
To qualify as a “printed publication,” 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)
(quoting In re Klopfenstein, 380 F.3d 1345, 1350 (Fed. Cir. 2004)).
“Because there are many ways in which a reference may be disseminated to

7 Declaration of Rachel J. Watters on authentication of publication, dated
Dec. 14, 2018 (Ex. 1017 (“Watters Declaration”)).
8 Declaration of Rachel J. Watters, dated Sept. 30, 2019 (Ex. 1030
(“Supplemental Waters Declaration”)).
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the interested public, ‘public accessibility’ has been called the touchstone in
determining whether a reference constitutes a ‘printed publication’ bar under
35 U.S.C. § 102(b).” In re Hall, 781 F.2d 897, 898–99 (Fed. Cir. 1986); see
also SRI Int’l, Inc. v. Internet Sec. Sys., 511 F.3d 1186, 1194 (Fed. Cir.
2008) (quoting Hall). “A reference will be 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.’” Blue Calypso, LLC v. Groupon, Inc.,
815 F.3d 1331, 1348 (Fed. Cir. 2016) (quoting Kyocera Wireless Corp. v.
ITC, 545 F.3d 1340, 1350 (Fed. Cir. 2008)). Petitioner bears the burden of
establishing public accessibility of the prior art references it relies upon for
its patentability challenges. See Blue Calypso, 815 F.3d at 1350 (finding that
petitioner in an AIA proceeding “failed to carry its burden of proving public
accessibility”). As the cases make clear, a document may be a printed
publication based on either (1) actual dissemination to people of ordinary
skill in the art or (2) being made available to the extent that persons
interested and ordinarily skilled in the subject matter or art, exercising
reasonable diligence, can locate it.
Petitioner relies the declarations from Ms. Waters, Dr. Fitzgerald, and
Dr. Voyksner to establish that Clarke is a printed publication. Pet. 13, n.1;
Pet. Reply 4–6. The first Waters Declaration describes the standard
processing procedures for receiving and cataloging new library holdings into
the Wisconsin-Madison library system. See Ex. 1017, 1. This Waters
Declaration includes a copy of a CD from the 49th ASMS Conference on
Mass Spectrometry and Allied Topics (Ex. 1017, 3), a copy of the CD sleeve
with the barcode (id. at 4), and a copy of the public library catalog screen
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(id. at 5). The Supplemental Waters Declaration clarifies the differences
between the handwritten numbering on the CD and the two bar codes
associated with the CD sleeve. Ex. 1030, 2–3. In addition, the Supplemental
Watters Declaration also provides a copy of the information downloaded
from the disk describing how the information can be viewed, searched, and
retrieved, including a list of key words. See Ex. 1030, 2, 4–17.
The Fitzgerald Declaration details that Dr. Fitzgerald is a member of
the ASMS but did not attend the 49th meeting held in Chicago, Illinois on
May 2001. Ex. 1002 ¶ 34. Dr. Fitzgerald avers that proceedings from this
meeting were distributed to all members of the ASMS. Id.
The Voyksner Declaration details that Dr. Voyksner is also a member
of ASMS and avers that members are routinely provided with copies of the
abstracts from the annual conference within a few months after the
conference. Ex. 1029 ¶¶ 4, 6.
Patent Owner contends that the Declarations of Dr. Fitzgerald,
Dr. Voyksner, and Ms. Watters are insufficient to support the position that
the Clarke reference was actually disseminated to people of ordinary skill in
the art. PO Resp. 32–37. Specifically, Patent Owner contends that “[t]he
Watters Declaration [(Ex. 1017)] provides no evidence that Clarke was
published, catalogued, indexed, or identified in any useful way by the
University of Wisconsin-Madison library system prior to the critical date of
the ’862 patent.” Id. at 37. In other words, Patent Owner contends that the
Watters Declaration (Ex. 1017) does not speak to the ability of persons
interested and ordinarily skilled in the subject matter or art, exercising
reasonable diligence, to have located the Clarke reference. Patent Owner
contends that a CD is very different from a textbook. Id. Even if a POSITA
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would have located the CD, “finding Clarke would have required a POSITA
to exhaustively sift through thousands of abstract pages at random without
any guidance or idea concerning what might be found.” Id.; PO Sur-Reply 8.
Because a CD “has no index or table of contents and its list of subject
keywords would not have led a POSITA to Clarke.” PO Resp. 37; see PO
Sur-Reply 10–11.
Petitioner responds that the two Watters Declarations and
accompanying exhibits sufficiently explain how the ASMS conference
proceeding, and therefore the Clarke reference, was available to the public.
Pet. Reply 4–6 (citing Ex. 1017 and Ex. 1030). Petitioner explains that a
search at the University of Wisconsin “library catalog could be done by title,
author, and/or subject key words based on the Proceedings’ title and notes
the CD itself was searchable.” Id. at 5 (citing Ex. 1017, 2). Thus, according
to Petitioner, a person interested in mass spectrometry would be able to
locate the CD of the ASMS conference proceedings at the library. Petitioner
explains that:
The CD containing abstracts is similar to a book with chapters
by different authors. A POSITA, exercising reasonable
diligence, could have searched the catalog records (like
searching for a book on MS) and then searched the CD (like
reviewing chapter titles or index of a book) to access the Clarke
abstract. Moreover, the content of the abstracts was searchable
at the ASMS website.
Id. (citing Ex. 1029; Ex. 1032).
We determine that the record supports the position that the ASMS
produced a compact disk from the 49th ASMS Conference on Mass
Spectrometry and Allied Topics, and that abstracts from this conference
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proceeding were available at the University of Wisconsin library in the form
of a compact disk at least on July 16, 2002. Ex. 1017, 5; see Ex. 1030, 1−3.
[I]ndexing is not ‘a necessary condition for a reference to be
publicly accessible’; it is but one among many factors that may
bear on public accessibility. . . . Moreover, indexing is no more
or less important in evaluating the public accessibility of online
references than for those fixed in more traditional, tangible
media.
Voter Verified, Inc. v. Premier Election Solutions, Inc., 698 F.3d 1374, 1380
(Fed. Cir. 2012) (citing Lister, 583 F.3d at 1312). Here, the University of
Wisconsin library system is treating the compact disk from the ASMS
Conference Proceeding as a “general (book),” i.e. tangible media. See Ex.
1017, 5; see Ex. 1030. Not all books are searchable by a computer search
engine. Indeed retrieval of information from a book (i.e. tangible media) can
require that the interested person physically open the book to access the
information contained inside. Here, the evidence supports the position that
“[a] POSITA, exercising reasonable diligence, could have searched the
catalog records (like searching for a book on MS)” and retrieved the CD of
the 49th ASMS conference proceeding. Pet. Reply 5.
In addition to being catalogued at the University of Wisconsin library,
the record supports that in the normal course of these ASMS meetings the
conference proceedings were regularly distributed to all 3500 ASMS
members. Ex. 1002 ¶ 34;9 Ex. 1029 ¶ 6.10 The purpose of presenting an

9 We note that Dr. Fitzgerald does not attest to when he received the copy of
the proceeding abstracts.
10 We note that Dr. Voyksner attested to attending the 49th ASMS
Conference (Ex. 1029 ¶ 4), but does not mention any specific abstract in the
declaration (Ex. 2008, 27:2–4).
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abstract at a conference is public communication of the relevant information.
This is true whether the abstract is physically displayed,11 presented in a talk,
or published as part of the proceeding – the purpose in any of these scenarios
is to communicate the information to the relevant interested audience. Here,
the evidence provided with the Petition supports the position that the Clarke
Abstract was disseminated to the relevant audience, i.e. members of ASMS,
as part of the information disclosed on the CD. See Ex. 1017, 3–5; Ex 1030,
8 (“A record number of 4,182 people attended the conference.”). Petitioner
relies on the declarations of Dr. Fitzgerald and Dr. Voyksner, both ASMS
members, to establish that as an ASMS member, one would receive meeting
abstracts whether or not one attends the meeting, which supports the position
that the meeting abstracts were publicly accessible by the relevant audience.
See Pet. Reply 3 (citing Ex. 1002 ¶ 34), 4 (citing Ex. 1029 ¶ 6).
Based on these disclosures, we find that the evidence supports that a
POSITA searching for information about mass spectrometry would have
been able to locate the 49th ASMS conference proceeding. In addition, the
evidence supports the position that the information was disseminated to
ordinarily skilled artisans, in this case ASMS members at the time of the 49th
ASMS conference. See Ex. 1002, ¶ 34; Ex. 1029, ¶ 6; Ex. 1030, 8.
Patent Owner contends that a CD differs from a book because it does
not have an index and its list of subject keywords would not have led the
POSITA to Clarke. PO Resp. 37 (citing 2009, 20:6–14); see PO Sur-Reply
8. Thus, Patent Owner’s position is that a POSITA could not have searched

11 We note there is no evidence in the record that establishes that the Clarke
Abstract was actually presented at the meeting.
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the CD for “testosterone” in order to retrieve the Clarke abstract. See Tr.
34:18–19.
We determine that the record sufficiently supports the position that the
CD of the 49th ASMS conference proceeding was searchable. The Voyksner
Declaration includes two exhibits that show that at the time of the
proceedings the abstracts of 49th ASMS conference proceeding were
searchable by keyword, title of the abstract, title of the session, author, and
author institution, similar to the index of a book. Ex. 1029 ¶ 5; Ex. 1030, 8–
18. We agree with Patent Owner that “testosterone” is not among the
keywords listed for the abstract entry on the CD. See PO Resp. 35; PO Sur-
Reply 8; Ex. 1030, 8–10. The Clarke abstract is titled “Determination of
Suppressed Testosterone Levels in Human Serum by LC-MS/MS.” Ex.
1003. A review of the keywords that are listed for the CD of the 49th ASMS
conference proceeding shows the following keywords: LC-MS/MS (use
instead MS/MS, Liquid Chromatography); MS/MS; MS/MS, Liquid
Chromatography-(LC-MS/MS); Tandem Mass Spectrometry (use instead:
MS/MS); and Plasma, human. Ex. 1030, 8–10. The key words LC-MS/MS
and human are present in the Clarke abstract. Accordingly, a POSITA
interested and LC-MS/MS would have been able to find the Clarke abstract
based on the keyword search capabilities of the CD.12 Thus, we are not
persuaded by Patent Owner’s contention that Clarke was not available

12 The CD has not been searched for human, LC-MS, or LC-MS/MS, but
based on the list of keywords provided with the CD, it is reasonable to
assume that the number of abstracts retrieved would have been reduced from
the initial 1600. See Tr. 36:2–25.
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because one could not have found Clarke among the more than 1600
abstracts presented at the meeting.
For the foregoing reasons, we determine that Petitioner has shown that
Clarke is a printed publication based on the CD of the proceedings of the
49th ASMS Conference on Mass Spectrometry and Allied Topics as
cataloged in the University of Wisconsin library system. See Ex. 1017, 3;
Ex. 1030, 2.
(b) Anticipation
Petitioner contends that “Clarke describes methods for determining
testosterone levels in [female] human serum by (a) purifying the
testosterone, (b) ionizing the testosterone to produce mass spectrometer
detectable ions, and (c) detecting the ions,” all without the need of
derivatization at concentration levels of less than 10 ng/dL in the sample.
Pet. 20.
Patent Owner contends that Clarke is not capable of detecting
testosterone at concentrations of less than 10 ng/dL in female samples.
PO Resp. 17. Patent Owner questions Clarke’s use of equine gelding serum
as a control noting that this is not a standard reference serum. Id. at 18.
Patent Owner contends that Clarke does not provide a sufficient description
on how the serum samples were “spiked.” Id. at 19 (citing Ex. 2013 ¶ 53).
Nor does Clarke describe how the endogenous levels of testosterone in
equine gelding serum are accounted for in the reference. Id. at 20 (citing Ex.
1003, 2; Ex. 2013 ¶ 79 (“Equine gelding serum has been reported to contain
trace amounts of endogenous testosterone. Ex. 2020 (Soma) at 1 (noting that
serum testosterone levels have been reported as being 15.3 ± 4.9 pg ⁄ mL in
geldings).”).
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Much of the discussion in the briefing revolves around the difference
between limit of detection (LOD or LoD) versus limit of quantitation (LOQ
or LoQ). A figure is helpful to visualize these concepts. The figure below is
from a review article and shows the relationship between limit of blank
(LoB), limit of detection (LoD), and limit of quantification (LoQ).

The Figure, reproduced above, shows the distribution results for LoB, LoD,
and LoQ. Ex. 1020, 3; see Ex. 2025, 34. “It can be expected that the LoD
lies somewhere below an assay’s functional sensitivity. The LoQ may be
equivalent to the LoD or it could be at a much higher concentration (Figure);
it cannot be lower than the LoD.” Ex. 1020, 3; see Ex. 2025, 27. Put another
way, the LoD is either the same or lower than LoQ.
Both Patent Owner’s and Petitioner’s experts agree that the limit of
detection (LOD) is the lowest amount of testosterone that one can detect. See
Ex. 1035, 135:1–3 (Patent Owner’s expert, Dr. Sluss testifies: “The limit of
detection is exactly that, what is the smallest amount that you can detect.”),
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138:19–20 (“[The claims] are talking about a limit of detection”); Ex. 2012,
150:3–6 (Petitioner’s expert, Dr. Fitzgerald testifies: “Q: So when you use
the word “capable” or the phrase “capable of detecting” in your report here,
are you referring to the limit of detection? A: Yes.”); Ex. 1002, ¶¶ 28, 29.
Based on our review of the arguments and the cited art, we determine
that Petitioner has demonstrated that claim 1 is anticipated by Clarke. Clarke
discloses that female serum is used as a quality control sample for measuring
low testosterone levels. Ex. 1003, 1 (“Control human (female) serum
containing an endogenous level of testosterone used as the low QC level”).
Clarke also discloses the production of calibration lines using both gelding
serum and female human serum. Id. at 2 (“A calibration line was prepared in
each of six different human female sera and compared against a calibration
line in equine gelding serum.”). Clarke discloses using labeled testosterone
for the production of calibration and quality control standards. Id. at 1
(“stable isotopically labelled testosterone for preparation of calibration and
quality control standards, quantifying the samples against the calibration line
for the isotopically labelled testosterone.”). Clarke also measured the
endogenous testosterone level (pg/ml) from human female 1–6. Id. at 2.
Based on these disclosures, we agree with Petitioner that Clarke uses
samples derived from a female human. Pet. 21 (citing Ex. 1003, 1
(Experimental) (“human (female) serum containing an endogenous level of
testosterone used as the low QC level” (emphasis removed)). We are not
persuaded by Patent Owner’s characterization that Clarke is missing any
element of the claim.
Clarke explains that normal female serum testosterone levels range
from 0.15 to 0.7 ng/ml, i.e., 17–70 ng/dL. Ex. 1003 at 1; footnote 6, supra.
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Clarke discloses that the experimental range of endogenous testosterone
level in the six female serum samples tested is 199 pg/ml–471 pg/ml, i.e.,
19.9–47.1 ng/dL. Ex. 1003, 1–2; see footnote 5, supra. That all of Clarke’s
female samples fall within the normal range expected for females is not
surprising because Clarke uses these samples only as a way to validate low
endogenous testosterone concentrations. Id. Claim 1 of the ’862 patent
requires that the method be able to detected below 10 ng/dL, the claim does
not require that the female sample tested needs to be at that level. See supra
Section II.B. The fact that Clarke’s female serum samples are not below the
level of detection recited in the claim does not detract from what the
reference teaches – a protocol that can be used to detect testosterone from
human female serum with an assay that has a lower limit of quantification at
50 pg/dL.13 Ex. 1003, 2. Because the limit of detection is either the same as
the limit of quantification or lower, the disclosure in Clarke meets the
claimed detection limit. See Ex. 1002 ¶¶ 28, 29, 57; Ex. 1020, 3; Ex. 2025,
27, 34.
Clarke exemplifies obtaining readings of a control sample at a
concentration of 50 pg/ml (5 ng/dL). Ex. 1003, 2; Ex. 1002 ¶ 57 (“Clarke
shows that, using the disclosed assay, a standard of 50 pg/mL had a mean
reading of 46.8 pg/ml (4.68 ng/dL), a CV14 (precision) of 14.1%, and
accuracy of 93.6%”). Based on this disclosure, we agree with Petitioner that
Clarke is capable of detecting concentrations of less than 10 ng/dL in a

13 This is equivalent to 5 ng/dL. See above footnote 5.
14 “The CV, or coefficient of variation, is also referred to as the RSD, or
relative standard deviation.” Ex. 1002 ¶ 29.
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sample. Pet. 20 (citing Ex. 1002 ¶ 50 (“Clarke reports that their assay has an
LOQ of 50 pg/ml (which equals 5 ng/dL)”).
Patent Owner contends that Petitioner is treating samples sourced
from different mammals as if they were interchangeable. PO Resp. 15 (citing
Ex. 2013 ¶ 55). From the background section of the ’862 patent we know
that “[t]estosterone strongly binds to plasma proteins such as sex hormone-
binding globulin (SHBG) or testosterone-estradiol binding globulin (TEBG).
Testosterone also binds with low affinity to CBG (cortisol-binding
globulins) and albumin.” Ex. 1001, 1:60–63. In accord with Patent Owner’s
argument, we agree that the degree of testosterone binding in native plasma
or serum may be species specific.
Petitioner’s position, however, is that the detection of testosterone in
the method occurs after a purification step that enriches the testosterone
while removing other components. See Pet. 47. In other words, once
testosterone is removed from its native matrix, such as blood, plasma, serum,
or urine, testosterone is interchangeable in the analysis method because the
testosterone molecule itself is the same molecule across species. Pet. 47
(citing Ex. 1002, ¶¶ 27 (“[T]he structure of testosterone is the same across
vertebrate species”), 62 (“Testosterone is the same chemical entity in both
bovine and human samples. . . . Once extracted, the testosterone from
various mammalian species behaves similarly in chromatography and mass
spectrometry steps.”); see also U.S. Patent No. 4,452,903, 5:12–15
(Ex. 1027) (describing testosterone standards prepared using human
testosterone in a bovine serum base); Tr. 24:13–15 (counsel for Patent
Owner stating “I’m not aware of any evidence of record that discuss species
difference in testosterone at a molecular level.”). We, therefore, agree with
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Petitioner that once purified from the native matrix, testosterone is not
structurally different between species. Compare Ex. 1003, 1 (ions monitored
289.2→97.1 (testosterone) testing human and gelding samples) with Ex.
1004 (m/z 289→97 for both 17α-testosterone and 17β-testosterone testing
bovine samples). Accordingly, based on our review of the arguments and the
cited art, we agree with Petitioner that purified testosterone is the same
molecule between species and therefore reasonably interchangeable across
testosterone assays. Pet. 47 (citing Ex. 1002 ¶¶ 25, 62; Ex. 1027).
Patent Owner contends that Clarke does not disclose how the
calibration lines are made and therefore it would be impossible to interpret
or believe the results. PO Resp. 21–22 (citing Ex. 2013 ¶¶ 48 (Patent
Owner’s expert, Dr. Sluss testifying: “Clarke does not provide sufficient
experimental detail to allow replication of the disclosed information or even
an objective evaluation of it by a POSITA.”), 83). Patent Owner contends
that there is a linearity problem at low concentration levels. Id. at 23–24
(citing Ex. 2013 ¶ 82). According to Patent Owner, “a POSITA would not
believe Clarke’s LLOQ disclosure of 50 pg/mL.” Id. at 25.
We determine that Petitioner has the better position in light of
evidence that routine experimental protocols that a POSITA would use in the
ordinary course of doing research, such as producing a calibration line,
would not require detailed instructions. See Pet. Reply 2 (citing Ex. 1035,
99:14–16 (deproteination); 156:20–157:9 (dissolving testosterone to make
standards); 165:6–15 (column selection); 214:19–215:2 (“[A]ny first year
analytical chemist knows how to” create a calibration line); 230:22–231:2
(checking for matrix effects); 242:4–243:24 (determining injection
volumes); 256:23–257:3 (adapting methods for animal testing to human
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testing)). Clarke discloses that “[t]he method described has been fully
validated to international standards for the rapid, specific and accurate
quantitation of suppressed levels of testosterone in human serum.” Ex. 1003,
2. Given that POSITA would know something about making calibration
lines, and given Clarke’s description that the method has been fully
validated to international standards, we are not persuaded by Patent Owner’s
position that Clarke’s method is so unsound that the results are unbelievable.
Patent Owner contends that Clarke does not describe how the
endogenous levels of testosterone in equine gelding serum are accounted for
in the reference. PO Resp. 20 (citing Ex. 1003, 2; Ex. 2013 ¶ 79 (Patent
Owner’s expert, Dr. Sluss testifying: “Equine gelding serum has been
reported to contain trace amounts of endogenous testosterone. Ex. 2020
(Soma) at 1 (noting that serum testosterone levels have been reported as
being 15.3 ± 4.9 pg ⁄ mL in geldings).”).
We are not persuaded by Patent Owner’s contention. Even assuming
that the gelding serum was not treated to remove endogenous testosterone,
which is standard practice in this art, 15 that would mean that 50 pg/ml
sample disclosed in Clarke could contain an additional 15.3 ± 4.9 pg ⁄ mL
(Ex. 2013 ¶ 51 (citing Ex. 2024 at 1)) bringing the sum total of testosterone
in Clarke’s lower limit sample to 65.3 pg/ml, i.e. 6.5 ng/dL. This amount,
however, would still meet less than 10 ng/dL detection limit as recited in

15 See e.g. Ex. 2025, 11 (“For endogenous compounds, blanks might be
samples that are stripped of the component, e.g., by precipitation by an
antibody, by enzymatic degradation, or by adsorption to charcoal, etc.”);
Ex. 2021, 2 (“Steroid-free sera were charcoal stripped sera prepared in the
laboratory.”).
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claim 1 of the ’862 patent. See Ex. 1002 ¶ 36 n.2 (conversion formula
“pg/ml X (1 ng/1000 pg) X (100 mL/1 dL) = ng/dL”).
Patent Owner contends that Clarke’s results are “dubious considering
that the coefficient of variation (CV%) is higher at 50 pg/mL in the ‘intra
batch’ data than the ‘inter batch’ data,” when the expectation is that “[i]ntra
batch numbers should have less variance (i.e., a lower CV%) than inter batch
numbers.” PO Resp. 25–26 (citing Ex. 2013 ¶¶ 60–61); see Sur-Reply 15–
16.
We are not persuaded by Patent Owner’s contention because the CV%
values assayed for the other points in the table are indeed less for the intra
batch variance than the inter batch variance. The lowest point measured is
the 50 pg/ml which has an accuracy at 93% and is still within the ±20%
precision limit set out by Clarke. A POSITA would understand that the limit
of detection is either the same or, more likely, lower than the limit of
quantification. See Ex. 1002 ¶¶ 28, 29, 57; Ex. 1020, S51; Ex. 2025, 27, 34.
Having determined that Clarke measures serum samples derived from
human females and is able to not only detect but quantify testosterone at a
level of 50 pg/ml (i.e. 5 ng/dL), we find that Petitioner has shown by a
preponderance of the evidence that claims 1, 2, 5–7 and 10–14 of the ’862
patent are unpatentable as anticipated by Clarke.
(c) Enabling Disclosure
Patent Owner contends that Clarke does not adequately describe the
method and thereby is not an enabling disclosure. PO Resp. 26–32.
To anticipate a claimed invention, a prior art reference must enable
one of ordinary skill in the art to make the prior invention without undue
experimentation. Amgen Inc. v. Hoechst Marion Roussel, Inc., 314 F.3d
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1313, 1354 (Fed. Cir. 2003). The burden of proving non-enablement of a
prior art reference rests on the Patent Owner. Impax Labs., Inc. v. Aventis
Pharms., Inc., 545 F.3d 1312, 1316 (Fed. Cir. 2008) (patentee may
overcome the presumption of enablement by establishing with persuasive
evidence that the prior art does not enable the claimed invention). See
Edmund Optics Inc. v. Semrock, Inc., IPR2014-00599, Paper 72, 26–28
(PTAB Sept. 16, 2015).
Anticipation does not require the actual creation or reduction to
practice of the prior art subject matter; anticipation requires only an enabling
disclosure. See Schering Corp. v. Geneva Pharms., Inc., 339 F.3d 1373,
1380 (Fed. Cir. 2003); citing In re Donohue, 766 F.2d 531, 533 (Fed. Cir.
1985).
Some experimentation, even a considerable amount, is not “undue” if,
e.g., it is merely routine, or if the disclosure provides a reasonable amount of
guidance as to the direction in which the experimentation should proceed.
Factors to be considered in determining whether a disclosure
would require undue experimentation . . . include (1) the
quantity of experimentation necessary, (2) the amount of
direction or guidance presented, (3) the presence or absence of
working examples, (4) the nature of the invention, (5) the state
of the prior art, (6) the relative skill of those in the art, (7) the
predictability or unpredictability of the art, and (8) the breadth
of the claims.
In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988).
(1). Wands Factors #1 and #2: The quantity of experimentation and
amount of direction or guidance presented
Patent Owner contends that the 2-page Clarke abstract is sparse on
detail and thereby it would require undue experimentation. PO Resp. 28
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(citing Ex. 2013 ¶ 137; Ex. 2012, 119:11–120:9, 144:8–156:9). For example,
Patent Owner notes that there is no description in how the samples were
“spiked” or other “[v]ariables like pre-column sample preparation (such as a
protein precipitation step), column preparation, flow rate, wash and
extraction solvents, temperature, bead size, and pH are all absent from
Clarke.” PO Resp. 27–29 (citing Ex. 2013 ¶¶ 76, 94, 137).
Clarke describes sample preparation using solid phase extraction
(SPE) using Isolute Array C18 cartridge, component separation using a
Genesis C18 chromatography column, and detection of the components
using a mass spectrometry SCIEX API 3000 instrument. Ex. 1003, 1; Pet.
Reply 12. Clarke also provides extraction details such as the starting sample
volume and the final extraction volume for the initial sample preparation.
Ex. 1003, 1. Clarke describes component separation by describing the
specific column used, the mobile phase applied, the flow rate, and the
injection volume as well as the runtime. Id. For the mass spectrometry
component Clarke provides the instrument, the mode, and interface as well
as the instructions for monitoring the particular ions 289.2 →97.1
(testosterone) and 292.2 → 97.1 (D3-testosterone). Ex. 1003, 1.
Clarke discloses that “[a] calibration line was prepared in each of six
different human female sera and compared against a calibration line in
equine gelding serum.” Ex. 1003, 2. Clarke may not have provided details
on how the sample was “spiked” or how the calibrations were made but a
POSITA would have understood how to perform such assays and would not
need to have every detail spelled out. See Pet. Reply 12; PO Resp. 22 (citing
Ex. 21013 ¶ 48); see Ex. 1035, 157:1–6 (Patent Owner’s expert, Dr. Sluss
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testifying: “You can’t put testosterone at reasonably high concentrations into
water or in aqueous solution. It has to first go into an organic [solvent]. That
is the nature of – that’s the non-polar nature of testosterone, and it would be
well known.”), 232:1–3 (“In principle. The details [of a standards assay] are
always a little different, but the basic concepts I would expect to be quite
similar.”). Because testosterone is very hydrophobic Patent Owner contends
that saying a sample was “spiked” is not enough to enable to procedure. PO
Resp. 28 (citing Ex. 2013 ¶ 76). We are not persuaded by this argument
because this presumes that the POSITA would have no knowledge about
testosterone, how to dissolve testosterone, how to set up calibration curves,
or how to run a standard LC-MS/MS assay. The POSITA is presumed to
have ordinary creativity and intelligence. KSR, 550 U.S. at 421; see also In
re Sovish, 769 F.2d 738, 743 (Fed. Cir. 1985).
Based on these disclosures, we agree with Petitioner that “a POSITA
necessarily adapts the information disclosed in or missing from the reference
to the particular parameters of the POSITA’s needs.” Pet. Reply 11 (citing
Ex. 2012, 119:11–120:9; Ex. 1035, 165:6–15). Just because some variables
need to be experimentally determined does not mean that the level of
experimentation is undue. The creation of calibration standards are routine
variables. See Hybritech Inc. v. Monoclonal Antibodies, Inc., 802 F.2d 1367,
1384 (Fed. Cir. 1986) (“[A] patent need not teach, and preferably omits,
what is well known in the art.” (Citation omitted)).
Accordingly, we find that Wands factors #1 and #2 weigh in favor of
enablement.
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(2). Wands Factor #3: The presence or absence of working
examples
Patent Owner contends that Clarke lacks working examples. PO Resp.
29 (citing Ex. 2013 ¶ 89). Patent Owner contends that Clarke is missing
certain information requiring experimentation to replicate Clarke’s work. Id.
29–30 (citing Ex. 2013 ¶ 89 (Patent Owner’s expert, Dr. Sluss testifying:
“Clarke lacks directions or working examples to guide a POSITA and those
gaps could only have been filled with extensive experimentation.”).
The question here is how much information is required for POSITA to
replicate Clarke’s experiments. Clarke discloses preparing calibration lines
for each of the six different human female samples tested as well as the
gelding serum. Ex. 1003, 2. Clarke describes that each of these lines were
then compared against the calibration line using equine gelding serum. Id.
Clarke also determines the endogenous testosterone levels in at least six
female samples. Id.; Pet. Reply 17 (citing Ex. 1003 1–2; Ex. 1002 ¶¶ 36, 50,
55). Clarke describes that the method was fully validated to international
standards. Ex. 1003, 2. Creating a calibration line or standard is something a
POSITA would know how to do. See Ex. 1035, 232:1–3 (Patent Owner’s
expert, Dr. Sluss testifying: “In principle. The details [of creating a standard]
are always a little different, but the basic concepts I would expect to be quite
similar.”). Based on these disclosures, in conjunction with what a POSITA
would know about making calibration lines and standards, we agree with
Petitioner that Clarke recites working examples for detecting testosterone in
samples derived from human females. Clarke’s human female sample may
not have low enough testosterone levels to fall within the claim detection
limit, but the levels are well within the normal range for human females. The
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claim does not require that the females’ samples have low testosterone
levels. Ex. 1003, 1. All that is required by claim 1 of the ’862 patent is that
the assay is able to detect low levels testosterone. We determine that
Clarke’s lower limit of quantification (LLOQ) at 50 pg/ml (5 ng/dL) meets
the claimed low detection level.
Accordingly, we find that Wands factor #3 weighs in favor of
enablement.
(3). Wands Factors #4, #5, #6, and #7: The nature of the invention;
state of the prior art; relative skill of those in the art; and the
predictability or unpredictability of the art
Patent Owner contends that the ’862 patent was a breakthrough in the
field and that the level of skill is relatively high. PO Resp. 30 (citing
Ex. 2013 ¶ 36). “It is undisputed that LC/MS-MS was a brand new
technique for the detection of testosterone in the early 2000s,” and thereby
unpredictable. PO Resp. 31 (citing Ex. 2013 ¶ 14; Ex. 2012, 66:16–67:8).
We are not persuaded that detecting testosterone using LC-MS/MS
method steps is unpredictable. As discussed above (see II.A), we find that
the relative skill of the artisan is one having a degree in chemistry, medicinal
chemistry, biochemistry, pharmaceutics, or a related discipline and several
years of experience using chromatography to perform analytical assays to
characterize organic and/or biological materials; years of experience
required is inverse to the degree held. With this skill level in mind we
address the nature of the invention, state of the art, and unpredictability of
the art.
We agree with Petitioner that LC/MS-MS is a known technique that
has been used for years at least with respect to the purification of other
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molecules. Pet. Reply 15 (citing Ex. 1026, Ex. 1023, 21–22); Ex. 1002
¶¶ 20–25.
We note that Draisci published in 1999, describes quantification of
testosterone using a combination of liquid chromatography (LC) with MS
(mass spectrometry) and MS-MS (tandem mass spectrometry). Ex. 1004, 10.
Specifically, Draisci describes that a serum “sample was purified by solid-
phase extraction (SPE) using a C18 cartridge (Baker C18, 500 mg, 3 ml
cartridges).” Id. at 11. Draisci describes using mass spectrometry for
quantification of the protonated molecule, [M +H]+ at m/z 275 for 17α-19-
nortestosterone and, m/z 289 for 17α-testosterone and 17β-testosterone, and
m/z 291 for [2H2]17β-testosterone) as deuterated internal standard (I.S.) and
two product ions for each anabolic hormone were identified for selected
reaction monitoring (SRM) LC-MS-MS analyses. Id. Draisci describes that
detection of the samples does not require the use of derivitization. Id. Based
on at least these disclosures in Draisci in conjunction with the other
references cited by Petitioner, we are not persuaded by Patent Owner’s
contention that LC/MS-MS was a brand new technique for the detection of
testosterone in the relevant time frame.
Accordingly, we find that Wands factors #4, #5, #6, and #7 weigh in
favor of enablement.
(4). Wands Factor #8: The breadth of the claims
Patent Owner contends that Clarke’s disclosure “contains no test
results from a female human sample that remotely approach the ’862
patent’s claimed detection limits.” PO Resp. 31. Patent Owner argues that
just because “Clarke purports to ‘report’ results does not mean that a
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POSITA could recreate the techniques used to obtain those results without
undue experimentation.” Id. at 32.
Petitioner contends that Patent Owner narrows the state of the art and
the breadth of the claims to LC-MS/MS methods as to only apply to
testosterone, thereby “ignoring that each of the individual claimed method
steps had been known and used for years and that characteristics of
testosterone had been known for years as well.” Pet. Reply 15 (citing
Ex. 1026; Ex. 1023, 21–22).
We agree with Petitioner that Patent Owner is narrowing the claims to
require that a human female sample test below the detection limit set out in
the claim. Claim 1 of the ’862 patent, does not require that the female
sample tested actually has a low testosterone level; the claim only requires
that the assay is able to detect testosterone at the recited low-level. Thus,
Patent Owner’s contention that Clarke did not test serum samples from a
human female in the range claimed by the ’862 patent is not persuasive. See
Ex. 1003, 2.
Patent Owner contends that Clarke does not provide sufficient
explanation on the methodologies used to arrive at the data disclosed and
therefore the data is unbelievable at the lowest point measured. PO Sur-
Reply 21–24 (citing Ex. 2013 ¶¶ 48, 80−83). Patent Owner contends
“[a]chieving these results [as presently claimed] was extremely difficult—so
much so that Dr. Fitzgerald needed to employ two different extraction steps
and a derivatization16 step in a LC/MS-MS assay he and colleagues

16 It is our understanding that derivatization is a way to improve the
ionization efficiency so that the molecule of interest is easier to detect by the
mass spectrometer. Derivatization adds additional steps and is often not
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developed more than three years after the ‘862 patent to even come close to
these levels.” PO Resp. 31(citing Ex. 2013 ¶ 97; Ex. 2010, 6–9). We are not
persuaded.
Clarke may not have disclosed how many samples were measured in
creating the calibration lines, but that does not mean that the results are
unbelievable. Ex. 1003, 2. Creating calibration lines and formulating stock
testosterone solutions to use as control would be something that a first-year
chemistry student is expected to perform and, thus, does not entail undue
experimentation. See Ex. 1035, 214:19–215:2 (Patent Owner’s expert, Dr.
Sluss testifying: “[A]ny first year analytical chemist knows how to” create a
calibration line.). Accordingly, we are not persuaded by Patent Owner’s
contention that the information disclosed in Clarke is insufficient. We agree
with Petitioner that the claimed methods do not require a clinical laboratory
application, thus, any arguments with respect to testing sufficiency or lack
thereof to clinical standards is not persuasive. Pet. Reply 15.

Moreover, Clarke’s results are consistent with other prior art of
record. Kushnir uses Strata X solid-phase extraction (SPE) columns, a 50 x
2.0 (i.d.) mm Phenomenex Luna C18 column with 5-μm particles, and an
API 4000™ triple-quadrupole mass spectrometer. Ex. 2010, 2. These are
different columns and instruments than those used by Clarke. Ex. 1003, 2. In
addition, “the serum samples [in Kushnir] are limited to 100 μl, the [HPLC]

desirable because it adds time and expense to a given procedure. See Ex.
1002 ¶ 35 (“[O]ne of the advantages of the HPLC method [for detecting
testosterone] was avoidance of the cost and time associated with a
derivatization step.” (Citing Ex. 1004, 10)).
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injection volume limited to 15 μl” which is different from the 500 μl sample
size used in Clarke. Pet. Reply 15 (citing Ex. 2010 at 2–3); Ex. 2012,
157:16–18; Ex. 1003, 2. It was understood by the POSITA that increasing
sample size is one way to get an improved signal of a low abundance
analyte. See Ex. 2012, 157:20–23. Petitioner’s expert Dr. Fitzgerald, one of
the authors of the Kushnir reference, explained that “this method [of
Kushnir] was being developed to be a high-volume lab method. It doesn’t
mean that we were optimizing it for -- to show that we could get down to an
LOD of 10.” Ex. 2012, 175:8–11. It is not surprising that an assay that starts
with less sample would show a reduced level of detection (LOD) because
less sample would have fewer testosterone molecules. Therefore, we are not
persuaded by Patent Owner’s contention that Clarke’s results are
unbelievable.
Accordingly, we find that Wands factor #8 weighs in favor of
enablement.
(5). Summary
A prior printed publication enjoys the same presumption of
enablement as does a patent disclosure. See In re Antor Media Corp., 689
F.3d 1282, 1288 (Fed. Cir. 2012). “[U]ndue experimentation
experimentation is determined based on both the nature of the invention and
the state of the art.” Id. at 1290 (citation omitted). Upon balancing the
Wands factors, we determine that Patent Owner has not met its burden of
production, i.e. sufficient arguments or evidence which overcome the
presumption that Clarke is enabled as to detecting testosterone at less than
10 ng/dL in the sample as required by claim 1.
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(d) Peer review
Patent Owner contends that “Clarke was not peer reviewed and there
is no evidence that its methods were properly validated.” PO Resp. 16.
Petitioner responds that “Clarke is cited for the method it discloses.”
Pet. Reply 10. “Neither length nor review status of a prior art reference is
determinative of enablement.” Pet. Reply 7 (citing Iovate Health Scis., Inc.
v. Bio-Engineered Supplements & Nutrition, Inc., 586 F.3d 1376, 1380–83
(Fed. Cir. 2009)). Clarke does not need to “include details known to a
POSITA.” Pet. Reply 8 (citing Genentech, Inc. v. Novo Nordisk A/S, 108
F.3d 1361, 1366 (Fed. Cir. 1997)).
We find that Petitioner has the better position. “[A reference] must be
read, not in isolation, but for what it fairly teaches in combination with the
prior art as a whole.” In re Merck & Co., Inc., 800 F.2d 1091, 1097 (Fed.
Cir. 1986). As discussed above, even if Clarke does not provide every
minutia of their experimental protocol the reference does provide the basic
information necessary from which a POSITA could reconstruct the
experimental design. The pertinent information includes the volume of
sample loaded and extracted from the SPE column, the make and brand of
the SPE column, the make and brand of the HPLC column, the flow rate, the
mobile phase and the injection volume loaded onto the HPLC column, as
well as information about the mass spectrometer used and the ions
monitored. Ex. 1003, 1. Creating calibration lines and formulating stock
testosterone solutions to use as control would be something that a first-year
chemistry student is expected to perform. See Ex. 1035, 214:19–215:2
(Patent Owner’s expert, Dr Sluss testifying: “[A]ny first year analytical
chemist knows how to” create a calibration line.). Additionally, we note that
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Clarke discloses that “[t]he method described has been fully validated to
international standards for the rapid, specific and accurate quantitation of
suppressed levels of testosterone in human serum.” Ex. 1003, 2. We
therefore, determine that Clarke provides sufficient detail from which to
replicate the experiments and determine that the results disclosed are on its
face believable.
3. Summary
Having determined that Clarke is a printed publication, and contains
an enabling disclosure, we find that Petitioner has shown by a
preponderance of the evidence that claims 1, 2, 5–7, and 10–14 are
anticipated by Clarke.
E. Ground 2: Obviousness based on Clarke
In its Petition, Petitioner asserts that the limitations of claims 8 and 9
are rendered obvious by Clarke. Pet. 33–42. Claim 8 recites that the “method
is capable of detecting testosterone at concentrations of less than 5 ng/dL in
the sample.” Claim 9 recites that the “method is capable of detecting
testosterone at concentrations of less than 1 ng/dL in the sample.” Petitioner
also relies on the declaration of Dr. Fitzgerald. Ex. 1002, ¶¶ 24–26, 36, 57–
59. Patent Owner opposes. PO Resp. 38–45.
Petitioner contends that one of ordinary skill in the art would have
known that detecting extremely low levels of testosterone is clinically
relevant. Pet. 37 (citing Ex. 1021, Ex. 1022, Ex. 1002 ¶¶ 24, 58). Petitioner
acknowledges that Clarke did not expressly test testosterone concentrations
below 5 ng/dL using their methods. Id. at 39. Based on the lowest level
tested in Clarke, however, it would be reasonable to infer that Clarke’s
protocol can achieve lower levels of detection. Specifically, Petitioner
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contends that “the CV for both the intra-batch and inter-batch analysis
[tested in Clarke] of a 50 pg/mL [(which is equivalent to 5 ng/dL)] standard
are better than the required 20%, namely, 15.8% and 14.1%.” Id. According
to Petitioner, Clarke’s lowest tested sample is well within accuracy and
precision limits described in the protocol, and therefore, it would be
reasonable to conclude that lower limits can be reached before the readings
fall outside these parameters. See id. (citing Ex. 1002, ¶ 57 (“[N]oting the
range and where the reported accuracy and precision data fell in Clarke, one
of skill in the art that was in search of a lower LOQ would have been
motivated to assess lower concentration standards to determine whether the
assay would be useful at detecting lower levels of testosterone.”), id. ¶ 58
(“[A] skilled artisan would have known how to modify the method of
Clarke. For example, instead of an injection volume of 50 μl, the person of
skill in the art could have injected a larger volume.”)).
Patent Owner contends that neither the “less than 5 ng/dL” nor the
“less than 1 ng/dL” detection “limits is disclosed in Clarke for any kind of
sample (whether taken from a female human or any other source).” PO
Resp. 38. Patent Owner contends that simply “optimizing” some random
variable is “speculative guesswork comes with neither a reason to make
specific changes nor a reasonable expectation of success.” Id. Patent Owner
contends that the seven (or possibly eight) parameters that could potentially
be modified would result in an excessively large number of combinations
that would need to be tested. Id. at 42 (citing Ex. 2012 at 134:1–15, 155:12–
159:18; Ex. 2013 ¶ 101).
Petitioner asserts that Clarke’s method would be capable of detecting
levels slightly lower than the 5 ng/dL is expressly disclosed in Clarke. See
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Pet. 39. Petitioner asserts that one of skill in the art in the field of
chromatography would have understood the various ways Clarke’s method
could be manipulated to further lower the threshold of detectability Pet. 41
(citing Ex. 1002 ¶ 58 (Petitioner’s expert, Dr. Fitzgerald testifying: “[A]
skilled artisan would have known how to modify the method of Clarke. For
example, instead of an injection volume of 50 μl, the person of skill in the
art could have injected a larger volume.”)). To reach a finding of
obviousness, it is proper to “take account of the inferences and creative steps
that a person of ordinary skill in the art would employ.” KSR, 550 U.S. at
418, see also id. at 421 (“A person of ordinary skill is also a person of
ordinary creativity, not an automaton.”). “Obviousness does not require
absolute predictability of success . . . all that is required is a reasonable
expectation of success.” In re Kubin, 561 F.3d 1351, 1360 (Fed. Cir. 2009).
Petitioner contends that the need to measure very low testosterone
levels in certain clinical subjects was known, thereby providing a motivation
to “optimize Clarke’s method to detect testosterone at concentrations of less
than 1 ng/dL.” Pet. 41 (citing Ex. 1002 ¶ 59), 37 (citing Ex. 1021, 1–2 (“sera
from children and women, in whom very low (0.17 nmol/L) and low (<1.7
nmol/L) testosterone concentrations are expected.”)). The evidence supports
Petitioner’s position that measuring low testosterone levels are known to be
clinically relevant, and therefore provides sufficient motivation to improve
the detection limits of Clarke’s testosterone assay.
Petitioner’s expert Dr. Fitzgerald avers that one of ordinary skill in the
relevant art would have recognized various ways to manipulate Clarke’s
method in order to further improve the limits of detection. Pet. 41 (citing
Ex. 1002 ¶ 59). Parameters for modification of an LC-MS/MS assay include:
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type of instrumentation used; type of extraction technique; resolution
settings for the instrument; volume of the sample used for extraction;
volume of the sample injected into the LC/MS system; column type; and
type of liquid chromatography. See Pet. 41–42 (citing Ex. 1002 ¶¶ 25, 58,
59); PO Resp. 41–42 (citing Ex. 1002 ¶ 25).
We are not persuaded by Patent Owner’s contention that the
parameters for modification are too numerous for one of ordinary skill in the
art to improve upon the methods of Clarke with any reasonable expectation
of success. See PO Resp. 41. When modifying an assay the POSITA would
not make a wholesale change with all parameters at the same time. The
POSITA would start with increasing sample volume used for extraction as
well as the volume injected into the LC/MS system before making changes
in the hardware (i.e. HPLC column, SPE column, mass spectrometer). See
Ex. 1002 ¶ 25 (Petitioner’s expert, Dr. Fitzgerald testifying: “[A] larger
injection volume would contain more testosterone than a smaller volume and
one of skill in the art would have routinely identified the suitable volume to
optimize sensitivity.”).
Patent Owner contends that optimizing Clarke’s method would have
been anything but routine. See PO Resp. 41–45. Specifically, Patent Owner
contends that increasing injection volume would not increase detection. Id.
at 43. Patent Owner contends that Petitioner’s expert, Dr. Fitzgerald,
acknowledges that the proposed specific suggestions such as injecting a
larger volume or the use of a more concentrated sample “would have
increased the signal but come at the cost of lower resolution and higher
background noise.” PO Resp. 43 (citing Ex. 1002 ¶ 58). Patent Owner’s
expert, Dr. Sluss, similarly suggests that increasing the volume “would come
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at the cost of resolution and higher background noise,” and this could lead to
peak overlap resulting in “inaccurate quantification of components.”
Ex. 2013 ¶ 129 (citing Ex. 2007 ¶ 26); PO Resp. 43 (citing 2007 ¶ 25).
Dr. Voyksner’s testimony also explains that increasing the injection volume
may cause different components to overlap or not be completely resolved
resulting in inaccurate quantification of the components. Ex. 2007 ¶¶ 25, 26;
PO Resp. 43; Ex. 1012 ¶ 102. We are not persuaded.
Just because increased volume can result in a lower accuracy with
respect to quantification does not mean that the component of interest –
testosterone – is not reasonably detected with the application of a larger
sample.
Here, both experts agree that the POSITA would have recognized that
increasing the volume of the sample would increase the signal even if it
comes at the peril that the signal may not be as clear. Ex. 2012, 157:16–23;
Ex. 2013 ¶ 129. The claims, however, are not directed to quantifying
testosterone where signal clarity and peak saturation may be an issue, the
claims are directed to detecting testosterone levels in a sample. As
Petitioner’s expert explains, the limit of quantification (LOQ) is generally
higher than the limit of detection (LOD). Ex. 1002 ¶ 28 (citing Ex. 1020);
Ex. 2025 at 27, 34. The evidence supports the position that one may detect
the presence of a component with an assay before one can accurately
quantify that component with the same assay. See Ex 1020 at 4; Ex. 2025 at
34; Ex. 1002 ¶ 28. Therefore, we are not persuaded by Patent Owner’s
position that increasing the volume of injection would not result in more
sensitive detection of testosterone. PO Resp. 43 (citing Ex. 2007 ¶ 25).
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Another way of improving assay sensitivity is by modernizing the
equipment. Petitioner’s expert Dr. Fitzgerald explained that by using a
newer more sensitive mass spectrometer they were able to develop a
simplified LC-MS/MS analysis for testosterone, which further supports the
position that improvements in instrumentation technology can improve assay
sensitivity. Ex. 2012 at 180:17–181:1; see Ex. 1002 ¶ 25; Ex. 2010 at 4
(“Evaluation of the method performance on API 3000 and API 4000 tandem
mass spectrometers (using conditions optimal for each instrument and the
oxime derivative of Te) revealed that the assay performed on the API 4000
was ~8-fold more sensitive.17”).
Patent Owner contends that Petitioner’s expert Dr. Fitzgerald also
tried to solve the need for more sensitive and specific testosterone assays but
could only reach the 1 ng/dL without the use of derivatization. PO Resp. 44
(citing Ex. 2010); Ex. 2013 ¶ 97. In other words, Patent Owner’s position is
that because others have tried and failed, therefore, the disclosure in Clarke
is unbelievable and should not be given any weight.
We are not persuaded by Patent Owner’s contention that failure by
others in the field undermines Clarke’s methods and results. In the paper by
Dr. Fitzgerald and collaborators, cited by Patent Owner, the method steps
include use of a different mass spectrometer, a different C18 column, and a
different solid extraction column than those used in Clarke’s reference.
Compare Ex. 2010 at 2–3 with Ex. 1003 at 1. As Dr. Voyksner explains
“[d]ifferent columns, even if they are same type of columns, such as C18

17 We would expect the same improvement in sensitivity if optimized for
non-derivatized testosterone. We note that Clarke uses the SCIEX API 3000
mass spectrometer. Ex. 1003 at 1.
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columns, have different surface chemistries, which will affect the retention
time, elution order, peak separation and peak height and peak area.”
Ex. 2007 ¶ 20. Thus, comparing Clarke with other methods that use different
instruments, different columns, and different sample preparation methods
does not persuade us that Clarke’s methods and results are unreliable.
Having determined that there is sufficient motivation to direct the
POSITA to improve on the testosterone detection limit disclosed in Clarke,
we determine that there is also a reasonable expectation of success in
lowering the detection to below the claimed limit by manipulating variables
such as injection volume, sample size, or even by upgrading the
instrumentation. We, therefore, find that Petitioner has shown by a
preponderance of the evidence that claims 8 and 9 of the ’862 patent are
unpatentable as obvious over Clarke.
F. Ground 3: Obviousness based on Clarke and Fitzgerald
Petitioner asserts that the combination of Clarke and Fitzgerald
teaches all the limitations of claim 4 to render the claim obvious. Pet. 42–43.
Petitioner relies on the declaration of Dr. Fitzgerald. Ex. 1002, ¶¶ 25, 35,
42–44, 60. Patent Owner opposes. PO Resp. 45–51.
1. Overview of Fitzgerald
Fitzgerald is titled “Serum total testosterone: immunoassay compared
with negative chemical ionization gas chromatography-mass spectrometry.”
Ex. 1005, 1. Fitzgerald teaches that there are no reported methods capable of
accurately quantifying serum testosterone over the entire clinically important
range of 0.69–69.3 nmol/L. Id. Fitzgerald teaches that “[p]revious GC-MS
methods for the analysis of serum testosterone involved rigorous purification
procedures combining liquid-liquid extraction, chromatography, and (or)
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solid-phase extraction.” Id. Fitzgerald describes its sample preparation as
follows:
Sample preparation for GC-MS. The internal standard (50 μL
of 3.5 μ.mol/L testosterone-d3) was added to 1 mL of plasma or
serum and samples were briefly vortex-mixed. Ethyl acetate
(3 mL) was added, followed by vortex-mixing for 1 min.
Samples were centrifuged (1850g for 10 min), and the organic
layer was pipetted into a 100 X 13 mm screw-cap test tube and
evaporated to dryness at 40 °C under a gentle stream of
nitrogen.
Id. at 2. Fitzgerald concludes that purification of testosterone before any
assay procedure is important not only for analyzing infant samples but also
when analyzing female samples. Id. at 7. Fitzgerald teaches that after liquid
purification, the sample was derivatized before analysis in the gas
chromatography-mass spectrometer analyzer. Id. at 2.
2. Analysis
Petitioner asserts that Clarke teaches all the limitations of claim 1. As
discussed above (see II.D.2) we determine that Petitioner has presented a
prima facie case that Clarke meets all limitations of claim 1. Claim 4
contains all the limitations of claim 1 and further recites purifying using a
liquid extraction step. Petitioner acknowledges that Clarke does not disclose
a liquid extraction step but relies on Fitzgerald for teaching that liquid
extraction is a known method for purifying testosterone from a sample.
Petition 42 (citing Ex. 1005, 1–2; Ex. 1002 ¶ 60). Petitioner asserts that one
of skill in the art would have been motivated to modify Clarke with the
liquid extraction step disclosed in Fitzgerald, based on the similarity of the
methods. Pet. 43.
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Patent Owner disagrees. PO Resp. 45–51. Patent Owner contends that
one of ordinary skill in the art would have had no motivation to combine
Clarke and Fitzgerald. Id. at 46. “The test for determining if there was a
reason or motivation cannot rest on the mere fact that certain substitutions
would have been feasible or appropriate.” Id. (citing Ruiz v. AB Chance Co.,
234 F.3d 654, 665 (Fed. Cir. 2000)). Patent Owner contends that Clarke and
Fitzgerald confronted different problems and the solutions identified in each
are not interchangeable. Id. at 46–47. Patent Owner contends that the mixing
and matching of extraction techniques as proposed by Petitioner is
impermissible hindsight. Id. at 47. “Petitioner’s contention that the methods
disclosed in Clarke (solid phase extraction) and Fitzgerald (liquid phase
extraction) were “similar” or “routine,” . . . is insufficient to establish a
motivation to combine.” Id. at 40.
The parties dispute whether a POSITA would have had a reason to use
the liquid extraction step taught in Fitzgerald in place of the SPE (“solid
phase extraction”) taught in Clarke. Here, both Clarke and Fitzgerald are
directed to detection of testosterone in serum samples indicating they are
from the same field of endeavor. Ex. 1003; Ex. 1005. Both Clarke and
Fitzgerald are interested in detecting low levels of testosterone in serum
samples. For example, Clarke discloses that in order to measure suppressed
levels of testosterone in castrated patients a lower limit of quantification of
50 pg/ml was required. Ex. 1003 at 1. Fitzgerald discloses that the relevant
clinical range for testosterone to detection is 0.69-69.3 nmol/L. Ex. 1005.
Based on these disclosures we find that both references are interested in
measuring low levels of testosterone.
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“[W]hen a patent claims a structure already known in the prior art that
is altered by the mere substitution of one element for another known in the
field, the combination must do more than yield a predictable result.” KSR,
550 U.S. at 416, citing United States v. Adams, 383 U.S. 39, 50–51 (1966).
It is obvious to those skilled in the art to substitute one known equivalent for
another, be those equivalents method steps or apparatus components. See In
re Omeprazole Patent Litig., 483 F.3d 1364, 1374 (Fed. Cir. 2007); see In re
Fout, 675 F.2d 297, 301, (CCPA 1982) (“Express suggestion to substitute
one equivalent for another need not be present to render such substitution
obvious.”).
Petitioner’s expert, Dr. Fitzgerald avers that a POSITA would have
had a reasonable expectation of success in combining the teachings of
Clarke and Fitzgerald. Ex. 1002 ¶ 60 (“One of skill in the art seeking an
alternative to solid phase extraction (SPE) would readily adopt the well-
accepted and tested method of liquid extraction from the limited options
available.”). We agree with Petitioner’s position that given the knowledge
that testosterone needs to be purified before applying the sample to an LC–
MS/MS detection system a POSITA trying to improve the method of Clarke
would be motivated to consider other well-known testosterone extraction
methods such as the liquid extraction step taught in Fitzgerald. Pet. Reply 22
(citing Ex. 2012, 155:12–16).
Additionally, we note that the claims of the ’862 patent are
sufficiently broad that they are not limited to a single extraction technique.
Fitzgerald teaches that regardless of the detection method when analyzing
infant or female samples better results are obtained when the samples are
first purified for testosterone before analysis. Ex. 1005, 7. Fitzgerald
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additionally teaches that there are numerous purification procedures
available to obtain serum testosterone and that these procedures can be used
either separately or in combination. Id. at 1. Thus, there is a reasonable
expectation that the combination of SPE and liquid extraction can be applied
to purifying testosterone before the application of LC-MS/MS for detection.
We find that under the KSR standard of obviousness the combined
teachings of Clarke and Fitzgerald would have rendered claim 4 obvious. In
particular, we note that the POSITA is also a person of ordinary creativity.
Such a person would be familiar with testosterone purification and
quantification, and based on the record before us, such as person would have
known to substitute known purification procedures such as liquid-liquid
extraction purification taught in Fitzgerald for the equivalent solid-phase
purification taught in Clarke because such a combination is merely a
“predictable use of prior art elements according to their established
functions.” KSR, 550 U.S. at 417.
3. Summary
Having determined that there is sufficient motivation to direct the
POSITA to improve on the testosterone detection limit disclosed in Clarke,
we determine that there is also a reasonable expectation of success in
substituting the liquid extraction procedure of Fitzgerald for the SPE
procedure described in Clarke because such substitution would potentially
improve the testosterone detection in Clarke. We, therefore, find that
Petitioner has shown by a preponderance of the evidence that claim 4 of the
’862 patent is unpatentable as obvious over Clarke and Fitzgerald.
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G. Ground 4: Obviousness over Draisci and Clarke
In its Petition, Petitioner asserts that the limitations of claims 1, 2, and
4–14 are rendered obvious over Draisci and Clarke. Pet. 44–63. Petitioner
also relies on the declaration of Dr. Fitzgerald. Ex. 1002, ¶¶ 24–27, 36, 39,
45, 46, 57–59, 61–71, 74, 75. Patent Owner opposes. PO Resp. 51–61.
1. Overview of Draisci
Draisci is titled “Quantitation of anabolic hormones and their
metabolites in bovine serum and urine by liquid chromatography-tandem
mass spectrometry.” Ex. 1004, 9. The hormones quantified include: 17α-19-
nortestosterone, 17β-testosterone, and progesterone and their major
metabolites (17α-19-nortestosterone and 17α-testosterone). Id.
Draisci describes purification of the samples using a combination of
liquid chromatography (LC) with mass spectrometry (MS) and tandem mass
spectrometry (MS-MS). Id. at 10. Draisci describes that a serum “sample
was purified by solid-phase extraction (SPE) using a C18 cartridge (Baker
C18, 500 mg, 3 ml cartridges).” Id. at 11.
Draisci describes using mass spectrometry for quantification of the
protonated molecule, [M +H]+ at m/z 275 for 17α-19-nortestosterone and,
m/z 289 for 17α-testosterone and 17β-testosterone, and m/z 291 for
[2H2]17β-testosterone as deuterated internal standard (I.S.) and two product
ions for each anabolic hormone were identified for selected reaction
monitoring (SRM) LC-MS-MS analyses. Id. at 11. Draisci describes
producing standard curves for quantification ranging from “2-600 ng/ml
[(200-60000 ng/dL)] by plotting peak area ratios of the analyte to I.S. versus
hormone concentrations using a least-squares linear regression model.
Calibration curves were prepared daily by spiking serum and urine control
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samples with mixtures of the anabolic compounds to obtain concentration in
the range 0.1-30 ng/ml [(10-3000 ng/dL)].” Id. at 11–12.
Draisci describes that detection of the samples does not require the
use of derivatization. “The combination of liquid chromatography (LC) with
MS and MS-MS offers a rapid, simplified, specific and sensitive alternative
to GC-MS methods involving simple extraction procedures and removing
the need for derivatization reactions.” Id. at 10.
2. Analysis
We agree with Petitioner and find that the combination of Drasci and
Clarke teaches each of the elements of claims 1, 2, and 10–14 for the reasons
set forth in the Petition and the declaration of Dr. Fitzgerald. Pet. 44–64; Ex.
1002 ¶¶ 61–74. We address Patent Owner’s contentions that the evidence is
insufficient below.
We are not persuaded by Patent Owner’s contention that there is no
reason to combine Draisci and Clarke because they are directed to equine
and bovine samples and are not directed to “female human sample” as
recited in the claims. PO Resp. 52.
The POSITA would have known that detecting extremely low levels
of testosterone is clinically relevant in humans. Pet. 37 (citing Ex. 1021, Ex.
1022, Ex. 1002 ¶¶ 24, 58). Both Draisci and Clarke are directed at detecting
low levels of testosterone in serum samples extracted from female mammals.
See Ex. 1004, 11 (bovine female sample); Ex. 1003, 1–2 (human female
sample). Draisci and Clarke are analogous art with respect to testosterone
detection and are therefore reasonably combined. See In re Clay, 966 F.2d
656, 658–9 (Fed. Cir. 1992). Both references purify testosterone from serum
samples before detecting the presence of testosterone with a mass
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spectrometer. See Ex. 1004, 11; Ex. 1003, 1–2. The purifying step is
understood to enrich the amount of testosterone relative to one or more other
components of the sample. Ex. 1036, 2. Thus, the POSITA would have
understood the process of purification to remove testosterone from the native
matrix before proceeding to the testosterone detection step.
Testosterone is the same chemical entity between species. See Pet. 47
(citing Ex. 1002 ¶¶ 25, 62; Ex. 1027); Tr. 24:13–15 (“I’m not aware of any
evidence of record that discuss species difference in testosterone at a
molecular level.”); compare Ex. 1003, 1 (ions monitored 289.2→97.1
(testosterone) testing human and gelding samples) with Ex. 1004 (m/z
289→97 for both 17α-testosterone and 17β-testosterone testing bovine
samples). Dr. Fitzgerald avers that testosterone is the same chemical entity
in bovine, equine, and human samples, and therefore, it is reasonable to
conclude that an assay disclosed in one vertebrate species is transferable to
another vertebrate species with a reasonable expectation of success.
Ex. 1002 ¶¶ 27 (“[T]estosterone is the same across vertebrate species”), 62
(“Testosterone is the same chemical entity in both bovine and human
samples. . . . Once extracted, the testosterone from various mammalian
species behaves similarly in chromatography and mass spectrometry
steps.”). Because testosterone is the same chemical entity between different
species we agree with Petitioner that it is reasonable to consider testosterone
assays as being interchangeable. Accordingly, we are not persuaded by
Patent Owner’s contention that there is no reason to combine Draisci and
Clarke.
Patent Owner contends that Petitioner does not provide support for the
position that sensitivity of the assay may be improved by manipulating
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variables. PO Resp. 56 (Dr. Fitzgerald “provides no citing references or
other evidence to demonstrate that the two variables he does identify
(injection volume and orifice potential voltage) were important to Clarke’s
sensitivity and would have similarly improved the sensitivity reported in
Draisci.”); see PO Sur-Reply 23.
Here, both Petitioner’s and Patent Owner’s experts agree that there are
at least eight variables that can be manipulated in an attempt to improve an
assay, but acknowledge that each variable would have to be empirically
determined to assess the level of success. See PO Sur-Reply 22–23 (citing
2013 ¶ 101; Ex. 2012, 134:1–15, 155:12–159:18, 160:22–161:9, 161:19–
25); PO Resp. 41–43; Ex. 1002 ¶¶ 25, 67, 68. Thus, the contention lies with
the predictability of manipulating these variables to make changes that
would result in improved signal for the detection of testosterone.
One approach for improving the sensitivity of an assay is to use “a
larger injection volume [that] would contain more testosterone than a
smaller volume and one of skill in the art would have routinely identified the
suitable volume to optimize sensitivity.” Ex. 1002 ¶ 25 (citing Ex. 1023).
Petitioner points out that Clarke already uses a larger injection volume than
the method disclosed in Draisci. Pet. 53 (citing Ex. 1003, 1; Ex. 1004, 11;
Ex. 1002 ¶ 67). The larger injection volume may explain why Clarke
established a limit of quantitation at 5 ng/dL versus 10 ng/dL disclosed in
Draisci. Compare Ex. 1003, 1, with Ex. 1004, 11.
Another way of improving the assay sensitivity is by modernizing the
equipment. Petitioner’s expert Dr. Fitzgerald explained that by using a
newer more sensitive mass spectrometer they were able to develop a
simplified LC-MS/MS analysis for testosterone. Ex. 2012, 180:17–181:1;
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see Ex. 1002 ¶ 25; Ex. 2010, 4 (“Evaluation of the method performance on
API 3000 and API 4000 tandem mass spectrometers (using conditions
optimal for each instrument and the oxime derivative of Te) revealed that the
assay performed on the API 4000 was ~8-fold more sensitive.18”). Improved
instrumentation sensitivity reasonably supports the position that
improvements in technology can improve component detection.
Patent Owner contends that the modifications Dr. Fitzgerald suggests
make no sense, because increasing sample volume could drastically affect
HPLC readings. PO Resp. 57 (citing Ex. 2007 ¶ 25 (“Sample injection
volumes can also impact the results since larger injection volumes can lead
to peak saturation and peak broadening and to measurements in the
non-linear range of the detector’s operation.”).
Both experts agree that one of skill in the art would have recognized
that increasing the volume of a sample would increase the signal even if it
comes at the peril that the signal may not be as clear. Ex. 2012, 157:16–23;
Ex. 2013 ¶ 129. The claims, however, are not directed to quantification of
testosterone where signal clarity and peak saturation may be an issue; the
claims are directed to detecting testosterone levels in a sample. As
Petitioner’s expert explains, the limit of quantification (LOQ) is generally
higher than the limit of detection (LOD). Ex. 1002 ¶ 28 (citing Ex. 1020);
Ex. 2025 at 27, 34. We find that the evidence in the record supports
Petitioner’s position that increasing sample volume to increase the amount

18 We would expect to see the same level of improved sensitivity for non-
derivatized testosterone, because the spectrometer technology provides the
improved sensitivity. We further note that Clarke uses the less sensitive API
3000 mass spectrometer. Ex. 1003, 1.
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of testosterone loaded into the detection system and thereby would
reasonably improve the limit of detection as required by the claims.
Patent Owner contends that there is lack of evidence that optimizing
the orifice potential voltage would have resulted in improved detection of
testosterone. PO Resp. 58.
Draisci explains that the ions were monitored at m/z 275, 289, 291 and
315. “The effect of varying orifice potential voltage [OR] was investigated
between the range 60-100 V. An OR of 90 V was adopted for all the
hormones as the best compromise in terms of signal-to-noise ratio.”
Ex. 1004, 12. Draisci recognizes that the orifice potential used in their assay
is a compromise setting, suggesting that each hormone has its own
optimized setting. We find that this disclosure provides sufficient support for
position that adjusting the orifice potential voltage could be optimized for
the individual hormone including testosterone. Petitioner’s expert
Dr. Fitzgerald avers that “[o]ne of skill in the art would recognize that
optimizing the orifice potential voltage to be the best value for testosterone
could have improved the LOD and LOQ.” Ex. 1002 ¶ 40, ¶ 68 (“In an assay
specific for testosterone, however, one of skill in the art, based on the
teachings of Draisci, would select an orifice potential voltage that gives the
best signal to noise ratio for testosterone, without regard for other
analytes.”), ¶ 71. Even if the recited 90V in Draisci is later determined to be
the optimum setting for testosterone, we find that the record never the less
supports the position that optimizing the potential is one way to increase
limit of detection of a sample.
For the reasons set out above, we determine that there is sufficient
reason to combine the references, and we determine that there is also a
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reasonable expectation of success in lowering the limit of detection by
manipulating variables such as increasing the injection volume or
modernizing the instrumentation. This optimization would reasonably be
expected to achieve the claimed detection limit. Ex. 2012, 154: 3–5
(Petitioner’s expert, Dr. Fitzgerald testifying: “I mean if you have a more
modern instrument, you have a much better chance of being more
sensitive.”); Ex. 1002, ¶ 25 (Dr. Fitzgerald testifying: “[A] a larger injection
volume would contain more testosterone than a smaller volume and one of
skill in the art would have routinely identified the suitable volume to
optimize sensitivity.”). We, therefore, find that Petitioner has shown by a
preponderance of the evidence that claims 1, 2, 4−7, and 10–14 of the ’862
patent are unpatentable as obvious over Draisci and Clarke.
Claims 8 and 9
Patent Owner contends that Petitioner fails to explain why the
combination of Draisci and Clarke would provide a reasonable expectation
to arrive at the lower limit of detection of “less than 5 ng/dL” or “less than 1
ng/dL” as recited in claims 8 and 9. PO Resp. 58–61. Patent Owner contends
that Dr. Fitzgerald’s inability to detect “testosterone in human females at
levels less than 10 ng/dL” in his own work published even after the filing of
the ’862 patent disclosure is evidence that the optimization argument is
unreasonable. Id. at 59–60; see PO Sur-Reply 23.
We are not persuaded by Patent Owner’s contention that failure by
others in the field undermines Petitioner’s position. We find that the prior art
and expert testimony cited by Petitioner provides a reasonable expectation of
success for improving testosterone detection by optimizing the method. See
Kubin, 561 F.3d at 1360 (“[o]bviousness does not require absolute
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predictability of success . . . all that is required is a reasonable expectation
of success.”); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364 (Fed. Cir.
2007) (“[T]he expectation of success need only be reasonable, not
absolute.”).
Patent Owner provides a table comparing the instrumentation between
Draisci and Clarke. The comparison highlights that there are differences in
the SPE extraction columns and HPLC columns used between Draisci and
Clarke’s methods. See PO Resp. 54–55. Patent Owner also cites
Dr. Fitzgerald’s post-patent method as allegedly showing failure by others to
detect testosterone at the levels claimed – less than 5 ng/dL and 1 ng/dL. Id.
at 59–60 (citing Ex. 2010, 6–7). Fitzgerald’s method uses yet a different
mass spectrometer, a different C18 column, and a different solid extraction
column from those used in Draisci and Clarke. Ex. 2010. Comparing
Draisci, Clarke, and Fitzgerald’s methods we note that each use different
instruments, different columns, and different sample preparation methods.
Compare Ex. 1003, 1, with either Ex. 1004, 11, or Ex. 2010, 2–3. It is
known that SPE and HPLC columns even if they are the same type can
behave differently. Ex. 2007 ¶ 20 (“Different columns, even if they are same
type of columns, such as C18 columns, have different surface chemistries,
which will affect the retention time, elution order, peak separation and peak
height and peak area.”). Because Clarke uses different matrixes in the SPE
and HPLC columns from those disclosed in Draisci and Fitzgerald, the
detection limits in Draisci and Fitzgerald cannot be imputed to Clarke. We,
therefore, are not persuaded by Patent Owner’s contention that just because
others could not detect testosterone below 10 ng/dL that Clarke’s methods of
quantification at a level of 5 ng/dL is unbelievable. See PO Resp. 60, see id.
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at 16; Ex. 2013 ¶ 56. Accordingly, we are not persuaded by Patent Owner’s
failure by others argument.
We are also not persuaded that the detection limit could not be further
improved by the routine optimization and manipulations as suggested by
Petitioner’s expert. For example, such as by increasing the sample volume or
using a newer instrument as suggested by Petitioner’s expert would
reasonably improve the level of detection of testosterone. Pet. 58 (citing Ex.
1002, ¶¶ 24–26, 57–59, 71–73); see Ex. 2010, 4 (“Evaluation of the method
performance on API 3000 and API 4000 tandem mass spectrometers (using
conditions optimal for each instrument and the oxime derivative of Te)
revealed that the assay performed on the API 4000 was ~8-fold more
sensitive.”); Ex. 2012, 154: 3–5 (Petitioner’s expert, Dr. Fitzgerald
testifying: “I mean if you have a more modern instrument, you have a much
better chance of being more sensitive.”). Improved instrumentation
sensitivity reasonably supports the position that improvements in technology
can improve component detection.
On this record, we find that Petitioner has shown by a preponderance
of the evidence that claims 8 and 9 of the ’862 patent are unpatentable as
obvious over Draisci and Clarke.
3. Summary
Having determined that there is sufficient reason to combine the
references, we determine that there is also a reasonable expectation of
success in lowering the detection limit by manipulating variables such as
increasing the injection volume, sample size, or even upgrading the
instrumentation. We, therefore, find that Petitioner has shown by a
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preponderance of the evidence that claim 1, 2, and 4–14 of the ’862 patent is
unpatentable as obvious over Draisci and Clarke.
III. CONCLUSION
We conclude that Petitioner has demonstrated that claims 1, 2, and
4−14 of the ’862 are unpatentable under 35 U.S.C. § 102(b) and § 103(a).
IV. ORDER
In consideration of the foregoing, it is hereby
ORDERED that on the record before us, Petitioner has shown by a
preponderance of the evidence that claims 1, 2, and 4–14 of the ’862 patent
are unpatentable;
FURTHER ORDERED that 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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PETITIONER:
Tina Williams McKeon
John Alemanni
Kathryn Wade
Allison W. Dobson
KILPATRICK TOWNSEND & STOCKTON
tmckeon@kilpatricktownsend.com
jalemanni@kilpatricktownsend.com
kwade@kilpatricktownsend.com
adobson@kilpatricktownsend.com

PATENT OWNER:
Peter J. Cuomo
Thomas Wintner
Pooja Varshneya
MINTZ, LEVIN, COHN, FERRIS,
GLOVSKY AND POPEO, P.C.
pjcuomo@mintz.com
twintner@mintz.com
pvarshneya@mintz.com